A 45-year-old man comes to the office due to a 2-month history of painless, nonpruritic, purple lesions on his legs. He has also had progressive fatigue, weakness, and fleeting joint pain in his knees and elbows for the past several months. The patient has had no fever, weight loss, diarrhea, or abdominal pain. Temperature is 36.7 C (98.1 F), blood pressure is 147/91 mm Hg, and pulse is 84/min. Cardiac examination reveals no murmurs or additional sounds. There are multiple palpable lesions on both lower extremities that do not blanch with pressure. Laboratory results are as follows:
| Hematocrit | 39% |
| Platelets | 160,000/mm3 |
| Leukocytes | 5,000/mm3 |
| Serum creatinine | 1.9 mg/dL |
| Aspartate aminotransferase (SGOT) | 78 U/L |
| Alanine aminotransferase (SGPT) | 99 U/L |
| C3 | low normal |
| C4 | very low |
| Rheumatoid factor | positive |
| Antinuclear antibody | negative |
| HIV-1 antibody | negative |
Urinalysis shows 3+ blood, 3+ protein, and a few dysmorphic red blood cells. Which of the following would be most helpful in establishing this patient's diagnosis?
Cryoglobulinemia | ||
Type I | Mixed = type II or III | |
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*Monoclonal RF (type II), polyclonal RF (type III). | ||
This patient with systemic symptoms (eg, fatigue) and evidence of multiorgan dysfunction affecting the skin (nonblanchable, palpable purpura), kidneys (glomerulonephritis), and joints (arthralgias), likely has small-vessel vasculitis (SVV). Given his elevated aminotransferases (raising suspicion for chronic hepatitis), the SVV is probably due to mixed cryoglobulinemia syndrome (MCS).
MCS is due to cryoglobulins (abnormal immunoglobulins that precipitate at <37 C) formed by IgM binding to the Fc region of IgG (ie, rheumatoid factor activity). These immune complexes activate complement (causing hypocomplementemia) and deposit in small vessels of multiple organs (causing SVV). Nonblanchable, palpable purpura (reflecting vasculitis-induced inflammation) is particularly classic. MCS likely results from B-cell hyperactivation, most commonly due to chronic hepatitis C infection. Therefore, all patients with suspected MCS require hepatitis serologies (even if aminotransferases are normal, which can occur despite infection).
Serum cryoglobulins must be confirmed; if negative, other SVV etiologies (eg, IgA vasculitis) should be considered. Other viral infections (eg, hepatitis B, HIV) and autoimmune disease (eg, systemic lupus erythematosus) are less common causes of MCS and are unlikely in this patient (negative HIV and antinuclear antibody titers).
(Choice A) B-cell lineage malignancies (eg, Waldenström macroglobulinemia), diagnosed using bone marrow biopsy, can produce type I cryoglobulins. These monoclonal immunoglobulins form cold-induced precipitates that cause multiorgan involvement. However, typical manifestations include vascular occlusive symptoms, such as livedo reticularis (blanchable vs nonblanchable purpura in MCS) and digital ischemia, and hyperviscosity-induced neurologic symptoms (eg, blurred vision, vertigo). Rheumatoid factor is negative, complement is normal, and frank vasculitis is rare.
(Choice B) Thrombotic thrombocytopenic purpura (TTP), due to decreased von Willebrand factor (vWF)–cleaving protease (ADAMTS13) activity, commonly causes fatigue and rash. However, TTP reflects microvascular thrombosis (from vWF-platelet binding), causing hemolysis and platelet consumption. Therefore, anemia/thrombocytopenia are severe, and the associated petechial rash is nonpalpable (vs palpable in MCS). Unlike MCS, TTP-induced kidney injury is typically mild and lacks significant hematuria; neurologic involvement (eg, confusion) is classic and hypocomplementemia is rare.
(Choice D) Antiphospholipid syndrome results from autoantibodies (eg, anticardiolipin) that cause thrombosis/thromboembolism. Patients typically have large-vessel venous or arterial thrombosis (eg, deep vein thrombosis, stroke), not seen in this patient. Microvascular thrombosis mimicking SVV (eg, rash, acute kidney injury) can occur but is rare.
Educational objective:
Mixed cryoglobulinemia syndrome is a small-vessel vasculitis that causes palpable purpura, glomerulonephritis, arthralgias, and peripheral neuropathy. Laboratory abnormalities include cryoglobulins, rheumatoid factor, and hypocomplementemia. Chronic hepatitis C infection is the most common cause, and serologies should be checked in all patients.