Portal-systemic encephalopathy is a neuropsychiatric syndrome. It most often results from high gut protein or acute metabolic stress (eg, GI bleeding, infection, electrolyte abnormality) in a patient with portal-systemic shunting. Symptoms are mainly neuropsychiatric (eg, confusion, flapping tremor, coma). Diagnosis is based on clinical findings. Treatment usually is correction of the acute cause, restriction of dietary protein, and oral lactulose.

(See also the American College of Gastroenterology's practice guideline Hepatic Encephalopathy.) Portal-systemic encephalopathy better describes the pathophysiology than hepatic encephalopathy or hepatic coma, but all 3 terms are used interchangeably.

Etiology

Portal-systemic encephalopathy may occur in fulminant hepatitis caused by viruses, drugs, or toxins, but it more commonly occurs in cirrhosis or other chronic disorders when extensive portal-systemic collaterals have developed as a result of portal hypertension. Encephalopathy also follows portal-systemic anastomoses, such as surgically created anastomoses connecting the portal vein and vena cava (portacaval shunts, transjugular intrahepatic portosystemic shunting [TIPS]).

Precipitants: In patients with chronic liver disease, acute episodes of encephalopathy are usually precipitated by reversible causes. The most common are the following:

• Metabolic stress (eg, infection; electrolyte imbalance, especially hypokalemia; dehydration; use of diuretic drugs)
• Disorders that increase gut protein (eg, GI bleeding, high-protein diet)
• Nonspecific cerebral depressants (eg, alcohol, sedatives, analgesics)

Pathophysiology

In portal-systemic shunting, absorbed products that would otherwise be detoxified by the liver enter the systemic circulation, where they may be toxic to the brain, particularly the cerebral cortex. The substances causing brain toxicity are not precisely known. Ammonia, a product of protein digestion, is an important cause, but other factors (eg, alterations in cerebral benzodiazepine receptors and neurotransmission by γ–aminobutyric acid [GABA]) may also contribute. Aromatic amino acid levels in serum are usually high and branched-chain levels are low, but these levels probably do not cause encephalopathy.

Symptoms and Signs

Symptoms and signs of encephalopathy tend to develop in progressive stages (see Table 8: Approach to the Patient with Liver Disease: Clinical Stages of Portal-Systemic Encephalopathy).

Table 8
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Clinical Stages of Portal-Systemic Encephalopathy Stage Cognition and Behavior Neuromuscular Function 0 (subclinical) Asymptomatic loss of cognitive abilities None 1 Sleep disturbances Impaired concentration Depression, anxiety, or irritability Monotone voice Tremor Poor handwriting Constructional apraxia 2 Drowsiness Disorientation Poor short-term memory Disinhibited behavior Ataxia Dysarthria Asterixis Automatisms (eg, yawning, blinking, sucking) 3 Somnolence Confusion Amnesia Anger, paranoia, or other bizarre behavior Nystagmus Muscular rigidity Hyperreflexia or hyporeflexia 4 Coma Dilated pupils Oculocephalic or oculovestibular reflexes Decerebrate posturing

Symptoms usually do not become apparent until brain function is moderately impaired. Constructional apraxia, in which patients cannot reproduce simple designs (eg, a star), develops early. Agitation and mania can develop but are uncommon. A characteristic flapping tremor (asterixis) is elicited when patients hold their arms outstretched with wrists dorsiflexed. Neurologic deficits are symmetric. Neurologic signs in coma usually reflect bilateral diffuse hemispheric dysfunction. Signs of brain stem dysfunction develop only in advanced coma, often during the hours or days before death. A musty, sweet breath odor (fetor hepaticus) can occur regardless of the stage of encephalopathy.

Diagnosis

• Clinical evaluation
• Often adjunctive testing with psychometric evaluation, ammonia level, EEG, or a combination
• Exclusion of other treatable disorders

Diagnosis is ultimately based on clinical findings, but testing may help:

• Psychometric testing may reveal subtle neuropsychiatric deficits, which can help confirm early encephalopathy.
• Ammonia levels are usually done.
• An EEG usually shows diffuse slow-wave activity, even in mild cases, and may be sensitive but is not specific for early encephalopathy.

CSF examination is not routinely necessary; the only usual abnormality is mild protein elevation.

Other potentially reversible disorders that could cause similar manifestations (eg, infection, subdural hematoma, hypoglycemia, intoxication) should be ruled out. If portal-systemic encephalopathy is confirmed, the precipitating cause should be sought.

Prognosis

In chronic liver disease, correction of the precipitating cause usually causes encephalopathy to regress without permanent neurologic sequelae. Some patients, especially those with portacaval shunts or TIPS, require continuous therapy, and irreversible extrapyramidal signs or spastic paraparesis rarely develops. Coma (stage 4 encephalopathy) associated with fulminant hepatitis is fatal in up to 80% of patients despite intensive therapy; the combination of advanced chronic liver failure and portal-systemic encephalopathy is often fatal.

Treatment

• Treatment of the cause
• Bowel cleansing using oral lactuloseSome Trade Names
  CEPHULAC
  CHRONULAC
  KRISTALOSE
  Click for Drug Monograph
  or enemas
• Dietary protein restriction

Treating the cause usually reverses mild cases. Eliminating toxic enteric products is the other goal and is accomplished using several methods. The bowels should be cleared using enemas or, more often, oral lactuloseSome Trade Names
CEPHULAC
CHRONULAC
KRISTALOSE
Click for Drug Monograph
syrup, which can be tube-fed to comatose patients. This synthetic disaccharide is an osmotic cathartic. It also lowers colonic pH, decreasing fecal ammonia production. The initial dosage, 30 to 45 mL po tid, should be adjusted to produce 2 or 3 soft stools daily. Dietary protein should be about 1.0 mg/kg/day, primarily from vegetable sources. Oral nonabsorbable antibiotics such as neomycinSome Trade Names
NEO-FRADIN
NEO-RX
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and rifaximinSome Trade Names
XIFAXAN
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are effective for hepatic encephalopathy. RifaximinSome Trade Names
XIFAXAN
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is usually preferred because neomycinSome Trade Names
NEO-FRADIN
NEO-RX
Click for Drug Monograph
is an aminoglycoside, which can precipitate ototoxicity or nephrotoxicity.

Sedation deepens encephalopathy and should be avoided whenever possible. For coma caused by fulminant hepatitis, meticulous supportive and nursing care coupled with prevention and treatment of complications increase the chance of survival. High-dose corticosteroids, exchange transfusion, and other complex procedures designed to remove circulating toxins generally do not improve outcome. Patients deteriorating because of fulminant hepatic failure may be saved by liver transplantation.

Other potential therapies, including levodopa, bromocriptineSome Trade Names
PARLODEL
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, flumazenilSome Trade Names
ROMAZICON
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, Na benzoate, infusions of branched-chain amino acids, keto-analogs of essential amino acids, and prostaglandins, have not proved effective. Complex plasma-filtering systems (artificial liver) show some promise but require much more study.

Last full review/revision July 2009 by Steven K. Herrine, MD

Content last modified July 2009