Mangesh R. Pagadala

Posttransplant Metabolic Syndrome: An Epidemic Waiting to Happen

With increasing survival after orthotopic liver transplantation (OLT), metabolic syndrome and its individual components, including diabetes mellitus, hypertension, dyslipidemia, and obesity, are increasingly being identified and contributing to cardiovascular complications and late morbidity and mortality. The prevalence of posttransplant metabolic syndrome (PTMS) and its individual components has been found to be higher post‐OLT versus a comparable population without OLT. The development of nonalcoholic fatty liver disease (NAFLD) after liver transplantation for non‐NAFLD cirrhosis is also being increasingly recognized. A number of predictors have been identified as potential risk factors related to these complications. The pretransplant risk factors include immunosuppression, a higher age at transplant, male gender, a history of smoking, the pretransplant body mass index, pre‐OLT diabetes, the etiology of the underlying liver disease that resulted in OLT (hepatitis C, cryptogenic cirrhosis, or alcohol), an increased donor body mass index, and marital status. Although there is an increased risk of cardiovascular events, rejection, and infection among patients with PTMS, the overall impact on long‐term survival and mortality remains inconclusive. Strategies to reduce the development of metabolic syndrome after transplantation should include lifestyle modifications involving alterations in diet and increased physical activity. Additional measures that may be potentially beneficial include the use of lipid‐lowering agents, the optimal control of blood glucose, and the use of tacrolimus instead of cyclosporine. Liver Transpl 15:1662–1670, 2009.

Role of ceramides in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a chronic disease with a histological spectrum ranging from steatosis alone, to nonalcoholic steatohepatitis (NASH). The latter is associated with an increased risk for progression to cirrhosis. Ceramides are a lipid species that exert biological effects through cellular proliferation, differentiation, and cell death, and interact with several pathways involved in insulin resistance, oxidative stress, inflammation, and apoptosis, all of which are linked to NAFLD. We propose a mechanism through which ceramides contribute to the development of NAFLD and progression to NASH, due in part to second messenger effects via tumor necrosis factor (TNF)-α. A better understanding of the role of ceramides in steatohepatitis has both diagnostic and therapeutic implications for the treatment of fatty liver disease.

Short-term exercise reduces markers of hepatocyte apoptosis in nonalcoholic fatty liver disease

Increased hepatocyte apoptosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and contributes to the profibrogenic state responsible for the progression to nonalcoholic steatohepatitis (NASH). Strategies aimed at reducing apoptosis may result in better outcomes for individuals with NAFLD. We therefore examined the effect of a short-term exercise program on markers of apoptosis-plasma cytokeratin 18 (CK18) fragments, alanine aminotransferase (ALT), aspartate aminotransferase (AST), soluble Fas (sFas), and sFas ligand (sFasL)-in 13 obese individuals with NAFLD [body mass index 35.2 ± 1.2 kg/m(2), >5% intrahepatic lipid (IHL) assessed by (1)H-MR spectroscopy]. Exercise consisted of treadmill walking for 60 min/day on 7 consecutive days at ∼85% of maximal heart rate. Additionally, subjects underwent an oral glucose tolerance test and a maximal oxygen consumption (Vo(2max)) test before and after the exercise intervention. The Matsuda index was used to assess insulin sensitivity. We observed significant decreases in CK18 fragments (558.4 ± 106.8 vs. 323.4 ± 72.5 U/l, P < 0.01) and ALT (30.2 ± 5.1 vs. 24.3 ± 4.8 U/l, P < 0.05), and an increase in whole body fat oxidation (49.3 ± 6.1 vs. 69.4 ± 7.1 mg/min, P < 0.05), while decreases in circulating sFasL approached statistical significance (66.5 ± 6.0 vs. 63.0 ± 5.7 pg/ml, P = 0.06), as did the relationship between percent change in circulating CK18 fragments and ALT (r = 0.55, P = 0.05). We also observed a significant correlation between changes in fat oxidation and circulating sFasL (rho = -0.65, P < 0.05). There was no change in IHL following the intervention (18.2 ± 2.5 vs. 17.5 ± 2.1%, NS). We conclude that short-term exercise reduces a circulatory marker of hepatocyte apoptosis in obese individuals with NAFLD and propose that changes in the proapoptotic environment may be mediated through improved insulin sensitivity and increased oxidative capacity.

The Relevance of Liver Histology to Predicting Clinically Meaningful Outcomes in Nonalcoholic Steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease. Nonalcoholic steatohepatitis (NASH), the more severe form of NAFLD, has an increased risk for progression to cirrhosis. The available data suggest increased morbidity and mortality among those patients with advanced histologic severity such as NASH and fibrosis. Despite the lack of a universally accepted histologic definition of NAFLD and inconsistency among pathologists regarding histologic findings essential to the diagnosis of NASH, a few studies have identified specific histologic findings (particularly fibrosis regardless of stage) that are able to predict NAFLD-related mortality as being most important.

Improved hepatic lipid composition following short-term exercise in nonalcoholic fatty liver disease.

CONTEXT Hepatic steatosis, insulin resistance, inflammation, low levels of polyunsaturated lipids, and adiponectin are implicated in the development and progression of nonalcoholic fatty liver disease (NAFLD). OBJECTIVE We examined the effects of short-term aerobic exercise on these metabolic risk factors. DESIGN AND PARTICIPANTS Obese individuals (N = 17, 34.3 ± 1.0 kg/m²) with clinically confirmed NAFLD were enrolled in a short-term aerobic exercise program that consisted of 7 consecutive days of treadmill walking at ~85% of maximal heart rate for 60 minutes per day. Preintervention and postintervention measures included hepatic triglyceride content, and a lipid saturation index and polyunsaturated lipid index (PUI) of the liver, obtained by (1)H magnetic resonance spectroscopy (N = 14). Insulin sensitivity was estimated from an oral glucose tolerance test (OGTT), and mononuclear cells were isolated to assess reactive oxygen species production during the OGTT. Circulating glucose, insulin, and high molecular weight (HMW) adiponectin were determined from plasma. MAIN OUTCOME Short-term aerobic exercise training improved hepatic lipid composition in patients with NAFLD. RESULTS Exercise training resulted in an increase in liver PUI (P < .05), increased insulin sensitivity (Matsuda Index: P < .05), HMW adiponectin (P < .05), and maximal oxygen consumption (P < .05). Reactive oxygen species production during the OGTT was reduced following exercise training (P < .05). HMW adiponectin was increased after the exercise program and the increase was positively correlated with the increase in liver PUI (r = 0.52, P = .05). Body weight remained stable during the program (P > .05). CONCLUSION Short-term exercise can target hepatic lipid composition, which may reduce the risk of NAFLD progression. The improvement in hepatic lipid composition may be driven by adiponectin.

Editorial: Non-Alcoholic Fatty Liver Disease and Obesity: Not All About Body Mass Index

Patients with nonalcoholic fatty liver (NAFLD) are typically obese and confounded by the metabolic syndrome. The body mass index (BMI) is often used as a surrogate marker of obesity defined as a BMI >30λkg/m2. However, it is now apparent that it is the distribution of body fat (not total fat) that is associated with NAFLD. Many patients (as many as 25%) with NAFLD are nonobese. This is particularly true in Asians who have a significantly increased risk of cardiovascular disease and diabetes even among those with a normal BMI. It is important for clinicians to be aware that these “metabolically obese” NAFLD patients should be monitored for the metabolic syndrome and its associated adverse outcomes irrespective of their BMI.

Diagnosis of Celiac Disease in Adults Based on Serology Test Results, Without Small-Bowel Biopsy

BACKGROUND & AIMS Celiac disease is underdiagnosed, with nonspecific symptoms and high morbidity. New diagnostic factors are needed. We aimed to estimate the frequency at which adult patients with positive results from serology tests are referred for small-bowel biopsies and to identify factors that improve the diagnosis of celiac disease. METHODS We performed a retrospective analysis of data from 2477 subjects who received serology tests for celiac disease between 2005 and 2007. We analyzed results for total levels of IgA, IgA against human tissue transglutaminase (hTTG), IgA and IgG against gliadin, as well as dilution titers of IgA against endomysial antibodies (EMA). Biopsy samples were analyzed by pathologists experienced in detecting mucosal changes associated with celiac disease and graded according to the Marsh system. RESULTS Of the 2477 patients, 610 (25%) had abnormal results from serology tests, and 39% of these patients (240 of 610) underwent small-bowel biopsy analyses. Of these patients, 50 (21%) had biopsy findings consistent with celiac disease (Marsh 3 lesions) and were placed on gluten-free diets. Titers of IgA hTTG greater than 118 U identified patients with celiac disease with a 2% false-positive rate. Titers of 21 to 118 U, in combination with an EMA dilution titer of 1:160 or greater, had a positive predictive value of 83% for celiac disease. IgA hTTG levels less than 20 U, in combination with an EMA dilution titer less than 1:10, had a negative predictive value of 92% for celiac disease. CONCLUSIONS Serum levels of IgA hTTG greater than 118 U, or 21 to 118 U in combination with an EMA dilution titer of 1:160 or greater, can be used to identify adult symptomatic patients with celiac disease, in the absence of a small-bowel biopsy.

Predictors of Steatohepatitis and Advanced Fibrosis in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease is the most common cause of chronic liver disease in the United States. The development of non-alcoholic steatohepatitis increases the risk for cirrhosis and its complications. The gold standard for diagnosis is liver biopsy, the costs and risks of which make it impractical. Some demographic factors, blood tests, and imaging studies can be used to predict a higher risk of steatohepatitis or advanced fibrosis, but are of limited sensitivity and specificity. More accurate predictors and scoring systems would allow identifying who would benefit most from liver biopsy and monitor disease progression and response to therapy.

Renin‐angiotensin system and fibrosis in non‐alcoholic fatty liver disease

Therapeutic options are limited for patients with non‐alcoholic fatty liver disease (NAFLD). One promising approach is the attenuation of necroinflammation and fibrosis by inhibition of the renin‐angiotensin system (RAS). We explored whether the risk of fibrosis was associated with the use of commonly used medications in NAFLD patients with hypertension. Specifically, we sought to determine the association between RAS blocking agents and severity of hepatic fibrosis in NAFLD patients with hypertension.

Fetuin-A is linked to improved glucose tolerance after short-term exercise training in nonalcoholic fatty liver disease

Fetuin-A is synthesized in the liver and may be associated with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. Lifestyle-induced weight loss reduces fetuin-A, but the effect of exercise alone is unknown. We determined the effect of short-term exercise training on plasma fetuin-A in 13 (50.5 ± 3.4 yr) obese adults (body mass index, 33.3 ± 0.9 kg/m(2)) with clinically diagnosed NAFLD. Subjects participated in 7 days of supervised exercise training (60 min/day at ∼85% maximum heart rate) and were instructed to maintain their normal caloric and macronutrient intake. Insulin resistance was assessed by an oral glucose tolerance test. Hepatic triglyceride content (HTGC) was determined by proton MRI. We used C2C12 skeletal muscle cells to examine the direct effect of fetuin-A on 2-deoxyglucose uptake, insulin signaling [phosphorylation of Akt and AS160 (pAkt and pAS160, respectively)], and glucose transporter-4 (GLUT-4) translocation. Insulin resistance was reduced by 29% (P < 0.05), and glucose area under the curve (AUC) was decreased by 13% (P < 0.01) after the 7 days of exercise. Furthermore, circulating fetuin-A was decreased by 11% (4.2 ± 03 vs. 3.6 ± 0.2 nM; P < 0.02), and this change correlated with reduced insulin resistance (r = 0.62; P < 0.04) and glucose AUC (r = 0.58; P < 0.04). Importantly, the exercise program did not change body weight (P = 0.12), HTGC (P = 0.73), or aerobic capacity (P = 0.14). In vitro experiments revealed that fetuin-A decreased skeletal muscle glucose uptake by downregulating pAkt and pAS160 and subsequent GLUT-4 translocation to the plasma membrane. Together, our findings highlight a role for fetuin-A in skeletal muscle insulin resistance and suggest that part of the exercise-induced improvement in glucose tolerance in patients with NAFLD may be due to lowering fetuin-A.