Gomez EV, Rodriguez YS, Berdot LC, Gonzalez AT, Perez YM, Soler EA, et al. The natural history of compensated HCV-related cirrhosis: a prospective long-term study. J Hepatol 2013;58:434-444. (Reprinted with permission.)
Background & Aims: The natural history of HCV-related compensated cirrhosis has been poorly investigated in Latin-American countries. Our study evaluated mortality and clinical outcomes in compensated cirrhotic patients followed for 6 years.
Methods: Four hundred and two patients with compensated HCV-related cirrhosis were prospectively recruited in a tertiary care academic center. At the time of admission, patients were stratified as compensated (absence [stage 1] or presence [stage 2] of esophageal varices) as defined by D'Amico et al. Subjects were followed to identify overall mortality or liver transplantation and clinical complication rates.
Results: Among 402 subjects, 294 were categorized as stage 1 and 108 as stage 2. Over a median of 176 weeks, 42 deaths occurred (10%), of which 30 were considered liver-related (7%) and 12 non-liver-related (3%); eight individuals (2%) underwent liver transplantation; 30 patients (7%) developed HCC, 67 individuals in stage 1 (22%) developed varices and any event of clinical decompensation occurred in 80 patients (20%). The 6-year cumulative overall mortality or liver transplantation was 15% and 45%, for stages 1 and 2, respectively (p < 0.001). The cumulative 6-year HCC incidence was significantly higher among patients with varices (29%) than those without varices (9%), p < 0.001. Similarly, the cumulative 6-year incidence of any clinical liver-related complication was higher in patients with stage 2 (66%) as compared to 26% in those with stage 1, respectively (p < 0.001).
Conclusions: Our results indicate significant morbidity and mortality and clinical outcome rates in compensated cirrhotic patients with varices (stage 2).
As cirrhosis progresses, clinical decompensation and occurrence of hepatocellular carcinoma increase the risk of death and transplantation. The severity of portal hypertension dictates the occurrence of ascites, hepatic encephalopathy, and variceal hemorrhage. D'Amico et al. demonstrated that the risk of death differs based on the absence or presence of certain features that allows staging of cirrhosis. Mortality increases with signs of progression such as the occurrence of varices, ascites, and hepatic encephalopathy. One of the benefits of staging cirrhosis is it allows a better understanding of the prognosis with increasing severity of cirrhosis. Also, as new therapies are introduced in the management of cirrhosis, better targeting of interventions by stage of disease may enhance efficacy.
In patients with clinically significant portal hypertension (hepatic venous pressure gradient [HVPG] ≥10 mmHg) higher rates of clinical decompensation, hepatocellular carcinoma (HCC), death, or transplantation can be expected. In contrast, in patients with clinically mild portal hypertension (HVPG < 10 mmHg), the risk of complications from cirrhosis or liver-related mortality is low. Patients with compensated cirrhosis without varices or stage 1 cirrhosis are more likely to have clinically mild portal hypertension. Clinically significant portal hypertension is more likely to be present in stage 2 cirrhosis with varices and at higher risk of complications.
Certain factors have also been shown to increase the risk of decompensation, including etiology of liver disease, alcohol use, and obesity. In one study, patients with a body mass index (BMI) >30 had a 37% 5-year risk of decompensation. Medical therapy may also reduce the risk of complications in cirrhosis. A hemodynamic response to beta blockers defined by a 20% reduction from baseline in the HVPG or its dropping below 12 mmHg is associated with a lower risk of decompensation of cirrhosis.
Numerous European groups have evaluated the risk of decompensation in cirrhosis. In one retrospective study of patients with compensated cirrhosis from hepatitis C, the 5-year risk of decompensation was 18%, HCC was 7%, and cumulative survival was 91%. Another study of 214 patients with compensated Child A cirrhosis followed for a median of 114 months showed the annual incidence rates of HCC, ascites, jaundice, upper gastrointestinal hemorrhage, and hepatic encephalopathy to be 3.9%, 2.9%, 2%, 0.7%, and 0.1%, respectively. The HALT-C trial, which analyzed a cohort of patients living in the U.S. with advanced fibrosis and cirrhosis, also showed similar findings. In 428 patients with compensated cirrhosis, the annualized incidence of HCC, ascites, variceal hemorrhage, and hepatic encephalopathy was 2.4%, 2.9%, 0.9%, and 1.9%, respectively. The overall annualized incidence ratio for decompensation was 3.9% and liver-related death or transplantation was 4.2%. In a Japanese cohort of 657 patients with compensated cirrhosis from hepatitis B and C virus (HBV, HCV), similar results were found. The group observed that HCV patients had a higher risk of HCC and death compared to HBV. Ongoing alcohol abuse was also found to predict poor outcome in the Japanese cohort.
Gomez et al. have further contributed to our understanding of decompensation in cirrhosis. In particular, the group focused on patients from Latin America with the main objective to evaluate the 6-year cumulative incidence of overall mortality or transplantation, HCC, and major clinical outcomes of hepatic decompensation. The authors evaluated a large Cuban cohort of HCV patients with cirrhosis with two different stages of compensated disease with the absence (stage 1) and presence of varices (stage 2). The study was conducted as a prospective longitudinal “inception cohort” study. Between 2004 and 2007, 402 patients were included in the study if they were >18 years of age, had confirmed diagnosis of cirrhosis based on clinical, laboratory, and imaging findings, or histology, without a history of decompensation and absence of alcoholism. Patients were excluded if there was concurrent liver disease, concomitant diseases with reduced life expectancy, psychiatric disease, or HCC. Noninvasive studies were relied on to make the diagnoses of cirrhosis in some patients. This may influence the findings, as noninvasive testing can occasionally misdiagnose cirrhosis. The primary outcome of the study was overall mortality or liver transplantation. Secondary outcomes were diagnosis of HCC, variceal hemorrhage, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, jaundice, and development of varices in patients (in stage 1 patients only).
Similar to previous studies, the authors found that patients with stage 2 disease with varices had poorer outcomes when compared to stage 1 disease without varices. The cumulative overall mortality or liver transplantation at 312 weeks was significantly lower in stage 1 cirrhosis without varices (15%) compared to stage 2 cirrhosis with varices (45%). Also consistent with previously published results, the incidence of HCC at 312 weeks was significantly lower in patients with stage 1 cirrhosis (9%) compared to stage 2 cirrhosis (29%). Notably, patients were screened for HCC every 6 months with liver ultrasonography and α-fetoprotein determination throughout the study. Similar to previous findings, ascites was the most common first decompensating event, at 15%. Variceal hemorrhage and hepatic encephalopathy each occurred as the first decompensating event in 5% of patients. The occurrence of clinical decompensation was different in patients with stage 1 and 2 cirrhosis. One possible explanation is that patients both with (higher HVPG) and without varices (lower HVPG) were included. Patients with stage 2 cirrhosis with varices had a higher 6-year cumulative incidence of decompensation at 66% but stage 1 patients without varices had a significantly lower incidence, at 26%. Interestingly, among patients who developed varices on follow-up, the rate of decompensation was 39% in the study, which was higher than the stage 1 cirrhosis group who did not develop varices and would be consistent with increasing portal pressures. Antiviral therapy against HCV did not appear to influence the findings of the study. However, some patients who achieved a sustained virological response decompensated, raising the possibility of a concurrent liver condition such as nonalcoholic steatohepatitis or alcoholism. The quantification of alcohol use during the study was not entirely clear. The effect of beta-blocker use during the study was also not addressed, which may affect the interpretation of the findings. Patients may have also experienced different management of cirrhosis-related complications which could affect their prognosis. For example, the use of different types of bridging therapy for transplant-listed patients with HCC or the use of variceal ligation for primary prophylaxis against variceal hemorrhage in patients intolerant to beta-blockers.
Findings from Gomez et al. confirm that there are two distinct stages of compensated cirrhosis (with and without varices) where the near-term risks and complications differ. Patients with stage 1 cirrhosis without varices are more likely to have mild portal hypertension (HVPG <10 mmHg) and their near-term risks may be related to HCC and comorbid nonhepatic conditions. In contrast, patients with compensated stage 2 cirrhosis with varices will be at higher near-term risk for portal hypertensive complications as well as HCC in addition to any risk from nonhepatic conditions. As the two stages of compensated cirrhosis are now well defined, further studies should appropriately stage patients, which may result in better treatment strategies and outcomes. Studies using beta-blockers in preprimary prophylaxis against varices with timolol and primary prophylaxis against variceal hemorrhage with nadolol and propranolol are examples of such a strategy.
Amir Ahmed Qamar, M.D.
Lahey Hospital and Medical Center
Transplantation and Hepatobiliary Medicine