As a side note, according to the HCV treatment guidelines published by the American Association for the Study of Liver Diseases, the Infectious Diseases Society of America and the International Antiviral Society, the only contraindication to current chronic HCV treatment is in a patient with a short life expectancy that cannot be lengthened with treatment, with liver transplant, or with any other treatments. Overtime we have learned that treating people with lower-stage fibrosis increases SVR rates, and for persons who inject drugs, adherence and efficacy rates are comparable to those of patients who do not use injected drugs. In other words, treat all.
Patients with stage 3 compared to stage 4 liver fibrosis have lower frequency of and longer time to liver disease complications
Page Axley,
Sandhya Mudumbi,
Shabnam Sarker,
Yong-Fang Kuo,
Ashwani Singal Published: May 10, 2018
https://doi.org/10.1371/journal.pone.0197117
Full-Text
Abstract
Background and aims
Advanced liver fibrosis is an important predictor of liver disease progression and mortality, and current guidelines recommend screening for complications of cirrhosis once patients develop F3 fibrosis. Our study compared liver disease progression and survival in patients with stage 3 (F3) and stage 4 (F4) fibrosis on liver biopsy.
Methods
Retrospective study of patients with F3 or F4 on liver biopsy followed for development of liver disease complications (variceal bleeding, ascites, and hepatic encephalopathy); hepatocellular carcinoma, and survival (overall and transplant free survival).
Results
Of 2488 patients receiving liver biopsy between 01/02 and 12/12, a total of 294 (171 F3) were analyzed. Over a median follow up period of 3 years, patients with F4 (mean age 53 years, 63% male) compared to F3 (mean age 49 years, 43% male) had higher five year cumulative probability of any decompensation (38% vs. 14%, p<0.0001), including variceal bleed (10% vs. 4%, p = 0.014), ascites (21% vs. 9%, p = 0.0014), and hepatic encephalopathy (14% vs. 5%, p = 0.003). F4 patients also had lower overall 5-year survival (80% vs. 93%, p = 0.003) and transplant free survival (80% vs. 93%, p = 0.002). Probability of hepatocellular carcinoma in 5 years after biopsy was similar between F3 and F4 (1.2% vs. 2%, p = 0.54).
Conclusions
Compared to F4 stage, patients with F3 fibrosis have decreased risk for development of liver disease complications and better survival. Prospective well designed studies are suggested with large sample size and overcoming the limitations identified in this study, to confirm and validate these findings, as basis for modifying guidelines and recommendations on follow up of patients with advanced fibrosis and stage 3 liver fibrosis.
Discussion Only
View full text article @ PLOS ONE
The main findings of our study are that patients with F4 fibrosis compared to those with F3 stage have a) higher probability of developing decompensation of liver disease including ascites, variceal bleeding, and hepatic encephalopathy and b) lower overall and transplant-free survival.
In patients with chronic HCV infection, several previous studies have reported increased rate of liver disease complications related to advanced fibrosis stage. In a study of 1050 HCV patients, 57% with Ishak stage 4 to 6, there was cumulative incidence of first liver-disease complication of 19.3% for stage 4, 37.8% for stage 5, and 49.3% for stage 6 in the 6 year follow up period.[8] The probability of liver disease complication, death, or liver transplant increased with successive fibrosis stages. Stages 4 and 5 of the Ishak system represent advanced bridging fibrosis and/or early nodule formation and have shown excellent correlation with F3 in the METAVIR system.[9]
Another study based on four large US-integrated health systems retrospectively examined 917 chronic HCV patients with F3 and F4 fibrosis for 5 years after liver biopsy.[10] For liver disease related complications comparing F4 vs. F3 fibrosis, there was increased risk for ascites (14 vs. 7.1%), esophageal varices with bleeding (4.4 vs. 1.2%), and hepatic encephalopathy (3.9 vs. 1.4%) in the 5 year observation period after liver biopsy. The 5-year survival was 77% in F4 fibrosis compared to 91% in F3 fibrosis. The 5-year probability for HCC development was 3.1% in F3 fibrosis and 8.8% in F4 fibrosis.
Huang et al. evaluated 153 patients with F3 fibrosis (mean age 45, 54% male) and F4 fibrosis (mean age 51, 54% male) over a mean follow up period of 9 years and found that F4 had significantly higher risk of liver-related complications, hepatocellular carcinoma, and death than F3 (p < 0.001).[11] Very similar to our findings, the 5-year survival in patients with F4 fibrosis was 83% compared to 96% in patients with F3 fibrosis. The 5-year probability for development of HCC patients with F3 fibrosis was 0% compared to 6% in F4 patients. At year 7, probabilities for HCC development jumped to 16% in patients with F4 fibrosis and increased to 2% in patients with F3 fibrosis. Unlike these previous 2 studies described, our study failed to show a difference in the risk for development of HCC in F3 compared to F4 fibrosis, likely because of the shorter follow up period of only 5 years and the inclusion of non-HCV patients who have lower risk for HCC development.
In NAFLD, advanced fibrosis has also been identified as leading to higher rates of liver-disease related complications and mortality.[12, 13] In a recent study of 646 patients (mean age 48, 62% male) with well-defined NAFLD followed for a mean of 20 years, patients with F4 fibrosis had a 3-fold increase in liver disease related complications and a 2-fold increase in overall mortality compared to those with F3 fibrosis.[14] The average time for patients with F3 fibrosis to develop severe liver disease as defined by the ICD-code diagnosis of cirrhosis, liver failure, HCC, or decompensated liver disease was 6 years (95% CI 2.3–9.6), however the study did not differentiate between these outcomes or provide data on HCC incidence. In another large multi-center cohort study of 619 NAFLD patients (11.5% with stage 3 or 4 fibrosis) followed for a median of 12.6 years, F4 patients compared to F3 patients had a four-fold increased probability for liver disease related complications overall and two-fold increased risk of liver-related mortality.[13] Only 3 patients in the study developed HCC, and fibrosis stage for these patients was not reported.
To our knowledge, this is the first study showing that patients with F3 compared to F4 fibrosis have lower frequency of and longer time to development of liver disease complications irrespective of liver disease etiology. Our large cohort is also well characterized with liver fibrosis stage confirmed by two separate pathologists. Further, studies have shown good inter- and intraobserver reproducibility on the fibrosis staging using any classification including the Metavir fibrosis staging system.[5] Also, potential confounders of alcohol use and HCV treatment were equally distributed in the two groups ruling out to a great extent their impact on the outcomes. However, apart from inherent limitations of a retrospective study design, our study does suffer from potential selection bias as not everyone presenting for liver disease evaluation at our center underwent a liver biopsy examination. Further, our study excluded patients with F2 fibrosis, which could be used as a control group and compare with F3 fibrosis on development of outcomes. Although for analysis on decompensation and liver disease complications, we only analyzed patients developing the respective event after 30 days from liver biopsy, it is possible that some of the F3 patients may have transitioned to F4 on follow up, and it is difficult to ascertain the stage of fibrosis at which the decompensation occurred. Repeat liver biopsy or non-invasive imaging with transient elastography was not performed and limits us from identifying the patients that may have progressed from F3 to F4 fibrosis stage.
Regardless of underlying liver disease etiology, advanced hepatic fibrosis portends increased liver-associated complications and mortality.[10–13, 15–21] However, physicians need to be vigilant as these patients unpredictably may transition to F4 stage. In this regard, data are needed on the use of non-invasive serum and radiological markers including fibroscan and transient elastography, as basis for cost-effective management of these patients in clinical practice.
In summary, our study shows lower rate of and slower development of decompensation and liver disease complications, with better overall and transplant free survival among patients with biopsy conformed bridging or advanced fibrosis (F3) as compared to patients with cirrhosis (F4) irrespective of liver disease etiology. We suggest larger multicenter prospective studies overcoming the limitations identified in this study, to confirm and validate these findings as basis for modifying guidelines and recommendations on follow up of patients with advanced fibrosis and stage 3 liver fibrosis.
The main findings of our study are that patients with F4 fibrosis compared to those with F3 stage have a) higher probability of developing decompensation of liver disease including ascites, variceal bleeding, and hepatic encephalopathy and b) lower overall and transplant-free survival.
In patients with chronic HCV infection, several previous studies have reported increased rate of liver disease complications related to advanced fibrosis stage. In a study of 1050 HCV patients, 57% with Ishak stage 4 to 6, there was cumulative incidence of first liver-disease complication of 19.3% for stage 4, 37.8% for stage 5, and 49.3% for stage 6 in the 6 year follow up period.[8] The probability of liver disease complication, death, or liver transplant increased with successive fibrosis stages. Stages 4 and 5 of the Ishak system represent advanced bridging fibrosis and/or early nodule formation and have shown excellent correlation with F3 in the METAVIR system.[9]
Another study based on four large US-integrated health systems retrospectively examined 917 chronic HCV patients with F3 and F4 fibrosis for 5 years after liver biopsy.[10] For liver disease related complications comparing F4 vs. F3 fibrosis, there was increased risk for ascites (14 vs. 7.1%), esophageal varices with bleeding (4.4 vs. 1.2%), and hepatic encephalopathy (3.9 vs. 1.4%) in the 5 year observation period after liver biopsy. The 5-year survival was 77% in F4 fibrosis compared to 91% in F3 fibrosis. The 5-year probability for HCC development was 3.1% in F3 fibrosis and 8.8% in F4 fibrosis.
Huang et al. evaluated 153 patients with F3 fibrosis (mean age 45, 54% male) and F4 fibrosis (mean age 51, 54% male) over a mean follow up period of 9 years and found that F4 had significantly higher risk of liver-related complications, hepatocellular carcinoma, and death than F3 (p < 0.001).[11] Very similar to our findings, the 5-year survival in patients with F4 fibrosis was 83% compared to 96% in patients with F3 fibrosis. The 5-year probability for development of HCC patients with F3 fibrosis was 0% compared to 6% in F4 patients. At year 7, probabilities for HCC development jumped to 16% in patients with F4 fibrosis and increased to 2% in patients with F3 fibrosis. Unlike these previous 2 studies described, our study failed to show a difference in the risk for development of HCC in F3 compared to F4 fibrosis, likely because of the shorter follow up period of only 5 years and the inclusion of non-HCV patients who have lower risk for HCC development.
In NAFLD, advanced fibrosis has also been identified as leading to higher rates of liver-disease related complications and mortality.[12, 13] In a recent study of 646 patients (mean age 48, 62% male) with well-defined NAFLD followed for a mean of 20 years, patients with F4 fibrosis had a 3-fold increase in liver disease related complications and a 2-fold increase in overall mortality compared to those with F3 fibrosis.[14] The average time for patients with F3 fibrosis to develop severe liver disease as defined by the ICD-code diagnosis of cirrhosis, liver failure, HCC, or decompensated liver disease was 6 years (95% CI 2.3–9.6), however the study did not differentiate between these outcomes or provide data on HCC incidence. In another large multi-center cohort study of 619 NAFLD patients (11.5% with stage 3 or 4 fibrosis) followed for a median of 12.6 years, F4 patients compared to F3 patients had a four-fold increased probability for liver disease related complications overall and two-fold increased risk of liver-related mortality.[13] Only 3 patients in the study developed HCC, and fibrosis stage for these patients was not reported.
To our knowledge, this is the first study showing that patients with F3 compared to F4 fibrosis have lower frequency of and longer time to development of liver disease complications irrespective of liver disease etiology. Our large cohort is also well characterized with liver fibrosis stage confirmed by two separate pathologists. Further, studies have shown good inter- and intraobserver reproducibility on the fibrosis staging using any classification including the Metavir fibrosis staging system.[5] Also, potential confounders of alcohol use and HCV treatment were equally distributed in the two groups ruling out to a great extent their impact on the outcomes. However, apart from inherent limitations of a retrospective study design, our study does suffer from potential selection bias as not everyone presenting for liver disease evaluation at our center underwent a liver biopsy examination. Further, our study excluded patients with F2 fibrosis, which could be used as a control group and compare with F3 fibrosis on development of outcomes. Although for analysis on decompensation and liver disease complications, we only analyzed patients developing the respective event after 30 days from liver biopsy, it is possible that some of the F3 patients may have transitioned to F4 on follow up, and it is difficult to ascertain the stage of fibrosis at which the decompensation occurred. Repeat liver biopsy or non-invasive imaging with transient elastography was not performed and limits us from identifying the patients that may have progressed from F3 to F4 fibrosis stage.
Regardless of underlying liver disease etiology, advanced hepatic fibrosis portends increased liver-associated complications and mortality.[10–13, 15–21] However, physicians need to be vigilant as these patients unpredictably may transition to F4 stage. In this regard, data are needed on the use of non-invasive serum and radiological markers including fibroscan and transient elastography, as basis for cost-effective management of these patients in clinical practice.
In summary, our study shows lower rate of and slower development of decompensation and liver disease complications, with better overall and transplant free survival among patients with biopsy conformed bridging or advanced fibrosis (F3) as compared to patients with cirrhosis (F4) irrespective of liver disease etiology. We suggest larger multicenter prospective studies overcoming the limitations identified in this study, to confirm and validate these findings as basis for modifying guidelines and recommendations on follow up of patients with advanced fibrosis and stage 3 liver fibrosis.
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