Nonalcoholic fatty liver disease: impact on healthcare resource utilization, liver transplantation and mortality in a large, integrated healthcare system.

BACKGROUND AND AIMS: NAFLD is the most prevalent liver disease globally, affecting 20% of the world population. Healthcare resource utilization (HRU) attributable to NAFLD has been difficult to define. METHODS: We performed a case control study on NAFLD patients from 2005 to 2015 in a large integrated healthcare system with an affiliated insurance company that prospectively captures HRU information. Outcomes encompassed costs, liver transplantation and mortality rates. RESULTS: There were 17,085 patients, of which 4512 were NAFLD cases and 12,573 were non-NAFLD controls. The cohorts were similar in age and gender distribution (p > 0.05). The NAFLD cohort had a younger mean age of death (60.9 vs. 63.3, p = 0.004) and had over twice the number of annual healthcare visits (14.6 vs. 7.1). The increased overall annual overall cost attributable to NAFLD (in 2015 $) was $449/year. Overall, NAFLD was independently associated with 17% higher annual attributable healthcare costs. More advanced NAFLD (FS 3-4) was associated with a 40% increase in median annual healthcare costs (vs. FS 0-2). The strongest predictors of HRU among patients with NAFLD were advanced fibrosis and medical co-morbidities. The rate of liver transplantation was 18 times greater (0.054%/year) in the NAFLD compared with the non-NAFLD cohort, while mortality rate was 1.7 times greater. CONCLUSIONS: Within a large, integrated healthcare system a diagnosis of NAFLD is independently associated with a 17% overall excess in HRU and a several-fold increase liver transplantation and mortality. Although the dollar amounts will change over time and between healthcare systems, the proportional need for HRU will have broad applicability and implications.

Nutrition in alcoholic liver disease.

The liver plays an important role in the metabolism, synthesis, storage, and absorption of nutrients. Patients with cirrhosis are prone to nutritional deficiencies and malnutrition, with a higher prevalence among patients with decompensated disease. Mechanisms of nutritional deficiencies in patients with liver disease are not completely understood and probably multifactorial. Malnutrition among patients with cirrhosis or alcoholic liver disease correlates with poor quality of life, increased risk of infections, frequent hospitalizations, complications, mortality, poor graft and patient survival after liver transplantation, and economic burden. Physicians, including gastroenterologists and hepatologists, should be conversant with assessment and management of malnutrition and nutritional supplementation.

Branched-chain amino acids as pharmacological nutrients in chronic liver disease.

Branched-chain amino acids (BCAAs) are a group of essential amino acids comprising valine, leucine, and isoleucine. A low ratio of plasma BCAAs to aromatic amino acids is a physiological hallmark of liver cirrhosis, and BCAA supplementation was originally devised with the intention of normalizing amino acid profiles and nutritional status. However, recent studies on BCAAs have revealed that, in addition to their role as protein constituents, they may have a role as pharmacological nutrients for patients with chronic liver disease. Large-scale, multicenter, randomized, double-blinded, controlled trials on BCAA supplementation have been performed in Italy and Japan, and results demonstrate that BCAA supplementation improves not only nutritional status, but also prognosis and quality of life in patients with liver cirrhosis. Moreover, accumulating experimental evidence suggests that the favorable effects of BCAA supplementation on prognosis may be supported by unforeseen pharmacological actions of BCAAs. This review summarizes the possible effects of BCAAs on albumin synthesis and insulin resistance from clinical and basic viewpoints. We also review the newly discovered clinical impact of BCAAs on hepatocellular carcinoma and the prognosis and quality of life of patients with liver cirrhosis.

Obesity, hyperlipidemia, and metabolic syndrome.

1. Obesity is increasingly common among liver transplantation (LT) recipients and donors. Outcomes following LT for selected patients with class I-III obesity are similar to those for nonobese recipients. In patients who are otherwise satisfactory candidates for LT, a high body mass index, as long as it does not present a technical barrier, should not be considered to be an absolute contraindication to LT. 2. The most common causes of death beyond the first year of LT are, in descending order of frequency, graft failure (especially secondary to hepatitis C virus recurrence), malignancy, cardiovascular disease, infections, and renal failure. Metabolic syndrome is an important risk factor for each of these etiologies of posttransplant death. Posttransplant diabetes, posttransplant hypertension, and an original diagnosis of cryptogenic cirrhosis, which is commonly associated with metabolic syndrome, are all associated with an increased risk of post-LT mortality. Features of metabolic syndrome should be screened for and treated in LT recipients. 3. Because of the physiological mechanism of post-LT hypertension, which includes renal arteriolar constriction secondary to calcineurin inhibition, calcium channel blocking agents are a good pharmacological treatment modality and have been shown to be effective in renal protection in randomized controlled trials of posttransplant hypertension. 4. It is rare for dietary changes and weight reduction to result in normalization of the lipid profile. Statins should thus be initiated early in the course of management of post-LT dyslipidemia. Forty milligrams of simvastatin per day, 40 mg of atorvastatin per day, and 20 mg of pravastatin per day are reasonable starting doses for post-LT hypercholesterolemia. It is important to remember that the effects of statin therapy are additive to those of a controlled diet (eg, a Mediterranean diet rich in omega-3 fatty acids, fruits, vegetables, and dietary fiber). 5. Nonalcoholic steatohepatitis, an increasingly common etiology of cirrhosis and liver failure, recurs commonly after LT and may also arise de novo. Treatment should be directed at managing obesity and complications of metabolic syndrome. Optimal immunosuppression in patients with nonalcoholic steatohepatitis is still evolving but should include steroid minimization.

Branched-chain amino acid enriched supplements as therapy for liver disease.

Altered amino acid metabolism is a hallmark of liver disease, characterized by low levels of circulating BCAAs and elevated levels of circulating aromatic amino acids, and methionine. Although overwhelming evidence indicates that the incidence of complications of liver disease increases with malnutrition, the reported impact of nutritional therapy, specifically BCAA supplementation, on outcomes in patients with liver disease has varied with the indication. Multiple small studies report the beneficial effects of BCAA supplementation, including improved metabolic profiles, as measured by protein sparing and/or normalization of respiratory quotients and clinical improvement of hepatic encephalopathy. Other studies have failed to show a clinical benefit of BCAA supplementation. The data concerning the impact of BCAA supplementation in prophylaxis of long-term morbidity and mortality in patients with cirrhosis is more promising and has been the subject of 2, large randomized controlled trials. In a study of 174 patients with advanced cirrhosis, who were randomized to either BCAA or 1 of 2 control arms, the combined event rates were seen to be significantly reduced in the BCAA supplementation arm, although this was not true for individual complications. In a more recent, larger, randomized controlled trial (n = 646) using a more palatable formulation, investigators demonstrated that long-term BCAA supplementation is associated with decreased frequency of hepatic failure and overall complication frequency. Both studies found improved nutritional status associated with BCAA supplementation. On balance, BCAA supplementation appears to be associated with decreased frequency of complications of cirrhosis and improved nutritional status when prescribed as maintenance therapy. Cost and palatability may limit the potential applicability of this treatment modality.

The selection and design of GPCR ligands: from concept to the clinic.

Virtual screening methods using structure-based, pharmacophore-based and descriptor based protocols may be used to identify ligands for the G-protein coupled receptor target family. A complementary approach is the synthesis and screening of compound libraries designed using privileged motifs and/or based on validated hit molecules. A virtual screening approach based on molecular docking performed with GOLD using a templated homology model and a consensus scoring procedure can identify vasopressin 1a receptor antagonists. In a separate project a library design and synthesis approach based around validated hit GPCR ligands led to the identification of potent oxytocin antagonists. Subsequent optimisation of the initial library compounds has provided compounds that are now being evaluated in the clinic for the treatment of preterm labour.