History

Fact Explanation
Pyrexia of unknown origin (PUO) Granulomatous hepatitis is a pathological entity rather than a disease. Etiological factors are Tuberculosis. mycobacteria, histoplasmosis, fungi, brucellosis, Q- fever, syphilis, parasites, viruses, sarcoidosis & other systemic granulomatous diseases, Neoplasia- Hogdkin's disease, vasculitis,berylliosis ,drug reactions (quinine, quinidine, sulphanamide, penecilline, allopurinol, phenylbutazone, methyldopa, hydralazine, carbamezapine, isoniazid, nitrofurantoin & diazepam[3]) & liver diseases- primary billiary cirrhosis. From these tuberculosis & sarcoidosis are the commonest(50%- 65%). 20%- 26% unknown etiology. Most patient present with fever of unknown origin, though the diagnosis of granulomatous hepatitis is rare, its important to bare in mind[1].Pyrexia of unknown origin is defined as fever of 38.3 Celsius or greater for at least 3 weeks with out an identifiable cause, after 3 days of hospital evaluation or 3 out patient visits[4]. Usually Fever is relapsing in character, but continuous & remittent fever patterns have been described[5]. Depending on the etiology they can have high spiking fever, drenching night sweats, shaking chills[1].
Abdominal pain These patients can have right sided abdominal pain. Mainly in right hypochondrium. Food is an aggravating factor & vomiting is a common association[2].
Arthralgia, myalgia Minority of the patients have these complaints[1].
Asymptomatic patients They are incidental, histological or ultra sound scan findings. The histological analysis helps to identify presence of granulomas in granulomatous hepatitis, The appearance of granulomas differ according to the etiology. -In idiopathic granulomatous hepatitis granuloma will show focal nodular aggregations of lymphocytes, mononuclear cells, epitheloid cells. Caseation is absent, granulomas are distributed in hepatic parenchyma[5]. USS- hepatic granulomas- nodular lesions. -E.g. in hodgkin lymphoma- diffuse, hypoechoic, small or large nodular lesions in the liver. This will also show the hepatomegaly[6].
References
  1. WOLFF SM, SIMON HB. Granulomatous hepatitis and prolonged fever of unknown origin. Trans Am Clin Climatol Assoc [online] 1973:149-65 [viewed 12 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/4729250
  2. SHEE CD, CREAMER B. Idiopathic granulomatous hepatitis and abdominal pain. Postgrad Med J [online] 1980 May, 56(655):342-3 [viewed 12 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/7443594
  3. KATZ B, WEETCH M, CHOPRA S. Quinine-induced granulomatous hepatitis. Br Med J (Clin Res Ed) [online] 1983 Jan 22, 286(6361):264-5 [viewed 12 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/6402064
  4. VARGHESE GM, TROWBRIDGE P, DOHERTY T. Investigating and managing pyrexia of unknown origin in adults. BMJ [online] 2010:C5470 [viewed 14 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22312655
  5. HOLLA RG, BAGGA A. Idiopathic granulomatous hepatitis. Indian Pediatr [online] 2004 Jun, 41(6):610-3 [viewed 14 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15235170
  6. BERGTER W, FETZER IC, SATTLER B, RAMADORI G. Granulomatous Hepatitis preceding Hodgkin's Disease (Case-Report and Review on Differential Diagnosis). Pathol Oncol Res [online] 1996, 2(3):177-180 [viewed 17 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/11173603

Examination

Fact Explanation
Febrile Most patient present with fever of unknown origin, though the diagnosis of granulomatous hepatitis is rare, its important to bare in mind. Depending on the etiology they can have high spiking fever, drenching night sweats, shaking chills[1]. Usually Fever is relapsing in character, but continuous & remittent fever patterns have been described[2].
Jaundice Usually they have is the intermittent jaundice, but few has had deep jaundice with hepatic failure[1].
Skin lesions Commonly encountered skin lesions are spider angiomata, Erythema nodosum, palmer erythema[1]. These are signs of chronic liver disease.
Edema[1] This is a sign of chronic liver disease.
Hepatic tenderness Occurs due to the underlying inflammation.
Hepatomegaly[1] Patients have some degree of hepatomegaly at least as a scan finding[1].
Splenomegaly[1] Patients can have some degree of splenomegaly at least as a scan finding[1].
Ascitis[1] This is a sign of chronic liver disease.
References
  1. WOLFF SM, SIMON HB. Granulomatous hepatitis and prolonged fever of unknown origin. Trans Am Clin Climatol Assoc [online] 1973:149-65 [viewed 12 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/4729250
  2. HOLLA RG, BAGGA A. Idiopathic granulomatous hepatitis. Indian Pediatr [online] 2004 Jun, 41(6):610-3 [viewed 14 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15235170

Differential Diagnoses

Fact Explanation
Sarcoidosis[1] Chronic multi system granulomatous illness. Non caseating granulomas are pathological hallmark. Prevalence 10- 20 per 100000. Common in African American women, 25- 40 year old. Exact etiology is unclear, but exaggerated immune response can have a role. 2/3 of patients have spontaneous remission[4].
Primary biliary cirrhosis[1] Chronic liver disease. There is an immune mediated destruction of small intrahepatic bile duct epithelial cells[5].
Hepatic Tuberculosis When presented with non specific, scant symptoms it is difficult to diagnose.Uaual clinical presentation- fever, weight loss, abdominal pain, hepatomegaly, elevated alkaline phosphatases. Identifying acid fast bacilli in ZN staining & caseous necrosis are pathological evidence. Most of the anti-TB drugs are hepato toxic[2].
Q fever [1] Zoonosis, causative organism- Coxiella burnetii. Transmission via infected droplets or aerosols. Occupational disease, male sex is a risk factor[3].
References
  1. RIHANA NANCY A., KANDULA MANASA, VELEZ ANA, DAHAL KUMUD, O’NEILL EDWARD B.. Histoplasmosis Presenting as Granulomatous Hepatitis: Case Report and Review of the Literature. Case Reports in Medicine [online] 2014 December, 2014:1-4 [viewed 13 August 2014] Available from: doi:10.1155/2014/879535
  2. SHASTRI MINAL. Isolated hepatic tuberculosis: An uncommon presentation of a common culprit. amj [online] 2014 June:247-250 [viewed 14 August 2014] Available from: doi:10.4066/AMJ.2014.2076
  3. NAKLáDALOVá M, PASTORKOVá R, LANDECKá I. [Q fever - an occupational disease leading to disability - case report]. Epidemiol Mikrobiol Imunol [online] 2014 Summer, 63(2):149-52 [viewed 14 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/25025682
  4. SALAMEH HASAN. Interferon-alpha-induced sarcoidosis in a patient being treated for hepatitis C. Am J Case Rep [online] 2014 December, 15:235-238 [viewed 14 August 2014] Available from: doi:10.12659/AJCR.890180
  5. BOWLUS CHRISTOPHER L., GERSHWIN M. ERIC. The diagnosis of primary biliary cirrhosis. Autoimmunity Reviews [online] 2014 April, 13(4-5):441-444 [viewed 14 August 2014] Available from: doi:10.1016/j.autrev.2014.01.041

Investigations - for Diagnosis

Fact Explanation
Liver biopsy The histological analysis helps to identify presence of granulomas in granulomatous hepatitis. The appearance of granulomas differ according to the etiology. e.g. -In tuberculosis- paucity of granulomas, scantiness of giant cells, mild surrounding inflammatory cell infiltrate, absence of reticulin. -Sarcoidosis- there will be numerous giant cells confined to portal areas, well marked surrounding non specific chronic inflammatory cell infiltrate[1]. - Hepatic bartonellosis -rare cause of granulomatous hepatitis, causative organism- Bartonella henselae,In this granulomas are necrotizing granulomas,there will be accumulations of activated macrophages, surrounded by lymphocytes & fibroblasts[2]. In idiopathic granulomatous hepatitis granuloma will show focal nodular aggregations of lymphocytes, mononuclear cells, epitheloid cells. Caseation is absent. distributed in hepatic parenchyma[4].
Abnormalities in liver function tests Alkaline phosphatase is elevated, Transaminases are also elevated. Serum LDH is high, bilirubin retention is also seen[3].
ESR elevated. This response to therapy & is a non specific but useful indicator of this patients[3].
References
  1. HUGHES M, FOX H. A histological analysis of granulomatous hepatitis. J Clin Pathol [online] 1972 Sep, 25(9):817-20 [viewed 12 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/5086225
  2. VANDERHEYDEN THOMAS R, YONG SHERRI L, BREITSCHWERDT EDWARD B, MAGGI RICARDO G, MIHALIK AMANDA R, PARADA JORGE P, FIMMEL CLAUS J. Granulomatous hepatitis due to Bartonella henselae infection in an immunocompetent patient. Array [online] 2012 December [viewed 12 August 2014] Available from: doi:10.1186/1471-2334-12-17
  3. WOLFF SM, SIMON HB. Granulomatous hepatitis and prolonged fever of unknown origin. Trans Am Clin Climatol Assoc [online] 1973:149-65 [viewed 12 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/4729250
  4. HOLLA RG, BAGGA A. Idiopathic granulomatous hepatitis. Indian Pediatr [online] 2004 Jun, 41(6):610-3 [viewed 14 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15235170

Investigations - Fitness for Management

Fact Explanation
Full blood count- Hb Patients can have anemia, prior to treatment correction is necessary[1].
References
  1. WOLFF SM, SIMON HB. Granulomatous hepatitis and prolonged fever of unknown origin. Trans Am Clin Climatol Assoc [online] 1973:149-65 [viewed 12 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/4729250

Management - Specific Treatments

Fact Explanation
Corticosteroid therapy In idiopathic granulomatous hepatitis prednisilone like steroids are administered[1].
Immuno suppressant therapy Use in idiopathic granulomatous hepatitis who is resistant to corticosteroid. Drugs used are methotrexate, cyclophosphamide. Infliximab has been used with success[1].
References
  1. KAPOOR S. R., SNOWDEN N.. The use of infliximab in a patient with idiopathic granulomatous hepatitis. Case Reports [online] December, 2009(jun01 2):bcr0620080319-bcr0620080319 [viewed 14 August 2014] Available from: doi:10.1136/bcr.06.2008.0319