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Anorexia, Jaundice, scleral icterus, Kayser-Fleischer rings (Wilson's disease, primary biliary cirrhosis'p, fetor hepaticus (musty, sweet breath odor), spider nevi, fatigue gynecomastla. caput medusa (dilation of the umbilical vessels), splenomegaly, aseites, xanthomas, palmar crythema, Dupuytren s contractures of the hands and feet

The onset of FHF is much more rapid and is typically associated with severe liver disease. Mental status changes, such as agitation, inappropriate behavior, and impaired judgment, appear early and may quickly progress to stupor and coma. Unlike PSE, cerebral edema with increased ICP is common and may result in cerebral herniation and death. Seizures and focal neurological signs are uncommon and suggest a co-existent process (e.g., subdural hematoma [SDH]).

In addition to developing encephalopathy, some patients with chronic liver disease develop hepatocerebral degeneration, a slowly progressive and irreversible neurodegenerative syndrome associated with extensive portosystemic shunting. It is characterized by tremor, rigidity, bradykinesia, ataxia, dysarthria, choreoathetosis, and dementia. Studies have shown a selective loss of dopaminergic D2 (postsynaptic) receptors in the globus pallidus of patients with PSE, suggesting that these extrapyramidal signs may reflect dopaminergic neuronal dysfunction. 137] Rarely, spinal cord degeneration (hepatic myelopathy), characterized by spastic paraparesis, hyperreflexia, and extensor plantar responses, is observed. The presence of polyneuropathy has been variably reported. When they are present, these signs are typically mild or asymptomatic. It is not known whether these neuropathic changes are directly related to hepatic dysfunction or to the disease process causing the liver impairment (e.g., alcohol abuse, hemochromatosis).

Differential Diagnosis and Evaluation. Any disorder resulting in liver failure may cause HE. Viral hepatitis is the most common cause of FHF in the United States, followed by drug-induced liver dysfunction (e.g., acetaminophen, isoniazid, rifampin, methyldopa [Aldomet], halothane), fatty infiltration, Reye's syndrome, infiltrative diseases, and less common causes.W , [138]

The diagnosis of HE is clinical and depends on the identification of precipitating factors and the observation of a good response to empirical treatment. [140] Unfortunately, there are no pathognomonic features of HE, and all of its typical features may be noted with encephalopathies of other etiologies. Patients suspected of having HE require a thorough neurological examination. Laboratory studies help exclude alternative etiologies of encephalopathy and identify other complications related to hepatic disease. Potentially helpful laboratory studies include a CBC, electrolytes, BUN, Cr, glucose, Ca, drug screen, B 12 level, ABGs, and liver function tests. There is no correlation between the degree of HE and the degree of liver function test abnormality. In fact, liver function tests may be normal in the setting of severe, chronic liver disease. An arterial blood ammonia level should be drawn, placed on ice, and immediately assayed. Venous samples are unacceptable because tourniquet-induced muscle ischemia can result in the release of ammonia from muscle (possible false-positive result), and muscle itself can take up variable amounts of ammonia producing false-negative results.^ Although it is infrequent, a normal value does not exclude HE, especially in the fasted state. , [140] Although its absolute value does not correlate with the degree of HE, the ammonia level is useful in following the individual patient's course and response to therapy.

The EEG typically reveals generalized slowing, and triphasic waves may also be seen. Triphasic waves, although characteristic of HE, are not specific for this disorder and can be observed in a wide variety of encephalopathic states and structural processes ( Fig.:...3§i3 ). Because the degree of slowing is proportional to the severity of encephalopathy, serial EEGs allow for the assessment of the subsequent clinical course and response to treatment. If the patient is febrile or if meningismus is observed, CSF analysis should be cautiously performed, because increased ICP or a coagulopathy may also be present in this patient population. The opening pressure should be recorded and routine CSF studies obtained. In HE, the CSF protein may be mildly elevated, and glutamine levels are usually elevated. The glutamine level has been cited as the biochemical parameter most closely correlated to the degree of HE. ^ , [141]

Once HE is diagnosed, the degree of impairment should be clinically graded and used as a baseline for future comparisons. Daily handwriting samples, number connection tests (e.g., trailmaking), and mental status examinations are helpful in the daily assessment of patients with HE. ^36 The most widely used grading system categorizes patients into one of four stages, based primarily on alterations in mentation and the EEG. ^ Stage I is characterized by subtle changes in thought processes and personality, such as dyscalculia, poor handwriting, impaired construction of simple figures, difficulty connecting a series of numbers, and sloppiness. At this stage, any abnormalities on the EEG are subtle. In stage II, more obvious changes in thought processes, such as confusion, inappropriate behavior, decreased attention, drowsiness, and abnormal sleep patterns, are noted. Asterixis and hyperreflexia are usually present, and clonus as well as extensor plantar responses may also be observed. The EEG shows generalized slowing. In stage III, further worsening of thought processes occurs, with confusion and an even shorter attention span. The patient is unable to perform fine motor movements and remains asleep most of the time. Asterixis is present, and the EEG shows more pronounced slowing; in addition, triphasic waves may be observed. In stage IV, the patient is comatose. Brain stem reflexes persist until the deepest stages of coma are reached. The EEG shows generalized delta frequency slowing. ICP monitoring can be helpful in the management of patients in stages III and IV by guiding therapy, facilitating the early detection of rising ICP, and identifying patients with sustained ICP elevations, so that they may be excluded from emergency liver transplantation procedures.^1 When ICP monitoring cannot be performed, the patient must be followed closely for evidence of cerebral herniation so that treatment can be provided at a time when the process may be reversible.

In HE, focal neurological features are unexpected and suggest a co-existent structural abnormality (e.g., SDH) or focal metabolic abnormality (e.g., postictal state). In these cases, CT or MRI studies of the head are warranted. In patients with hepatocerebral degeneration, reversible MRI abnormalities, which are most pronounced in the globus pallidus, may be seen. A recent expedited publication reported that proton magnetic resonance spectroscopy can be used to detect specific metabolic abnormalities in this region of the brain, thereby constituting an early marker of metabolic alteration. [142]

Management. Prevention is an important aspect of treatment among patients with chronic liver disease. Known precipitants of HE should be avoided and, if they are identified, reversed. Because the onset of PSE is slow, insidious, and often subclinical, patients with chronic liver disease should undergo periodic psychometric testing.[143] As many as 70 percent of patients with cirrhosis and without evidence of an overt encephalopathy have significant impairment when tested. W Because the visuospatial sphere is the most frequently affected, the Reitan Trials A and B,

Figure 38-3 A 58-year-old patient with hepatic encephalopathy. The patient's EEG demonstrates classic triphasic waves that are more prominent ante(FromL uders HO, Koechter S: Atlas und Klassifikation der Elektroenzephahpgraphie, Verlag, CIBA-Geigy 1994, p 118.)

Block Design, and Symbol-Digit subtests of the Wechsler Adult Intelligence Scale-Revised (WAIS-R), as well as the Purd Pegboard test are frequently employed and commonly found to yield abnormal results. Wi

In the patient with HE, empiric therapy should be initiated, whereas other causes of encephalopathy are being excluded and precipitating factors are being sought. Thiamine hydrochloride, 100 mg IV, is administered and should be followed by a daily dosage of 50 mg PO to prevent Wernicke-Korsakoff syndrome.

General measures in the treatment of HE include maintaining adequate nutrition, good renal function, and acid-base status, as well as reducing colonic ammonia production. Because normal brain pH is 6.95 and blood pH is 7.4, there is a tendency for ammonia to enter the brain. By minimizing the interaction between enteric bacterial flora and nitrogenous substances, colonic ammonia production is reduced. Dietary protein restriction, avoidance of constipation, and GI tract evacuation are helpful in this respect. The GI tract is evacuated through the use of cathartics (e.g., lactulose) and enemas. Lactulose is a synthetic disaccharide capable of reducing arterial ammonia levels. In the colon, it is converted into acidic metabolites, which create a pH gradient across the intestinal wall. Colon acidification was thought to select for bacteria that did not contain urease. Instead, colon acidification decreases blood ammonia by trapping it in the acidified feces, thereby making it unavailable for absorption.^] In addition, the pH gradient causes movement of ammonia into the colon. The dosage is usually titrated to yield 2 to 3 soft bowel movements per day, typically requiring 30 to 40 g four times daily. If the patient is comatose, hourly doses of 20 to 30 g are provided until a catharsis is produced, after which the dosage can be reduced.^ Some patients do not tolerate lactulose, presumably because of the associated contaminants, such as lactose, galactose, and other carbohydrates. Lactitol, another synthetic disaccharide, is better tolerated. It is purer than commercial lactulose and, therefore, has less adverse effects, such as nausea, diarrhea, and intestinal cramping. Unfortunately, it is more expensive and not available in the United States. Neomycin, a nonabsorbable antibiotic, kills colonic bacteria, and thereby decreases both the bacterial nitrogen content and the synthesis of urea. Compared with lactulose, it has more side effects without increased efficacy. In addition, there is some evidence that aminoglycosides contribute to the development of hepatorenal syndrome, and for that reason, they are rarely used today. In the setting of neomycin resistance, metronidazole is an alternative. Dietary protein restriction (less than 1 g/kg dry weight of high biological value protein) and the administration of multivitamins, folate and thiamine supplements, vitamin K, and at least 2000 calories per day should be provided. [138] , Therapies considered to be nonbeneficial include branched-chain amino acid solutions, serotonin reuptake inhibitors, L-dopa, and bromocriptine. W1 Sodium benzoate was also shown to reduce blood ammonia levels in a double-blinded and randomized trial of 38 patients with PSE. [145] Improvement within 1 to 3 days of starting empirical therapy is expected. Failure to respond suggests the wrong diagnosis, a missed precipitant, multiple causes of the encephalopathy, or the most common cause, a missed nosocomial infection.^ In addition to the general measures listed earlier, more specific treatments may be required. Orthotopic liver transplantation (OLT) represents an alternative for patients with little chance of recovery. A review of the patients undergoing OLT reported a number of neurological sequelae, including severe quadriplegia, perioperative mononeuropathies, and herpes zoster-related radiculopathies. [146] A recent review of the causes and outcome of seizures in the post-OLT patient population revealed that the majority of new-onset seizures after OLT were related to immunosuppressive treatment, did not require antiepileptic drug (AED) therapy for favorable long-term outcome, and were not as ominous as previously thought. [w]

Prognosis and Future Perspectives. The mortality rate for patients with FHF, despite aggressive therapy, is approximately 85 percent. W Age, etiology, and degree of encephalopathy influence survival in FHF. Younger patients have a more favorable outcome, with the discriminatory age lying between 30 and 50 years. ^ Recovery from FHF is expected when the condition is due to hepatitis A and acetaminophen hepatotoxicity, yet the rate is only 40 percent when it is associated with hepatitis B and 20 percent when it is associated with hepatitis C or drug-induced hepatitis. When FHF is associated with Wilson's disease, recovery almost never occurs.^ , [149] The recovery rate approaches 75 percent for patients who do not progress beyond stage II, whereas less than 20 percent of those patients reaching stage IV survive.^ In patients with FHF, death is commonly caused by complications involving other organ systems, two thirds of which are neurological. ^38 OLT has increased the survival rate significantly (50 to 90 percent) and, in the case of patients with cirrhosis, can normalize their neuropsychiatric status. Ultimately, the prognosis is related to the ability of the liver to regenerate or the availability of livers for transplantation.

Typically, patients with PSE have a good prognosis for full recovery, especially if a precipitating factor can be identified and reversed. When the cause cannot be reversed, continuous therapy is required (e.g., surgical portacaval shunts). Still, the underlying etiology, the occurrence of secondary complications, and the degree of encephalopathy affect survival. Favorable prognosticators include an identifiable and treatable precipitant, mild encephalopathy, and lack of secondary complications.[134]

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