Vitamin D-Supplementation bei Patienten mit nicht alkoholischer Fettlebererkrankung und Vitamin D-Mangel

1.1 Einleitung Die nicht-alkoholische Fettlebererkrankung ist als Steatosis hepatis (Fetteinlagerung in den Hepatozyten) ohne signifikanten Alkoholkonsum definiert. Sie ist die hepatische Komponente des metabolischen Syndroms und in den westlichen Ländern die häufigste Ursache chronischer Lebererkrankungen. Eine neue nicht-invasive Methode zur Quantifizierung der Steatosis hepatis durch die Anwendung von transienter Elastographie ist die Controlled attenuation parameter-Messung. Diese ist eine einfache und vielversprechende Methode, die schon ab Grad I (Fetteinlagerung bei 11 - 33% der Hepatozyten) eine hohe Sensitivität zur Aufdeckung der Steatose aufweist. Die Prävalenz eines Vitamin D-Mangels (Serum-25-Hydroxyvitamin D-Konzentration < 20 ng/ml) beträgt bei Erwachsenen 5% bis 30% und bei Patienten mit chronischen Lebererkrankungen bis zu 90%. Zahlreiche Studien weisen auf einen Zusammenhang zwischen nicht-alkoholischer Fettlebererkrankung und Vitamin D-Mangel hin. Durch Metaanalysen konnte bei Patienten mit nicht-alkoholischer Fettlebererkrankung niedrige Vitamin D-Konzentrationen im Serum belegt werden. Die Hypothese dieser Studie war es, dass eine Vitamin D-Supplementation bei Patienten mit Vitamin D-Mangel und Steatose zu einer quantitativen und durch den Controlled attenuation parameter messbaren Verbesserung der Steatose führt. 1.2 Patienten und Methoden In diese prospektive, nicht verblindete Studie wurden 40 Patienten eingeschlossen. Die Haupteinschlusskriterien waren eine 25-Hydroxyvitamin D-Konzentration im Serum 280 dB/m). Patienten mit relevantem Alkoholkonsum und Patienten mit Leberzirrhose wurden ausgeschlossen. Bei den Patienten wurde für sieben Tage eine Therapie mit täglich 20.000 IE Colecalciferol und danach für 6 Monate wöchentlich 20.000 IE durchgeführt. Verlaufskontrollen erfolgten nach vier Wochen, drei Monaten und sechs Monaten. Primärer Endpunkt war es, Veränderungen der Leberfettkonzentration festzustellen; sekundärer Endpunkt war eine Veränderung bei den Leberwerten. 1.3 Ergebnisse Es wurden 40 Patienten untersucht, davon waren 19 (48 %) Frauen und 21 (53%) Männer. Der mittlere Alter lag bei 54,9 ± 12,1 Jahren und der mittlere Body Mass Index bei 29,5 ± 3,0 kg/m². Alle Patienten der Studie waren übergewichtig, 45% davon waren sogar adipös (Body Mass Index > 30 kg/m²). Die mittlere Vitamin D-Konzentration war niedrig und lag bei 11,8 ± 4,8 ng/ml. Es konnte unter Vitamin D-Supplementation und im Vergleich zur Baseline eine signifikante (P = 0,007) Verbesserung des Controlled attenuation parameter-Wertes beobachtet werden (307 ± 41 vs. 330 ± 32 dB/m). Die mittlere Controlled attenuation parameter-Reduktionen hatten nach 4 Wochen, 3 Monaten und 6 Monaten um 5,3 ± 13,8%, 6.0 ± 14.6% bzw. 6,4 ± 13,0% abgenommen. Während der Vitamin D-Supplementation konnte bei den Verlaufskontrollen jeweils eine signifikante (P < 0,0001) Verbesserung der Vitamin D-Konzentration beobachtet werden (34,6 ± 12,9; 36,3 ± 10,2; 34,8 ± 9,8 ng/ml). Bei den Leberwerten und der Körperzusammensetzung ließen sich keine signifikante Veränderungen feststellen. 1.4 Schlussfolgerungen Bei Patienten mit Steatosis hepatis und Vitamin D-Mangel führt die Vitamin D-Supplementation zu einer signifikanten Verbesserung der mittels controlled attenuation parameter quantifizierten Steatosis hepatis, und diese Veränderung tritt bereits nach nur vierwöchiger Intervention auf. Die Steatosis hepatis ist ein dynamischer Prozess, der durch kurzfristige therapeutische Interventionen moduliert werden kann. Durch große randomisierte und kontrollierte Studien sollte dieser Zusammenhang in der Zukunft erhärtet werden.2.1 Introduction In Western countries, non-alcoholic fatty liver disease is emerging as the leading cause of chronic liver disease. Patients with non-alcoholic fatty liver disease often display decreased serum 25-hydroxyvitamin D concentrations, as confirmed in meta-analysis. The aim of this intervention study is to assess the effects of vitamin D on hepatic steatosis. 2.2 Patients and Methods Overall, 40 patients with vitamin D deficiency (serum 25-hydroxyvitamin D < 20 ng/ml) were prospectively recruited from the outpatient liver clinic. Hepatic steatosis was measured using Controlled attenuation parameter during transient elastography. Patients with Controlled attenuation parameter values ≥ 280 dB/m (indicating significant liver fat accumulation) were included. Patients received 20,000 IU vitamin D/week for six months, and during this time vitamin D status, liver function tests, Controlled attenuation parameter and body composition were monitored. 2.3 Results The cohort comprised of 19 women and 21 men (age 54.9 ± 12.1 years; body mass index 29.5 ± 3.0 kg/m2). Mean serum vitamin D concentration was 11.8 ± 4.8 ng/ml. A significant (P = 0.007) decrease in Controlled attenuation parameter from baseline was observed during supplementation (307 ± 41 vs. 330 ± 32 dB/m). Relative to baseline, mean Controlled attenuation parameter reductions for the follow up time periods of four weeks and three and six months were: -5.3 ± 13.8%; -6.0 ± 14.6% and -6.4 ± 13.0%, respectively. During these time points, mean serum vitamin D concentrations returned to normal levels (34.6 ± 12.9, 36.3 ± 10.2, 34.8 ± 9.8 ng/ml; P < 0.0001). Liver function tests and body composition did not change. 2.4 Conclusions Significant improvements in hepatic steatosis, as assessed by CAP, were observed after only 4 weeks of vitamin D supplementation. Hepatic steatosis appears to be a dynamic process, and the use of non-invasive methods can adequately be used to monitor this condition

Hepatic steatosis in patients with acromegaly

Objective Comorbid NAFLD is increasingly being diagnosed in patients with diabetes and nondiabetic endocrinopathies. The aim of this study was to assess hepatic steatosis noninvasively by transient elastography in patients with acromegaly. Design A cross‐sectional study including 22 patients with acromegaly. Methods Hepatic steatosis was quantified using controlled attenuation parameter (CAP) during elastography. Anthropometric measurements were obtained, serum liver function tests and lipid and hormone profiles were measured, and prosteatogenic gene variants were genotyped using standard assays. Results In total, 41% of patients were women (mean age 60 ± 14.7 years, mean BMI 31.2 ± 4.6 kg/m2). Hepatic steatosis, as defined by CAP > 248 dB/m, was present in 66% of patients. Five (45%) of the patients with hepatic steatosis also had fibrosis, and one presented with cirrhosis. Nine patients were carriers of the PNPLA3 p.I148M prosteatogenic [M] risk allele, eight of whom were heterozygotes. CAP values were significantly (P = .045) higher in these patients and corresponded to advanced steatosis, as compared to patients with the wild‐type genotype, who demonstrated CAP values consistent with mild steatosis (311 ± 33 dB/m. vs 254 ± 62 dB/m). CAP values did not differ significantly in carriers of distinct TM6SF2 and MBOAT7 genotypes; however, carriers of the risk alleles displayed higher CAP as compared to wild‐type patients. Conclusions This study shows that in patients with acromegaly, carriers of the PNPLA3 susceptibility allele are at risk of developing hepatic steatosis, as assessed by CAP. Comorbid NAFLD might compound prognosis in such patients; thus, further research into the pathomechanisms and treatment of NAFLD in acromegaly is warranted

Liver phenotypes in PCOS: Analysis of exogenous and inherited risk factors for liver injury in two European cohorts

Background & Aims Fatty liver disease (FLD) is common in women with polycystic ovary syndrome (PCOS). Here, we use non-invasive tests to quantify liver injury in women with PCOS and analyse whether FLD-associated genetic variants contribute to liver phenotypes in PCOS. Methods Prospectively, we recruited women with PCOS and controls at two university centres in Germany and Poland. Alcohol abuse was regarded as an exclusion criterion. Genotyping of variants associated with FLD was performed using TaqMan assays. Liver stiffness measurements (LSM), controlled attenuation parameters (CAP) and non-invasive HSI, FLI, FIB-4 scores were determined to assess hepatic steatosis and fibrosis. Results A total of 42 German (age range 18–53 years) and 143 Polish (age range 18–40 years) women with PCOS, as well as 245 German and 289 Polish controls were recruited. In contrast to Polish patients, Germans were older, presented with more severe metabolic profiles and had significantly higher LSM (median 5.9 kPa vs. 3.8 kPa). In the German cohort, carriers of the PNPLA3 p.I148M risk variant had an increased LSM (p = .01). In the Polish cohort, the minor MTARC1 allele was linked with significantly lower serum aminotransferases activities, whereas the HSD17B13 polymorphism was associated with lower concentrations of 17-OH progesterone, total testosterone, and androstenedione (all p < .05). Conclusions FLD is common in women with PCOS. Its extent is modulated by both genetic and metabolic risk factors. Genotyping of variants associated with FLD might help to stratify the risk of liver disease progression in women suffering from PCOS.Peer Reviewe

Liver phenotypes in PCOS : Analysis of exogenous and inherited risk factors for liver injury in two European cohorts

Background & Aims Fatty liver disease (FLD) is common in women with polycystic ovary syndrome (PCOS). Here, we use non-invasive tests to quantify liver injury in women with PCOS and analyse whether FLD-associated genetic variants contribute to liver phenotypes in PCOS. Methods Prospectively, we recruited women with PCOS and controls at two university centres in Germany and Poland. Alcohol abuse was regarded as an exclusion criterion. Genotyping of variants associated with FLD was performed using TaqMan assays. Liver stiffness measurements (LSM), controlled attenuation parameters (CAP) and non-invasive HSI, FLI, FIB-4 scores were determined to assess hepatic steatosis and fibrosis. Results A total of 42 German (age range 18–53 years) and 143 Polish (age range 18–40 years) women with PCOS, as well as 245 German and 289 Polish controls were recruited. In contrast to Polish patients, Germans were older, presented with more severe metabolic profiles and had significantly higher LSM (median 5.9 kPa vs. 3.8 kPa). In the German cohort, carriers of the PNPLA3 p.I148M risk variant had an increased LSM (p = .01). In the Polish cohort, the minor MTARC1 allele was linked with significantly lower serum aminotransferases activities, whereas the HSD17B13 polymorphism was associated with lower concentrations of 17-OH progesterone, total testosterone, and androstenedione (all p < .05). Conclusions FLD is common in women with PCOS. Its extent is modulated by both genetic and metabolic risk factors. Genotyping of variants associated with FLD might help to stratify the risk of liver disease progression in women suffering from PCOS

Hepatic steatosis in patients with acromegaly

Objective Comorbid NAFLD is increasingly being diagnosed in patients with diabetes and nondiabetic endocrinopathies. The aim of this study was to assess hepatic steatosis noninvasively by transient elastography in patients with acromegaly. Design A cross‐sectional study including 22 patients with acromegaly. Methods Hepatic steatosis was quantified using controlled attenuation parameter (CAP) during elastography. Anthropometric measurements were obtained, serum liver function tests and lipid and hormone profiles were measured, and prosteatogenic gene variants were genotyped using standard assays. Results In total, 41% of patients were women (mean age 60 ± 14.7 years, mean BMI 31.2 ± 4.6 kg/m2). Hepatic steatosis, as defined by CAP > 248 dB/m, was present in 66% of patients. Five (45%) of the patients with hepatic steatosis also had fibrosis, and one presented with cirrhosis. Nine patients were carriers of the PNPLA3 p.I148M prosteatogenic [M] risk allele, eight of whom were heterozygotes. CAP values were significantly (P = .045) higher in these patients and corresponded to advanced steatosis, as compared to patients with the wild‐type genotype, who demonstrated CAP values consistent with mild steatosis (311 ± 33 dB/m. vs 254 ± 62 dB/m). CAP values did not differ significantly in carriers of distinct TM6SF2 and MBOAT7 genotypes; however, carriers of the risk alleles displayed higher CAP as compared to wild‐type patients. Conclusions This study shows that in patients with acromegaly, carriers of the PNPLA3 susceptibility allele are at risk of developing hepatic steatosis, as assessed by CAP. Comorbid NAFLD might compound prognosis in such patients; thus, further research into the pathomechanisms and treatment of NAFLD in acromegaly is warranted