Hepatic encephalopathy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]

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.

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.

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.

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.

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.

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).

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.

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.

There is insufficient evidence to recommend routine screening for hepatic encephalopathy.

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.

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.

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.

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.

There are no x-ray findings associated with hepatic encephalopathy.

Common CT findings of hepatic encephalopathy include cerebral edena in early stages of encephalopathy.

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.

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.

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.

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).

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.

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.

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.

Measuring of blood ammonia level may be helpful in early diagnosis of hepatic encephalopathy in patients with hepatic cirrhosis.

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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]

Hepatic encephalopathy was first discovered by G.B. Morgagni, an italian anatomist, in the 18th century who described a case of hepatic encephalopathy. 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 detailed 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 microbes which could be modulated by antibiotics to revert coma.

• In 18th century, G.B. Morgagni, an italian anatomist, was the first to discover and describe a case of hepatic encephalopathy.^[1]
• In the 19th century, Friedrich Theodor Von Frerichs for the first time reported the existence of episodes of delirium, somnolence and coma in liver disease in his famous treatise on liver disease.^[1]
• In 1954, Dame Sheila Patricia Violet Sherlock and her disciples in London gave a deatiled description of the clinical findings, the pathophysiology and treatment of hepatic encephalopathy.
• For the first time, she also confirmed the role of hyperammonaemia in the pathophysiology of the hepatic encephalopathy and the role of gut microbes, that could be modulated by antibiotics to revert coma.^[2]

• In 1954, Dame Sheila Patricia Violet Sherlock and her disciples published a detailed description of the treatment of hepatic encephalopathy.^[2]

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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]

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.

According to world congress of gastroenterology, hepatic encephalopathy can be subdivided based on underlying liver disease association into type A, B, and C^[1][2][3]

• Type A (acute): Describes hepatic encephalopathy associated with acute liver failure
• Type B (bypass): Is caused by portal-systemic shunting without associated intrinsic liver disease
• Type C (cirrhosis): Occurs in patients with cirrhosis (chronic liver disease)

Based on the duration and characteristics of hepatic encephalopathy, it can be classified into episodic, persistent, and minimal^[4]

• Episodic hepatic encephalopathy: Has a short time span and fluctuates in severity
• Persistent hepatic encephalopathy: Occurs as a chronic clinical condition of cognitive deficits
• Minimal hepatic encephalopathy (MHE): Occurs in patients with cirrhosis who do not demonstrate clinically overt cognitive dysfunction, but who show a cognitive impairment on neuropsychological studies^[5][6]

The evaluation of severity of persistent hepatic encephalopathy is based on the West Haven Criteria.^[2][1]

West Haven Criteria

• Grade 1:
  • Trivial lack of awareness
  • Euphoria or anxiety
  • Short attention span
  • 67% of cirrhotic patients may have minimal hepatic encephalopathy^[7]

• Grade 2:
  • Lethargy or apathy
  • Minimal disorientation to time or place
  • Subtle personality change
  • Impaired performance in doing mathematical problems (specially subtraction)
• Grade 3:
  • Somnolence to semi-stupor, but responsive to verbal stimuli
  • Confusion
  • Gross disorientation
• Grade 4:
  • Coma (unresponsive to verbal or noxious stimuli)

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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]

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.

Following important aspects about pathophysiology of hepatic encephalopathy:^[1][2][3][4]

• Due to the presence of scarring within the liver, cirrhosis leads to obstruction of the passage of blood through the liver causing portal hypertension.
• Portal hypertension makes it difficult for blood from the intestines to go through the liver to the heart.
• As a result 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.
• Furthermore, in cirrhosis and other forms of liver disease, the liver will not be fully functional, so even blood that does travel through the liver may not be as detoxified as it otherwise would be.
• The toxic substances accumulate, of which ammonia (NH₃) and mercaptans are the most common toxic substrates responsible for encephalopathy.
• Ammonia is normally converted to urea by the liver and, as with mercaptans, is produced by the bacterial breakdown of protein in the intestine.
• Ammonia and mercaptans can cross the blood-brain barrier, which causes astrocytes (support cells) to swell and subsequent inflammation.
• The swelling of the brain tissue increases intracranial pressure, and can lead to coma or death via herniation of the brainstem.

There is no established relation between hepatic encephalopathy and genetic inheritance.

Any disorders with liver failure may lead to hepatic encephalopathy.

• Disorders and conditions which may lead to hepatic encephalopathy include:^{[5][6][7][8][9][10]}
  • Alcoholic liver disease
  • Hepatitis C
  • Hepatitis B
  • Hemochromatosis
  • Wilson’s disease
  • Age above 50 years
  • Male gender
  • Eating too much protein
  • Bleeding from the intestines, stomach, or esophagus
  • Shunt placement or complications (Transjugular intrahepatic portosystemic shunt)

Microscopic studies of specimens from patients with hepatic encephalopathy suggests:^[3]

• Astrocytic changes
• Cellular swelling

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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]

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.

Common causes of hepatic encephalopathy include:^[1]

• Hepatic cirrhosis
• Drugs and toxins (acetaminophen^[2], amoxicilin/clavulanate^[3], halothane^[4], iron^[5], isoniazid^[6] ,carbon tetrachloride^[7], Wild mushroom Amanita phalloides^[8])
• Acute fulminant viral hepatitis^[9]

Less common causes of hepatic encephalopathy include:

• Wilson’s disease^[10]
• Alpha-1-antitripsin deficiency^[11]
• Autoimmune hepatitis^[12]
• Budd-chiari syndrome^[13]
• Cancer (primary hepatic cancer or metastasis to liver)^[14]
• HELLP syndrome (hemolysis, elevated liver function tests, and low platelets)^[15]
• Sepsis^[16]
• Right heart failure^[17]

Cardiovascular	Budd-chiari syndrome Right heart failure
Chemical/Poisoning	Drug and toxins(acetaminophen, amoxicilin/clavulanate, halothane, iron, NSAIDs, isoniazid ,carbon tetrachloride, Wild mushroom Amanita phalloides)
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	No underlying causes
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastrohepatic	Hepatic cirrhosis, acute fulminant viral hepatitis, Wilson’s disease, hemochromatosis, alpha-1-antitripsin deficiency, autoimmune hepatitis, cancer (primary hepatic cancer or metastasis to liver)
Genetic	No underlying causes
Hematologic	Porphyria, HELLP syndrome (hemolysis, elevated liver function tests, and low platelets)
Iatrogenic	No underlying causes
Infectious Disease	Sepsis
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	No underlying causes
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

List the causes of the disease in alphabetical order.

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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]

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).

Hepatic encephalopathy must be differentiated from other diseases that cause personality changes, altered level of consciousness and hand tremors (asterixis). The differentials include the following:^{[1][2][3][4][5][6][7][8][9][10][11]}

Diseases	History and Symptoms			Physical Examination				Laboratory Findings
	Personality changes	Altered level of consciousness	Hand tremors (asterixis)	Slurred speech	Writing disturbances	Voice monotonous	Impaired memory	Elevated blood ammonia	Hyponatremia	hypokalemia
Hepatic encephalopathy	++	++	++	++	++	++	++	++	++	++
Alcohol intoxication	+	+	-/+	++	+	–	+	–	-/+	-/+
Alcohol withdrawal	+	+	–	++	+	–	+	–	-/+	-/+
Uremia	++	++	+	-/+	-/+	-/+		–	++	Hyperkalemia
Wernicke encephalopathy	+	+	-/+	+	+	+	++	–	–	–
Toxic encephalopathy from drugs	+	+	-/+	-/+	+	-/+	+	+	-/+	-/+
Altered intracranial pressure	+	-/+	–	-/+	-/+	–	-/+	–	–	–
Intoxication by chemical agents	-/+	-/+	-/+	-/+	-/+	–	–	–	-/+	-/+
Malnutrition	-/+	–	–	–	-/+	–	-/+	–	-/+	-/+
Hypoxic brain injury	–	-/+	–	-/+	-/+	-/+	-/+	–	–	–
Meningitis and encephalitis	-/+	-/+	–	-/+	+	–	–	–	-/+	–
Hypoglycemia	-/+	-/+	–	-/+	-/+	–	–	–	-/+	-/+

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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]

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.

• The incidence of hepatic encephalopathy is unknown.
• The prevalence of subclinical hepatic encephalopathy estimated to be 62,000 cases per 100,000 in patients with hepatic cirrhosis.^[1]

The survival probability of hepatic encephalopathy is approximately 42% at 1 year and 23% at 3 years in follow-up.^[2]

• The incidence of hepatic encephalopathy increases with aging.

• Men are more commonly affected by hepatic encephalopathy than women.

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.^[3]

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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]

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.

• Common risk factors leading to the development of hepatic encephalopathy include:^[1][2][3][4]
  • Cirrhosis
  • Acute hepatic failure
  • Gastrointestinal bleeding
  • Portacaval shunt

• Less common risk factors leading to the development of hepatic encephalopathy include:^[5][6][7]
  • Epilepsy
  • Diabetes mellitus
  • Hyponatraemia
  • Renal failure
  • Hyperblilirubinemia
  • Hypokalemia
  • Metabolic alkalosis
  • Sepsis
  • Hypovolemia

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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]

There is insufficient evidence to recommend routine screening for hepatic encephalopathy.

There is insufficient evidence to recommend routine screening for hepatic encephalopathy.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]

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.

• 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.^[1]

• 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)^[2]

• Common complications of hepatic encephalopathy include:^[3][4]
  • Status epilepticus
  • Aspiration(due to overuse of lactulose)
  • Hypernatremia(due to overuse of lactulose)
  • Severe perianal skin irritation(due to overuse of lactulose)
  • death

• Prognosis of patients with hepatic encephalopathy is generally poor:^[5][6]
  • One year survival rate of patients with hepatic encephalopathy is approximately 42%.
  • Three year survival rate of patients with hepatic encephalopathy is approximately 23%.
• The presence of some factors is associated with a particularly poorer prognosis among patients with hepatic encephalopathy. These factors include the following:
  • Elevated plasma ammonia (≥79.5 µmol/L)^[7]

• • Male sex

• • Increased serum bilirubin
  • Increased alkaline phosphatase
  • Increased potassium and blood urea nitrogen
  • Decreased serum albumin
  • Decreased prothrombin activity

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