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2008-01-29T21:10:00.000-08:00

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http://www.healtycenter.com/2007/12/

Boerhaave Syndrome

2007-11-28T21:20:00.000-08:00

Background: Herman Boerhaave first described spontaneous rupture of the esophagus in 1724. It typically occurs after forceful emesis. Boerhaave syndrome is a transmural perforation of the esophagus to be distinguished from Mallory-Weiss syndrome, a nontransmural esophageal tear also associated with vomiting. Because it usually is associated with emesis, Boerhaave syndrome usually is not truly spontaneous. However, the term is useful for distinguishing it from iatrogenic perforation, which accounts for 85-90% of cases of esophageal rupture.

Diagnosis can be difficult because often no classic symptoms are present and delays in presentation for medical care are common. Approximately one third of all cases are clinically atypical. Prompt recognition of this potentially lethal condition is vital to ensure appropriate treatment. Mediastinitis, sepsis, and shock frequently are seen late in the course of illness, which further confuses the diagnostic picture.

A reported mortality estimate is approximately 35%, making it the most lethal perforation of the GI tract. The best outcomes are associated with early diagnosis and definitive surgical management within 12 hours of rupture. If intervention is delayed longer than 24 hours, the mortality rate (even with surgical intervention) rises to higher than 50% and to nearly 90% after 48 hours. Left untreated, the mortality rate is close to 100%.

Pathophysiology: Esophageal rupture in Boerhaave syndrome is postulated to be the result of a sudden rise in intraluminal esophageal pressure produced during vomiting, as a result of neuromuscular incoordination causing failure of the cricopharyngeus muscle to relax. The syndrome commonly is associated with overindulgence in food and/or alcohol. The most common anatomical location of the tear in Boerhaave syndrome is at the left posterolateral wall of the lower third of the esophagus, 2-3 cm proximal to the gastroesophageal junction, along the longitudinal wall of the esophagus. The second most common site of rupture is in the subdiaphragmatic or upper thoracic area.

Frequency:

Internationally: Although likely underreported, incidence is relatively rare. A 1980 review by Kish cited 300 cases in the literature worldwide. A 1986 summary by Bladergroen and Postlethwait described 127 cases. Of these, 114 were diagnosed antemortem; the others were diagnosed at autopsy. Overall, Boerhaave syndrome accounts for 15% of all traumatic rupture or perforation of the esophagus.

Mortality/Morbidity: The mortality rate is high. It is the most lethal perforation of the GI tract. Survival is contingent largely upon early recognition and appropriate surgical intervention.

Overall mortality rate is approximately 30%. Mortality is usually due to subsequent infection including mediastinitis, pneumonitis, pericarditis, or empyema

Patients who undergo surgical repair within 24 hours of injury have a 70-75% chance of survival. This falls to 35-50% if surgery is delayed longer than 24 hours and to approximately 10% if delayed longer than 48 hours.

Cases of patients surviving without surgery exist but are rare enough to warrant case reports in the medical literature.

Race:

Cases have been reported in all races and on virtually every continent.

strong>Sex:

The syndrome is described more commonly in males than in females, with ratios ranging from 2:1 to 5:1.

Age:

It is seen most frequently among patients aged 50-70 years.

Reports suggest that 80% of all patients are middle-aged men.

Cases have been described in neonates and in persons older than 90 years. Although no clear explanation exists for this, the least susceptible age group appears to be children aged 1-17 years.

Treatment
Medical Care:

Ideal management involves a combination of both conservative and surgical interventions.
Mainstays of therapy include the following:

Intravenous volume resuscitation
Administration of broad-spectrum antibiotics
Prompt surgical intervention

The decision to use a conservative (medical intervention only) or an aggressive (medical plus surgical intervention) approach depends on the following factors:
- Time delay in presentation and diagnosis
- Extent of perforation
- Overall medical condition of the patient

Surgical intervention is the standard of care in most cases, but Cameron et al established a set of criteria in which conservative (nonsurgical) management might be appropriate. These include the following:

The esophageal disruption should be well contained in the mediastinum.
The cavity should be well drained back into the esophagus.
Few symptoms should be present.
Evidence of clinical sepsis should be minimal.

Conservative management consists of the following:
- Intravenous fluids should be instituted.
- Antibiotics: Imipenem/cilastatin (Primaxin) offers good broad-spectrum coverage.
- Nasogastric suction should be applied.
- Keep the patient NPO.
- Adequate drainage with tube thoracostomy or formal thoracotomy is vital.
- Early use of nutritional supplementation: Recent evidence suggests that, for hastening recovery, a jejunostomy tube feeding may be favored over hyperalimentation.

Surgical Care:

Barrett described the first successful surgical repair of the esophagus in 1947. Prior to this, Boerhaave syndrome had virtually 100% mortality.
Most physicians advocate surgical intervention if the diagnosis is made within the first 24 hours after perforation.
Direct repair of the rupture and adequate drainage of the mediastinum and pleural cavity provide the best survival rates.

A left thoracotomy is the preferred approach, although laparotomy may be necessary if the tear extends into the distal esophagus.

Various techniques, such as the use of an omental flap, may be used to support the primary closure.
Gastrostomy and jejunostomy tubes often are placed to aid in drainage and nutrition, respectively.

The vitality of the surrounding tissue is an important factor in selecting the surgical procedure.

For patients in whom a delay in diagnosis (>24 h) occurred, primary repair may not be possible.
After 24 hours, the wound edges frequently are edematous, stiff, and friable.

Various alternatives to primary repair are available.

The most common includes the creation of an esophageal diversion through the use of a loop or end-cervical esophagostomy. This allows the wound to heal by secondary intention.
The use of T-tubes also has been described. T-tubes result in the formation of a controlled fistula and a route for drainage of esophageal secretions and refluxed gastric materials.
One recent study noted that the option of primary repair may be considered for perforations as old as 72 hours.

Newer techniques involve the use of plastic-covered self-expanding metallic stents.

They are considered acceptable alternatives only when all other interventional options have been exhausted. Their use in nonmalignant disease is highly controversial because they cannot be removed without considerable risks or not at all.
Currently, the use of stents in Boerhaave syndrome is recommended for cases that involve extreme delays in diagnosis or a failure of conservative management.
Expandable metal stents are most commonly used as palliative interventions for unresectable malignant esophageal obstruction.
These devices bridge the esophageal tear.
Several types of stents are available, and they vary in flexibility. Recent research holds the promise of biodegradable stents, obviating the necessity for removal.
Esophageal stents have been associated with a risk of delayed massive hemorrhage in patients with esophageal malignancy.
The long-term effects of stent placement in Boerhaave syndrome have not been adequately evaluated.

Late complications of surgical intervention may include the following:
- Empyema that often requires tube drainage or decortication
- Esophagotracheal or esophagobronchial fistulas

Consultations:

Consultation with a thoracic or general surgeon is indicated as soon as the diagnosis is suspected.

Infectious disease specialist should be consulted for assistance with antimicrobial therapy.

Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Antibiotics -- Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. A broad-spectrum antibiotic, such as imipenem/cilastatin (Primaxin), is recommended.

Drug Name	Imipenem/cilastatin (Primaxin) -- Offers good broad-spectrum coverage. For treatment of multiple-organism infections in which other agents do not have wide-spectrum coverage or are contraindicated due to potential for toxicity.
Adult Dose	Base initial dose on severity of infection, and administer in equally divided doses 250-500 mg IV q6h, not to exceed 3-4 g/d Alternatively, 500-750 mg IM q12h or intra-abdominally
Pediatric Dose	<12>3 months Fully susceptible organisms: not to exceed 2 g/d Infections with moderately susceptible organisms: not to exceed 4 g/d
Contraindications	Documented hypersensitivity
Interactions	Coadministration with cyclosporine may increase adverse CNS effects of both agents; coadministration with ganciclovir may result in generalized seizures
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adjust dose in renal insufficiency; avoid use in children <12>

Bilirubin, Impaired Conjugation

2007-11-28T21:18:00.000-08:00

Background: Bilirubin is the potentially toxic catabolic product of heme metabolism. There are elaborate physiologic mechanisms for its detoxification and disposition. Understanding these mechanisms is necessary for interpretation of the clinical significance of high serum bilirubin concentrations.

In adults, 250-400 mg of bilirubin is produced daily. Approximately 70-80% of daily bilirubin is derived from degradation of the heme moiety of hemoglobin. The remaining 20-25% is derived from the hepatic turnover of heme proteins, such as myoglobin, cytochromes, and catalase. A small portion of daily bilirubin is derived from the destruction of young or developing erythroid cells.

Bilirubin is poorly soluble in water at physiologic pH because of internal hydrogen bonding that engages all polar groups and gives the molecule an involuted structure. The fully hydrogen-bonded structure of bilirubin is designated bilirubin IX-alpha-ZZ. The intramolecular hydrogen bonding shields the hydrophilic sites of the bilirubin molecule, resulting in a hydrophobic structure. Water-insoluble unconjugated bilirubin is associated with all known toxic effects of bilirubin. Thus, the internal hydrogen bonding is critical in producing bilirubin toxicity and also prevents its elimination.

Conversion of bilirubin IX-alpha to a water-soluble form by disruption of the hydrogen bonds is essential for elimination by the liver and kidney. This is achieved by glucuronic acid conjugation of the propionic acid side chains of bilirubin. Bilirubin glucuronides are water-soluble and are readily excreted in bile. Bilirubin is primarily excreted in normal human bile as diglucuronide; unconjugated bilirubin accounts for only 1-4% of pigments in normal bile.

Pathophysiology: Unconjugated bilirubin is transported in the plasma bound to albumin. At the sinusoidal surface of the liver, unconjugated bilirubin detaches from albumin and is transported through the hepatocyte membrane by facilitated diffusion. Within the hepatocyte, bilirubin is bound to 2 major intracellular proteins, cytosolic Y protein (ie, ligandin or glutathione S-transferase B) and cytosolic Z protein (also known as fatty acid–binding protein [FABP]). The binding of bilirubin to these proteins decreases the efflux of bilirubin back into the plasma and, therefore, increases net bilirubin uptake.

In order for bilirubin to be excreted into bile and, therefore, eliminated from the body, it must be made more soluble. This water-soluble or conjugated form of bilirubin is produced when glucuronic acid enzymatically is attached to one or both of the propionic side chains of bilirubin IX-alpha (ZZ). Enzyme-catalyzed glucuronidation is one of the most important detoxification mechanisms of the body. Of the various isoforms of the UGT family of enzymes, only one isoform, bilirubin-UGT-1 (BUGT1), is physiologically important in bilirubin glucuronidation.

This attachment occurs through an ester linkage and, therefore, is called esterification. This esterification is catalyzed by the microsomal enzyme bilirubin uridine-diphosphate glucuronosyltransferase (ie, bilirubin-UGT), which is located in the endoplasmic reticulum of the hepatocyte. This reaction leads to the production of water-soluble bilirubin monoglucuronide and bilirubin diglucuronide. Other compounds, such as xylose and glucose, also can undergo esterification with bilirubin.

Bilirubin diglucuronide is the predominant pigment in healthy adult human bile, representing over 80% of the pigment. However, in subjects with reduced bilirubin-UGT activity, the proportion of bilirubin diglucuronide decreases, and bilirubin monoglucuronide may constitute more than 30% of the conjugates excreted in bile. Reduction of conjugating enzyme activity to approximately 30% of normal results in a mild but discernible increase in serum bilirubin concentrations. This conjugation reaction is essential for bilirubin excretion into bile.

Deficiency of bilirubin-UGT leads to ineffective esterification of bilirubin, which, in turn, results in an unconjugated hyperbilirubinemia. Reduced bilirubin conjugation as a result of a decreased or absent UDP-glucuronosyltransferase activity is found in several acquired conditions and inherited diseases, such as Crigler-Najjar syndrome (types I and II) and Gilbert syndrome. Bilirubin conjugating activity is also very low in the neonatal liver.

UGT activity toward bilirubin is modulated by various hormones. Excess thyroid hormone and ethinyl estradiol, but not other oral contraceptives, inhibit bilirubin glucuronidation. In comparison, the combination of progestational and estrogenic steroids results in increased enzyme activity. Bilirubin glucuronidation can also be inhibited by certain antibiotics (eg, novobiocin or gentamicin at serum concentrations exceeding therapeutic levels) and by chronic hepatitis, advanced cirrhosis, and Wilson disease.

Three primary diseases result from abnormal bilirubin-UGT production. The severity of the resulting illness depends on the degree of bilirubin-UGT deficiency.

Crigler-Najjar syndrome, also referred to as congenital nonhemolytic jaundice with glucuronosyltransferase deficiency, is a rare, autosomal recessive disorder of bilirubin metabolism. It has been divided into 2 distinct forms (types I and II) based upon the severity of the disease. The molecular defect in Crigler-Najjar syndrome can be caused by a variety of alterations in the coding sequences of the bilirubin-uridine diphosphate glucuronosyltransferase (UGT1A1) gene, and these mutations lead to the production of an abnormal protein, resulting in complete loss or very low levels of hepatic bilirubin-UGT (UGT1A1) activity.

n contrast, the defect in Gilbert syndrome is in the promoter region, the TATAA element, rather than in the gene itself; as a result, reduced amounts of the normal protein are produced.

The absence of bilirubin-UGT leads to Crigler-Najjar type I syndrome. Crigler-Najjar type I syndrome is a disease that causes kernicterus in infants, which usually leads to death. Crigler-Najjar type II syndrome results from decreased levels of bilirubin-UGT. Kernicterus usually does not develop in this disease; therefore, the long-term prognosis is better.

Gilbert syndrome results from decreased levels of bilirubin-UGT. Gilbert syndrome results in a mild hyperbilirubinemia without any clinical sequelae. The long-term prognosis is good.

Other disease states that are seen in the neonatal period consist of physiologic jaundice and breast milk jaundice.

hysiologic jaundice is a mild unconjugated hyperbilirubinemia that affects nearly all newborns and resolves within the first several weeks after birth. It is caused by increased bilirubin production, decreased bilirubin clearance, and increased enterohepatic circulation.

It has been shown that bilirubin production in a term newborn is 2-3 times higher than in adults. This increased production is due to the shorter life span and the greater turnover of neonatal red blood cells. Bilirubin clearance is decreased in newborns, mainly due to the deficiency of the enzyme UGT. UGT activity in term neonates is approximately 1% of that in adults. Also, newborns have fewer intestinal bacteria than adults, resulting in a decreased capacity to reduce bilirubin to urobilinogen and subsequent higher intestinal bilirubin concentrations. In addition, the activity of beta-glucuronidase also is increased, which leads to greater hydrolysis of conjugated to unconjugated bilirubin. The unconjugated bilirubin is reabsorbed from the intestine through the process of enterohepatic circulation, further increasing the bilirubin load in the infant.

The peak total serum bilirubin level in physiologic jaundice typically is 5-6 mg/dL (86-103 µmol/L), occurs at 48-120 hours of age, and does not exceed 17-18 mg/dL (291-308 µmol/L). Higher levels of unconjugated hyperbilirubinemia are pathologic and occur in various conditions, as previously mentioned.

Breast milk jaundice results from increased enterohepatic circulation. It is thought to result from an unidentified component of human milk that enhances intestinal absorption of bilirubin. One possible mechanism for hyperbilirubinemia in breast-fed infants compared to formula-fed infants is the increased concentration of beta-glucuronidase in breast milk. Beta-glucuronidase deconjugates intestinal bilirubin, increasing its ability to be absorbed (ie, increasing enterohepatic circulation). Blocking the deconjugation of bilirubin through beta-glucuronidase inhibition may provide a mechanism to reduce intestinal absorption of bilirubin in breast-fed infants; however, this has yet to be proven.

strong>Frequency:

In the US: The frequency of the various diseases resulting from impaired bilirubin conjugation is based on the disease process. Crigler-Najjar type I syndrome is rare in the US population; reported cases number only in the hundreds. Crigler-Najjar type II syndrome also is an uncommon disease.
Gilbert syndrome affects approximately 3-7% of the population.
Breast milk jaundice affects approximately 0.5-2.4% of live births, and there is a familial incidence of 13.9%, indicating that, in some cases, a unique genetic factor may be expressed.

Mortality/Morbidity: The various diseases resulting from impaired bilirubin conjugation have differing prognoses.

The Crigler-Najjar type I syndrome usually results in death during infancy, with only a few patients surviving to adolescence. The cause of death is encephalopathy from kernicterus.

Crigler-Najjar type II syndrome results in elevated unconjugated bilirubin levels, but patients with Crigler-Najjar type II syndrome tend to live into old age and are not at risk for kernicterus. The morbidity associated with the disease is low. Many patients with Crigler-Najjar type II syndrome are unaffected by this condition.

ilbert syndrome is a benign disorder associated with no increase in mortality or morbidity. Patients who are affected are anicteric, with a normal life expectancy. Patients usually do not experience complications from their hyperbilirubinemia. Fasting, febrile illness, alcohol, or exercise can exacerbate jaundice in patients with Gilbert syndrome. Hemolysis and mild icterus usually occur at times of stress, starvation, and infection.
Physiologic jaundice is a benign disorder as well.
Breast milk jaundice is also a benign disorder. The bilirubin levels need to be checked to avoid complications of hyperbilirubinemia. However, late neurodevelopment or hearing defects have not been observed in neonates, thus enabling the pediatrician to encourage continuation of breastfeeding in most cases of healthy infants with breast milk jaundice.

Race: In Gilbert syndrome, differences exist in the mutation of the UGT1A1 gene in certain ethnic groups. As mentioned previously, the TATAA element in the promoter region is the most common site of mutation in the Caucasian population.

No racial predilection exists for Crigler-Najjar syndrome.

A racial variation exists in the development of neonatal jaundice. A common mutation in the UGT gene (Gly71Arg) leads to an increased incidence of severe neonatal hyperbilirubinemia (approximately 20%) in Asians.

Sex: No sexual predilection exists in Crigler-Najjar type I and II syndromes. In Gilbert syndrome, males are affected more frequently than females. Neonatal physiologic jaundice is increased in males. Breast milk jaundice is seen equally in males and females.

Age: All of the diseases are inherited and, therefore, are present from birth. The age at which symptoms appear may vary.

In Crigler-Najjar type I syndrome, symptoms appear within the first few days of life, and most patients die in infancy. A few patients have survived into adolescence.

In Crigler-Najjar type II syndrome, patients have jaundice during the first few years of life.

Patients with Gilbert syndrome usually are diagnosed when aged 10-30 years.
Physiologic jaundice affects nearly all newborns, occurs in the first 2-5 days, and resolves within the first several weeks after birth.
Breast milk jaundice typically begins after the first 3-5 days, peaks within 2 weeks after birth, and progressively declines to normal levels over 3-12 weeks.

Treatment
Medical Care:

Crigler-Najjar type I syndrome: The therapeutic goal is to produce a sustained reduction in plasma bilirubin concentration. Many different therapies have been tried in experimental protocols. No medical therapy has been found to be effective in patients with Crigler-Najjar type I syndrome; therefore, the treatment of choice for Crigler-Najjar type I syndrome is liver transplantation. Performance of liver transplantation should occur prior to the onset of kernicterus.
- Medical therapies consist of phototherapy, plasmapheresis, calcium phosphate supplementation, calcium phosphate, and orlistat.
- Hepatocyte transplantation is being studied as an alternative to liver transplantation.
- Introduction of a normal bilirubin-UGT gene (UGT1A1) has the potential for curing the genetic defect leading to Crigler-Najjar syndrome.

Crigler-Najjar type II syndrome: Phenobarbital therapy has been shown to be effective in reducing plasma bilirubin levels in patients with Crigler-Najjar type II syndrome. This can be accomplished by the administration of phenobarbital (60-180 mg/d in divided doses), which reduces serum bilirubin levels by at least 25%. A response should be expected within 2-3 weeks. A similar benefit can be observed with clofibrate, which is associated with fewer adverse effects. However, patients often do well, even in the absence of therapy.

Gilbert syndrome: No therapy is necessary; however, many therapeutic approaches have been used. As with Crigler-Najjar type II syndrome, phenobarbital has been shown to decrease bilirubin production. The prognosis is excellent. The most important aspect in the care of these patients is recognition of the disorder and its inconsequential nature.

Physiologic jaundice: No treatment is needed.

Breast milk jaundice and other pathologic causes of jaundice in the neonate: Phototherapy can be used.

hototherapy consists of exposing the infant's skin to light. It is a safe and efficient method to reduce the toxicity of bilirubin and to increase its elimination. The use of phototherapy decreases the risk that the total serum bilirubin concentration will reach the level at which exchange transfusion is recommended.
Phototherapy converts bilirubin into lumirubin in a process of structural isomerization that is not reversible. Lumirubin is a more soluble substance than bilirubin and is excreted without conjugation into bile and urine.
Maintaining adequate hydration and urine output is important during phototherapy to prevent dehydration.
An uncommon complication of phototherapy is the so-called bronze baby syndrome. This occurs in some infants with cholestatic jaundice and is manifested by a dark, grayish brown discoloration of the skin, serum, and urine. The condition gradually resolves without sequelae within several weeks after discontinuation of therapy.

strong>Surgical Care: Liver transplantation has been performed for the treatment
of Crigler-Najjar type I syndrome.

Medication
For Crigler-Najjar type I, no medications are effective. Combined phototherapy and exchange transfusions are beneficial in infants to prevent kernicterus. Liver transplantation is the treatment of choice.

For Crigler-Najjar type II, phenobarbital produces a fall in plasma bilirubin levels. Therapy only benefits patients cosmetically.

For Gilbert syndrome, no medical therapy is needed. As with Crigler-Najjar type II syndrome, phenobarbital has been shown to decrease bilirubin production.

Drug Category: Barbiturates -- Presumably works through trophic action on the endoplasmic reticulum by increasing bilirubin-UGT activity.

Drug Name	Phenobarbital (Barbita, Luminal) -- Although the mechanism of action is uncertain, enzyme induction is probably the major action. Has been shown to be effective in the treatment and prevention of neonatal hyperbilirubinemia.
Adult Dose	1-5 mg/kg/d PO/IV
Pediatric Dose	3-5 mg/kg/d PO/IV divided bid
Contraindications	Documented hypersensitivity; acute intermittent porphyria; severe respiratory disease
Interactions	May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may produce additive CNS effects and death; chloramphenicol, valproic acid, and MAOIs may increase phenobarbital toxicity; rifampin may decrease phenobarbital effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy; menstrual irregularities also may occur)
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in patients with fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions (eg, nystagmus, ataxia, sedation) can occur; caution in myasthenia gravis and myxedema

Biliary Obstruction

2007-11-28T21:14:00.000-08:00

Background

Disorders of the biliary tract affect a significant portion of the worldwide population, and the overwhelming majority of cases are attributable to cholelithiasis (gallstones). In the United States, 20% of persons older than 65 years have gallstones and 1 million newly diagnosed cases of gallstones are reported each year.

To better understand these disorders, a brief discussion of the normal structure and function of the biliary tree is needed. Bile is the exocrine secretion of the liver and is produced continuously by hepatocytes. It contains cholesterol and waste products, such as bilirubin and bile salts, which aid in the digestion of fats. Half the bile produced runs directly from the liver into the duodenum via a system of ducts, ultimately draining into the common bile duct (CBD). The remaining 50% is stored in the gallbladder. In response to a meal, this bile is released from the gallbladder via the cystic duct, which joins the hepatic ducts from the liver to form the CBD. The CBD courses through the head of the pancreas for approximately 2 cm before passing through the ampulla of Vater into the duodenum.

Pathophysiology

Biliary obstruction refers to the blockage of any duct that carries bile from the liver to the gallbladder or from the gallbladder to the small intestine. This can occur at various levels within the biliary system. The major signs and symptoms of biliary obstruction result directly from the failure of bile to reach its proper destination.

The clinical setting of cholestasis or failure of biliary flow may be due to biliary obstruction by mechanical means or by metabolic factors in the hepatic cells. For the sake of simplicity, the primary focus of this article is mechanical causes of biliary obstruction, further separating them into intrahepatic and extrahepatic causes. The discussion of intracellular/metabolic causes of cholestasis is very complex, the pathogenesis of which is not always clearly defined. Therefore, these causes are mentioned but are not discussed in detail.

Intrahepatic cholestasis generally occurs at the level of the hepatocyte or biliary canalicular membrane. Causes include hepatocellular disease (eg, viral hepatitis, drug-induced hepatitis), drug-induced cholestasis, biliary cirrhosis, and alcoholic liver disease. In hepatocellular disease, interference in the 3 major steps of bilirubin metabolism, ie, uptake, conjugation, and excretion, usually occurs. Excretion is the rate-limiting step and is usually impaired to the greatest extent. As a result, conjugated bilirubin predominates in the serum.

Extrahepatic obstruction to the flow of bile may occur within the ducts or secondary to external compression. Overall, gallstones are the most common cause of biliary obstruction. Other causes of blockage within the ducts include malignancy, infection, and biliary cirrhosis. External compression of the ducts may occur secondary to inflammation (eg, pancreatitis) and malignancy. Regardless of the cause, the physical obstruction causes a predominantly conjugated hyperbilirubinemia.

Accumulation of bilirubin in the bloodstream and subsequent deposition in the skin causes jaundice (icterus). Conjunctival icterus is generally a more sensitive sign of hyperbilirubinemia than generalized jaundice. Total serum bilirubin values are normally 0.2-1.2 mg/dL. Jaundice may not be clinically recognizable until levels are at least 3 mg/dL. Urine bilirubin is normally absent. When it is present, only conjugated bilirubin is passed into the urine. This may be evidenced by dark-colored urine seen in patients with obstructive jaundice or jaundice due to hepatocellular injury. However, reagent strips are very sensitive to bilirubin, detecting as little as 0.05 mg/dL. Thus, urine bilirubin may be found before serum bilirubin reaches levels high enough to cause clinical jaundice.

The lack of bilirubin in the intestinal tract is responsible for the pale stools typically associated with biliary obstruction. The cause of itching (pruritus) associated with biliary obstruction is not clear. Some believe it may be related to the accumulation of bile acids in the skin. Others suggest it may be related to the release of endogenous opioids.

Frequency

United States

The incidence of biliary obstruction is approximately 5 cases per 1000 people.

Mortality/Morbidity

The mortality and morbidity of biliary obstruction depend on the cause of the obstruction.

Race

The racial predilection depends on the cause of the biliary obstruction.

Gallstones are the most common cause of biliary obstruction. Persons of Hispanic origin and Northern Europeans have a higher risk of gallstones compared to people from Asia and Africa.

Native Americans (particularly Pima Indians) have an increased incidence of obesity and diabetes within their population and are especially prone to developing gallstones. Pima women have a lifetime chance of developing gallstones as high as 80%.

Sex

The sexual predilection depends on the specific cause of the biliary obstruction.

Gallstone disease is the most common cause of biliary obstruction. Women are much more likely to develop gallstones than men. By the sixth decade, almost 25% of American women develop gallstones, with as many as 50% of women aged 75 years developing gallstones. This increased risk is likely caused by the effect of estrogen on the liver, causing it to remove more cholesterol from the blood and diverting it into the bile.
Approximately 20% of men aged 75 years have gallstones, with more complicated disease courses occurring in those who have had cholecystectomies.

Treatment

Medical Care

Treatment of the underlying cause is the objective of the medical treatment of biliary obstruction. Do not subject patients to surgery until the diagnosis is clear. Thus, make every effort to visualize the biliary tree in patients who are jaundiced, with appropriate use of noninvasive and invasive techniques. Importantly, however, a delay in moving on to more invasive therapeutic modalities in a patient who does not initially respond to medical and supportive care increases the risks of an adverse outcome.

In cases of cholelithiasis in which either the patient refuses surgery or surgical intervention is not appropriate, an attempt to dissolve noncalcified calculi may occasionally be made by the administration of oral bile salts for as long as 2 years.
- Because gallbladder emptying is an important determinant of stone clearance, normal gallbladder function must first be established via oral cholecystography.
- Ursodeoxycholic acid (10 mg/kg/d) works to reduce biliary secretion of cholesterol. In turn, this decreases the cholesterol saturation of bile. In 30-40% of patients, this results in the gradual dissolution of cholesterol-containing stones. However, stones may recur within 5 years once the drug is stopped (50% of patients).

- Extracorporeal shock-wave lithotripsy may be used as an adjunct to oral dissolution therapy. By increasing the surface-to-volume ratio of the stones, it both enhances dissolution of stones and makes clearing the smaller fragments easier. Contraindications include complications of gallstone disease (eg, cholecystitis, choledocholelithiasis, biliary pancreatitis), pregnancy, and coagulopathy or anticoagulant medications (ie, because of the risk of hematoma formation). Lithotripsy is associated with a 70% recurrence rate for gallstones, is not approved by the US Food and Drug Association, and is restricted to investigational programs only.

Bile acid–binding resins, cholestyramine (4 g) or colestipol (5 g), dissolved in water or juice 3 times a day may be useful in the symptomatic treatment of pruritus associated with biliary obstruction. However, deficiencies of vitamins A, D, E, and K may occur if steatorrhea is present and can be aggravated by the use of cholestyramine or colestipol. Therefore, include an individualized regimen for replacement of these vitamins as needed in the patient's treatment.

Antihistamines may be use for the symptomatic treatment of pruritus, particularly as a sedative at night. Their effectiveness is modest. Endogenous opioids have been suggested as possibly playing a role in the development of pruritus of cholestasis. Treatment with parentally administered naloxone and, more recently, nalmefene, has improved pruritus in some patients.

Rifampin has been suggested as a medical adjunct to the treatment of cholestasis. By decreasing intestinal flora, it slows the conversion of primary to secondary bile salts and may reduce serum bilirubin levels, ALP levels, and pruritus in certain patients.
Discontinuation of medications that may be causing or exacerbating cholestasis and/or biliary obstruction often leads to full recovery. Similarly, appropriate treatment of infections (eg, viral, bacterial, parasitic) is indicated.

Surgical Care

As with medical care, the need for surgical intervention depends on the cause of biliary obstruction.

Cholecystectomy is the recommended treatment in cases of symptomatic cholelithiasis because these patients have an increased risk of developing complications.
- Open cholecystectomy is relatively safe, with a mortality rate of 0.1-0.5 %.

- Laparoscopic cholecystectomy remains the treatment of choice for symptomatic gallstones, partially because of the shorter recovery period (return to work in an average of 7 d), decreased postoperative discomfort, and improved cosmetic result.

- Approximately 5% of laparoscopic cases are converted to an open procedure secondary to difficulty visualizing the anatomy or a complication.

Resectability of neoplastic causes of biliary obstruction varies with respect to the location and extent of the disease. Photodynamic therapy (PDT) has been shown to have good results in the palliative treatment of advanced biliary tract malignancies, particularly when used in conjunction with a biliary stenting procedure. PDT produces localized tissue necrosis by applying a photosensitizing agent, which preferentially accumulates in the tumor tissue, and then exposing the area to laser light, which activates the medication and results in destruction of tumor cells.
Liver transplantation may be considered in appropriate patients.

Consultations

Gastroenterologist
Radiologist
General surgeon

Diet

Obesity, excess energy intake, and rapid weight loss can lead to stone formation, with potential biliary obstruction as a consequence. Gradual and modest weight reduction may be of value in patients who are at risk.

Reduce intake of saturated fats.
High intake of fiber has been linked to a lower risk for gallstones.
Reduce intake of sugar because a high intake of sugar may be associated with an increased risk of gallstones.

Activity

Regular exercise may reduce the risk of gallstones and gallstone complications.

Medication

Bile acid–binding resins and ursodeoxycholic acid are used to treat cholelithiasis when surgery is refused or is inappropriate. Normal gallbladder function must be established by oral cholecystography findings prior to the initiation of drug therapy.

Drug Category: Gallstone solubilizing agents

Ursodeoxycholic acid (ursodiol) is a naturally occurring bile acid present in small quantities in human bile. Suppresses liver synthesis and secretion of cholesterol. Inhibits intestinal cholesterol absorption.

Drug Name	Ursodiol (Actigall)
Description	Used to treat biliary stasis and dissolve gallstones.
Adult Dose	8-10 mg/kg/d PO divided bid/tid pc until 3 mo after stone is dissolved
Pediatric Dose	10-15 mg/kg/d PO divided tid pc
Contraindications	Documented hypersensitivity; calcified cholesterol, radiopaque or radiolucent bile pigment stones
Interactions	Decreased effect/absorption with aluminum-containing antacids and bile acid–binding resins; estrogens or oral contraceptives may antagonize effect by promoting gallstone formation
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Transaminases (ie, AST, ALT) should be monitored periodically for hepatotoxicity; may cause adverse GI effects, perform US imaging every 6 mo for 1 y to monitor effect, effectiveness dependent on gallstone size/composition, effect unlikely if gallstones are not partially dissolved after 1 y

Drug Category: Narcotic antagonists

Endogenous opioids may effect pruritic development associated with cholestasis. Treatment with narcotic antagonists may attenuate pruritus.

Drug Name	Naloxone (Narcan)
Description	Prevents or reverses opioid effects (eg, hypotension, respiratory depression, sedation, pruritus), possibly by displacing opiates from their receptors.
Adult Dose	0.4 mg IV initially, followed by 0.2 mcg/kg/min
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Decreased effects of captopril, clonidine, and opioid analgesia
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in cardiovascular disease and impaired liver or kidney function; may precipitate withdrawal symptoms in patients dependent on opiates

Drug Category: Antibiotics

Rifampin, in particular, has been suggested as a treatment for cholestasis in certain patients. By reducing intestinal flora, it slows conversion of primary to more toxic secondary bile salts. Has also been shown to decrease serum levels of bilirubin and ALP, perhaps in part contributing to its effectiveness in minimizing associated pruritus.

Drug Name	Rifampin (Rifadin, Rifadin IV, Rimactane)
Description	Inhibits DNA-dependent bacterial by binding to the beta subunit of DNA-dependent RNA polymerase, blocking RNA transcription.
Adult Dose	5-17 mg/kg/d PO/IV qd; not to exceed 600 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Induces microsomal enzymes, which may decrease effects of acetaminophen, PO anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, PO contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; BP may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFTs occur)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Heartburn, epigastric distress, anorexia, nausea, vomiting, jaundice, flatulence, cramps, and diarrhea may occur; pseudomembranous colitis has been reported; thrombocytopenia, headache, fever, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion, behavioral changes, muscular weakness, pain in extremities, and generalized numbness have been observed Rarely, hemolysis, hemoglobinuria, hematuria, interstitial nephritis, acute tubular necrosis, renal insufficiency, and acute renal failure have occurred; liver dysfunction may occur and, thus, patients with impaired liver function or taking other hepatotoxic drugs concomitantly should be given rifampin only in cases of necessity and then with caution and under strict medical supervision; in these patients, carefully monitor liver function prior to therapy and then every 2-4 wk during therapy; if signs of hepatocellular damage occur, withdraw; has enzyme induction properties that can enhance the metabolism of endogenous and exogenous substrates, including adrenal hormones, thyroid hormones, vitamin D, and PO hormonal/contraceptive therapy; diabetes may become more difficult to control; may produce a reddish coloration of the urine, sweat, sputum, and tears; soft contact lenses may be permanently stained

Drug Category: Bile acid–binding resins

Inhibit enterohepatic reuptake of intestinal bile salts.

Drug Name	Cholestyramine (Questran)
Description	Acts as a cholesterol-lowering agent. Forms a nonabsorbable complex with bile acids in the intestine, which inhibits enterohepatic reuptake of intestinal bile salts.
Adult Dose	4-6 g PO tid ac (4 g resin/packet or level scoopful); alternatively, 8-12 g PO with breakfast and 4-6 g PO with lunch; not to exceed 24 g/d
Pediatric Dose	240 mg/kg/d PO divided tid ac; not to exceed 8 g/d
Contraindications	Documented hypersensitivity; complete biliary obstruction
Interactions	Inhibits absorption of numerous drugs (eg, amiodarone, digoxin, fat-soluble vitamins, folic acid, hydrocortisone, niacin, HMG-CoA inhibitors, thyroid, PO antidiabetic agents, ursodiol, phenobarbital, phosphates, valproate); separating doses by 2-4 h may minimize interaction if drug does not undergo enterohepatic recirculation; monitor serum levels and adjust doses accordingly
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Mix powder with water, juice, or milk; discontinue cautiously with concurrent drugs, adjust doses accordingly; causes constipation, heartburn, nausea, and vomiting; caution in PKU when aspartame-containing product is used

Drug Name	Colestipol (Colestid)
Description	Binds bile acids in the intestine, facilitates partial removal of bile acids from enterohepatic circulation, and prevents their reabsorption.
Adult Dose	2-g tab PO qd/bid initially, increase dose by 2 g q1-2mo; not to exceed 16 g/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; complete biliary obstruction
Interactions	Inhibits absorption of numerous drugs (eg, amiodarone, digoxin, fat-soluble vitamins, folic acid, hydrocortisone, niacin, HMG-CoA inhibitors, thyroid, PO antidiabetic agents, ursodiol, phenobarbital, phosphates, valproate); separating doses by 2-4 h may minimize interaction if drug does not undergo enterohepatic recirculation; monitor serum levels and adjust doses accordingly; conflicting result with digoxin, colestipol preferred over cholestyramine for patients taking digoxin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Swallow tabs whole (ie, do not crush, cut, or chew) one at a time with water; discontinue cautiously with concurrent drugs, adjust doses accordingly; may cause GI obstruction, constipation, or nausea

Biliary Disease

2007-11-28T21:12:00.000-08:00

Background: A diverse spectrum of disease affects the biliary system, often presenting with similar clinical signs and symptoms.

Pathophysiology: Bile is produced by the liver and channeled by the biliary ductal system into the intestinal tract for the emulsification and absorption of fats. Biliary disease is caused by abnormalities in bile composition, biliary anatomy, or function. The liver determines the chemical composition of bile, and this may be modified later by the gallbladder and biliary epithelium. Cholesterol, ordinarily insoluble in water, comes into solution by forming vesicles with phospholipids (principally lecithin) or mixed micelles with bile salts and phospholipids.

When the ratio of cholesterol, phospholipids, and bile salts is outside an optimum range, cholesterol monohydrate crystals may come out of solution from multilamellar vesicles. Cholesterol supersaturation of bile appears to be a prerequisite for gallstone formation, which involves a variety of factors that affect the activity of low-density lipoprotein (LDL) uptake, hepatic 3-methylglutaryl coenzyme A reductase (HMG CoA), acyl cholesterol-lecithin acyltransferase, and 7-alpha hydroxylase.

By itself, cholesterol supersaturation is inadequate for explaining gallstone pathogenesis. Nucleation, the initial step in gallstone formation, is the transition of cholesterol from a soluble state into a solid crystalline form. Within gallbladder bile, biologic molecules influence the process in a positive or negative fashion.

For example, mucus may function to promote nucleation, while bile-specific glycoproteins may function to inhibit nucleation. Mucin hypersecretion by the gallbladder mucosa creates a viscoelastic gel that fosters nucleation. Arachidonyl lecithin, which is absorbed from the alimentary tract and secreted into the bile, stimulates prostanoid synthesis by gallbladder mucosa and promotes mucus hypersecretion, while inhibitors of prostaglandin inhibit mucus secretion.

Finally, gallbladder hypomotility and bile stasis appear to promote gallstone formation and growth, which may be important in diabetes, pregnancy, oral contraceptive use in women, and prolonged fasting in critically ill patients on total parenteral nutrition.

Frequency:

In the US: Gallstone disease is one of the most common and costly of all digestive diseases. The third National Health and Nutrition Examination Survey estimated that, in the United States, 6.3 million men and 14.2 million women aged 20-74 years had gallbladder disease.
The incidence of gallstones is 1 million new cases per year. The prevalence is 20 million cases among Americans.
Approximately 2-7 cases per 100,000 population of primary sclerosing cholangitis (PSC) exist. About 5% of patients with chronic ulcerative colitis develop PSC.
The incidence of gallbladder cancer is 2.5 cases per 100,000 population.

Internationally: The incidence of primary biliary cirrhosis (PBC) is 5.8-15 cases per 1 million population. The incidence of PBC appears to be increasing, but the cause of the increase is unclear. However, the increase is possibly due to better detection and increased awareness rather than a true change in disease incidence.

Mortality/Morbidity:

Gallstones are a rare cause of mortality, accounting for 5000 of the 2.2 million deaths annually in the United States.

PBC accounts for 0.6-2% of deaths from cirrhosis worldwide. The median time of patient survival was 9.3 years from diagnosis. Independent predictors of survival included age and alkaline phosphatase, serum albumin, and bilirubin levels. Liver failure developed in 26% of patients by 10 years after diagnosis. Neither the presence of antimitochondrial antibodies nor their titer affects disease progression or survival.

PSC is a leading reason for liver transplantation. Median survival without liver transplantation after diagnosis is approximately 12 years. Variables that appear to predict prognosis in PSC include age, histological stage, hepatomegaly, splenomegaly, and serum alkaline phosphatase and serum bilirubin levels.

Race: Mexican Americans and several American Indian tribes, particularly the Pima Indians in the Southwest, have very high prevalence rates of cholesterol gallstones. Decreased bile acid secretion is believed to be the common denominator in these ethnic groups.

Gallbladder cancer is the most common GI malignancy in both Southwestern Native Americans and Mexican Americans. A prominent geographic variability exists in the incidence of gallbladder cancer that correlates with the prevalence of cholelithiasis. High rates of gallbladder cancer are also seen in South American countries, particularly Chile and Bolivia. These populations all share a high prevalence of gallstones and/or Salmonella infection, both recognized risk factors for gallbladder cancer.

Sex: The prevalence of cholesterol gallstones is higher among females than males (lifetime risk of 35% vs 20%, respectively). This likely is due to endogenous sex hormones, which enhance cholesterol secretion and increase bile cholesterol saturation. Progesterone also may contribute by relaxing smooth muscle and impairing gallbladder emptying.

PSC: Males are affected twice as frequently as females.

PBC: Females are affected 9 times as often as males.

Age: Increased age is associated with lithogenic bile and an increased rate of gallstones.

PSC: Mean age of onset is 40 years.

PBC: Among the autoimmune diseases, PBC is unique in that it never occurs in childhood and is rarely found before age 30 years. The onset is usually between the ages of 30-65 years, but the disease has been reported in women as young as 22 years and as old as 93 years.

Treatment
Medical Care:

b>Gallstones

edical management of gallstone disease has decreased in recent years with the advent of laparoscopic cholecystectomy. Cholecystectomy remains the preferred method because of its reduced cost, definitive nature, safety, and increased convenience to the patient.

Medical management may be an effective alternative to cholecystectomy in selected patients with symptomatic gallstone disease. Three methods used alone or in combination are available for the nonsurgical management of patients with gallstone disease, as follows: (1) oral bile salt therapy, primarily ursodeoxycholic acid, (2) contact dissolution, and (3) extracorporeal shock-wave lithotripsy. The method of choice depends upon the number, size, and composition of the stone(s); many symptomatic patients have stones that are not ideally suited to any of these methods, producing less than optimal results.

Several years of treatment may be necessary to completely dissolve a stone, and a 50% chance of stone recurrence over a period of 5 years exists. Some evidence supports using nonsteroidal anti-inflammatory drugs (NSAIDs) in the setting of recurrent biliary pain; inhibition of prostaglandins may arrest the inflammatory process and reduce the chance of developing acute cholecystitis.

There is consensus that incidentally discovered asymptomatic gallstones should not be treated. Once a patient develops symptoms or complications related to gallstones (eg, acute cholecystitis), treatment to eliminate the gallstones is recommended because the likelihood of subsequent symptoms or complications is high. The National Cooperative Gallstone Study demonstrated that the risk of recurrent symptoms was approximately 70% during the 2 years following initial presentation.

Acute cholecystitis

Patients with a clinical diagnosis of acute cholecystitis should be admitted to the hospital, where they should have nothing by mouth (NPO) and be administered IV fluid hydration; correction of any associated electrolyte disorders is an important initial measure. In most cases, inflammation is initiated by mechanical obstruction of the cystic duct and mediated by a chemical irritation of the gallbladder mucosa (by lysolecithin).

However, in 20% of patients, bacterial infection complicates the picture. The most frequent isolates from the gallbladder or the common bile duct are Escherichia coli (41%), Enterococcus (12%), Klebsiella (11%), and Enterobacter (9%).

When poor clinical appearance, fever, and leukocytosis are prominent features of the illness, broad-spectrum antibiotics are indicated. Empiric antibiotic therapy should be directed at the organisms most frequently recovered. While the use of a second-generation cephalosporin, such as cefuroxime, is fairly common, cephalosporins do not treat Enterococcus. The combination of ampicillin (2 g IV q4h) and gentamicin (dosed according to weight and renal function) as empiric treatment can be used. The aminoglycoside is included for coverage of E coli and other gram-negative bacilli and also for synergy with ampicillin against Enterococcus. Routine coverage of anaerobic organisms is not required for acute cholecystitis since these organisms are recovered infrequently.

NSAIDs are useful in reducing inflammation, but narcotic analgesics often are needed to alleviate pain. Unless severe comorbid disease is a contraindication, these patients should undergo a cholecystectomy once their condition is stabilized.

Cholangitis

The treatment of cholangitis is similar to that of acute cholecystitis, except that endoscopic intervention is indicated. The mainstays of therapy are antibiotics and the establishment of biliary drainage. Broad-spectrum antibiotics are indicated initially to cover gram-negative bacteria and Enterococcus. Antibiotics include ampicillin plus gentamicin, carbapenems (imipenem or meropenem), and fluoroquinolones (levofloxacin). Other agents that have good activity against intestinal anaerobes and lack the nephrotoxicity of aminoglycosides are piperacillin (4 g IV q6h), piperacillin-tazobactam (4/0.5 g IV q6-8h), ampicillin/sulbactam (3 g q6h), or ticarcillin-clavulanate (3.1 g q4h). Unlike acute cholecystitis, in patients with a more toxic appearance, metronidazole is often added to cover anaerobes, although the contribution of anaerobes to infection is low in patients who have not had previous biliary tract instrumentation or surgery.

Depending on the etiology of the cholangitis and the comorbid status of the patient, biliary drainage is established by endoscopic retrograde cholangiopancreatography (ERCP)–guided sphincterotomy and stone extraction or biliary stent placement. In a patient with sepsis, the least aggressive intervention to establish biliary drainage often is best, with subsequent plans for definitive therapy (cholecystectomy) once the patient's condition is stabilized.

Percutaneous drainage should be considered when ERCP is unavailable, unsuccessful, or contraindicated. A percutaneous cholecystostomy tube may be an option in patients with an intact gallbladder.

Primary sclerosing cholangitis

Two major goals of treatment in PSC are retardation and reversal of the disease process and management of progressive disease and its complications. A variety of immunosuppressive and anti-inflammatory agents have been studied in patients with PSC, including ursodeoxycholic acid (UDCA), corticosteroids, cyclosporine, methotrexate, azathioprine/6-mercaptopurine, tacrolimus, and D-penicillamine.

No effective medical treatment exists for PSC.

UDCA, a hydrophilic bile acid, is the most extensively studied of all medical treatments of PSC. Ursodiol, used to create a less toxic population of bile acids, initially showed promise; however, subsequent clinical studies showed no difference in the time to treatment failure. It has also been hypothesized that UDCA given in higher than standard doses (20-30 mg/kg/d vs 13-15 mg/kg/d) may increase the benefit. Larger scale prospective studies of high-dose UDCA are currently underway.

Reduction of hepatic copper levels using D-penicillamine showed no benefits; immunosuppressives either failed or worsened patient status. Oral corticosteroids might help early stage disease with marked inflammatory changes as observed on biopsy specimens. Steroids administered by nasobiliary lavage complicated matters by introducing bacterial cholangitis.

While colchicine and steroids together improve laboratory test results, the development of cirrhosis is not diminished, and metabolic bone disease is aggravated, causing some patients to develop compression fractures. Colchicine alone showed no improvement in symptoms, serum biochemistry, liver histology, or survival rate. While methotrexate decreased serum alkaline phosphatase levels, it produced no appreciable improvement in bilirubin, AST, ALT, or albumin levels, and it had minimal effect on symptoms or histologic progression. Cyclosporine decreased serum alkaline phosphatase levels but did not improve symptoms, histologic progression, or the development of complications.

Endoscopic therapy to dilate and/or stent dominant strictures is reasonable in centers with considerable expertise in therapeutic biliary endoscopy. An important potential clinical benefit is relief of jaundice and pruritus, although a benefit on disease progression has not been clearly established.

Liver transplantation is now the treatment of choice for patients with advanced liver disease secondary to PSC.

Primary biliary cirrhosis

The management of this disorder has 2 goals, as follows: (1) the treatment of symptoms and complications that result from chronic cholestasis, and (2) the suppression of the underlying pathogenic process (ie, the destruction of small intralobular hepatic bile ducts). The complications that occur in PBC that require therapy include pruritus, metabolic bone disease, hypercholesterolemia/xanthomas, atherosclerosis, malabsorption, vitamin deficiencies, hypothyroidism, and anemia.

ata exist showing that medical therapy benefits patients with PBC. The only approved treatment is UDCA, which is the only treatment (aimed at modifying the natural history of the disease) recommended in the guidelines issued by the American Association for the Study of Liver Diseases (AASLD). UDCA alone (13-15 mg/kg/d is given in divided doses with meals and at bedtime) in asymptomatic patients with stages I-III disease. Blood tests are monitored every 3 months. If normalized within 6 months, UDCA is continued and liver biopsy is repeated within 18-24 months. If the biopsy result is stable or improved, UDCA is continued indefinitely and a liver biopsy is repeated after 2-3 years and then less often if still improved.

In clinical studies, colchicine had no effect on symptoms, physical findings, or histology, but it improved levels of serum albumin, bilirubin, alkaline phosphatase, cholesterol, and aminotransferases. One study showed improved mortality rates (21% vs 47%, P = 0.05). In a double-blind randomized clinical trial, azathioprine was well tolerated, slowed incapacitation, and improved actuarial survival by 20 months. However, the development of major complications or the need for liver transplantation was not influenced. In a small prospective randomized trial, chlorambucil reduced the inflammatory cell infiltrate, but it did not improve serum alkaline phosphatase levels, fibrosis, or histologic severity. Methotrexate, used in pilot studies only, has been said to have beneficial effects on the symptoms and biochemical and histological features of PBC. However, one randomized controlled trial of methotrexate therapy suggested that, even at low doses (2.5 mg 3 times per wk), methotrexate may be toxic over a 6-year period. Hence, at the present time, insufficient data support the use of immunosuppressive therapy for PBC.

Similar to the experience with PSC, corticosteroids worsened metabolic bone disease and D-penicillamine induced serious adverse effects without providing a clinical benefit.

Liver transplantation in PBC is recommended for cases of liver failure. Liver transplantation may be recommended in appropriately selected patients for uncontrollable pruritus and severe osteoporosis.

Symptomatic treatment

The pruritus associated with cholestasis may respond to cholestyramine, rifampin, and even large-volume plasmapheresis. Naloxone also reduces the severity of itching but requires parenteral administration. Oral naltrexone may be an effective and well-tolerated alternative.

Steatorrhea

Patients with steatorrhea may benefit from pancreas enzyme supplements and fat-soluble vitamins A, D, E, and K.

Endoscopic management

Endoscopic management of biliary stones: Because choledocholithiasis frequently causes abdominal pain, pancreatitis, cholangitis, and secondary biliary cirrhosis, treatment is recommended once stones are identified. The standard approach is to perform an ERCP with biliary sphincterotomy and stone extraction using a balloon-tipped catheter or wire basket. Clearance rates range from 80-95%, depending on the experience of the endoscopist, with an associated morbidity rate of 5-10% and a mortality rate of 0.5%. Refractory stones usually can be cleared using a mechanical lithotripsy device; however, electrohydraulic lithotripsy (EHL) and laser lithotripsy also can be used. Refractory biliary stones can be managed with biliary stent placement and ursodiol. In selected patients, percutaneous choledochoscopy can be used to remove intrahepatic stones using EHL or holmium laser lithotripsy (a holmium laser is used to fracture the stones).

Endoscopic management of benign biliary strictures: Benign postoperative strictures are managed successfully by endoscopic balloon dilation and stent placement on a quarterly basis for a period of a year. This approach has an 83% success rate, with 17% of cases eventually requiring surgical intervention. In patients with sclerosing cholangitis, mechanical dilation of dominant extrahepatic strictures decreases bilirubin but does not improve liver-associated enzymes. It primarily is helpful in preventing a dominant stricture from causing further damage to the liver, and it may delay the need for a liver transplant. Patients with a symptomatic or complicated distal biliary stricture caused by chronic pancreatitis usually are best managed surgically. In selected patients with high operative risk, placement of a metal mesh stent may be helpful; however, a tendency exists for biliary epithelial hyperplasia to obstruct these stents within several years.

Endoscopic management of malignant biliary strictures: The technical success rate of endoscopic dilation and stent placement for palliation of malignant biliary strictures is greater than 90%. It is associated with fewer complications than percutaneous transhepatic biliary drainage, and clinical studies show that the results are equal to that achieved with surgical bypass. Although the patency rate of metal mesh stents exceeds plastic stents, tumor ingrowth still may obstruct the stent and require subsequent procedures. Suppurative cholangitis can develop as a serious complication of an obstructed biliary prosthesis.

Surgical Care:

Cholecystectomy: Prophylactic cholecystectomy is not recommended for people with asymptomatic gallstones. It is recommended routinely for patients with symptomatic cholelithiasis (ie, biliary-type pain, complications), porcelain gallbladder, the finding of gallstones during a planned abdominal operation in patients with hemoglobinopathy, or in a child.

Laparoscopic cholecystectomy is the current standard of care; the stone clearance rate approaches 100%, the operative mortality rate is less than 1%, the morbidity rate is 2-5%, and the disability time is 7 days, with minimal scarring.

Open cholecystectomy occasionally is necessary and has a stone clearance rate of 100%, a mortality rate of less than 1%, a morbidity rate of about 6%, a disability time of about 30 days, and leaves a moderate scar. Retained common bile duct stones, (ie, those stones that elude detection during open cholecystectomy) occur in 5-10% of patients.

Patients with biliary-type pain and a gallbladder ejection fraction of less than 35% may have a 70-90% chance of achieving pain relief following cholecystectomy.

Transduodenal sphincteroplasty: This is a surgical procedure used to treat recurrent biliary-type pain due to papillary stenosis. F.G. Moody (1991), who developed and refined the procedure, emphasizes the technical details of the procedure as the key to a successful outcome. In his initial experience, 58% of patients remained totally free of pain and 26% had occasional pain not requiring narcotic analgesics when observed 5-15 years after operation. His subsequent experience was less favorable, with only 43% remaining pain free and 24% experiencing poor results. Based on these poor results, the presence of chronic pancreatitis is regarded as a contraindication to the procedure; however, patients with recurrent pancreatitis may achieve a good outcome.

Ampullectomy: This procedure is indicated in a patient with a tumor partially or completely obstructing the ampulla. Depending on clinical factors and local expertise, it can be performed by endoscopic or surgical techniques. Endoscopic snare excision is appropriate for relatively small lesions without evidence of severe dysplasia or malignancy and also is an option in periampullary malignancy in patients in whom pancreaticoduodenectomy is unsuitable because of underlying comorbid or metastatic disease.

Pancreaticoduodenectomy: This procedure is indicated in otherwise healthy patients with a periampullary adenoma harboring severe atypia, periampullary villous adenomas larger than 3 cm, or periampullary malignancy. Appropriately selected patients have a reasonably good outcome, and even those with malignancy achieve 5-year survival rates of 25-30%.

Liver transplantation: In patients with end-stage cholestatic liver disease, liver transplantation continues to offer hope. Initial 1- and 2-year survival rates were 71% and 57%, respectively. Recently, 1-, 2-, and 5-year survival rates have reached 90%, 86%, and 85%, respectively. Recurrent PSC developed in 20% of patients. In those patients found to have unexpected cholangiocarcinoma at the time of liver transplantation, all experienced a recurrence within 6 months and had a significantly worse outcome. In a recent study, the recurrence rate of PBC was 18% at 5 years and 30% at 10 years.

Diet: When biliary disease associated with decreased bile flow causes steatorrhea, a diet low in neutral triglycerides often is prescribed. Supplementation with medium-chain triglycerides also is helpful.

Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Gallstone dissolution agents -- Ursodeoxycholic acid is a naturally occurring bile acid used successfully in the dissolution of gallstones, microlithiasis, and in primary biliary cirrhosis. Some benefit may exist in patients with Caroli disease.

Drug Name	Ursodiol (Actigall) -- Decreases cholesterol content of bile and bile stones probably by reducing secretion of cholesterol from the liver and the amount reabsorbed by intestines.
Adult Dose	Gallstone dissolution: 8-10 mg/kg/d PO divided tid Primary biliary cirrhosis: 10-15 mg/kg/d PO divided tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; calcified cholesterol stones; radiopaque stones; bile pigment stones
Interactions	Decreased effect with aluminum-containing antacids, cholestyramine, colestipol, clofibrate, and oral contraceptives
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in patients with a nonvisualizing gallbladder

span >Drug Category: Antipruritics -- Alleviation of itching associated with excessive bile acid levels.

Drug Name	Cholestyramine (Questran) -- Forms a nonabsorbable complex with bile acids in the intestine, which in turn inhibits enterohepatic reuptake of intestinal bile salts.
Adult Dose	4 g 2-6 times/d mixed in 4 oz water or juice; not to exceed 24 g/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; complete biliary obstruction; hyperlipidemia types III, IV, or V
Interactions	Inhibits absorption of numerous drugs, including warfarin, thyroid hormone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, phenobarbital, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, penicillin G, cephalexin, and metronidazole; thiazide diuretics; valproic acid; troglitazone; coadministration with pravastatin increases effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Documented hypersensitivity; caution in constipation and phenylketonuria; chronic use may lead to insufficiency of fat-soluble vitamins and contribute to bleeding.

Drug Name	Rifampin (Rifadin) -- Antimycobacterial agent noted to alleviate pruritus in 79% of patients with primary biliary cirrhosis. Effect may be a result of changed metabolism of liver bile acids or by altered bacterial metabolism by intestinal bacteria.
Adult Dose	300 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Induces microsomal enzymes, which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFTs occur)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in liver impairment and adrenal insufficiency; perform LFTs before and during treatment, may increase alkaline phosphatase levels

Drug Name	Naloxone (Narcan) -- Opioid antagonist useful in treatment of pruritus.
Adult Dose	0.4 mg IV bolus initial, followed by continuous infusion of 0.2 mg/kg/min
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Decreases analgesic effects of narcotics; increases effects of clonidine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in cardiovascular disease; may precipitate withdrawal symptoms in patients addicted to opiates

Biliary Colic

2007-11-28T21:10:00.000-08:00

Background: Biliary colic is a symptom of discomfort and is often not accompanied by any clinical signs. It represents one of the causes of epigastric pain. It is the most common presentation of symptomic gallstone disease (cholelithiasis/choledocholithiasis). Because this is a symptom, numerous other disease processes may result in pain that is similar to biliary colic, and, certainly, biliary colic is not the most common cause of epigastric pain. For this reason, other disease processes should be considered during the evaluation of patients being considered to have biliary colic.

Careful history and examination are cornerstones to making an accurate clinical diagnosis, essentially because of the high incidence of gallstones in the population and because most gallstones are asymptomatic. The potential disastrous implications of a misdiagnosis as biliary colic instead of alternative diagnoses that may present with epigastric pain (eg, atypical myocardial ischemia) cannot be overemphasized. Patients also can be particularly unhappy and frustrated when their pain is not resolved following cholecystectomy. The differential diagnosis section lists other important medical conditions one should consider in patients who present with possible biliary colic.

History should elicit the nature, intensity, location, duration, onset, cessation, associated factors, aggravating factors, relieving factors, radiation, and frequency (NILDOCARRF) of the pain. The pain of biliary colic is listed inaccurately as a colic. This term implies a paroxysmal pain that waxes and wanes, when, in actuality, the pain of biliary colic is generally a constant and slowly progressive pain. The pain generally follows a meal and may wake up a person several hours later. In fact, pain immediately with a meal is not characteristic of biliary colic.

It is important while taking the history that one evaluates the risk factors for stone formation, addresses and excludes other potential causes for the pain, and concurrently evaluates medical comorbidities that may influence management (eg, cardiovascular disease).

This visceral pain is believed to result from impaction of a gallstone in the cystic duct and/or ampulla of Vater. The resulting impaction causes distension of the gallbladder and/or biliary tract, and this distension activates visceral afferent sensory neurons. The resultant pain is commonly localized poorly and general refers midline to the representative dermatomes T8/9 (mid epigastrium, right upper quadrant), although it may radiate to the right upper quadrant. Localized pain or persistent pain generally represents a complication of cholelithiasis or choledocholithiasis (eg, cholecystitis, cholangitis, pancreatitis).

Biliary colic is the presenting symptom in 80% of patients with gallstone disease who seek medical care; however, only 10-20% of all individuals with gallstones experience severe gallstone pain. The risk of developing biliary pain or stone-related complications in asymptomatic patients is low, at 1-2% per year. For this reason, clinical practice favors treatment of only symptomatic disease, with the exception of a few unique circumstances. Two thirds of patients presenting with their first attack of biliary colic have recurrent pain within 2 years.

Pathophysiology: A gallstone produces visceral pain by obstructing the cystic duct or ampulla of Vater, resulting in distention of the gallbladder or biliary tree. Pain is relieved when the gallstone migrates back into the gallbladder, passes through the ampulla, or falls back into the common bile duct (CBD). The pain of biliary colic may accompany sphincter of Oddi spasm.

Frequency:

In the US: Asymptomatic individuals with gallstones develop pain at an annual rate of 1-4%, with approximately 10% of individuals developing symptoms in 10 years and 20% developing symptoms in 20 years.

Internationally: Limited international data appear to support a similar incidence of biliary colic in all populations with gallstones. The incidence of gallstones is greater in some races and cultures than in others.

Mortality/Morbidity: By definition, uncomplicated gallstone disease is not associated with signs or symptoms of systemic disease such as fever, jaundice, or leukocytosis. Patients with uncomplicated gallstone disease experience self-limited pain. Presentation is associated with only limited morbidity and never mortality, despite some patients' perception of the severity of pain and its significance. The frequency of progression to acute cholecystitis is 10-30%. Ibuprofen use possibly may decrease the likelihood of progression.

Race: In the United States, the prevalence of gallstone disease is highest among Hispanic Americans and Native Americans, especially the Pima Indians of Arizona, with 75% of women developing cholesterol gallstones by early adulthood.

Sex: Biliary colic is more common in women than in men, primarily related to the 2- to 3-fold increased incidence of cholelithiasis in women.

Age: The incidence of biliary colic depends on the incidence of gallstones. For this reason, the condition is rare in patients younger than 20 years and increases with age, occurring in approximately 2-4% of men older than 60 years and approximately 3-8% of age-matched women.

Treatment
Medical Care: Supportive measures are indicated for patients with uncomplicated biliary colic, with symptoms usually resolving within 2-3 hours. Continuous or recurrent symptoms despite analgesia likely herald a complication of gallstone disease, most commonly acute cholecystitis.

Pain

Most authors favor narcotic analgesics over other agents for the immediate relief of pain. Meperidine (pethidine) at 1-1.5 mg/kg intramuscular injection (not to exceed 100 mg) every 3 hours is preferred. In view of the theoretical association with increased biliary motility and spasm, morphine generally is avoided.

Several controlled trials of diclofenac, tenoxicam, and ketorolac seem to have demonstrated therapeutic benefits in both pain relief and decreased likelihood of progression to acute cholecystitis. An increase in adverse effects in patients who are dehydrated or elderly should be considered. In the setting of nausea and vomiting, a parenteral route is favored.

Antispasmodics (eg, papaverine, atropine) and nitrates have a very limited, if any, role in the treatment of biliary colic.

Nausea: Use metoclopramide or prochlorperazine intravenously.

Surgical Care: No acute surgical intervention is warranted because uncomplicated biliary colic resolves with conservative treatment.

Several studies have reviewed the treatment of symptoms believed to be related to gallstones.

Patients who undergo elective cholecystectomy for biliary colic have shorter lengths of stay in the hospital and less complicated operative courses than those presenting with complications of gallstone disease. Relief of symptoms occurs in approximately 85% of individuals. The procedures performed were, on the average, shorter and with shorter periods of convalescence. Many authors favor elective surgery for patients with biliary colic.

Patients with atypical (ie, nonpain) symptoms show inconsistent relief of these symptoms (eg, fatty food intolerance, flatulent dyspepsia). Laparoscopic therapy is favored.

In patients with symptoms of biliary colic without gallstones, the treatment options become more difficult. A combination of a positive biliary scintography with CCK (an ejection fraction <50%)>

Nonsurgical treatment is selected for high-risk surgical candidates.

Consultations: Early surgical consultation is appropriate if symptoms do not resolve in the expected time frame. Persistent symptoms suggest the possibility of acute cholecystitis. In those in whom a diagnosis is established and symptoms resolve, elective consultation is appropriate.

Diet: During the acute attack, patients typically are anorectic. After resolution of the attack, some authors favor avoidance of high-fat meals. Controlled data are lacking to support this approach, and a liberal healthy diet is not unreasonable. A diet to prepare an individual for surgery is advised (eg, weight reduction in patients who are obese).

Activity: Bed rest usually is recommended until the pain resolves; patients may resume full activity thereafter.

Medication
NSAIDs and/or opiate agonists are used to provide pain relief. Nausea is treated with antiemetics and intravenous fluids for consequent dehydration.
Drug Category: Analgesic agents -- Pain control is essential to quality patient care. NSAIDs have analgesic, anti-inflammatory, and antipyretic activities. They are used for mild to moderate pain. Their mechanism of action is unknown, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may exist (eg, inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, various cell membrane functions). Opioid analgesics act at the CNS mu receptors. They are inexpensive and have proven effective.

Drug Name	Meperidine (Demerol) -- Analgesic with multiple actions similar to those of morphine; may produce less constipation, smooth-muscle spasm, and depression of cough reflex than equal analgesic doses of morphine.
Adult Dose	50-150 mg PO/IV/IM/SC q3-4h prn
Pediatric Dose	Not established; problem rare <20>
Contraindications	Documented hypersensitivity; within 2 wk of MAOIs; upper airway obstruction or significant respiratory depression; intracranial lesions; multiple doses in patients with renal failure; predisposition to seizures; during labor when delivery of premature infant is anticipated
Interactions	Increased respiratory and CNS depression with coadministration of cimetidine; hydantoins may decrease effects; protease inhibitors (eg, ritonavir) may increase normeperidine levels, enhancing risk of CNS toxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Pregnancy category D with prolonged use or high doses at term; caution in patients with head injuries, may increase respiratory depression and CSF pressure; caution postoperatively and in patients with history of pulmonary disease (suppresses cough reflex); increased doses due to tolerance may aggravate or cause seizures (even without prior history); caution in patients with renal dysfunction (decrease dose), do not use in patients with severe renal dysfunction, normeperidine metabolite accumulation may induce CNS toxicity

Drug Name	Hydromorphone (Dilaudid) -- Potent semisynthetic opiate agonist similar in structure to morphine. Approximately 7- to 8-times as potent as morphine on mg-to-mg basis, with shorter or similar duration of action (ie, 4-5 h).
Adult Dose	1-2 mg IV/IM/SC q4h; adjust dose according to pain scale assessment
Pediatric Dose	Not established; problem rare <20>
Contraindications	Documented hypersensitivity; do not use for obstetrical analgesia, increased intracranial pressure, or respiratory depression; ulcerative colitis; Crohn disease; relative contraindications include abdominal cramping and distention
Interactions	Additive sedation and respiratory depression with other drugs causing CNS depression; drugs inducing CYP450 metabolism (eg, rifampin, phenytoin, carbamazepine) may decrease hydromorphone effect
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Pregnancy category D with prolonged use or high doses at term; caution in patients with head injuries, may increase respiratory depression and CSF pressure; caution postoperatively and in patients with history of pulmonary disease (suppresses cough reflex); caution in patients with impaired hepatic function (decrease dose), hypothyroidism, Crohn disease, ulcerative colitis, Addison disease, or prostatic hypertrophy

Drug Name	Ibuprofen (Motrin, Advil, Ibuprin) -- Indicated for patients with mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.
Adult Dose	Mild to moderate pain: 400 mg PO q4-6h prn; not to exceed 3.2 g/d; IM dosing for those with concurrent nausea
Pediatric Dose	Not established; problem rare <20>
Contraindications	Documented hypersensitivity; active peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding
Interactions	Coadministration with aspirin increases risk of serious NSAID-related adverse effects; probenecid may increase concentrations and possibly toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase methotrexate toxicity; phenytoin levels may increase when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; caution in patients with congestive heart failure, hypertension, and decreased renal and hepatic function; caution in patients with coagulation abnormalities or during anticoagulant therapy

Drug Name	Ketorolac (Toradol) -- Inhibits prostaglandin synthesis by decreasing activity of cyclooxygenase, which results in decreased formation of prostaglandin precursors.
Adult Dose	30-60 mg IM initially, followed by 15-30 mg q6h; alternatively 15-30 mg IV initially, followed by 15-30 mg IV prn; not to exceed 120 mg/d (60 mg/d in renal failure, >65 y, or <50>
Pediatric Dose	Not established; problem rare <20>
Contraindications	Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding; do not administer into CNS
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and possibly toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Category D in third trimester of pregnancy; may cause acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; leukopenia (rare) usually returns to normal during ongoing therapy; discontinue therapy if persistent leukopenia, granulocytopenia, or thrombocytopenia occur; decrease dose in renal failure, >65 y, or <50>

Drug Category: Antiemetic agents -- The CNS vomiting center (VC) may be stimulated directly by GI irritation. Increased activity of central neurotransmitters, dopamine in the chemoreceptor trigger zone, or acetylcholine in the VC appears to be a major mediator for inducing vomiting. Antidopaminergic agents (eg, metoclopramide, phenothiazines) are effective for nausea due to GI irritation.

Drug Name	Metoclopramide (Reglan) -- Dopamine antagonist that stimulates acetylcholine release in the myenteric plexus. Acts centrally on chemoreceptor triggers in the floor of the fourth ventricle, which provides important antiemetic activity.
Adult Dose	10 mg IV q6h prn
Pediatric Dose	Not established; problem rare <20>
Contraindications	Documented hypersensitivity; pheochromocytoma; GI hemorrhage, obstruction, or perforation; history of seizure disorders
Interactions	Opioid analgesics may increase toxicity in CNS; may cause additive effect with other drugs that cause extrapyramidal reactions; hypertension observed with coadministration of MAOIs, tricyclic antidepressants, or sympathomimetics; may increase serum levels of cyclosporine, sirolimus, or tacrolimus; may decrease digoxin serum levels
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in breastfeeding women, patients with depression, hypertension, Parkinson disease, and conditions aggravated by anticholinergic or antidopaminergic effects; may cause tardive dyskinesia

Drug Name	Prochlorperazine (Compazine) -- May relieve nausea and vomiting by blocking postsynaptic mesolimbic dopamine receptors through anticholinergic effects and depressing reticular activating system.
Adult Dose	5-10 mg PO/IM tid/qid; not to exceed 40 mg/d; alternatively, 2.5-10 mg IV q3-4h prn; not to exceed 10 mg/dose or 40 mg/d 25 mg PR bid
Pediatric Dose	Not established; problem rare <20>
Contraindications	Documented hypersensitivity; bone marrow suppression; narrow-angle glaucoma; severe hypotension; children <2>
Interactions	Coadministration with other CNS depressants or anticonvulsants may cause additive effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Drug-induced Parkinson syndrome or pseudoparkinsonism occurs frequently, akathisia is most common extrapyramidal reaction in elderly persons; tardive dyskinesia may occur, especially in elderly persons (up to 40%); extrapyramidal effects most pronounced in children <5>

Drug Name	Ondansetron (Zofran) -- 5-HT-3 receptor antagonist used when other classes fail or are contraindicated.
Adult Dose	4 mg IV q6h prn; 8 mg PO tid prn
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Although potential exists for cytochrome P-450 inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) to change half-life and clearance, dosage adjustment usually not required
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in impaired liver function; medication administered for prevention of nausea and vomiting, not for rescue of nausea and vomiting

Bile Duct Strictures

2007-11-28T21:08:00.000-08:00

Background: Bile duct stricture is an uncommon but challenging clinical condition requiring a coordinated multidisciplinary approach involving gastroenterologists, radiologists, and surgical specialists. Unfortunately, most benign bile duct strictures are iatrogenic, resulting from operative trauma. Bile duct strictures may be asymptomatic but, if ignored, can cause life-threatening complications, such as ascending cholangitis, liver abscess, and secondary biliary cirrhosis. However, not all strictures are benign. Pancreatic cancer is the most common cause of malignant biliary strictures. Most of these patients die of complications of tumor invasion and metastasis rather than from the biliary stricture, per se. Nonetheless, both benign and malignant strictures can be associated with distressing symptoms and excessive morbidity.

Pathophysiology: Strictures of the bile duct can be benign or malignant. Benign strictures develop when the bile ducts are injured in some way. The injury may be a single acute event, such as damage to the bile ducts during surgery or trauma to the abdomen; a recurring condition, such as pancreatitis or bile duct stones; or a chronic disease, such as primary sclerosing cholangitis (PSC). After the injury, an inflammatory response ensues, which is followed by collagen deposition, fibrosis, and narrowing of the bile duct lumen.

Depending on the nature of the insult, bile duct strictures can be single or multiple. Atrophy of the hepatic segment or lobe drained by the involved bile ducts, associated with hypertrophy of the unaffected segments, can occur, especially with chronic high-grade strictures. These changes can eventually progress to secondary biliary cirrhosis and portal hypertension. Malignant strictures usually are the result of either a primary bile duct cancer (ie, causing a narrowing of the bile duct lumen and obstructing the flow of bile) or extrinsic compression of the bile ducts by a neoplasm in an adjacent organ, such as the gallbladder, pancreas, or liver.

Frequency:

In the US: Although quite uncommon, the exact prevalence of bile duct strictures is unknown. One major category of bile duct strictures is postoperative bile duct stricture, which usually occurs as a result of a technical mishap during cholecystectomy, causing bile duct injury. Data from many large series of patients in the United States have revealed that the incidence rate of major bile duct injury is 0.2-0.3% after open cholecystectomy and 0.4-0.6% after a laparoscopic cholecystectomy.

Internationally: Data from Europe have shown a similar rate of occurrence of postoperative bile duct strictures.

Mortality/Morbidity:

Bile duct strictures, independent of etiology, can cause significant morbidity from recurrent obstructive jaundice, right upper quadrant abdominal pain, biliary stones, and recurrent episodes of ascending cholangitis.

The major determinant of mortality in patients with bile duct strictures is the underlying disease condition. Patients with biliary strictures due to operative injury, radiation, trauma, or chronic pancreatitis generally have a good prognosis. Conversely, patients with bile duct strictures due to PSC and malignancy have a less favorable outcome.

Sex:

Data on the overall sex ratio of bile duct strictures are lacking. Some conditions causing bile duct strictures, such as PSC and chronic pancreatitis, are more common in men. The incidence of postcholecystectomy strictures is comparable in men and women.

Treatment
Medical Care: Medical treatment consists of managing complications of bile duct strictures until definitive therapy can be instituted. Most patients presenting with cholangitis respond to antibiotics and supportive management. Patients who are elderly and frail and those presenting with hypotension or altered mental status are best treated in an intensive care unit.

The common organisms causing cholangitis are Escherichia coli and Klebsiella, Enterococcus, Proteus, Bacteroides, and Clostridium species. Empiric antibiotic therapy should be effective against these organisms.

A combination of a penicillin, aminoglycoside (gentamicin), and metronidazole traditionally has been the preferred regimen. Newer penicillins, such as piperacillin/tazobactam or imipenem/cilastatin, also have excellent activity against anaerobes, enterococci, and gram-negative cocci.

Approximately 70-80% of patients respond to medical therapy and do not need urgent intervention. Patients not responding to empiric antibiotic therapy within 24 hours or those with hypotension requiring vasopressors, disseminated intravascular coagulation, or multiorgan system failure should be considered for immediate biliary decompression, which can be performed surgically, percutaneously, or endoscopically. Endoscopic or percutaneous decompression often is associated with lower morbidity and should be considered first.

Surgical Care: Patients with cholangitis whose conditions fail to improve with conservative treatment usually require urgent decompression of the obstructed biliary system. Treatment options for bile duct strictures include (1) endoscopic or percutaneous balloon dilatation and insertion of an endoprosthesis or (2) surgery.

Decompression of the biliary system

Decompression usually is performed endoscopically, with placement of a nasobiliary tube or stent after sphincterotomy.
Alternatives to ERCP are percutaneous transhepatic biliary drainage and surgical decompression. However, operative biliary decompression is associated with much higher morbidity and mortality compared to endoscopic therapy.

Endoscopic management

Benign biliary strictures (eg, postcholecystectomy, after liver transplantation) can be treated effectively with endoscopic therapy, which achieves a symptomatic and biochemical response in most cases.
Recent studies show that the long-term success rate of endoscopic stenting is comparable to that of surgery, with similar recurrence rates. Therefore, surgery should probably be reserved for those patients with complete ductal obstruction or those in whom endoscopic therapy has failed.
Endoscopic therapy generally involves a sphincterotomy, which is performed at the first endoscopic session simultaneously with the placement of one or two 10F-12F stents across the area of obstruction. Dilatation of the stricture may be necessary if the stricture is too tight.
The insertion of a second stent may be possible only during a second endoscopy session. Thereafter, elective replacement of the stents seems desirable to prevent cholangitis by stent occlusion because polyethylene stents generally clog in 3-4 months.

Sphincterotomy and endoscopic balloon dilation
- The combination of sphincterotomy and endoscopic balloon dilation alone is not a reliable method of treating benign strictures.
- Dilation followed by short- to intermediate-term stent placement appears to provide a more durable result.

Endoscopic biliary stenting

Endoscopic therapy for PSC

Endoscopic therapy for malignant strictures

Percutaneous transhepatic cholangioplasty and biliary stenting

Operative treatment

Consultations:

Gastroenterologist

Surgeon

Infectious disease specialist

Interventional radiologist

Oncologist

Diet:

No special diet is required.

Activity:

No restriction on physical activity is required.

Medication
The goals of pharmacotherapy are to eradicate the infection, prevent complications, and reduce morbidity.
Drug Category: Antibiotics -- Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of this clinical setting.

Drug Name	Piperacillin and tazobactam sodium (Zosyn) -- Antipseudomonal penicillin plus beta-lactamase inhibitor. Inhibits biosynthesis of cell wall mucopeptide and is effective during stage of active multiplication.
Adult Dose	3/0.375 g (piperacillin 3 g and tazobactam 0.375 g) IV q6h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe pneumonia; bacteremia; pericarditis; emphysema; meningitis and purulent or septic arthritis should not be treated with an oral penicillin during the acute stage
Interactions	Tetracyclines may decrease effects of ticarcillin; high concentrations of ticarcillin may physically inactivate aminoglycosides if administered in same IV line; effects when administered concurrently with aminoglycosides are synergistic; probenecid may increase penicillin levels
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Perform CBC count prior to initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT during therapy; exercise caution in patients diagnosed with hepatic insufficiencies; perform urinalysis and BUN and creatinine determinations during therapy, and adjust dose if values become elevated; monitor blood levels to avoid possible neurotoxic reactions

Drug Name	Imipenem and cilastatin (Primaxin) -- For treatment of multiple-organism infections in which other agents do not have broad-spectrum coverage or are contraindicated due to potential toxicity.
Adult Dose	1 g IV/IM q6-8h
Pediatric Dose	<12> >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Coadministration with cyclosporine may increase adverse CNS effects of both agents; coadministration with ganciclovir may result in generalized seizures
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adjust dose in renal insufficiency

Drug Name	Metronidazole (Flagyl, Protostat) -- Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Used in combination with other antimicrobial agents (except for Clostridium difficile enterocolitis).
Adult Dose	500 mg IV q6-8h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May increase toxicity of anticoagulants, lithium, and phenytoin; cimetidine may increase toxicity; disulfiram reaction may occur with orally ingested ethanol
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in hepatic disease; monitor for seizures and development of peripheral neuropathy

Drug Name	Gentamicin (Garamycin, Gentacidin) -- Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes. Not the DOC. Consider if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms. Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution. May be given IV/IM.
Adult Dose	Loading dose: 1-2.5 mg/kg IV Maintenance dose: 1-1.5 mg/kg IV q8h Extended dosing regimen for life-threatening infections: 5 mg/kg/d IV/IM q6-8h Monitor each regimen by drawing at least a trough level on the third or fourth dose (0.5 h before dosing); may draw a peak level 0.5 h after 30-min infusion
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions	Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; because aminoglycosides enhance effects of neuromuscular blocking agents, prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
Pregnancy	D - Unsafe in pregnancy
Precautions	Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment

Drug Name	Penicillin G (Pfizerpen) -- Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.
Adult Dose	2.4 million U IM (single dose) in 2 injection sites
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid can increase effects; coadministration of tetracyclines can decrease effects
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in impaired renal function

Barrett Esophagus and Barrett Ulcer

2007-11-28T21:06:00.000-08:00

Background: The definition of Barrett esophagus (BE) has evolved considerably over the past 100 years. In 1906, Tileston, a pathologist, described several patients with "peptic ulcer of the oesophagus" in which the epithelium around the ulcer closely resembled that normally found in the stomach. The debate for the next 4 decades centered on the anatomical origin of this mucosal anomaly. Many investigators, including Barrett in his treatise published in 1950, supported the view that this ulcerated columnar-lined organ was, in fact, the stomach tethered within the chest by a congenitally short esophagus.

In 1953, Allison and Johnstone argued that the columnar organ was more likely esophagus because the intrathoracic region lacked a peritoneal covering, contained submucosal glands and muscularis propria characteristic of the esophagus, and could harbor islands of squamous cells within the columnar segment. In 1957, Barrett agreed and suggested that the condition that bears his name be referred to as "lower esophagus lined by columnar epithelium." For the next 2 decades, descriptions of the histology of BE varied considerably from acid-secreting, fundic-type epithelium to intestinal-type epithelium with goblet cells.

Finally, in 1976 Paull et al published a report on the histologic spectrum of BE in which they used manometric guidance for their biopsies. These patients had 1 or a combination of 3 types of columnar epithelium—a gastric fundic-type, a junctional type, and a distinctive type of intestinal metaplasia the investigators called "specialized columnar epithelium." This specialized intestinal metaplasia (SIM), complete with goblet cells, has become the sine qua non for the diagnosis of BE.

While the histologic lesion became clearly evident, the endoscopic definition of BE has continued to change over the past 25 years. Many people believed that the distal esophagus could contain a normal region of columnar mucosa. In addition, determining the exact location of the esophagogastric junction (EGJ) in patients with BE often is difficult. To avoid false-positive diagnoses, investigators selected arbitrary lengths of columnar-lined esophagus to establish a diagnosis for their studies. Eventually, community endoscopists embraced this practice and biopsy of this so-called normal distal columnar-lined esophagus was avoided.

The last 10 years have brought convincing evidence that SIM, the hallmark histologic lesion of BE, predisposes to dysplasia and cancer regardless of the endoscopic location. Thus, the definition of BE currently is the finding of SIM anywhere within the tubular esophagus.

Pathophysiology: BE is well recognized as a complication of gastroesophageal reflux disease (GERD). Patients with GERD who develop BE tend to have a combination of clinical features, including hiatal hernia, reduced lower esophageal sphincter (LES) pressures, delayed esophageal acid clearance time, and duodenogastric reflux (as documented by the presence of bile in the esophageal lumen). First understanding the pathogenesis of GERD is necessary to understand the relationship between GERD and BE. Esophageal defense mechanisms against the noxious substances in the refluxate include an antireflux barrier, an efficient clearing mechanism, and epithelial defense factors. The antireflux barrier is a high-pressure zone at the EGJ that is generated by tonic contraction of the LES coupled with extrinsic compression by the right crus of the diaphragm. The phrenoesophageal ligament, intra-abdominal location of the LES, and maintenance of an acute angle of entry into the stomach help to reinforce this barrier.

This system is imperfect due to the existence of physiologic transient LES relaxations (TLESR). TLESR occur primarily after meals but in the absence of a preceding swallow. Studies indicate that about 95% of reflux episodes in healthy controls occur during the TLESR. Most reflux in patients with GERD occurs via this same mechanism. The duration of esophageal acidification, and not the frequency, correlates best with presence of erosive esophagitis.

A healthy individual clears the esophagus through various means, including gravity, bicarbonate secretion from the salivary and esophageal glands, and peristalsis. Dysfunctional esophageal motility with failed or weak peristalsis is a contributing factor in 34-48% of patients with GERD.

An acid (pH <4)>+ into both cells and intercellular spaces. In addition, scattered submucosal glands in the distal esophagus that secrete bicarbonate and have an adequate blood supply to deliver bicarbonate and remove H⁺ help to maintain tissue acid-base balance.

The aggressors in the GERD battle reside in the refluxate. Mucosal injury depends on the pH of the refluxate and the duration of contact with the esophageal mucosa. Lower pH of the refluxate and extended contact with the esophagus increases the time required for intraesophageal pH to return to normal and increases the risk for mucosal injury.

Prolonged exposure of the esophagus to the refluxate can erode the esophageal mucosa, promote inflammatory cell infiltrate, and ultimately cause epithelial necrosis. This chronic damage is believed to promote the replacement of healthy esophageal epithelium with the metaplastic columnar cells, the cellular origin of which remains unknown. This likely is an adaptive response of the esophagus, which, if not for the increased risk of cancer, would have been beneficial. GERD symptoms and strictures are less common in the columnarized segment.

Interestingly, the features of GERD in relation to long-segment Barrett esophagus (LSBE >3 cm) and short-segment Barrett esophagus (SSBE <3>

Current clinical practice guidelines recommend screening for BE in patients with GERD when the patients have had long-standing symptoms (>5 y), especially in those older than 50 years.

Epidemiology

Distinction of BE on the basis of the length of columnar-lined mucosa, however, turns out not to be entirely arbitrary. Endoscopically, the columnar-lined esophagus has been divided into 2 entities, with each having different prognostic implications. Long-segment BE is the finding of SIM longer than 3 cm, while short-segment BE is anything less than 3 cm. When the EGJ and squamocolumnar junction (SCJ) are contiguous and SIM is discovered on biopsy below the SCJ, the condition is termed cardia-SIM. The average age of patients with BE is 55-65 years. More than 80% are white males, with some studies indicating a higher prevalence of smoking and alcohol intake.

The prevalence of LSBE in patients undergoing endoscopy for any clinical indication has been reported at 0.3-2% but is much higher, 8-20%, in patients with symptoms of GERD. A study conducted at the Mayo Clinic showed an autopsy prevalence about 17 times higher than a clinically matched population, suggesting that most cases of LSBE are asymptomatic and thus unrecognized. In patients undergoing endoscopy, the prevalence of SSBE ranges from 5-30%. The combined prevalence of SSBE and cardia-SIM is 7-8 times greater than LSBE, but the prevalence of dysplasia and cancer is much less.

Frequency:

In the US: Cameron (1997) estimated the prevalence of LSBE in the general US population to be 376 cases per 100,000 population.

Internationally: The frequency of BE internationally probably parallels that in the United States by ethnicity. It is most common in people who are white and is rare in individuals of African descent.

Mortality/Morbidity: The most significant morbidity associated with BE is the development of adenocarcinoma in the esophagus. The incidence of esophageal adenocarcinoma is rising faster than any other cancer in the United States. From 1926-1976, 4 large surgical series reported that only 0.8-3.7% of esophageal cancers were adenocarcinomas. From 1979-1992, this increased to 54-68%.

In 1991, Blot et al reported their findings in a review of data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute. The incidence of esophageal adenocarcinoma in 1988-1990 was 3 times that in 1976-1978. In Olmstead County, Minnesota, Pera et al (1993) conducted a population-based study and found that the incidence of esophageal adenocarcinoma rose from 0.13 cases per 100,000 person-years in 1935-1971 to 0.74 cases per 100,000 person-years in 1974-1989. The incidence of adenocarcinoma of the cardia rose from 0.25 to 1.34 cases per 100,000 person-years in the same time period, an increase of more than 5-fold for both locations. Patients with LSBE have the greatest risk for development of dysplasia and adenocarcinoma of the esophagus.

Recent studies report the prevalence of dysplasia in LSBE at 20-35%, SSBE at 6-8%, and cardia-SIM at 0-6%, with the prevalence of adenocarcinoma being 7-15 times greater in LSBE versus SSBE and cardia-SIM. However, the total number of patients with SSBE and cardia-SIM is 7-8 times that of LSBE. Thus, even with a higher prevalence of dysplasia and cancer in the LSBE population, a greater total number of patients are likely to develop cancer from within the SSBE and EGJ-SIM group.

Race: BE primarily affects white people. It is rare in people of African ancestry, at this time.

Sex: BE is found in both men and women, with a 2:1 male-to-female ratio.

Age: The average age of patients with demonstrated BE is 55-65 years.

Treatment
Medical Care: The diagnosis of BE does not lead to specific therapy. Little evidence supports the assumption that antisecretory agents or antireflux surgery prevents the occurrence of adenocarcinoma or leads to regression of BE. Haag et al conducted a comprehensive MEDLINE search in 1999 to determine the effect of medical, surgical, and ablative therapy in producing regression of BE.

In the early-to-mid 1980s, histamine 2 (H2)-receptor antagonists were the most commonly prescribed agents for treatment of GERD. A number of studies were conducted with either cimetidine or ranitidine, and none documented regression of BE. In the late 1980s, proton pump inhibitors (PPIs) were introduced and proved to be much more efficacious at reducing gastric acid secretion. The supposition that better acid suppression could induce BE regression was met with optimism. Studies to date, however, have been inconclusive. Only 2 of 7 investigators demonstrated some regression. Most were unable to detect any regression, despite documentation of complete normalization of esophageal pH by pH testing.

Currently, the indication for medical therapy in BE is the same as that for GERD—control of symptoms and healing of esophageal mucosa. An important, as yet unanswered, question is whether abolishing acid completely with high-dose PPIs decreases the risk for adenocarcinoma of the esophagus and warrants the cost and possible adverse effects of this therapy.

In addition to acid, the reflux of pancreatic and biliary secretions into the esophagus has been implicated in the pathogenesis of BE. Because medications are effective only at reducing the acid component, surgical therapy may have an advantage. While studies have shown surgery to be efficacious in the control of GERD symptoms, the results regarding BE regression are inconclusive. No good evidence indicates that surgical therapy provides regression in BE. Thus, antireflux surgery is not indicated for eradication of BE, but it certainly is reasonable for appropriate patients who desire surgery for control of GERD symptoms.

Barrett esophagus screening and surveillance

The Practice Parameters Committee of the American College of Gastroenterology recommends that patients with long-standing GERD symptoms (>5 y), particularly those aged 50 years or older, have an upper endoscopy to detect or screen for BE. Once identified, patients with BE should undergo periodic surveillance endoscopy to identify histological markers for increased cancer risk (dysplasia) or cancer that is at an earlier stage and is amenable to therapy. Preliminary data suggest that surveillance endoscopy does just that. Still, esophageal cancer is an uncommon cause of death.

In a cohort study of patients with BE not undergoing surveillance, only 2.5% of 155 patients died as a result of esophageal cancer, with a mean of 9 years follow-up. Patients with BE should be considered candidates for surveillance only if a potential to prolong life expectancy exists and only if they are eligible for therapy when dysplasia or early cancer is detected. Age and comorbidity are important factors to consider.

The goal of surveillance is the detection of dysplasia or early cancer. Currently, dysplasia is the best histological marker for cancer risk. The appropriate surveillance interval is based on published data on the natural history of dysplasia and primarily is a function of the grade of dysplasia. Surveillance involves repeated upper endoscopy with systematic 4-quadrant biopsies at 2-cm intervals along the entire length of the segment of BE, with additional biopsy of any mucosal abnormalities.
Patients with BE in whom dysplasia is lacking for 2 consecutive yearly endoscopies may be extended to follow-up at 3-year intervals. Patients with persistent low-grade dysplasia on repeat endoscopy should undergo surveillance every 6 months for 2 cycles; if no progression of disease is noted, surveillance may be extended to yearly follow-up. Management of high-grade dysplasia is more controversial.
Observer variation is a problem in the grading of dysplasia, and the first step in management of a patient with high-grade dysplasia always is confirmation of the diagnosis by a pathologist who is an expert at reading esophageal biopsies. The surgical literature suggests that as many as 40% of patients who undergo esophagectomy for high-grade dysplasia have concomitant cancer in the resected specimen.
Currently, 2 alternatives for management of high-grade dysplasia exist. One is surveillance endoscopy, with intensive biopsy at 3-month intervals until cancer is detected. The other is surgical resection.
Because dysplasia and cancer are patchy and cannot be visualized endoscopically, the diagnosis is difficult with even the most intensive surveillance. Current research is focused on developing endoscopic techniques that would highlight dysplastic tissue to allow directed biopsy and also finding surrogate cellular markers and the like that might help predict which patients will develop cancer in the absence of biopsy-proven dysplasia.

Ablative therapy for Barrett esophagus

The goal of ablative therapy is to destroy the Barrett epithelium to a sufficient depth to eliminate the intestinal metaplasia and allow regrowth of squamous epithelium. A number of modalities have been tried, usually in combination with medical or surgical therapy because successful ablation appears to require an anacid environment.
Human studies have been performed with photodynamic therapy (PDT), argon plasma coagulation (APC), multipolar electrocoagulation (MPEC), heater probes, and various forms of lasers, endoscopic mucosal resection (EMR), cryotherapy, and radiofrequency ablation. Ablative therapy remains largely investigational with the exception of PDT, which is approved by the Food and Drug Administration (FDA) for high-grade dysplasia only.
PDT involves the use of a photosensitizing agent that accumulates in tissue and induces local necrosis by means of production of intracellular free radicals following exposure to light at a certain wavelength. Typically, a hematoporphyrin is used as the photosensitizing agent because it has a greater affinity for neoplastic tissue.
Recently, 5-aminolevulinic acid (ALA), which induces endogenous protoporphyrin IX and has selectivity for the mucosa over deeper submucosal layers, also has been used. The results have been promising for regression of BE, as well as for treatment of dysplasia and superficial carcinoma.
Overholt et al treated 100 patients, 73 with high-grade dysplasia and 13 with superficial adenocarcinoma. Ablation of BE with regeneration of squamous epithelium reportedly was accomplished in 75-80% of patients. Other studies have shown similar response rates, but Barrett epithelium beneath the superficial squamous layer has been observed, indicating that deeper-placed pluripotent cells may be preserved. Additionally, PDT is an expensive and time-consuming endeavor, and early use was complicated by esophageal stricture requiring dilation in 58% of patients.
APC is a method of contact-free high-frequency current coagulation in which the burning of tissue stops as soon as the area is ablated. One recent study using high-power APC was reported to result in complete restoration of squamous mucosa in 33 out of 33 patients after a mean of 1.96 sessions. The major complication was chest pain and odynophagia, which occurred in 57.5% of patients and lasted 3-10 days. Only 3 patients experienced stricture, which was treated easily with dilation. Only 1 endoscopic, as well as histologic, recurrence was observed at 10.6-months mean follow-up, but this was in a patient with an ineffective Nissan fundoplication.
Other studies have been less encouraging, with persistence of residual foci of Barrett epithelium under the neosquamous lining in 22-29%, and deep esophageal ulceration with massive bleeding, perforation, and even death has been reported.
MPEC is a method in which the mucosa is ablated by direct contact with an electrocautery probe. Sampliner et al (1996) used this technique to treat 10 patients with LSBE, using half of the patient's own esophagus as an internal control. All 10 patients had the treated segment eliminated by visual and biopsy criteria at 6 months, with the untreated segment unchanged despite acid suppression. Treatment took an average of 2.5 sessions, and 5 patients had complications in 75 total sessions (2 transient odynophagia, 1 transient dysphagia, 1 chest pain, and 1 upper gastrointestinal bleed).
Lasers have been used in numerous small studies for eradication of BE. Results were less consistent with this modality than those listed above. Studies that demonstrated full or partial regression endoscopically were confounded by the persistence of glandular elements beneath the neosquamous epithelium in as many as one third of cases.
Relatively new to the scene of endoscopic ablation is balloon-based, bipolar radiofrequency ablation (Stellartech Research Coagulation System; BARRx, Inc, Sunnyvale, Calif). This technique requires the use of sizing balloons to determine the inner diameter of the targeted portion of the esophagus. This is followed by placement of a balloon-based electrode with a 3-cm long treatment area that incorporates tightly spaced, bipolar electrodes that alternate in polarity. The electrode is then attached to a radiofrequency generator and a preselected amount of energy is delivered in less than 1 second at 350 W.
One of the newer ablative techniques is low-pressure spray cryoablation using liquid nitrogen pioneered at the author's institution.
- The components of the low-pressure spray cryoablation device are the following: liquid nitrogen tank; electronic console for monitoring and control of cryogen release; dual foot pedal for control of cryogen release and heating of the catheter; and the catheter, which is a multilayered, 7-9F, open-tipped catheter for spray of supercold nitrogen gas through an upper endoscope. The mechanism of injury is unique relative to the other ablative techniques. Cryoablation induces apoptosis, causes cryonecrosis at supercold temperatures (-76° to -158° C), results in transient ischemia, and can cause immune stimulation. The Barrett epithelium is resistant to apoptosis and, therefore, may be uniquely suited for treatment by cryoablation.
- A recent pilot study at the author's institution using cryoablation in BE with degrees of dysplasia ranging from no dysplasia to multifocal high-grade dysplasia achieved complete endoscopic reversal of BE in 78% of cases, with no subsquamous SIM or dysplasia at 6-month follow-up. These results will need confirmation at other institutions.

Surgical Care: Antireflux surgeries, such as a Nissen fundoplication, have not been shown to reverse the outcome of BE. Surgery seems to play no role in preventing the progression of BE to cancer. However, when high-grade dysplasia is discovered and confirmed by a second pathologist, esophagectomy is the standard of care.

Diet: The diet for patients with BE is the same as that recommended for patients with GERD. Patients should avoid fried or fatty foods, chocolate, peppermint, alcohol, coffee, carbonated beverages, citrus fruits or juices, tomato sauce, ketchup, mustard, vinegar, aspirin, or other nonsteroidal anti-inflammatory drugs (NSAIDs). They also should decrease the size of portions at mealtime, avoid eating 3 hours prior to bedtime, elevate the head of the bed 6 inches, lose weight (if overweight), and stop smoking.

Medication
Treatment of BE should be the same as that of GERD. However, most authorities agree that it should be used with a proton pump inhibitor versus an H2-receptor antagonist due to the relative acid insensitivity of patients with BE.
Drug Category: H2-receptor antagonists -- These agents are reversible competitive blockers of histamine at the H2 receptors, particularly those in the gastric parietal cells, where they inhibit acid secretion. The H2 antagonists are highly selective, do not affect the H1 receptors, and are not anticholinergic agents.

Drug Name	Ranitidine (Zantac) -- Inhibits histamine stimulation of the H2 receptor in gastric parietal cells, which reduces gastric acid secretion, gastric volume, and hydrogen concentrations. Indicated in acid/peptic disorder, erosive esophagitis, gastrointestinal hypersecretion, mastocytosis, gastroesophageal reflux, peptic ulcer, and Zollinger-Ellison syndrome.
Adult Dose	150 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal or liver impairment; CrCl <10>

Drug Name	Famotidine (Pepcid) -- Competitively inhibits histamine at H2 receptor of gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.
Adult Dose	40 mg/d PO bid for 4-8 wk
Pediatric Dose	Not established; suggested dose is 1-2 mg/kg/d PO/IV divided q6h; not to exceed 40 mg per dose
Contraindications	Documented hypersensitivity
Interactions	May decrease effects of ketoconazole and itraconazole
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	If changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment

Drug Name	Nizatidine (Axid) -- Competitively inhibits histamine at the H2 receptor of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.
Adult Dose	300 mg PO hs or 150 mg bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment

Drug Category: Proton pump inhibitors -- Inhibit gastric acid secretion by inhibition of the H⁺/K⁺-ATPase enzyme system in the gastric parietal cells. These agents are used in cases of severe esophagitis and in patients not responding to H2 antagonist therapy.

Drug Name	Omeprazole (Prilosec) -- Decreases gastric acid secretion by inhibiting parietal cell H⁺ and K⁺ pump.
Adult Dose	20 mg PO qd; up to 40 mg qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May decrease effects of itraconazole and ketoconazole; may increase toxicity of warfarin (increased plasma levels of warfarin are observed only with high doses)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Bioavailability may increase in elderly people; adjust dose in hepatic impairment, half-life can increase as much as 4-fold

Drug Name	Lansoprazole (Prevacid) -- Inhibits gastric acid secretion. Used for as long as 8 wk to treat all grades of erosive esophagitis.
Adult Dose	30 mg PO qd for 4-8 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May decrease effects of ketoconazole and itraconazole; may increase theophylline clearance
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Consider adjusting dose in liver impairment

Drug Name	Esomeprazole (Nexium) -- S-isomer of omeprazole. Inhibits gastric acid secretion by inhibiting H⁺/K⁺-ATPase enzyme system at secretory surface of gastric parietal cells.
Adult Dose	20-40 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Concurrent use with amoxicillin or clarithromycin may increase plasma levels of esomeprazole; may reduce absorption of dapsone; may increase levels of diazepam and GI absorption of digoxin; may decrease absorption of iron, ketoconazole, and itraconazole
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Symptomatic relief with PPIs may mask symptoms of gastric malignancy

Drug Category: Photosensitizers -- These agents are used with photodynamic therapy (PDT). Upon light absorption, photosensitizer transform to a short-lived singlet state followed by a transition to the reactive triplet state. When in the triplet state, produces reactive free radicals in the presence of oxygen, which react with cell membranes, causing direct damage to the mitochondria, endoplasmic reticulum, and/or plasma membranes.

Drug Name	Porfimer (Photofrin) -- Indicated to treat high-grade dysplasia in Barrett esophagus. Elicits a photosensitizing effect used in the photodynamic therapy (PDT).
Adult Dose	2 mg/kg IV infused over 3-5 min; may repeat treatment courses separated by at least 30 d, not to exceed a total of 3 treatment courses
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to porphyrins; tracheoesophageal or bronchoesophageal fistula; tumors eroding into a major blood vessel
Interactions	Allow sufficient time between radiotherapy treatment to ensure inflammation has decreased; coadministration with other photosensitizing agents (eg, tetracycline, sulfonamides; hypoglycemic agents, thiazides) may increase photosensitivity risk; coadministration with drugs that inhibit oxygen species or free radicals (eg, DMSO, beta-carotene, ethanol, mannitol), allopurinol, calcium channel blockers, glucocorticoids, or prostaglandin synthesis inhibitors may decrease effect
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use extravasation precautions; treatment-induced inflammation may obstruct main airway or cause chest pain; esophageal varices (increases bleeding risk); ocular sensitivity; monitor for respiratory distress

Autoimmune Hepatitis

2007-11-28T21:01:00.001-08:00

Background

During the past 30 years, remarkable advances have occurred in the understanding of the epidemiology, natural history, and pathogenesis of chronic hepatitis. The development of viral serologic tests has permitted hepatologists to differentiate chronic viral hepatitis from other types of chronic liver disease, including autoimmune hepatitis. Autoimmune hepatitis is now accepted as a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation and necrosis, which tends to progress to cirrhosis. Immune serum markers frequently are present, and the disease often is associated with other autoimmune diseases. Autoimmune hepatitis cannot be explained on the basis of chronic viral infection, alcohol consumption, or exposure to hepatotoxic medications or chemicals.

In 1950, Waldenstrom first described a form of chronic hepatitis in young women.¹ This condition was characterized by cirrhosis, plasma cell infiltration of the liver, and marked hypergammaglobulinemia. Kunkel, in 1950, and Bearn, in 1956, described other features of the disease, including hepatosplenomegaly, jaundice, acne, hirsutism, cushingoid facies, pigmented abdominal striae, obesity, arthritis, and amenorrhea.^{2, 3} In 1955, Joske first reported the association of the lupus erythematosus (LE) cell phenomenon in active chronic viral hepatitis.⁴ This association led to the introduction of the term lupoid hepatitis by Mackay and associates in 1956. Researchers currently know that no direct link exists between systemic lupus erythematosus (SLE) syndrome and autoimmune hepatitis; thus, lupoid hepatitis is not associated with SLE.

Autoimmune hepatitis now is recognized as a multisystem disorder that can occur in males and females of all ages. This condition can coexist with other liver diseases (eg, chronic viral hepatitis) and also may be triggered by certain viral infections (eg, hepatitis A) and chemicals (eg, minocycline).

The histopathologic description of autoimmune hepatitis has undergone several revisions over the years. In 1992, an international panel codified the diagnostic criteria. The term autoimmune hepatitis was selected to replace terms such as autoimmune liver disease and autoimmune chronic active hepatitis. The panel waived the requirement of 6 months of disease activity to establish chronicity, expanded the histologic spectrum to include lobular hepatitis, and reaffirmed the nonviral nature of the disease. The panel also designated incompatible histologic features, such as cholestatic histology, the presence of bile duct injury, and ductopenia.

Pathophysiology

Evidence suggests that liver injury in a patient with autoimmune hepatitis is the result of a cell-mediated immunologic attack. This attack is directed against genetically predisposed hepatocytes. Aberrant display of human leukocyte antigen (HLA) class II on the surface of hepatocytes facilitates the presentation of normal liver cell membrane constituents to antigen-processing cells. These activated cells, in turn, stimulate the clonal expansion of autoantigen-sensitized cytotoxic T lymphocytes. Cytotoxic T lymphocytes infiltrate liver tissue, release cytokines, and help to destroy liver cells.

The reasons for the aberrant HLA display are unclear. It may be initiated or triggered by genetic factors, viral infections (eg, acute hepatitis A or B, Epstein-Barr virus infection), and chemical agents (eg, interferon, melatonin, alpha methyldopa, oxyphenisatin, nitrofurantoin, tienilic acid). The asialoglycoprotein receptor and the cytochrome mono-oxygenase P-450 IID6 are proposed as the triggering autoantigens.

Some patients appear to be genetically susceptible to developing autoimmune hepatitis. This condition is associated with the complement allele C4AQO and with the HLA haplotypes B8, B14, DR3, DR4, and Dw3. C4A gene deletions are associated with the development of autoimmune hepatitis in younger patients. HLA DR3-positive patients are more likely than other patients to have aggressive disease, which is less responsive to medical therapy; these patients are younger than other patients at the time of their initial presentation. HLA DR4-positive patients are more likely to develop extrahepatic manifestations of their disease.

Evidence for an autoimmune pathogenesis includes the following:

Hepatic histopathologic lesions composed predominantly of cytotoxic T cells and plasma cells
Circulating autoantibodies (ie, nuclear, smooth muscle, thyroid, liver-kidney microsomal, soluble liver antigen, hepatic lectin)
Association with hypergammaglobulinemia and the presence of a rheumatoid factor
Association with other autoimmune diseases
Response to steroid and/or immunosuppressive therapy

The autoantibodies described in these patients include the following:

Antinuclear antibody (ANA), primarily in a homogenous pattern
Anti–smooth muscle antibody (ASMA) directed at actin
Anti–liver-kidney microsomal antibody (anti–LKM-1)
Antibodies against soluble liver antigen (anti-SLA) directed at cytokeratins types 8 and 18
Antibodies to liver-specific asialoglycoprotein receptor or hepatic lectin
Antimitochondrial antibody (AMA) - AMA is the sine qua non of primary biliary cirrhosis (PBC) but may be observed in the so-called overlap syndrome with autoimmune hepatitis.
Antiphospholipid antibodies

Based on autoantibody markers, autoimmune hepatitis is recognized as a heterogeneous disorder and has been subclassified into 3 types. The distinguishing features of these types are noted in Table 1.

Table 1. Clinical Characteristics of Autoimmune Hepatitis

Clinical Features	Type 1	Type 2	Type 3
Diagnostic autoantibodies	ASMA

ANA

Antiactin

Anti-LKM

P-450 IID6

Synthetic core motif peptides 254-271

Soluble liver-kidney antigen

Cytokeratins 8 and 18
Age	10 y-elderly	Pediatric (2-14 y)

Rare in adults	Adults (30-50 y)
Women (%)	78	89	90
Concurrent immune disease (%)	41	34	58
Gamma globulin elevation	+++	+	++
Low IgA*	No	Occasional	No
HLA association	B8, DR3, DR4	B14, Dr3, C4AQO	Uncertain
Steroid response	+++	++	+++
Progression to cirrhosis (%)	45	82	75

*Immunoglobulin A

Frequency

United States

The frequency of autoimmune hepatitis among patients with chronic liver disease ranges from 11-23%. The disease accounts for about 6% of liver transplantations in the United States.

International

The incidence of type 1 autoimmune hepatitis is estimated to be 0.1-1.9 cases per 100,000 persons per year in Caucasian populations. The incidence is lower in Japan. Type 2 autoimmune hepatitis is more commonly described in southern Europe than in northern Europe, the United States, or Japan. Articles describe the prevalence of autoimmune hepatitis in Europe as being in the range of 11.6-16.9 cases per 100,000 persons. This is approximately the same prevalence as PBC and twice as high as the prevalence of primary sclerosing cholangitis (PSC). Autoimmune hepatitis accounts for about 3% of liver transplantations in Europe.

Mortality/Morbidity

Without treatment, nearly 50% of patients with severe autoimmune hepatitis die in approximately 5 years.

Race

The disease is most common in Caucasians of northern European ancestry with a high frequency of HLA-DR3 and HLA-DR4 markers. The Japanese population has a low frequency of HLA-DR3 markers. In Japan, autoimmune hepatitis is associated with HLA-DR4.

Sex

Women are affected more often than men (70-80% of patients are women).

Age

Classic descriptions of type 1 autoimmune hepatitis spoke of a bimodal age distribution (10-30 y and 40-50 y). However, more recent work shows that infants, young children, and older adults may be affected. The diagnosis should not be overlooked in individuals older than 70 years. Men may be affected more commonly than women in older age groups.

Treatment

Medical Care

For more than 3 decades, prednisone and azathioprine have been the mainstays of drug therapy for patients with autoimmune hepatitis. Considerable variation in practice style exists when answering the following common clinical questions:

How high a dose of prednisone should be used when initiating therapy?
When should azathioprine be added to the patient's treatment regimen?
When should a reduction in steroid dosing be considered?
How long should treatment continue beyond a patient's biochemical remission?
Should liver biopsy be performed in order to document histologic remission, prior to attempting to withdraw immunosuppression?
Should patients receive life-long low-dose maintenance therapy with azathioprine?

Approximately 65% of patients respond to initial therapy and enter histological remission; however, 80% of these patients relapse after drug withdrawal.

The practice guideline of the American Association for the Study of Liver Diseases (AASLD) provides recommendations for therapy.⁶ See Table 2.

Absolute indications for treatment
- Serum AST – Equal or greater than 10-fold upper limit of normal
- Serum AST – Equal or greater than 5-fold upper limit of normal and gamma-globulin level equal or greater than twice normal
- Bridging necrosis or multiacinar necrosis on histologic examination
Relative indications for treatment
- Symptoms (eg, fatigue, arthralgia, jaundice)
- Serum AST and/or gamma-globulin less than absolute criteria
- Interface hepatitis
No indication for treatment
- Treatment might not be necessary in patients with inactive cirrhosis, preexistent comorbid conditions, or drug intolerances.
- Treatment might not be appropriate in patients with decompensated liver disease. Such individuals might be better served by undergoing liver transplantation.
Table 2. Indications for Treatment

Absolute

Relative

Serum AST > 10-fold upper limit of normal

Symptoms (eg, fatigue, arthralgia, jaundice)

Serum AST > 5-fold upper limit of normal

and gamma-globulin level > twice normal

Serum AST and/or gamma-globulin less than absolute criteria

Bridging necrosis or multiacinar necrosis on

histologic examination

Interface hepatitis

The AASLD guidelines suggest 2 potential initial treatment regimens for adults (see Table 3).
Table 3. Treatment Regimens for Adults

Prednisone only (mg/d)

Combination


Prednisone (mg/d)

Azathioprine (mg/d)

Week 1

Week 2

Week 3

Week 4

Maintenance until

end point

Reasons for Preference

Cytopenia

Thiopurine

Methyltransferase deficiency

Pregnancy

Malignancy

Short course (£6 mo)

Postmenopausal state

Osteoporosis

Brittle diabetes

Obesity

Acne

Emotional lability

Hypertension

Patients whose liver chemistries normalize after initial therapy then require maintenance therapy. In the authors' opinions, prednisone dosing can be further reduced after achieving normalization of liver chemistries. The authors commonly use azathioprine alone as a maintenance drug. Azathioprine therapy is withdrawn approximately 1 year after the patient's liver chemistries have normalized.
The AASLD guidelines also propose an initial treatment regimen for children (see Table 4).
Table 4. Treatment Regimens for Children

Initial Regimen

Maintenance Regimen

End Point

Prednisone, 2 mg/kg/d (up to 60 mg/d),

for 2 weeks, either alone or in combination with azathioprine, 1-2 mg/kg/d

a. Prednisone taper over 6-8 weeks to 0.1-0.2 mg/kg daily or 5 mg daily

b. Azathioprine at constant dose if added initially

c. Continue daily prednisone dose with or without azathioprine or switch to

alternate day prednisone dose adjusted to response with or without azathioprine

a. Normal liver tests for 1-2 years during treatment

b. No flare during entire interval

c. Liver biopsy examination discloses no inflammation

Treatment endpoints: Patients may achieve 1 of 4 treatment endpoints.
- Complete remission is indicated by the absence of symptoms, a serum AST level less than 2 times the reference range, and histologic improvement to normal or minimal inflammatory activity on liver biopsy. Patients achieving remission may be able to discontinue azathioprine and be tapered off of prednisone over a 6-week period.
- Treatment failure is defined as deterioration in a patient's clinical condition, laboratory tests, or histologic features during therapy. Some patients will respond to reinstitution of treatment with high-dose prednisone, with or without combined azathioprine.
- An incomplete patient response is defined as an improvement that is insufficient to satisfy remission criteria. Many such patients will require indefinite treatment with as low an immunosuppressant dose as is needed to prevent clinical deterioration.
- Drug toxicity may occur. Patients must be tapered off of the culprit medication. Some patients successfully achieve treatment goals on alternative medications.
Treatment results and duration of therapy
- It has been clear for many years that immunosuppressant therapy improves survival for patients with autoimmune hepatitis. The 10-year life expectancies for treated patients with and without cirrhosis at presentation are 89% and 90%, respectively.
- There are no firm guidelines regarding the duration of therapy in either adults or children. However, relatively long courses of immunosuppressant therapy are needed for most patients. It is common for treatment to continue for 1.5-2 years or longer before an attempt is made to withdraw medications. Indeed, adults infrequently achieve clinical, laboratory, and histologic remission in less than 12 months. Immunosuppressant therapy can achieve remission in 65% of patients within 18 months and in 80% of patients by 3 years.
- Histologic remission tends to lag behind clinical and laboratory remission by 3-6 months. Some clinicians recommend that a follow-up liver biopsy be performed. This is done in an effort to avoid medication withdrawal in a patient who is not yet in histologic remission.
- Patients with a histologic diagnosis of cirrhosis still may respond well to therapy and should be offered treatment in an attempt to slow disease progression.
- Patients with severe disease (eg, acute liver failure due to autoimmune hepatitis) have a high short-term mortality rate if they fail to show normalization of at least 1 laboratory parameter after starting prednisone-based therapy or if pretreatment hyperbilirubinemia fails to improve during a 2-week treatment trial. Early liver transplantation should be considered in such individuals. In contrast, patients in acute liver failure whose liver chemistries improve rapidly after starting prednisone have an excellent short-term prognosis. Many such patients ultimately achieve clinical remission on immunosuppressant therapy.
Treatment failures and incomplete responses
- Nine percent of patients experience treatment failure with standard therapy. Treatment with high-dose prednisone (60 mg/d) alone or prednisone (30 mg/d) plus azathioprine (150 mg/d) is an alternative approach to therapy. Patients who are resistant to steroids can be treated with cyclosporine or tacrolimus. The use of these medications is supported by a number of small cases series. However, the potential toxicity of these calcineurin inhibitors must be assessed carefully before initiating treatment. Similarly, a few studies have supported the use of mycophenolate mofetil in patients who were refractory to standard therapy. The authors have seen a number of patients who experienced treatment failure with prednisone plus azathioprine but achieved treatment success with low-dose prednisone plus mycophenolate mofetil.
- Thirteen percent of patients improve with standard therapy but do not achieve remission criteria. A low-dose, long-term prednisone schedule, similar to that used after relapse (10 mg/d), is reasonable. The goal of therapy is to control disease activity on the lowest dose of medication possible. Azathioprine may help to serve as a steroid-sparing agent.
- Patients should be referred for consideration of liver transplantation if they manifest signs of hepatic decompensation (eg, new onset of hypoalbuminemia, coagulopathy, variceal bleeding, ascites, hepatic encephalopathy).
Relapse after drug withdrawal
- Relapse occurs in 50% of patients within 6 months of treatment withdrawal and in 80% of patients within 3 years of treatment. Reinstitution of the original treatment regimen usually induces another remission; however, relapse commonly recurs after a second attempt at terminating therapy. The major consequence of relapse and re-treatment is the development of drug-related complications, which occurs in 70% of patients.
- Patients who relapse twice require indefinite therapy with either prednisone or azathioprine. The dose is titrated as low as possible in order to prevent symptoms and to maintain AST 5-fold below the reference range. The median dose of prednisone required to achieve this is 7.5 mg/d.
- Some authors advocate indefinite treatment with azathioprine only. One article assessed long-term therapy with azathioprine at a dose of 2 mg/kg/d; 60 (83%) of the 72 patients remained in remission under such immunosuppression, with a median follow-up period of 67 months (range, 12-128 mo).
- Patients should be cautioned against premature withdrawal of drug therapy. Abrupt discontinuation of medical therapy is not infrequently complicated by an acute flare of disease activity. Such flares may be severe and potentially life-threatening.
Treatment adverse effects
- Cushingoid features, acne, and hirsutism develop in 80% of patients after 2 years of prednisone-based therapy. Osteoporosis with vertebral compression, diabetes, cataracts, severe emotional lability, and hypertension may develop in patients who are treated with prolonged courses of high-dose prednisone. Premature treatment withdrawal is justified in patients who develop intolerable obesity, cosmetic changes, or osteoporosis.
- Azathioprine can function as a steroid-sparing agent. The authors have had great success and minimal drug-related adverse effects using a regimen of prednisone 10 mg/d plus azathioprine 50 mg/d. Patients should be co-treated with calcium and vitamin D in order to prevent the development of steroid-induced osteoporosis. Regular exercise should be encouraged. Bone densitometry performed every 1-2 years should be used to monitor patients. Signs of early osteoporosis may warrant the institution of treatment with alendronate.
- Azathioprine therapy can be complicated by cholestatic hepatotoxicity, nausea, vomiting, rash, cytopenia, and pancreatitis. These complications occur in fewer than 10% of patients treated with azathioprine at 50 mg/d.
- Teratogenicity has been ascribed to treatment with azathioprine; however, the gastroenterology literature is replete with references that describe the safe use of azathioprine and 6-mercaptopurine in pregnant women with inflammatory bowel disease. Whether this observation can be extended to pregnant women with autoimmune hepatitis and whether azathioprine can be employed safely in these patients is unclear.
- Hematologic malignancy has been reported in patients undergoing treatment with azathioprine; however, the risk of malignancy is thought to be low in patients with autoimmune hepatitis who are treated with low doses of the drug.

Surgical Care

Liver transplantation
- This procedure is an effective form of therapy for patients with decompensated cirrhosis caused by autoimmune hepatitis. This procedure also may be used to rescue patients who present with fulminant hepatic failure secondary to autoimmune hepatitis.
- The long-term outlook after liver transplantation is excellent, with 5-year survival rates reported at 90% or more. Positive autoantibodies and hypergammaglobulinemia tend to disappear within 2 years of transplantation.
- Recurrence of autoimmune hepatitis is described after liver transplantation. It has been reported primarily in inadequately immunosuppressed patients. It may occur more often in HLA DR3-positive recipients of HLA DR3-negative donors. Recurrent disease is seen in 10-35% of patients undergoing transplant for autoimmune hepatitis. Although such recurrences are often mild events, one paper described a need for retransplantation in one half of patients experiencing recurrent disease.

Diet

Patients with acute autoimmune hepatitis and symptoms of nausea and vomiting may require intravenous fluids and even total parenteral nutrition; however, most patients can tolerate a regular diet. A high caloric intake is desirable.
Patients with cirrhosis secondary to autoimmune hepatitis may develop ascites. A low-salt diet (generally <2000>1.3 g protein per kg body weight) given the catabolic nature of the disease and patients' high risk for developing muscle wasting.

Activity

Most patients do not need hospitalization, although this may be required for clinically severe illness. Forced and prolonged bed rest is unnecessary, but patients may feel better with restricted physical activity.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Medications used include prednisone, prednisolone, and azathioprine.

Drug Category: Corticosteroids

See Treatment. Rapid institution of treatment with high-dose corticosteroids may rescue patients whose disease ultimately would have progressed to either fulminant hepatic failure or cirrhosis. Treatment with corticosteroids has been shown to improve the chances for survival significantly.

Drug Name	Prednisone (Deltasone, Orasone, Meticorten)
Description	Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.
Adult Dose	5-60 mg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve
Pediatric Dose	4-5 mg/m²/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular infections; osteoporosis
Interactions	Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteoporosis and osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Name	Prednisolone (Delta-Cortef, Econopred, Articulose-50)
Description	Decreases autoimmune reactions, possibly by suppressing key components of immune system.
Adult Dose	5-60 mg/d PO/IV/IM in divided doses
Pediatric Dose	0.1-2 mg/kg/d PO/IV/IM qd or divided tid/qid
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular infections; peptic ulcer disease; osteoporosis
Interactions	Decreases effects of salicylates and toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease the effect of corticosteroids
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in hyperthyroidism, osteoporosis, cirrhosis, nonspecific ulcerative colitis, peptic ulcer, diabetes, and myasthenia gravis

Drug Category: Immunosuppressant agents

These agents inhibit immune reactions resulting from diverse stimuli.

Drug Name	Azathioprine (Imuran, Azasan)
Description	Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.
Adult Dose	1 mg/kg/d PO for 6-8 wk; increase by 0.5 mg/kg q4wk until response or dose reaches 2.5 mg/kg/d
Pediatric Dose	Initial: 2-5 mg/kg/d PO/IV Maintenance: 1-2 mg/kg/d PO/IV
Contraindications	Documented hypersensitivity; low levels of serum thiopurine methyl transferase (TPMT)
Interactions	Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; some authors recommend that TPMT level be checked prior to therapy; liver, renal, and hematologic function needs follow-up; pancreatitis rarely associated; see text regarding new data on azathioprine in pregnancy

Ascites

2007-11-28T21:00:00.000-08:00

Background

The word ascites is of Greek origin (askos) and means bag or sac. Ascites describes the condition of pathologic fluid accumulation within the abdominal cavity. Healthy men have little or no intraperitoneal fluid, but women may normally have as much as 20 mL depending on the phase of the menstrual cycle. This article focuses only on ascites associated with cirrhosis.

Pathophysiology

The accumulation of ascitic fluid represents a state of total-body sodium and water excess, but the event that initiates the unbalance is unclear. Three theories of ascites formation have been proposed.

The underfilling theory suggests that the primary abnormality is inappropriate sequestration of fluid within the splanchnic vascular bed due to portal hypertension and a consequent decrease in effective circulating blood volume. This activates the plasma renin, aldosterone, and sympathetic nervous system, resulting in renal sodium and water retention.

The overflow theory suggests that the primary abnormality is inappropriate renal retention of sodium and water in the absence of volume depletion. This theory was developed in accordance with the observation that patients with cirrhosis have intravascular hypervolemia rather than hypovolemia.

The most recent theory, the peripheral arterial vasodilation hypothesis, includes components of both of the other theories. It suggests that portal hypertension leads to vasodilation, which causes decreased effective arterial blood volume. As the natural history of the disease progresses, neurohumoral excitation increases, more renal sodium is retained, and plasma volume expands. This leads to overflow of fluid into the peritoneal cavity. According to the vasodilation theory, the underfilling theory is proposed to be operative early and the overflow theory is proposed to be operative late in the natural history of cirrhosis.

Although the sequence of events that occurs between the development of portal hypertension and renal sodium retention is not entirely clear, portal hypertension apparently leads to an increase in nitric oxide levels. Nitric oxide mediates splanchnic and peripheral vasodilation. Patients with ascites have greater hepatic artery nitric oxide synthase activity compared to patients without ascites.

Regardless of the initiating event, a number of factors contribute to the accumulation of fluid in the abdominal cavity. Elevated levels of epinephrine and norepinephrine are well-documented factors. Hypoalbuminemia and reduced plasma oncotic pressure favor the extravasation of fluid from the plasma to the peritoneal fluid, and, thus, ascites is infrequent in patients with cirrhosis unless both portal hypertension and hypoalbuminemia are present.

Mortality/Morbidity

Ambulatory patients with an episode of cirrhotic ascites have a 3-year mortality rate of 50%. The development of refractory ascites carries a poor prognosis, with a 1-year survival rate of less than 50%.

Sex

Healthy men have little or no intraperitoneal fluid, but women may normally have as much as 20 mL depending on the phase of the menstrual cycle.

Treatment

Medical Care

Sodium restriction (20-30 mEq/d) and diuretic therapy constitute the standard medical management for ascites and are effective in approximately 95% of patients.

Water restriction is used only if persistent hyponatremia is present.

Therapeutic paracentesis should be reserved for patients who need rapid symptomatic relief of tense ascites.

TIPS is an interventional radiologic technique that reduces portal pressure and may be the most efficacious for treatment of patients with diuretic-resistant ascites. This procedure consists of inserting a long metal needle from the right jugular vein into the hepatic vein. This is slowly becoming the standard of care in patients with diuretic-refractory ascites.

Surgical Care

The peritoneovenous shunt is an alternative for patients with medically intractable ascites. This is a megalymphatic shunt that returns the ascitic fluid to the central venous system. Beneficial effects of these shunts include increased cardiac output, renal blood flow, glomerular filtration rate, urinary volume, and sodium excretion and decreased plasma renin activity and plasma aldosterone concentration. No evidence indicates that these shunts improve patient survival. With the advent of the TIPS procedure, this form of therapy is almost obsolete.

Consultations

Consultation with a gastrointestinal specialist and/or hepatologist should be considered for all patients with ascites, particularly if the ascites is refractory to medical treatment.

Diet

Sodium restriction of 500 mg/d (22 mmol/d) is feasible in a hospital setting; however, it is unrealistic in most outpatient settings. A more appropriate sodium restriction is 2000 mg/d (88 mmol). Indiscriminate fluid restriction is inappropriate. Fluids need not be restricted unless the serum sodium level drops below 120 mmol/L.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Diuretics

Mainstay of medical therapy in ascites.

Drug Name	Spironolactone (Aldactone)
Description	For management of edema resulting from excessive aldosterone excretion. Competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions. The peak effect of Aldactone is approximately 3 d.
Adult Dose	25-200 mg/d PO qd or divided bid
Pediatric Dose	1.5-3.5 mg/kg/d PO in divided doses q6-24h
Contraindications	Documented hypersensitivity; anuria; renal failure; hyperkalemia
Interactions	May decrease effect of anticoagulants; potassium and potassium-sparing diuretics may increase toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal and hepatic impairment; may cause gynecomastia and impotence in men

Drug Name	Furosemide (Lasix)
Description	Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Dose must be individualized to patient. Depending on response, administer at increments of 20-40 mg, no sooner than 6-8 h after the previous dose, until desired diuresis occurs. When treating infants, titrate in increments of 1 mg/kg/dose until a satisfactory effect is achieved.
Adult Dose	20-80 mg/d PO/IV/IM; titrate up to 600 mg/d for severe edematous states
Pediatric Dose	1-2 mg/kg/dose PO; not to exceed 6 mg/kg/dose; do not administer >q6h 1 mg/kg IV/IM slowly under close supervision; not to exceed 6 mg/kg
Contraindications	Documented hypersensitivity; hepatic coma; anuria; state of severe electrolyte depletion
Interactions	Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides, hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently; increased plasma lithium levels and toxicity are possible when taken concurrently
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

Drug Name	Amiloride (Midamor)
Description	A pyrazine-carbonyl-guanidine unrelated chemically to other known antikaliuretic or diuretic agents. Potassium-conserving (antikaliuretic) drug which, compared with thiazide diuretics, possesses weak natriuretic, diuretic, and antihypertensive activity.
Adult Dose	5-20 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; elevated serum potassium levels (>5.5 mEq/L); impaired renal function, acute or chronic renal insufficiency, and evidence of diabetic nephropathy; monitor electrolytes closely if evidence of renal functional impairment is present, BUN is >30 mg/100 mL, or serum creatinine level is >1.5 mg/100 mL
Interactions	Concomitant therapy with potassium supplementation may increase serum potassium levels; if concomitant use of these agents is indicated because of demonstrated hypokalemia, use caution and monitor serum potassium level frequently; generally, lithium should not be administered with diuretics because may reduce renal clearance and add a high risk of lithium toxicity; administration of NSAIDs can reduce diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics; when used concomitantly, observe patient closely to determine if desired effect of diuretic obtained Indomethacin and potassium-sparing diuretics, including amiloride, may be associated with increased serum potassium levels; consider potential effects on potassium kinetics and renal function
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Potassium retention associated with use of an antikaliuretic agent accentuated in presence of renal impairment and may result in rapid development of hyperkalemia; monitor serum potassium level; mild hyperkalemia usually not associated with abnormal ECG findings

Drug Name	Metolazone (Mykrox, Zaroxolyn)
Description	Helps treat edema in congestive heart failure. Increases excretion of sodium, water, potassium, and hydrogen ions by inhibiting reabsorption of sodium in distal tubules. May be more effective in those with impaired renal function.
Adult Dose	5-20 mg/dose PO q24h
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; hepatic coma or anuria
Interactions	Thiazides may decrease effect of anticoagulants, sulfonylureas, and gout treatments; anticholinergics and amphotericin B may increase toxicity of thiazides; effects of thiazides may decrease when used concurrently with bile acid sequestrants, NSAIDs, or methenamine; when administered concurrently, thiazides increase toxicity of anesthetics, diazoxide, digitoxin, lithium, loop diuretics, antineoplastics, allopurinol, calcium salts, vitamin D, and nondepolarizing muscle relaxants
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in hepatic or renal disease, diabetes mellitus, gout, or lupus erythematosus

Drug Name	Mannitol (Osmitrol)
Description	Inhibits tubular reabsorption of electrolytes by increasing osmotic pressure of glomerular filtrate. Increases urinary output.
Adult Dose	0.5-2 g/kg IV over 30-60 min as a 15-25% solution; repeat q6-8h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; anuria, severe pulmonary congestion, progressive renal damage, severe dehydration, active intracranial bleeding, and progressive heart failure
Interactions	May decrease serum lithium levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Carefully evaluate cardiovascular status before rapid administration because a sudden increase in extracellular fluid may lead to fulminating CHF; avoid pseudoagglutination; when blood given simultaneously, add at least 20 mEq of sodium chloride to each liter of mannitol solution; do not give electrolyte-free mannitol solutions with blood

Angiodysplasia of the Colon

2007-11-28T20:58:00.000-08:00

Background

Phillips first described a vascular abnormality that caused bleeding from the large bowel in a letter to the London Medical Gazette in 1839. During the 1920s, neoplasms were considered the major source of GI hemorrhage. However, in the 1940s and 1950s, diverticular disease was recognized as an important source of bleeding. In 1951, Smith described active bleeding from a diverticulum visualized through a sigmoidoscope. An association between colonic angiodysplasia and aortic stenosis was described by Heyde in 1958.

Vascular abnormalities as a source of active bleeding were controversial. In 1960, Margulis and colleagues identified a vascular malformation in the cecum of a 69-year-old woman who presented with massive bleeding. This diagnosis was accomplished with operative mesenteric arteriography.

Galdabini first used the name angiodysplasia in 1974; however, confusion about the exact nature of these lesions resulted in a multitude of terms that included arteriovenous malformation, hemangioma, telangiectasia, and vascular ectasia. These terms have varying pathophysiologies, with a common presentation of GI bleeding.

Angiodysplasia is a degenerative lesion of previously healthy blood vessels found most commonly in the cecum and proximal ascending colon. Seventy-seven percent of angiodysplasias are located in the cecum and ascending colon, 15% are located in the jejunum and ileum, and the remainder are distributed throughout the alimentary tract. These lesions typically are nonpalpable and small.

Angiodysplasia is the most common vascular abnormality of the GI tract. After diverticulosis, it is the second leading cause of lower GI bleeding in patients older than 60 years. Angiodysplasia may account for approximately 6% of cases of lower GI bleeding. It may be observed incidentally at colonoscopy in as many as 0.8% of patients older than 50 years. The prevalence for upper GI lesions is approximately 1-2%. Small bowel angiodysplasia may account for 30-40% of cases of GI bleeding of obscure origin.

Angiodysplasia may present as an isolated lesion or as multiple vascular lesions. Unlike congenital or neoplastic vascular lesions of the GI tract, this lesion is not associated with angiomatous lesions of the skin or other viscera.

Clinical presentation is usually characterized by maroon-colored stool, melena, or hematochezia. Bleeding is usually low grade but can be massive in approximately 15% of patients. In 20-25% of episodes, only tarry stools are passed. Iron deficiency anemia and stools that are intermittently positive for occult blood can be the only manifestations of angiodysplasia in 10-15% of patients. Bleeding stops spontaneously in over 90% of cases but is often recurrent.

Pathophysiology

The exact mechanism of development of angiodysplasia is not known. One prominent hypothesis accounts for the high prevalence of these lesions in the right colon and is based on the Laplace law. The Laplace law relates wall tension to luminal size and transmural pressure difference in a cylinder whereby the wall tension is equal to the pressure difference multiplied by the radius of the cylinder. In the case of the colon, wall tension refers to intramural tension, pressure difference is that between the bowel lumen and the peritoneal cavity, and cylinder radius is the radius of the right colon. Wall tension is highest in bowel segments with the greatest diameter, such as the right colon.

This theory suggests that repeated episodes of colonic distention are associated with transient increases in lumen pressure and size. This results in multiple episodes of increasing wall tension with obstruction of submucosal venous outflow, especially where these vessels pierce the smooth muscle layers of the colon. Over many years, this process causes gradual dilation of the submucosal veins and, eventually, dilation of the venules and arteriolar capillary units feeding them.

Ultimately, the capillary rings dilate, the precapillary sphincters lose their competency, and a small arteriovenous communication forms. This accounts for the characteristic early-filling vein observed during mesenteric angiography.

The developmental theory of angiodysplasia accounts for several clinical and pathologic features, including occurrence in older individuals, location in the cecum and proximal right colon, and prominent submucosal veins that dilate after traversing the muscularis propria. In addition, it also accounts for the lack of pathologic changes in arterioles supplying vascular ectasias and the absence of any mucosal lesion associated with them. Previous studies demonstrating that colonic motility, increased tension in the bowel wall, and increased intraluminal pressure can diminish venous flow lend further support to this theory. Dilated submucosal veins have been one of the most consistent histological findings and may represent the earliest abnormality in colonic angiodysplasia. This histological feature supports the theory of chronic venous obstruction in the genesis of angiodysplasia.

Of note, the aforementioned pathophysiological mechanisms responsible for the development of cecal lesions are unlikely to apply to lesions in the upper GI tract, despite being morphologically identical.

Recently, a link between a deficiency of high molecular-weight multimers of von Willebrand factor, aortic stenosis, and colonic angiodysplasia has been proposed.

Frequency

United States

The prevalence of angiodysplasia is 0.8% in healthy patients older than 50 years who are undergoing screening colonoscopy.

Foutch et al noted the prevalence of angiodysplasia to be 0.93% from 3 prospective studies in which screening colonoscopies were performed in 964 asymptomatic individuals (mean age, 61 y).

Patients with von Willebrand disease may have an increased incidence of gastrointestinal bleeding from colonic angiodysplasia.

International

No widespread studies to determine the incidence of angiodysplasia have been conducted, but the incidence probably is similar to that in the United States.

Mortality/Morbidity

Bleeding from angiodysplasia usually is self-limited, but it can be chronic, recurrent, or even acute and life threatening.
Approximately 90% of bleeding angiodysplasias spontaneously cease bleeding.
Mortality is related to the severity of bleeding, hemodynamic instability, age, and the presence of comorbid medical conditions.

Race

No racial predilection exists.

Sex

Angiodysplasia occurs with equal frequency in men and women.

Age

Most patients found to have angiodysplasia are older than 60 years; of these patients, most are older than 70 years. However, case reports exist of occurrence in young people.

Treatment

Medical Care

Medically manage each patient in accordance with the severity of bleeding, hemodynamic stability, and recurrence of symptoms. A conservative approach to patients who are hemodynamically stable is recommended because most bleeding angiodysplasias will cease spontaneously. Treatment usually is not advocated for asymptomatic patients when angiodysplasias are found incidentally.

Initially, hemodynamically stabilize all patients with active bleeding with intravenous fluid and packed red blood cells as needed. In addition, correct coagulopathies.

When intervention is warranted, institute steps to control hemorrhage. Endoscopic techniques have been employed most frequently.

Gastric and duodenal angiodysplastic lesions have been managed most commonly with endoscopic obliteration techniques. Rebleeding after these techniques has been attributed to other areas of bleeding angiodysplasia rather then failure of obliteration. These techniques include monopolar electrocautery, heater probe, sclerotherapy, band ligation, and argon and neodymium:yttrium-aluminum-garnet (Nd:YAG) lasers.

Monopolar electrocautery has been used to obliterate angiodysplasia; however, bleeding recurs in approximately 50% of subjects. A reduction in the posttherapy transfusion requirement was not reported to be statistically superior to no therapy. Heater probe or multipolar coagulation devices have more favorable results. Monopolar electrocautery has a higher risk of perforation.
Sclerotherapy using 0.5-1 mL of 1.5% sodium tetradecyl sulfate has been used to obliterate upper tract lesions; however, bleeding recurs in half of the subjects. In each case, bleeding arose from another area of angiodysplasia. A significant rate of complications has been reported with sclerotherapy, including perforation, embolism, bacteremia, and stricture. The authors do not recommend its use for obliteration of colonic angiodysplasia.
Argon and Nd:YAG lasers are the most successful endoscopic obliterative techniques for upper tract lesions. Argon beam coagulation is a no-touch electrocoagulation technique in which high-frequency alternating current is delivered to the tissue through ionized argon gas. A reduction in both the bleeding rate and transfusion requirement has been demonstrated for at least 12 months after laser therapy. Effectiveness appeared to be reduced in patients with more numerous lesions, those with coagulation disorders, and those who are older. Rebleeding commonly occurred over time.
New endoscopic techniques such as Olympus EVIS LUCERA variable indices of hemoglobin chart function have been developed to assess completeness of vascular mucosal ablation. However, their clinical use is still experimental. Argon coagulation appears the best endoscopic option at the moment to control bleeding in these patients with a low rate of adverse effects and complications and relatively lower costs.
Fifty percent of patients with distal small bowel lesions and no other defined GI bleeding sites have benefited from enteroscopy and lesion obliteration. In one report, blood replacement requirements for a group of 13 patients decreased by more than 50%, comparing the years before and after endoscopic treatment, and 31% required no further transfusion. This group of patients had small bowel angiodysplastic lesions and unexplained bleeding. New endoscopic techniques to examine the small bowel, such as double-balloon enteroscopy, have been developed but are still time demanding and operator dependent.
- Angiodysplasia of colonic origin has been managed by endoscopic obliteration. Heater probe and multipolar electrocoagulation probe have been more successful than monopolar electrocoagulation. Rebleeding rates for monopolar electrocoagulation have been approximately 50%, with the transfusion requirement resembling that of patients receiving no therapy.
- Endoscopic laser photocoagulation has been successful in controlling bleeding from colonic angiodysplasia. However, complications occur in as many as 15% of patients and are more common when the Nd:YAG laser is used in the right colon. Complications may be attributed to the deeper coagulation of the vascular abnormalities from laser sources, which incidentally has been responsible for more effective bleeding cessation. Patients with colonic angiodysplasia generally have a 60% chance of remaining free of bleeding at 24 months after laser obliteration.
- Endoclips have been used in anecdotal case reports for bleeding angiodysplasia of the cecum and right colon.
- Angiodysplasia that presents with acute hemorrhage can be controlled effectively with angiography, although it seldom is needed. Angiography is appropriate in severely ill patients who are not candidates for surgical intervention. In these patients, transcatheter embolization of selected mesenteric arteries has been quite effective. However, the rate of complications is sufficiently high and must be balanced against the risk of surgical resection.
- Selective infusion of vasopressin is less effective than embolization as a definitive therapy because of a high rebleeding rate. Despite the fact that intra-arterial vasopressin can achieve hemostasis for massive lower GI bleeding in 70-91% of patients, bleeding recurs after discontinuation of vasopressin in 22-71% of patients.
- Angiography plays a more important role in preoperative localization of small bowel lesions immediately before surgical resection because intraoperative palpation, endoscopy, and visual inspection through multiple enterotomies are of little value with angiodysplasia.
- Injection of dyes, such as methylene blue, indigo carmine, and fluorescein, has been used to assist in localization of angiodysplasia before surgical resection.

Surgical Care

Surgical resection is the definitive treatment.

Partial or complete gastrectomy for management of gastric angiodysplasia was followed by bleeding in as many as 50% of patients. Rebleeding was attributed to other angiodysplastic lesions.
Right hemicolectomy for angiodysplasia is second-line therapy after endoscopic ablation, if repeated endoscopic coagulation has failed, if endoscopic therapies are not available, and for life-threatening hemorrhage.
The mortality rate associated with surgical resection ranges from 10-50%. This is based on the view that surgery carries a much higher risk in elderly patients who often have multiple coexisting medical problems, including coronary artery disease, coagulopathy, and renal and pulmonary dysfunction.
- In one study by Meyer, right hemicolectomy resulted in 63% of the subjects remaining free of intestinal bleeding (mean follow-up, 3.6 y), and 37% had some degree of recurrent bleeding.
- Trends toward reduced transfusion requirements have been observed after surgical resection, as well as after electrocoagulation as the only mode of therapy, and in patients who received no specific intervention.
- Surgical resection is preferred for acute management of severe hemorrhage or for management of recurrent hemorrhage over a relatively short period accompanied by a large transfusion requirement.

Consultations

Consultation with both a gastroenterologist and a surgeon is recommended. Interventional radiology often plays a critical role in the management of these patients.

Diet

Withhold oral intake until diagnosis has been made and treatment has been initiated.

Activity

Restrict activity until hemodynamic stability can be maintained.

Medication

Medical treatment has been used in active and recurrent bleeding from colonic angiodysplasia with controversial results. Hormonal treatment with estrogen and progesterone has been evaluated by randomized trials but remains controversial and is probably not effective. Octreotide, both short and long acting, has been described effective in few case reports and case series only. Other agents, such as thalidomide, remain experimental. DDAVP has also been used in specific subsets of patients. At the moment, no medical therapy has been proven to effectively treat bleeding from angiodysplasia.

Drug Category: Oral contraceptives

Only use hormonal therapy for the small subset of patients who are transfusion-dependent from bleeding angiodysplasia refractory to conservative and endoscopic therapy and who are poor surgical candidates. This is not for routine management of bleeding angiodysplasia. No large-scale, randomized, double-blinded studies have demonstrated its effectiveness.

Estrogen-progesterone therapy, previously used to treat bleeding associated with hereditary hemorrhagic telangiectasia, also has been tried in patients with GI bleeding from angiodysplasia.

Proposed mechanisms by which hormonal therapy might affect bleeding include improvement in coagulation, alterations in microvascular circulation, and improvements in endothelial integrity.

Data from a double-blinded, crossover trial using 0.05 mg ethinyl estradiol and 1 mg norethisterone administered daily to 10 elderly patients with GI ectasia (6 of the patients had hereditary hemorrhagic telangiectasia) have indicated that the combination significantly reduced bleeding and transfusion requirements. Several other small series with anecdotal success have been described, but one must be skeptical.

One study by Lewis refutes the benefits of hormonal therapy in angiodysplasia.This involved a retrospective cohort study of 64 patients. Thirty patients were administered 5-10 mg of norethynodrel with mestranol (0.075-0.15 mg) or with conjugated estrogens (0.625 mg), and the bleeding rates did not differ before and after therapy and did not differ from bleeding rates of historical controls or from patients who refused therapy. Treatment adverse effects in this study included vaginal bleeding, fluid retention, and stroke (23% of the treated patients).

Overall the current data do not support the use of hormonal therapy in patients with colonic angiodysplasia.

Drug Name	Ethinyl estradiol and norethindrone (Ovcon 50)
Description	Suggested mechanisms by which hormonal therapy might affect bleeding include improvement in coagulation, alterations in the microvascular circulation, and improvements in endothelial integrity. One active tab contains ethinyl estradiol 0.05 mg and norethindrone 1 mg.
Adult Dose	1 tab PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; thrombophlebitis; undiagnosed vaginal bleeding; pregnancy; estrogen-dependent neoplasia; severe hepatic disease; breast cancer
Interactions	May reduce hypoprothrombinemic effects of anticoagulants; estrogen levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes; an increase in corticosteroid levels may occur when administered concurrently with ethinyl estradiol; use of ethinyl estradiol with hydantoins may cause spotting, breakthrough bleeding, and pregnancy; increase in fluid retention caused by estrogen intake may reduce seizure control
Pregnancy	X - Contraindicated; benefit does not outweigh risk
Precautions	Cigarette smoking increases risk of serious cardiovascular adverse effects; caution in hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, or thromboembolic disease; associated adverse effects include GI distress, breakthrough bleeding, breast tenderness, weight change, and contact lens intolerance; in males, adverse effects include gynecomastia and decreased libido

Drug Category: Somatostatin analogs

These agents have been reported to decrease the rate of bleeding from intestinal angiodysplasia. In our experience is usually well tolerated and may decrease the rate of chronic bleeding. Octreotide should be first choice in patients with portal hypertension.

Drug Name	Octreotide (Sandostatin)
Description	Mechanism of action in this setting not fully understood. Used in acute variceal bleeding and for recurrent bleeding after endoscopic therapy. May reduce transfusion requirement.
Adult Dose	100 mcg SC bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May reduce effects of cyclosporine; patients on insulin, oral hypoglycemics, beta-blockers and calcium channel blockers may need dosage adjustments
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adverse effects primarily related to altered GI motility, and include nausea, abdominal pain, diarrhea and increased incidence of gallstones and biliary sludge; because of alteration in counter-regulatory hormones, (insulin, glucagon and GH) hypo- or hyperglycemia may be seen; bradycardia, cardiac conduction abnormalities and arrhythmias have been reported; due to inhibition of TSH secretion, hypothyroidism may also occur; exercise caution in patients with renal impairment; cholelithiasis may occur

Amebic Hepatic Abscesses

2007-11-28T20:57:00.000-08:00

Background: Amebic liver abscess is the most frequent extraintestinal manifestation of Entamoeba histolytica infection. This infection is caused by the protozoa E histolytica, which ascends the portal venous system. Amebic liver abscess is an important cause of space-occupying lesions of the liver, mainly in developing countries. Prompt recognition and appropriate treatment of amebic liver abscess lead to improved morbidity and mortality rates.

Pathophysiology: E histolytica exists in 2 forms. The cyst stage is the infective form, and the trophozoite stage causes invasive disease. People who chronically carry E histolytica shed cysts in their feces; these cysts are transmitted primarily by food and water contamination. Rare cases of transmission via oral and anal sex or direct colonic inoculation through colonic irrigation devices have occurred. Cysts are resistant to gastric acid, but the wall is broken down by trypsin as it passes through the small intestine. Trophozoites are released and colonize the cecum. To initiate symptomatic infection, E histolytica trophozoites present in the lumen must adhere to the underlying mucosa and penetrate the mucosal layer.

Liver involvement occurs following invasion of E histolytica into mesenteric venules. Amebae then enter the portal circulation and travel to the liver where they typically form large abscesses. The abscess contains acellular proteinaceous debris, which is thought to be a consequence of induced apoptosis and is surrounded by a rim of amebic trophozoites invading the tissue.

The right lobe of the liver is more commonly affected than the left lobe. This has been attributed to the fact that the right lobe is supplied predominantly by the superior mesenteric vein, whereas the left lobe is supplied by the splenic vein.

Frequency:

In the US: Amebic liver abscess is rare and currently is seen almost exclusively in immigrants or travelers. In 1994, 2,983 cases of amebiasis were reported to the Centers for Disease Control (CDC). The disease was removed from the National Notifiable Diseases Surveillance System in 1995. The overall prevalence of amebic infection can be as high is 4%. An estimated 4% of patients with amebic colitis develop an amebic liver abscess.
An estimated 10% of the population is infected with Entamoeba dispar. Previously thought to be a nonpathogenic strain of E histolytica, this type of amoeba does not produce clinical symptoms even in the immunocompromised host.

Internationally: Worldwide, approximately 40-50 million people are infected annually, with the majority of infections occurring in developing countries. The prevalence of infection may be as high as 50% in less-developed areas. The highest prevalence is found in developing countries in the tropics, particularly in Mexico, India, Central and South America, and tropical areas of Asia and Africa.

Mortality/Morbidity: Infection with E histolytica ranks second worldwide among parasitic causes of death, following malaria.

Annually, 40,000-100,000 deaths are caused by infection with E histolytica.

Per year, a 10% risk of developing symptomatic invasive amebiasis exists after the acquisition of a pathogenic strain.

Race: All races can be affected by amebic liver abscess. Risk factors for infection include travel or residence in endemic areas.

Sex: Amebic liver abscess is marked by a 7-12 times higher incidence in males than in females despite an equal sex distribution of noninvasive colonic amebic disease among adults. However, no sexual preponderance exists among children.

Age: Peak incidence of amebic liver abscess occurs in people in their third, fourth, and fifth decades, although it can occur in any age group.

Treatment
Medical Care: Most uncomplicated amebic liver abscesses can be treated successfully with amebicidal drug therapy alone. Use tissue amebicides to eradicate the invasive trophozoite forms in the liver. After completion of treatment with tissue amebicides, administer luminal amebicides for eradication of the asymptomatic colonization state. Failure to use luminal agents can lead to relapse of infection in approximately 10% of patients. In general, metronidazole, tinidazole, emetine, and dehydroemetine are active in invaded tissues; chloroquine is active only in the liver; tetracycline acts on the bowel wall; and diloxanide furoate, paromomycin, and iodoquinol are luminal agents only. The details on tissue and luminal amebicidal agents are discussed.

Metronidazole remains the drug of choice for amebic liver abscess. Metronidazole enters the protozoa by passive diffusion and is converted to reactive cytotoxic nitroradicals by reduced ferredoxin or flavodoxin. Tinidazole, another nitroimidazole closely related to metronidazole, was recently approved for the treatment of amebic liver abscess and invasive amebiasis. Tinidazole is well tolerated by patients. Tinidazole may be administered once daily and appears to be at least as effective as metronidazole, with a clinical cure rate of more than 90%.

Metronidazole, 750 mg 3 times a day orally for 10 days, was reported to be curative in 90% of patients with amebic liver abscess. The drug also is available for intravenous administration for those patients who are unable to take medication by the oral route.
Resolution of symptoms is fairly rapid and is observed within 3 days in most of the patients in the United States. In endemic areas outside the United States, it takes relatively longer to resolve symptoms because the abscesses are quite large or multiple by the time patients seek medical attention.
Surprisingly, in vivo resistance to metronidazole by E histolytica has not been reported, although metronidazole is a frequently used drug. Nevertheless, in vitro studies have shown an association between metronidazole resistance and decreased expression of ferredoxin 1 and flavodoxin and increased expression of iron-containing superoxide dismutase and peroxiredoxin in E histolytica.
Usual adverse effects of metronidazole include nausea, headache, and metallic taste. Abdominal cramps, vomiting, diarrhea, and dizziness also may occur. Dark urine may occur from a metabolite of the drug.

Anecdotal evidence suggests that the addition of dehydroemetine for the first few days of therapy hastens the recovery in severe cases, with less cardiotoxicity, compared to a full 10-day course of dehydroemetine. However, no randomized controlled trials exist that demonstrate the benefits of combination therapy over monotherapy.
Outside the United States, other closely related amebicidal agents, such as secnidazole or ornidazole, can be substituted in appropriate dosages. These drugs are not available in the United States.
Chloroquine phosphate may be substituted or added in the event of failure of resolution of clinical symptoms with metronidazole or another nitroimidazole within 5 days or intolerance to metronidazole or a nitroimidazole. Chloroquine has the disadvantage of being associated with higher relapse rates than nitroimidazoles. Adverse effects include gastrointestinal upset, headache, dizziness, and blurred vision. Retinopathy does not occur at the dose used for amebic liver abscess.
Emetine or dehydroemetine has a direct lethal action on the trophozoites of E histolytica. These agents are very toxic and, therefore, should be used only as a second-line therapy. Their toxicity includes cardiac arrhythmias, precordial pain, muscle weakness, vomiting, and diarrhea. Dehydroemetine is less toxic than emetine.
Administer a luminal amebicidal agent to eradicate the intestinal carriage after the amebic liver abscess has been treated with one of the above tissue amebicides. Failure to use luminal agents can lead to relapse of infection in approximately 10% of patients. Luminal agents with proven efficacy include diloxanide furoate, iodoquinol, and paromomycin.

Diloxanide furoate is free of major adverse effects. The most common adverse effect is flatulence and occasional gastrointestinal upset.
Iodoquinol (diiodohydroxyquin) rarely causes abdominal pain, diarrhea, or rash. A structurally related diiodohydroxyquin caused subacute myelopticoneuropathy and is obsolete now.

Although paromomycin may occasionally cause nausea, abdominal cramps, or diarrhea, it is the preferred luminal amebicidal.

The details on the luminal amebicides are discussed.

Surgical Care:

Consider therapeutic aspiration of amebic liver abscess in the following situations: (1) high risk of abscess rupture, as defined by cavity size greater than 5 cm; (2) left lobe liver abscess, which is associated with higher mortality and frequency of peritoneal leak or rupture into the pericardium; (3) failure to observe a clinical medical response to therapy within 5-7 days; and (4) cannot differentiate from a pyogenic liver abscess.

Imaging-guided needle aspiration or catheter drainage is the procedure of choice. Simple needle aspiration is less invasive, less expensive, and has the advantage of being able to drain multiple abscesses in the same session. Simple needle aspiration avoids problems related to catheter care

Rajak et al compared the efficacy of sonographically guided percutaneous needle aspiration and percutaneous catheter drainage in the treatment of patients with liver abscesses, two thirds of which were amebic abscesses.

Although percutaneous needle aspiration was successful in only 60% of cases after 1 or 2 aspirations, catheter drainage was curative in all patients.

The average time for clinical improvement and mean hospital stay were similar among the patients who were successfully treated in the 2 treatment groups.

The average time taken for total resolution of the abscesses was the same in both groups.

Generally, surgical drainage is not necessary and should be avoided; however, consider open surgical drainage when the abscess is inaccessible to needle drainage or a response to therapy has not occurred in 4-5 days.

Consultations:

Interventional radiologist for imaging-guided aspiration of the abscess

General surgeon for open surgical drainage of the abscess under rare circumstances

Diet: No specific diet change or modification is required. However, discuss food hygiene with patients because amebiasis is associated with suboptimal personal or food hygiene.

Activity:

No restriction of activity is needed, except during the first few days of acute illness with pain.

If emetine or dehydroemetine is used, the patient should remain sedentary for approximately 4 weeks after completing therapy because of their toxicity.

Alcoholic Hepatitis

2007-11-28T20:55:00.000-08:00

Background

Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol. The pathogenesis is not completely understood.

Patients who are severely affected present with subacute onset of fever, hepatomegaly, leukocytosis, marked impairment of liver function (eg, jaundice, coagulopathy), and manifestations of portal hypertension (eg, ascites, hepatic encephalopathy, variceal hemorrhage). However, milder forms of alcoholic hepatitis often do not cause any symptoms.

Upon microscopic examination, the liver exhibits characteristic centrilobular ballooning necrosis of hepatocytes, neutrophilic infiltration, megamitochondria, and Mallory hyaline inclusions. Steatosis (fatty liver) and cirrhosis frequently accompany alcoholic hepatitis.

Disease that is sufficiently severe to cause an acute development of encephalopathy is associated with substantial early mortality, which may be ameliorated by treatment with glucocorticoids.

Alcoholic hepatitis usually persists and progresses to cirrhosis if heavy alcohol use continues. If alcohol use ceases, alcoholic hepatitis resolves slowly over weeks to months, sometimes without permanent sequelae but often with residual cirrhosis.

Pathophysiology

Although the association of alcohol and liver disease has been known since antiquity, the precise mechanism of alcoholic liver disease remains in dispute. Genetic, environmental, nutritional, metabolic, and, more recently, immunologic factors and cytokines have been invoked

Ethanol metabolism

Most tissues of the body, including the skeletal muscles, contain the necessary enzymes for the oxidative or nonoxidative metabolism of ethanol. However, the major site of ethanol metabolism is the liver. Within the liver, the following 3 enzyme systems can oxidize ethanol.

Cytosolic alcohol dehydrogenase (ADH) uses nicotinamide adenine dinucleotide (NAD) as an oxidizing agent. ADH exists in numerous isoenzyme forms in the human liver and is encoded by 3 separate genes, designated as ADH1, ADH2, and ADH3. Variations in ADH isoforms may account for significant differences in ethanol elimination rates.

The microsomal ethanol-oxidizing system (MEOS) uses nicotinamide adenine dinucleotide phosphate (NADPH) and molecular oxygen. The central enzyme of MEOS is cytochrome P-450 2E1 (CYP2E1). This enzyme, in addition to catalyzing ethanol oxidation, is also responsible for the biotransformation of other drugs, such as acetaminophen, haloalkanes, and nitrosamines. Ethanol up-regulates CYP2E1, and the proportion of alcohol metabolized via this pathway increases with the severity and duration of alcohol use.

Peroxisomal catalase uses hydrogen peroxide as an oxidizing agent.

The product of all 3 reactions is acetaldehyde, which is then further metabolized to acetate by acetaldehyde dehydrogenase (ALDH). Acetaldehyde is a reactive metabolite that can produce injury in a variety of ways.

Mechanisms of liver injury

Genetic factors

Although the evidence to prove a genetic predilection to alcoholism is adequate, the role of genetic factors in determining susceptibility to alcoholic liver injury is much less clear. Most people who are alcoholics do not develop severe or progressive liver injury. Attempts to link persons who are susceptible with specific HLA groups have yielded inconsistent results, as have studies of genetic polymorphisms of collagen, ADH, ALDH, and CYP2E1.

Similar conclusions were reached in a recent meta-analysis of 50 studies pertaining to the association of alcoholic liver disease and genetic polymorphism. Nonetheless, the fact remains that only a small fraction of even heavy alcoholics develop severe liver disease (ie, cirrhosis). Thus, future case-control studies investigating the genetic basis of alcohol-induced liver disease are urgently needed.

The genetic factor that most clearly affects susceptibility is sex. For a given level of ethanol intake, women are more susceptible than men to developing alcoholic liver disease.

Malnutrition

Most patients with alcoholic hepatitis exhibit evidence of protein-energy malnutrition (PEM). In the past, nutritional deficiencies were assumed to play a major role in the development of liver injury. This assumption was supported by several animal models in which susceptibility to alcohol-induced cirrhosis could be produced by diets deficient in choline and methionine. This view changed in the early 1970s after key studies by Lieber and DeCarli performed in baboons demonstrated that alcohol ingestion could lead to steatohepatitis and cirrhosis in the presence of a nutritionally complete diet.However, more recent studies suggest that enteral or parenteral nutritional supplementation in patients with alcoholic hepatitis may improve survival.

Toxic effects on cell membranes

Ethanol and its metabolite, acetaldehyde, have been shown to damage liver cell membranes. Ethanol can alter the fluidity of cell membranes, thereby altering the activity of membrane-bound enzymes and transport proteins. Ethanol damage to mitochondrial membranes may be responsible for the giant mitochondria (megamitochondria) observed in patients with alcoholic hepatitis. Acetaldehyde-modified proteins and lipids on the cell surface may behave as neoantigens and trigger immunologic injury.

Hypermetabolic state of the hepatocyte

Hepatic injury in alcoholic hepatitis is most prominent in the perivenular area (zone 3) of the hepatic lobule. This zone is known to be sensitive to hypoxic damage. Ethanol induces a hypermetabolic state in the hepatocytes, partially because ethanol metabolism via the MEOS does not result in energy capture via formation of ATP. Rather, this pathway leads to loss of energy in the form of heat. In some studies, antithyroid drugs, such as propylthiouracil, that reduce the basal metabolic rate of the liver have shown to be beneficial in the treatment of alcoholic hepatitis.

Generation of free radicals and oxidative injury

Free radicals, superoxide and hydroperoxides, are generated as byproducts of ethanol metabolism via the microsomal and peroxisomal pathways. In addition, acetaldehyde reacts with glutathione and depletes this key element of the hepatocytic defense against free radicals. Other antioxidant defenses, including selenium, zinc, and vitamin E, are often reduced in individuals with alcoholism. Peroxidation of membrane lipids accompanies alcoholic liver injury and may be involved in cell death and inflammation.

Steatosis

Oxidation of ethanol requires conversion of NAD to the reduced form NADH. Because NAD is required for the oxidation of fat, its depletion inhibits fatty acid oxidation, thus causing accumulation of fat within the hepatocytes (steatosis). Some of the excess NADH may be reoxidized in the conversion of pyruvate to lactate. Accumulation of fat in hepatocytes may occur within days of alcohol ingestion; with abstinence from alcohol, the normal redox state is restored, the lipid is mobilized, and steatosis resolves. Although steatosis has generally been considered a benign and reversible condition, rupture of lipid-laden hepatocytes may lead to focal inflammation, granuloma formation, and fibrosis, and it may contribute to progressive liver injury. Nonoxidative metabolism of ethanol may lead to the formation of fatty acid ethyl esters, which may also be implicated in the pathogenesis of alcohol-induced liver damage.

Formation of acetaldehyde adducts

Acetaldehyde may be the principal mediator of alcoholic liver injury. The deleterious effects of acetaldehyde include impairment of the mitochondrial beta-oxidation of fatty acids, formation of oxygen-derived free radicals, and depletion of mitochondrial glutathione. In addition, acetaldehyde may bind covalently with several hepatic macromolecules, such as amines and thiols, in cell membranes, enzymes, and microtubules to form acetaldehyde adducts. This binding may trigger an immune response through formation of neoantigens, impair function of intracellular transport through precipitation of intermediate filaments and other cytoskeletal elements, and stimulate hepatic stellate cells to produce collagen.

Levels of acetaldehyde in the liver represent a balance between its rate of formation (determined by the alcohol load and activities of the 3 alcohol-dehydrogenating enzymes) and its rate of degradation by ALDH. ALDH is down-regulated by long-term ethanol abuse, with resultant acetaldehyde accumulation.

Role of the immune system

Active alcoholic hepatitis often persists for months after cessation of drinking. In fact, its severity may worsen during the first few weeks of abstinence. This observation suggests that an immunologic mechanism may be responsible for perpetuation of the injury. Levels of serum immunoglobulins, especially the immunoglobulin A class, are increased in persons with alcoholic hepatitis. Antibodies directed against acetaldehyde-modified cytoskeletal proteins can be demonstrated in some individuals. Autoantibodies, including antinuclear and anti–single-stranded or anti–double-stranded DNA antibodies, have also been detected in some patients with alcoholic liver disease.

B and T lymphocytes are noted in the portal and periportal areas, and natural killer lymphocytes are noted around hyalin-containing hepatocytes. Patients have decreased peripheral lymphocyte counts with an associated increase in the ratio of helper cells to suppressor cells, signifying that lymphocytes are involved in a cell-mediated inflammatory process. Lymphocyte activation upon exposure to liver extracts has been demonstrated in patients with alcoholic hepatitis. Immunosuppressive therapy with glucocorticoids appears to improve survival and accelerate recovery in patients with severe alcoholic hepatitis.

Cytokines

Tumor necrosis factor-alpha (TNF-alpha) can induce programmed cellular death (apoptosis) in liver cells. Several studies have demonstrated extremely high levels of TNF and several TNF-inducible cytokines, such as interleukin (IL)–1, IL-6, and IL-8, in the sera of patients with alcoholic hepatitis. Both inflammatory cytokines (TNF, IL-1, IL-8) and hepatic acute-phase cytokines (IL-6) have been postulated to play a significant role in modulating certain metabolic complications in alcoholic hepatitis, and they are probably instrumental in the liver injury of alcoholic hepatitis and cirrhosis.

Role of concomitant viral disease

Alcohol consumption may exacerbate injury caused by other pathogenic factors, including hepatitis viruses. Extensive epidemiologic studies suggest that the risk of cirrhosis in patients with chronic hepatitis C infection is greatly exacerbated by heavy alcohol ingestion. Possible mechanisms include the impairment of immune-mediated viral killing or enhanced virus gene expression due to the interaction of alcohol and hepatitis C virus.

Acetaminophen-alcohol interactions

Long-term alcohol abuse has been established as potentiating acetaminophen toxicity via induction of CYP2E1 and depletion of glutathione. Alcoholic patients may develop severe, even fatal, toxic liver injury after ingestion of standard therapeutic doses of acetaminophen.

Frequency

United States

Alcohol abuse is the most common cause of serious liver disease in Western societies. In the United States alone, alcoholic liver disease affects more than 2 million people (ie, approximately 1% of the population). The true prevalence of alcoholic hepatitis, especially of its milder forms, is unknown because patients may be asymptomatic and never seek medical attention.

International

The prevalence appears to differ widely among different countries. In the Western hemisphere, when liver biopsies were performed in people who drank moderate-to-heavy amounts of alcohol and were asymptomatic, the prevalence of alcoholic hepatitis was found to be approximately 25-30%.

Mortality/Morbidity

Mild alcoholic hepatitis is a benign disorder with negligible short-term mortality. However, when alcoholic hepatitis is of sufficient severity to cause hepatic encephalopathy, jaundice, or coagulopathy, mortality can be substantial

The overall 30-day mortality rate in patients hospitalized with alcoholic hepatitis is approximately 15%; however, in patients with severe liver disease, the rate approaches or exceeds 50%. In those lacking encephalopathy, jaundice, or coagulopathy, the 30-day mortality rate is less than 5%. Overall, the 1-year mortality rate after hospitalization for alcoholic hepatitis is approximately 40%.

In a recent study, the overall mortality among patients with severe alcoholic hepatitis was 66%. Age, white blood cell count, prothrombin time (PT), and female gender were all independent risk factors for the dismal outcome.

The long-term prognosis depends heavily on whether patients have established cirrhosis and whether they continue to drink. With abstinence, patients with alcoholic hepatitis exhibit progressive improvement in liver function over months to years and histologic features of active alcoholic hepatitis resolve. If alcohol abuse continues, alcoholic hepatitis invariably persists and progresses to cirrhosis over months to years.

Race

Although no genetic predilection is noted for any particular race, alcoholism and alcoholic liver disease are more common in minority groups, particularly among Native Americans. Likewise, since the 1960s, death rates of alcoholic hepatitis and cirrhosis have consistently been far greater for the nonwhite population than the white population. The nonwhite male rate of alcoholic hepatitis is 1.7 times the white male rate, 1.9 times the nonwhite female rate, and almost 4 times the white female rate.

Sex

Women are more susceptible than men to the adverse effects of alcohol. Women develop alcoholic hepatitis after a shorter period and smaller amounts of alcohol abuse than men, and alcoholic hepatitis progresses more rapidly in women than in men.

The estimated minimum daily ethanol intake required for the development of cirrhosis is 40 g for men and 20 g for women older than 15-20 years. Furthermore, for patients who continue to drink after a diagnosis of alcoholic liver disease, the 5-year survival rate is approximately 30% for women compared with 70% for men.

To date, no single factor can account for this increased female susceptibility to alcoholic liver damage. Lower gastric mucosal ADH content in women has been suggested to possibly lead to less first-pass clearance of alcohol in the stomach. A higher prevalence of autoantibodies has been found in the sera of alcoholic females compared with alcoholic males, but their clinical significance is questionable. Perhaps hormonal influences on the metabolism of alcohol or the higher prevalence of immunologic abnormalities is responsible for the differences described in the prevalence of alcoholic liver damage between men and women.

Age

Alcoholic hepatitis can develop at any age. However, its prevalence parallels the prevalence of ethanol abuse in the population, with a peak incidence in individuals aged 20-60 years.

Treatment

Medical Care

In most patients with alcoholic hepatitis, the illness is mild. Their short-term prognosis is good, and no specific treatment is required. Hospitalization is not always necessary. Alcohol use must be stopped. Care should be taken to ensure good nutrition. Providing supplemental vitamins and minerals, including folate and thiamine, is reasonable. Patients who are coagulopathic should receive vitamin K parenterally. Anticipate symptoms of alcohol withdrawal, and manage them appropriately.

In contrast, patients with severe acute alcoholic hepatitis are at high risk of early death, at a rate of 50% or greater within 30 days. In multiple studies, the strongest factor predictive of short-term mortality was hepatic encephalopathy. In some studies, a combination of hyperbilirubinemia and coagulopathy has also been found to independently predict a high short-term mortality rate. Individuals with these findings or with other complications, such as azotemia or gastrointestinal bleeding, should be hospitalized. Usually, observing the patient in an intensive care unit until liver function is stable and the patient is clinically improving is prudent.

Patients with severe alcoholic hepatitis may benefit over the short term from specific therapies directed toward reducing liver injury, enhancing hepatic regeneration, and suppressing inflammation. Glucocorticosteroids are widely used for this purpose, although their benefits have not been proven unequivocally. Various other treatments remain experimental. For the long term, goals include improvement of liver function, prevention of progression to cirrhosis, and reduction of mortality. Only prolonged alcohol abstinence is of demonstrated benefit in all these areas.

Cessation of alcohol use is the mainstay of treatment of alcoholic hepatitis.
- In general, alcoholic hepatitis resolves or improves greatly following 6-12 months of alcohol abstinence, and continued improvement may be observed for several years. Mild alcoholic hepatitis often resolves completely, but, following severe alcoholic hepatitis, residual cirrhosis can usually be demonstrated. If alcohol abuse persists, alcoholic hepatitis invariably persists and progresses to cirrhosis, and the prognosis is dramatically worse.
- Some experts have questioned whether complete abstinence is necessary or whether reduced amounts of alcohol would be sufficient for recovery in most patients. Given the addictive nature of alcohol in most patients who use it heavily, counseling complete abstinence is prudent. Patients should be referred to a program of rehabilitation and support, and they should be strongly encouraged to attend. Also, patients should be fully informed regarding the serious potential health consequences of continued ethanol use.

Additional treatment includes nutritional support.
- PEM is almost universal in patients hospitalized for alcoholic hepatitis. In a large Veterans Administration Cooperative Study of Alcoholic Hepatitis, the severity of PEM correlated with the severity of alcoholic hepatitis and the predicted mortality rate. In patients with alcoholic hepatitis and severe PEM, the mortality rate was 50%, compared with a mortality rate of less than 10% in patients with mild PEM.
- Some studies have suggested that improved energy and protein intake may improve the survival rate in patients with severe alcoholic hepatitis. However, complications associated with parenteral hyperalimentation (eg, sepsis, hemothorax) or enteral hyperalimentation (eg, aspiration pneumonia) may outweigh the benefits of these approaches. Thus, if patients are able to take food orally, this is the route of choice, and formal nutritional support can be reserved for those instances in which patients are unable to ingest enough by mouth to meet their needs. Energy (caloric) intake should be carefully measured to ensure adequate consumption. Use of nutritional supplements and appetite stimulants may be appropriate.
- Except in patients with severe encephalopathy, protein restriction is unnecessary and should be avoided because a protein-deficient diet impairs liver regeneration and worsens liver function. Even in the presence of hepatic encephalopathy, patients are usually able to ingest a minimum of 60-100 g/d of dietary protein if other measures to control encephalopathy have been aggressively pursued. In rare instances, restricting dietary proteins may be necessary. In these cases, alternatives include provision of high-quality protein via the parenteral route or provision of oral amino acid supplements that are selectively enriched with branched-chain amino acids.
Use of medications in alcoholic hepatitis remains controversial.
- Despite decades of research and multiple clinical trials, a consensus has not been reached regarding effective therapy for alcoholic hepatitis. At present, only glucocorticosteroid treatment can be considered of probable established benefit, and even this well-studied therapy continues to be a source of controversy.
- Treatments discussed have met with limited success in small clinical trials but have not been evaluated thoroughly and should be considered investigational.

Surgical Care

Patients with acute alcoholic hepatitis are at high risk of developing hepatic failure following general anesthesia and major surgery. Because postoperative mortality rates are high, surgery should be avoided in the setting of acute alcoholic hepatitis unless it is absolutely necessary. If patients remain abstinent, alcoholic hepatitis usually resolves over time, permitting surgery to be undertaken with a substantially reduced risk.

Orthotopic liver transplantation is widely used in patients with end-stage liver disease. Most patients with active alcoholic hepatitis are excluded from transplantation because of ongoing alcohol abuse. In most US programs, patients must abstain from alcohol for at least 6 months before they can be considered for transplantation, and a thorough psychosocial evaluation must demonstrate that patients have a low likelihood of reverting to alcohol abuse.

Current policies pertaining to liver transplantation in patients with end-stage alcoholic liver disease (ie, cirrhosis), especially those with severe alcoholic hepatitis, have been recently challenged.
- First, the societal aspects of the issue (ie, the public perception and reservation regarding the use of donated livers for self-inflicted disease) should not be any different than those of IV drug addicts with the hepatitis C virus or even the fast-food generation of obese persons with NASH.
- Second, the current fixed interval of ethanol abstinence, often at the behest of third-party payers, as a prerequisite for transplantation remains controversial as a predictor of future alcoholic relapse (ie, recidivism).
- Finally, other investigators have proposed the conduct of pilot studies, on only a small cohort of patients, to determine whether liver transplantation improves the survival of patients with severe alcoholic hepatitis.
Patients with alcoholic hepatitis may be informed that their liver injury can be expected to subside and liver function will improve following at least 6 months of abstinence. If they still develop cirrhosis and its complications, they can be considered for transplantation if they remain committed to sustained abstinence.
The prospect of liver transplantation can be a powerful motivational tool for encouraging abstinence.

Consultations

Largely, mild and moderate alcoholic hepatitis can be managed on a hospital medical floor, requiring only a brief hospital stay. In fact, patients with the mildest forms of the disease may never seek medical attention, or they can be treated safely in outpatient settings. By contrast, severe acute alcoholic hepatitis requires intensive medical care and often a multidisciplinary approach.

Adequate nutritional support is of paramount importance for the survival and recovery of patients with alcoholic hepatitis. The complexity of the disease and the wide variation in nutritional regimens and modalities mandate consultation with a nutritionist. Customarily, the gastroenterology service of the hospital should be able to handle this issue and should be instrumental in treatment.
The onset of acute renal failure may indicate the development of hepatorenal syndrome or, alternatively, an episode of acute tubular necrosis resulting either from the use of nephrotoxic drugs or from acute intravascular volume changes. In these instances, obtaining consultation with a nephrologist is advisable.
If a patient with alcoholic hepatitis exhibits mental status changes, focal neurologic findings, or seizures, consider consultation with a neurologist.
The fever and leukocytosis that accompany alcoholic hepatitis often raise concerns regarding possible sepsis or other infectious processes. Routine evaluation with urinalysis, chest radiography, and cultures of blood and urine is appropriate, and findings from these tests are usually negative. If concerns persist, consultation with an infectious disease specialist is appropriate
In patients with alcoholic hepatitis who have developed cirrhosis, especially those with coexistent chronic viral hepatitis B or C, consider periodic surveillance for hepatocellular carcinoma. A common algorithm includes determination of serum alpha-fetoprotein levels at 6-month intervals along with annual diagnostic ultrasonography. The finding of a liver nodule or an elevated alpha-fetoprotein level should lead to referral to a liver specialist and additional diagnostic studies.
In general, for patients with severe alcoholic hepatitis or cirrhosis, observation by a gastroenterologist or a hepatologist is desirable, particularly if the illness is of sufficient severity or complexity to require intensive care.

Diet

For patients with milder alcoholic hepatitis, a general diet containing 100 g/d of protein is appropriate.
Provide supplemental multivitamins and minerals, including folate and thiamine.
Salt restriction may be required in patients with ascites.

Medication

Infliximab (Remicade) is a monoclonal antibody against TNF-alpha that has been used successfully in immunologically mediated inflammatory diseases, such as Crohn disease and rheumatoid arthritis. In 2 small pilot studies of subjects with alcoholic hepatitis, infliximab improved the Maddrey scores, serum bilirubin and C-reactive protein levels, and, more importantly, patient survival.

In contrast, a subsequent randomized, double-blinded, controlled trial of 36 subjects with severe alcoholic hepatitis failed to confirm the findings of the pilot studies.In fact, the trial was discontinued because of the high rate of infections and because of mortality in the infliximab group. This study was criticized for the concomitant use of corticosteroids, the high dose of infliximab (10 mg/kg vs 5 mg/kg), and the selection of infliximab instead of an anti-TNF agent with a limited duration and action (ie, etanercept). Better-designed controlled clinical trials are probably necessary to resolve the controversy and avoid a possible type I error. Currently, corticosteroids are the only recommended pharmaceutical therapy for severe alcoholic hepatitis (ie, Maddrey discriminant factor >32).

Pentoxifylline (Trental) is a hemorheologic agent that lowers blood viscosity and has been shown to decrease portal hypertension in experimental animals with cirrhosis. Recently, pentoxifylline was found to have inhibitory effects on TNF. Following 2 encouraging pilot studies in a small number of subjects, a large, randomized, double-blinded, placebo-controlled trial in 101 subjects with acute alcoholic hepatitis was conducted and showed significant improvement in short-term survival.¹ The benefit of pentoxifylline appears to be related to a significant decrease in the risk of developing hepatorenal syndrome.

Anabolic steroids (eg, oxandrolone) have been used to treat alcoholic hepatitis because of their ability to stimulate protein synthesis and cell repair. They may also enhance nutrition through increased appetite. In a large study of 273 subjects with severe alcoholic hepatitis, treatment with both oxandrolone and nutritional supplementation showed no benefit on survival when the results of all subjects were analyzed. However, when subjects were stratified according to their nutritional status upon admission to the hospital, a significant improvement in short- and long-term survival was noted in those with moderate malnutrition. The survival rate in subjects who were severely malnourished did not improve.

This landmark study was recently confirmed in a meta-analysis of 5 randomized control trials that included 499 patients with alcoholic hepatitis who were treated with anabolic-androgenic steroids. According to the study results, anabolic steroids had no significant effect on mortality, liver-related mortality, liver complications, or liver histology.

To date, propylthiouracil has been used in several clinical trials in patients with alcoholic hepatitis. The combined results of 6 randomized clinical trials, which included 710 patients, were recently reported in a meta-analytical study.According to the authors' assessment, propylthiouracil had no beneficial effect on all-cause mortality, liver-related mortality, liver complications, or liver histology.

Insulin and glucagon are hepatotropic hormones that may play an important role in promoting liver cell regeneration in response to injury. In 2 clinical trials, administration of insulin and glucagon along with glucose (to prevent hypoglycemia) led to a modest improvement of liver function in patients with alcoholic hepatitis; however, severe insulin-induced hypoglycemia resulted in several deaths. Other promoters of hepatic regeneration include prostaglandins and malotilate, which appeared to improve survival in a multicenter European trial. Peptide growth factors, such as hepatocyte growth factor, are candidates for future study.

Colchicine interferes with transcellular movement and transport of collagen from the cytoplasm to the extracellular space, thus inhibiting fibrogenesis. In the 2 randomized double-blinded trials in the literature, colchicine was ineffective in treating patients with severe alcoholic hepatitis. By contrast, of 7 studies on the use of colchicine in patients with cirrhosis (mostly alcoholic), 4 studies demonstrated improvement and 3 studies demonstrated a tendency toward improvement.

Penicillamine inhibits collagen synthesis in vitro by decreasing cross-linking. Penicillamine has been used successfully for other liver diseases (eg, Wilson disease) for its copper-chelating properties. No controlled trial with this agent has been performed in alcoholic hepatitis.

Sulfhydryl agents can act as free radical scavengers and promote formation of reduced glutathione, an important element of hepatic antioxidant defense. S-adenosyl-l-methionine (SAM) protects against alcoholic liver injury in animal models. A recent, randomized, double-blinded, placebo-controlled trial in patients with alcoholic hepatitis resulted in improved survival of patients administered SAM compared with controls.

N-acetyl-L-cysteine (NAC) is widely used as an antidote to acetaminophen hepatotoxicity. Data from limited case-controlled studies suggest a beneficial effect of NAC in alcoholic liver disease. The beneficial effect is particularly apparent in patients who are alcoholics and also consume therapeutic doses of acetaminophen; however, preliminary evidence from prospective randomized trials did not show benefit. Vitamin E, a potent antioxidant substance, has been found to be hepatoprotective in both experimental animals and humans. However, a double-blinded trial among patients with alcoholic liver disease failed to improve liver chemistry, the hospitalization rate, and the cumulative mortality rate when the patients were administered 500 mg of vitamin E daily compared with the placebo-treated control group.

Polyunsaturated lecithin (PPC, phosphatidyl choline) has been studied because of the empiric observation that choline deficiency in rats (which impairs endogenous lecithin synthesis) increases sensitivity to alcoholic liver injury. The precise mechanism is unknown. Beneficial effects have also been demonstrated in preventing alcoholic liver injury in baboons. PPC failed to demonstrate any hepatoprotective effects in alcohol-induced liver injury in a recent multicenter Veterans Affairs cooperative study among 789 subjects.In fact, approximately 20% of these subjects showed progressive liver fibrosis with continued moderated amounts of alcohol ingestion. Thus, PPC does not appear to have a viable role in acute alcoholic hepatitis.

Several preliminary reports on alcoholic hepatitis have indicated a beneficial effect from calcium channel blockers (eg, diltiazem, verapamil); however, the only randomized double-blinded trial of amlodipine failed to demonstrate any improvement in patients with alcoholic hepatitis.

Hepatoprotective bile acids include ursodeoxycholic acid (Ursodiol), a tertiary bile acid that has been used extensively either as monotherapy or as an adjuvant therapy in various cholestatic liver diseases, such as primary biliary cirrhosis and primary sclerosing cholangitis. Preliminary data from a small clinical trial in patients with alcoholic hepatitis showed a significant improvement in liver chemistry test results.

Herbal agents have been tried. Silymarin is the active ingredient in milk thistle, is a member of the flavonoids, and has shown remarkable hepatoprotective effects in experimental toxic liver injury. The precise mechanism of its hepatoprotective mediation is not known, but it is probably related to its antioxidant properties. In humans with mild alcoholic hepatitis, silymarin improves liver chemistry test results. In a single controlled trial among 170 subjects with alcoholic liver disease, silymarin reduced the liver-related deaths. However, in a recent meta-analysis of 13 clinical trials (about half of them double-blind), it was concluded that milk thistle did not significantly influence the clinical course of patients with alcoholic hepatitis.

Cyanidanol-3 (catechin) is a naturally occurring flavonoid with antioxidant properties. As a hepatoprotective agent, it has been studied extensively in experimental toxic liver injury. Cyanidanol gained popularity in Europe in the mid 1980s and was used for a wide variety of liver diseases. Unfortunately, prospective randomized trials in subjects with alcoholic hepatitis failed to show any benefit. Moreover, the administration of cyanidanol is associated with adverse effects, such as allergic hyperthermia and autoimmune hemolytic anemia.

Several other antioxidant agents have been used in the treatment of alcoholic hepatitis, albeit with little success. In a recent randomized clinical trial, corticosteroids were far superior to a "cocktail" of antioxidants in improving the usually measured clinical parameters and liver histology.

Among future therapeutic directions, gene therapy is perhaps the most appealing modality. Various genes involved in hepatic fibrogenesis, inflammatory response, and oxidative stress are overexpressed in alcoholic hepatitis. Moreover, some candidate genes correlate well with histologic findings and disease severity, thus suggesting that they may be potential targets for such therapy.

Drug Category: Corticosteroids

Strong evidence of immunologic and inflammatory liver injury in alcoholic hepatitis provides the rationale for use of glucocorticosteroids. Over the past 30 years, more than 50 clinical trials have been published evaluating the use of glucocorticosteroids in treating alcoholic hepatitis. In most studies, treatment consists of the equivalent of 30-40 mg/d of prednisolone for 30 days, followed by a rapid taper and withdrawal over the subsequent 2-4 weeks. Study results have not been uniform. Larger studies demonstrate a significant benefit in severe alcoholic hepatitis, including reduction in mortality. Two meta-analyses of 12 randomized, prospective, placebo-controlled trials support the conclusion that glucocorticosteroid treatment reduces early mortality in patients with severe acute alcoholic hepatitis.

All studies conclude that in mild alcoholic hepatitis, no benefit can be demonstrated with glucocorticosteroid treatment; therefore, it is only appropriate in individuals with severe alcoholic hepatitis characterized by encephalopathy, hyperbilirubinemia, and/or coagulopathy.

Glucocorticosteroids may suppress inflammatory and immune-mediated hepatic destruction, but their marked antianabolic effect suppresses regeneration and may slow healing. They may increase complications and mortality associated with gastrointestinal bleeding, pancreatitis, or sepsis, and they should be withheld or used judiciously if any of these are present.

Drug Name	Methylprednisolone (Solu-Medrol, Adlone, Medrol, Depo-Medrol)
Description	Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. May be preferable to other glucocorticoids (eg, prednisone) because hepatic metabolism is not required.
Adult Dose	32 mg/d PO/IV for 30 d; taper and discontinue over 2-4 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active sepsis; GI bleeding; acute pancreatitis
Interactions	Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor for hypokalemia when taking concurrently with diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Only sodium succinate salt should be administered IV; commonly leads to impaired glucose tolerance and increases insulin requirements in diabetes; femoral osteonecrosis; increased susceptibility to fungal and other infections; impaired wound healing; increased risk of peptic ulcer hemorrhage or perforation; altered mental status with depression or psychosis

Alcoholic Fatty Liver

2007-11-28T20:53:00.000-08:00

Background: Pathologic changes observed in patients with alcohol-induced liver disease can be divided into the following 3 groups: alcoholic fatty liver (simple steatosis), alcoholic hepatitis, and alcohol-related cirrhosis. Alcoholic fatty liver is an early and reversible consequence of excessive alcohol consumption.

Pathophysiology: The amount of fatty acid in the liver depends on the balance between the processes of delivery and removal. Fatty liver develops in every individual who consumes more than 60 g/d of alcohol. Many mechanisms of ethanol-induced fatty liver have been proposed. Increased hepatic levels of glycerol 3-phosphate (3-GP) following ethanol ingestion are related to an increase in the ratio of nicotinamide adenine dinucleotide, reduced form, (NADH) to nicotinamide adenine dinucleotide (NAD) in the liver. Increasing concentration of 3-GP results in enhanced esterification of fatty acids.

An increased level of free fatty acids also has been incriminated in the pathogenesis of fatty liver. Large amounts of alcohol enhance lipolysis because of direct stimulatory effect on the adrenal and pituitary axis. In addition, chronic ingestion of ethanol inhibits oxidation of fatty acids in the liver and release of very low-density lipoprotein (VLDL) into the blood. All of these mechanisms favor steatosis. Centrilobular localization of steatosis results from decreased energy stores from relative hypoxia and a shift in lipid metabolism, along with a shift in the redox reaction caused by the preferential oxidation of alcohol in the central zone.

Recent advancement in the understanding of the pathogenesis of alcoholic steatosis has provided some novel insights, including the role of peroxisome proliferator-activated receptor alpha, which is crucial for the regulation of hepatic fatty acid metabolism. Its blockade, in animal models, along with ethanol consumption, contributes to the development of alcoholic fatty liver. In addition, induction of adiponectin, a hormone secreted by adipocytes, has been implicated in the protective action of saturated fat against the development of alcoholic fatty liver in mice. Another recent finding is the role of early growth response-1 transcription factor (EGr-1), which is thought to be essential for ethanol-induced fatty liver injury in mice. Hepatocyte death by apoptosis occurs in the alcoholic fatty liver and has been demonstrated in rats and mice after ethanol feeding. This may be related to mitochondrial proteins that regulate apoptosis and necrosis and that are shown to be induced in mouse fatty liver models.

Frequency:

In the US: Approximately 15.3 million people in United States abuse or depend on alcohol. Fatty liver develops in 90-100% of patients with heavy alcohol use.

Internationally: One observational study from northern Italy demonstrated prevalence rates of steatosis in 46.4% of heavy drinkers (>60 g/d of alcohol) and in 94.5% of obese heavy drinkers.

Mortality/Morbidity:

Simple steatosis rarely is fatal. With complete abstinence, histologic changes can return to normal within 2-4 weeks.

Continued alcohol consumption may result in more advanced forms of liver disease, either alcoholic hepatitis or cirrhosis.

Recently, a study from Denmark, which used the Danish National Registry, noted an increase in mortality among patients with a hospital discharge diagnosis of alcoholic fatty liver, which remained increased after censoring patients upon a diagnosis of cirrhosis.

Race: Very little data are available on racial differences in the incidence of alcoholic fatty liver. However, overall differences in alcoholic liver disease have been noted in various studies.

One study of 42,862 US adults showed differences in drinking patterns among different races. Whites were the most likely to drink, but blacks had the highest volume of intake and frequency of heavy drinking.

Another study showed a higher rate of cirrhosis among blacks.

Sex:

Women develop more severe alcoholic liver disease (ALD) more quickly and at lower doses of alcohol than men.

Increased susceptibility of females possibly is related to sex-dependent differences in the hepatic metabolism of alcohol, cytokine production, and the gastric metabolism of alcohol.

Treatment
Medical Care:

No specific medical treatment is needed for patients with alcoholic fatty liver. Steatosis usually resolves within 2 weeks of discontinuing alcohol.

Abstinence and adequate diet are the mainstays in therapy for alcohol-induced steatosis.

Bed rest has no proven benefit.

Anabolic steroids may be detrimental.

Management of patients with alcoholism and fatty liver often requires recognition and treatment of alcohol withdrawal.

These patients may have deficiencies of vitamins, minerals, and trace elements. Adequate replacement of these deficiencies should be a part of management.
Although alcohol-induced hyperhomocysteinemia (which has been associated with endoplasmic reticulum stress leading to apoptosis and up-regulation of lipid synthesis) and its correction by betaine have been studied in animal models, no definite role of the use of betaine in alcoholic fatty liver in humans is available.

Consultations:

Offer alcohol rehabilitation to all patients, with an understanding of the addictive problem of alcoholism.

Counsel patients on the detrimental effects of alcohol on the current liver problem and the likely progression to a more advanced form of liver disease with continued alcohol use.

Diet:

No specific dietary restrictions are needed in patients with simple steatosis.

Protein-calorie malnutrition is a common finding for patients with ALD and is associated with major complications observed with cirrhosis. Consequently, recognizing and understanding the significance of malnutrition in these patients is very important.

Afferent Loop Syndrome

2007-11-20T19:01:00.000-08:00

Background Afferent loop syndrome (ALS) is a purely mechanical complication that infrequently occurs following construction of a gastrojejunostomy. Creation of an anastomosis between the stomach and jejunum leaves a segment of small bowel, most commonly consisting of duodenum and proximal jejunum, lying upstream from the gastrojejunostomy. This limb of intestine conducts bile, pancreatic juices, and other proximal intestinal secretions toward the gastrojejunostomy and is thus termed the afferent loop.

History of the Procedure

The operations most commonly associated with this complication include distal or subtotal gastrectomies for peptic ulcer disease or gastric malignancies with Billroth II reconstructions, pancreaticoduodenectomies, and gastrojejunostomies performed to bypass other foregut pathology. The pathophysiology and signs and symptoms associated with ALS result from partial or complete obstruction of the afferent loop.

ALS is included in the constellation of resectional gastric surgical complications known as the postgastrectomy syndromes. The following syndromes are included:

Early dumping syndrome
Late dumping syndrome
Postvagotomy diarrhea
Chronic gastric atony
Roux stasis syndrome
Small gastric remnant syndrome
Alkaline reflux gastritis
Afferent loop syndrome
Efferent loop syndrome

Patients with ALS may present with an acute, completely obstructed form or with a chronic, partially obstructed form. The syndrome can manifest at any time from the first postoperative day to many years after surgery. The acute form usually occurs in the early postoperative period (1-2 wk), but it has been described to occur 30-40 years after surgery.

In 1942, McNealy first described acute ALS as a cause of early postoperative duodenal stump leakage. Lake is credited with recognizing the chronic form in 1948. Roux and coworkers coined the term afferent loop syndrome in 1950. The first detailed exegesis in the English literature on the etiology, clinical presentation, and treatment of ALS was contributed by Wells and Welbourn in 1951.

Problem

ALS manifests in acute and chronic forms. Acute ALS represents complete obstruction of the afferent loop and is a true surgical emergency. It must be diagnosed and corrected expeditiously. Chronic ALS is associated with partial obstruction. It is not a surgical emergency but does require corrective surgery.

Frequency

In the United States, ALS affects approximately 1% of patients undergoing gastric resection and Billroth II gastrojejunostomies. This figure may be an underestimation because this complication is probably underdiagnosed. Overall, the incidence of this complication decreased dramatically during the final quarter of the 20th century as elective gastric surgery for complications of peptic ulcer disease underwent a logarithmic decline.

Internationally, rates for the development of this complication appear to be similar in other nations.

Mortality/Morbidity: Mortality rates of up to 57% have been reported for acute ALS. Mortality is most frequently associated with a delay in diagnosis that leads to bowel infarction or rupture and peritonitis. Patients in whom a timely diagnosis is made or who present with chronic manifestations of the disease can undergo corrective surgery with acceptably low morbidity and mortality rates.

Sex: According to Tovey et al, one or more of the postgastrectomy syndromes is more likely to occur in female patients.

Age: ALS favors no particular age group on a per capita basis.

Etiology

Postoperative conditions

Each of the following postoperative conditions can cause ALS in a patient with a gastrojejunostomy:

Entrapment or compression of the afferent loop by postoperative adhesions
Internal hernia (eg, through a mesocolic defect)
Volvulus of the intestinal segment
Enteroenteral or enterogastric intussusception
Kinking of the afferent limb at the gastrojejunostom
Scarring due to marginal (stomal) ulceration
Recurrence of cancer at or near the anastomotic site
Enteroliths in the afferent limb
Bezoars in the afferent limb or at the anastomosis
Foreign bodies in the afferent limb or at the anastomosis

Surgical technique

Patients have an increased chance of developing ALS if one or more of the following conditions is met:

The jejunal portion of the afferent limb is longer than 10-15 cm
The gastrojejunostomy is placed in an antecolic position instead of a retrocolic position.
Mesocolic defects are not properly closed after construction of a retrocolic gastrojejunostomy.

Bushkin and Woodward reported an equal incidence of ALS in patients with short, retrocolic afferent limbs. However, according to Eagon and coworkers, most authors opine that longer, redundant, and antecolic afferent limbs are more prone to kinking, volvulus, and entrapment by adhesions.

Pathophysiology

An afferent loop is composed of the duodenal stump, the remainder of the duodenum, and the segment of jejunum located proximal to a Billroth II–type gastrojejunostomy. ALS is caused by complete or partial mechanical obstruction at the gastrojejunostomy or at a point along the jejunal portion of the afferent loop.

Passage of food and gastric secretions through the gastrojejunostomy and into the efferent loop triggers release of secretin and cholecystokinin. These enteric hormones stimulate secretion of bile, pancreatic enzymes, and pancreatic bicarbonate and water into the afferent loop. Under gastrointestinal hormonal influence, up to 1-2 L of pancreatic and biliary secretions can enter the afferent loop each day.

Symptoms associated with ALS are caused by increased intraluminal pressure and distension due to accumulation of enteric secretions in a partially or completely obstructed afferent limb. ALS is one of the main causes of duodenal stump blowout in the early postoperative period and is also an etiology for postoperative obstructive jaundice, ascending cholangitis, and pancreatitis due to transmission of high pressures back to the biliopancreatic ductal system. High luminal pressures and distension increase bowel wall tension in the afferent loop (in accord with the Laplace law) and can lead to ischemia and gangrene with subsequent perforation and peritonitis.

Secondarily, prolonged stasis and pooling of secretions with partial obstruction facilitate bacterial overgrowth in the afferent loop. Bacteria deconjugate bile acids, which can lead to steatorrhea, malnutrition, and vitamin B-12 deficiency. Iron deficiency can occur because of bypassing of the proximal small bowel.

The severity at presentation mainly depends on the degree and duration of obstruction.

Clinical

History

Acute ALS

Acute ALS is caused by complete obstruction of the afferent loop. Patients with acute ALS typically present with a sudden onset of epigastric and/or right or left upper quadrant abdominal pain, with associated nausea and vomiting.

With acute ALS, the vomitus is not bilious because the biliary and pancreatic secretions remain trapped in the obstructed bowel loop. If the afferent loop is not decompressed, the patient becomes acutely ill and can subsequently develop peritonitis and shock if intestinal perforation or infarction ensues.

Chronic ALS

Chronic ALS is caused by partial obstruction of the afferent loop. Approximately 10-20 minutes to an hour postprandially, the patient experiences abdominal fullness and epigastric pain. These symptoms usually last from several minutes to an hour, although they occasionally last as long as several days.

Projectile bilious vomiting is a classic manifestation of ALS with partial obstruction. The distended afferent loop decompresses forcefully, providing rapid relief of symptoms. Note that the vomitus usually contains no food because it has progressed along the unobstructed efferent limb. Vomiting may occur after each meal or only occasionally. Also, symptoms in the immediate postprandial period may be minimized if the patient assumes a recumbent position.

Prolonged chronic ALS with stasis and bacterial overgrowth can be further complicated by steatorrhea, diarrhea, and vitamin B-12 deficiency anemia. These effects are primarily due to bacterial deconjugation of bile salts. The aforementioned factors, in addition to bypassing the duodenum and proximal jejunum, can result in iron deficiency anemia.

Physical

Physical examination can reveal one or more of the following findings:

An ill-defined mass in the right upper abdominal quadrant
Localized midepigastric or right upper abdominal quadrant tenderness
Peritonitis and/or a rigid abdomen if necrosis or perforation of the bowel wall has occurred
Jaundice
Signs of pancreatitis (eg, upper abdominal pain radiating to the flank or back

Differential diagnoses

Abdominal abscess
Abdominal hernias
Acute mesenteric ischemia
Anemia
Bacterial overgrowth syndrome
Benign gastric tumors
Benign neoplasm of the small intestine
Bile duct strictures
Bile duct tumors
Biliary colic
Biliary obstruction
Carcinoma of the ampulla of Vater
Choledochal cysts
Choledocholithiasis
Esophagogastroduodenoscopy
Gastric outlet obstruction
Gastric sarcoma
Gastric ulcers
Gastric volvulus
Gastritis (acute, atrophic, or chronic)
Intestinal perforation
Mesenteric artery ischemia
Mesenteric artery thrombosis
Mesenteric tumors
Omental torsion

Other problems to be considered

Bile reflux gastritis
Pancreatic pseudocyst or cystic tumor
Mesenteric cyst
Mesenteric lymphoid hamartoma
Intra-abdominal abscess
Cystic metastases

Treatment

Medical therapy

Acute ALS

In patients with acute ALS, a favorable outcome is correlated with an expedient diagnosis and corrective surgery. Medical therapy has no role.

Chronic ALS

Patients with chronic ALS can be severely malnourished and anemic. They may benefit from preoperative specialized nutritional support or transfusion before undergoing corrective surgery. However, do not delay surgery if signs and symptoms consistent with complete obstruction develop.

Surgical therapy

The treatment of ALS is surgical. Conservative measures can be temporarily used to resuscitate the patient, but the definitive treatment is corrective surgery. When ALS is caused by recurrent or unresectable malignancies, successful palliation is frequently accomplished using interventional radiologic techniques. Several references are described in the preceding section.

Surgical correction is effected by deconstructing the Billroth II gastrojejunostomy and restoring gastrointestinal continuity with an alternate method. Several procedures have been described, but the 2 predominant operations are Billroth I gastroduodenostomy and Roux-en-Y gastrojejunostomy.

Vettoretto and associates reported a case of afferent loop obstruction caused by an adhesive band following distal gastrectomy and reconstruction for gastric cancer. The authors performed diagnostic laparoscopy and laparoscopic lysis of adhesions, resulting in resolution of the ALS.

Aimoto and colleagues described 2 cases of malignant ALS in patients who had undergone pancreaticoduodenectomy. In both patients, recurrence of pancreatic cancer was found at laparotomy. Bypass procedures were performed in each case to effect palliation.

Consultations: Early consultation with a surgeon is mandatory.

Preoperative details

The patient is properly identified. The patient (or a legal representative) is counseled about the operation and signs the informed consent documents.

Intravenous access is established, and intravenous fluid resuscitation is begun. A nasogastric tube is placed to decompress the stomach, and preoperative antibiotics are administered.

Intraoperative details

Billroth I gastroduodenostomy

This procedure creates a direct anastomosis between the stomach and duodenum. It is the most physiologic procedure and is therefore the operation of choice. Several factors may preclude its use, including previous subtotal gastrectomy or extensive scarring around the duodenum. In these situations, the surgeon may be unable to gain enough mobility on the stomach and duodenum to create an anastomosis without excessive tension.

Roux-en-Y gastrojejunostomy

For a Roux-en-Y gastrojejunostomy, the jejunum is divided several centimeters distal to the ligament of Treitz. The proximal portion of the distal jejunal segment is anastomosed to the stomach. The distal end of the Roux limb is anastomosed to the distal jejunal segment. This jejunojejunostomy is created approximately 40 cm downstream from the gastrojejunostomy in order to minimize the possibility of developing alkaline (bile) reflux gastritis.

Van Stiegmann and Goff described a variant of this operation in which the jejunum is not divided. This is the so-called uncut Roux-en-Y gastrojejunostomy. The procedure was developed to avoid Roux stasis syndrome, which was thought to be caused by interruption of jejunal intestinal pacesetting potentials.

In an uncut Roux procedure, a loop gastrojejunostomy is fashioned. The afferent limb of this loop is occluded—but not divided—by a staple line. A jejunojejunostomy is made between the afferent and efferent jejunal limbs just proximal to the occluding staple line. This operation has not gained wide acceptance, partially because of the problem of dehiscence of the occluding staple line, as reported by Mulholland and colleagues.

Other surgical procedures

The following remedial operations have also been used:

Revision of the gastrojejunostomy
Side-to-side enteroenterostomy
Jejunal segment interposition (between the gastric remnant and duodenum to create a modified Billroth I–type anastomosis)
Resection of the redundant portion of the afferent jejunal loop

Postoperative details

Further inpatient care

Intravenous fluids

Resuscitative and maintenance intravenous fluids are provided postoperatively. These are usually administered as a balanced salt solution (eg, lactated Ringer solution). If the patient has hypochloremic metabolic alkalosis due to nasogastric suctioning or other causes, normal saline can be substituted. Intravenous fluid support is continued until the patient successfully resumes oral intake.

Activity

Early activity, including arising from the bed to a chair and ambulating frequently, is encouraged.

Diet and nutrition

Patients are kept nil per os (NPO) for varying durations depending on the preference of the operating surgeon. Because correction of ALS entails reoperative gastric and small bowel surgery, many surgeons choose to advance patients slowly.

Following nasogastric tube removal, patients can be started on liquids and advanced to a full diet as tolerated. Postgastrectomy diet counseling by a registered dietitian is helpful. Patients may find that they tolerate 5-6 smaller feedings per day better than the traditional 3 meals.

Depending on the patient's preoperative nutritional status, a period of specialized nutritional support might be warranted. This can range from enteral tube feedings to peripheral hyperalimentation to total parenteral nutrition. In addition, multivitamin and iron supplementation may be indicated.

Drains

A nasogastric tube is typically left in place postoperatively. Ensuring that the tube functions continuously and remains unclogged is crucial. Criteria for removal of a nasogastric tube include diminishing output and return of bowel function as manifested by bowel sounds or the passage of flatus.

A Foley catheter remains in place in the early postoperative period to monitor hydration status and to serve as a guide for fluid resuscitation. Once the patient is stabilized and no further major fluid shifts occur, the catheter can be removed.

Pulmonary toilet

Instruct patients to cough and to take frequent deep breaths. The incentive spirometer is an important adjunct and should be used every 1-2 hours while the patient is awake. Early mobilization of the patient assists with maintaining good pulmonary toilet.

Monitoring

Vital signs are monitored per protocol. Intake and output records are kept to monitor intravenous fluids given, oral intake, and urine and nasogastric tube outputs. Pulse oximetry may be used to measure oxygen saturation.

Antibiotics

Unless bowel perforation has occurred, a single dose of antibiotics as prophylaxis against wound infection usually suffices. Patients with abdominal catastrophes, such as bowel perforation or infarction, require a full course of antibiotic therapy aimed at gut flora.

Pain control

An epidural catheter can be placed by anesthesia personnel for postoperative pain control. Alternately, a patient-controlled anesthesia regimen can be ordered.

Deep venous thrombosis prophylaxis

Prophylaxis against deep venous thrombosis is crucial because deep venous thrombosis and pulmonary embolism are significant sources of postoperative morbidity and mortality. Available modalities include subcutaneous heparin, subcutaneous fractionated heparin preparations, and sequential compression stockings.

Aspiration precautions

The head of the bed can be kept elevated at 30-45° or sometimes higher in elderly patients or during sleep.