Liver stiffness and the prediction of clinically significant portal hypertension and portal hypertensive complications.

OBJECTIVE: Clinically significant portal hypertension (CSPH) is associated with increased risk of liver disease complications, but its identification requires invasive methods. Liver stiffness (LS) measurement via transient elastography correlates with the presence of CSPH. We, therefore, evaluated LS as a noninvasive tool in the prediction of CSPH and portal hypertensive complications. MATERIAL AND METHODS: Ninety-five consecutive patients successfully underwent measurement of hepatic venous pressure gradient (HVPG) and LS on the same day. Recent laboratory tests were correlated. Patients were followed up for development of portal hypertensive complications. Predictors of CSPH and complications were identified. RESULTS: Seventy-six (80%) were male and mean age was 56.8 ± 9.3 years. Ninety-three percent and 72% of patients had cirrhosis and esophageal varices, respectively. Only LS (r(2) = 0.38; p < 0.0001) and international normalized ratio (r(2) = 0.21; p = 0.02) were independently associated with HVPG. An LS >29.0 kilopascal (kPa) predicted CSPH with 71.9% sensitivity, 100% specificity, 100% positive predictive value (PPV), and 56.0% negative predictive value (NPV). An LS <25.0 kPa in those with platelet count >150 × 10(9)/L excluded CSPH with 91.7% sensitivity, 100% specificity, 100% PPV, and 90% NPV. Ninety patients were followed up for a median duration of 15.1 months. CSPH and LS >34.5 kPa predicted portal hypertensive complications with 100% and 75.0% sensitivity, 40.3% and 69.4% specificity, 43.1% and 52.5% PPV, and 100% and 86.2% NPV, respectively. CONCLUSION: LS shows promise as a noninvasive marker of CSPH and portal hypertensive complications. Combining LS with platelet count improves diagnostic accuracy in the exclusion of CSPH.

Vitamin D level and sustained virologic response to interferon-based antiviral therapy in chronic hepatitis C: a systematic review and meta-analysis.

BACKGROUND & AIMS: The baseline 25-hydroxyvitamin D (25[OH]D) level has recently been reported to be an independent predictor of sustained virologic response (SVR) to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) for chronic hepatitis C virus (HCV) infection. However, studies have yielded inconsistent results. Thus, we conducted a systematic review and meta-analysis to clarify any association between baseline 25(OH)D level and SVR in HCV therapy. METHODS: Two reviewers searched four electronic databases (Medline, Embase, PubMed, and Cochrane trials register) and relevant international conference proceedings up to March 2014 for studies treating chronic HCV infection with PEG-IFN plus RBV where baseline 25(OH)D level was tested. Studies involving patients with HIV co-infection, previous liver transplantation or those receiving vitamin D supplementation were excluded. The mean baseline 25(OH)D level was compared between those who achieved and those who failed to achieve SVR. Pooled standard difference in mean 25(OH)D level, odds ratios (OR) and 95% confidence intervals (CI) were calculated with the Comprehensive Meta-Analysis software (version 2.0) using a random effects model. RESULTS: 11 studies comprising 2605 patients were included in the meta-analysis. There was no significant association between the baseline mean 25(OH)D level and SVR (OR 1.44, 95% CI 0.92-2.26; p=0.11), either in patients infected with genotypes 1/4/5 (OR 1.48, 95% CI 0.94-2.34; p=0.09) or genotypes 2/3 (OR 1.51, 95% CI 0.26-8.87; p=0.65). CONCLUSIONS: The baseline 25(OH)D level is not associated with SVR to PEG-IFN plus RBV therapy in chronic HCV infection, regardless of genotype. Any effect of vitamin D supplementation on SVR is yet to be definitively determined.

Interleukin-28B rs12979860 C allele: Protective against advanced fibrosis in chronic hepatitis C genotype 1 infection.

Background and Aim: While genetic polymorphisms upstream of the interleukin-28B(IL28B) gene are associated with necroinflammatory activity grade in chronic hepatitis C virus genotype 1 (HCV-1) infection, any association with fibrosis is less definitive. Pretreatment liver biopsies in a cohort of treatment-naïve patients with HCV-1 were analyzed to evaluate associations between liver histology, and the rs12979860 and rs8099917 IL28B single nucleotide polymorphisms.Methods: Two hundred sixty-six patients with HCV-1 infection and pretreatment liver biopsy were tested for the rs12979860 and rs8099917 single nucleotide polymorphisms.Predictors of advanced fibrosis (METAVIR F3/4) and high activity grade (A2/3) were identified using multivariable logistic regression analysis.Results: Forty-four patients (16.5%) had advanced fibrosis and 141 patients (53.0%) high activity grade. Prevalence of rs12979860 IL28B genotype was: CC 45.7%, CT 42.7%, and TT 11.6%. Prevalence of advanced fibrosis was lower in those with IL28B CC genotype compared with those without (11.0% vs 21.3%; P = 0.03), with an increasing number of Talleles associated with a higher frequency of advanced fibrosis: CC 11.0%, CT 18.0%, TT33.3% (P = 0.01). Predictors of advanced fibrosis on multivariate analysis were platelet count (odds ratio [OR] 0.98, 95% confidence interval [CI] 0.97­0.99; P < 0.0001), high activity grade (OR 5.68, 95% CI% 1.86­17.32; P = 0.002), IL28B rs12979860 CC genotype(OR 0.36, 95% CI 0.14­0.93; P = 0.03), and aspartate aminotransferase (OR 1.02,95% CI 1.00­1.03; P = 0.046). No association was found between rs8099917 IL28B genotype and liver histology.Conclusions: IL28B rs12979860 CC genotype appears to be independently associated with a lower prevalence of advanced fibrosis stage in HCV-1 infection. This association warrants further evaluation.

Vitamin D status does not predict sustained virologic response or fibrosis stage in chronic hepatitis C genotype 1 infection.

BACKGROUND & AIMS: The relationship between vitamin D status and response to antiviral therapy and liver histology in hepatitis C virus genotype 1 (HCV-1) infection remains unclear, with studies to date yielding inconsistent results and failing to use reference assay methodology. We therefore analyzed pre-treatment 25-hydroxyvitamin D [25(OH)D] level, using reference liquid chromatography-tandem mass spectrometry methodology, in a cohort of treatment-naïve patients with HCV-1 to evaluate the association between vitamin D status, virologic response, and liver histology. METHODS: 274 patients, with pre-treatment liver biopsy and up to 48 weeks of pegylated interferon alfa-2a plus ribavirin therapy, were tested for serum 25(OH)D level. Predictors of sustained virologic response (SVR), and variables associated with fibrosis stage, activity grade and 25(OH)D status were identified using multivariate analysis. RESULTS: Mean 25(OH)D level was 79.6 nmol/L, with a prevalence of 25(OH)D <75 nmol/L and <50 nmol/L of 48% and 16%, respectively. Season, race and geographic latitude were independent predictors of 25(OH)D status, while vitamin D deficiency was more prevalent in those with high activity grade (21% vs. 11%; p=0.03). Mean 25(OH)D level was lower (76.6 vs. 84.7 nmol/L; p=0.03) and 25(OH)D <75 nmol/L more prevalent (53% vs. 40%; p=0.03) in patients with an SVR, but no association between 25(OH)D status and SVR was found in multivariate analysis. Mean 25(OH)D level did not vary between fibrosis stage or activity grade. CONCLUSIONS: Baseline 25(OH)D level is not independently associated with SVR or fibrosis stage in HCV-1, but vitamin D deficiency is associated with high activity grade.

Utility of transient elastography in the non-invasive evaluation of cystic fibrosis liver disease.

BACKGROUND: Liver disease frequently complicates cystic fibrosis (CF), with CF liver disease (CFLD) a leading cause of death. Liver biopsy is rarely performed because of the patchy nature of the disease. Transient elastography can reliably stage liver fibrosis via liver stiffness measurement (LSM). AIMS: To evaluate LSM as a diagnostic tool in adults with CFLD. METHODS: Fifty adult patients with CF were prospectively studied: 25 with CFLD and 25 without CFLD. The presence of CFLD and portal hypertension (PHT) was assessed according to strict established criteria based on serial biochemistry and imaging. All patients underwent LSM; APRI, Hepascore(®) and Forns score were calculated. RESULTS: Median LSM was higher in those with CFLD [8.1 kPa (IQR 6.8-9.5) vs. 5.0 kPa (IQR 4.1-5.6); P < 0.001]. On multivariate analysis, LSM was the only variable associated with CFLD (OR 2.74, 95% CI 1.53-4.89; P = 0.001). AUROC for LSM predicting CFLD was 0.87 (95% CI 0.77-0.98) and an LSM ≥ 6.8 kPa predicted CFLD with 76.0% sensitivity and 92.0% specificity. Median LSM was higher in those with PHT [15.7 kPa (IQR 9.2-17.2) vs. 5.4 kPa (IQR 4.3-6.8); P < 0.001]. The AUROC for LSM predicting the presence of PHT was 0.96 (95% CI 0.92-1.00). An LSM cut-off of ≥ 8.9 kPa predicted the presence of PHT with 87.5% sensitivity, 90.5% specificity, 63.6% positive predictive value and 92.9% negative predictive value. CONCLUSIONS: LSM is an accurate and reliable non-invasive tool in assessing CFLD and PHT. An LSM ≥ 6.8 kPa is highly suggestive of CFLD and an LSM <8.9 kPa reliably excludes PHT.

D-livering the message: the importance of vitamin D status in chronic liver disease.

Vitamin D is synthesized predominantly in the liver and functions as an important secosteroid hormone with pleiotropic effects. While its key regulatory role in calcium and bone homeostasis is well established, recently there is increasing recognition that vitamin D also regulates cell proliferation and differentiation, and has immunomodulatory, anti-inflammatory and anti-fibrotic properties. These non-skeletal effects are relevant in the pathogenesis and treatment of many causes of chronic liver disease. Vitamin D deficiency is frequently present in chronic liver disease and may predict non-response to antiviral therapy in chronic hepatitis C. Small studies suggest that vitamin D supplementation improves sustained viral response rates, while 1α-hydroxylase polymorphisms and vitamin D-binding protein are also implicated in therapeutic outcomes. Vitamin D deficiency also closely relates to the severity of non-alcoholic fatty liver disease (NAFLD) and is implicated in the pathogenesis of insulin resistance, a key factor in the development of NAFLD. In preclinical studies, phototherapy and vitamin D supplementation ameliorate NAFLD histopathology, while vitamin D is a powerful anti-fibrotic against thioacetamide liver injury. In liver transplant recipients severe vitamin D deficiency predicts, and vitamin D supplementation prevents, acute cellular rejection. The role of vitamin D in the activation and regulation of both innate and adaptive immune systems may explain its importance in the above liver diseases. Further prospective studies are therefore warranted to investigate the therapeutic impact of vitamin D supplementation in chronic liver disease.

Transient Elastography in the Evaluation of Cystic Fibrosis-Associated Liver Disease: Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Complications of cystic fibrosis-associated liver disease (CFLD) are a leading nonpulmonary cause of death. Transient elastography (TE) has recently been investigated to detect CFLD. This study reviews the current literature for TE in the detection CFLD. A meta-analysis was performed to determine the ideal liver stiffness measurement (LSM) cutoff. METHODS: PubMed, Medline, EMBASE and Web of Science were searched from inception until April 2016 for publications involving the detection of CFLD with TE. Data were extracted using a fixed protocol (a priori design) including study design, population characteristics, probe size and AST Platelet Ratio Index (APRI). RESULTS: Diagnostic properties were summarized from six studies of 605 patients. Cutoff for LSM was determined using pooled data submitted by authors. The cutoff for LSM and APRI were ≥5.95 kPa and ≥0.329 respectively, yielding a sensitivity, specificity and area under receiver operator characteristic of 55%, 87%, 0.76, 52%, 93% and 0.84 for LSM and APRI, respectively. When LSM ≥5.95 kPa and APRI ≥0.329, the sensitivity, specificity, positive predictive value and negative predictive value were 43%, 99%, 92% and 87% with a diagnostic odds ratio of 74.9. A bivariate metaregression model showed that pediatric specific cutoffs for liver stiffness and APRI may not be necessary. CONCLUSION: Individually, LSM and APRI have poor sensitivity but good specificity for detecting CFLD. They are most useful when combined. We propose that patients with LSM ≥5.95 kPa and APRI ≥0.329 be investigated thoroughly for the presence of cystic fibrosis-associated liver disease.

Treatment of hepatitis C in patients with cirrhosis: remaining challenges for direct-acting antiviral therapy.

Chronic hepatitis C virus (HCV) infection is a major global health concern, resulting in significant morbidity and mortality. Treatment using interferon-based therapy in patients with HCV-related cirrhosis has been problematic due to toxicity and poor tolerability. Furthermore, interferon therapy is contraindicated in those with advanced cirrhosis or clinical decompensation, who are arguably the group most in need of viral eradication. The arrival of the direct-acting antiviral (DAA) era has resulted in the development of well-tolerated and highly effective interferon-free drug regimens that promise to dramatically change the therapeutic landscape for those with advanced HCV-related liver disease, including patients with clinical decompensation or pre-liver transplantation. Many successful DAA combinations have emerged; however, a number of challenges remain including the establishment of the optimal treatment duration, the ideal combination of drug classes and determining the role of ribavirin. Moreover, the identification of treatment-experienced patients with genotype 3 HCV cirrhosis as a difficult-to-treat subgroup is a significant impediment to overcome, as are those who have failed prior DAA therapy. Despite these barriers, the ongoing prolific development of safe and effective DAA combinations indicates the future is optimistic for the ultimate goal of HCV eradication.