Longitudinal changes in fibrosis markers are associated with risk of cirrhosis and hepatocellular carcinoma in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Currently, there is no consistent information on the course of fibrosis-4 (FIB-4) score changes in non-alcoholic fatty liver disease (NAFLD) or their association with subsequent risk of cirrhosis and/or hepatocellular carcinoma (HCC). Thus, we aimed to evaluate the association between longitudinal changes in FIB-4 and subsequent risk of HCC and a composite endpoint of cirrhosis and HCC in patients with NAFLD. METHODS: We conducted a retrospective cohort study of patients with NAFLD seen in 130 Veterans Administration hospitals between 1/1/2004-12/31/2008, with follow-up through to 12/31/2018. We calculated FIB-4 longitudinally and categorized patients based on risk of advanced fibrosis (low-risk FIB-4 <1.45, indeterminate-risk FIB-4 1.45-2.67, and high-risk FIB-4 >2.67). We used landmark Fine-Gray competing risks models to determine the effects of change in FIB-4 between NAFLD diagnosis date and 3-year landmark time on the subsequent risk of HCC and a composite endpoint. RESULTS: Among the 202,319 patients with NAFLD in the 3-year landmark analysis, 473 progressed to HCC at an incidence rate of 0.28 per 1,000 person years (PY) (95% CI 0.26-0.30). The incidence rate of the composite endpoint was 1.31 per 1,000 PY (95% CI 1.25-1.37). At baseline, 74.7%, 21.4%, and 3.8% of patients had a low, indeterminate, and high FIB-4, respectively. Compared to patients who were at stable low FIB-4 at both time points, the risk of HCC and that of the composite endpoint was higher for all other subgroups with the highest risk in patients with persistently high FIB-4 (HCC adjusted sub-distribution hazard ratio 57.7, 95% CI 40.5-82.2 and composite endpoint hazard ratio 28.6, 95% CI 24.6-33.2). CONCLUSION: Longitudinal changes in FIB-4 were strongly associated with progression to cirrhosis and HCC. IMPACT AND IMPLICATIONS: Tools to stratify the risk of HCC development in patients with NAFLD are currently lacking. The fibrosis-4 (FIB-4) score is a widely available non-invasive test for liver fibrosis, a primary determinant of the development of cirrhosis and HCC. In a large retrospective cohort of patients with NAFLD, we found that serial changes in FIB-4 over time were strongly associated with progression to cirrhosis and HCC. Integrating serial measurements of non-invasive tests for fibrosis into the care pathway for patients with NAFLD could help tailor HCC risk prevention.

Diagnosis of HDV: From virology to non-invasive markers of fibrosis.

Hepatitis D viral infection in humans is a disease that requires the establishment of hepatitis B, relying on hepatitis B surface Ag and host cellular machinery to replicate and propagate the infection. Since its discovery in 1977, substantial progress has been made to better understand the hepatitis D viral life cycle, pathogenesis and modes of transmission along with expanding on clinical knowledge related to prevention, diagnosis, monitoring and treatment. The availability of serologic diagnostic assays for hepatitis D infection has evolved over time with current widespread availability, improved detection and standardized reporting. With human migration, the epidemiology of hepatitis D infection has changed over time. Thus, the ability to use diagnostic assays remains essential to monitor the global impact of hepatitis D infection. Separately, while liver biopsy remains the gold standard for the staging of this rapidly progressive and severe form of chronic viral hepatitis, there is an unmet need for clinical monitoring of chronic hepatitis D infection for management of progressive disease. Thus, exploration of the utility of non-invasive fibrosis markers in hepatitis D is ongoing. In this review, we discuss the virology, the evolution of diagnostics and the development of non-invasive markers for the detection and monitoring of fibrosis in patients with hepatitis D infection.

Cohort study: Apparent redundancy of fibrosis assessment in young persons with HCV; development of realistic approaches to break the paradigm.

INTRODUCTION AND OBJECTIVES: Hepatitis C Virus (HCV) is a blood-borne, hepatotropic RNA virus causing both acute and chronic infection. Chronic HCV infection predisposes individuals to liver fibrosis, cirrhosis and hepatocellular carcinoma. Staging of fibrosis prior to treatment to determine either treatment choice or required follow up, is standard practice. However, this often acts as a barrier to treatment initiation. We sought to validate the hypothesis that those individuals; mono-infected with HCV, ≤35 years of age; with no additional hepatic insult were unlikely to have significant fibrosis. METHODS: We performed a retrospective analysis of a Hepatitis C Virus database; with collation of relevant basic demographics including age, sex and baseline Transient Elastography measurements pre-treatment. Additionally, we compared the reliability of biochemical fibrosis scores with corresponding transient elastography scores. RESULTS: Our results support the hypothesis that those individuals with chronic HCV ≤35 years old, with no additional risk for fibrogenesis did not have significant liver fibrosis within our cohort. CONCLUSION: Patients ≤35 years old likely do not necessitate fibrosis assessment prior to Direct Acting Antiviral (DAA) treatment in the absence of other significant risk factors for fibrosis. Given the emerging evidence that DAA treatment results in a significant decrease in all-cause mortality and hepatocellular carcinoma development, treatment of those with chronic HCV represents a global priority.

Prevalence and risk factors for biopsy-proven non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in a prospective cohort of adult patients with gallstones.

BACKGROUND & AIMS: Relationship between gallstones and non-alcoholic fatty liver disease (NAFLD), and largely non-alcoholic steatohepatitis (NASH), is uncertain. AIM: To determine the prevalence, non-invasive fibrosis markers profile and risk factors for biopsy-proven NAFLD and NASH among patients with gallstones. METHODS: Anthropometric and laboratory evaluation, an abdominal ultrasound and a liver biopsy were performed to 215 consecutive patients with gallstones referred for cholecystectomy. RESULTS: Prevalence of NASH was 10.2% whereas that of simple steatosis (SS) was 41.4%. In the cohort of NAFLD patients, negative predictive values for advanced fibrosis of FIB-4 and NAFLD fibrosis score were 96 and 95% respectively. Gallstone patients with NASH had a higher mean homeostatic model assessment (HOMA) score than those with SS (P = 0.015). Noteworthy, NASH was 2.5-fold more frequent in patients with gallstones who had metabolic syndrome than in those who did not (P < 0.001). Fatty liver on ultrasound was observed in 90.9% of gallstone patients with NASH compared with 61.8% of those with SS (P = 0.044). Using multivariate logistic regression, increased HOMA score (OR, 3.47; 95% CI, 1.41-8.52; P = 0.007) and fatty liver on ultrasound (OR, 23.27; 95% CI, 4.15-130.55; P < 0.001) were the only factors independently associated with NASH. CONCLUSIONS: Prevalence of NASH among patients with gallstones is lower than estimated previously, but NASH is frequent particularly in those patients with concurrent metabolic syndrome. The combination of an increased HOMA score with fatty liver on ultrasound has a good accuracy for predicting NASH in patients with gallstones.

GPR, King's Score and S-Index are superior to other non-invasive fibrosis markers in predicting the liver fibrosis in chronic Hepatitis B patients.

Background and study aims: In this study, we investigated the efficacy of nine non-invasive fibrosis markers in the assessment of the degree of fibrosis in patients with chronic Hepatitis B (CHB) in comparison with liver biopsy. Patients and methods: A total of 1454 untreated CHB patients from two different centers who underwent liver biopsy were included in the study. Laboratory results of patients were reviewed retrospectively and the pathology slides were re-evaluated in accordance with the Ishak score. Degree of fibrosis ≥ 3 was accepted as "significant fibrosis", ≥ 4 as "advanced fibrosis", and ≥ 5 as cirrhosis. The diagnostic performance of the markers Aspartate aminotransferase to Platelet Ratio Index (APRI), Fibrosis-4 score (FIB-4), Aspartate aminotransferase to Alanine aminotransferase Ratio (AAR), AAR to Platelet Ratio Index (AAPRI), Gamma-glutamyl transpeptidase to Platelet Ratio (GPR), King's Score, Fibro quotient (Fibro-Q), S Index and Platelet to Lymphocyte Ratio (PLR) were evaluated with ROC analysis. Results: In detecting significant fibrosis, APRI, GPR, King's Score and S Index had AUROC values over 0.70. For advanced fibrosis, all of the models except AAPRI; and for cirrhosis, all of the models had AUROC values over 0.70. In accordance with the chosen staging system, GPR, King's Score and S Index had high diagnostic efficacy whereas APRI, FIB-4, FibroQ and PLR had moderate diagnostic efficacy, AAR and AAPRI had low diagnostic efficacy. Conclusions: GPR, King's Score and S Index had moderate diagnostic performance in detecting significant fibrosis and advanced fibrosis, and high diagnostic performance in detecting cirrhosis.

Non-Invasive Indirect Markers of Liver Fibrosis after Interferon-Free Treatment for Hepatitis C.

The effectiveness of interferon-free therapy during the course of HCV infection has already been confirmed. Liver fibrosis can be assessed in several ways, from biopsies to imaging tests. The present study evaluates the usefulness of non-invasive indirect biomarkers of liver fibrosis (APRI, GAPRI, FORNS, FIB-4, the AP index and HUI score) as markers of the effective treatment of HCV with the 3D regimen. Blood samples were collected from 70 patients suffering from chronic hepatitis C. Patients received the 3D AbbVie regimen for hepatitis C. All patients had HCV genotype 1b. The APRI, GAPRI, FIB-4, FORNS, HUI and AP index (age-platelet score) values were calculated with their respective algorithms. The stage of fibrosis was evaluated on the basis of a liver biopsy and confirmed by FibroScan-based transient elastography. An undetectable level of HCV RNA after 12 weeks of treatment with the 3D regimen indicates 100% eradication of hepatitis C virus. After the treatment, non-invasive indirect markers of liver fibrosis achieved levels below the limit for significant fibrosis, Thus, non-invasive indirect biomarkers of hepatic fibrosis failed to detect the presence of significant fibrosis, which was proved in histopathological examination. However, the eradication of hepatitis C virus by means of the 3D regimen treatment does not mean that patients were completely cured.

Determining the role for uric acid in non-alcoholic steatohepatitis development and the utility of urate metabolites in diagnosis: An opinion review.

There has long been a recognised association between non-alcoholic fatty liver disease (NAFLD) and the composite aspects of the metabolic syndrome. Part of this association highlighted the supposed co-existence of elevated uric acid levels in those with NAFLD. There is interest in exploitation of this as a putative diagnostic and prognostic biomarker in NAFLD. Given the increased economic and health burden associated with the NAFLD epidemic, improved methods of population-based, minimally-invasive methods and biomarkers are clearly highly sought and necessary. In this opinion review we review the proposed role of uric acid in the pathogenesis of NAFLD and its potential utilisation in the diagnosis and monitoring of the disease process.

Matrix metalloproteases and their tissue inhibitors in non-alcoholic liver fibrosis of human immunodeficiency virus-infected patients.

AIM: To investigate the relationships among diverse metalloproteases (MMPs) and their tissue inhibitors (TIMPs) and non-alcoholic liver fibrosis in human immunodeficiency virus (HIV)-infected patients. METHODS: Single nucleotide polymorphisms (SNPs) in MMPs, TNF-α and CCR5 genes, and serum levels of MMPs and TIMPs were determined in HIV-infected individuals with/out hepatitis C virus (HCV) coinfection. A total of 158 patients were included, 57 of whom were HCV-coinfected. All patients drank < 50 g ethanol/day. Diverse SNPs (MMP-1 -1607 1G/2G, MMP-8 -799C/T, MMP-9 -1562 C/T, MMP-13 -77A/G, TNF-α -308 G/A, CCR5-∆32), and serum levels of MMPs (2, 3, 8, 9 and 10) and TIMPs (1, 2 and 4) were assessed. Liver fibrosis was determined by transient elastometry, although other non-invasive markers of fibrosis were also considered. Significant liver fibrosis (F ≥ 2) was defined by a transient elastometry value ≥ 7.1 kPa. RESULTS: A total of 34 patients (21.5%) had liver fibrosis ≥ F2. MMP-2 and TIMP-2 serum levels were higher in patients with liver fibrosis ≥ F2 (P = 0.02 and P = 0.03, respectively) and correlated positively with transient elastometry values (P = 0.02 and P = 0.0009, respectively), whereas MMP-9 values were negatively correlated with transient elastometry measurements (P = 0.01). Multivariate analyses showed that high levels of MMP-2 (OR = 2.397; 95%CI: 1.191-4.827, P = 0.014) were independently associated with liver fibrosis ≥ F2 in the patients as a whole. MMP-2 (OR = 7.179; 95%CI: 1.210-42.581, P = 0.03) and male gender (OR = 10.040; 95%CI: 1.621-62.11, P = 0.013) were also independent predictors of fibrosis ≥ F2 in the HCV-infected subgroup. Likewise, MMP-2, TIMP-2 and MMP-9 were independently associated with transient elastometry values and other non-invasive markers of liver fibrosis. None of the six SNPs evaluated had any significant association with liver fibrosis ≥ F2. CONCLUSION: Certain MMPs and TIMPs, particularly MMP-2, seems to be associated with non-alcoholic liver fibrosis in HIV-infected patients with/without HCV coinfection.