1. GRANULOMATOUS HEPATITIS Dr. Shiyas Mohammed JR Pulmonary Medicine

2. 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”.

3. AETIOLOGY INFECTIONS Bacterial: Brucella, Salmonella Mycobacterial: TB, Leprosy, NTM Ricketssiae: Q fever Spirochaetal: Syphilis Fungal: Histoplasma, coccidiodomycosis, cryptococcosis Parasitic: Schistosomias Viral: Hepatitis C, Hepatitis B, Cytomegalovirus

4. AETIOLOGY SARCOIDOSIS 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.

5. 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.

6. MORPHOLOGICAL TYPES Epitheloid cell granulomas – Caseating(necrotizing) granulomas – Non caseating granulomas Fibrin ring granulomas Granulomatoid reactions with poorly formed granulomas. Bile granulomas Lipogranulomas Microgranulomas

7. 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

8. 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.

9. 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.

10. 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

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. SARCOIDOSIS Sarcoidosis 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.

19. SARCOIDOSIS CENTRAL 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.

20. SARCOIDOSIS CLINICAL 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. CAUSES OF HEPATIC GRANULOMAS IN PATIENTS WITH AIDS Mycobacterium tuberculosis. Mycobacterium avium-intracellulare complex Cytomegalo virus Histoplasmosis Toxoplasmosis Cryptococcosis Neoplasms hodgkins lymphoma NHL Drugs.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. Thanks………