102 Fulminant Hepatic Failure
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.
Etiology
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
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).
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.
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.
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
King’s College Criteria24
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
Encephalopathy
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.
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