1. Liver Unit - Hadassah Clinical Manifestations of Hepatitis C Virus Infection Daniel Shouval Liver Unit Hadassah Hospital Hebrew University JerusalemIsrael

2. Liver Unit - Hadassah Clinical Manifestations of Hepatitis C Virus Infection Key Concepts Disease is usually insidious and subclinical  Disease is usually insidious and subclinical  Persistent HCV infection may progress over decades to chronic hepatitis with fibrosis, cirrhosis, portal to chronic hepatitis with fibrosis, cirrhosis, portal hypertension, encephalopathy and hepatocellular ca. hypertension, encephalopathy and hepatocellular ca.  HCV is the main indication for liver transplantation  Although the liver is the main target for HCV, extra- hepatic manifestations are common hepatic manifestations are common  HCV may complicate the course of other diseases I.e. HIV, HBV, chronic liver disease,hemophilia, I.e. HIV, HBV, chronic liver disease,hemophilia, renal failure, organ transplantation renal failure, organ transplantation

3. Liver Unit - Hadassah Clinical Manifestations of Hepatitis C Virus Infection Background - Pathology Viral hepatitis is defined as a diffuse necro- Viral hepatitis is defined as a diffuse necro- inflammatory liver disease caused by hepato- inflammatory liver disease caused by hepato- tropic viruses tropic viruses The basic morphologic pattern of acute or The basic morphologic pattern of acute or chronic hepatitis due to different hepatitis chronic hepatitis due to different hepatitis viruses are very similar irrespective of viruses are very similar irrespective of causative virus causative virus Despite of the above, there are unique Despite of the above, there are unique characteristic morphologic patterns in chronic characteristic morphologic patterns in chronic HCV infection incl: lymphoid aggregates(57%), HCV infection incl: lymphoid aggregates(57%), bile duct injury (60%) and steatosis (52%). bile duct injury (60%) and steatosis (52%).

4. Liver Unit - Hadassah Liver Biopsy in Chronic Hepatitis C – is it still necessary? Background: Little correlation between the inflammatory process Little correlation between the inflammatory process observed by microscopy and the clinical or observed by microscopy and the clinical or laboratory manifestations laboratory manifestations The impact of clinical presentation on the rational for performing a biopsy: rational for performing a biopsy: Establish diagnosis Establish diagnosis Assess grade and stage (Metavir score etc) Assess grade and stage (Metavir score etc) Exclude other or additional conditions Exclude other or additional conditions (i.e alcohol, NASH, CLD, HBV ) (i.e alcohol, NASH, CLD, HBV ) Guide management Guide management Follow-up of therapy Follow-up of therapy

5. Liver Unit - Hadassah Clinical Manifestations of Hepatitis C Virus Infection Incubation period: Acute hepatitis C 15-150 days (M 50d) Acute hepatitis C 15-150 days (M 50d) Most cases of acute HCV infection (~75%) are Most cases of acute HCV infection (~75%) are not recognized not recognized Clinical symptoms in patients with acute HCV when Clinical symptoms in patients with acute HCV when present, are usually milder as compared to other present, are usually milder as compared to other hepatitis viruses hepatitis viruses ~80% of patients who contract acute HCV infection ~80% of patients who contract acute HCV infection will develop persistent infection which often lasts will develop persistent infection which often lasts for decades for decades

6. Liver Unit - Hadassah Hepatitis C Virus Infection Lab Markers Hepatitis C Virus Infection Lab Markers Symptoms (if any) Time after Exposure Titer anti- HCV ALT Normal 012345 61234 Years Months HCV - RNA IIIIIIII IIIIIIIIIIIIIIIIIIII

7. Liver Unit - Hadassah Clinical Presentation of Chronic HCV Infection* Clinical presentation may vary depending on the host Immune status, the source and duration of infection Immune status, the source and duration of infection Often asymptomatic Frequently detected during routine lab testing Frequently detected during routine lab testing or blood donation or blood donation Non specific signals: - mild to moderate fatigue Non specific signals: - mild to moderate fatigue - fluctuating ALT levels are - fluctuating ALT levels are *Sharara AL et al. Hepatitis c. Review Ann Int Med 1996; 125:658

8. Liver Unit - Hadassah Clinical Manifestations of Hepatitis C Virus Infection Symptoms * Fatigue  Fatigue Malaise  Malaise  Nausea  Abdominal discomfort*  Dark urine and acholic stools  Vomitting  Jaundice  Pruritus  Arthralgia  Fever * May be present in acute as well as in chronic hepatitis

9. Liver Unit - Hadassah Clinical Manifestations of HCV oFatigue oMalaise oMyalgia oDepression oCognitive dysfunction

10. Liver Unit - Hadassah Musculoskeletal Pain and Fatigue in HCV* 239 patients; age M 46.7y; Males 52%  239 patients; age M 46.7y; Males 52%Results: Musculoskeletal pain – 70% for M of 7y Musculoskeletal pain – 70% for M of 7y Fatigue – 56% for a M 3.3y Fatigue – 56% for a M 3.3y Backache - 54% Backache - 54% Morning stiffness – 45% Morning stiffness – 45% Arthralgia – 42% Arthralgia – 42% Myalgia – 38% Myalgia – 38% Neck pain – 33% Neck pain – 33% * Barhuizen A et al. Am J Gastroenterology 1999;94:1355

11. Liver Unit - Hadassah Hepatitis C and Cognitive Impairment of Patients with Mild Disease I* *Forton DM et al. Hepatology 2002;35:433 Material and Methods Material and Methods  27 HCV patients with biopsy proven mild HCV 17 control patients with resolved HCV 17 control patients with resolved HCV  Testing through computor based cognitive assessment battery assessment battery  Completing depression, fatigue and quality of life questionnairs of life questionnairs

12. Liver Unit - Hadassah Hepatitis C and Cognitive Impairment of Patients with Mild Disease II* *Forton DM et al. Hepatology 2002;35:433 RESULTS HCV patients wereimpaired on more HCV patients wereimpaired on more cognitive tasks than patients who cognitive tasks than patients who cleared HCv ( P < 0.02) cleared HCv ( P < 0.02) HCV patients showed impairment in: HCV patients showed impairment in: - concentration power - concentration power - speed of working memory - speed of working memory (irrespective of fatigue or depression) (irrespective of fatigue or depression) Cerebral proton magnetic resonance spectro- Cerebral proton magnetic resonance spectro- scopy showed elevated choline/creatine ratios scopy showed elevated choline/creatine ratios suggesting a possible organic etiology for suggesting a possible organic etiology for cognitive impairment in HCV infection cognitive impairment in HCV infection

13. Liver Unit - Hadassah Complications of Acute HCV Infection (I) Fulminant hepatitis – rare Chronic hepatitis - ~80% Chronic hepatitis - ~80% Cirrhosis* ~20-35% Cirrhosis* ~20-35% Hepatocellular carcinom** - ` 1-4% Hepatocellular carcinom** - ` 1-4% annually, after prolonged infection annually, after prolonged infection * Maybe clinically silent but eventually * Maybe clinically silent but eventually may lead to portal hypertension, ascites, may lead to portal hypertension, ascites, esophageal and gastric varices which may bleed, esophageal and gastric varices which may bleed, or hepatic encephalopathy or hepatic encephalopathy ** As * with additional extra hepatic manifestations

14. Liver Unit - Hadassah Complications of Acute HCV Infection (II)* average time between acute hepatitis c and  “Clinically significant” liver disease ~10 years ~10 years  Cirrhosis ~ 21.2 years  Hepatocellular carcinoma ~ 29 years *Sharara AL et al. Hepatitis c. Review Ann Int Med 1996; 125:658

15. Liver Unit - Hadassah Association of HCV infection with other Diseases and Conditions and Impact on Clinical Presentation Infection with other viruses: HIV, HBV, Infection with other viruses: HIV, HBV, HTLV, Herpes HTLV, Herpes Infection of patients with schistosomiasis Infection of patients with schistosomiasis IVDA IVDA Hemophilia, Thalassemia, Sickle cell anemia etc. Hemophilia, Thalassemia, Sickle cell anemia etc. Hemodialysis and kidney transplantation Hemodialysis and kidney transplantation Iron overload Iron overload Alcoholic liver disease Alcoholic liver disease Autoimmune hepatitis. PBC, PSC Autoimmune hepatitis. PBC, PSC

16. Liver Unit - Hadassah Extrahepatic Manifestations of Hepatitis C Virus Infection* Endocrine Endocrine Salivary Glands (sialadenitis) Salivary Glands (sialadenitis) Ophtalmic ( uveitis, ulcers) Ophtalmic ( uveitis, ulcers) Hematologic/lymphoid organs Hematologic/lymphoid organs Skin Skin Renal Renal Autoimmune diseases Autoimmune diseases Neurologic and Cognitive impairment Neurologic and Cognitive impairment Miscellaneous Miscellaneous * S.J. Hadziyannis. (Review). J Viral Hepatitis 1997; 4:9

17. Liver Unit - Hadassah Extrahepatic Manifestations of Hepatitis C Endocrine Hyperthyroidism  Hyperthyroidism  Hypothyroidism  Hashimoto’s Disease and Thyroiditis  Thyroid antibodies*  Diabetes Mellitus Higher prevalence of anti-thyroid antibodies; also inducedHigher prevalence of anti-thyroid antibodies; also induced through interferon Rx and leading to hyper and hypothyroidism through interferon Rx and leading to hyper and hypothyroidism

18. Liver Unit - Hadassah Extrahepatic Manifestations of Hepatitis C Thyroid dysfunction Anti-thyroid Antibodies and Interferon Treatment Author % Patients < Interferon > Interferon DiBiscegli (USA) 9.500 Lisker-Melman(USA)7.012 Berris (Canada) 5.503 Pateron (France) 9.022 Baudin (France) 1214 Kodama (Japan) 1246 Deutsch (Greece) 10.91931

19. Liver Unit - Hadassah Extrahepatic Manifestations of Hepatitis C Diabetes Mellitus High prevalence reported in USA, UK, Turkey High prevalence reported in USA, UK, Turkey UK : DM in 17/34 (50%) in HCV cirrhosis patients UK : DM in 17/34 (50%) in HCV cirrhosis patients Reports on de-novo appearance of DM post IFN Rx Reports on de-novo appearance of DM post IFN Rx Putative mechanism linked to destruction of Putative mechanism linked to destruction of pancreatic islet cells directly by HCV or indirectly pancreatic islet cells directly by HCV or indirectly via immune response to HCV via immune response to HCV

20. Liver Unit - Hadassah Extrahepatic Manifestations of HCV Salivary Glands Mild lymphocytic sialadenitis reported in  Mild lymphocytic sialadenitis reported in 3 studies in 14-57% patients 3 studies in 14-57% patients  Lymphocytic “capillaritis” reported by Pawlotsky in ~50% of patients while symptomatic in ~50% of patients while symptomatic lymphocytic sialadenitis reported in 7/49 patients lymphocytic sialadenitis reported in 7/49 patients  Clinical presentation - Sjoegren syndr.-rare; antinuclear SSA antibodies are absent antinuclear SSA antibodies are absent  Lacrimal dysfunction reported in 17/34 asymptomatic patients without xerophtalmia asymptomatic patients without xerophtalmia

21. Liver Unit - Hadassah Extrahepatic Manifestations of HCV Ocular Involvement Peripheral ulcerative keratitis  Peripheral ulcerative keratitis (Mooren ulcers) reported during Interferon (Mooren ulcers) reported during Interferon therapy and also during post Rx relapse therapy and also during post Rx relapse  Challenge with interferon may lead to exacerbation of ulcers exacerbation of ulcers  A few cases of Uveitis have been reported

22. Liver Unit - Hadassah Extrahepatic Manifestations of HCV Renal Involvement Mild to moderate proteinuria detected in up to 27% of patients with microscopic hematuria 27% of patients with microscopic hematuria Glomerular deposition of IgG, IgM and C3 Glomerular deposition of IgG, IgM and C3 have been reported in cryoprecipitate conaining have been reported in cryoprecipitate conaining HCV-RNA and anti-HCv antibodies HCV-RNA and anti-HCv antibodies Membrano-proliferative glomerulonephritis Membrano-proliferative glomerulonephritis reported in association with HCV and reported in association with HCV and cryoglobulinemia cryoglobulinemia

23. Liver Unit - Hadassah Extrahepatic Manifestations of HCV Hematological and Lymphoid Disorders * Mixed cryoglobulinemia  Mixed cryoglobulinemia  Non-Hodgkin B-cell lymphoma (NHL)  Aplastic anemia ( association ????)  Idiopathic thrombocytopenic purpura * Linked to lymphotropism of HCV to PBLs, dendritic cells, BM,megacariocyte,vascular endothelium BM,megacariocyte,vascular endothelium and/or chronic antigenic stimulation and/or chronic antigenic stimulation

24. Liver Unit - Hadassah Extrahepatic Manifestations of HCV Cryoglobulinemia with or without Vasculitis*  Association between HCV and Mixed Cryoglobulinemia (MCG) established Cryoglobulinemia (MCG) established through HCV-RNA testing in cryoprecipitate through HCV-RNA testing in cryoprecipitate  Often missed due to inadequate handling of blood specimen of blood specimen  Cryoglobulinemia may signal a pre-malignant state state  Affects up to 40% of HCV patients with cirrhosis (mean cryocrit >2%) but only ~10% cirrhosis (mean cryocrit >2%) but only ~10% have symptoms of vasculitis have symptoms of vasculitis * S.J. Hadziyannis. (Review). J Viral Hepatitis 1997; 4:9 Dammacco F et al. The cryoglobulins:an overview. Dammacco F et al. The cryoglobulins:an overview. Eur J Clin Invest. 2001;31:628 Eur J Clin Invest. 2001;31:628

25. Liver Unit - Hadassah HCV Associated Arthritis *  Commonly presents as rheumatoid arthritis like symptoms ( severe morning stiffness and pain) symptoms ( severe morning stiffness and pain) with symmetrical arthritis of small joints with symmetrical arthritis of small joints  Mono or oligo-arthritis less common  Clinical course usually benign without deformities  Absence of subcutaneous nodules  >70% of patients complain of fatigue Zuckerman E et al. BioDrugs 2001;15:573 * Zuckerman E et al. BioDrugs 2001;15:573

26. Liver Unit - Hadassah Extrahepatic Manifestations of HCV Non-Hodgkin Lymphoma *  Some evidence suggests that persistent HCV infection leading to lymphoproliferation and infection leading to lymphoproliferation and cryoglobulinemia may switch over to lymphoma cryoglobulinemia may switch over to lymphoma  HCV-RNA has repeatedly been demonstrated in lymphoid and BM cells in lymphoid and BM cells  HCV viremia reported in up to 35% of patients with B cell lymphoma and almost 90% of with B cell lymphoma and almost 90% of non-Hodgkin lymphoma patients with non-Hodgkin lymphoma patients with cryoglobulinemia cryoglobulinemia  Diagnosis sometime overlooked due to occult presentation and /or similarity of symptoms presentation and /or similarity of symptoms to chronic HCV infection to chronic HCV infection * Dammacco F. et al. Seminars in Liver-Disease. 2000;20:143

27. Liver Unit - Hadassah Extrahepatic Manifestations of HCV Neurological and Musculoskeletal Involvement  Peripheral neuropathy reported but rare  Muscle weakness and myopathy are frequent complaints in fatigued HCV frequent complaints in fatigued HCV patients, often with cryoglobulinemia patients, often with cryoglobulinemia  Some rare.latent muscle disorders may exacerbate in HCV patients receiving exacerbate in HCV patients receiving interferon treatment interferon treatment  Myasthenia Gravis rarely observed in interfeon treated patients interfeon treated patients

28. Liver Unit - Hadassah Extrahepatic Manifestations of HCV Dermatologic Involvement* Pruritus – Non specific Leukocytoclastic-cutaneous necrotizing vasculitis with cryoglobulinemia Lichen Planus Lichen Planus Erythema Multiforme Erythema Multiforme Erythema Nodosum Erythema Nodosum Urticaria Urticaria Porphyria Cutanea Tarda Porphyria Cutanea Tarda Malaplakia Malaplakia * S.J. Hadziyannis. (Review). J Viral Hepatitis 1997; 4:9

29. Liver Unit - Hadassah Rare (anecdotal?) Association with HCV Behcet Syndrome  Behcet Syndrome  Generalized vasculitis in polyarteritis nodosa  Interstitial pulmonary fibrosis and vasculitis  Anti-phospholipid syndrome  Auto-antibodies in autoimmune hepatitis

30. Liver Unit - Hadassah Effect of Interferon-alpha Treatment on Extrahepatic Manifestations of HCV CONDITIONImprove. No Change Worse Cryoglobulinemia++++ Glomerulonephritis++++ Autoimmune Markers +++ Muscular distrophy + Lichen Planus + Corneal ulcer + Porphyria CT + ITP++ Thyroid Disease ++

31. Liver Unit - Hadassah Clinical Presentation of Hepatitis C Virus Infection Summary The liver is the primary target The liver is the primary target for the hepatotropic HCV for the hepatotropic HCV Yet infection with HCV is a Yet infection with HCV is a systemic disease and can systemic disease and can involve most organs involve most organs Clinicians taking care of patients Clinicians taking care of patients with HCV must pay attention to with HCV must pay attention to the multisystemic nature of the the multisystemic nature of the disease including the effects on disease including the effects on general well being and quality general well being and quality of life of life