Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease spanning from simple benign steatosis to steatohepatitis with fibrosis and scarring that can eventually lead to cirrhosis. Its prevalence is rising rapidly and is developing into the leading indication for liver transplantation worldwide. Abnormalities in endocrine axes have been associated with NALFD, including hypogonadism, hypothyroidism, GH deficiency and hypercortisolaemia. In some instances, correction of the endocrine defects has been shown to have a beneficial impact. While in patients with type 2 diabetes the association with NAFLD is well established and recognised, there is a more limited appreciation of the condition among common endocrine diseases presenting with hormonal excess or deficiency. In this review, we examine the published data that have suggested a mechanistic link between endocrine abnormalities and NAFLD and summarise the clinical data endorsing these observations.
Jonathan M Hazlehurst and Jeremy W Tomlinson
Rachel K Crowley, Beverly Hughes, Joanna Gray, Theresa McCarthy, Susan Hughes, Cedric H L Shackleton, Nicola Crabtree, Peter Nightingale, Paul M Stewart, and Jeremy W Tomlinson
Dysregulation of enzymes that control local tissue steroid metabolism has been implicated in the pathogenesis of obesity and insulin resistance; however, longitudinal changes in glucocorticoid metabolism have not been investigated. This study was performed to evaluate the role of glucocorticoid metabolism in the development of insulin resistance and obesity and to identify biomarkers for future development of metabolic disease.
This was a prospective longitudinal observation study conducted over 5 years.
A 24-h collection was used to serially analyze urinary glucocorticoid and mineralocorticoid metabolites in 57 obese and overweight patients with no prior diagnosis of diabetes mellitus, recruited from the community.
Baseline higher 5α-reductase (5αR) activity, but not 11β-hydroxysteroid dehydrogenase type 1 activity, was predictive of increased fasting insulin at final visit (11.4 compared with 7.4 mU/l in subjects with lower 5αR activity, P<0.05), area under the curve insulin response to oral glucose tolerance test (176.7 compared with 89.1 mU/l.h, P<0.01), and homeostasis model assessment (HOMA2-IR; 1.3 compared with 0.8, P<0.01). Higher total glucocorticoid production was associated with abnormal glucose tolerance and increased BMI. During this study, systolic blood pressure increased (equivalent to ∼1 mmHg/year), as did plasma sodium levels; this evidence of increased mineralocorticoid activity was associated with increased aldosterone metabolites and decreased 11β-hydroxysteroid dehydrogenase type 2 activity.
Increased 5αR activity and glucocorticoid secretion rate over time are linked with the development of metabolic disease, and may represent targets for therapeutic intervention, which merits further study.
Susanna Wiegand, Anna Richardt, Thomas Remer, Stefan A Wudy, Jeremy W Tomlinson, Beverly Hughes, Annette Grüters, Paul M Stewart, Christian J Strasburger, and Marcus Quinkler
Objective: The incidence of childhood obesity and type 2 diabetes has reached epidemic proportions. Glucocorticoid excess causes central obesity and diabetes mellitus as seen in Cushing’s syndrome. The 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1) regenerates active cortisol from inactive cortisone. Altered 11β-HSD1 may cause tissue-specific Cushing’s syndrome with central obesity and impaired glucose homeostasis.
Design, patients, and methods: Clinical and laboratory characteristics, and anthropometric measurements were determined in 15 male and 6 female obese pubertal children (aged 12–18 years, Tanner stages 2–5). In addition, analyses of 24-h excretion rates of glucocorticoids were also performed in 21 age-, sex-, and pubertal stage-matched non-obese children using gas chromatographic–mass spectrometric (GC–MS) analysis.
Results: 11β-HSD1 activity (urinary tetrahydrocortisol (THF) + 5α-THF/tetrahydrocortisone (THE) ratio) was lower in obese when compared with non-obese boys. In addition, obese children had a higher total cortisol metabolite excretion than non-obese children. 11β-HSD1 activity was significantly related to age in lean and obese children. Standard deviation score (SDS)-body mass index did not correlate with 11β-HSD1 activity, or with total cortisol metabolite excretion within each group. In obese children, 11β-HSD1 activity and total cortisol metabolite excretion showed no correlation to waist-to-hip ratio, fat mass (percentage of body mass), or the homeostasis model assessment of insulin resistance index.
Conclusions: In conclusion, our findings strongly suggest that 11β-HSD1 activity increases with age, and is reduced in obese boys. In addition, obese children have a higher total cortisol metabolites excretion suggesting a stimulated hypothalamus–pituitary–adrenal axis.
Conor P Woods, Nicola Argese, Matthew Chapman, Christopher Boot, Rachel Webster, Vijay Dabhi, Ashley B Grossman, Andrew A Toogood, Wiebke Arlt, Paul M Stewart, Rachel K Crowley, and Jeremy W Tomlinson
Up to 3% of US and UK populations are prescribed glucocorticoids (GC). Suppression of the hypothalamo–pituitary–adrenal axis with the potential risk of adrenal crisis is a recognized complication of therapy. The 250 μg short Synacthen stimulation test (SST) is the most commonly used dynamic assessment to diagnose adrenal insufficiency. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost.
We performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting.
In total, 2773 patients underwent 3603 SSTs in a large secondary/tertiary centre between 2008 and 2013 and 17.9% (n=496) failed the SST. Of 404 patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, 33.2% (n=134) had a subnormal SST response. In patients taking inhaled GCs without additional GC therapy, 20.5% (34/166) failed an SST and suppression of adrenal function increased in a dose-dependent fashion. Using receiver operating characteristic curve analysis in patients currently taking inhaled GCs, a basal cortisol ≥348 nmol/l provided 100% specificity for passing the SST; a cortisol value <34 nmol/l had 100% sensitivity for SST failure. Using these cut-offs, 50% (n=83) of SSTs performed on patients prescribed inhaled GCs were unnecessary.
Adrenal suppression due to GC treatment, particularly inhaled GCs, is common. A basal serum cortisol concentration has utility in helping determine which patients should undergo dynamic assessment of adrenal function.
Irina Bacila, Nicole Freeman, Eleni Daniel, Marija Sandrk, Jillian Bryce, Salma Rashid Ali, Zehra Yavas Abalı, Navoda Atapattu, Tania A Bachega, Antonio Balsamo, Niels Birkebæk, Oliver Blankenstein, Walter Bonfig, Martine Cools, Eduardo Correa Costa, Feyza Darendeliler, Silvia Einaudi, Heba Hassan Elsedfy, Martijn Finken, Evelien Gevers, Hedi L Claahsen-van der Grinten, Tulay Guran, Ayla Güven, Sabine E. Hannema, Claire E Higham, Violeta Iotova, Hetty J. van der Kamp, Marta Korbonits, Ruth E Krone, Corina Lichiardopol, Andrea Luczay, Berenice Bilharinho Mendonca, Tatjana Milenkovic, Mirela C Miranda, Klaus Mohnike, Uta Neumann, Rita Ortolano, Sukran Poyrazoglu, Ajay Thankamony, Jeremy W Tomlinson, Ana Vieites, Liat de Vries, S Faisal Ahmed, Richard J Ross, and Nils P Krone
Objective: Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH.
Design: This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry.
Methods: Data was collected from 461 patients aged 0-18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 – 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement was analyzed from 4174 patient visits.
Results: The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0 – 14.5) mg/ m2/ day at age 1 - 8 years and the highest dose of 14.0 (11.6 - 17.4) mg/ m2/ day at age 12-18 years. Glucocorticoid doses decreased after 2010 in patients 0-8 years (p<0.001) and remained unchanged in patients aged 8-18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement.
Conclusions: Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.