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Extrahepatic manifestations of Hepatitis C

Extrahepatic manifestations of Hepatitis C. Curtis Barry, MD UMASS ECHO April 28, 2017. Disclosure. I have no financial disclosures related to this subject. Background. HCV primarily affects the liver but other organ systems can become involved

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Extrahepatic manifestations of Hepatitis C

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  1. Extrahepatic manifestations of Hepatitis C Curtis Barry, MD UMASS ECHO April 28, 2017

  2. Disclosure • I have no financial disclosures related to this subject

  3. Background • HCV primarily affects the liver but other organ systems can become involved • % patients infected who have extrahepatic manifestations (EHM) is unclear and estimations vary

  4. CryoglobulinemiaDefinition • presence of one or more immunoglobulins in the serum, which reversibly precipitate in vitro at temperatures below normal body temp. These immunoglobulins dissolve again when reheating the serum

  5. CryoglobulinemiaMechanism of Disease • Immune complexes that contain HCV particles deposit in the walls of capillaries, venules, or arterioles causing small vessel inflammation. • Mixed cryoglobulinemia vasculitis • Renal disease • Palpable purpura • Neuropathy • Sicca syndrome/Sjogren’s

  6. Mixed Cryoglobulinemia • Cryoglobulins are immunoglobulin complex that precipitate in the cold and dissolve on rewarming • Rheumatoid Factor: Ig capable of binding to IgG (IgM kappa in HCV MC) • Type II or mixed cryoglobulinemia: Cryoglobulin that contains both a polyclonal IgG and a monoclonal IgM rheumatoid factor directed against the IgG. • Since the identification of HCV in 1989, it has been recognized as the cause of >90% of MC

  7. Testing for Cryoglobulins • Serum preparation must be performed at 37degrees C to prevent premature immune complex precipitation • Serum is stored at 4 degrees C for 7 days, inspected daily for a precipitate, and spun for calculation of cryocrit • A cryocrit >2% is positive (Cryocrit is % of cryoglobulin in serum) • The cryocrit is then typed using immunofixation

  8. MC Clinical Manifestations • Initially described in 1966 as a clinical triad of palpable purpura, arthralgia, and weakness accompanied by organ involvement (e.g., nephropathy and neuropathy) and elevated serum RF • Now known that this triad is rare, as many MC patients are asymptomatic • Primarily affects the small- and medium sized vessels of the skin, kidneys, and peripheral nerves

  9. Skin Involvement • Palpable purpura, primarily of the lower legs, occurs in more than 90% of patients with symptomatic HCV MC • Frequently intermittent • Often initial manifestation of HCV MC • Purpuric lesions may occasionally progress to chronic ulcers and frank gangrene

  10. Cryoglobulinemiadiagnosis • Combination of history, skin purpura, low complement levels, circulating cryoglobulins and histology that shows small vessel inflammation with immune deposits found in the vascular walls

  11. CryoglobulinemiaTreatment • The most effective treatment for HCV MC is eradication of the underlying HCV infection • HCV RNA relapse is associated with recurrence of MC and clinical symptoms • for those who have failed to reach sustained virological response after antiviral therapy, symptomatic treatment of vasculitis with plasmapheresis or rituximab have been used

  12. Renal disorders • 3 potential mechanisms 1. Direct viral tissue damage 2. Systemic immune response 3. Insulin resistance

  13. Clinical syndromes • Membranoproliferative glomerulonephritis • Generally occurs in the setting of cryoglobulinemia • Develop HTN which can be severe and difficult to control • Rarely develop oliguric acute renal failure • Lab findings: proteinuria, microscopic hematuria, low serum concentrations of complement components • Cr may or may not improve after treatment

  14. Diagnosis • Renal biopsy • Pattern of membranoproliferative glomerulonephritis with immune complex deposition in glomeruli inflammatory cells

  15. Outcomes • Overall outcomes with HCV-related nephritis tends to be poor due to high incidence of CV disease. • One study showed HCV infected patients had 40% higher likelihood for developing CKI (Cr >1.5)

  16. Dermatology • Leukocytoclastic vasculitis • Porphyria CutaneaTarda • Lichen Planus

  17. Leukocytoclastic vasculitis • Pathological term that describes the microscopic findings of neutrophilic small vessel vasculitis • petechia, palpable purpura, nodules, ulcers • Lower extremities and biopsy needed • May occur with cryoblobulinemia • May involve lower extremity peripheral nerves (typically asymmetric)

  18. Porphyria CutaneaTarda • Disproportionately occurs in those with cirrhosis • Skin fragility, bruising, vesicles, bullae (which may become hemorrhagic in sun exposed areas) • Marked elevated urine uroporphyrin levels • PCT often, but not always improves with clearance of HCV

  19. Lichen Planus • 2-6x more likely to have HCV • Results from immunologically mediated reaction to an unknown stimulus • Flat-topped, violaceous, pruritic papules with a generalized distribution, particularly on the extremities. • Can involve mucous membranes, hair and nails • Most resolve spontaneously within 1 year • Topical corticosteroids

  20. Insulin Resistance • Independent risk factor for insulin resistance/DM • ? HCV direct viral effect on inflammatory cytokines • ? Alters insulin signaling cascade • SVR may decrease the risk of DM

  21. Lymphomas • Associated with B-cell non-hodgkins lymphoma • 2x increase risk of non-hodgkins lymphoma • risk may be reduced but maybe not eliminated after eradication of HCV • HCV may directly infect B cells and lead to their malignant transformation • Survival worse for HCV pts possible due to hepatotoxicity of chemotherapy for lymphoma

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