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.
https://www.nejm.org/doi/full/10.1056/NEJMra1505550
8. Answer: D
Diabetic nephropathy (DN) is the most common cause of end stage kidney disease in developed countries and is associated with increased cardiovascular morbidity and mortality.
Intensive glycaemic control can reduce the incidence and progression of DN in type 1 diabetes, and this benefit can persist even if the patient subsequently returns to suboptimal glycaemic control, termed the ‘legacy’ effect.
In patients with type 2 diabetes, several studies showed that intensive blood glucose control reduced the relative risk of developing microalbuminuria or worsening of albuminuria by 30–35% when compared to conventional control. However, mortality rates were not reduced or higher in one study in the intensive control group. This may be higher occurrence of significant hypoglycaemia, weight gain, increased use of medications of different classes, and higher use of insulin.
ACE inhibitors and ARBs have similar renoprotective effects in patients with DN but ACE inhibition has been shown to have superior cardiac benefits. Therefore, if a patient has DN and CCF, they should be treated with an ACE inhibitor in preference to an ARB.
The renoprotective effect of an ACE inhibitor or ARB is dose‐related. If the medication is tolerated well the dose should be gradually increased to the maximum recommended dose. An initial 10% reduction in eGFR before plateauing is common after the commencement of ACE inhibitor or ARB and the drug should be continued unless there is further reduction of eGFR.
Dual renin–angiotensin–aldosterone system (RAAS) blockade with both ACE inhibitor and ARB has shown a superior antiproteinuric effect compared to monotherapy with either agent, but the effect on slowing DN progression is unknown. Significant rates of serious adverse events; including AKI, hyperkalaemia and need for dialysis were observed with dual therapy in the ONTARGET, ALTITUDE and VA‐NEPHRON D trials with no significant benefit. Therefore, dual therapy is not currently recommended.
Umanath K. Update on diabetic nephropathy: Core Curriculum 2018. Am J Kidney Dis. 2018;71:884–95.https://www.ajkd.org/article/S0272-6386(17)31102-2/fulltext
9. Answer: B
Diabetic ketoacidosis (DKA) is a life‐threatening complication of type 1 diabetes. It can also occur in patients with type 2 diabetes and is known to occur in patients taking SGLT2 inhibitors; in this situation, blood glucose may not be elevated. In its classical form, DKA is a complex disordered metabolic state characterised by ketonaemia, hyperglycaemia, and metabolic acidosis. This results from absolute or relative insulin deficiency accompanied by an increase in counter‐regulatory hormones (glucagon, epinephrine, cortisol, growth hormone). DKA is often triggered by other medical or surgical conditions such as sepsis and is associated with significant morbidity and mortality. Therefore, it must be diagnosed promptly and managed intensively.
The diagnostic criteria of DKA include:
1 Blood ketones ≥3 mmol/L or urine ketones ≥2+ on dipsticks.
2 Blood glucose >11 mmol/L or known diabetes.
3 Bicarbonate (HCO3‐) <15 mmol/L and/or venous pH <7.3.
The goals of treatment for DKA include:
Restoration of circulatory volume.
Clearance of ketones.
Correction of electrolyte losses (mainly hypokalaemia).
Normalisation of blood glucose and prevention of hypoglycaemia.
Prevention of other potential complications such as cerebral oedema, venous thromboembolism (VTE), and sepsis.
Intravenous 0.9% sodium chloride solution is the principal fluid to restore circulating volume and reverse dehydration. The first litre is administered over 1 hour. If the systolic BP remains <90 mmHg, 500 mL should then be administered over 15 min and reassessed. Caution should be exercised in the elderly or patients with CCF where too rapid rehydration may precipitate pulmonary oedema, but insufficient fluid resuscitation may fail to reverse AKI. Regular reassessment of cardiovascular status is mandatory.
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