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The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 patients†
Article first published online: 25 MAY 2006
Copyright © 2006 American Association for the Study of Liver Diseases
Volume 43, Issue 6, pages 1303–1310, June 2006
How to Cite
Sangiovanni, A., Prati, G. M., Fasani, P., Ronchi, G., Romeo, R., Manini, M., Del Ninno, E., Morabito, A. and Colombo, M. (2006), The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 patients. Hepatology, 43: 1303–1310. doi: 10.1002/hep.21176
Potential conflict of interest: Nothing to report.
- Issue published online: 25 MAY 2006
- Article first published online: 25 MAY 2006
- Manuscript Accepted: 28 FEB 2006
- Manuscript Received: 21 JUL 2005
- FIRST 2004
- IRCCS Maggiore Hospital RF 2002
- Consorzio Interuniversitario Trapianti d'Organo
Large databases of consecutive patients followed for sufficiently long periods are needed to establish the rates, chronology, and hierarchy of complications of cirrhosis as well as the importance of other potential causes of liver disease. In accordance with this goal, a cohort of patients with compensated cirrhosis due to hepatitis C virus (HCV) was followed for 17 years. Two hundred and fourteen HCV RNA–seropositive patients with Child-Pugh class A cirrhosis who had no previous clinical decompensation were prospectively recruited and followed up with periodic clinical and abdominal ultrasound examinations. During 114 months (range 1–199), hepatocellular carcinoma (HCC) developed in 68 (32%), ascites in 50 (23%), jaundice in 36 (17%), upper gastrointestinal bleeding in 13 (6%), and encephalopathy in 2 (1%), with annual incidence rates of 3.9%, 2.9%, 2.0%, 0.7%, and 0.1%, respectively. Clinical status remained unchanged in 154 (72%) and progressed to Child-Pugh class B in 45 (21%) and class C in 15 (7%). HCC was the main cause of death (44%) and the first complication to develop in 58 (27%) patients, followed by ascites in 29 (14%), jaundice in 20 (9%), and upper gastrointestinal bleeding in 3 (1%). The annual mortality rate was 4.0% per year and was higher in patients with other potential causes of liver disease than in those without them (5.7% vs. 3.6%; P = .04). In conclusion, hepatitis C–related cirrhosis is a slowly progressive disease that may be accelerated by other potential causes of liver disease. HCC was the first complication to develop and the dominant cause for increased mortality. (HEPATOLOGY 2006;43:1303–1310.)
Chronic hepatitis C infection leads to cirrhosis in a substantial number of patients.1, 2 Although the course of hepatitis C–related cirrhosis is generally considered to be slow, it shows substantial variations at an individual level, probably due to the interplay with other potential host and environmental causes of liver disease.3, 4 Alcohol abuse, hepatitis B virus (HBV) infection, and metabolic liver diseases have emerged as major determinants of clinical decompensation, development of hepatocellular carcinoma (HCC), and survival of patients with compensated cirrhosis.5–8 However, lack of cohort enrollment and sufficiently long periods of follow-up might have limited the correct understanding of the natural history and prognostication of hepatitis C virus (HCV)-related cirrhosis—particularly when epiphenomena like ascites, jaundice, and encephalopathy are selected, all of which are indirect indicators of liver function not central to the disease process.9 In 1986, a cohort of 417 HCC-free patients with compensated cirrhosis of different etiologies was enrolled into a surveillance program for HCC, whose secondary end point was clinical decompensation and patient survival.10, 11 As a result of a retrospective reclassification of the etiology of cirrhosis through the assessment of serum HCV RNA with sensitive polymerase chain reaction, we could analyze the evolution of hepatitis C–related cirrhosis with respect to other relevant potential causes of liver disease over an observation period of 17 years. To gain more insight into the natural course of the disease, we excluded all patients with previous episodes of clinical decompensation and those with more advanced liver impairment, such as Child-Pugh class B patients. Because a negligible number of patients in the cohort ultimately received interferon therapy, this retrospective study offered a unique opportunity to evaluate the course of hepatitis C–related cirrhosis independently of HCV antiviral therapy. In fact, a prospective study of interferon-naïve patients would be hardly feasible today due to the high-rate of patients cured with the currently available interferon regimens, which would allow for few HCV patients with untreated disease.
Patients and Methods
Between October 1985 and October 1986, all patients attending the liver clinic at Maggiore Hospital were enrolled in the study if they had a histological diagnosis of cirrhosis, had preserved liver function (Child-Pugh class A or B), were 35 years of age or more, had no hepatic tumors, were willing to cooperate by visiting the clinic at scheduled intervals, and consented to the performance of invasive procedures if they became necessary. Informed consent was given verbally in the presence of an independent witness.
A cohort of 417 HCC-free patients with compensated cirrhosis was established that included patients with liver disease of different etiologies.10, 11 The present study includes 214 antibody to HCV/HCV RNA–seropositive patients with Child-Pugh class A cirrhosis,12 no evidence of HCC at enrollment, and no history of previous clinical decompensation. (Table 1). The present analysis excludes antibody to HCV–positive/HCV RNA–seronegative patients (n = 27), HCV RNA–positive patients with Child-Pugh class B cirrhosis (n = 33), and patients with a previous history of upper gastrointestinal hemorrhage (n = 1), jaundice (n = 2), ascites (n = 1), and those treated with a low-salt diet and aldosterone antagonists (n = 3). Between May 1989 and November 1993, 23 (11%) patients received standard interferon alpha for a median of 9 months (range 6–12). None of them achieved a sustained virological response.
|Patient Characteristics||All (n = 214)||Cofactors (−) (n = 171)||Cofactors (+) (n = 43)*||P|
|Males||144 (67%)||106 (62%)||38 (88%)||.001†|
|Mean age ± SD, years||55 ± 7||55 ± 7||53 ± 8||.2‡|
|Source of infection||.24†|
|Blood transfusion||23 (11%)||21 (12%)||2 (5%)|
|Health care workers||5 (2%)||3 (2%)||1 (2%)|
|Intravenous drug users||4 (2%)||2 (1%)||2 (5%)|
|Unknown||182 (85%)||145 (85%)||38 (88%)|
|1a||37 (17%)||29 (17%)||8 (19%)|
|1b||107 (53%)||89 (53%)||18 (42%)|
|2c||68 (30%)||51 (30%)||17 (39%)|
|Not typed||2 (1%)||2 (1%)||0|
|Anti-HBc+/HBsAg−||119 (56%)||99 (58%)||20 (67%)||.37†|
|AFP <20 ng/mL||166 (78%)||135 (79%)||31 (72%)||.33†|
|Gastro-esophageal varices||50 (22%)||38 (22%)||12 (28%)||.43†|
|Hepatic steatosis grade 3§||42 (20%)||34 (20%)||8 (19%)||.85†|
|Diabetes mellitus||31 (15%)||26 (15%)||5 (12%)||.55†|
Investigations at Enrollment.
The routine evaluation of the patients included a detailed medical history, a physical examination and a complete blood count, biochemical tests, and markers for viral hepatitis. In addition, all patients underwent abdominal ultrasound (US) (gray-scale, real-time) (Aloka, Tokyo [SSD630]) and serum alpha-fetoprotein (AFP) measurement (IRMA; Abbott Laboratories, North Chicago, IL; normal values ≤20 ng/mL per liter) to exclude pre-existing HCC. Patients with a focal lesion on US or a serum AFP level above 100 μg/mL were considered as possibly having HCC and were further investigated with CT with contrast media. In selected instances, patients were further investigated with hepatic arteriography and echo-guided fine needle liver biopsy.
Serum samples were tested for hepatitis B surface antigen (HBsAg) and its antibody (anti-HBs), antibody to hepatitis B core antigen, hepatitis B e antigen and its antibody, and antibody to delta antigen via commercially available ELISA (Abbott Laboratories). Antibody to HCV and HCV RNA were tested on serum samples kept frozen at −30°C that were collected at the time of patients' enrollment into the study (1985–1986). Antibody to HCV was assessed via second-generation ELISA (Ortho Diagnostic Systems, Raritan, NJ). Serum HCV RNA was tested via nested polymerase chain reaction, with a limited sensitivity of approximately 50 virus particles per milliliter of serum,13 and typed by Line Probe Assay (InnoLipa, Innogenetics, Zwijndrecht, Belgium). HBV DNA was tested via polymerase chain reaction (Versant 1.0; Bayer Corporation, Tarrytown, NJ). Non–organ-specific autoantibodies and antinuclear, anti–smooth muscle, antimitocondrial, and anti-liver–kidney microsomes were searched for via indirect immunofluorescence assay performed on 4-μm cryostat sections from rat liver, kidney, and stomach at a sera dilution of 1:40. The International Autoimmune Hepatitis Group score was employed for the diagnosis of autoimmune hepatitis.14 Hereditary hemochromatosis was diagnosed using standard criteria (i.e., excluding known causes of iron overload and assessing hepatic iron index [liver iron concentration/age] greater than 1.9) and liver siderosis from periportal hepatocytes to centrolobular veins.15 An experienced liver pathologist (G. R.) evaluated all the liver biopsy samples. Hepatic steatosis was graded on the basis of the percentage of hepatocytes involved: grade 0, no steatosis; grade 1, 1%–33%; grade 2, 34%–66%; grade 3, > 66%.
Diabetes mellitus was diagnosed according to Internationally accepted criteria.16
Liver function was assessed via plasma prothrombin time expressed as international normalized ratio (normal values: 0.8–1.2), serum gamma-glutamyltranspeptidase (GGTP) (normal values: 7–32 IU/L), alkaline phosphatase (normal values: 39–117 IU/L), bilirubin (normal values: <1.0mg/dL), albumin (normal values: 3.5–5.0 g/dL), alanine aminotransferase (normal values: <39 IU/L), creatinine (normal values: <1.3 mg/dL), and platelet count (PLT) (normal values: 140–440 × 109/L).
All patients underwent esophago-gastroduodenoscopy before the study. Esophageal varices were classified according to the North Italian Endoscopic Club.17 The amount and duration of alcohol intake were recorded on interview and confirmed by relatives. The amount of alcohol was calculated from the type and gradation of alcoholic beverage and classified in a semiquantitative scale as (1) no alcohol consumption, (2) mild intake (consumption of <40 g/d); (3) moderate intake (40–80 g/d in men and 40–60 g/d in women); and (4) high intake (>60 g/d in women and >80 g/d in men). Alcohol abuse was defined by a daily intake of more than 60 g of ethanol in women or more than 80 g in men for more than 10 years.
Definition of Nosological Categories.
Patients were classified according to the following nosological categories for the cause of cirrhosis: (1) positivity for the antibody to hepatitis C virus and HCV RNA; (2) positivity for the antibody to hepatitis C virus and HCV RNA and one or more of the following factors: HBsAg, alcohol abuse, autoimmunity, or metabolic liver disease (e.g., hereditary hemochromatosis, alfa-1-antitrypsin deficiency, Wilson's disease).
Surveillance and End Points of the Study.
The time of observation was calculated from the date of enrollment into the study until death or December 2003. Liver function tests and a complete physical examination were performed every 6 months. The AFP assay and US scanning were repeated at yearly intervals in all patients with normal AFP levels and no US evidence of hepatic tumors. Patients with AFP levels above 20 ng/mL and no focal lesions on US had AFP and US scanning repeated every 6 months, because they were thought to be at a particularly high risk of developing liver cancer.
An esophago-gastroduodenoscopy was repeated every other year in patients lacking varices at previous endoscopy, or repeated at yearly intervals in patients with documented gastro-oesophageal varices.
Whenever possible, the diagnosis of HCC was made using US-guided fine needle biopsy of a node detected via US. A 21-gauge needle (Tru-Cut; TSK Laboratories, Tokyo, Japan) was used to obtain samples for histological assessment. Diagnostic criteria for HCC were: (1) histological, based on internationally accepted criteria (i.e., existence of a pattern of invasive growth or replacing growth18), and (2) clinical, in patients with AFP levels above 400 ng/mL and evidence of focal liver lesion on US or CT.
Tumors were staged via conventional abdominal CT, hepatic arteriography, chest X ray, and bone scintigraphy. Tumor size was defined as the maximum diameter of tumor nodes measured via abdominal US at the time of diagnosis of HCC.
Ascites was diagnosed via clinical examination and/or US. Whenever possible, patients with ascites underwent diagnostic paracentesis. Porto-systemic encephalopathy was defined by clinical parameters and confirmed by psychometric tests and electroencephalogram. Gastrointestinal bleeding was defined as hematemesis and/or melena, or gastric aspirate containing blood and confirmed by endoscopy whenever possible. Gastro-esophageal bleeding was defined as active bleeding or signs of recent bleeding confirmed via endoscopy or, in cases of endoscopy performed within 24 hours of hematemesis and/or melena, the presence of blood in the stomach and varices without other potential bleeding sites.
Treatment of Complications.
The criteria for HCC resectability were: Child-Pugh class A, performance status19 of 0, a less than 5 cm peripheral nodule, and the absence of vascular invasion or extrahepatic metastases.20 Similar criteria were adopted for transplantation, including patients with fewer than 3 nodes less than 3 cm in diameter, Child-Pugh class C, and an age cutoff of 65 years. Patients with compensated cirrhosis and no more than 2 focal lesions and a maximum tumor size smaller than 5 cm in whom surgical treatment was precluded or who refused surgery were treated via percutaneous ethanol injection and, beginning in 1996, via radiofrequency interstitial thermal ablation according to standard criteria.20–22 Transcatheter arterial chemoembolization was performed in patients with compensated liver disease (Child-Pugh class A or B), performance status 0–2, who were not eligible for surgical or interstitial ablative treatments. Tamoxifen (20 mg/d) was administered in patients who did not meet the above criteria for surgical or locoregional treatment. Patients with F2 and F3 esophageal varices were given prophylaxis with beta-blockers in the absence of specific contraindications.
The chi-square test and Student t test were used to evaluate differences in demographic, clinical, and etiological features of the patient groups and in tumor characteristics. Average annual rates were estimated as number of events divided by at-risk person time. Estimated survival function was calculated using the Kaplan-Meier method, and survival curves were compared via log-rank test. All information about variables were collected at the time of enrollment. Variables considered for univariate analysis were: AFP, prothrombin time, GGTP, alkaline phosphatase, bilirubin, albumin, alanine aminotransferase, PLT, gamma-globulin, presence of esophageal varices, age, sex, alcohol consumption, HBsAg, antibody to hepatitis B core antigen, HCV genotype, other potential causes of liver disease, diabetes mellitus, and hepatic steatosis. The median value of age at enrollment, and the upper limit of normal for AFP (20 ng/mL) were the cutoff points used to generate 2 groups of patients using continuous variables. The Cox proportional hazards regression was used to evaluate overall survival, risk of HCC development, and liver decompensation in relation to the covariate. All assumptions of the Cox model were tested by plotting the log(−log(survival)) versus time according to the stratification variable and met. Variables with a P value equal to or less than .10 on univariate analysis were introduced in the Cox model. The cumulative probability of events was calculated via product limit method. Survival analysis was performed with STATA 7.0 statistical software.
The 214 HCV RNA seropositive patients were followed for an average period of 114 months (range 1–199). One hundred fifty-two patients were followed for more than 5 years, 97 for more than 10 years, and 42 for more than 15 years. Sixty-six patients were lost during follow-up, corresponding to an annual rate of 3.4%. Patients were lost because they moved home (33 [50%]), because they preferred to be followed in other hospitals (13 [20%]), or because of lack of compliance to the screening program (20 [30%]). All the patients not attending the scheduled visit and classified as lost were contacted by telephone to ensure they were alive and they were censored at the time of last visit. Forty-three patients (20%) had other potential causes of liver disease such as serum HBsAg, high alcohol intake, or metabolic liver disease (Table 1). Daily alcohol intake was absent in 58 (27%), mild in 89 (42%), moderate in 37 (17%), and high in 30 (14%). A history of alcohol abuse was recorded in 30 (14%). At the time of enrollment and during surveillance, 35 users (16%) became abstainers, and the remaining patients consumed less than 40 g/d alcohol.
Chronology and Hierarchy of Complications.
HCC developed in 68 patients (32%), ascites in 50 (23%), jaundice in 36 (17%), upper gastrointestinal bleeding in 13 (6%), and encephalopathy in 2 (1%). The corresponding annual incidence rates were 3.9%, 2.9%, 2.0%, 0.7%, and 0.1%, respectively (Fig. 1). Overall, 110 (51%) patients reached at least 1 of the above-mentioned end points for an annual incidence of 6.9%. HCC was the first clinical complication to be detected in 58 (27%) patients, followed by ascites in 29 (14%), jaundice in 20 (9%), and gastrointestinal hemorrhage in 3 (1%). Ten additional patients developed clinical decompensation following the onset of HCC (i.e., ascites in 7, jaundice in 7, gastrointestinal bleeding in 4, and encephalopathy in 2). De novo gastro-oesophageal varices developed in 48 (22%) patients, corresponding to an annual incidence of 3.5%. During the study period, the clinical status remained unchanged in 154 (72%) patients, whereas it progressed to Child-Pugh class B in 45 (21%) and class C in 15 (7%). Thirty-two patients (47%) had a single node tumor that in 29 (43%) was less than 5 cm in size. Thirty-six patients (53%) had multiple-node cancer; of these, 5 (7%) had equal or less than 3 nodes equal or less than 3 cm in size. Four (6%) patients with HCC underwent tumor resection, 5 (7%) orthotopic liver transplantation, 17 (26%) percutaneous ethanol injections or radiofrequency interstitial thermal ablation, 14 (21%) transarterial chemoembolization, and 7 (10%) hormonal therapy. Twenty (30%) patients received no treatment.
Predictors of Complications.
By univariate analysis, esophageal varices (P = .0001), serum HBsAg (P = .023), PLT below 146 × 109/L (P < .0001), prothrombin time above 1.09 international normalized ratio (P = .002), GGTP above 58 IU/mL (P = .04), bilirubin above 0.84 mg/dL (P < .0001), albumin below 4.3 g/dL (P = .0013), and gamma-globulin above 1.85 mg/dL (P = .018) were associated with an increased risk of clinical decompensation (Table 2). By multivariate analysis, esophageal varices (hazard ratio 2.6; CI 1.2–4.0; P = .009), and bilirubin (hazard ratio 2.6; 95% CI 1.0–3.6; P < .037) were the only independent predictors associated with increased risk of clinical decompensation. Esophageal varices (P = .001), serum AFP above 20 ng/mL (P = 0.0001), male sex (P < .004), PLT below 146 × 109/L (P = .003), GGTP above 58 IU/mL (P < .0001), bilirubin above 0.84 mg/dL (P = .012), and albumin below 4.3 g/dL (P = .017) were associated with an increased risk of HCC development. By multivariate analysis, serum AFP above 20 ng/mL (hazard ratio 1.5; 95% CI 1.0–2.2; P = .02), male sex (hazard ratio 2.7; 95% CI 1.3–4.9; P = .009), and GGTP (hazard ratio 2.1; 95% CI 1.2–3.7; P = .008) were independently associated with increased risk of developing HCC.
|Age > 55 yr||.455||.490||.226|
|AFP > 20 ng/mL||<.0001||.35||.008|
|PT (INR) > 1.09||.067||.002||.017|
|GGTP > 58 U/L||<.0001||.04||.001|
|Alkaline phosphatase > 177 U/L||.659||.15||.7|
|Bilirubin > 0.84 mg/dL||.012||<.0001||.002|
|Albumin < 4.3 g/dL||.017||.0013||<.0001|
|ALT > 96 U/L||.67||.18||.686|
|PLT < 109/L||.003||.0001||.0001|
|Gamma-globulin 1.85 g/dL||.116||.018||.004|
|Other causes of liver disease||.224||.125||.042|
Patients with additional causes of liver disease (alcohol abuse, HBV, and hemochromatosis) showed a higher annual incidence of jaundice (4.1% vs. 1.6%; P = .01) and annual mortality (5.7% vs. 3.6%; P = .04) than patients without any additional cause (Table 3). No significant association was detected between liver decompensation, HCC development, HCV genotype, or interferon treatment. Serum antibody to hepatitis B core antigen was not associated with an increased risk of HCC. During surveillance, we found no differences between abstainers and patients who continued to have mild or moderate alcohol intake in terms of clinical decompensation and HCC risk.
|Complication||Incidence Rate (95% CI)||P Value*|
|All (n = 214)||Cofactors (−) (n = 171)||Cofactors (+) (n = 43)|
Seventy-five (35%) patients died, yielding an annual mortality rate of 4.0% (Fig. 2). Thirty-three (44%) died of tumor progression, 6 (8%) of gastro-esophageal bleeding, 15 (20%) of liver decompensation, 1 (1%) following orthotopic liver transplantation, 8 (11%) of nonhepatic neoplasia, 6 (8%) of non–liver-related causes, and 6 (8%) of unknown causes. In 6 patients, clinical decompensation was preceded by a flare of hepatitis B. AFP (P < .002), esophageal varices (P = .003), additional causes of liver disease (P < .04), PLT (P = .0001), prothrombin time (P < .017), GGTP (P = .011), bilirubin (P = .0025), albumin (P = .0001) and gamma-globulin (P = .0045) were significantly associated with increased mortality. By multivariate analysis, GGTP (hazard ratio 1.8; CI 1.0–3.2; P = .037), PLT (hazard ratio 2.1; CI 1.1–4.0; P = .031), albumin (hazard ratio 2.9; CI 1.6–5.5; P = .001), and additional causes of liver disease (hazard ratio 1.6; CI 1.1–2.2; P = .006) were independently associated with mortality. The annual mortality in tumor-free patients was 15.1% per year following ascites development, 16.6% after jaundice, and 27.7% after gastrointestinal hemorrhage. Annual mortality was 31.5% per year after diagnosis of HCC.
This study clearly demonstrates a slow evolution of cirrhosis in patients chronically infected with HCV who lack previous episodes of clinical decompensation, a course that can be accelerated by other potential causes of liver disease. With the use of sensitive polymerase chain reaction assay for HCV RNA, we found that the vast majority (89%) of patients with antibody to HCV were viremic, confirming the figures of a recent study in Italy.8 Cirrhosis in serum HCV RNA–negative patients was likely the result of liver disease other than HCV. However, because the number of patients who tested seronegative for HCV RNA was limited, we could not assess whether the course of the disease in these latter patients was substantially different from that of HCV RNA–seropositive ones.
The present study confirms that HCC is the prevalent complication and prime cause of death in patients with HCV-related cirrhosis, an event that occurs independently of other potential causes of liver disease. We acknowledge that the 3.9% annual incidence of HCC we found is somewhat higher than the 2.8% rate reported in a single-center study in Italy8 and the 1.4% rate reported by a multicenter study in Europe.23 However, differences in HCC incidence between studies in patients with compensated cirrhosis might well reflect differences in patient selection, with particular reference to the recruitment of patients with liver disease of verified duration and length of follow-up. In at least 3 studies,11, 24, 25 older age and prolonged disease duration were associated with an increased risk of developing liver cancer. In our cohort, most patients (85%) had community-acquired hepatitis of unspecified duration as the likely cause of cirrhosis, a condition that increases the chance that hepatitis will not be diagnosed until late in life. Conversely, in the European multicenter study,23 44% of patients had parenteral risks for hepatitis C, which increased the chances of hepatitis to be recognized earlier in life.
Interestingly, we found that HCC and clinical decompensation developed at similar incidences during follow-up, the former being more likely to be predicted by sex, AFP, and GGTP, the latter by esophageal varices and serum bilirubin.
In a previous study in France,25 esophageal varices, sex, age, platelets, and bilirubin had emerged as predictors of HCC risk in patients with compensated cirrhosis due to HCV, suggesting that duration and severity of the disease were important contributors to liver carcinogenesis. In another study in Italy, coinfection with HBV and alcohol abuse was shown to dramatically increase the progression of HCV-related cirrhosis to HCC, which was in fact the primary complication.8 In our study, esophageal varices and bilirubin were the only predictors of clinical decompensation, whereas HBV, alcohol abuse, and hemochromatosis defined a subgroup of patients with compensated cirrhosis that were more prone than others to decompensate. We acknowledge that in patients with HBV and HCV it may be difficult to weigh the exact role of either virus on development of liver pathology, and that this could be better assessed with sequential monitoring of both virus' replication.26 Because of the lack of follow-up biopsies, uncertainty as to where to assess the histological markers of HBV, and exhaustion of several archival serum samples taken during follow-up to test for virus replication, we could not properly reconstruct the impact of HBV on the course of HCV-related cirrhosis. HBV and alcohol abuse were found by Benvegnù and coworkers8 to accelerate decompensation in patients with HCV cirrhosis to the point of anticipating HCC in the natural course of the disease.
In our cohort, the 4% mortality in patients with HCV-related compensated cirrhosis favorably compares with a previous study in France indicating that the evolutionary course of the disease is slow.25 Survival was shortened in patients with other potential causes of liver disease (i.e., patients with a history of alcohol abuse, HBV infection, or iron overload due to genetic hemochromatosis) and was predicted by markers of liver disease severity. Additional causes of liver disease were also identified as relevant predictors of HCC and patient survival in studies enrolling patients with previous episodes of clinical decompensation.5, 27–29 At variance with previous studies, we could not confirm the relationship between HCV genotype and outcome of cirrhosis, probably because in those studies the analysis of risk was biased by the inclusion of older patients with more severe liver impairment.30, 31
In conclusion, cirrhosis resulting from ongoing HCV replication is a slowly progressing disease whose course in individual patients may be accelerated by alcohol abuse, HBV, or iron overload. The finding that liver cancer was the dominant cause of death in patients with compensated cirrhosis due to HCV indirectly suggests the importance of an early diagnosis of a tumor.
The authors thank Caterina M. Puricelli for her expert secretarial assistance.
- 1National Institutes of Health Consensus Development Conference Panel statement: Management of hepatitis C. HEPATOLOGY 1997; 26(Suppl 1): 2S–10S.
- 2EASL International Consensus Conference on hepatitis C. Paris, 26–27 February 1999. Consensus statement. J Hepatol 1999; 31(Suppl 1): 3–8.
- 26Associazione Italiana Studio Fegato Cooperative Group. Longitudinal evaluation reveals a complex spectrum of virological profiles in hepatitis B virus/hepatitis C virus-coinfected patients. HEPATOLOGY 2006; 43: 100–107., , , , , , et al.