HE presentation can be classified based on the grading of its symptoms with the West Haven classification system. According to this system, there are five different grades of HE described as follows:

Grade 0: No detectable changes in the patient’s personality; minimal changes in memory, coordination, intellectual function and concentration.

Grade 1: Minimal lack of awareness; decreased attention capability; hypersomnia, insomnia, or inverted sleep pattern; depression usually accompanied by alternated moments of euphoria and irritability; slowed mental task performance (especially mathematical operations); mild confusion.

Grade 2: Marked personality changes usually accompanied by inappropriate behavior and slurred speech; heavily reduced mental task performance; recurrent/intermittent time disorientation; frequent lethargy/apathy.

Grade 3: Compromised mental task performance; time and space disorientation; marked personality changes with confusion, incomprehensible speech, fits of rage and amnesia.

Grade 4: Coma frequently accompanied by the absence of painful stimuli response.

In grade zero and one HE is also defined as “covert”, because of the minimal evidence of symptoms. By contrast, in the remaining three grades HE is defined as “overt” because of the marked evidence of these symptoms [12] [13]. The 11th World Congress of Gastroenterology in Vienna (1998) decided to further classify HE based on the underlying cause [14], in a system which includes three types of disease: type A, associated with acute liver failure, type B, associated with portal-systemic shunting, and type C associated with cirrhosis.

• Fatigue

  The 59-year-old patient had esophageal varices bleeding due to primary biliary cirrhosis (ammonium blood level: 140 mmoL/L) and presented with sensory Jacksonian seizures, dysarthria, and increased drowsiness and fatigue. [ncbi.nlm.nih.gov]

  Signs and Symptoms [ ✎ edit | edit source ] Signs of chronic hepatic disease: [ ✎ edit | edit source ] icterus anorexia and fatigue ascites splenomegaly Neurological changes: [ ✎ edit | edit source ] mind disorder changes in behavior flapping tremor drowsiness [wikilectures.eu]

  […] poor judgement poor concentration change in sleep patterns worsening of handwriting or small hand movement Severe symptoms of hepatic encephalopathy unusual movements or shaking of hands or arms extreme anxiety seizures severe confusion sleepiness or fatigue [britishlivertrust.org.uk]

  As the condition progresses, symptoms may include: Changes in behavior and personality Shortened attention span Depression or anxiety Insomnia Fatigue Forgetfulness Disorientation Slurred speech Tremor, particularly a flapping tremor of the hands Confusion [uvahealth.com]

• Constipation

  Although the true mechanism of hyperammonemia in this case is unclear, we speculate that organic constipation following chronic obstruction of the colon might have played a role in the development of the condition. [ncbi.nlm.nih.gov]

  [edit] Lactulose is used in the treatment of chronic constipation in patients of all ages as a long-term treatment.[14] The dosage of lactulose for chronic idiopathic constipation is adjusted depending on the constipation severity and desired effect, [en.wikipedia.org]

  • Excessive nitrogen load- excess protein consumption, gastro- intestinal bleeding, renal failure, constipation. • Electrolyte or metabolic disturbance-hypokalaemia, hyponatremia, alkalosis, dehydration, excess vomiting. • Infections- pneumonia, UTI [slideshare.net]

  Opiates are particularly problematic as they potentiate constipation and, therefore, must be used at the lowest possible dose with appropriate laxatives prescribed concomitantly. [bsg.org.uk]

• Nausea

  In a fixed-effect meta-analysis, we found that BCAA increased the risk of nausea and vomiting (RR 5.56; 2.93 to 10.55; moderate quality of evidence). [ncbi.nlm.nih.gov]

  There was no placebo group.11 Routine use has been limited due to concerns regarding sodium load and increased frequency of adverse gastrointestinal symptoms, particularly nausea. [the-hospitalist.org]

  The non-absorbable disaccharides were associated with adverse events including diarrhoea, nausea, bloating, and flatulence. None of the RCTs comparing lactulose versus lactitol reported quality of life. [cochrane.org]

  Side effects might include nausea, bloating, abdominal discomfort, diarrhea, and dehydration. [badgut.org]

• Asterixis

  Asterixis can be detected. 26 27. Grade 2 Lethargy or apathy. Disorientation. Inappropriate behavior. Slurred speech. Obvious asterixis. [slideshare.net]

  Secondary end points were mortality from HE or any other cause, decrease in mental status grade, asterixis grade, serum Ammonia grade, NCT grade. [ncbi.nlm.nih.gov]

  Clinical features include lethargy and confusion (frequently progressing to coma); asterixis; nystagmus, pathologic; brisk oculovestibular reflexes; decorticate and decerebrate posturing; muscle spasticity; and bilateral extensor plantar reflexes (see [icd9data.com]

  Component Description 1 Mental state (West Haven) 2 EEG findings (mean cycle frequency) 3 Serum ammonia concentration 4 Intellectual function (number connection test) 5 Severity of asterixis Table 4 The portal-systemic encephalopathy score Component [doi.org]

• Jaundice

  There is described the case of a 27-year-old patient with jaundice and hepatic encephalopathy with long history of alcohol dependence and substance abuse. The patient was successfully treated using liver dialysis method (Prometheus® system). [ncbi.nlm.nih.gov]

  Skin may be jaundiced (yellow skin and eyes). Ascites (fluid collection in the abdomen) may be noted because of increased body weight, abdominal enlargement, and abdominal examination that shows free fluid in the abdomen. [hepatitiscentral.com]

  Examination reveals a jaundiced male who appears older than stated age. Abdominal exam is positive for a fluid wave and shifting dullness to percussion. [medbullets.com]

  As HE most often occurs as a complication of liver failure, there may be other symptoms present, reflective of the underlying severity of liver disease, such as yellow discolouration of skin (jaundice) and/or eyes (scleral icterus), and fluid accumulation [badgut.org]

• Fetor Hepaticus

  Fetor hepaticus • This is a sour, musty odour in the breath, due to volatile substances normally formed in the stool by bacteria. • These mercaptans if not removed by the liver are excreted through the lungs and appear in the breath. • Fetor hepaticus [slideshare.net]

  There is accompanying fetor hepaticus and asterixis. Patients are stuporous with marked confusion. They are barely responsive to painful stimuli. If it can be elicited, asterixis should be present. [enotes.tripod.com]

  Moderate Confusion Asterixis Fetor hepaticus Hypothermia Hyperventilation Video on the pathophysiology of hepatic encephalopathy Investigations in hepatic encephalopathy Full septic screen Ascitic tap to check for SBP Digital rectal exam (DRE) to check [oxfordmedicaleducation.com]

  Symptoms There is a disturbance of consciousness that may progress to deep coma (hepatic coma), psychiatric changes of varying degree, flapping tremor, and fetor hepaticus (breath odor associated with hepatic disease). [healthcentral.com]

  A musty, sweet breath odor (fetor hepaticus) can occur regardless of the stage of encephalopathy. [msdmanuals.com]

• Euphoria

  • Changes in personality childish behaviour irritability loss of concern for family aggressive outburst euphoria defaecation and micturating in inappropriate places Fetor hepaticus 17 18. [slideshare.net]

  View/Print Table West Haven Criteria for Grading of Mental Status Grade Criteria Grade 0 No signs or symptoms Grade 1 Trivial lack of awareness Euphoria or anxiety Shortened attention span Impaired performance of addition Grade 2 Lethargy or apathy Minimal [aafp.org]

  SX of encephalopathy: may begin with mild confusion, irrational behavior, euphoria, or psychosis. It is usually associated with a widely fluctuating but progressive deterioration of the mental state. [enotes.tripod.com]

  Grade 1 : mild confusion, euphoria or depression, decreased attention, slowing of ability to perform mental tasks, irritability, disorder of sleep pattern such as inverted sleep cycle. [oxfordmedicaleducation.com]

  간질환> 간경화> 간성 뇌증 간성 뇌증 (Hepatic Encephalopathy) 단계(Grading) 0단계(Grade 0) 정상소견 혹은 약간의 정신기능의 이상(Clinically normal mental status but minimal changes in memory, concentration, intellectual function, and coordination) 1단계(Grade 1) 약한 혼돈(Mild confusion), 다행증(euphoria [clinicclinic2.cafe24.com]

• Psychiatric Manifestation

  HE produces a wide spectrum of nonspecific neurological and psychiatric manifestations. Minimal HE is diagnosed by abnormal psychometric tests. [ncbi.nlm.nih.gov]

• Confusion

  From Wikidata Jump to navigation Jump to search brain disease that is characterized by loss of brain function, the occurrence of confusion, altered level of consciousness, and coma that results when the liver is unable to remove toxins from the blood [wikidata.org]

  Mild confusion. Slowing of ability to perform mental tasks. Asterixis can be detected. 26 27. Grade 2 Lethargy or apathy. Disorientation. Inappropriate behavior. Slurred speech. Obvious asterixis. [slideshare.net]

  Clinical features include lethargy and confusion (frequently progressing to coma); asterixis; nystagmus, pathologic; brisk oculovestibular reflexes; decorticate and decerebrate posturing; muscle spasticity; and bilateral extensor plantar reflexes (see [icd9data.com]

  People become confused, disoriented, and drowsy, with changes in personality, behavior, and mood. Doctors base the diagnosis on symptoms, results of the examination, and response to treatment. [merckmanuals.com]

• Seizure

  The 59-year-old patient had esophageal varices bleeding due to primary biliary cirrhosis (ammonium blood level: 140 mmoL/L) and presented with sensory Jacksonian seizures, dysarthria, and increased drowsiness and fatigue. [ncbi.nlm.nih.gov]

  All told, between 30 and 45 percent of people with cirrhosis will develop some signs of hepatic encephalopathy, whether it be mild forms of forgetfulness or more severe bouts of amnesia or seizures. [verywell.com]

  However, sometimes is the brain damage reversible and the seizures recur (so called chronic hepatic encephalopathy). Unfortunatelly, they still progress and after months or years they lead to the irreversible damage. [wikilectures.eu]

  EEG reflects high-amplitude low-frequency waves and triphasic ones, though seizures have to be excluded here in the first order. This method is quite informative in differential diagnosis of cirrhosis and mental disorders. [lecturio.com]

  Anticonvulsants may be prescribed to reduce or halt any seizures. Changes to diet and nutritional supplements may help some patients. In severe cases, dialysis or organ replacement surgery may be needed. [marefa.org]

• Irritability

  We present a case of decompensated liver cirrhosis with ascites, which had history of asterixis, impaired balance with swaying gait along with mild irritability since 1 month. [ncbi.nlm.nih.gov]

  Their ability to concentrate is reduced and they become more anxious and irritable. Untreated, patients with hepatic encephalopathy progress to coma and, ultimately, death. [drfalkpharma.com]

  • Changes in personality childish behaviour irritability loss of concern for family aggressive outburst euphoria defaecation and micturating in inappropriate places Fetor hepaticus 17 18. [slideshare.net]

  […] blood brain barrier and is metabolized by astrocytes to synthesize glutamine Glutamine increases the osmotic pressure within the astrocyte and is thought to cause mitochondrial dysfunction Clinical features Behavioral and personality changes, including irritability [pathologyoutlines.com]

  Hepatic encephalopathy Pathology Type Systemic Cause(s) Declining liver function Symptoms Forgetfullness, confusion, irritability, inverted sleep-wake pattern, tremors, coordination difficulties, difficulty writing, Mortality Rate High if untreated Treatments [house.wikia.com]

• Somnolence

  Clinically overt HE includes personality changes, alterations in consciousness progressive disorientation in time and space, somnolence, stupor and, finally, coma. Except for clinical studies, no specific tests are required for diagnosis. [ncbi.nlm.nih.gov]

  CLINICAL FEATURES • Disturbance in consciousness disturbance in sleep pattern hypersomnia-earliest feature progress to inversion of sleep pattern fixed stare impaired memory mental confusion apathy drowsiness somnolence coma 16 17. [slideshare.net]

  Back to the Case Our patient has severe HE manifested by worsening somnolence. [the-hospitalist.org]

  […] awareness Euphoria or anxiety Shortened attention span Impaired performance of addition Grade 2 Lethargy or apathy Minimal disorientation for time or place Subtle personality change Inappropriate behavior Impaired performance of subtraction Grade 3 Somnolence [aafp.org]

  […] turning into lethargy, impairment of performance of mental tasks, obvious changes of personality, time disorientation Grade 3 – somnolent but may be awakened, completely unable to conduct intellectual tasks, place and time disorientation, significant [lecturio.com]

• Cognitive Impairment

  RESULTS: Compared with control subjects, the patients with cirrhosis had lower psychometric HE scores, indicating cognitive impairments. [ncbi.nlm.nih.gov]

Diagnosis of HE is very difficult, as diseases with similar symptoms are many and differential diagnoses is very frequent [15]. Therefore, diagnosis of HE can only be made when the presence of a liver disorder or a portosystemic shunt has been confirmed with a liver function test or ideally a liver biopsy [16] [17].

Hemorrhage and seizures also have symptoms very similar to those of HE, but this conditions can be easily detected with CT scan of the brain or electroencephalography. The presence of HE can be further confirmed with other examinations such as chest X-ray, blood tests or urinalysis. In addition, there are a number of neurological tests [14] [18] [19] which might be very useful to diagnose the disorder, but they are not very frequently employed and the decision to use them should be based on the severity of the patient’s mental dysfunction.

• Triphasic Waves

  waves (5 cycles/s) 2 Lethargy, slow responses Asterixis, dysarthria, ataxia and hypoactive reflexes Triphasic waves (5 cycles/s) 3 Somnolence but rousable, confusion Disorientation as regards place; amnesia; disinhibited; and inappropriate behaviour [doi.org]

  Electroencephalography may demonstrate triphasic waves. [icd9data.com]

  EEG High-amplitude low-frequency waves and triphasic waves – not specific for hepatic encephalopathy. [oxfordmedicaleducation.com]

  ELECTROENCEPHALOGRAPHY may demonstrate triphasic waves. [fpnotebook.com]

• Electroencephalogram Abnormal

  Søren Schou Olesen, Carina Graversen, Tine Maria Hansen, Rolf Ankerlund Blauenfeldt, Jesper Bach Hansen, Kristoffer Steimle and Asbjørn Mohr Drewes, Spectral and dynamic electroencephalogram abnormalities are correlated to psychometric test performance [dx.doi.org]

• Hyponatremia

  Risk Factors that increase your chances of developing hepatic encephalopathy include: Certain conditions that affect the levels of fluids and electrolytes such as hyponatremia and hyperkalemia Kidney failure Infections Gastrointestinal bleeding Certain [uvahealth.com]

  […] most common): 50% 4 excessive nitrogen-containing intestinal load gastrointestinal bleed (e.g. from varices) dietary intake of large quantities of protein (e.g. meat) reduced nitrogen excretion constipation renal failure metabolic or drug interactions hyponatremia [radiopaedia.org]

  • Electrolyte or metabolic disturbance-hypokalaemia, hyponatremia, alkalosis, dehydration, excess vomiting. • Infections- pneumonia, UTI, spontaneous bacterial peritonitis. • Unknown- 20-30% 7 8. PATHOGENESIS 1. [slideshare.net]

  Electrolyte abnormalities • Renal insufficiency: creatinine > 1.5 mg/dL • Perform laboratory tests (pH, sodium, potassium, creatinine) • Hyponatremia: Na < 130 mEq/L • Hypophosphatemia: <3 mEq/L • Hypokaliemia: <3 mEq/L • Hypochloremia 1. [aasldpubs.onlinelibrary.wiley.com]

  Laboratory Abnormalities in Hepatic Encephalopathy Laboratory abnormalities typically include evidence of hepatic biochemical and synthetic dysfunction, and electrolyte disturbances (such as hyponatremia and hypokalemia). [clevelandclinicmeded.com]

Treatment for patients affected by HE depends on the its underlying cause, be it an acute liver failure (type A), a portal-systemic shunting (type B) or cirrhosis (type C). If necessity requires it, the physician might choose to send the patient to a specialist centre and receive the appropriate procedures, such as liver transplant or shunt occlusion. In regard to the treatments themselves, these can be divided in two groups, those which aim at decreasing intestinal ammonia production and those which aim at increasing ammonia clearance.

Among the treatments which aim at decreasing intestinal ammonia production there is the modification of diet. Risk of HE can be decreased in subjects affected with chronic liver disease by using a diet with adequate protein supply [16] [20], and the addition of suitable substances like lactulose can help treat the disorder when it occurs. In fact, the conversion of disaccharides lactulose to lactic acid causes gut lumen acidification and conversion of NH4 to NH3, which in turn inhibits ammoniagenic coliform bacteria and increases levels of nonammoniagenic lactobacilli. Ammoniagenic bacteria population can also be decreased by using a number of appropriate antibiotics, such as neomycin, metronizadole and especially rifaximin [21].

Among the treatments which aim at decreasing ammonia clearance there is the regimen with LOLA, a stable salt of the two constituent amino acids l-ornithine and l-aspartate. LOLA stimulates the urea cycle and both amino acids are substrates for glutamate transaminase, whose activity increases glutamate levels. Ammonia is then used to convert glutamate to glutamine through the activity of glutamine synthetase.  The urea cycle can be further increased by zinc administration, as zinc improves the activity of  ornithine transcarbamylase, one of the key enzymes of the urea cycle. Other substances with similar effects on ammonia clearance include sodium benzoate, sodium phenylbutyrate, sodium phenylacetate and glycerol phenylbutyrate [22] [23] [24].

HE presents frequent complications which affect daily life activities, like deficits in working memory, psychomotor speed, attention, and response inhibition [5] [6] [7]. These effects significantly decrease the patients quality of life [8] [9] [10] and financial status, which in addition to the high rates of hospital admissions [11] make HE a serious burden for healthcare programs.

As previously mentioned, the major function of the liver is to break down the substances in the body and, if these are poisonous, make them harmless. When a liver dysfunction occurs, these toxins begin to build up in the bloodstream, until they reach particularly dangerous high concentrations. A classical example of poisonous compound is ammonia, produced in the body as a protein metabolism waste product. Other examples of putative neurotoxic substances include short-chain fatty acids, mercaptans, false neurotransmitters (like tyramine) or gamma-aminobutyric acid.

At present the exact cause of HE is unknown. A number of theories have been proposed to explain its development, and the scientific consensus in this regard appears to mainly support the idea of HE being a disorder of the astrocytes. Astrocytes are the characteristic star-shaped glial cells in the central nervous system collectively known as astroglia. They perform several supportive functions, including nutrients supply, biochemical support, ion-balance maintenance and repair. The neurotoxins which enter the brain contribute to several morphological changes in astrocytes, such as swelling and the appearance of large pale nuclei, that in the end lead to brain dysfunction. These physiological changes might even involve changes in gene expression, especially for those genes which code for transporter proteins.

The majority of the epidemiological data comes from the subjects affected by advanced liver diseases. When it comes to understanding the origin of HE, it is often difficult to assess the burden of a chronic liver disease, as this often has an insidious onset and a long period of latency. Therefore, most patients start seeking for medical assistance when the disease is well on its way to reaching its full development.

HE can appear in patients in both a mild form known as minimal hepatic encephalitis (MHE) and a fully symptomatic overt form know as over hepatic encephalopathy (OHE). Data about the incidence and prevalence of HE is still insufficient. Anyway, according to some studies carried out in the United States, of the 150,000 individuals which are annually diagnosed with chronic liver diseases, cirrhosis accounts for 20% of the cases while chronic hepatitis C accounts for almost two-thirds [1]. Furthermore, while the prevalence of hepatitis C is decreasing, that of cirrhosis is expected to increase in the next two decades [2].

It is believed that most of the patients affected by cirrhosis will develop some degree of HE at some point of the course of their liver disease. According to recent data, it appears that MHE occurs in up to 80% of the cirrhotic patients, while OHE occurs in up to 45% of the cases. OHE also appears in up to 50% of the patient with surgical complications and sometime as complication of an acute liver failure [3]. After the first episode of OHE, the probability to survive is 42% in the first year of follow-up and 23% in the third [4].

One of the most important theories used to explain why liver dysfunction and portosystemic shunting lead to HE is the theory of the nitrogen-containing compounds. Nitrogen-containing compounds come from the gastrointestinal system through the portal vein. After getting into the liver, 80-90% of them will then be metabolized through the urea cycle and excreted through the urogenital system. In all the subtypes of HE the nitrogen-compounds disposal mechanism is impaired, either because hepatocytes are no longer capable of metabolizing these substances or because the shunt that bypasses the liver leads the nitrogen-rich compounds right into the systemic circulation. The shunt can be the product of either a collateral circulation or of a surgery.  

One of the most important nitrogen-rich compounds is ammonia (NH3), a substance which crosses the blood-brain barrier and is absorbed by astrocytes. Astrocytes use ammonia to synthesize glutamine from glutamate, through the activity of the glutamine synthetase. However, in contrast to what happens in other types of cells, such as skeletal muscles and kidney cells, astrocytes are not capable of increasing the glutamine synthetase activity in the setting of hyperammonemia, making the brain extremely vulnerable to the high ammonia concentrations. The high ammonia concentration has multiple neurotoxic effects, like altered transits of amino acids, water and other electrolytes across astrocytes and neurons, in addition to reduced amino acid metabolism, modified energy utilization, and impaired capacity to generate excitatory and inhibitory postsynaptic potentials.

Another important hypothesis used to explain why liver dysfunction and portosystemic shunting lead to HE is the GABA theory. GABA is a neuroinhibitory substance produced in the gastrointestinal tract and found in around 25% of the brain nerve endings. It is believed that the increased GABA plasma levels during HE would cause an influx of chloride ions into the postsynaptic neurons and the subsequent generation of inhibitory potentials. However, experimental data shows no change in the brain GABA levels or in the sensitivity of GABA receptor complex in subjects affected by HE [5].

Since HE often comes as a complication of a liver disease, the best way to prevent it is to take steps to prevent the liver disease itself. These include avoiding alcohol and high-fat food consumption, losing weight in excess and steps to prevent viral hepatitis, like frequent hand washing and having no contact with infected subjects. 

This physiological dysfunction prevents the liver from breaking down and removing several toxic substances which begin to flow freely around the body. The main features of hepatic encephalopahty (HE) include intellectual impairment, personality changes and severely reduced consciousness levels, possibly due to the presence of substances with neurotoxic effects. HE usually occurs in subjects affected by liver cirrhosis and in those with either spontaneous or surgically created vascular shunts.

Hepatic encephalopathy (HE) is a pathological condition defined by the spectrum of neuropsychiatric abnormalities which result from a liver dysfunction. This physiological dysfunction prevents liver from breaking down and removing several toxic substances, which begin to flow freely around the body. A classical example of poisonous compound is ammonia, produced in the body as protein metabolism waste product. Ammonia has a number of toxic effects over the brain, which ultimately cause the typical neural impairments of HE. The disease can be classified using a number of systems, the most used of which recognizes three types  of HE according to the underlying cause: type A, associated with acute liver failure, type B, associated with portal-systemic shunting, and type C, associated with cirrhosis.

Treatment of HE is largely based on the integration in the diet of substances which can affect ammonia intestinal production and ammonia clearance. Since it often comes as a complication of a liver disease, the best way to prevent HE is to take steps to prevent the liver disease itself, such as avoiding alcohol consumption and having no contact with subjects affected by viral hepatitis.

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