Acute Liver Failure
September 1st, 2008Dr. D.S. Merchant is a Gold Medalist in (Anatomy & Histology), Fellow Nephrology in Pakistan. For more information on Acute Liver Failure or visit www.explorearticle.com is a popular website that offers information on liver disease and liver treatment.
• Acute liver failure (ALF), also known as fulminant hepatic failure, is a rare manifestation of liver disease and constitutes a medical emergency.
• The syndrome arises from loss of hepatic parenchyma that may result from a variety of insults to the liver.
• Despite advances in medical management and the availability of liver transplantation, mortality rates in patients with ALF remain substantial. It has been estimated that in the United States, 2000 deaths a year are attributable to ALF.
Definition:
• ALF has been defined by three criteria: (1) rapid development of hepatocellular dysfunction (e.g., jaundice, coagulopathy), (2) encephalopathy, and (3) absence of a prior history of liver disease
• ALF originally was defined by an interval between the onset of illness and appearance of encephalopathy of 8 weeks or less,but there is marked heterogeneity among affected patients with respect to the temporal progression of disease.
Definition:
• The time course of ALF has etiologic, biologic, and prognostic significance. For example, an illness of 1 week or less before the development of encephalopathy is characteristic of ALF caused by hepatic ischemia or acetaminophen toxicity.
• In contrast, an interval longer than 4 weeks is more likely to be caused by viral hepatitis or ALF of unknown etiology.
Definition:
• Patients with a duration of illness longer than 2 weeks before the onset of encephalopathy have a higher likelihood of developing manifestations of portal hypertension, such as ascites or renal failure.
Definition:
• Some investigators have suggested that the term fulminant hepatic failure be reserved for cases in which encephalopathy develops within 2 weeks of the onset of jaundice and that the term subfulminant hepatic failure be applied to cases in which encephalopathy develops between 2 weeks and 3 months of the onset of jaundice
• Others have proposed that ALF be redefined to comprise three distinct syndromes:
Definition:
• Hyperacute liver failure (onset of encephalopathy within 1 week of jaundice), acute liver failure (development of encephalopathy between 1 and 4 weeks of jaundice), and subacute liver failure (development of encephalopathy within 5 to 12 weeks of jaundice).
• Unfortunately, there is great overlap in prognosis among patients with varying presentations, regardless of which nomenclature is used. Moreover, no universally accepted nomenclature has yet been adopted.
Causes:
• The most common causes of ALF are :
• Drugs
• Hepatotropic viruses
• However, many other conditions can lead to ALF, albeit uncommonly . Despite serologic and molecular advances in the diagnosis of viral infections, ALF of unknown etiology continues to represent a substantial proportion of the patients affected by this syndrome .
Drugs:
• Most cases of drug-related ALF result from acetaminophen overdose. In fact, acetaminophen is the most common single cause of ALF .
• Acetaminophen is directly hepatotoxic and predictably produces hepatocellular necrosis with an overdose (>12 g). Because of its easy availability, acetaminophen is a common mode of suicide and, occasionally, a cause of unintentional overdose.
Drugs:
• Even recommended therapeutic dosages of acetaminophen (as low as 4 g) can sometimes result in ALF in patients who are fasting or who chronically use alcohol or drugs that induce cytochrome oxidases .
• Numerous other drugs, including halothane, isoniazid, valproate, sulfonamides, phenytoin, thiazolidinediones, and certain herbal remedies, have been implicated in ALF. In most cases, drug-related ALF is rare and idiosyncratic.
Hepatotropic Viruses:
• Hepatitis A and hepatitis B viruses are major causes of ALF .
• Infection with hepatitis A virus (HAV) rarely leads to ALF, and when it does, the prognosis is relatively good.
• . Although hepatitis B virus (HBV) is the most common viral cause of ALF , ALF is an uncommon manifestation of HBV infection.
Hepatotropic Viruses:
• Infection with hepatitis D virus (HDV) requires coinfection with HBV. In certain geographic regions, HDV can account for almost 5% of the cases of ALF in patients who are positive for hepatitis B surface antigen and approximately 4% of the cases of ALF in patients who are positive for IgM antibody to hepatitis B core antigen.
Acute Liver Failure of Unknown Etiology
• ALF of unknown etiology, defined by negative serologic testing for hepatitis A and B and the absence of other known causes, constitutes 15% to 44% of the total cases of ALF .
• It had been anticipated that new sensitive molecular methods such as the polymerase chain reaction (PCR) would identify a viral etiology for ALF of unknown cause, but most cases remain cryptogenic.
Acute Liver Failure of Unknown Etiology
• Although hepatitis C virus (HCV) has been implicated as a cause of ALF in a few patients, it appears that HCV is an exceedingly rare cause of ALF in Western countries. In Japan, however, HCV may be a more common cause of ALF.
• Hepatitis E virus (HEV), an acknowledged cause of ALF in central Asia and other parts of the developing world, has not been found to cause ALF in the United States or the European continent.
Acute Liver Failure of Unknown Etiology
• Despite the identification of hepatitis G virus (HGV) in patients with ALF of unknown etiology, HGV does not appear to cause ALF.
• Several other viruses merit comment. Togavirus-like particles have been identified by electron microscopy in 7 of 18 liver explants from patients who underwent transplantation for ALF but are unlikely to be responsible for a substantial portion of these cryptogenic cases. The TT virus has been found in patients with ALF in the United States and Japan, but it is uncertain whether this virus can cause ALF.
Acute Liver Failure of Unknown Etiology
• Finally, parvovirus B19 has been postulated to be an important cause of ALF, but this postulate remains to be verified .
• Although these viruses warrant further investigation as causes of ALF, it is doubtful that any of these viral causes will explain the etiology of a significant portion of the cases of cryptogenic ALF.
Clinical Presentation:
• The initial presentation of ALF may include nonspecific complaints such as nausea, vomiting, fatigue, and malaise, but jaundice develops soon after .
• Hepatocellular Dysfunction:
? Hepatocellular injury or loss leads to impaired elimination of bilirubin .
? depressed synthesis of coagulation factors I, II, V, VII, IX, and X; diminished glucose synthesis; and decreased lactate uptake or increased generation of intracellular lactate as a result of anaerobic glycolysis.
Clinical Presentation:
? These derangements manifest clinically as jaundice, coagulopathy, hypoglycemia, and metabolic acidosis, respectively.
? Hepatic Encephalopathy and Cerebral Edema
? Encephalopathy is a defining criterion for ALF
? The severity of encephalopathy can range from subtle changes in affect, insomnia, and difficulties with concentration (stage 1); to drowsiness, disorientation, and confusion (stage 2); to marked somnolence and incoherence (stage 3); to frank coma (stage 4).
Clinical Presentation:
• The pathophysiologic mechanisms underlying ALF-associated encephalopathy are multifactorial.
• Many features of ALF, including hypoglycemia, sepsis, hypoxemia, occult seizures, and cerebral edema, can contribute to neurologic abnormalities.
• Continuous monitoring of cerebral activity by electroencephalogram (EEG) identifies subclinical seizures in almost 33% of ALF patients with at least stage 3 encephalopathy who are mechanically ventilated and paralyzed.
Clinical Presentation:
• Cerebral edema is found in up to 80% of patients who die in the setting of ALF and is virtually universal among patients with coma .
• Progressive cerebral edema will produce intracranial hypertension, which results in cerebral hypoperfusion and irreversible neurologic damage .
• The pathogenesis of cerebral edema in ALF is poorly understood. It has been proposed to result from the actions of gut-derived neurotoxins that escape hepatic clearance and are released into the systemic circulation.
Clinical Presentation:
• Two principal mechanisms appear to contribute to the development of cerebral edema in this setting: brain cell swelling (cytotoxic edema) and disruption of the blood-brain barrier (vasogenic edema).
• Progressive cerebral edema can impair cerebral perfusion, which may lead to irreversible neurologic damage or even result in uncal herniation and death .
Clinical Presentation:
• Infection
• Infections develop in as many as 80% of patients with ALF, and bacteremia is present in 20% to 25%.
• Uncontrolled infection accounts for approximately 25% of patients with ALF who are excluded from liver transplantation and approximately 40% of postoperative deaths.
Clinical Presentation:
• At least three factors place patients with ALF at increased risk for infection. First, gut-derived microorganisms may enter the systemic circulation from portal venous blood as a result of damage to hepatic macrophages (Kupffer cells).
• Second, impaired neutrophil function may result from reduced hepatocellular synthesis of acute-phase reactants, such as components of the complement cascade.
Clinical Presentation:
• Third, patients with ALF are often subjected to invasive procedures (e.g., intravascular and urethral catheterization, endotracheal intubation), and physical barriers to infection, including skin and airway, are thus breached.
• the major sites of infection are the respiratory and urinary tracts.
• It is not surprising therefore that the most common bacteria isolated are staphylococcal and streptococcal species and gram-negative rods.
Clinical Presentation:
• Fungal infections develop in up to one third of patients with ALF.
• The majority of these infections are caused byCandida albicans. Although Aspergillus infections have been thought to be uncommon in the setting of ALF.
• Risk factors for fungal infections are renal failure and prolonged antibiotic therapy for bacterial infections.
• Characteristically, fungal infection is associated with fever or leukocytosis refractory to broad-spectrum antibiotics.
Clinical Presentation:
• Gastrointestinal Bleeding.
? Patients with ALF have an increased risk of hemorrhage because of deficiencies in coagulation factors and thrombocytopenia.
? Such critically ill patients thus have a propensity for gastrointestinal stress ulceration and consequent bleeding.
? In contrast to patients with chronic liver failure, those with ALF rarely exhibit bleeding from varices.
Clinical Presentation:
• Multiple Organ Failure Syndrome
• A potential consequence of ALF is the syndrome of multiple organ failure .
• This syndrome manifests clinically as peripheral vasodilation with hypotension, pulmonary edema, acute tubular necrosis, and disseminated intravascular coagulation.
• Multiple organ failure is a significant contributor to patient mortality and a major contraindication to liver transplantation.
Clinical Presentation:
• For example, acute tubular necrosis is associated with a 50% decrease in survival among patients with acetaminophen-induced ALF, and the mortality rate is more than doubled in patients with multiple organ failure.
• Respiratory failure commonly is associated with ALF. In one series, 37% of patients with ALF had pulmonary edema.
• In another study, acute respiratory distress syndrome (ARDS) was present in 33% of patients with acetaminophen-associated ALF.
Clinical Presentation:
• The cause of renal failure in ALF (seen in more than one third of patients in one series) is multifactorial.
• Hepatorenal syndrome is often difficult to differentiate from intravascular volume depletion, which is also a common finding in ALF.
• Acute renal tubular acidosis is a prominent component of multiple organ failure syndrome .
Differential Diagnosis:
• The differential diagnosis includes sepsis, preeclampsia/eclampsia, and an acute decompensation of chronic liver disease.
• In particular, both sepsis and ALF have similar hemodynamic pictures, with decreases in peripheral vascular resistance accompanied by high cardiac output.
• Encephalopathy, a hallmark of ALF, also may be a manifestation of the sepsis syndrome.
Differential Diagnosis:
• If the hepatic manifestations of sepsis are severe, the clinical picture can be mistaken for ALF .
• Measurement of levels of factor VIII, which is not synthesized by the liver, may be helpful in differentiating sepsis (low factor VIII level) from ALF (factor VIII level generally not suppressed .
• In the pregnant patient, preeclampsia/eclampsia also can be difficult to differentiate from ALF, particularly ALF resulting from fatty liver of pregnancy.
Differential Diagnosis:
• an acute exacerbation of liver dysfunction in patients with underlying chronic liver disease is occasionally confused with ALF.
• Examples include alcoholic hepatitis in patients with alcoholic cirrhosis and flares of chronic viral hepatitis.
Predictors of outcome:
• Patients with ALF fall into two broad categories:
• (1) those in whom intensive medical care enables recovery of hepatic function
• (2) those who require liver transplantation to survive
• Thus, it is critical to determine rapidly the group into which a particular patient may belong. It is also critical to avoid the following two scenarios:
• (1) death of the patient despite intensive medical care without consideration of transplantation .
Predictors of outcome:
• (2) unnecessary liver transplantation when recovery would have occurred spontaneously.
• The etiology of disease and clinical presentation have predictive relevance
• For example, patients with ALF caused by hepatitis A have a better prognosis than those with ALF of unknown etiology.
• Patients who reach stage 3 or stage 4 encephalopathy tend to do worse than those who reach only stage 1 or stage 2.
Predictors of outcome:
• However, these indicators do not allow accurate prediction of the need for transplantation .
• The most extensive analysis has been performed by investigators at King"s College in London.
• These investigators performed a multivariate analysis of clinical and biochemical variables and their relation to mortality in 588 patients with ALF.
Predictors of outcome:
• The following characteristics were associated with a poor outcome:
• negative serology for hepatitis A or B, younger (<10 years) or older (>40 years) age, prolonged duration of jaundice, markedly elevated serum bilirubin level, marked prolongation of the prothrombin time, and in patients with acetaminophen toxicity, arterial acidosis, and an elevated serum creatinine level.
Predictors of outcome:
• Among patients with a cause of ALF other than acetaminophen toxicity, the presence of any single adverse prognostic characteristic was associated with a mortality rate of 80%, and the presence of three adverse characteristics was associated with a mortality rate of more than 95%.
• For patients with acetaminophen-induced liver failure, the presence of any one adverse characteristic was associated with a mortality rate of at least 55%, and severe acidosis was associated with a mortality rate of 95%.
Predictors of outcome:
• Liver histology does not predict outcome.
• Other investigators have examined the prognostic utility of measuring plasma factor V levels and hepatic volumetry, but these parameters do not appear to add significantly to the assessment of outcome.
Management:
• Historically, the mortality rate associated with ALF was very high, and management consisted of hopeful supportive care.
• Although intensive medical care enabled some patients with ALF to survive long enough to allow the liver to regenerate, the majority of patients still died .
• A wide variety of therapies have been proposed and utilized for the specific treatment of ALF, including glucocorticoids, prostaglandins, and exchange transfusions, but none of these have proved efficacious.
Management:
• Only liver transplantation has permitted salvage of patients with irreversible liver failure.
• Unfortunately, many patients with irreversible ALF do not undergo transplantation because of contraindications or the unavailability of donor livers.
Issues in Medical Management:
• Initial Evaluation and Management
• The initial management of ALF should include an attempt to identify the cause of ALF .
• A small number of causes of ALF can be treated specifically. For example, acetaminophen toxicity can be treated with N-acetylcysteine, and herpes-induced fulminant hepatitis has been reported to respond to intravenous acyclovir.
• Therapy of ALF caused by fatty liver of pregnancy is emergency delivery.
Issues in Medical Management:
• Especially critical in the early evaluation of patients with ALF is the decision regarding the patient"s candidacy for liver transplantation.
• Intensive medical care is warranted in all patients with ALF .
• Initial laboratory studies should include tests to determine the cause (e.g., viral serologic profiles, toxicology screening for acetaminophen and other drugs) and assess the severity of liver failure (e.g., liver biochemical and renal function tests, arterial blood gas measurements).
Issues in Medical Management:
• The management of coagulopathy in patients with ALF requires careful consideration. The risk of upper gastrointestinal hemorrhage can be reduced by agents such as intravenous H2 receptor antagonists.
• Placement of a nasogastric tube to monitor bleeding and gastric pH has been recommended in intubated patients.
• It is also reasonable to administer a trial of subcutaneous vitamin K to treat coagulopathy possibly related to vitamin K deficiency.
Issues in Medical Management:
• Empiric administration of fresh-frozen plasma has not been shown to improve the clinical outcome of patients with ALF.
• Hypoglycemia
• Hypoglycemia commonly occurs in patients with ALF. It is thus critical to monitor blood glucose levels frequently. Hypoglycemia generally responds to parenteral administration of glucose .
Issues in Medical Management:
• Encephalopathy and Cerebral Edema
• Unlike chronic hepatic encephalopathy, the encephalopathy associated with ALF tends to be progressive unless liver failure is reversed.
• Sedative-hypnotic drugs, which may exacerbate encephalopathy, should be avoided.
• Lactulose is of no proven benefit. Reversible conditions associated with ALF that could contribute to altered mental status (e.g., hypoglycemia, hypoxemia) must be treated immediately.
Issues in Medical Management:
• Patients with profound encephalopathy (i.e., stage 3 and stage 4) should undergo endotracheal intubation and mechanical ventilation for airway protection .
• many mechanically ventilated patients are also deeply sedated or paralyzed, and evidence of generalized seizure activity may be concealed .
Issues in Medical Management:
• Thus, it may be valuable to monitor deeply sedated or paralyzed patients for subclinical seizures by EEG. Treatment of subclinical seizures with phenytoin or other antiepileptic medications is appropriate, but the efficacy of prophylactic therapy to prevent seizure activity has not been proved .
• Computed tomographic (CT) scanning of the head is valuable for identifying mass lesions, intracranial hemorrhage, and evidence of brainstem herniation.
Issues in Medical Management:
• ICP monitoring represents the most accurate way to detect intracranial hypertension.
• Elevation of the head of the bed (and avoidance of the head-down position) is a simple measure to reduce ICP. If this maneuver fails, specific treatment is required .
• Osmotherapy with mannitol requires preserved renal function (or hemofiltration) and is effective in controlling intracranial hypertension in approximately 60% of cases.
Issues in Medical Management:
• Glucocorticoids are of no benefit.
• Infection
• Clinical recognition of infection may be difficult, because signs such as hypothermia, hypotension, leukocytosis, and acidosis may reflect the underlying liver failure .
• surveillance cultures in patients with ALF are extremely helpful .
• The advisability of prophylactic antibiotics in the setting of ALF is debatable.
Issues in Medical Management:
• Patients treated with prophylactic intravenous cefuroxime had a significant reduction in the rate of documented infections (from 61% to 32%) compared with those treated conservatively and a modest (but statistically insignificant) increase in the rate of survival (from 45% to 67%).
Issues in Medical Management
• If infection is suspected, the choice of antibiotics should be based on the spectrum of likely bacterial pathogens (e.g.,Staphylococcus, gram-negative aerobes) and local hospital microbial sensitivities.
• A reasonable empiric regimen is vancomycin and a third-generation cephalosporin.
• Multiple Organ Failure Syndrome
• Ideally, the mean arterial pressure (MAP) should be maintained above 60 mm Hg. If the MAP falls below this value, cerebral perfusion can drop precipitously.
Issues in Medical Management:
• Nephrotoxic drugs, especially aminoglycosides and nonsteroidal anti-inflammatory agents, must be avoided, and care must be taken when contrast dye is used.
• Liver Transplantation
• Liver transplantation has transformed the management of patients with ALF
Liver Transplantation:
• survival rates for patients with ALF who undergo liver transplantation have been substantially higher, with an overall rate of 63% for all transplants performed for ALF in the United States between 1987 and 1991.
• contraindications to transplantation, particularly irreversible brain damage, active extrahepatic infection, or multiple organ failure syndrome, must be considered.
Experimental Therapy:
• Treatment strategies, such as charcoal hemoperfusion and administration of prostaglandin E1, which showed early promise, have not been shown to be superior to standard care when analyzed in randomized studies.
• Plasmapheresis and hepatectomy have been suggested as possible "bridging" mechanisms to liver transplantation, but prospective trials have yet to be performed .
Experimental Therapy:
• Four additional forms of therapy may provide a bridge to liver transplantation or to regeneration of the native liver with spontaneous recovery: auxiliary liver transplantation, bioartificial liver devices, nonhuman liver transplantation, and hepatocyte transplantation.
