Endocrine

T1DM - Formulate an appropriate management plan, including newly diagnosed and established diabetic patients to prevent short and long term complications

1) acute - see DKA 2) ongoing - a) 1st line - basal-bolus insulin eg/ insulin glargine or isophane human (NPH) or detemir or degludec + insulin neutral or lispro or aspart or glulisine or pump: uses regular insulin or insulins lispro, aspart, or glulisine i) initial total daily dose of insulin in adults = 0.2-0.4 units/kg/day. In children = 0.5-1.0 units/kg/day, puberty = may inc to 1.5 units/kg/day. Often, when first started on insulin, patients may have a honeymoon period & only need 10-15 units/day. ½ total dose = basal insulin + ½ as bolus dosing. Bolus is divided and given before meals. Patients need to self-monitor their blood glucose levels. The insulin doses can be adjusted every 2-3 days to maintain pre-meal and post-meal blood glucose targets ii) simplest approach for mealtime insulin requirements - suggest 4 units for a small meal, 6 units for a medium-sized meal, and 8 units for a larger meal. Can also carb count for inc flexibility eg/ 1 unit of mealtime insulin for every 15 g of carb. Using a food diary and 2-hour postprandial blood glucose, the insulin-to-carbohydrate ratio can be adjusted. Regular insulin given 30 mins prior to the meal, rapid-acting insulins (lispro, aspart, or glulisine) 15 mins before to shortly after a meal. NPH and insulin detemir = BD, insulin glargine = OD. Pts with interest and good self-management skills may prefer to use an insulin pump. b) +/- pre-meal insulin correction dose: may be added to bolus insulin based on the pre-meal blood glucose level. Correction dosing = 1800/TDD = the predicted point drop in blood glucose per unit of rapid acting insulin. For example, if the TDD is 40 units of insulin, 1800/40 = 45 point drop per unit of insulin. Number used for correction dose may be 1500-2200. Lower number for obese, insulin-resistant patients, higher for lean, insulin-sensitive patients. This correction dose can be added to the patient's mealtime insulin requirement and given as the total bolus dose c) +/- amylin analogue eg/ pramlintide (protein co-secreted with insulin by pancreatic B cells, dec postprandial glucose inc by prolonging gastric emptying time, dec postprandial glucagon secretion, and dec food intake through centrally mediated appetite suppression), given as injection before each meal to get more stable glycaemic control. At initiation pre-meal insulin dose should be dec by 50% to avoid hypoglycaemia, and then titrated up. Used eg/ when pt has high postprandial glucose, then late hypoglycaemia when pre-meal insulin is inc d) 2nd line - fixed-dose insulin: insulin isophane human/insulin neutral: (50/50, 70/30) or aspart protamine/insulin aspart: (70/30) or lispro protamine/insulin lispro: (50/50, 75/25) or degludec/insulin aspart: (70/30). Fixed-dose insulin used when pts doing well on a fixed-dose regimen; or cannot manage 3-4 insulin injections daily; or have trouble mixing insulin 3) pregnant - a) 1st line - basal-bolus insulin: insulin isophane human (NPH) or detemir + insulin neutral or lispro or aspart i) blood sugar goals - fasting <5 mmol/L, 1-hour postprandial <7.2 mmol/L, 2-hour postprandial <6.7 mmol/L ii) pts should monitor their blood glucose 4-7 times per day and the pattern examined every few weeks early in pregnancy so that nutrition content and timing, exercise patterns, and the insulin doses can be modified to achieve optimal control iii) insulin requirements inc early in pregnancy, then dec from 8-16 weeks then rise again b) + low-dose aspirin (75mg) starting at end of 1st trimester to dec risk of pre-eclampsia

Elucidate a full diabetic medical history

1) ask about common s/s - a) weight gain or loss b) polyuria/polydypsia/polyphagia c) weakness/fatigue d) blurred vision e) recent skin or other infection f) vulvovaginitis/balanitis g) abdominal pain NB/ for T2DM may be asymptomatic or may present with some of the above 2) meds - check if using: a) corticosteroids (both short term and long term use can ↑ blood glucose) b) medication compliance/adherence (inadequately controlled blood glucose can be a manifestation of a problem with adherence to therapy) 3) fmx of DM (more common in T2DM) 4) social history including alcohol and cigarettes 5) disease complications - check for end-organ complications - a) cardiac symptoms b) autonomic postural hypotension c) gastroparesis d) diarrhoea or constipation e) urinary retention f) impotence g) lower extremity pain or numbness 6) diet history - a) home glc monitoring results b) total caloric intake c) intake of sugar-containing foods, saturated fat & cholesterol d) physical activity level e) timing of meals in type I diabetes

T2DM - Formulate an appropriate management plan, including newly diagnosed and established diabetic patients to prevent short and long term complications

1) at initial diagnosis - a) lifestyle changes: personalised self-management programme developed by a diabetes education nurse or nutritionist - healthy diet (optimal mix of carbs, fats, and protein depends upon renal status, achieved lipid levels, BMI, and level of glycaemic control) + exercise (3-4 sessions of aerobic physical activity per week, with each session lasting ~ 40 mins and involving moderate- to vigorous-intensity physical activity) + dec alcohol + smoking cessation b) + glycaemic management: stratified glycaemic management upon diagnosis - meds based on HbA1c, for most metformin will be initial therapy, but insulin may be required for marked hyperglycaemia c) + BP management eg/ hydrochlorothiazide or chlortalidone or indapamide +/- lisinopril or enalapril or captopril or candesartan or irbesartan or losartan +/- amlodipine or felodipine or nifedipine or diltiazem (adults with T2DM have 2x risk of stroke/MI, aim BP <140/90 mmHg or <130/80 mmHg if diabetes + CV disease or CV risk >15%) NB/ often need combo therapy - ACEI = best choice for T2DM (careful with insulin or sulfonylureas as may cause hypos), black = thiazide diuretic or CCB, CKD = ACEI or AGIIRA d) + lipid management - dose dependant on CV risk eg/ atorvastatin, simvastatin (adults with T2DM have 2x risk of stroke/MI, >40x inc risk of death from macrovascular than microvascular complications of diabetes) NB/ high-intensity statin therapy if atherosclerotic CV disease or 10-year CV risk >20% or LDL-cholesterol ≥4.9 mmol/L. Otherwise moderate-intensity statin if 45-70 yo, individual approach if >75 e) +/- antiplatelet therapy (if CV disease or >50) eg/ aspirin 75mg +/- clopidogrel 75 mg 2) acute - a) marked hyperglycaemia non-pregnant: serum glucose ≥16.6 mmol/L or HbA1c ≥86 mmol/mol or symptomatic - i) 1st line - basal-bolus insulin + CV risk reduction/lifestyle measures: insulin isophane human (NPH - subcut BD) + insulin neutral (subcut BD); or insulin glargine or detemir or degludec + insulin lispro or aspart or glulisine or isophane human/insulin neutral: (50/50, 70/30) or aspart protamine/insulin aspart: (70/30) or lispro protamine/insulin lispro or degludec/insulin aspart: (70/30) NB/ immediate insulin therapy should be considered for marked hyperglycaemia. Start with long-acting insulin at 0.1 to 0.2 units/kg/day in the morning or bedtime, then adjust by 2-4 units every 3 days until fasting blood sugar within target range. If pre-meal sugars remain over target, rapid-acting insulin+ can be added at meals (~4 units) and titrated by 2 units every 3 days. Pre-mixed insulin may start with 0.3 units/kg/day dose of insulin - 2/3 in AM & 1/3 in PM ii) +/- metformin: 500 mg orally (immediate-release) OD, inc by 500 mg/day increments every week, maximum 1000 mg BD b) without marked hyperglycaemia non-pregnant asymptomatic: serum glucose <16.6 mmol/L or HbA1c <86 mmol/mol - i) CV risk reduction/lifestyle measures ii) if HbA1c below goal = metformin iii) if HbA1c above goal on metformin = + sodium-glucose co-transporter 2 (SGLT2) inhibitor eg/ empagliflozin or canagliflozin or dapagliflozin or ertugliflozin (NB/ may lead to ketoacidosis); or glucagon-like peptide 1 (GLP-1) agonist eg/ liraglutide or dulaglutide or semaglutide or exenatide or lixisenatide or dipeptidyl peptidase-4 (DPP-4) inhibitor eg sitagliptin or linagliptin or alogliptin or saxagliptin or sulfonylurea or meglitinide eg/ glimepiride or glipizide or gliclazide or basal insulin + metformin + continued cardiovascular risk reduction/lifestyle measures iii) 2nd line - metformin + continued cardiovascular risk reduction/lifestyle measures + alpha-glucosidase inhibitor eg/ acarbose or miglitol or thiazolidinedione eg/ pioglitazone iv) HbA1c above goal on metformin + either basal insulin or second non-insulin agent - 3 drug combination including metformin + 2 of the above; or switch to basal-bolus insulin +/- metformin +/- bariatric surgery (BMI >35 + hyperglycaemia not controlled by lifestyle and optimal medical mx) 3) pregnant - diet + basal-bolus insulin: insulin isophane human (NPH - BD) + insulin neutral (BD/TDS) or insulin lispro (TDS) or insulin aspart (TDS) NB/ blood glucose targets in pregnant women with pre-existing T2DM (or gestational diabetes): <5.3 mmol/ fasting and either ≤7.8 mmol/L 1-hour postprandially or ≤6.7 mmol/L 2-hour postprandially; HbA1c target 42-48 mmol/mol (6-6.5%)

Definition & pathophysiology & epidemiology of Turner's

1) chromosomal disorder involving a complete or partial absence of the second sex chromosome in phenotypic females. Occurs equally in all races. <10% diagnosed antenatally; 20% in infancy (lymphoedema, neck webbing, or congenital heart defects). Most at 10-16 (short stature + delayed puberty). 10% adulthood (secondary amenorrhoea). Incidence of about 1/5000 live female births due to antenatal diagnosis associated with terminations of pregnancies 2) aetiology - no known predisposing or causative factors. Sporadic except for rare cases in which a small X chromosome deletion may be passed from mother to daughter 3) pathophysiology - specific pathophysiology behind the developmental anomalies seen in Turner's syndrome is poorly understood: a) impaired long-bone growth and skeletal development leading to short stature linked with haplo-insufficiency for a specific sex chromosome gene, SHOX, located in the PAR, which encodes a transcription factor expressed in developing bone and cartilage b) haplo-insufficiency for other pseudo-autosomal genes causes the congenital cardiovascular defects that produce high mortality in Turner's syndrome c) cause of premature ovarian failure unclear ?genes on both short and long arms of the X chromosome. X-inactivation centre (XIC) is located on the long arm, Xq. Deletion of Xq distal to the XIC is associated with premature ovarian failure d) haplo-insufficiency for genes located on Xp results in distinctive neurocognitive traits, such as higher verbal versus visual-spatial performance scores and difficulties in recognition of facial expressions 4) cytogenetic classification - a) non-mosaic 45,X - single X chromosome in all somatic cells (monosomy X); 60% pts b) fragmented X or Y - Xp deletions (46,X,delXp), isoXq chromosomes (46,X,iXq), Xq deletions, and ring X or Y chromosomes with substantial interstitial deletions. The isoXq chromosome, consisting of deletion of Xp and fusion of 2 long arms, is the most common structural anomaly associated with Turner's syndrome. Deletion of major portion of Xp is also associated with the syndrome. Often, the abnormal sex chromosome is lost in some cells during embryonic development c) mosaic 45,X - 2 types: loss of a sex chromosome during early embryonic cell divisions can cause mix of normal 46,XX cells and 45,X cells in variable proportions; by contrast, formation of a 46,X,abnX embryo is often accompanied by loss of the fragmented X during some embryonic cell divisions, resulting in mosaicism for a monosomic, 45,X cell line along with a cell line containing a fragmented X chromosome: for example, iXq. This individual has no normal cells, and the full phenotype is expected.

Definition & pathophysiology & epidemiology of non-acidotic hyperosmolar coma / severe hyperglycaemia

1) definition - a) Hyperosmolar Hyperglycaemic State (HHS) aka non-ketotic hyperglycaemic hyperosmolar syndrome (NKHS) = profound hyperglycaemia (glucose >33.3 mmol/L) + hyperosmolality (serum osmolality ≥320 mmol/) + volume depletion without significant ketoacidosis (pH >7.3 and HCO3 >15 mmol/L), and is a serious complication of diabetes b) HHS may be the first presentation of T2DM. Both HHS and DKA are characterised by relative or absolute insulin deficiency + inc counter-regulatory hormones. 2) epidemiology - overall prevalence <1% of all diabetes-related hospital admissions. Incidence of HHS ~ 17.5 per 100,000 patient years. Most commonly in elderly & African-Americans. Mortality rate 5-20% (10x more than DKA) 3) aetiology - most commonly caused by infection (eg/ UTI, pneumonia), can be acute illness (eg/ stroke, MI, other medical-surgical illnesses, or trauma that provokes the release of counter-regulatory hormones - catecholamines, glucagon, cortisol, and growth hormone), severe dehydration (eg/ elderly, neurological), post op, non-adherence to meds, some meds (eg/ corticosteroids, thiazide diuretics, B-blockers, didanosine) 4) pathophysiology - a) insulin-sensitive tissues take up glucose during meals - glycemic rise of ingested carbs stimulates insulin secretion - inhibits glucagon release from pancreatic islets, so ratio of plasma insulin:glucagon becomes high (favors storage of glucose as glycogen in liver & muscle + lipogenesis in adipocytes)b) between meals, insulin not released - glucagon levels rise = breakdown of glycogen in the liver and muscle and gluconeogenesis by the liver. Dec insulin:glucagon ratio favors lipolysis & formation of ketone bodies by the liverc) pts with a lack of or resistance to insulin + physiologic stress eg/ acute illness = further dec in circulating insulind) underlying mechanism of HHS = relative or absolute reduction in effective circulating insulin (relative insulin deficiency = serum glucose >33 mmol/L + concomitant elevation of counterregulatory hormones (serum osmolarity >320 mOsm) = excessive urination (osmotic diuresis) = volume depletion and haemoconcentration = more inc in blood glucose levelKetosis is absent because the presence of some insulin inhibits hormone-sensitive lipase mediated fat tissue breakdown

Definition & pathophysiology & epidemiology of hypercalcaemia

1) definition - a) hypercalcaemia = concn of serum calcium is 2 SD above mean value, in at least 2 samples taken at least 1 week apart. Normal serum or plasma total calcium = 2.13 to 2.63 mmol/L and ionised calcium should be 1.15 to 1.27 mmol/L b) calcium is a critical cation involved in cellular transport, membrane function, and bone metabolism. Hypercalcaemia harms function of excitable membranes leading to skeletal muscle and gastrointestinal smooth muscle fatigue. Effects on cardiac muscle = shortened QT interval and inc risk of cardiac arrest at very levels. Hypercalcaemia quickly exceeds renal capacity for calcium re-absorption, and calcium spills into urine, complexing with phosphate = nephrolithiasis. High calcium can deposit in soft tissues eg/ kidney where renal function may be severely damaged. Hypercalcaemia causes dehydration by inducing renal resistance to vasopressin = nephrogenic diabetes insipidus 2) pathophysiology - a) ~1% total body calcium in extracellular fluid, rest in bone and intracellular compartments; ½ circulating calcium bound to proteins (esp albumin), rest ionised & physiologically pertinent b) calcium levels controlled by PTH, released from parathyroid glands when ionised calcium low. PTH inc calcium by enhancing vit D metabolism in kidney, stimulating bone resorption, and inc phosphate excretion in kidney. When calcium high, parathyroid glands stop releasing PTH. Thyrocalcitonin from 'c' cells of thyroid can lower calcium, but its role in calcium balance is minor c) calcium is absorbed at ~10% efficiency & absorption relies upon vit D. Vitamin D₃ synthesised in skin by reaction of its cholesterol antecedents with UV B light; reaction triggered when sunlight strikes exposed skin. Dietary sources are usually negligible. Vitamin D₃ is converted to 25-hydroxy metabolite by hepatic pathways and a second hydroxylation to calcitriol or 1,25-dihydroxy vitamin D₃ occurs in renal parenchyma. 1,25-dihydroxy vitamin D₃ inc intestinal calcium absorption. Phosphate solubility is closely related to calcium balance. Anything inc phosphate eg/ renal failure = dec ionised calcium 3) aetiology - a) hypercalcaemia caused by either primary hyperparathyroidism or cancer in over 90% b) primary hyperparathyroidism - pathologic & unregulated excess of PTH = inc calcium, most common cause - prevalence in population of 0.86%, more common in women, ~85% due to single adenoma of 1 parathyroid glands while most of the other 15% is four-gland disease, <1% = parathyroid cancer. Primary hyperparathyroidism ranges from very mild and asymptomatic, to severe disease with fractures and osteitis fibrosa cystica (von Recklinghausen disease) c) malignancy - bony involvement by tumour may lead to massive osteoclastic activity (osteolytic lesions) when calcium flux simply overwhelms homeostatic mechanisms; also many tumours release PTH-related protein acting on PTH receptors. 25-30% pts with cancer will develop hypercalcaemia (advanced tumours). Common malignancies causing hypercalcaemia - multiple myeloma, leukaemia, lung cancer, breast cancer, multiple endocrine neoplasia (MEN) type 1 (Wermer) and MEN type 2a (Sipple) or isolated familial hyperparathyroidism d) less common - metabolic: excess vit D, hyperthyroidism, milk-alkali syndrome, inc oral calcium, granulomatous disease eg/ sarcoidosis, Paget's, excess vit A intake; iatrogenic - lithium, thiazides; congenital - familial hypocalciuric hypercalcaemia 3) epidemiology - prevalence ~1-2% population

Definition & pathophysiology & epidemiology of Cushing's syndrome

1) definition - Cushing syndrome is the clinical manifestation of pathological hypercortisolism from any cause. Can be caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours (Cushing's disease), by autonomous adrenal cortisol overproduction, and, rarely, by ectopic ACTH-secreting tumours 2) epidemiology - uncommon in the general population, hypercortisolism reported in 0.5%-1% of patients with HTN, 2-3% of patients with uncontrolled diabetes, 6-9% of patients with adrenal masses, and 11% of patients with osteoporosis and vertebral fractures. Cushing syndrome due to adrenal disease occurs 4x more in women, Cushing's disease (adrenocorticotropic hormone-secreting pituitary tumour) has a 3.5:1 female:male predominance. No ethnic disparities. Most adults are diagnosed between 20-50. 3) aetiology - a) exogenous corticosteroid exposure is the most common cause of Cushing syndrome b) 70-80% of endogenous Cushing syndrome is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas; however, only 10-15% of all pituitary adenomas secrete excessive ACTH. A new gene, ubiquitin-specific protease 8, has been found to be frequently mutated in Cushing's disease c) ~10% of endogenous Cushing syndrome is caused by adrenal adenomas with unregulated secretion of cortisol, but only 6-9% of all adrenal adenomas develop autonomous cortisol secretion. No specific exposures or modifiable factors have been identified that cause endogenous hypercortisolism. Aetiology of pituitary adenoma overproduction of ACTH and adrenal adenoma overproduction of cortisol is poorly understood d) only ~ 1% of Cushing syndrome cases are caused by adrenal carcinoma. On the other hand, adrenal overproduction of cortisol is seen in 30-40% of adrenal carcinomas, resulting in ACTH-independent Cushing syndrome 4) pathophysiology - a) clinical manifestations result from excess tissue exposure to cortisol. Degree to which symptoms manifest is largely based on the degree of cortisol excess b) pts with mild to moderate hypercortisolism have a less prominent phenotype with glucose intolerance, dyslipidaemia, metabolic bone disease, and abnormal weight gain, but are difficult to differentiate from other patients with the metabolic syndrome c) as hypercortisolism inc, physical features inc with striae, supraclavicular fat pads, and proximal muscle weakness developing. Ectopic adrenocorticotropic hormone (ACTH) secretion from neuroendocrine tumours may manifest as more-severe cases with the abrupt presentation of symptoms and greatly elevated cortisol and ACTH. These patients may also have severe muscle weakness and weight loss

Definition & pathophysiology & epidemiology of diabetes insipidus

1) definition - Diabetes Insipidus (DI) is a metabolic disorder characterised by an absolute or relative inability to concentrate urine causing large quantities of dilute urine. May result from an absolute or relative deficiency of arginine vasopressin (AVP) aka antidiuretic hormone (ADH), produced by the hypothalamus and secreted via the posterior pituitary, or by resistance to its action within the renal collecting ducts. Clinically it manifests as polydipsia, polyuria, and hypotonic urine 2) epidemiology - DI is uncommon, exact prevalence is difficult to estimate. No differences in prevalence between sexes or ethnic groups. Inherited causes for both central and nephrogenic DI account for <10% of all cases 3) aetiology - DI may be central in origin - due to absolute or relative deficiency of arginine vasopressin (AVP); or nephrogenic - renal insensitivity or resistance to AVP. Both mechanisms dec permeability of ducts within nephron to water = dec water resorption & inc renal water loss a) central DI - acquired: post trans-sphenoidal pituitary surgery, usually for a pituitary adenoma (common cause); craniopharyngioma (common); infiltrative hypothalamic/pituitary stalk lesions (in Langerhans' cell histiocytosis); pituitary metastases; post-traumatic head injury (common); autoimmune disorders (Hashimoto's thyroiditis, T1DM); CNS infections (late complication of meningitis or encephalitis); SA haemorrhage (anterior communicating artery); meds (phenytoin, temozolamide), carbon monoxide poisoning (rare) b) central DI - congenital/inherited: congenital malformations involving pituitary or hypothalamus and midline forebrain defects can develop central DI; may be a component of Wolfram syndrome (autosomal-recessive, neurodegenerative disorder = DM + optic atrophy +/- central DI + sensorineural deafness) c) nephrogenic DI - acquired: meds (lithium - may be irreversible, demeclocycline, cisplatin, colchicine, gentamicin, and rifampin); systemic disease, electrolyte imbalance, and post-obstructive uropathy (CKD, renal sarcoidosis, renal amyloidosis) d) nephrogenic DI - inherited: mutations in AVPR2 receptor (mediates antidiuretic action of AVP in collecting duct - X-linked recessive, familial nephrogenic DI); aquaporin-2 (AQP2 - AVP-dependent water channel that renders distal collecting duct permeable to water and allows AVP-mediated distal renal water resorption - loss-of-function mutations in AQP2 gene = autosomal recessive familial nephrogenic DI) e) pregnancy and DI: osmotic thresholds for thirst and AVP release are altered in pregnancy. 4x inc in metabolic clearance of AVP due to placental production of vasopressinase/oxytocinase 4) pathophysiology - a) plasma volume & osmolality are maintained within a narrow range by neuro-humoral system coordinating balance between thirst-directed drinking (intake) & renal water loss (output) b) key regulator of renal water loss = 9-amino acid peptide hormone arginine vasopressin (AVP) aka antidiuretic hormone (ADH). AVP is synthesised in magnocellular neurones in supraoptic (SON) and paraventricular (PVN) nuclei of hypothalamus. AVP is produced from a large precursor peptide, undergoes significant post-translational processing then released in posterior pituitary. Each molecule of AVP is co-secreted with 2 fragments of the original precursor: copeptin and neurophysin II (NPII) c) linear relationship between plasma AVP concentration & plasma osmolality. Plasma osmolality is sensed by osmoreceptors within hypothalamus - sensory afferents regulate AVP synthesis and release. AVP release is also regulated by circulating volume and BP. Baroregulation can = AVP production & release at plasma osmolalities < standard osmolar threshold ~290 mmol/kg (290 mOsm/kg). Similar relationship of thirst to plasma osmolality d) AVP acts on type-2 AVP receptors (AVPR2) on interstitial surface of renal distal collecting duct cells, inc water permeability through inc synthesis of aquaporin-2 water channels. These are assembled and inserted into apical membrane of collecting duct cells, resulting in AVP-dependent water resorption and concentration of urine i) central DI results from any condition that impairs production, transportation, or release of AVP ii) nephrogenic DI results from conditions that impair renal collecting ducts' ability to respond to AVP e) both central and nephrogenic DI characterised by impaired renal water re-absorption = production of excessive, hypotonic (dilute) urine (polyuria), in volumes from 3 litres to >20 litres per day. Accompanied by significant thirst & inc drinking (polydipsia), as central osmo-sensing and peripheral baro-sensing drive central thirst and thirst-dependent behaviours to maintain circulating volume and osmolar status f) pts with DI due to a non-traumatic aetiology have insidious onset of symptoms. Pts with central DI following TBI or pituitary surgery have more rapid onset of symptoms 5) classification - a) primary polydipsia: clinical syndrome due to excessive fluid intake with subsequent polyuria; may be induced by any structural lesion in hypothalamus that causes central DI, or produced by drugs that cause a dry mouth, be associated with psychiatric syndromes, or be habitual b) central (hypothalamic/neurohypophyseal) diabetes insipidus: due to defective synthesis or release of arginine vasopressin (AVP) from the hypothalamo-pituitary axis; may be congenital (inherited) or acquired (eg/ neurosurgical procedures for tumours, trauma, autoimmune, infiltrative, vascular) c) nephrogenic diabetes insipidus: due to renal insensitivity or resistance to AVP, with a resultant lack of permeability of the collecting duct to water; may be congenital (inherited) or acquired (eg/ drug-induced, particularly lithium; hypercalcaemia, hypokalaemia; obstructive uropathy)

Definition & pathophysiology & epidemiology of polycystic ovarian syndrome

1) definition - Polycystic ovary syndrome (PCOS) includes symptoms of hyper-androgenism, presence of hyper-androgenaemia, oligo-/anovulation, and polycystic ovarian morphology on ultrasound 2) epidemiology - PCOS affects ~10% women of reproductive age, accounts for 80-90% of cases of hyper-androgenism in women 3) aetiology - a) aetiology of PCOS is unknown. Multiple systems are affected & site of primary defect is unclear. Various lines of evidence support primary defects in hypothalamic-pituitary axis, postulating inc amplitude and frequency of pulses of LH, or defects involving ovaries through an intrinsic problem leading to androgen over-production. Some theories postulate defects in insulin sensitivity with insulin resistance leading to compensatory hyper-insulinaemia b) appears to be inherited as a common complex disorder 4) pathophysiology - a) pathophysiology not well understood as lack of knowledge of location of primary defect eg/ ovary, adrenal, hypothalamus, pituitary, or insulin-sensitive tissues. It is possible that there are subsets of women with PCOS wherein each of these proposed mechanisms serves as the primary defect b) insulin resistance = compensatory insulin hypersecretion by pancreas to maintain normoglycaemia. Resulting hyperinsulinaemia = inc ovarian androgen output & inc adrenal androgen output. High insulin levels suppress hepatic production of sex hormone-binding globulin, which exacerbates hyper-androgenaemia as inc free circulating androgens. Another factor that promotes ovarian androgen output is the fact that women with PCOS are exposed long term to high levels of luteinising hormone, due to inc frequency of gonadotrophin-releasing hormone pulses from hypothalamus. Abnormal hormonal milieu may contribute to incomplete follicular development that results in polycystic ovarian morphology

Definition & pathophysiology & epidemiology of acutely ill diabetic

1) definition - any patient with acute illness/stress with an underlying diagnosis of DM (T1 or T2) 2) pathophysiology - a) when stressed (any period of disease) the body makes inc levels of catecholamines - reaction is modulated by suprarenal glands & activated by SNS in acute stress & by feedback to pituitary gland in chronic stress. Some degree of hyperglycemia is normal with stress, and is initially protective and part of the adaptive response for survival. However, in acute and severe diseases, the resulting hyperglycemia can be much too high. Severe hyperglycemia is a marker of illness severity & often subsides after the affecting illness (i.e., sepsis) has resolved. In the acute setting the resulting hyperglycemia is due to insufficient insulin secretion. Insulin resistance plays a factor in chronic disease with significant tissue injury. b) stress-induced hyperglycemia (SIH) is common among critically ill patients, particularly CV patients, neurocritical patients, and patients undergoing surgical procedures, even in the absence of preexisting DM. In non-diabetic SIH = blood glucose >7mmol/L or glycosylated Hb (HbA1c) > 6.5%. In diabetics SIH = blood glucose >11.1mmol/L. SIH inc morbidity & mortality in critically ill patients and leads to poor outcomes and prognosis c) in diabetics with persistent hyperglycemia, significantly lowering glucose levels and strict glycemic control may lead to symptomatic and life-threatening hypoglycemia and glycemic variability. Glycemic variability - acute glycemic fluctuations both up and down = inc oxidative stress = endothelial dysfunction & vascular damage. Glycemic variability is much more dangerous than persistent hyperglycemia in critically ill patients 3) epidemiology - diabetes affects ~7% population, prevalence highest in >65 years old

Definition & pathophysiology & epidemiology of hypoglycaemia

1) definition - clinical syndrome present when blood glucose concentration <3.3 mmol/L. When glucose values drop below the normal fasting range, glucose meters are not accurate and laboratory serum or plasma testing is useful to confirm the actual blood sugar value. Whipple's triad should be present in cases of true hypoglycaemia: hypoglycaemic symptoms + low blood glucose concentration + resolution of symptoms after raising the blood glucose concentration to normal 2) epidemiology - severe hypoglycemia ~ 4800 per 100.000 patient per year, moderate events ~13100 per 100.000 patient per year. Rates inc in children < 6 3) aetiology - due to excess insulin, exogenous or endogenous; meds eg/ sulfonylurea, meglitinide, synthetic insulin; growth hormone deficiency and adrenal insufficiency (eg/ hypopituitarianism or Addison's) 4) pathophysiology - a) sympathoadrenal symptoms are the result of inc secretion of glucagon, adrenaline, cortisol, and growth hormone in an effort to elevate blood sugar levels: begins when blood glucose <3.0 mmol/L, s/s - sweating, anxiety, nausea, tremor, hunger, tingling, palpitations b) meuroglycopenic symptoms result from insufficient glucose to the brain despite sympathoadrenal attempts to raise blood sugar: typically with glucose <2.8 mmol/L, s/s - blurred vision, dizziness, confusion, dysarthria, and somnolence, at extremes - convulsion, coma, and even death may occur 5) classification - a) factitious - surreptitious use of insulin b) endocrine - adrenal insufficiency (mostly kids), growth hormone deficiency (mostly kids), hypopituitarism (kids and adults), hyperthyroidism c) tumours - eg/ insulin-like growth factor [IGF]-II), neuroendocrine tumours eg/ insulinoma d) iatrogenic - insulin, aspirin, quinolones, quinine, haloperidol, disopyramide, sulfonylurea, B-adrenergic blockers e) neonatal - nesidioblastosis, pancreatic islet hypertrophy, newborn of a diabetic mother (transient) f) toxins - alcohol abuse, especially with starvation, ackee fruit (hypoglycin) g) congenital - glycogen storage disorders h) miscellaneous - early pregnancy (late reactive hypoglycaemia can occur during pregnancy), hypoglycaemia of inanition (terminal cancer), acute or chronic liver disease, chronic renal failure, congestive heart failure, autoimmune: insulin receptor abnormalities, following gastric surgery: gastric bypass, vagotomy with pyloroplasty, subtotal or total gastrectomy. Early reactive hypoglycaemia can occur after gastric surgery

Definition & pathophysiology & epidemiology of hypocalcaemia

1) definition - hypocalcaemia = low circulating serum calcium level (both total and ionised) 2) pathophysiology - a) calcium levels are tightly controlled by parathyroid hormone and vitamin D. Calcium is essential for cell function, cell membrane stability, neuronal transmission, bone physiology, blood homeostasis, and cell signalling b) circulating calcium levels are impaired by several factors, but hypocalcaemia is mainly secondary to the imbalance of calcium absorption, excretion, and distribution c) 40% circulating calcium bound to albumin, in a ratio of 1 mg albumin:0.8 mg calcium, measuring albumin is essential in interpreting total serum calcium levels. However, if ionised calcium is determined, there is no need to measure albumin, ~15% circulating calcium is bound to sulfates, phosphates, lactate, and citrate & other 45% = biologically active calcium in an ionised form 3) aetiology: classified on PTH levels, or physiologically (eg/ insufficient entry into or increased loss of calcium from the circulation). Aetiologies may be interrelated eg/ many causes of hypomagnesaemia, hypoalbuminaemia, or vitamin D deficiency - a) hypocalcaemia with inappropriately low serum PTH - i) destruction of parathyroid glands - surgery, autoimmune, radiation, infiltration (iron, copper, tumour) ii) developmental parathyroid disorders - isolated hypoparathyroidism; autosomal recessive, autosomal dominant, or X-linked; syndromes of hypoparathyroidism associated with complex developmental anomalies (e.g., DiGeorge sequence); dec PTH secretion/function; constitutively activating calcium sensing receptor (CaSR) mutations/autoimmune activation of the CaSR; hypomagnesaemia; hungry bone disease following parathyroidectomy iii) hypocalcaemia with secondary hyperparathyroidism - vit D deficiency (inadequate UV exposure, poor diet, malabsorption); chronic renal disease, enzyme-induced drug resistance to PTH; pseudohypoparathyroidism; hypomagnesaemia; resistance to vit D; mutations in vit D receptor (mutations in 1-alpha hydroxylase enzyme) iv) miscellaneous - following drug treatment (IV bisphosphonates in untreated vitamin D deficiency; gadolinium salts used in MRI; foscarnet); osteoblastic metastases; hyperphosphataemia; severe illness (acute pancreatitis, acute rhabdomyolysis, tumour lysis, post massive transfusion) b) dec entry of calcium into the circulation - i) hypoparathyroidism - often by accidental removal of all parathyroid glands during surgery or radiation-induced parathyroid destruction. Low levels PTH secretion are sometimes congenital (DiGeorge syndrome and velocardiofacial syndrome); hypoparathyroidism may be autosomal dominant (hypocalcaemia with hypercalciuria) or autoimmune (isolated entity or part of polyglandular failure type 1, in association with adrenal insufficiency and mucocutaneous candidiasis) ii) infiltration of parathyroid glands by heavy metal deposition (iron, copper), or less commonly tumour, may also impair PTH secretion iii) nutritional - vit D deficiency is most common cause of hypocalcaemia. Circulating vit D levels may be dec by dec sunshine & dec vitamin D intake = calcium malabsorption iv) Mg imbalance - hypomagnesaemia = hypocalcaemia as interferes with secretion and action of PTH. Hypomagnesaemia generally secondary to defects in intestinal absorption and renal absorption or secondary disorder due to nutritional deficiency eg/ chronic alcoholism v) PTH resistance, or pseudohypoparathyroidism = hereditary disorders causing resistance to effects of PTH (eg/ renal and bone unresponsiveness to PTH). In contrast to hypoparathyroidism, pseudohypoparathyroidism = inc PTH + phosphorus + hypocalcaemia. Pseudohypoparathyroidism has other phenotypes such as Albright's hereditary osteodystrophy (short stature, round facies, short digits, and intellectual impairment) and pseudopseudohypoparathyroidism (physical appearances of pseudohypoparathyroidism but with normal biochemistry) c) inc loss of calcium from the circulation - i) 'hungry bone syndrome' - severe hypocalcaemia seen after parathyroidectomy (or thyroidectomy). Calcium rapidly taken from the circulation and deposited in bones. In severe cases pts may develop CV collapse, arrhythmias, and hypotension unresponsive to fluids and vasopressors ii) acute pancreatitis can lead to hypocalcaemia iii) extensive osteoblastic skeletal metastases eg/ breast or prostate cancer iv) hyperphosphataemia - after massive tissue breakdown in rhabdomyolysis or accidental ingestion of phosphate-containing drugs, or critically ill patients. Phosphate binds to calcium, leading to acute hypocalcaemia v) chelating agents eg/ citrate, EDTA, lactate, and foscarnet can inc loss of calcium from circulation d) drug-induced hypocalcaemia and other causes - i) hypocalcaemia can be induced by drugs eg/ bisphosphonates (esp IV), chemotherapies (glucocorticoids; anticonvulsants; and chelating agents such as EDTA, citrate, foscarnet, and lactate), cinacalcet (given to pts with renal failure to inhibit PTH release), PPIs (may cause hypomagnesaemia, which in turn causes hypocalcaemia) ii) critically ill patients may have transient hypocalcaemia eg/ sepsis or extensive burns or after multiple blood transfusions iii) use of gadolinium-based MRI contrast agents eg/ gadodiamide and gadoversetamide can interfere with colorimetric assay of measuring calcium and lead to falsely lowered serum calcium levels

Recall diagnostic criteria for diabetes mellitus

1) diabetes mellitus: chronic hyperglycaemia + disturbances in carb, fat and protein storage due a dec/defect in action or release of insulin from the endocrine pancreas a) symptoms - polyuria, polydipsia, unexplained weight loss, visual blurring, genital thrush, lethargy, UTIs b) risk factors: inc age; overweight, BME, fx, prev gestational diabetes, pre-diabetes, inactivity, PCOS, HTN, dyslipidaemia, known CV disease. c) criteria: 1 of (then again or different one checked) i) random venous plasma glucose concn ≥ 11.1 mmol/l ii) fasting plasma glucose concn ≥ 7.0 mmol/l iii) raised venous plasma glucose - fasting, random iv) OGTT (plasma glucose concn ≥ 11.1 mmol/l 2hrs after 75g anhydrous glucose) v) HbA1C >48mmol/L (6.5%) 2) impaired glucose tolerance: fasting plasma glucose <7.0 mmol/l + OGTT of 7.8-11.0 mmol/l 3) impaired fasting glycaemia: fasting plasma glucose between 6.1-6.9 mmol/l a) pts identified with IFG should have OGTT to rule out IGT

Definition & pathophysiology & epidemiology of diabetic ketoacidosis

1) diabetic ketoacidosis = biochemical triad of hyperglycaemia + ketonaemia + metabolic acidosis, with rapid symptom onset 2) epidemiology -annual incidence of DKA ~ 15%, overall mortality ~ 4% 3) aetiology - a) DKA = dec net effective concentration of circulating insulin + inc counter-regulatory hormones (glucagon, catecholamines, cortisol, and growth hormone) = extreme metabolic derangements that can occur in diabetes b) 2 most common precipitating events - infection and discontinuation of, or inadequate, insulin therapy c) underlying medical conditions eg/ MI or pancreatitis, that provoke the release of counter-regulatory hormones can result in DKA in patients with diabetes. Drugs that affect carb metabolism eg/ corticosteroids, thiazides, sympathomimetic agents (e.g., dobutamine and terbutaline), 2nd-generation antipsychotics, immune checkpoint inhibitors, cocaine, and cannabis may contribute to DKA 4) pathophysiology - a) dec insulin concentration or action + inc insulin counter-regulatory hormones, leads to hyperglycaemia, volume depletion, and electrolyte imbalance b) hormonal alterations lead to inc gluconeogenesis, hepatic and renal glucose production, and impaired glucose utilisation in peripheral tissues = hyperglycaemia & hyperosmolarity. Insulin deficiency = release of FFA from adipose tissue (lipolysis), hepatic fatty acid oxidation, and formation of ketone bodies (B-hydroxybutyrate and acetoacetate) = ketonaemia and acidosis 5) severe DKA - 1+ of: blood ketones >6 mmol/L; bicarbonate <5 mmol/L; venous/arterial pH <7.0; hypokalaemia on admission (<3.5 mmol/L); GCS <12; O2 <92%; SBP <90 mmHg; HR >100 or <60; anion gap >16, pregnant, heart or kidney failure or other serious comorbidities - in any of these need continuous cardiac monitoring + discussion with crit care

Outline common insulin regimens for type 1 diabetes mellitus

1) different types of insulin regimen - a) 1, 2, or 3 insulin injections per day — usually short-acting or rapid-acting insulin analogue mixed with intermediate-acting insulin (biphasic regimen) i) premixed analogue insulins = mix of a rapid-acting insulin analogue + intermediate-acting insulin analogue eg/ Humalog® Mix 25 and 50, and NovoMix® 30 ii) premixed human insulins = mix of a soluble insulin + intermediate-acting insulin eg/ Humulin M2®, M3®, and M5®, and Insuman® Comb 15, 20, 50. b) multiple daily injection basal-bolus insulin regimens —recommended regime, injections of short-acting insulin or rapid-acting insulin analogue before meals + 1+ daily injection of intermediate-acting insulin or long-acting insulin analogue for basal requirement. This regimen offers greater flexibility for blood glucose control c) continuous subcutaneous insulin infusion (insulin pump) —programmable pump and insulin storage reservoir that gives a regular or continuous amount of insulin (usually as rapid-acting insulin analogue or short-acting insulin) by a subcutaneous needle or cannula i) dispenses with the need for an intermediate-acting or long-acting insulin to provide basal cover ii) pump can be programmed to deliver different basal rates of insulin at different times of the day and night, with higher infusion rates triggered by the push of a button at meal times iii) insulin requirement can be matched more closely to the person's basal requirement, pre-prandial glucose levels, carbohydrate intake, and physical activity iv) can be used in pts 12+ if attempts to achieve target HbA1c levels with multiple daily injection therapy result in the person experiencing disabling hypoglycaemia, or HbA1c levels have remained high (69+ mmol/mol [8.5%+]) during multiple daily injection therapy (including, if appropriate, the use of long-acting insulin analogues) despite a high level of care. 2) non-basal-bolus insulin regimens (2x/day mixed [biphasic], basal-only, or bolus-only regimens) not recommended for adults with newly diagnosed type 1 diabetes 3) for basal insulin replacement - 2x/day insulin detemir offered, unless: pt is achieving their agreed target on an existing regimen, BD basal insulin is not acceptable to the person (then use OD insulin glargine or detemir) 4) for bolus/mealtime insulin replacement - a rapid-acting insulin analogue injected before meals is recommended, rather than rapid-acting soluble human or animal insulins; routine use of rapid-acting insulin analogues after meals should be discouraged; if pt has a strong preference for an alternative mealtime insulin, they should be offered their preferred insulin 5) if a multiple daily injection basal-bolus insulin regimen is not possible and BD insulin regimen is preferred: a trial of a twice-daily analogue mixed insulin regimen should be considered if the person has hypoglycaemia that affects their quality of life. 6) children & young people - multiple daily injection basal-bolus insulin regimens offered from diagnosis: child & family should be encouraged to adjust the insulin dose if appropriate after each blood glucose measurement. If that's unsuitable can offer an alternative insulin regimen as well as additional support, such as increased contact with their specialist diabetes team. 7) insulins available - human insulins, human insulin analogues, and animal insulins (rarely used) a) human insulins - produced by recombinant DNA technology & have same amino acid sequence as endogenous human insulin b) human insulin analogues - produced in same way as human insulins, but insulin is modified to produce a specific desired kinetic characteristic (eg/ extended duration of action or faster absorption and action) c) animal insulins - extracted and purified from animal sources eg/ cows (bovine) or pigs (porcine), no longer initiated in people with diabetes but still used in some people who cannot, or do not wish to, change to human insulins 8) short-acting insulins —work like the insulin normally produced by the body to cope with glucose absorbed from a meal or drink. Rapid onset of action & short duration. 2 types: a) soluble insulins —injected 30 mins before food & onset of action of 30-60 mins, peak 1-4hrs, & duration of action of up to 8 hours eg/ Human Actrapid® and Humulin S® (usually subcut but some can be given IV or IM - given IV in DKA and peri-operatively) b) rapid-acting insulin analogues —faster onset of action than soluble insulins (within 15 mins) & shorter duration of action (2-5 hours); so can be injected 5-15 minutes before meals, with meals, or soon after meals eg/ Humalog® (insulin lispro) and Novorapid® (insulin aspart) and insulin glulisine c) these insulins should be injected immediately before meals. Rapid-acting insulin, administered before meals, is better than short-acting soluble insulin as inc glucose control, dec HbA1c, and dec incidence of severe hypos eg/ nocturnal hypos. Routine use of post-meal injections of rapid-acting insulin should be avoided as dec glucose control, inc risk of high postprandial-glucose concentration, and subsequent hypos 9) intermediate-acting (isophane or NPH [Neutral Protamine Hagedorn]) insulins — mimics effect of basal insulin secreted continuously throughout the day. Onset of action of 1-2 hours, maximal effects between 4-12 hours, and a duration of action of 16-35 hours eg/ Humulin I®, Insuman basal®, and Human Insulatard®. Isophane insulin = insulin + protamine; given as 1+ daily injections & separate meal-time short-acting insulin injections, or mixed with a short-acting (soluble or rapid-acting) insulin in the same syringe eg/ biphasic isophane insulin, biphasic insulin aspart and biphasic insulin lispro. % of short-acting insulin varies from 15% to 50%. These preparations should be administered by subcut injection immediately before a meal 10) long-acting insulin analogues — also mimic basal insulin but can last for a longer period than intermediate-acting insulins. OD or BD and achieve a steady-state level after 2-4 days to produce a constant level of insulin eg/ Lantus® (insulin glargine OD), Levemir® (insulin detemir OD or BD), and Tresiba® (insulin degludec OD) see also - word document

Microvascular complications of diabetes

1) eyes: ~1/3 young diabetics will suffer from retinal damage, 5% blind after 30 yearsa) retinopathy, cataracts & external ocular palsies, progression of retinopathy faster in T1DM than T2DM - good diabetic + BP control slows progressionb) background retinopathy: microaneurysms around posterior pole, cotton wool spots = microinfarcts within retina c) non perfusion = ischaemia = VEGF = new intraretinal + preretinal vessels which bleed = blood into vitreous fluid & obscures vision. As vessels age have collagenous change = fibrotic traction bands which may pull on retina = further haemorrhage & possible retinal detachment. Finally (after new vessels & possible vitreous bleeds) = large exudative plaque in central macular area 2) kidneys: glomerular disease manifest 15-25 years after diagnosis a) ischaemia (hypertrophy of afferent & efferent arterioles) or ascending infection = kidney hypertrophies (inc GFR) = dilation afferent arteriole = inc intraglomerular filtration pressure, leading to damage to glomerular capillaries = sclerosis + thickening in basement membrane b) progressive leak of large molecules into urine eg/ early microalbuminuria, then persistent proteinuria, at which point pts are 5-10 years from end-stage renal failure3) nerves: dec in nerve conduction velocity caused by damage to Schwann cells, due to direct metabolic damage or microvascular (vasa nervorum) damagea) 5 varieties of neuropathy: i) symmetrical distal sensorimotor polyneuropathy - glove & stocking, dec vibration + pain + temp, motor nerves so high arch & clawing of toes, callouses & ulcers, eventually Charcot, distal to proximal, slow ii) acute painful neuropathy - burning in feet + leg esp at night, can resolve iii) mononeuropathy - often CN3 + 6, normal pupil reflexes, can resolve iv) diabetic amotrophy - asymmetrical, painful wasting of muscles - quad or shouldersv) autonomic neuropathy - often no s/s, can affect SNS + PNS eg/ hypotension, bladder, penis

S/s, DD, ix, mx, complications & prevention of DKA

1) history - a) consider DKA if: known diabetes & unwell (esp if T1DM), or pts with features of diabetes + any of: N&V, abdo pain (?pancreatitis), inc RR, dehydration, dec consciousness b) features of diabetes: inc thirst, polyuria, recent unexplained weight loss, v. tired, N&V c) abdo pain - DKA can cause & mimic pancreatitis, check for abdo distension (?bowel obstruction), palpate for rebound tenderness and guarding (irritation of peritoneum), auscultate for bowel sounds (hyperactive 'tinkling' = ?early bowel obstruction, dec or absent bowel sounds ? late bowel obstruction, perforated viscus, haemoperitoneum etc), DRE (assess for blood, pain or mass) d) dehydration - dry mucous membranes, dec skin turgor or skin wrinkling, dec CRT, tachy, weak pulse, dec BP e) hyperventilating - late sign of DKA as severe acidosis, deep sighing respirations at a slow or normal rate f) dec consciousness - access GCS to monitor for cerebral oedema. Dec consciousness = more severe DKA & worse prognosis. Can range from alert (mild DKA) to coma (severe). Cerebral oedema can develop during treatment of DKA due to rapid correction of hyperglycaemia eg/ headache, irritability, dec HR, inc BP, dec conscious level, papilloedema - involve immediate critical care input and give mannitol (mortality of 70%) g) risk factors - infection (most common cause DKA eg/ pneumonia and urinary tract infections), discontinuation or inadequate insulin (unintentional or deliberate eg/ fear of weight gain or hypoglycaemia, financial barriers, psychological factors eg/ needle phobia and stress, malfunctioning insulin pen or pump, storage at incorrect temperature), new onset diabetes, acute illness (eg/ MI - often atypical s/s in diabetics, sepsis, pancreatitis), physiological stress (pregnancy - DKA can occur at lower blood glucose and faster as inc insulin resistance, trauma, and surgery) h) meds - corticosteroids (inc insulin resistance), thiazides (?inc insulin resistance, inhibit glucose uptake, and dec insulin release), sympathomimetics (alter glucose metabolism), 2nd-gen antipsychotics (alter glucose metabolism), immune checkpoint inhibitors (cause insulin deficiency), cocaine, cannabis, and acute intoxication with alcohol, SGLT2 inhibitors (prevent reabsorption of glucose and facilitate its excretion in urine) i) acetone smell breath - pear drops or nail varnish remover due to high ketone levels 2) ix - a) VBG - use pH to determine severity of DKA (>7 = mild/moderate, <7 = severe - discuss with critical care) + assess anion gap (>16 = severe DKA); hyperkalaemia - replace if ≤5.5 mmol/L, discuss with critical care if potassium is <3.5 mmol/L); calculate the plasma osmolality (2 Na + 2 K + Glucose + Urea ( all in mmol/L) - inc (>320mmol/kg) in DKA and is an indication of dehydration NB/ if data from VBG does not appear to match the patient's clinical condition, ABG needed b) blood ketones (urinary if blood not available) - ketonaemia (ketones ≥3.0 mmol/L) NB/ drugs eg/ ACEI captopril can cause false +ve c) blood glucose - blood glucose >11.1 mmol/L d) U&E - hyponatraemia common, hypernatraemia + hyperglycaemia = severe dehydration, hyperkalaemia is common but hypokalaemia is an indicator of severe DKA (due to diuresis). Can have hypomagnesaemia and hypophosphataemia e) FBC - leukocytosis is common, if >25 may indicate infection f) consider - urinalysis (for ketones if blood ketones not attainable or thinking UTI); ECG (check for MI and cardiac effects of electrolyte abnormalities); pregnancy test (all women childbearing age); amylase and lipase (inc amylase, normal lipase - elevated in pancreatitis); cardiac enzymes (if worried MI); CK (inc if rhabdomyolysis); CXR (if dec O2 sats); LFTs (check for liver disease); blood, urine + sputum cultures (?infection) 3) DD - a) hyperosmolar hyperglycaemic state (HHS) - pts older, usually T2DM, s/s over days - weeks, mental obtundation and coma more frequent, focal neurological signs (hemianopia and hemiparesis) and seizures also seen. Serum glucose is >33.3 mmol/L (>600 mg/dL), serum osmolality >320 mOsm/kg, ketones -ve, anion gap <12 mmol/L, ABG: pH >7.30 b) lactic acidosis - presentation is identical to DKA, serum glucose & ketones normal, serum lactate inc c) starvation ketosis - dec carbs = inc lipolysis and ketones, blood glucose normal, +ve urinary but -ve serum ketones, arterial pH normal d) alcoholic ketoacidosis - often long-standing alcohol use disorder - ethanol is main caloric source for days to weeks, ketoacidosis when alcohol and caloric intake decreases, metabolic acidosis is usually mild to moderate, inc anion gap, +ve ketones, blood alcohol may be undetectable, pt may be hypoglycaemic e) salicylate poisoning - anion gap metabolic acidosis usually with a respiratory alkalosis, normal glucose, ketones -ve, salicylates are positive in blood and/or urine f) uraemic acidosis - inc serum urea and creatinine with normal plasma glucose. The pH and anion gap are usually mildly abnormal 4) mx - a) IVI - i) 500ml NaCl 0.9% stat if SBP <90 & rpt if needed, if no improvement consider crit care ii) if SBP >90 give 1 L bags every - 2hrs, 2hrs, 4hrs, 4hrs, 6hrs (NB/ more cautious IVI/more careful monitoring if 18-25 (inc risk cerebral oedema), elderly, pregnancy, heart/kidney disease) iii) if K+ <3.5 add K+ to 2nd litre IVI - involve senior or critical care as high dose K+ needs to be given, make sure K+ added when K+ <5.5 v) when plasma glucose reaches 11.1 mmol/L change to 5% dextrose with 0.45% NaCl at 150-250 mL/hour in order to avoid hypoglycaemia b) supportive care and referral to critical care - protect airway, insert NG & aspirate if pt unresponsive to commands or is persistently vomiting; continuous cardiac monitoring & crit care if: persistent hypotension (SBP <90) or oliguria despite IVI, GCS <12, blood ketones >6, venous bicarb <5, pH <7, K+ <3.5, O2 <92% on RA, HR >100 or <60, anion gap >16, pregnant, heart or heart or kidney failure or other serious comorbidities i) + catheter if incontinence or no urine passed after 1 hour of starting treatment c) insulin - fixed-rate IV insulin infusion @ 0.1 units/kg/hour after IVI started i) switch to subcut when E+D - have IV insulin for 30-60 mins after + have eaten a meal to prevent relapse ii) continue IVI if not E+D, if DKA resolved start VRII d) identify and treat any precipitating acute illness eg/ MI, sepsis, pancreatitis e) monitor biochemical markers - at 0hrs, 1hr, 2hr, 3hr, 4hr, 5hr, 6hr, 12hrs - ketones + glucose, at 0, 1, 2, 4, 6, 12 - also bicarbonate, K+, pH i) aim for dec blood ketones of 0.5 mmol/L/hour or inc venous bicarbonate of 3.0 mmol/L/hour or dec blood glucose of 3.0 mmol/L/hour. If not falling at target rates - check everything working, inc insulin infusion by 1 unit/hour ii) assess for resolution of DKA: pH >7.3 + blood ketone level <0.6 mmol/L + bicarbonate >15 mmol/L f) monitor and treat complications - hourly GCS for cerebral oedema (if suspect - immediate senior support, give mannitol, consider CTB, CXR if O2 sats dec as ?pulmonary oedema, consider ABG g) +/- sodium bicarbonate on crit care if pH <6.9; +/- VTE 5) complications - a) hypokalaemia - can occur with excessive high-dose insulin therapy and bicarbonate therapy b) hypoglycaemia - excessive high-dose insulin therapy c) arterial or venous thromboembolic events d) cerebral oedema/brain injury - hourly GCS, features - recurrent vomiting, incontinence, irritability, abnormal respirations, cranial nerve dysfunction. Usually several hours after starting treatment. Urgent senior review, mannitol, sometimes CTB e) pulmonary oedema/acute respiratory distress syndrome (ARDS) - pulmonary oedema and acute respiratory distress syndrome (ARDS) are rare but significant complications of treatment for DKA and present with fluid overload and low oxygen saturations. More common if severely dehydrated. Get CXR, consider ABG f) non-anion gap hyperchloraemic acidosis - due to urinary loss of ketoanions needed for bicarbonate regeneration & inc reabsorption of chloride secondary to intensive administration of chloride-containing fluids. Acidosis usually resolves. More likely if pregnant 6) prevention - pt education about mx of diabetes during periods of mild illness (sick-day management) is vital for preventing DKA. Counsel patients about the precipitating cause and early warning symptoms of DKA. Consider: a) review of their usual glycaemic control, injection technique, blood glucose monitoring, equipment, and injection sites b) prevention of recurrence (e.g., provide written 'sick day rules') c) checking the patient's insulin prior to reuse (this may be expired or denatured) d) assessing the need for provision of handheld ketone meters for use at home e) provision of a contact number on how to contact the diabetes specialist team out of hours & a written care plan which allows the patient to have an active role in their diabetes management, with a copy of this sent to their GP NB/ SGLT2 inhibitors can cause DKA in T2DM when insulin omitted or pt unwell - withhold SGLT2 inhibitors when precipitants are present, and avoid insulin omission or large insulin dose reduction

Outline drug management of type 2 diabetes mellitus: oral hypoglycaemics, glitazones, primary and secondary vascular preventative agents

1) metformin - 500 mg orally (immediate-release) OD, inc by 500 mg/day increments every week, maximum 1000 mg twice daily a) dec hyperglycaemia by dec hepatic gluconeogenesis & glycogenolysis. At maximal effective doses, metformin may reduce HbA1c by 10-20 mmol/mol (1-2%). It confers a CV benefit, is rarely associated with weight gain, is inexpensive, and has a beneficial effect on LDL cholesterol b) most common SE: diarrhoea, gas, and nausea, which can be attenuated by initiating slowly 500 mg orally OD with a meal, inc PRN by 500 mg/day every 1-2 weeks until full dose of 1000 mg twice a day is reached c) CI if eGFR <30 mL/minute/1.73 m². Should not be initiated if GFR is <45mL & for pts taking metformin whose eGFR is 30-45 mL, continued use can be considered with close monitoring of renal function and a dose reduction d) metformin should be stopped before surgery or contrast dye studies with radiographic dye injection until adequate post-event renal function is documented e) periodic testing for vitamin B12 deficiency and B12 supplementation may be needed 2) sodium-glucose co-transporter 2 (SGLT2) inhibitor eg/ empagliflozin, canagliflozin, dapagliflozin, ertugliflozin a) SGLT2 inhibitors canagliflozin and empagliflozin dec CV risk in people with CVD & T2DM, and have renal benefits. Canagliflozin also dec CV mortality, but may have more adverse effects than empagliflozin b) SGLT2 inhibitor class of drugs (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin) may lead to ketoacidosis. Inc risk of leg and foot amputations with canagliflozin. Some cases of necrotising fasciitis of the perineum (eg/ Fournier's gangrene) observed in post-marketing surveillance of SGLT2 inhibitors 3) glucagon-like peptide 1 (GLP-1) agonist eg/ liraglutide, dulaglutide, semaglutide, exenatide, lixisenatide a) GLP-1 agonist treatment has beneficial effects on CV, mortality, and kidney outcomes in patients with T2DM. Liraglutide shown to dec major CV events, CV mortality, and all-cause mortality in diabetes patients with CHD. Dulaglutide and semaglutide both shown to dec major CV events, but not all-cause or cardiovascular mortality. Exenatide and lixisenatide shown not to reduce major CV events. Semaglutide is only GLP-1 agonist available in both oral and injectable formulations; the other GLP-1 agonists are only available in injectable formulations b) GLP-1 agonists stimulate glucose-dependent release of insulin, suppress glucagon levels, and may slow gastric emptying and increase satiety. GLP-1 agonists may be associated with modest initial weight loss ~ 2-7 kg in some. GLP-1 agents may lower HbA1c up to 9 mmol/mol (0.9%) and may lower postprandial glucose c) response to the drug is quite variable and some patients will lose ground on glycaemic control due to dec doses of other glycaemic medicine when used as part of multi-drug regimens. Patients should be cautioned about this as well as potential risk of hypoglycaemia, and advised to check blood sugars frequently when initiating therapy. Patients should report any new problems with high or low readings d) some cases of DKA in patients with type 2 diabetes on a combination of a GLP-1 receptor agonist and insulin who had doses of concomitant insulin rapidly reduced or discontinued 4) dipeptidyl peptidase-4 (DPP-4) inhibitor eg/ sitagliptin, linagliptin, alogliptin, saxagliptin a) DPP-4 inhibitors do not confer CV benefit, and do not lower glucose as much as metformin, sulfonylureas, or thiazolidinediones b) advantages - few SE, less hypos than sulfonylureas, less risk of weight gain or congestive heart failure than thiazolidinediones, and easy dosing. DPP-4 inhibitors do not appear to confer major risk of hypoglycaemia when studied as monotherapy 5) sulfonylurea or meglitinide eg/ glimepiride, glipizide, gliclazide, repaglinide, nateglinide a) sulfonylureas (e.g., glimepiride, glipizide, glicazide) inc release of insulin by pancreatic islet cells by altering potassium and sodium influx b) sulfonylureas may dec HbA1c by 10-20 mmol/mol (1-2%). Hypos is a major concern, esp if irregular or unpredictable eating and exercise habits. Hypos exacerbated by alcohol, salicylates, sulphonamides, gemfibrozil, or warfarin. In general, longer-acting sulfonylureas such as glibenclamide are avoided because of concern about hypoglycaemia c) in older adult patients start low dose. Glimepiride preferred sulfonylurea in older individuals, due to its dual hepatic/renal clearance and potentially lower risk of hypoglycaemia d) meglitinides (e.g., repaglinide, nateglinide) are an alternative to sulfonylureas, and can also be used as a first-choice secretagogue in people with known allergy to sulphur-containing drugs. Meglitinides have a modest effect on HbA1c, with an average reduction of only 5 mmol/mol (0.5%), but may help with postprandial hyperglycaemia. May cause hypoglycaemia; if a meal is skipped, the dose of meglitinide should be held to avoid hypoglycaemia 6) alpha-glucosidase inhibitor eg acarbose, miglitol a) a-glucosidase inhibitors impede the enzyme needed to split disaccharides into monosaccharides prior to absorption from the gut b) may be combined with most other classes of glucose-lowering medicine. May be useful in older adult patients with marked postprandial glucose excursions c) modest impact on HbA1c, must be taken multiple times a day, and costly. Adverse effects dec by low initial doses and by very slow titration of doses d) hypos must be treated with glucose tablets, as meds blocks gut absorption of carbs eg/ sucrose or fructose 7) thiazolidinedione eg/pioglitazone a) neither pioglitazone nor rosiglitazone confers a mortality benefit. Thiazolidinediones may cause fluid retention and exacerbate heart failure. Pioglitazone may be linked to an increased risk of bladder cancer b) enhance action of endogenous or exogenous insulin by acting at PPAR-gamma receptors. Dec HbA1c 10-15 mmol/mol (1-1.5%): less than insulin, metformin, or sulfonylureas c) hypos rare unless combined with sulfonylurea or insulin d) rosiglitazone removed from European market due to persistent safety concerns 8) drug combinations - metformin is basis for most 3-drug combos. Additional agents for 3-drug regimens are selected from: sulfonylureas/meglitinides, dipeptidyl-peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, alpha-glucosidase inhibitors, thiazolidinediones, basal insulin, or sodium-glucose co-transporter 2 (SGLT2) inhibitors. Evidence doesn't support combining DPP-4 inhibitor + GLP-1 agonist in the same regimen a) liraglutide, empagliflozin, or canagliflozin considered if CV disease 9) lipid management - a) 1st line - atorvastatin: moderate intensity: 10-20 mg OD, high intensity: 40-80 mg OD; or rosuvastatin: moderate 5-10 mg OD, high 20-40 mg OD; or simvastatin: moderate 20-40 mg OD, inc risk of myopathy with 80 mg/day dose b) 2nd line - as above + ezetimibe + evolocumab or alirocumab c) pts with T2DM have 2x inc risk of stroke or MI & 40x more likely to die of macrovascular than microvascular complications of diabetes. High-intensity statin recommended as tolerated in pts with atherosclerotic CV disease, 10-year CV risk >20%, or low-density lipoprotein (LDL)-cholesterol ≥4.9 mmol/L. pts aged 40-75 moderate-intensity statin therapy considered. Individualised approach for people aged >75 years. Moderate-intensity statin = lowers LDL-cholesterol level by 30-50%, while a high-intensity statin lowers LDL-cholesterol level by ≥50% d) combo using statins + other lipid-lowering agents considered in pts with very high CVD risk. Risks of complications eg/ impaired liver or renal function, myositis, or rhabdomyolysis may inc when using statins in combination with other agents 10) antiplatelet therapy - if also have CV disease or 50-70 with inc CV risk: aspirin (75-162 mg OD) or clopidogrel (75 mg OD) or both

Recognise vital importance of patient education and a multidisciplinary approach for the successful long-term care of diabetes

1) optimal diabetes care requires a long-term relationship with pt, appropriate use of consultants when needed, and regular monitoring and control of BP, HbA1c, tobacco use, and statin/aspirin use 2) most need diabetes assessments every 3-4 months, and some benefit from more frequent (monthly) visits, especially when motivated to improve their care 3) use of diabetes educators is recommended & MDT team with access to nurses, educators, dieticians, clinical pharmacologists, psychologists, and other specialists as needed 4) pt readiness to change is a strong predictor of improved care, and readiness to change may vary across domains of BP, statin use, aspirin use, glucose, smoking, physical activity, and nutrition 5) self-monitoring of blood glucose is recommended if: on insulin; have had prior hypos; drive or operate machinery and use oral meds that inc risk of hypos; or pregnant/trying 6) advise: dilated eye exam every 1 to 2 years; annual assessment of renal function including urinary albumin excretion test + serum creatinine test with eGFR; annually or more frequent foot examinations including assessment of ankle reflexes, dorsalis pedis pulse, vibratory sensation, and 10-gram monofilament touch sensation (if insensate feet, foot deformities, or a history of foot ulcers exam at every visit, may need specialised footwear) 7) due to disease progression, comorbidities, and non-adherence to lifestyle or medication relapse in any area above is common & usually asymptomatic; frequent monitoring of clinical parameters needed to detect relapse early and adjust therapy 8) factors that may lead to loss of adequate glycaemic control: medication non-adherence, depression, MSK injury or worsening arthritis, competing illnesses (seen by pt as more serious), stress at home or at work, substance abuse, occult infections, some meds (eg/corticosteroids, certain depression meds [paroxetine], mood stabilisers, atypical antipsychotics) that elevate weight or glucose, or other endocrinopathies such as Cushing's disease

S/s, DD, ix, mx, complications & prevention of non-acidotic hyperosmolar coma / severe hyperglycaemia

1) s/s - a) altered mental status - correlates with the severity of hyperglycaemia and serum osmolality. Coma is rare b) features of hyperglycaemia - polyuria, polydipsia, weight loss, weakness c) signs of dehydration - dec skin turgor, dry mucous membranes, tachycardia, dec BP d) seizures - seen in up to 25% of patients and can be either focal or generalised. Epilepsia partialis continua is an unusual form of seizure that is present in 6% of HHS patients in the early phase. Seizures related to hyperglycaemia in HHS are usually resistant to anticonvulsive therapy, and phenytoin may further exacerbate HHS e) uncommon - hypothermia, shock, abdo pain (but present in DKA), focal neurological signs (hemianopia or hemiparesis) f) differentiating DKA and HHS - pts with HHS do not develop significant ketoacidosis (insulin in amounts sufficient to inhibit ketogenesis but insufficient to prevent hyperglycemia); DKA = T1DM, HHS = T2DM; HHS = longer history (1 week) + marked dehydration + glucose >35mmol/L 2) DD - a) DKA - pts are often younger and leaner; usually T1DM; can have abdo pain; venous pH <7.3; HCO3 <15 mmol/; anion gap >12 mmol/L; presence of serum ketones or beta-hydroxybutyrate b) lactic acidosis - may be clinically indistinguishable from HHS and DKA, although most patients do not have a history of diabetes, venous pH <7.3, lactic acid >5 mmol/L c) alcohol ketoacidosis - hx of chronic alcohol abuse, produced by starvation due to poor food intake, s/s of chronic liver disease eg/ spider naevi, leukonychia, palmar erythema, bruising, jaundice, scratch marks, and hepatomegaly; serum glucose is low or normal but serum ketones or beta-hydroxybutyrate is elevated, lactate usually inc but not enough to account for acidosis d) ingestion of toxic substances - ethanol, methanol, ethylene glycol (automobile antifreeze), and/or propylene glycol (diluent in many IV medications, such as lorazepam), osmolar gap + anion gap e) paracetamol overdose - confusion, tinnitus, hyperventilation, and pulmonary oedema, urine and serum paracetamol levels +ve f) salicylate overdose - serum salicylate levels will be elevated. g) seizures - widespread motor manifestations, electroencephalogram (EEG) will show epileptiform activity h) stroke - rapid onset of limb and/or facial weakness (typically face, leg, and arm equally); may show visual disturbance, cranial CT or MRI demonstrates haemorrhage or attenuation 3) ix - a) plasma glucose level - >33.3 mmol/L b) serum or urinary ketone level - negative or low c) serum urea + creatinine - inc as volume depletion d) serum sodium - low due to osmotic flux of water from the intracellular to the extracellular space in the presence of hyperglycaemia. Hypernatraemia + hyperglycaemia = profound volume depletion (chloride + Mg + Ca + PO4 also low) e) serum potassium - inc as extracellular shift of potassium caused by insulin insufficiency, hypertonicity, and acidaemia. If low = severe total-body potassium deficit. f) serum osmolality - serum osmolality = 2 Na + 2 K + Glucose + Urea (all in mmol/L). ≥320 mmol/kg (≥320 mOsm/kg) g) anion gap calculation - (Na)-(Cl + HCO3), as mmol/L, levels ≥10 to 12 mmol/L signify an anion gap acidosis (i.e., lactic or ketoacidosis) h) serum lactate level - usually normal i) ABG/VBG - venous pH sample is usually 0.03 units lower than arterial pH, arterial pH >7.30; arterial bicarbonate is >15 mmol/L (>15 mEq/L) j) urinalysis - to exclude infection k) LFTs - usually normal; FBC - leukocytosis is present in hyperglycaemic crises, leukocytosis >25 x 10^9/L may indicate infection and requires further evaluation l) consider - CXR (exclude infection), ECG (to exclude MI or if severe electrolyte abnormalities are present), cardiac biomarkers (if suspect MI), blood, urine, or sputum cultures - if indicated as ?infection 4) mx - a) IVI - as long as no cardiac compromise give 0.9% NaCl 1L 1 hr, 4hr, 4hr; switch to 5% dextrose with 0.9% sodium chloride when plasma glucose <16 b) supportive care ± ICU admission - i) glucose checked every 2 hours and electrolytes, urea, venous pH, and creatinine checked every 2 to 6 hours, until resolution of hyperosmolar hyperglycaemic state (HHS). Urinary output should be monitored ii) diagnosis of precipitating factors (eg/ infection or causative medications) and appropriate treatment with antibiotics and removal of the offending medication should be initiated c) pts with haemodynamic, CV, or respiratory instability or altered mental status may require ICU d) +/- vasopressor eg/ NA or dopamine e) potassium - i) if <3.3 mmol/L (<3.3 mEq/L) - 40 mmol/L potassium given with IVI over 2 hours, insulin started after this & when serum potassium is ≥3.3 mmol/L. K+ measured every 2hrs f) insulin - when K+ >3.3, continuous infusion - bolus of 0.1 units/kg followed by 0.1 units/kg/hour continuous infusion. If serum glucose does not fall by at least 10% in 1st hr, give bolus of 0.14 units/kg of IV insulin while continuing the previous insulin infusion rate (i.e., either 0.1 units/kg/hour or 0.14 units/kg/hour). Once the blood glucose reaches 300 mg/dL or less, the insulin infusion should be reduced to 0.02-0.05 units/kg/hour, while maintaining the blood glucose between 200 and 300 mg/dL, until the patient is mentally alert g) +/- phosphate therapy - if severe hypophosphataemia (<0.32 mmol/L) in patients with cardiac dysfunction, symptomatic anaemia, or respiratory depression h) when awake & HHS resolved restart subcut insulin. Resolution = plasma glucose <12.2 mmol/L, plasma effective osmolality <315 mmol/kg & better haemodynamic & mental status. Subcut given 2 hrs before stopping insulin infusion 5) complications - a) insulin-related hypoglycaemia or treatment-related hypokalaemia - with excessive high-dose insulin therapy b) stroke, MI, PE, DIC, mesenteric vessel thrombosis - volume depletion with inc viscosity, hyperfibrinogenaemia, and inc plasma plasminogen activator inhibitor (PAI-1). Aggressive early hydration is helpful in reducing the incidence of these complications to approximately 2 c) cerebral oedema - rare, presents with headache, lethargy, pupillary changes, and seizure. Mortality is high. Give mannitol, mechanical ventilation. Cerebral oedema can be prevented by avoiding a reduction in plasma osmolality of more than 3 mmol/kg/hour (3 mOsm/kg/hour). This can be achieved by monitoring plasma osmolality, adding dextrose to IVI once plasma glucose <16 d) coma - asociated with serum osmolality levels >330 to 340 mmol/kg, most often more hypernatraemic than hyperglycaemic in nature. Needs ICU and aggressive fluid and insulin therapy 6) prevention - HHS evolves over several days, so frequent blood glucose monitoring may help recognition of patients at risk, especially in older people and in those in long-term care facilities. Pts & family should be educated about the following: which symptoms or blood sugar readings should prompt the patient to contact the diabetes care team; importance of insulin use during an illness, and never discontinuing insulin without contacting their healthcare provider; frequent monitoring of blood sugars (at least every 3-4 hours including overnight; this is especially important in children); blood glucose goals and the use of supplemental short- or rapid-acting insulins to correct elevated blood sugars; initiation of an easily digestible, liquid carbohydrate diet when nauseated.

S/s, DD, ix, mx, complications & prevention of hypoglycaemia

1) s/s - a) diaphoresis + tremor + anxiety + hunger + generalised tingling + nausea + palpitations - possible sympathoadrenal symptom of hypoglycaemia, although constellation of several symptoms is more specific than any one symptom alone b) confusion + irritability + blurred vision + drowsiness - possible neuroglycopenic symptoms, but the constellation of several symptoms is more specific than any one symptom alone c) uncommon - unexplained weight gain (+ hypoglycaemic symptoms = ?insulinoma), hyperpigmentation (in folds and scars and includes areas not exposed to sun = ?adrenal insufficiency) , hypotension (frank or orthostatic = ? adrenal insufficiency), short stature (?growth hormone deficiency) NB/ adrenal insufficiency - lack of a cortisol response to low serum glucose levels = failure to counteract hypoglycaemia. Typically, only a significant component of hypoglycaemia in paediatric cases 2) DD - a) idiopathic postprandial syndrome (pseudohypoglycaemia) - hypoglycaemic symptoms after ingesting a meal, glucose level >3.3 mmol/L + symptoms b) insulin autoimmune hypoglycaemia - extremely rare condition that usually spontaneously resolves, can assay for insulin antibodies as well as antibodies to insulin receptors 3) ix - a) serum glucose - when s/s start or at conclusion of 72-hour fast (after glucagon administration at end of 72-hour fast, glucose inc >1.4 mmol/L is consistent with insulinoma or IGF-II secretion), every 6 hours or at the onset of symptoms of hypoglycaemia confirmed by finger stick blood sugar of <2.8 b) LFTs - screening test to rule out hepatic causes (eg/ acute hepatitis, hepatic cirrhosis, hepatorenal syndrome) c) renal function testing - screening test to rule out renal causes (eg/ CHF, chronic renal failure, hepatorenal syndrome) d) serum insulin - measured when glucose <3.3 mmol/L or at the end of 72-hour fast. Should be undetectable, inc levels = factitious hypoglycaemia or insulinoma, inappropriate inc of C-peptide, proinsulin, and insulin suggest either insulinoma or sulfonylurea use e) serum C-peptide - measured when glucose level <3.3 mmol/L or at the end of 72-hour fast. Inc if insulin is endogenous f) serum beta-hydroxybutyrate - measured at the time of hypoglycaemic symptoms or at the end of 72-hour fast. Excessive insulin or IGF-II inhibits ketogenesis and dec beta-hydroxybutyrate eg/ mesenchymal tumour g) serum sulfonylurea - indicates iatrogenic hypoglycaemia. Test assays chlorpropamide, tolazamide, tolbutamide, glipizide, glyburide, acetohexamide, glimepiride, or gliclazide h) TSH levels - rule out thyroid function disorders i) serum cortisol - low indicates adrenal glands (primary) or hypopituitarism as source of adrenal insufficiency. To be confirmed by ACTH stimulation test j) consider - 48- to 72-hour fast under observation (if hypoglycaemic symptoms but blood glucose >2.8 mmol/L, blood glucose checked 6hrly. Once blood sugar <3.3 mmol/L, blood glucose levels checked hourly + serum proinsulin + C-peptide + insulin levels; oral glucose tolerance test (rule out DM); serum IGF-II (to confirm IGF-II hypersecretion if suspicion is raised by results of 72-hour fasting test); serum ACTH (low = secondary or tertiary cause for adrenal insufficiency); serum human growth factor (HGH - low = pituitary disorder); insulin suppression test (if hypoglycaemic but blood glucose >2.8 mmol/L); serum proinsulin (measured when glucose level <3.3 mmol/L or at end of 72-hour fast - inc = insulin is endogenous, esp with insulinoma); CT AP (order after non-factitious hypoglycaemia diagnosed to see if small islet cell tumours, insulinoma or large tumours that may be producing IGF-II); transabdominal US (order after non-factitious hypoglycaemia diagnosed and no tumours identified on CT scan - detect small islet cell tumours not seen on CT scan); endoscopic ultrasound (ordered when both CT scan & transabdominal ultrasound failed to identify the site of an insulinoma); nuclear imaging with octreotide scan (to identify a neuroendocrine tumour) 4) mx - a) reactive hypoglycaemia - dietary changes (often treats successfully) - go high in proteins and low in carbs, with frequent but smaller feeds to avoid the big fluctuations in the insulin secretion from the pancreas b) exposure/overdose medication, toxin, ethanol - supportive care ± psychiatric evaluation and treatment: tx with glucose +/- glucagon eg/ D10 or D50 infusion or glycogen infusion or injection, closely monitored with frequent blood glucose checks or, as glucose stabilises in the normal range, glucometer readings. The aim is to monitor for sustained hypoglycaemia and prompt correction c) bariatric surgery, anorexia, malnutrition, ackee fruit ingestion - supportive care ± referral to specialist, supportive care with glucose +/- glucagon, referral or consultation with endocrinology, toxicology, or GI disease specialists may be necessary d) insulinoma - i) 1st line - surgical excision - if hypoglycaemic continue after surgery consider repeating surgery to look for incomplete excision of primary tumour or rare malignant transformation with metastases + supportive care - self-administered glucagon injections ii) 2nd line - medical therapy - diazoxide or octreotide or streptozocin + supportive care - D10 or D50 infusion or glycogen infusion or injection, closely monitored with frequent blood glucose checks or, as glucose stabilises in the normal range, glucometer readings iii) metastatic disease: + focal embolisaton or chemotherapy e) IGF-II-secreting tumour - i) 1st line - surgical excision + supportive care - intermittent glucose infusion or glucagon administration f) renal failure, liver failure, sepsis, or other endocrinopathy - management of underlying condition + supportive care - glucose infusion may be necessary until the condition resolves, especially if the patient cannot tolerate oral intake 5) complications - a) seizure - if acute significant hypoglycaemia, glucose levels may be low enough to cause CNS manifestations such as seizures. The seizures should resolve with correction of glucose levels and not recur so long as hypoglycaemia is avoided b) coma - extreme hypo, resolves with correction of glucose levels and not recur so long as extreme hypoglycaemia is avoided. Permanent neurological sequelae are possible: for example, focal neurological deficits, memory loss c) diabetes mellitus

S/s, DD, ix, mx, complications & prevention of diabetes insipidus

1) s/s - a) hx of pituitary/hypothalamic disease - strong risk factors for central DI: pituitary surgery, craniopharyngioma, pituitary stalk lesions, traumatic head injury, and congenital pituitary malformations b) fmx/genetic mutations - nephrogenic DI may occur with loss-of-function mutations in AVP receptor pathway - inherited in X-linked or autosomal-recessive pattern. Central DI may occur in Wolfram syndrome and AVP-neurophysin gene mutations (autosomal-dominant pattern) c) hx of lithium therapy, others include: demeclocycline, cisplatin, colchicine, gentamicin, rifampin d) hx endocrine autoimmune disorders - Hashimoto's thyroiditis, T1DM e) polyuria + nocturia - ranging from 3 litres to >20 litres per day; inc thirst/polydipsia f) signs of volume depletion - dry mucous membranes, poor skin turgor, tachy, dec BP, if shock g) if dec thirst (primary pathology, dec consciousness) or access to free water dec (non-availability, disability, intercurrent illness) pt may become dehydrated and develop hypernatraemia - irritability, restlessness, lethargy, spasticity, and hyper-reflexia. If severe, delirium, seizures, and coma may be present h) uncommon: visual field defects (may indicate a previous or existing pituitary mass); focal motor deficits (due to previous or co-presenting intracranial pathology eg/ tumour, head injury, hydrocephalus, meningitis, or encephalitis); sensorineural deafness and visual failure (components of Wolfram syndrome); skin lesions (papular rashes or ulcers may suggest systemic Langerhans' cell histiocytosis, erythema nodosum may suggest sarcoidosis) 2) DD - a) psychogenic polydipsia - similar s/s, commonly associated with an underlying psychiatric disorder, daytime symptoms only or waking at night with the need to drink rather than to pass urine is more suggestive of primary polydipsia. Perform water deprivation test: normal response to dehydration is inc urine osmolality to >700 mmol/kg (>700 mOsm/kg); however, long-standing polyuria secondary to primary polydipsia may limit renal concentrating ability. Also - hypertonic saline stimulation test and measurement of copeptin: copeptin level ≤4.9 picomol/L b) DM - similar s/s, glucose inc c) diuretics - similar s/s, hx diuretic use d) hypercalcaemia - usually asymptomatic, pts may report abdo pain, constipation, low mood, renal stones, fatigue, or anorexia, inc calcium/corrected calcium 3) ix - a) urine + urine osmolality - low urine osmolality + high serum osmolality or elevated sodium strongly suggests DI. Urine osmolality <300 mOsm/kg; predicted serum osmolality calculated on basis of serum sodium, potassium, glucose, and blood urea nitrogen (Osm = (2Na) + (Glucose / 18) + (BUN / 2.8) b) serum glucose - normal, excludes diabetes as diagnosis c) serum sodium - normal if intact thirst mechanism & unrestricted access to fluids, inc serum sodium + hypotonic urine (urine osmolality <300 mmol/kg) strongly suggests DI d) serum potassium - hypokalaemia associated with nephrogenic DI e) serum urea nitrogen - inc with volume depletion or co-existent renal disease f) serum calcium - hypercalcaemia is associated with nephrogenic DI g) urine dipstick - considered to help exclude DM & look for evidence of wider renal disease and tubulopathies (proteinuria) h) 24-hour urine collection for volume - polyuria is a key feature, with volumes ranging from 3 litres to >20 litres per day i) water deprivation test - used to confirm DI. Pts deprived of fluids for 8hrs or until 3% loss of body weight is reached. Serum osmolality, urine volume, and urine osmolality measured hourly. If pt has severe DI, dehydration can develop rapidly. Normal response to dehydration = inc urine osmolality to >700 mmol/kg; in DI can't concentrate urine in response to dehydration so urine remains inappropriately dilute (urine osmolality <300 mmol/kg with serum osmolality >290 j) AVP (desmopressin) stimulation test - to distinguish central & nephrogenic DI following a water deprivation test. Given desmopressin 2 micrograms subcut, and serum osmolality, urine osmolality, and urine volumes measured hourly over next 4 hours. Central DI - respond to desmopressin with dec urine output & inc urine osmolality to >750 mmol/kg. Nephrogenic DI - don't respond to desmopressin, with no or little dec in urine output & no inc urine osmolality k) hypertonic saline-stimulated test with measurement of copeptin - to differentiate central DI, nephrogenic DI, and primary polydipsia. Baseline copeptin level >21.4 picomol/L is diagnostic of nephrogenic DI; copeptin level >4.9 picomol/L differentiates central DI from primary polydipsia l) consider - many check pituitary function: cranial MRI with contrast (may show pituitary or para-pituitary mass, congenital abnormalities, abnormal pituitary stalk; evidence of previous surgery; absence of posterior pituitary bright spot); genetic testing (WFSI mutation; AVP-neurophysin gene mutation; AVPR2 receptor gene mutation; aquaporin-2 gene mutation); antithyroid peroxidase autoantibodies (Hashimoto's thyroiditis); serum and CSF alpha-fetoprotein and beta-human chorionic gonadotrophin (in kids/adolescents to check for germinoma); serum growth hormone (GH) + insulin-like growth factor 1 (IGF-1) + provocative growth hormone (GH) tests + serum LH - check pituitary function; serum LH + serum follicle-stimulating hormone + morning serum testosterone (to diagnose gonadotrophin hormone deficiency); serum thyroid-stimulating hormone and triiodothyronine/thyroxine (T3/T4); morning serum cortisol and adrenocorticotrophic hormone (ACTH, blood taken & 8/9am when high cortisol - diagnose adrenal insufficiency); serum prolactin (inc if sellar or parasellar mass compressing pituitary stalk) 4) mx - a) hypernatraemia at any stage - i) 1st line - oral/IV fluids: hypotonic fluids, oral and enteral fluid is preferred. IV 5% dextrose and 0.45% sodium chloride may be necessary. Infusion rates determined by choice of infusate, degree of hypernatraemia, desired rate of correction, & estimated deficit in total body water. Regular serum sodium tests are required ii) if hypernatraemia is acute, dec serum sodium concentration by up to 1 mmol/L per hr may be appropriate. If longstanding or uncertain max dec of 0.5 mmol/L per hour iii) dec serum sodium limited to 10 mmol/L per 24 hours, to a target serum sodium of 145 mmol/L b) acute central DI with no hx of recent pituitary surgery or trauma - i) 1st line - desmopressin: 0.1 to 1 mg/day orally in 2-3 divided doses, or 0.5-4 micrograms/day IV/subcut; via parenteral or oral DDAVP (a synthetic analogue of arginine vasopressin [AVP]) ii) +/- oral/intravenous fluids - oral, or IV 5% dextrose and 0.45% sodium chloride c) acute central DI with recent pituitary surgery or trauma - i) 1st line - desmopressin: 0.1 to 1 mg/day orally in 2-3 divided doses, or 0.5-4 micrograms/day IV/subcut. If polyuria or low urine osmolality or hypernatraemia - central DI is likely & tx with DDAVP ii) +/- oral/intravenous fluids d) chronic central DI - i) 1st line - desmopressin: as above or nasal: 10-40 micrograms/day intranasally in 1-3 divided doses e) nephrogenic DI - i) 1st line - maintenance of adequate fluid intake + tx underlying cause eg/ stop drugs (eg lithium), underlying renal disease, tx of electrolyte disorders (hypercalcaemia or hypokalaemia) ii) +/- sodium restriction and/or pharmacotherapy: hydrochlorothiazide: 12.5-50 mg orally OD or indometacin: 25-50 mg orally two to three times daily, maximum 200 mg/day; low-sodium diet (<500 mg/day), thiazide diuretics, or indometacin may reduce urine output 5) complications - a) Complications a) hypernatraemia - normal thirst response is protective against hypernatraemia in patients with DI. Hypernatraemia can occur if patients have impaired free access to water. Mild to moderate hypernatraemia = irritability, restlessness, lethargy, muscle twitching, spasticity, or hyper-reflexia. Severe = delirium, seizures, or coma b) thrombosis - hypernatraemia + dehydration = inc risk of thrombosis c) bladder and renal dysfunction - if nephrogenic DI may develop bladder dysfunction in response to excess urine production. If unrecognised, can lead to renal impairment (eg/ CKD). Monitoring with regular serum creatinine assessment and periodic renal and bladder ultrasound is recommended d) iatrogenic hyponatraemia - common if chronic central DI & on replacement desmopressin (DDAVP). Most of this hyponatraemia remains asymptomatic. Tx through DDAVP dose adjustment

S/s, DD, ix, mx, complications & prevention of hypercalcaemia

1) s/s - a) may be mild and occur without symptoms b) lethargy, easy fatigue c) confusion - can also have N&V, abdo pain, peptic ulcer disease, pancreatitis d) depression, irritability e) constipation, polyuria, polydipsia f) renal stones typical of hyperparathyroidism g) chronic symptoms consistent with hyperparathyroidism, recent onset of symptoms suggests malignancy (along with weight loss) h) bone pain - may suggest metastases in long bones NB/ 'Bones, stones, groans and moans' 2) DD - a) primary hyperparathyroidism - usually asymptomatic but may have a history of renal stones, long bone pain, constipation, fatigue, abnormal psyche, slow thought, depression; ix - inc calcium, parathyroid hormone inc; 24-hour urine calcium inc; bone densitometry T-score <-2.5 b) malignancy - hx primary malignancy; ix - inc calcium, parathyroid hormone usually dec; parathyroid hormone-related protein (PTHrP) can be inc c) multiple myeloma - weight loss, bone or back pain, fmx myeloma, infections, renal failure, history of monoclonal gammopathy of unknown significance; inc calcium, low PTH, serum protein electrophoresis - monoclonal gammopathy, ionised calcium - normal or elevated, skeletal survey - osteopenia, osteolytic lesions, pathological fractures d) familial hypocalciuric hypercalcaemia - asymptomatic; ix - inc calcium, PTH - variable, low urine calcium e) drugs - vit D intoxication, lithium, thiazide diuretics, hypervitaminosis A f) chronic renal failure and secondary hyperparathyroidism - chronic renal failure and dialysis with bone pain & tenderness; ix - variable serum calcium, inc PTH, inc creatinine, urinalysis - haematuria +/- proteinuria, kidney US - small kidney, presence of obstruction/hydronephrosis, kidney stones g) hyperthyroidism - anxiety, weight loss, inc appetite, sleep disturbance, palpitations, heat intolerance, sweating, eye pain, bone pain; ix - inc calcium, normal or dec PTH, low TSH h) milk-alkali syndrome - excess milk or alkali (eg/ because of dyspepsia), excess calcium supplementation (eg/ post-menopausal women), bone pain; inx calcium, PTH normal or low i) sarcoidosis - age 20-40 , cough, dyspnoea, chronic fatigue, arthralgia, wheezing, photophobia, painful red eye, blurred vision, may be asymptomatic, fmx, rhonchi, lymphadenopathy, erythema nodosum, lupus pernio, conjunctival nodules, facial palsy; inc calcium, PTH normal or dec, CXR - hilar +/- paratracheal adenopathy with upper lobe predominant, bilateral infiltrates j) prolonged immobilisation - inc calcium, PTH nondetectable k) Paget's disease - bone pain (esp pelvis), fmx Paget's disease, may be asymptomatic; ix - inc calcium, PTH nondetectable, alkaline phosphatase - markedly inc, x-ray - lytic changes in early stage; sclerotic picture predominates over osteolytic in later stage 3) ix - a) calcium level - raised b) PTH level - i) normal or inc = primary hyperparathyroidism, familial hypocalciuric hypercalcaemia, lithium associated hypercalcaemia, bisphosphonates ii) low = malignancy, or granulomatous disease c) FBC & LFTs - anaemia raises the possibility of malignancy or chronic disease, LFTs deranged in malignancy; ESR - inc in renal or inflammatory disease; U&E - hypercalcaemia may be associated with dehydration and renal failure d) bone profile - baseline calcium level needs to be interpreted with albumin to determine corrected calcium, alkaline phosphatise (ALP) and serum phosphate levels may give an indication of likely cause - low phosphate and normal ALP = primary hyperparathyroidism, inc ALP = malignancy with bone metastases e) TSH & fT4/T3 f) prolactin - related to MEN1 g) vitamin D - deficiency is common and can lead to diagnostic confusion, usually occurs in the context of a low or normal calcium, with inc PTH secondary hyperparathyroidism. h) calcium to creatinine clearance ratio - 24hr urinary collection for calcium and creatinine, with paired serum sample for calcium and creatinine - demonstrates level of hypercalciuria which indicates risk of renal stone formation, and allows calculation of the calcium to creatinine clearance ratio. This may be calculated using the following formula: Urine Calcium (mmol/l) x [Plasma Creatinine (micromol/l)/1000] divided by Plasma Calcium (mmol/l) x Urine Creatinine (mmol/l) ratios <0.01 consistent with familial benign hypocalciuric hypercalcaemia i) others - serum and urine protein electrophoresis (when PTH is undetectable - used for ? haematological malignancy); CXR (if smoker or s/s of lung malignancy or sarcoidosis); AXR (for asymptomatic renal tract calcification); calcium sensing receptor gene sequencing (for confirmation of familial benign hypocalciuric hypercalcaemia); bone densitometry; neck US/neck sesta-MIBI scan (if primary hyperparathyroidism & suitable for surgery); skeletal survey (specific bony pain +/- inc ESR + protein electrophoresis - consider skeletal survey prior to haematology referral); liver US (if ALP and other liver enzymes are elevated & PTH low, look for metastatic disease); oesophagogastroduodenoscopy (if severe UGI s/s & red flags); serum ACE (if ?sarcoidosis) 4) mx - a) PTH results low or undetectable - stop offending drugs eg/ in milk alkali syndrome, or after psychiatric liaison for lithium use; start definitive tx for thyrotoxicosis or Addison's if appropriate b) PTH results normal or elevated - i) calcium to creatinine clearance ratio <<0.01 and patient asymptomatic - likely familial hypocalciuric hypercalcaemia; no further ix or tx necessary; family members should be informed about this diagnosis to prevent unnecessary investigations in the future ii) calcium to creatinine clearance ratio close to 0.01 and or possible symptoms - inconclusive results, repeat 24hr collection 3x for both calcium and magnesium:creatinine clearance ratios, or consider sequencing of the calcium sensing receptor iii) calcium to creatinine clearance ratio >>0.01 - FHH excluded iv) vitamin D deficiency detected <25ng/ml and calcium <3mmol/l - 10,000 units ergocalciferol orally per week or 100,000 units intra-muscularly c) confirmed primary hyperparathyroidism - i) high fluid intake and normal calcium diet in all patients ii) stop interfering medications - specifically calcium or vitamin D containing supplements or antacids iii) consider surgery - after neck ultrasound scan and MIBI, refer to parathyroid surgeon for minimally invasive surgery, if imaging fails to localise an adenoma & pt has not had previous neck surgery, consider bilateral neck exploration. iv) follow up post surgery - need to monitor serum calcium, U&E three months post surgery and review results and histology. If calcium is within the normal range post operatively, discharge v) conservative management - if unsuitable for surgery, arrange six monthly monitoring of serum calcium, reassess pts if they develop new symptoms or complications, or their calcium rises, or they reconsider surgery. Other options include: bisphosphonates, cinacalcit vi) arrange long term six monthly monitoring of serum calcium d) emergency treatment of hypercalcaemia - hypercalcaemia associated with acute renal failure, confusion, or other emergency features requires emergency treatment. Rapidly increasing and very high levels should also be treated immediately i) IVI with 0.9% saline, 4L/24hrs usually sufficient to bring calcium levels down. Patients with unstable cardiac disease, or who may not tolerate fluid resuscitation should be discussed with a nephrologist to consider dialysis ii) urgent parathyroid surgery or treatment of underlying disease, such as malignancy or sarcoidosis, will also usually bring calcium levels down quickly iii) if initial measures fail to control the hypercalcaemia, bisphosphonate infusion may be considered, after all initial investigations have been completed 5) complications - a) osteoporosis - can lead to bone fractures, spinal column curvature and loss of height b) kidney stones & kidney failure c) nervous system problems - severe hypercalcemia can lead to confusion, dementia and coma, which can be fatal d) arrhythmia 6) prevention - avoiding excess intake of calcium pills and calcium-based antacid tablets

S/s, DD, ix, mx, complications & prevention of Cushing's syndrome

1) s/s - a) presence of risk factors - exogenous corticosteroid use, pituitary or adrenal adenoma, or adrenal carcinoma b) facial plethora - most specific physical finding + facial rounding c) supraclavicular fullness - inc subcut fat in supraclavicular fossa + dorsocervical fat pads d) violaceous striae - worsening or significant violaceous striae are commonly associated with hypercortisolism in younger individuals e) menstrual irregularities - women with hypercortisolism have irregular menses or amenorrhoea f) need to exclude other causes for hypercortisolism including: pregnancy, malnutrition, alcoholism, physiological stress g) linear growth deceleration in children - >95% show dec linear growth velocity. Dec linear growth + weight gain in children is suggestive of Cushing syndrome h) female predisposition - 4:1 i) HTN j) glucose intolerance or diabetes mellitus k) premature osteoporosis or unexplained fractures - low bone density in younger men should raise suspicion. Premature osteoporosis and fracture seen in 50% female patients with Cushing syndrome l) weight gain and central obesity - based on degree of hypercorticolism m) acne - especially on face, back, and chest n) psychiatric symptoms - mood changes are common, depression is most common, but can have anxiety and even psychosis. Improve or resolve with treatment of hypercortisolism o) dec libido - true gonadal dysfunction is common. Men generally complain of decreased libido initially. As the hypercortisolism persists, erectile dysfunction may develop p) easy bruisability q) weakness - proximal weakness being most prominent r) uncommon - unexplained nephrolithiasis, hirsutism (can be a sign of adrenal carcinoma) 2) DD - a) obesity - usually lack facial plethora, unexplained bruising, proximal muscle weakness, violaceous striae, supraclavicular fullness, and osteoporotic fractures i) ix - normal late-night salivary cortisol, dexamethasone suppression testing, or 24-hour urinary free cortisol b) metabolic syndrome - usually lack facial plethora, unexplained bruising, proximal muscle weakness, violaceous striae, supraclavicular fullness, and osteoporotic fractures i) ix - normal late-night salivary cortisol, dexamethasone suppression testing, or 24-hour urinary free cortisol 3) ix - a) urine pregnancy test - exclude pregnancy b) serum glucose - Cushing syndrome commonly leads to diabetes and glucose intolerance c) late-night salivary cortisol - 1st line: samples collected by saturating a collection swab with saliva or passively drooling into a collection tube between 23-0:00. 2+ samples on 2+ nights = inc sensitivity. Elevated result in Cushing's. +ve results should be confirmed with dexamethasone suppression testing or 24-hour urinary free cortisol d) 1 mg overnight dexamethasone suppression test - 1st line: +ve test = morning cortisol >50 nanomol/L (>1.8 micrograms/dL). 1st line unless taking meds affecting dexamethasone metabolism (phenytoin, carbamazepine, rifampicin, and cimetidine). Pt given 1 mg of dexamethasone at 11 p.m., and a plasma cortisol level is obtained the following morning at 8 a.m. Dexamethasone levels are measured simultaneously with cortisol to ensure appropriate levels are achieved. +ve results should be confirmed with late-night salivary cortisol or 24-hour urinary free cortisol. e) 24-hour urinary free cortisol - 1st line: >50 micrograms/24 hour. 1st line expect in renal failure. Sensitivity lower than late-night salivary cortisol or 1 mg overnight dexamethasone suppression testing. Need 24-hour urine collection, and should avoid excessive fluid intake. Need 2+ 24-hour urinary free cortisol samples. +ve results should be confirmed with late-night salivary cortisol or 1 mg overnight dexamethasone suppression testing f) 48-hour 2 mg (low-dose) dexamethasone suppression test: morning cortisol >50 nanomol/L (>1.8 micrograms/dL). May be considered 1st line unless meds known to affect metabolism of dexamethasone eg/ phenytoin, carbamazepine, rifampicin, and cimetidine. Pts given 0.5 mg of dexamethasone at 9 a.m. and at 6hly- for 48 hours, with a plasma cortisol obtained at 9 a.m., 6 hours after the last dose. +ve should be confirmed with late-night salivary cortisol or 24-hour urinary free cortisol. g) consider: plasma dehydroepiandrosterone sulphate (DHEAS) level (inc is non-specific ?adrenal carcinoma); morning plasma adrenocorticotropic hormone (ACTH) (>4 picomol/L (>20 picograms/mL) = pituitary or ectopic source of disease, <1 picomol/L (<5 picograms/mL) = adrenal source of disease; high-dose dexamethasone suppression test (to differentiate pituitary versus ectopic source of adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome - +ve = suppression of cortisol <50% of the baseline value); pituitary MRI/adrenal CT (if adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome, most adenomas <1cm); inferior petrosal sinus sampling (adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome without an obvious pituitary lesion on MRI; central/peripheral ACTH ratio >2:1 at baseline or >3:1 after corticotrophin-releasing hormone (CRH) stimulation); CTCAP (determine the source of ectopic adrenocorticotropic hormone syndrome); MRI chest/PET scan/ octreotide scanning (ectopic adrenocorticotropic hormone syndrome to localise tumour) 4) mx - a) Cushing's disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumour) - i) 1st line - transsphenoidal pituitary adenomectomy ii) +/- medical therapy before surgery: mifepristone (glucocorticoid receptor antagonist - used for all forms of Cushing syndrome): 300 mg OD, inc in 300 mg/day increments every 2-4 weeks according to response; or pasireotide (somatastatin analogue - used for corticotroph adenomas): 0.6 mg subcut BD, inc to 0.9 mg BD after 8 weeks according to response; or ketoconazole (steroidogenesis inhibitors): 200 mg BD, titrate by 200-400 mg/day increments at monthly intervals; or metyrapone (steroidogenesis inhibitors): 250 mg QDS initially, increase every few days according to response; rarely - mitotane or etomidate iii) +/- post-surgical corticosteroid replacement therapy: hydrocortisone: 10-25 mg per m2 body surface area/day orally given in 2-3 divided doses; larger dose in the morning (10-15 mg) and a smaller dose in the late afternoon (5-10 mg) - need to monitor BP, check for orthostatic symptoms, and assess general sense of energy or fatigue iv) +/- post-surgical non-corticosteroid pituitary hormone replacement therapy: levothyroxine (1.8 micrograms/kg/day) +/- testosterone transdermal (2.5-7.5 mg OD in men) or testosterone cipionate (200 mg IM every 2 weeks in men) or estradiol (2 mg OD in women) or conjugated oestrogens: (0.625-1.25 mg OD in women) + medroxyprogesterone (5-10 mg OD on 10 days of each month if woman has intact uterus and on estradiol or oestrogen) +/- somatropin +/- desmopressin (0.1 mg OD-TDS) v) 2nd line - repeat transsphenoidal pituitary adenomectomy +/- medical therapy before surgery: mifepristone or pasireotide or ketoconazole or metyrapone +/- post-surgical corticosteroid replacement therapy: hydrocortisone +/- post-surgical non-corticosteroid pituitary hormone replacement therapy: levothyroxine +/- testosterone or estradiol or conjugated oestrogens + medroxyprogesterone +/- somatropin +/- desmopressin vi) 2nd line - medical therapy alone: mifepristone or pasireotide or ketoconazole or metyrapone vii) 3rd line - pituitary radiotherapy (risk of damage to optic chiasm) +/- medical therapy before radiotherapy +/- post-radiation corticosteroid replacement therapy +/- post-radiation non-corticosteroid pituitary hormone replacement therapy viii) 4th line -bilateral adrenalectomy: if severe hypercortisolism following ineffective reoperation, or not a candidate for reoperation, depending on patient preference and risk of complications. Provides cure for all endogenous hypercortisolism, inc risk of Nelson's syndrome; + permanent post-surgical corticosteroid replacement therapy: hydrocortisone: 10-25 mg per m2 body surface area/day orally in 2-3 divided doses; larger dose in the morning (10-15 mg) and a smaller dose in the late afternoon (5-10 mg) + fludrocortisone: 0.05-0.1 mg orally once daily - need to monitor BP, check for orthostatic symptoms, and assess general sense of energy or fatigue at regular intervals +/- medical therapy before surgery b) ectopic ACTH or corticotrophin-releasing hormone (CRH) syndrome - i) 1st line - surgical resection or ablation of tumour and metastases +/- medical therapy (mifepristone or pasireotide or ketoconazole or metyrapone or mitotane or etomidate) +/- chemotherapy or radiotherapy for primary tumour ii) 2nd line - bilateral adrenalectomy: if surgical resection is not possible, depending on patient preference and risk of complications, cure for all endogenous hypercortisolism + permanent post-surgical corticosteroid replacement therapy: hydrocortisone + fludrocortisone +/- medical therapy before surgery +/- chemotherapy or radiotherapy for primary tumour iii) 3rd line - medical therapy +/- chemotherapy or radiotherapy for primary tumour c) ACTH-independent due to unilateral adrenal carcinoma or adenoma - i) 1st line - unilateral adrenalectomy or tumour resection +/- medical therapy before surgery +/- chemotherapy or radiotherapy for adrenal carcinoma ii) 2nd line - medical therapy +/- chemotherapy or radiotherapy for adrenal carcinoma d) ACTH-independent due to bilateral adrenal disease (hyperplasia or adenoma) - i) 1st line - bilateral adrenalectomy: cure for all endogenous hypercortisolism + permanent post-surgical corticosteroid replacement therapy: hydrocortisone + fludrocortisone; +/- medical therapy before surgery ii) 2nd line - medical therapy 5) complications - a) adrenal insufficiency secondary to adrenal suppression (following surgery - usually for months) b) CV disease - major cause of mortality in Cushing's c) HTN - in 70-80% of pts d) DM - 20-60% pts e) osteoporosis - premature osteoporosis & fracture seen in 50% pts f) nephrolithiasis g) Nelson's syndrome after bilateral adrenalectomy - progression of pituitary adenoma after bilateral adrenalectomy can = intracranial mass effect from inc tumour size & inc adrenocorticotropic hormone (ACTH) levels. Pts with Cushing's disease who undergo bilateral adrenalectomy should have plasma ACTH levels and pituitary MRI 6 to 12 months after surgery h) treatment-related central hypothyroidism +/- growth hormone deficiency +/- adrenal insufficiency +/- hypogonadism +/- diabetes insipidus i) surgery- or radiation-related hypopituitarism +/- hyponatraemia 6) prevention - exogenous Cushing's syndrome may be prevented in patients who require exogenous corticosteroid treatment, by reducing corticosteroid use to an absolute minimum required dose and frequency whenever possible

S/s, DD, ix of PCOS

1) s/s - a) presence of risk factors: premature adrenarche or fmx of PCOS b) female of reproductive age - s/s start at puberty, but if oral contraceptives begun at a young age, symptoms may be masked until therapy is stopped c) irregular menstruation - manifestation of oligo- or anovulation, occurring in 75% of PCOS pts d) infertility e) hirsutism - terminal hairs (thick, pigmented) in androgen-dependent areas (upper lip, chin, chest, back, upper arm, shoulders, linea alba, peri-umbilical region, thigh, buttocks). f) acne g) overweight or obesity h) HTN i) uncommon - alopecia, oily skin or excessive sweating, acanthosis nigricans (brown or grey, velvety, occasionally verrucous, hyperpigmented areas over nape of neck, vulva, axillae, groin, umbilicus, sub-mammary areas, elbows, and knuckles) 2) DD - a) 21-hydroxylase deficiency - similar s/s, ix - morning, follicular-phase 17-hydroxyprogesterone level <6 nanomol/L (<200 nanograms/dL) rules out the disorder. A value >24 nanomol/L (>800 nanograms/dL) rules it in b) thyroid dysfunction - s/s of hypothyroidism (eg/ lethargy, cold intolerance) or hyperthyroidism (eg/ weight loss, nervousness, heat intolerance) may be present, ix - TSH inc (hypo) or dec (hyper) c) hyperprolactinaemia - oligo- or amenorrhoea, mild hyper-androgenic, galactorrhoea, headache or visual field deficit, ix - inc prolactin level d) Cushing's syndrome - obesity, hirsutism, acne, menstrual irregularity, moon facies, central fat deposition, hypertension, muscle wasting, abdominal striae, and osteoporosis, ix - 24-hour urinary free cortisol (normal <248 nanomol/24 hours or low-dose dexamethasone suppression test (e.g., overnight: 1 mg at 11 p.m. or midnight), with 8 a.m. plasma cortisol the next morning <138 nanomol/L (<5 micrograms/dL) e) androgen-secreting neoplasms (steroid-producing tumours of adrenal or ovary) - progressive virilisation eg/ frontal balding, severe hirsutism, inc muscle bulk, deepened voice, clitoromegaly, ix - baseline total testosterone >6.9 nanomol/L (>200 nanograms/dL) (or free testosterone >0.7 nanomol/L [>2 nanograms/dL]) then US ovaries, dehydroepiandrosterone sulfate >7000 nanograms/mL = CT scan of the adrenals f) syndromes of severe insulin resistance - more severe insulin resistance, hyperinsulinaemia, and hyper-androgenism, acanthosis nigricans, ix - fasting insulin >556 picomol/L (>80 micro-units/mL) and/or peak insulin >2084 picomol/L (>300 micro-units/mL) during a 3-hour 75 g oral glucose tolerance test g) androgenic/anabolic drugs - hx of use of testosterone, anabolic steroids, danazol, dehydroepiandosterone, androstenedione, 19-norprogestins, norgestrel, levonorgestrel, or norethisterone, show hyper-androgenism, ix - depending on agent used, blood evaluation for androgen levels may or may not be diagnostically useful h) hypogonadotrophic hypogonadism - oligo-anovulation, but no hyper-androgenism, ix - low serum follicle-stimulating hormone and estradiol i) premature ovarian failure - anovulation, but no hyper-androgenism, ix - high serum follicle-stimulating hormone and low serum estradiol j) apparent cortisone reductase deficiency - s/s similar to PCOS, ix - ratio of tetrahydrocortisols to tetrahydrocortisone is very low (0.04-0.08, normally 0.5 to 2.0), both adrenals often enlarged, urinary free cortisol may appear elevated 3) ix - a) serum 17-hydroxyprogesterone - to exclude 21-hydroxylase-deficient non-classic (adult-onset) adrenal hyperplasia (NCAH), -ve = 6-24 nanomol/L (200 and 800 nanograms/dL) 60 mins after adrenocorticotrophic hormone stimulation, +ve = >30 nanomol/L (1000 nanograms/dL) b) serum prolactin - to exclude hyperprolactinaemia, inc = prolactinoma, PCOS = normal or c) serum thyroid-stimulating hormone - rule out thyroid disease d) oral glucose tolerance test - check for DM, fasting glucose measurement then glucose level 2 hours after 75 g oral glucose, DM = fasting glucose ≥7 mmol/L or 2-hour glucose ≥ 11 mmol/L, abnormal glucose tolerance common in PCOS e) fasting lipid panel - dyslipidaemia common in PCOS, inc total cholesterol, LDL-cholesterol, triglycerides; low HDL-cholesterol f) consider - serum total and free testosterone (often inc), serum dehydroepiandrosterone sulfate (DHEAS - often inc), serum androstenedione (often inc), pelvic ultrasound (polycystic ovaries - can be present in other conditions), basal body temperature monitoring (if normal menses, biphasic pattern indicates ovulation has occurred; flat pattern indicates anovulation), luteal phase progesterone measurement (if normal menses - >6.4-25.4 nanomol/L (>2-8 nanograms/mL) indicates ovulation has occurred, serum LH and FSH (LH/FSH ratio >3 suggests PCOS)

S/s, DD, ix of Turner's

1) s/s - a) short stature - <5th centile for height by 10yo (smaller than mid-parental height prediction) b) delayed/absent pubertal development - sparse pubic hair, pubertal development minimal. Mostly detected at 10-16 yo as combination of marked short stature and delayed puberty c) primary amenorrhoea - ovaries form normally but most demonstrate accelerated oocyte death and ovarian degeneration into fibrous streaks; can have secondary amenorrhoea - functional ovarian tissue with spontaneous puberty & menstruate then have premature ovarian failure d) congenital heart defects - aortic coarctation and bicuspid aortic valves are the most common abnormalities. Others: partial anomalous pulmonary veins, left heart hypoplasia, dilated aorta e) skeletal abnormalities - wide carrying angle (>30 degrees) owing to in-turned elbows (cubitus valgus), short fourth metacarpals or metatarsals, and, rarely, a Madelung deformity (prominent distal ulna), as well as scoliosis. f) dysmorphic features - low-set or malrotated ears, down-sloping eyes, ptosis or hooded eyes, and low posterior hairline are pathognomonic. A high-arched palate, although common, is not specific g) others - multiple melanocytic naevi; recurrent/severe otitis media; systolic ejection murmur and/or click (suggests bicuspid aortic valve); poor social skills; webbed neck - common manifestation of fetal lymphoedema (swelling of fetal tissues, especially of the head and neck, due to impaired lymphatic development); peripheral lymphoedema - puffy dorsum of hands or feet; upper extremity hypertension (suggests aortic coarctation); dystrophic and/or hyper-convex nails 2) differentials - a) constitutional delay of growth and development - no dysmorphic features or congenital defects b) Noonan's syndrome - hypertrophic cardiomyopathy and pulmonic stenosis, triangular facies, prominent chest wall deformity, possible mental retardation, all not common in Turner's c) 46,XX gonadal dysgenesis - primary amenorrhoea, no dysmorphic features typical of Turner's d) 46,XY complete gonadal dysgenesis - genetic defect in testis development, primary amenorrhoea, no dysmorphic features e) complete androgen insensitivity - genetic defect in androgen receptor, primary amenorrhoea, no pubic hair, dysmorphic features, no short stature or congenital heart defects 3) ix - a) karyotype - abnormalities include non-mosaic 45,X; mosaic 45,X (proportion of cells with a normal chromosome constitution); and fragmented X or Y (Xp deletions, isoXq chromosomes, Xq deletions, and ring X or Y chromosomes with substantial interstitial deletions) - find at least 10% of the cells with a complete or partial loss of a sex chromosome b) consider: audiology testing (can be abnormal); bone age (xray, typically 2 years less than chronological age); echo (eg/ coarctation of the aorta, bicuspid aortic valve); cardiac MRI (more reliable than echo but needs sedation); serum FSH and anti-Müllerian hormone (AMH - inc FSH +/- dec AMH predicts complete ovarian failure; skeletal survey (Madelung deformity (prominent distal ulna) is found in 5% pts, can also have wrist deformities and scoliosis); pelvic ultrasound (immature uterus and streak ovaries); renal ultrasound (renal structural abnormalities in ~ 25% pts); TFTs + antithyroid antibodies (autoimmune thyroid disease (Hashimoto's & Graves' disease)); LFTs/gamma GT (Turner's hepatitis); fasting glucose and HbA1c (diabetes); serum lipids (dyslipidaemia); IgA level and tissue transglutaminase IgA (coeliac)

S/s, DD, ix, mx, complications & prevention of hypocalcaemia

1) s/s - a) varies from a mild asymptomatic biochemical abnormality to a life-threatening disorder b) acute hypocalcaemia can lead to paraesthesia, tetany, and seizures, characteristic physical signs may be observed, including Chvostek's sign (brief contraction/twitching of perioral muscles, resulting in contraction of the corner of the mouth, ipsilateral nasal musculature, and ipsilateral eye musculature - elicited by tapping over cranial nerve VII at the ear), and Trousseau's sign (carpopedal spasm in response to ischaemia that occurs when a BP cuff is used for several minutes) c) chronic hypocalcaemia can lead to papilloedema, cataracts, basal ganglia calcifications, and skin, hair, and dental changes d) neuropsychiatric manifestations include dementia, anxiety, depression, lethargy, and extrapyramidal symptoms (parkinsonism) e) skin examination may show dermatitis, eczema, hyperpigmentation, psoriasis, brittle hair with patchy alopecia, and brittle nails with characteristic transverse grooves f) if hypocalcaemia occurs at an early age, congenital aetiologies should be investigated; if it occurs in an older person living in a nursing home, where there may be little access to sunshine, then vitamin D deficiency is a likely cause g) surgery - hx of neck surgery eg/ thyroidectomy (may have parathyroid glands accidentally removed), damaged, or devascularised; hypocalcaemia after surgery - 'hungry bone' syndrome (usually occurs during first 2 postoperative days of parathyroid adenoma surgery) h) fatigue, muscle weakness, cramps, and pain may suggest vitamin D deficiency i) chronic complaints of numbness and tingling in the fingertips, toes, and perioral region can indicate hypocalcaemia j) pts taking immunosuppressives +/- hx of skin cancer become vit D deficient if they follow rigorous sun avoidance advice. People who routinely use high SPF sunscreen, have dark skin and live in northern latitudes, wear concealing clothing, are chronically housebound, or have fat-soluble vitamin malabsorption are at risk of severe vitamin D deficiency k) short 4th metacarpal bone (brachydactyly) is an important sign of pseudohypoparathyroidism l) pts with congenital abnormalities may have highly variable features, ranging from mild learning disabilities to complete spectrum of congenital malformations (eg/ classic triad of cardiac anomalies, hypoplastic thymus, and hypocalcaemia seen in DiGeorge syndrome) 2) DD - a) iatrogenic postsurgical hypoparathyroidism - hx of parathyroid surgery or thyroid surgery with inadvertent removal of or trauma to the parathyroid glands; ix - low calcium + PTH, high phosphorus, normal ALP b) vitamin D deficiency - dec sunshine; nutritional deficiency; aches and pains; hx of bone fracture; gastric bypass surgery; GI diseases eg/ coeliac, that cause chronic diarrhoea/steatorrhoea; use of anticonvulsant therapy eg/ phenobarbital or diphenylhydantoin; s/s - bone tenderness, pathological fracture, proximal muscle weakness; ix - low calcium, inc PTH + ALP, low vit D, bone densitometry - in the range of osteoporosis: T score <-2.5, x-ray of pelvic bones or other areas of pain: fractures and Looser's zone (pseudofracture) c) hypomagnesaemia - may have hx of PPI use; chronic malnutrition and malabsorption; alcoholism; or coeliac disease; s/s - usually asymptomatic, but when magnesium is very low, cardiac arrhythmias may occur resulting in irregular heart beat; ix - low calcium, variable PTH, ECG - cardiac arrhythmias with prolonged PR and QT intervals, low serum magnesium d) hyperventilation - excess anxiety and worry, panic attack; recent anaesthesia; deep or rapid breathing, paraesthesias; s/s - agitated; inc HR + RR; signs of hypocalcaemia such as Trousseau's sign, carpopedal spasm, Chvostek's sign, seizure disorder, neuromuscular irritability, or muscle cramps; papilloedema could occur in severe cases of hypocalcaemia; ix - low calcium + potassium, ABG - low PaCO2 e) uncommon - isolated hypoparathyroidism (usually kids, neurological s/s of hypocalcaemia; ix - low calcium & PTH, high phosphorus, low vit D); pseudohypoparathyroidism (asymptomatic or hypocalcaemia s/s, short stature, mental retardation, round facies, and short fourth fingers; ix - low calcium, normal-high PTH + phosphorus); autoimmune hypoparathyroidism (hypocalcaemic symptoms; ix - low calcium + PTH, parathyroid antibodies may be +ve); HIV-related hypoparathyroidism (rare; ix - low calcium + PTH, serum HIV ELISA +ve); hypermagnesaemia (renal dysfunction +/- massive exogenous magnesium intake; ix - low calcium, variable PTH, inc Mg); hyperphosphataemia (renal impairment, hypoparathyroidism, excessive intake of oral or parenteral phosphate; ix - low calcium, variable PTH, high phosphorus); hypercalciuria (multiple kidney stones, renal impairment, fmx; ix - low calcium, variable PTH, 24-hour urinary calcium secretion inc); sepsis; burns; renal failure (pallor, skin bruising, lung rales, pericardial rub, oedema; ix - low calcium, high urea & creatinine, normal or inc PTH, low vit D, high phosphorus); acute pancreatitis (Grey-Turner sign, Cullen's sign, Fox's sign etc; low calcium, inc lipase & amylase, US abdo); extensive osteoblastic skeletal metastasis (eg/ prostate ca; ix - low calcium, inc PTH + ALP, xray- inc bone formation, isotope bone scan - inc tracer uptake in the affected areas with osteoblastic changes); hungry bone syndrome (after parathyroid surgery for hyperparathyroidism or thyroidectomy for thyrotoxicosis; ix - low calcium + PTH + Mg + phosphorus, bone biopsy); drug-induced hypocalcaemia (PPIs, bisphosphates, chemotherapy; ix - low calcium + Mg, inc phosphorus); multiple transfusions; hypoalbuminaemia (low calcium + albumin); drug interference with assay; infiltrative hypoparathyroidism (ix - low calcium + PTH); DiGeorge syndrome and other developmental complexes (abnormal facial features; cleft lip and palate; signs of heart failure, such as hepatomegaly, oedema, poor feeding, or cardiogenic shock; cyanosis; ix - low calcium + PTH + T cell count, fluorescence in situ hybridisation (FISH) - 1 copy of probe per cell confirms 22q11.2 deletion); rhabdomyolysis (ix- low calcium, inc creatinine + CK + K + phosphorus); tumour lysis syndrome (recent diagnosis of a malignancy and initiation of chemotherapy and/or radiotherapy; ix - low calcium, inc K + phosphorus); constitutively activating calcium sensing receptor (CaSR) abnormalities (mutations or autoimmune activation; ix - low calcium + urine calcium, normal PTH); vit D resistance or receptor mutations (presentation in early childhood with severe hypocalcaemia and rickets; ix - low calcium, inc ALP + PTH, x-ray - rickets, vit D - variable) 3) ix - a) serum total calcium concentration - adjusted for albumin (also tested) - >40% circulating calcium is bound to albumin ratio of 0.8 mg calcium to 1 mg albumin. Ratio is used to adjust total calcium after measuring albumin. Formula for adjusted serum calcium = (0.02 × [normal albumin - patient's albumin]) + serum calcium. However, the formula is superseded when ionised calcium is measured (where available) b) magnesium & phosphorus & U&E - inc phosphate without renal failure and tissue breakdown = hypoparathyroidism or pseudohypoparathyroidism; hypomagnesaemia can cause hypocalcaemia and may indicate underlying aetiology; inc urea and creatinine can indicate renal dysfunction. Any cause of hypomagnesaemia (eg/ PPIs) can result in hypocalcaemia. c) serum intact PTH - low in overt hypoparathyroidism (eg/ iatrogenic or infiltrative damage, congenital absence) & inc in vitamin D deficiency, renal disease, and skeletal metastases d) 25-hydroxyvitamin D levels - if suspect vitamin D deficiency. Serum alkaline phosphatase may also be useful - inc levels = ?skeletal metastases e) amylase +/- lipase levels checked if abdominal pain for ?acute pancreatitis f) T-cell counts useful in suspected DiGeorge syndrome - T-cell lymphopenia. Fluorescence in situ hybridisation (FISH) analyses can confirm 22q11.2 deletion g) ECG should be performed to evaluate arrhythmias and prolonged QT intervals. Hypocalcaemia prolongs phase II action potential, leading to prolonged QT intervals, which may be the only electrocardiographic sign of hypocalcaemia h) x-rays should be performed when multiple fractures or signs of osteomalacia are observed i) isotope bone scans should be performed for patients with possible malignant metastasis 4) mx - a) urgent treatment needed if severe symptoms such as seizures, severe tetany, laryngospasm, bronchospasm, altered mental status or ECG abnormalities, even if serum calcium level only mildly reduced i) IV calcium (eg/ calcium gluconate over 10 mins) can irritate the veins & be necrotic if extravasates = needs to IV access, preferably central vein ii) IV calcium bolus will raise serum calcium for 2-3 hours, so patients with hypocalcemia should also be started on a longer-lasting treatment eg/ IV infusion - calcium gluconate @ 1-3mg/kg/hr, serum calcium should rise by 0.3-0.5 mmol/L over 4-6 hours, ionized calcium levels should be measured every 1-2 hours with adjustment of the infusion rate as indicated. When levels stable on a steady infusion rate, calcium levels measured every 6-8 hours iii) IV calcium infusions often used for patients with adjusted calcium levels <1.9 mmol/L, even if they are asymptomatic. Once no s/s & calcium levels are stable in the lower part of the normal range, the calcium infusion may be gradually tapered over 24-48 hours while oral calcium and vitamin D are initiated and titrated iv) dysrhythmias may occur with rapid correction, continuous clinical and cardiac monitoring is recommended v) calcium infusion may be administered for 1-3 days to maintain serum calcium and minimize symptoms until oral therapy is effective. Pts with hungry bone syndrome may require aggressive calcium replacement for longer periods b) active form of vit D = calcitriol (1,25 dihydroxy vitamin D) - most active metabolite, needs no hydroxylation at liver or kidney i) helps to maintain a normal serum calcium by inc GI absorption of intestinal calcium and phosphorus, promotes bone resorption of calcium, and inc renal tubular calcium reabsorption. Pts with vit D insufficiency or deficiency should receive vit D replacement with ergocalciferol or cholecalciferol. Patients with renal failure or hypoparathyroidism are unable to activate vit D & require administration of calcitriol (1,25 dihydroxy vitamin D) to treat hypocalcemia ii) as vit D levels can take time, it is prudent to treat a patient with severe hypocalcemia and possible hypoparathyroidism or vitamin D deficiency with calcitriol in addition to calcium. c) outpatient therapy - oral calcium - typically 1-2 grams elemental calcium divided twice or three times daily. Doses may need to be adjusted based on tolerance, compliance, and treatment goals. i) calcium carbonate is best absorbed in an acidic environment - with meals, not if on PPI, main SE - GI, particularly constipation ii) calcium citrate used if achlorhydria, PPI, GI intolerance of calcium carbonate. It does not need to be taken with food iii) other oral calcium supplements eg/ calcium lactate, gluconate, and glubionate have a smaller percentage of elemental calcium than calcium citrate or calcium carbonate, so a larger number of pills is required for treatment of hypocalcemia iv) encourage inc dietary calcium d) outpatient therapy - oral vit D - intoxication can cause hypercalcemia, hypercalciuria, and hyperphosphatemia as well as GI disturbance, altered mental status, soft tissue calcification or renal damage. Calcium, phosphorus, creatinine and 25 hydroxy vitamin D levels should be monitored regularly during vitamin D therapy to avoid toxicity. 24hr urine calcium levels monitored annually for patients on vitamin D - dosing doesn't need to be dec due to hypercalciuria i) if no hypoparathyroidism or renal failure, ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) used. If hypocalcemia due to vit D deficiency, ergocalciferol 50,000 IU weekly for 12 weeks, then maintenance 1,000-2,000 IU daily once 25 hydroxy vitamin D levels > 75 nmol/L. Higher doses may be needed if vit D deficiency due to malabsorption ii) onset of action ~2 weeks, with effects lasting several months, levels may be checked and doses adjusted every 1-3 months iii) calcitriol (1,25 dihydroxy vitamin D) does not require hydroxylation so used if renal failure or hypoparathyroidism (PTH needed for renal activation of vitamin D). Starting dose is 0.25-1 mcg 1-2 times daily, which may be administered IV or by mouth. Calcitriol has its peak effect in ten hours and its effect lasts 2-3 days e) electrolyte abnormalities - hypomagnesemia (Mg supplementation IV or oral can be stopped once oral intake improves and serum Mg remains consistently above 2 mg/dL), hyperphosphatemia (low phosphate diet, and oral phosphate binders prior to administering calcium supplementation if phosphate remains >1.5 mmol/L), metabolic acidosis (if pt has metabolic acidosis & hypocalcemia, correct hypocalcemia first f) coexisting medical conditions - renal failure (large doses of calcitriol may be required, IV or PO); liver failure (activation of vit D may be impaired, so give calcitriol rather than ergocalciferol or cholecalciferol); congestive heart failure (parenteral correction of hypocalcemia + medical treatment eg/ oxygen and); digoxin use (inc cardiac sensitivity to fluctuations in serum calcium, so IV calcium given with caution and ECG monitoring); malnutrition (treat underlying disease & very high doses vit D) g) adjusting treatment in patients with hypoparathyroidism - need close monitoring as don't have PTH-mediated regulation of calcium. Bloods every 3-6 months and urinary calcium and creatinine levels annually to ensure an adjusted total calcium level in the low-normal range. 5) complications - cardiac hyperexcitability, tetany, hypotension, seizures, mental confusion, carpopedal spasms, respiratory failure, arrythmia, 6) prevention - inc oral calcium in diet, adequate sunlight for vit D

S/s, DD, ix, mx, complications & prevention of acutely ill diabetic

1) s/s - unwell, often with fever, illnesses most likely to effect blood glucose - common cold or flu, sore throats, urine infections, bronchitis or chest infections, stomach upsets and diarrhoea, skin abscesses. Presentation can vary, be wary of signs of DKA/HHS 2) ix - blood glucose + ketones 3) mx - based on Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) multicenter trial - moderate glycemic control lead to dec CV mortality in critically ill patients a) non-diabetic ICU patients - aim glucose 7-11.1mmol/L b) diabetic ICU patients - if HbA1c <7% = 7-10mmol/L; if HbA1c >7% = >11.1mmol/L c) surgical ICU - if ICU stay >3 days, ventilator dependant, on dialysis, or cardiac co-morbidities - aim blood glucose <8mmol/L d) neurocritical ICU patients - if hypoglycamia can be prevented aim 6-8mmol/L, otherwise <10 e) STEMI ICU patients - <11.1mmol/L; sepsis patients - <10mmol/L f) have a treatment plan if hypoglycemia were to develop & change current therapy if glucose < <4mmol/L g) monitor blood glucose every 2-4hrs unless fluctuating greatly then may need to be 30-60mins NB/ no consensus for pregnant patients (maternal cells have inc insulin resistance as inc human placental lactogen, progesterone, and estrogen - inc insulin resistance is protective, and allows glucose absorption to be prioritized in the foetus, but in some this mild resistance + baseline insulin resistance = persistent hyperglycemia) 4) complications - severe hypoglycaemia or hyperglycaemia, glycaemic variability, coma, death 5) prevention - follow sick day rules: a) keep taking long acting insulin, stop taking SGLT2i & check ketones and your blood sugars (inc risk of DKA), may need to stop metformin (if dehydrated or severe infection - will need to start another tx), sulphonylureas (eg/ glicazide) - may need inc dose when unwell. Contact diabetes team about other meds if not eating b) if you check your blood sugar at home do it more often - at least 4hrly, including during the night. If you don't test your blood sugar levels at home, be aware of the signs of a hyper (hypergylcaemia) c) stay hydrated - have 2L of unsweetened drinks, and eat little and often, if only eating small amount go for carbs, sweetened drinks (fruit juice, cola) or suck on sweets d) for T1DM - check ketones if blood sugar level >15mmol/l, or 13mmol/l if using insulin pump, if ketones are present, contact diabetes team i) if BG 10-13: inc usual insulin by 10%, check BG 4hrly, if no improvement after 24hrs inc by another 10%, if no improvement after 48hrs follow guideline for BG >13 ii) if BG >13: inc normal insulin by 10% + give extra dose of quick acting insulin (~10% of total daily insulin) & rpt quick acting every 2-4 hrs, also test for ketones (if raised test 2hrly to see if decrease), if not improving after 6hrs of trying to dec insulin go to hospital ii) if BG >15 + have moderate or large amount of urinary ketones: continue usual insulin + give 20% total daily insulin in form of extr quick acting insulin + test blood glucose & urinary ketones 2hrly & rpt extra quick insulin doses until BG <15 & ketones dec. if BG not <15 after 48hrs contact doctor/diabetes nurses NB/ quick acting insulin: Novorapid (Aspart), Humalog (Lispro), Humulin S, Actrapid NB2/ for all the above go back to normal insulin after BG back to normal e) if on steroids eg/ Addison's disease, severe asthma, RA and lupus, continue steroids but discuss with doctor when unwell (steroid can inc blood sugars) f) T2DM on insulin: i) BG 10-15: inc insulin by 20%, check BG 4hrly, if not better after 24hrs inc insulin by another 10%, if no improvement after 48hrs follow below guidance ii) BG >15: inc usual daily dose by 20% + give extra dose of quick acting insulin ~10% daily dose & rpt 4hrly as needed, if BG not <15 after 24hrs inc usual insulin by another 10%, if not controlled after 48hrs contact for advice

Peri-operative diabetes care including pre-assessment (not applicable to those on diet-only)

1) surgery is frequently accompanied by a period of starvation, which induces a catabolic state. If starvation is short (1 missed meal), the patient can usually be managed without IV insulin infusion, however need to avoid hypoglycaemia as will stimulate secretion of counter-regulatory hormones and exacerbate catabolic effect of surgery 2) insulin should never be stopped in T1DM as leads to ketoacidosis 3) if starvation period requires omission of 2+ meals, a VRIII with 0.45% sodium chloride and 5% glucose with either 0.15% or 0.3% potassium chloride (as appropriate) should be used. With VRII consider 80% dose of long-acting analogues (Glargine/Lantus®, Degludec/Tresiba®,Detemir/Levemir®) alongside VRIII during peri-operative period (dec risk of rebound hyperglycaemia when VRII stopped). If the infusion is stopped, there will be no insulin in the circulation after 3-5 minutes leading to immediate catabolism 4) insulin requirements inc by: obesity, long or major surgery, infection, glucocorticoid treatment 5) major surgery = metabolic stress with inc catabolic hormone secretion + inhibition of anabolic hormones, particularly insulin = transient hyperglycaemia. T1DM have no insulin secretory capacity & can't respond to inc demand for insulin. T2DM have pre-existing insulin resistance with limited insulin reserve, so dec ability to respond to inc demand 6) pts with diabetes have inc risk of infection, poor peri-operative glycaemic control has big impact on risk of post-operative infection 7) emergency surgery - high levels of catabolic hormones in response to crisis = hyperglycaemia, thus complicating the situation. Many emergencies result from infection which will add further to the hyperglycaemia. Prompt action with IVII 8) pre-op: aim HbA1c <69mmol/mol, 8.5% - balance risk of proceeding against urgency of operation if HbA1c not optimal; optimisation of other comorbidities; identify pts likely to need critical care post-op; ensure mx plan in place to prevent peri-op dysglycaemia 9) include Diabetes Inpatient Specialist Nurses (DISN) for optimisation of pre-op and post op care service through pt education, diabetes mx as inpatient etc 10) target blood glucose pre-operative, anaesthetised or sedated = 6-10mmol/L (up to12mmol/L may be acceptable). 11) diabetes pts to be at beginning of morning list to minimise starvation time & have early resumption of normal diet and normal meds at the normal time 12) prevent hospital acquired foot pathology - if known PVD or ulcers etc make sure others are aware and consider suitability of TED stockings 13) ensure that Glucogel®, glucagon and rapid acting insulin is routinely prescribed to allow prompt treatment of hypo- or hyperglycaemia in unconscious pt 14) fluids - if VRII use 0.45% saline with 5% glucose and 0.15% or 0.3% potassium chloride (KCl) - need glucose to prevent catabolism of proteins & lipids, if no VRII use Hartmann's 15) Continuous Subcutaneous InsulinInfusion (CSII) Pump - limited data, recommend: if starvation period is short, pump therapy continued & pts should remain on their basal rate until E&D normally. Generally, patients on a CSII are very well educated & can self-manage their diabetes appropriately. Anaesthetist should not give bolus insulin doses via CSII. If hypos occurs treat as normal. Regular CBGs needed+ electrolyte measurements if pump stopped for any length of time (significant hyperkalaemia may occur after discontinuation of insulin pump). If 2+ meals missed or cannot maintain BG in target range the pump should be removed and a VRIII should be used. To restart once pt is E&D, VRIII discontinued 30mins after irst mealtime bolus 16) stress hyperglycaemia may occur in people not known to have diabetes. High risk of post-op morbidity and mortality. Treat as per diabetes protocol. If BG normalises - formal oral glucose tolerance test or fasting blood glucose carried out 6 weeks later. If BG remains elevated once acute episode has resolved can diagnose diabetes 17) check CBG prior to induction of anaesthesia & monitor at least hourly - more frequently if readings outside target range 18) start IV glucose infusion if the pt hypoglycaemic

Assess diabetic patient to detect long term complications

1) urine testing - idea of glucose levels but not exact, and ketones 2) self-monitored blood glucose testing - fingerprick glucose for insulin - advises on dose, best day-day assessment 3) HBA1C - mean glucose levels over last 8 weeks - complications inc as HbA1C inc, but target values depend on pt situations (eg/ elderly more at risk of fall when hypoglycaemic = less tight control), normally 48-57mmol/LNB/ figure misleading in anaemia, thalassaemia, haemoglobinopathy or pregnancy - shorter-term fructosamine test may be used4) continuous glucose monitoring (ask about hypos) 5) in annual review assess: HbA1C, cholesterol, BP, BMI, fundoscopy, check feet for ulcers & neuropathy, urine dip (kidney function), if inject insulin check sites, screen for depression or sexual dysfunction