Prevalence and incidence of cryoglobulins in hepatitis C virus-related chronic hepatitis patients: a prospective study
Marcello PersicoFedele Antonio De MarinoGianluca RussoEliana PersicoAristide MoranteBruno PalmentieriRoberto Torella
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Abstract:
A high prevalence of cryoglobulins has been reported in patients with hepatitis C virus (HCV)-related liver disease. The aim of this study was to evaluate the prevalence and the incidence of cryoglobulins and their association with clinical symptoms in chronic hepatitis and cirrhosis patients.The prevalence of cryoglobulins and cryoglobulinemic syndrome was investigated at enrollment in 237 patients (213 with chronic hepatitis and 24 with cirrhosis). A 7-yr follow-up was conducted evaluating the occurrence of cryoglobulins and/or cryoglobulinemic syndrome every 6 months. Rheumatoid factor was also tested in all patients.Prevalence of rheumatoid factor, cryoglobulins, and cryoglobulinemic syndrome in chronic hepatitis patients were 2%, 0.8%, and 0%, respectively. In cirrhosis patients the prevalence was 4%, 8%, and 0%, respectively. No statistically significant differences were found between the two groups. During the follow-up only one patient for each group abruptly developed cryoglobulinemic syndrome, and none of the patients who showed signs of cryoglobulinemia developed the syndrome or showed signs of evolution of the disease.Our data demonstrate that the presence of cryoglobulins and/or cryoglobulinemic syndrome in HCV-related liver disease is unusual, as is the occurrence of cryoglobulinemia over time in these patients. This leads us to think that HCV-related cryoglobulinemic syndrome and HCV-related liver disease are independent diseases. This supports new and indirect evidence for an independent and direct role of HCV in liver and blood disorders.Keywords:
Cryoglobulins
Rheumatoid factor
Liver disease
Hepatitis C
Chronic liver disease
Cryoglobulins are immunoglobulins or immune complexes which precipitate at a temperature lower than 37 degrees C and redissolve when rewarmed. Cryoglobulins can be asymptomatic. When not, clinical features are in most cases cutaneous, renal or neurological. Cryoglobulinemia are associated with malignant haematological disorder, connective tissue disease or infection process especially infection with hepatitis C virus. In some case, no aetiology can be found, in theses cases cryoglobulinemia are called primary or essential cryoglobulinemia. For the last ten years it has been widely demonstrated that virus C infection causes the most part of essential cryoglobulinemia.
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Cryoglobulinemia (CR) is a disease characterized by the presence, in the serum, of abnormal proteins that precipitate reversibly at low temperatures, and generally the cryoglobulins lead to a systemic inflammatory syndrome characterized by myalgia, arthralgia, purpura (Meltzer's triad), neuropathy, and glomerulonephritis [1]. According to immunochemical characteristic, cryoglobulins have been classified into 3 distinct groups:
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myalgia
Purpura (gastropod)
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Cryoglobulinemia is one of rare disorders characterised by presence of cryoglobulins( abnormal proteins)in the blood. Cryoglobulins clump together at cold temperatures, usually below 98.6degree Fahrenheit. The cause varies from person to person. Some of the most common causes include having an abundance of cryoglobulin in blood. To reve about this rare disorder, skin biopsy is done, 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 cryoglobulinemia.
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Cryoglobulinemia can be among the causes of sperm bad quality. But conventional examination algorithm for patients with idiopathic oligozoospermia makes no provision for cryoglobulin determination in blood serum.We examined 55 patients with idiopathic spermatogenesis disorder. Each patient had cryoglobulin determined in blood serum. For this purpose, optical density of the patient's blood serum before and after its 7-day cooling at a temperature of 4°C was compared. Type of cryoglobulins was established by the method evaluation of serum optic density in different periods of cooling incubation (before and after cooling) using the curves of temperature resistance for comparison. Patients with cryoglobulinemia underwent intracutaneous immunization with autoleukocytes separated from heparinized venous blood.Cryoglobulins were revealed in 16 patients of all 55 examined (29.09%): in six patients' cryoglobulins of second type; in nine - third type and in one patient - cryoglobulins of first type were detected. In a control group, which consisted of 50 men is blood - donors' frequency of cryoglobulinemia was 2%. Pathogenetic connection between cryoglobulinemia and disturbances in sperm quality is also supported by the fact that after autoleukocyte immunization in patients who positively responded to cryoglobulinemia treatment (14 persons of 16 or 87.5%) spermogram was found to be improved. Thus, in 12 patient number of spermatozoa. In all patients progressive motility and precentage of normal forms increased with spermatoza concentration.It is reasonable to include determination of cryoglobulins in blood serum for patients with idiopathic oligo- and zoospermia.
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Rheumatoid factor
Serum sickness
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Mixed cryoglobulinemia is frequently seen in liver disease and chronic viral hepatitis. The aim of this study is to determine the prevalence and clinical findings of cryoglobulins in patients with chronic hepatitis B and chronic hepatitis C.Cryoglobulins were precipitated from serum stored for up to 7 days. The precipitates were washed five times at 4 degrees C with 0.15 mol/L NaCl and total protein concentration was measured by reading absorbance at 280 nm.The prevalence of cryoglobulinemia was higher in patients with hepatitis C than in patients with hepatitis B (16.6% and 4.6% respectively). Patients with cryoglobulinemia had several symptoms such as arthralgia and weakness.Cryoglobulin-positive chronic hepatitis B and C patients should be investigated in terms of cryoglobulinemia symptoms and complications.
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Twenty-four hemophilic patients positive for hepatitis C virus were evaluated for the presence of serum cryoglobulins and associated symptoms. Eight (33.3%) of them had serum cryoglobulins (type II mixed cryoglobulinemia in all cases). The average time lapse between infection and appearance of serum cryoglobulins was 14.4 years (range 7-22 years). Two (25%) out of the 8 patients presented symptoms: one had systemic vasculitis, the other mild purpura. Hemophiliacs are a particularly suitable model for studying cryoglobulinemia in patients with hepatitis C virus infection since the onset of the infection is known and there is a long-term follow-up period.
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Purpura (gastropod)
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Clinical Significance
Hepatitis C
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Interest in cryoglobulins recently las increased because of the mounting suspicion that cryoglobulins may be symptomatic and even pathogenic in certain connective tissue diseases. It was once thought that cryoglobulins were homogeneous IgG or IgM globulins found in such disorders as multiple myeloma, Waldenström's macroglobulinemia, and proliferative lymphocytic diseases.1Now, however, combinations of IgG-IgM or IgG-IgA are also known to occur as cryoglobulins and to account for nearly one third of all cases of cryoglobulinemia.2An important feature of mixed cryoglobulins is their association with connective tissue diseases such as rheumatoid arthritis, Sjögren's syndrome, polyarteritis nodosa, etc, and a new syndrome described as "arthralgia-purpura -weakness -cryoglobulinemia."2
Patient Summary
A 55-year-old white male store clerk had been in good health until he began having intermittent episodes of purpura, edema, and migratory joint swelling of his lower extremities about five years before admission. Urinalysis and hemogram during an attackCryoglobulins
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Purpura (gastropod)
Rheumatoid factor
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A patient with mononeuropathy multiplex, hepatitis C viral infection, and mixed cryoglobulinemia had axonal degeneration by EMG and vasculitis of the epineurial vessels on sural nerve biopsy. There was no evidence of viral particles in the nerve by immunofluorescence. Treatment with interferon alfa improved the patient's symptoms and cleared the hepatitis C viral RNA and cryoglobulins from the serum.
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Nerve biopsy
Interferon alfa
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Mononeuritis Multiplex
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