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.

While the use of vitamin E (Vit E) in nondiabetic patients with NASH has proven to be effective in the PIVENS study (NEJM 2010), there is no information about its effect in patients with NASH and T2DM. To examine this, we performed a randomized, double blind, controlled trial assessing the efficacy of Vit E, alone or combined with pioglitazone (PIO) in this population. Patients (n=105) were randomized 1:1:1 to Vit E 400 U BID, Vit E 400 U BID + PIO 45mg QD, or placebo for 18 months. The primary endpoint was histological improvement, defined as a 2-point reduction in the NAFLD activity score from 2 different parameters, without worsening of fibrosis. Secondary outcomes: resolution of NASH, individual histological scores, and metabolic parameters. Based on 2 planned primary comparisons, a p<0.025 was considered to indicate statistical significance. Groups were well matched at baseline. A total of 87 patients completed 18 months of follow-up. More patients on Vit E and PIO combination achieved the primary outcome compared to placebo (65% vs. 22%, p<0.001), but not in the Vit E alone group (36% vs. 22%, p=0.18). The same trend was observed for resolution of NASH, with a significant improvement only in the combination group (57% vs. 18%, p<0.001), but not with Vit E alone (42% vs. 18%, p=0.036). While steatosis grade improved with either combination (p<0.001) or Vit E alone (p=0.018), inflammation (p=0.018) and ballooning (p=0.022) grades only improved with Vit E + PIO. No improvement in fibrosis was observed in any group. Four patients died of cardiovascular causes during the study (2 on Vit E alone and 2 on combination). Weight gain, peripheral edema and hypoglycemia were more frequent in the combination group. Conclusion: Vit E alone was ineffective to treat NASH in patients with T2DM. While the combination of Vit E and PIO was significantly better than placebo, response rate was similar to that reported for PIO alone in patients with T2DM, suggesting no role of Vit E in this population. Disclosure F. Bril: None. D.M. Biernacki: None. R. Lomonaco: None. S. Kalavalapalli: None. S.K. Subbarayan: None. J. Lai: None. F.O. Tio: None. A. Suman: None. B.K. Orsak: None. J. Hecht: None. K. Cusi: Consultant; Self; Janssen Global Services, LLC., Eli Lilly and Company. Research Support; Self; Cirius Therapeutics. Other Relationship; Self; Nordic Bioscience. Research Support; Self; Novartis Pharmaceuticals Corporation, Novo Nordisk Inc.. Other Relationship; Self; Quest Diagnostics. Research Support; Self; Zydus Pharmaceuticals (USA) Inc.. Other Relationship; Self; OWL metabolomics, Echosens. Research Support; Self; Janssen Global Services, LLC.. Consultant; Self; Tobira Therapeutics, Pfizer Inc..

In a previous publication (Journal of the American Society of Hypertension 2014;8(4):e35-e36 we did a comparison study of arterial stiffness in diabetic pts taking oral antidiabetic agents (ODA) v/s those taking Insulin. The aim of the present study was to compare aortic stiffness determined from resting and exercise pulse pressure (PP) in a group of pts taking ODA v/s a group of pts taking a combination of ODA and insulin. We studied 86 diabetic pts referred to us for the performance of a maximal treadmill exercise test as part of a workup for chest pain. They were divided into 46 pts taking ODA (group 1) v/s 46 pts taking a combination of ODA plus insulin (group 2). Their age, heart rate(HR) both rest and exercise, PP both rest and exercise, exercise duration in seconds and HbA1C are noted in the table. There was no significant difference in the HR and PP both at rest and during exercise between both groups. Also, no significant difference was found in their ages and exercise duration although group 2 pts were older, had greater PP both at rest and exercise and had shorter exercise duration. The only significant difference was that goup 2 had a sinificantly higher A1C than group 1(p<0.003) reflecting the severity of their diabetes. We conclude from this small study, that the addition of Insulin to oral antidiabetic agents did not affect aortic stiffness as determined by PP which is a surrogate for other measures of aortic stiffness.

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.

The aim of or study was to see if an exaggerated BP response during the Bruce exercise test could differentiated target organ damage (TOD) in a population of diabetics v/s nondiabetic pts . We studied 105 pts for the performance of a stress test because of chest pain whose systolic BP rose 50mmHg or more at their peak exercise compared to their resting BP. There were 45 diabetics pts (DM) and 60 nondiabetic pts (NDM) pts. All pts were hypertensive on medication but their beta blocker medication was on hold for the performance of the stress test. The echocardiograms were performed using a Phillips IE 33 echo machine and the LV mass was calculated using the Deveraux formula using single plane views. The was no statistical difference between both groups with respect to age, BMI and systolic and diastolic BP’s during rest and exercise. The HR at rest was not different between both groups but the HR at peak exercise was significantly higher for NDM compared to DM (p < 0.016). The LVMI was significantly higher in DM compared to NDM pts ( p = 0.04). In conclusion, an elevated LVMI which is evidence for hypertensive target organ damage should be suspected in hypertensive pts who have an exaggerated BP response to the exercise Bruce stress test. The reason for a significantly higher HR at peak exercise for NDM patients compared to DM pts may be related to better physical performance and therefore longer duration of exercise. Other possibilities will be discussed.

The aim of this study was to see if there is any association between masked hypertension (MHTN) and orthostatic HTN (OHTN). In addition, we evaluated if MHTN was associated with diabetes (DM). Lastly we compared BP and HR changes between DM and non-diabetics (NDM)pts. We performed ambulatory BP monitoring (ABPM) in 70 consecutive pts referred to us for evaluation of hypertension. From this number of pts there were 20 pts with OHTN for an incidence of 28%. There were 8 pts with MHTN for an incidence of 11.4%. There were 26 pts with DM and 44 pts were NDM The studies were performed after 5 minutes of rest. We obtained BP’s in the dominant arm. We subsequently performed the 24hs ABPM using Space Lab On Trak 90227 monitors. Out of 8pts with MHTN, none had OHTN and only 2 were pts with DM. In addition, we compared age, weight, BP sitting and standing as well as HR sitting and standing in our 70 patients that were divided in 2 groups, DM v/s NDM. The following table depicted our results: In summary, we found a higher sitting diastolic BP in nondiabetic pts. There was no significant difference between both groups in the remaining parameters. In conclusion, in our small population of pts there was no association between MHTN and OHTN. The association between MHTN and DM was very low. When comparing 8 different parameters depicted in the table the only significant difference between DM and NDM was on the sitting diastolic BP.

I read with great interest the recent comprehensive review by Rotman and Sanyal.1 I would just like to point out an error in table 1 (row 1), where the authors inadvertently state that pioglitazone has shown histological benefit only in secondary analyses and not been studied in patients with diabetes and nonalcoholic fatty liver disease (NAFLD). Benefit with the thiazolidinedione has been reported for the primary histological outcome in two randomised controlled trials (RCTs) in patients with prediabetes or type 2 diabetes mellitus (T2DM). This is most likely an oversight as in the …

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 (1H-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/m2; glycated hemoglobin [A1c], 7.6 ± 1.3%). We measured the following: 1) liver triglyceride content by 1H-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.

Clinical guidelines recommend that women with a history of adequate screening and not otherwise at high risk may discontinue cervical cancer screening after 65 years of age. However, screening remains common among US women over 65 years old. This study was conducted to examine whether overutilization was attributable to provider's recommendation or patient choice.This cross-sectional study used data from 1752 female participants (70 + years) from the 2013 National Health Interview Survey (NHIS). We quantitatively assessed the proportions of provider-recommended and patient self-initiated Pap smears.Among female respondents, 40.8% had a Pap smear within the past 3 years, 19.4% had a Pap smear in the last year, and 39.7% reported receiving a recommendation for a Pap smear from their provider in the past year. Among women who received a recommendation to obtain a Pap smear, 39.8% did so within the past 12 months compared to 5.9% of women who did not receive a recommendation (adjusted odds ratio 10.5, 95% confidence interval 7.39–15.0). About 70% of women who visited an obstetrician/gynecologist and reported receiving a recommendation to have a Pap smear did so in the past year, while 32.3% of women who visited an obstetrician/gynecologist but did not receive a recommendation obtained one.Pap smears were common among women ≥ 70 years of age. Health care providers may need additional education on current guidelines regarding indications for Pap smears in this age group to help reduce screening of patients who may not benefit.

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.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).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).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.

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. (Hepatology 2014;59:2178–2187)

Two potash plants at the Qarhan Salt Lake in Qinghai Province, Peoples Republic of China, were visited in July 2012 to discuss processing strategies, particularly flotation technology. The first plant, operated by Qinghai Avic Resources Co., Ltd., in Mahai, is using the traditional KCl flotation from NaCl with an amine as collector after selective decomposition of carnallite (KCl.MgCl2⋅6H2O). The second plant is operated by the Qinghai Salt Lake Group in Geermu where NaCl is floated from carnallite with an alkyl-morpholine as collector prior to carnallite decomposition for KCl production. These two major potash flotation technologies being used in the Qinghai Province of the Peoples Republic of China are reviewed and discussed with respect to recent research findings regarding the use of alkyl-morpholine collectors in reverse flotation of NaCl from carnallite.

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.