Differential Outcomes and Clinical Challenges of NAFLD With Extreme Obesity.

Nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity. The prevalence of extreme obesity, defined as body mass index (BMI) of 50 kg/m2 or higher, is rising more rapidly than overall obesity. We aimed to compare the clinical outcomes and performance of noninvasive fibrosis assessment tools in NAFLD with or without extreme obesity. A retrospective analysis was performed in 304 patients with NAFLD with extreme obesity and compared them to patients with NAFLD with BMI of 40 kg/m2 or less, matched for age, gender, race, and liver fibrosis stage. The mean age of the NAFLD with extreme obesity cohort was 55.9 years, BMI 55 kg/m2, and 49.7% had cirrhosis at initial evaluation. Baseline cirrhosis and coronary artery disease were associated with increased risk of death, and dyslipidemia with decreased risk of mortality. Age, insulin use, hypertension, albumin and platelet count were associated with cirrhosis. Fifteen percent of patients had weight-loss surgery, but this was not associated with survival or risk of cirrhosis. Of the 850 abdominal ultrasound scans performed in 255 patients, 24.1% were deemed suboptimal for hepatocellular carcinoma screening. The mean NAFLD fibrosis score (NFS) in the extreme obesity cohort, versus a propensity-matched cohort with BMI of 40 kg/m2 or less, was significantly different for both low fibrosis (F0-F2) (0.222 vs. -1.682, P < 0.0001) and high fibrosis (F3-F4) (2.216 vs. 0.557, P < 0.001). Conclusion: NAFLD with extreme obesity is associated with increased risk of liver-related and overall mortality. Accurate noninvasive assessment of liver fibrosis, low rates of weight loss surgery, and high failure rate of ultrasound were identified as clinical challenges in this population.

The ZJU index is a powerful surrogate marker for NAFLD in severely obese North American women.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the western world and is highly associated with multiple cardiometabolic complications. The Zhejiang University (ZJU) index was first developed to predict NAFLD in Chinese populations, where it was shown to have better predictive value than other currently used indices. The aims of the present study were to 1) determine the diagnostic accuracy of ZJU index in identifying NAFLD in a well-phenotyped cohort of obese middle-aged American women and 2) compare its performance with other non-invasive indices for NAFLD identification. METHODS: To achieve this goal, we performed a retrospective analysis of a prospectively-collected cohort of participants enrolled in a weight loss trial for severe obesity (RENEW, clinicaltrials.gov identifier: NCT00712127). One hundred and seven women between the age of 30 and 55 with obesity class II (BMI 35-39.9 kg/m2) or class III (BMI ≥ 40 kg/m2) were recruited for analyses. Hepatic steatosis was measured using liver/spleen attenuation ratio (L/S ratio) from unenhanced abdominal computed tomography. Beside ZJU index, hepatic steatosis index (HSI), lipid accumulation production index (LAPI), and visceral adiposity index (VAI) were also determined and to compare their performance in predicting NAFLD. RESULTS: Of 107 obese women in the study, 40 (37.4%) met imaging criteria for NAFLD using cut-off value of L/S ratio < 1.1. The ZJU index was positively correlated with HIS, LAPI, but not VAI. The area under the curve was highest for the ZJU index (AUC = 0.742, 95% CI:0.647-0.837), followed by HSI (AUC = 0.728, 95% CI:0.631-0.825), LAPI (AUC = 0.682, CI:0.583-0.781), and VAI (AUC = 0.621, 95% CI:0.518-0.725), respectively, using the Youden method. CONCLUSION: The ZJU index is a powerful surrogate marker for NAFLD in severely obese western females and its predictive value was better than that of other commonly used indices for predicting NAFLD. Our study is the first to suggest that the ZJU index could be a promising model for use in western as well as Chinese populations.

Impact of Hepatic Steatosis on Resting Metabolic Rate and Metabolic Adaptation in Response to Intentional Weight Loss.

Weight loss is the primary intervention for nonalcoholic fatty liver disease (NAFLD). A decrease in resting metabolic rate (RMR) out of proportion to the degree of weight loss may promote weight regain. We aimed to determine the impact of hepatic steatosis on weight loss-associated changes in RMR and metabolic adaptation, defined as the difference between predicted and measured RMR after weight loss. We retrospectively analyzed prospectively collected data from 114 subjects without diabetes (52 with NAFLD), with body mass index (BMI) >35, and who enrolled in a 6-month weight loss intervention. Hepatic steatosis was determined by unenhanced computed tomography scans by liver:spleen attenuation ratio <1.1. RMR was measured by indirect calorimetry. At baseline, patients with hepatic steatosis had higher BMI, fat mass (FM), fat-free mass (FFM), and RMR (RMR, 1,933 kcal/day; 95% confidence interval [CI], 841-2,025 kcal/day; versus 1,696; 95% CI, 1,641-1,751; P < 0.0001). After 6 months, the NAFLD group experienced larger absolute declines in weight, FM, and FFM, but percentage changes in weight, FFM, and FM were similar between groups. A greater decline in RMR was observed in patients with NAFLD (-179 kcal/day; 95% CI, -233 to -126 kcal/day; versus -100; 95% CI, -51 to -150; P = 0.0154) for the time × group interaction, and patients with NAFLD experienced greater metabolic adaptation to weight loss (-97 kcal/day; 95% CI, -143 to -50 kcal/day; versus -31.7; 95% CI, -74 to 11; P = 0.0218) for the prediction × group interaction. The change (Δ) in RMR was significantly associated with ΔFM, ΔFFM, and baseline RMR, while metabolic adaptation was significantly associated with female sex and ΔFM only. Conclusion: Hepatic steatosis is associated with a greater reduction in FM, which predicts RMR decline and a higher metabolic adaptation after weight loss, potentially increasing the risk of long-term weight regain.

Targeting Cholinergic System to Modulate Liver Injury.

Over the past few decades, evidence accumulated to indicate that parasympathetic innervation regulates liver injury and regeneration. Liver derives its parasympathetic input via vagus nerve. In animal models, vagus nerve stimulation and transection are frequently used to determine the impact of parasympathetic input on liver injury responses. Such strategies provide limited understanding of postneuronal mechanisms involved in the regulation of liver injury. The hepatic branch of vagus nerve releases acetylcholine (ACh), which activates muscarinic and nicotinic receptors in hepatocytes as well as non-parenchymal cells to modulate cellular functions. Moreover, vagus nerve releases other neurotransmitters such as vasoactive intestinal peptide (VIP), which also modulates liver injury responses and hemodynamics. Therefore, our understanding of the post-neuronal modulation of liver injury in models utilizing vagus nerve activity remains limited. Gene-silencing technologies and pharmacological manipulation of receptor activity have not only improved our understanding of the role of specific cholinergic receptors but also elucidated the role of various liver cell sub-populations in modulating liver injury response. With advent of organ- and cell-specific transgenic mice, our understanding of neural regulation of liver injury is likely to improve further. This review comprehensively provides current understanding of cholinergic regulation of liver injury, and points to potential therapeutic targets to treat liver injury.

Serum autotaxin is independently associated with hepatic steatosis in women with severe obesity.

OBJECTIVE: Autotaxin (ATX) is an adipocyte-derived lysophospholipase that generates the lipid signaling molecule lysophosphatidic acid (LPA). The aim of this study was to determine the relationship between serum ATX and nonalcoholic fatty liver disease (NAFLD) in females with obesity. METHODS: 101 nondiabetic women with obesity (age: 31.5-55.8 years; BMI: 35.0-64.5 kg/m2) were classified as having NAFLD (36.3%) or not having NAFLD (63.7%) based on the degree of hepatic steatosis on abdominal CT. Subjects were characterized for metabolic phenotype including measures of energy, glucose, and lipid homeostasis. Fasting serum adipokines and inflammatory markers were determined by ELISA. Linear regression analysis was used to determine features independently associated with NAFLD. RESULTS: Subjects with and without NAFLD differed in several key features of metabolic phenotype including BMI, waist circumference, fasting glucose and insulin, HOMA-IR, VLDL, triglycerides, and ALT. Serum adipokines, including ATX and leptin, were higher in subjects with NAFLD. Serum ATX was significantly correlated with alkaline phosphatase, fasting glucose, fasting insulin, and HOMA-IR. Linear regression analysis revealed that serum triglycerides and log-transformed ATX were independently associated with hepatic steatosis. CONCLUSIONS: Serum ATX may be a potential pathogenic factor and/or biomarker for NAFLD in nondiabetic women with obesity.

Unusually late-onset mycophenolate mofetil-related colitis.

PURPOSE: Serious gastrointestinal complications arising 13 years after the initiation of posttransplant immunosuppressant therapy with mycophenolate mofetil are reported. SUMMARY: Over a three-month period, a male heart transplant recipient who had taken oral mycophenolate mofetil (2 g daily) for 13 years as part of an immunosuppressant maintenance regimen developed diarrhea and weight loss leading to renal failure and metabolic acidosis. There was no evidence of opportunistic infection, and immunostaining for cytomegalovirus yielded negative results. Colonoscopy revealed areas of congested, erythematous, and nodular mucosa. Histological examination of mucosal biopsy specimens revealed pathological abnormalities typical of those seen in cases of mycophenolate mofetil-associated colitis. On discontinuation of mycophenolate mofetil use, the patient's diarrhea resolved and his renal function improved. Colitis, diarrhea, and other gastrointestinal complications are commonly reported in patients receiving mycophenolate mofetil, an immunosuppressant widely used to prevent rejection of solid organ or bone marrow transplants; however, the onset of such symptoms after more than a decade of continuous use of the drug has not been previously reported. This case suggests that mycophenolate mofetil toxicity should be considered in the evaluation of late-onset posttransplant diarrhea regardless of the duration of therapy. CONCLUSION: A 33-year-old man maintained on mycophenolate mofetil for 13 years after heart transplantation developed diarrhea, weight loss, and acute kidney injury over a three-month period. Colonoscopy and biopsy revealed pathological changes consistent with mycophenolate mofetil toxicity, and the patient's symptoms resolved after the drug was discontinued.