Abstract Because of global epidemics of obesity and type 2 diabetes, the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing both in Europe and USA becoming one of the most frequent ...causes of chronic liver disease and predictably, one of the leading causes of liver transplantation (LT) both for end-stage liver disease and hepatocellular carcinoma. For most transplant teams around the world this will raise many challenges in terms on pre- and post-transplant management. Here we review the multifaceted impact of NAFLD on liver transplantation and will discuss: (1) NAFLD as frequent cause of cryptogenic cirrhosis, end-stage chronic liver disease and hepatocellular carcinoma; (2) prevalence of NAFLD as an indication for LT both in Europe and US; (3) the impact of NAFLD on the donor pool; (4) the access of NAFLD patients to LT and their management on the waiting list in regard to metabolic, renal and vascular comorbidities; (5) the prevalence and consequences of post-transplant metabolic syndrome, recurrent and de novo NAFLD; (6) the alternative management and therapeutic options to improve the long-term outcomes with particular emphasis to the correction and control of metabolic comorbidities.
Background and Aims
The prevalence of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is increasing at an alarming rate. The role of bile acids in the development and progression ...of NAFLD to NASH and cirrhosis is poorly understood. This study aimed to quantify the bile acid metabolome in healthy subjects and patients with non-cirrhotic NASH under fasting conditions and after a standardized meal.
Methods
Liquid chromatography tandem mass spectroscopy was used to quantify 30 serum and 16 urinary bile acids from 15 healthy volunteers and 7 patients with biopsy-confirmed NASH. Bile acid concentrations were measured at two fasting and four post-prandial time points following a high-fat meal to induce gallbladder contraction and bile acid reabsorption from the intestine.
Results
Patients with NASH had significantly higher total serum bile acid concentrations than healthy subjects under fasting conditions (2.2- to 2.4-fold increase in NASH; NASH 2595–3549 µM and healthy 1171–1458 µM) and at all post-prandial time points (1.7- to 2.2-fold increase in NASH; NASH 4444–5898 µM and healthy 2634–2829 µM). These changes were driven by increased taurine- and glycine-conjugated primary and secondary bile acids. Patients with NASH exhibited greater variability in their fasting and post-prandial bile acid profile.
Conclusions
Results indicate that patients with NASH have higher fasting and post-prandial exposure to bile acids, including the more hydrophobic and cytotoxic secondary species. Increased bile acid exposure may be involved in liver injury and the pathogenesis of NAFLD and NASH.
Diagnosis of drug-induced liver injury (DILI) is difficult. We reviewed cases in the DILI Network prospective study that were adjudicated to have liver injury due to other causes to discover pearls ...for improved diagnostic accuracy.
Cases were adjudicated by expert opinion and scored from 1 (definite DILI) to 5 (unlikely DILI). Confirmed cases (1-3) were compared with unlikely cases (5).
One hundred thirty-four of the 1,916 cases (7%) were unlikely DILI. Alternative diagnoses were autoimmune hepatitis (20%), hepatitis C (20%), bile duct pathology (13%), and hepatitis E (8%).
Thorough evaluation, including follow-up, is essential to minimize incorrect diagnosis of idiosyncratic DILI.
In contrast with other developed nations, life expectancy is decreasing in the United States, in part due to increasing mortality from alcohol-associated liver disease (ALD). Up-to-date estimates of ...ALD mortality are necessary for setting public health priorities to reverse this concerning trend. We therefore aimed to assess current (2017) estimates of ALD mortality and temporal trends from 1999 to 2017.
Using national data from the Centers for Disease Control and Prevention, we analyzed stratified ALD mortality rates between 1999 and 2017. We determined the age-adjusted death rates, stratified by sex and categorized by age, race/ethnicity, urbanization, and census region. We also identified statistically significant changes in the annual rate difference (ARD), annual percentage change (APC), and average APC in ALD mortality.
In 2017, mortality from ALD was higher than any other year since 1999 with age-adjusted rates of 13.1 per 100,000 (95% confidence interval CI 12.9-13.3) in men and 5.6 per 100,000 (95% CI 5.4-5.7) in women. Mortality was highest among men and women who were middle aged, Native American, and from rural areas. Since 2006, ALD mortality has increased in almost every age group and race with the exception of non-Hispanic black men. Absolute increases in mortality rates have been particularly pronounced in Native American women (2005-2017 ARD 0.8, 95% CI 0.6-0.9), non-Hispanic/white men (2006-2017 ARD 0.4, 95% CI 0.3-0.4), and non-Hispanic/white women (2013-2017 ARD 0.4, 95% CI 0.3-0.5).
Mortality from ALD is increasing over time in most demographic groups. Increased effort is needed to develop targeted public health strategies to address high and increasing ALD mortality.
Obesity is a growing epidemic in the United States, now affecting >40% of adults and ∼20% of children.1,2 The first step in managing obesity is improving lifestyle choices, and while fad diets and ...quick fixes abound, we all know they are not the right answer. The authors endorse multidisciplinary care with a registered dietician and follow the evidence from clinical trials: “Data from trials suggest that soluble fiber is effective for patients with chronic constipation, irritable bowel syndrome, and fecal incontinence. A diet low in select fermentable, oligo-, di-, and monosaccharides and polyols may benefit patients with irritable bowel syndrome.
Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease that is driven by the metabolic syndrome. NAFLD encompasses nonalcoholic fatty liver, >5% fat in the liver without ...inflammation of fibrosis, nonalcoholic steatohepatitis (NASH), fat plus varying degrees of inflammation and fibrosis, and cirrhosis of the liver from NASH. As facets of the metabolic syndrome, particularly diabetes and obesity, become more common worldwide, the incidence of new NAFLD is increasing.
A qualitative systematic review was performed via searches of PubMed and ClinicalTrials.gov for therapeutic interventions for NAFLD.
Current therapies rely on metabolic syndrome risk factor control and lifestyle changes to achieve weight loss. Because sustained weight loss is difficult for many patients, there is a critical unmet need for pharmacotherapy to treat NAFLD, especially the progressive form, NASH, to prevent cirrhosis of the liver. New therapies for NAFLD focus on the subset of patients with NASH and some degree of fibrosis. Novel mechanisms of action, including farnesoid X nuclear receptor agonism, C–C motif chemokine receptor 2 and receptor 5 antagonism, stearoyl-CoA desaturase-1, and thyroid hormone receptor β agonism, are currently under investigation as monotherapy. The products also hold potential for use in combination with and without insulin sensitizers and other established drugs in the future.
This review of NASH treatments details the interventions that are currently available as well as those in late-stage clinical trials that may represent the future of NASH therapy.
Summary
Background
Non‐alcoholic steatohepatitis (NASH) is characterised by hepatic lipid accumulation, cell injury, inflammation and fibrosis. Insulin resistance, a hallmark of type 2 diabetes (T2D) ...and obesity, is a key pathogenic driver of NASH. Other than difficult‐to‐maintain lifestyle changes, there are no approved treatments for NASH. Due to their effects on multiple pathophysiological processes, glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have been tested in disorders related to insulin resistance and metabolic defects.
Aims
To summarise studies of GLP‐1RAs relevant to the treatment of NASH.
Methods
PubMed searches were performed and results were compiled.
Results
Large trials with GLP‐1RAs in T2D demonstrate highly effective glucose lowering, with body weight loss, and in some cases, reduced cardiovascular events and improved liver transaminases. The GLP‐1RAs, liraglutide and semaglutide, were associated with clinically relevant, sustained body weight reduction in individuals with overweight or obesity and without T2D. In a phase II trial in NASH, liraglutide reduced metabolic dysfunction, insulin resistance and lipotoxicity in key organs associated with NASH pathogenesis. Furthermore, liraglutide and semaglutide led to histological resolution of NASH in ~40% to 60% of patients, although a statistically significant effect on fibrosis has not been confirmed. Regarding safety, GLP‐1RAs are associated with gastrointestinal and gallbladder‐related adverse events, with the latter perhaps related to weight loss. Meta‐analyses do not indicate increased risk of acute pancreatitis, pancreatic cancer or other malignancies with GLP‐1RAs.
Conclusions
These studies support the use of GLP‐1RAs for the improvement of underlying metabolic dysfunction observed in NASH and suggest further long‐term phase III trials are warranted.
GLP‐1RAs have a variety of hepatic and extra‐hepatic physiological effects which may impact the natural history of nonalcoholic fatty liver disease and serve as the rational for potential therapeutic use in this population. GLP‐1RA, glucagon‐like peptide‐1 receptor agonist; NASH, non‐alcoholic steatohepatitis.
To evaluate the cost effectiveness of early treatment with direct-acting antiviral therapy in adolescent patients with chronic hepatitis C virus (HCV) infection compared with treatment deferral.
We ...constructed a Markov model to assess the cost effectiveness of treating a hypothetical cohort of 30 000 adolescent patients with chronic HCV at age 12 years compared with deferring treatment until adulthood from a societal perspective. Model inputs for transition probabilities, HCV treatment and medical care costs, and quality-adjusted life-year (QALY) utilities were derived from the literature and wholesale acquisition estimates. Deterministic sensitivity analyses varied parameters for non-HCV medical care and treatment cost, reinfection rates, treatment uptake, disease progression, liver transplant survival, and treatment with recently approved pangenotypic direct-acting antiviral agents. Discounted costs and total QALYs per person were quantified after 30 years. Cost effectiveness was evaluated as the incremental change in total medical costs per QALY gained.
The incremental cost effectiveness of early treatment initiation compared with deferred treatment was approximately $27 000 per QALY gained after 30 years and considered cost effective. In a scenario analysis, hypothetical treatment initiation with currently available pangenotypic agents would be even more cost effective, ranging from $10 000 to $21 000 per QALY gained. Cost-effectiveness estimates were sensitive to variations in decompensated cirrhosis progression in adolescence, adult reinfection, and treatment uptake in adults.
Early treatment in adolescent patients with chronic HCV infection with currently available direct-acting antivirals seems to be cost effective compared with deferred treatment. Future efforts to control the HCV epidemic should include increasing the number of children treated.
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