Hepatic encephalopathy overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]
Overview
Hepatic encephalopathy (sometimes hepatoencephalopathy) is a potentially reversible neuropsychiatic abnormality in the setting of liver failure, whether chronic (as in cirrhosis), or acutely. It can be diagnosed only after exclusion of other neurological, psychiatric, infectious and metabolic etiologies. With severe liver impairment, toxic substances normally removed by the liver accumulate in the blood and impair the function of brain cells. If there is also portal hypertension, and subsequent bypassing of the liver filtration system of blood flowing in from the intestines, these toxic substances can travel directly to the brain, without being modified or purified. Signs can include impaired cognition, a flapping tremor (asterixis), and a decreased level of consciousness including coma (hepatic coma or coma hepaticum), cerebral edema, and, ultimately, death.
Historical Perspective
Hepatic encephalopathy was first discovered by GB. Morgagni, an italian anatomist, in the 18th century. Friedrich Theodor von Frerichs, in the 19th century clearly reported the existence of episodes of delirium, somnolence and coma in liver disease in his famous treatise on liver disease. In 1954, Dame Sheila Patricia Violet Sherlock and her disciples in London gave a definite improvement in the description of the clinical findings, the pathophysiology and treatment of hepatic encephalopathy. For the first time she confirmed the role of hyperammonaemia in the pathophysiology of the hepatic encephalopathy and the role of gut microbiota that could be modulated by antibiotics to revert coma. In 1954, Dame Sheila Patricia Violet Sherlock and her disciples in London gave a definite improvement in the description of the treatment of hepatic encephalopathy.
Classification
Hepatic encephalopathy may be classified based on underlying liver disease into three types type A (acute), Type B (bypass) and type C (cirrhosis). The evaluation of severity of persistent hepatic encephalopathy is based on the West Haven Criteria. It includes mental status, level of impairment of autonomy, changes in consciousness, intellectual function, behavior, and the dependence on therapeutic factors into grading.
Pathophysiology
Due to the presence of scarring within the liver, cirrhosis leads to obstruction of the passage of blood through the liver causing portal hypertension. This means it is difficult for blood from the intestines to go through the liver to get back to the heart. Portal-systemic anastamoses ("shunts") develop, and portal blood (from the intestinal veins) will bypass the liver and return to the heart via another route without undergoing first-pass detoxification by the liver. The toxic substances which accumulate in the setting of liver failure and affect the brain have been thought to include ammonia (NH3) and mercaptans. Ammonia is normally converted to urea by the liver and, as with mercaptans, is produced by the bacterial breakdown of protein in the intestines. Ammonia can cross the blood-brain barrier, where it causes the support cells of the brain (astrocytes) to swell. The swelling of the brain tissue increases intracranial pressure, and can lead to coma or death via herniation of the brainstem. Disorders and conditions such as alcoholic liver disease, hepatitis C, hepatitis B, hemochromatosis, Wilson disease, age above 50 years and male gender may lead to hepatic encephalopathy.
Causes
The most common cause of hepatic encephalopathy is hepatic cirrhosis, drugs/toxins and acute fulminant hepatitis. Less common causes of hepatic encephalopathy include Wilson's disease, alpha-1-antitripsin deficiency, autoimmune hepatitis, Budd-chiari syndrome, cancer or metastasis to liver), HELLP syndrome(hemolysis, elevated liver function tests, and low platelets) and sepsis.
Differentiating Hepatic Encephalopathy from other Diseases
Hepatic encephalopathy must be differentiated from other diseases that cause personality changes, altered level of consciousness and jerking movement of the limbs(asterixis) such as, complicated alcohol withdrawal, Wernicke encephalopathy, alcohol intoxication, metabolic abnormalities(hypoglycemia, electrolyte imbalance, hypercarbia, and uremia) ,toxic encephalopathy from drugs(sedative, salicylates, antidepressants and antipsychotic drugs), altered intracranial pressure(intracranial tumors, ,subdural hematoma, intracranial bleeding and abscesses), intoxication by chemical agents, malnutrition, hypoxia of brain, and sever intracranial or systemic infections(meningitis and encephalitis).
Epidemiology and Demographics
The prevalence of subclinical hepatic encephalopathy estimated to be 62,000 cases per 100,000 in patients with hepatic cirrhosis. The survival probability of hepatic encephalopathy is approximately 42% at 1 year and 23% at 3 years in follow-up. Chronic liver disease and cirrhosis which are the main causes of hepatic encephalopathy, affect more than 5.5 million people in the United States and hundreds of millions all over the world.
Risk Factors
Common risk factors leading to the development of hepatic encephalopathy include cirrhosis, acute hepatic failure, portacaval shunt, and gastrointestinal bleeding. Less common risk factors include, epilepsy, diabetes mellitus, hyponatremia, renal failure, hyperbilirubinemia, hypokalemia, metabolic alkalosis, sepsis and hypovolemia.
Screening
There is insufficient evidence to recommend routine screening for hepatic encephalopathy.
Natural History, Complications and Prognosis
Hepatic encephalopathy may occur as an acute, potentially reversible disorder or it may occur as a chronic, progressive disorder that is associated with chronic liver disease. If left untreated, patients with hepatic encephalopathy may progress to develop brain edema (may lead to brain herniation, secondary structural damage to the brain, and death. Common complications of hepatic encephalopathy include status epilepticus, aspiration, hypernatremia, severe perianal irritation and eventually death. Prognosis of patients with hepatic encephalopathy is generally poor. Factors known to be associated with a poorer prognosis in cases of hepatic encephalopathy include, male sex, hyperbilirubinemia, increased alkaline phosphatase levels, hyperkalemia, hyperalbuminemia and decreased prothrombin activity.
Diagnosis
History and Symptoms
In patients with hepatic encephalopathy, symptoms may have an insidious onset and progression, or may begin suddenly and progress rapidly. The hallmark of hepatic encephalopathy is hyperammonemia. A positive history of hepatic failure is suggestive of hepatic encephalopathy. The most common symptoms of hepatic encephalopathy include inverted sleep-wake pattern (combination of restless nights and excessive daytime sleepiness), personality changes, altered level of consciousness, bilateral flapping hand tremors on arm extension (asterixis), confusion and irritability.
Physical Examination
In addition to changed level of consciousness, the hallmark of hepatic encephalopathy on the physical examination is the presence of asterixis. This is detected by having the patient hold out his outstretched arms and hands and cock his wrists back. In the presence of asterixis, there is a non-synchronized, intermittent flapping motion at the wrists. Asterixis is not specific to hepatic encephalopathy. It may also be seen in states such as renal failure and carbon dioxide retention.
Laboratory Findings
In addition to changed level of consciousness, the hallmark of hepatic encephalopathy on the physical examination is the presence of asterixis. This is detected by having the patient hold out his outstretched arms and cocking his wrists back. In the presence of asterixis, there is a non-synchronized, intermittent flapping motion at the wrists. Asterixis is not specific to hepatic encephalopathy. It may also be seen in states such as renal failure and carbon dioxide retention.
X-ray
There are no x-ray findings associated with hepatic encephalopathy.
CT scan
Common CT findings of hepatic encephalopathy include cerebral edena in early stages of encephalopathy.
MRI
Brain MRI may be helpful in the diagnosis of hepatic encephalopathy. Findings on MRI suggestive of of hepatic encephalopathy include symmetric high signal within the insula, thalamus, posterior limbs of the internal capsule, and cingulate gyrus in mild cases and diffuse cortical edema and hyperintensity with typically spared perirolandic and occipital regions in sever cases.
Ultrasound
There are no ultrasound findings associated with hepatic encephalopathy, but ultrasound may be helpful in the diagnosis of underlying causes of hepatic encephalopathy like hepatic cirrhosis.
Other Imaging Findings
Electroencephalography may be helpful in the diagnosis of hepatic encephalopathy but, the findings in Electroencephalography are not specific for diagnosis of hepatic encephalopathy. Findings on an electroencephalography suggestive of hepatic encephalopathy include reduced frequency in the posterior derivations and increase in interhemispheric parietal relative coherence within the theta band.
Other Diagnostic Studies
Psychometric testing may be helpful in the diagnosis of hepatic encephalopathy. The number connection test (trail making test or Reitan Test) can help. The Psychometric Hepatic Encephalopathy Score (PHES) may help including a simplified version (SPHES). The SPHES drops the trail making tests and so includes digit symbol test (DST), serial dotting test (SDT), line tracing test (LTT).
Treatment
Medical Therapy
Supportive therapy for hepatic encephalopathy includes reduce protein intake, endotracheal intubation and mechanical ventilation in high grade hepatic encephalopathy. Pharmacologic medical therapies for hepatic encephalopathy include lactulose, antibiotics, rifaximin, benzodiazepine receptor antagonists, L-ornithine-L-aspartate and correction of hypokalemia.
Surgery
Surgical intervention is not recommended for the management of hepatic encephalopathy but liver transplant may be used to treat the liver diseases which are the underlying causes of hepatic encephalopathy.
Primary Prevention
Treating liver disorders may prevent some cases of hepatic encephalopathy. Avoiding heavy drinking and intravenous drug use can prevent many liver disorders. If there are any nervous system symptoms in a person with known or suspected liver disease, calling for immediate medical attention helps. Usage of lactulose is helpful in prevention of HE in patients with cirrhosis and acute variceal bleeding. Lactulose may be effective to prevent of recurrence of hepatic encephalopathy in patients with cirrhosis.
Secondary Prevention
Measuring of blood ammonia level may be helpful in early diagnosis of hepatic encephalopathy in patients with hepatic cirrhosis.