Cryoglobulinemia

AUTHOR: Rebecca Soinski, MD

Definition

Cryoglobulins are serum immunoglobulins that precipitate when cooled and redissolve when heated. A classification of cryoglobulins is described in Table E1 and Fig. E1. Cryoglobulinemia is a clinical syndrome that re-sults from systemic inflammation caused by cryoglobulin-containing immune complexes. Mixed cryoglobulinemia is a vasculitis of small and medium-sized arteries and veins due to the deposition of complexes of antigen, cryoglobulin, and complement in the vessel walls.¹

Figure E1 Cryoglobulin immunotyping and related underlying diseases. Ig, Immunoglobulin.

From Cacoub P et al: Cryoglobulinemia vasculitis, Am J Med 128[9]:950-955, 2015.

TABLE E1 Classification of Cryoglobulins

Type	Composition	Associated Disease
I	Monoclonal IgG, IgA, or IgM	Multiple myeloma (IgG, IgM)Chronic lymphocytic leukemiaWaldenström macroglobulinemiaIdiopathic monoclonal gammopathyLymphoproliferative disorders
II	Polyclonal IgG and monoclonal IgM (with rheumatoid factor activity)	Hepatitis C, hepatitis B, HIV neoplasms: Chronic lymphocytic leukemia, diffuse lymphoma, B lymphocytic neoplasia
III	Polyclonal IgG and polyclonal IgM	Infections: Viral (hepatitis B and C, Epstein-Barr virus, cytomegalovirus), bacterial (endocarditis, leprosy, poststreptococcal glomerulonephritis), parasitic (schistosomiasis, toxoplasmosis, malaria)Autoimmune disorders: Systemic lupus erythematosus, rheumatoid arthritisLymphoproliferative disordersChronic liver disease

HIV, Human immunodeficiency virus; Ig, immunoglobulin.

From Floege J et al: Comprehensive clinical nephrology, ed 4, Philadelphia, 2010, Saunders.

Synonyms

Cryoglobulinemic vasculitis

Cryoproteinemia

Mixed cryoglobulinemia

Essential cryoglobulinemia

ICD-10CM CODE
D89.1		Cryoglobulinemia

Epidemiology & Demographics

Prevalence

Prevalence of mixed cryoglobulinemia is approximately 1:100,000. With the success of direct acting antivirals for treatment of HCV, incidence of mixed cryoglobulinemia has steadily decreased.¹
In the 1990s, 90% of cryoglobulinemic patients were found to have HCV; approximately 25% to 30% of patients with HCV were found to have mixed cryoglobulinemia ¹ with only 5% to 10% developing vasculitis.²
Three types: I (monoclonal), II (IgM monoclonal and IgG polyclonal), and III (polyclonal).³

Predominant Sex

Female-to-male ratio of 3:1.

Predominant Age

Mean age reported is 42 to 52 yr.

Risk Factors ⁴

Hepatitis C virus (HCV) infection
Connective tissue disorders
Lymphoproliferative disorders

Physical Findings & Clinical Presentation

Meltzer triad of purpura, arthralgias/myalgia, and weakness is seen in one third of patients.⁴
Other symptoms include fatigue, peripheral neuropathy, Raynaud’s phenomenon, renal involvement, sicca syndrome, confluent purpura (Fig. E2), and skin ulcers.²
Hypertension, hepatosplenomegaly, and in severe cases, distal necrosis and ulcerations of lower limbs (Fig. E3).

Figure E2 Confluent Purpura in Mixed Cryoglobulinemia

Extensive Purpuric Lesions are Often So Numerous that They Form Confluent Areas of Cutaneous Involvement.

From Firestein GS et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia, 2021, Elsevier.

Figure E3 Cryoglobulinemia.

From Hoffman R et al: Hematology, basic principles and practice, ed 6, New York, 2013, Elsevier.

Etiology

Intravascular deposition of cryoglobulins leading to ischemic insults in territory supplied by vasa nervorum
Necrotizing vasculitis caused by cryoglobulin precipitation in cooler areas (distal extremities) and kidneys (increased concentration due to ultrafiltration)³
Infections: HCV, mycosis fungoides, HBV, HIV, Epstein-Barr virus, cytomegalovirus, Treponema pallidum, Mycobacterium leprae, and in post-streptococcal glomeru-lonephritis
Lymphoproliferative disorders: Chronic lymphocytic leukemia, Waldenström macroglobulinemia, multiple myeloma ⁴
Connective tissue disorders: Rheumatoid arthritis, systemic lupus erythematosus (SLE), scleroderma, Sjögren syndrome, vasculitis ⁴
Renal diseases including proliferative glomerulonephritis ⁴

Differential Diagnosis

Antiphospholipid syndrome
SLE
Churg-Strauss syndrome
Cirrhosis
Glomerulonephritis
Goodpasture syndrome
Hemolytic uremic syndrome
Hepatitis
Lymphoma
Sarcoidosis
Waldenström hypergammaglobulinemia

Workup

History and physical examination; laboratory tests; imaging tests depending on patient’s presentation.

Laboratory Tests

Serum cryoglobulins, rheumatoid factor, serum complement, hepatitis C titer, urinalysis, CBC, ALT, AST, BUN, creatinine
Electromyogram/nerve conduction studies may demonstrate axonal changes and distal muscle denervation
Sural nerve and skin biopsy

Imaging Studies

Chest x-ray for pulmonary involvement, CT scan to evaluate for malignancy, and angiography for vasculitis.

Management of type I cryoglobulinemia is directed at treating the underlying disorder.³
For noninfectious mixed cryoglobulinemia, treatment is based on disease severity. Low-dose corticosteroids, NSAIDs, and colchicine should be given for mild symptoms. Rituximab, high-dose corticosteroids, cyclophosphamide, and/or plasmapheresis should be given for severe disease.⁴
In patients with HCV, mild symptoms can be managed by treatment with direct-acting antivirals (DAA). Therapy is aimed at eradicating the HCV infection, suppressing B-cell clonal expansion and cryoglobulin production, and ameliorating symptoms.¹
For severe disease in HCV-infected patients, initial immunosuppression with rituximab is warranted, followed by initiation of antiviral therapy.⁴
Fig. E4 illustrates the treatment of HCV-related mixed cryoglobulinemia vasculitis according to presentation.
Sustained virologic response due to DAA does not always fully eradicate cryoglobulinemia but can help mitigate its manifestations.¹

Figure E4 Treatment of HCV-Related Mixed Cryoglobulinemia Vasculitis According to the Presentation

CNS, Central Nervous System; Gn, Glomerulonephritis; HCV, Hepatitis C Virus.

From Cacoub P et al: Cryoglobulinemia vasculitis, Am J Med 128[9]:950-955, 2015.

Nonpharmacologic Therapy

Avoidance of cold exposure, diabetic food care guidelines

Acute General Rx

NSAIDs in those with general fatigue and arthralgia; see “Treatment” for further management.

Disposition

Overall prognosis is worse with concomitant renal disease. Mean survival rate is ∼50% at 10 yr.

Referral

Consider referring to a:

Nephrologist if there is renal involvement
Hematologist in patients with lymphoproliferative disorders
Gastroenterologist/hepatologist in patients with hepatitis
Rheumatologist in patients with connective tissue disease cases
Clinical immunologist in severe cases

Comments

Always look for underlying cause of cryoglobulinemia.

Prevention

Avoidance of cold exposure, avoidance of late complications.

Patient & Family Education

Inform patients about early signs/symptoms of cryoglobulinemia so that treatment can be rendered before the development of complications.

Dammacco F. : The wide spectrum of cryoglobulinemic vasculitis and an overview of therapeutic advancementsClin Exp Med. ;28:1-18, 2022.
Desbois A.C. : Cryoglobulinemia vasculitis: how to handleCurr Opin Rheumatol. ;29(4):343-347, 2017.
Muchtar E. : How I treat cryoglobulinemiaBlood. ;129(3):289-298, 2017.
Cacoub P. : Cryoglobulinemia vasculitisAm J Med. ;128:950-955, 2015.

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Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

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