Hepatic encephalopathy is a neuropsychiatric syndrome occurring in patients with severe impairment of liver function and consequent accumulation of toxic products not metabolized by the liver. It is characterized by gradual impairment of the ability to perform mental tasks and to react to external stimuli. Fig. 1 illustrates the hepatic encephalopathy grades in acute liver failure. Minimal hepatic encephalopathy refers to patients with hepatic cirrhosis and mild cognitive impairment, but no history of overt encephalopathy.

Figure 1 Hepatic encephalopathy grade in acute liver failure.

From Parrillo JE, Dellinger RP: Critical care medicine: principles of diagnosis and management in the adult, ed 4, Philadelphia, 2014, Elsevier.

Hepatic coma

Portal systemic encephalopathy

HE

Hepatic encephalopathy can be classified by clinical stages described in Table 1. Other widely used scales are the four score criteria and the West Haven criteria. The West Haven criteria for grading hepatic encephalopathy is as follows:

• Grade (0): No abnormalities noted
• Grade (1): Unawareness (mild), euphoria or anxiety, shortened attention span, impairment of calculation ability, lethargy, or apathy
• Grade (2): Disorientation to time, obvious personality change, inappropriate behavior
• Grade (3): Somnolence to stupor, responsiveness to stimuli, gross disorientation, bizarre behavior
• Grade (4): Coma

The physical examination in hepatic encephalopathy varies with the stage and may reveal the following abnormalities:

• Skin: Jaundice, palmar erythema, spider angiomata, ecchymosis, dilated superficial periumbilical veins (caput medusae) in patients with cirrhosis
• Eyes: Scleral icterus, Kayser-Fleischer rings (Wilson disease)
• Breath: Fetor hepaticus
• Chest: Gynecomastia in men with chronic liver disease
• Abdomen: Ascites, small nodular liver (cirrhosis), tender hepatomegaly (congestive hepatomegaly)
• Rectal examination: Hemorrhoids (portal hypertension), guaiac-positive stool (alcoholic gastritis, bleeding esophageal varices, peptic ulcer disease, bleeding hemorrhoids)
• Genitalia: Testicular atrophy in males with chronic liver disease
• Extremities: Pedal edema from hypoalbuminemia
• Neurologic: Flapping tremor (asterixis), obtundation, coma with or without decerebrate posturing

• Hepatic encephalopathy is thought to be caused mainly by accumulation of unmetabolized ammonia. The shunting of ammonia into the systemic circulation results in neuronal dysfunction leading to hepatic encephalopathy
• Precipitating factors in patients with underlying cirrhosis (upper gastrointestinal bleeding, hypokalemia, hypomagnesemia, analgesic and sedative drugs, sepsis, alkalosis, increased dietary protein)
• Acute fulminant viral hepatitis
• Drugs and toxins (e.g., isoniazid, acetaminophen, diclofenac and other NSAIDs, statins, methyldopa, loratadine, propylthiouracil, lisinopril, labetalol, halothane, carbon tetrachloride, erythromycin, nitrofurantoin, troglitazone, herbal products, flavocoxid)
• Reye syndrome
• Shock and/or sepsis
• Fatty liver of pregnancy
• Metastatic carcinoma, hepatocellular carcinoma
• Other: Autoimmune hepatitis, ischemic venoocclusive disease, sclerosing cholangitis, heat stroke, amebic abscesses

• Delirium caused by medications or illicit drugs
• Cerebrovascular accident, subdural hematoma
• Meningitis, encephalitis
• Hypoglycemia
• Uremia
• Cerebral anoxia
• Hypercalcemia
• Metastatic neoplasm to brain
• Alcohol withdrawal syndrome/Wernicke-Korsakoff syndrome
• Hyponatremia
• Postictal state

Hepatic encephalopathy should be considered in any patient with cirrhosis who presents with neuropsychiatric manifestations. Exclude other etiologies with comprehensive history (obtained from patient, relatives, and others), physical examination, and laboratory and imaging studies. A pertinent history should include exposure to hepatitis, ethanol intake, drug history, exposure to toxins, IV drug abuse, measles or influenza with aspirin use (Reye syndrome), and history of carcinoma (primary or metastatic). Minimal hepatic encephalopathy may not be obvious on clinical examination but can be detected with neurophysiologic and neuropsychiatric testing.

• Alanine aminotransferase, aspartate aminotransferase, bilirubin, alkaline phosphatase, glucose, calcium, electrolytes, blood urea nitrogen, creatinine, albumin
• Complete blood count, platelet count, prothrombin time, partial thromboplastin time
• Serum and urine toxicology screen in suspected medication or illegal drug use
• Blood and urine cultures, urinalysis
• Venous ammonia level. Measurement of serum ammonia level is useful in the evaluation of acute liver failure because levels correlate with the severity of encephalopathy and elevated levels are predictive of severe encephalopathy and cerebral edema. It is not useful for the evaluation or screening of hepatic encephalopathy in patients with chronic liver disease because it can neither rule in nor rule out hepatic encephalopathy, and levels do not correlate with the degree of encephalopathy
• Arterial blood gases

CT scan or MRI of the brain may be useful in selected patients to exclude other etiologies when diagnosis is unclear.

• Identification and treatment of precipitating factors (Table 2).
• Restriction of protein intake is ill-advised and not necessary since normal protein intake does not appear to exacerbate hepatic encephalopathy.

The approach to patients with high grade hepatic encephalopathy is shown in Fig. 2. Table 3 summarizes the management of fulminant hepatic failure.

Figure 2 Initial management of patient with high-grade encephalopathy.

CVVH, Continuous venovenous hemofiltration; ICH, intracranial hypertension; ICP, intracranial pressure.

From Parrillo JE, Dellinger RP: Critical care medicine: principles of diagnosis and management in the adult, ed 5, Philadelphia, 2019, Elsevier.

Reduction of colonic ammonia production:

• Lactulose 25 ml twice daily initially; dose is subsequently adjusted depending on clinical response to achieve production of three bowel movements daily. IV ornithine aspartate should be considered for those not responding to lactulose.
• The oral antibiotic rifaximin (550 mg PO bid) is effective in reducing the risk of recurrent hepatic encephalopathy in patients with cirrhosis and preventing post TIPS hepatic encephalopathy. It can be taken with lactulose, and the combination of lactulose and rifaximin is superior to lactulose alone in reversing hepatic encephalopathy. Rifaximin has also been shown to be effective in improving psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy. It is well tolerated but expensive.¹
• Probiotics (e.g., one capsule containing 112.5 billion viable lyophilized bacteria tid) might also be beneficial in altering gut flora to reduce ammonia production.

Treatment of cerebral edema:

• Cerebral edema is often present in patients with acute liver failure, and it accounts for nearly 50% of deaths. Monitoring intracranial pressure by epidural, intraparenchymal, or subdural transducers and treatment of cerebral edema with mannitol (100 to 200 ml of 20% solution [0.3 to 0.4 g/kg of body weight]) given by rapid IV infusion are helpful in selected patients (e.g., potential transplantation patients).
• Fig. 3 illustrates the management of a sustained rise in intracranial pressure in liver failure.
• Dexamethasone and hyperventilation (useful in head injury) are of little value in treating cerebral edema from liver failure.

Figure 3 Management of a sustained rise in intracranial pressure.

CPP, Cerebral perfusion pressure; ICP, intracranial pressure; JV, jugular venous; Sats, saturation.

From Parrillo JE, Dellinger RP: Critical care medicine: principles of diagnosis and management in the adult, ed 5, Philadelphia, 2019, Elsevier.

• Avoidance of any precipitating factors (e.g., high-protein diet, medications).
• Consideration of liver transplantation in selected patients with progressive or recurrent encephalopathy (Box 1). Liver transplantation remains the only curative therapeutic option.

Prognosis varies with the underlying etiology of the liver failure and the grade of encephalopathy (generally good for grades 1 or 2; poor for grades 3 or 4). Without proper therapy, the survival rate at 1 yr is 42% and decreases to 23% at 3 yr.

The early stages of hepatic encephalopathy can be managed in the outpatient setting, whereas stages III or IV require hospital admission.

• Trials have shown that adding IV albumin to lactulose may improve outcomes in severe hepatic encephalopathy by reducing oxidative stress through reduction of levels of circulating cytokines and endotoxins.
• Long-acting benzodiazepines should not be used to treat anxiety and sleep disorders in patients with cirrhosis, as they may precipitate encephalopathy.
• Patients not responding to supportive therapy should be evaluated for liver transplantation.
• Not all patients with cirrhosis develop hepatic encephalopathy. It has been shown that 40% of persons with cirrhosis and minimal hepatic encephalopathy do not develop overt hepatic encephalopathy in long-term follow-up. There are genetic factors associated with development of hepatic encephalopathy in patients with cirrhosis. Genetic analyses have shown that glutaminase TACC and CACC haplotypes are linked to the risk for overt hepatic encephalopathy.

Encephalopathy (Patient Information)

Cirrhosis (Related Key Topic)

Hepatic Encephalopathy (Related Key Topic)