102 Fulminant Hepatic Failure

Su Min Cho, Raghavan Murugan, Ali Al-Khafaji

Acute liver failure (ALF), also known as fulminant hepatic failure (FHF), embraces a spectrum of clinical entities characterized by acute liver injury, severe hepatocellular dysfunction, and hepatic encephalopathy. This condition is uncommon but not rare; it affects approximately 2000 to 2800 people annually in the United States, with a mortality of 3.5 per million despite intensive support.¹ Loss of hepatocyte function sets in motion a vicious multiorgan dysfunction syndrome, with ensuing death even when the liver has begun to recover. Complications of FHF include encephalopathy, cerebral edema, sepsis, acute respiratory distress syndrome (ARDS), hypoglycemia, coagulopathy, gastrointestinal bleeding, pancreatitis, and acute renal failure (ARF). Acetaminophen toxicity, idiosyncratic drug reactions, and hepatotropic viruses remain the most common cause of FHF in the United States. FHF accounts for 5% to 6% of liver transplantation, which is currently the only proven and definitive treatment option for patients who are unlikely to recover spontaneously. Unfortunately, many patients die before a suitable organ can be identified. Thus, the dominant medical interventions for acute liver failure in the critical care setting are supportive. Alternative “liver replacement” therapeutic strategies are under clinical investigation.

Definitions

The terms fulminant hepatic failure and acute liver failure are often used interchangeably. FHF is defined as the presence of encephalopathy (regardless of grade) and coagulopathy (international normalized ratio [INR] > 1.5) within 26 weeks of the appearance of symptoms in patients with no previous history of underlying liver disease. Since the original definition of FHF proposed by Trey and Davidson in 1970, several other classifications have emerged (Box 102-1).²^–⁶ In different classifications, the interval between the onset of symptoms or jaundice and the appearance of encephalopathy allows grouping of patients with similar causes, clinical characteristics, and prognosis.

Box 102-1

Classifications of Acute Liver Failure

Trey and Davidson ²

Fulminant hepatic failure: development of HE within 8 weeks of onset of symptoms

Etiology

Viral hepatitis remains the most common identifiable cause of FHF in the developing world, whereas acetaminophen toxicity and idiosyncratic drug reactions have replaced viral hepatitis as the most frequent apparent causes of FHF in the United States and Europe. Both prognosis and management are determined in part by the underlying etiology of FHF.

Acetaminophen Toxicity

Acetaminophen overdose is now the leading cause of FHF in the United States and accounts for 40% to 50% of cases. This type of liver injury occurs both after attempted suicide by acetaminophen overdose and after unintentional “therapeutic misadventures” caused by use of the drug for pain relief in excess of the dose specified in the package labeling, typically over a period of several days.⁷ A careful medical history clarifies the quantity ingested; blood levels can be confirmatory but may not be elevated in cases of unintentional overdose. Doses considered nontoxic (<4 g/day in adults, <8 mg/kg in infants) might cause hepatotoxicity if other concurrent factors exist, such as alcohol ingestion, fasting, or malnutrition. Hepatotoxicity usually develops 1 to 2 days after the overdose, and circulating alanine aminotransferase (ALT) levels and INR values reach their peak around day 3. A continued increase of INR after day 3 is associated with a 90% mortality rate. Acetaminophen is also nephrotoxic, and renal failure may occur in the absence of liver necrosis.

Acetaminophen undergoes phase 1 metabolism by hepatic cytochrome P₄₅₀ 2E1 (CYP2E1) enzymes to a toxic intermediate compound, N-acetyl-p-benzoquinone imine (NAPQI), which is rapidly detoxified by hepatic glutathione into a nontoxic metabolite. Under normal conditions, little NAPQI accumulates. However, in an overdose, owing to depletion of glutathione stores, unconjugated NAPQI accumulates and causes hepatocellular necrosis. The amount of liver injury is directly related to the amount of ingested acetaminophen and the amount of NAPQI produced. In a recent study, the dose of acetaminophen ingested did not correlate with the overall prognosis.⁸ Enzyme inducers such as alcohol, antiepileptic drugs, and cigarette smoke can enhance acetaminophen-mediated hepatotoxicity. Chronic alcohol consumption induces synthesis of CYP2E1 enzymes and, to a lesser extent, depletes glutathione stores. Substrate competition for CYP2E1 occurs between ethanol and acetaminophen when the two drugs are taken simultaneously. During the metabolism of acetaminophen, NAPQI formation is diminished when alcohol is present. The rate at which CYP2E1 degrades is also slowed, and the half-life of the enzyme increases from 7 hours to 37 hours. As long as ethanol remains in the body, there is competition between acetaminophen and ethanol for CYP2E1; however, once ethanol is removed, NAPQI formation is enhanced, resulting in enhanced hepatic injury in the 24 hours after cessation of alcohol consumption. Genetic variability within the population affecting expression of the cytokine, tumor necrosis factor alpha (TNF-α), also has been implicated as a determining factor in the severity of drug reactions related to acetaminophen.⁹

Idiosyncratic Drug Reactions

Drug-induced liver damage is a significant cause of death in patients with FHF in Western countries (Box 102-2). The most common implicated drugs are antibiotics, central nervous system (CNS) agents, herbal/dietary supplements, and immunomodulatory agents.¹⁰ Hepatocellular injury is common in younger patients, whereas a cholestatic picture is more common in the elderly. Dose, duration, and the hepatic metabolism of the drug all may play a role in the development of drug-induced liver injury.

Box 102-2

Etiologic Classification of Acute Liver Failure

Acetaminophen Toxicity

Toxins

CCL₄

Amanita phalloides

Yellow phosphorus

Herbal products

Vascular

Ischemic

Veno-occlusive disease

Budd-Chiari syndrome

Malignant infiltration

Non-Hodgkin’s lymphomas

Miscellaneous

Wilson’s disease

Autoimmune hepatitis

Acute fatty liver of pregnancy

Reye syndrome

Most idiosyncratic drug reactions are due to single agent, but multiple medications are implicated in some patients. Women generally predominate among patients with idiosyncratic drug-induced liver injury. Other risk factors for drug-induced hepatotoxicity include extremes of age, abnormal renal function, obesity, preexisting liver disease, and concurrent use of other hepatotoxic drugs. Idiosyncratic drug toxicities are immunologically mediated by the drug itself or its metabolites. Most idiosyncratic reactions occur within 4 to 6 weeks after initiation of treatment, although rare cases have occurred months or years later.

Idiosyncratic hepatic injury is mediated by several mechanisms, including disruption of intracellular calcium homeostasis, injury to canalicular transport pumps, such as multidrug resistance–associated protein 3 (MRP3), T cell–mediated immunologic injury, triggering of apoptotic pathways by TNF-α, and inhibition of mitochondrial beta oxidation.¹¹ Isoniazid, pyrazinamide, antimicrobials (amoxicillin-clavulanate, tetracyclines, and macrolides), anticonvulsants, antidepressants, nonsteroidal antiinflammatory drugs (NSAIDs), and halothane are most frequently implicated in FHF. There is an association between certain HLA genotypes (e.g., B*5701) and the risk of flucloxacillin-induced liver injury.¹² Two histologic patterns are usually distinguished, one being characterized by confluent necrosis (isoniazid or halothane) and the other by hepatocyte microvesicular fatty change (valproic acid or tetracyclines). Reemergence of tuberculosis—a public health problem in the past decade—has increased the frequency of FHF caused by isoniazid. Concurrent treatment with rifampicin and pyrazinamide may increase the risk of isoniazid toxicity.

Hepatotoxic herbal medicines (kava kava, St. John’s wort) and certain dietary supplements are emerging as potential causes in a high proportion of patients with FHF. Mushroom poisoning due to Amanita phalloides is relatively common in Europe, and more sporadic cases occur in the United States. Florid muscarinic effects such as sweating or watery diarrhea occur early, whereas FHF usually occurs 4 to 8 days after mushroom ingestion. Other toxins (e.g., carbon tetrachloride, yellow phosphorus, aflatoxins) are rare causes of FHF. Liver biopsy is seldom helpful for establishing the diagnosis. Treatment with N-acetylcysteine (NAC) has been shown to improve transplant-free survival compared to placebo and should be used in drug-induced liver injury, even if not related to acetaminophen.¹³

Viral Hepatitides

Whereas viral hepatitides remain the most common identifiable cause of FHF worldwide, considerable geographic variation exists in the subtype of hepatitides. Thus, hepatitis B virus (HBV) is a common cause of FHF in the Far East, and hepatitis E virus (HEV) is more prevalent in the Indian subcontinent.¹⁴ In the United States, approximately 12% of FHF referred for liver transplants are due to hepatitis A and B. Occurrence of FHF within the larger number of patients with viral hepatitis, however, is rare (0.2%-0.4% for hepatitis A, 1%-4% for hepatitis B).

Hepatitis A virus (HAV) is associated with a higher risk of developing FHF if infection is acquired in older adulthood. Thus, vaccination is recommended for adults traveling from developed countries to endemic areas. The relevance of HAV as a cause of FHF in patients with preexisting chronic liver disease has been recognized recently. HAV vaccination in this high-risk group has been suggested. Postexposure prophylaxis with immune serum globulin may reduce the incidence of hepatitis A, but only when administered within 14 days of exposure.

HBV can result in FHF through several mechanisms: acute primary HBV infections, reactivation of hepatitis B in patients with chronic HBV, or superinfection with hepatitis D virus. Acute HBV infection is diagnosed by the detection of immunoglobulin M (IgM) antibodies against hepatitis B core antigen (HbcAg), because a substantial number of patients have negative serum hepatitis B surface antigen (HBsAg) and serum HBV-DNA. Low or absent levels of HBsAg and HBV-DNA are associated with better prognosis and lower rate of recurrence after orthotopic liver transplantation (OLT). FHF after reactivation of chronic hepatitis B has been described mainly in immunosuppressed male patients; this form of the disease usually has a subfulminant course and a poor prognosis.

Most studies indicate that hepatitis C virus (HCV) infection alone does not result in FHF. However, isolated cases of HCV-RNA in serum or tissue of patients with FHF and negative markers for other viruses have been noted in Western countries.¹⁵ Involvement of HCV in FHF is slightly more common in the Far East.¹⁶ An increased risk of FHF in patients with chronic hepatitis B and superinfection by HCV has been suggested.

FHF is seen in 2.5% to 6% of hepatitis D virus cases. Coinfection with HBV and hepatitis D virus (HDV) or superinfection by HDV in patients with chronic hepatitis B also can cause FHF. The incidence of coinfection is higher when intravenous (IV) drug abuse is present. Diagnosis of acute infection by HDV is made by the presence of HDV antigen, anti-HDV IgM antibody, or HDV-RNA.

Infection by hepatitis E virus (HEV) is uncommon in Western countries but occurs in travelers to endemic areas. Pregnant women infected by HEV seem to have a special propensity for developing FHF. Diagnosis is made by detection of anti-HEV IgM antibodies.

Other viruses have been implicated in the pathogenesis of FHF of indeterminate etiology. These viruses include cytomegalovirus (CMV), human herpesvirus-6 (HHV-6),^17,¹⁸ Epstein-Barr virus (EBV), hepatitis G virus (HGV),¹⁹ herpes simplex virus (HSV),^20,²¹ varicella-zoster virus (VZV), parvovirus B19 in children, and togavirus, adenovirus, paramyxovirus, yellow fever, Q fever, and most recently, SEN virus and TT virus.²² Although these causes are rare, they must be excluded, because some patients may benefit from specific antiviral therapy.

Miscellaneous cardiovascular, metabolic, and other disorders account for 2% to 10% of cases of FHF. Acute liver ischemia secondary to shock states can result in hepatocellular necrosis; however, the prognosis remains good if the primary condition can be corrected. The prognosis is worse when FHF is due to other causes such as Budd-Chiari syndrome, veno-occlusive disease, or malignancies associated with impaired hepatic blood flow. Rarely, the first manifestation of Wilson’s disease is FHF, which sometimes occurs in patients without evidence of chronic liver disease. Death is universal without OLT. Acute fatty liver of pregnancy is rare, occurring in the third trimester of pregnancy, and usually responds well to fetal delivery. Other causes of FHF are autoimmune hepatitis, non-Hodgkin’s lymphoma, or Reye syndrome, the last being less common in the pediatric population since aspirin use has been curtailed.

Prognostic Scoring Systems

Survival in patients with FHF depends on many factors, including etiology, age, severity of liver dysfunction, degree of liver necrosis, nature of complications, and duration of illness. Patients with grade IV encephalopathy have a higher than 80% mortality without OLT. The successful use of OLT in FHF has created a need for early prognostic indicators to select patients most likely to benefit from OLT. Various prognostic scoring systems exist (Box 102-3), However, many of these are subject to debate because of bias and equating death with liver transplant, which falsely elevates the positive predictive value of any prognostication method.²³

Box 102-3

Various Prognostic Criteria Used for Liver Transplantation in Patients with Fulminant Hepatic Failure

Cliché Criteria ²⁶

• Factor V < 20% in person < 30 years or both of the following:

Factor V < 30% in patients > 30 years

Grade III or IV encephalopathy

Serum Gc Globulin Levels ^27,²⁸

Decreasing Gc levels due to dying hepatocytes

Serum α-Fetoprotein Level

Serial increase from day 1 to day 3 has shown correlation with survival

Liver Biopsy ³²

70% necrosis is discriminant of 90% mortality

Gc, plasma group-specific component protein; INR, international normalized ratio; PT, prothrombin time.

For patients with acetaminophen overdose, HAV infection, shock liver, or pregnancy-related acute liver failure, the short-term survival without transplantation is over 50%. Short-term transplant-free survival is lower (<25%) for patients with FHF of indeterminate cause or FHF caused by these factors: drugs other than acetaminophen, HBV infection, autoimmune hepatitis, Wilson’s disease, Budd-Chiari syndrome, or cancer. The King’s College prognostic criteria are the most widely used. These criteria provide a reasonable prediction of the likelihood of death and the need for transplantation in FHF patients.²⁴ The criteria are different for acetaminophen and non–acetaminophen-induced FHF (see Box 102-3), and experts have criticized the King’s College criteria on the basis of low sensitivity and negative predictive value, especially for causes of FHF other than acetaminophen poisoning.

The APACHE II system has been found to be equal to King’s College criteria for accuracy in predicting death in acetaminophen-induced FHF.²⁵ Other approaches include the Cliché criteria,²⁶ which use factor V assay, factor VIII/V ratio, serial α-fetoprotein levels, and plasma group-specific component protein (Gc globulin) levels.^27,²⁸ Liver volume decreases with progression of the disease, and its measurement with computed tomography (CT) may help assess prognosis. Other proposed prognostic tools include the proportion of necrosis as assessed by histologic examination of specimens obtained by liver biopsy, amount of fresh frozen plasma (FFP) required to correct coagulopathy, or determination of somatosensory evoked potentials. Other proposed markers for poor prognosis include serum levels of phosphate above 1.2 mmol/L on day 2 or 3, blood lactate concentration over 3.0 mmol/L, or Model for End-stage Liver Disease (MELD) score higher than 32.²⁹^–³¹

Role of Liver Biopsy

Liver biopsy can confirm the suspected cause of FHF and determine the degree of hepatocyte necrosis. Greater than 70% necrosis in a liver biopsy specimen is associated with 90% mortality without transplantation.^31,³² Because severe coagulopathy precludes safe percutaneous liver biopsy, the transjugular approach is often preferred. Although a liver biopsy is not mandatory, it can be valuable for determining prognosis, ruling out the presence of cirrhosis, and making the decision for early transplantation. Liver biopsy can help exclude occult malignancy in enigmatic cases and also can be used to assess the liver for evidence of regeneration, as manifested by the presence of liver cell mitosis. In rare cases, the liver biopsy can provide etiologic information that enables specific therapy to be instituted, as in the cases of HSV, CMV, adenovirus, and paramyxovirus hepatitis infections. Because of the variable nature of liver biopsies in patients with FHF, a minimum of three, and ideally six, specimens of the hepatic parenchyma should be obtained for histologic evaluation. In addition, if Wilson’s disease or hepatic iron toxicity is a possible diagnosis, a separate core of liver tissue should be obtained for quantitative hepatic iron and copper determinations.

Pathogenesis and Clinical Features of Acute Liver Failure

FHF has a particular constellation of clinical features that are distinct from those seen with chronic hepatic insufficiency, regardless of the etiology. Typically, nonspecific symptoms such as malaise or nausea develop in a previously healthy person, followed by jaundice, rapid onset of altered mental status, and coma. Altered mentation and a prolonged INR are the hallmarks of the diagnosis. Supportive laboratory findings include high levels of ALT, a variable elevation of serum total bilirubin concentration, low serum glucose levels, and arterial blood gas studies showing respiratory alkalosis and/or metabolic acidosis. Patients with subfulminant hepatic failure (SFHF) have a more gradual onset of hepatic insufficiency accompanied by ascites, renal failure, and a very poor prognosis. Cerebral edema is infrequent in such patients. The magnitude of elevation of aminotransferase levels and rate of decline does not affect the prognosis. When patients spontaneously recover, the serum bilirubin concentration and INR normalize, whereas when the disease progresses, bilirubin levels continue to increase (due to intrahepatic cholestasis), and INR remains prolonged despite declining ALT levels. The high mortality rates associated with FHF are caused by complications such as cerebral edema, renal failure, sepsis, pancreatitis, and cardiopulmonary collapse, which results in multisystem organ failure.

Encephalopathy

The presence of encephalopathy is the essential clinical feature that differentiates FHF from acute severe hepatitis, and the time to onset after the appearance of jaundice distinguishes FHF from SFHF. The onset of encephalopathy is often abrupt and occasionally may precede the appearance of jaundice. Agitation, delusional ideas, and hyperkinesis are common but short-lived symptoms; coma rapidly ensues. The overall prognosis for those with stable grade I or II encephalopathy is good, whereas the prognosis for patients with grade III or IV encephalopathy is much poorer. In cases of acetaminophen overdose, encephalopathy usually occurs on the third or fourth day after ingestion and rapidly progresses to grade IV within 24 to 48 hours.

The pathophysiology of hepatic encephalopathy is poorly understood and is probably multifactorial. Ammonia buildup in the brain is believed to be the main offender.³³^–³⁵ Elevated serum ammonia concentration is exacerbated by decreased urea synthesis in the injured liver.³⁶ Endogenous substances, false neurotransmitters, short-chain fatty acids, benzodiazepines, and γ-aminobutyric acid are additional factors that lead to encephalopathy. The electroencephalogram (EEG) typically shows diffuse slowing of cortical activity and high-amplitude waveforms at 5 to 7 cycles per second. Subclinical seizure activity is often present in patients with grade III and IV encephalopathy, emphasizing the importance of EEG monitoring in these patients. Prophylactic therapy with phenytoin has been shown to reduce seizure activity and reduce cerebral edema.³⁷ Seizure activity in FHF has been linked to excessive CNS glutamine, the main excitatory neurotransmitter in the brain. Newly synthesized glutamine is transported from the cytoplasm into mitochondria and is metabolized by glutaminase, yielding glutamate and ammonia. The generation of ammonia in the small mitochondrial compartment may reach extremely high levels, leading to induction of the mitochondrial permeability transition (MPT), production of free radicals, and potentially to oxidative damage of mitochondrial constituents. Thus, glutamine acts like a “Trojan horse,” serving as a carrier of ammonia into mitochondria.³⁸ The glutamine-derived ammonia within mitochondria leads to astrocyte dysfunction, including cell swelling.

< div class='tao-gold-member'>

Only gold members can continue reading. Log In or Register to continue