Boerhaave Syndrome

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

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

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.

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• 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).

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  • 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

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

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