Cryoglobulinemia Clinical Presentation
- Author: Adam M Tritsch, MD; Chief Editor: Herbert S Diamond, MD more...
Specific clinical manifestations associated with type I cryoglobulinemia are related to hyperviscosity and thrombosis, as would be expected given the usual high concentrations of immunoglobulins and limited interference with complement function. These manifestations include the following:
Severe Raynaud phenomenon with digital ulceration
Specific clinical manifestations associated with types II and III cryoglobulinemia include the following:
Joint involvement (usually, arthralgias in the proximal interphalangeal [PIP] joints, metacarpophalangeal [MCP] joints, knees, and ankles)
Renal immune-complex disease
Meltzer triad (ie, purpura, arthralgia, and weakness) was first described in 1966 by Meltzer and Franklin in cases of essential mixed cryoglobulinemia. This triad is generally seen with types II and III cryoglobulinemia and is seen in up to 25-30% of patients.[25, 26]
These manifestations are nearly always present in cryoglobulinemia. Observed lesions have a predilection for dependent areas (particularly the lower extremities) and include erythematous macules and purpuric papules (90-95%), as well as ulcerations (10-25%).[19, 26, 18, 27]
Lesions in nondependent areas are more common in type I cryoglobulinemia (head and mucosa), as are livedo reticularis, Raynaud phenomenon, and ulcerations. Nailfold capillary abnormalities are common and include dilatation, altered orientation, capillary shortening, and neoangiogenesis. See the image below.
Symptoms such as arthralgias and myalgias are rare in type I cryoglobulinemia and are common in types II and III disease. Frank arthritis and myositis are rare. Arthralgias commonly affect the proximal interphalangeal and metacarpophalangeal joints of the hands, knees, and ankles. Musculoskeletal symptoms are described in more than 70% of persons with cryoglobulinemia.[29, 30, 26]
Renal disease may occur secondary to thrombosis (type I cryoglobulinemia) or immune complex deposition (types II and III). The incidence of renal disease varies from 5-60%. Histologically, membranoproliferative glomerulonephritis is almost always the lesion in mixed cryoglobulinemia. Clinically, isolated proteinuria and hematuria are more common than nephrotic syndrome, nephritic syndrome, or acute renal failure. Renal involvement is one of the most serious complications of cryoglobulinemia and typically manifests early in the course of the disease (within 3-5 y of diagnosis). Failure to treat may result in renal failure.[19, 31, 32]
A reduction in forced expiratory flow rates and the presence of interstitial infiltrates revealed by chest radiographs are common in mixed cryoglobulinemia. Approximately 40-50% of patients are symptomatic with dyspnea, cough, or pleuritic pain. Severe pulmonary disease is rare.[33, 34, 35, 36]
Neuropathy is common in types II and III disease (as determined with electromyographic and nerve conduction studies), affecting 70-80% of patients. Symptomatic disease was once reported as less common (5-40%); however, more recently, subjective symptoms have been reported up to 91% of patients. Sensory fibers are more commonly affected than motor fibers, with pure motor neuropathy in approximately 5% of patients.[37, 26, 38, 39]
Patients with cryoglobulinemia may also present with the following:
Abdominal pain has been reported in 2-22% of patients; vasculitis of the small mesenteric vessels that leads to acute abdomen has been reported
Sicca symptoms have been reported in 4-20% of patients [26, 33]
Acrocyanosis has been reported in up to 9% of patients
Arterial thrombosis has been reported in 1% of patients
A high incidence of new cases of thyroid autoimmunity and dysfunction hase been found in patients (particularly women) with hepatitis C–associated mixed cryoglobulinemia. 
Skin manifestations include the following:
Ischemic necrosis (40% in type I, 0-20% in mixed types)
Palpable purpura (15% in type I, 80% in mixed types)
Livedoid vasculitis (1% in type I, 14% in type III)
Cold-induced urticaria (15% in type I, 10% in type III)
Hyperkeratotic spicules in areas exposed to cold
Scarring of tip of nose, pinnae, fingertips, and toes
Nailfold capillary abnormalities
Pulmonary manifestations include the following:
Gastrointestinal manifestations include the following:
Abdominal pain (2-22%)
Hepatomegaly or signs of cirrhosis (ie, palmar erythema, abdominal wall collateral vessels, spider angiomata)
Renal manifestations include the following:
Membranoproliferative glomerulonephritis described in all types (more common in type II)
Intraluminal cryoglobulin deposition
Nephrotic-range proteinuria with resultant edema
Joint manifestations include the following:
Arthralgias (5% of type I, 20-58% of mixed)
Frank arthritis and progressive joint deformity (distinctly rare)
Nervous system manifestations include the following:
CNS involvement (rare, although pseudotumor cerebri and cerebral vascular events have been described)
Fever is another manifestation.
Disease associations vary with the type of cryoglobulinemia, as follows:
Type I is observed in lymphoproliferative disorders (eg, multiple myeloma, Waldenström macroglobulinemia).
Types II and III are observed in chronic inflammatory diseases such as chronic liver disease, infections (chronic HCV infection), and coexistent connective-tissue diseases (SLE, Sjögren syndrome). Mixed cryoglobulinemia is rarely associated with lymphoproliferative disorders.
Infections associated with cryoglobulinemia include the following:
Viral - Hepatitis A, B, and C (see Differentials); HIV; Epstein-Barr virus (EBV); cytomegalovirus (CMV); adenovirus; chikungunya
Bacterial - Endocarditis, streptococcal infections, syphilis, Lyme disease, leprosy, Q fever, brucellosis
Parasitic -Malaria, toxoplasmosis, others
Other disorders associated with cryoglobulinemia include the following:
Autoimmune diseases - SLE, rheumatoid arthritis, Sjögren syndrome
Vasculitis -Polyarteritis nodosa (especially hepatitis B–associated), Henoch-Schönlein purpura
Lymphoproliferative disorders - Waldenström macroglobulinemia, multiple myeloma, lymphoma, leukemia (eg, chronic lymphocytic leukemia, hairy cell leukemia)
Renal diseases -Proliferative glomerulonephritis
Liver diseases - Hepatitis A, B, and C (30-98% of patients with HCV infection have cryoglobulins, especially type II); cirrhosis
Cryoglobulinemia may occur as a familial or idiopathic disorder. Finally, cases have been reported following vaccination (eg, with pneumococcal vaccine).
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