Alkhouri, Naim

Abstract There is ongoing recognition of the burden of non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH), with fibrosis being the most important histological feature that is associated with progression to cirrhosis and the occurrence of major adverse liver outcomes. Liver biopsy is the gold standard applied to detect NASH and determine the stage of fibrosis, but its use is limited. There is a need for non‐invasive testing (NIT) techniques to identify patients considered at‐risk NASH (NASH with NAFLD activity score > 4 and ≥ F2 fibrosis). For NAFLD‐associated fibrosis, several wet (serological) and dry (imaging) NITs are available and demonstrate a high negative predictive value (NPV) for excluding those with advanced hepatic fibrosis. However, identifying at‐risk NASH is more challenging; there is little guidance on how to use available NITs for these purposes, and these NITs are not specifically designed to identify at‐risk NASH patients. This review discusses the need for NITs in NAFLD and NASH and provides data to support the use of NITs, focusing on newer methods to non‐invasively identify at‐risk NASH patients. This review concludes with an algorithm that serves as an example of how NITs can be integrated into care pathways of patients with suspected NAFLD and potential NASH. This algorithm can be used for staging, risk stratification and the effective transition of patients who may benefit from specialty care.

AbstractBackgroundLiver biopsy is the gold standard to stage fibrosis in liver disease. Several scoring systems have been studied to predict advanced fibrosis in liver disease. Those scores have not been validated in pediatric liver transplant patients.AimEvaluate the performance of three fibrosis scores (FSc) in assessing the presence of advanced fibrosis (AF) in children after orthotopic liver transplantation (OLT).MethodsPatients < 20 years of age who underwent liver biopsy post‐OLT with laboratory values within 1 month of the biopsy were included. Fibrosis was determined by an experienced pathologist (F0‐4). We defined AF as F3‐4. The following FSc were calculated: AST/ALT ratio, APRI, and FIB‐4 index. Receiver operating characteristic curve analysis was done to assess the FSc performance in predicting AF.ResultsA total of 232 biopsies were analyzed, of those 42 (18.1%) showed AF (F3‐4). FIB‐4 was significantly higher in patients with AF compared to those without AF [median value of 1.1 [0.7, 3.0] and 0.6 [0.2, 1.4], respectively (p = .02)]; however, FIB‐4 had satisfactory accuracy to diagnose AF with significant overlap and AUC of 0.68 (CI 0.56–0.81). Cutoff points of 0.2 and 3.03 were used to rule in and rule out AF, respectively. AST/ALT and APRI were not significantly different between patients with and without AF.ConclusionEven though FIB‐4 had satisfactory accuracy in detecting AF in pediatric transplant patients, noninvasive hepatic FSc developed in adults still performed poorly. Our results highlight the need to develop a reliable pediatric FSc.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) has become the most common form of chronic liver disease. Determining the severity of NAFLD using the presence of nonalcoholic steatohepatitis (NASH) and stage of liver fibrosis is important, yet liver biopsy remains the gold standard despite limitations to its use. This study surveyed pediatric gastroenterologists across the United States to determine which guidelines are used to determine the severity of NAFLD in children, which patients undergo liver biopsy, and how these guidelines compare to each other and to clinical practice. METHODS: 140 pediatric gastroenterologists were surveyed electronically regarding current diagnostic practices for NAFLD. Responses were reviewed in Survey Monkey and compared to current North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), American Association for the Study of Liver Diseases (AASLD) and European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines regarding liver biopsy for evaluation of NAFLD. RESULTS: 140 surveys were distributed with 54 responses, a 38.6% response rate. Participants included pediatric gastroenterologists, hepatologists and transplant hepatologists. 96.2% reported familiarity with NASPGHAN guidelines, 22.6% with ESPGHAN and 39.6% with AASLD. 88.7% of responders desired a generalized consensus regarding proper diagnosis. Pediatric gastroenterologists referred obese patients with abnormal liver enzymes suspected to have NAFLD 22% of the time, pediatric hepatologists 27.2%, and transplant hepatologists 39.9% (one-way ANOVA with P -value of 0.324). 61.5% of responders reported using Fibroscan and 59.6% used MR elastography to assess severity of NAFLD and presence of liver fibrosis when not pursuing liver biopsy. 92.5% of responders believed the presence of autoimmune antibodies was important in deciding when to proceed to liver biopsy, as well as 88.7% using abnormal screening labs and 75.5% using imaging suggestive of liver fibrosis. CONCLUSION: Comparison between the criteria that providers believed warranted a liver biopsy versus those included in society guidelines differed. The presence of autoimmune antibodies, abnormal screening labs, and liver fibrosis suggested on imaging all appeared to be important factors regardless of current guidelines. Providers also seem to rely on Fibroscan and MR elastography over liver ultrasound despite the lack of validated cutoff values in children.

Goals: To analyze the frequency and trend of liver transplantation (LT) for nonalcoholic steatohepatitis (NASH) cirrhosis in young adults aged 18 to 40 years and to assess post-LT outcomes in this age group. Background: NASH is currently the fastest-growing indication for LT in US adults. It is believed that NASH is a rare indication for LT among young adults. Study: Using the United Network for Organ Sharing database, we performed a retrospective cohort analysis of all LTs in young adults between 2002 and 2012. Incidence rate ratio was calculated for each indication. Results: A total of 5157 young adults underwent LT over the study period—54% were male, 23% obese. Mean (±SD) age and body mass index were 31.6±6.7 years and 26.3±6.1 kg/m2, respectively. The incidence of LTs performed for NASH cirrhosis increased from 0.53% in 2002 to 4.46% in 2012. NASH was the most rapidly growing indication for LT among all other etiologies with a 14% increment per year (incidence rate ratio, 1.14; 95% confidence interval, 1.09-1.20, P<0.001). The 5-year post-LT outcomes were comparable between NASH and non-NASH recipients, but graft survival was lower and retransplantation cumulative rates were higher in NASH recipients compared with those with other metabolic liver diseases (63.5% vs. 81.4%, P=0.003 and 12.7% vs. 4.2%, P=0.046, respectively). Conclusions: NASH is the fastest-growing indication for LT among young US adults aged 18 to 40 years and now accounts for almost 5% of all LTs in this age group.

Nonalcoholic fatty liver disease (NAFLD) is a significant health burden in adolescents and young adults (AYAs) which has substantially risen in prevalence over the last decades. The occurrence of NAFLD parallels high rates of obesity and metabolic syndrome in this age group, with unhealthy lifestyle also playing an independent role. Genetic factors, sex, and ethnicity should be considered in a risk stratification model. NAFLD and nonalcoholic steatohepatitis (NASH) in AYAs often go unrecognized and, if untreated, can progress eventually to cirrhosis requiring liver transplantation (LT) before the age of 40. Recently, NASH has increased as an indication for LT in this age group. Important knowledge gaps include the feasibility of noninvasive diagnostic tests and imaging modalities as well as uncertainty about unique histological features and their predictive value. Future clinical trials focused on AYAs are needed to determine effectiveness of therapies. Tools for increasing awareness and prevention of NAFLD in AYAs are greatly needed. (H epatology 2017;65:2100‐2109).

ABSTRACTBackground:The relations between hepatic steatosis and histological features of hepatocyte injury in children with nonalcoholic fatty liver disease have yet to be examined. The aims of the present study were to establish associations between steatosis amount, type, and distribution in a well‐characterized group of children with biopsy‐proven nonalcoholic fatty liver disease (NAFLD).Patients and Methods:One hundred eight children with NAFLD seen in 5 centers were studied. Clinical and laboratory data were collected. Hematoxylin‐eosin and Masson trichrome stains were evaluated by 2 expert liver pathologists. Steatosis grade (0–3), type (macrovesicular, microvesicular, or mixed), and zone (1, 3, azonal, or panacinar) were determined. The NAFLD activity score and fibrosis stage were determined.Results:Median patient age was 12 years and median body mass index was 31 kg/m2. Fibrosis was present in 87%. The median NAFLD activity score was 4. Mild, moderate, and severe steatosis were present in 42%, 34%, and 24% of biopsies, respectively. Macrovesicular steatosis was present in 81% and mixed steatosis was present in 19%. Panacinar distribution of steatosis was most frequent (40%), followed by azonal (27%). Steatosis grade positively correlated with portal inflammation (P = 0.018). Azonal distribution positively correlated with presence of hepatocyte ballooning (P = 0.03). Biopsies with mixed steatosis were approximately 20 times more likely to have megamitochondria than those with macrovesicular steatosis alone (95% confidence interval 2.3–204.9). There was no relation between steatosis amount, type, or distribution to fibrosis stage.Conclusions:Specific histological patterns of steatosis in children are associated with histological markers of steatohepatitis. Ballooning and portal inflammation correlated well with features of steatosis.