The symptoms and signs of MC-associated vasculitis are caused by the vascular deposition of cryoprecipitate components. In type II MC, the cryoprecipitate contains polyclonal IgG, a highly restricted monoclonal IgM that has RF activity, low-density lipoprotein and, in cases of HCV-associated disease, HCV RNA. In general, the diagnosis of MC is made by some combination of the following: (1) recognition of a compatible clinical syndrome, accompanied nearly invariably by cutaneous vasculitis of small blood vessels (Figure 36–1); (2) isolation of cryoglobulins from serum; (3) detection of antibodies to HCV or HCV RNA; and (4) biopsy of other apparently involved organs as necessary to exclude other diagnoses. Because assays for cryoglobulins are not 100% sensitive and because HCV does not cause all cases of MC, all four of these conditions are not required.
A major hallmark of MC is a small-vessel vasculitis of the skin. Medium-vessel vasculitis may also be present, but this type of involvement generally does not occur without small-vessel disease. Biopsy of the skin with immunofluorescence studies shows an immune complex–mediated leukocytoclastic vasculitis, with deposition of IgG, IgM, C3, and other immunoreactants in and around the walls of small- and medium-sized vessels. Vascular thrombi are also prominent in many cases. Palpable purpura with a predilection for the lower extremities is the typical skin rash, but the rash is also found sometimes on the upper extremities, trunk, or buttocks. In addition, a host of other types of vasculitic rashes may be encountered, depending on the size of blood vessel involved. Such findings may include macules, papules, vesiculobullous lesions, urticarial lesions in the setting of small-vessel involvement, and ulcers above the malleoli—potentially extensive—in the context of medium-vessel disease.
Arthralgias are a prominent symptom in most cases of MC. The typically involved joints are the proximal interphalangeal and metacarpophalangeal joints and the knees. Frank arthritis, much less common than arthralgias, occurs in a small minority of patients. The arthritis of MC is nondeforming. Raynaud phenomenon and acrocyanosis may also complicate MC.
In the peripheral neuropathy of MC, sensory involvement predominates over motor nerve disease. The typical presentation is an axonal sensory neuropathy, associated with pain and paresthesias for years before the development of motor deficits. Motor mononeuritis multiplex may also occur, but never in the absence of sensory symptoms. HCV-induced vasculitis of the vasa nervorum is the pathogenetic mechanism of this peripheral nerve dysfunction.
Renal involvement is present in up to 20% of patients at diagnosis. The most frequent manifestations are asymptomatic microscopic hematuria, proteinuria, and variable degree of renal insufficiency. A small proportion may present as acute nephrotic syndrome and acute nephritic syndrome. The most frequent histologic picture is membranoproliferative glomerulonephritis, which can mimic lupus nephritis. Three specific histologic findings serve to distinguish glomerulonephritis secondary to MC: intraluminal thrombi composed of precipitated cryoglobulins; diffuse IgM deposition in the capillary loops; and subendothelial deposits presenting a crystalloid aspect on electron microscopy. MC-related renal disease may lead to nephrotic-range proteinuria, but progression to end-stage renal disease is uncommon. Rapidly progressive glomerulonephritis occurs in only a small number of patients.
Although HCV is obviously a hepatotropic virus, the clinical manifestations of liver disease in MC are few. Moreover, correlations between clinical liver disease and histology are poor. Most patients with HCV-related MC have various degrees of periportal inflammation, fibrosis, and even cirrhosis on liver biopsy. The formation of lymphoid follicles in the liver is a characteristic histologic feature of chronic HCV infection. Within these follicles (and in the bone marrow), most of the IgM RF is formed. Immunophenotyping of mononuclear cells within liver biopsy specimens from patients with HCV-associated MC reveals that they are mostly B cells that express IgM.
In addition to its hepatotropism, HCV also tends to infect lymphocytes, and in many cases, MC is truly a lymphoproliferative condition. Infection of lymphocytes often leads to lymphoproliferation and a type III (polyclonal) MC. If a dominant B-cell clone emerges, a type II (monoclonal) MC is produced. In some cases, the emergence of a dominant B-cell clone results from a genetic alteration that favors B-cell survival, eg, a bcl-2 gene mutation (translocation of the bcl-2 gene from chromosome 18 to chromosome 14). Such a mutation leads to overexpression of the antiapoptotic bcl-2. B-cell lymphoma is the most frequent form of malignancy complicating MC. Hepatocellular carcinoma is also found with an increased incidence among patients with MC, almost certainly related to the effects of underlying viral hepatitis infections in most cases.
Central Nervous System (CNS)
CNS disease in MC usually results from hyperviscosity and symptoms secondary to “sludging” of blood within the brain. Hyperviscosity, a rare complication of types II or III MC, is more common in type I cryoglobulinemia, a condition in which the cryoglobulin levels are often substantially higher. The occurrence of a hyperviscosity syndrome is an indication for plasma exchange. In addition to hyperviscosity syndromes, true CNS vasculitis also occurs in a very small number of patients with MC.
Clinically evident gastrointestinal tract involvement is uncommon, but patients with MC present occasionally with acute abdomen. Acute cholecystitis and mesenteric vasculitis secondary to MC have both been reported.
Miscellaneous Organ Involvement in MC
Pulmonary disease, consisting chiefly of interstitial lung lesions, has been described in MC. This manifestation remains poorly understood; cases are usually mild or even asymptomatic. Dryness of the mouth and eyes caused by lymphocytic salivary gland infiltration is not uncommon in MC. This type of organ involvement occurs in the absence of specific serologic evidence of Sjögren syndrome, ie, the finding of anti-Ro/SS-A or anti-La/SS-B antibodies. Bilateral parotid swelling and lymphadenopathy have also been described.
MC is associated with a number of laboratory findings that offer clues to the diagnosis. These tests are of limited value in the assessment of disease activity, however, because in general their levels correlate very poorly with disease. An overview of laboratory test results is shown in Table 36–2.
Table 36–2. Laboratory and Radiologic Evaluation in Possible Mixed Cryoglobulinemia. ||Download (.pdf)
Table 36–2. Laboratory and Radiologic Evaluation in Possible Mixed Cryoglobulinemia.
|Complete blood cell count|
- Mild anemia common.
- Thrombocytopenia may be present if liver disease is advanced.
|Renal and hepatic function|
- Renal function may be impaired in patients with glomerulonephritis.
- Hepatic dysfunction often subclinical but evident in most cases on liver biopsy. Liver transaminases may be normal.
|Urinalysis with microscopy||Abnormal in cases with renal involvement. Proteinuria may reach nephrotic range.|
|Erythrocyte sedimentation rate/C-reactive protein||Moderate to severe elevations common, generally reflecting disease activity when very high.|
|ANA||Positive in the majority of cases.|
|Rheumatoid factor||Positive in types II and III.|
|C3, C4||Low, particularly C4 levels.|
|Hepatitis B and C serologies||Hepatitis C serologies positive in approximately 90% of patients.|
|Antiphospholipid antibodies||Negative rapid plasma reagin and anticardiolipin antibody assays. Normal Russell viper venom time (for lupus anticoagulant).|
Assays for cryoglobulins are associated with a high false-negative rate, caused principally by insufficient care in handling. After phlebotomy, the blood sample must be transported to the laboratory at 37°C and allowed to clot at that same temperature. Specimens are then centrifuged at 37°C and stored at 4°C for up to 1 week. The presence of cryoglobulins is indicated by the development of a white precipitate at the bottom of the tube.
The percentage of serum composed of cryoglobulins may be determined by the centrifugation of serum at 4°C. The cryocrit may then be measured in precisely the same fashion as a hematocrit. As with other laboratory indicators, the cryocrit correlates poorly with clinical status and treatment. Cryocrit levels should not dictate therapeutic decisions, which are driven more appropriately by patients’ clinical condition.
Because complement proteins are involved in the formation of immune complexes, C3 and C1q are often found on specific immunofluorescence testing of biopsy specimens. Serum complement levels—C3, C4, and CH50—are also low in MC. The finding of a very low serum C4 level in the setting of a normal or only moderately reduced level of C3 is a strong clue to the presence of MC.
Rheumatoid Factor Positivity
Eighty percent of the monoclonal IgMs found in HCV-associated MC share a major complementarity region termed “WA.” (“WA” refers to the initials of the patient in whom it was initially reported.) This cross idiotype has a high degree of RF activity. Virtually all patients with type II MC are RF positive.
Anti-HCV Antibodies and Quantification of HCV RNA
Anti-HCV assays are typically performed by enzyme immunoassay or immunoblotting. Levels of HCV RNA may be used to follow the treatment response to specific antiviral therapies. HCV genotyping may also be performed by polymerase chain reaction, but no specific viral genotype has been associated with a predisposition to the development of MC.