Apr. 03, 2021
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Hepatic encephalopathy is a reversible brain disorder associated with liver disease or portosystemic shunts. It may be due to hepatotoxicity of drugs. Clinical manifestations vary from confusion, somnolence, and disorientation to stupor and coma. This article describes the diagnosis as well as management of the condition. Medical therapy may suffice in early and less severe cases, but severe acute hepatic failure may require liver transplantation. As an interim measure, cell therapy by transplantation of genetically modified hepatocytes or hematopoietic stem cells may reduce disease and extend survival until a donor becomes available for liver transplant or the patient's own liver recovers function.
• Hepatic encephalopathy is a potentially reversible metabolic disturbance of the brain in liver disease.
• The most common cause is cirrhosis of the liver, but other hepatotoxic agents may lead to hepatic encephalopathy.
• Manifestations of hepatic encephalopathy range from minimal cognitive deficits to stupor and coma.
• Most of the cases can be managed medically, but liver transplant is required in some cases.
Hepatic encephalopathy is defined as a metabolically induced, potentially reversible functional disturbance of the brain that may occur in acute or chronic liver disease. It is characterized by disturbances of consciousness and other neuropsychiatric manifestations, which are due to metabolic disturbances associated with liver disease or portosystemic shunts. The association between liver disease and mental disorders has been recognized since the time of Hippocrates (11). Galen, the Roman physician of the 2nd century, described neurologic and psychiatric symptoms resulting not only from brain diseases but also from diseases of other organs, including the liver (46). An oil painting by Rubens (1577 to 1640), The Drunken Silen, is exhibited in Munich, Germany, and shows characteristic symptoms of hepatic insufficiency. Morgagni, the father of pathologic anatomy, described the relation between liver failure and mental disorder in the 18th century (Morgagni 1769). The fourth case of his study may have been 1 of hepatic encephalopathy. In this case report, Morgagni described an alcoholic man with a history of abdominal pain and delirium who died in coma. Autopsy showed liver cirrhosis, but the brain was grossly normal. Further studies of hepatic encephalopathy continued in the 19th century. Hepatolenticular degeneration associated with cirrhosis of the liver was described in the early part of the 20th century and was later determined to be a hereditary disorder of copper metabolism (56). The classical works in which the modern concepts of hepatic encephalopathy are based were published in the 1950s (01; 47).
Classification. A simplified classification of hepatic encephalopathy is as follows:
(1) Acute hepatic encephalopathy associated with acute liver failure and characterized by cerebral edema and raised intracranial pressure. This is likely to be manifested as hepatic coma.
(2) Subacute or subclinical hepatic encephalopathy associated with hepatic cirrhosis and associated with abnormal findings on neuropsychological testing.
(3) Chronic hepatic encephalopathy associated with hepatic cirrhosis. This classification of hepatic encephalopathy takes several forms. The most common form of presentation is "precipitant-induced encephalopathy" in which cirrhotic patients develop progressive changes of mental function with several precipitating factors. One type is called portal-systemic encephalopathy because of extensive portosystemic shunting or surgical portacaval shunt. Another form is hepatocerebral degeneration, wherein patients present with dementia and extrapyramidal disorders.
The American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) consider hepatic encephalopathy to be a continuum ranging from unimpaired cognitive function with intact consciousness through coma and use a grading system of 1 to 3 and recommend classification according to the type of underlying disease, severity of manifestations, time course, and precipitating factors (52). Accordingly, 3 types of hepatic encephalopathy are traditionally differentiated according to the underlying cause: type A as an essential component of acute liver failure, type B as a consequence of porto-systemic shunts in the absence of liver dysfunction, and type C in patients with liver cirrhosis and porto-systemic bypass.
Patients with chronic hepatic encephalopathy may present with delirium. According to the 1994 DSM-IV criteria, delirium due to liver disease or portosystemic shunting belongs to the section on cognitive disorders because deficits of cognition are the primary symptoms of delirium. Prior to the development of predominant cognitive changes, the patients may be evaluated according to the presenting symptoms, which may be mood disorders, sleep disturbances, or personality changes. If cognitive impairment dominates without impairment of consciousness, the patient is considered to have dementia due to liver disease or portosystemic shunting.
The 4 stages of acute hepatic encephalopathy are: (1) lethargy and confusion, (2) somnolence and disorientation, (3) stupor, and (4) coma.
The symptoms of patients with acute hepatic encephalopathy may start with mental confusion and then progress to decreased motor activity and drowsiness. Asterixis or flapping tremor may be present. A pungent odor, fetor hepaticus, can be detected in the exhaled breath of patients. The patient may become stuporous and then comatose in a matter of days. Seizures may occur occasionally. The patient may have various manifestations of raised intracranial pressure and a positive Babinski sign, but there may be no localizing neurologic signs. Rigidity may be observed during passive flexion or extension. Decerebrate posturing may be seen in deep coma.
Minimal hepatic encephalopathy is defined as the presence of neurocognitive impairments in patients with cirrhosis or portal-systemic shunting that show a normal neurologic and psychiatric status on clinical examination. This mild manifestation of hepatic encephalopathy is estimated to affect up to 60% of patients with cirrhosis and may seriously impair a patient's daily functioning (43). Manifestations may be psychomotor slowing, with deficits in attention and visual perception that may be detectable on neuropsychological testing. Although ammonia has the central role in the pathogenesis of minimal hepatic encephalopathy, factors such as infection, oxidative stress, manganese, or intestinal bacterial overgrowth contribute to the development of the neurocognitive deficits associated with this disease (04).
EASL/AASLD guidelines for hepatic encephalopathy (HE) proposed the alternative use of the term “covert HE” combining minimal HE (mHE) and grade 1 HE into a single entity. Grades 2, 3, and 4 were combined into “overt HE”. A clinical study of long-term follow-up of clinically-stable cirrhotic patients with no previous history of “overt HE with grade 1 HE” had significantly more complications requiring hospitalization and higher mortality compared to patients with no HE or mHE respectively (50). Patients with mHE and grade 1 HE had similar ammonia levels, but higher than the no HE group. This study indicates that “covert HE” is not a homogenous but a heterogeneous entity and needs further study. In recurrent or chronic forms, the patient presents with cognitive impairment that develops into dementia. Various extrapyramidal movement disorders may also occur.
Mild hepatic encephalopathy occurs in 25% of patients with acute viral hepatitis with raised arterial ammonia during the icteric phase and resolves on follow-up with recovery of hepatitis (45). The prognosis of patients with hepatic coma after acute liver failure depends on the extent and type of hepatic injury. Those who survive with medical management may make a good recovery. Others with fulminant hepatic failure may require liver transplantation. Although hepatic encephalopathy is considered potentially reversible, posttransplant neurologic deficits are encountered, and it is difficult to ascertain if they are residual effects of degenerative brain injury or independent neurologic insults (03). Complications of hepatic encephalopathy include the following:
• Hepatic coma with cerebral edema may lead to death due to transtentorial herniation.
• Rarely, the visual cortex may be affected, and cortical blindness may occur; this resolves following treatment of the hepatic encephalopathy.
• Chronic, recurrent, or persistent hepatic encephalopathy may lead to hepatocerebral degeneration with extrapyramidal disorders and dementia.
• Subclinical cognitive brain dysfunction in cirrhotic patients can deteriorate after a transjugular intrahepatic portosystemic shunt in the absence of clinically detectable hepatic encephalopathy.
• Cognitive impairment may persist after resolution of overt hepatic encephalopathy.
• Patients suffering from hepatic encephalopathy at the time of liver transplant are at significant risk for the development of neurologic complications in the postoperative period, such as altered mental status and seizures. Contributing factors for these complications are preexisting neuropathology, metabolic stress of surgery, and the neurotoxicity of the drugs used.
• Falls are more frequent in cirrhotic patients with minimal hepatic encephalopathy.
Persons with chronic hepatic encephalopathy are at risk for motor vehicle accidents, which require mandatory reporting to the Department of Motor Vehicles in some states.
A 74-year-old woman with hepatitis C of long duration was admitted to the hospital in hyperammonemic coma and did not respond to aggressive treatment of hepatic encephalopathy. Investigation for other causes of coma revealed that she was markedly hypothyroid. Thyroid replacement therapy led to recovery of consciousness and normalization of blood ammonia levels. This case illustrates that hypothyroidism can exacerbate hyperammonemia and produce a clinical picture resembling encephalopathy in patients with otherwise well-compensated liver disease.
The cause of acute hepatic encephalopathy is acute liver failure that can be due to several causes, including viral hepatitis and the hepatotoxic drugs shown in Table 1. The cause of chronic hepatic encephalopathy is liver disease, usually cirrhosis. Various precipitating factors that can induce hepatic encephalopathy in patients with cirrhosis are:
(1) Increased nitrogen load due to gastrointestinal hemorrhage, uremia, or excessive dietary protein
• Acetaminophen, overdose
• Antiepileptic drugs: valproic acid
*The exact mechanism is not known, but various explanations include direct hepatotoxicity, direct cerebral neurotoxicity, and hyperammonemia.
Portal-hepatic shunt is known to occur in the cirrhotic liver. Rarely, intrahepatic portal-hepatic vein shunts can produce neuropsychological manifestations and MRI changes like those described in patients with cirrhosis and subclinical hepatic encephalopathy in the absence of parenchymal liver disease.
Valproate-induced hyperammonemic encephalopathy is a rare but serious complication in patients after craniotomy and is diagnosed by mental state changes and elevated blood ammonia. A patient who developed hyperammonemic encephalopathy following perioperative administration of valproic acid recovered completely following discontinuation of the drug (21).
Neuropathology. No gross abnormalities are present in the brains of patients dying of hepatic coma, but microscopic examination shows diffuse hyperplasia of astrocytes of the cerebral cortex, lenticular and dentate, and of the diencephalic and other brain stem nuclei. Astrocytic swelling is of sufficient severity to cause cytotoxic cerebral edema. In patients with liver cirrhosis who die in hepatic coma, microscopic examination shows characteristic Alzheimer type 2 astrocytes in the cerebral cortex. These have a large vacuolated nucleus with chromatin displaced to 1 side. Hepatic encephalopathy in chronic liver disease is a manifestation of astrocyte swelling and low-grade cerebral edema.
Neuronal atrophy is rare in hepatic encephalopathy, but cortical atrophy may be the result of chronic alcoholism. A diffuse laminar necrosis of the cerebral cortex is a feature of hepatocerebral degeneration. There may be microcavitation in the striatum like that seen in Wilson disease. Parkinsonian signs in hepatic encephalopathy correlate with basal ganglia alterations detected by magnetic resonance imaging and proton spectroscopy. Neuronal cell damage and death are well documented in liver failure patients.
Pathogenesis. Various pathomechanisms have been proposed for hepatic encephalopathy. The best known of these hypotheses concern hyperammonemia, neuroinflammation, false neurotransmitters, and increased GABA neurotransmission.
Hyperammonemia. A substantial amount of clinical and experimental evidence suggests that ammonia toxicity is a major factor in the pathogenesis of hepatic encephalopathy. Ammonia has been proven to be neurotoxic in animal experiments. Arterial blood ammonia concentrations are frequently elevated in all forms of hepatic encephalopathy. Altered mitochondrial metabolism appears to be an important mechanism responsible for the cerebral abnormalities associated with hepatic encephalopathy and other hyperammonemic states. However, hyperammonemia does not fully explain hepatic encephalopathy because 10% of affected patients have normal blood ammonia levels.
Although cerebral metabolic rates for both glucose and oxygen are reduced in hepatic encephalopathy, the rate at which ammonia is taken up and metabolized by the brain is increased. Brain ammonia concentrations are difficult to determine accurately in humans, but they are elevated up to more than 20-fold as determined in animal models. Ammonia has an adverse effect on the brain. The exact mechanism of ammonia toxicity is not properly understood, but the following explanations should be considered:
• A direct blocking effect of ammonia on the glutamate transmitter system could contribute to cerebral depression caused by hyperammonemia.
• Hyperammonemia disturbs the electrophysiological function of the neurons (eg, interference with inhibitory postsynaptic potentials).
• Hyperammonemia interferes with brain energy metabolism, possibly by inhibiting discrete steps of the tricarboxylic acid cycle and, in part, by interfering with malate aspartate shuttle.
• Hyperammonemia is a major factor responsible for cerebral edema due to astrocyte swelling, and aquaporin-4, a water channel protein that is abundantly expressed in astrocytes, is implicated in this process.
Supporting evidence for the role of ammonia in hepatic encephalopathy is as follows:
• Administration of ammonia to experimental animals reproduces the Alzheimer type 2 astrocyte change.
• High cerebrospinal fluid ammonia is found in hepatic encephalopathy as well as in other disorders with disturbances of mental function such as Reye syndrome and valproic acid toxicity.
• Measures to reduce blood ammonia levels improve hepatic encephalopathy.
Hyponatremia. Hyponatremia is a common complication of liver disease, and the resultant depletion of organic osmolytes from brain cells contribute to cerebral edema, which plays an important role in the pathogenesis of hepatic encephalopathy. Hyponatremia is a major risk factor in the development of hepatic encephalopathy in patients with cirrhosis. Correction of hyponatremia should be considered for prevention of hepatic encephalopathy in liver disease.
Neuroinflammation. In animal models of toxic liver injury, microglial activation and concomitantly increased expression of genes coding for proinflammatory cytokines in the brain occur early in the progression of encephalopathy indicating that hepatic encephalopathy may be a neuroinflammatory disorder (10). Raised serum IL-6 levels, an indicator of inflammation, are associated with the presence of minimal hepatic encephalopathy in patients with liver cirrhosis and are a biomarker of the development of overt hepatic encephalopathy (31). The beneficial effect of antiinflammatory agents in mild hepatic encephalopathy supports the role of inflammation in the pathogenesis.
False neurotransmitters. According to this theory, neurotransmitters, such as dopamine and noradrenaline, are replaced by weaker false neurotransmitters, such as octopamine and phenylethanolamine, which have increased levels in the plasma, cerebrospinal fluid, and urine of patients with hepatic encephalopathy. False neurotransmitters are generated by the action of bacteria on proteins in the gastrointestinal tract; they reach the systemic circulation via portosystemic shunts and then cross the blood-brain barrier. An imbalance of amino acids entering the brain by depletion of branched chain amino acids and elevation of aromatic amino acids (the result of decreased hepatic intake) facilitates the entry of these substances into the brain. Furthermore, false neurotransmitters are produced in the brain from aromatic amino acid precursors. The points against this hypothesis are that behavioral changes cannot be produced in experimental animals by intracerebral administration of octopamine and that therapeutic efforts to normalize plasma amino acid ratio do not lead to improvement in hepatic encephalopathy.
Increased GABA neurotransmission. The basis of this hypothesis for hepatic encephalopathy is that GABA generated within the nervous tissue from decarboxylation of glutamate causes neuroinhibition by facilitating entry of chloride into cells, resulting in decrease of neurotransmission. An extension of this hypothesis is that endogenous benzodiazepine ligands, rather than GABA, are mediators of hepatic encephalopathy. Activation of peripheral benzodiazepine receptors is considered a contributing factor to the pathogenesis of symptoms of portal-systemic encephalopathy. Supporting evidence for this theory is the susceptibility of hepatic encephalopathy patients to the neuroinhibitory effects of benzodiazepines and the beneficial effects on hepatic encephalopathy of flumazenil, a benzodiazepine antagonist.
Neurosteroids that are synthesized in the brain are modulators of the GABA-A receptors, which cause enhancement of inhibitory neurotransmission in the central nervous system and an increased GABA-ergic tone. This has been suggested as a pathophysiological mechanism in hepatic encephalopathy. The mechanisms that trigger brain neurosteroid changes in hepatic encephalopathy could also involve ammonia-induced translocator protein activation and neuroinflammation (02).
Other neurotransmitters. Molecular biological studies have demonstrated increased expression of genes coding for neurotransmitter-related proteins in chronic liver failure. Such genes include monoamine oxidase, the peripheral-type benzodiazepine receptor, and nitric oxide synthase. Activation of these genes can cause alterations in neurotransmitter function as well as cerebral perfusion in hepatic encephalopathy. Other neurotransmitter systems implicated in the pathogenesis of hepatic encephalopathy include the serotonin system, where a synaptic deficit has been suggested, as well as the catecholaminergic and opioid systems.
Disturbance of blood-brain barrier. In hepatic encephalopathy, there are significant alterations in the tight junction elements of the blood-brain barrier, including occludin and claudin-5, suggesting a vasogenic injury (40). Increased permeability of blood-brain barrier leads to cerebral edema.
Disturbances of cerebral metabolism. Positron emission studies of the brain in hepatic encephalopathy show a relative decrease of the glucose utilization of the cingulate gyrus and the frontomedial, frontolateral, and parieto-occipital cortices, whereas the glucose utilization of the basal ganglia, the hippocampus, and the cerebellum is relatively increased. Cerebral oxygen uptake and blood flow are reduced to two thirds in cirrhotic patients with clinically overt hepatic encephalopathy, but not in cirrhotic patients with minimal or no hepatic encephalopathy as compared to healthy subjects (29). The primary event in the pathogenesis of hepatic encephalopathy in patients with cirrhosis could be inhibition of cerebral energy metabolism by increased blood ammonia, which may explain low cerebral oxygen consumption and blood flow seen in cerebral blood flow and positron emission studies (25).
Disturbance of oxygen metabolism. Low values of cerebral metabolic rate of oxygen and cerebral blood flow observed during hepatic encephalopathy increase after recovery and are thus associated with encephalopathy rather than the liver disease (14). These are not linked to blood ammonia concentration.
Pathomechanism of hepatic encephalopathy in acute liver failure. In contrast to the hepatic encephalopathy in chronic liver disease, hepatic encephalopathy in acute liver failure is sudden in onset. Brain ammonia levels are markedly increased. Glutamate plays an important role in the pathogenesis of this condition, as cerebrospinal fluid glutamate is increased in acute liver failure due to its decreased uptake. Exposure of the astrocytes to glutamate results in swelling and explains the marked cerebral edema. Increased glutamatergic neurotransmission explains the hyperexcitability and seizures.
One proposed mechanism of pathogenesis of hepatic encephalopathy is an increased synthesis of glutamine by brain glutamate in astrocytes due to excessive blood ammonia, followed by a compensatory loss of myoinositol to maintain astrocyte volume homeostasis.
Predisposing factors. Events precipitating hepatic encephalopathy in cirrhotic patients are:
• Genetic: microsatellite in the promoter region of the phosphate-activated glutaminase gene is associated with risk of hepatic encephalopathy (36).
There are approximately 1 million patients in the United States with cirrhosis, of whom approximately 140,000 have overt hepatic encephalopathy (09). Approximately 25,000 Americans die each year from cirrhosis of the liver, making it the seventh leading cause of death.
The prevalence of cognitive alterations detected by neuropsychological tests in patients with cirrhosis of the liver is approximately 20%. The prevalence of hepatic encephalopathy is reported to be higher in another study that estimated its occurrence in 30% to 45% of patients with liver cirrhosis and in 10% to 50% of patients with transjugular intrahepatic portosystemic shunts (17). Transjugular intrahepatic portosystemic stent-shunts are increasingly used for the management of portal hypertension, and the overall rate of hepatic encephalopathy in such patients was reported to be 29.9% in a study from the United Kingdom (51). The incidence of hepatic encephalopathy after placement of transjugular intrahepatic portosystemic shunts in Japanese patients was reported to be 52% (35). The background disease, cirrhosis, is common among alcoholics, but exact figures for prevalence are not available because many of these cases are asymptomatic and are not diagnosed.
Geographical variations exist in the epidemiology of hepatic encephalopathy. Acute hepatic failure in India almost always presents with encephalopathy within a few weeks of the onset of acute hepatitis, and viral hepatitis is the cause in nearly all of these patients. More than half of the patients with hepatic cirrhosis in China have subclinical hepatic encephalopathy.
Neuropsychological testing and MRI enable detection of subclinical stages of hepatic encephalopathy without overt clinical manifestations. Measurement of changes in cerebral blood flow might be useful in detecting subclinical hepatic encephalopathy.
An effort should be made to identify and minimize the risk factors for precipitating overt hepatic encephalopathy in these patients. Exposure to drugs known to have hepatotoxic effect should be avoided. The primary prevention should be directed at cirrhosis of the liver.
Several disorders related to acute and chronic alcoholism can mimic hepatic encephalopathy (ie, alcohol intoxication, delirium tremens, and Korsakoff syndrome). Other metabolic encephalopathies also should be considered in the differential diagnosis, particularly uremic encephalopathy. Septic encephalopathy and other metabolic encephalopathies in the intensive care unit setting should also be included in the differential diagnosis. Hepatic encephalopathies can mimic West Nile encephalitis.
Wilson disease should be excluded in patients with liver disease and neurologic abnormalities. Other conditions to be considered in the differential diagnosis are meningitis, subdural hematoma, hypothyroidism, and hypoglycemia. History and physical examination can differentiate hepatic encephalopathy from most of these conditions. Chronic cases of hepatic encephalopathy with dementia need to be differentiated from other causes of dementia. Cirrhosis-related parkinsonism may be a manifestation of acquired hepatocerebral degeneration, but its features are entirely different from acute hepatic encephalopathy episodes. Hepatic coma, especially in alcoholic patients, should be diagnosed only after coma due to intracranial space occupying and vascular lesions, trauma, infection, epilepsy, and metabolic, endocrine, and drug-induced causes have been excluded.
Epilepsy is a risk factor for developing hepatic encephalopathy, which is a strong predictor of mortality (27). Status epilepticus may rarely occur in hepatic cirrhosis and may be misdiagnosed. When a patient presents in an emergency situation, differential diagnosis between status epilepticus and hepatic encephalopathy is important, as some antiepileptic medications may aggravate hepatic encephalopathy (44).
The most important initial evaluation is a thorough general medical examination with emphasis on the nervous system. Several scales have been proposed for assessing or staging hepatic encephalopathy. Diagnosis of hepatic encephalopathy should only be made after exclusion of other possible causes of brain dysfunction, and several scales are available for grading the extent of hepatic encephalopathy (53). The most commonly used is the West Haven criteria to differentiate between 4 grades of clinically overt hepatic encephalopathy, in which patients with liver cirrhosis without clinically overt symptoms of hepatic encephalopathy but neuropsychological or neurophysiological findings indicating brain dysfunction are considered to have minimal hepatic encephalopathy. The Hepatic Encephalopathy Scoring Algorithm (HESA) combines clinical impressions with neuropsychological performances to characterize encephalopathy. A simple scale is based on assessment of the patient's orientation, alertness, ability to respond to commands, and ability to talk. A list of 9 items is proposed as a linear scale from normality, depicted as Clinical Hepatic Encephalopathy Staging Scale 0, to deep coma, depicted as Clinical Hepatic Encephalopathy Staging Scale 9.
Serum electrolytes should be checked. No diagnostic liver function test abnormalities occur, although elevated blood ammonia levels are suggestive of diagnosis of hepatic encephalopathy in the proper clinical setting. A venous ammonia level of 150 to 200 μmol per liter is a risk factor for increased intracranial pressure in patients with fulminant hepatic failure (55). Determination of blood ammonia, however, is not regarded a useful screening test for hepatic encephalopathy and reliance on it as the sole indicator for hepatic encephalopathy in the emergency department may frequently results in misdiagnosis. A study on inpatients with hepatic encephalopathy showed that management with lactulose was not influenced by either the presence or level of ammonia level, indicating that ammonia levels are not useful for guiding therapy in clinical practice (22). Serum S100b, an astrocyte-specific protein, is a useful biomarker of hepatic encephalopathy in patients with fulminant hepatitis. A pilot study has shown that determination of 3-nitro-tyrosine in serum is a useful biomarker in patients with minimal hepatic encephalopathy (38). Examination of cerebrospinal fluid is not remarkable. No "gold standard" exists for diagnosing hepatic encephalopathy, but special examinations that should be carried out are as follows:
Neuropsychological testing. This is important in the early stages. Some patients with cirrhosis of the liver, who appear to be otherwise normal on general physical examination, show impairment on 1 or more neuropsychological tests. The term “minimal hepatic encephalopathy” is used for neurocognitive dysfunction that is present in most patients with cirrhosis but cannot be diagnosed on clinical examination. Several test batteries are available for this purpose. Reitan's trail-making test is simple and enables serial assessment of the mental state. In patients with overt hepatic encephalopathy, one should document the cognitive deficits for follow-up assessment. Cognitive improvement has been documented following successful treatment of minimal hepatic encephalopathy even though there were no changes in regional brain volume, which implies that mechanisms unrelated to astrocyte volume regulation are involved in this improvement (37).
Hepatic encephalopathy score (PHES) analyses are widely used to diagnose hepatic encephalopathy. This battery consists of 5 tests: the number connection tests A and B, digit symbol test, serial dotting test, and line tracing test.
Two other psychometric tests are useful. Combined continuous reaction time test and portosystemic encephalopathy syndrome test showed satisfactory prediction by identifying three-fourths of cases who later developed overt hepatic encephalopathy (54).
Critical flicker frequency (CCF). Critical flicker frequency is a visual test that determines the minimum number of flashes of light per second at which an intermittent light stimulus no longer stimulates a continuous visual sensation. It is also used as a simple, reliable, and accurate method for the diagnosis of minimal hepatic encephalopathy. In a comparative study, CFF distinguished between patients with overt hepatic encephalopathy and controls (30). PHES testing produced a statistically significant difference among groups; however, there was considerable overlap between controls and patients with overt hepatic encephalopathy.
Neurophysiological assessment. EEG is the most widely used test for this purpose. Abnormalities include bilateral synchronous delta waves and triphasic waves, seen mostly in the frontal regions; however, these are not specific for hepatic encephalopathy as they are also seen in other metabolic encephalopathies and in patients under the influence of psychotropic medications. EEG provides diagnostic information, but no good correlation exists between the stage of hepatic encephalopathy and degree of EEG abnormality.
Brain imaging. Brain imaging studies do not provide diagnostic information. CT scan may document cerebral edema in acute stages and cerebral atrophy in chronic cases; if doubt rests in the diagnosis, then CT scan also may rule out other intracranial pathology.
Proton magnetic resonance spectroscopy detects changes in brain biochemistry including direct measurement of cerebral osmolytes such as myoinositol, glutamate, and glutamine, which correlate with the severity of neuropsychiatric impairment. This technique may be useful for patient monitoring and in assessing the effectiveness of treatment.
MRI may also be useful in monitoring cerebral edema and response to treatment. Multimodality MRI is a useful tool for early diagnosis, prognosis, and monitoring of hepatic encephalopathy, particularly the combination of fMRI and diffusion tensor imaging (57). Default mode network function determined by resting-state-fMRI, particularly when it shows decreased medial prefrontal cortex connectivity, might be a useful imaging biomarker for differentiating minimal hepatic encephalopathy from cirrhotic patients without encephalopathy (41).
An fMRI study on patients with minimal hepatic encephalopathy showed significant decrease of gray matter volume and lesser degree of resting-state functional connectivity in different networks related to attention and executive functions as compared to controls (18). These changes correlated with decreased cognitive performance and are useful for detecting minimal hepatic encephalopathy.
Altered diffusion kurtosis imaging, which is an extension of diffusion tensor imaging by estimating the kurtosis (skewed distribution) of water diffusion based on a probability distribution function, indicates microstructure abnormalities of the brain in minimal hepatic encephalopathy patients, some of which may be used as neuroimaging biomarkers for early diagnosis (32).
Positron emission tomography is of academic interest and can be used to evaluate ammonia and glucose metabolism as well as investigate the neural response to drugs and other treatments. Brain imaging integrated with computerized neuropsychological tests can also be used to evaluate the effectiveness of treatments for hepatic encephalopathy.
Intracranial pressure monitoring. Intracranial pressure monitoring is done rarely in hepatic encephalopathy and carries a risk of inducing intracranial hemorrhage but may be considered in cases with CT evidence of cerebral edema to monitor measures for lowering of pressure.
General measures in severe acute hepatic encephalopathy include tracheal intubation and placement of a nasogastric tube. Oral intake is withheld for a day, and intravenous glucose is provided until the patient improves and enteral nutrition can be started. Management of encephalopathy from acute hepatic failure is aimed at control and reduction of intracranial hypertension. Intracranial pressure monitoring should be started, and mannitol (1 g/kg) should be administered as an intravenous bolus. Two other measures for management of cerebral edema, hypothermia and hyperbaric oxygen, have been used in open studies with good results, but these have not been proven by controlled studies. Hypothermia has been shown to be safe and useful as a bridging measure in patients with acute liver failure and uncontrolled intracranial hypertension when waiting for orthotopic liver transplant.
Management of chronic hepatic encephalopathy is focused on the identification and correction of precipitating factors. These include the correction of diuretic-induced hypokalemia and the removal of nitrogenous load from the intestine. The latter is accomplished by agents that increase the frequency of stools to remove blood from the intestine, by reduction of protein content in the diet, and by use of nonabsorbable carbohydrates or antibiotics to reduce the activity of intestinal flora. Lactulose, 15 to 30 ml at 2 to 4 times per day, is the most commonly used nonabsorbable carbohydrate for these patients. In the cecum, it is metabolized by anaerobic bacteria into short-chain fatty acids that then promote the passage of ammonia into the intestinal lumen and promote conversion to the impermeable ammonium ion that is then consumed by the intestinal bacteria. A metaanalysis of randomized controlled clinical trials showed that lactulose has significant beneficial effects on patients with minimal hepatic encephalopathy compared with placebo or no intervention (33). Results of HELP (Hepatic Encephalopathy: Lactulose vs. Polyethylene Glycol 3350-Electrolyte Solution) randomized clinical trial showed that polyethylene glycol is superior to lactulose (42).
Antibiotics. These were found to be superior to nonabsorbable carbohydrates in improving hepatic encephalopathy in clinical trials. Neomycin, 2 to 4 g per day, is the most commonly used antibiotic, although a controlled trial failed to show its efficacy. Alternative antimicrobial agents are vancomycin and metronidazole. Rifaximin is a nonabsorbable derivative of rifamycin with a broad spectrum of activity against aerobic and anaerobic gram-positive and gram-negative organisms. Rifaximin's clinical effect is likely due to effects on metabolic function of the gut microbiota, rather than a change in the relative bacterial abundance (05). Treatment of hepatic encephalopathy with rifaximin is associated with lower hospitalization frequency and duration, lower hospital charges, better clinical status, and fewer adverse events as compared to treatment with lactulose and neomycin. A double-blind, placebo-controlled trial showed that treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than placebo over a 6-month period (08). A double-blind randomized pilot study (RIME Trial) in cirrhotic patients with minimal hepatic encephalopathy showed that rifaximin was well tolerated and significantly improved both cognitive functions as well as health-related quality of life (49). A meta-analysis of clinical trials has indicated that rifaximin is at least as effective as other conventional oral agents for the treatment of hepatic encephalopathy and has a better safety profile (16). An open label 2-year extension study has confirmed the repeatability of results from the randomized controlled trials regarding safety and efficacy of rifaximin 550 mg twice daily in reducing the risk of hepatic encephalopathy recurrence, and it suggests these findings are translatable into practice setting (06). A retrospective study has shown that rifaximin treatment is associated with reduced risk of cirrhotic complications and prolonged overall survival in patients with hepatic encephalopathy (28). A review of published evidence indicates that although lactulose is effective for the prevention of recurrence of overt hepatic encephalopathy, addition of rifaximin to lactulose significantly reduces the risk of recurrence and related hospitalization, compared with lactulose therapy alone (24).
Other treatments that have been investigated in the management of hepatic encephalopathy are the following:
Flumazenil. This is a benzodiazepine antagonist, and the rationale for its use is that endogenous benzodiazepines may be involved in the pathogenesis of hepatic encephalopathy. A double-blind, placebo-controlled, crossover study showed that flumazenil was beneficial only in a selected subset of hepatic encephalopathy patients (07). In another randomized, double-blind, placebo-controlled study, continuous intravenous infusion of flumazenil was found to be safe and effective in the treatment of hepatic encephalopathy patients (15). Its role in the treatment of unselected patients with severe hepatic encephalopathy remains to be established.
L-ornithine-L-aspartate. The mechanism of action in lowering ammonia level is by stimulation of the urea cycle (which metabolizes ammonia to urea) in the liver and glutamine synthesis as well as increased glutamine synthesis in the muscles and the brain. A systematic study of randomized clinical trials of L-ornithine-L-aspartate found low quality evidence of a possible beneficial effect on hepatic encephalopathy, but there was uncertainty about these findings because of poor quality of the evidence (20).
Branched-chain amino acids. Several studies have shown the effectiveness of branched-chain amino acids in improving low-grade hepatic encephalopathy and protein tolerance; however, other studies have shown conflicting and inconclusive results. An updated review of randomized controlled clinical trials showed that branched-chain amino acids had a beneficial effect on hepatic encephalopathy, but they had no effect on mortality, quality of life, or nutritional parameters (19). There is a need for additional trials to evaluate these outcomes.
Surgery. Two surgical procedures are done in patients with hepatic encephalopathy. A portacaval shunt may be occluded either with the use of balloon technique or obliterated at surgery along with an esophageal procedure to prevent variceal rebleeding. Liver transplantation may be the definitive treatment in suitable candidates. Hepatocerebral degeneration has been reported to improve following liver transplantation.
Investigational drugs and procedures. Because no current treatments have proven to be effective, placebo-controlled trials of newer agents are necessary. Future management will likely be directed at the correction of alterations in neurotransmission or protection from the putative neurotoxins that cause secondary defects in neurotransmission.
Acetyl-L-carnitine. Results of a randomized, double-blind, placebo-controlled study showed that acetyl-L-carnitine reduces ammonia, modifies EEG, and improves cognitive functions in severe hepatic encephalopathy (34).
Probiotics. These are live microorganisms that are used for health benefit on the host and have been used in hepatic encephalopathy. A Cochrane review of controlled clinical trials of probiotics in hepatic encephalopathy concluded that compared with placebo or no intervention, probiotics probably improve recovery, quality of life, and plasma ammonia concentrations, but make little or no difference in mortality (13). It is uncertain if probiotics are better than lactulose for hepatic encephalopathy because of the poor quality of the available evidence.
Extracorporeal albumin dialysis. A prospective, randomized, controlled, multicenter trial of extracorporeal albumin dialysis using molecular adsorbent recirculating system showed that the treatment was well tolerated and may be associated with an earlier and more frequent improvement of hepatic encephalopathy (23).
Cell therapy. Cell therapy is used in some patients with liver failure as an interim measure or bridging therapy (26). Genetically modified hepatocytes or hematopoietic stem cells may be transplanted. The aim is to reduce disease and extend survival until a donor becomes available for liver transplant or the patient's own liver recovers function. Artificial liver support systems may also play a role in the management of hepatic encephalopathy.
Hepatic encephalopathy in pregnancy is due to a variety of causes in addition to complications of pregnancy involving the liver. Treatment is like that of hepatic encephalopathy in nonpregnant patients. Termination of pregnancy may be considered in patients with acute fatty liver of pregnancy and preeclampsia-related liver injury.
Benzodiazepines and opioids should be avoided in patients with cirrhosis of the liver. The anesthetic management for liver transplantation can be difficult in patients because the anesthesia agents affect hepatic blood flow, and anesthetic drug distribution, metabolism, and elimination may be altered in end-stage liver disease (12). Other nonanesthetic agents such as nitric oxide, epoprosterenol, hypertonic saline, fibrinogen concentrates, fresh frozen plasma, platelets, packed red blood cells, recombinant plasminogen activator, calcium chloride, and epinephrine may play a vital role in the perioperative management of these patients.
K K Jain MD
Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.See Profile
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