PDB68 Maximum-Likelihood Estimation of Transition Probabilities between Fibrosis Stages in Nonalcoholic Steatohepatitis (NASH)

Nonalcoholic Fatty Liver Disease and Fibrosis Progression: The Good, the Bad, and the Unknown

A Revisit of the Natural History of Nonalcoholic Fatty Liver Disease

The Impact of Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome on Progression of Fibrosis in Patients With Recurrent HCV After Liver Transplantation

Disease progression in nonalcoholic steatohepatitis (NASH) is highly heterogenous and remains poorly understood. Fibrosis stage is currently the best predictor for development of end-stage liver disease and mortality. Better understanding and quantifying the impact of factors affecting NASH and fibrosis is essential to inform a clinical study design. We developed a population Markov model to describe the transition probability between fibrosis stages and mortality using a unique clinical nonalcoholic fatty liver disease cohort with serial biopsies over 3 decades. We evaluated covariate effects on all model parameters and performed clinical trial simulations to predict the fibrosis progression rate for external clinical cohorts. All parameters were estimated with good precision. Age and diagnosis of type 2 diabetes (T2D) were found to be significant predictors in the model. Increase in hepatic steatosis between visits was the most important predictor for progression of fibrosis. Fibrosis progression rate (FPR) was twofold higher for fibrosis stages 0 and 1 (F0-1) compared to fibrosis stage 2 and 3 (F2-3). A twofold increase in FPR was observed for T2D. A two-point steatosis worsening increased the FPR 11-fold. Predicted fibrosis progression was in good agreement with data from external clinical cohorts. Our fibrosis progression model shows that patient selection, particularly initial fibrosis stage distribution, can significantly impact fibrosis progression and as such the window for assessing drug efficacy in clinical trials. Our work highlights the increase in hepatic steatosis as the most important factor in increasing FPR, emphasizing the importance of well-defined lifestyle advise for reducing variability in NASH progression during clinical trials.

The natural history of chronic hepatitis C acquired in infancy is not well understood. The progression of fibrosis was analyzed in untreated children with chronic hepatitis C virus infection and no other hepatotoxic cofactors. A total of 112 pediatric patients (13 with paired liver biopsies) were considered. Fibrosis was assessed by METAVIR score (i.e., stage F1 to F4). The ratio between the stage of fibrosis (METAVIR units) and the presumed duration of infection represented the "estimated" rate of fibrosis progression per year. In patients with paired biopsies, the "observed" rate of fibrosis progression was defined as the difference between the stage of fibrosis in the two biopsies divided by the time interval between them. Both age of patients at biopsy and duration of infection correlated with stage of fibrosis (p < 0.002 and p < 0.0005, respectively). Stage of fibrosis differed significantly between patients with infection lasting less or more than 10 yr (p < 0.0006). Sex, hepatitis C virus genotype, and route of infection did not correlate with stage of fibrosis. Among the 13 patients with paired biopsies, stage of fibrosis increased in seven and did not change in six; the median rate of estimated fibrosis progression per year was 0.142. The difference between estimated and observed fibrosis progression rates was significant (coefficient of determination, r(2) = 0.031), which demonstrated that the prediction of the fibrosis progression was unreliable in 97% of patients. Chronic hepatitis C acquired in childhood is a progressive, slow-moving, fibrotic disease. Fibrosis progression inferred on the basis of linear mathematical models should be critically evaluated in the clinical practice.

Disease severity and antiviral response in patients with chronic hepatitis B with non-obese NAFLD

Nonalcoholic steatohepatitis (NASH) is known to recur following liver transplantation (LT). Metabolic risk factors increase with immunosuppression. However, the rate of fibrosis progression following LT for NASH while on immunosuppression is less clear. The incidences of steatosis, NASH, and fibrosis following LT for NASH were quantified and compared with those transplanted for alcoholic liver disease (ALD). Records of all NASH patients and 1 : 2 match with ALD transplant recipients between 2001 and 2006 were reviewed retrospectively. Patients without liver biopsies beyond 2 months following LT were excluded. NASH patients (n=77) were older (P=0.0006) and less likely male (P<0.001) than ALD patients (n=108). The incidence of steatosis, NASH, and fibrosis stage increased at 1, 3, and 5 years in both groups. Although steatosis and nonalcoholic fatty liver disease activity scores were higher, fibrosis was lower in NASH compared with ALD (0.43 vs. 1.0 stage/year; P=0.0045). The incremental increase in the rate of fibrosis was faster in the first year compared with 4-5 years (0.8 vs. 0.04 stage/year) following LT. The rate of fibrosis progression during 4-5 years was decreased in NASH compared with ALD recipients (0.04 vs. 0.33 stage/year; P=0.015). NASH etiology was associated with reduced rate of fibrosis progression (odds ratio=0.67) on multivariate analysis. Despite having more steatosis and inflammation, progression of fibrosis was slower in NASH compared with ALD recipients. Fibrosis progression slows with time following LT on immunosuppression and approximates the pretransplant progression rate by year 5.

Introduction Non-alcoholic fatty liver disease (NAFLD) has become a major public health issue with an increasing prevalence worldwide. Accurate diagnosis and staging of the disease is important in determining the long-term management and follow-up of these patients. The aim of our study is to investigate the correlation between non-invasive tests and different stages of liver fibrosis in NAFLD. Methods 905 patients with NAFLD underwent Fibroscan at Aberdeen Royal Infirmary from March 2013 to November 2016. 417 patients with liver stiffness measurement >7 kPa underwent electronic medical record reviews to identify patients who had liver biopsies within a year from the date of their Fibroscan. 54 out of 417 patients underwent liver biopsies. 42 of the 54 patients were identified to have biopsy-proven NAFLD. The histological reports of the liver biopsies were reviewed and different stages of fibrosis were recorded. Liver fibrosis was classified as no fibrosis (F0), mild fibrosis (F1), moderate fibrosis (F2), severe/bridging fibrosis (F3) and cirrhosis (F4). Clinical, radiological and biochemical data of these patients were also analysed, provided they were within 1 year from the dates of liver biopsies. Results Out of the 42 patients identified, the mean age was 56 (±14) with a male preponderance (55%). 1 patient had no fibrosis (F0), 14 patients had mild fibrosis (F1), 1 patient had moderate fibrosis (F2), 14 patients had severe fibrosis (F3) and 12 patients had cirrhosis (F4). Correlation between different variables and stages of fibrosis were tested using the non-parametric Spearman’s correlation coefficient. Data are summarised in the table 1 below and are expressed as median ±IQR. Conclusions Our study indicated that there were statistically significant positive correlations between LSM, NALFD score and FIB-4 score with different stages of fibrosis in patients with NAFLD. However, the correlations between AST to Platelet Ratio Index (APRI), United Kingdom Model for End-Stage Liver Disease (UKELD) score and different stages of fibrosis were not statistically significant. The difference may be due to the inclusion of clinical variables in the NAFLD score. The addition of LSM to the NAFLD score could potentially improve the diagnostic accuracy of fibrosis in NAFLD patients.

Centrilobular ductular reaction correlates with fibrosis stage and fibrosis progression in non-alcoholic steatohepatitis

Мета: оцінити жорсткість печінки у хворих на стабільну ішемічну хворобу серця (ІХС) на тлі неалкогольної жирової хвороби печінки (НАЖХП) залежно від вираженості коронарного атеросклерозу. Матеріали і методи. Обстежено 220 хворих на стабільну ІХС, поєднану з НАЖХП. Серед них були виділені пацієнти з неалкогольним жировим гепатозом (НАЖГ) та неалкогольним стеатогепатитом (НАСГ). Контрольну групу становили 20 практично здорових осіб. Усім хворим проведено загальноклінічне обстеження, електрокардіографію, коронарографію, еластографію, оцінку функціонального стану печінки. Результати. Аналіз отриманих результатів виявив підвищення жорсткості печінки в усіх групах хворих порівняно з контролем. Зокрема, у хворих із НАЖГ швидкість зсувної хвилі вірогідно перевищувала показник здорових осіб у всіх групах хворих. За умов НАСГ показник жорсткості паренхіми печінки більше ніж вдвічі перевищував рівень контрольної групи. Встановлено вірогідну відмінність стану паренхіми печінки залежно від стадії НАЖХП. Аналіз стадійності фібротичних змін печінки виявив певні закономірності залежно від прогресування НАЖХП. Зокрема, стадія F1 фіброзу печінки мала місце у більше ніж половини хворих групи ІА (р &lt; 0,05). У хворих групи ІБ на фоні НАСГ близько у 60 % осіб спостерігали стадію F2 фіброзу (р &lt; 0,05), а у 25 % пацієнтів — стадію F3. У хворих ІІ групи стадійність фіброзу суттєво не відрізнялась від пацієнтів І групи. Найбільш прогностично несприятливий перебіг НАЖХП виявлено у ІІІ групі. Зокрема, у 34,8 % осіб групи ІІІА спостерігали стадію F2 фіброзу, у випадку НАСГ у понад 70 % хворих групи ІІІБ виявляли значні фібротичні зміни паренхіми печінки стадії F3 (р &lt; 0,05). Більше того, понад 13 % пацієнтів групи ІІІБ мали стадію F4 фіброзу. Висновки. Перебіг НАЖХП у хворих на стабільну ІХС характеризується підвищенням жорсткості паренхіми печінки, що вірогідно залежить від стадії НАЖХП та є більш вираженою на тлі НАСГ. Прогресування фіброзу печінки у хворих із НАЖХП, що поєднана зі стабільною ІХС, залежить від вираженості коронарного атеросклерозу та є найбільш прогностично несприятливим у хворих із перенесеним гострим коронарним синдромом та вираженими рубцевими змінами міокарда.

Evaluation and management of non-alcoholic steatohepatitis

Association Between Fibrosis Stage and Outcomes of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

Disease State Transition Probabilities Across the Spectrum of NAFLD: A Systematic Review and Meta-Analysis of Paired Biopsy or Imaging Studies

Fibrosis Progression in Nonalcoholic Fatty Liver vs Nonalcoholic Steatohepatitis: A Systematic Review and Meta-analysis of Paired-Biopsy Studies

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease seen in adults and children worldwide with a prevalence rate of 24% in adults and 10% in children in the United States. Many factors influence the development of NAFLD, including ethnicity, genetics, body weight, environment, coexisting diseases, and access to health care.1, 2 Childhood obesity is concerning because of its association with end-stage liver disease in adulthood. For each 1-unit gain in body mass index (BMI) z score among children aged 7 to 13 years, the risk for cirrhosis increases by 16% in adulthood.3 Moreover, the rate of fibrosis progression in adults with NAFLD is on average one stage of progression over 14 years; however, some adults exhibit the rapid fibrosis phenotype with accelerated fibrosis development in less than 10 years.4, 5 Consequently, early identification and longitudinal management of NAFLD from childhood to adulthood are crucial for preventing progression and complications. Pediatric patients with NAFLD are best managed with a multidisciplinary team, including a gastroenterologist or hepatologist, dietician, exercise specialist, and psychological and other supportive services; however, there are currently no NAFLD-specific models that seamlessly transition patients from the pediatric to adult provider. During this period, patients are at high risk for recidivism and loss of integrated care. Here, we propose a NAFLD-specific model based on other models for chronic diseases to successfully transition pediatric patients with NAFLD to adult care. Transition of care is defined as the "purposeful, planned movement" of pediatric patients from child-centered to adult-oriented care,6 whereas transfer of care involves the direct handoff of a patient from the pediatric to adult provider. The concept of pediatric to adult transition of care programs is relatively new because many children with previously life-threatening conditions, such as sickle cell disease and cystic fibrosis, did not survive into adulthood. Transition of care initiatives developed in large part to prevent the growing disparities in health care outcomes before and after transition. For instance, among patients with sickle cell disease in England, newly transitioned patients accounted for the highest number of emergency department visits between 2001 and 2010.7 Moreover, according to the type 1 diabetes US Exchange Clinic Registry, mean hemoglobin A1c and diabetic ketoacidosis incidence were highest in adolescence and young adults aged 18 to 25 years, respectively.8 In 2011, the American Academy of Pediatrics, American Association of Family Physicians, and American College of Physicians proposed the basis for the Six Core Elements of Health Care Transition9: (1) incorporation of a transition policy, (2) transition tracking and monitoring, (3) assessment of transition readiness, (4) the actual transfer to adult-centered care, (5) transition completion, and (6) ongoing adult-centered care. The Got Transition Program incorporated these elements into guidelines with detailed instructions for implementing a transition program.10 Transition of care requires recognition and intervention on numerous barriers to care to ensure successful outcomes in adulthood. Low socioeconomic status (SES), switching providers, and poor health literacy present major challenges for transition of care. In one study of patients with type 1 diabetes, patients with low SES had a 2-fold increased risk for hospitalizations after transition compared with patients with high SES.11 This study also found that demographically matched control subjects who did not switch physicians were 77% less likely to be hospitalized compared with those who transferred to a new physician (RR: 0.23 [confidence interval: 0.05-0.79]). Although the specific reasons for increased rates of hospitalization are incompletely understood, poor health literacy contributes to this disparity. Indeed, only 60% of adolescents and young adults are estimated to have adequate health literacy, and many struggle with communicative and critical health literacy, the higher level of health literacy required to analyze and integrate complex information to impact one's own health care.12 Addressing this modifiable barrier to care will help ensure a successful transfer of care. Many adolescents with NAFLD struggle with obesity, self-esteem, or body image issues that also impact transition of care. According to the Endocrine Society, transition programs for obesity are an uncharted area that requires further research.13 Transition of care plays a role in obesity because adolescents and young adults are more likely to sustain a healthy diet and physical activity if they are encouraged to do so from an early age. A meta-analysis commissioned by the Endocrine Society found that lifestyle interventions directed toward children and adolescents significantly decreased sedentary behavior (P = 0.05), but with a more significant impact in children (P = 0.02).14 Obesity development can be tied to environmental factors that develop from a young age, including consumption of sugary beverages, unhealthy sleeping patterns, long technology-related screen time, and family stressors.13 These unhealthy habits often worsen when adolescents move away from home to attend college or start employment, particularly unhealthy eating and sedentary activity.15 Thus, addressing these behavioral and environmental causes of obesity early during the transition period will ensure better preparation for adult NAFLD care. Intense parental involvement has been shown to be beneficial for steering adolescents toward implementing healthy lifestyle changes.16 Yet, a restrictive and critical family environment can worsen outcomes by causing compensatory binge-eating behavior and anxiety.13 Obesity is associated with other psychosocial stressors, including lower quality of life, poor self-esteem, increased risk for depression and anxiety, higher-than-average risk for eating disorders, and increased risk for substance abuse.13 Heavier weight and body image dissatisfaction were found to predict lower self-esteem in adolescent girls.17 A meta-analysis of self-esteem in overweight and obese adolescents determined that weight loss alone was insufficient to improve self-esteem.18 Therefore, a team-based approach involving health care providers, counselors, and family members is needed to address psychological and behavioral barriers to transition of care in patients with NAFLD, the majority of whom suffer from obesity. Finally, substance abuse, and particularly alcohol consumption, presents another challenge for transitioning adolescents with NAFLD because, increasingly, the likely synergistic relationship between alcohol and obesity is being recognized.19 Many transitioning adolescents will attend college with increased access to alcohol and social pressure to drink. In one university survey, 77% of students reported drinking alcohol with the explicit purpose of getting drunk.20 Other risk factors for alcohol abuse in adolescence include family history of substance abuse and/or mood disorders, poor parental supervision, poor academic achievement and/or aspiration, and attention deficit disorder/attention deficit hyperactivity disorder.21 Early transitioning of care ensures ample preparation for transfer to adult care. Conversations surrounding transition of care should ideally begin at age 12 years22 with a discussion of personal and professional goals. Providers should gradually begin to empower adolescents to assume control of their own health. Providers should also engage adolescents early in NAFLD education and discuss behaviors that can impact both liver and general health, such as smoking, vaping, drug use, and sex. Due to limited office visits, parents should play an active role in discouraging substance abuse. The Substance Abuse and Mental Health Services Association developed strategies for parents on how to counsel adolescents about alcohol (Fig. 1).21 These conversations can also be applied to other health-related behaviors. As the transfer to adult care approaches, pediatric gastroenterologists and hepatologists should address their patients directly and, if possible, privately to simulate a typical adult NAFLD clinic experience. This would give them the opportunity to answer and pose their own questions without parental influence. According to the social-ecological model of adolescent and young adult readiness for transition (SMART), patients should hone skills of self-advocacy throughout the transition process with help from parents and providers.23 Invariably, adolescents will feel ready to transition at different time points. Families are an important part of the care team and transition process and should be involved at each step. Providers can objectively assess transition readiness by using the disease-neutral Transition Readiness Assessment Questionnaire (TRAQ).24 According to a review of disease-neutral and disease-specific transition readiness questionnaires, TRAQ was the best validated transition readiness tool.25 In addition to TRAQ, measures of self-efficacy and self-esteem may be important indicators of transition readiness.26 Self-efficacy is the belief that one's own abilities can overcome challenges. For chronic illness, self-efficacy is positively linked to self-management, adherence, and coping. Moreover, self-esteem is correlated with an internal sense of achievement, motivation, and optimism. A low self-esteem is associated with depression in patients with inflammatory bowel disease (IBD).27 Self-efficacy and self-esteem are dynamic and predict transition readiness better than patient demographics, SES, or disease knowledge itself.26 The General Self-Efficacy Scale28 and the Rosenberg Self-Esteem Scale29 can be used by NAFLD providers to perform these measurements. Low scores on these assessments can improve if addressed at a young age and should prompt referral to counseling. Although transitioning may be daunting, a few key interventions can usher adolescents into adult care. Pairing patients with adult providers before their last pediatric visit can alleviate the stress of switching providers. The European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Association for the Study of the Liver (EASL) formulated a comprehensive strategy to transition youth with liver disease to adult care.30 According to this joint society paper, essential documents should be prepared for patients to summarize the transition of care plan. These documents include the pediatric provider's letter with a synthesis of their patient's medical history, an emergency care plan, a transition checklist, a transition roadmap, and educational information on NAFLD. The transition checklist developed by the Royal College of Nursing31 and modified by the ESPGHAN/EASL ensures that pediatric providers cover key topics before transfer of care, including self-advocacy, independent health care behavior, sexual health, psychological support, educational and vocational planning, and their patients' health and lifestyle. The checklist also allows providers to categorize their patients' mastery of each topic (early, middle, and late-stage transition). Pairing patients with adult providers before their last pediatric visit can alleviate the stress of switching providers. Transition programs should offer their patients the opportunity for combined visits or alternating visits between pediatric and adult provider before the final pediatric visit.15 This phase of transition of care ensures that adolescents and young adults are given a sufficient amount of time to build rapport with their adult provider before graduating from pediatric care. Another intervention includes the implementation of transition coordinators who can facilitate scheduling, augment NAFLD education and management, and troubleshoot barriers to care.22 In IBD, the use of a one-time transition coordinator significantly improved transition readiness (P < 0.001), as well as the number of patients in disease remission (P < 0.01).32 Comprehensive transition clinics that include coordinators and nutrition, psychological, and social services can provide added support for patients with identified barriers to care. Finally, virtual support groups can be arranged to discuss shared challenges and successes. Transition programs should collect objective and qualitative data for analysis and quality improvement (Fig. 2). Clinical, laboratory, and imaging data can be used to track NAFLD progression among those who have transferred to the adult NAFLD provider. Anthropometric data, including weight, BMI with z scores, waist circumference, and blood pressure, should be collected. Laboratory markers of liver injury, from steatosis to advanced fibrosis and cirrhosis, should be assessed. Metabolic indicators, including a total lipid panel, glucose, insulin, and hemoglobin A1c, should be followed longitudinally. Other laboratory markers associated with NAFLD progression, such as Fibrosis-4 (FIB-4) and aspartate aminotransferase-to-platelet ratio index (APRI) scores, can be used. Other markers, such as α2-macrolobulin, haptoglobin, apolipoprotein A1, leptin, and fibroblast growth factor-21, are not readily available and can be considered in the context of research studies.33 Regarding noninvasive studies, transient elastography with controlled attenuation parameter can be used as an office-based tool to estimate steatosis and fibrosis. Providers can also track individual quantifiable outcomes, including quality of life, satisfaction with adult care, adherence to a healthy lifestyle, understanding of disease process and medications, and attendance to clinic visits and social support groups.30 These data taken together can ultimately be used by NAFLD programs to tailor both individual care and the transition and transfer processes themselves. Regular interdisciplinary meetings should be held to assess patient outcomes and areas for improvement. The end goal of transition of care is to build a strong foundation by which patients are encouraged to take control of their own health maintenance and to stave off disease progression. In our experience, we link patients directly from the pediatric NAFLD clinic to the adult NAFLD clinic located within the same medical campus. Pediatric patients are provided with educational resources on NAFLD, as well as a guideline for the transition process. We have created video resources to concisely describe the transition process and introduce transitioning patients to the adult NAFLD clinic. After transfer, newly transitioned patients are followed closely within the first 2 years of transfer of care with frequent clinic visits and phone check-ins to ensure successful integration into adult care. Finally, pediatric and adult NAFLD providers continue to collaborate and review and discuss patients. A Cochrane Review of four small studies (n = 238) concluded that transition of care interventions improved patients' knowledge of their condition, as well as their confidence and self-efficacy at 4- to 12-month follow-up time.34 With the development of a comprehensive transition of care model (Fig. 3), we hope to create a durable program with long-lasting impacts on patients, as well as a reduction in NAFLD-associated morbidity and mortality.