Skin And Hepatitis C Virus Mohammad Jafferany, MD Dermatologist Ajyad General Hospital Makkah Viral Hepatitis - Historical Perspectives “Infectious” A Enterically E transmitted Viral hepatitis NANB Parenterally “Serum” B D C transmitted F, G, TTV ? other HEPATITIS C INFECTION • Primary cause of transfusion-associated hepatitis. • I/V drug abuser. • Organ transplant recipients. • Hemodialysis patients. • Medical personnel. ALARMING FEATURES • Very high frequency of chronic infection. • Major causative agent for Primary hepatocellular carcinoma. • 45% of HCV cases have no obvious risk factors including parenteral exposure. • Leading indication of Liver transplantation. Alter et al. JAMA 1990,264:2231 - 5 Risk Groups for HCV in USA 43% 35% Drug Abuse Transfusion Promiscuity Medical Pers. 5% Unidentified 20% 7% http:sites.netscape.net/derekwongkk/viruses/hepatitisc.htm Selected Risk Factors Prevalence by Age & Ethnicity Most Striking Features • Circulates in extremely low concentrations. • Extremely virulent and infectious. • Both triggers and mimics autoimmune disease. • Rapid mutation, evolving into different strains. • Extremely resilient, hard to kill. • ALT levels can be normal while viral load is high. http://hcvglobal.org/infobklt.html W.H.O estimates …………. • One in every hundred humans have HCV. • Worldwide 100,000m are chronically infected. • 28.5 times MORE people are infected with HCV than HIV. • The most prevalent chronic viral infection in US. • Around one third of HCV cases result from unknown sources. http://www.hep.org/articles/hepa.html Co-infection With HCV & HIV • Frequently co-exist, because of some common risk factors. • In HIV population, the prevalence of HCV ranges from 3 – 78%. • HIV via i/v drug abuse, co-infection rate is 64 – 78%, while with homosexual population it is 3 – 5%. • 400,000 individuals in US are co-infected with HIV & HCV. http://www.ajj.com/services/pblshng/dnj/ceonline/06163169.htm HCV Statistics vs. AIDS Statistics HCV HIV Infected people - 4.5 millions in US - 700,000 in US - 200-400m worldwide - 20m worldwide New cases 170,000 in US 40,000 in US People who will 80m worldwide 20m worldwide Die http://www.nih.gov.org/hcvhivstatistics.html CLINICAL FEATURES • Fatigue is a common clinical manifestation. • Jaundice • Dark Urine • Abdominal Pain • Loss of appetite • Nausea Hepatitis C Virus Infection Typical Serologic Course anti- HCV Symptoms Titre ALT Normal 0 1 2 3 4 5 6 1 2 3 4 Months Years Time after Exposure Long Term Effects • 75 – 85% of infected persons develop chronic infection. • 70% of chronic patients, develop chronic liver disease, leading to eventual cirrhosis in 20%. • Once the cirrhotic process begins, the incidence of hepatic carcinoma ranges from 1 – 4%. • Leading indication of liver transplantation. Doutre,M. Arch Derm 2000. 135(11):432-5 Factors Leading To More Severe Injury • Excessive alcohol consumption • Older age at the time of infection • Immunosuppression • Specific genotype http://archderm.ama-assn.org/issues/v135n11/ffull/ded9016.html TRANSMISSION • Blood or body fluids. • Sharing needles, Drug abuse, Exposure on the job, Infected mother to her baby during childbirth. • Persons at risk for HCV, might also be at risk for HBV or AIDS. HCV is NOT spread by: • Breast Feeding • Sneezing or Coughing • Hugging • Food or Water • Eating utensils • Drinking glasses • Casual contact RECOMMENDATIONS FOR TESTING PERSONS RISK TEST Drug Abuse High Yes Recipient of clotting factors before 1987 High Yes Hemodialysis Patients Intermediate Yes Recipient of blood/solid organs before 1992 Intermediate Yes People with undiagnosed liver problems Intermediate Yes Infants born to infected mothers Intermediate 12-18 months Healthcare workers Low Known exposure Having sex with multiple partners Low No Having sex with an infected steady partner Low No http://www.cdc.gov./ncidod/diseases/hepatitis/c/fact.htm PREVENTION • There is no vaccine • No role of Immunoglobulins • Do not share personal care items, that have blood on them e.g Razors, Toothbrushes. • For healthcare workers, follow routine barrier precautions. • If you are HCV positive, do not donate blood or organs. • Safe Sex Laboratory Diagnosis • HCV antibody: Generally used to diagnose HCV infection. Not useful in acute phase, as it takes 4 weeks after infection, before the antibody appears. • HCV-RNA: Various techniques like PCR, branched DNA. May be used to diagnose in acute phase. Main use in monitoring the response to antiviral therapy. • HCV antigen: As ELISA, used in the same capacity as HCV-RNA tests, but much easier to carry out. Biochemical Features • Aminotransferase levels are lower and fluctuant. • AlkPh. And GGT usually normal • Rh factor and low platelets and WBCs are common • Albumin levels and Prothrombin time are normal • Iron and Ferritin levels may be slightly elevated. Immune Response To HCV • Cryoglobulins • Rheumatoid factor • Antinuclear antibodies • Anti-cardardiolipn antibody • Antithyroid antbody • Microsomal antibody • HCV/anti-HCV immune complexes Prevalence of Auto antibodies • Rheumatoid factor 70% • Antinuclear antibody 21% • Anti Smooth Mm antibody 21% • Anti-LKM antibody 15% • Antithyroglobulin antibody 7% • Anticardiolipin antibodies • Lupus anticoagulant Pawlotsky JM, et al. Hepatology. 1994; 19:841-8 TREATMENT • Interferon Alpha: The response rate is around 50%, but 50% of responder will relapse upon withdrawal of therapy. • Ribavarin: There is less experience than Interferon. • Interferon can be taken alone or in combination with Ribavarin. • Combination therapy is currently the treatment of choice. Interferon Monotherapy • Interferon alfa 2, was the first agent approved. • Two forms of IFN alfa,that differ by single amino acid residue. IFN alfa 2b & IFN alfa 2a. • Doze: 3 million units 3 times each week for up to 12 months. • Because of the low overall response rate, newer regimes have been developed. NEWER REGIMENS • Combination Therapy IFN alfa 2b + Ribavarin • Synthetic IFN ( IFN alfacon 1 or Consensus IFN), a genetically engineered compound by combining the most common AA sequences from naturally occurring IFNs. • Pegylated IFNs ( Longer acting IFNs), involves the addition of non toxic long acting formulation of IFN, by addition of polyethylene glycol molecules. Response To Newer Regimes SIDE EFFECTS OF TREATMENT Interferon Ribavirin Combination Skin irritation Anemia Autoimmune disorders Hair Loss Fatigue Bacterial infection Fatigue, M aches Irritability Thrombocytopenia Headache, N / Vomit. Itching Neutropenia Depression Skin Rash Seizures Irritability Nose stuffiness Depression, Suicide Wt. Loss, Fever Sinusitis, cough Retinopathy http://content.health.msn.com/content/article/1680.51408 A New Drug • A new therapy called Zadaxin, originally isolated from Thymus gland. • Promotes maturation of T cells and thus enhance the immune system. • In an Italian study, in combination with INF, it performed well in immune stimulation. • Not approved by FDA. http://www.hep.org/articles/hepa.html Statistics & Trends • Number of new infections per year has declined from 240,000 in 1980s to about 40,000 in 1998. • Most infections are due to I/v drug abuse. • Transfusion-associated cases are decreasing due to blood donor screening facilities. • Estimated 4 millions (1.8%) Americans have been infected with HCV, of whom 2.7 millions are chronically infected. http://www.cdc.gov./ncidod/diseases/hepatitis/c/fact.htm What about Saudi Arabia ? Prevalence of anti-HCV antibody in Healthy Saudis 5.00% 4.50% 4.00% 3.50% 3.00% 2.50% 2.00% 1.50% 1.00% 0.50% 0.00% 1-9y 10-19y 20-29y 30-39y 40-49y >50y Bakir,TMF. Saudi Med Journal 1992;13:321-324 Prevalence of anti-HCV antibodies in Saudi High Risk Groups STDs Sickle Cell Anemia Beta Thalassemia Thalassemia & SC dis Hemophiliac 0 10 20 30 40 50 60 70 80 90 Bahakim,H et al. vox Sang 1991;60:162-4 Prevalence of anti-HCV ab in Saudi Hemodialysis Patients Western Region (4 Centers) Madinah Munawwara Jeddah Area (3 Centers) Eastern Region (4 Centers) National study 0 10 20 30 40 50 60 70 80 Huraib,SO Saudi J Kid Dis Transpl. 1995;6:197-205 Summary of HCV in Saudi Arabia • Endemic. Acquired in early life and exposure increases with age reaching a prevalence of 3.5% - 5.5% in over 50 years. • Major health problem in patients with Ch. Renal failure, maintained on dialysis. • Major etiological agent for Ch. Liver disease. More important than HBV. • Lack of evidence of intrafamilial and sexual transmission. • Genotype 4 is the predominant type of HCV. http://www.kfshrc.edu.sa/annals/171/96.044ra.html L e t ’s g o t o D e r m a t o l o g y ! CUTANEOUS MANIFESTATIONS • Pruritus • Mixed Cryoglobulinemia / Vasculitis • Porphyria Cutanea Tarda • Lichen Planus • Salivary Gland Lesions • Urticaria http://www.ajj.com/services/pblshng/dnj/ceonline/06163169.htm Cutaneous Manifestations ……….. • Polyarteritis Nodosa • Arterovenous haemangioma • Erythema Nodosum • Granuloma annulare • Erythema Multiforme • Dissminated superficial Porokeratosis • Cutaneous Sarcoidosis • Necrolytic acral erythema • Behcet’s Disease • Thrombotic microangiopathy • Non Hodgkin’s Lymphoma • Lymphoma Associated Autoimmune Diseases • Sjogren’s Syndrome • Glomerulonephritis • Ch. Polyarthropathy • Thrombocytop. Purpura • Rheumatoid Arthritis • Symmetric leg ulcers • Polydermatomyositis • Autoimmune hepatitis • S L Erythematosus • Thrombotic Microangiop. • Fibromyalgia • Aplastic Anemia • Autoimmune Thyroiditis • Irritable bowel syndrome • Diabetes Mellitus • Crohn’s disease Why Do Skin Signs Appear Only In Certain Patients ? • Viral Genotypes HCV genotypes varies according to to the region but does not influence the occurrence of cutaneous signs. • Viral Load May be a reliable marker of disease status, but does not influence the occurrence of skin signs. • Genetic Predisposition HLA A1, B8, DR3 and DR4 • Environmental Co infection with HBV & HCV and HIV & HCV is frequent . http://archderm.ama-assn.org/issues/v135nll/ffull/ded9016.html PRURITUS • Cholestasis. • A non-bile pruritogen associated with hepatocyte cell membrane. • Crusts, Excoriations, Xerosis, Papules and Prurigo. • UVB phototherapy, Cholestyramine, Ursodiol and Naloxone. Characteristics of Pruritus in HCV • High serum bile acids • Advanced pathology • Bile duct abnormalities • Clinical course is relapsing • Response to therapy is inconsistent Lebovics et al. Dig. Dis. Sci. 1997 May; 42 (5): 1094-1099 PRURITUS Vasculitis / Cryoglobulinemia • Type II & III mixed cryoglobulinemia (MC). • The classic triad of MC consists of Purpura, Weakness and Arthralgia. • Manifested as Livedo, Ulcers, Urticaria, Vasculitis & Raynaud’s phen. • 50 – 90% of patients with MC have anti-HCV antibodies and 35 – 54% of patients with HCV have MC. (Cosserat J et al. Neph Dialysis and Transplant 1996:11(4)31-35) How Does The Virus Act ? • Immune complexes (HCV & anti-HCV antibodies) activation of endothelial cells altered vascular permeability neutrophil infiltration vessel wall damage. • Antibodies or T cells sensitized to HCV containing vascular endothelial cells , may initiate the process. VASCULITIS Porphyria Cutanea Tarda • HCV antibodies found in 50-90% of cases of PCT. • Geographical variation. • HCV as a risk factor for development of PCT, along with Alcohol, Estrogen or Iron overload. • Clinical changes of PCT are not related to the virologic findings, suggesting an indirect role of HCV. • Hepatocellular carcinoma complicating PCT, is due to HCV infection. Bernard et al. Archives of Dermatology 1995; 131:801-804 A Clinical & Virologic Study • Out of 12 patients with sporadic PCT, 7 were HCV +ve. • Age of onset was lower in HCV positive patients, suggesting HCV as major triggering factor. • HCV RNA was detected in all positive patients. • Genotype I was seen in 4, genotype II was in 4 and co- infection with I & II in one patient. • The clinical changes of PCT were not related to the virologic findings, suggesting an indirect role. Bernard et al. Archives of Dermatology 1995; 131:801-804 How Does The Virus Act ? • Not known exactly • The HCV probably act as a non specific factor, that reveals the enzymatic defect of uroporphyrinogen decarboxylase in genetically determined persons. • It interferes with Glutathione metabolism in liver,thus triggering the development of PCT. http://www.hepnet.com/boca/scully1.html Porphyria Cutanea Tarda Porphyria Cutanea Tarda Porphyria Cutanea Tarda SALIVARY GLAND • Lymphocytic capillaritis and sialadenitis on biopsy. • HCV patients have likelihood of signs of Sjogren’s syndrome. (Kerato-conjunctivitis sicca) • Questions to be answered: - A coincidence between the two disorders ? - HCV plays a pathogenetic role in SS ? LICHEN PLANUS • Up to 35% of patients with LP have some sort of chronic liver disease. (Cosserat, J. et al. Neph. Dial. Transpl. 1996; 11:31-35) • Prevalence in HCV 3.8 – 62% • HCV-associated LP : Prolonged disease duration, Generalized distribution, Mucosal involvement and variable geographical distribution. • Chronic LP justifies the search for underlying HCV. http://www.ajj.com/services/pblshng/dnj/ceonline/06163169.htm 10 Proven Lichen Planus Cases With Positive HCV Serology No.of patients Characteristics 9 Mucosal Involvement 4 Erosive form 7 Liver disease preceded Lichen Planus 3 Liver disease followed Lichen Planus 3 INF alfa 2b therapy worsened the lesions Jauregui, et al. Gasroenterol Hepatol. 1996; 19:507-510 How Does The Virus Act ? Unclear Alteration in epidermal antigenecity induced by HCV Interaction with activated T cells with production of gamma IFN Causes Keratinocytes to express HLA-DR To be destroyed by T cells Sanches-Perez et al. Brit J Derm. 1996, 134:715-9 Erosive Lichen Planus Erosive Lichen Planus URTICARIA • Two Mechanisms • Urticaria few weeks after blood transfusion (during seroconversion to HCV positivity) should raise the suspicion. • Also associated with combination treatment. (Macedo et al. Gastroenerology 2000;34:655-658) • Chronic Urticaria is not significantly associated with HCV. (Cribier,BJ, et al. Arch Derm. 1999 Nov. 135 (11): 1335-9) Lymphoma & Non-Hodgkin Lymph. • Mazzaro et al in Italy reported that 28.4% of his 199 pts. with NHL were HCV positive as compared to 2.9% of general population. • Postulated Mechanism of Action : Long term HCV infection Expansion of clones of Ig(cryoglobulins) secreting lymphocytes Genetic & Environmental factors Mutational Event Activation of Oncogens NHL http://www.hepnet.com/boca/scully1.html B-LYMPHOMA Necrolytic Acral Erythema • A newly reported entity • Erythematous lesions with blisters, exclusively on the dorsum of feet in patients with HCV. • Treatment with INF alfa and Zinc. (Khanna VJ et al. Arch Derm. 2000;136:755-757) • Questions to be answered: - Why lesions are confined to the dorsa of feet? - Are the lesions related to low AA level or virus ? - What is the exact incidence in HCV infection? Mohamed E.Darouti & Abu El Ela. Int J Derm. 1996 April; 35(4):252-257 How Does it Differ From Other Necrolytic Erythemas ? • It shares the microscopic and some clinical features of other necrolytic erythemas except: - Almost exclusively on dorsa of feet - Typically not associated with central clearing - Always associated with deterioration of liver function. - Not annular Dissem. Superficial Porokeratosis • Reported during the development of HCC in HCV+ve liver cirrhotics. • No signs of malignancy found, before the development of DSP. • HCV induced immunomodulation or its effects on p53 enzyme system. • As a paraneoplastic condition. Kono T et al. J Am Acad Derm.. 2000;43:966-968 Dissem. Superf. Porokeratosis Granuloma Annulare • Generalized granuloma annulare in a 65 year old chronic HCV infected patient. • Totally regressed during Alfa INF therapy. • A link between two diseases is strongly suspected. Granel, B. J Am Acad Derm 2000; 43:918-919 PSORIASIS • Two Mechanisms • HCV infection may be one of the triggering factors. (Yamamoto et al. Arch Derm Venereol 1995;75(6):482-3) • Precipitated or exacerbated by IFN therapy. (http://www.ajj.com/services/pblshng/dnj/ceonline/06163169.htm) • In the presence of liver disease in Psoriasis patients, HCV infection should be considered as an alternative diagnosis. (Chouela E. et al. Int J Derm 1996;35(11):797-9) Cutaneous Response to IFN Therapy • Cryoglobulinemia: Positive with clearing of the purpuric lesions. (Hadziannis,SJ. J Europ Acad Derm Ven. 1998;10(1):12-21) • Lichen Planus: May flair the disease, Improve the disease or have no effect. (Gordon,SC. Dig Dis. 1998; 14(3):157-168) • PCT: Unknown & variable. (Takikawa,H et al. J hepatol. 1995; 22(2):249-250) • Psoriasis: Precipitates and exacerbates pre- existing psoriasis. (Georgetson,MJ. et al. Am J of Gastroenterol. 1993;88(10):1756-1758) Combination Therapy • IFN + Ribavarin(800-1200 mg/day) • A clear association with the dermatological side effects, when combined after IFN monotherapy. - Transient urticaria - Skin rash with pruritus - Exacerbation of lichen Planus - Acute Leukocytoclastic vasculitis - Eczematous rash Macedo et al. Gastroenerology 2000;34:655-658 MISCELLANEOUS • Erythema nodosum (Domingo P et al. Lancet. 1991,337:428) • Erythema multiforme (Antonori S. et al. Lancet. 1990,336:1377) • Polyarterits nodosa (Schwaber & Zlotogorski ,Int.J Derm 1997,36:251) • Cutaneous Sarcoidosis (Hoffman et al.J Hepatol 1998, June; 28(6):1058-1063) • Behcet’s Disease (Albert et al. New Eng J Med 1995,333:322-3) • Granuloma Annulare (Granel,B., J Am Acad Derm 2000,43:918-919) • If few weeks after transfusion, be screened for HCV. Treatment Associated Diseases • Psoriasis (http://www.ajj.com/services/pblshng/dnj/ceonline/06163169.htm) • Sarcoidosis (Hoffman RM et al. J Hepatol. 1998 June;28(6):1058-1063) • Polyarteritis nodosa (Dohmen K et al.J Gastroenterol 2000;35:789-793) • Urticaria (http://www.ajj.com/services/pblshng/dnj/ceonline/06163169.htm) • Alopecia (http://content.health.msn.com/content/article/1680.51408) • Skin rash & Itching (http://content.health.msn.com/content/article/1680.51408) • Pigmented purpuric dermatosis (Gupta et al. J Am Acad Derm. 2000;43:937-8) CONCLUSION • Currently documented dermatoses. • Further studies needed. • Physician awareness to dermatological findings. • Potential cure at early stage.
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