Hepatic Encephalopathy The 5 Minute Pediatric Consult


	Hepatic Encephalopathy

Andrew E. Mulberg

Database
Differential Diagnosis
Data Gathering
Physical Examination
Laboratory Aids
Therapy
Follow-Up
Common Questions and Answers
Bibliography

DATABASE

DEFINITION

Abnormal mental status in patients with severe hepatic insufficiency.

CAUSES

Hepatic failure
Viral hepatitis
Drug-induced hepatotoxicity
End-stage chronic liver disease secondary to biliary atresia, a-1-antitrypsin deficiency, Wilson disease
Inborn errors of metabolism: urea cycle enzyme disorders, organic acidemias, and fatty acid oxidation disorders. All hypotheses depend somewhat on the accompanying features of liver failure, such as porto-systemic shunting and an increased blood-brain barrier permeability to chemical substrates.
- Appears to be of a metabolic origin because the damage is nonstructural and the manifestations are reversible with a protein-restricted diet. Treatment with lactulose, neomycin, and occasionally branched-chain amino acid supplementation may imrpove the clinical signs and symptoms.
- May be secondary to accumulation of end-stage toxic products such as ammonia, short-chain fatty acids, and methylmercaptans, which bypass the portal circulation and may exert direct toxic effects on the brain, especially with an altered blood-brain barrier
- Altered neurotransmission secondary to inhibitory effects of g-amino benzoic acid (GABA)
- Lack of nutrients such as glucose may impair brain energy metabolism. Even with glucose infusion, the brain’s demands for energy may not be met in liver failure.
- Endogenous benzodiazepine theory: Increased substances identified biochemically as benzodiazepines are found on human autopsy in liver failure patients. Whether the source is in fact endogenous or whether they may be synthesized by bacteria is unknown.
- Increased aromatic amino acids and decreased branched-chain amino acids in plasma and in the brain in liver failure. Various studies testing this hypothesis by supplying protein with a high branched-chain amino acid load have been done with conflicting results. These may act as false neurotransmitters, competing for catecholamine receptor sites.

PATHOLOGY

In patients with cerebral edema associated with hepatic encephalopathy (HE), astrocyte neuronal swelling is noted in the brain upon autopsy.

DIFFERENTIAL DIAGNOSIS

Infection: meningitis, encephalitis
Tumors: intracranial lesions
Trauma: cerebral hemorrhage, cerebral hematoma
Metabolical: inborn errors of metabolism, lactic acidemias, urea cycle deficiencies
Immunological: AIDS dementia

DATA GATHERING

HISTORY

Question: Alteration in mental status and personality?
Significance: Classic feature

PHYSICAL EXAMINATION

Finding: Neurological exam
Significance: Mainly see central nervous system and neuromuscular abnormalities

Finding: Central nervous system manifestations
Significance: Range from altered mood to frank coma. Four clinical stages of hepatic coma are described, based on changes in conscious intellectual functioning and behavior. Usually, the clinical picture starts slowly.

Trivial lack of awareness, euphoria, or anxiety, shortened attention span. (Therefore, in a child with acute onset of combative or irrational behavior in the classroom, liver disease should always be ruled out.)
Lethargy, apathy, disorientation, change in personality
Somnolence, but responsive to stimuli, confused
Coma

Finding: Neuromuscular signs
Significance: May include varying degrees of asterixis and loss of tone. Asterixis (a hand-flapping tremor) is characteristic of hepatic encephalopathy, although it may also be seen with uremia, respiratory failure, and hypokalemia. Asterixis is due to sudden inappropriate relaxation of muscle groups.

Finding: Signs of end-stage liver failure
Significance: Portal systemic shunting, varices, and ascites.

Finding: Evaluation: Check for asterixis.
Significance: Ask the patient to stand with both arms raised horizontally in front of him, palms down. Patient should dorsiflex the wrist and hold fingers far apart for at least 15 seconds. A flap will be seen when the patient has small brief intermittent movements of the individual fingers, either in flexion or laterally in the ulnar direction, with a rapid return of fingers to the original position. In more severe cases, this flap can spread more proximal including the wrist and even the shoulders.

LABORATORY AIDS

TESTS

Test: EEG
Significance: May show a decrease in wave frequency, with an increase in wave amplitude. In more advanced cases delta waves are seen. These findings are non-specific and may be seen in other disease processes.

Test: Visual evoked potentials
Significance: May become more useful than EEGs.

Test: Number connection test
Significance: Connect randomly placed numbers 1 to 25 on a sheet of paper; better used to follow a course of HE rather than in initial diagnoses.

IMAGING

Head CT scan checks for signs of increased intracranial pressure or cerebral edema. These do not help with diagnosis but may indicate severity of encephalopathy and suggest prognosis.

THERAPY

SUPPORTIVE CARE

Fluids and electrolyte monitoring, vital signs, paying close attention to development of infection (respiratory, urinary)

DRUGS

Flumazenil in animal studies reverses the electrophysiological and clinical abnormalities in HE. As a benzodiazepine receptor antagonist, the agent may block the binding receptor for GABA in the brain. In some human studies, the benefits of flumazenil have also been seen but are not consistent for all patients.
Branched-chain amino acids may reverse the altered ratio of branched-chain to aromatic amino acids, and clinical improvements have been seen. Results are not permanent and clinical deterioration resumes.
Neomycin reduces intestinal bacterial flora responsible for ammonia synthesis.
Lactulose: a disaccharide not able to be digested in the human intestine hydrolyzed by bacteria in the colon. Hypernatremia may result with therapy.

DURATION

These methods to improve HE are generally used as long as the acute state of HE continues.

DIET

A low protein or even protein-free diet is recommended, to avoid increase in levels of ammonia.
Conflicts with other treatment
Placement of a portosystemic shunt before the onset of the acute development of neurological deterioration may suggest that the shunt is not allowing enough circulation through the liver. Suppression of the shunt, either by ballooning or by surgical ligation, may improve the clinical picture.
Liver transplantation

FOLLOW-UP

WHEN TO EXPECT IMPROVEMENT

Often, improvement (a change in the level of HE by 1 or 2 stages) is seen 2 to 3 days after initiation of therapy.

SIGNS TO WATCH FOR

Progression of mental status through deeper stages of HE

PROGNOSIS

Depends to some degree on stage of encephalopathy. In stage 4 encephalopathy, the most common cause of death is increased intracranial pressure and brain edema. Prognosis also depends on underlying cause and, therefore, methods of reversibility of liver failure. Orthotopic liver transplantation should be performed in children with severe and worsening encephalopathy before the development of radiographically apparent cerebral edema. In one study, on multiple logistic regression analysis, presence of GI hemorrhage (p = 0.005), degree of coma (p = 0.02) and serum bilirubin level (p = 0.025) were identified as independent predictors of mortality.

COMMON QUESTIONS AND ANSWERS

Q: My child has chronic liver failure and has experienced two episodes of hepatic encephalopathy managed in the ICU. Is there any special diet I should be providing him?
A: Because dietary intake of protein can lead to accumulation of nitrogenous waste that can accumulate into ammonia, it is best to keep your child on a low-protein diet.

ICD-9-CM 572.2

BIBLIOGRAPHY

Alper G, Jarjour IT, Reyes JD, Towbin RB, Hirsch WL, Bergman I. Outcome of children with cerebral edema caused by fulminant hepatic failure [Review]. Pediatr Neurol 1998;18(4):299–304.

Basile SA, Jones EA, Skolnick P. The pathogenesis and treatment of hepatic encephalopathy: evidence for involvement of benzodiazepine receptor ligands. Pharmacol Rev 1991;32:27–71.

Butterworth RF. Pathogenesis and treatment of porto-systemic encephalopathy. Digest Dis Sci 1992;37(3):321–327.

Ferenci P. Brain dysfunction in fulminant hepatic failure. J Hepatol 1994;21:487–490.

Hawkins RA, Mans AM. Brain metabolism in hepatic encephalopathy and hyperammonemia. In: Felipo V, Grisola S, eds. Cirrhosis, hyperammonemia, and hepatic encephalopathy. New York: Plenum, 1994:13–19.

Mullen KD, Weber FL. Role of nutrition in hepatic encephalopathy. Semin Liver Dis 1991;11(4):292–304.

Riegler JI, Lake JR. Fulminant hepatic failure. Med Clin North Am 1993;77(5):1057–1083.

Rodes J. Clinical manifestations and therapy of hepatic encephalopathy. In: Felipo V, Grisola S, eds. Cirrhosis, hyperammonemia, and hepatic encephalopathy. New York: Plenum, 1994:39–44.

Srivastava KL, Mittal A, Kumar A, Gupta S, Natu SM, Kumar R, Govil YC. Predictors of outcome in fulminant hepatic failure in children. Indian J Gastroenterol 1998;17(2):43–45.

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