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