Chronic HepatitisDr Manoj K Ghoda M.D., M.R.C.P.

Consultant GastroenterologistVisiting faculty at GCS Hospital

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12 yrs old boy

•Jaundice•Abdominal distention•Edema feet•Ascites

•Abdominal distention was there for past few years (in retrospect)•History of repeated epistaxis

What was absent...

•Fever, •Malaise•Nausea or vomiting•Aversion to food

On examination•Thin and lean•Jaundice+•Moderate edema feet•Ascites ++•There was wasting of proximal muscles of arms and legs

•Liver ++, firm with rounded edges; Spleen ++•Visible veins on upper part of abdomen•Other systems were normal

From above findings we know that we are dealing with liver disease, most probably of longstanding durationWhat features suggestive of long standing problem?

•Long history of liver disease•Repeated epistaxis•Blackening of face•Edema•Ascites, Umbilical hernia•Visible veins•Proximal muscle wasting•Spider nevi•Palmer erythema

•Liver enlarged ++•Spleen enlarged ++•Shrunken nodular liver or coarse parenchymal echo•Dilated portal vein and splenic veins, collaterals in splenic hilum

Features suggestive of long standing Liver problem

Chronic hepatitis: Long standing inflammation of liver; six months is an arbitrary limit.

Coming back to our case....One elder and one younger sibling were having similar problems.

What could be causing this?

•Hepatorenal Tyrosinemia (chronic form)•Uncorrected biliary atresia

•GSDs•Wilson’s•Auto Immune Hepatitis•Celiac

•Hep B and C•Wilson’s,•AIH, •PBC, PSC•Hemochromatosis,•Celiac, •NAFLD, •Drugs

Etiology and epidemiology of chronic liver disease/ cirrhosis

Pathogenesis

•Direct toxicity

•Immune mediatedTo hepatocytes/its constituteTo biliary epithelium/ its constitute

•Promotion of fibrosis

Or a combination of above

Pathology:

CHRONIC HEPATITIS B. Hepatocytes show pathognomonic ground glass hepatocytes (arrows), distributed singly in a haphazard fashion with no zoning preference. Inclusions have an amorphous or finely granular and paler look

CHRONIC HEPATITIS C. Although portal tracts may contain lymphoid nodules in chronic hepatitis of any cause it is more commonly seen in chronic hepatitis C.

AIH

Hepatic macrosteatosis (>5%). Variable hepatocellular inflammation and injury. Inflammation may be predominantly neutrophilic or lymphocytic. Hepatocellular ballooning, apoptoic (acidophil) bodies, and Mallory’s bodies. Variable pericellular / perisinusoidal fibrosis.

Wilson's disease --> Cu2+ deposits --> Rhodanine stain

Cirrhosis of liver

Clinical features:

Sometimes there are no specific symptoms. When present, symptoms could be very vague.

•Fatigue, lethargy, body ache could be present for a long time.•Anorexia.•Edema, ascites in decompensated stage.•Easy bruising.•Blackening of the skin.•Progressive weight loss.

On examination:

•Jaundice may or may not be present.•Spider nevi may be present in the upper half of the body.•There may be ascites or pedal edema in decompensated stage. •Umbilical hernia is frequently seen in patients with decompensated chronic hepatitis.•There may be visible veins on abdominal wall.•Muscle wasting may be present.

Investigations: Diagnostic•LFT may show elevated bilirubin, SGPT or SGOT.•Serum albumin may be decreased and globulin raised, reversing the A/G ratio. In autoimmune hepatitis, there may be marked rise in globulin.Sonography may show altered liver size and echo texture, splenic enlargement and dilated portal and splenic veins and varices may be seen in splenic hilum, stomach and lower end of esophagus. Ascites may be present. •CBC may show anemia, generally normochromic, and normocytic, but occasionally microcytic hypochromic if there is frank or occult blood loss or macrocytic if alcohol is the etiology. ESR may be high in autoimmune variety.•WCC and Platelets may be decreased due to hypersplenism.

Investigations:

UGI endoscopy for varices or PHG

Snake skin

Investigations: Etiological

•HBsAg, Total HBcAb•HCV-Ab

•Ceruloplasmin, 24hr urinary copper, KF ring, liver copper content•Transferrin saturation and ferritin

•ANA, Anti SMA, Anti LKM1-2•TTGA

•Urinary succinyl acetone•Liver biopsy

Investigations: Prognostic

The MELD score (UNOS MELD score calculator)Above 20= Need for transplant is nearLess than 20= Need for transplant is not near

(www.mayoclinic.org/meld/mayomodel6.html)(optn.transplant.hrsa.gov/resources/MeldPeldCalculator)

Progression:

If left untreated there is progression of the disease leading to cirrhosis of liver

Treatment:•Treatment of liver failure and portal HT if present: Albumin, non selective B blockers, diuretics, high protein diet, Lactulose

•Treatment of causeHep B infection: If the disease is active, Interferon or Nucleoside/tide analogues like Tenofovir or EntecavirHep C: Inf+ RBV; Direct Acting Agents (DAA)Wilson’s: d-Penicillamine, TrientinAIH: Prednisolon + AzathioprineCeliac: Gluten withdrawlHemochromatosis: Venesection

Prognosis:

Excellent if treated in time

Hepatic Encephalopathy

Hepatic encephalopathy consists of a wide spectrum of often-reversible neuropsychiatric syndromes that complicate acute or chronic liver disease, occurring with a frequency of 10-50% in cirrhotics at some time during their illness.

Incidence of coma following acute liver failure is fairly low, around 0.1 % in general population and up to 20% in pregnant women with hepatitis E. It has high mortality and morbidity

Pathophysiology:

•Neuropathologically, encephalopathy is characterized by enlarged astrocytes with prominent nucleoli; margination of chromatin; and large, pale nuclei without any significant neuronal changes.

•Neurophysiologically, there is no one single mechanism. Current hypothesis suggest that a combination of chronic low-grade glial edema and potentiation of the effects of gamma-amino butyric acid (GABA) on the central nervous system by ammonia may be responsible for many of the symptoms of hepatic encephalopathy.

Neuropathology (2)

Of prime importance is ammonia which has direct effect on neural membrane or on postsynaptic inhibition and indirect effect on neuronal function via increased level of glutamine. GABA, which is an inhibitory neurotransmitter, enters circulation without being metabolized in liver and causing encephalopathy. Moreover dopamine and catecholamine mediated neurotransmission is inhibited by false neurotransmitters generated by bacterial action in the colon.There is an increased levels of manganese in the basal ganglia and also other areas of the brain which may have a role to play.

Clinical manifestations:

•Range from mildly altered mental status to coma.

•In subclinical or minimal hepatic encephalopathy there are only subtle changes, detected only by psychomotor testing and easily reversible with therapy.

•Acute hepatic encephalopathy associated with acute fulminant liver failure is characterised by quick progression to coma. •Onset is abrupt with confusion, disorientation which quickly leads to convulsions, coma, and decerebrate rigidity.•Pupils may be fixed and there could be paroxysmal hypertension and rapid breathing. •Fetor hepaticus, a musty smell in breath, may be present.•There may be high grade fever.•Jaundice may or may not be visible. •Mortality is 70-80% and is usually due to hypoxia and cerebral herniation caused by cerebral edema, increased intracranial pressure, and reduced cerebral perfusion.

Chronic hepatic encephalopathy is more common and is associated with end-stage cirrhosis.

1.It is slow in onset with milder symptoms and is usually triggered by precipitating factors such as infection, electrolyte disturbances, constipation, and gastrointestinal bleeding, etc., and is reversible in a majority of the cases. 2.In sub-acute onset the patient may fluctuate from drowsy but rousable state to deeply comatose. Flapping tremors or rigidity may be present. 3.Chronic onset may be missed for some time. There may be personality changes, forgetfulness, altered sleep pattern and deteriorating hand writings. They fail on number connection tests. Flaps and rigidity may be present. 4.Following the first episode of overt hepatic encephalopathy, 1-year survival is approximately 40%. This rate falls to about 15% after 3 years.

Grading of coma:•Drowsy but rousable.•Confused, agitated.•Not rousable, comatose but responds to painful stimuli.•Deep coma, not responding to painful stimuli.

Investigations:•CBC and peripheral smear to rule out any infection.•Electrolytes. •Blood sugar. Ammonia to confirm hepatic origin of encephalopathy. •Urea and creatinine. •Prothrombin time, bilirubin, SGPT, albumin to gauge the extent of dysfunction.•If already not obtained, viral markers and other tests like 24 hour urinary copper , antinuclear antibodies etc. to find out the etiology of underlying liver disease.•EEG could be required in an atypical case of chronic encephalopathy.

Treatment: •Correction or removal of the underlying precipitant, such as hypovolemia, electrolyte imbalance, hypoxia, constipation, gastrointestinal bleeding, metabolic derangement, infection, and sedatives or tranquilisers.

•Protein restriction is not required. Protein intake could be 1.5 gm/Kg body weight to avoid negative nitrogen balance.

•Treating constipation with lactulose is the mainstay of therapy for hepatic encephalopathy, but has no significant benefit on mortality. Lactulose is catabolised by colonic bacterial flora to short-chain fatty acids which lowers the colonic pH. This reduction in pH favors the formation of the nonabsorbable NH4+ from NH3, trapping NH3 in the colon and thereby reducing plasma ammonia concentrations.

Treatement:•Sodium benzoate, 250mg/Kg body weight/ day in divided doses IV or orally is the drug of choice to reduce ammonia levels. •Sod Phenyl buterate at the same dose is used simultaneously, if available.•L-ornithine , L-aspartate is of no proven value. •Cerebral edema could be life threatening and is treated with mannitol, if there is adequate urine output and plasma osmolality is not higher than 340 mmol.•Antibiotics are also used as second-line therapy. •Flumazenil is recommended only if the patient has received benzodiazepines.

•Pentothal sodium may be used in the dose of 1-4 mg , as infusion if there are no cardiac arrhythmia.

•Hypothermia is a recent concept which tends to lower the intracranial pressure. Mild hypothermia results in a delay in onset of encephalopathy and prevention of brain edema. Mild hypothermia could be beneficial in the prevention of severe encephalopathy and brain edema in patients with ALF awaiting liver transplantation.

Prognosis

Any questions?

Dr Manoj K Ghoda M.D., M.R.C.P.Consultant GastroenterologistVisiting faculty at GCS hospital

gujarat gastro group