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Clinical Manifestations of Hepatitis C Virus Infection

Clinical Manifestations of Hepatitis C Virus Infection. Daniel Shouval Liver Unit Hadassah Hospital Hebrew University Jerusalem Israel. Clinical Manifestations of Hepatitis C Virus Infection Key Concepts. Disease is usually insidious and subclinical

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Clinical Manifestations of Hepatitis C Virus Infection

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

  2. Clinical Manifestations of Hepatitis C Virus InfectionKey Concepts • Disease is usually insidious and subclinical • Persistent HCV infection may progress over decades to chronic hepatitis with fibrosis, cirrhosis, portal 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 • HCV may complicate the course of other diseases I.e. HIV, HBV, chronic liver disease,hemophilia, renal failure, organ transplantation

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

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

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

  6. Hepatitis C Virus Infection Lab Markers HCV - RNA IIIIIIIIIIIIIIIIIIII IIIIIIII anti-HCV Symptoms (if any) Titer ALT Normal 6 1 2 3 4 0 1 2 3 4 5 Years Months Time after Exposure

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

  8. Clinical Manifestations of Hepatitis C Virus InfectionSymptoms * • Fatigue • 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. Clinical Manifestations of HCV • Fatigue • Malaise • Myalgia • Depression • Cognitive dysfunction

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

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

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

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

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

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

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

  17. Extrahepatic Manifestations of Hepatitis CEndocrine • Hyperthyroidism • Hypothyroidism • Hashimoto’s Disease and Thyroiditis • Thyroid antibodies* • Diabetes Mellitus • Higher prevalence of anti-thyroid antibodies; also induced • through interferon Rx and leading to hyper and hypothyroidism

  18. Extrahepatic Manifestations of Hepatitis CThyroid dysfunction Anti-thyroid Antibodies and Interferon Treatment

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

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

  21. Extrahepatic Manifestations of HCVOcular Involvement • Peripheral ulcerative keratitis (Mooren ulcers) reported during Interferon therapy and also during post Rx relapse • Challenge with interferon may lead to exacerbation of ulcers • A few cases of Uveitis have been reported

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

  23. Extrahepatic Manifestations of HCVHematological and Lymphoid Disorders* • 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 and/or chronic antigenic stimulation

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

  25. HCV Associated Arthritis* • Commonly presents as rheumatoid arthritis like symptoms ( severe morning stiffness and pain) 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

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

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

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

  29. Rare (anecdotal?) Associationwith HCV • Behcet Syndrome • Generalized vasculitis in polyarteritis nodosa • Interstitial pulmonary fibrosis and vasculitis • Anti-phospholipid syndrome • Auto-antibodies in autoimmune hepatitis

  30. Effect of Interferon-alpha Treatment on Extrahepatic Manifestations of HCV

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

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