GranulomatousGranulomatous HepatitisHepatitis

Luis S. Marsano, MD Professor of Medicine Division of Gastroenterology, Hepatology and Nutrition University of Louisville, Louisville VAMC, and Jewish Hospital GranulomaGranuloma

¾ Morphology: z Nodular reaction with transformed macrophages called “epithelioid cell”. z Sometimes the epitheliod cells adhere to each other under IFN- gamma stimultation, and form “giant multinucleated cells”. z Other inflammatory cells may be found within or around the granuloma, including lymphocytes, and eosinophiles. z They are usually 1-2 mm and very distinct from the surrounding liver. May coalesce to form up to 40 mm nodules. ¾ Incidence: 2-10% of liver biopsies and liver autopsies. ¾ Pathogenesis: Granulomas occur from overstimulation of macrophages by IFN-gamma and IL-2 derived from T- helper lymphocytes responding to a persistently retained antigen. TypesTypes ofof GranulomasGranulomas

¾ NonNon--NecrotizingNecrotizing (Non(Non--caseating)caseating):: z Admixture of epitheliod cells, giant cells, and lymphocytes. z Classic for sarcoidosis, beryllium, Crohn’s, drug reaction, tuberculoid leprosy. ¾ NecrotizingNecrotizing (Caseating)(Caseating):: z Admixture of epitheliod cells, giant cells and lymphocytes, with central necrosis. May be “palisading”. z May co-exist with non-necrotizing granulomas. z Classic for Tuberculosis, Fungal infections, Rheumatoid arthritis, Wegener’s & Hodgkin Disease. TypesTypes ofof GranulomasGranulomas

¾ Fibrin-ring: z Macrophages and lymphocytes that enclose a central empty space (or lipid vacuole) often encased by a fibrin ring. z Classic for Q fever. z May be seen in CMV, EBV, Hepatitis A, MAI, leishmania, Lyme disease, Boutonnuese fever, toxoplasma, Hodgkin disease, non- Hodgkin lymphoma, and drug reaction. ¾ Suppurative: z Have central microabscess. z Often large and irregular; may be stellate. z Classic in cat scratch fever, lymphogranuloma, tularemia. z Less often in yersinia, actinomycosis, nocardiosis, fungal, or mycobacterial infection. ¾ Lipogranuloma: z Lipid vacuole (without fibrin ring) surrounded by macrophages or lymphocytes. z Classic in mineral oil, ASH, NASH, lipid-gold injections. Palisading Necrotizing Non-Necrotizing Granuloma Granuloma Granuloma

Fibrin-Ring Lipogranuloma Granuloma SpecialSpecial FindingsFindings

¾ a) Asteroid bodies: 5-20 mm, seen in sarcoidosis, fungal infections, silicone or teflon exposure. ¾ b) Schaumann bodies: 25-200 mm, oval, with Ca oxalate, Ca carbonate, Ca phosphate, or Fe; seen in sarcoidosis but not specific. ¾ c) Fibrosis, suggest sarcoidosis (usually periportal or portal). ¾ d) Associated bile duct destruction, suggest PBC (granuloma usually in portal area). ¾ e) Associated with eosinophiles suggests drug, or parasite (granuloma anywhere in the lobule). Asteroid Body Schaumann body SpecialSpecial StudiesStudies inin BiopsyBiopsy

¾ Stains:Stains: ¾ PCR:PCR:

z z Ziehl-Neelsen (TB, z B. henselae, MAC, …), z L. monocytogenes, z Silver (fungus), z M. tuberculosis, z Whartin-Starry (spirochetes, z M. avium, Bartonella), z Y. enterocolitica,

z z Giemsa (parasites), z Y. pseudotuberculosis, z Birefringent bodies, z CMV, z Red O (lipid), z EBV, z Trichrome (fibrin). z T. gondii

z Leishmania EtiologyEtiology ofof HepaticHepatic GranulomasGranulomas SeveralSeveral WorldWorld SeriesSeries

¾ Sarcoidosis 35% ¾ Misc. Infections 5% ** ¾ Tuberculosis 20% ¾ Schistosoma 2% ¾ Undetermined 11% ¾ Lymphoma 2% ¾ Misc. non-infectious 9% * ¾ BrucellosisBrucellosis 2%2% ¾ PBC 5% ¾ Drug induced 2% ¾ Other cirrhosis 5% ¾ Acute viral hepatitis 1% ¾ Fungal infection 1%

*Pancreato/biliary disease, berylliosis, malignancy, NASH, temporal arteritis, Crohn disease, Wegener granulomatosis, erythema nodosum, eosinophilic granuloma, starch, CVID, celiac disease.

**Typhoid fever, EBV, syphilis, other bacterial infection, other viral infection, leprosy, toxoplasma, CMV, lymphogranuloma venereum, actinomycosis, influenza B, visceral larva migrans, BCG. ClinicalClinical ManifestationsManifestations ofof GranulomatousGranulomatous HepatitisHepatitis

¾ SymptomsSymptoms::

z Many patients are asymptomatic.

z When symptomatic, they may have fever, fatigue, weight loss, abdominal pain, or malaise.

z May have symptoms of the underlying disease. ¾ PhysicalPhysical examexam::

z May have hepatomegaly, splenomegaly, lymphadenomegaly.

z May have findings of the underlying disease. ClinicalClinical ManifestationsManifestations ofof GranulomatousGranulomatous HepatitisHepatitis

¾ Laboratory:

z Elevated alkaline phosphatase is the main finding.

z May have some ALT & AST elevation.

z May have high ACE and Calcium.

z Anemia, high or low WBC count, or hypoalbuminemia reflect advanced or prolonged illness.

z Elevated bilirrubin is less common. ¾ Imaging:

z CT scan or ultrasound may be normal, or show hepatomegaly, diffuse non-homogeneous liver appearance, or a focal lesion.

z Granulomas > 5 mm diameter may show as nodular lesions on MRI; sometimes they form pseudotumors. ClinicalClinical EvolutionEvolution

¾ In most patients is asymptomatic and non-progressive. ¾ Granulomas are important because they may indicate the presence of a serious disorder otherwise non- suspected. ¾ Frequently just a “finding” over a background of a known diagnosis (HCV, Crohn, PBC, lymphoma staging, …). ¾ Granulomas do not change progression of disease (but in HCV, may increase risk if IFN related sarcoidosis) ¾ Progressive granulomatous disease may lead to portal hypertension (PBC, sarcoidosis, Schistosomiasis, CVID with MTX therapy). ¾ May be part of “Fever of Unknown Origen”, in which case extensive investigations are needed to find cause and direct therapy. ChoosingChoosing thethe DiagnosticDiagnostic WorkWork--upup

DominantDominant ManifestationManifestation DiseaseDisease FrequencyFrequency ExposureExposure HistoryHistory CombinationCombination DiagnosticDiagnostic ApproachApproach GranulomaGranuloma--typetype workwork--upup z LIPOGRANULOMA z FIBRING-RING • Mineral oil • Q fever • ASH • Boutonneuse fever • NASH • Leishmania • Gold (lipid injection) • Toxoplasma z SUPPURATIVE • CMV GRANULOMA • EBV • Cat scratch fever, • Hepatitis A • Lymphogranuloma, • Lyme disease • Tularemia. • MAI • Yersinia, • Staphylococcus epidermidis • Actinomycosis, sepsis • Nocardiosis, • Hodgkin Disease • Fungal infection, • Non-Hodgkin • Mycobacterial infection. • Giant cell arteritis • Allopurinol DiagnosticDiagnostic ApproachApproach GranulomaGranuloma--typetype workwork--upup z NECROTIZING z PALISADING GRANULOMA GRANULOMA • Tuberculosis • Rheumatoid Arthritis • Hodgkin Lymphoma • Churg-Strauss disease, • Fungal Infection • Foreign body, • Rheumatoid Arthritis • Wegener’s granulomatosis, • Wegener’s • Non-TB mycobacteriosis, • Churg-Strauss • Cat scratch disease, • Cat scratch fever • Phaeohyphomycosis, • Syphilis • Sporotrichosis, • Visceral larva migrans • Cryptococcosis, (toxocara, capillaria) • Coccidioidomycosis, • Syphilis • Visceral larva migrans (toxocara, capillaria) DiagnosticDiagnostic ApproachApproach DominantDominant ManifestationManifestation

¾ Presence of Portal Hypertension work up: z PBC z Sarcoidosis z Cirrhosis with HCV, HBV, PSC (incidental finding) z CVID + MTX z Amiodarone ¾ Febrile or systemic illness work up: z Sarcoidosis z Infection (including Whipple) z Infestation. z Lymphoma (Hodgkin, or non-Hodgkin) z Rheumatologic disease/ Vasculitis. z Renal cell Carcinoma z Idiopathic Granulomatous Hepatitis z Drug DiagnosticDiagnostic ApproachApproach DiseaseDisease frequencyfrequency workwork--upup

¾ DiseaseDisease--frequencyfrequency workwork--up:up: z Sarcoidosis z Tuberculosis z PBC z Schistosomiasis z Lymphoma z Brucellosis z Fungal infection (histoplasma in Ohio valley) DiagnosticDiagnostic ApproachApproach ExposureExposure historyhistory workwork--upup

¾ ExposureExposure--HistoryHistory directeddirected workwork--up:up: z Geographic exposure (travel, birthplace) z Work history (farm, veterinarian, slaughter house, nuclear plant, …) z Leisure activity history (hunting, gardening, …) z Animal contact history (pets, work, farm) z Food preferences (unpasteurized, “organic”, uncooked) z Sexual contacts & practices (promiscuity, oral sex) z Medications (prescription, “natural”, or OTC) z Substance abuse (alcohol, IVDA, …) PotentialPotential CausesCauses byby ExposureExposure HistoryHistory EnvironmentalEnvironmental ExposureExposure HistoryHistory

¾ Outdoors, farm: z Whipple ¾ Contaminated water or soil: z Toxocara, - Strongyloides, z Ancylostoma, - Necator, z Ascaris, - Toxoplasma, z Melioidosis, - Thyphoid fever, z Nocardiosis, - Coccidioidomycosis, z Aspergillosis, - Hepatitis A, z Schistosoma (S. America, Caribbean, Southeast Asia, China, Philippines), z Capillaria (Philippines, Thailand, Taiwan, Japan, Korea, Egypt, China, Indonesia, and Iran), z Pentastomiasis (Asia, Africa), z Paracoccidioidomycosis (from Mexico south to Argentina). ¾ Bird or bat droppings: z Histoplasma, - Chlamydia psitacii, z Cryptococcus FoodFood ExposureExposure HistoryHistory

¾ Unpasteurized dairy: z Brucella, Listeria, Q fever. ¾ Luncheon meats, undercooked chicken: z Listeria ¾ Undercooked/raw crayfish or crabs: z Paragonimus. ¾ Undercooked or raw fish: z Opisthorchis (Thailand, Laos, Russia, Ukraine) ¾ Unwashed vegetables: z Ameba, Ascaris, Fasciola InsectInsect ExposureExposure HistoryHistory

¾ Tick bite:

z Tularemia,

z Borrelia (B. burgdorferi: Lyme Disease),

z Boutonneuse fever (Rickettsia conorii: Africa, S. Europe) . ¾ Tabanid fly, mosquito:

z Tularemia. ¾ Sand fly:

z Leishmania. Tabanid fly Ticks

Sand Fly Mosquito AnimalAnimal ExposureExposure HistoryHistory

¾ Pig, goat, sheep, cattle:

z Brucella, Yersinia, Q fever. ¾ Horse:

z Yersinia. ¾ Rabbit, squirrel, beaver:

z Tularemia, Yersinia ¾ Dog, cat:

z Toxocara ¾ Kitten:

z Bartonella henselae. ¾ Birds:

z Tularemia.

ActivityActivity ExposureExposure HistoryHistory

¾ Unprotected sex:

z Chlamydia trachomatis, Syphilis, Hepatitis B, Hepatitis C. ¾ Oral sex:

z Typhoid fever. ¾ Poor oral hygiene:

z Actinomycosis. ¾ IVDA:

z Hepatitis C, Hepatitis B, CMV, HSV, EBV. ¾ Work with fluorescent lights, aerospace, nuclear reactor/weapons, electronics:

z Berylliosis ¾ Vineyard Spraying:

z Copper SubstanceSubstance ExposureExposure HistoryHistory

DrugsDrugs MineralsMinerals DrugDrug ReactionReaction

¾ Aspirin ¾ Diphenylhydantoin (*) ¾ Acetaminophen ¾ Diltiazem ¾ Allopurinol (*) ¾ Fluothane ¾ Amiodarone ¾ Glyburide ¾ Amoxicillin-Clavulanate ¾ Halothane ¾ Carbamazepine (*) ¾ HCTZ ¾ Cephalexin ¾ Hydralazine (*) ¾ Chlorpropamide ¾ INH ¾ Clofibrate ¾ Interferon (sarcoid) ¾ Diazepam ¾ Methyldopa (*)

(*) Most common & better studied DrugDrug ReactionReaction

¾ Metahydrin ¾ Quinine ¾ Metolazone ¾ Quinidine (*) ¾ Mebendazole ¾ Pyrazinamide ¾ Mesalamine ¾ Quinidine ¾ Nitrofurantoin ¾ Rosiglitazone ¾ Norfloxacin ¾ Sulfonamides (*) ¾ Penicillin ¾ Sulfasalazine ¾ Phenylbutazone (*) ¾ Silicone ¾ Procainamide ¾ Tocainide ¾ Procarbazine ¾ Thorotrast

(*) Most common & better studied MineralsMinerals

¾¾ BerylliumBeryllium ¾¾ CopperCopper ¾¾ SilicaSilica ¾¾ TalcTalc ¾¾ GoldGold (in(in lipidlipid injection)injection) ¾¾ MineralMineral oiloil NonNon--EnvironmentalEnvironmental CausesCauses ofof HepaticHepatic GranulomasGranulomas MalignanciesMalignancies && VasculitisVasculitis

¾ Hodgkin Disease ¾ Non-Hodgkin Lymphoma ¾ Renal cell Carcinoma ¾ Giant cell arteritis ¾ Lupus Erythematosus ¾ Polyarteritis nodosa ¾ Polymyalgia rheumatica ¾ Rheumatoid arthritis ¾ Wegener granulomatosis ¾ Churg-Strauss MiscellaneousMiscellaneous

¾ Sarcoidosis ¾ Eosinophilic ¾ Primary Biliary Cirrhosis gastroenteritis ¾ PSC ¾ Celiac disease ¾ Crohn Disease ¾ Chronic Granulomatous Disease ¾ Ulcerative Colitis ¾ Idiopathic Granulomatous ¾ Jejuno-ileal bypass Jejuno-ileal bypass Hepatitis ¾ Eosinophilic granuloma of ¾ NASH lung NASH ¾ ASH ¾ Immunodeficiency (CVID) ¾ Preservation injury ¾ Graves-Basedow hyperthyroidism ¾ Acute cellular rejection ¾ Rheumatic Fever ¾ Chronic ductopenic rejection. DiagnosticDiagnostic InvestigationsInvestigations ForFor InfectionsInfections && MineralsMinerals MycobacterialMycobacterial InfectionsInfections

¾ Tuberculosis ¾ CXR, BAL, Liver/BM culture, PCR in liver (sens 53%, specif 96%), ¾ Atypical Mycobacteria (M. Quantiferon/PPD, Adenosine xenopi, M. genavense, M. deaminase in ascites/pleural effusion. kansasii, M. mucogenicum)

¾ M Avium Complex ¾ Sputum, blood & liver culture, PCR in liver. HIV test, CD4< 50

¾ Disseminated BCG (bladder ¾ History BCG bladder irrigation. immunotherapy) ¾ Leprosy L ¾ AFB stain, geographic exposure, clinical features, anti-phenolic glycolipid-1 (PGL-1) by ELISA BacterialBacterial InfectionsInfections

¾ Exposure to pig/goat/cpig/goat/caattle.ttle. Unpasteurized ¾ BrucellaBrucella dairy. Blood/BM culture, agglutinin test. ¾ Kitten scratch. Serology. PCR in liver. ¾ BartonellaBartonella HenselaeHenselae ¾ Unpasteurized milk/cheese,milk/cheese, luncheon ¾ ListeriaListeria meats, undercooked chicken. Blood/CBlood/CNNS fluid culture. PCR in liver. ¾ ¾ Ticks, tabanid fly, mosquito. Rabbit, squirrel, ¾ TularemiaTularemia birds, beaver, …Blood culture, serology. ¾ Pig, rabbit, sheep,sheep, cattle, horse…Blood/stool ¾ YersiniaYersinia enterocoliticaenterocolitica culture. Agglutinin test. PCR in liver. ¾ Wound contaminated with water or soil. ¾ MelioidosisMelioidosis Blood, skin Bx, liver Bx culture. PCR in liver. ¾ Unprotected sex. Serovar L1, L2, L3 give ¾ ChlamydiaChlamydia LGV. PCR in urine. Serology (acute + conv) trachomatistrachomatis ¾ Aerosol of soil with bird droppings. Blood & ¾ ChlamydiaChlamydia psittacipsittaci liver culture. Serology. ¾ Middle age with outdoors work/activity. ¾ TrophirellaTrophirella whippleiiwhippleii Small bowel Bx (8+ in distal D or J) + PCR ¾ Contaminated food/water,food/water, oral sex. ¾ TyphoidTyphoid feverfever Blood/BM/stool culture, serology. BacterialBacterial InfectionsInfections

¾ Borrelia (Lyme Disease) ¾ Ixodes tick bite. Serology, serum PCR ¾ Poor oral hygiene. Liver Bx culture ¾ Actinomycosis ¾ Nocardiosis ¾ Contaminated soil. Liver Bx culture

¾ Botryomycosis (bacterial ¾ Culture pseudomycosis) Staph aureus & Pseudomona

¾ Propionibacterium ¾ Skin flora. Culture. Rickettsial,Rickettsial, Spirochetal,Spirochetal, && ViralViral InfectionsInfections ¾ Sheep, cattle, goats, unpasteurized dairy. ¾ Q fever Serology. PCR CoxielCoxiellala burnetii in liver. ¾ Tick bite. Southern Europe & Africa. ¾ Boutonneuse fever Serology (Rickettsia conorii) ¾ ¾ Unprotected sex, promiscuity. VDRL, skin ¾ Secondary Syphillis lesion, ¾ CMV ¾ Ubiquitous. PCPCRR blood & liver

¾ EBV ¾ Ubiquitous. PCR blood/liver, serology

¾ HSV ¾ Ubiquitous. PCPCRR blood & liver ¾ Human respiratory secretions. Bx culture, ¾ V-Z virus serum PCR ¾ ¾ Seasonal. Nasal swab for culture or rapid Influenza B ? test. ¾ Hepatitis A ¾ Serology: anti-HA IgM

¾ Hepatitis B ¾ Serology, HBV-DNA

¾ Hepatitis C ¾ Serology, HCV-RNA FungalFungal InfectionsInfections

¾ Soil with bird/bat droppings. Bx/blood ¾ Histoplasmosis (isolator) culture, urine/serum Ag, comp. ¾ Blastomycosis fixation, immunodifusion Blastomycosis ¾ Warm, moist soil. Bx culture ¾ Coccidioidomycosis ¾ Soil. Bx culture, complement fixation ¾ Soil with bird droppings. Bx culture, Ag in ¾ Cryptococcosis serum/CSF ¾ Soil, water, plants, stool. Urine/blood culture. ¾ Trichosporonosis ¾ Ubiquitous. Bx culture, blood culture. ¾ Systemic candidiasis Ubiquitous. Bx culture, blood culture. ¾ Aspergillosis ¾ Decaying vegetation, sosoil,il, water. Bx culture, BAL, serology. ¾ Mucormycosis ¾ Environment. Bx study & culture.

¾ Paracoccidioidomycosis ¾ From Mexico south to Argentina. Soil?. Areas with coffee andand tobacco. Bx culture, complement fixation, immunodifusion. ParasiticParasitic InfestationsInfestations

¾ Infested water. S. America, Caribbean, ¾ SchistosomiasisSchistosomiasis Southeast Asia, China, Philippines. (Bilharziasis)(Bilharziasis) Stool/urine O&P. Rectal Bx. Serology. ¾ VisceralVisceral larvalarva migransmigrans ¾ Dogs, cats, soil. Eosinophilia. Serology (Toxocariasis)(Toxocariasis) (ELISA). ¾ South USA, Worldwide. Barefoot in ¾ StrongyloidiasisStrongyloidiasis contaminated soil. Stool O&P. Larvae in tissue.

¾ Ancylostomiasis ¾ Worldwide. Barefoot in contaminated Ancylostomiasis soil. Unwashed vegetables. Stool O&P.

¾ NecatorNecator ¾ Worldwide. Barefoot in contaminated soil. Unwashed vegetables. Stool O&P. ParasiticParasitic InfestationsInfestations

¾ ¾ Worldwide. Contaminated soil or ¾ AscariasisAscariasis unwashed vegetables. Stool O&P. ¾ CapillariasisCapillariasis ¾ Ingestion of contaminated food, water or soil. Liver Bx with C. hepatica eggs (O&P not useful) ¾ Hand-to-mouth. Cellophane tape ¾ EnterobiasisEnterobiasis test (Graham test) ¾ Worldwide. Contaminated water, ¾ ToxoplasmosisToxoplasmosis food, soil. Serology. Tissue PCR. ¾ LeishmaniasisLeishmaniasis ¾ Sandfly bite. Spleen/liver/BM (visceral(visceral && culture. Serology. PCR in tissue. viscerotropic)viscerotropic) ParasiticParasitic InfestationsInfestations

¾ Amebiasis ¾ Worldwide. South USA. Contaminated water Amebiasis or vegetables. MSM. Stool O&P. Serology. ¾ Giardiasis ¾ Worldwide. Fecal-oral. Contaminated water or food. Stool O&P/giardia Ag.

¾ ¾ Asia & Africa. IngesIngestiotionn of contaminated Pentastomiasis water with eggs. Bx exam. (Linguatula serrata) ¾ ¾ Worldwide. Contaminated watercress. Stool ¾ Fasciolasis O&P (low sensitivity). ELISA. ¾ Paragonimiasis ¾ Far East, West Africa, Central & South America. Undercooked crayfish/crabs. O&P sputum & stool. ¾ Thailand, Laos, Russia, Ukraine. ¾ Opisthorchiasis Undercooked fish. O&P in duodenal aspirate/stool. MineralsMinerals

¾ Fluorescents, aerospace,aerospace, nuclear ¾ BerylliumBeryllium reactors/weapons, electronics. Beryllium lymphocyte transformation test. Tissue ¾ CopperCopper analysis. ¾ Vineyard spraying. Copper containers. ¾ SilicaSilica ¾ Labrador lung.

¾ TalcTalc ¾ Talc (Mg silicate). IVDA of tablets. Polarized microscopy (birefringent). ¾ GoldGold (in(in lipidlipid injection)injection) ¾ Parenteral gold. ¾ MineralMineral oiloil ¾ Oil laxative, “waxed” fruits. SomeSome SpecificSpecific CausesCauses SarcoidosisSarcoidosis

¾ Signs and Symptoms: z Fever, pulmonary infiltrates, dry cough, lymphadenomegaly, weight loss, papular skin rash, uveitis. z Rare jaundice. z Hepato/ Splenomegaly in 5-10%. ¾ Pathology: z Almost all patients have liver granulomas. ¾ Laboratory: z Very high alk phosph. z ACE is elevated in 50-85% (non-specific). z May have hypercalcemia or hyperglobulinemia. ¾ Rare portal hypertension z pre-sinusoidal from granulomas, or z sinusoidal from fibrotic “healing” of granulomas. SarcoidosisSarcoidosis

¾ CirrhosisCirrhosis isis extremelyextremely rare.rare. ¾ GranulomasGranulomas maymay causecause venousvenous stasisstasis leadingleading toto BuddBudd--ChiariChiari S.S. ¾ PatientsPatients maymay havehave PBCPBC--likelike cholestasis,cholestasis, oror ““vanishingvanishing bilebile--ductduct syndromesyndrome””.. ¾ RarelyRarely maymay havehave PSCPSC--likelike periductalperiductal fibrosis.fibrosis. ¾ Treatment:Treatment: z Only when with progressive symptoms (Wt loss, fever) and/or portal HTN. z Prednisone +/- Azathioprine. Anti-TNF therapy. TuberculosisTuberculosis

¾ Liver granulomas in: z 25% of pure pulmonary TB, z 71% of pulmonary + other organ TB, z 94% of miliary TB (caseating in 52%). ¾ Only 10% of livers with TB granulomas stain AFB(+), or grow TB in culture. ¾ TB liver granulomas are PCR (+) in 53 %, with specificity of 96% (PPV = 90%, NPV = 76%). ¾ Most patients will be PPD or Quantiferon (+); false negatives due to anergy are more common in miliary TB. ¾ Patients may have tuberculoma that can cause cholangitis if it ruptures in bile duct. ¾ Liver Bx is superior to BM Bx for diagnosis of TB (Liver 94% vs BM 53% in miliary TB) SchistosomiasisSchistosomiasis

¾ 200200 millionmillion infestedinfested worldwide;worldwide; z 400000 in USA. ¾ AdultAdult wormworm liveslives inin mesenterymesentery veinsveins oror periperi-- vesicalvesical veins.veins. z embolizes eggs into liver, intestine, and/or bladder. z eggs cause granulomas + “pipe-stem” fibrosis of Symmers following portal veins trayectory. ¾ AcuteAcute infectioninfection (Katayama(Katayama fever):fever): z occurs 4-10 wks after infestation. z gives fever, chills, cough, diarrhea, arthralgia, malaise, hepato-splenomegaly and eosinophilia. ¾ ChronicChronic infectioninfection causescauses portalportal hypertension.hypertension. BrucellosisBrucellosis

¾ SignsSigns && Symptoms:Symptoms:

z Intermittent episodes of fever, profuse sweats, fronto- occipital headache, musculoskeletal pain (back pain), chest and abdomen pain, malaise, anorexia, and hepato-splenomegaly.

z Patient often feels well between episodes. ¾ HistoryHistory ofof contactcontact withwith goats,goats, pigs,pigs, cattlecattle

z aerosolized, or

z contact with wound, or

z ingestion of unpasteurized dairy. QQ feverfever

¾ Contact with goats, sheep, or cattle.

z Most commonly by aerosolized rickettsia (Coxiella burnetii) during “lambing”.

z Also by tick-bite, or ingestion of unpasteurized dairy. ¾ Incubation 2-3 weeks. ¾ Sign $ Symptoms:

z High fever, malaise, bi-frontal headache, and pneumonia.

z Hepatomegaly in 65%.

z May cause endocarditis. ¾ Elevated liver related enzymes in 11-65%. CatCat--scratchscratch DiseaseDisease

¾ ContactContact withwith kittens.kittens. ¾ SignsSigns && Symptoms:Symptoms:

z Lymphadenomegaly, malaise, osteomuscular pain, abdominal pain.

z May have fever and/or cholestasis.

z May cause “pseudotumor cerebri”.

z In immunocompromised patient may cause bacillary angiomatosis/ peliosis hepatis.

z Bacillary angiomatosis may cause pseudotumors of liver and spleen. LymphomaLymphoma

¾¾ Both,Both, HodgkinHodgkin && NonNon--Hodgkin.Hodgkin. ¾¾ MoreMore thanthan 50%50% ofof stagingstaging liverliver biopsiesbiopsies showshow granulomas.granulomas. ¾¾ PresencePresence ofof granulomasgranulomas doesdoes notnot indicateindicate liverliver involvementinvolvement byby thethe lymphoma.lymphoma. ¾¾ PatientsPatients withwith HodgkinHodgkin diseasedisease andand granulomasgranulomas havehave aa strongerstronger immuneimmune system,system, andand aa moremore favorablefavorable course.course. HepatitisHepatitis CC

¾ 5%5% ofof liverliver biopsiesbiopsies withwith HCVHCV havehave granulomas.granulomas. ¾ DoesDoes notnot causecause cholestasis.cholestasis. ¾ SometimesSometimes theythey areare presentpresent beforebefore therapy,therapy, andand otherother timestimes theythey developdevelop afterafter interferoninterferon therapy.therapy. ¾ PatientsPatients maymay developdevelop interferoninterferon--inducedinduced sarcoidosis,sarcoidosis, whichwhich oftenoften (but(but notnot always)always) resolvesresolves withwith discontinuationdiscontinuation ofof therapy.therapy. RarelyRarely needsneeds steroidsteroid therapy.therapy. AtypicalAtypical MycobacteriaMycobacteria && BCGBCG

¾ Atypical Mycobacteria ¾ BCG:

z Immunocompetent host: z Dissemination of BCG Well formed granulomas; instilled in bladder as AFB stain rarely (+). cancer treatment.

z Immunocompromised host: z Fever, hypotension, weight Poorly formed granulomas loss, elevated liver with large amount of enzymes.

AFB(+) organisms. z Rarely recovered in culture, or seen in AFB stein.

z Treatment: 6 months Rifampin + INH +/- steroids. DrugDrug InducedInduced

¾ Requirements for diagnosis:

z there should not be other apparent cause,

z symptoms leading to liver biopsy should have a close temporal relation to use of the drug,

z symptoms and liver enzyme abnormalities should resolve with drug discontinuation. ¾ Rechallenge is not required and may be dangerous. ¾ Granulomas may be associated to triaditis or lobular hepatitis; eosinophiles may or may not be present. ¾ Patients may have fever, arthralgia, skin rash, lymphadenomegaly, and/or peripheral blood eosinophilia. ¾ Hepatomegaly and jaundice may also be present. ¾ Jaundice is a marker of severity. IdiopathicIdiopathic GranulomatousGranulomatous HepatitisHepatitis

¾ Diagnosis of exclusion after full work-up (in case of symptomatic disease). ¾ In many patients granulomas are an incidental finding without clinical relevance. ¾ Patient may have recurrent fever, fatigue, weight loss. They have variable cholestasis and may have severe pruritus. ¾ Treatment:

z If PPD/Quantiferon (+) or anergic, empirical anti-TB therapy is reasonable.

z Prednisone +/- MTX (or Azathioprine ?) is helpful, but close observation is needed in case of “unmasking” of TB or other infection.