NATAP: cryoglobulins in chronic HCV

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American Journal of Gastroenterology

Volume 98 Issue 11 Page 2568 - November 2003

doi:10.1111/j.1572-0241.2003.08688.x

Prevalence and incidence of cryoglobulins in chronic hepatitis C patients

TO THE EDITOR: In the April issue, Persico et al. (1) published an article on the prevalence and incidence of cryoglobulinemia in chronic hepatitis C patients. They showed that the prevalence of cryoglobulins in chronic hepatitis and cirrhosis was 0.8% and 8%, respectively, and they concluded that the presence of cryoglobulins and/or cryoglobulinemic syndrome in hepatitis C virus (HCV)-related liver disease is unusual. The data are in sharp contrast with all studies published thus far on the topic, which report a prevalence of cryoglobulins in chronic hepatitis C ranging from 40% to 66%(29). A recent meta-analysis (10) of 19 studies published between 1994 and 2001, with a total of 2323 patients with chronic hepatitis C, showed that the prevalence of cryoglobulinemia was 44% and highly associated with liver cirrhosis. Persico et al. justified the discrepancy by a geographic or selected population bias. I believe that the Persico article deserves some consideration to avoid that some author's conclusions, not supported by the data, may mislead the reader. In particular, attention should be paid to two critical points: first, the methodology used to assess the presence of cryoglobulinemia; i.e., the amount of sera used, the way blood was withdrawn and sera separated (omitted in the text), and the technique used, which might have reduced the real prevalence of cryoglobulins, particularly in patients with a low serum cryocrit (approximately 70% of cases); and second, perhaps more pertinent, the criteria of patient selection.

In 1996, my group (11) published the largest study on prevalence, incidence, and clinical relevance of cryoglobulins in chronic hepatitis C patients. The study, conducted in the same geographic area as was the Persico et al. study, included 432 consecutive patients with the entire spectrum of HCV liver disease, ranging from chronic HCV carriers with normal transaminases to all grades and stages of chronic hepatitis, to compensated and decompensated cirrhosis. The median age of cryoglobulinemic patients was 59 yr for cirrhosis and 52 yr for chronic hepatitis. The overall prevalence of cryoglobulinemia was 46% (cirrhosis, 33%; chronic active hepatitis, 10%; chronic persistent hepatitis, 1.8%). Type II cryoglobulins were present in 39% and type III in 61%. The male:female ratio was 1:2.6. The "classic syndrome" was present in 17% of cryoglobulinemic patients. We never found cryoglobulins in patients with less than a 4-yr duration of HCV infection. These data are in agreement with all data in the literature. During a median observation period of 3 yr, the yearly incidence of cryoglobulins was 3%, with rates of about 6% in cirrhosis, 1.6% in chronic active hepatitis, and 0% in chronic persistent hepatitis. During the same period of follow-up, asymptomatic cryoglobulinemic patients developed a yearly incidence of symptoms in 1.5% of cases.

Persico et al. (1) studied 237 consecutive HCV-infected patients, 213 with chronic hepatitis, and 24 with Child A cirrhosis to evaluate the occurrence of cryoglobulinemia at the beginning and during a follow-up of 6 yr. The HCV patients studied deserve some consideration to understand the results. Generally, a Liver Unit admits patients with different grades and stages of chronic hepatitisnaive or previously treated patients, compensated or decompensated cirrhotics; most of these patients undergo an appropriate medical treatment. The population studied by Persico et al. seems highly selected and as such it is not representative of the full natural history of HCV infection. That is, the series was not made up of the full spectrum of HCV chronic liver disease when first seen. The authors do not report whether the patients included in the study were previously untreated or given interferon treatment, which might have affected results. In addition, subjects were mostly young (median age, 39 yr), male (72%), and 90% had minimal/mild chronic hepatitis; advanced or decompensated cirrhosis patients were not included. The characteristics of selected patients highly anticipated a low association with the presence of cryoglobulinemia, because HCV-infected patients with cryoglobulins are older, have longer duration of infection and advanced stage of liver disease (mainly liver cirrhosis), and there is a higher prevalence among women (10). Thus, because of the bias in the selection of patients included in the study, the results presented by Persico et al. are of uncertain significance. The authors might infer that cryoglobulins have a low prevalence in the particular subgroup of patients studied, but the data cannot be generalized to the entire population of HCV patients, and neither can it be used for general pathogenetic speculation. With this restriction, the results are in concert with those previously reported.

Another point that needs to be raised is that the authors reported a negligible incidence of cryoglobulins in patients with chronic hepatitis C during follow-up. Although in our experience (11) patients with chronic hepatitis developed cryoglobulins with a low incidence (overall less than 1% per year), the data of Persico et al. should be interpreted in relation to factors that might have affected the appearance of cryoglobulins negatively. In particular, treatment with interferon (12), which was certainly indicated for most patients enrolled, and the initial bias of selection.

I agree with the hypothesis of Persico et al., although it is not supported by their data, that HCV-related chronic hepatitis and HCV-related cryoglobulinemia can follow two different fates, but the progression of both is related to the duration of HCV infection. In our experience, asymptomatic cryoglobulins, in particular when renal involvement is present, might affect survival of patients (11), but it does not seem to enhance the liver damage per se. In this respect, I have some doubts regarding the conclusion of the recent meta-analysis (10), which identifies cryoglobulins as a prognostic factor for increased risk of progression of chronic hepatitis C to cirrhosis.