Case Presentation: A 54-year-old female with hepatitis C, liver cirrhosis, and history of intravenous heroin use presented with bilateral lower extremity swelling, weakness, multiple aphthous ulcers and a progressive, painful rash for 1 month. Physical examination revealed periorbital violaceous, erythematous rash, and non-blanching, non-palpable purpura extending from the bilateral lower extremities to the trunk and arms.
Lab work was remarkable for impaired renal function, decreased C3 Complement 23.5 mg/dl (normal 88-252 ), C4 Complement <1.5 mg/dl (normal 12-72) and positive cryoglobulins. ANCA panel and anti-dsDNA studies were negative. Regarding her hepatitis C – she had an elevated HCV RNA 426000 IU/L and was HCV Genotype 3. Skin biopsy revealed leukocytoclastic vasculitis with abundant eosinophils associated with dermal edema and purpura, along with 1+ granular C3 deposition in the upper dermal small vessels. Lab work also notable for an elevated myoglobin at 360 ng/ml (normal 25-72), CPK 243 U/L (normal 22-198), and aldolase 11.2 U/L (normal 1-7.5). A hyperintense signal within the upper medial right thigh musculature was observed with MRI, indicating concomitant polymyositis. Investigations for other infectious and malignant etiologies were negative. In light of her history of hepatitis C combined with positive cryoglobulins, decreased C4 complement and skin biopsy results, our patient was concluded to have hepatitis C related cryoglobulinemic leukocytoclastic vasculitis. Treatment of her hepatitis C was therefore initiated, with plans to initiate rituximab upon stabilization.
Discussion: Cryoglobulins are defined by their unique tendency to precipitate and aggregate in vessels at low temperatures, explaining why patients frequently develop flares at cooler temperatures. Cryoglobulinemic vasculitis is an immune-complex mediated systemic vasculitis that involves small-to medium-sized vessels. It has been recognized as an important extrahepatic manifestation of HCV chronic infection. Over 90% of patients with mixed cryoglobulinemia have been shown to be infected with hepatitis C virus whilst cryoglobulins can be detected in up to 25-30% of HCV patients. Of note, polymyositis is a well-known phenomenon associated with this multi-systemic disease. This case demonstrates the clinical manifestations of cryoglobulinemic vasculitis and highlights the importance of recognizing the relationship between chronic hepatitis C and Type II/III cryoglobulinemia. Intervention and treatment modalities are specific to this condition and include use of immunosuppressive therapy, specifically rituximab and cyclophosphamide as well as treating the underlying hepatitis C itself with direct acting antivirals.
Conclusions: Upon approaching a patient with purpura, arthralgias, neuropathy and nephropathy, cryoglobulinemic vasculitis is not the initial differential diagnosis that most consider. Cryoglobulinemic vasculitis typically eludes us as it is such a rare and lesser-known entity compared to the other forms of vasculitis. It is easily missed if not specifically considered or associated with hepatitis C. Being aware of this diagnostic possibility will allow clinicians to avoid mistaking it for other vasculitides and ensure appropriate, definitive treatment for the vasculitis as well as the underlying hepatitis C.