Hepatic encephalopathy

The mildest form of hepatic encephalopathy is difficult to detect clinically, but may be demonstrated on neuropsychological testing. It is experienced as forgetfulness, mild confusion, and irritability. EEG can reveal a slowing of alpha waves. The first stage of hepatic encephalopathy is characterised by an inverted sleep-wake pattern (sleeping by day, being awake at night). The second stage is marked by lethargy and personality changes. The third stage is marked by worsened confusion. The fourth stage is marked by a progression to coma. ==Causes==

In a small proportion of cases, the encephalopathy is caused directly by liver failure; this is more likely in acute liver failure. More commonly, especially in chronic liver disease, hepatic encephalopathy is triggered by an additional cause, and identifying these triggers can be important to treat the episode effectively. TIPS-related encephalopathy occurs in about 30% of cases, with the risk being higher in those with previous episodes of encephalopathy, higher age, female sex, and liver disease due to causes other than alcohol. ==Pathogenesis==

in the bloodstream is associated with hepatic encephalopathy. There are various explanations why liver dysfunction or portosystemic shunting might lead to encephalopathy. In healthy subjects, nitrogen-containing compounds from the intestine, generated by gut bacteria from food, are transported by the portal vein to the liver, where 80–90% are metabolised through the urea cycle and/or excreted immediately. This process is impaired in all subtypes of hepatic encephalopathy, either because the hepatocytes (liver cells) are incapable of metabolising the waste products or because portal venous blood bypasses the liver through collateral circulation or a medically constructed shunt. Nitrogenous waste products accumulate in the systemic circulation (hence the older term "portosystemic encephalopathy"). The most important waste product is ammonia (NH3). This small molecule crosses the blood–brain barrier and is absorbed and metabolised by the astrocytes, a population of cells in the brain that constitutes 30% of the cerebral cortex. Astrocytes use ammonia when synthesising glutamine from glutamate. The increased levels of glutamine lead to an increase in osmotic pressure in the astrocytes, which become swollen. There is increased activity of the inhibitory γ-aminobutyric acid (GABA) system and the energy supply to other brain cells is decreased. This can be thought of as an example of brain edema of the "cytotoxic" type. Despite numerous studies demonstrating the central role of ammonia, ammonia levels do not always correlate with the severity of the encephalopathy; it is suspected that this means that more ammonia has already been absorbed into the brain in those with severe symptoms whose serum levels are relatively low. Benzodiazepine-like compounds have been detected at increased levels as well as abnormalities in the GABA neurotransmission system. An imbalance between aromatic amino acids (phenylalanine, tryptophan and tyrosine) and branched-chain amino acids (leucine, isoleucine and valine) has been described; this would lead to the generation of false neurotransmitters (such as octopamine and 2-hydroxyphenethylamine). Dysregulation of the serotonin system, too, has been reported. Depletion of zinc and accumulation of manganese may play a role. Inflammation elsewhere in the body may precipitate encephalopathy through the action of cytokines and bacterial lipopolysaccharide on astrocytes. ==Diagnosis==

of Alzheimer type II astrocytes, as may be seen in hepatic encephalopathy Investigations The diagnosis of hepatic encephalopathy can only be made in the presence of confirmed liver disease (types A and C) or a portosystemic shunt (type B), as its symptoms are similar to those encountered in other encephalopathies. To make the distinction, abnormal liver function tests and/or ultrasound suggesting liver disease are required, and ideally a liver biopsy. • Grade 0 - No obvious changes other than a potentially mild decrease in intellectual ability and coordination • Grade 1 - Trivial lack of awareness; euphoria or anxiety; shortened attention span; impaired performance of addition or subtraction • Grade 2 - Lethargy or apathy; minimal disorientation for time or place; subtle personality change; inappropriate behaviour • Grade 3 - Somnolence to semistupor, but responsive to verbal stimuli; confusion; gross disorientation • Grade 4 - Coma Types showing liver cirrhosis, a condition that often precedes hepatic encephalopathy. Trichrome stain. A classification of hepatic encephalopathy was introduced at the World Congress of Gastroenterology 1998 in Vienna. According to this classification, hepatic encephalopathy is subdivided in type A, B and C depending on the underlying cause. • Type A (=acute) describes hepatic encephalopathy associated with acute liver failure, typically associated with cerebral oedema • Type B (=bypass) is caused by portal-systemic shunting without associated intrinsic liver disease • Type C (=cirrhosis) occurs in people with cirrhosis - this type is subdivided in episodic, persistent and minimal encephalopathy The term minimal encephalopathy (MHE) is defined as encephalopathy that does not lead to clinically overt cognitive dysfunction, but can be demonstrated with neuropsychological studies. This is still an important finding, as minimal encephalopathy has been demonstrated to impair quality of life and increase the risk of involvement in road traffic accidents. and PSE-Syndrom-Test may be used for this purpose. The PSE-Syndrom-Test, developed in Germany and validated in several other European countries, incorporates older assessment tools such as the number connection test. ==Treatment==

Those with severe encephalopathy (stages 3 and 4) are at risk of obstructing their airway due to decreased protective reflexes such as the gag reflex. This can lead to respiratory arrest. Transferring the person to a higher level of nursing care, such as an intensive care unit, is required, and intubation of the airway is often necessary to prevent life-threatening complications (e.g., aspiration or respiratory failure). Hepatic encephalopathy type B may arise in those who have undergone a TIPS procedure; in most cases this resolves spontaneously or with the medical treatments discussed below, but in a small proportion of about 5%, occlusion of the shunt is required to address the symptoms. Given the frequency of infection as the underlying cause, antibiotics are often administered empirically (without knowledge of the exact source and nature of the infection). Lactulose does not appear to be more effective than lactitol for treating people with hepatic encephalopathy. The rationale of their use was that ammonia and other waste products are generated and converted by intestinal bacteria, and killing these bacteria would reduce the generation of these waste products. Neomycin was chosen because of its low intestinal absorption, as neomycin and similar aminoglycoside antibiotics may cause hearing loss and kidney failure if used by injection. Later studies showed that neomycin was indeed absorbed when taken by mouth, with resultant complications. Metronidazole, similarly, is less commonly used because prolonged use can cause nerve damage, in addition to gastrointestinal side effects. Very weak evidence from clinical trials indicates that LOLA treatment may benefit people with hepatic encephalopathy. LOLA may be combined with lactulose and/or rifaximin if these alone are ineffective at controlling symptoms. ==Epidemiology and prognosis==

In those with cirrhosis, the risk of developing hepatic encephalopathy is 20% per year, and at any time about 30–45% of people with cirrhosis exhibit evidence of overt encephalopathy. The prevalence of minimal hepatic encephalopathy detectable on formal neuropsychological testing is 60–80%; this increases the likelihood of developing overt encephalopathy in the future. Once hepatic encephalopathy has developed, the prognosis is determined largely by other markers of liver failure, such as the levels of albumin (a protein produced by the liver), the prothrombin time (a test of coagulation, which relies on proteins produced in the liver), the presence of ascites and the level of bilirubin (a breakdown product of hemoglobin which is conjugated and excreted by the liver). Together with the severity of encephalopathy, these markers have been incorporated into the Child–Pugh score; this score determines the one- and two-year survival and may assist in a decision to offer liver transplantation. In acute liver failure, the development of severe encephalopathy strongly predicts short-term mortality and is almost as important as the nature of the underlying cause of the liver failure in determining the prognosis. Historically, widely used criteria for offering liver transplantation, such as King's College Criteria, are of limited use and recent guidelines discourage excessive reliance on these criteria. The occurrence of hepatic encephalopathy in people with Wilson's disease (hereditary copper accumulation) and mushroom poisoning indicates an urgent need for a liver transplant. ==History==

The occurrence of disturbed behaviour in people with jaundice may have been described in antiquity by Hippocrates of Cos (–370 BCE). Celsus and Galen (first and third century respectively) both recognised the condition. Many modern descriptions of the link between liver disease and neuropsychiatric symptoms were made in the eighteenth and nineteenth century; for instance, Giovanni Battista Morgagni (1682–1771) reported in 1761 that it was a progressive condition. Professor Dame Sheila Sherlock (1918–2001) performed many of these studies at the Royal Postgraduate Medical School in London and subsequently at the Royal Free Hospital. The same group investigated protein restriction The West Haven classification was formulated by Professor Harold Conn (1925–2011) and colleagues at Yale University while investigating the therapeutic efficacy of lactulose. ==References==