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Objective: The objective of this study was to determine the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in young compared with older adults., Methods: Individuals (n = 1420) with (63%) and without type 2 diabetes mellitus (T2D; 37%) who attended internal medicine clinics and did not have a known history of MASLD underwent laboratory evaluation and transient elastography to assess for hepatic steatosis and fibrosis. Magnetic resonance elastography and liver biopsy were recommended when indicated., Results: A total of 243 participants were ages <45 years, and 1177 were ages ≥45 years. Obesity, T2D, and metabolic syndrome were highly prevalent in young adults. Frequencies of steatosis and fibrosis were high in young adults (50.2% and 7.5% vs. older adults 52.7% and 9.9%, respectively) and were significantly higher in those with both obesity and T2D (71.1% and 15.7%, respectively; p < 0.01). In young adults, T2D and obesity were the strongest risk factors for hepatic fibrosis (odds ratios 4.33 [95% CI: 1.37-13.68] and 1.16 [95% CI: 1.07-1.25], respectively; p < 0.05)., Conclusions: There is a high prevalence of clinically significant hepatic fibrosis in young adults with cardiometabolic risk factors. Up to one in seven young adults with obesity and T2D had clinically significant hepatic fibrosis on elastography. This highlights the need to screen young adults with cardiometabolic risk factors for MASLD for early detection and intervention., (© 2024 The Obesity Society.)

Background & Aims: It has been postulated that carriers of PNPLA3 I148M (CG [Ile/Met] or GG [Met/Met]) develop metabolic dysfunction-associated steatotic liver disease (MASLD) in the absence of insulin resistance or metabolic syndrome. However, the relationship between insulin resistance and MASLD according to the PNPLA3 allele has not been carefully assessed., Methods: A total of 204 participants were recruited and underwent PNPLA3 genotyping, an oral glucose tolerance test, liver proton magnetic resonance spectroscopy and percutaneous liver biopsy if diagnosed with MASLD. A subgroup of patients (n = 55) had an euglycemic hyperinsulinemic clamp with glucose tracer infusion., Results: As expected, patients with the CG/GG genotype had worse intrahepatic triglyceride content and worse liver histology. However, regardless of PNPLA3 genotype, patients with a diagnosis of MASLD had severe whole-body insulin resistance (Matsuda index, an estimation of insulin resistance in glucose metabolic pathways) and fasting and postprandial adipose tissue insulin resistance (Adipo-IR index and free fatty acid suppression during the oral glucose tolerance test, respectively, as measures of insulin resistance in lipolytic metabolic pathways) compared to patients without MASLD. Moreover, for the same amount of liver fat accumulation, insulin resistance was similar in patients with genotypes CC vs. CG/GG. In multiple regression analyses, A1c and Adipo-IR were associated with the presence of MASLD and advanced liver fibrosis, independently of PNPLA3 genotype., Conclusions: PNPLA3 variant carriers with MASLD are equally insulin resistant as non-carriers with MASLD at the level of the liver, muscle, and adipose tissue. This calls for reframing "PNPLA3 MASLD" as an insulin-resistant condition associated with increased hepatic susceptibility to metabolic insults, such as obesity or diabetes, wherein early identification and aggressive intervention are warranted to reverse metabolic dysfunction and prevent disease progression., Impact and Implications: It has been proposed that the PNPLA3 G allele is associated with the presence of metabolic dysfunction-associated steatotic liver disease (MASLD) in the absence of insulin resistance. However, our results suggest that regardless of PNPLA3 alleles, the presence of insulin resistance is necessary for the development of MASLD. This calls for reframing patients with "PNPLA3 MASLD" not as insulin sensitive, but on the contrary, as an insulin-resistant population with increased hepatic susceptibility to metabolic insults, such as obesity or diabetes., (© 2024 The Authors.)

Context: Although type 2 diabetes (T2D) is a risk factor for liver fibrosis in nonalcoholic fatty liver disease (NAFLD), the specific contribution of insulin resistance (IR) relative to other factors is unknown., Objective: Assess the impact on liver fibrosis in NAFLD of adipose tissue (adipose tissue insulin resistance index [adipo-IR]) and liver (Homeostatic Model Assessment of Insulin Resistance [HOMA-IR]) IR in people with T2D and NAFLD., Design: Participants were screened by elastography in the outpatient clinics for hepatic steatosis and fibrosis, including routine metabolites, cytokeratin-18 (a marker of hepatocyte apoptosis/steatohepatitis), and HOMA-IR/adipo-IR., Setting: University ambulatory care practice., Participants: A total of 483 participants with T2D., Intervention: Screening for steatosis and fibrosis with elastography., Main Outcome Measures: Liver steatosis (controlled attenuation parameter), fibrosis (liver stiffness measurement), and measurements of IR (adipo-IR, HOMA-IR) and fibrosis (cytokeratin-18)., Results: Clinically significant liver fibrosis (stage F ≥ 2 = liver stiffness measurement ≥8.0 kPa) was found in 11%, having more features of the metabolic syndrome, lower adiponectin, and higher aspartate aminotransferase (AST), alanine aminotransferase, liver fat, and cytokeratin-18 (P < 0.05-0.01). In multivariable analysis including just clinical variables (model 1), obesity (body mass index [BMI]) had the strongest association with fibrosis (odds ratio, 2.56; CI, 1.87-3.50; P < 0.01). When metabolic measurements and cytokeratin-18 were included (model 2), only BMI, AST, and liver fat remained significant. When fibrosis stage was adjusted for BMI, AST, and steatosis (model 3), only Adipo-IR remained strongly associated with fibrosis (OR, 1.51; CI, 1.05-2.16; P = 0.03), but not BMI, hepatic IR, or steatosis., Conclusions: These findings pinpoint to the central role of dysfunctional, insulin-resistant adipose tissue to advanced fibrosis in T2D, beyond simply BMI or steatosis. The clinical implication is that targeting adipose tissue should be the priority of treatment in NAFLD., Competing Interests: Conflict of Interest K.C. has received research support as principal investigator from the University of Florida from the National Institutes of Health, Cirius, Echosens, Inventiva, Novartis, Novo Nordisk, Poxel, and Zydus. K.C. is also a consultant for Allergan, Altimmune, Arrowhead, AstraZeneca, BMS, Boehringer Ingelheim, Coherus, Eli Lilly, Fractyl, Hanmi, Genentech, Gilead, Intercept, Janssen, Pfizer, Prosciento, Madrigal, and Novo Nordisk. All other authors have no potential conflicts of interest relevant to this article., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes (T2D), causing substantial burden from hepatic and extrahepatic complications. However, endocrinologists often follow people who are at the highest risk of its more severe form with nonalcoholic steatohepatitis or NASH (i.e., T2D or obesity with cardiometabolic risk factors). Endocrinologists are in a unique position to prevent cirrhosis in this population with early diagnosis and treatment., Objective: This work aims to offer endocrinologists a practical approach for the management of patients with NAFLD, including diagnosis, fibrosis risk stratification, and referral to hepatologists., Patients: (1) An asymptomatic patient with obesity and cardiometabolic risk factors, found to have hepatic steatosis; (2) a patient with T2D and NASH with clinically significant liver fibrosis; and (3) a liver transplant recipient with a history of NASH cirrhosis, with significant weight regain and with recurrent NAFLD on the transplanted organ., Conclusion: NASH can be reversed with proper management of obesity and of T2D. While no agents are currently approved for the treatment of NASH, treatment should include lifestyle changes and a broader use of structured weight-loss programs, obesity pharmacotherapy, and bariatric surgery. Diabetes medications such as pioglitazone and some glucagon-like peptide 1 receptor agonists may also improve liver histology and cardiometabolic health. Sodium-glucose cotransporter-2 inhibitors and insulin may ameliorate steatosis, but their effect on steatohepatitis remains unclear. Awareness by endocrinologists about, establishing an early diagnosis of fibrosis (ie, FIB-4, liver elastography) in patients at high-risk of cirrhosis, long-term monitoring, and timely referral to the hepatologist are all critical to curve the looming epidemic of cirrhosis from NAFLD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: The optimal screening strategy for advanced liver fibrosis in overweight and obese patients is unknown. The aim of this study is to compare the performance of different strategies to select patients at high risk of advanced liver fibrosis for screening using non-invasive tools., Methods: All patients underwent: liver 1 H-MRS and percutaneous liver biopsy (in those with nonalcoholic fatty liver disease [NAFLD]). Unique selection strategies were compared to determine the best screening algorithm: (A) A "metabolic approach": selecting patients based on HOMA-IR ≥ 3; (B) A "diabetes approach": selecting only patients with type 2 diabetes; (C) An "imaging approach": selecting patients with hepatic steatosis based on 1 H-MRS; (D) A "liver biochemistry approach": selecting patients with elevated ALT (i.e., ≥ 30 IU/L for males and ≥ 19 IU/L for females); and (E) Universal screening of overweight and obese patients. FIB-4 index, NAFLD fibrosis score, and APRI were applied as screening strategies., Results: A total of 275 patients were included in the study. Patients with advanced fibrosis ( n = 29) were matched for age, gender, ethnicity, and BMI. Selecting patients by ALT elevation provided the most effective strategy, limiting the false positive rate while maintaining the sensitivity compared to universal screening. Selecting patients by any other strategy did not contribute to increasing the sensitivity of the approach and resulted in more false positive results., Conclusion: Universal screening of overweight/obese patients for advanced fibrosis with non-invasive tools is unwarranted, as selection strategies based on elevated ALT levels lead to the same sensitivity with a lower false positive rate (i.e., fewer patients that would require a liver biopsy or referral to hepatology)., Competing Interests: Conflicts of interest Nothing to disclose in relation to this manuscript.

In this paper, Mixed Reality (MR) has been exploited in the operating rooms to perform laparoscopic and open surgery with the aim of providing remote mentoring to the medical doctors under training during the Covid-19 pandemic. The employed architecture, which has put together MR smartglasses, a Digital Imaging Player, and a Mixed Reality Toolkit, has been used for cancer surgery at the IRCCS Hospital 'Giovanni Paolo II' in southern Italy. The feasibility of using the conceived platform for real-time remote mentoring has been assessed on the basis of surveys distributed to the trainees after each surgery.

Context: Patients with nonalcoholic fatty liver disease (NAFLD) are characterized by insulin resistance and hyperinsulinism. However, insulin resistance measurements have not been shown to be good diagnostic tools to predict NAFLD in prior studies., Objective: We aimed to assess a newly validated method to measure intact molecules of insulin by mass spectrometry to predict NAFLD., Methods: Patients underwent a 2-hour oral glucose tolerance test (OGTT), a liver magnetic resonance spectroscopy (1H-MRS), and a percutaneous liver biopsy if they had a diagnosis of NAFLD. Mass spectrometry was used to measure intact molecules of insulin and C-peptide., Results: A total of 180 patients were recruited (67% male; 52 ± 11 years of age; body mass index [BMI] 33.2 ± 5.7 kg/m2; 46% with diabetes and 65% with NAFLD). Intact fasting insulin was higher in patients with NAFLD, irrespective of diabetes status. Patients with NAFLD without diabetes showed ~4-fold increase in insulin secretion during the OGTT compared with all other subgroups (P = 0.008). Fasting intact insulin measurements predicted NAFLD in patients without diabetes (area under the receiver operating characteristic curve [AUC] of 0.90 [0.84-0.96]). This was significantly better than measuring insulin by radioimmunoassay (AUC 0.80 [0.71-0.89]; P = 0.007). Intact fasting insulin was better than other clinical variables (eg, aspartate transaminase, triglycerides, high-density lipoprotein, glucose, HbA1c, and BMI) to predict NAFLD. When combined with alanine transaminase (ALT) (intact insulin × ALT), it detected NAFLD with AUC 0.94 (0.89-0.99) and positive and negative predictive values of 93% and 88%, respectively. This newly described approach was significantly better than previously validated noninvasive scores such as NAFLD-LFS (P = 0.009), HSI (P < 0.001), and TyG index (P = 0.039)., Conclusion: In patients without diabetes, accurate measurement of fasting intact insulin levels by mass spectrometry constitutes an easy and noninvasive strategy to predict presence of NAFLD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Assess the prevalence of nonalcoholic fatty liver disease (NAFLD) and of liver fibrosis associated with nonalcoholic steatohepatitis in unselected patients with type 2 diabetes mellitus (T2DM)., Research Design and Methods: A total of 561 patients with T2DM (age: 60 ± 11 years; BMI: 33.4 ± 6.2 kg/m 2 ; and HbA 1c : 7.5 ± 1.8%) attending primary care or endocrinology outpatient clinics and unaware of having NAFLD were recruited. At the visit, volunteers were invited to be screened by elastography for steatosis and fibrosis by controlled attenuation parameter (≥274 dB/m) and liver stiffness measurement (LSM; ≥7.0 kPa), respectively. Secondary causes of liver disease were ruled out. Diagnostic panels for prediction of advanced fibrosis, such as AST-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) index, were also measured. A liver biopsy was performed if results were suggestive of fibrosis., Results: The prevalence of steatosis was 70% and of fibrosis 21% (LSM ≥7.0 kPa). Moderate fibrosis (F2: LSM ≥8.2 kPa) was present in 6% and severe fibrosis or cirrhosis (F3-4: LSM ≥9.7 kPa) in 9%, similar to that estimated by FIB-4 and APRI panels. Noninvasive testing was consistent with liver biopsy results. Elevated AST or ALT ≥40 units/L was present in a minority of patients with steatosis (8% and 13%, respectively) or with liver fibrosis (18% and 28%, respectively). This suggests that AST/ALT alone are insufficient as initial screening. However, performance may be enhanced by imaging (e.g., transient elastography) and plasma diagnostic panels (e.g., FIB-4 and APRI)., Conclusions: Moderate-to-advanced fibrosis (F2 or higher), an established risk factor for cirrhosis and overall mortality, affects at least one out of six (15%) patients with T2DM. These results support the American Diabetes Association guidelines to screen for clinically significant fibrosis in patients with T2DM with steatosis or elevated ALT., (© 2020 by the American Diabetes Association.)

Background & Aims: Proof-of-concept studies frequently assess changes in intrahepatic triglyceride (IHTG) content by magnetic resonance-based techniques as a surrogate marker of histology. The aim of this study was to establish how reliable this strategy is to predict changes in liver histology in patients with non-alcoholic steatohepatitis (NASH)., Methods: Patients with NASH who had participated in our prior randomized controlled trials of pioglitazone with complete paired data for IHTG content by magnetic resonance spectroscopy and liver histology were included in the study., Results: A total of 121 patients were included. Changes in IHTG were assessed in several ways: as a continuous variable (correlations), as categorical groups (IHTG change ≥0%; or IHTG reduction of 1-30%; 31-50%; 51-70%; or >70%), and in a binomial way as steatosis resolution or not (defined as achieving IHTG <5.56%). Changes in IHTG correlated with steatosis on histology (r = 0.54; p <0.01). However, the magnitude of IHTG reduction was not associated with the rate of response of the primary histological outcome (2-point improvement in the NAFLD activity score from 2 different parameters, without worsening of fibrosis) or resolution of NASH without worsening of fibrosis, neither in patients receiving pioglitazone nor placebo. Changes in lobular inflammation, hepatocyte ballooning, or liver fibrosis were also independent of changes in IHTG, irrespective of treatment arm. Steatosis resolution was not associated with better histological outcomes either., Conclusions: Changes in IHTG predict changes in steatosis but not of other liver histological parameters. This implies that IHTG response to treatment should be interpreted with caution, as it may not be as reliable as previously believed to predict a treatment's overall clinical efficacy in patients with NASH., Lay Summary: Quantification of liver fat by magnetic resonance imaging (MRI) is currently used to assess treatment responses in patients with fatty liver, with the assumption that improvements in liver fat translate into less inflammation, necrosis, and fibrosis in the liver. However, in this article, we showed that changes in liver fat do not necessarily translate into changes in these parameters. This means that MRI may not be as useful to assess treatment response in patients with fatty liver as previously believed., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Although the second most common site of the accessory spleen is the tail of the pancreas, intrapancreatic accessory spleens (IPAS) are rarely recognized radiologically. When an accessory spleen is located in the pancreas, it may mimic a hypervascular pancreatic tumor. We report a case of intrapancreatic accessory spleen which radiologically (on TC) mimicked a neuroendocrine pancreatic tumor (PNET). It was not possible to be sure that the pancreatic nodule had no malignant potential; because of the close proximity to splenic vessel we performed en bloc resection of the spleen and distal pancreas. Postoperative course was uneventful. IPAS must be considered in the differential diagnosis of pancreatic tail tumors, particulary an asymptomatic small PNET; new and adequate diagnostic studies have demonstrated utility in defining these lesions. We review pertinent literature. KEY WORD: Intrapancreatic accessory spleen, Pancreatic neuroendocrine tumor.

Objective: While vitamin E has shown to improve nonalcoholic steatohepatitis (NASH) in patients without diabetes, information on patients with type 2 diabetes mellitus (T2DM) is lacking. The aim of this study was to determine whether vitamin E, alone or combined with pioglitazone, improves histology in patients with T2DM and NASH., Research Design and Methods: This was a proof-of-concept, randomized, double-blind, placebo-controlled trial conducted from 2010 to 2016. Patients with T2DM and biopsy-proven NASH ( n = 105) were randomized to vitamin E 400 IU b.i.d., vitamin E 400 IU b.i.d. plus pioglitazone 45 mg/day, or placebo. Eighty-six patients completed the 18-month study. The primary end point was a two-point reduction in the nonalcoholic fatty liver disease activity score from two different parameters, without worsening of fibrosis. Secondary outcomes were resolution of NASH without worsening of fibrosis, individual histological scores, and metabolic parameters., Results: More patients on combination therapy achieved the primary outcome versus placebo (54% vs. 19%, P = 0.003) but not with vitamin E alone (31% vs. 19%, P = 0.26). Both groups showed improvements in resolution of NASH compared with placebo (combination group: 43% vs. 12%, P = 0.005; vitamin E alone: 33% vs. 12%, P = 0.04). While steatosis assessed by histology improved with combination therapy ( P < 0.001) and vitamin E alone ( P = 0.018), inflammation ( P = 0.018) and ballooning ( P = 0.022) only improved with combination therapy. No improvement in fibrosis was observed in any group., Conclusions: In this proof-of-concept study, combination therapy was better than placebo in improving liver histology in patients with NASH and T2DM. Vitamin E alone did not significantly change the primary histological outcome., (© 2019 by the American Diabetes Association.)

Background: The effects of pioglitazone on bone metabolism are unclear. This study evaluated the long-term effects of pioglitazone on bone mineral density (BMD) and bone metabolism in patients with prediabetes or type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH)., Methods: Ninety-two patients with prediabetes or T2DM and biopsy-proven NASH with BMD and baseline biochemical bone measurements were included. Patients (mean [±SEM] age 51 ± 1 years, 71% male, mean body mass index 34.5 ± 0.5 kg/m 2 ) were randomly assigned to pioglitazone (45 mg/day) or placebo for 18 months, followed by an 18-month open-label pioglitazone treatment phase. Baseline, 18- and 36-month evaluations included plasma vitamin D and bone turnover biomarker levels, and BMD measurements at the spine, femoral neck, total hip, and one-third radius., Results: After 18 months of pioglitazone treatment, there were no differences in BMD versus placebo at either the femoral neck (P =0.87), total hip (P =0.78), or one-third radius (P =0.44); however, bone density decreased at the level of the spine with pioglitazone (-3.5%; P =0.002). During the extension phase (18-36 months), patients had no further decreases in BMD or plasma biomarkers of bone turnover during pioglitazone treatment. No patient experienced a low-energy bone fracture., Conclusions: Treatment of patients with prediabetes or T2DM with pioglitazone for up to 3 years was associated with decreased BMD at the level of the lumbar spine. This reduction in BMD at the lumbar spine at 18 months versus placebo suggests an early deleterious effect of pioglitazone on bone metabolism., (© 2018 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background & Aims: Pioglitazone is effective for long-term treatment of patients with nonalcoholic steatohepatitis (NASH) with prediabetes or type 2 diabetes. However, it is not clear how the presence of type 2 diabetes affects the drug's efficacy. We compared metabolic and histologic responses to pioglitazone in patients with NASH and prediabetes vs type 2 diabetes., Methods: We performed a prospective study of adults with biopsy-proven NASH (52 with type 2 diabetes and 49 with prediabetes), enrolled from the general population of San Antonio, Texas, from 2008 through 2014. After a run-in period of approximately 4 weeks, when all baseline measurements were made (liver magnetic resonance proton spectroscopy, euglycemic insulin clamp with glucose turnover measurements, dual-energy absorptiometry, and liver biopsy), subjects were randomly assigned to groups given pioglitazone or placebo (45 mg/d) for 18 months; all procedures performed at baseline were then repeated. The primary outcome was a reduction in nonalcoholic fatty liver disease activity score of 2 points or more (for at least 2 components) without worsening of fibrosis (and expressed as difference vs placebo). Secondary outcomes included NASH resolution, individual histologic components, intrahepatic triglyceride content (measured by 1 H magnetic resonance spectroscopy), and insulin sensitivity (measured by euglycemic insulin clamp)., Results: The primary outcome was met by 48% of patients with type 2 diabetes vs 46% without diabetes. Resolution of NASH was achieved in 44% of patients with type 2 diabetes vs 26% without diabetes. A significant reduction in fibrosis, from baseline, was observed only in patients with type 2 diabetes (P = .035). Intrahepatic triglyceride content was reduced by 11% ± 2% in patients with diabetes vs a reduction of 9% ± 2% in patients without diabetes (P = .62); the plasma level of alanine aminotransferase was reduced by 50 ± 10 U/L in patients with diabetes vs a reduction of 36 ± 5 U/L in patients without diabetes (P = .22). Pioglitazone was associated with a significantly greater insulin sensitivity in adipose tissue of patients with diabetes vs without diabetes (P < .001), but nonsignificant differences in responses in hepatic (P = .49) and skeletal muscle (P = .32) insulin sensitivity., Conclusions: In a prospective study, we found pioglitazone to be effective in patients with and without type 2 diabetes. However, pioglitazone reduced liver fibrosis and increased adipose tissue insulin sensitivity at significantly greater levels in patients with type 2 diabetes than in patients with prediabetes. Further studies are needed to determine the mechanisms by which pioglitazone reduces liver disease in patients with type 2 diabetes. ClinicalTrials.gov: NCT00994682., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Context: Patients with nonalcoholic fatty liver disease have a high cardiovascular risk, but statins are rarely prescribed because of fear of hepatotoxicity., Objective: To prospectively assess the long-term safety of statins in patients with prediabetes/type 2 diabetes mellitus (T2DM) and nonalcoholic steatohepatitis (NASH)., Design: Post hoc analysis of statin use during a randomized, controlled trial assessing pioglitazone vs placebo for NASH., Patients: A total of 101 patients (86 receiving statins) with biopsy-proven NASH and prediabetes/T2DM were followed for up to 36 months., Interventions: Oral glucose tolerance test and percutaneous liver biopsy (baseline, month 18, and month 36); liver magnetic resonance spectroscopy and euglycemic insulin clamp (baseline and month 18)., Main Outcome Measures: Histologic and biochemical safety of statin use among patients with NASH., Results: Only 37% of patients were receiving statins at enrollment despite their high cardiovascular risk. Statin nonusers had higher plasma alanine aminotransferase levels but similar histologic severity of liver disease at baseline. In both statin users and nonusers, the same number of patients (n = 4) had a twofold or greater increase in plasma aminotransferases during follow-up. One statin nonuser was discontinued from the study because of this elevation. Values returned to normal without any active measure in all other cases. No changes on liver histology or hepatic insulin resistance were observed in patients with NASH newly started on a statin and receiving placebo during the main study., Conclusions: Statin therapy is safe in patients with prediabetes/T2DM and NASH. Given their high cardiovascular risk, statin therapy should be encouraged in this population., (Copyright © 2017 Endocrine Society)

The cut-off point of intrahepatic triglyceride (IHTG) content to define nonalcoholic fatty liver disease (NAFLD) by proton magnetic resonance spectroscopy ( 1 H-MRS) was established based on the 95th percentile in a group of healthy individuals (i.e., ≥5.56%). Whether this threshold correlates with metabolic and histological changes and whether a further accumulation of IHTG is associated with worsening of these parameters has not been properly assessed in a large cohort of patients. In this cross-sectional study, 352 subjects were carefully characterized with the following studies: liver 1 H-MRS; euglycemic insulin clamp with measurement of glucose turnover; oral glucose tolerance test; and a liver biopsy. Hepatic insulin sensitivity (suppression of endogenous glucose production by insulin) was affected early on after IHTG content was ∼1.5% and remained uniformly impaired (∼40%-45%), regardless of further IHTG accumulation. Skeletal muscle insulin sensitivity showed a gradual impairment at low degrees of IHTG accumulation, but remained unchanged after IHTG content reached the ∼6 ± 2% threshold. A similar pattern was observed for metabolic changes typically associated with NAFLD, such as hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C). In contrast, adipose tissue insulin sensitivity (suppression of free fatty acids by insulin) showed a continuous worsening across the spectrum of IHTG accumulation in NAFLD (r = -0.38; P < 0.001). Histological severity of liver disease (inflammation, ballooning, and fibrosis) was not associated with the amount of IHTG content., Conclusion: IHTG accumulation is strongly associated with adipose tissue insulin resistance (IR), supporting the current theory of lipotoxicity as a driver of IHTG accumulation. Once IHTG accumulation reaches ∼6 ± 2%, skeletal muscle IR, hypertriglyceridemia, and low HDL-C become fully established. Histological activity appears to have an early threshold and is not significantly influenced by increasing amounts of IHTG accumulation. (Hepatology 2017;65:1132-1144)., (© 2016 by the American Association for the Study of Liver Diseases.)

Background: The metabolic defects of nonalcoholic steatohepatitis (NASH) and prediabetes or type 2 diabetes mellitus (T2DM) seem to be specifically targeted by pioglitazone. However, information about its long-term use in this population is limited., Objective: To determine the efficacy and safety of long-term pioglitazone treatment in patients with NASH and prediabetes or T2DM., Design: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT00994682)., Setting: University hospital., Participants: Patients (n = 101) with prediabetes or T2DM and biopsy-proven NASH were recruited from the general population and outpatient clinics., Intervention: All patients were prescribed a hypocaloric diet (500-kcal/d deficit from weight-maintaining caloric intake) and then randomly assigned to pioglitazone, 45 mg/d, or placebo for 18 months, followed by an 18-month open-label phase with pioglitazone treatment., Measurements: The primary outcome was a reduction of at least 2 points in the nonalcoholic fatty liver disease activity score in 2 histologic categories without worsening of fibrosis. Secondary outcomes included other histologic outcomes, hepatic triglyceride content measured by magnetic resonance and proton spectroscopy, and metabolic parameters., Results: Among patients randomly assigned to pioglitazone, 58% achieved the primary outcome (treatment difference, 41 percentage points [95% CI, 23 to 59 percentage points]) and 51% had resolution of NASH (treatment difference, 32 percentage points [CI, 13 to 51 percentage points]) (P < 0.001 for each). Pioglitazone treatment also was associated with improvement in individual histologic scores, including the fibrosis score (treatment difference, -0.5 [CI, -0.9 to 0.0]; P = 0.039); reduced hepatic triglyceride content from 19% to 7% (treatment difference, -7 percentage points [CI, -10 to -4 percentage points]; P < 0.001); and improved adipose tissue, hepatic, and muscle insulin sensitivity (P < 0.001 vs. placebo for all). All 18-month metabolic and histologic improvements persisted over 36 months of therapy. The overall rate of adverse events did not differ between groups, although weight gain was greater with pioglitazone (2.5 kg vs. placebo)., Limitation: Single-center study., Conclusion: Long-term pioglitazone treatment is safe and effective in patients with prediabetes or T2DM and NASH., Primary Funding Source: Burroughs Wellcome Fund and American Diabetes Association.

Objective: Nonalcoholic steatohepatitis (NASH) is increasingly common in obese patients. However, its metabolic consequences in patients with type 2 diabetes mellitus (T2DM) are unknown., Research Design and Methods: We studied 154 obese patients divided in four groups: 1) control (no T2DM or NAFLD), 2) T2DM without NAFLD, 3) T2DM with isolated steatosis, and 4) T2DM with NASH. We evaluated intrahepatic triglycerides by proton MRS ((1)H-MRS) and assessed insulin secretion/resistance during an oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp with glucose turnover measurements., Results: No significant differences among groups were observed in sex, BMI, or total body fat. Metabolic parameters worsened progressively with the presence of T2DM and the development of hepatic steatosis, with worse hyperinsulinemia, insulin resistance, and dyslipidemia (hypertriglyceridemia and low HDL cholesterol) in those with NASH (P < 0.001). Compared with isolated steatosis, NASH was associated with more dysfunctional and insulin-resistant adipose tissue (either as insulin suppression of plasma FFA [33 ± 3 vs. 48 ± 6%] or adipose tissue insulin resistance index [9.8 ± 1.0 vs. 5.9 ± 0.8 mmol/L ⋅ µIU/mL]; both P < 0.03). Furthermore, insulin suppression of plasma FFA correlated well with hepatic steatosis (r = -0.62; P < 0.001) and severity of steatohepatitis (rs = -0.52; P < 0.001). Hepatic insulin sensitivity was also more significantly impaired among patients with T2DM and NASH, both fasting and with increasing insulin levels within the physiological range (10 to 140 µIU/mL), compared with other groups., Conclusions: In obese patients with T2DM, the presence of NAFLD is associated with more severe hyperinsulinemia, dyslipidemia, and adipose tissue/hepatic insulin resistance compared with patients without NAFLD. The unfavorable metabolic profile linked to NAFLD should prompt strategies to identify and treat this population early on., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Context: Patients with nonalcoholic fatty liver disease (NAFLD) are at increased risk of cardiovascular disease, and atherogenic lipoproteins may play an important role., Objective: The objective of the study was to determine the contribution of the severity of steatohepatitis to atherogenic dyslipidemia in patients with NAFLD., Design: This was a cross-sectional study., Setting: The study was conducted at a university hospital., Patients: Patients were recruited from outpatient clinics or from the general population (n = 188)., Interventions: Measurement of hepatic triglyceride content by magnetic resonance spectroscopy, histology (liver biopsy), metabolic profile by means of an oral glucose tolerance test, and lipoprotein analyses were performed., Outcomes: Outcomes measured included standard lipids, lipoprotein subfraction analysis (apolipoprotein B/A1 levels, low-density lipoprotein (LDL) particle size/phenotype, and LDL/high-density lipoprotein subfractions), and insulin resistance., Results: Patients with NAFLD had severe insulin resistance, especially at the level of the adipose tissue, when compared with patients without NAFLD. Despite small differences in triglycerides and high-density lipoprotein-cholesterol, patients with NAFLD had a significantly higher plasma apolipoprotein B to apolipoprotein A1 ratio (0.66 ± 0.02 vs 0.58 ± 0.02, P = .01) and smaller LDL particle size (216.2 ± 0.7 vs 219.4 ± 1.1 Å, P = .01). Of note, these differences between patients with/without NAFLD were independent of the presence of obesity. Severity of steatohepatitis did not significantly influence the lipoprotein profile. Worse atherogenic dyslipidemia was best predicted by the degree of liver fat accumulation and adipose tissue and systemic insulin resistance., Conclusions: NAFLD was associated with a worse atherogenic lipoprotein profile, regardless of similar body mass index and other clinical parameters. We speculate that this lipoprotein profile is driven mostly by liver fat content and insulin resistance and appears not to be worsened by obesity or the severity of liver disease (nonalcoholic steatohepatitis).

The underlying mechanisms responsible for the development and progression of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) are unclear. Since the thyroid hormone regulates mitochondrial function in the liver, we designed this study in order to establish the association between plasma free T4 levels and hepatic triglyceride accumulation and histological severity of liver disease in patients with T2DM and NAFLD. This is a cross-sectional study including a total of 232 patients with T2DM. All patients underwent a liver MR spectroscopy ((1)H-MRS) to quantify hepatic triglyceride content, and an oral glucose tolerance test to estimate insulin resistance. A liver biopsy was performed in patients with a diagnosis of NAFLD. Patients were divided into 5 groups according to plasma free T4 quintiles. We observed that decreasing free T4 levels were associated with an increasing prevalence of NAFLD (from 55% if free T4≥1.18 ng/dL to 80% if free T4<0.80 ng/dL, p=0.016), and higher hepatic triglyceride accumulation by (1)H-MRS (p<0.001). However, lower plasma free T4 levels were not significantly associated with more insulin resistance or more severe liver histology (ie, inflammation, ballooning, or fibrosis). Decreasing levels of plasma free T4 are associated with a higher prevalence of NAFLD and increasing levels of hepatic triglyceride content in patients with T2DM. These results suggest that thyroid hormone may play a role in the regulation of hepatic steatosis and support the notion that hypothyroidism may be associated with NAFLD. No NCT number required., (Copyright © 2016 American Federation for Medical Research.)

Background & Aims: Liver ultrasound (US) is usually used in the clinical setting for the diagnosis and follow-up of patients with nonalcoholic fatty liver disease (NAFLD). However, no large study has carefully assessed its performance using a semiquantitative ultrasonographic scoring system in overweight/obese patients, in comparison to magnetic resonance spectroscopy ((1) H-MRS) and histology., Methods: We recruited 146 patients and performed: a liver US using a 5-parameter scoring system, a liver (1) H-MRS to quantify liver fat content, and a liver biopsy to assess histology. All measurements were repeated in a subgroup of patients (n = 62) after 18 months of follow-up., Results: The performance of liver US (parenchymal echo alone) was rather modest, and significantly worse than (1) H-MRS (AUROC: 0.82 [0.69-0.94] vs. 0.96 [0.90-1.00]; P = 0.04). However, the AUROC improved when different echographic parameters were taken into account (AUROC: 0.89 [0.83-0.96], P = 0.15 against (1) H-MRS). Optimum sensitivity for liver US was achieved at a liver fat content ≥12.5%, suggesting that below this threshold, liver US is less sensitive. Liver (1) H-MRS showed a high accuracy for the diagnosis of NAFLD, and correlated strongly with histological steatosis (r = 0.73, P < 0.0001). None of the imaging tests was adequate enough to predict changes over time in histology., Conclusions: Despite its widespread use, liver US has several important limitations that healthcare providers should recognize, particularly because of its low sensitivity. Using a combination of echographic parameters, liver US showed a significant improvement in its diagnostic performance, but still was of limited value for monitoring treatment over time., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Context and Objective: Nonalcoholic fatty liver disease (NAFLD) and its more severe form with steatohepatitis (NASH) are common in patients with type 2 diabetes mellitus (T2DM). However, they are usually believed to largely affect those with elevated aminotransferases. The aim of this study was to determine the prevalence of NAFLD by the gold standard, liver magnetic resonance spectroscopy ((1)H-MRS) in patients with T2DM and normal aminotransferases, and to characterize their metabolic profile., Participants and Methods: We recruited 103 patients with T2DM and normal plasma aminotransferases (age, 60 ± 8 y; body mass index [BMI], 33 ± 5 kg/m(2); glycated hemoglobin [A1c], 7.6 ± 1.3%). We measured the following: 1) liver triglyceride content by (1)H-MRS; 2) systemic insulin sensitivity (homeostasis model assessment-insulin resistance); and 3) adipose tissue insulin resistance, both fasting (as the adipose tissue insulin resistance index: fasting plasma free fatty acids [FFA] × insulin) and during an oral glucose tolerance test (as the suppression of FFA)., Results: The prevalence of NAFLD and NASH were much higher than expected (50% and 56% of NAFLD patients, respectively). The prevalence of NAFLD was higher in obese compared with nonobese patients as well as with increasing BMI (P = .001 for trend). Higher plasma A1c was associated with a greater prevalence of NAFLD and worse liver triglyceride accumulation (P = .01). Compared with nonobese patients without NAFLD, patients with NAFLD had severe systemic (liver/muscle) and, particularly, adipose tissue (fasting/postprandial) insulin resistance (all P < .01)., Conclusions: The prevalence of NAFLD is much higher than previously believed in overweight/obese patients with T2DM and normal aminotransferases. Moreover, many are at increased risk of NASH. Physicians should have a lower threshold for screening patients with T2DM for NAFLD/NASH.

Background & Aims: The role of plasma vitamin D deficiency in the development of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) remains poorly understood. Previous studies have suggested a role for vitamin D deficiency in the pathogenesis of NAFLD/NASH, but they have been rather small, and/or NAFLD was diagnosed using only aminotransferases or liver ultrasound. This study aimed to assess the role of vitamin D deficiency in relationship to liver fat accumulation and severity of NASH., Methods: A total of 239 patients were recruited and state-of-the-art techniques were used to measure insulin resistance (euglycemic insulin clamp with 3-(3)H-glucose), liver fat accumulation (magnetic resonance spectroscopy or (1)H-MRS), total body fat (dual energy X-ray absorptiometry), and severity of liver disease (liver biopsy)., Results: Patients were divided into 3 groups according to plasma 25-hydroxyvitamin D levels (normal: >30 ng/ml; insufficiency: 20-30 ng/ml; deficiency: <20 ng/ml). When well-matched for clinical parameters (BMI, total adiposity, or prevalence of prediabetes/type 2 diabetes), no significant differences were observed among groups in terms of skeletal muscle, hepatic, or adipose tissue insulin sensitivity, the amount of liver fat by (1)H-MRS, or the severity of histological inflammation, ballooning, or fibrosis. Patients were then divided according to liver histology into those with definite NASH and those without NASH. Although patients with NASH had higher insulin resistance, plasma vitamin D concentrations were similar between both groups., Conclusions: Our results suggest that plasma vitamin D levels are not associated with insulin resistance, the amount of liver fat accumulation, or the severity of NASH., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Unlabelled: Plasma aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) are usually increased in patients with nonalcoholic fatty liver disease (NAFLD). However, the factors behind their elevation remain unclear. The aim of this study was to assess the role of insulin resistance (IR) and liver triglyceride content in relation to histology in patients with NAFLD/nonalcoholic steatohepatitis (NASH) with normal or elevated ALT levels. To this end, we enrolled 440 patients, divided into three groups: no NAFLD (n = 60); NAFLD with normal ALT (n = 165); and NAFLD with elevated ALT (n = 215). We measured: (1) liver fat by proton magnetic resonance spectroscopy ((1)H-MRS); (2) severity of liver disease by biopsy (n = 293); and (3) insulin sensitivity in liver, muscle, and adipose tissue by a euglycemic hyperinsulinemic clamp with 3-(3)H-glucose. Patients with NAFLD and elevated ALT, even when well matched for body mass index to those with normal ALT, had worse adipose tissue insulin resistance (ATIR; P < 0.0001), higher liver triglyceride content (P < 0.0001), and lower plasma adiponectin (P < 0.05), but no differences in hepatic insulin resistance. Similar results were found when only patients with NASH were compared: both ATIR (P < 0.0001) and liver triglyceride content by (1)H-MRS (P < 0.0001) were worse in NASH with elevated ALT. Consistent with the (1)H-MRS data, steatosis on liver biopsy was also significantly increased in patients with NASH and elevated ALT levels (P < 0.0001). However, and most important, there were no differences in inflammation (P = 0.62), ballooning (P = 0.13), or fibrosis (P = 0.12)., Conclusion: In patients with NAFLD or NASH, ATIR (but not HIR) and liver triglyceride content are major factors in the elevation of plasma aminotransferase levels. Patients with normal versus elevated ALT had similar severity of NASH, suggesting that plasma aminotransferase levels are misleading parameters for guiding clinical management., (© 2014 by the American Association for the Study of Liver Diseases.)

Context and Objective: NAFLD, and its more severe form with steatohepatitis (NASH), are common in patients with T2DM. However, they are usually believed to affect largely those with elevated aminotransferases. The aim of this study was to determine the prevalence of NAFLD (by the gold-standard liver magnetic resonance and spectroscopy or (1)H-MRS) in patients with T2DM and normal aminotransferases, and to characterize their metabolic profile., Participants and Methods: We recruited 103 patients with T2DM and normal plasma aminotransferases (age: 60±8 years, BMI: 33±5 kg/m(2), A1c: 7.6±1.3%). We measured: i) liver triglyceride content by (1)H-MRS; ii) systemic insulin sensitivity (HOMA-IR), and iii) adipose tissue insulin resistance (IR), both fasting (as the adipose tissue IR index: fasting plasma FFA x insulin) and during an OGTT (as the suppression of FFA)., Results: The prevalence of NAFLD and NASH were much higher than expected (76% and 56%, respectively). The prevalence of NAFLD was higher in obese compared to non-obese patients, as well as with increasing BMI (p=0.03 for trend). Higher plasma A1c was associated with a greater prevalence of NAFLD and worse liver triglyceride accumulation (p<0.01). Compared to non-obese patients without NAFLD, patients with NAFLD had severe systemic (liver/muscle), and particularly, adipose tissue (fasting/postprandial) insulin resistance (all p<0.01)., Conclusions: The prevalence of NAFLD is much higher than previously believed in overweight/obese patients with T2DM and normal aminotransferases. Moreover, many are at increased risk of severe liver disease (NASH). Physicians should have a lower threshold for screening patients with T2DM for NAFLD/NASH.

Unlabelled: Hyperinsulinemia is believed to play a key role in the pathogenesis of nonalcoholic steatohepatitis (NASH) and associated cardiovascular risk. However, the relative contribution of insulin clearance to hyperinsulinemia and its relationship to liver histology have not been carefully evaluated before. To examine this, we enrolled 190 patients (32 without nonalcoholic fatty liver disease [NAFLD], 36 with simple steatosis [SS], and 122 with biopsy-proven NASH). Insulin secretion and hepatic insulin clearance were estimated by means of an oral glucose tolerance test, whereas peripheral insulin sensitivity and whole-body insulin clearance were measured during a euglycemic insulin clamp. A liver biopsy was performed to assess histology (grade/stage). Patients with NASH had similar hepatic insulin sensitivity, compared to patients with SS, but more severe adipose tissue insulin resistance and worse hyperinsulinemia. Patients with SS and NASH had a similar ∼30% reduction (P<0.01) in hepatic insulin clearance, when compared to patients without NAFLD. Reduced hepatic insulin clearance was not associated with severity of inflammation, ballooning, and fibrosis. In contrast, worse histological inflammation and ballooning (but not steatosis or fibrosis) were associated with a progressive reduction in whole-body insulin clearance (P<0.001 for trend). There was no significant difference in insulin secretion between patients with SS versus NASH., Conclusion: Decreased hepatic insulin clearance develops with a mild increase in liver fat (LFAT) accumulation. It appears to be largely driven by hepatic steatosis, whereas steatohepatitis is more closely associated with reduced whole-body insulin clearance. Hyperinsulinemia in NAFLD correlated strongly with impaired insulin clearance, but not with insulin secretion. Strategies that reduce LFAT and improve insulin clearance hold the potential to revert the unfavorable effects of hyperinsulinemia in these patients., (© 2014 by the American Association for the Study of Liver Diseases.)

Background & Aims: Liver biopsy is the only reliable way of diagnosing and staging NASH but its invasive nature limits its use. Plasma caspase-generated cytokeratin-18 fragments (CK-18) have been proposed as a non-invasive alternative. We studied its clinical value in a large multiethnic NAFLD population and examined its relationship to clinical/metabolic/histological parameters., Methods: 424 middle-aged subjects in whom we measured adipose tissue, liver and muscle insulin resistance (IR), liver fat by MRS (n=275) and histology (n=318)., Results: Median CK-18 were elevated in patients with vs. without NAFLD by MRS (209 [IQR: 137-329] vs. 122 [IQR: 98-155]U/L) or with vs. without NASH (232 [IQR: 151-387] vs. 170 [IQR: 135-234]U/L, both p<0.001). Plasma CK-18 raised significantly with any increase in steatosis, inflammation and fibrosis, but there was a significant overlap across disease severity. The CK-18 AUROC to predict NAFLD, NASH or fibrosis were 0.77 (95% CI=0.71-0.84), 0.65 (95% CI=0.59-0.71) and 0.68 (95% CI=0.61-0.75), respectively. The overall sensitivity/specificity for NAFLD, NASH and fibrosis were 63% (57-70%)/83% (69-92%), 58% (51-65%)/68% (59-76%) and 54% (44-63%)/85% (75-92%), respectively. CK-18 correlated most strongly with ALT (r=0.57, p<0.0001) and adipose tissue IR (insulin-suppression of FFA: r=-0.43; p<0.001), less with steatosis, lobular inflammation and fibrosis (r=0.28-0.34, all p<0.001), but not with ballooning, BMI, metabolic syndrome or T2DM., Conclusions: Plasma CK-18 has a high specificity for NAFLD and fibrosis, but its limited sensitivity makes it inadequate as a screening test for staging NASH. Whether combined as a diagnostic panel with other biomarkers or clinical/laboratory tests may prove useful requires further study., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Since their approval, thiazolidinediones (TZDs) have been used extensively as insulin-sensitizers for the management of type 2 diabetes mellitus (T2DM). Activation of peroxisomal proliferator-activated receptor gamma (PPARγ) nuclear receptors by TZDs leads to a vast spectrum of metabolic and antiinflammatory effects. In the past decade, clinicians and scientists across the fields of metabolism, diabetes, liver disease (NAFLD), atherosclerosis, inflammation, infertility, and even cancer have had high hopes about the potential for TZDs to treat many of these diseases. However, an increasing awareness about undesirable "off-target" effects of TZDs have made us rethink their role and be more cautious about the long-term benefits and risks related to their use. This review examines the most relevant work on the benefits and risks associated with TZD treatment, with a focus on the only PPARγ agonist currently available (pioglitazone), aiming to offer the reader a balanced overview about the current and future role of TZDs in the management of insulin-resistant states and T2DM.

Nonalcoholic fatty liver disease (NAFLD) is considered the most common liver disorder in the Western world. It is commonly associated with insulin resistance, obesity, dyslipidaemia, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Nonalcoholic steatohepatitis (NASH) is characterized by steatosis with necroinflammation and eventual fibrosis, which can lead to end-stage liver disease and hepatocellular carcinoma. Its pathogenesis is complex, and involves a state of 'lipotoxicity' in which insulin resistance, with increased free fatty acid release from adipose tissue to the liver, play a key role in the onset of a 'lipotoxic liver disease' and its progression to NASH. The diagnosis of NASH is challenging, as most affected patients are symptom free and the role of routine screening is not clearly established. A complete medical history is important to rule out other causes of fatty liver disease (alcohol abuse, medications, other). Plasma aminotransferase levels and liver ultrasound are helpful in the diagnosis of NAFLD/NASH, but a liver biopsy is often required for a definitive diagnosis. However, there is an active search for plasma biomarkers and imaging techniques that may non-invasively aid in the diagnosis. The treatment of NASH requires a multifaceted approach. The goal is to reverse obesity-associated lipotoxicity and insulin resistance via lifestyle intervention. Although there is no pharmacological agent approved for the treatment of NAFLD, vitamin E (in patients without T2DM) and the thiazolidinedione pioglitazone (in patients with and without T2DM) have shown the most consistent results in randomized controlled trials. This review concentrates on our current understanding of the disease, with a focus on the existing therapeutic approaches and potential future pharmacological developments for NAFLD and NASH.

Unlabelled: The role of adipose tissue insulin resistance in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains unclear. To evaluate this, we measured in 207 patients with NAFLD (age = 51 ± 1, body mass index = 34.1 ± 0.3 kg/m(2) ) and 22 controls without NAFLD (no NAFLD) adipose tissue insulin resistance by means of a validated index (Adipo-IR(i) = plasma free fatty acids [FFA] x insulin [FPI] concentration) and as the suppression of plasma FFA during an oral glucose tolerance test and by a low-dose insulin infusion. We also explored the relationship between adipose tissue insulin resistance with metabolic and histological parameters by dividing them based on quartiles of adipose tissue insulin resistance (Adipo-IR(i) quartiles: Q1 = more sensitive; Q4 = more insulin resistant). Hepatic insulin resistance, measured as an index derived from endogenous glucose production x FPI (HIRi), and muscle insulin sensitivity, were assessed during a euglycemic insulin clamp with 3-[(3) H] glucose. Liver fat was measured by magnetic resonance imaging and spectroscopy, and a liver biopsy was performed to assess liver histology. Compared to patients without steatosis, patients with NAFLD were insulin resistant at the level of adipose tissue, liver, and skeletal muscle and had higher plasma aspartate aminotransferase and alanine aminotransferase, triglycerides, and lower high-density lipoprotein cholesterol and adiponectin levels (all P < 0.01). Metabolic parameters, hepatic insulin resistance, and liver fibrosis (but not necroinflammation) deteriorated as quartiles of adipose tissue insulin resistance worsened (all P < 0.01)., Conclusion: Adipose tissue insulin resistance plays a key role in the development of metabolic and histological abnormalities of obese patients with NAFLD. Treatment strategies targeting adipose tissue insulin resistance (e.g., weight loss and thiazolidinediones) may be of value in this population., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Objective: Prediabetes and type 2 diabetes mellitus (T2DM) are believed to be common and associated with a worse metabolic profile in patients with nonalcoholic fatty liver disease (NAFLD). However, no previous study has systematically screened this population., Research Design and Methods: We studied the prevalence and the metabolic impact of prediabetes and T2DM in 118 patients with NAFLD. The control group comprised 20 subjects without NAFLD matched for age, sex, and adiposity. We measured 1) plasma glucose, insulin, and free fatty acid (FFA) concentration during an oral glucose tolerance test; 2) liver fat by magnetic resonance spectroscopy (MRS); 3) liver and muscle insulin sensitivity (euglycemic insulin clamp with 3-[(3)H]glucose); and 4) indexes of insulin resistance (IR) at the level of the liver (HIR(i)= endogenous glucose production × fasting plasma insulin [FPI]) and adipose tissue (Adipo-IR(i)= fasting FFA × FPI)., Results: Prediabetes and T2DM was present in 85% versus 30% in controls (P < 0.0001), all unaware of having abnormal glucose metabolism. NAFLD patients were IR at the level of the adipose tissue, liver, and muscle (all P < 0.01-0.001). Muscle and liver insulin sensitivity were impaired in patients with NAFLD to a similar degree, whether they had prediabetes or T2DM. Only adipose tissue IR worsened in T2DM and correlated with the severity of muscle (r = 0.34; P < 0.001) and hepatic (r = 0.57; P < 0.0001) IR and steatosis by MRS (r = 0.35; P < 0.0001)., Conclusions: Patients with NAFLD may benefit from early screening for T2DM, because the prevalence of abnormal glucose metabolism is much higher than previously appreciated. Regardless of glucose tolerance status, severe IR is common. In patients with T2DM, adipose tissue IR appears to play a major role in the severity of NAFLD.

Endocrinologists are encountering patients with obesity-related complications such as metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) on a daily basis. Nonalcoholic fatty liver disease (NAFLD) is a liver condition characterized by insulin resistance, hepatic steatosis and frequently T2DM. This is now the most common chronic liver condition in adults and is present in the majority of obese subjects. Liver fat accumulation may range from simple steatosis to severe steatohepatitis with hepatocyte necroinflammation (or nonalcoholic steatohepatitis [NASH]). Although the natural history is incompletely understood, NAFLD may lead to serious medical consequences ranging from cirrhosis and hepatocellular carcinoma to earlier onset of T2DM and cardiovascular disease (CVD). The diagnosis of NAFLD may be challenging because signs and symptoms are frequently absent or nonspecific, and thus easily missed. Liver aminotransferases may be helpful if elevated, but most times are normal in the presence of the disease. Liver imaging may assist in the diagnosis (ultrasound or MRI and spectroscopy) but a definitive diagnosis of NASH still requires a liver biopsy. This may change in the near future as novel biomarkers become available. Treatment of NAFLD includes aggressive management of associated cardiovascular risk factors and many times control of T2DM. Pioglitazone and vitamin E appear promising for patients with NASH, although long-term studies are unavailable. In summary, this review hopes to address the common clinical dilemmas that endocrinologists face in the diagnosis and management of NAFLD and increase awareness of a potentially serious medical condition.

Unlabelled: The role of ethnicity in determining disease severity in nonalcoholic steatohepatitis (NASH) remains unclear. We recruited 152 patients with biopsy-proven NASH, 63% of whom were Hispanic and 37% of whom were Caucasian. Both groups were well matched for age, sex, and total body fat. We measured: (1) liver fat by magnetic resonance imaging and spectroscopy; (2) fasting plasma glucose, fasting plasma insulin (FPI), and free fatty acid (FFA) levels; (3) total body fat by dual energy x-ray absorptiometry (DXA); (4) liver and muscle insulin sensitivity (insulin clamp with 3-[(3)H] glucose); (5) insulin resistance at the level of the liver (fasting endogenous glucose production derived from 3-[(3)H] glucose infusion × FPI) and adipose tissue (fasting FFA × FPI). Liver fat was slightly, but not significantly, higher in Hispanic vs. Caucasian patients (27 ± 2% vs. 24 ± 2%, p = 0.16). However, this trend did not translate into worse liver steatosis, necroinflammation or fibrosis. Patients with NASH had severe hepatic, adipose tissue and muscle insulin resistance versus healthy subjects without NASH nonalcoholic fatty liver disease, but there were no differences between both ethnic groups on these parameters. However, Hispanics versus Caucasians with type 2 diabetes mellitus (T2DM) had a trend for worse hepatic/adipose tissue insulin resistance and fibrosis., Conclusion: When Hispanic and Caucasian patients with NASH are well matched for clinical parameters, particularly for adiposity, slightly higher liver fat content is not associated with worse hepatic insulin resistance or more severe NASH on histology. Hispanic ethnicity does not appear to be a major determinant of disease severity in NASH, although those with diabetes may be at greater risk of fibrosis. Given the higher risk of T2DM in Hispanics, long-term studies are needed to define their risk of disease progression., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Background: The cancerogenic process of colorectal cancer depends on a series of events involving oncogenes and inactivation of suppressor genes. This study concerns changes in DNA content, p53 and PCNA expression in human colon in dysplastic, precancerous and cancerous tissues., Materials and Methods: These characteristics were analyzed in a series of hyperplastic polyps (HP), adenomas (AD), adenocarcinomas evolved within adenomas (AC-AD) and adenocarcinomas (AC) of the large bowel. DNA ploidy was analyzed by flow cytometry and PCNA and p53 expression was evaluated by immunohistochemistry using monoclonal antibodies PC10 and PAb 1801., Results: Aneuploidy was found in 43/67 (64%) of AC and only occasionally in other subgroups (AC vs all other groups: 64% vs 99%; p = 0.00002). PCNA positivity gradually increased in the sequence from HP to AC and were significantly higher in AC compared to HP (90% vs 44%; p = 0.00007). p53 positive cells were found in 67% of AC while only occasionally in other groups (HP vs AC: p = 0.0002, AD (low dysplasia) vs AC: p = 0.001; AD (moderate dysplasia) vs AC: p = 0.001)., Conclusions: These results demonstrated a progressive immunoreactivity for PCNA in the HP to AC sequence, while p53 positivity and aneuploidy seemed specific for colon carcinoma.