Endocrinology + metabolic

Hormones released by anterior pituitary gland

• TSH

• ACTH

• FSH + LH

• GH

• Prolactin

Hormones released by posterior pituitary gland

• oxytocin

• ADH

Thyroid Axis

• hypothalamus → TRH

• AP → TSH

• thyroid gland → T3 (primary active hormone) + T4 (prohormone)

T3 + T4 suppress TSH + TRH release (-ve feedback)

Adrenal axis

• hypothalamus → CRH

• AP → ACTH

• Adrenal gland → cortisol (zona fasciculata)

Growth Hormone axis

• hypothalamus → GHRH

• AP → GH

• liver → IGF-1

Parathyroid axis

Parathyroid glands → PTH (in response to low Ca2+)

Calcitonin if Ca2+ high

• increased osteoclast activity = bone resporption → increased serum Ca

• increased Ca reabsorption in kidneys (less excreted via urine)

• kidneys convert D3 to calcitriol (active Vit D = increased Ca2+ intestinal absorption)

cortisol functions

• increased gluconeogenesis, lipolysis + proteolysis

• increased BP → upregulates arteriole a1 receptors

• increased bone resorption

• decreased inflammatory + immune response

Types of hyperthyroidism

• primary: thyroid pathology = excess T3 + T4

• secondary: pathology in hypothalamus or pituitary gland = excess TRH/TSH

• subclinical: Normal T3 +4 but low TSH (asymptomatic or mild symptoms)

Hyperthyroidism causes (GIST)

• Graves’ disease (30-60)

• Inflammation (thyroiditis)

• Solitary toxic thyroid nodule

• Toxic multi-nodular goitre (>50) → nodules develop on thyroid gland + produce excess T3 + T4

Thyroiditis + causes

Inflammation of thyroid gland causes initial period of hyperthyroidism followed by hypothyroidism

• De Quervain’s → painful goitre + raised ESR

• Hashimoto’s

• postpartum

• drug-induced (lithium, amiodarone)

hyperthyroidism presentations

• Anxiety + irritability

• Sweating + heat intolerance

• Tachycardia

• Weight loss

• Fatigue

• Insomnia

• Frequent loose stools

• Brisk reflexes on examination
  
  

Graves’ disease + specific presentations

autoimmune condition → IgG TSH receptor antibodies = primary hyperthyroidism

Smoking risk factor

• diffuse goitre (w/o nodules)

• Exophthalmos

• Pretibial myxoedema

• Thyroid acropachy (hand swelling + clubbing)

Hyperthyroidism management

• Carbimazole → taken for 12-18m then titrated to maintain normal levels (titration block)

• or Block + replace → high dose blocks production + Levothyroxine titrated

• propylthiouracil (second-line)

• Radioactive iodine (followed by levothyroxine) → Toxic multinodular goitre

• propanolol

• thyroidectomy (followed by levothyroxine)

Carbimazole rare side effects

• acute pancreatitis

• agranulocytosis (also PTU) → sore throat

• bone marrow disorder

• Congenital malformations

Thyroid storm

life-threatening complication of established thyrotoxicosis

Precipitating events:

• thyroid or non-thyroidal surgery

• trauma

• infection

• acute iodine load e.g. CT contrast media

Types of Hypothyroidism

• primary: thyroid pathology = inadequate T3 + T4, no negative feedback so raised TSH

• secondary: pituitary pathology = inadequate TSH, T3 +T4

• Subclinical: High TSH but normal T3/4, asymptomatic

• Congenital

Primary Hypothyroidism causes

• Hashimoto’s thyroiditis (most common) → autoimmune condition assoc w/ anti-TPO + anti-Tg

• Iodine deficiency (most common in developing world)

• hyperthyroidism treatment

• drugs (lithium + amiodarone)

Secondary hypothyroidism causes

assoc w/ hypopituitarism

• pituitary adenoma/tumours

• pituitary surgery

• radiotherapy

• Sheehan’s syndrome

Hypothyroidism presentations

• Weight gain

• Fatigue

• Dry skin, coarse hair + hair loss

• Fluid retention (including non-pitting oedema, pleural effusions and ascites)

• Heavy/irregular periods

• Constipation

• Carpal tunnel syndrome

hypothyroidism management

oral levothyroxine

• starting dose 50-100 mcg

• CVD/Severe hypothyroidism/>50s =25mcg

• pregnant = increase by 25-50mchg

check after 8-12w following change

Acromegaly

• excessive GH secretion in adulthood

• typically due to pituitary adenoma

• rarely caused by paraneoplastic syndrome (ectopic GHRH secreted by lung or pancreatic cancer)

Acromegaly presentations

• Frontal bossing

• Coarse, sweaty skin

• Large nose

• Macroglossia

• Large hands and feet

• prognathism

space-occupying pituitary tumour = headaches + bitemporal hemianopia (optic chiasm compression)

Acromegaly complications

• T2DM

• hypertension

• bilateral carpal tunnel syndrome

• hypertrophic heart (+HF)

• colorectal cancer

acromegaly investigations

• IGF-1 (gold standard)

• GH suppression test: 75g glucose drink w/ GH tested at baseline + rechecked after 2hrs (glucose normally suppresses GH level)

• MRI

Acromegaly treatment

• Trans-sphenoidal surgery (remove pituitary tumour)

• radiotherapy

• Pegvisomant S/C injections (GH receptor antagonist)

• Somatostatin analogues (octreotide)

• dopamine agonists (bromocriptine)

what hormones inhibit GH release

• somatostatin

• dopamine (weaker)

Type 1 diabetes

autoimmune condition linked to Beta cells failing to produce insulin = cells unable to use glucose + hyperglycaemia

• polyuria

• polydipsia

• weight loss

assoc antibodies: anti-islet cell, anti-insulin, anti-GAD

Diabetic Ketoacidosis (DKA)

• Complication of inadequate insulin → uncontrolled lipolysis = excess fatty acids

• May be initial presentation, acute infection, steroids or poor insulin compliance

DKA presentations

• dehydration

• nausea + vomiting

• kussmaul breathing

• altered consciousness

• acetone breath

DKA diagnostic criteria

• hyperglycaemia (>11mmol/L)

• ketosis (>3mmol/L)

• metabolic acidosis (<7.3) + bicarbonate (<15)

DKA management

1) IV 0.9% NaCl 1L for 60mins

2) IV ActRapid 0.1 units/kg/hr (don’t start if k+ <3.5)

3) if k+ <5.5mmol add 10-20mmol/hr KCl

4) add 10% dextrose 125ml/hr if glucose <14mmol

complications of DKA treatment

• hypoglycaemia

• hypokalaemia

• cerebral oedema

• pulmonary oedema

Serum C-peptide

Measure of insulin production

low w/ low insulin production + vice versa

Insulin pumps

• devices that continuously infuses insulin at different rates to control blood sugar levels

• alternative to basal-bolus regimes

• insulin pushed through cannula (replaced every 2-3 days) → insertion site rotated to precent lipodystrophy

closed/hybrid loop system

• AKA artificial pancreas

• continuous glucose monitoring + insulin pump

• devices communicate + adjust insulin based on glucose readings

• pts input carb intake + adjust for strenuous exercise

Macrovascular complications of diabetes

• CAD

• PVD

• stroke

• hypertension

Microvascular complications of diabetes

• neuropathy

• nephropathy

• retinopathy

infection-related complications of diabetes

• UTIs

• Pneumonia

• skin + soft tissue infections

• fungal esp. oral/vaginal candidiasis

why should insulin injection sites be rotate

prevents lipodystrophy → hardened subcutaneous fat = poor absorption

Type 2 diabetes

insulin resistance + reduced pancreatic function due to repeated glucose + insulin exposure = chronic hyperglycaemia

T2DM risk factors

• older age

• ethnicity (south asian + black)

• FHx

• Obesity

• sedentary lifestyle

• high carb diet

T2DM presentations

• tiredness

• polyuria + polydipsia

• weight loss

• opportunistic infections

• slow wound healing

• glucosuria

• acanthosis nigrican

T2DM diagnosis

• HbA1c of 48mmol or above → repeat in 1m (dx if symptomatic after 1st)

• pre diabetes/IGR: 42-47

painful neuropathy management

• amitriptyline (TCA)

• duloxetine (SNRI)

• gabapentin (anticonvulsant)

• pregabalin (anticonvulsant)

T2DM drug management

• 1st line: metformin M/R (up to 2g/day) + SGLT2 inhibitor

• 2nd line: add DPP-4 inhibitor (or sulfonylurea/pioglitazone/insulin if not tolerated)

HbA1c targets:

48mmol/L lifestyle mod or 1 drug not assoc w/ hypoglycaemia

53mmol/L for if taking drug assoc w/ hypoglycaemia

Metformin (Biguanides)

• inhibits hepatic gluconeogenesis + decreased intestinal glucose absorption

• increased insulin sensitivity + peripheral glucose uptake

• side effects: abdominal pain, nausea, diarrhoea

• risk of lactic acidosis (secondary to AKI)

SGLT-2 inhibitors

• eg dapagliflozin

• Inhibits SGLT-2 in PCT = glucose not reabsorbed + excreted via urine

• side effects: polyuria, increased frequency, UTIs/vulvovaginitis, weight loss, Fournier’s gangrene

• risk of DKA

DPP-4 inhibitors

• Eg sitagliptin

• increased incretin activity → stimulates insulin release, inhibits glucagon production + slows gastric emptying

• side effects: headaches, constipation, N+V

• low risk of acute pancreatitis

• contraindicated in pregnancy/breastfeeding, heart + liver failure

sulfonylureas

• eg glipizide

• increased intracellular k+ = depolarisation → Ca2+ influx so Insulin release

• decreased hepatic gluconeogenesis + increased peripheral insulin sensitivity

• side effects: weight gain, hypoglycaemia, nausea, rash/SJS

Pioglitazone (thiazolidinedione) → Fat Bastards Won’t Feel Lighter

• increased insulin sensitivity in adipose, skeletal m + liver

• increased lipid metabolism protein synthesis (HDL +LDL)

• Side effects: Fluid retention, Bladder cancer, Weight gain, Fractures, LFT derangement

• contraindicated in liver + heart failure, previous/active bladder cancer

GLP-1 mimetics

• eg semaglutide

• GLP-1 agonists = increased insulin + decreased glucagon released, slows gastric emptying

• side effects: reduced appetite, weight loss, abdominal pain, nausea, diarrhoea, sarcopaenia in elderly

• risk of acute pancreatitis

Hyperosmolar hyperglycaemic state (HHS)

Rare + potentially lifethreating complication → risk of blood clots (older pts w/ low GFR)

hyperosmolarity, hyperglycaemia + absence of ketones

• polyuria + polydipsia

• weight loss

• dehydration

• tachycardia

• hypotension

• confusion

Tx: IV fluid resuscitation + monitoring

Addison’s disease

• Primary adrenal insufficiency

• Adrenal cortex destruction = less glucocorticoids, Mineralcorticoids (+ androgens)

mineralocorticoids (aldosterone) actions

Regulates electrolytes + BP

• increased sodium reabsorption in DCT → water follows

• increased potassium secretion in DCT

• increased H+ secretion in collecting ducts

Addison’s disease causes

• Primary: autoimmune (most common UK) + TB, HIV (secondary to CMV infection)

• secondary: pituitary adenomas, radiotherapy, Sheehan’s syndrome, trama

• tertiary: long-term steroids (suppress CRH from hypothalamus)

Addison’s disease presentations

• Fatigue

• Muscle weakness + cramps

• postural hypotension + syncope

• Thirst and craving salt

• Weight loss

• Abdominal pain

• bronze hyperpigmentation (ACTH stimulate melanocytes- NOT in secondary or tertiary)

Addison’s disease investigations

• U+Es: hyperkalaemia, hyponatraemia

• hypoglycaemia

• hypercalcaemia

• Short synacthen test

• CT/MRI

Short Synacthen Test

• dose of synacthen given in morning

• cortisol checked before, 30+60 mins after dose

• synthetic ACTH stimulates adrenal gland → cortisol level should double

• failure to increase = primary or secondary adrenal insufficiency

• long synacthen test distinguishes between → ACTH high in primary, low in secondary

Addison’s disease management

• long term hydrocortisone (glucocorticoid)

• fludrocortisone (mineralcorticoid)

doses doubled on sick days

Addisonian/adrenal crisis

Acute px of severe adrenal insufficiency → life-threatening

may be triggered by infection, trauma or missed steroids

• reduced consciousness

• hypotension

• hypoglycaemia

• hyponatraemia + hyperkalaemia

addisonian crisis management

• IV fluids

• IV/IM hydrocortisone 100mg (followed by infusion or 6 hourly doses)

• IV dextrose

• fluid + electrolyte monitoring

Conn’s syndrome

• Primary hyperaldosteronism due to adrenal adenoma

• Adrenal zona glomerulosa = increased Mineralcorticoids

• Increased aldosterone = increased Na+ + H2O reabsorption → increased blood vol. (high BP)

primary hyperaldosteronism causes

• bilateral adrenal hyperplasia (most common)

• adrenal adenoma/conn’s (secretes aldosterone)

• familial hyperaldosteronism

Secondary hyperaldosteronism cause

due to excess renin release disproportionately to low BP in kidneys

• renal artery stenosis

• heart failure

• liver cirrhosis

Conn’s/hyperaldosteronism investigations

• aldosterone-renin ratio (ARR) → high aldosterone + low renin = primary, high aldosterone + high renin = secondary

• U+Es - hypokalaemia

• AGB - alkalosis

• CT/MRI

Conn’s/hyperaldosteronism management

• aldosterone antagonists: eplerenone + spironolactone

• treat underlying cause eg adrenal adenoma surgery

Syndrome of inappropriate ADH (SIADH)

• Excessive ADH secreted by posterior pituitary gland or ectopic

• Increased water reabsorption dilutes blood =hyponatriaemia

• high urine osmolarity (more concentrated) + urine sodium

SIADH causes

• SCLC

• post-op

• SSRIs

• atypical pneumonia (legionella) or abscess

• head injury, stoke, intercranial haemorrhage

• carbamazepine

SIADH management

• treat underlying cause

• fluid restriction (750-1000ml)

• Vasopressin receptor antagonists (tolvaptan)

• Slowly correct Na+ → no more than 10mmol/L in 24hrs

Osmotic Demyelination Syndrome (central pontine myelinolysis)

• complication of long-term severe hyponatraemia corrected too quickly

• water crosses BBB as serum Na+ drops → brain adapts by reducing solutes in cells to prevent cerebral oedema (low osmolarity)

• when serum Na+ increased rapidly water moves out

• phase 1: encephalopathic + confused (headache, vomiting, seizures)

• phase 2: pons neurone demyelination (spastic quadriparesis, pseudobulbar palsy, cognitive changes)

Phaeochromocytoma

• neuroendocrine tumour in adrenal medulla → chromaffin cells secretes excess catecholamines

• 30-40% genetic cause

• 10% rule: 10% bilateral, 10% cancerous, 10% outside adrenal gland

Genetic conditions associated with Phaeochromocytoma

• Multiple endocrine neoplasia type 2 (MEN2)

• Neurofibromatosis type 1

• Von Hippel-Lindau disease

Phaeochromocytoma presentations (5Ps)

• Pain → Headaches

• Palpitations + tachycardia

• Perspiration

• Pallor

• hyPertension

Phaeochromocytoma investigations

• plasma free metanephrines (catecholamines unreliable as levels fluctuate + short half-life)

• 24hr urine metanephrines

• CT/MRI

• Genetic testing

Phaeochromocytoma management

• alpha blockers (doxazosin/phenoxybenzamine) followed by beta blockers

• surgical removal of tumour

complication → paroxysmal hypertension (+180/+120) risk of HF + pulmonary oedema, tx: IV alpha blocker

Hypercalaemia presentations (moans, groans, thrones)

• kidney stones

• bone pain

• muscle weakness

• constipation

• polyuria

• depression, confusion

• shortened QT interval

Primary Hyperparathyroidism

Parathyroid adenoma = excess PTH secretion independent to serum Ca2+

• PTH normal/high

• Calcium high

• low phosphate

Secondary Hyperparathyroidism

Vitamin D insufficiency or CKD = low serum Ca2+ stimulates parathyroid gland to secrete PTH

• PTH high

• calcium + vitamin D low

• phosphate high

Tertiary Hyperparathyroidism

Chronic secondary hyperparathyroidism = parathyroid hyperplasia

Autonomous PTH secretion independent to serum Ca2+

• PTH high

• calcium normal/high

• vitamin D low

• ALP raised

Hyperprolactinaemia causes

Excess prolactin secreted by lactrotrophs

• prolactinoma

• drugs (dopamine receptor antagonists, antipsychotics)

• idiopathic

• primary hypothyroidism

• pregnancy

• PCOS

Hyperprolactinaemia presentations

• low libido

• gynaecomastia

• galactorrhea

• amenorrhoea/oligomenorrhoea

hyperprolactinaemia investigations + management

• prolactin (sensitive to sexual activity, exercise, stress)

• TFTs

• MRI

Tx: dopamine agonists (bromocriptine, cabergoline)

Sheehan’s syndrome

• pituitary gland increases in size during pregnancy but blood supply does not

• risk of decreased perfusion

• postpartum haemorrhage = pituitary gland necrosis

• MRI shows pituitary ring sign

hypoglycaemia clinical features

BG <3.3mmol/L causes autonomic symptoms, <2.8mmol/L causes neuro symtoms

• sweating

• tremors

• irritability

• hunger + nausea

• confusion

• weakness

• rare: convulsions, coma

hypoglycaemia investigations + causes

Insulin + C-peptide

• high insulin + C-peptide: insulinoma, sulfonylurea abuse

• high insulin + low C-peptide: exogenous insulin overdose

• low insulin + C-peptide: alcohol, critical illness, adrenal insufficiency, GH deficiency, starvation

Hypoglycaemia management

• alert: 15-20g oral fast-acting carbs

• IV 20% dextrose 100-200ml (impaired GCS)

• IM glucagon

re-check BG after 10/15mins + f/u w/ long acting carbs once >4mmol/L

Refeeding syndrome physiology

• occurs when someone with an extended severe nutritional deficit resumes eating (lower BMI + longer period of malnutrition = higher risk)

• During starvation intracellular K+/PO3/Mg2+ move into blood to maintain normal serum levels

• Druing refeeding carbohydrates increase insulin levels driving glucose/K+/PO3 into cells + Na+ out (extra sodium reabsorption by kidneys)

Refeeding syndrome electrolyte imbalances + complications

• hypomagnesaemia

• Hypokalaemia

• Hypophosphataemia

• Fluid overload

Risk of arrhythmia, tissue hypoxia/respiratory failure, haemolytic, rhabdomyolysis

Refeeding syndrome management

• slowly reintroduce food (w/ limited calories)

• Electrolyte + glucose monitoring

• Fluid monitoring

• ECG

• Electrolyte + B vitamins supplementation

diabetic neuropathy

peripheral: glove + stocking sensory loss (legs affected first) → amitriptyline, gabapentin, pregabalin first-line drugs

gastrointestinal autonomic:

• gastroparesis causing erratic BG control, bloating + vomiting → metoclopramide, erythromycin (prokinetics)

• chronic diarrhoea (often at night)

• GORD

diabetic nephropathy

most common cause of CKD

• excess glucose = arteriosclerosis of efferent arteriole → increased glomerular pressure (causes high eGFR)

• damage to GBM + podoctyes → glomerulus unable to filter blood = decreased eGFR

• ACR screening annually → >3mg/mmol indicates significant albuminuria

management: glycaemic control, ACEi/ARA, SGLT2i, consider finerenone

Diabetic retinopathy pathophysiology

• chronic hyperglycaemia = damage to small retinal vessels/endothelial cells

• Increased vascular permeability = leaking vessels, blot haemorrhages + hard exudates

• Damage to nerve fibres = cotton wool spots

• Proliferative (neovascularisation) or Non-proliferative

• Can progress to vision loss due to complications (macular oedema)

Diabetic retinopathy management

• non-proliferative: close monitoring (can progress to proliferative)

• Pan-retinal photocoagulation (PRP)

• Anti-VEGF intravitreal injection

• Surgery

Hypopituitarism causes

inadequate production of one or more pituitary hormones

• non-secretory pituitary macroadenoma (most common)

• pituitary apoplexy

• Sheehan’s syndrome

• hypothalamic tumours

• infiltrative → haemochromatosis, sarcoidosis

• trauma

Hypopituitarism clinical features (+ sequence of loss)

• GH → short stature (if occurs during childhood)

• LH/FSH → amenorrhoea, infertility, loss of libido

• TSH → cold, constipation

• ACTH → fatigue, hypotension

• prolactin → lactation issues

Hypopituitarism investigations + management

• hormone profile testing

• CT/MRI

management: treat underlying cause + replace deficient hormones → adrenal insufficiency must be corrected prior to levothyroxine

pituitary adenomas

• benign tumour → common + typically asymptomatic

• microadenoma <1cm + macroadenoma >1cm

• secretory or non-secretory

• prolactinomas most common then non-secretory, GH + ACTH secreting

tx: medical therapy, transphenoidal surgery + radiotherapy

Metabolic syndrome

• hypertension

• T2DM

• obesity

increase risk of CVD + other conditions/complications

Diabetic foot disease + presentations

occurs secondary to neuropathy (sensation loss) or peripheral arterial disease (ischaemia)

• neuropathy

• absent pulses

• low ABPI

• intermittent claudication

diabetic foot disease complications

• calluses

• ulcers

• Charcot’s arthropathy

• cellulitis

• osteomyelitis

• gangrene