Natural History and Clinical Impact of Cryoglobulins in Chronic Hepatitis C: 10-Year Prospective Study of 343 Patients
2007; Elsevier BV; Volume: 133; Issue: 3 Linguagem: Inglês
10.1053/j.gastro.2007.06.064
ISSN1528-0012
AutoresMauro Viganò, Pietro Lampertico, Maria Grazia Rumi, Christian Folli, L. Maggioni, Alberto Morabito, E. Del Ninno, Marco Cicardi, Massimo Colombo,
Tópico(s)Liver Disease and Transplantation
ResumoBackground & Aims: Serum cryoglobulins (CGs) are present in patients with chronic hepatitis C virus (HCV) infection, but their long-term clinical importance has not been established. We assessed the development rates, morbidity, and influence on the evolutionary course of hepatitis C of CG. Methods: A cohort of 343 HCV-RNA seropositive outpatients (173 men; age, 58 y; 82 with cirrhosis; 61 treated with interferon) with persistently increased aminotransferase levels and histologically defined liver disease was investigated. Patients initially were investigated for the presence, amount, and type of CG and prospectively followed up with clinical and laboratory examinations every 6 months. Results: At enrollment, CGs were found in 163 (47%) patients at a mean level of 173 ± 142 mg/L; 80% were type III, and associated to female sex (61% vs 40%, P = .0002) and cirrhosis (29% vs 19%, P = .04). Over the course of 17–130 months (median, 116 mo), de novo CG developed in 25 patients (2.3% per year), including 5 with cryoglobulinemic syndrome (.3% per year). The 10-year rates of progression to cirrhosis and of liver and extrahepatic complications were similar in CG (+) and CG (−) patients (32% vs 34%; 23% vs 16%; 5% vs 3%). The 10-year survival rates were lower for cirrhotic than for noncirrhotic patients (57% vs 91%, P < .00001), independently of CGs. Conclusions: CGs are common in patients with chronic HCV infection, mainly are type III, and do not influence the clinical course of hepatitis C during the first decades, except for the few rare cases of cryoglobulinemic syndrome. Background & Aims: Serum cryoglobulins (CGs) are present in patients with chronic hepatitis C virus (HCV) infection, but their long-term clinical importance has not been established. We assessed the development rates, morbidity, and influence on the evolutionary course of hepatitis C of CG. Methods: A cohort of 343 HCV-RNA seropositive outpatients (173 men; age, 58 y; 82 with cirrhosis; 61 treated with interferon) with persistently increased aminotransferase levels and histologically defined liver disease was investigated. Patients initially were investigated for the presence, amount, and type of CG and prospectively followed up with clinical and laboratory examinations every 6 months. Results: At enrollment, CGs were found in 163 (47%) patients at a mean level of 173 ± 142 mg/L; 80% were type III, and associated to female sex (61% vs 40%, P = .0002) and cirrhosis (29% vs 19%, P = .04). Over the course of 17–130 months (median, 116 mo), de novo CG developed in 25 patients (2.3% per year), including 5 with cryoglobulinemic syndrome (.3% per year). The 10-year rates of progression to cirrhosis and of liver and extrahepatic complications were similar in CG (+) and CG (−) patients (32% vs 34%; 23% vs 16%; 5% vs 3%). The 10-year survival rates were lower for cirrhotic than for noncirrhotic patients (57% vs 91%, P < .00001), independently of CGs. Conclusions: CGs are common in patients with chronic HCV infection, mainly are type III, and do not influence the clinical course of hepatitis C during the first decades, except for the few rare cases of cryoglobulinemic syndrome. Cryoglobulins (CGs) are by far the most common extrahepatic manifestation of hepatitis C virus (HCV), being found in approximately half of the patients with chronic hepatitis C attending liver clinics.1Agnello V. Chung R.T. Kaplan L.M. A role for hepatitis C virus infection in type II cryoglobulinemia.N Engl J Med. 1992; 327: 1490-1495Crossref PubMed Scopus (1337) Google Scholar, 2Kayali Z. Buckwold V.E. Zimmerman B. et al.Hepatitis C, cryoglobulinemia, and cirrhosis: a meta-analysis.Hepatology. 2002; 36: 978-985Crossref PubMed Scopus (158) Google Scholar HCV-related CGs primarily consist of mixed polyclonal immunoglobulin (Ig)G and monoclonal (type II) or polyclonal (type III) IgM with rheumatoid factor activity,3Brouet J.C. Clauvel J.P. Danon F. et al.Biologic and clinical significance of cryoglobulins A report of 86 cases.Am J Med. 1974; 57: 775-788Abstract Full Text PDF PubMed Scopus (1454) Google Scholar and result from the accumulation of circulating immune complexes and the production of monoclonal rheumatoid factor stimulated by HCV.4Agnello V. De Rosa F. Extrahepatic disease manifestations of HCV infection: some current issues.J Hepatol. 2004; 40: 341-352Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar In a minority of patients, CGs are responsible for the development of the mixed cryoglobulinemia syndrome, which is characterized by the triad of palpable purpura, arthralgias, and weakness, that may be accompanied by other clinical features such as glomerulonephritis and lymphoadenopathies.5Meltzer M. Franklin E.C. Elias K. et al.Cryoglobulinemia—a clinical and laboratory study II. Cryoglobulins with rheumatoid factor activity.Am J Med. 1966; 40: 837-856Abstract Full Text PDF PubMed Scopus (530) Google Scholar One major point of dispute is whether extrahepatic manifestations of HCV are an expression of extrahepatic tropism of the virus, which would explain also the potential, albeit debated, link between HCV, CGs, and non-Hodgkin's B-cell lymphoma.6Silvestri F. Pipan C. Barillari G. et al.Prevalence of hepatitis C virus infection in patients with lymphoproliferative disorders.Blood. 1996; 87: 4296-4301PubMed Google Scholar, 7Ohsawa M. Shingu N. Miwa H. et al.Risk of non-Hodgkin's lymphoma in patients with hepatitis C virus infection.Int J Cancer. 1999; 80: 237-239Crossref PubMed Scopus (83) Google Scholar, 8Zuckerman E. Zuckerman T. Levine A.M. et al.Hepatitis C virus infection in patients with B-cell non-Hodgkin's lymphoma.Ann Intern Med. 1997; 127: 423-428Crossref PubMed Scopus (363) Google Scholar, 9Collier J.D. Zanke B. Moore M. et al.No association between hepatitis C and B-cell lymphoma.Hepatology. 1999; 29: 1259-1261Crossref PubMed Scopus (105) Google Scholar, 10Rasul I. Shepherd F.A. Kamel-Reid S. et al.Detection of occult low-grade B-cell non-Hodgkin's lymphoma in patients with chronic hepatitis C infection and mixed cryoglobulinemia.Hepatology. 1999; 29: 543-547Crossref PubMed Scopus (93) Google Scholar, 11Sansonno D. Dammacco F. Hepatitis C virus, cryoglobulinemia, and vasculitis: immune complex relations.Lancet Infect Dis. 2005; 5: 227-236Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar The fact that patients with extrahepatic manifestations of HCV rarely are seen in liver units because they preferentially are referred to nephrology and dermatology units12Lunel F. Musset L. Cacoub P. et al.Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage.Gastroenterology. 1994; 106: 1291-1300Abstract PubMed Google Scholar, 13Adinolfi L.E. Utili R. Attanasio V. et al.Epidemiology, clinical spectrum and prognostic value of mixed cryoglobulinemia in hepatitis C virus patients: a prospective study.Ital J Gastroenterol. 1996; 28: 1-9PubMed Google Scholar, 14Pawlotsky J.M. Ben Yahia M. Andrè C. et al.Immunulogical disorders in C virus chronic active hepatitis: a prospective case-control study.Hepatology. 1994; 19: 841-848Crossref PubMed Scopus (582) Google Scholar, 15El-Serag H.B. Hampel H. Yeh C. et al.Extrahepatic manifestations of hepatitis C among United States male veterans.Hepatology. 2002; 36: 1439-1445Crossref PubMed Scopus (249) Google Scholar might have led to the underestimation of the clinical importance of CGs in patients with chronic hepatitis C. Little is known, in fact, about the rates at which CGs develop in HCV patients, to what extent CGs correlate with and may affect the course of chronic hepatitis C, and whether distinct types of CGs are associated with the onset of extrahepatic manifestations and hepatitis outcome. The few, short-term, prospective studies examining the clinical consequences of CGs in patients with HCV have provided unreliable data, in particular as far as the progression of hepatitis C toward cirrhosis is concerned.2Kayali Z. Buckwold V.E. Zimmerman B. et al.Hepatitis C, cryoglobulinemia, and cirrhosis: a meta-analysis.Hepatology. 2002; 36: 978-985Crossref PubMed Scopus (158) Google Scholar, 13Adinolfi L.E. Utili R. Attanasio V. et al.Epidemiology, clinical spectrum and prognostic value of mixed cryoglobulinemia in hepatitis C virus patients: a prospective study.Ital J Gastroenterol. 1996; 28: 1-9PubMed Google Scholar, 16Donada C. Crucitti A. Donadon V. et al.Systemic manifestations and liver disease in patients with chronic hepatitis C and type II or III mixed cryoglobulinemia.J Viral Hepat. 1988; 5: 179-185Crossref Scopus (72) Google Scholar, 17Siagris D. Christofidou M. Tsamandas A. et al.Cryoglobulinemia and progression of fibrosis in chronic HCV infection: cause or effect?.J Infect. 2004; 49: 236-241Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar The prospective study of a large cohort of patients with HCV for a sufficiently long time might provide better insights into these issues, particularly when epiphenomena-like ascites, jaundice, and esophageal bleeding, which are not central to the disease process, are taken as end points of the investigation.18Christensen E. Prognostic models including the Child-Pugh, MELD and Mayo risk scores Where are we and where should we go?.J Hepatol. 2004; 41: 344-350Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar In a 10-year prospective cohort study, we assessed the development rates and clinical importance of serum CGs in 343 patients with chronic hepatitis C. Between November 1994 and October 1995, all patients with histologically proven chronic hepatitis C who were seen consecutively at the Liver Unit at Maggiore Hospital in Milan, were tested for the presence of serum CGs.19Cicardi M. Cesana B. Del Ninno E. et al.Prevalence and risk factors for the presence of serum cryoglobulins in patients with chronic hepatitis C.J Viral Hep. 2000; 7: 138-143Crossref PubMed Scopus (67) Google Scholar Included were patients with longer than 1 year serum positivity for anti-HCV and HCV-RNA, alanine aminotransferase (ALT) levels 1.5 times the upper limit of normal or more, and compensated liver disease. Excluded were interferon-experienced patients and those with other causes of liver disease, including hepatitis B, autoimmune hepatitis, primary biliary cirrhosis, drug-related hepatitis, or alcohol abuse (defined as an intake of more than 60 g/day for men and more than 40 g/day for women). Additional causes for exclusion were hepatocellular carcinoma (HCC), extrahepatic neoplasia, and human immunodeficiency virus antibodies. Duration of HCV infection was calculated by considering the date of the first injection of illicit drugs or any blood transfusion before 1992 as the time of infection. In patients with an unknown source of infection, the date of the first abnormal ALT test result arbitrarily was taken as the start of infection. Sustained virologic responders to interferon treatment were patients who cleared serum HCV RNA during therapy and had undetectable serum HCV-RNA levels by polymerase chain reaction assay 6 months after the end of treatment. Nonresponders were those who had maintained detectable serum HCV-RNA levels throughout the treatment period. Patients underwent laboratory and clinical examinations at 6-month intervals, whereas abdominal ultrasound examinations were performed at 6- or 12-month intervals in patients with or without cirrhosis, respectively. All patients gave their written consent and details of the study were approved by the local Institutional Review Committee. The end points of the study were 3-fold: to assess the prevalence, incidence, and type of CGs and their impact on the development of extrahepatic manifestations and outcome of hepatitis C. The outcome of hepatitis C included the progression of chronic hepatitis to cirrhosis, HCC, and clinical decompensation (ie, ascites, variceal bleeding, hepatic encephalopathy, or jaundice). Progression to cirrhosis was based on histology (Ishak score, 5 or 6), clinical evaluation (platelet count < 100,000 mm3; ultrasound features including surface nodularity, splenomegaly, and portal vein diameter > 15 mm; and esophageal varices), and transient elastography values greater than 14.6 kPa. Extrahepatic manifestations included cryoglobulinemic syndrome, defined as palpable purpura, arthralgia, and weakness; extrahepatic autoimmune diseases, defined as systemic signs and symptoms associated to serum organ and non–organ-specific autoantibodies; peripheral sensory-motor neuropathy or paresthesias with loss of muscular strength; cryoglobulinemic nephropathy defined as overt CG-related kidney impairment requiring chronic hemodialysis; and lymphoma. All patients were assessed for extrahepatic complications at 6-month intervals. The end point was the first complication recorded, whereas recurrence of the same complication during the follow-up period was not considered for the purpose of this analysis. Overall survival was the time from enrollment to death or liver transplantation. Liver-related death was defined as death caused by the occurrence of end-stage liver disease or HCC progression. CGs were isolated from patients' sera, and purified and characterized according to Musset et al.20Musset L. Diemert M.C. Taibi F. et al.Characterization of cryoglobulins by immunoblotting.Clin Chem. 1992; 38: 798-802Crossref PubMed Scopus (215) Google Scholar In brief, blood was drawn into prewarmed tubes and maintained at 37°C until separation of serum. CGs were precipitated from serum containing 0.1 g/L sodium azide and stored at 4°C for 7 days. The precipitates were washed 4 times at 4°C with 0.15 mol/L of NaCl and measured by reading the absorbance at 280 nm with a purified Ig preparation used as a standard. According to Cacoub et al,21Cacoub P. Fabiani F.L. Musset L. et al.Mixed cryoglobulinemia and hepatitis C virus.Am J Med. 1994; 96: 124-132Abstract Full Text PDF PubMed Scopus (284) Google Scholar patients were considered to have significant CGs if they had a serum CG level greater than 50 mg/L. The immunoglobulin composition of the cryoprecipitates was determined by agarose gel electrophoresis followed by immunoblotting. CGs were classified as type II when associated with monoclonal rheumatoid factor, or type III when associated with polyclonal rheumatoid factor.3Brouet J.C. Clauvel J.P. Danon F. et al.Biologic and clinical significance of cryoglobulins A report of 86 cases.Am J Med. 1974; 57: 775-788Abstract Full Text PDF PubMed Scopus (1454) Google Scholar De novo development of serum CGs was evaluated at yearly intervals. Liver function tests, protime, cholinesterases, albumin, Ig, serum creatinine, and rheumatoid factor were assessed by standard methods. C3 and C4 serum levels were measured by immunoturbidimetric assay. Hepatitis B surface antigen was detected by a microparticle enzyme immunoassay (AXSYM; Abbott Laboratories, North Chicago, IL). Anti-HCV was detected by a second-generation test system (Ortho DS, Raritan, NJ), whereas serum HCV RNA was detected by Amplicor HCV (Roche Molecular System, Nutley, NJ: limited sensitivity of 650 IU/mL) and genotyped by INNO-LiPA HCV (Innogenetics NV, Ghent, Belgium). Antibody to the human immunodeficiency virus (anti–human immunodeficiency virus) was detected by a third-generation assay (AXSYM HIV 1/2, Abbott Laboratories). Nuclear, smooth muscle, mitochondrial, and liver-kidney-microsome antibodies were detected by an indirect immunofluorescence assay performed on 4-μm cryostat sections from rat liver, kidney, and stomach at a sera dilution of 1:40. Anti–double-strand DNA were detected by an indirect immunofluorescence assay performed on Crithidia luciliae substrate (Immuno Concepts, Sacramento, CA) and anti-extractable nuclear antigen antibodies were detected by an enzyme-linked immunosorbent assay (DIAMEDICS, Miami, FL). Thyroid antibodies (thyroglobulin antibodies and thyroperoxidase antibodies) were measured using the AutoDELFIA technique (Perkin Elmer–Life Sciences, Wallac Oy, Turku, Finland) with less than 35 IU/L normal values. Serum thyroid stimulating hormone receptor antibodies, detected as thyroid stimulating hormone binding inhibitory immunoglobulins, were measured using a second-generation TRAK human lumitest (B.R.A.H.M.S., AG, Henningsdorf/Berlin, Germany). A liver biopsy specimen (Uro-Cut 16 G; TSK, Tokyo, Japan) was obtained from all patients at enrollment. A second liver biopsy examination was offered to assess liver disease severity as part of the decision-making process for anti-HCV therapy. All patients with an initial diagnosis of cirrhosis and patients with chronic hepatitis who developed clinical signs of cirrhosis during the follow-up period did not undergo a second liver biopsy. The severity of hepatic disease was evaluated by the Ishak score in separate reports for grading and staging.22Ishak K. Baptista A. Bianchi L. et al.Histological grading and staging of chronic hepatitis.J Hepatol. 1995; 22: 696-699Abstract Full Text PDF PubMed Scopus (4174) Google Scholar The maximum score for grading was 18, ranging from 0 to 4 for piecemeal necrosis, focal necrosis, and portal inflammation, and from 0 to 6 for confluent necrosis. The score for staging ranged from 0, representing no fibrosis, to 6, representing cirrhosis. Histologic progression was defined as a 1-point or greater increase in staging score. In patients with fibrosis progression, the annual fibrosis progression rate was calculated as the ratio between delta staging (ΔS) (final − initial fibrosis stage) and the number of years elapsed between the 2 biopsy procedures.23Boccato S. Pistis R. Noventa F. et al.Fibrosis progression in initially mild chronic hepatitis C.J Viral Hepat. 2006; 13: 297-302Crossref PubMed Scopus (70) Google Scholar Between October and December 2006, transient elastography (FibroScan, Echosens, Paris)24Fraquelli M. Rigamonti C. Casazza G. et al.Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease.Gut. 2007; 56: 968-973Crossref PubMed Scopus (699) Google Scholar was performed in all patients who did not clinically progress to cirrhosis during the study period and refused to undergo a second liver biopsy procedure. In a previous study,25Ziol M. Handra-Luca A. Kettaneh A. et al.Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C.Hepatology. 2005; 41: 48-54Crossref PubMed Scopus (1269) Google Scholar the cut-off value of 14.6 kPa was shown to accurately differentiate HCV patients with severe fibrosis/cirrhosis from those with less severe liver disease. Patients with 6 point or higher grading and 1 point or higher staging were offered treatment with interferon according to pre-established criteria of patient selection based on patient age, disease severity, HCV genotype, and comorbidities.26EASL International Consensus Conference on Hepatitis C. Paris, 26–28, February 1999, Consensus Statement European Association for the Study of the Liver.J Hepatol. 1999; 30: 956-961Abstract Full Text Full Text PDF PubMed Scopus (797) Google Scholar, 27Rumi M.G. Del Ninno E. Parravicini M.L. et al.A prospective randomized trial comparing lymphoblastoid to recombinant interferon alfa 2a as therapy for chronic hepatitis C.Hepatology. 1996; 24: 1366-1370Crossref PubMed Google Scholar Patients with compensated cirrhosis underwent abdominal ultrasound every 6 months and the diagnosis of HCC was made according to internationally agreed on criteria.28Bruix J. Sherman M. Llovet J.M. et al.EASL panel of experts on HCCClinical management of hepatocellular carcinoma Conclusions of the Barcelona-2000 EASL conference.J Hepatol. 2001; 35: 421-430Abstract Full Text Full Text PDF PubMed Scopus (3779) Google Scholar Data were expressed as counts and percentages for qualitative variables and as medians and ranges of discrete variables. Significance of differences in the distribution of quantitative and qualitative variables was assessed with the Student t test, Fisher exact test, or the Wilcoxon rank sum test. All P values were 2-tailed and a level of .05 was considered statistically significant. The probability of patient survival was assessed by the Kaplan–Meier method. The difference between the cumulative curves was tested by the log-rank test. By using time-independent multivariate analysis, independent predictors of hepatitis progression to cirrhosis were identified among the following variables: age, sex, CGs (present/absent), staging (0–2 vs 3–4), HCV genotype (1/non-1), duration of liver disease, and interferon therapy (yes/no). Cox's regression model was used for univariate and multivariate analysis of predictors of complication-free survival and survival. The following variables were assessed: age, sex, CGs (present/absent), cirrhosis (present/absent), HCV genotype (1/non-1), duration of liver disease, and interferon therapy (yes/no). By replacing staging (0–2 vs 3–4) with cirrhosis (present/absent), the earlier-cited variables were included in the predictive model for survival. Statistical analysis was performed with STATA (Stata Statistical Software: release 7.0; Stata Corporation, Collage Station, TX). A total of 343 patients were enrolled (Table 1, Table 2). A total of 162 (47%) had HCV genotype 1, 97 (28%) had genotype 2, 12 (4%) had genotype 3, 6 (2%) had genotype 4, and 66 (19%) were not typed. A total of 163 (47%) patients had detectable levels (mean, 173 ± 142 mg/L) of CGs, which were predominantly (80%) type III. CGs were detected more frequently in female and cirrhotic patients than in male and noncirrhotic patients (Table 1). Among 261 noncirrhotic patients, 49 (19%) CG (+) and 53 (20%) CG (−) patients had moderate fibrosis (ie, staging 3–4). Among 82 cirrhotic patients, the Child–Pugh score, ALT levels, platelet count, and duration of liver disease were similar in the 48 CG (+) and the 34 CG (−) patients. The number of patients with esophageal varices was similar in the 2 groups (38% vs 44%). The median serum levels of albumin, cholinesterase, and C4 were significantly lower in CG (+) patients than in the CG (−) patients, whereas the median levels of rheumatoid factor, IgM, and IgG were significantly higher in the former patients than in the latter ones (Table 2). Among the 163 CG (+) patients, 5 (3%) had cryoglobulinemic syndrome. The clinical and demographic features of patients with type II CGs were similar to those of patients with type III CGs (data not shown).Table 1Demography and Clinical Characteristics of the 343 Patients at the Time of Enrollment in the Study According to the Presence or Absence of Serum CGsFeaturesAll patients (n = 343)CG (+) (n = 163)CG (−) (n = 180)P valueFemales, n170 (50%)99 (61%)71 (40%).0002Median age, y (range)58 (22–76)58 (22–74)59 (22–76)NSMedian ALT level, IU/mL (range)88 (62–657)88 (62–657)89 (65–332)NSHistologic stagingaIshak score. 0–2159 (46%)66 (41%)93 (52%) 3–4102 (30%)49 (30%)53 (29%) 5–682 (24%)48 (29%)34 (19%).04bStage 5–6 vs 0–4.Genotype 1 HCV, n162 (58%)71 (58%)91 (58%)NSNon-1 HCV genotype, n115 (42%)58 (42%)57 (42%)NSMedian duration of liver disease, y (range)11 (1–42)11 (1–42)10 (1–42)NSCryoglobulinemic syndrome, n5 (1.5%)5 (3%)0 (0%)NSMedian follow-up period, mo (range)116 (17–130)115 (17–127)116 (22–130)NSa Ishak score.b Stage 5–6 vs 0–4. Open table in a new tab Table 2Baseline Laboratory Findings in the 343 Patients Enrolled in the Study According to the Presence or Absence of CGsAll patients (n = 343)CG (+) (n = 163)CG (−) (n = 180)P valueAlbumin level, g/dL4.5 (3.2–5.6)4.4 (3.2–5.4)4.5 (3.4–5.6).003Cholinesterase level, IU/L9767 (1272–14,970)9413 (1272–14,970)10,112 (1300–8078).02Protime, INR1.05 (.8–1.87)1.04 (.8–1.4)1.03 (.8–1.87)NSBilirubin level, mg/dL.8 (.3–3.4).8 (.3–3.4).8 (.3–3.3)NSRheumatoid factor, mg/dL39 (39–2700)48 (39–2700)39 (39–446)<.0001C3 level, mg/dL100 (31–164)100 (35–164)102 (31–141)NSC4 level, mg/dL72 (1–144)63 (1–144)82 (1–127)<.0001Platelet level, no/mm3167,000 (39,000–395,000)158,000 (39,000–376,000)178,500 (43,000–395,000)NSIgM level, mg/dL171 (26–1085)213 (26–1085)139 (20–638)<.0001IgA level, mg/dL225 (53–875)212 (53–875)231 (33–869)NSIgG level, mg/dL1958 (775–3553)2095 (1071–3553)1900 (775–3815)<.0001NOTE. Medians (ranges) shown.INR, International Normalized Ratio. Open table in a new tab NOTE. Medians (ranges) shown. INR, International Normalized Ratio. The median duration of the study was 116 months (range, 17–130 mo), with no differences between CG (+) and CG (−) patients (115 vs 116 months duration of the study). Forty patients (19 with CGs and 21 without CGs), were lost to follow-up evaluation. One patient was lost in the first, 5 in the second, 8 in the third, 9 in the fourth, 7 in the fifth, 4 in the sixth, 3 in the seventh, and 3 in the eighth year of the study. Among the 61 (18%) patients who were treated with either interferon monotherapy (n = 19) or with interferon plus ribavirin (n = 42), the number of treated patients and the rates of sustained virologic responders were similar in CG (+) and CG (−) patients (16% vs 19%; 64% vs 51%). The prevalence of CGs was similar in patients undergoing antiviral treatment and patients who were left untreated. All but 4 CG (+) responders lost serum CGs, including the 3 patients with cryoglobulinemic syndrome, in whom the syndrome resolved along with the disappearance of CGs. Twenty-five (14%) patients developed de novo CGs at a 2.3% yearly rate. The incidence rates of CGs were similar between patients treated and untreated with interferon, and those with or without cirrhosis. A total of 261 noncirrhotic patients were offered a second follow-up biopsy procedure; 95 (36%) accepted (40% CG [+] vs 33% CG [−], NS). The time elapsed from enrollment to the second biopsy procedure was 63 months (range, 16–97 mo) vs 64 months (range, 17–97 mo) in the 2 groups, respectively. Twenty-six CG (+) and 33 CG (−) patients showed fibrosis progression in terms of a greater than 1-point increase in staging score (57% vs 67%, NS), with similar annual rates of fibrosis progression (.14 vs .18, ns) (Table 3). The 10-year cumulative probability of fibrosis progression was 56% in the former and 61% in the latter patients, respectively (NS). Liver disease progressed to cirrhosis in 3 CG (+) and in 7 CG (−) patients (7% vs 14%, NS) (Table 4).Table 3Modification of the Ishak Stage in the Second Liver Biopsy Specimen From 95 Noncirrhotic Patients, Stratified by Baseline Staging Scores and Presence or Absence of CGsFirst liver biopsy specimenSecond liver biopsy specimensIshak stagePatients with stable or reduced Ishak stagePatients with increased Ishak stageaA 1-point or greater increase in staging score.All patients0 CG (+)358 CG (−)1341 CG (+)459 CG (−)5382 CG (+)5611 CG (−)618243 CG (+)3811 CG (−)37104 CG (+)527 CG (−)123Overall CG (+)20 (43%)26 (57%)bPatients with increased overall Ishak stage: P = .19.46 CG (−)16 (33%)33 (67%)bPatients with increased overall Ishak stage: P = .19.49a A 1-point or greater increase in staging score.b Patients with increased overall Ishak stage: P = .19. Open table in a new tab Table 4Progression to Cirrhosis in 261 Patients With Chronic Hepatitis C According to the Presence or Absence of CGs at EnrollmentDiagnosis of cirrhosisPatients investigatedAll (n = 261)CG (+) (n = 115)CG (−) (n = 146)Second liver biopsy Patients evaluated, n95 (36%)46 (40%)49 (33%) Cirrhosis, naIshak score of 5 or 6.10 (4%)3 (3%)7 (5%)Clinical evaluation Patients evaluated, nbPatients without histologic progression to cirrhosis and patients who refused to undergo a second liver biopsy procedure.251 (96%)112 (97%)139 (95%) Cirrhosis, ncPlatelet count < 100,000 mm3; ultrasound features including surface nodularity, splenomegaly, and portal vein diameter > 15 mm; and esophageal varices.57 (22%)25 (22%)32 (22%)Transient elastography Patients evaluated, ndPatients still on follow-up evaluation without histologic or clinical evidence of progression to cirrhosis.93 (36%)40 (35%)53 (36%) Cirrhosis, neTransient elastography values >14.6 kPa.20 (8%)9 (8%)11 (8%)Overall cirrhosis, nfOverall, that is, combining histologic, clinical, and transient elastography results.87 (33%)37 (32%)50 (34%)NOTE. Cirrhosis was diagnosed by combining the results of a second liver biopsy procedure, clinical evaluation, and transient elastography.a Ishak score of 5 or 6.b Patients without histologic progression to cirrhosis and patients who refused to undergo a second liver biopsy procedure.c Platelet count < 100,000 mm3; ultrasound features including surface nodularity, splenomegaly, and portal vein diameter > 15 mm; and esophageal varices.d Patients still on follow-up evaluation without histologic or clinical evidence of progression to cirrhosis.e Transient elastography values >14.6 kPa.f Overall, that is, combining histologic, clinical, and transient elastography results. Open table in a new tab NOTE. Cirrhosis was diagnosed by combining the results of a second liver biopsy procedure, clinical evaluation, and transient elastography. Cirrhosis was diagnosed on clinical grounds (ie, the presence of portal hypertension detected with ultrasound, thrombocytopenia, and esophageal varices at endoscopy), in an additional 25 CG (+) and 32 CG (−) patients (22% vs 22%) (Table 4). Overall, histologic and clinical progression of chronic hepatitis to cirrhosis was observed in 28 CG (+) and 39 CG (−) patients (24% vs 27%, NS), with a 10-year cumulative probability of 25% in CG (+) and 24% in CG (−) patients (Figure 1), respectively. A total of 109 patients (44 CG [+] and 65 CG [−]) without histologic or clinical eviden
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