Correspondence

Hepatitis C Virus and Cryoglobulinemia

N Engl J Med 1993; 328:1121-1124April 15, 1993

Article

To the Editor:

Agnello et al. (Nov. 19 issue)1 report the detection of hepatitis C virus (HCV) RNA in serum samples from 16 of 19 patients with type II cryoglobulinemia. Using three different assays, they demonstrated antibodies to HCV in the samples from only 8 of the 16 patients positive for HCV RNA and in one of four cryoprecipitates from the patients positive for antibodies to HCV. These findings are surprisingly different from those obtained by several investigators using quite similar assays2-4. In our series of 51 patients with essential mixed cryoglobulinemia4 and in 24 additional patients subsequently studied, we found antibodies to HCV in serum from 19 of 51 patients (37 percent) with a first-generation enzyme-linked immunosorbent assay (ELISA), in 72 of 75 patients (96 percent) with a second-generation ELISA, and in 48 of 75 patients (64 percent) with a recombinant immunoblot assay. The prevalence of antibodies to HCV in the cryoprecipitates, after rheumatoid factor was eliminated by the use of dithiothreitol, was 94 percent and 96 percent with a first-generation ELISA and a second-generation ELISA, respectively. The extremely high prevalence of HCV antibodies detected by the second-generation ELISA in both serum samples and cryoprecipitates was the result of the invariable presence in these patients of antibodies to the structural c22-3 HCV antigen. We found HCV RNA in serum samples from 26 of 28 unselected patients with essential mixed cryoglobulinemia. However, in contrast to the results reported by Agnello et al., only 1 of these 26 HCV RNA-positive patients had serum and cryoprecipitate negative for HCV antibodies.

It may well be that some of the discrepancies between these studies are due to differences in criteria for selecting patients or to epidemiologic factors. Agnello et al. included in their study patients with Waldenstrom's macroglobulinemia, patients with Sjogren's syndrome, and patients with positive results on tests for antinuclear antibodies whom we would have classified as having secondary mixed cryoglobulinemia. The prevalence of HCV antibodies in the general population is also probably much higher in our area than in the United States. Nevertheless, the low prevalence of these antibodies as compared with that of HCV RNA in the patients studied by Agnello et al. remains to be explained, even though the authors postulate an unusual immunologic response leading to the production of HCV antibodies undetectable by the current available tests.

Rocco Misiani, M.D.
Piermario Bellavita, M.D.
Ospedali Riuniti, 24128 Bergamo, Italy

Domenico Fenili, Biol.Sc.D.
Ospedale di Treviglio e Caravaggio, 24047 Treviglio, Italy

4 References

1. 1

   Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in Type II cryoglobulinemia. N Engl J Med 1992;327:1490-1495
   Full Text | Web of Science | Medline

2. 2

   Ferri C, Greco F, Longombardo G, et al. Association between hepatitis C virus and mixed cryoglobulinemia. Clin Exp Rheumatol 1991;9:621-624
   Web of Science | Medline

3. 3

   Galli M, Monti G, Monteverde A, et al. Hepatitis C virus and mixed cryoglobulinaemias. Lancet 1992;339:989-989
   CrossRef | Web of Science | Medline

4. 4

   Misiani R, Bellavita P, Fenili D, et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 1992;117:573-577
   Web of Science | Medline

To the Editor:

We examined the prevalence of mixed cryoglobulinemia in a prospective study of 127 patients with chronic HCV hepatitis. Chronic HCV hepatitis was defined by an alanine aminotransferase level twice the normal level for more than six months; the detection of HCV antibodies by a second-generation ELISA (Ortho HCV ELISA), with confirmation by a second-generation recombinant immunoblot assay (Chiron RIBA HCV, Ortho Diagnostic Systems); liver lesions compatible with chronic hepatitis C infection on histologic examination (with severity expressed as a Knodell score1); and the exclusion of other causes of liver dysfunction. Patients were considered to have cryoglobulinemia if the serum cryoglobulin level, after purification and characterization by immunoblotting at 37 °C as previously described,2 was above 0.05 g per liter on two successive determinations. HCV RNA sequences were searched for in 44 patients (21 with cryoglobulins) with use of the polymerase chain reaction. Patients receiving antiviral or immunosuppressive therapy were excluded, as were those with diseases associated with secondary cryoglobulinemia (i.e., cancer, an autoimmune disease, or a bacterial or parasitic infection or infection with the human immunodeficiency virus [HIV]).

Our main results are summarized in Table 1Table 1Characteristics of 69 Patients with Chronic Hepatitis C and Type II or Type III Mixed Cryoglobulinemia.. Mixed cryoglobulinemia was found in 69 of 127 patients (54 percent) with HCV chronic hepatitis. According to the classification of Brouet et al.,3 22 patients had type II and 47 had type III mixed cryoglobulinemia. Among the 22 patients with type II disease, the monoclonal component was IgM in 19 patients, IgG in 1, and IgA in 2. When compared with the patients with type III disease, those with type II had a higher mean cryoglobulin level and a longer duration of hepatitis.

This study found a high prevalence of mixed cryoglobulinemia among patients with chronic HCV hepatitis and suggests that HCV might be directly involved in the pathogenesis of cryoglobulinemia. The following sequence can be hypothesized: persistence of HCV in the host; continuous B-cell stimulation, as in infection with other persistent viruses such as cytomegalovirus, Epstein-Barr virus, or HIV; hyperproduction of polyclonal immunoglobulin, leading to type III mixed cryoglobulinemia in about half of the patients with chronic HCV hepatitis; and a second, uncharacterized B-cell event then occurring in some patients, leading to the production of monoclonal immunoglobulin and then type II mixed cryoglobulinemia. Interestingly, we found that patients with type II mixed cryoglobulinemia had a longer duration of hepatitis and a higher cryoglobulin level, suggesting that the probability of transformation from polyclonal to monoclonal increases with the duration of HCV infection.

Patrice Cacoub, M.D.
Francoise Lunel, M.D., Ph.D.
Lucile Musset, M.D.
Pierre Opolon, M.D.
Jean-Charles Piette, M.D.
Centre Hospitalier Universitaire Pitie-Salpetriere, 75013 Paris, France

3 References

1. 1

   Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431-435
   CrossRef | Web of Science | Medline

2. 2

   Musset L, Diemert M-C, Taibi F, et al. Characterization of cryoglobulins by immunoblotting. Clin Chem 1992;38:798-802
   Web of Science | Medline

3. 3

   Brouet J-C, Clauvel J-P, Danon F, Klein M, Seligmann M. Biologic and clinical significance of cryoglobulins: a report of 86 cases. Am J Med 1974;57:775-788
   CrossRef | Web of Science | Medline

To the Editor:

To assess further the importance of HCV in cryoglobulinemia, we studied patients with biopsy-proved chronic active hepatitis C. Of 13 patients tested, HCV RNA was detected by the polymerase chain reaction in serum samples from 12 patients and anti-HCV antibodies in samples from all 13 (Table 1Table 1Frequency of Cryoglobulins in Patients with Chronic Active Hepatitis C and in HCV-Positive Essential Cryoglobulinemia.). However, only 2 of the 13 patients were positive for a type III cryoglobulin (IgG and IgM). In both cases the cryoglobulin was associated with neither a rheumatoid factor nor a decrease in the complement factors C3c or C4, the immunologic features characteristic of essential mixed cryoglobulinemia. Of the 11 cryoglobulin-negative serum samples, 6 contained low amounts of rheumatoid factor (Table 1). On the other hand, our study of a group of 13 patients with the purpura, arthralgia, and nephritis associated with mixed cryoglobulins of type II or type III and high concentrations of rheumatoid factor confirmed the remarkable prevalence of anti-HCV antibodies, HCV RNA, or both in this disease (Table 1) as reported by Agnello and coworkers.

One may conclude from our data on chronic active hepatitis C that chronic HCV infection does not itself give rise to mixed cryoglobulinemia and is not necessarily associated with rheumatoid factor and complement abnormalities. Thus, the development of cryoprecipitable HCV immune complexes with rheumatoid factor activity as seen in so-called essential cryoglobulinemia may depend not only on HCV but also on additional factors not yet defined, including differences in the distribution of HCV-antibody IgG subclasses, glycosylation, calcium binding and affinity of antiviral antibodies, and unfavorable arrangements of the complementarity-determining region and framework region of immunoglobulin genes, or concomitant abnormalities in the complement or reticuloendothelial system. All these factors have been thought to contribute to the pathogenesis of essential mixed cryoglobulinemia1-4.

Christine Werner, M.D.
Helen I. Joller-Jemelka, M.D.
Adriano Fontana, M.D.
University Hospital, CH-8044 Zurich, Switzerland

4 References

1. 1

   Garson JA, Ring CJA, Tuke PW. Improvement of HCV genome detection with “short” PCR products. Lancet 1991;338:1466-1467
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   Abdelmoula M, Spertini F, Shibata T, et al. IgG3 is the major source of cryoglobulins in mice. J Immunol 1989;143:526-532
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   Qi M, Steiger G, Schifferli JA. A calcium-dependent cryoglobulin IgM kappa/polyclonal IgG. J Immunol 1992;149:2345-2351
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   Haydey RP, Patarroyo de Rojas M, Gigli I. A newly described control mechanism of complement activation in patients with mixed cryoglobulinemia (cryoglobulins and complement). J Invest Dermatol 1980;74:328-332
   CrossRef | Web of Science | Medline

To the Editor:

To evaluate the role of interferon alfa in the management of cryoglobulinemia, we started a multicenter controlled therapeutic trial in 1990. Thirty-seven patients (8 men and 29 women) with a median age of 60 years (range, 33 to 73) were classified according to the system of Brouet et al. 1: 5 patients had type I cryoglobulinemia, 19 had type II, and 13 had type III. Nine had essential cryoglobulinemia; the other 28 had secondary cryoglobulinemia associated with chronic liver disease (23 patients), Waldenstrom's macroglobulinemia (2 patients), non-Hodgkin's lymphoma (2 patients), and multiple myeloma (1 patient). With respect to antibodies to HCV and hepatitis B virus (HBV), 22 patients were negative for HBV and positive for HCV, 4 were positive for HBV and negative for HCV, 2 were positive for HBV and HCV, and 9 were negative for HBV and HCV. We administered four doses of recombinant interferon alfa-2b (1.5 million units) for induction and then 3 million units three times a week for six months. At six months, patients with complete or partial responses then received 3 million units per week; those with minor responses or documented disease progression were withdrawn from the study. Two of the patients with disease progression had early progression of their primary disease (multiple myeloma and Waldenstrom's macroglobulinemia).

At this writing 30 patients have been evaluated for response and toxicity; the length of follow-up has ranged from 6 to more than 40 months. Only one patient discontinued treatment because of severe thrombocytopenia. Mild side effects, such as a flu-like syndrome, were frequent, but there was no severe toxicity. The evaluation of the results after 3, 6, and 12 months of therapy showed that 13 patients (43 percent) had complete responses (complete disappearance of any clinical and serologic evidence of disease, with a cryocrit less than 10 percent of the initial value), 10 (33 percent) had partial responses (complete disappearance of all clinical manifestations, but with a cryocrit more than 10 percent of the initial value), and 7 (23 percent) had minor responses (persistence of some clinical signs of vasculitis). The response rate for interferon as a single agent was 77 percent after 12 months of therapy. Our preliminary results support the effectiveness of interferon alfa in the management of cryoglobulinemia, with a significant reduction of the cryocrit (P = 0.005 at 12 months), and confirm the high prevalence of HCV infection in type II and type III cryoglobulinemia.

Michele Bibas, M.D.
Alessandro Andriani, M.D.
Latial Cryoglobulinemia Cooperative Study Group, Ospedale S. Giacomo, 00186 Rome, Italy

1 References

1. 1

   Brouet J-C, Clauvel J-P, Danon F, Klein M, Seligmann M. Biologic and clinical significance of cryoglobulins: a report of 86 cases. Am J Med 1974;57:775-788
   CrossRef | Web of Science | Medline

To the Editor:

The patient described in Case 51-1990 (Dec. 20, 1990, issue) was a 57-year-old man with hepatic cirrhosis, cryoglobulinemia, and impaired renal function1. Dr. Agnello himself discussed the case and mentioned the role of hepatotropic virus, citing HBV but not HCV. It would be interesting to know his current opinion about the role of HCV in that patient. In our experience, nephropathy is frequent in the cryoglobulinemia-HCV infection syndrome.2...

Patrick Disdier, M.D.
Jean-Robert Harle, M.D.
Pierre-Jean Weiller, M.D.
Hopital de la Timone, 13385 Marseille Cedex 5, France

2 References

1. 1

   Case Records of the Massachusetts General Hospital (Case 51-1990). N Engl J Med 1990;323:1756-1765
   Full Text | Web of Science | Medline

2. 2

   Harle JR, Disdier P, Kaplanski G, et al. Virus de l'hepatite C et cryoglobulinemie mixte: a propos de 6 cas. Rev Med Interne 1990;11:S258-S258
   CrossRef

Author/Editor Response

The authors reply:

To the Editor: Dr. Misiani and colleagues have underscored the differences that we noted between the prevalence of HCV antibody found in our study of type II cryoglobulinemia and those previously reported. It is unlikely that the differences are due to patient selection, because eliminating the data on patients with Waldenstrom's macroglobulinemia and Sjogren's syndrome from our study changes the value for false negative serologic results only from 50 percent to 44 percent. Furthermore, it is well established that HCV antibody is absent from some patients with HCV infection1. The possibility that HCV antibody may not have been detected because of the presence of antigen or rheumatoid factors was excluded by studies of IgG dissociated from the cryoglobulins, which is a more rigorous approach than eliminating rheumatoid factor by means of dithiothreitol. The postulated antibodies to HCV envelope antigens in type II cryoglobulins would not be “an unusual immunologic response” as suggested by these correspondents; rather, this is the expected type of immune response to a circulating virus. The definitive characterization of antibodies in mixed cryoglobulinemia associated with HCV infection must await the isolation of the HCV.

It remains to be determined whether cryoglobulinemia occurs in a subgroup of patients with HCV infection or with progressive disease, as suggested by Cacoub et al. In view of the latter possibility and the variable criteria for assaying cryoglobulins, the data described by Werner and colleagues indicate that mixed cryoglobulinemia is not detected in all patients with chronic HCV infection. One cannot conclude from these data that “chronic HCV infection does not itself give rise to mixed cryoglobulinemia.”

The results of the Latial study reported by Drs. Bibas and Andriani confirm the effectiveness of interferon alfa in the treatment of patients with mixed cryoglobulinemia reported by Casato et al.2 and further strengthen the indication for treatment of these patients with this drug. Our findings on HCV in mixed cryoglobulinemia suggest that the effectiveness of interferon alfa may be the result of its antiviral rather than its immunomodulatory activity, and strengthen the rationale for using antiviral agents in the therapy of mixed cryoglobulinemia.

With regard to Case 51-1990, the patient died before serologic studies for HCV were routinely available. Although HCV may have been involved, we cannot conclude that this was highly probable, because it was not established that the cryoglobulin was type II, and an IgMlambda monoclonal component was present rather than the IgMkappa typically associated with mixed cryoglobulinemia and HCV infection.

Vincent Agnello, M.D.
Lahey Clinic Medical Center, Burlington, MA 01805

Raymond T. Chung, M.D.
Lee M. Kaplan, M.D.
Massachusetts General Hospital, Boston, MA 02114

2 References

1. 1

   Alter MJ, Margolis HS, Krawczynski K, et al. The natural history of community-acquired hepatitis C in the United States. N Engl J Med 1992;327:1899-1905
   Full Text | Web of Science | Medline

2. 2

   Casato M, Lagana B, Antonelli G, Dianzani F, Bonomo L. Long-term results of therapy with interferon-alpha for type II essential mixed cryoglobulinemia. Blood 1991;78:3142-3147
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