Pathogenesis of EHMs of HCV

Ahmed Alwassief, MD
• HCV has emerged as a major worldwide public
health problem. HCV infection affects
approximately 3% of the world population.
• Currently Hepatitis C infection is considered A
systemic disease with extrahepatic
manifestations
• According to different studies, 40-74% of patients
infected with HCV might develop at least one
EHM during the course of the disease.
 Classifications

HCV related EHDs

Prevalence and
Clinical
pathogenesis
 Evidence based classification
A: Association on the basis of high D: Anecdotal observations
prevalence and clear pathogenesis • Psoriasis
MC (complete or incomplete clinical • Peripheral/central neuropathies
syndrome) • Chronic polyarthritis
B: Associations defined on the basis of • Rheumatoid arthritis
higher prevalences than in controls
• Polyartheritis nodosa
 B-cell NHL
• Bechet’s syndrome
 Monoclonal gammopathies
• Poly/dermatomyositis
 Porphyria cutanea tarda
• Fibromyalgia
 Lichen planus
• Chronic urticaria
C: Associations to be confirmed
• Chronic pruritus
• Autoimmune thyroiditis
• Kaposi’s pseudo-sarcoma
• Thyroid cancer
• Vitiligo
• Sicca syndrome
• Cardiomyopathies
• Alveolitis-lung fibrosis
• Mooren corneal ulcer
• Diabetes mellitus
• Erectile dysfunctions
• Non-cryoglobulinaemic
• Necrolytic acral erythema
nephropathies
• Aortic atherosclerosis
 Pathogenesis
• HCV is both hepato- and lympho-tropic. The infection
of the lymphoid tissue is a “reservoir” of the virus in
the host, that is important for the persistence of the
infection .

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) .
Consequences of immune system dysfunction
• HCV infection induce nonspecific autoimmune reactions, as
demonstrated by the high prevalence of various non-organ-
specific autoantibodies, usually in low titers. The clinical
significance 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
 MC
• Mixed cryoglobulinemia (MC) is the most known
and studied syndrome associated with HCV
Infection.
• Cryoglobulins are usually found at low
concentrations and only 10% of patients are
symptomatic.
• 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 in
HCV
• After viral clearance Improvement of clinical MC is
reported in 50 to 70% of cases.
Strong associations exist between HCV and mixed cryoglobulinemia
types II and III.
some studies also suggest an association between type I and HCV, in
particular the HCV 2a/c genotype.
• Skin : Is commonly involved (95% of cases) with
acutaneous vasculitis (leukocytoklastic vasculitis).

• Kidney: is frequently involved (35-60%) (MPGN)

Renal biopsy demonstrates immunocomplexes
deposits of IgG, IgM with rheumatoid factor (RF)
activity and C3 in capillary loops.Clinically the
patient may present by haematuria and protienuria
In 20% of patients the disease is characterized by
recurrent episodes of nephritic syndrome
• Neuropathy: In 7 up to 90% of cases of MC there
is a peripheral . Neuropathy is mostly sensory.
 Mangment of MC
 Diagnosis:
o Clinical “ skin, renal, neuropathy”
o Laboratory diagnosis
 C4 reduction
 Concentrations of cryoglobulins “fluctations”
 RF
– Asymptomatic patients and those with mild symptoms
(artralgias and/or asthenia), may show one or more
altered laboratory data.
– Monitoring serum CGs at regular time points (1–2
times/year in patients with mild manifestation of the
disease; every 1–2 months in case of severe symptoms,
e.g. nephropathy)
• Treatment:
• IFN+ Ribavirin
• Steroid
• Rituximab: Monoclonal antibody against
CD 20, a B-cell specific surface antigen in
MC with renal disease
 Lymphoproliferative disorders
 A frequent reported association is that between HCV infection and
non-Hodgkin lymphoma (NHL) .
 The MC may be the intermediary disorder. Some persistent forms of
cyoglobulinemia can switch over to a more aggressive hematological
disorder in up to 11% of cases.

Pathogenesis of Lymphoproliferative disorders is a 3 steps process

1. 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 HCVinfected

lymphocytes by t(18;14) traslocation. IFN treatment resulted in the
loss of t(18;14) in 86% of HCV-infected patients with no lymphoma.
• Several investigators also demonstrated a strong
link between HCV infection and mucosa-
associated lymphoid tissue (MALT) lymphoma.

• HCV RNA has been isolated in the gastric mucosa

of patients with MALT lymphoma, raising the
possibility that HCV may play a role in its
pathogenesis.
 Dermatological manifestations

• Porphyria cutanea tarda

• This is caused by the reduction of hepatic
uroporphyrinogen decarboxylase activity, resulting in
an over production and build up of the protein
uroporphyrinogen in the blood and urine of patients

• HCV seems to replicate in the epithelial (skin and

mucosal) cells. Some studies suggest an association
between and lichen planus.
 Endocrinal manifestations

• Thyroid
• Thyroid disease (usually hypothyroidism) is more
commonly seen in people with HCV than in the general
population . About 13% of HCV infected patients have
hypothyroidism and up to 25% have thyroid Antibodies

• Sub-clinic hypothyroidism was observed in 2–9% of

patients with chronic HCV infection and particularly in
those with MC
• Several studies reported a high prevalence of papillary
thyroid cancer in patients with HCV infection.
 Diabetes mellitus
• Diabetes mellitus (T2DM) is found more
commonly in patients with chronic HCV
infection than in the general population .
• Pathogenesis may include
1. 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 with
morphological cell changes and reduced glucose-
stimulated insulin release in vitro.
Is it over
yet?
 Take home note

• EHMs are common but may be subclinical

• Complete screening of HCV positive patients at
first examination should stress on finding EHMs
like:
• Purpura, asthenia, arthralgias, arthritis,
xerostomia, Raynaud, dermatitis, cutaneous ulcers,
neuromuscular abnormalities, oedema, and
proteinuria.
• Urin examination, Blood glucose test are
important screening tests in HCV patients