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Hepatitis C Virus and Skin

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					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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