Sasan Sakiani

AASLD clinical practice guidelines: a critical review of scientific evidence and evolving recommendations.

The American Association for the Study of Liver Diseases (AASLD) practice guidelines provide recommendations in diagnosing and managing patients with liver disease from available scientific evidence in combination with expert consensus opinions. The aim was to systematically review the evolution of recommendations from AASLD guidelines and identify gaps limiting the evidence‐based foundations of these guidelines. Initial and current AASLD guidelines published from January 1998 to August 2012 were reviewed. The AGREE II instrument was used to evaluate rigor and transparency of guideline development. The number of recommendations, distribution of grades (strength or certainty), classes (benefit versus risk), and types of recommendations were evaluated. Whenever possible, multiple versions were evaluated for evolving scientific evidence. A total of 991 recommendations from 28 guidelines on 17 topics were evaluated. From initial to current guidelines, the total number of recommendations increased by 36% (512 to 699). The largest increases were from chronic hepatitis B virus (HBV) (+71), liver transplantation (+53), and autoimmune hepatitis (AIH) (+27). Most current recommendations are grade II (44%) and less than 20% are grade I. The AGREE II evaluation showed global improvement in guideline quality. Both HBV and chronic hepatitis C guidelines had greatest increases in grade I recommendations (+383% and +67%, respectively). The greatest increases in treatment recommendations were from HBV (grade I, +1,150%), liver transplantation (grade II, +112%), and AIH (grade III, +105%). Conclusion: Despite significant increases in the numbers of recommendations within AASLD practice guidelines over time, only a minority are supported by grade I evidence, highlighting the need for developing well‐designed investigations to provide evidence for areas of uncertainty and improving the quality of future guidelines in hepatobiliary diseases. (Hepatology 2013; 58:2142–2152)

Adult‐onset cystic fibrosis liver disease: Diagnosis and characterization of an underappreciated entity

Cystic fibrosis (CF) liver disease (CFLD), a leading cause of death in CF, is mostly described in pediatric populations. Adult‐onset CFLD lacks sufficient characterization and diagnostic tools. A cohort of CF patients without CFLD during childhood were followed for up to 38 years with serologic testing, imaging, and noninvasive fibrosis markers. Historical CFLD diagnostic criteria were compared with newly proposed CFLD criteria. Thirty‐six CF patients were followed for a median of 24.5 years (interquartile range 15.6‐32.9). By the last follow‐up, 11 (31%) had died. With conventional criteria, 8 (22%) patients had CFLD; and by the new criteria, 17 (47%) had CFLD at a median age of 36.6 years (interquartile range 26.5‐43.2). By the new criteria, those with CFLD had higher median alanine aminotransferase (42 versus 27, P = 0.005), aspartate aminotransferase (AST; 26 versus 21, P = 0.01), direct bilirubin (0.13 versus 0.1, P = 0.01), prothrombin time (14.4 versus 12.4, P = 0.002), and AST‐to‐platelet ratio index (0.31 versus 0.23, P = 0.003) over the last 2 years of follow‐up. Subjects with a FibroScan >6.8 kPa had higher alanine aminotransferase (42 versus 28U/L, P = 0.02), AST (35 versus 25U/L, P = 0.02), AST‐to‐platelet ratio index (0.77 versus 0.25, P = 0.0004), and Fibrosis‐4 index (2.14 versus 0.74, P = 0.0003) and lower platelet counts (205 versus 293, P = 0.02). One CFLD patient had nodular regenerative hyperplasia. Longitudinally, mean platelet counts significantly declined in the CFLD group (from 310 to 230 U/L, P = 0.0005). Deceased CFLD patients had lower platelet counts than those alive with CFLD (143 versus 258 U/L, P = 0.004) or those deceased with no CFLD (143 versus 327U/L, P = 0.006). Conclusion: Adult‐onset CFLD may be more prevalent than previously described, which suggests a later wave of CFLD that impacts morbidity; routine liver tests, radiologic imaging, noninvasive fibrosis markers, and FibroScan can be used algorithmically to identify adult CFLD; and further evaluation in other CF cohorts should be performed for validation. (Hepatology 2017;66:591–601).

Important Factors in Reliable Determination of Hepatitis C Virus Genotype by Use of the 5′ Untranslated Region

ABSTRACT Accurate genotyping of hepatitis C virus (HCV) is important for determining the optimal regimen, dose, and duration of antiviral therapy for chronic HCV infection, as well as for estimating the response rate. The 5′ untranslated region (UTR) of HCV RNA is used in commercial genotyping, but the probes and the lengths of the amplicons are proprietary and vary among the assays. In this study, factors involved in the reliable determination of HCV genotypes utilizing the 5′ UTR were evaluated. Serum samples from four subjects with chronic HCV infection and disparate results on commercial genotyping and four controls were analyzed. HCV RNA was extracted from serum samples, and the 5′ UTR and NS5B region were sequenced. Ten clones from each region were compared to prototype sequences and analyzed for genotype assignment using five programs. The results were compared to those from commercial assays. 5′ UTR sequences were sequentially shortened from either the 5′ end, the 3′ end, or both ends, with genotyping of the resultant fragments. Sequences were obtained for the 5′ UTR in all eight subjects and for the NS5B region in five subjects. The genotype assignments were identical between the two regions in the five subjects with complete sequencing. Genotyping by sequencing gave different results than those from the commercial assays in the four experimental samples but agreed in the four controls. Shortening of the sequences affected the results, and the results for sequences of <200 bases were inaccurate. Neither the Hamming distance nor the quasispecies affected the results. Sequencing of the HCV 5′ UTR provided reliable genotyping results and resolved discrepancies identified in commercial assays, but genotyping by sequencing was highly dependent upon sequence length.

Understanding the Presence of False-Positive Antibodies in Acute Hepatitis

Although false-positive antibodies (FPAs) have been well described in chronic hepatitis C virus (HCV), this has not been evaluated in acute viral hepatitis. Patients with acute viral hepatitis underwent antibody testing for other causes of liver disease and sexually transmitted diseases. Those with antibody positivity underwent confirmatory testing and monitoring. Patients with FPAs were compared with patients with acute hepatitis C infection without FPAs. In total 7 of 24 patients (29%) had FPAs. FPAs during acute viral hepatitis are associated with higher IgM levels and higher ESR in acute HCV. This has both mechanistic and clinical implications and should be evaluated further.

AASLD clinical practice guidelines: A critical review of scientific evidence and evolving recommendations: Hepatology

The American Association for the Study of Liver Diseases (AASLD) practice guidelines provide recommendations in diagnosing and managing patients with liver disease from available scientific evidence in combination with expert consensus opinions. The aim was to systematically review the evolution of recommendations from AASLD guidelines and identify gaps limiting the evidence‐based foundations of these guidelines. Initial and current AASLD guidelines published from January 1998 to August 2012 were reviewed. The AGREE II instrument was used to evaluate rigor and transparency of guideline development. The number of recommendations, distribution of grades (strength or certainty), classes (benefit versus risk), and types of recommendations were evaluated. Whenever possible, multiple versions were evaluated for evolving scientific evidence. A total of 991 recommendations from 28 guidelines on 17 topics were evaluated. From initial to current guidelines, the total number of recommendations increased by 36% (512 to 699). The largest increases were from chronic hepatitis B virus (HBV) (+71), liver transplantation (+53), and autoimmune hepatitis (AIH) (+27). Most current recommendations are grade II (44%) and less than 20% are grade I. The AGREE II evaluation showed global improvement in guideline quality. Both HBV and chronic hepatitis C guidelines had greatest increases in grade I recommendations (+383% and +67%, respectively). The greatest increases in treatment recommendations were from HBV (grade I, +1,150%), liver transplantation (grade II, +112%), and AIH (grade III, +105%). Conclusion: Despite significant increases in the numbers of recommendations within AASLD practice guidelines over time, only a minority are supported by grade I evidence, highlighting the need for developing well‐designed investigations to provide evidence for areas of uncertainty and improving the quality of future guidelines in hepatobiliary diseases. (Hepatology 2013; 58:2142–2152)

The AASLD Clinical Practice Guidelines: A Critical Review of Scientific Evidence and Evolving Recommendations

The American Association for the Study of Liver Diseases (AASLD) practice guidelines provide recommendations in diagnosing and managing patients with liver disease from available scientific evidence in combination with expert consensus opinions. The aim was to systematically review the evolution of recommendations from AASLD guidelines and identify gaps limiting the evidence‐based foundations of these guidelines. Initial and current AASLD guidelines published from January 1998 to August 2012 were reviewed. The AGREE II instrument was used to evaluate rigor and transparency of guideline development. The number of recommendations, distribution of grades (strength or certainty), classes (benefit versus risk), and types of recommendations were evaluated. Whenever possible, multiple versions were evaluated for evolving scientific evidence. A total of 991 recommendations from 28 guidelines on 17 topics were evaluated. From initial to current guidelines, the total number of recommendations increased by 36% (512 to 699). The largest increases were from chronic hepatitis B virus (HBV) (+71), liver transplantation (+53), and autoimmune hepatitis (AIH) (+27). Most current recommendations are grade II (44%) and less than 20% are grade I. The AGREE II evaluation showed global improvement in guideline quality. Both HBV and chronic hepatitis C guidelines had greatest increases in grade I recommendations (+383% and +67%, respectively). The greatest increases in treatment recommendations were from HBV (grade I, +1,150%), liver transplantation (grade II, +112%), and AIH (grade III, +105%). Conclusion: Despite significant increases in the numbers of recommendations within AASLD practice guidelines over time, only a minority are supported by grade I evidence, highlighting the need for developing well‐designed investigations to provide evidence for areas of uncertainty and improving the quality of future guidelines in hepatobiliary diseases. (Hepatology 2013; 58:2142–2152)

848 Cystic Fibrosis Liver Disease -Development of a Novel Criteria to Identify a Second Wave of Liver Disease in Adults

Introduction: Cystic fibrosis liver disease (CFLD) is the 3rd leading cause of death in cystic fibrosis (CF) patients, contributing to 2.5-5% of overall mortality. Onset of CFLD has been mostly described in pediatric populations, but with improving life expectancy, adult onset CFLD is increasingly recognized with an estimated prevalence of 2-37%. Criteria for the diagnosis of adult CFLD are lacking and inconsistent; with few studies evaluating noninvasive biomarkers and radiographic data for classification systems. Aims: To characterize adult CFLD and develop a set of novel criteria for the diagnosis of adult CFLD utilizing biochemical, clinical and radiographic markers in an adult CF cohort followed at the NIH Clinical Center for up to 37 years (yrs). Methods: Patients with CF were evaluated with hepatic biomarkers of inflammation, synthetic function, portal hypertension, radiologic imaging, and transient elastography (TE). Charts were extracted for clinical data. Utilizing these biomarkers along with TE, APRI, and FIB-4, criteria were defined for the diagnosis CFLD. Patients who met CFLD criteria were compared to CF patients without evidence of liver disease. Results: 36 patients with CF (33% F508 homozygous, 23% F508 heterozygous) were studied (65% males, 97% white). The median age of CF diagnosis was 11 yrs, and the median follow-up duration was 23 yrs (range 2 to 37). At the time of last follow-up (mean age=46 yrs), 11 (31%) had died (respiratory failure=3, infection=3, complications of transplantation=2, or other causes=3). 17 of 36 (47%) patients met criteria for CFLD (mean age of diagnosis=31 yrs). Patients with CFLD had significantly higher mean ALT (44.3 vs 28.1, p=0.01), direct bilirubin (0.2 vs 0.1, p =0.04), PT (14.4 vs 12.8, p=0.01), and APRI (0.6 vs 0.2, p=0.04) over the last year of follow-up. In the CFLD group, 4 patients had radiographic evidence of advanced liver disease and 1 patient had nodular regenerative hyperplasia and experienced hepatic decompensation. On longitudinal comparison, platelet counts significantly declined in the CFLD group (312 to 237 U/L, p=0.007) as compared to patients without CFLD (328 to 297 U/L, p=0.11). Conclusions: By evaluating non-invasive markers of liver disease, a novel criteria can be employed to identify adult CFLD. These biomarkers not only suggest that a second wave of liver disease exists in adult CF patients, but also that it may be more prevalent than previously described. Further evaluation of this diagnostic criteria in other CF cohorts should be performed to evaluate its utility in adult CFLD.