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1. Answer: D

This patient has typical clinical features of acromegaly. She has elevated insulin like growth factor 1 (IGF‐1) and growth hormone (GH) levels. The MRI demonstrates a large pituitary tumour. There is NO need for further investigation. She needs referral for neurosurgery.

Acromegaly is a severe disease resulting from GH hypersecretion, usually caused by a pituitary adenoma. It is associated with cardiovascular, cerebrovascular, and respiratory disorders, malignancies, and a high mortality. The onset of acromegaly in adults is usually insidious. Typical physical examination findings include hand and foot enlargement, facial bone enlargement and acral/soft tissue changes.

Investigation in a suspected patient involves measurement of IGF‐1 and GH. Elevated IGF‐I levels in a patient with clinical features of acromegaly almost always indicate GH excess. In subjects with elevated or equivocal serum IGF‐1 concentrations, guidelines recommended confirmation of the diagnosis with a lack of suppression of GH to less than 1 mcg/l following an oral glucose load. In a patient with signs and symptoms of acromegaly and a clearly elevated IGF‐1 value, an oral glucose suppression test is not needed for diagnosis.

GH, produced by the somatotroph cells of the pituitary gland in a pulsatile fashion, circulates and stimulates hepatic secretion of IGF‐1. A random GH measurement is not useful in diagnosis because of the lack of a well‐defined normal range, although a markedly elevated random GH level is consistent with the disease.

After biochemical diagnosis of acromegaly, imaging studies are needed; a MRI scan of the head is the preferred modality and should be obtained to determine tumour size, location, and invasiveness. Visual field testing is performed if the tumour is touching or compressing the optic chiasm. A thorough ophthalmologic examination should be performed if the patient describes diplopia and the tumour is invading the cavernous sinus. Further endocrine testing is also necessary to determine general pituitary function and need for hormone replacement therapy.

Acromegaly is associated with diabetes, hypertension, OSA, and cardiovascular disease. There is also increased risk for colonic polyps and colonoscopy is indicated when acromegaly is diagnosed. Excess GH is also associated with an increase in thyroid nodules and thyroid cancer. A thyroid ultrasound may be performed if there is palpable thyroid nodularity.

The goals of therapy for acromegaly are to normalise GH and IGF‐1 activity, reduce tumour size, prevent local mass effects, reduce signs and symptoms of disease, prevent or improve medical comorbidities, and prevent premature mortality. Surgery is the treatment of choice. Surgery is useful to debulk or resect the somatotroph adenoma, decompress local mass effects, and rapidly lower or normalise GH and IGF‐1 values.

Surgery is recommended for all patients with microadenomas, and in experienced hands >85% are curable. Surgery is also recommended for all patients with macroadenomas and mass effects. Surgical cure rates for macroadenomas range from 40–50%, likely reflecting the high prevalence of extrasellar extension and parasellar invasion of the cavernous sinus. The transsphenoidal approach is the most common procedure, with craniotomy reserved for select cases involving large, extrasellar lesions. Transnasal endoscopic endonasal procedures offer improved visibility and are rapidly replacing microscopic transsphenoidal techniques.

Medical therapy is largely used in an adjuvant role for patients with residual disease following surgery. However, primary medical therapy may be considered in subjects with macroadenomas and extrasellar involvement (especially involving the cavernous sinus) but no evidence of local mass effects such as chiasmal compression. In this situation, surgery will unlikely be curative and primary medical therapy in lieu of surgery may be considered. Primary medical therapy may also be considered in patients, who are at high risk from surgery and according to patient preferences. In a patient who is undergoing primary medical therapy, surgery can always be reconsidered for tumour debulking to improve response to medical therapy. Somatostatin receptor ligands (SRLs) such as octreotide are the mainstay of medical treatment. Octreotide acts primarily on somatostatin receptor subtypes II and V, inhibiting GH secretion. Dopamine agonist such as cabergoline can also be used. Cabergoline monotherapy results in biochemical control rates of approximately 35%; similar benefits have also been seen with the addition of cabergoline to an SRL in patients with inadequate control on SRL therapy. GH receptor antagonist, pegvisomant monotherapy administered as second‐line therapy yields biochemical control rates of 90% or more in clinical trials and closer to 60% in real‐world surveillance studies. Radiation therapy is largely relegated to an adjuvant role.

Melmed, S., Bronstein, M., Chanson, P., Klibanski, A., Casanueva, F., Wass, J., Strasburger, C., Luger, A., Clemmons, D. and Giustina, A. (2018). A Consensus Statement on acromegaly therapeutic outcomes. Nature Reviews Endocrinology, 14(9), pp.552–561.

https://www.nature.com/articles/s41574-018-0058-5

2. Answer: C

The patient is likely to have a diagnosis of adrenal crisis with symptoms of nausea, vomiting, hypotension, severe lethargy, weakness, altered mental state, hyponatraemia, hyperkalaemia, and a known history of adrenal insufficiency. Her low BP suggests that she has adrenal crisis with haemodynamic instability, rather than adrenal insufficiency. Septic shock can clinically mimic adrenal insufficiency with symptoms of hypotension, fever, and gastrointestinal symptoms, thus it is important not to miss either the diagnosis of sepsis or adrenal crisis and initiate appropriate investigations and treatment. Administration of appropriate dosage of corticosteroids is imperative to avoid adverse sequalae.

In patients with vomiting and diarrhoea, administration of 100 mg IV hydrocortisone initially is recommended followed by IV hydrocortisone 100 mg qid then 50 mg qid the next day until it is safe to change to oral hydrocortisone after 24 hours. Oral hydrocortisone is usually prescribed at 2 to 3 times the normal oral hydrocortisone dose, with a gradual taper back to the patient's regular dose over the following 2 to 3 days. Administration of oral fludrocortisone is not required if the initial hydrocortisone doses exceed 50 mg over 24 hours for patients with primary adrenal insufficiency as high doses of hydrocortisone will exert mineralocorticoid activity. Oral fludrocortisone can be resumed once the patient is able to have oral hydrocortisone.

Biochemical abnormalities observed in patients with adrenal crisis include hyponatraemia, hyperkalaemia, hypercalcaemia, hypoglycaemia, neutropenia, lymphocytosis, eosinophilia, and mild normocytic anaemia. IV fluid resuscitation with 0.9% normal saline 1L within the first hour is recommended. If the patient is hypoglycaemic, intravenous dextrose 5% in normal saline is given.

It is important for patients with a medical history of adrenal insufficiency and adrenal crisis to have a sick day plan and ongoing education about the condition. Without appropriate recognition and treatment of adrenal crisis, patients may potentially take longer to diagnose, leading to poorer outcomes. MedicAlert bracelets, necklaces, easy access to intramuscular hydrocortisone, oral corticosteroid medications, ambulance services and hospitals are important measures to prevent subsequent adrenal crisis in patients with past history of adrenal crisis or insufficiency.

Rushworth R, Torpy D, Falhammar H. Adrenal Crisis. New England Journal of Medicine. 2019;381(9):852–861.

https://www.nejm.org/doi/full/10.1056/NEJMra1807486?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed

3. Answer: D

An ‘adrenal incidentaloma’ is an adrenal mass, greater than 1 cm in diameter, that is found serendipitously when a patient undergoes a radiological examination for reasons unrelated to adrenal disease. There has been an increased incidence of ‘adrenal incidentalomas’ due to the widespread use of CT and MRI. The prevalence of adrenal incidentalomas during autopsies ranges from 1 to 9% and increases with increasing age.

Most adrenal tumours are non‐hypersecreting, benign adrenocortical adenomas. Adrenal masses, such as cortisol‐secreting adrenocortical adenoma, unilateral or bilateral congenital adrenal hyperplasia, pheochromocytoma, adrenocortical carcinoma, and metastatic carcinoma, are also frequently described. Metastases to the adrenal glands are usually bilateral; primary malignancies that are commonly associated with adrenal metastasis include carcinoma of the lung, kidney, colon, breast, oesophagus, pancreas, liver, and stomach.

Focused history taking and clinical examination is important to rule out functioning and malignant adrenal tumours to diagnose the underlying medical conditions, e.g. Cushing's syndrome, pheochromocytoma, primary aldosteronism, adrenocortical carcinoma, and metastatic cancer.

In patients with a positive overnight dexamethasone (1 mg) suppression test, that is a morning serum cortisol >139 nmol/L, confirmatory tests including serum corticotropin, 24‐hr urine cortisol collection, midnight salivary cortisol, and a formal 2‐day high‐dose dexamethasone suppression test, are required to establish the diagnosis of Cushing's syndrome.

The size of the adrenal tumour does not affect recommendations regarding biochemical testing. However, adrenal tumours that are greater than 4 cm in diameter raise concern for potential primary adrenocortical malignancy.

Due to its high cost and a greater (FDG‐PET) uptake in a small percentage of benign adrenal lesions compared to the background uptake, PET scans are not routinely recommended to evaluate patients with adrenal incidentaloma without a history of malignancy.

Image‐guided fine‐needle aspiration (FNA) biopsy is generally not recommended to differentiate between adrenal vs non‐adrenal tissues (metastases or infection), due to risks associated with possible biopsy of a phaeochromocytoma or seeding of metastasis. It is important to biochemically rule out pheochromocytoma before considering performing an FNA biopsy of the adrenal mass due to the potential hypertensive crisis and bleeding complications associated with pheochromocytoma.

Young W. The Incidentally Discovered Adrenal Mass. New England Journal of Medicine. 2007;356(6):601–610.

https://www.nejm.org/doi/full/10.1056/NEJMcp065470

4. Answer: C

Amiodarone, is a potent class III antiarrhythmic drug and an iodine‐rich compound with a molecular structure similar to thyroxine (T₄) and triiodothyronine (T₃). It has a long half‐life (107 days), which allows effects to occur months after stopping treatment. Therapeutic doses of amiodarone contain much more iodine (up to 50–100 times), than the recommended daily iodine intake and significantly increases systemic and thyroidal iodine pools. Amiodarone can cause changes in thyroid function tests and serious thyroid dysfunction, such as amiodarone‐induced hypothyroidism (AIH) and type I and type II amiodarone‐induced thyrotoxicosis (AIT 1 and AIT 2, respectively) in patients with or without underlying thyroid disease.

AIH does not require cessation of amiodarone and is easily managed. In patients with overt hypothyroidism second to AIH, levothyroxine replacement is recommended. In patients with subclinical hypothyroidism, patients will require ongoing monitoring of the thyroid function; treatment is only required if there is overt hypothyroidism.

The diagnosis of AIT requires increased serum FT4 and FT3 and suppressed serum TSH levels. Anti‐thyroid antibodies, such as anti‐thyroid peroxidase antibodies, are often positive in AIT 1 and negative in AIT 2.

The clinical presentation of AIT is variable and there is poor correlation between the clinical findings and biochemical severity of the condition. Extreme weight loss and myopathy may indicate life‐threatening thyrotoxicosis.

AIT 1 occurs in patients with pre‐existing multinodular goitre or latent Graves’ disease. The excess iodine from amiodarone provides increased substrate, resulting in enhanced thyroid hormone production. Treatment of AIT 1 includes antithyroid therapy with thionamides (carbimazole or propylthiouracil) that may be combined for a few weeks with sodium perchlorate to make the thyroid gland more sensitive to thionamides.

AIT 2 results from direct toxic effect on the thyroid cells by amiodarone causing thyroiditis in a normal thyroid gland without increased hormone synthesis and is treated with glucocorticoids. It occurs in patients without underlying thyroid disease.

Mixed forms of AIT 1 and AIT 2 exist secondary to underlying mechanisms. Mixed/indefinite forms of AIT are treated with thionamides. Empirical dual therapy with a high‐dose glucocorticoid therapy and a high‐dose antithyroid mediation can be started from the beginning if it is difficult to distinguish the subtypes of AIT. Urgent endocrinologist consultation and cardiologist opinion will be important to guide the diagnosis and treatment of AIT and discontinuation of amiodarone.

Serum thyroglobulin concentrations are higher in patients with AIT 1. Thyroid ultrasonography can assess thyroid volume, nodularity, parenchymal echogenicity, and vascularity. Overall, most evidence suggests that thyroid ultrasonography has low diagnostic value in AIT. The color flow Doppler sonography (CFDS) may distinguish AIT 1 (increased vascularity) from AIT 2 (absent vascularity). Nuclear medicine imaging using technetium‐99m (99mTc)‐sestamibi thyroid uptake and scintigraphy can help to distinguish AIT 1 (normal or increased) from AIT 2 (decreased). The presence of thyrotropin receptor antibodies suggests Graves' disease.

The diagnosis of AIT 2 is based on the absence of goitre, reduced radioiodine uptake in areas of iodine deficiency, absence of hypervascularity on CFDS, and, in most cases, anti‐thyroid and anti‐TSH receptor antibodies negativity. Patients who are refractory to antithyroid drug therapy after 4 to 6 weeks of medical treatment should be considered for thyroidectomy.

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 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.

Bag number	Time (hr)	Fluid	Infusion rate	Potassium replacement
1	0–1	0.9% sodium chloride	1000 ml/hour	May be required if >1000 ml of fluid has been given due to hypotension
2	1–3	0.9% sodium chloride	500 ml/hour	Monitor potassium level & replace with IV potassium chloride as per table below
3	3–5	0.9% sodium chloride	500 ml/hour
4	5–9	0.9% sodium chloride	250 ml/jour
5	9–13	0.9% sodium chloride	250 ml/hour
6	13–19	0.9% sodium chloride	166 ml/hour

Potassium level in first 24hrs (mmol/L)	Potassium replacement
>5.5	Nil
3.5–5.5	30 mmol
<3.5	ICU admission, replacement 10 mmol/L/hr

Intravenous insulin infusion with Actrapid should be started as soon as possible and boluses of insulin should be avoided unless there is significant delay (≥1 hour) in setting up an insulin infusion. Insulin infusion should not be stopped until the patient is eating and drinking normally and ketones <0.3 mmol/L, venous pH >7.35, and the patient has received a bolus of long‐acting subcutaneous insulin as part of transition to subcutaneous basal bolus insulin regimen.

Sodium bicarbonate should not be administered in patients with DKA unless the arterial plasma pH falls below 7. However, this decision should be individualised. Most patients with DKA do not require the administration of sodium bicarbonate, since infused insulin will slow the rate of ketoacid production, and bicarbonate ions will be produced when ketoacid anions are oxidised.

Karslioglu French E, Donihi A, Korytkowski M. Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: review of acute decompensated diabetes in adult patients. BMJ 2019;365:l1114

https://www.bmj.com/content/365/bmj.l1114

10. Answer: C

Erectile dysfunction (ED) is defined as persistent inability to achieve or maintain an erection adequate for satisfactory sexual activity. After premature ejaculation, it is the most common disorder of sexual function in men. ED is a natural part of ageing and prevalence increases with age. Due to its effects on blood vessels and nerves systemically and in the penis, diabetes is a common aetiology of ED. Men with diabetes are four times more likely to experience ED, and on average, ED develops 15 years earlier than in men without diabetes. ED and/or decreased libido are common side‐effects of many medications; drugs which can cause this include β‐blockers, hydrochlorothiazides, and SSRIs. The pathogenesis of organic ED is related to dysfunction of the endothelium.

Guidelines recommend screening for low testosterone with a morning total testosterone assay (08.00–11.00 a.m.) in men with ED and hypoactive sexual desire, incomplete response to phosphodiesterase type 5 (PDE5) inhibitors, delayed ejaculation, and in all men with known diabetes. The prevalence of low total testosterone levels in men with ED varies widely across studies and ranges from 12.5% to 35%. The threshold of testosterone to maintain an erection is low (< 5.5 nmol/L) and ED is usually a symptom of more severe cases of hypogonadism. If total testosterone level is ≥ 12 nmol/L, testosterone deficiency is unlikely. If total testosterone is < 12 nmol/L, a second morning venous blood sample drawn after an interval of at least one week, together with serum luteinising hormone and prolactin levels is required.

ED may be a precursor of cardiovascular disease. Men with proven or suspected vasculogenic ED or multiple vascular risk factors, especially diabetes, should be screened for silent myocardial ischaemia with exercise electrocardiography, a coronary artery calcium score, or coronary CT angiography.

Lifestyle modifications are the first‐line therapy. Other treatment options include testosterone replacement therapy (TRT), PDE5 inhibitors, intracavernosal injection therapy, vacuum constriction devices (VCDs), intraurethral prostaglandin suppositories and surgical placement of a penile prosthesis. PDE5 inhibitors enhance blood flow in the corpora cavernosa. 60–65% of men who have ED, including those with hypertension, diabetes, spinal cord injury, and other comorbid medical conditions, can successfully complete intercourse in response to the PDE5 inhibitors. There is no evidence that currently approved ED treatments add to the overall cardiovascular risk in patients with or without previously diagnosed cardiovascular disease.

McMahon CG. Current diagnosis and management of erectile dysfunction. MJA 2019;210:469–76.

https://www.mja.com.au/journal/2019/210/10/current-diagnosis-and-management-erectile-dysfunction

11. Answer: A

Fertility preservation may be requested by women who experience disease processes or treatments that carry a risk of premature ovarian failure, thereby potentially extending their ability to have children. Treatments causing premature ovarian failure include alkylating chemotherapeutic agents, multi‐agent chemotherapy, ovarian radiation therapy, and sometimes pelvic surgery. Alkylating agents include nitrogen‐mustard agents such as cyclophosphamide, nitrosureas, and busulfan carry the highest risk of premature ovarian insufficiency, with increasing risk in a dose dependent manner. Other agents with alkylating like actions such as platinum containing agents also carry increased risk, as do other treatments for malignancy such as pelvic radiotherapy.

Counselling about risk of premature ovarian failure is recommended for women of childbearing age undergoing high risk treatments, and parents of children undergoing the same. The probability of premature ovarian failure following chemotherapy is dependent on individual ovarian reserve, which varies greatly between women. For prepubertal girls, ovarian tissue cryopreservation is most likely to result in successful outcome. In adults, this strategy is emerging in cases where there is an urgent indication to initiate treatment, leaving no time for oocyte or embryo cryopreservation. However, where treatment can be safely delayed, mature oocyte cryopreservation or embryo cryopreservation are currently the methods endorsed by the Clinical Oncology Society of Australia. Successful pregnancy rates are higher when larger numbers of oocytes are used, or where the donor is of younger age at the time of cryopreservation.

Donnez J, Dolmans M. Fertility Preservation in Women. New England Journal of Medicine. 2017;377(17):1657–1665.

https://www.nejm.org/doi/full/10.1056/NEJMra1614676

12. Answer: C

Hypogonadism is common in older age men and is most commonly due to functional suppression of sex hormones by chronic disease, medications, and obesity. Hypogonadism as a consequence of testicular or pituitary pathology (organic hypogonadism) is rarer in this age group and occurs in inverse frequency to the level of testosterone, BMI, and degree of comorbidity. First line treatment of functional hypogonadism is lifestyle advice as non‐specific symptoms, including sexual dysfunction, responds well to exercise and weight loss.

Testosterone treatment, with the goal of keeping total serum testosterone within the normal range for a young male can be helpful for some symptoms. Libido and erectile function improved with testosterone in comparison to placebo, but its effect on erectile function is not as significant compared with phosphodiesterase‐5 inhibitors. Poor glycaemic control is better treated with changes to diabetic medications over and above testosterone treatment. Effects on mood, vitality, and physical function are not consistently seen in randomised trials.

Testosterone treatment has some minor effects on muscle mass, fat mass, and bone mineral density, but it is unlikely that these changes are enough to be clinically relevant.

Snyder P, Bhasin S, Cunningham G, Matsumoto A, Stephens‐Shields A, Cauley J et al. Effects of Testosterone Treatment in Older Men. New England Journal of Medicine. 2016;374(7):611–624.

https://www.nejm.org/doi/full/10.1056/NEJMoa1506119

13. Answer: A

Secondary hyperparathyroidism is a common complication in patients with CKD and ESKD. Despite optimised medical treatment, patients with severe secondary hyperparathyroidism may still require parathyroidectomy.

Severe, prolonged, and symptomatic hypocalcaemia is a common post‐operative complication in patients following parathyroidectomy. ‘Hungry Bone Syndrome’ (HBS) is defined as prolonged and severe hypocalcaemia (corrected serum calcium level of 2.1 mmol/L or below) lasting 4 or more days, occurring anytime within 1 month of parathyroidectomy. The measurement of ionised calcium up to 2 to 4 times a day for the first few days postoperatively is preferred to total calcium since it is difficult to predict ionised calcium from total calcium in patients with CKD. Loading with calcitriol pre‐operatively can reduce occurrence of severe hypocalcaemia.

Treatment strategies for hypocalcaemia include giving intravenous calcium, oral calcium, and Vitamin D supplementation such as calcitriol, and even providing haemodialysis treatment using a higher calcium dialysate (1.75 mmol/L) to avoid complications related to hypocalcaemia, such as paraesthesia, tetany, laryngeal spasm, seizures, cardiac arrhythmia, and heart failure.Other biochemical abnormalities which can occur post‐parathyroidectomy include hypomagnesaemia, hypophosphataemia, and hyperkalaemia. The correction of hypomagnesaemia may contribute to correction of the hypocalcaemia. The correction of hypophosphataemia in HBS is usually avoided since phosphate can bind to calcium and worsens hypocalcaemia unless the phosphate level is critically low (<0.16 to 0.32 mmol/L) or hypophosphataemia is associated with severe muscle weakness or heart failure. Hyperkalaemia is more common than hypokalaemia as a complication post‐parathyroidectomy since this group of patients have ESKD and are often oliguric or anuric after chronic dialysis and can be managed post‐operatively with dialysis.

Ho L, Wong P, Sin H, Wong Y, Lo K, Chan S et al. Risk factors and clinical course of hungry bone syndrome after total parathyroidectomy in dialysis patients with secondary hyperparathyroidism. BMC Nephrology. 2017;18(1).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223390/pdf/12882_2016_Article_421.pdf

14. Answer: A

The tricarboxylic acid (TCA) cycle, also known as the Krebs cycle or citric acid cycle, is important in cell metabolism. The Krebs cycle is a series of chemical reactions in mitochondria used by all aerobic organisms to release stored energy from carbohydrates, fats, and proteins through the oxidation of acetyl‐CoA into adenosine triphosphate (ATP) and carbon dioxide. The cycle also generates precursors of some amino acids and reducing agent (NADH), that can be used in other reactions.

Citrate, a metabolite in the Krebs cycle, has been linked to fatty‐acid synthesis and protein acetylation, which is important for macrophage and dendritic cells activation. Macrophages and dendritic cells play important roles in the innate immune system as the first line of defence against pathogens by producing inflammatory mediators, phagocytosis of pathogens, and releasing chemokines to recruit other inflammatory cells to the site of infection. Dendritic cells are also antigen presenting cells and play an important role in the adaptive immune response.

Itaconate is derived from citrate and has a direct antibacterial effect and is an important immunomodulator.

Williams N, O’Neill L. A Role for the Krebs Cycle Intermediate Citrate in Metabolic Reprogramming in Innate Immunity and Inflammation. Frontiers in Immunology. 2018;9.

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00141/full

15. Answer: C

Multiple endocrine neoplasia (MEN) is characterised by the occurrence of tumours involving two or more endocrine glands. There are four major forms of MEN (Table 4.1), which are autosomal dominant disorders.

Table 4.1 Four major forms of MEN with their characteristics and associated genetic abnormalities.

Syndrome	Gene mutation	Encoded protein	Clinical criteria
MEN1	MEN1 (tumour suppressor gene) mutation	Mentin	Parathyroid, pancreatic islet and anterior pituitary tumours
MEN2 (MEN2A)	Rearranged during transfection (RET) mutation	Tyrosine kinase receptor	Medullary thyroid carcinoma (MTC) in association with phaeochromocytoma and parathyroid tumours
MEN3 (MEN2B)	RET mutation	Tyrosine kinase receptor	MTC and phaeochromocytoma in association with a marfanoid habitus, mucosal neuromas, medullated corneal fibrese and intestinal autonomic ganglion dysfunction, leading to megacolon
MEN4	CDNK1B mutation	Cyclin‐dependent kinase inhibitor	Parathyroid and anterior pituitary tumours in possible association with tumours of the adrenals, kidneys, and reproductive organs

RET (‘rearranged during transfection)’ is located on chromosome 10 (10q11.2) and contains 21 exons. The RET proto‐oncogene encodes a receptor tyrosine kinase for members of the glial cell line‐derived neurotrophic factor family of extracellular signalling molecules. ‘Loss of function’ RET mutations are associated with the development of Hirschsprung's disease, while ‘gain of function’ germline mutations are associated with the development of various types of human cancers, including medullary thyroid carcinoma, MEN type 2A and 2B, phaeochromocytoma and parathyroid hyperplasia.

MEN2A is characteriseds by MTC, phaeochromocytoma and primary hyperparathyroidism. If MEN2A is suspected, the RET gene should be examined for an underlying mutation. Autosomal dominant inheritance of MEN2 means that the offspring of an affected person has a 50% chance of inheriting the mutated gene. Identification of the underlying genetic mutation also allows predictive testing in relatives, monitoring for early detection of disease in mutation carriers, and reassurance for non‐carriers.

Von Hippel‐Lindau (VHL) gene mutation is associated with renal cell cancer, phaeochromocytoma, retinal angioma and haemangioblastoma.

McDonnell J, Gild M, Clifton‐Bligh R, Robinson B. Multiple endocrine neoplasia: an update. Internal Medicine Journal. 2019;49(8):954–961.

https://onlinelibrary.wiley.com/doi/full/10.1111/imj.14394

16. Answer: D

Maturity‐onset diabetes of the young (MODY) is a group of inherited, non‐autoimmune diabetes which usually present in adolescence or young adulthood. It is caused by single gene mutations related to beta cell development, regulation, and function. These defects lead to impaired glucose sensing and insulin release. MODY should be suspected in patients with early‐onset diabetes in adolescence or young adulthood (typically age <35 years). They usually have atypical features for both type 1 and 2 diabetes.

Features atypical for type 1 diabetes:

 Absence of pancreatic islet autoantibodies

 Evidence of endogenous insulin production

 Measurable C‐peptide in the presence of hyperglycemia

 Low insulin requirement for treatment (<0.5 U/kg/day)

 Lack of ketoacidosis when insulin is omitted from treatment.

Features atypical for type 2 diabetes:

 Onset of diabetes before age 45 years

 Lack of obesity (unless south‐east Asian ethnicity, where type 2 diabetes occurs at lower BMIs)

 Normal triglyceride levels and/or HDL‐C

 Mild, stable fasting hyperglycemia that does not progress or respond appreciably to pharmacologic therapy

 Extreme sensitivity to sulfonylureas.

Ketonuria is often seen in type 1 diabetes especially when the patient develops DKA. However, it can occur in MODY during other complications such as sepsis, acute myocardial infarction, excessive alcohol intake, and prolonged fasting and is therefore not a useful test to differentiate between type 1 diabetes and MODY.

There are at least 14 genes that are associated with MODY. The four most common causes of MODY are the following: GCK‐MODY (MODY2) and HNF1A‐MODY (MODY3), each accounting for 30%–60% of all MODY. While HNF4A‐MODY (MODY1) and HNF1B‐MODY (MODY5), together account for about 10% of all MODY. Approximately 20% of all MODY has been attributed to pathogenic variants in ten other genes.

Establishing a specific genetic cause of MODY can help in management of the proband, genetic counseling of family members, and medical surveillance of at‐risk family members. Moreover, in certain cases, it can also assist in optimising diabetes therapy. A MODY multigene panel that includes the 14 known MODY‐related genes and other genes of interest is most likely to identify the genetic cause of MODY at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype.

Bishay R, Greenfield J. A review of maturity onset diabetes of the young (MODY) and challenges in the management of glucokinase‐MODY. The Medical Journal of Australia. 2016;205(10):480–485.

https://www.mja.com.au/journal/2016/205/10/review-maturity-onset-diabetes-young-mody-and-challenges-management-glucokinase

17. Answer: A

Paget's disease of bone (PDB) is a non‐malignant bone disease, characterised by abnormal bone remodelling at one or multiple sites. Increased osteoblast activity leads to increased bone formation which is paired with increased osteoclast activity. Although bone formation is increased, it is disorganised, mechanically weak, and prone to deformity and fractures. Risk factors of PDB include increasing age, male sex (1.4:1), and certain ethnicities (most commonly in Caucasians). Genetic mutations in the SQSTM1 gene, are identified in up to 50% patients with a family history of PDB and in 5–10% of patients without a family history of PDB. This genetic mutation impairs the ability of p62 to bind ubiquitin, leading to activation of receptor activator of nuclear kappa B ligand (RANKL)‐induced NF‐kB which increases the osteoclast activity.

PDB most commonly affects the pelvis, spine, femur, tibia, and skull. Clinical symptoms, signs, and complications of PDB are the results of abnormal bone remodelling, enlarged bones, marrow fibrosis, and increased vascularity of bone. Depending on the affected sites, hearing loss, obstructive hydrocephalus, spinal canal stenosis, paraplegia, and high‐output cardiac failure may occur. Although, bone pain is the most commonly presenting symptom, and classically presents with pain at rest and up to 25% of patients are asymptomatic.

Serum total ALP is recommended as a first‐line screening biochemical test in combination with the liver function test to identify metabolically active PDB. Radionuclide bone scans, and targeted XX‐ray of the abdomen, tibias, skull, and facial bones are recommended to determine the extent of active bone disease in patients with PDB. X‐rays typically demonstrate a mixed pattern of osteolysis and sclerosis in keeping with disease pathophysiology.

The treatment aim in PDB is to relieve symptoms rather than achieving normalising ALP. Bisphosphonates, especially zolendronic acid, may help alleviate bone disease associated pain. Total hip or knee replacements are recommended in patients with PDB who develop osteoarthritis and in whom medical management is inadequate to manage symptoms.

Ralston S, Corral‐Gudino L, Cooper C, Francis R, Fraser W, Gennari L et al. Diagnosis and Management of Paget's Disease of Bone in Adults: A Clinical Guideline. Journal of Bone and Mineral Research. 2019;34(4):e3657.

https://asbmr.onlinelibrary.wiley.com/doi/full/10.1002/jbmr.3657

18. Answer: B

Approximately 50% of patients who have had diabetes for >25 years will develop neuropathy. The most common form of diabetic neuropathy is distal symmetric, nerve‐length‐dependent polyneuropathy. Of these, approximately 50% will have pain as a symptom of neuropathy that is painful diabetic neuropathy (PDN). The prevalence of PDN in type 2 diabetes is more than twice that seen in type 1 diabetes.

Among patients with the same degree of neuropathy, some experience more pain than others. Pain is mediated by small fibresr, which may be damaged or destroyed in diabetic neuropathy, resulting in sensory loss. However, these small fibresr have the capacity to regenerate and to lead to ectopic generation of impulses and hyperexcitability, resulting in highly painful neuropathy in some patients. Moreover, pain nociception is complex and involves various other factors. Patients with normal findings on clinical examination and small‐fibre testing may also experience painful neuropathy.

Tight glycaemic control in patients with type 1 diabetes reduced the occurrence of clinical neuropathy by 60% in 5 years according to the Diabetes Control and Complications Trial. But it appears not to be enough to ameliorate the onset and progression of the disease in patients with type 2 diabetes. One of the reasons could be that the neuropathic process starts early in type 2 diabetes. The underlying mechanisms for the development of neuropathy in type 1 diabetes and type 2 diabetes appear to be different.

Sundara Rajan R, de Gray L, George E. Painful diabetic neuropathy. Continuing Education in Anaesthesia Critical Care & Pain. 2014;14(5):230–235.

https://www.sciencedirect.com/science/article/pii/S1743181617300847?via%3Dihub

19. Answer: A

Gastroparesis is a syndrome characterised by delayed gastric emptying in the absence of mechanical obstruction of stomach. The main symptoms include post‐prandial fullness, early satiety, bloating, nausea and vomiting. Gastroparesis is a serious complication of diabetes and is reported by 5 to 12% of patients with diabetes. It typically develops after at least 10 years of diabetes, and these patients generally have additional evidence of autonomic dysfunction. Other non‐diabetic causes of gastroparesis are neurologic disorders, surgery, medication, and idiopathic causes.

Gastric emptying involves integration of fundic tone and antral phasic contractions with inhibition of pyloric and duodenal contractility. Gastric emptying requires interactions between smooth muscle, enteric nerves, vagus nerve, and specialised pacemaker cells, the interstitial cells of Cajal (ICC).

 Autonomic neuropathy: Vagal neuropathy results in reduced pyloric relaxation, impaired antral contraction, disturbed antropyloric coordination, and reduced gastric secretion.

 Enteric neuropathy: The enteric nervous system (ENS) is the myenteric plexus, a network of nerves that is layered between the longitudinal and circular muscle layer of the gut and coordinates gastric motor function. Pathological changes in these pathways due to hyperglycaemia affect motor control and may contribute to delay emptying, impaired accommodation, and gastric dysrhythmia.

 Loss of ICC: This is the most common enteric neuropathological abnormality in diabetic and idiopathic gastroparesis. ICC generate slow waves that control smooth muscle contractility, are involved in aspects of neurotransmission, set the smooth muscle membrane potential gradient. A range of diabetes related mechanisms induce ICCs damage including insulinopaenia, IGF‐1 deficiency, and oxidative stress. Diabetes is a high oxidative stress state, which can cause loss of ICCs and delay gastric emptying.

 Glucagon like peptide‐1 (GLP‐1) treatment: Known causes of iatrogenic gastroparesis include vagal inhibition and pharmacological blockade such as GLP‐1 receptor agonist in the treatment of type 2 diabetes.

 Fluctuations in blood glucose: Acute increases in blood glucose may further delay gastric emptying, which in turn exacerbates blood glucose fluctuations that can then further impair gastric emptying rate. Delayed emptying can be the result of the pyloric contractions and antral hypomotility induced by the hyperglycaemic state. Once established, diabetic gastroparesis tends to persist, despite amelioration of glycaemic control.

Grover M. Gastroparesis: A turning point in understanding and treatment. Gut Published Online First: 28 September 2019.

https://gut.bmj.com/content/68/12/2238.abstract

20. Answer: B

Polycystic ovarian syndrome (PCOS) is the most common endocrinopathy in women and is associated with significant adverse sequelae that can affect overall health and well‐being. Physicians need to have a good understanding of the complications and develop strategies to prevent long‐term health morbidities for women who have been diagnosed with PCOS.

PCOS is diagnosed, after exclusion of other causes, and if the woman meets two of the following three features, including: (1) clinical and/or biochemical signs of hyperandrogenism, (2) oligo‐ or anovulation, and (3) polycystic ovaries (PCO) on abdominal USS. In adolescents or those within 8 years of menarche, ultrasound is not a reliable discriminator for PCOS. PCOS is classified into four phenotypes, which plays an important role in determining the metabolic and possibly long‐term complications of PCOS. The phenotypes are differentiated based on presence and absence of the three criteria of hyperandrogenism, ovulatory dysfunction, and ultrasound features of PCO and outlined in the table below. Phenotypes A and B account for two‐thirds of all cases.

	Hyperandrogenism	Oligomenorrhoea	Ultrasound features of PCO
Type A	Yes	Yes	Yes
Type B	Yes	Yes	No
Type C	Yes	No	Yes
Type D	No	Yes	Yes

Phenotypes A, B and C are associated with an increased risk of metabolic syndrome, whereas phenotype D is not associated with an increased metabolic risk as compared with the general population. Phenotypes A and B have higher rates of insulin resistance compared with the general population irrespective of BMI while the other phenotypes do not possess this characteristic, implying that hyperandrogenism contributes to insulin resistance. PCOS is responsible up to 80% of cases of anovulatory infertility. As women with PCOS have greater degrees of insulin resistance and secondary hyperinsulinemia than weight‐matched controls, they are at greater risk of developing long‐term complications including a higher lifetime risk of type 2 diabetes, non‐alcoholic fatty liver disease, metabolic syndrome, hypertension, dyslipidaemia, and possibly vascular complications (coronary artery disease and CVA). Venous thromboembolism is also more common in women with PCOS.

Studies have demonstrated an increased risk of endometrial cancer in women with PCOS but no increased risk of breast cancer in association with PCOS. Evidence has been mixed regarding the association of PCOS and ovarian cancer risk. Multiple studies have also demonstrated a consistent link between PCOS and mental health issues, including an increased prevalence of depression, anxiety, and decreased sexual satisfaction and quality of life.

Escobar‐Morreale H. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nature Reviews Endocrinology. 2018;14(5):270‐284.

https://www.nature.com/articles/nrendo.2018.24

21. Answer: A

Catecholamines produced by phaeochromocytomas are metabolised within chromaffin cells. Norepinephrine is metabolised to normetanephrine and epinephrine is metabolised to metanephrine. As conversion occurs within the tumour, independently of catecholamine release, phaeochromocytomas are best diagnosed by measurement of these metabolites rather than by measurement of the parent catecholamines.

Plasma fractionated metanephrines can be measured as a first‐line test for phaeochromocytoma. The negative predictive value for this test is extremely high. However, despite a high sensitivity of 96%, specificity of plasma fractionated metanephrine is low at 85%, and falls to 75% in patients older than 60 years and taking multiple antihypertensive medications. One study suggested that 97% of patients with hypertension seen in a tertiary care clinic who have a positive plasma fractionated metanephrine measurement will not have a phaeochromocytoma.

As such, 24‐hour urinary fractionated catecholamines and metanephrines should be performed first after a high level of plasma metanephrine. Specificity is highest for urinary epinephrine (99.9%), followed by urinary norepinephrine and dopamine (99.5% and 99.3%, respectively), and urinary total metanephrines (99.7%). If there is high clinical suspicion and elevated 24‐hour urinary fractionated catecholamines and metanephrines, clonidine suppression test can be used as a confirmatory test.

Plasma catecholamines no longer have a role in investigation for phaeochromocytoma because of poor overall accuracy. The 24‐hour urinary vanillylmandelic acid (VMA) excretion has poor diagnostic sensitivity and specificity compared with 24‐hour urinary fractionated metanephrines.

Biochemical confirmation of the diagnosis should be followed by radiological evaluation to locate the tumour. About 10% of the tumours are extra‐adrenal, but 95% are within the abdomen and pelvis. MRI can distinguish phaeochromocytomas from other adrenal masses: on T2‐weighted images, phaeochromocytomas appear hyperintense whilst other adrenal tumours appear isointense, as compared with the liver. However, MRI lacks the superior spatial resolution of CT. If abdominal and pelvic CT or MRI is negative in the presence of clinical and biochemical evidence of phaeochromocytoma, a metaiodobenzylguanidine (MIBG) scan should be ordered. MIBG is a compound resembling norepinephrine that is taken up by adrenergic tissue. It can detect tumours not detected by CT or MRI, or multiple tumours when CT or MRI is positive.

Neumann H, Young W, Eng C. Pheochromocytoma and Paraganglioma. New England Journal of Medicine. 2019;381(6):552–565.

https://www.nejm.org/doi/full/10.1056/NEJMra1806651

22. Answer: C

Iron deficiency anaemia is a common cause of a falsely elevated HbA1c. HbA1c is a marker of the average blood glucose levels over a 90–120 day period (the average life span of a RBC). This is because haemoglobin, like other plasma proteins, glycate in response to glucose exposure, and the degree of glycation is proportional to the average plasma glucose concentration. HbA1c is subsequently used to both diagnose and monitor diabetes treatment efficacy.

HbA1c is advantageous as there is low biological variability, so HbA1c is relatively stable during states of fasting or fed, well or unwell, and whether a sample is processed quickly or delayed. However HbA1c is also reliant on stable haemoglobin concentration. When this is not the case it can be falsely elevated or depressed:

 Factors which falsely decrease HbA1c (expose haemoglobin to less glucose):Decreased average RBC age, i.e. blood loss, haemolytic anaemia, CKD (chronic anaemia with decreased cell survival)Increased RBC turnover, i.e. pregnancy, erythropoietin therapy, chronic liver disease (secondary to splenomegaly)Decreased protein glycation, i.e. high dose vitamin C and E, alcohol, antivirals (e.g. ribavirin), antibiotics (e.g. trimethoprim)

 Factors which falsely increase HbA1c (expose haemoglobin to more glucose):Increased average age of RBCs, e.g. aspleniaDecreased RBC turnover, e.g. anaemia secondary to iron deficiency, vitamin B12 and folate deficiency.Increased protein glycation, e.g. iron deficiency anaemia.

In situations where HbA1c is not suitable for monitoring patients with diabetes, alternatives to consider include glucose profiling, total glycated haemoglobin, fructosamine, or glycated albumin.

Sodi, R., McKay, K., Dampetla, S. and Pappachan, J. (2018). Monitoring glycaemic control in patients with diabetes mellitus. BMJ, p.k4723.

https://www.bmj.com/content/363/bmj.k4723

23. Answer: A

This patient has a large symptomatic pituitary tumour and encroachment of surrounding structures resulting in visual field deficit. With pituitary tumours, prolactin levels correlate with the tumour size. In other words, the bigger the tumour size the higher the prolactin level. This patient has a large tumour but only slightly elevated prolactin level relative to the tumour size, so this tumour is unlikely to be a prolactinoma. Therefore, the appropriate management is surgical, not conservative management using cabergoline. In contrast, if the tumour is small but the prolactin level is very high, then it is likely a prolactinoma and a dopamine receptor agonist such as cabergoline treatment should be the first choice.

Based on its size, a pituitary adenoma can be classified as a microadenoma (<10 mm diameter) or a macroadenoma (>10 mm diameter). Approximately 50% are microadenomas. Prolactinomas are the most common hormone‐secreting pituitary tumours accounting for 32 to 66% of adenomas. Symptoms and signs of prolactinomas are shown in Table 4.2. Female patients usually have small prolactinomas at diagnosis because the symptoms of galactorrhoea and amenorrhoea result in an early presentation. Patients may present with headaches which can have variable quality and location due to stretching of the dura.

Table 4.2 Clinical features for prolactinoma.

Female clinical features	Male clinical features	Both male and female features
Galactorrhoea	Hypogonadism	Headache
Amenorrhoea	Reduced libido	Visual field deficit
Infertility	Erectile dysfunction	Osteoporosis
	Gynaecomastia
	Infertility

Laboratory investigations for suspected prolactinoma include the following:

 Serum prolactin level and macroprolactin level if clinically needed

 Serum pregnancy test

 Serum TSH

 Serum testosterone or bioavailable testosterone: In males presenting with symptoms of hypogonadism

 Basal cortisol level and short Synacthen test in patients with a history suggestive of adrenal insufficiency or any patient before surgery

 Renal function tests, impaired renal function can lead to impaired prolactin clearance.

After performing biochemical and hormonal tests, MRI or CT head with contrast is used to determine if a mass lesion is present. If no mass lesion is present, it is also important to note that prolactin may be elevated due to a range of medications, including dopamine antagonists such as antipsychotics, drugs that affect gastric motility such as metoclopramide and domperidone and certain antihypertensives such as methyldopa.

Patients with pituitary adenomas should be identified at an early stage so that effective treatment can be planned. For all other pituitary adenomas, initial therapy is generally transsphenoidal surgery with medical therapy being reserved for those not cured by surgery. For prolactinomas, treatment is indicated if mass effects from prolactinoma and/or significant effects from hyperprolactinemia are present. The initial therapy is generally dopamine agonists, which not only decrease the synthesis and secretion of prolactin but also the rate of tumour cell division and the growth of individual cells. Cabergoline, an ergot derivative, is a long‐acting dopamine agonist. It is usually better tolerated than bromocriptine and its efficacy profiles are superior to bromocriptine. It offers the convenience of twice‐a‐week administration, with a usual starting dose of 0.5 mg. Bromocriptine is an ergoline derivative and dopamine agonist. It had been used in the treatment of prolactinoma because of its long track record and safety. In macroprolactinomas, bromocriptine treatment results in some reduction of tumour size in up to 80–85% of the patients.

Transsphenoidal pituitary adenomectomy is the preferred surgical treatment in patients with macroprolactinoma and patients with microprolactinoma who fail to respond to medical treatment. A combination of surgery followed by postoperative medical treatment with bromocriptine or one of the other agents is used in patients with incomplete resolution of elevated prolactin levels and in patients with residual tumours seen on follow‐up imaging studies.

Molitch ME. Diagnosis and treatment of pituitary adenomas A Review. JAMA. 2017;317:516–524.

https://jamanetwork.com/journals/jama/article-abstract/2600472

24. Answer: D

Two types of continuous glucose monitoring (CGM) systems are now available: real‐time CGM (rtCGM) and intermittently scanned CGM (isCGM). Current rtCGM system automatically transmits a continuous stream of glucose data (trend and numerical) in real time to a receiver, smart watch, or smartphone and provides alerts and active alarms. The current isCGM system provides the same type of glucose data but requires the user to purposely scan the sensor to obtain information and does not have alerts and alarms. CGM systems provide continuous measurement at 1–5 min increments of glucose concentrations in the interstitial fluid, which correlate with blood glucose levels. The lag time between the interstitial fluid glucose measured by rtCGM and plasma glucose is a limitation to the real‐time actionable data provided by devices. Moreover, all current systems for rtCGM are less accurate in the lower glucose ranges but are improving in this regard.

Numerous recent studies have demonstrated the clinical efficacy and other benefits of rtCGM use in individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D) regardless of the insulin delivery method used. There is a modest reduction in HbA1c. rtCGM reduced the time spent in the hypoglycaemic (T1D only) and hyperglycaemic ranges and demonstrated reductions in moderate to severe hypoglycaemia in individuals with T1D and T2D compared with traditional self‐monitoring of blood glucose (SMBG).

Recent studies have also demonstrated the benefits of rtCGM as an integrated component of sensor‐augmented insulin pumps with predictive low glucose suspend functionality. Automatic insulin pump suspension can help individuals with T1D avoid hypoglycaemia without significantly increasing hyperglycaemia or the risk of diabetic ketoacidosis. Guidelines recommended the use of rtCGM in individuals with recurrent severe hypoglycaemia and/or impaired hypoglycaemia awareness. The beneficial effects of rtCGM use have not only been shown in poorly controlled T1D, but also in individuals who have achieved good control, by reducing glycaemic variability.

Individuals who could benefit from data sharing capability (e.g. paediatric patients, the elderly, patients with mental health illness and patients who travel alone) are also good candidates for rtCGM. Other candidates for rtCGM use include individuals who have a high HbA1c, are physically active, want to use insulin pump systems that offer predictive low glucose suspend functionality, experience hypoglycaemia fear, or desire tighter glucose control than obtained with their current monitoring system.

In summary, based upon the current evidence, use of rtCGM is now recognised as the standard of care for individuals with T1D and a subset of those with insulin‐requiring T2D.

Edelman S, Argento N, Pettus J, Hirsch I. Clinical Implications of Real‐time and Intermittently Scanned Continuous Glucose Monitoring. Diabetes Care. 2018;41(11):2265–2274.

https://care.diabetesjournals.org/content/41/11/2265.long

25. Answer: D

Multiple side effects have been identified for treatment with SGLT‐2 inhibitors, including those listed as answer options as well as bone fracture. However, individual trials lack the power to detect significant differences in these rare adverse outcomes. As a result multiple meta‐analyses have been performed with the intention of clarifying these post‐marketing observations. The most recent of which showed no overall difference in fracture, or UTI – except that dapagliflozin alone independently increases the risk of UTI. Despite some reports, SGLT‐2 inhibitors are strongly protective against AKI and recent evidence suggests it is protective against progression of chronic diabetic kidney disease. DKA can occur in the setting of acute physiological stress without hyperglycaemia when treated with SGLT‐2 inhibitors, but the overall rate of DKA is not greater in treated patients. There is some suggestion that SGLT‐2 inhibitors may increase the risk of limb amputation, although meta‐analysis of available trial data is significantly underpowered to draw this conclusion, and absolute risk is very low.

Overall the fairly significant medium‐term benefits of this class of drug are compelling reasons for significantly expanded use, and individual practitioners need to be aware of individual situations that pose excess risk for a patient on this class of medication. Two significant such situations are physiological stress and volume depletion, where relative insulin insufficiency and excess diuresis can lead to DKA and AKI, respectively.

Donnan J, Grandy C, Chibrikov E, Marra C, Aubrey‐Bassler K, Johnston K et al. Comparative safety of the sodium glucose co‐transporter 2 (SGLT2) inhibitors: a systematic review and meta‐analysis. BMJ Open. 2019;9(1):e022577.

https://bmjopen.bmj.com/content/9/1/e022577

26. Answer: D

The tests are most indicative of subclinical hypothyroidism, which is most likely due to autoimmune (Hashimoto) thyroiditis. Randomised trial data suggests that treatment of subclinical hypothyroidism is not warranted in older adults, however observational data suggests that treatment may be considered in pregnant women, or if TSH is over 7.0 mIU/L. Treatment can also be considered in younger individuals, particularly females with a possibility of becoming pregnant and patients with multiple symptoms attributable to hypothyroidism. Certainly, there is a general recommendation for treatment in individuals with TSH equal to or greater than 10.0 mIU/L. Other possible indications for treatment are thyroid peroxidase antibody positivity or presence of a goitre. Observational data also suggest that individuals with subclinical hypothyroidism have a greater prevalence of heart failure, coronary heart disease mortality and fatal stroke.

Diagnosis of subclinical hypothyroidism requires measurement of normal FT4 despite elevated TSH. As levels fluctuate for an individual, repeat measurements are required to confirm subclinical hypothyroidism or progression to hypothyroidism. For measurements of TSH between 4.5 and 14.9 mIU/L, reassessment should be conducted in 1–3 months to maximise clinical relevance. However, if the TSH is over 14.9 mIU/L, assessment should be repeated more expediently as a transition to overt hypothyroidism is more likely.

If treatment is initiated for subclinical hypothyroidism, TSH should be measured after six weeks of levothyroxine therapy in order to adjust the dosage accordingly. Annual measurements of TSH are generally sufficient thereafter.

Biondi B, Cappola A, Cooper D. Subclinical Hypothyroidism. JAMA. 2019;322(2):153.

https://jamanetwork.com/journals/jama/article-abstract/2737687

27. Answer: C

Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, and the most common form of thyroid cancer caused by exposure to radiation. Total thyroidectomy is the mainstay of treatment in patients with PTC. Radioactive iodine ablation and long‐term TSH suppression using thyroxine are also important adjuvant therapies.

An excellent response to the initial treatment is defined by an undetectable serum thyroglobulin, the absence of both thyroglobulin antibodies and abnormal findings on neck ultrasound.

The purpose of follow‐up is for early detection and treatment of persistent or recurrent locoregional or distant PTC. Most local recurrences develop within the first 5 years after treatment. However, in a few cases, local or distant recurrence may develop within 10–20 years after the initial treatment.

Three months after initial treatment, TFTs should be done to check the adequacy of thyroxine suppressive therapy. Follow‐up at six to twelve months should ascertain whether or not the patient is free of disease. This follow‐up should include a physical examination, neck ultrasound, and a check of basal and recombinant human TSH (rhTSH)‐stimulated serum thyroglobulin measurement. At this time, about 80% of the patients will have a normal neck ultrasound, an undetectable (<1.0 ng/ml) stimulated serum thyroglobulin in the absence of serum thyroglobulin antibodies, and will be classified in the low‐risk category or in complete remission. The rate of subsequent recurrence is very low (<1.0% at 10 years). Diagnostic whole‐body bone scan does not add any clinical information in this setting and is not required.

Recently, new methods for obtaining serum thyroglobulin measurement with functional sensitivity below 0.1 ng/ml have become available. An undetectable basal serum thyroglobulin (<0.1 ng/ml) may give the same information as a stimulated thyroglobulin test, thus negating the need for thyroglobulin stimulation. However, the higher negative predictive value of these tests comes at the expense of a very low specificity, and risks exposing large numbers of patients, who are probably free of disease, to extensive testing and/or unnecessary treatment.

In clinical practice, when basal serum thyroglobulin is ≤0.1 ng/ml and neck ultrasound is unremarkable, patients may be considered free of disease (negative predictive value, NPV = 100%) and a rhTSH stimulation can be avoided. However, if basal serum thyroglobulin is between 0.1 ng/ml and 1.0 ng/ml, it is not possible to distinguish between the absence or presence of disease; rhTSH stimulation testing is then necessary.

The subsequent follow‐up of patients considered free of disease at 6–12 months should consist of physical examination, basal serum thyroglobulin measurement on thyroxine and neck ultrasound once per year.

Patients with a high risk of disease recurrence who do not respond excellently to treatment should be followed up with serum TSH, thyroglobulin and anti‐thyroglobulin antibody determination and neck ultrasound every 6–12 months.

Measurement of the serum thyroglobulin level with anti‐thyroglobulin antibodies to validate accuracy of the thyroglobulin assay is important. In the absence of residual normal thyroid tissue (after surgical and radioiodine ablation), thyroglobulin is a marker of residual or recurrent papillary or follicular thyroid carcinoma.

Lamartina L, Grani G, Durante C, Borget I, Filetti S, Schlumberger M. Follow‐up of differentiated thyroid cancer – what should (and what should not) be done. Nature Reviews Endocrinology. 2018;14(9):538–551.

https://www.nature.com/articles/s41574-018-0068-3

28. Answer: A

The vast majority of driver mutations in thyroid carcinoma come from the MAPK pathway, which dominates the oncogenesis of both papillary and follicular thyroid cancers, and together account for around 85% of thyroid cancer diagnoses. Of these mutations, alterations in BRAF V600E accounts for the majority, and less commonly RAS, NTRK, ALK, or RET. Anaplastic thyroid cancers have high mutational variation involving multiple pathways, but are rare, and associated with poor mean survival. Medullary thyroid cancers are typically associated with gain‐of‐function mutations in RET, a proto‐oncogene in the MAPK pathway.

Fagin J, Wells S. Biologic and Clinical Perspectives on Thyroid Cancer. New England Journal of Medicine. 2016;375(11):1054–1067.

https://www.nejm.org/doi/10.1056/NEJMra1501993

29. Answer: C

Thyroid nodules are common in the general population. They are palpable in 4–7% of the population and have been detected using ultrasound in up to 60% of adults. The majority of nodules are benign but approximately 7–15% of thyroid nodules are thyroid cancer.

TFTs should be performed in all patients with a thyroid nodule on examination. While most patients will be euthyroid, a suppressed TSH level indicates a hyperfunctioning nodule and the risk of malignancy is extremely low. Serum calcitonin levels should only be requested when a medullary thyroid carcinoma is suspected.

The ultrasound assessment provides key information regarding the size and sonographic features of the nodules, which form the basis for risk stratification. A decision to proceed to fine‐needle aspiration (FNA) is typically made based on ultrasound appearance. Features taken into consideration include size and shape of the nodule and other features including homogeneity, presence of micro‐calcifications and vascularity. Ultrasound‐guided FNA is the most sensitive and cost‐effective method to assess the nature of thyroid nodules and the need for surgery. The Thyroid Imaging Reporting and Data System (TIRADS) score and size of the nodule are used to guide whether FNA should be performed. Guidelines recommend FNA for nodules ≥1 cm that have a high pattern of suspicion on ultrasound, ≥1.5 cm that have a moderate suspicion pattern on ultrasound, and nodules ≥2.5 cm that have a mildly‐suspicion pattern on ultrasound. If the cytologic findings are interpreted as non‐diagnostic, FNA should be repeated within 3 months to obtain sufficient cells for a more definitive diagnosis.

Molecular analysis should be performed in patients with atypia of undetermined significance, follicular lesions of undetermined significance (AUS/FLUS), follicular neoplasm or suspicious for a follicular neoplasm in FNA. One molecular approach is to analyse the specimen by means of a gene‐expression classifier to rule out cancer. The other molecular approach is to directly assess the FNA for BRAF and RAS mutations. If the FNA is positive for a BRAF mutation, the chance of cancer is close to 100%, and if the FNA is positive for a RAS mutation, the chance of cancer is 80 to 90%.

Durante C, Grani G, Lamartina L, Filetti S, Mandel S, Cooper D. The Diagnosis and Management of Thyroid Nodules. JAMA. 2018;319(9):914–924.

https://jamanetwork.com/journals/jama/article-abstract/2673975

30. Answer: C

Transgender (TGD) people are individuals whose gender identity is markedly and persistently incongruent with their sex assigned at birth. About 0.6% of the population identifies as TGD in Western countries. Gender‐affirmation treatment should be multidisciplinary and include diagnostic assessment, psychotherapy, counselling, real‐life experience, hormone therapy, and surgical therapy.

Hormonal therapy is effective at aligning physical characteristics with gender identity and improving mental health symptoms.

 Masculinising hormone therapy options include transdermal or intramuscular testosterone at standard doses.

 Feminising hormone therapy options include transdermal or oral estradiol. Additional anti‐androgen therapy with cyproterone acetate or spironolactone is typically required.

No data exists on gradual versus rapid titration or comparison of formulations in feminising TGD individuals. The value of biochemical monitoring is uncertain; when performed, trough estradiol levels should be used. Target estradiol levels should be between 250–600 pmol/L and total testosterone levels is < 2 nmol/L. Despite anecdotal reports that progestins increase breast growth, no data supports their use. Furthermore, progestins can increase risk of coronary artery disease, thrombosis, and weight gain. Cyproterone acetate, a commonly used anti‐androgen agent, has progestogenic effects. Anti‐androgens are often required in addition to estradiol therapy to lower endogenous testosterone levels or inhibit testosterone effects. Spironolactone (100–200 mg daily) or cyproterone acetate (12.5–25 mg daily) are both effective. Gonadotrophin‐releasing hormone analogues are used as puberty blockers in adolescents only.

Hormonal therapy can impair fertility and patients should receive counselling for this prior to commencing gender affirming treatment. Sperm cryopreservation should be discussed before estradiol therapy due to expected changes in spermatogenesis. Oocyte storage can be considered; however, ovulation typically resumes on cessation of testosterone therapy.

Cheung A, Wynne K, Erasmus J, Murray S, Zajac J. Position statement on the hormonal management of adult transgender and gender diverse individuals. Medical Journal of Australia. 2019;211(3):127–133.

https://www.mja.com.au/journal/2019/211/3/position-statement-hormonal-management-adult-transgender-and-gender-diverse

31. Answer: E

32. Answer: F

33. Answer: D

34. Answer: H

Obesity is a complex, multifactorial disorder that has genetic, biological, and environmental origins. Traditional treatments consist of counseling, restrict calories intake, and lifestyle changes such as eating a nutrient‐dense diet, participating in regular physical activity, and other behaviour modifications. Medications commonly used in the treatment of obesity include orlistat, phentermine, topiramate, naltrexone, and liraglutide. Many patients with severe obesity (BMI≥40) are unable to lose and maintain significant weight loss. Bariatric surgery is an effective treatment morbid obesity because it leads to sustained weight loss, reduction of obesity‐related comorbidities and mortality, and improvement of quality of life.

There are three types of bariatric surgery:

1 Restrictive: Laparoscopic sleeve gastrectomy (LSG), laparoscopic adjustable gastric banding (LAGB, a restrictive procedure to induce early satiety through reduction of gastric capacity).

2 Malabsorptive: Biliopancreatic diversion (BPD) with or without duodenal switch comprises this category of bariatric surgery. Each has only a minimal restrictive component that involves the creation of a sleeve like stomach.

3 Restrictive Malabsorptive: Proximal Roux‐en‐Y gastric bypass (RYGB) is a restrictive‐malabsorptive technique. Gastric capacity is reduced by 90%. The section of the gastrointestinal tract bypassed is called the biliopancreatic limb, which includes the majority of the stomach, the duodenum, and part of the jejunum. This limb drains bile, digestive enzymes, and gastric secretions to assist digestion and absorption further down the gastrointestinal tract. The proximal to mid‐end of the jejunum is anastomosed to the gastric pouch for malabsorption. This creates the common limb. The food and enzymes ingested are mixed only in the small area of the common limb, compromising absorption of certain nutrients.

Macro‐ and micronutrient deficiencies are common in patients after obesity surgery. It is estimated that BPD with or without duodenal switch can cause a 25% decrease in protein absorption and a 75% reduction in fat absorption. Ten vitamins and minerals that depend on fat absorption for optimal bioavailability, such as vitamins A, D, E, and K and zinc, will have impaired absorption. Moreover, the delay in gastrointestinal transit time may increase the risk of many other micronutrient deficiencies, including iron, calcium, vitamin B12, and folate. Low serum levels of fat‐soluble vitamins (vitamin A, K and E) have been found after BPD and RYGB. Water‐soluble vitamins such as thiamine deficiency can occur in up to 49% of patients after surgery as a result of bypass of the jejunum, where it is primarily absorbed, or in the presence of impaired nutritional intake from persistent, severe vomiting. Patients may have preexisting thiamin deficits. Thiamin deficiency can cause high‐output heart failure, wet beriberi. Gastric banding patients also may be at risk, particularly if they experience intractable vomiting because thiamin has a short half‐life, meaning that thiamin stores last only a few days in the body.

A vitamin B12 deficiency is uncommon among gastric banding patients. A study found a 10 to 26% prevalence of vitamin B12 deficiency among gastric sleeve patients. Clinical manifestation of vitamin B12 deficiency includes paraesthesias, difficulty maintaining balance, poor memory, depression, loss of proprioception and vibratory sensation, peripheral neuropathy, gait abnormalities, cognitive impairment, glossitises, and macrocytic anemia.

Zinc is a mineral that helps maintain the immune system and is associated with cell division, cell growth, wound healing, and carbohydrate metabolism. A zinc deficiency also exacerbate hair loss, which is common within the first six months after bariatric surgery. Furthermore, patients who are zinc deficient may experience a metallic taste in their mouths. Studies had shown that BPD and RYGB patients are more likely to be at risk of zinc deficiency. However, one study found that 34% of gastric sleeve patients experienced zinc deficiency post‐surgery.

During routine clinic follow‐up after bariatric surgery, it is important to monitor weight loss progress and complications each visit, monitor adherence to appropriate diet and physical activity levels, review medications (avoid NSAIDs, adjust antihypertensives, cholesterol‐lowering medications, and diabetes medications as appropriate). Changes in drug absorption and bioavailability in post‐bariatric surgery patients make dosage adjustment important for some of the prescribed medications. The requirement for diabetes medications often reduced after bariatric surgery.

In terms of nutritional supplements, patients should be taking adult multivitamin and multimineral which contain iron, folic acid, thiamine, vitamin B12 (doses: two tablets daily for LSG or RYGB; one daily for adjustable LAGB), calcium 1200–1500 mg/day, titrate 25‐OH vitamin D levels >30 ng/mL, typical dose of Vitamin D required is 3000 IU/day. Additional iron and vitamin B12 supplementation is usually required and dosage is based on lab results. Laboratory assessments should include FBE, urea, creatinine and electrolytes, LFTs, uric acid, glucose, lipids (every 6–12 months), 25‐OH vitamin D, PTH, calcium, albumin, phosphate, B12, folate, iron studies annually, more frequently if deficiencies identified.

Lee P, Dixon J. Bariatric–metabolic surgery: A guide for the primary care physician. Austral Family Physician. 2017;46(7):465–471.

https://www.racgp.org.au/download/Documents/AFP/2017/July/AFP-Focus-Bariatric-metabolic-surgery-2017.pdf

35. Answer: F

36. Answer: H

Hypothyroidism is one of the most common endocrine disturbances alongside diabetes. It may present in the elderly with very non‐specific symptoms and signs. It should be considered in the differential diagnosis of anyone presenting with confusion (so‐called part of the ‘dementia’ screen) and general deterioration with no readily identifiable cause. It should not be missed as a cause of a range of symptoms from neurological signs, typically bradykinesia, reduced deep tendon reflexes, and paraesthesias from nerve entrapment (especially carpal tunnel syndrome) to abdominal pain from chronic constipation to mental disturbance manifest as confusion and apparent memory impairment. Other subtle signs of hypothyroidism include loss of the outer one‐third of the eyebrows with male‐pattern frontal balding, hypothermia, bradycardia, non‐pitting oedema (myxoedema), and dry, coarse skin.

TFTs are usually diagnostic and demonstrate a low free thyroxine (T4) with a high TSH in primary hypothyroidism. Very occasionally a low TSH and a low free T4 may be seen in the context of panhypopituitarism and assay of levels of sex hormones, ACTH, and other pituitary hormones will confirm the diagnosis.

Lithium is used in the treatment of bipolar disorder. It can cause major disturbance in water balance, manifest by polyuria and secondary polydipsia. This is because of decreasing urinary concentrating ability resulting from impaired responsiveness of the distal nephron to anti‐diuretic hormone (ADH) which is known as nephrogenic diabetes insipidus. In most cases there is a correlation between impaired urinary concentrating ability and duration of lithium therapy or total lithium dose.

Nephrogenic diabetes insipidus in adults is usually partial with mild symptoms. Usually the serum sodium is normal or mildly elevated, the plasma osmolality is within normal range, the urine osmolality is low (<300 mOsmol/kg) and the urine volume is between 2.5 and 6 L/day. However when patients are fluid depleted, there is a marked rise in serum sodium, a rise in plasma osmolality urine osmolality that may exceed that of plasma. The water deprivation test is useful in diagnosis: the urine osmolality is usually <300 mOsmol/kg after dehydration with no further or a minimal (<95) rise after desmopressin. In partial nephrogenic diabetes insipidus, the urine osmolality is between 300 and 750 mOsmol/kg after dehydration and is <750 mOsmol/kg after desmopressin. Lithium‐induced nephrogenic diabetes insipidus is usually reversible on stopping therapy but a few patients remain symptomatic long after the lithium has been discontinued. If the urine volume exceeds 4 L/day, treatment with thiazides and amiloride has been advocated. Preventive measures include education of patients and their carers about maintaining adequate hydration. The serum lithium level should be kept between 0.5 and 0.8 mmol/L. Annual measurement of 24‐hour urine volume is a simple and effective screening test.

Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. International Journal of Bipolar Disorders. 2016;4(1).

https://journalbipolardisorders.springeropen.com/articles/10.1186/s40345-016-0068-y