Bartalena L, Bogazzi F, Chiovato L, Hubalewska‐Dydejczyk A, Links T, Vanderpump M. 2018 European Thyroid Association (ETA) Guidelines for the Management of Amiodarone‐Associated Thyroid Dysfunction. European Thyroid Journal. 2018;7(2):55–66.
https://www.karger.com/Article/Pdf/486957
5. Answer: D
This patient has type 1 diabetes, and her general heath has been deteriorating with symptoms of fatigue, nausea, poor appetite and significant weight loss. She is now hypotensive after an infection. Investigations reveal hyponatraemia, hyperkalaemia, a disproportionally higher urea compared to serum creatinine, and hypercalcaemia which is likely secondary to dehydration. These features are highly suggestive of a diagnosis of primary adrenal insufficiency. She has type 1 diabetes, hypothyroidism, and Addison's disease which are features of type 2 autoimmune polyendocrine syndrome (APS). The coexistence of adrenal failure with either autoimmune thyroid disease and/or type 1 diabetes is known as Schmidt's syndrome. It is imperative to prescribe intravenous hydrocortisone when a patient is suspected of having Addison's disease/crisis. Her hypothyroidism may be undertreated as she has only been taking thyroxine intermittently but replacing thyroxine without adequate adrenal steroid replacement in a patient with hypothyroid and Addison's disease can predispose them to an adrenal crisis. Replacement of thyroxine increases the cortisol turnover rate in the liver, and this may further tax a failing adrenal gland.
APS comprises a diverse group of clinical conditions characterised by functional impairment of multiple endocrine glands due to loss of immune tolerance. There are three main syndromes.
Type 1 APS (APS‐1) results from mutations in the AIRE gene on chromosome 21 and is inherited in an autosomal recessive manner. This mutation leads to the loss of central tolerance – a process by which developing T cells with potential reactivity for self‐antigens are eliminated during early differentiation in the thymus. It is a very rare disease. It usually manifests in infancy or childhood with a persistent mucocutaneous candidiasis, the presence of acquired hypoparathyroidism, and Addison's disease. In most patients, mucocutaneous candidiasis precedes the other disorders, usually followed by hypoparathyroidism.
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
