hepatic encephalopathy310812

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my presentation during my MGE posting,IIM,MMC


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INTRODUCTION Hepatic encephalopathy describes the spectrum of potentially reversible neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of unrelated neurologic and/or metabolic abnormalities. The term implies that altered brain function is due to metabolic abnormalities, which occur as a consequence of liver failure. The full reversibility of symptoms after improvement of liver function is considered to be direct proof of this causal relation.

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Both hepatocellular failure and porto sytemic shunting are key elements in its development. Ammonia plays a very important role. Condition is generally underdiagnosed . No specific treatment.


Incidence/prevalence Universal feature of acute liver failure 50%~70% in chronic hepatic failure exact incidence is difficult to estimate

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Causes: Chronic parenchymal liver- Due to one or more potentially reversible precipitating factors Chronic hepatitis: Cirrhosis. Fulminating hepatic failure :Due to acute hepatic necrosis Acute viral hepatitis Drugs Toxins e.g. Wilson’s Disease, CCL 4 , acute fatty liver of pregnancy Surgical Portal-systemic anastomoses , - portacaval shunts, or Transjugular intrahepatic portal-systemic shunting [TIPS]).

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liver cirrhosis with reduced functional hepatic mass underlies the development /HCC Triggered by precipitating factors Incresed NH3 Increased protien intake Constipation GI bleeding Blood TX Infections Sepsis Renel failure Hypovolumia /hepatic hypoxia Overdiuresis Large volume paracentesis Diarrhoea vomiting Circulatory shock Drugs Tranqulizers Narcotic analegesics Diuretics Electrolyte Imbalance Hypokalemia Hyponateremia Metabolic acidosis / alkolosis Portosytemic shunts Spontaeous Surgical TIPS

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Type Description Subcategory Subdivision A Encephalopathy associated with acute liver failure _____ ______ B Encephalopathy with porto -systemic bypass and no intrinsic hepatocellular disease _____ ______ C Encephalopathy associated with cirrhosis or portal hypertension ⁄ porto -systemic shunts Episodic Persistent Minimal Percipated Spontaneous Recurrent Mild Severe Treatment dependent Classification

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Clinical Detection Relationship Of HE Subtypes

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Changes in mental state- Personality changes Intellectual detioration Disturbed consciousness

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a. Changes of Personality Childish behavior. Irritable-May be aggressive ,outbursts of anger. Euphoric. Loss of concern for friends or family These features are usually first noticed by family members

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B. Intellectual deterioration :- Varies from slight impairment of mental function to gross confusion inability to produce simple designs with blocks or matches Reitan trail-making test writing indistinct and oblivious to ruled lines. Failure to distinguish objects of similar size and shape

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C Disturbance in consciousness Disturbances in sleep rhythm. Reduction of spontaneous movement, a fixed stare, apathy, and slowness and brevity of response are early signs. Impaired memory/ apraxia Mental confusion. Apathy. Drowsiness / Somnolence Coma.

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C Neurological signs: Bradykinesia,rigidity ,resting tremors. Choreathetoid movements. Movement tremors,diadochokinetic movements. Hyperreflexia,hypertonia flexor plantar in early stages. Hypotonia,areflexia and extensor plantar in late stages.


ASTERIXIS The most characteristic neurological abnormality is the ‘flapping’ tremor ( asterixis ). This is due to impaired inflow of joint and other afferent information to the brainstem reticular formation resulting in lapses in posture. It is demonstrated with the patient’s arms outstretched and fingers separated or by hyperextending the wrists with the forearm fixed. The rapid flexion–extension movements at the metacarpophalangeal and wrist joints are often accompanied by lateral movements of the digits.

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Speech is slow and slurred and the voice is monotonous. In deep stupor, dysphasia becomes marked. fetor hepaticus . This is a sour, faecal smell 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 does not correlate with the degree or duration of encephalopathy and its absence does not exclude hepatic encephalopathy

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Clinical stages of HE

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Clinical stages of HE

Diagnosis of Hepatic Encephalopathy :

Diagnosis of Hepatic Encephalopathy

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There is no gold standard for diagnosing hepatic encephalopathy in patients with cirrhosis. There are a number of individual techniques that access different aspects of cerebral function, which can be used, singly or in combination, to provide diagnostic information

Neurological examination mental state assessment:

Neurological examination mental state assessment a careful and detailed neuropsychiatric history and examination. use of two - grading systems to assess mental status the West Haven criteria and the Glasgow Coma Scale comprehensive neurological examination the exclusion of other potential causes of neuropsychiatric abnormalities,

West Haven criteria:

West Haven criteria

The Glasgow Coma Score:

The Glasgow Coma Score

Psychometric performance:

Psychometric performance Impaired psychometric performance defines the presence of minimal hepatic encephalopathy in patients with cirrhosis who appear clinically unimpaired. Patients with minimal hepatic encephalopathy show deficits in attention,visuo spatial abilities, fine motor skills and working memory while other cognitive abilities are relativelypreserved

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Psychometric Hepatic Encephalopathy Score (PHES), assesses the required domains of attention, visual perception and visuoconstructive abilities It uses five paper and pencil tests, namely Number Connection Tests A and B, and the line tracing,serial dotting and digit symbol tests


Neurophysiology-EEG The EEG primarily reflects cortical neuronal activity. Hepatic encephalopathy is characterized by progressive slowing of the normal alpha frequency of 8 to13 Hz. Bursts of slow activity are observed in the theta (4 – 8 Hz) range, initially in the temporal areas, and then more diffusely over the scalp further slowing into the delta (1 – 4 Hz) range may then occur. Triphasic waves or arrhythmic delta activity occur with more severe grades of encephalopathy coma is characterized by slow, low -voltage delta activity with sequences of electric silence

Evoked potentials:

Evoked potentials Abnormalities of exogenous EPs which reflect cortical function have been described in patients with both minimal and overt hepatic encephalopathy. Cognitive or endogenous EPs are triggered by cognitive activity. The best known is P300 which is triggered when the subject receives an infrequent visual or auditory stimulus embedded in a series of otherwise irrelevant, frequent stimuli. The potential occurs about 300 ms after exposure to the rare stimulus, hence its name. Assessmentof P300 latency has diagnostic potential for detecting thepresence of minimal hepatic encephalopathy and formonitoring the status of patients with mild to moderate hepatic encephalopathy over time

Critical flicker frequency:

Critical flicker frequency Retinal glial cells are involved in ammonia detoxification by glutamine synthesis. In patients with liver failure, they exhibit morphological changes similar to those observed in brain astrocytes , suggesting that retinal gliopathy could serve as a marker of cerebral gliopathy in patients with hepatic encephalopathy. These observations provided the rationale for the development of a visual test (the critical flicker/fusion frequency) for determining whether hepatic encephalopathy is present. Initial experience suggests that the critical flicker/fusion frequency may be a highly objective and sensitive measure of minimal hepatic encephalopath

Imaging studies:

Imaging studies Conventional cerebral CT and MR imaging may show evidence of cerebral and sometimes cerebellar atrophy in patients with cirrhosis. These changes are related to the severity of the liver dysfunction and do not relate to changes in cerebral function. They are most prominent in patients with a history of alcohol abuse. Hyperintensity in the basal ganglia on MRI T 1 - weighted images may also be observed but does not correlate with either the presence or severity of hepatic encephalopathy

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Volumetric MRI provides precise measurements of whole or regional brainand allows small difference in brain size to be monitored (co - registered MRI). Functional MRI provides measurements of the haemodynamic responses related to neural activity in the brain

Cerebral MRS:

Cerebral MRS In vivo MRS can provide localized biochemical information on cerebral metabolic processes. Characteristic alterations have been observed in cerebral 1 H MRS in patients with cirrhosis, which correlate with the degree of neuropsychiatric impairment. These alterations, which are typified by relative reductions in the myoinositol and choline resonances and a relative increase in the composite glutamine/ glutamate resonance, are thought to reflect changes in astrocyte volume homeostasis

Blood ammonia :

Blood ammonia Measurement of blood ammonia may be of value in thedifferential diagnosis of hepatic encephalopathy. It can be particularly useful when a patient not known to have cirrhosis presents with fluctuating neurological symptoms and signs of seemingly unknown origin. The pH - dependent partial pressure of gaseous ammonia in arterial blood correlates more closely with the clinical and neurophysiological changes observed than plasma ammonia concentrations

Cerebrospinal fluid :

Cerebrospinal fluid The cerebrospinal fluid (CSF) is usually clear and undernormal pressure. Patients with severe Grade III/ IVencephalopathy may have increased CSF protein concentrations, but the cell counts are normal. CSF glutamine concentrations may be increased and correlate significantly with both the presence and the degree of hepatic encephalopathy

Neuropathological changes:

Neuropathological changes Microscopically Alzheimer type II astrocytosis found particularly in the cerebral cortex basal ganglia and cerebellum. More signifi cant changes are seen in patients with persistent hepatic encephalopathy including: patchy cortical laminar or pseudolaminar necrosis with polymicrocavitation at the corticomedullary junctions and in the striatum and uneven degeneration of neurones and medullated fi bres in the cerebral cortex, cerebellum and lenticular nuclei. Demyelination in the pyramidal tracts is observed in patients with hepatic myelopathy .

Choice of diagnostic v ariables:

Choice of diagnostic v ariables Current guidelines suggest: (1) a detailed clinical assessment to identify or exclude clinically apparent change (2) an assessment of psychometric performance using the PHES battery or a validated computer – based system (3) an electrophysiological assessment, for example an EEG or somatosensory / cognitive EPs, if accessible; (4) an assessment of health – related quality of life

Other causes of encephalopathy or disturbed consciousness in cirrhotic patients:

Other causes of encephalopathy or disturbed consciousness in cirrhotic patients Severe hyponatremia Respiratory failure Severe sepsis Intracranial bleed Acute alcoholism Wernicke ’ s encephalopathy Status epilepticus Zinc deficiency Drug overdose Hypoglycemia Post ictal CNS sepsis Delirium tremens Hepato-lenticular degeneration (Wilson ’ s disease) Functional psychoses



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Any hypothesis regarding the pathogenesis of this syndrome must adequately explain the following: 1 the broad spectrum of clinical findings which appear to reflect dysfunction of multiple cerebral systems; 2 the fluctuant nature of the clinical picture, in particular its rapid evolution and its complete reversibility; 3 the mechanisms by which a variety of diverse condition precipitate deterioration in the clinical picture; 4 the mechanisms that result in alleviation of the clinical symptoms in response to treatment.

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Pathogenesis (acute & chronic ) The basic cause is same in both forms but the mechanism is somewhat different Diminished detoxification of toxic intestinal nitrogenous compounds Dr S Chakradhar 46 Increased in blood NH3 etc Toxic effect on brain Appearance of abnormal amines in systemic circulation Interference with neurotransmission

Key concepts:

Key concepts Hepatocellular failure Portal – systemic shunting


KEY FACTORS Gut - derived neurotoxins Brain water homeostasis Oxidative/ nitrosative stress Astrocyte dysfunction Neurotransmitter dysfunction Infection and inflammation

Gut-derived neurotoxins:

Gut-derived neurotoxins Ammonia -most important Indoles - produced by bacterial degradation of tryptophan mercaptans phenols- produced by bacterial degradation of phenylalanine and tyrosine short - and medium - chain fatty acids .

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Ammonia is produced in the intestine from dietary protein, deamination of glutamine via glutaminase and bacterial action in the colon. It is absorbed by non – ionic diffusion; concentrations in the portal vein are tenfold higher than in arterial blood. The hepatic extraction rate is high. The ammonia in portal blood, together with the ammonia derived from hepatic amino acid metabolism, is taken up by periportal hepatocytes and metabolized to urea via the urea cycle. ammonia is also taken up by perivenous hepatocytes where it is converted to glutamine via glutamine synthetase .

Causes of increased ammonia:

Causes of increased ammonia Small bowel colonization with urease - containing bacteria Enhanced intestinal absorption of ammonia secondary to the increased splanchnic blood flow associated with portal hypertension Intra - and extra - hepatic portal systemic shunting Reduction in functioning hepatocyte mass Decreased ammonia metabolism in muscle as a result of loss of muscle mass Increased renal production of ammonia secondary to the respiratory alkalosis commonly seen in these patients, which is the result of primary hyperventilation and hypokalamia .

Ammonia and CNS dysfunction:

Ammonia and CNS dysfunction Ammonia is detoxified, in astrocytes , by the synthesis of glutamine through amidation of glutamate via glutamine synthetase Ammonia exerts deleterious effect particularly on astrocytes causing morphological changes and astrocyte dysfunction. Astrocytes undergo Alzheimer type II astrocytosis,most prominent in the cerebral cortex, basal ganglia and cerebellum

Brain water homeostasis :

Brain water homeostasis The influx of excess ammonia into the brain results in accumulation of osmotically active glutamine within astrocytes . This results in astrocyte swelling. This is countered by efflux from the cell of other osmotically active compounds, principally myoinositol , but also taurine and α - glycerophosphorylcholine . The net result is the development of low - grade cerebral oedema . The small increases in astrocyte water content may have important functional consequences despite the absence of a clinically overt increase in intracranial pressure. Hyponatraemia , inflammatory cytokines and BZD also promote astrocyte swelling, most probably in synergy with ammonia.

Oxidative/ nitrosative stress:

Oxidative/ nitrosative stress Ammonia, hypo-osmotic swelling, inflammatory cytokines and benzodiazepines induce an oxidative/ nitrosative stress response in astrocytes . They stimulate NMDA receptors which increase NADPH oxidase causing O2 free radicals and nitric oxide synthase which forms nitric oxide. NMDA activation and oxidative stress trigger astrocyte swelling which inturn stimulate free radical production thus causing a vicious cycle.

Astrocytic dysfunction:

Astrocytic dysfunction Oxidative/ nitrosative stress can promote covalent modification of tyrosine residues in astrocytic proteins.This process, which is known as protein tyrosine nitration,interferes with protein function and intracellular signal transduction Oxidative stress can induce RNA oxidation, which compromises translational accuracy/efficacy and results in the formation of defective or unstable proteins. Nitrosative stress promotes mobilization of zinc from metallothionein and other proteins. Zn ++ may affect the activities of multiple enzymes and transcription factors and may augment GABAergic neurotransmission and decrease glutamate uptake

Alterations in cerebral neurotransmission:

Alterations in cerebral neurotransmission Hepatic encephalopathy is associated with a shift in balance between inhibitory and excitatory neurotransmission favouring inhibition. This has been attributed to either alteration in the glutamatergic system or to an increase in GABAergic tone

Glutamate :

Glutamate Total brain levels of glutamate are decreased in patients with cirrhosis dying in hepatic coma most probably reflecting its consumption in the formation of glutamine in the presence of hyperammonaemia The increase in extracellular glutamate concentrations may result in NMDA receptor activation in astrocytes , which is a key factor inthe development of the oxidative stress response

Gamma - Aminobutyric a cid and the neurosteroid system:

Gamma - Aminobutyric a cid and the neurosteroid system Hepatic encephalopathy is associated with an increase in GABA - ergic tone. The changes in GABA - ergic tone are now thought to be mediated by neurosteroids which are primarily synthesised in astrocytes . Neurosteroids such as 3 α - 5 α - tetrahydroprogesterone (allopregnanolone) are potent, endogenous, positive allosteric modulators of both the GABA and benzodiazepine sites on the GABA - A receptor complex

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The neurosteroids may also act synergistically with other potential neurotoxins such as ammonia and benzodiazepine - like compounds to further modulate GABA - A receptor function. The net effect is an increase in GABAergic tone and neural inhibition. Involvement of the GABA - ergic system in the pathogenesis of hepatic encephalopathy is consistent with the increased sensitivity to benzodiazepines observed in these patients [23] , and the short - term improvement in neuropsychiatric status seen in some patients with cirrhosis treated with the benzodiazepine antagonist,flumazenil .


Serotonin Decreased levels of serotonin seen in cirrhosis patients in hepatic coma Appearance of encephalopathy in patients with cirrhosis treated with the 5 - HT blocker ketanserin for portal hypertension ,implicate the serotonin system in hepatic encephalopathy


Dopamine Decreased levels of dopamine seen in cirrhosis patients in hepatic coma. Extrapyramidal features are common in hepatic encephalopathy. In some patients these symptoms, together with the more general aspects of the syndrome, respond well to treatment with the dopamine agonist bromocriptine , further implicating the dopamine system in this condition.

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Alterations have also been described in histaminergic and opioidergic neurotransmission but their role in the genesis of hepatic encephalopathy is uncertain.

Neuromodulatory systems:

Neuromodulatory systems Alterations have also been reported in the activities of the neuromodulators acetylcholine and adenosine

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Acetylcholine levels are considerably reduced in the brains of patients with cirrhosis dying in hepatic coma because of an increase in the activity of the acetylcholine - hydrolysing enzyme, acetylcholinesterase . Nicotinic receptor density is significantly lower in the brains of these patients while the affi nity of acetylcholine for the muscarinic receptor is reduced. Activation of nicotinic receptors mediates neuronal excitation while activation of muscarinic receptors suppresses GABAergic synaptic transmission. These changes result in a net increase in inhibitory neurotransmission. Rivastigmine , a reversible cholinesterase inhibitor, improves psychometric performance in patient with hepatic encephalopathy when used in conjunction with lactulose


ADENOSINE Both A 1 and A 2A binding are reduced in the brains of patients with cirrhosis dying in hepatic coma

Inflammation and infection:

Inflammation and infection Patients with cirrhosis have impaired host defence mechanisms; their neutrophils and macrophages have a reduced capacity to phagacytose and eliminate microbes.In addition, bacterial translocation from the gut resultsin chronic endotoxaemia . These patients are at increased risk of infection; infection frequently precipitates hepatic encephalopathy. Recent interest has focused on the possible synergistic roles of infl ammation and infection in modulating the cerebral effects of ammonia. Infe ction and inflammation will lead to the production of chemokines , proinflammatory cytokines and ROS, which will contribute to astrocyteoxidative stress.

Unifying hypothesis:

Unifying hypothesis

Treatment of HE:

Treatment of HE

Management of precipitating factors:

Management of precipitating factors Management Precipitating factor Endoscopic intervention, vasoconstrictors,volume resuscitation, prophylaxis for stress ulcers GI bleed Antibiotics Sepsis Correct abnormality, avoid diuretics, fluid restriction Electrolyte abnormalities Flumazenil, naloxone challenge Exogenous sedatives Avoid NSAIDs, control sepsis, correct circulating volume abnormalities Azotemia

Diet :

Diet Guidelines recommend daily energy intakes of 35 to 45 kcal/kg Guidelines recommend that the daily protein intake in patients with liver disease should if possible be around 1-1.5g/kg depending upon the degree of hepatic decompensation . vegetable protein are preferred to animal protein. It is also important that food intake is spread evenly through out the waking day to avoid protein loading; six snack -type meals are preferable to three main meals [

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It may be difficult to maintain oral intake in patients presenting with gastrointestinal bleeding and in thosewith severe encephalopathy. It may be necessary, under these circumstances, to restrict dietary intake. A short period of dietary deprivation of up to 24 to 36 h may not be harmful but prolonged restriction should be avoided. During recovery, protein is added in 10g increments on alternate days.

Protein restriction in HE: necessary evil or illogical dogma?:

Protein restriction in HE: necessary evil or illogical dogma? The role of protein restriction in patients with chronic HE has been questioned recently as the efficacy of protein withdrawal in patients with chronic HE has never been subjected to a controlled trial. Evidence suggests that protein intake plays only a limited role in precipitating encephalopathy. In fact, measures taken to suppress endogenous protein breakdown are more effective than dietary restrictions in reducing the load of amino acids on the decompensated liver.

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A protein intake of less than 40 g per day, as has been indicated contributes to a negative nitrogen balance, which along with increased endogenous protein breakdown, worsens encephalopathy. A positive nitrogen balance may have positive effects on encephalopathy. Depressed plasma BCAA levels, also supervene in cirrhosis only when malnutrition is present as well.

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The emphasis in the nutritional management of patients with HE should not be on the reduction of protein intake . Instead, the goal should be to promote synthesis by making available ample amounts of amino acids, while instituting other measures to reverse the ongoing catabolism . Different protein sources have varying effects on HE and efforts should be made to identify the most tolerated protein source to prevent malnutrition and maintain these patients on a long-term basis.

Non-absorbable disaccharides (lactulose and lactilol):

Non-absorbable disaccharides (lactulose and lactilol) Since the 1980s, non-absorbable disaccharides have been considered as the standard treatment for HE. Recent guidelines state that lactulose ( -galactosido-fructose) is the first line pharmacological treatment for HE. When given by mouth lactulose reaches the cecum where it is broken down by bacteria predominantly to lactic acid. The osmotic volume of the colon is increased. The fecal pH drops. The growth of lactose-fermenting organisms is favored and organisms such as bacteroides, which are ammonia formers, are suppressed .

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The mode of action is uncertain. Fecal acidity would reduce the ionisation and hence absorption of ammonia (also amines and other nitrogenous compounds). Lactulose more than doubles the colonic output of bacterial mass and ‘ soluble ’ nitrogen which is no longer available for absorption as ammonia. The aim of treatment is to produce acid stools without diarrhea. The dose is 10-30 ml, 3 times a day and is adjusted to produce 2 semi-soft stools daily . Lactulose is also effective when delivered rectally (250 mL lactulose in 750 mL water) Side-effects include flatulence, diarrhea and intestinal pain.

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Lactilol ( - galactoside sorbitol ) is a second-generation disaccharide easily produced in chemically pure crystalline form, which can be dispensed as a powder. It is not broken down or absorbed in the small intestine, but is metabolized by colonic bacteria. It seemed to be as effective as lactulose in chronic and acute portal-systemic encephalopathy. Patients responded more quickly to lactilol than lactulose , and there was less diarrhea and flatulence . The dosage required to ensure passage of two semisoft stools/day ranges from 10 to 90 g.

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However, in their systematic review of randomised trials on non-absorbable disaccharides for HE, Als-Nielsen et al, (2004), stated that there is insufficient evidence to determine whether non-absorbable disaccharides are of benefit to patients with HE.


ENEMAS The value of enemas in patients with hepatic coma must be emphasized. Lactulose or lactose enemas may be used and are superior to water. All enemas must be neutral or acid to reduce ammonium absorption.

Antibiotics :

Antibiotics Neomycin given orally, is very effective in decreasing gastrointestinal ammonium formation. Little neomycin is absorbed from the gut although blood levels have been detected and impaired hearing or deafness may follow its long-term use. Thus it should only be used for the acute case for 5-7 days (4-6 g/day in divided doses). It should be used with particular caution in patients with renal insufficiency. In acute hepatic coma, lactulose is given, and neomycin added if the response is slow or partial.

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Metronidazole (200 mg 4 times per day orally) seems to be as effective as neomycin. Because of dose-related CNS toxicity, it should not be used long term. Antibiotics can be considered a therapeutic alternative to non-absorbable disaccharides in acute HE but in chronic encephalopathy should be reserved for patients who respond poorly to non-absorbable disaccharides

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The analysis of Als -Nielsen et al, (2004) indicated that antibiotics were statistically superior to non-absorbable disaccharides in improving HE and lowering blood ammonia concentrations. However, it was unclear whether the effects were clinically important. Considering this, the lack of effect of antibiotics in placebo controlled trials, the risk of multi-resistance, and the potential risk of severe adverse events lead them to conclude that there is insufficient evidence to recommend the use of antibiotics for HE.


Rifaximin A synthetic antibiotic structurally related to rifamycin. Displays a wide spectrum of antibacterial activity against Gram-negative and Gram-positive bacteria, both aerobic and anaerobic A very low rate of systemic absorption. This will minimize both antimicrobial resistance and systemic adverse events. Safe in all patient populations and also in the long term. It has been studied extensively in the treatment of HE and appears to confer therapeutic benefits greater than those of placebo and non-absorbable disaccharides and at least comparable with those of systemic antibiotics. It was well tolerated and is not associated with clinical drug interactions or clinically relevant bacterial antibiotic resistance.

Oral antibiotic therapy for HE:

Oral antibiotic therapy for HE Efficacy Potential adverse effects Regimen g/day Antibacterial activity Drug Good Resistant strains 4 Wide spectrum Ampicillin Good Nephro/ototoxicity 4 Wide spectrum Paromomycin Good Nephro/ototoxicity 4-6 Aerobic bacteria Neomycin Good Neurotoxicity 0.8 Anaerobic bacteria Metronidazole Good Not reported 1.2 Wide spectrum Rifaximin

Sodium benzoate:

Sodium benzoate Sodium benzoate conjugates with glycine and the excess nitrogen is excreted in the urine as hippurate . In the only large, randomized, controlled trial, available to date, this compound was equally as effi cacious as lactulose for the treatment of hepatic encephalopathy but possibly less well tolerated. The recommended dose is 5 g twice daily but patients rarely tolerate more than 2 g twice daily, because of the gastrointestinal side effects. The sodium content is also a concern.

L ornitine L aspartate:

L ornitine L aspartate - Lornithine - L- aspartate (LOLA) treatment promotes hepatic removal of ammonia by stimulating residual hepatic urea cycle activity and promoting glutamine synthesis, particularly in skeletal muscle. Controlled studies show that intravenous LOLA administration reduces ammonia levels and improves mental state and psychometric performance in cirrhotic patients with overt hepatic encephalopathy. Treatment with oral LOLA, in a dose of 6 g three times per day, confers some benefi t but only in patients with at least Grade II encephalopathy. Overall, however, the evidence for a beneficial effect of oral LOLA is not strong

Dopaminergic agonists-Bromocriptine:

Dopaminergic agonists- Bromocriptine Patients with stable, chronic, persistent hepatic encephalopathy with prominent extrapyramidal features, HE resistant to treatment with other agents well - compensated liver disease The dose is gradually increased from 2.5 mg once daily to a maximum of 5 mg twice daily Ototoxicity is reported.

Benzodiazepine-receptor antagonists:

Benzodiazepine-receptor antagonists Flumazenil had a significant beneficial effect on short-term improvement of HE in patients with cirrhosis and a highly favorable prognosis. Flumazenil had no significant effect on recovery or survival. At the moment, flumazenil may be considered for patients with chronic liver disease and HE, but cannot be recommended for routine clinical use..

Branched-chain amino acids (BCAA):

Branched-chain amino acids (BCAA) Infusions of solutions containing a high concentration of BCAA have been used to treat acute and chronic HE. Results have been extremely conflicting, perhaps related to differences in the nature of amino acid solutions, the ways of administration and the patients studied. Analysis of controlled trials shows that there is no consensus that intra-venous BCAA control HE. This procedure is now rarely employed, although oral supplements of BCAA continue to be used as a complementary therapy in cases of protein-intolerant patients with chronic HE.

Gut flora-based therapy:

Gut flora-based therapy Gut flora clearly matters for the pathogenesis of HE. Indeed lactulose , works in part by altering gut flora to decrease ammonia production and absorption. Moreover, evidence suggests that the latter effects occur because lactulose serves as a ‘ prebiotic ’ ingredient, encouraging the growth of endogenous bacteria that resemble those found in many probiotics . Thus, therapeutic manipulation of the endogenous gut bacterial flora (gut flora therapy) by prebiotics , probiotics , or a combination of the 2 ( synbiotics ) might work for HE.

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Since patients with cirrhosis are considered to be immunosuppressed , they may be more vulnerable to real or theoretical risks of ingesting living bacteria. While probiotics are thought to be extremely safe by many experts, few have been rigorously evaluated in open label safety studies. However, since fermentable fiber and other “ prebiotics ” contain no living organisms, some safety and regulatory concerns are obviated.


Acarbose Inhibits the upper gastrointestinal enzymes (alpha-glucosidases) that convert carbohydrates into monosaccharides. It also promotes the proliferation of intestinal saccharolytic bacterial flora that produce mercaptans, benzodiazepine-like substances, and ammonia. Their reduction could improve hepatic encephalopathy. This hypothesis appeared to be confirmed by a randomized controlled crossover trial (Gentile, et al., 2005) involving 107 cirrhotic patients with diabetes mellitus and grade 1 to 2 HE. Treatment was associated with a significant reduction in blood ammonia levels and improvement in encephalopathy.

Shunt occlusion:

Shunt occlusion Many patients with persistent hepatic encephalopathy have evidence of significant spontaneous portal – systemic shunting . These patients often have well – preserved iver function but respond poorly, if at all, to standard treatment. Interventional radiological techniques can be used to close the shunts vascular embolization vascular plugging with an Amplatzer device balloon occlusion Reduction or even occlusion of the TIPS may be required Shunt occlusion should be considered as a prelude to transplantation, particularly in those with TIPS or surgical shunts, if they are otherwise suitable. .

Artificial Extracorporeal Liver Support ‘Liver dialysis':

Artificial Extracorporeal Liver Support ‘ Liver dialysis' Patients frequently die while on the transplantation waiting list because of organ scarcity. Systems supporting liver function may be useful to: Avoid further complications due to the typical toxic state. ‘ Bridging' the patients to the transplantation. In the event of an acute decompensation of a chronic liver disease, sustain liver function long enough to permit the organ's regeneration and functional recovery.

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An ideal liver support system should substitute the main functions of the liver (detoxification, synthesis and regulation). Extracorporeal systems now available may be: Totally artificial Detoxification Bioartifical Synthesis (plasma proteins, coagulation factors Regulation (neurotransmitters)

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Novel treatments introduced to improve detoxification, mainly of the protein-bound substances: Molecular adsorbent recirculation system (MARS): albumin dialysis Prometheus systems: novel device for fractionated plasma separation via an albumin-permeable filter that was developed to improve removal of albumin-bound toxins. Different experiences have proved the efficacy of MARS mainly in the treatment of HE, while data on survival are still limited to small case series. Initial studies have proven clinical use of Prometheus to be feasible and safe.

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Nevertheless, liver dialysis must still be thought of as experimental because its contribution to improved patient survival has not been proven in large randomized trials. In a meta-analysis ( Kjaergard , 2003), the positive effects, including improvement in HE of the artificial and bioartificial liver support systems in patients with liver failure, seemed to be restricted to the ‘ acute-on-chronic ’ situation, while their efficacy in patients with acute liver failure remained doubtful. Stem cells are the real great hope for the future of patients with end-stage liver disease.

Liver transplantation:

Liver transplantation The features of overt hepatic encephalopathy usually resolve following liver transplantation, even in patients with major physical manifestations such as spastic paraparesis and parkinsonian features resistant to treatment. In addition, resolution of the EEG ,cerebral MRI,cerebral MRS and cerebral PET abnormalities have also been reported. Cognitive function also improves following transplantation The prevalence of neurological complications following liver transplantation is 10 to 47%

Management of recurrent or episodic HE:

Management of recurrent or episodic HE

Management of minimal hepatic encephalopathy:

Management of minimal hepatic encephalopathy

Management of persistent hepatic encephalopathy:

Management of persistent hepatic encephalopathy

Future therapy:

Future therapy L carnitine Endocarbinoids Sildenafil mGluR1 antagonists Rivastigmine

To conclude:

To conclude Identification and treatment of the precipitating cause. Intervention to reduce the production and absorption of gut-derived ammonia and other toxins. Prescription of agents to modify neurotransmitter balance directly or indirectly. These are of limited clinical value at present.

Thank You:

Thank You

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