Hepatic Encephalopathy

Hardik makwana

• Hippocrates (460-370 BC) described a patient with hepatitis who ‘barked like a dog, could not be held and said things which could not be comprehended’.

• Hepatic encephalopathy (HE) is a potentially reversible , neuropsychiatric syndrome characterized by changes in cognitive function, behaviour, and personality, as well as by transient neurological symptoms and characteristic EEG patterns associated with acute and chronic liver failure.

• Clinical spectrum ranges from minor signs of altered brain function to deep coma.

• The concordance of neuropsychiatric manifestation in pt of liver dis should be treated as HE unless proved otherwise.

Classification of HE

• Type A: HE associated with Acute liver failure• Type B: HE associated with portal-systemic Bypass,

no intrinsic hepatocellular disease• Type C: HE associated with Cirrhosis and portal

hypertension or portal-systemic shunts:– Episodic HE: precipitated, spontaneous, recurrent– Persistent HE: mild, severe, treatment-dependent– Minimal HE

Pathogenesis Ammonia intoxication hypothesis Amino acid imbalance hypothesis(BCAA/AAA↓) The gamma-aminobutyric acid hypothesis Neurosteroids hypothesis False neurotransmitters Trace elements like zinc Role of associated inflammation

Clinical features of HE

• For descriptive purposes, features of encephalopathy can be separated into changes in – Consciousness – Personality – Intellect– Speech

Disturbed consciousness

• Hypersomnia appears early and progresses to reversal of the normal sleep pattern. Reduction of spontaneous movement, a fixed stare, apathy, and slowness and brevity of response are early signs.

• Further deterioration results in reaction only to intense or noxious stimuli.

• Coma at first resembles normal sleep, but progresses to complete unresponsiveness.

Personality changes

• These include childishness, irritability and loss of concern for family.

• Even in remission the patient may present similar personality features suggesting frontal lobe involvement.

Intellectual deterioration Varies from slight impairment of organic

mental function to gross confusion.

Speech• Slow and slurred and the voice is

monotonous. In deep stupor, dysphasia becomes marked.

Fetor hepaticus

• This is a sour, fecal 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 HE.

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.

• Absent at rest, less marked on movement and maximum on sustained posture, the tremor is usually bilateral, although not bilaterally synchronous, and one side may be affected more than the other. In coma the tremor disappears.

• A ‘flapping’ tremor is not specific for hepatic precoma.

• Deep tendon reflexes are usually exaggerated. Increased muscle tone is present at some stage and sustained ankle clonus is often associated with rigidity. During coma patients become flaccid and lose their reflexes.

• The plantar responses are usually flexor becoming extensor in deep stupor or coma.

• The clinical course fluctuates, and frequent observation of the patient is necessary.

Clinical grading of HEFlapping tremor Clinical signs Clinical grade

Infrequent at this stage

Alert, euphoric, occasionally depression. Poor concentration, slow mentation and affect, reversed sleep rhythm.

Grade 1(prodrome)

Easily elicited Drowsiness, lethargic, inappropriate behavior, disorientation.

Grade 2 (impending coma)

Usually present Stuporose but easily rousable, marked confusion, incoherent speech

Grade 3(early coma)

Usually absent Coma, unresponsive but may respond to painful stimulus

Grade 4(deep coma)

Minimal hepatic encephalopathy (MHE)• Alternative terms were proposed to avoid medical

errors induced by a name that could implicate that the condition is below the threshold of significance.

• The current consensus is to use the term ‘MHE’, as proposed by the Working Party commissioned by the 11th World Congress of Gastroenterology in 1998.

• Prevalence is as high as 84% in patients with hepatic cirrhosis.

Predisposing factors for HE developmentOthers Drugs Metabolic

alterationNitrogen products

Infections Opiates Hypokalemia GI bleedingSurgery Benzodiazepin

esAlkalosis Hyperazotemia

Renal failure Diuretics Hypoxia ConstipationShort fatty acids

Sedatives Hyponatremia High-protein diet

Superimposed hepatic injury

Phenol Hyperkalemia H. Pylori

Alcohol Dehydration Uraemia

Rarely,hepatoma and/or vascular occlusion

Hypoglycemia Porto-systemic shunt creation (including TIPPS)

Investigations

• Electroencephalogram – Bilateral synchronous slowing of the waves frequency

(with an increase in wave amplitude) from the normal -rhythm down to the range

– Useful for diagnosis and to assess treatment– Occur early– Non-specific. However, in a conscious patient with liver

disease are virtually diagnostic.

• CSF– Usually clear and under normal pressure– Maybe increased protein conc. but cell count

is normal

– Glutamic acid and glutamine may be increased

• Neuropsychological tests:– Especially used in clinical research– Psychometric Hepatic Encephalopathy Score (PHES): • A standardized test battery including 5 different tests• Its use is restricted to the study of mild and minimal HE.

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

Treatment of HE

Management of precipitating factors

Management Precipitating factorEndoscopic intervention, vasoconstrictors, 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 • It is important in cirrhotic patients to avoid protein

restriction any longer than is necessary.

• In the acute case, a short period of protein deprivation may not be harmful but prolonged restriction of protein in the cirrhotic patient without encephalopathy is inappropriate.

• If animal protein is not well tolerated, vegetable protein may be used.

• In the acute attack of HE dietary protein is reduced to 20 g/day.

• During recovery, protein is added in 10g increments on alternate days.

• Any relapse is treated by a return to the previous level.

Protein restriction in HE: necessary or illogical ?

• 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.

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.

• 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.

• Side-effects include flatulence, diarrhea and intestinal pain.

• 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 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 • 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.

• 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.

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.

Sodium benzoate and L-ornithine-L-aspartate• Sodium benzoate promotes urinary excretion of

ammonia and is as effective as lactulose and is less expensive.

• L-ornithine-L-aspartate treatment promotes hepatic removal of ammonia by stimulating residual hepatic urea cycle activity and promoting glutamine synthesis, particularly in skeletal muscle.

Dopaminergic agonists

• The use of bromocriptine or L-dopa is restricted to cases of chronic HE with important extrapyramidal signs.

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)

• 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.

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.

Shunt occlusion

• In cases of chronic HE the reduction or obliteration of large spontaneous porto-systemic anastomoses, or shunts previously done by surgery or TIPSS, can be a therapeutic option.

• A surgical shunt occlusion or the shunt may be occluded by invasive radiology with the insertion of a balloon or a steel coil.

• Risk of bleeding.

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.

• 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.

Liver transplantation

• This may be the ultimate answer to the problem of chronic HE.

• Any patient who has presented an episode of HE should be evaluated for this procedure.

• Proceed with early liver transplantation before the development of important organic brain lesions on sustained HE.

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