Life-Threatening Cryoglobulinemic Patients With Hepatitis C

Cryoglobulinemia is characterized by a wide range of causes, symptoms, and outcomes. Hepatitis C virus (HCV) infection is detected in 30%Y100% of patients with cryoglobulins. Although more than half the patients with cryoglobulinemic vasculitis present a relatively benign clinical course, some may present with potentially lifethreatening situations. We conducted the current study to analyze the clinical characteristics and outcomes of HCV patients presenting with life-threatening cryoglobulinemic vasculitis. We evaluated 181 admissions from 89 HCV patients diagnosed with cryoglobulinemic vasculitis consecutively admitted to our department between 1995 and 2010. In addition, we performed a systematic analysis of cases reported to date through a MEDLINE search. The following organ involvements were considered to be potentially life-threatening in HCV patients with cryoglobulinemic vasculitis: cryoglobulinemic, biopsy-proven glomerulonephritis presenting with renal failure; gastrointestinal vasculitis; pulmonary hemorrhage; central nervous system (CNS) involvement; and myocardial involvement. A total of 279 patients (30 from our department and 249 from the literature search) fulfilled the inclusion criteria: 205 presented with renal failure, 45 with gastrointestinal vasculitis, 38 with CNS involvement, 18 with pulmonary hemorrhage, and 3 with myocardial involvement; 30 patients presented with more than 1 life-threatening cryoglobulinemic manifestation. There were 146 (52%) women and 133 (48%) men, with a mean age at diagnosis of cryoglobulinemia of 54 years (range, 25Y87 yr) and a mean age at life-threatening involvement of 55 years (range, 25Y87 yr). In 232 (83%) patients, life-threatening involvement was the first clinical manifestation of cryoglobulinemia. Severe involvement appeared a mean of 1.2 years (range, 1Y11 yr) after the diagnosis of cryoglobulinemic vasculitis. Patients were followed for a mean of 14 months (range, 3Y120 mo) after the diagnosis of life-threatening cryoglobulinemia. Sixty-three patients (22%) died. The main cause of death was sepsis (42%) in patients with glomerulonephritis, and cryoglobulinemic vasculitis itself in patients with gastrointestinal, pulmonary, and CNS involvement (60%, 57%, and 62%, respectively). In conclusion, HCV-related cryoglobulinemia may result in progressive (renal involvement) or acute (pulmonary hemorrhage, gastrointestinal ischemia, CNS involvement) life-threatening organ damage. The mortality rate of these manifestations ranges between 20% and 80%. Unfortunately, this may be the first cryoglobulinemic involvement in almost two-thirds of cases, highlighting the complex management and very elevated mortality of these cases. (Medicine 2013;92: 273Y284) Abbreviations: BVAS = Birmingham Vasculitis Activity Score, CI = confidence interval, CNS = central nervous system, FFS = FiveFactor Score, HBV = hepatitis B virus, HCV = hepatitis C virus, HIV = human immunodeficiency virus, HR = hazard ratio, IFN-> = interferon, GFR = glomerular filtration rate, MDRD = Modification of Diet in Renal Disease, MRI = magnetic resonance imaging. INTRODUCTION C ryoglobulins are immunoglobulins that precipitate in vitro at temperatures less than 37-C and redissolve after rewarming.78 Cryoglobulinemia refers to the presence of cryoglobulins in serum, while the terms cryoglobulinemic disease or cryoglobulinemic vasculitis are used to describe patients with symptoms related to the presence of cryoglobulins, since many patients with cryoglobulinemia remain asymptomatic.78 Cryoglobulinemic vasculitis mainly affects the small and, less frequently, medium-size arteries and veins, which are thought to be damaged by the deposition of immune complexes on their walls, with the subsequent activation of the complement cascade.90 The distinctive etiopathogenic feature of cryoglobulinemia is an underlying B-cell clonal expansion that mainly involves rheumatoid factor-secreting cells. Cryoglobulins have been observed in a wide variety of diseases, principally infections, neoplasia, and systemic autoimmune diseases.1,30 A viral origin of cryoglobulinemia was long suspected, but it was not until the early 1990s that evidence emerged of a close relationship with the hepatitis C virus (HCV),1,30,76 which is responsible for more than 80% of cases. In 1966, Meltzer et al described the typical clinical symptoms associated with cryoglobulinemia (purpura, arthralgia, and weakness). Subsequent studies have described a broad spectrum of clinical features involving the skin, joints, kidneys, and nervous system. Although more than 50% of patients with cryoglobulinemia have a relatively benign clinical course with a good prognosis and survival, some may present with potentially life-threatening situations involving the internal organs and resulting in progressive (renal involvement) or acute (pulmonary hemorrhage, gastrointestinal ischemia, central nervous system Medicine & Volume 92, Number 5, September 2013 www.md-journal.com 273 From Josep Font Laboratory of Autoimmune Diseases (SR, CDL, AB, PBZ, MEG, MRC) and Vasculitis Research Unit (MCC), Department of Autoimmune Diseases; Department of Internal Medicine (XB); Department of Immunology (JY); and Viral Hepatitis Unit (XF), Department of Hepatology; CIBERehd, Hospital Clı́nic, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Financial support and conflicts of interest: Pilar Brito-Zerón was supported by Grant ‘‘Ajut per a la Recerca Josep Font’’ from Hospital Clinic-Barcelona (2012). Maria C. Cid was funded by Ministerio de Ciencia e Innovación (SAF11/30073). The other authors have no funding or conflicts of interest to disclose. Reprints: Dr. Manuel Ramos-Casals, Department of Autoimmune Diseases, Hospital Clı́nic, C/Villarroel, 170, 08036-Barcelona, Spain (e-mail: [email protected]). Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0025-7974 DOI: 10.1097/MD.0b013e3182a5cf71 Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. ECNS^ involvement) organ damage as occurs in other systemic vasculitides. Ferri et al found that 35% of patients with cryoglobulinemic vasculitis had a moderate-to-severe clinical course, with the prognosis being severely affected not only by cryoglobulinemic involvement, but also by associated processes such as HCV-related chronic liver disease. In a previous study, we found life-threatening cryoglobulinemia in 14% of patients with cryoglobulinemic syndrome, irrespective of the underlying etiologies, with a differentiated prognosis according to the organ involved. It remains unclear why some patients present with this severe form of vasculitis, and there is very limited information on the clinical presentation and prognosis of these patients. We conducted the current study to analyze the clinical characteristics and outcomes of HCV patients presenting with lifethreatening cryoglobulinemic vasculitis.