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==Overview==
==Overview==
Hepatic encephalopathy (sometimes hepatoencephalopathy) is a potentially reversible neuropsychiatic abnormality in the setting of [[liver failure]], whether chronic (as in [[cirrhosis]]), or [[acute liver failure|acutely]]. It can be diagnosed only after exclusion of other neurological, psychiatric, infectious and metabolic etiologies.
Hepatic encephalopathy (sometimes hepatoencephalopathy) is a potentially reversible neuropsychiatic abnormality in the setting of [[liver failure]], whether chronic (as in [[cirrhosis]]), or [[acute liver failure|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.
 
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==
==Historical Perspective==
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==Classification==
==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==
==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 [[Intestine|intestines]] to go through the liver to get back to the [[heart]]. Portal-systemic [[Anastomosis|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]] (NH<sub>3</sub>) and [[Mercaptan|mercaptans]]. [[Ammonia]] is normally converted to [[urea]] by the liver and, as with [[Mercaptan|mercaptans]], is produced by the [[Bacterium|bacterial]] breakdown of protein in the intestines. [[Ammonia]] can cross the [[blood-brain barrier]], where it causes the support cells of the brain ([[Astrocyte|astrocytes]]) to swell. The swelling of the brain tissue increases [[intracranial pressure]], and can lead to [[coma]] or death via [[Brain herniation|herniation]] of the brainstem. Disorders and conditions such as [[alcoholic liver disease]], [[hepatitis C]], [[hepatitis B]], [[hemochromatosis]], [[Wilson's disease|Wilson disease]], age above 50 years and male gender may lead to hepatic encephalopathy.


==Causes==
==Causes==
Hepatic encephalopathy is caused by disorders that affect the liver. These include disorders that reduce liver function (such as [[cirrhosis]] or [[hepatitis]]) and conditions in which [[blood]] circulation does not enter the liver. The exact cause of hepatic encephalopathy is unknown.
The most common cause of hepatic encephalopathy is [[hepatic cirrhosis]], drugs/toxins and [[Fulminant hepatitis|acute fulminant hepatitis]]. Less common causes of hepatic encephalopathy include [[Wilson's disease]], [[Alpha 1-antitrypsin deficiency|alpha-1-antitripsin deficiency]], [[autoimmune hepatitis]], [[Budd-Chiari syndrome|Budd-chiari syndrome]], [[cancer]] or [[metastasis]] to [[liver]]), [[HELLP syndrome]]([[hemolysis]], elevated [[liver function tests]], and low [[Platelet|platelets]]) and [[sepsis]].


==Differentiating Hepatic Encephalopathy from other Diseases==
==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's encephalopathy|Wernicke encephalopathy]], [[alcohol intoxication]], [[Metabolic diseases|metabolic abnormalities]]([[hypoglycemia]], [[Electrolyte disturbance|electrolyte imbalance]], [[hypercarbia]], and [[uremia]]) ,toxic [[encephalopathy]] from drugs([[sedative]], [[Salicylic acid|salicylates]], [[antidepressants]] and [[antipsychotic drugs]]), altered [[intracranial pressure]](intra[[cranial]] [[Tumor|tumors]], ,[[subdural hematoma]], [[Intracranial hemorrhage|intracranial bleeding]] and [[Intracranial abscess|abscesses]]), [[intoxication]] by chemical agents, [[malnutrition]], [[hypoxia]] of brain, and sever intra[[Cranial|crania]]<nowiki/>l or systemic [[Infection|infections]]([[meningitis]] and [[encephalitis]]).


==Epidemiology and Demographics==
==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==
==Risk Factors==
Common risk factors leading to the development of hepatic encephalopathy include [[cirrhosis]], [[Acute liver failure|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==
==Screening==
There is insufficient evidence to recommend routine [[screening]] for hepatic encephalopathy.


==Natural History, Complications and Prognosis==
==Natural History, Complications and Prognosis==
Hepatic encephalopathy leads to changed cognitive function. This can range from subtle deficits in higher mental functions (in mild cases) to [[obtundation]] and coma (in severe cases). Left untreated, severe hepatic encephalopathy can cause death.
Hepatic encephalopathy may occur as an [[acute]], potentially reversible disorder or it may occur as a [[Chronic (medical)|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.
 
===Natural History===
 
===Complications===
 
===Prognosis===


==Diagnosis==
==Diagnosis==
===Diagnostic Criteria===


===History and Symptoms===
===History and Symptoms===
One of the earliest manifestations of hepatic encephalopathy is "day-night reversal". In other words, affected individuals tend to sleep during the day and stay awake at night. Another early manifestation is impairment in spatial perception. This can be made apparent by noting the patient's poor ability to copy or draw various simple images, e.g cube, star, clock. This deficit can also be demonstrated by administering a test which has the patient connect a number of randomly placed dots on a sheet of paper (the "trail test" or "numbers connecting test").
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 schedule|sleep-wake pattern]] (combination of restless nights and [[excessive daytime sleepiness]]), [[personality changes]], [[Altered mental status|altered level of consciousness]], bilateral flapping hand [[tremors]] on [[arm]] [[extension]] ([[asterixis]]), [[confusion]] and [[irritability]].


===Physical Examination===
===Physical Examination===
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===Laboratory Findings===
===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 [[Wrist|wrists]] back. In the presence of [[asterixis]], there is a non-synchronized, intermittent flapping motion at the [[Wrist|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-rays|x-ray]] findings associated with hepatic encephalopathy.


===Imaging Findings===
=== CT scan ===
Common CT findings of hepatic encephalopathy include cerebral edena in early stages of encephalopathy.
 
=== MRI ===
Brain [[Magnetic resonance imaging|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 wave|theta band]].


===Other Diagnostic Studies===
===Other Diagnostic Studies===
[[Psychometrics|Psychometric]] testing may be helpful in the diagnosis of hepatic encephalopathy. The number connection test (trail making test or Reitan Test) can help. The [[Psychometrics|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==
==Treatment==


===Medical Therapy===
===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]], [[Antibiotic|antibiotics]], [[rifaximin]], [[benzodiazepine]] receptor antagonists, L-[[ornithine]]-L-[[aspartate]] and correction of [[hypokalemia]].


===Surgery===
===Surgery===
Surgical intervention is not recommended for the management of hepatic encephalopathy but [[Liver transplantation|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]].


===Prevention===
=== Secondary 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.
Measuring of blood [[ammonia]] level may be helpful in early diagnosis of hepatic encephalopathy in patients with hepatic [[cirrhosis]].


==References==
==References==

Latest revision as of 05:34, 6 July 2020

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Overview

Historical Perspective

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Pathophysiology

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Differentiating Hepatic Encephalopathy from other Diseases

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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.

References

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