Hepatic Failure

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Because of the complexity of liver metabolism, patients with liver disease may develop many complications, including neurological dysfunction. This problem can be expected, considering the important role the liver plays in both nutrient metabolism (glycolysis, nutrient biosynthesis) and detoxification. The term HE refers to diffuse cerebral dysfunction occurring secondary to liver disease. When HE develops acutely in patients with liver disease of less than 8 weeks' duration, the term fulminant hepatic failure (FHF) is used, whereas the term portal-systemic encephalopathy (PSE) is used when HE develops in patients with chronic liver disease. This differentiation has therapeutic implications because a number of treatments exist for patients with PSE, whereas no specific form of treatment has been proved beneficial in FHF, except urgent liver transplantation.

Pathogenesis and Pathophysiology. Although neither the responsible toxin nor the pathogenesis of HE is known, it is believed to result from impaired hepatic degradation of neurotoxic substances arising from the GI metabolism of nitrogenous compounds. Normally, these GI products are delivered to the liver by the portal vein. There are two mechanisms by which hepatic impairment may result in the systemic accumulation of these gut-derived substances: (1) direct entry of portal vein-derived blood into the systemic circulation (shunting) secondary to the formation of portal systemic collaterals (e.g., PSE) and (2) impaired detoxification secondary to hepatocyte dysfunction (e.g., FHF). HE results in increased BBB permeability, which, in turn, enhances the entry of these substances into the CNS, facilitating the development of HE. This may explain the reason patients with liver disease can become symptomatic with only minimal hyperammonemia and their sensitivity to precipitation by ammonia-producing processes. [134] Normally, the brain removes ammonia by converting it to glutamine. If glutamine accumulates rapidly, the increased intracellular osmolality of the brain can cause cerebral edema. [i3&i

A variety of substances have been implicated in the pathogenesis of HE, including ammonia, endogenous benzodiazepines, Na/K ATPase inhibitors (e.g., glutamine, short-chain fatty acids, aromatic amino acids, and mercaptans), false neurotransmitters (e.g., octopamine), and gamma-aminobutyric acid. [i36 The leading hypothesis relates to the effects of ammonia and states that HE results from its systemic accumulation. Findings supporting this hypothesis include (1) patients with He usually have elevated arterial ammonia levels, (2) the degree of hyperammonemia correlates with the depth of coma, (3) ammonia metabolites (alpha-ketoglutarate and glutamine) are elevated in the brains and CSF of patients with HE, (4) the BBB permeability increases for ammonia, (5) the cerebral metabolic rate increases for ammonia, (6) experimental administration of ammonium salts results in reversible HE, (7) ammonia-forming compounds in the GI tract (e.g., protein meals, blood) reproducibly precipitate coma, (8) all proven treatments reduce blood ammonia levels, and (9) patients with urea cycle enzyme defects develop hyperammonemia and encephalopathy in the setting of normal liver function. W , [i35] , Wi A second hypothesis is the false neurotransmitter theory. This theory suggests that the increased ratio of aromatic to branched-chain amino acids occurring in liver failure causes an increased entry of aromatic amino acids into the brain (i.e., less competition). The enhanced entry of aromatic amino acids, in turn, increases the synthesis of serotonin and false neurotransmitters (e.g., octopamine). The increased quantities of false neurotransmitters could theoretically competitively inhibit the normal function of true neurotransmitters. However,

although false neurotransmitters do accumulate in PSE, there is no evidence that they are responsible for the encephalopathy. Because the pathogenesis of HE is probably not due to the accumulation of any single cerebral toxin, a multifactorial process is more likely, with the accumulation of multiple substances synergistically contributing to its development.

Epidemiology and Risk Factors. FHF is rare, with an incidence of approximately 2000 cases per year in the United States. Wi Viral hepatitis, usually hepatitis B or hepatitis C, is the most common cause of FHF in the United States and accounts for approximately 75% of cases. Among patients with hepatitis B, approximately 1 percent develop FHF. Drug-induced liver dysfunction is second in frequency. yi Abnormalities associated with liver disease, such as hypoxia, acid-base disturbances, and electrolyte abnormalities, predispose patients to the development of encephalopathy. Retrospective epidemiological studies have shown a correlation between intracranial hemorrhage and hepatic disease, with the relative risk for intracranial hemorrhage increased roughly five-fold among patients with liver disease.

Clinical Features and Associated Disorders. The neurological manifestations of HE range from subtle psychomotor abnormalities to coma and death. The exact clinical picture depends on the rapidity of onset, the degree of liver dysfunction, and the degree of portal-systemic shunting. PSE, the much more commonly encountered form, is mostly observed among patients with chronic liver disorders (e.g., cirrhosis). In addition to the neurological features, these patients may have numerous other clinical findings (l...Table..,38-13 ). PSE is typically precipitated by ammonia-producing processes, such as GI bleeding, increased dietary protein, constipation, and azotemia. Other known precipitants include infection, hypokalemia, hypoglycemia, hypoxia, and medications (e.g., sedative-hypnotics, analgesics).[137] Usually, the onset of encephalopathy is slow and insidious, often beginning with anxiety, altered sleep patterns and mood, agitated delirium, or a decreased attention span. Eventually, lethargy progresses to stupor and coma. Wi Asterixis is almost always present, and as the encephalopathy progresses, increased muscle tone, hyperreflexia, and extensor plantar responses are commonly noted. As part of the coma, decorticate and decerebrate posturing may also be observed. Unless a superimposed acute event occurs, cerebral edema is uncommon in these patients. [136] Unlike UE, seizures are infrequent and suggest the presence of a coexistent disorder.


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