Kellogg, Todd A.

AbstractObjectiveNonalcoholic fatty liver disease can lead to hepatic inflammation/damage. Understanding the physiological mechanisms that contribute to excess hepatic lipid accumulation may help identify effective treatments.DesignWe recruited 25 nondiabetic patients with severe obesity scheduled for bariatric surgery. To evaluate liver export of triglyceride fatty acids, we measured very-low-density lipoprotein (VLDL)–triglyceride secretion rates the day prior to surgery using an infusion of autologous [1-14C]triolein-labeled VLDL particles. Ketone body response to fasting and intrahepatic long-chain acylcarnitine concentrations were used as indices of hepatic fatty acid oxidation. We measured intraoperative hepatic uptake rates of plasma free fatty acids using a continuous infusion of [U-13C]palmitate, combined with a bolus dose of [9,10-3H]palmitate and carefully timed liver biopsies. Total intrahepatic lipids were measured in liver biopsy samples to determine fatty liver status. The hepatic concentrations and enrichment from [U-13C]palmitate in diacylglycerols, sphingolipids, and acyl-carnitines were measured using liquid chromatography/tandem mass spectrometry.ResultsAmong study participants with fatty liver disease, intrahepatic lipid was negatively correlated with VLDL-triglyceride secretion rates (r = −0.92, P = 0.01) but unrelated to hepatic free fatty acid uptake or indices of hepatic fatty acid oxidation. VLDL-triglyceride secretion rates were positively correlated with hepatic concentrations of saturated diacylglycerol (r = 0.46, P = 0.02) and sphingosine-1-phosphate (r = 0.44, P = 0.03).ConclusionWe conclude that in nondiabetic humans with severe obesity, excess intrahepatic lipid is associated with limited export of triglyceride in VLDL particles rather than increased uptake of systemic free fatty acids.

The lack of reliable, noninvasive methods to diagnose early nonalcoholic steatohepatitis (NASH) is a major unmet need. We aimed to determine the diagnostic accuracy of three‐dimensional magnetic resonance elastography (3D‐MRE), with shear stiffness measured at 60 Hz, damping ratio at 40 Hz, and magnetic resonance imaging proton density fat fraction (MRI‐PDFF) in the detection of NASH in individuals undergoing bariatric surgery. Obese adults at risk for NASH were enrolled between 2015 and 2017 (prospective cohort, n = 88) and 2010 and 2013 (retrospective cohort, n = 87). The imaging protocol consisted of multifrequency 3D‐MRE (mf3D‐MRE) with shear waves delivered at different frequencies to explore parameters that best correlated with histologic NASH, and MRI‐PDFF to estimate steatosis. The prospective cohort was used to establish the optimal mf3D‐MRE technical parameters for NASH detection. The two cohorts were then combined to derive predictive models of NASH and disease activity by nonalcoholic fatty liver disease activity score (NAS) using the three imaging parameters that correlated with NASH. A total of 175 patients (median age 45, 81% women, and 81 [46%] with histologic NASH) were used for model derivation. From the complex shear modulus output generated by mf3D‐MRE, the damping ratio at 40 Hz and shear stiffness at 60 Hz best correlated with NASH. The fat fraction obtained from MRI‐PDFF correlated with steatosis ( P < 0.05 for all). These three parameters were fit into a logistic regression model that predicted NASH with cross‐validated area under the receiver operating characteristic curve (AUROC) = 0.73, sensitivity = 0.67, specificity = 0.80, positive predictive value = 0.73 and negative predictive value = 0.74, and disease activity by NAS with cross‐validated AUROC = 0.82. Conclusion: The mf3D‐MRE allows identification of imaging parameters that predict early NASH and disease activity. This imaging biomarker represents a promising alternative to liver biopsy for NASH diagnosis and monitoring. The results provide motivation for further studies in nonbariatric cohorts.

Obesity is increasingly common before and after liver transplantation (LT), yet optimal management remains unclear. The aim of this study was to analyze the long‐term outcomes for obese patients undergoing LT, including a noninvasive weight loss program and combined LT and sleeve gastrectomy (SG). Since 2006, all patients referred for LT with a body mass index (BMI) ≥35 kg/m2 were enrolled. Patients who achieved weight loss (BMI <35) underwent LT alone, and those who did not underwent simultaneous LT + SG. Analysis of long‐term outcomes for patients ≥3 years posttransplant was performed. Since 2006, there were 36 in the weight loss intervention (LT cohort) and 13 in the LT + SG cohort with >3 years of follow‐up, whereas overall, a total of 29 patients underwent LT + SG. Patients in the LT cohort had less severe obesity at enrollment (40.0 ± 2.7 vs. LT + SG cohort 46.0 ± 4.5; P < 0.001). In the LT cohort, 83.3% (30 of 36) achieved >10% loss in total body weight (TBW) pre‐LT. Three years posttransplant, 29.4% of patients in the LT cohort maintained >10% loss in TBW, whereas 100% of the LT + SG patients did (P < 0.001). Patients who underwent LT + SG maintained a significantly higher percentage of total body weight loss after 3 years of follow‐up (LT cohort 3.9 ± 13.3% vs. LT + S G cohort 34.8 ± 17.3%; P < 0.001). Patients in the LT + SG also had a lower prevalence of hypertension, insulin resistance, and hepatic steatosis and required fewer antihypertensive medications and lipid agents at last follow‐up. Conclusion: Whereas weight loss before transplantation was achieved by obese patients, weight regain was common in the LT cohort. Combined LT + SG resulted in more effective and more durable weight loss, as well as fewer metabolic complications at last follow‐up. (Hepatology 2018).

AbstractBackgroundAnimal studies have increasingly highlighted the role of macrophages in the development of delayed gastric emptying. However, their role in the pathophysiology of human gastroparesis is unclear. Our aim was to determine changes in macrophages and other cell types in the gastric antrum muscularis propria of patients with diabetic and idiopathic gastroparesis.MethodsFull thickness gastric antrum biopsies were obtained from patients enrolled in the Gastroparesis Clinical Research Consortium (11 diabetic, 6 idiopathic) and 5 controls. Immunolabeling and quantitative assessment was done for interstitial cells of Cajal (ICC) (Kit), enteric nerves protein gene product 9.5, neuronal nitric oxide synthase, vasoactive intestinal peptide, substance P, tyrosine hydroxylase), overall immune cells (CD45) and anti‐inflammatory macrophages (CD206). Gastric emptying was assessed using nuclear medicine scintigraphy and symptom severity using the Gastroparesis Cardinal Symptom Index.ResultsBoth diabetic and idiopathic gastroparesis patients showed loss of ICC as compared to controls (Mean [standard error of mean]/hpf: diabetic, 2.28 [0.16]; idiopathic, 2.53 [0.47]; controls, 6.05 [0.62]; P=.004). Overall immune cell population (CD45) was unchanged but there was a loss of anti‐inflammatory macrophages (CD206) in circular muscle (diabetic, 3.87 [0.32]; idiopathic, 4.16 [0.52]; controls, 6.59 [1.09]; P=.04) and myenteric plexus (diabetic, 3.83 [0.27]; idiopathic, 3.59 [0.68]; controls, 7.46 [0.51]; P=.004). There was correlation between the number of ICC and CD206‐positive cells (r=.55, P=.008). Enteric nerves (PGP9.5) were unchanged: diabetic, 33.64 (3.45); idiopathic, 41.26 (6.40); controls, 46.80 (6.04).ConclusionLoss of antral CD206‐positive anti‐inflammatory macrophages is a key feature in human gastroparesis and it is associates with ICC loss.

ObjectiveTo report the impact of bariatric surgery on metabolic outcomes in patients with type 1 diabetes (DM1) versus insulin‐requiring type 2 diabetes mellitus (IRDM2).MethodsTen subjects with DM1 were compared with 118 subjects with IRDM2 at baseline and at 1 and 2 years post‐bariatric surgery for: anthropometric measures, HbA1c, and number of medications (anti‐hyperglycemic, anti‐hypertensive, lipid‐lowering).ResultsDM1 and IRDM2 groups lost similar amounts of weight 2 years post‐bariatric surgery (39.5 ± 14.7 kg vs. 40.3 ± 24.4 kg). IRDM2 subjects had significant improvements in HbA1c (7.8% ± 1.4% vs. 6.8% ± 1.4%, P value <0.0001) and decreases in number of anti‐hyperglycemic (2.4 ± 0.8 vs. 0.7 ± 0.8, P value <0.0001), anti‐hypertensive (2.2 ± 1.3 vs. 1.3 ± 1.2, P value <0.0001), and lipid‐lowering (1.1 ± 0.8 vs. 0.6 ± 0.6, P value <0.0001) medications. DM1 subjects had no improvement in HbA1c (8.2% ± 1.6% vs. 7.8% ± 0.9%) or use of anti‐hypertensive medications (2.1 ± 1.4 vs. 2.3 ± 1.5). Their use of lipid‐lowering medications improved (1.0 ± 0.5 vs. 0.5 ± 0.8, P value 0.04).ConclusionsOur study suggests that improved glycemic control may not be an expected outcome when considering bariatric surgery in patients with DM1; however, additional investigation is warranted.