GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on ‘around the clock’ glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification

Presence of Fatty Liver and the Relationship between Alcohol Consumption and Markers of Inflammation

Background and Aims. Local and systemic inflammation represent a major feature of atherosclerotic cardiovascular disease (CVD) and are also linked to nonalcoholic fatty liver disease (NAFLD). Studies indicate that NAFLD might be a risk factor for CVD whereas low-to-moderate alcohol consumption is associated with lower cardiovascular morbidity and mortality compared to abstainers and heavy drinkers. We hypothesize that FLD interacts with the effect of alcohol intake on markers of inflammation, and thus potentially on cardiovascular risk. Methods and Results. We evaluated alcohol consumption, markers of inflammation and sonographic criteria of FLD in 515 subjects, representing a subsample of a cross-sectional population based study (Echinococcus multilocularis and Internal Diseases in Leutkirch (EMIL) Study). Presence of FLD was markedly reduced in subjects drinking 0–20 g alcohol/d (19%), compared to nondrinkers (35%) and heavy drinkers (34–44.9%). Serum concentrations of inflammatory markers were substantially higher in subjects with FLD. However, presence of FLD showed no effect on the association between alcohol consumption and inflammatory biomarkers. Conclusions. Based on data from a population-based sample, there is no evidence for a link between FLD, alcohol consumption, and inflammatory cardiovascular risk markers. However, larger prospective studies are needed to confirm this

Subclinical and clinical hypothyroidism and non-alcoholic fatty liver disease: a cross-sectional study of a random population sample aged 18 to 65 years

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common disorders of the liver worldwide. Recently, a correlation between thyroid dysfunction and NAFLD has been discussed. Objective of the present study was to investigate the association between thyroid dysfunction and hepatic steatosis. Methods: Data from 2,445 subjects (51.7 % females) aged 18 to 65 years participating in a population-based cross-sectional study were assessed based on a standardized questionnaire and documentation of physical, biochemical and ultrasonographic findings. After application of exclusion criteria, a total of 1,276 subjects were included in the study collective. The influence of potential factors on the development of hepatic steatosis was assessed using multivariate logistic regression. Results: The prevalence of hepatic steatosis in the study collective was 27.4 % (n = 349). The serum thyroxin (TT4) concentration in subjects with hepatic steatosis was reduced (p = 0.0004). Adjusting for age, or BMI, there was an increased prevalence of hepatic steatosis in subjects with reduced TT4 concentrations (p = 0.0143; p = <.0001). Conclusions: The findings of the present study confirm an association between both subclinical and clinical hypothyroidism and hepatic steatosis.Published versio

Contrast-Enhanced Ultrasound Algorithms (CEUS-LIRADS/ESCULAP) for the Noninvasive Diagnosis of Hepatocellular Carcinoma – A Prospective Multicenter DEGUM Study

Background This prospective multicenter study funded by the DEGUM assesses the diagnostic accuracy of standardized contrast-enhanced ultrasound (CEUS) for the noninvasive diagnosis of hepatocellular carcinoma (HCC) in high-risk patients. Methods Patients at high risk for HCC with a histologically proven focal liver lesion on B-mode ultrasound were recruited prospectively in a multicenter approach. Clinical and imaging data were entered via online entry forms. The diagnostic accuracies for the noninvasive diagnosis of HCC were compared for the conventional interpretation of standardized CEUS at the time of the examination (=CEUS on-site) and the two CEUS algorithms ESCULAP (Erlanger Synopsis for Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at risk) and CEUS LI-RADS (Contrast-Enhanced UltraSound Liver Imaging Reporting and Data System). Results 321 patients were recruited in 43 centers; 299 (93.1%) had liver cirrhosis. The diagnosis according to histology was HCC in 256 cases, and intrahepatic cholangiocarcinoma (iCCA) in 23 cases. In the subgroup of cirrhotic patients (n=299), the highest sensitivity for the diagnosis of HCC was achieved with the CEUS algorithm ESCULAP (94.2%) and CEUS on-site (90.9%). The lowest sensitivity was reached with the CEUS LI-RADS algorithm (64%; p<0.001). However, the specificity of CEUS LI-RADS (78.9%) was superior to that of ESCULAP (50.9%) and CEUS on-site (64.9%; p<0.001). At the same time, the negative predictive value (NPV) of CEUS LI-RADS was significantly inferior to that of ESCULAP (34.1% vs. 67.4%; p<0.001) and CEUS on-site (62.7%; p<0.001). The positive predictive values of all modalities were high (around 90%), with the best results seen for CEUS LI-RADS and CEUS on-site. Conclusion This is the first multicenter, prospective comparison of standardized CEUS and the recently developed CEUS-based algorithms in histologically proven liver lesions in cirrhotic patients. Our results reaffirm the excellent diagnostic accuracy of CEUS for the noninvasive diagnosis of HCC in high-risk patients. However, on-site diagnosis by an experienced examiner achieves an almost equal diagnostic accuracy compared to CEUS-based diagnostic algorithms. Zusammenfassung Hintergrund Diese prospektive, multizentrische, DEGUM-geforderte Studie untersucht die diagnostische Genauigkeit standardisierter Algorithmen fur die Kontrastmittelsonografie (CEUS-Algorithmen) in der nichtinvasiven Diagnostik des hepatozellularen Karzinoms (HCC) bei Hochrisikopatienten. Methoden HCC-Hochrisikopatienten mit histologisch gesicherter Leberlasion im B-Bild-Ultraschall wurden prospektiv multizentrisch eingeschlossen. Klinische Daten und Bildgebungsbefunde wurden uber Online-Eingabemasken erfasst. Es erfolgte ein direkter Vergleich der diagnostischen Genauigkeiten fur die konventionelle CEUS-Befundung zum Untersuchungszeitpunkt (CEUS-on-site) und die CEUS-Algorithmen ESCULAP (Erlanger Synopsis for Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at risk) und CEUS LI-RADS (Contrast-Enhanced UltraSound Liver Imaging Reporting and Data System). Ergebnisse 321 Patienten an 43 Zentren wurden eingeschlossen (93,1% Leberzirrhose). Der histologische Befund ergab 256 HCCs und 23 intrahepatische cholangiozellulare Karzinome (iCCA). Die hochste Sensitivitat bei Zirrhose-Patienten (n=299) erzielten der CEUS-Algorithmus ESCULAP (94,2%) und CEUS-on-site (90,9%), die geringste Sensitivitat der CEUS LI-RADS-Algorithmus (64%; p<0,001). Die Spezifitat war hoher fur CEUS LI-RADS (78,9%) versus ESCULAP (50,9%) und CEUS on-site (64,9%; p<0,001). Der negativ pradiktive Wert (NPW) war fur CEUS LI-RADS niedriger als fur ESCULAP (34,1% vs. 67,4%; p<0,001) und CEUS-on-site (62,7%; p<0,001). Der positiv pradiktive Wert (PPW) war fur alle Modalitaten hoch (rund 90%). Schlussfolgerungen Dies ist die erste prospektive, multizentrische Studie zum Vergleich der standardisierten Kontrastmittelsonografie mit den kurzlich entwickelten CEUS-Algorithmen in histologisch gesicherten Leberlasionen bei Zirrhose-Patienten. Unsere Ergebnisse bestatigen die exzellente diagnostische Genauigkeit der Kontrastmittelsonografie in der nichtinvasiven HCC-Diagnostik bei Hochrisikopatienten. Die On-site-Diagnose eines erfahrenen Untersuchers erzielt dabei eine beinahe ebenso gute diagnostische Genauigkeit wie die CEUS-basierten Diagnosealgorithme