Cryoglobulinemia associated with Hepatitis C

I. What every physician needs to know.

Cryoglobulinemia is a systemic disease characterized by the presence of immunoglobulins in the serum that reversibly precipitate at low temperature (temperature below 37°C).

Cryoglobulins are immunochemically categorized into 3 types:

  • Type 1: Monoclonal immunoglobulins found in lymphoproliferative disorders

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  • Type 2: Polyclonal IgG with monoclonal rheumatoid factor (RF) activity

  • Type 3: Polyclonal IgG and polyclonal rheumatoid factor (RF) activity

Type 2&3 are often referred to as mixed cryoglobulins (MC).

Monoclonal cryoglobulinemia is usually associated with lymphoproliferative disorders. Mixed cryoglobulinemia has strong association with Hepatitis C (HCV) infection. Mixed cryoglobulinemia can be detected in 36%-55% of patients with chronic HCV. However, overt vasculitic manifestations are seen only in 2%-3% of these patients. HCV associated mixed cryoglobulinemia (MC) typically involves small and medium sized vessels of skin, kidneys and peripheral nerves.

Patients may have clinical features such as palpable purpura, arthralgia, peripheral neuropathy, leg ulcers, etc. Immunological findings include cryoglobulins, low C4 complement level, etc. This is thought to be immune complex mediated. HCV is a hepatotropic and lymphotropic virus. HCV is felt to be a chronic stimulus for the immune system through different viral proteins leading to lymphoproliferation and production of immunoglobulins and rheumatoid factor (RF).

II. Diagnostic Confirmation: Are you sure your patient has cryoglobulenemia?

Cutaneous manifestations

Palpable purpura is the most common skin manifestation (up to 90% of patients). Purpura is felt to be secondary to small subcutaneous hemorrhages and associated inflammation. Purpura is usually localized to lower extremities and orthostatic. Purpura is initially bright red colored which will gradually fade away. Reynaud’s phenomenon and acrocyanosis were also reported. Over a period of time, perimalleolar leg ulcers may occur secondary to chronic venous stasis.

Joint manifestations

Arthralgias are reported in 40%-80% of patients with HCV associated MC. They are usually bilateral, symmetric and non-deforming, involving knees and hands.

Peripheral neuropathy

Peripheral neuropathy is reported in 50%-86% of MC patients. It can be sensory resulting in painful paresthesias or sensori-motor with concomitant weakness. Isolated mononeuritis is also reported which is manifested by foot or wrist drop. Axonal damage due to deposition of cryoglobulins in vasovasorum is thought to initiate the vasculitis process.

Renal involvement

Renal involvement occurs in one third of HCV associated MC patients. Renal involvement is usually type 1 membranoproliferative glomerulonephritis (MPGN). The resultant glomerulonephritis can range from asymptomatic proteinuria and hematuria to overt nephrotic (20%-30%) or nephritic syndrome (20%). End-stage renal failure is rare (about 10% of the cases).

Other vasculitic manifestations: Abdominal pain and gastrointestinal bleeding due to mesenteric vasculitis were reported in 20% of MC patients. coronary vasculitis may happen complicated by myocardial infarction, pericarditis and congestive heart failure. Pulmonary involvement can cause diffuse interstitial pulmonary fibrosis.

A. History Part I: Pattern Recognition:

A typical patient with this disease presents with purpura, arthralgia and/or weakness. Cutaneous manifestations are common followed by joints, peripheral nerves and renal involvement as described above.

B. History Part 2: Prevalence:

MC has strong association with HCV infection. Mixed cryoglobulinemia can be detected in 36%-55% of patients with chronic HCV. However, overt vasculitic manifestations are seen only in 2%-3% of these patients.

C. History Part 3: Competing diagnoses that can mimic cryoglobulenemia.

Rheumatoid arthritis (RA)

MC associated arthritis can be differentiated from RA by absence of joint destruction and anti-cyclic citullinated peptide (aCCP) antibodies. aCCP is a highly specific test for RA and is absent in HCV associated MC.

Sjogren's syndrome

Anti SS-A and anti SS-B antibodies are specific to Sjogren’s syndrome and can be helpful in differentiation.

B-cell lymphoma

Cytogenetic studies can be helpful in differentiation.

D. Physical Examination Findings.

As described above.

E. What diagnostic tests should be performed?

Physical examination findings are described above.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?


Serum should be tested for presence of cryoglobulins. False negative rates are high as the testing for cryoglobulins requires strict temperature control. Over-heating of the specimen leads to protein denaturation while cooling of the specimen causes cryoprecipitation. Blood should be collected in pre-warmed collection tube and should be transported at 37°C. Swift processing of the sample is very important. Once the cryoglobulinemia is diagnosed, immunoglobulins and rheumatoid factor (RF) should be checked.

Complement levels

Low C4 levels

Pathology findings

Skin biopsy of vasculitic lesions show leukocytoclastic vasculitis involving medium and small-sized blood vessels.

III. Default Management.

Treatment depends on severity of disease. Features such as rapidly progressive nephritis, progressive motor neuropathy and extensive skin ulcers signify severe disease. Disease can be classified as mild to moderate severity if no such features were found.

Treatment of mild to moderate disease is mainly antiviral therapy for HCV. As HCV associated MC is thought to be immune mediated process, effective treatment for HCV associated MC is eradication of underlying HCV infection. Symptomatic MC is an indication for treatment of HCV infection. A number of anti-HCV treatment medications became available for clinical usage in the past few years with much improved cure rates. The guidelines for treatment of various genotypes of HCV are evolving to include new medications such as Sofosbuvir, Simeprevir and Ledipasvir. Hepatology consultation is warranted to evaluate the most current treatment options

Alternative symptomatic strategies may be considered in patients who have severe renal disease or who failed to reach sustained virological response (SVR) on HCV treatment.


High dose oral corticosteroids (prednisone 0.5-1.5mg/kg/day) or intravenous pulses (methylprednisone 1gm/day) for 3 days followed by oral prednisone 1mg/kg/day for 2-4 weeks with subsequent gradual tapering. This regimen is effective for acute nephritis, motor neuropathy and other vasculitic complications.

Cytotoxic agents

Cyclophosphamide and mycophenolate moefetil are also used to induce remission.


Plasmapheresis can be used as adjuvant therapy to treat active cryoglobulinemic glomerulonephritis. Plasmapheresis induces remission by removing circulating cryoglobulins.


Rituximab is a monoclonal antibody directed against CD20 antigen on B cells. It reduces the production of cryoglobulins by reducing the number of plasma cells. Combination therapy with rituximab and anti-HCV regimen is also used.

A. Immediate management.

If features signifying the presence of severe disease are present, corticosteroid therapy should be started.

IV. Management with Co-Morbidities

F. Malignancy

Incidence of non-Hodgkin’s Lymphoma (NHL) in patients with symptomatic MC is 35 times higher than in the general population.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

As mesenteric vasculitis and coronary vasculitis are possible complications, patient complaints such as chest pain and abdominal pain need to be investigated further.

B. Anticipated Length of Stay.

The length of stay for this disorder is most often determined by the underlying presentation and can vary widely.

C. When is the Patient Ready for Discharge.

In case of renal failure, as the creatinine continues to improve for 3 consecutive days.

D. Arranging for Clinic Follow-up

  • Follow-up with hepatology clinic is essential to initiate the anti-HCV therapy

  • If vasculitis causes renal failure – needs nephrology follow-up

  • For motor symptoms – neurology follow-up

1. When should clinic follow up be arranged and with whom.

As above.

F. Prognosis and Patient Counseling.

Overall 5-year survival after diagnosis of vasculitis ranges from 50% in case of renal involvement to 90% in patients without renal involvement. Worse prognostic indicators are age older than 60 years at the time of diagnosis and renal involvement.