Care provision in congenital adrenal hyperplasia – all doom and gloom or light at the end of the tunnel?

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common inborn conditions following an autosomal recessive inheritance.1 After the introduction of life-saving glucocorticoid treatment in the 1950s, CAH has become a lifelong chronic condition. Increasing evidence suggests significant risk of patients with CAH to develop health problems in later life. The reported outcomes including bone health, metabolic status and cardiovascular risk are variable,2 which is potentially caused by relatively small cohorts of the individual studies and potentially differences in healthcare provision. In addition, a significant number of adults with CAH appear to be lost to follow-up potentially leading to an ascertainment bias when evaluating care provision. The two most recent large outcome studies from the UK3 and the United States4 show relatively gloomy outcomes with adult CAH patients having poor hormonal control and significant rates of comorbidities including obesity, insulin resistance, osteopenia and impaired gonadal function at relatively young adult age. A significant milestone in the guidance of care provision for children and young persons with CAH has been the European Society for Paediatric Endocrinology/Lawson Wilkinson Pediatric Endocrine Society (ESPE/LWPES) consensus statement on 21-hydroxylase deficiency published in 2002.5 This statement recommended the change of replacement strategies and dose reduction in glucocorticoids and mineralocorticoids in the late 1990s and early 2000s. Therefore, until now almost all adults with CAH will have been treated with far higher steroid doses during all phases of their early life than patients born around the new millennium. Consequently, these changes will only become increasingly apparent by the end of this decade and have a significant lag effect. In this issue of Clinical Endocrinology, Subbarayan et al.6 present a retrospective case note study assessing cardiovascular risk factors in 107 children and young persons with classic CAH due to 21-hydroxylase deficiency. Similar to the situation described in adults3, 4, the therapeutic control assessed by androstenedione was suboptimal with only 33% of patients having normal concentrations. However, the percentage of overtreated patients appears to be lower in the present study. Only 4% of patients had low androstenedione levels, whereas 63% of patients had raised androstenedione concentrations. This was despite glucocorticoid doses having been within the mid-to-higher end of the suggested range (13·3 ± 4·4 (SD) mg/m2 per day). Particular emphasis was put on mineralocorticoid replacement with fludrocortisone to aim for doses of 100 μg/m2 per day and below after infancy. About 24% of patients from this cohort were obese representing a higher rate than observed in the background population. However, the obesity rate is lower than in the recent report from the NIH group (about 35% in children).4 Interestingly, in 2006, an even lower obesity rate of 17% was reported in a paediatric cohort from Bavaria. In contrast to the present study, where no statistically significant correlation between BMI-SDS and glucocorticoid dose was found, Volkl et al.7 showed a correlation between hydrocortisone dose and BMI-SDS. Variable findings regarding hypertension in patients with CAH have been reported in the literature across age groups (reviewed in2). The present study demonstrates hypertension in 21% of patients and prehypertension in 11% of patients. Despite obesity and hypertension are remaining health problems in children and young persons with CAH, it appears that changed clinical practice has led to a reduction in obesity and hypertension compared with previous data from the same group.8 It is highly likely that this is the consequence of lower replacement doses of glucocorticoids and mineralocorticoid similar to recommendations by 2002 consensus statement5 and the most recent Endocrine Society guidelines.9 The lag effect of changed clinical practice is exemplified within this study analysing the final height of patients over 15 years. These patients had similar height outcomes as described in the most recent meta-analysis.10 However, this subcohort will have been treated with higher doses during infancy than used since 2002 leading inevitably to an impairment of the infantile growth spurt and impairment of final height. Striking findings of the current report are lower fasting glucose concentrations and lower HOMA-IR values in patients with CAH compared to normal controls. This adds, however, to the unclear metabolic situation describing a variety of constellations ranging from increased insulin resistance to normal insulin sensitivity in CAH (reviewed in2). Commonly, dyslipidaemia is not found in patients with CAH. The present study identifies elevated triglyceride levels in about 10% and raised cholesterol concentrations in 3% of patients. It is, however, unclear how this differs from the background population. The overall metabolic situation in CAH remains puzzling as alterations of the leptin axis have been suggested.11 On the other hand, even increased adiponectin concentrations have been found.12 All these metabolic studies have two limiting factors. Firstly, the studies have been conducted in small- or medium-sized cohorts, and secondly, different metabolic parameters have been assessed without directly correlating these markers. Thus, in an ideal world, these important questions should be approached in future by large-scale clinical research consortia. In conclusion, the report published in the current issue of Clinical Endocrinology suggests some light at the end of the tunnel of bad news regarding long-term outcomes in patients with CAH. Despite the fact that there seems to be further room for improvement of care provision in CAH, the authors clearly demonstrate the possibility of improving health outcomes and reducing risk of comorbidities in CAH by modifying health care provision. A significant cornerstone represents the tailored and personalized approach to the patients with CAH including dosing and timing of replacement therapy. One has to consider the balance between practicality and health benefits and can include various simple aspects to achieve a more physiological glucocorticoid replacement such as early morning dosing and four daily doses as well as potential future treatment options such as modified release glucocorticoid preparations.13 An important aspect in optimizing glucocorticoid therapy is the timing of replacement, which has not been systematically studied in patients with CAH. However, data from adults with adrenal insufficiency suggest that increased cortisol concentrations at the wrong time of the day might well contribute to alterations in glucose tolerance, insulin sensitivity and insulin secretion.14 The authors of the present paper suggest ongoing audit of cardiovascular risk factors. A broader approach in CAH, representing one of the most common inborn conditions, might be even more desirable. Similar to the situation with type 1 diabetes, the implementation of national or international registries or databases would be ideal for ongoing audits into the healthcare provision of CAH. The first step in this direction is the recent implementation of the international CAH registry (I-CAH, https://www.i-cah.org/). Such approaches should ultimately support the improvement of healthcare provision for patients with CAH on a broad level. Nothing to declare.