Relationship between NAFLD and coronary artery disease: A Mendelian randomization study.

BACKGROUND AND AIMS: There is an ongoing debate on whether NAFLD is an active contributor or an innocent bystander in the pathogenesis of coronary artery disease (CAD). The aim of the present study was to assess the causal relationship between NAFLD and CAD. APPROACH AND RESULTS: We performed two-sample Mendelian randomization (MR) analyses using summary-level data to assess the association between genetically predicted NAFLD (i.e., chronically elevated serum alanine aminotransferase levels [cALT], imaging-based and biopsy-confirmed NAFLD) and risk of CAD. Analyses were repeated after exclusion of NAFLD susceptibility genes that are associated with impaired VLDL secretion.Inverse-variance weighted MR analyses showed a statistically significant association between genetically predicted cALT and risk of CAD (OR: 1.116, 95% CI: 1.039, 1.199), but not for the other NAFLD-related traits (OR: 1.046, 95% CI: 0.764, 1.433 and OR: 1.014, 95% CI: 0.968, 1.062 for imaging-based and biopsy-confirmed NAFLD, respectively). MR-Egger regression revealed a statistically significant intercept, indicative of directional pleiotropy, for all traits. Repeat analyses after exclusion of genes associated with impaired VLDL secretion showed consistent associations between genetically predicted NAFLD and CAD for all traits (i.e., cALT [OR: 1.203, 95% CI: 1.113, 1.300]), imaging-based (OR: 2.149, 95% CI: 1.276, 3.620) and biopsy-confirmed NAFLD (OR: 1.113, 95% CI: 1.041, 1.189), which persisted when more stringent biopsy-confirmed NAFLD criteria were used (OR: 1.154, 95% CI: 1.043, 1.278) or when more stringent MR methods were applied. MR-Egger regression did not show a statistically significant intercept. CONCLUSION: The two-sample MR analyses showed a robust association between genetically predicted NAFLD and CAD after exclusion of genetic variants that are implicated in impaired VLDL secretion.

Towards precision medicine in diabetes? A critical review of glucotypes.

In response to a study previously published in PLOS Biology, this Formal Comment thoroughly examines the concept of 'glucotypes' with regard to its generalisability, interpretability and relationship to more traditional measures used to describe data from continuous glucose monitoring.

Serum sex hormone-binding globulin is a mediator of the association between intrahepatic lipid content and type 2 diabetes: the Maastricht Study.

AIMS/HYPOTHESIS: Serum sex hormone-binding globulin (SHBG) has been proposed to act as a hepatokine that contributes to the extrahepatic complications observed in non-alcoholic fatty liver disease (NAFLD). However, it remains uncertain whether serum SHBG mediates the association between intrahepatic lipids (IHL) and type 2 diabetes. Therefore, we studied whether, and to what extent, serum SHBG mediates the association between IHL content and type 2 diabetes. METHODS: We used cross-sectional data from the Maastricht Study (n=1554), a population-based cohort study with oversampling of individuals with type 2 diabetes. Type 2 diabetes status was assessed by oral glucose tolerance test, and IHL content was measured using 3T Dixon MRI. Mediation analyses were performed to assess the role of serum SHBG in mediating the association between IHL content and type 2 diabetes. RESULTS: IHL content was significantly associated with type 2 diabetes in women and men (OR 1.08 [95% CI 1.04, 1.14] and OR 1.12 [95% CI 1.08, 1.17], respectively). Serum SHBG significantly mediated the association between IHL content and type 2 diabetes. The contribution of serum SHBG was higher in women (OR 1.04 [95% CI 1.02, 1.07]; proportion mediated 50.9% [95% CI 26.7, 81.3]) than in men (OR 1.02 [95% CI 1.01, 1.03]; proportion mediated 17.2% [95% CI 9.6, 27.6]). Repeat analyses with proxies of type 2 diabetes and adjustment for covariates did not substantially affect the results. CONCLUSIONS/INTERPRETATION: In this large-scale population-based cohort study, serum SHBG was found to be a mediator of the association between IHL content and type 2 diabetes. These findings extend our understanding of the potential mechanisms by which NAFLD is a risk factor for type 2 diabetes, and further elaborate on the role of SHBG as a hepatokine.

Quality of life of adult patients with hereditary fructose intolerance.

BACKGROUND: Although patients with hereditary fructose intolerance (HFI) generally have a good prognosis on a fructose-restricted diet, relatively little is known about their quality of life. The aim of this study was to investigate the quality of life in adult patients with HFI in comparison to patients with dietary-treated, classical phenylketonuria (PKU). METHODS: Patients with HFI and patients with classical PKU were recruited from the adult metabolic centers in The Netherlands and Belgium and via social media. Patients were asked to fill out the 36-item Short Form Health survey (SF-36) and a modified PKU Quality Of Life (PKU-QoL) questionnaire. RESULTS: Patients with HFI (n = 19) did not report any restrictions in their health-related quality of life, except for vitality and general mental health, which were scored more unfavorable compared to patients with PKU (n = 19) (p < 0.05, adjusted for level of education and country of origin). The results from the modified PKU-QoL demonstrated a statistically significantly greater impact of the disease in the social domain in HFI. A substantial proportion of both HFI and PKU patients (21%) reported a great to severe emotional impact of their disease. Finally, patients with HFI experienced statistically significantly less food temptations, less guilt if dietary restrictions not followed, and less overall difficulty following dietary restrictions. CONCLUSIONS: Although patients with HFI showed to have a generally good quality of life, they scored lower on vitality and general mental health, and reported a greater social impact of the disease. These aspects deserve further study and clinical attention.

Associations between plasma sulfur amino acids and specific fat depots in two independent cohorts: CODAM and The Maastricht Study.

PURPOSE: Sulfur amino acids (SAAs) have been associated with obesity and obesity-related metabolic diseases. We investigated whether plasma SAAs (methionine, total cysteine (tCys), total homocysteine, cystathionine and total glutathione) are related to specific fat depots. METHODS: We examined cross-sectional subsets from the CODAM cohort (n = 470, 61.3% men, median [IQR]: 67 [61, 71] years) and The Maastricht Study (DMS; n = 371, 53.4% men, 63 [55, 68] years), enriched with (pre)diabetic individuals. SAAs were measured in fasting EDTA plasma with LC-MS/MS. Outcomes comprised BMI, skinfolds, waist circumference (WC), dual-energy X-ray absorptiometry (DXA, DMS), body composition, abdominal subcutaneous and visceral adipose tissues (CODAM: ultrasound, DMS: MRI) and liver fat (estimated, in CODAM, or MRI-derived, in DMS, liver fat percentage and fatty liver disease). Associations were examined with linear or logistic regressions adjusted for relevant confounders with z-standardized primary exposures and outcomes. RESULTS: Methionine was associated with all measures of liver fat, e.g., fatty liver disease [CODAM: OR = 1.49 (95% CI 1.19, 1.88); DMS: OR = 1.51 (1.09, 2.14)], but not with other fat depots. tCys was associated with overall obesity, e.g., BMI [CODAM: ß = 0.19 (0.09, 0.28); DMS: ß = 0.24 (0.14, 0.34)]; peripheral adiposity, e.g., biceps and triceps skinfolds [CODAM: ß = 0.15 (0.08, 0.23); DMS: ß = 0.20 (0.12, 0.29)]; and central adiposity, e.g., WC [CODAM: ß = 0.16 (0.08, 0.25); DMS: ß = 0.17 (0.08, 0.27)]. Associations of tCys with VAT and liver fat were inconsistent. Other SAAs were not associated with body fat. CONCLUSION: Plasma concentrations of methionine and tCys showed distinct associations with different fat depots, with similar strengths in the two cohorts.

Thiazolidinediones and Glucagon-Like Peptide-1 Receptor Agonists and the Risk of Nonalcoholic Fatty Liver Disease: A Cohort Study.

BACKGROUND AND AIMS: Thiazolidinediones (TZDs) and glucagon-like peptide-1 (GLP-1) receptor agonists are potential pharmacological treatment options for patients at risk of NAFLD. Therefore, we examined the association between the risk of NAFLD and the use of TZDs and GLP-1 receptor agonists compared with the use of sulfonylureas (SUs) and insulins. Additionally, we calculated the incidence of HCC in users of TZDs and GLP-1 receptor agonists. APPROACH AND RESULTS: We conducted a population-based cohort study using primary care data from the Clinical Practice Research Datalink database (2007-2018). All patients aged ≥18 with a prescription of an oral glucose-lowering agent or GLP-1 receptor agonist were included. The first prescription defined the start of follow-up. The primary outcome was a new diagnosis of NAFLD. Cox proportional hazards regression was used to estimate HRs and 95% CIs of the primary outcome. Incidence rates of HCC were determined per 1,000 person-years for all exposures. The study identified 207,367 adults with a prescription for a glucose-lowering agent. The risk of NAFLD was lower in patients prescribed a TZD than in those prescribed an SU (adjusted HR [aHR], 0.32; 95% CI, 0.20-0.51). No difference in risk of NAFLD was observed comparing GLP-1 receptor agonist use with insulin use (aHR, 1.22; 95% CI, 0.91-1.63). CONCLUSIONS: Results of our study endorse the use of TZDs for selected patients at risk of NAFLD but do not support previous findings regarding the beneficial effect of GLP-1 receptor agonists. The low number of events in several subgroups may affect the generalizability of the current findings.

Causal relationship between polycystic ovary syndrome and coronary artery disease: A Mendelian randomisation study.

OBJECTIVE: Polycystic ovary syndrome (PCOS) has been associated with an increased risk of coronary artery disease (CAD). However, it remains uncertain whether this increased risk is the result of PCOS per se or, alternatively, is explained by obesity, a common feature of PCOS. The aim of this study was to assess the causal association between PCOS and CAD and the role of obesity herein. DESIGN AND METHODS: We conducted two-sample Mendelian randomisation analyses in large-scale, female-specific datasets to study the association between genetically predicted (1) risk of PCOS and risk of CAD, (2) body mass index (BMI) and risk of PCOS and (3) BMI and risk of CAD. Primary analyses were conducted with the inverse-variance weighted (IVW) method. Simple median, penalized weighted median and contamination mixture analyses were performed to assess the robustness of the outcomes. RESULTS: IVW analyses did not show a statistically significant association between PCOS and CAD (odds ratio [OR]: 0.99, 95% confidence interval [CI]: 0.89, 1.11). In contrast, genetically predicted BMI was statistically significantly associated with an increased odds of PCOS (OR: 3.21, 95% CI: 2.26, 4.56) and CAD (OR: 1.38, 95% CI: 1.14, 1.67). Similar results were obtained when secondary analyses were performed. CONCLUSION: These sex-specific analyses show that the genetically predicted risk of PCOS is not associated with the risk of CAD. Instead, the genetically predicted risk of obesity (and its downstream metabolic effects) is the common denominator of both PCOS and CAD risk.

Novel insights in intestinal and hepatic fructose metabolism: from mice to men.

PURPOSE OF REVIEW: The rise in fructose consumption in parallel with the current epidemic of obesity and related cardiometabolic disease requires a better understanding of the pathophysiological pathways that are involved. RECENT FINDINGS: Animal studies have shown that fructose has various effects on the intestines that subsequently affect intrahepatic lipid accumulation and inflammation. Fructose adversely affects the gut microbiome - as a producer of endotoxins and intermediates of de novo lipogenesis - and intestinal barrier function. Furthermore, intestinal fructose metabolism shields fructose away from the liver. Finally, fructose 1-phosphate (F1-P) serves as a signal molecule that promotes intestinal cell survival and, consequently, intestinal absorption capacity. Intervention and epidemiological studies have convincingly shown that fructose, particularly derived from sugar-sweetened beverages, stimulates de novo lipogenesis and intrahepatic lipid accumulation in humans. Of interest, individuals with aldolase B deficiency, who accumulate F1-P, are characterized by a greater intrahepatic lipid content. First phase II clinical trials have recently shown that reduction of F1-P, by inhibition of ketohexokinase, reduces intrahepatic lipid content. SUMMARY: Experimental evidence supports current measures to reduce fructose intake, for example by the implementation of a tax on sugar-sweetened beverages, and pharmacological inhibition of fructose metabolism to reduce the global burden of cardiometabolic disease.

Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria: A comparison between two genetic disorders affecting the same metabolic pathway.

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism.

Association between de novo lipogenesis susceptibility genes and coronary artery disease.

BACKGROUND AND AIMS: Coronary artery disease (CAD) is the principal cause of death in individuals with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to use genetic epidemiology to study the association between de novo lipogenesis (DNL), one of the major pathways leading to NAFLD, and CAD risk. METHODS AND RESULTS: DNL susceptibility genes were used as instruments and selected using three approaches: 1) genes that are associated with both high serum triglycerides and low sex hormone-binding globulin, both downstream consequences of DNL (unbiased approach), 2) genes that have a known role in DNL (biased approach), and 3) genes that have been associated with serum fatty acids, used as a proxy of DNL. Gene-CAD effect estimates were retrieved from the meta-analysis of CARDIoGRAM and the UK Biobank (∼76014 cases and ∼264785 controls). Effect estimates were clustered using a fixed-effects meta-analysis. Twenty-two DNL susceptibility genes were identified by the unbiased approach, nine genes by the biased approach and seven genes were associated with plasma fatty acids. Clustering of genes selected in the unbiased and biased approach showed a statistically significant association with CAD (OR:1.016, 95%CI:1.012; 1.020 and OR:1.013, 95%CI:1.007; 1.020, respectively), while clustering of fatty acid genes did not (OR:1.004, 95%CI:0.996-1.011). Subsequent exclusion of potential influential outliers did reveal a statistically significant association (OR:1.009, 95%CI:1.000; 1.018). CONCLUSIONS: DNL susceptibility genes are associated with an increased risk of CAD. These findings suggest that DNL may be involved in the pathogenesis of CAD and favor further development of strategies that target NAFLD through DNL.

Greater daily glucose variability and lower time in range assessed with continuous glucose monitoring are associated with greater aortic stiffness: The Maastricht Study.

AIMS: CVD is the main cause of morbidity and mortality in individuals with diabetes. It is currently unclear whether daily glucose variability contributes to CVD. Therefore, we investigated whether glucose variability is associated with arterial measures that are considered important in CVD pathogenesis. METHODS: We included participants of The Maastricht Study, an observational population-based cohort, who underwent at least 48 h of continuous glucose monitoring (CGM) (n = 853; age: 59.9 ± 8.6 years; 49% women, 23% type 2 diabetes). We studied the cross-sectional associations of two glucose variability indices (CGM-assessed SD [SDCGM] and CGM-assessed CV [CVCGM]) and time in range (TIRCGM) with carotid-femoral pulse wave velocity (cf-PWV), carotid distensibility coefficient, carotid intima-media thickness, ankle-brachial index and circumferential wall stress via multiple linear regression. RESULTS: Higher SDCGM was associated with higher cf-PWV after adjusting for demographics, cardiovascular risk factors and lifestyle factors (regression coefficient [B] per 1 mmol/l SDCGM [and corresponding 95% CI]: 0.413 m/s [0.147, 0.679], p = 0.002). In the model additionally adjusted for CGM-assessed mean sensor glucose (MSGCGM), SDCGM and MSGCGM contributed similarly to cf-PWV (respective standardised regression coefficients [st.ßs] and 95% CIs of 0.065 [-0.018, 0.167], p = 0.160; and 0.059 [-0.043, 0.164], p = 0.272). In the fully adjusted models, both higher CVCGM (B [95% CI] per 10% CVCGM: 0.303 m/s [0.046, 0.559], p = 0.021) and lower TIRCGM (B [95% CI] per 10% TIRCGM: -0.145 m/s [-0.252, -0.038] p = 0.008) were statistically significantly associated with higher cf-PWV. Such consistent associations were not observed for the other arterial measures. CONCLUSIONS: Our findings show that greater daily glucose variability and lower TIRCGM are associated with greater aortic stiffness (cf-PWV) but not with other arterial measures. If corroborated in prospective studies, these results support the development of therapeutic agents that target both daily glucose variability and TIRCGM to prevent CVD.

Relationship between de novo lipogenesis and serum sex hormone binding globulin in humans.

OBJECTIVE: Obesity and liver fat are associated with decreased levels of serum sex hormone binding globulin (SHBG). Laboratory studies suggest that hepatic de novo lipogenesis (DNL) is involved in the downregulation of SHBG synthesis. The aim of the present study was to address the role of DNL on serum SHBG in humans. DESIGN: A cross-sectional study examining the association between DNL, measured by stable isotopes, and serum SHBG, stratified by sex. PARTICIPANTS: Healthy men (n = 34) and women (n = 21) were combined from two cross-sectional studies. Forty-two per cent of participants had hepatic steatosis, and the majority were overweight (62%) or obese (27%). RESULTS: DNL was inversely associated with SHBG in women (ß: -0.015, 95% CI: -0.030; 0.000), but not in men (ß: 0.007, 95% CI: -0.005; 0.019) (p for interaction = .068). Adjustment for study population, age and body mass index did not materially change these results, although statistical significance was lost after adjustment for serum insulin. CONCLUSIONS: An inverse association between DNL and SHBG may explain the decreased SHBG levels that are observed in obesity, at least in women.

Metformin and carotid intima-media thickness in never-smokers with type 1 diabetes: The REMOVAL trial.

AIM: To determine whether metformin's effects on carotid artery intima-media thickness (cIMT) in type 1 diabetes differ according to smoking status. METHODS: Regression model effect estimates for the effect of metformin versus placebo (double-blind) on carotid IMT were calculated as a subgroup analysis of the REMOVAL trial. RESULTS: In 428 randomized participants (227 never-smokers, 201 ever-smokers), averaged mean carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.012 mm, 95% CI -0.021 to -0.002; p = .0137) but not in ever-smokers (0.003 mm, 95% CI -0.008 to 0.014; p = .5767); and similarly in non-current smokers (-0.008 mm, 95% CI -0.015 to -0.00001; p = .0497) but not in current smokers (0.013 mm, 95% CI -0.007 to 0.032; p = .1887). Three-way interaction terms (treatment*time*smoking status) were significant for never versus ever smoking (p = .0373, prespecified) and non-current versus current smoking (p = .0496, exploratory). Averaged maximal carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.020 mm, 95% CI -0.034 to -0.006; p = .0067) but not in ever-smokers (-0.006 mm, 95% CI -0.020 to 0.008; p = .4067), although this analysis was not supported by a significant three-way interaction term. CONCLUSIONS: This subgroup analysis of the REMOVAL trial provides additional support for a potentially wider role of adjunct metformin therapy in cardiovascular risk management in type 1 diabetes, particularly for individuals who have never smoked cigarettes.

Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease.

Hereditary fructose intolerance (HFI) is a rare inborn disease characterized by a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules. In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP, which are believed to cause symptoms, such as nausea, vomiting, hypoglycemia, and liver and kidney failure. These sequelae can be prevented by a fructose-restricted diet. Recent studies in aldolase B-deficient mice and HFI patients have provided more insight into the pathogenesis of HFI, in particular the liver phenotype. Both aldolase B-deficient mice (fed a very low fructose diet) and HFI patients (treated with a fructose-restricted diet) displayed greater intrahepatic fat content when compared to controls. The liver phenotype in aldolase B-deficient mice was prevented by reduction in intrahepatic Fru 1P concentrations by crossing these mice with mice deficient for ketohexokinase, the enzyme that catalyzes the synthesis of Fru 1P. These new findings not only provide a potential novel treatment for HFI, but lend insight into the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD), which has raised to epidemic proportions in Western society. This narrative review summarizes the most recent advances in the pathogenesis of HFI and discusses the implications for the understanding and treatment of fructose-induced NAFLD.

Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality.

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent among individuals with type 2 diabetes. Although epidemiological studies have shown that NAFLD is associated with cardiovascular disease (CVD), it remains unknown whether NAFLD is an active contributor or an innocent bystander. Plasma lipids, low-grade inflammation, impaired fibrinolysis and hepatokines are potential mediators of the relationship between NAFLD and CVD. The Mendelian randomisation approach can help to make causal inferences. Studies that used common variants in PNPLA3, TM6SF2 and GCKR as instruments to investigate the relationship between NAFLD and coronary artery disease (CAD) have reported contrasting results. Variants in PNPLA3 and TM6SF2 were found to protect against CAD, whereas variants in GCKR were positively associated with CAD. Since all three genes have been associated with non-alcoholic steatohepatitis, the second stage of NAFLD, the question of whether low-grade inflammation is an important mediator of the relationship between NAFLD and CAD arises. In contrast, the differential effects of these genes on plasma lipids (i.e. lipid-lowering for PNPLA3 and TM6SF2, and lipid-raising for GCKR) strongly suggest that plasma lipids account for their differential effects on CAD risk. This concept has recently been confirmed in an extended set of 12 NAFLD susceptibility genes. From these studies it appears that plasma lipids are an important mediator between NAFLD and CVD risk. These findings have important clinical implications, particularly for the design of anti-NAFLD drugs that also affect lipid metabolism.

The endothelial function biomarker soluble E-selectin is associated with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Plasma soluble E-selectin (sE-selectin) is a frequently used biomarker of systemic endothelial dysfunction. The present study explored the relationship between nonalcoholic fatty liver disease (NAFLD) and plasma sE-selectin levels. METHODS: Expression of E-selectin in liver, visceral adipose tissue (VAT) and muscle was studied in relation to plasma sE-selectin in severely obese individuals (n = 74). The course of hepatic E-selectin expression in relation to hepatic steatosis and inflammation was examined in C57BL/6J LDLR-/- mice on a Western-type diet. The relationship between biomarkers of NAFLD, that is, plasma aminotransferase (ALT) and NAFLD susceptibility genes (rs738409 [PNPLA3] and rs1260326 [GCKR]), and plasma sE-selectin was studied in the combined CODAM (n = 571) and Hoorn (n = 694) studies. RESULTS: E-selectin expression in liver, not VAT or muscle, was associated with plasma sE-selectin in severely obese individuals (ß = 0.26; 95% CI: 0.05-0.47). NAFLD severity was associated with hepatic E-selectin expression (P = .02) and plasma sE-selectin (P = .003). LDLR-/- mice on a Western-type diet displayed increased hepatic E-selectin expression that followed the same course as hepatic inflammation, but not steatosis. In the CODAM study, plasma ALT was associated with plasma sE-selectin, independent of potential confounders (ß = 0.25; 95% CI: 0.16-0.34). Both rs738409 and rs1260326 were associated with higher plasma sE-selectin in the combined CODAM and Hoorn studies (P = .01 and P = .004 respectively). CONCLUSIONS: NAFLD and related markers are associated with higher expression of hepatic E-selectin and higher levels of plasma sE-selectin. Further studies are required to investigate the role of E-selectin in the pathogenesis of NAFLD and the applicability of sE-selectin as a plasma biomarker of NAFLD/NASH.

Retrospective evaluation of the Dutch pre-newborn screening cohort for propionic acidemia and isolated methylmalonic acidemia: What to aim, expect, and evaluate from newborn screening?

Evidence for effectiveness of newborn screening (NBS) for propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) is scarce. Prior to implementation in the Netherlands, we aim to estimate the expected health gain of NBS for PA and MMA. In this national retrospective cohort study, the clinical course of 76/83 Dutch PA and MMA patients, diagnosed between January 1979 and July 2019, was evaluated. Five clinical outcome parameters were defined: adverse outcome of the first symptomatic phase, frequency of acute metabolic decompensations (AMD), cognitive function, mitochondrial complications, and treatment-related complications. Outcomes of patients identified by family testing were compared with the outcomes of their index siblings. An adverse outcome due to the first symptomatic phase was recorded in 46% of the clinically diagnosed patients. Outcome of the first symptomatic phase was similar in 5/9 sibling pairs and better in 4/9 pairs. Based on the day of diagnosis of the clinically diagnosed patients and sibling pair analysis, a preliminary estimated reduction of adverse outcome due to the first symptomatic phase from 46% to 36%-38% was calculated. Among the sibling pairs, AMD frequency, cognitive function, mitochondrial, and treatment-related complications were comparable. These results suggest that the health gain of NBS for PA and MMA in overall outcome may be limited, as only a modest decrease of adverse outcomes due to the first symptomatic phase is expected. With current clinical practice, no reduced AMD frequency, improved cognitive function, or reduced frequency of mitochondrial or treatment-related complications can be expected.

The oral glucose tolerance test-derived incremental glucose peak is associated with greater arterial stiffness and maladaptive arterial remodeling: The Maastricht Study.

BACKGROUND: Daily glucose variability may contribute to vascular complication development irrespective of mean glucose values. The incremental glucose peak (IGP) during an oral glucose tolerance test (OGTT) can be used as a proxy of glucose variability. We investigated the association of IGP with arterial stiffness, arterial remodeling, and microvascular function, independent of HbA1c and other confounders. METHODS: IGP was calculated as the peak minus baseline plasma glucose value during a seven-point OGTT in 2758 participants (age: 60 ± 8 years; 48% women) of The Maastricht Study, an observational population-based cohort. We assessed the cross-sectional associations between IGP and arterial stiffness (carotid-femoral pulse wave velocity [cf-PWV], carotid distensibility coefficient [carDC]), arterial remodeling (carotid intima-media thickness [cIMT]; mean [CWSmean] and pulsatile [CWSpuls] circumferential wall stress), and microvascular function (retinal arteriolar average dilatation; heat-induced skin hyperemia) via multiple linear regression with adjustment for age, sex, HbA1c, cardiovascular risk factors, lifestyle factors, and medication use. RESULTS: Higher IGP was independently associated with higher cf-PWV (regression coefficient [B]: 0.054 m/s [0.020; 0.089]) and with higher CWSmean (B: 0.227 kPa [0.008; 0.446]). IGP was not independently associated with carDC (B: - 0.026 10-3/kPa [- 0.112; 0.060]), cIMT (B: - 2.745 µm [- 5.736; 0.245]), CWSpuls (B: 0.108 kPa [- 0.054; 0.270]), retinal arteriolar average dilatation (B: - 0.022% [- 0.087; 0.043]), or heat-induced skin hyperemia (B: - 1.380% [- 22.273; 19.513]). CONCLUSIONS: IGP was independently associated with aortic stiffness and maladaptive carotid remodeling, but not with carotid stiffness, cIMT, and microvascular function measures. Future studies should investigate whether glucose variability is associated with cardiovascular disease.

Movement disorders and nonmotor neuropsychological symptoms in children and adults with classical galactosemia.

Although movement disorders (MDs) are known complications, the exact frequency and severity remains uncertain in patients with classical galactosemia, especially in children. We determined the frequency, classification and severity of MDs in a cohort of pediatric and adult galactosemia patients, and assessed the association with nonmotor neuropsychological symptoms and daily functioning. Patients from seven centers in the United Kingdom and the Netherlands with a confirmed galactosemia diagnosis were invited to participate. A videotaped neurological examination was performed and an expert panel scored the presence, classification and severity of MDs. Disease characteristics, nonmotor neuropsychological symptoms, and daily functioning were evaluated with structured interviews and validated questionnaires (Achenbach, Vineland, Health Assessment Questionnaire, SIP68). We recruited 37 patients; 19 adults (mean age 32.6 years) and 18 children (mean age 10.7 years). Subjective self-reports revealed motor symptoms in 19/37 (51.4%), similar to the objective (video) assessment, with MDs in 18/37 patients (48.6%). The objective severity scores were moderate to severe in one third (6/37). Dystonia was the overall major feature, with additional tremor in adults, and myoclonus in children. Behavioral or psychiatric problems were present in 47.2%, mostly internalizing problems, and associated with MDs. Daily functioning was significantly impaired in the majority of patients. Only one patient received symptomatic treatment for MDs. We show that MDs and nonmotor neuropsychological symptoms are frequent in both children and adults with classical galactosemia.