Clinical Predictors of Fibrosis in Patients With Chronic Liver Disease: Discussion
".....Worldwide, HBV, HCV and NAFLD are the most common causes of CLD, affecting millions of people. Progressive liver disease leads to cirrhosis and its complications as well as liver failure and death. Recent epidemiological data indicate that the incidence of cirrhosis is expected to triple during the next 10–15 years as a result of chronic infection with viral hepatitis infection and possibly, an increase in the prevalence of NAFLD. Although chronic inflammation related to chronic viral infection or NAFLD are the main culprit, host-related factors may also play an important role. Therefore, in this study, we investigated all potential clinical and laboratory factors that can be associated with advanced fibrosis and progression of fibrosis in patients with chronic liver disease.
The study included a large cohort of patients with the most common causes of chronic liver disease (NAFLD, HBV, HCV) for whom extensive clinico-laboratory data were available. The results show that several components of metabolic syndrome (diabetes mellitus, hypertension, high serum glucose, low HDL) are associated with moderate-to-severe fibrosis in these important types of chronic liver disease, especially NAFLD and HCV. However, diabetes mellitus was independently associated with moderate-to-severe fibrosis only in patients with NAFLD. Nevertheless, similar trends were seen in viral hepatitis. Additionally, older age (HBV), elevated aminotransferases (HCV) and low platelet count (HBV and HCV) were independently associated with advanced fibrosis in viral hepatitis. Furthermore, Hispanic patients with HCV also had more advanced fibrosis.
Finally, patients with sequential liver biopsies provided us with an opportunity to assess progression of fibrosis over time. In this study, we confirm that having significant fibrosis at baseline liver biopsy and elevated liver enzymes are independently associated with fibrosis progression. Additionally, our data show that among patients with CLD included in this study, HCV infection is independently associated with progressive fibrosis. Although previous studies have suspected that HCV may progress faster than HBV and NAFLD, this is the first study showing that the rate of fibrosis progression in HCV patients is almost double the rates of fibrosis progression in HBV and NAFLD patients.
The strength of this study is the large cohort size and availability of follow-up data. Important shortcomings, however, include a limited number of patients with at least two liver biopsies, which constrained our ability to study progression of each type of chronic liver disease separately. Also, potential referral bias or ascertainment bias may have contributed to a higher prevalence of severe fibrosis in patients undergoing sequential liver biopsies. Another potential limitation of this study (or any other study using liver biopsies) is the potential for sampling error that can be associated with liver biopsy. This sampling error can potentially misclassify different stages of fibrosis; especially in those with early stages of fibrosis. However, by studying only moderate and severe fibrosis, we partially avoided this limitation. It is important to note that this limitation of liver biopsy may be overcome with newer non-invasive tests for fibrosis such as Fibroscan or serum fibrosis markers. However, a non-invasive test for fibrosis that is fully validated for all patents with different types of liver disease is currently not available. Therefore, currently, the liver biopsy remains the 'imperfect' gold standard for diagnosis and staging of chronic liver disease. Nevertheless, increasing number of these non-invasive diagnostic tests are being developed and their future clinical applications remain quite promising.[25–27]
In conclusion, our study shows that some components of metabolic syndrome are associated with advanced fibrosis in patients with CLD. However, DM is an independent predictor of moderate or severe fibrosis only in NAFLD patients. Furthermore, the rate of progression of fibrosis is almost double in HCV patients as compared with patients with HBV and NAFLD. These findings can be important in developing strategies to manage better, patients with these important causes of chronic liver diseases."
Thanks for posting, Mike. This is a really good article, and on task for me personally.
Their conclusion that “…DM is an independent predictor of moderate or severe fibrosis only in NAFLD patients…” surprises me; this contradicts my presupposed notion that diabetes tended to accelerate damage in HCV patients.
They do admit though, that a study weakness might be due to “potential referral bias or ascertainment bias may have contributed to a higher prevalence of severe fibrosis in patients undergoing sequential liver biopsies.” This is a valid point, yes? If a clinician suspects the patient has little fibrosis, they are probably much less likely to be referred for multiple biopsy, I suppose.
Thanks again, Michael; you always dig up the good stuff—
Have you seen this? I was going to start a new thread but I decided to tack it on. It sounds good but there are no clinical studies yet.
A nutritional supplement for treating chronic hepatitis C: Viusid
The pathogenesis of chronic hepatitis C (CHC) is associated with severe oxidative stress and non-selective immunological disturbance that lead to necroinflammation and the progression of fibrosis. Several trials have suggested that antioxidant and immunostimulant therapies may have a beneficial effect. Two previous clinical studies have reported that the Viusid related effect on histologic features, especially fibrosis, appears to be associated with antioxidant and/or immunomodulatory properties. However, the putative mechanism of action of Viusid is unknown.
A research article to be published on June 7, 2010 in the World Journal of Gastroenterology addresses this question. The authors reported the results of a randomized double-blind and placebo-controlled study to evaluate the effect of Viusid on oxidative stress and cytokine parameters in patients with CHC who had been nonresponders to previous antiviral therapy with peginterferon plus ribavirin and infected with genotype 1.
Their results show that Viusid improves oxidative stress through reduction of lipid peroxidation products and has an immunomodulatory effect on cytokine secretion via increased production of IFN-γ and IL-10, decreased production of IL-1α, and stabilized TNF-α secretion in patients with CHC who have failed previous antiviral treatment. Thus, Viusid is an interesting strategy of treatment for those patients who don't eradicate their viral infection or when antiviral treatment is contraindicated (decompensated cirrhosis). The administration of Viusid was well tolerated. Further studies are needed to evaluate the clinical impact of the administration of Viusid in patients with end-stage liver disease secondary to CHC.
Reference: Gomez EV, Perez YM, Sanchez HV, Forment GR, Soler EA, Bertot LC, Garcia AY, del Rosario Abreu Vazquez M, Fabian LG. Antioxidant and immunomodulatory effects of Viusid in patients with chronic hepatitis C. World J Gastroenterol 2010; 16(21): 2638-2647 http://www.wjgnet.com/1007-9327/full/v16/i21/2638.htm
Correspondence to: Dr. Eduardo Vilar Gomez, PhD, Associated Professor, Department of Hepatology, National Institute of Gastroenterology, 25th Avenue, 503, Vedado, Havana 10400, Cuba. ***@****
Telephone: +53-7-8325067 Fax: +53-7-8333253
About World Journal of Gastroenterology
World Journal of Gastroenterology (WJG), a leading international journal in gastroenterology and hepatology, has established a reputation for publishing first class research on esophageal cancer, gastric cancer, liver cancer, viral hepatitis, colorectal cancer, and H pylori infection and provides a forum for both clinicians and scientists. WJG has been indexed and abstracted in Current Contents/Clinical Medicine, Science Citation Index Expanded (also known as SciSearch) and Journal Citation Reports/Science Edition, Index Medicus, MEDLINE and PubMed, Chemical Abstracts, EMBASE/Excerpta Medica, Abstracts Journals, Nature Clinical Practice Gastroenterology and Hepatology, CAB Abstracts and Global Health. ISI JCR 2008 IF: 2.081. WJG is a weekly journal published by WJG Press. The publication dates are the 7th, 14th, 21st, and 28th day of every month. WJG is supported by The National Natural Science Foundation of China, No. 30224801 and No. 30424812, and was founded with the name of China National Journal of New Gastroenterology on October 1, 1995, and renamed WJG on January 25, 1998.
Regarding DM: Here are 2 excerpts that may be relevant.
".....Several studies have demonstrated that metabolic syndrome and its components are independent risk factors for development of liver fibrosis in patients with NAFLD.[6–9] Some recent data suggest that patients with chronic liver disease who also have type 2 diabetes or other components of metabolic syndrome may be at risk for more advanced fibrosis. This is especially true for NAFLD and possibly HCV. Additionally, type 2 diabetes and other components of metabolic syndrome may have a negative impact on the efficacy of anti-HCV therapy, and the preliminary findings suggest that insulin sensitizing medications may allow a higher virological response rate to anti-HCV treatment.[11–13] Hepatitis C infection alone may directly influence glucose and lipid metabolism and increases the risk for development of type 2 diabetes.[14–16] Some studies suggest that the prevalence of diabetes and metabolic syndrome is increased in patients with HCV and that these patients are significantly more likely to have evidence of steatosis and fibrosis. However, other reports conflict with these findings....."
"......Nonalcoholic fatty liver disease patients without fibrosis or with minimal fibrosis (n = 128) were compared with NAFLD patients who had moderate-to-severe fibrosis (n = 33). Briefly, patients with moderate-to-severe fibrosis were more frequently diabetic (51.5% vs. 27.6%, P = 0.008), had lower platelets (188 ± 87 vs. 259 ± 56 × 109/L, P = 0.0005), higher bilirubin (1.13 ± 1.08 vs. 0.65 ± 1.08 mg/dL, P = 0.0001) and lower albumin (3.95 ± 0.64 vs. 4.26 ± 0.39 g/dL, P = 0.02) (Table 2).
By using multivariate analysis, the model predicting moderate-to-severe fibrosis in NAFLD included the presence of diabetes mellitus and increased AST and ALT levels (model P-value = 0.0005). The summary of the resulting model is given in Table 3. Specifically, the model shows that the odds ratio of having moderate-to-severe fibrosis is approximately three times higher in NAFLD patients with diabetes in comparison with NAFLD patients without diabetes. When tested with ten-fold cross-validation, this model demonstrated the predictive performance as follows: AUC (95% CI) = 0.710 (0.628–0.782), sensitivity (95% CI) = 83.9% (66.3–94.5%), specificity (95% CI) = 66.4% (56.9–75.0%), positive predictive value (PPV) = 40.6%, negative predictive value = 93.7%....."
Interesting, Mike; another maintenance substance to consider, huh? This sounds like something Hepatitis Researcher would like to dissect; it’d be interesting to see him open this up a bit further. I wonder if you posted it anew with an appropriate title, if you could draw him out :o)?
I dealt with some pretty capable doctors out here that work with Gish and company (CPMC), and their take on managing fibrosis via managing oxidative stress/dietary means was luke warm at best; they termed the subject ‘oversimplified’. Then again, I might not have been asking them the questions correctly, either. In any event, those talks left me a little skeptical about this topic in general. Sure is some research going on in this direction though…
Thanks for posting the information, I know this wasn't the point of the study, but I wish they had come up with an average rate of progression from stage to stage depending on your status. One of my doctors team told me about 6 years is average, It seems to vary greatly from there.
which one of the Gish team did you see. I saw Dr Bonacini a few times. He said that three cups of coffee a day is supposed to slow fibrosis. I had seen some studies that seemed to confirm that possibility.
Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C.
Freedman ND, Everhart JE, Lindsay KL, Ghany MG, Curto TM, Shiffman ML, Lee WM, Lok AS, Di Bisceglie AM, Bonkovsky HL, Hoefs JC, Dienstag JL, Morishima C, Abnet CC, Sinha R; HALT-C Trial Group.
Szabo G, Banner BF, Cormier M, Giansiracusa D, Kelley M, Bacon B, Neuschwander-Tetri B, Brunt EM, King D, Chung RT, Reid AE, Bhan AK, Molchen WA, Everson GT, Nash SR, DeSanto J, McKinley C, Morgan TR, Craig JR, Jamal MM, Sheikh M, Park C, Rogers TE, Shelton J, Crowder N, Elbein R, Liston N, Govindarajan S, Jones CB, Milstein SL, Fontana RJ, Greenson JK, Richtmyer PA, Bonham RT, Sterling RK, Contos MJ, Mills AS, Hofmann C, Smith P, Liang TJ, Kleiner D, Park Y, Rivera E, Haynes-Williams V, Seeff LB, Robuck PR, Hoofnagle JH, Wright EC, Gretch DR, Chung Apodaca M, Shankar R, Snow KK, Stoddard AM, Bell MC, Goodman ZD, Garcia-Tsao G, Kutner M, Lemon SM, Perrillo RP.
Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD 20852, USA. ***@****
Higher coffee consumption has been associated inversely with the incidence of chronic liver disease in population studies. We examined the relationship of coffee consumption with liver disease progression in individuals with advanced hepatitis C-related liver disease. Baseline coffee and tea intake were assessed in 766 participants of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had hepatitis C-related bridging fibrosis or cirrhosis on liver biopsy and failed to achieve a sustained virological response to peginterferon plus ribavirin treatment. Participants were followed for 3.8 years for clinical outcomes and, for those without cirrhosis, a 2-point increase in Ishak fibrosis score on protocol biopsies. At baseline, higher coffee consumption was associated with less severe steatosis on biopsy, lower serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, alpha-fetoprotein, insulin, and homeostatic model assessment (HOMA2) score, and higher albumin (P < 0.05 for all). Two hundred thirty patients had outcomes. Outcome rates declined with increasing coffee intake: 11.1/100 person-years for none, 12.1 for less than 1 cup/day, 8.2 for 1 to fewer than 3 cups/day, and 6.3 for 3 or more cups/day (P-trend = 0.0011). Relative risks (95% confidence intervals) were 1.11 (0.76-1.61) for less than 1 cup/day; 0.70 (0.48-1.02) for 1 to fewer than 3 cups/day; and 0.47 (0.27-0.85) for 3 or more cups/day (P-trend = 0.0003) versus not drinking. Risk estimates did not vary by treatment assignment or cirrhosis status at baseline. Tea intake was not associated with outcomes. CONCLUSION: In a large prospective study of participants with advanced hepatitis C-related liver disease, regular coffee consumption was associated with lower rates of disease progression.
AASLD 2008: High Coffee Consumption May Slow Hepatitis C Progression
Maintenance ribavirin monotherapy delays fibrosis progression in liver transplant recipients with recurrent hepatitis C at high risk of progression.
Lionetti R, Tisone G, Palmieri G, Almerighi C, Anselmo A, Tariciotti L, Lenci I, De Luca L, Monaco A, Angelico M.
Hepatology Unit, University of Rome Tor Vergata, Via Montpellier 1, Rome, Italy.
BACKGROUND: Fibrosis in liver transplant recipients with recurrent HCV is fast, yet, different patterns of progression are recognized. AIMS: To investigate histological findings associated with maintenance ribavirin monotherapy in patients with recurrent HCV transplanted > or =4 years earlier. METHODS: 14 recipients at high risk of progression (fibrosis progression rate >0.33 units/year and/or persistently elevated ALT) were assigned to receive ribavirin for 3 years. 11 patients at lower risk of progression (FPR or =2 grading) was observed in 7 treated with ribavirin and 3 untreated patients, while 1 and 3 patients worsened respectively. Fibrosis improved (reduction >1 staging) in 2 ribavirin-treated patients, unchanged in 10 and worsened (increase > or =1 staging) in 2. Fibrosis progression decreased from 0.48+/-0.27 observed during the 3-year pre-treatment period to 0.04+/-0.31 units/year (p=0.003) during the 3 years of ribavirin. Among untreated fibrosis remained unchanged in 1 and worsened in 10 (p<0.001), yearly fibrosis progression rate increasing from 0.15+/-0.17 units/year to 0.42+/-0.39 units/year (p=0.10). CONCLUSIONS: Maintenance ribavirin monotherapy delays fibrosis progression in high risk patients, offering an alternative strategy for those failing to respond to conventional treatment. Copyright (c) 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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