Presentation by Dr. Mishal Saleem on the topic of Extra hepatic manifestation of hep C, which is a grey area nut very important topic for FCPS Residents.

2. EXTRAHEPATIC
MANIFESTATION OF
HEPATITIS C
Dr. MISHAL SALEEM
RESIDENT PHYSICIAN
POF HOSPITAL, WAH CANTT

3.  PATIENT'S PROFILE:
• Name: Abdullah
• Age: 47 Years
• Gender: Male
• Civil status: Married
• Date of admission: 10- 02- 2020
• Weight: 60kg
• Height: 5.5f
CASE STUDY:

4.  PRESENTING COMPLAINTS:
• Severe joints pain for 10 days
• Rashes on both legs 10 days
• Abdomianl pain and distension for 3 days
• Severe Headache for 2 days
 HISTORY OF PRESENTING ILLNESS:
• Hypertensive for 12 years
• Diabetic for 10 years
• Diagnosed case of Hepatitis C for 10 years
• Documented weight loss and generalized weakness for 1 year.
• Mild headache and restlessness for 6 months.
• There weren't any addditional symptoms.
 PAST MEDICAL AND SURGICAL HISORY: Nil
 PERSOANL HISTORY: Smoker. No history of IV drug abuse or
blood transfusion. Currently on antihypertensive and oral
hypoglycemics

5.  On Examinaion:
• Depressed gentleman, lying restlessly on bed.
• Pale.
• Grade II Clubbing on nails.
• lymph nodes: palpable cervical
• CNS: 15/15 GCS, power is 4/5 in all limbs, with decreased
sensation on lower limb upto knee joint.
• Respiratory: normal vesicular breathing, bilaterally clear.
• Abdomen: Distended, Fluid thrill +ve, Shifting dullness +ve
• CVS: S1+S2
• Swelling on Ankle joints.
• Rashes on both legs.
• Pedal edema in both legs
• Pain at ankle joints on movement

6. VITALS:
• BP: 169/95 mmHg
• HEART RATE: 90/min
• SPO2: 96% @ RA
• TEMP: A/F
INVESTIGATIONS:
• Hb: 9.0g/dl
• TLC: 11 X 10^3/mL
• Plt: 110 X 10^3/mL
• PT/INR: 14/1.9
• Hep C Elisa -- positive
• PCR for hep C -- Reactive
• RF: Positive
• Cryoglobulin: positive
• ANC-A: positive
• Anti CCP: negative
• Anti Ro/SSA and L/SSB: negative
• Urine R/E: proteinuria
• Usg abdomen + KUB: coarse liver + hyperechoic renal cortex
• ECG : strain pattern

8. A wide series of manifestations involving
other organ systems
Kidneys
Endocrine
system
Blood
vessels
Eyes
Lymphatic
system
health-related
quality of life
(HRQOL)
skin, joints
&
peripheral
nerves
CNS

9. Extrahepatic manifestations include:
mixed cryoglobulinemia (MC)
vasculitis
lymphoproliferative disorders
autoantibody production
fatigue
rheumatoid arthritis–like
polyarthritis
renal disease
sicca syndrome
type 2 diabetes
insulin resistance
depression & cognitive
impairment

10. 1) Mixed Cryoglobulinemia Vasculitis
• MC vasculitis is the best-known manifestation of HCV
infection
• Virus-triggered immune-mediated mechanism.
• Deposition of circulating immunoglobulin G and
immunoglobulin M immune complexes containing HCV
particles in the vasculature.
• Infection or, more likely, chronic stimulation of lymphocytes
is thought to induce the B-cell clonal expansion underlying
the production of antibodies, including rheumatoid factor,
that are incorporated into cryoglobulins.
• Tissue damage in MC vasculitis is probably T-cell induced.

13. Manifestations of MC associated with
HCV infection include
• Vasculitis (prevalence, 4%–40%),
• Palpable Purpura (18%–33%)
• Fatigue (35%–54%)
• Arthralgia-myalgia (35%–54%)
• Sicca syndrome (10%–25%)
• Neuropathy (11%–30%)
• Renalcomplications such as membranoproliferative
glomerulonephritis(27%)
Given the similarity of some of these symptoms with
other disorders, including RA and primary Sjögren’s syndrome,
careful evaluation is required to ensure correct diagnosis of MC
vasculitis by presence of mixed cryoglobulins in
serum.

14. TREATMENT:
• Mild–moderate: HCV clearance via peginterferon/Ribavirin.
• Severe: potent immunosuppressive regimens,
plasmapheresis before initiation of antiviraltherapy.
• Novel: rituximab + peginterferon/RBV
Note: rituximab is reported to reduce signs of vasculitis, with a
clinical response noted in
 32 of 40 patients (80%) for skin involvement,
 27 of 34 (79.4%) for arthralgia,
 27 of 29 (93.1%) for neuropathy,
 15 of 18 (83.3%) for glomerulonephritis

22. 2) Renal Manifestations
• Potentially life-threatening renal complications such as
membranoproliferative glomerulonephritis have been
reported in patients with HCV infection who have
also developed MC.
• However, HCV is also associated with glomerulonephritis in
the absence of MC.
• There is some evidence that renal insufficiency might be
higher in HCV-infected patients than in the general
population
• the Kidney Disease Improving Global Outcomes (KDIGO)
group recommends that all patients with chronic kidney
disease should be tested for HCV

25. Renal complications
CLINICAL MANIFESTATIONS:
Glomerulonephritis, proteinuria, microscopic hematuria, hypertension
TREATMENT:
• Moderate proteinuria/slow progressive kidney
failure:
rituximab and then HCV clearance via peginterferon/RBV
treatment.
• With renal insufficiency: rituximab and then lower dose
peginterferon plus RBV (RBV not recommended if glomerular
filtration rate 50 mL/min per 1.73 m2 unless closely monitored).
• Nephrotic range proteinuria and/or rapidly progressive
kidney function: rituximab, plasmapheresis,immunosuppression
(corticosteroids/cytotoxicagent)

26. 3)Lymphomas
• There is a high prevalence of HCV seropositivity (15%) in patients
with B-cell lymphoproliferative disorders, particularly B-cell NHL
• The biological mechanism linking HCV infection with the
development of lymphoma remains under debate. However, it is likely that
the mechanisms involved in MC and NHL pathogenesis share similar
features.
• Consistent with this, the lymphomas in HCV patients frequently express
the same rheumatoid factor–encoding immunoglobulin genes as do the
cells involved in cryoglobulinemia, strongly suggesting an antigen-
dependent component common to both conditions.

28. Lymphoproliferative disorders
CLINICAL MANIFESTATIN:
Nodal or extranodal lymphoproliferative pathology, bone marrow
substitution 30%, peripheral-blood cytopenia.
TREATMENT:
• Antiviral therapy, monotherapy against biological targets
(rituximab) downstream of viral infection, or a combination.
• HCV clearance via peginterferon/RBV might be effective for
some HCV-related lowgrade lymphomas.
• If chemotherapy is given, monitor for hepatotoxicity

33. CLINICAL MANIFESTATION:
Oral or ocular dryness, histologic evidence of Sjögren-like sialadenitis;
more rarely: Sjögren syndrome. Patients might exhibit xerostomia, an
absence of classic systemic symptoms of primary Sjögren syndrome, and
anti–Sjögren syndrome A/anti–Sjögren syndrome B antibody negativity.
TREATMENT:
No improvement of sicca syndrome associated with
HCV treatment. Topical agents to increase
moisture and decrease inflammation might reduce
symptoms
4) Sicca syndrome

34. CLINICAL MANIFESTATION:
Joint symptoms: small joints affected, resembling mild RA;
rheumatoid factor identified in 50%–80% of cases;
arthralgia; synovitis (rare); no erosive joint changes
ANTI CCP-- NEGATIVE
TREATMENT:
• Peginterferon/RBV might induce complete or partial
response.
• NSAIDs, hydroxychloroquine, and lowdose corticosteroid
(although HCV arthritis does not often respond to anti-
inflammatory therapy).
• Severe: immunosuppression (eg, methotrexate) might be
used with caution to avoid liver-related adverse events
5) RA-like polyarthritis

35. CLINICAL MANIFESTATION:
Insulin resistance, metabolic syndrome,
type 2 diabetes
TRATMENT:
• HCV clearance by using peginterferon/RBV can
improve insulin resistance and reduce risk of
glucose abnormalities.
• Efficacy of antiviral therapy might be diminished in insulin-
resistant, HCVinfected patients.
6) Glucose disorders

37. Production of mixed cryoglobulins;
antibodies: antinuclear; anti–smooth
muscle cell; antithyroglobulin;
anticardiolipin.
7) Autoantibody production:

38. 8) FATIGUE:
Fatigue is associated with:
• Female gender
• Age > 50 years
• Arthralgia
• Myalgia
• Sicca

39. Clinical Manifestation:
Depressive symptoms
TREATMENT:
Antidepressant or anxiolytic treatment might be
considered before initiating HCV therapy
9) Depression:

40. 10) HCV NEUROPATHY

44. THANK YOU!
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