GRANULOMATOUS HEPATITIS

Dr. Shiyas MohammedJR Pulmonary Medicine

INTRODUCTION• Granulomas represent the inflammatory

response of the mononuclear phagocytic system to the presence of a foreign antigen.

• Granulomas in the liver may be found incidentally, but more often reflect an underlying clinically relevant disease.

• However, inspite of an extensive work up and evaluation, the aetiology remains obscure in 10-25% pts with hepatic granulomas and these patients have been labelled as having “granulomatous hepatitis”.

AETIOLOGYINFECTIONSBacterial: Brucella, SalmonellaMycobacterial: TB, Leprosy, NTMRicketssiae: Q feverSpirochaetal: SyphilisFungal: Histoplasma, coccidiodomycosis, cryptococcosisParasitic: SchistosomiasViral: Hepatitis C, Hepatitis B, Cytomegalovirus

AETIOLOGYSARCOIDOSIS

PRIMARY BILIARY CIRRHOSIS

HODGKINS DISEASE

AIDS RELATED OPPURTUNISTIC INFECTIONS

DRUGS: Carbamazepine, chlorpromazine,chlorpropamide,

phenylbutazone, procainamide

TB and Sarcoidosis are the most common causes of hepatic

granulomas in various studies.

With the advent of AIDS , hepatic granulomas due to rare causes

such as NTM, Cryptococcosis, etc are being increasingly encountered.

PATHOLOGY• Hepatic granulomas are the result of a cell mediated immune response by

hepatic reticulo endothelial system to antigen or foreign substances.

• Histopathological features of hepatic granulomas depend on the aetiology.

• Generally hepatic granulomas consists of pale staining epitheloid cells with

sorrounding lymphocytes.

• Sometimes, the foreign body or infecting organism can be identified within

the granuloma.

• Central areas of caseation necrosis, foreign body and langhans giant cells

can also be seen.

• Fibrous capsule and hyaline change representing healing may also be

found.

MORPHOLOGICAL TYPES

• Epitheloid cell granulomas– Caseating(necrotizing) granulomas– Non caseating granulomas

• Fibrin ring granulomas• Granulomatoid reactions with poorly formed

granulomas.• Bile granulomas• Lipogranulomas• Microgranulomas

MORPHOLOGICAL TYPES• Caseating granulomas have been classically associated

with TB.• Fibrin ring granulomas with a charecteristic doughnut

appearance occur in Q fever.• Granulomatoid reactions with poorly formed granulomas

occurs in pts with hematological malignancy and AIDS.• Bile granulomas has been described in areas of

cholestasis.• Lipo granulomas can be seen in fatty liver.• Micro granulomas can occur in pts with AIDS, CMV

hepatitis and can occur along with other type of granulomas

CLINICAL PRESENTATION

• Depends on aetiology.• Patients often presents with PUO.• Mild to moderate hepatomegaly which is

usually non-tender , is common.• When the disease is due to TB/Sarcoidosis,

associated perepheral mediastinal lymphadenopathy,erythema nodosum, jaundice may be found.

LABORATORY ABNORMALITIES• In a patient with PUO, marked elevation of serum alkaline

phosphatase (3-6 times) with mild elevation of serum

transaminases (2-6 times), well preserved hepatic

synthetic function, normal pro-thrombin time, serum

albumin and a normal to slightly raised bilirubin should

arouse a suspicion regarding the presence of hepatic

granulomas.

• Perepheral blood eosinophilia may suggest Hodgkins

disease, parasitic infestation and drug sensitivity.

HEPATO BILIARY TUBERCULOSIS

• CLINICAL SYNDROMES OF HEPATOBILIARY TB

– Congenital TB

– Primary hepatic TB

– Disseminated/miliary TB

– Tuberculoma

– TB of biliary tract

– Drug induced hepatic failure

– Granulomatous hepatitis

– TB Pylephlebitis

CONGENITAL TB

• Hepatic involvement is very common in congenital TB

and has been recently incorporated to the diagnostic

criteria.

• When an infant born to a mother with active TB

manifests hepatomegaly, jaundice and failure to

thrive, congenital TB should be considered as a DD.

• Porta hepatis area is commonly involved.

PRIMARY HEPATIC TB

• Is said to occur when there is involvement of the hepato biliary tract by TB

without apparent involvement elsewhere or only with local lymphnode or

splenic involvement.

• TB bacilli reach liver via portal vein as opposed to miliary TB where

organism reach liver by hepatic artery.

Two major forms of clinical presentation are there.

1) A hard nodular liver with fever and weight loss mimicking cancer

in 65% pts.

2) chronic recurrent jaundice mimicking extra hepatic obstruction.

PRIMARY HEPATIC TB

DIAGNOSIS

• The charecteristic serum profile included hyponatremia,

raised ALP, transaminases,GGT, Hypo albuminemia and hyper

gamma globulinemia.

• Per cutaneous liver biopsy and laproscopy are the main

methods of confirmation of diagnosis.

• Histopathologically, AFB, caseation and granulomas are seen

in 9%,80% and 96& of cases respectively.

PRIMARY HEPATIC TB

CT Findings:

1. multiple nodular lesions in the subcapsule of liver

2. multiple, miliary micronodular and low density lesions with

miliary calcfcns

3. singular, low density mass with multiple flecked

calcifications.

4. multiple cystic lesions and

5. multiple micro nodular and low density lesions fusing into

multi loculated cystic mass or cluster sign.

MRI Findings

1) Diffuse nodular involvement was visualized in all pts.

2) Nodules were consistent with granulomas and 0.5-4.5 cm in

diameter.

3) Caseating granulomas were of intermediate and high signal

intensity on T2 weighted images and low-signal on T1 weighted

images

4) Non caseating granulomas revealed intermediate signal on T1 and

T2 weighted images and increased enhancement in arterial phase

images with persisting enhancement in late phase findings.

TREATMENT

• Most patients respond to ATT.

• For pts with obstructive jaundice, in addition to ATT,

biliary decompression should be performed either

by stent insertion during ERCP, by percutaneous

trans hepatic biliary drainage or by surgical

decompression whenever feasible.

TUBERCULOMA LIVER• Sometimes, hepatic TB lesions can present as masses larger

than 2mm in diameter and can mimic the appearance of a SOL

liver on liver scan and arteriography.

• They may also be confused with pyogenic or amoebic liver

abscess.

• Blind percutaneous needle biopsy wasn’t very helpful in the

diagnosis,aspiration cytology at the time of laparoscopy was

more useful in confirming the diagnosis

• Most often these lesions resolve with effective ATT.

SARCOIDOSISSarcoidosis is a multi system granulomatous disorder

of unknown etiology.

PATHOLOGY

• The granulomas are made of epitheloid cells and giant cells,

some of them containing stellate(asteroid) bodies.

• The granulomas may show charecteristic clustering which is

also seen in the lymph nodes.

• As the granuloma ages, there may be deposition of collagen in

a lamellar manner at the periphery of granuloma.

SARCOIDOSISCENTRAL NECROSIS/CASEATION IS RARE as compared to TB.

• Granulomas are widely distributed in the liver, very often in

the portal and peri portal regions.

• Granulomas are numerous enough to make it unlikely that

could be missed in a liver biopsy sample of even moderate

size.

SARCOIDOSISCLINICAL PRESENTATIONS

• Often, hepatic involvement seems incidental, but a few pts

may present with signs and symptoms of hepatic dysfunction.

• In some patients, the clinical presentation may resemble

primary biliary cirrhosis.

• Sarcoidosis can also present with signs of chronic cholestasis.

PRIMARY BILIARY CIRRHOSIS

• In early stages , the hepatic granulomas in primary biliary

cirrhosis may be in distinguishasble from sarcoidosis.

• But in these multi nucleated giant cells are not common and

necrosis is not present.

SYSTEMIC MYCOSES

• Histoplasma capsulatum and Coccidiodes immitis usually

infects humans by inhalation of organism with primary

infection in the lungs.

• Rarely there is a wide spread dissemination involving liver.

• Hepatic reaction to this fungi is usually by granuloma

formation.

• Histoplasma usually colonises immuno compromised pts but

occasionally immuno competent individuals may also be

affected.

• Usually manifest as fever with hepatosplenomegaly and oral

ulcers.

• Liver granulomas sometimes has central caseation necrosis

resembling TB.

• So use of spl stains like methenamine silver, Hotchkiss-

McManus stain makes identifcation easier and diagnosis

certain.

• Diagnosis is best confirmed by culture of organisms from

blood, bone marrow, sputum and oral ulcer scrappings.

SCHISTOSOMIASIS

• Hepatic amoebiasis are caused by S.mansoni and

S.japonicum.

• Presence of eosinophils and the ova of parasite in the centre

of granuloma clinches the diagnosis.

HODGKINS LYMPHOMA

• Hepatic granulomas are seen in 8-17% of pts.

• Presence of hepatic granulomas doesn’t change the disease

outcome or prognosis.

CAUSES OF HEPATIC GRANULOMAS IN PATIENTS WITH AIDS

• Mycobacterium tuberculosis.

• Mycobacterium avium-intracellulare complex

• Cytomegalo virus

• Histoplasmosis

• Toxoplasmosis

• Cryptococcosis

• Neoplasms

• hodgkins lymphoma

• NHL

• Drugs.

IDIOPATHIC GRANULOMATOUS HEPATITIS

• Despite extensive investigations, 10-25% of pts are

labelled as idiopathic hepatic granulomas.

• It’s a condition characterised by recurrent fever and

granulomas in the liver and other organs where other

causes of hepatic granulomas have been carefully

excluded.

CLINICAL FEATURES

• Prominent feature is fever which is often relapsing in

character, although continuous and remittent fever pattern

has also been described.

• Other symtoms include malaise, chills, weightloss, abd.pain,

anorexia, night sweats, nausea, jaundice, diorrhoea and abd

distension.

• The natural history of disease is marked by multiple

remissions and exacerbations.

• Response to corticosteroids is usually dramatic.

DIAGNOSIS

• Patients with hepatic granulomas should be thoroughly

investigated for a possible aetiological cause.

• Detailed history must be obtained specifically focusing on

exposure to an infectious source, and occupational or

environmental agents including drugs.

• Cultures of blood, body fluids and biopsy material must be

done keeping in mind the common infectious causes of

hepatic granulomas.

• Anti-mitochondrial antibodies may be raised in primary biliary cirrhosis.

• Elevated serum ACE levels suggest sarcoidosis.

• LIVER BIOPSY IS ESSENTIAL FOR THE DIAGNOSIS

• Biopsy material must be subjected to microbiological and

histopathological examination.

• Special stains may be required to identify infectious agents.

• Examn under polarized light may help in visualizing foreign

bodies.

TREATMENT

• When the investigations are conclusive, treatment

should be directed towards the aetiological agent.

• In a country like India, when aetiology is unclear, a

therapeutic trial with ATT is often given.

• If this fails then cortico-steroid treatment may be

tried.

Thanks………