ALF is a broad term and encompasses both fulminant hepatic failure (FHF) and subfulminant hepatic failure (or late-onset hepatic failure). FHF is generally used to describe the development of encephalopathy within 8 weeks of the onset of symptoms in a patient with a previously healthy liver. Subfulminant hepatic failure is reserved for patients with liver disease for up to 26 weeks prior to the development of hepatic encephalopathy. Some patients with previously unrecognized chronic liver disease decompensate and present with liver failure; although, this is not technically FHF, discriminating this at the time of presentation may not be possible. Patients with Wilson disease, vertically acquired hepatitis B virus (HBV), or autoimmune hepatitis may be included in spite of the possibility of cirrhosis if their disease has been less than 26 weeks.
Drug-related hepatotoxicity is the leading cause of ALF in the United States. The outcome of ALF is related to the etiology, the degree of encephalopathy, and related complications. Unfortunately, despite aggressive treatment, many patients die from FHF. Prior to orthotopic liver transplantation (OLT) for FHF, the mortality rate was generally greater than 80%. Approximately 6% of OLTs performed in the United States are for FHF. However, with improved intensive care, the prognosis is much better now than in the past, with some series reporting approximately a survival rate of 60%.
The development of liver support systems provides some promise for this particular circumstance, although it remains a temporary measure and, to date, has no impact on survival. Other investigational therapeutic modalities, including hypothermia, have been proposed but remain unproven.
Pathophysiology: The development of cerebral edema distinguishes FHF from portosystemic encephalopathy, although certain mechanisms appear to be common to both clinical entities. Briefly, hyperammonemia may be involved in the development of cerebral edema. Another consequence of FHF is multisystem organ failure, which often is observed in the context of a hyperdynamic circulatory state that mimics sepsis (low systemic vascular resistance); therefore, circulatory insufficiency and poor organ perfusion possibly either initiate or promote complications of FHF.
Many hemodynamic features of FHF may be mediated by elevated systemic concentrations of nitric oxide, which acts as a potent vasodilator. However, in this setting, cytokine profiles are deranged, and a distinct possibility exists that neurohumoral effects mediate extrahepatic organ dysfunction, with the circulatory manifestations simply representing epiphenomena. Elevated serum concentrations of bacterial endotoxin, tumor necrosis factor-a, and interleukin-1 and interleukin-6 have been found in FHF, but the specific roles of these inflammatory mediators are unclear.
The development of liver failure represents the final common outcome of a wide variety of potential causes, as the broad differential diagnosis suggests. A complete discussion is beyond the scope of this article, and the reader is directed to consult the literature dealing specifically with these underlying etiologic factors. However, mechanisms of acetaminophen hepatotoxicity are worth discussing briefly.
As with many drugs that undergo hepatic metabolism (in this case, by cytochrome P-450), the oxidative metabolite of acetaminophen is more toxic than the drug. An active metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), appears to mediate much of the damage to liver tissue by forming covalent bonds with cellular proteins. Therefore, the presence of highly reactive free radicals following acetaminophen ingestion poses a threat to the liver parenchyma, but it usually is addressed adequately by intrahepatic glutathione reserves. The reduced glutathione quenches the reactive metabolites and acts to prevent nonspecific oxidation of cellular structures that may result in severe hepatocellular dysfunction.
This mechanism fails in 2 different yet equally important settings. The first is an overdose (accidental or intentional) of acetaminophen. This simply overwhelms the hepatic stores of glutathione, allowing reactive metabolites to escape. The second and less obvious scenario occurs with a patient who consumes alcohol regularly. This does not necessarily require a history of alcohol abuse or alcoholism. Even a moderate or social drinker who consistently consumes 1-2 drinks daily may sufficiently deplete intrahepatic glutathione reserves. This results in potentially lethal hepatotoxicity from what is otherwise a safe dose of acetaminophen (below the maximum total dose of 4 g/d) in an unsuspecting individual.
Frequency:
- In the US: Incidence of FHF appears to be low, with approximately 2000 cases annually occurring in the United States. Drug-related hepatotoxicity comprises more than 50% of ALF cases, including acetaminophen toxicity (42%) and idiosyncratic drug reactions (12%). Nearly 15% of cases remain of indeterminate etiology. Other causes seen in the United States are HBV, autoimmune hepatitis, Wilson disease, fatty liver of pregnancy, and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome.
- Internationally: Acetaminophen or paracetamol overdoses are prominent causes of FHF in Europe and, in particular, Great Britain. In the developing world, acute HBV infection dominates as a cause of FHF because of the high prevalence of HBV. Hepatitis delta virus (HDV) superinfection is much more common in developing countries than in the United States because of the high rate of chronic HBV infection. Hepatitis E virus (HEV) is associated with a high incidence of FHF in women who are pregnant and is of concern in pregnant patients living in or traveling through endemic areas. These regions include, but are not limited to, Mexico and Central America, India and the subcontinent, and the Middle East.
Mortality/Morbidity: Several factors contribute to morbidity and mortality. The etiologic factor leading to hepatic failure and the development of complications is key. In general, the best prognoses occur in the absence of complications. Cerebral edema, renal failure, adult respiratory distress syndrome, bleeding, and sepsis pose challenges that reduce the probability of survival.
- Viral hepatitis: In patients with FHF due to hepatitis A virus (HAV), survival rates are greater than 50-60%. These patients account for a substantial proportion (10-20%) of the pediatric liver transplants in some countries despite the relatively mild infection that is observed in many children infected with HAV. The outcome for patients with FHF as the result of other causes of viral hepatitis is much less favorable.
- Acetaminophen toxicity: FHF due to acetaminophen toxicity generally has a relatively favorable outcome, and prognostic variables permit reasonable accuracy in determining the need for OLT. Patients presenting with deep coma (hepatic encephalopathy grades 3-4) on admission have increased mortality compared to patients with milder encephalopathy. An arterial pH of lower than 7.3 and either a prothrombin time (PT) greater than 100 seconds or serum creatinine greater than 300 mcg/mL (3.4 mg/dL) are independent predictors of poor prognosis.
- Non-acetaminophen-induced FHF: In non-acetaminophen-induced FHF, a PT of greater than 100 seconds and any 3 of the following 5 criteria are independent predictors: (1) age younger than 10 years or older than 40 years, (2) FHF due to non-A, non-B, non-C hepatitis, halothane hepatitis, or idiosyncratic drug reactions, (3) jaundice present more than 1 week before onset of encephalopathy, (4) PT greater than 50 seconds, and (5) serum bilirubin greater than 300 mmol/L (17.5 mg/dL). Once these patients are identified, arrange appropriate preparations for OLT. These criteria were developed at King's College Hospital in London and have been validated in other centers; however, significant variability occurs in terms of the patient populations encountered at any center, and this heterogeneity may preclude widespread applicability. Many other prognosticating tests are proposed. Reduced levels of group-specific component (Gc)-globulin (a molecule that binds actin) are reported in FHF, and a persistently increasing PT portends death. These and other parameters are not validated widely yet.
- Wilson disease: When presenting as FHF without OLT, it is almost uniformly fatal.
- Age: Patients younger than 10 years and older than 40 years tend to fare relatively poorly.
- Rate of development and degree of encephalopathy: A short time from jaundice (usually the first unequivocal sign of liver disease recognized by the patient or family) to encephalopathy is associated paradoxically with improved survival. When this interval is less than 2 weeks, patients have hyperacute liver failure. Although the grade of encephalopathy is a prognostic factor in cases of acetaminophen overdose, it does not correlate with outcome in other settings.
Race: ALF is seen among all races. In the US multicenter study of ALF, the ethnic distribution included whites (74%), Hispanics (10%), African Americans (3%), Asians (5%), and Latin Americans (2%).
Sex: Viral hepatitis E and autoimmune liver disease are more common in women than in men. In the US multicenter study group, ALF was seen more often in women (73%) than in men.
Treatment
Medical Care: The most important step is to identify the cause of liver failure. Prognosis of ALF is dependent on etiology. A few etiologies of ALF demand immediate and specific treatment. It is also critical to identify those patients who will be candidates for liver transplant.
The most important aspect of treatment is to provide good intensive care support. Patients with grade II encephalopathy should be transferred to ICU for monitoring. As the patient develops progressive encephalopathy, protection of the airway is important. Most patients with ALF tend to develop some degree of circulatory dysfunction. Careful attention should be paid to fluid management, hemodynamics, metabolic parameters, and surveillance of infection. Maintenance of nutrition and prompt recognition of gastrointestinal bleeding are crucial. Coagulation parameters, complete blood count, and metabolic panel should be checked frequently. Serum aminotransferases and bilirubin are generally measured daily to follow the course of infection. Intensive care management includes recognition and management of complications.
- Airway protection
- As the patients with FHF drift deeper into coma, their ability to protect their airway from aspiration decreases. Patients who are in stage III coma should have a nasogastric tube for stomach decompression. When patients progress to stage III coma, the intubation should be performed.
- Short-acting benzodiazepines in low doses (eg, midazolam 2-3 mg) may be used prior to intubation or propofol (50 mcg/kg/min) may be initiated before intubation and continued as an infusion. It is also known to decrease the cerebral blood flow and intracranial hypertension. It may be advisable to use endotracheal lidocaine prior to endotracheal suctioning.
- Encephalopathy and cerebral edema
- Patients with grade I encephalopathy may sometimes be safely managed on a medicine ward. Frequent mental status checks should be performed with transfer to an ICU warranted with progression to grade II encephalopathy.
- Head imaging with computerized tomography (CT) is used to exclude other causes of decline in mental status, such as intracranial hemorrhage.
- Sedation should be avoided if possible; unmanageable agitation may be treated with short-acting benzodiazepines in low doses.
- Patients should be positioned with the head elevated at 30°.
- Efforts should be made to avoid patient stimulation. Maneuvers that cause straining or, in particular, Valsalva-like movements may increase ICP.
- There is increasing evidence that ammonia may play a pathogenic role in the development of cerebral edema. Reducing elevated ammonia levels with enteral administration of lactulose might help prevent or treat cerebral edema.
- ICP monitoring helps in the early recognition of cerebral edema. The clinical signs of elevated ICP, including hypertension, bradycardia, and irregular respirations (Cushing triad), are not uniformly present; these and other neurological changes, such as pupillary dilatation or signs of decerebration, are typically evident only late in the course.
- CT of the brain does not reliably demonstrate evidence of edema, especially at early stages. A primary purpose of ICP monitoring is to detect elevations in ICP and reductions in cerebral perfusion pressure (CPP; calculated as mean arterial pressure minus ICP) so that interventions can be made to prevent herniation while preserving brain perfusion.
- The ultimate goal of such measures is to maintain neurological integrity and prolong survival while awaiting receipt of a donor organ or recovery of sufficient functioning hepatocyte mass. Additionally, refractory ICH and/or decreased CPP is considered a contraindication to liver transplantation in many centers.
- Cardiovascular monitoring
- Homodynamic derangements consistent with multiple organ failure occur in ALF. Hypotension (systolic, <80>
- A Swan–Ganz catheter should be placed and fluid replacement with colloid albumin should be guided by filling pressure. If needed, dopamine or norepinephrine can be used to correct hypotension.
- Management of renal failure: Hemodialysis may significantly lower the mean arterial pressure such that cerebral perfusion pressure is compromised. Continuous veno-venous hemofiltration is preferred.
- Management of coagulopathy
- In the absence of bleeding, it is not necessary to correct clotting abnormalities with fresh frozen plasma (FFP); the exception is when an invasive procedure is planned or with profound coagulopathy (INR >7). (PT and PTT become prolonged when plasma coagulation components are diluted to less than 30%, and abnormal bleeding occurs when they are less than 17%. One unit of FFP increases the coagulation factor by 5%; 2 units increases it by 10%.) FFP of 15 mL/kg of body weight or 4 units correct deficiency. If fibrinogen is very low (<80>
- Recombinant factor VII A may be used in patients nonresponsive to FFP. It is used in a dose of 4 µg/kg IV push over 2-5 minutes. PT is normalized in 20 minutes and remains normalized for 3-4 hours.
- Platelet transfusions are not used until the count is less than 10,000/µL or if an invasive procedure is being done and the platelet count is less than 50,000/µL. Six to 8 random donor platelets (1 random donor unit platelet/10 kg) will increase the platelet count to greater than 50,000/µL. The platelet count should be checked after 1 hour and 24 hours. Transfused platelets survive 3-5 days.
- Managing poisonings (eg, acetaminophen, mushroom) requires specific treatment distinct from other, more general issues related to FHF.
Treat acetaminophen (paracetamol, APAP) overdose with NAC. Researchers theorize that this antidote works by a number of protective mechanisms. Early after overdose, NAC prevents the formation and accumulation of NAPQI, a free radical that binds to intracellular proteins, nonspecifically resulting in toxicity.- NAC increases glutathione stores, combines directly with NAPQI as a glutathione substitute, and enhances sulfate conjugation. NAC also functions as an anti-inflammatory and antioxidant and has positive inotropic and vasodilating effects, which improve microcirculatory blood flow and oxygen delivery to tissues. These latter effects decrease morbidity and mortality once hepatotoxicity is well established.
- The protective effect of NAC is greatest when administered within 8 hours of ingestion; however, when indicated, administer regardless of the time since overdose. Therapy with NAC has been shown to decrease mortality in late-presenting patients with FHF (in the absence of acetaminophen in the serum).
- A phalloides mushroom intoxication is much more common in Europe as well as in California. Treat with intravenous penicillin G, even though its mode of action is unclear. Silibinin, a water-soluble derivative of silymarin, may be administered orally, and oral charcoal may be helpful by binding the mushroom toxin.
Surgical Care: Liver transplantation is the definitive treatment, but a detailed discussion is beyond the scope of this article. Preoperative management is emphasized here.
- In selected patients for whom no allograft is immediately available, consider support with a bioartificial liver. This is a short-term measure that only leads to survival if the liver spontaneously recovers or is replaced.
- In the future, hepatocyte transplantation may provide long-term support, but it remains investigational. It has shown dramatic results in animal models of ALF.
- Artificial liver support systems
- Artificial liver support systems can be divided into 2 major categories: biologic (bioartificial) and nonbiologic.
- The bioartificial liver is composed of a dialysis cartridge with mammalian or porcine hepatocytes filling the extra capillary spaces. These devices have undergone controlled trials. One recent multicenter trial did report improved short-term survival for a subgroup of patients with ALF who were treated with a porcine hepatocyte based artificial liver.
- Nonbiologic extracorporeal liver support systems, such as hemodialysis, hemofiltration, charcoal hemoperfusion, plasmapheresis, and exchange transfusions, have been used; however, no controlled study has shown long-term benefit.
- These modalities permit temporary liver support until a suitable donor liver is found. Although extracorporeal hemoperfusion of charcoal and other inert substances provide some measure of excretory function, no synthetic capacity is provided.
- Among the liver support systems currently available, albumin dialysis using the molecular adsorbent recirculating system (MARS) is the one that has been most extensively investigated. In this device, blood is dialyzed across an albumin-impregnated membrane against 20% albumin. Charcoal and anion exchange resins columns in the circuit cleanse and regenerate the albumin dialysate. Clinical studies have shown that it improves hyperbilirubinemia and encephalopathy.
- Two other systems based on the removal of albumin bound toxins, the Prometheus using the principle of fractionated plasma separation and adsorption (FPSA) and the single pass albumin dialysis (SPAD), are also undergoing clinical studies for ALF.
- Currently available liver support systems are not routinely recommended outside of clinical trials.
Consultations: Managing FHF is a team effort. Consultations in the areas of intensive care, gastroenterology, infectious diseases, hematology, neurology, neurosurgery, and transplantation surgery may be needed to address the myriad complex issues that can confront the medical staff.
Diet:
- Patients are, by necessity, nothing by mouth (NPO). They may require large amounts of intravenous glucose to avoid hypoglycemia.
- When enteral feeding via a feeding tube is not feasible (eg, as in a patient with paralytic ileus), institute total parenteral nutrition (TPN).
- stricting protein (amino acids) to 0.6 g/kg body weight per day was previously routine in the setting of hepatic encephalopathy, but this may not be necessary.
Medication
Multiple medications may be necessary because of the wide variety of complications that may develop from FHF. Decreased hepatic metabolism and potential for hepatotoxicity become central issues. Antidotes that effectively bind or eliminate A phalloides toxin and toxic metabolites of acetaminophen are essential.
| Drug Name | Penicillin G (Pfizerpen) -- First DOC. Treatment of Amanita poisoning is with IV penicillin G, although mode of action is unclear. |
|---|---|
| Adult Dose | 1 mg/kg/d or 1.8 million U/kg/d IV |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Probenecid can increase effects; tetracycline can decrease effects |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in impaired renal function |
| Drug Name | Silibinin (Silibinin Plus) -- Water-soluble derivative of silymarin, which is active ingredient in herbal preparation milk thistle. Possesses antioxidant properties that may benefit liver disease management. |
|---|---|
| Adult Dose | 20-50 mg/kg/d PO |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Alcohol decreases effect |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Continued alcohol ingestion may damage liver |
| Drug Name | Activated charcoal (Actidose-Aqua, Liqui-Char, CharcoAid) -- If ingestion has been recent, Amanita toxin may be bound to charcoal and absorption prevented. |
|---|---|
| Adult Dose | 50 g PO or NG tube |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalies; do not use with sorbitol in fructose intolerance; sorbitol not recommended in children aged <1> |
| Interactions | May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases adsorptive properties of activated charcoal) |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Activated charcoal not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before administering activated charcoal; after emesis with ipecac syrup, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black |
| Drug Name | N-acetylcysteine (Mucomyst, Mucosil) -- First DOC. Provides reducing equivalents to help restore depleted intrahepatic glutathione levels. Not available in IV form in US. |
|---|---|
| Adult Dose | Loading dose: 140 mg/kg PO Maintenance: 70 mg/kg PO q4h, beginning 4 h after loading, for a total of 17 maintenance doses If dose is vomited within 1 h of administration, readminister |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Studies are inconclusive regarding administration with charcoal |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Possible GI distress |
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