From the Dermatologikum Hamburg: Quiz

Oct – Dec 2010 | Vol. 16, No. 4
Böer, Almut

The Patient

A 45-year-old man presented himself with acute onset of a figurate and purpuric exanthema (Figs. 1A-C), arthralgia, and peripheral edema. He had a history of intravenous drug abuse.

Figs. 1A-C

Figurate purpuric erythema on the legs.

A biopsy was taken and photomicrographs of it are shown in Figures 2A-N.

Figs. 2A-N


What is your diagnosis?

Answer and Explanation

HCV-associated mixed cryoglobulinemia

Cryoglobulins are defined as circulating immunoglobulins that precipitate when serum is cooled below core body temperature and that resolubilize when rewarmed. This is an in vitro phenomenon and the actual mechanism of cryoprecipitation in vivo remains obscure. [1]

Cryoglobulins have been categorized by Brouet et al. into three types. [2] Type I cryoglobulins are composed of a single monoclonal immunoglobulin, usually IgM. They are most commonly encountered in patients with multiple myeloma or Waldenström macroglobulinemia. Type II cryoglobulins have a polyclonal IgG component and a monoclonal component, usually IgM, which acts as rheumatoid factor. Types III cryoglobulins are composed of polyclonal IgM and IgG molecules. Types II and III are often referred to as mixed cryoglobulins. [3]

Mixed cryoglobulinemia (MC) was first described in 1966 by Meltzer as distinct disorder typified by the clinical triad of palpable purpura, arthralgia, and asthenia accompanied by organ involvement, such as nephropathy and neuropathy, and elevated serum rheumatoid factor. [4] This triad, however, is rare and many MC patients are clinically asymptomatic. [5]

Circulating mixed cryoglobulins are frequently detected in HCV-infected patients (40-60%). The patient presented here was identified to be HCV positive. Persistence of HCV infection leads to chronic overstimulation of B-lymphocytes and production of mixed cryoglobulins. [3] HCV infection is primarily associated with type II mixed cryoglobulins and to a lesser extent, with type III mixed cryoglobulins.

Clinical signs develop in only 5-10% of patients with HCV-associated cryoglobulines. The most frequent target organs are skin, joints, nerves, and kidney. The disease expression is variable, ranging from mild purpura, and/or arthralgia to life-threatening complications such as glomerulonephritis. [3] Besides the purpuric exanthem, the patient presented here had also arthralgia and glomerulonephritis with acute renal failure.

Palpable purpura in patiens with MC always begins at the lower limbs but it may also involve the trunk and upper limbs. Lesions are petechia or purpuric papules, sometimes becoming necrotic. Malleolar ulcers, Raynaud’s syndrome, and digital ulcerations also have been described. [3] Palpable purpura is frequently intermittent and it is often the initial manifestation of HCV associated MC. On histopathology, perivascular infiltrates of neutrophils, nuclear dust of neutrophils, and extravasated erythrocytes are seen. In contrast to lesions in type 1 cryoglobulinemia, endovascular thrombi in vessels of the superficial and deep plexus are an inconsistent finding in MC and histopathologic features have been described as very similar to those of leukocytoclastic vasculitis. [1] In the example shown here, however, intravascular deposits of cryoglobulins were a prominent finding while accompanying infiltrates were rather sparse.

Renal manifestations are reported in 20-35% of the MC patients. The most frequent clinical and histopathological picture is that of acute or chronic type-I membranoproliferative glomerulonephritis (MPGN). It represents >70-80% of cryoglobulinaemic renal diseases and it is strongly associated with the type II cryoglobulinaemia. MPGN is characterized histopathologically by endocapillary mesangial cell proliferation, monocytic infiltration, double contour membranes, eosinophilic PAS-positive intraluminal deposits, and vasculitis of the small and medium-sized renal arteries. [5]

Arthralgia is reported in 40-80% of HCV-infected patients with MC. They are bilateral and symmetric, non-deforming mainly involving knees and hands, rarely elbows and ankles.

The prevalence of peripheral nervous system involvement varies in the literature and ranges from pure sensory axonopathy to mononeuritis multiplex. The most frequently described form is a distal sensory or sensory-motor polyneuropathy. Sensorimotor neuropathy arises from cryoglobulin deposition in the vasa vasorum. [5]

Cardiac involvement including mitral valvular damage, coronary vasculitis complicated by myocardial infarction, pericarditis, or congestive cardiac failure have been described. [1] In the patient shown here, mitral valvular damage was present and bacterial endocarditis requiring surgical intervention developed as a complication.

The course and prognosis of MC are variable and depend mostly on renal involvement. The overall 5-year survival ranges from 90% to 50%. In the historic series by Meltzer et al. renal involvement was the main cause of death. [4]

The first-line treatment of MC in the setting of HCV infection usually focuses on eradication of HCV by combined interferon and ribavirin treatment. Positive response to treatment with rituximab has also been observed.

MC may be associated with other infectious agents, such as HIV infection or HBV infection, and autoimmune disorders such as systemic lupus erythematosus, Sjögren syndrome, and systemic sclerosis. A shared feature of all these disorders is chronic inflammation in the setting of high antigenic load, suggesting that antigen-driven B cell dysregulation is a prerequisite for the development of MC.


A patient with hepatitis C-associated cryoglobulinemia is presented as a quiz. Clinical findings of a figurate purpuric exanthema were typified histopathologically by deposits of bright eosinophilic material in the lumina of vessels of the superficial and deep plexus in the dermis. A sparse infiltrate of neutrophils, nuclear dust of neutrophils, and lymphocytes was accompanying together with extensive extravasation of erythrocytes. Pathophysiology of cryoglobulinemia is discussed.

Almut Böer-Auer, M.D., is a dermatopathologist at the Dermatologikum Hamburg, Germany. Contact author via email: .


1. Ferri C. Mixed cryoglobulinemia. Orphanet J Rare Dis. 2008;3:25.

2. Brouet JC, Clouvel JP, Danon F, Klein M, Seligmann M: Biologic and clinical significance of cryoglobulins. Am J Med. 1974, 57:775-88.

3. Saadoun D, Landau DA, Calabrese LH, Cacoub PP. Hepatitis C-associated mixed cryoglobulinaemia: a crossroad between autoimmunity and lymphoproliferation. Rheumatology (Oxford). 2007;46(8):1234-42.

4. Meltzer M, Franklin EC, Elias K, McCluskey RT, Cooper N. Cryoglobulinemia. A clinical and laboratory study. II. Cryoglobulins with rheumatoid factor activity. Am J Med. 1966;40:837-56.

5. Charles ED, Dustin LB. Hepatitis C virus-induced cryoglobulinemia. Kidney Int. 2009;76(8):818-24.