Portosystemic encephalopathy: causes, symptoms, diagnosis, treatment

Portosystemic encephalopathy is a reversible neuropsychiatric syndrome that develops in patients with portosystemic shunting. The symptoms of portosystemic encephalopathy are primarily neuropsychiatric (eg, confusion, flapping tremor, coma). Diagnosis is based on clinical features. Treatment of portosystemic encephalopathy usually involves eliminating the acute cause, restricting dietary protein, and administering oral lactulose.

The term "portosystemic encephalopathy" better reflects the pathophysiology of the condition than hepatic encephalopathy or hepatic coma, but all three terms are used interchangeably.

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Causes of Portosystemic Encephalopathy

Portosystemic encephalopathy may occur in fulminant hepatitis caused by viral infection, drugs, or toxins, but is more common in cirrhosis or other chronic diseases in which significant portosystemic collaterals form as a result of portal hypertension. Encephalopathy occurs after portosystemic shunting, such as anastomoses between the portal vein and the vena cava [portacaval anastomosis or transjugular intrahepatic portosystemic shunt (TIPS)].

In patients with chronic liver disease, acute episodes of encephalopathy are usually precipitated by causes that can be corrected. The most common of these are metabolic stress (eg, infection; electrolyte imbalance, especially hypokalemia; dehydration; diuretic use), conditions that increase intestinal protein absorption (eg, gastrointestinal bleeding, high-protein diet), and nonspecific CNS depressants (eg, alcohol, sedatives, analgesics).

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Pathophysiology of portosystemic encephalopathy

Portosystemic shunting results in the release of metabolites into the systemic circulation that must be cleared by the liver and are toxic to the brain, particularly the cortex. The exact substances that cause brain toxicity are not known. Ammonia, a product of protein digestion, plays an important role, but other factors [eg, changes in brain benzodiazepine receptors and gamma-aminobutyric acid (GABA) neurotransmission] may also contribute. Serum aromatic amino acid levels are usually high and branched-chain amino acids are low, but these ratios are unlikely to cause encephalopathy.

Symptoms of portosystemic encephalopathy

The symptoms and manifestations of encephalopathy tend to develop progressively. Until moderate impairment of brain function occurs, the signs of encephalopathy are usually subtle. Constructional apraxia, in which the patient is unable to reproduce a simple pattern (such as a star), develops early. Excitement and mania may or may not develop. A characteristic "fluttering" tremor (asterixis) is detected if the patient holds his or her arms outstretched with the wrists bent downward. Neurological deficits are usually symmetrical. Neurological manifestations in coma usually reflect bilateral diffuse hemispheric dysfunction. Signs of brainstem dysfunction develop only as the coma progresses, often several hours or days before death. A musty, sweetish odor on the breath (hepatic odor from the mouth) may be observed regardless of the stage of encephalopathy.

Diagnosis of portosystemic encephalopathy

Diagnosis is usually clinical, but additional testing may help. Psychometric testing may reveal subtle neuropsychiatric abnormalities that may help verify early signs of encephalopathy. Ammonia levels generally serve as a laboratory marker for encephalopathy, but are neither specific nor highly sensitive and do not indicate the severity of encephalopathy. EEG typically shows diffuse weak-wave activity even in mild encephalopathy and may be sensitive enough to be specific for early encephalopathy. CSF testing is usually unnecessary; the only consistent abnormality is a mild increase in protein.

Differential diagnosis should exclude other potential disorders that may cause similar manifestations (e.g. infection, subdural hematoma, hypoglycemia, intoxication). If portosystemic encephalopathy is confirmed, the cause of its progression should be clarified.

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Treatment of portosystemic encephalopathy

In mild cases, removal of the cause usually results in reversal of the encephalopathy. The second goal of therapy is to remove toxic digestive products from the body, which is achieved by a number of methods. The intestines should be cleansed by an enema or, more commonly, by oral administration of lactulose syrup, which can be used for tube feeding in comatose patients. This synthetic disaccharide is an osmotic cleanser. It also lowers the pH in the colon, reducing the formation of ammonia in the stool. The initial dosage (30-45 ml orally three times daily) should be adjusted so that the patient has two or three soft stools daily. Dietary protein should also be eliminated (20-40 g per day is allowed in moderate cases), and the lack of calories is compensated for by oral or intravenous carbohydrates.

Sedation worsens encephalopathy and should be avoided if possible. In coma due to fulminant hepatitis, careful nursing and dietary management, together with prevention and treatment of complications, increase the chance of survival. High-dose glucocorticoids, exchange transfusions, and other complex measures aimed at eliminating circulating toxins usually do not improve the outcome. Clinical deterioration occurs due to the rapid development of liver failure, and patients can only be saved by liver transplantation.

Other treatments, including levodopa, bromocriptine, flumazenil, sodium benzoate, branched-chain amino acid transfusions, keto analogues of essential amino acids, and prostaglandins, have been ineffective. Results from sophisticated plasma filtration systems (artificial liver) are encouraging but require further study.

Prognosis of portosystemic encephalopathy

In chronic liver disease, removal of the cause of encephalopathy usually results in its reversal without persistent neurological sequelae. Some patients, especially those with portocaval shunting or TIPS, require permanent drug therapy; irreversible extrapyramidal impairment or spastic paraparesis rarely develop. Coma (stage 4 encephalopathy) in fulminant hepatitis is fatal in 80% of patients despite intensive therapy; the combination of progressive chronic liver failure and portosystemic encephalopathy is also often fatal.

Clinical stages of portosystemic encephalopathy

Stage	Cognitive sphere and behavior	Neuromuscular function
0 (subclinical)	Asymptomatic loss of cognitive abilities	Absent
1	Sleep disturbance; difficulty concentrating; depression; anxiety or irritability	Monotone voice; tremor; poor handwriting; constructional apraxia
2	Drowsiness; disorientation; poor short-term memory; behavioral disturbances	Ataxia; dysarthria; fluttering tremor; automatism (yawning, blinking, sucking)
3	Drowsiness; confusion; amnesia; anger; paranoia or other strange behavior	Nystagmus; muscle rigidity; hyper- or hyporeflexia
4	Coma	Dilated pupils; oculocephalic or oculovestibular reflexes; decerebrate posture

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