Jonathan Gleadle - How to Pass the FRACP Written Examination

In type 2 APS (APS‐2), alleles of HLAs determine the targeting of specific tissues by autoreactive T cells, which leads to organ‐specific autoimmunity as a result of this loss of tolerance. Non‐HLA genes also contribute to autoimmunity in APS‐2 and, depending on the polymorphism, potentially predisposes to a loss of tolerance or influence which organ is specifically targeted.

The prevalence of APS‐2 is 1:20,000. It is more frequently seen in women, and the peak incidence is between the age of 30 to 40 years. It is common for multiple generations to be affected by one or more components of disease. The inheritance of APS‐2 is complex, with genes on chromosome 6 playing a predominant role. Within some families, autoimmune endocrine disease susceptibility appears to be inherited as an autosomal dominant form associated with a specific HLA haplotype. The presence of one autoimmune endocrine disease is associated with an increased risk of developing autoimmunity in other organs or tissues.

Each of these disorders is characterised by several stages beginning with active autoimmunity and followed by metabolic abnormalities and overt clinical disease. Type 1 diabetes is a very frequent component disorder of APS‐2 and is often its first symptom. Other autoimmune diseases such as coeliac disease, autoimmune gastritis, pernicious anaemia, vitiligo, primary ovarian insufficiency, and alopecia areata may occur in APS‐2.

Many of the endocrine disorders of APS can be adequately treated with hormonal replacement therapy. Subjects with pathological ACTH levels and increased levels of basal plasma ACTH require close clinical follow‐up with repetition of the test every 6 months. Replacement therapy with hydrocortisone or cortisone acetate should be considered in the case of physiological stress.

IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X‐linked) syndrome results from mutations in the forkhead box protein P3 (FOXP3) gene, which is necessary for normal function of regulatory T cells, leading to severe autoimmunity and immune deficiency. IPEX is an extremely rare inherited syndrome characterised by early‐onset type 1 diabetes, autoimmune enteropathy with intractable diarrhoea and malabsorption, dermatitis, eosinophilia, and elevated IgE levels. IPEX is frequently fatal in the first few years of life unless patients are promptly treated with immunosuppressants or, if possible, with allogeneic bone marrow transplantation, which can cure the disease.

Husebye E, Anderson M, Kämpe O. Autoimmune Polyendocrine Syndromes. New England Journal of Medicine. 2018;378(12):1132–1141.

https://www.nejm.org/doi/full/10.1056/NEJMra1713301

6. Answer: D

There are three types of adipocytes.

White adipocytes are the main cell type found in human adipose tissue. Energy‐yielding triglycerides and cholesterol ester are stored within the large intracellular lipid droplets. They secrete leptin, adiponectin, and other adipokines. Large amounts of white adipocytes around the abdominal area are associated with a higher risk of metabolic syndrome.

Brown adipocytes contain many small lipid droplets, and a high number of uncoupling protein 1 (UCP1) and iron containing mitochondria. Deposits of brown adipocytes are observed within supraclavicular, paravertebral, and mediastinal regions. Compared to adults, newborns have a higher proportion of brown fat. Brown fat has more capillaries than white fat and requires higher oxygen consumption. Brown fat also has many unmyelinated nerves, providing sympathetic stimulation to the fat cells. Brown fat can be activated through sympathetic nervous system stimulation to generate heat by burning calories after cold exposure.

Thermogenic beige (brown‐and‐white) adipocytes are found scattered within white adipose tissue. They are characteriseds by multiple lipid droplets and uncoupling protein 1–containing mitochondria. ‘Browning’ of white adipose tissue can be induced with cold exposure, exercise, and some endocrine hormones.

Brown fat is emerging as a promising target for therapeutic intervention in obesity and metabolic syndrome. Activation of brown fat in humans is associated with marked improvement in metabolic parameters such as levels of free fatty acids and insulin sensitivity. Brown adipocytes possess a unique cellular mechanism to convert chemical energy into heat: UCP1, which can short‐circuit the mitochondrial proton gradient.

Betz M, Enerbäck S. Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease. Nature Reviews Endocrinology. 2017;14(2):77–87.

https://www.nature.com/articles/nrendo.2017.132

7. Answer: A

This patient's clinical features and investigation results are consistent with Cushing's syndrome. She has very low adrenocorticotropic hormone (ACTH) level which is indicative that the likely pathology is an adrenal adenoma.

Cushing's syndrome is characterised by endogenous hypercortisolism due to excessive ACTH production, or autonomous adrenal cortisol production. It is associated with significant comorbidities, including hypertension, diabetes, cardiovascular disease, infections, and osteoporosis. It can be difficult to recognises, especially when it is mild and the presenting features overlap with common conditions such as metabolic syndrome in the general population. However, there is a need to diagnose Cushing's syndrome at an early stage, as it tends to progress, accruing additional morbidity, and increasing mortality rates.

Two of three different screening tests are recommended: 24‐hour urine free cortisol (UFC) excretion, late night/bedtime salivary cortisol levels and the 1 mg overnight dexamethasone suppression test (DST) or alternatively the 2 mg 2‐day DST. The screening tests all reflect different physiologic abnormalities in Cushing's syndrome: high integrated daily cortisol production (UFC), loss of bedtime salivary or serum cortisol nadir, and impaired response to glucocorticoid negative feedback. Thus, they are complimentary, and the use of more than one test is extremely helpful, as the results generally should corroborate each other.

After establishing the diagnosis, its cause must be determined. The causes of Cushing's syndrome divide into disorders of ACTH excess (either from a pituitary or non‐pituitary [ectopic] tumour) and disorders of ACTH‐independent primary adrenal overproduction of cortisol (adenoma, carcinoma, or bilateral macronodular/micronodular hyperplasias), in which plasma ACTH values are low or undetectable. Those patients with low/undetectable values should next undergo adrenal gland imaging with CT and/or MRI to identify unilateral masses with adjacent and contralateral atrophy or bilateral disease. Those with normal or elevated ACTH levels should undergo additional testing, usually with pituitary MRI, inferior petrosal sinus sampling, corticotropin releasing hormone, and/or 8 mg dexamethasone suppression which can determine whether ACTH excess is coming from pituitary or ectopic tumour. The ideal treatment is surgical resection of the abnormal tissue or tumour which will induce remission of hypercortisolism and preserve the normal hypothalamic‐pituitary‐adrenal axis. If surgery is not possible or there is recurrent or metastatic disease, medical therapy is chosen to normalises cortisol levels.

Loriaux, D. (2017). Diagnosis and Differential Diagnosis of Cushing's Syndrome. New England Journal of Medicine, 376(15), pp.1451–1459.