Pathology of Extra Hepatic HCV Manifestations

8/8/2019 Pathology of Extra Hepatic HCV Manifestations

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Pathogenesis of EHMs of HCV

Ahmed Alwassief, MD


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HCV has emerged as a major worldwide publichealth problem. HCV infection affects

approximately 3% of the world population.Currently Hepatitis C infection is considered Asystemic disease with extrahepaticmanifestationsAccording to different studies, 40-74% of patientsinfected with HCV might develop at least oneEHM during the course of the disease.


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Classifications

HCV related EHDs

Prevalence and pathogenesis Clinical


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Evidence based classificationA: Association on the basis of high

prevalence and clear pathogenesisMC (complete or incomplete clinicalsyndrome)

B: Associations defined on the basis of higher prevalences than in controls

B-cell NHLMonoclonal gammopathiesPorphyria cutanea tardaLichen planus

C: Associations to be confirmed Autoimmune thyroiditisThyroid cancer

Sicca syndromeAlveolitis-lung fibrosisDiabetes mellitusNon-cryoglobulinaemic

nephropathiesAortic atherosclerosis

D: Anecdotal observations

PsoriasisPeripheral/central neuropathiesChronic polyarthritisRheumatoid arthritisPolyartheritis nodosaBechets syndrome

Poly/dermatomyositisFibromyalgiaChronic urticariaChronic pruritusKaposis pseudo-sarcomaVitiligo

CardiomyopathiesMooren corneal ulcer Erectile dysfunctionsNecrolytic acral erythema


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Pathogenesis

HCV is both hepato- and lympho-tropic . The infectionof the lymphoid tissue is a reservoir of the virus inthe host, that is important for the persistence of theinfection .

1. Dysregulation of anti-idiotype networks and expansion of autoantibody-producing B-cells.

2. Molecular mimicry between viral and self-antigens.3. Immune complex formation {fragments of IgG or

complement components }.4. Th1/Th2 response imbalance and autoantibody

production.5. Host genetic factors (e.g., HLA) .


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Consequences of immune system dysfunction

HCV infection induce nonspecific autoimmune reactions , asdemonstrated by the high prevalence of various non-organ-specific autoantibodies, usually in low titers. The clinicalsignificance of most of these autoantibodies is not clear.Cryoglobulins

Rheumatoid factor Antinuclear antibodies (ANA)Anticardiolipin (aCL)Antithyroid (ATA)

Anti-liver/Kidney/Microsomal antibodies (anti-LKM).HCV/anti-HCV immune complex formation and deposition


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MC

Mixed cryoglobulinemia (MC) is the most knownand studied syndrome associated with HCVInfection.Cryoglobulins are usually found at low

concentrations and only 10% of patients aresymptomatic.The prevalence of MC increases with the duration of the disease

MC and liver damage . Presence and level of cryoprecipitate is a negative prognostic factor inHCVAfter viral clearance Improvement of clinical MC is

reported in 50 to 70% of cases.


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Strong associations exist between HCV and mixed cryoglobulinemiatypes II and III.

some studies also suggest an association between type I and HCV, in particular the HCV 2a/c genotype.


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Sk in : Is commonly involved (95% of cases) withacutaneous vasculitis (leukocytoklastic vasculitis).

Kidney: is frequently involved (35-60%) (MPGN)Renal biopsy demonstrates immunocomplexesdeposits of IgG, IgM with rheumatoid factor (RF)activity and C3 in capillary loops.Clinically the

patient may present by haematuria and protienuriaIn 20% of patients the disease is characterized byrecurrent episodes of nephritic syndrome

Neuropathy: In 7 up to 90% of cases of MC there

is a peripheral . Neuropathy is mostly sensory.


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Treatment:IFN+ RibavirinSteroidRituximab: Monoclonal antibody againstCD 20, a B-cell specific surface antigen inMC with renal disease


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L ymphoproliferative disorders

A frequent reported association is that between HCV infection andnon-Hodgkin lymphoma (NHL) .The MC may be the intermediary disorder. Some persistent forms of cyoglobulinemia can switch over to a more aggressive hematologicaldisorder in up to 11% of cases.

Pathogenesis of L ymphoproliferative disorders is a 3 steps process1. Clonal B cell expansion of immunoglobulin (cryoglobulin)-secreting

lymphocytes.2. Combination of genetic and environmental factors result in a

mutational event .3. Activation of oncogenes and resulting in NHL.

Another possibility is the inhibition of apoptosis of HCVinfectedlymphocytes by t(18;14) traslocation. IFN treatment resulted in theloss of t(18;14) in 86% of HCV-infected patients with no lymphoma.


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Several investigators also demonstrated a stronglink between HCV infection and mucosa-

associated lymphoid tissue (MALT) lymphoma.

HCV RNA has been isolated in the gastric mucosaof patients with MALT lymphoma, raising the

possibility that HCV may play a role in its pathogenesis.


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D ermatological manifestations

Porphyria cutanea tardaThis is caused by the reduction of hepatic

uroporphyrinogen decarboxylase activity, resulting inan over production and build up of the proteinuroporphyrinogen in the blood and urine of patients

HCV seems to replicate in the epithelial (skin andmucosal) cells. Some studies suggest an association

between and lichen planus.


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E ndocrinal manifestations

ThyroidThyroid disease (usually hypothyroidism) is morecommonly seen in people with HCV than in the general

population . About 13% of HCV infected patients havehypothyroidism and up to 25% have thyroid Antibodies

Sub-clinic hypothyroidism was observed in 29% of

patients with chronic HCV infection and particularly inthose with MCSeveral studies reported a high prevalence of papillarythyroid cancer in patients with HCV infection.


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D iabetes mellitus

Diabetes mellitus (T2DM) is found morecommonly in patients with chronic HCVinfection than in the general population .

Pathogenesis may include1. Insulin resistance may lead to the development of

T2D in HCV+ patients.2. HCV infection was present in human pancreatic

beta-cells, which was associated withmorphological cell changes and reduced glucose-stimulated insulin release in vitro.


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Is it over yet?


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Take home note

EHMs are common but may be subclinicalComplete screening of HCV positive patients at

first examination should stress on finding EHMslike:Purpura, asthenia , arthralgias , arthritis,xerostomia, Raynaud, dermatiti s, cutaneous ulcers,neuromuscular abnormalities, oedema, and

proteinuria. U rin examination, Blood glucose test areimportant screening tests in HCV patients


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Pathology of Extra Hepatic HCV Manifestations

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