Endocrinology & Diabetes

Key Facts

T2DM is a major public health crisis with significant cardiovascular, renal, and microvascular complications. Modern management emphasises individualised therapy, cardiovascular risk reduction, and early use of drugs with proven cardiorenal benefits (SGLT2i, GLP-1 RA).

Epidemiology

~4.3 million in UK (~3.4 million diagnosed + ~1 million undiagnosed). Prevalence ~6-7% of adult population. Increasing - linked to obesity epidemic. Higher prevalence in South Asian (2-4× risk), African-Caribbean, and deprived populations. Increasingly diagnosed in younger adults and adolescents.

Aetiology

Multifactorial: genetic susceptibility + environmental/lifestyle factors. >400 genetic loci identified. Strongest modifiable risk factor: obesity (especially central/visceral). Other: physical inactivity, high-calorie diet, South Asian/African-Caribbean ethnicity, advancing age, PCOS, prior GDM.

Pathophysiology

Two core defects: peripheral insulin resistance (skeletal muscle, liver, adipose tissue) + progressive beta cell dysfunction (failure to compensate → relative insulin deficiency). Also: increased hepatic glucose output, impaired incretin effect, increased lipolysis, increased renal glucose reabsorption, CNS appetite dysregulation (collectively: 'ominous octet' - DeFronzo). Beta cell mass declines ~50% by time of diagnosis. Progressive nature means most patients eventually require combination therapy and many require insulin.

Typical Presentation

• Often asymptomatic - diagnosed on screening (NHS Health Check, routine bloods)
• Polyuria, polydipsia, nocturia: osmotic diuresis (if significantly hyperglycaemic)
• Fatigue, blurred vision
• Recurrent infections: UTIs, thrush (candidiasis), skin infections
• Slow wound healing
• Acanthosis nigricans: velvety hyperpigmentation in skin folds (axillae, neck) - marker of insulin resistance

Complications at Diagnosis (~25%)

• Up to 25% of T2DM patients have complications at diagnosis (delayed diagnosis)
• Retinopathy, neuropathy, nephropathy, cardiovascular disease

Red Flags

• Young, lean patient with diabetes → consider T1DM, LADA, MODY
• DKA in apparent T2DM → may be T1DM or ketosis-prone T2DM
• HHS (hyperosmolar hyperglycaemic state) → emergency (see HHS)

Diagnosis (NICE NG28)

• HbA1c ≥48 mmol/mol (6.5%): on 2 occasions if asymptomatic; single measurement if symptomatic
• Fasting glucose ≥7.0 mmol/L or random ≥11.1 mmol/L (with symptoms)
• OGTT: 2-hour glucose ≥11.1 mmol/L (not routinely needed for T2DM diagnosis; used in GDM)

Baseline Assessment

• HbA1c: baseline and every 3-6 months
• Renal: eGFR, urine ACR (microalbuminuria screening)
• Lipid profile: total cholesterol, HDL, LDL, triglycerides
• LFTs: baseline (NAFLD very common)
• BP: target <140/90 (or <130/80 if renal/eye/cerebrovascular disease - NICE NG136)
• BMI, waist circumference

Complication Screening (Annual)

• Retinal screening: from diagnosis (unlike T1DM which is from age 12)
• Foot: annual assessment (monofilament, pulses)
• Renal: ACR + eGFR annually
• Cardiovascular risk assessment: QRISK3

Lifestyle (Foundation - Throughout)

• Weight loss: target 5-10% body weight; very-low-calorie diets may achieve remission (DiRECT trial - 46% remission at 1 year with intensive weight management)
• Diet: Mediterranean style, reduced refined carbohydrates, portion control
• Exercise: ≥150 min/week moderate intensity
• Smoking cessation
• Structured education: DESMOND (Diabetes Education and Self-Management for Ongoing and Newly Diagnosed)

Pharmacological (NICE NG28 - Stepwise)

• Mechanism: reduces hepatic glucose output, improves insulin sensitivity
• Benefits: weight neutral/loss, cardiovascular benefit (UKPDS), no hypoglycaemia
• Side effects: GI (nausea, diarrhoea - use modified-release if not tolerated), B12 deficiency, lactic acidosis (rare - avoid in severe renal/hepatic impairment)
• Contraindicated: eGFR <30

Step 2 (if HbA1c above target on metformin):

• Add one of: SGLT2 inhibitor (preferred if CVD, HF, or CKD), GLP-1 RA (preferred if BMI ≥35 or weight management priority), DPP-4 inhibitor, pioglitazone, sulfonylurea

Key Drug Classes:

• SGLT2 inhibitors (empagliflozin 10-25mg OD, dapagliflozin 10mg OD, canagliflozin 100-300mg OD): block renal glucose reabsorption; weight loss, BP reduction, CV benefit (EMPA-REG OUTCOME), renal protection (CREDENCE, DAPA-CKD); risk: UTI, genital thrush, DKA (rare - euglycaemic), Fournier gangrene (very rare)
• GLP-1 receptor agonists (semaglutide 0.25-1mg SC weekly or oral 14mg OD, liraglutide 0.6-1.8mg SC OD, dulaglutide 0.75-4.5mg SC weekly): incretin mimetics; significant weight loss (5-15%), CV benefit (LEADER, SUSTAIN-6, REWIND); SE: nausea, vomiting; contraindicated in pancreatitis history/medullary thyroid cancer
• DPP-4 inhibitors (sitagliptin 100mg OD, linagliptin 5mg OD): weight neutral, well-tolerated; moderate efficacy
• Sulfonylureas (gliclazide 40-320mg/day): rapid efficacy; risk of hypoglycaemia and weight gain
• Pioglitazone 15-45mg OD: insulin sensitiser; weight gain, fluid retention; avoid in HF; bladder cancer concern (debated)

Step 3 (triple therapy or insulin):

• Triple oral/injectable combination
• Insulin: when oral agents insufficient; usually basal insulin (glargine, degludec) added to metformin + other agents

Cardiovascular Risk Management

• Statin: atorvastatin 20mg OD for primary prevention (QRISK ≥10%); 80mg for secondary prevention
• BP: target <140/90 (NICE NG136); ACEi/ARB first-line; ramipril 1.25-10mg OD
• Antiplatelet: only for established CVD (not primary prevention)

Bariatric Surgery

• Consider if BMI ≥35 with recent-onset T2DM (or ≥30 if South Asian); significant evidence for diabetes remission (>60% at 5 years for gastric bypass)

Referral Criteria

• Specialist diabetes team: insulin initiation, complex management
• Diabetic foot team: any foot ulceration
• Bariatric surgery: BMI ≥35 (or ≥30 in high-risk ethnic groups) with T2DM

T2DM is progressive; most patients require treatment intensification over time. UKPDS: tight glycaemic control reduces microvascular complications by ~25%. Cardiovascular disease is the leading cause of death (~60-70%). SGLT2i and GLP-1 RA have demonstrated cardiovascular and renal benefits beyond glucose lowering. DiRECT trial: ~46% of patients achieved diabetes remission at 1 year with intensive weight management. Life expectancy reduced by ~6-8 years on average. Early diagnosis and aggressive multifactorial risk management (glucose, BP, lipids) improves outcomes.

NICE NG28 Treatment Ladder (Simplified)

Key T2DM Cardiovascular/Renal Trials

Key Facts

GDM requires close glycaemic monitoring to minimise maternal and fetal complications. Most resolves postpartum but confers significant long-term risk of T2DM. Postnatal follow-up with OGTT at 6-13 weeks is essential.

Epidemiology

Affects ~4-5% of UK pregnancies (higher in high-risk populations). Incidence increasing with rising obesity rates. Recurrence risk in subsequent pregnancies ~30-50%.

Aetiology

Pregnancy is a state of progressive insulin resistance (human placental lactogen, cortisol, progesterone, growth hormone). GDM develops when beta cell function is insufficient to overcome this resistance. Risk factors: pre-existing insulin resistance (obesity), genetic susceptibility, ethnicity, older maternal age.

Pathophysiology

Often Asymptomatic

• Usually detected by screening (OGTT)
• Rarely symptomatic hyperglycaemia (polyuria, polydipsia, thrush)

Maternal Complications

• Pre-eclampsia (increased risk)
• Polyhydramnios
• Operative delivery (caesarean section, instrumental)
• Perineal trauma (macrosomia)

Fetal/Neonatal Complications

• Macrosomia (birthweight >4kg or >4.5kg)
• Shoulder dystocia and birth injury (Erb palsy, clavicular fracture)
• Neonatal hypoglycaemia (fetal hyperinsulinaemia persists after cord clamping)
• Neonatal jaundice, polycythaemia
• Respiratory distress syndrome
• Stillbirth (if severe/uncontrolled GDM)

Long-Term Risks

• Mother: ~50% risk of T2DM within 10 years; increased cardiovascular risk; recurrence in future pregnancies
• Offspring: increased risk of obesity, T2DM, metabolic syndrome in later life

Red Flags

• Fasting glucose ≥7.0 mmol/L at booking → may be pre-existing T2DM (not GDM)
• Large-for-dates fetus + GDM → close monitoring, consider earlier delivery
• Polyhydramnios → poor glycaemic control

Screening (NICE NG3)

• 75g OGTT at 24-28 weeks: for all women with risk factors (BMI >30, previous GDM, previous macrosomia, first-degree relative with DM, South Asian/African-Caribbean/Middle Eastern)
• Early OGTT (at booking): if previous GDM; repeat at 24-28 weeks if normal

Diagnostic Criteria (NICE)

• Fasting glucose ≥5.6 mmol/L OR
• 2-hour glucose ≥7.8 mmol/L

Monitoring

• Self-monitoring of blood glucose (SMBG): fasting + 1-hour post-meal (NICE NG3)
• Targets: fasting <5.3, 1-hour <7.8, 2-hour <6.4 mmol/L
• Serial USS: growth scans (28, 32, 36 weeks) to monitor for macrosomia, polyhydramnios

Postnatal

• Fasting glucose at 6-13 weeks postpartum (NICE NG3): exclude persistent diabetes
• Annual HbA1c or fasting glucose: lifelong screening for T2DM

Dietary/Lifestyle (First-Line)

• Low glycaemic index diet, regular meals, limit refined carbohydrates
• Exercise: 30 min moderate activity daily
• Trial of diet alone for 1-2 weeks before pharmacotherapy

Pharmacological (NICE NG3)

• Metformin 500mg-2g/day: first-line if diet fails; crosses placenta but no evidence of harm; NICE recommends
• Insulin: if metformin insufficient or fasting glucose ≥7.0 mmol/L at diagnosis (start insulin immediately); basal ± bolus; isophane (NPH), insulin aspart/lispro
• Glibenclamide 2.5-20mg/day: if metformin contraindicated/not tolerated AND insulin refused; less preferred (neonatal hypoglycaemia risk)

Obstetric Management

• Serial growth scans (28, 32, 36 weeks)
• Timing of delivery: NICE recommends delivery by 40+6 (diet-controlled) or 39+0-40+6 (on medication); earlier if complications
• Intrapartum: variable-rate insulin sliding scale if poor glycaemic control; hourly glucose monitoring

Postnatal

• Stop all glucose-lowering medication immediately after delivery (insulin resistance resolves)
• Monitor neonatal blood glucose (risk of neonatal hypoglycaemia)
• Breastfeeding encouraged (reduces future T2DM risk for both mother and child)
• Fasting glucose at 6-13 weeks postpartum: exclude persistent diabetes
• Annual HbA1c screening: lifelong
• Pre-conception counselling: before future pregnancies

Referral Criteria

• Joint obstetric-diabetes clinic: all GDM
• Specialist diabetic midwife/team
• Postnatal: GP for annual T2DM screening

GDM usually resolves after delivery. ~50% of women with GDM develop T2DM within 10 years (hence lifelong screening). Higher risk of T2DM with: obesity, need for insulin in pregnancy, higher glucose levels, earlier gestational diagnosis. Recurrence in subsequent pregnancies ~30-50%. Well-controlled GDM: near-normal pregnancy outcomes. Poorly controlled: increased macrosomia, operative delivery, and neonatal morbidity.

GDM Glucose Targets (NICE NG3)

OGTT Diagnostic Criteria Comparison

Key Facts

DKA is a medical emergency requiring prompt treatment. The UK JBDS-IP (Joint British Diabetes Societies) guidelines standardise management. The key priorities are fluid resuscitation, insulin administration, and potassium monitoring. Resolution is defined by ketone clearance, not glucose normalisation.

Epidemiology

Incidence: ~4-8 per 1,000 person-years in T1DM. DKA is the presenting feature in ~25% of new T1DM (higher in children). Mortality ~1% in UK (higher in elderly and those with comorbidities). Recurrent DKA: associated with psychosocial factors, eating disorders, insulin omission.

Aetiology

Precipitants (the 5 I's):

• Infection (commonest precipitant - UTI, pneumonia, skin)
• Insulin omission/insufficient insulin (commonest cause in known T1DM)
• Infarction (MI, stroke)
• Intercurrent illness (surgery, trauma)
• Intoxication/drugs (steroids, SGLT2 inhibitors, cocaine)

Pathophysiology

Symptoms

• Polyuria, polydipsia (hyperglycaemia)
• Nausea, vomiting, abdominal pain (ketosis - may mimic acute abdomen)
• Weakness, fatigue, malaise
• Confusion, drowsiness → coma (severe)

Signs

• Kussmaul breathing: deep, rapid respiration (respiratory compensation for metabolic acidosis)
• Ketotic breath: fruity/pear-drops smell (acetone)
• Dehydration: dry mucous membranes, reduced skin turgor, tachycardia, hypotension
• Tachycardia: dehydration + sympathetic drive
• Hypothermia: may occur (infection may not cause fever in DKA)

Severity (JBDS-IP)

• Mild: pH 7.25-7.3, bicarb 15-18
• Moderate: pH 7.0-7.24, bicarb 10-14
• Severe: pH <7.0, bicarb <10, GCS <12, SpO₂ <92%, SBP <90, HR >100 or <60, anion gap >16

Red Flags

• GCS <12 → severe DKA; consider HDU/ITU
• K⁺ <3.5 → do NOT start insulin until K⁺ corrected (risk of cardiac arrest)
• pH <7.0 → severe; consider bicarbonate (rarely needed)
• Persistent acidosis despite treatment → search for precipitant (sepsis, MI)

Immediate

• Capillary blood glucose: elevated (usually >14 mmol/L; may be near-normal in euglycaemic DKA)
• Blood ketones: ≥3.0 mmol/L (β-hydroxybutyrate); urine ketones ≥2+ if blood ketones not available
• VBG (venous blood gas): pH, bicarbonate, potassium, lactate
• U&Es: potassium (critical - guide replacement), sodium (corrected Na⁺), renal function
• FBC: WCC may be raised (stress response - does not necessarily indicate infection)
• CRP: infection screen
• Blood cultures, urine MC&S, CXR: identify precipitant
• ECG: hyperkalaemia/hypokalaemia changes; MI screen
• Serum osmolality: if HHS suspected (>320 mOsm/kg = HHS)

Monitoring (JBDS-IP)

• Hourly: capillary glucose, blood ketones (target fall ≥0.5 mmol/L/hr)
• 2-hourly: VBG (pH, bicarb, K⁺)
• K⁺: every 1-2 hours initially (falls rapidly with insulin)
• Fluid balance: strict input/output; consider urinary catheter if oliguric
• GCS: regular neurological observations (especially children - cerebral oedema)

IV Fluids (JBDS-IP Protocol)

• When glucose <14 mmol/L: add 10% glucose infusion (alongside 0.9% NaCl) to prevent hypoglycaemia while continuing insulin to clear ketones
• Caution in young patients (<25), elderly, HF, renal impairment - risk of fluid overload

Fixed-Rate Insulin Infusion (FRII)

• 0.1 units/kg/hour IV (e.g., 50 units Actrapid in 50mL 0.9% NaCl via syringe pump)
• Target: blood ketones fall ≥0.5 mmol/L/hr, glucose fall 3 mmol/L/hr
• Continue long-acting basal insulin (if already prescribed) - do NOT stop
• If blood ketones not falling adequately: increase FRII rate by 1 unit/hr

Potassium Replacement (Critical)

• K⁺ <3.5 mmol/L: add 40 mmol KCl per litre; DO NOT start insulin until K⁺ >3.5 (risk of cardiac arrest)
• K⁺ 3.5-5.5 mmol/L: add 40 mmol KCl per litre of fluid
• K⁺ >5.5 mmol/L: no potassium replacement; recheck in 1-2 hours
• Maximum rate: 20 mmol/hr via peripheral line; cardiac monitoring if giving >10 mmol/hr

Other

• VTE prophylaxis: LMWH (enoxaparin 40mg SC OD) - DKA is prothrombotic
• Treat precipitant: antibiotics if infection, MI pathway if infarction
• Bicarbonate: NOT routinely recommended; consider only if pH <6.9 (seek senior advice)
• Phosphate: routine replacement not recommended unless severely low

Resolution and Transition

• Resolution criteria: pH >7.3, bicarb >15 mmol/L, blood ketones <0.6 mmol/L, patient eating/drinking
• Transition to SC insulin: give SC rapid-acting insulin with a meal; continue FRII for 30-60 minutes AFTER SC dose before stopping
• If new diagnosis T1DM: initiate basal-bolus regimen; specialist diabetes team review

Cerebral Oedema (Mainly Children)

• Rare (<1% of paediatric DKA) but ~25% mortality
• Risk factors: young age, new diagnosis, excessive fluid, rapid glucose correction, failure of Na⁺ to rise
• Symptoms: headache, confusion, GCS decline, Cushing response
• Treatment: hypertonic saline 3% (2.5-5 mL/kg IV over 10-15 min) or mannitol 20% 0.5-1 g/kg IV; reduce fluids; intubation if needed

Referral Criteria

• All DKA: acute medical team (may need HDU/ITU for severe)
• Specialist diabetes team: before discharge
• Recurrent DKA: psychology, specialist nursing (assess adherence, psychosocial factors)

UK mortality ~1% overall; higher in elderly and those with significant comorbidities. Recurrent DKA is associated with insulin omission (psychosocial factors, eating disorders) and is a marker of poor long-term prognosis. With modern protocol-driven management, outcomes are excellent. Cerebral oedema mortality ~25% (children). Long-term: each DKA episode may accelerate cognitive decline and residual beta cell loss.

DKA vs HHS

JBDS-IP DKA Monitoring Summary

Key Facts

HHS has much higher mortality than DKA. The cornerstone of treatment is careful rehydration. Insulin is secondary and given at lower doses than DKA. Rapid correction of osmolality must be avoided.

Epidemiology

Incidence increasing with T2DM prevalence. Primarily affects elderly (>60 years). Mortality 15-20% (vs ~1% for DKA). Often occurs in residential care settings with poor fluid access.

Aetiology

Precipitants: infection (30-60% - UTI, pneumonia), MI, stroke, surgery, drugs (steroids, thiazides), poor fluid intake (dementia, reduced mobility), new diagnosis of T2DM.

Pathophysiology

Symptoms

• Insidious onset over days-weeks (slower than DKA)

• Weakness, leg cramps

Signs

• Severe dehydration: dry mucous membranes, reduced skin turgor, tachycardia, hypotension
• Altered consciousness (often GCS <12)
• Focal neurological signs may occur (seizures, hemiparesis - can mimic stroke)
• No Kussmaul breathing (not acidotic)
• No ketotic breath

Red Flags

• GCS <12 → severe HHS; ITU
• Focal neurological deficit → exclude stroke (CT head)
• Serum Na⁺ >160 mmol/L → very high osmolality; extreme caution with fluid correction
• K⁺ abnormalities → cardiac monitoring

Immediate

• Blood glucose: often >30 mmol/L (may be >100)
• Serum osmolality: >320 mOsm/kg (calculated: 2(Na⁺ + K⁺) + glucose + urea)
• Blood ketones: <3.0 mmol/L (minimal)
• VBG: pH >7.3, bicarb >15 (no significant acidosis)
• U&Es: Na⁺ (often raised; calculate corrected Na⁺), K⁺, renal function
• FBC, CRP: infection screen
• Blood cultures, urine MC&S, CXR: identify precipitant
• ECG: MI, arrhythmia, electrolyte changes
• CT head: if focal neurological deficit (exclude stroke)

Monitoring (JBDS-IP)

• Hourly glucose, 2-hourly Na⁺ and osmolality
• Target: osmolality fall 3-8 mOsm/kg/hr
• Fluid balance: strict I/O; catheterise if oliguric

IV Fluids (Cornerstone - JBDS-IP)

• Aim to replace ~50% of fluid deficit in first 12 hours, remainder over next 12-24 hours
• Slower than DKA (avoid rapid osmolality shifts)
• If osmolality not falling despite 0.9% NaCl → consider 0.45% NaCl (half-normal saline); ONLY under specialist guidance
• When glucose <14 mmol/L: add 5% or 10% glucose

Insulin

• NOT first-line in HHS (unlike DKA) - fluids alone often reduce glucose significantly
• Start 0.05 units/kg/hr FRII ONLY if: ketones >1.0 mmol/L, or glucose not falling at ≥5 mmol/L/hr with fluids alone
• Target glucose fall: 4-6 mmol/L/hr (NOT faster - risk of cerebral oedema)

Potassium

• Replace as per DKA protocol (guided by serum K⁺)
• K⁺ <3.5: replace BEFORE insulin

VTE Prophylaxis (Essential)

• LMWH (enoxaparin 40 mg SC OD) for ALL patients - HHS is extremely prothrombotic
• Continue throughout admission

Other

• Treat precipitant (antibiotics, MI pathway)
• Foot care (neuropathy + dehydration → high ulceration risk)
• Monitor for complications: VTE, rhabdomyolysis, acute kidney injury

Referral Criteria

• Medical/endocrine emergency admission
• ITU/HDU: GCS <12, severe comorbidity
• Diabetes team: before discharge

Mortality ~15-20% (primarily due to age, comorbidities, and thromboembolic complications rather than hyperglycaemia per se). VTE is a major contributor to mortality. Full recovery is common with prompt appropriate treatment. Cerebral oedema from over-rapid correction is avoidable. Many patients diagnosed with HHS were previously undiagnosed T2DM. Post-discharge: optimise diabetes management, educate on sick-day rules.

HHS vs DKA

Key Facts

Hypoglycaemia is the major acute barrier to tight glycaemic control. It can be fatal and causes significant morbidity including falls, fractures, cardiac arrhythmias, and cognitive impairment. Identification and management of hypoglycaemia unawareness is critical in T1DM.

Epidemiology

Most T1DM patients experience ~2 mild hypoglycaemic episodes per week; ~1 severe episode per year. T2DM on insulin: ~0.5-1 severe episodes per year. Severe hypoglycaemia is more common with long duration of diabetes, tight HbA1c targets, and hypoglycaemia unawareness.

Aetiology

Diabetic patients: insulin (too much, wrong timing, wrong type), sulfonylureas, missed/delayed meals, excess exercise, alcohol, renal impairment (reduced insulin clearance), adrenal insufficiency (associated with T1DM). Non-diabetic: insulinoma, post-bariatric surgery (dumping syndrome), adrenal insufficiency (Addison, secondary), alcohol, drugs (quinine, pentamidine, salicylates), critical illness (liver failure, sepsis, renal failure), non-islet cell tumour (IGF-2 secreting).

Pathophysiology

Adrenergic/Autonomic Symptoms (Glucose ~3.0-3.9 mmol/L)

• Sweating, tremor, palpitations, anxiety, hunger, pallor, nausea

Neuroglycopaenic Symptoms (Glucose <3.0 mmol/L)

• Confusion, difficulty concentrating, behavioural change (aggression, uncooperativeness)
• Visual disturbance, slurred speech
• Incoordination, weakness
• Seizures, coma
• Focal neurological deficit (may mimic stroke)

Severity Classification

• Mild: self-treated; adrenergic symptoms only
• Moderate: self-treated with difficulty; neuroglycopaenic symptoms but conscious
• Severe: requires third-party assistance; may be unconscious or seizing

Red Flags

• Recurrent unexplained hypoglycaemia in non-diabetic → insulinoma, adrenal insufficiency
• Hypoglycaemia unawareness in T1DM → needs CGM, relaxed targets
• Factitious hypoglycaemia: low glucose + high insulin + low C-peptide = exogenous insulin; high insulin + high C-peptide = sulfonylurea/insulinoma

Immediate

• Capillary/venous blood glucose: confirm hypoglycaemia

During Hypoglycaemia (Critical - Before Treatment if Possible)

• Paired samples: blood glucose, insulin, C-peptide, beta-hydroxybutyrate, sulfonylurea screen, proinsulin
• Interpretation: high insulin + high C-peptide = endogenous insulin source (insulinoma, sulfonylurea); high insulin + low C-peptide = exogenous insulin
• Beta-hydroxybutyrate: appropriately elevated in hypoglycaemia with suppressed insulin (normal); suppressed if hyperinsulinaemic hypoglycaemia

If Insulinoma Suspected

• 72-hour supervised fast: gold standard; monitor glucose, insulin, C-peptide; symptomatic hypoglycaemia with inappropriate insulin confirms diagnosis
• CT/MRI pancreas: localise tumour
• Endoscopic ultrasound: most sensitive for small pancreatic lesions

Other

• Short Synacthen test: if adrenal insufficiency suspected
• LFTs, U&Es: hepatic/renal failure
• Cortisol: if adrenal cause suspected

Acute Treatment

Conscious (mild-moderate):

• 15-20g fast-acting glucose: dextrose tablets (3-4 × Dextrosol), 150-200mL juice, 4-5 glucose tablets
• Recheck glucose after 15 minutes; repeat if <4.0 mmol/L
• Follow with long-acting carbohydrate (toast, biscuits, next meal)

Unconscious/Unable to Swallow (severe):

• IM glucagon 1mg (GlucaGen HypoKit): acts within 10-15 minutes; may cause nausea/vomiting; less effective if alcohol-related or glycogen-depleted
• IV glucose 10% 200mL (20g glucose): if IV access available; preferred in hospital
• Avoid IV 50% glucose: causes thrombophlebitis; use 10% or 20% instead
• Recovery position; protect airway

Sulfonylurea-Induced:

• May need prolonged glucose infusion (sulfonylureas have long half-life - gliclazide up to 20h)
• IV 10% glucose infusion; monitor for 24-48 hours
• Consider octreotide 50-100 mcg SC 8-hourly (inhibits insulin secretion)

Prevention

• Diabetes review: adjust insulin/sulfonylurea doses; education on carb counting, sick-day rules
• CGM: for hypoglycaemia unawareness (alarms for low glucose)
• Relaxed HbA1c targets: if recurrent severe hypoglycaemia
• Structured programmes: DAFNE, BGAT (Blood Glucose Awareness Training)

Non-Diabetic Hypoglycaemia

• Insulinoma: surgical excision (curative in >90%); diazoxide 3-8 mg/kg/day if inoperable
• Adrenal insufficiency: hydrocortisone replacement
• Post-bariatric: dietary modification (low GI, small frequent meals); acarbose

Referral Criteria

• Recurrent severe hypoglycaemia in T1DM: specialist diabetes team, pump/CGM assessment
• Non-diabetic hypoglycaemia: endocrinology
• Suspected insulinoma: endocrine surgery

Mild hypoglycaemia: fully reversible with prompt glucose. Severe prolonged hypoglycaemia: can cause permanent brain injury (hippocampal damage - memory impairment) and death. Severe hypoglycaemia is associated with increased cardiovascular mortality (NICE-SUGAR trial). Recurrent hypoglycaemia causes hypoglycaemia unawareness (reversible with strict avoidance for 2-3 weeks). Insulinoma: >90% cure rate with surgical excision.

Causes of Hypoglycaemia in Diabetic vs Non-Diabetic

Biochemical Diagnosis of Hypoglycaemia

Key Facts

Diabetic nephropathy is preventable and its progression can be significantly slowed. Annual screening, early ACEi/ARB initiation, SGLT2 inhibitors, and glycaemic/BP optimisation are the cornerstones of management.

Epidemiology

~30-40% of T1DM and ~20-30% of T2DM develop nephropathy. Accounts for ~25% of patients starting renal replacement therapy in UK. Peak incidence of ESRD in T1DM: 15-20 years after diagnosis.

Aetiology

Chronic hyperglycaemia → microvascular damage to glomerular capillaries. Risk factors: poor glycaemic control, hypertension, genetic susceptibility, smoking, dyslipidaemia.

Pathophysiology

Stages

• Stage 1: hyperfiltration (GFR may be supranormal); no albuminuria
• Stage 2: normoalbuminuria; GBM thickening on biopsy
• Stage 3: microalbuminuria (ACR 3-30 mg/mmol); earliest clinical marker; reversible with treatment
• Stage 4: macroalbuminuria (ACR >30); GFR declining; usually accompanied by retinopathy
• Stage 5: ESRD (GFR <15); requiring renal replacement therapy

Clinical Features

• Usually asymptomatic until advanced (detected on screening)
• Peripheral oedema (nephrotic syndrome if heavy proteinuria)
• Hypertension (often precedes or accompanies albuminuria)
• Uraemic symptoms (advanced): fatigue, nausea, pruritis, confusion

Red Flags

• Absence of retinopathy with nephropathy in T1DM → consider non-diabetic kidney disease
• Rapid GFR decline → consider renal artery stenosis, RPGN, obstruction
• Active urinary sediment → glomerulonephritis (not typical of diabetic nephropathy)

Screening (Annual - NICE)

• Urine ACR: first morning void; confirm positive result on 2 of 3 samples
• eGFR: calculated from serum creatinine
• Staging: ACR + GFR → KDIGO CKD classification

Additional

• U&Es: creatinine, potassium, bicarbonate
• Serum albumin: if nephrotic range proteinuria
• Renal USS: if rapid decline, haematuria, obstruction suspected
• Renal biopsy: if atypical features (no retinopathy in T1DM, haematuria, rapid decline, short duration of DM)

Glycaemic Control

• HbA1c ≤48 mmol/mol (individualised; avoid hypoglycaemia in advanced CKD)
• Adjust medication doses for GFR (metformin: stop if eGFR <30; sulfonylureas: reduce/stop)

Blood Pressure (Target <130/80)

• ACEi/ARB first-line: ramipril 1.25-10mg OD or losartan 25-100mg OD; titrate to maximum tolerated; start when ACR ≥3 mg/mmol even if normotensive
• Monitor K⁺ and eGFR 1-2 weeks after starting/dose change (accept up to 25% eGFR fall; >30% → investigate)
• Do NOT combine ACEi + ARB (ONTARGET trial - no benefit, increased harm)

SGLT2 Inhibitors

• Dapagliflozin 10mg OD: DAPA-CKD trial - 39% reduction in renal composite; recommended for all T2DM with CKD and ACR ≥3 (NICE NG28); can initiate down to eGFR 20
• Empagliflozin, canagliflozin: also renoprotective

Finerenone

• Non-steroidal MRA: FIDELIO-DKN/FIGARO-DKN trials - additional renal and CV benefit on top of ACEi/ARB + SGLT2i; NICE TA877

Lipids

• Atorvastatin 20-80mg OD

Advanced CKD

• Dietitian: low-protein diet consideration
• Erythropoiesis-stimulating agents (ESAs) for renal anaemia
• Phosphate binders, vitamin D analogues for CKD-MBD
• Pre-dialysis planning: nephrology referral when eGFR <30
• Renal replacement: haemodialysis, peritoneal dialysis, transplant

Referral Criteria

• Nephrology: ACR >70 mg/mmol, eGFR <30, rapid decline (>5 mL/min/year), resistant HTN, suspected non-diabetic kidney disease

With modern management (ACEi/ARB + SGLT2i + glycaemic/BP control), progression to ESRD has significantly decreased. Microalbuminuria: ~30% progress to macroalbuminuria over 10 years; ~30% regress to normoalbuminuria with treatment. Macroalbuminuria: higher risk of progression to ESRD (~50% at 10 years without intervention). T1DM with ESRD: median survival on dialysis ~5 years. Cardiovascular disease remains the leading cause of death in diabetic nephropathy.

KDIGO CKD Classification (Simplified)

Key Renoprotection Trials

Key Facts

Diabetic retinopathy is largely preventable with good glycaemic and BP control. The UK screening programme has significantly reduced blindness. Anti-VEGF therapy has revolutionised treatment of DMO.

Epidemiology

Affects ~40% of T1DM and ~30% of T2DM. Nearly all T1DM patients have some retinopathy after 20 years. Sight-threatening retinopathy (PDR or DMO) in ~10% of diabetic patients.

Aetiology

Duration of diabetes and glycaemic control are the strongest risk factors. Other: hypertension, dyslipidaemia, smoking, pregnancy, renal disease (proteinuria), anaemia.

Pathophysiology

Non-Proliferative DR (NPDR)

• Background: microaneurysms (earliest), dot/blot haemorrhages, hard exudates (lipid deposits)
• Pre-proliferative: cotton wool spots (nerve fibre layer infarcts), venous beading/loops, IRMA (intraretinal microvascular abnormalities), extensive haemorrhages
• Often asymptomatic

Proliferative DR (PDR)

• Neovascularisation: disc (NVD) or elsewhere (NVE)
• Vitreous haemorrhage: sudden painless visual loss (floaters → dense loss)
• Tractional retinal detachment: progressive visual loss
• Rubeosis iridis: new vessels on iris → neovascular glaucoma

Diabetic Macular Oedema (DMO)

• Central visual loss, distortion (metamorphopsia)
• Can occur at any NPDR or PDR stage
• Commonest cause of visual impairment in diabetic patients

Red Flags

• New floaters/flashes → possible PDR complication
• Gradual central vision loss → DMO

Screening

• Annual digital retinal photography: NHS Diabetic Eye Screening Programme
• Two 45° retinal images per eye (macula-centred and disc-centred)
• Classification: R0 (no retinopathy), R1 (background), R2 (pre-proliferative), R3 (proliferative); M0 (no maculopathy), M1 (maculopathy)

Specialist Assessment

• Slit-lamp biomicroscopy: detailed retinal examination
• OCT (optical coherence tomography): quantifies macular oedema thickness; essential for DMO management
• Fluorescein angiography (FFA): identifies ischaemia, neovascularisation, leakage; guides laser treatment
• Ultra-widefield imaging: peripheral retinal assessment

Prevention (Most Important)

• Glycaemic control: HbA1c target ≤48 mmol/mol (DCCT: 76% reduction in retinopathy risk)
• BP control: <130/80 mmHg (UKPDS: 34% risk reduction)
• Lipid management: statins; fenofibrate has specific retinal benefit (FIELD, ACCORD-Eye trials)

NPDR

• Background (R1): annual screening; optimise glycaemic/BP control
• Pre-proliferative (R2): refer to ophthalmology; more frequent monitoring (3-6 monthly)

PDR (R3)

• Panretinal photocoagulation (PRP): laser burns to peripheral retina; reduces VEGF production; reduces severe visual loss by ~50% (DRS/ETDRS trials)
• Intravitreal anti-VEGF: ranibizumab, aflibercept - increasingly used as alternative to PRP for PDR (CLARITY trial)

DMO

• Intravitreal anti-VEGF injections: ranibizumab 0.5mg (NICE TA274), aflibercept 2mg (NICE TA346) - first-line for centre-involving DMO; monthly loading then PRN
• Intravitreal steroid implant: dexamethasone implant (Ozurdex - NICE TA349) or fluocinolone acetonide (Iluvien - NICE TA301) - if anti-VEGF insufficient, pseudophakic, or poor anti-VEGF response
• Macular laser: focal laser for non-centre-involving DMO

Surgical

• Vitrectomy: non-clearing vitreous haemorrhage (>1 month), tractional retinal detachment, combined tractional-rhegmatogenous detachment

Referral Criteria

• R2 (pre-proliferative): routine ophthalmology referral
• R3 (proliferative): urgent ophthalmology referral (within 2 weeks)
• DMO: ophthalmology referral
• Sudden visual loss: emergency ophthalmology (same-day)

With screening and modern treatment (anti-VEGF, laser), rates of severe visual loss have decreased significantly. DCCT: intensive glycaemic control reduces retinopathy risk by 76% in T1DM. Untreated PDR: ~50% develop severe visual loss within 2 years. With PRP: risk reduced by >50%. DMO treated with anti-VEGF: ~30-40% gain ≥3 lines of visual acuity.

DR Classification (UK National Screening Programme)

Key Retinopathy Trials

Key Facts

Diabetic foot disease is largely preventable with screening, education, and prompt management. The diabetic foot MDT approach has significantly reduced amputation rates. Charcot foot requires early recognition to prevent deformity.

Epidemiology

Lifetime risk of foot ulceration ~25% in diabetes. ~7,000 amputations/year in UK. 5-year mortality after major amputation ~50% (comparable to many cancers). PAD present in ~50% of diabetic foot ulcers.

Aetiology

Pathophysiology

PAD: impaired blood supply → ischaemic ulceration, poor healing, gangrene.

Diabetic Foot Ulcer Types

Neuropathic (60%): painless, punched-out margins, plantar surface (metatarsal heads, heel), warm foot, bounding pulses, callus surrounding, often infected silently Ischaemic (10%): painful, irregular margins, toes/lateral border, cold foot, absent pulses, pale/mottled, may have gangrene Neuroischaemic (30%): features of both; commonest in clinical practice

Charcot Foot

• Acute: hot, red, swollen foot; often unilateral; easily mistaken for cellulitis, DVT, or gout
• Temperature difference >2°C between feet
• X-ray: may be normal initially; later: fractures, joint destruction, subluxation
• MRI: bone marrow oedema (earliest detectable change)
• Chronic: rocker-bottom deformity, midfoot collapse

Infection

• Cellulitis, deep soft tissue infection, osteomyelitis
• Often polymicrobial: S. aureus, streptococci, anaerobes, Gram-negatives
• Systemic sepsis: fever, tachycardia, raised WCC/CRP
• Probe-to-bone test: if probe reaches bone → osteomyelitis likely

Red Flags

• Spreading cellulitis, systemic sepsis, gas gangrene → emergency
• Charcot: acute hot swollen foot in diabetic → immobilise immediately
• Critical limb ischaemia: rest pain, tissue loss, ABPI <0.5

Foot Assessment (NICE NG19)

• 10g monofilament: loss of sensation at ≥1 site = at-risk
• Pulse palpation: dorsalis pedis, posterior tibial
• ABPI: <0.9 suggests PAD; >1.3 suggests calcified arteries (unreliable - use toe pressures instead)

Ulcer Assessment

• Size, depth, location, base (granulating, sloughy, necrotic)
• Probe-to-bone test: if bone palpable → osteomyelitis (sensitivity ~90%)
• Wound swab/deep tissue culture: for infected ulcers

Imaging

• X-ray foot: osteomyelitis (periosteal reaction, bone destruction - may take 2 weeks to appear), Charcot changes
• MRI foot: gold standard for osteomyelitis and Charcot (bone marrow oedema)

Vascular

• Duplex USS: PAD assessment
• CT/MR angiography: if revascularisation considered

Bloods

• FBC, CRP, ESR: infection markers
• HbA1c: glycaemic control
• Blood cultures: if systemic sepsis

Prevention (NICE NG19)

• Annual foot screening and risk stratification
• Patient education: daily foot inspection, appropriate footwear, avoid walking barefoot, prompt reporting of injury
• Podiatry: regular nail care, callus management
• Customised footwear/orthotics for high-risk feet

Ulcer Management (MDT - Diabetic Foot Team)

• Offloading: non-removable total contact cast or irremovable walker boot (NICE NG19 - reduces healing time)
• Wound care: debridement (sharp, autolytic), appropriate dressings, negative pressure wound therapy (complex wounds)
• Infection: mild - oral flucloxacillin 500mg QDS + amoxicillin-clavulanate 625mg TDS; moderate-severe - IV antibiotics (piperacillin-tazobactam, or co-amoxiclav + metronidazole); osteomyelitis - prolonged IV antibiotics (6 weeks) ± surgical debridement
• Vascular assessment: all ulcers; revascularisation (angioplasty/bypass) if significant PAD
• Glycaemic optimisation: insulin if needed for acute management

Charcot Foot

• Immediate immobilisation: total contact cast (TCC) or aircast boot; non-weight-bearing initially
• Continue immobilisation until temperature difference between feet <2°C and inflammatory markers normalised (may take 6-12 months)
• Bisphosphonates: limited evidence (not routine)
• Surgical reconstruction: for severe deformity causing ulceration

Surgical

• Revascularisation: angioplasty or bypass for PAD-related ischaemia
• Amputation: if life-threatening infection, non-reconstructable PAD, extensive necrosis; aim for most distal level possible

Referral Criteria

• Diabetic foot team: ALL active foot problems (ulcer, infection, Charcot) - seen within 24 hours (NICE NG19)
• Vascular surgery: PAD, critical limb ischaemia
• Orthopaedics: Charcot deformity requiring surgery

Diabetic foot ulcers: ~60% heal with appropriate management within 6 months; ~10-15% require amputation. 5-year mortality after major amputation ~50%. Charcot foot: if recognised and treated early, deformity can be minimised; late diagnosis leads to rocker-bottom deformity and recurrent ulceration. Recurrence rate for foot ulcers: ~40% at 1 year, ~60% at 3 years. MDT care has reduced amputation rates by ~40%.

Neuropathic vs Ischaemic Foot Ulcer

Diabetic Foot Risk Classification (NICE NG19)

Key Facts

Diabetic neuropathy is the commonest microvascular complication of diabetes. Prevention through glycaemic control and early detection through screening are the most important interventions.

Epidemiology

~50% of diabetic patients have some neuropathy; ~25% have painful neuropathy. Risk increases with duration and poor control. Both T1DM and T2DM affected.

Aetiology

Hyperglycaemia is the primary driver. Other risk factors: dyslipidaemia, hypertension, smoking, obesity.

Pathophysiology

Polyol pathway (sorbitol accumulation), AGEs, PKC activation, oxidative stress, microvascular disease (vasa nervorum) → axonal degeneration and segmental demyelination.

DSPN

• Gradual onset; sensory > motor; glove-and-stocking
• Numbness, tingling, burning pain (worse at night)
• Absent ankle jerks, loss of monofilament sensation
• Risk of painless injuries → neuropathic ulceration

Autonomic Neuropathy

• CV: resting tachycardia, orthostatic hypotension, silent MI
• GI: gastroparesis, constipation, diarrhoea
• GU: erectile dysfunction, neurogenic bladder

Other Forms

• Diabetic amyotrophy: painful proximal thigh weakness; self-limiting 12-18 months
• CN III palsy: pupil-sparing (key distinction from compressive cause)

Red Flags

• Loss of protective sensation → high amputation risk
• Charcot foot (hot, swollen, painless joint destruction)

Bedside

• 10g monofilament, vibration (128 Hz tuning fork), ankle reflexes

Bloods

• HbA1c, B12 (metformin-induced deficiency), TFTs, SPEP, U&Es

Neurophysiology

• NCS: axonal sensorimotor polyneuropathy (if diagnostic uncertainty)

Autonomic

• Lying/standing BP, heart rate variability, gastric emptying study

Prevention

• Optimise glycaemic control: DCCT (~60% reduction T1DM), UKPDS (T2DM)
• Cardiovascular risk management

Pain Management (NICE CG173)

• First-line: amitriptyline 10-75 mg ON, duloxetine 60-120 mg OD, gabapentin 300-3600 mg/day, or pregabalin 150-600 mg/day
• Combination therapy if monotherapy inadequate
• Topical capsaicin 0.075% for localised pain
• Pain clinic referral for refractory cases

Autonomic

• Orthostatic hypotension: fludrocortisone, midodrine
• Gastroparesis: domperidone 10mg TDS (short-term), dietary modification
• Erectile dysfunction: PDE5 inhibitors

Foot Care (NICE NG19)

• Annual risk assessment, podiatry, patient education

DSPN is slowly progressive. Tight glycaemic control slows but does not reverse established neuropathy. Diabetic foot ulceration: lifetime risk ~25%; 5-year mortality after amputation ~50%. Autonomic neuropathy with cardiac involvement: 5-year mortality ~25-50%.

Types of Diabetic Neuropathy

Key Trials

Key Facts

Hypothyroidism is common and easily treated with levothyroxine. Autoimmune thyroiditis is the commonest cause in iodine-sufficient countries. Dose adjustments require 6-8 weeks before rechecking TSH.

Epidemiology

Prevalence ~2-5%. F:M 5-10:1. Incidence increases with age. Subclinical hypothyroidism: ~5-10% of women >60 years.

Aetiology

Primary (most common): Hashimoto thyroiditis (autoimmune - anti-TPO +), post-radioiodine treatment, post-thyroidectomy, iodine deficiency (developing world), drugs (amiodarone, lithium, checkpoint inhibitors), infiltrative (amyloid, haemochromatosis). Secondary (central): pituitary tumour, surgery, radiation, Sheehan syndrome, infiltrative (sarcoidosis).

Pathophysiology

Symptoms

• Fatigue, lethargy, somnolence
• Weight gain (modest - due to fluid retention more than fat)
• Cold intolerance
• Constipation
• Dry skin, brittle hair, hair loss (diffuse alopecia; lateral third of eyebrows - madarosis)
• Menorrhagia (early), oligomenorrhoea/amenorrhoea (severe)
• Depression, impaired concentration, memory problems
• Hoarse voice

Signs

• Bradycardia
• Periorbital/facial puffiness (myxoedema)
• Goitre (Hashimoto - initially; may atrophy late)
• Delayed relaxation of deep tendon reflexes
• Dry, cool, pale skin
• Non-pitting oedema (myxoedema - glycosaminoglycan deposition)
• Carpal tunnel syndrome
• Hyperlipidaemia, anaemia (normocytic or macrocytic)

Red Flags

• Severe hypothyroidism with altered consciousness → myxoedema coma (see separate topic)
• Hypothyroidism in pregnancy → urgent treatment (risk of fetal neurodevelopmental impairment)
• Rapid thyroid enlargement in Hashimoto → exclude thyroid lymphoma

TFTs

• TSH: raised in primary hypothyroidism (>4.5 mU/L); low/normal in central
• Free T4: low
• Free T3: usually low (but may be maintained initially)

Autoantibodies

• Anti-TPO (thyroid peroxidase): positive in ~95% of Hashimoto
• Anti-thyroglobulin: positive in ~60-80%

Additional Bloods

• FBC: normocytic or macrocytic anaemia
• Lipid profile: hyperlipidaemia (raised LDL)
• U&Es: hyponatraemia (dilutional - impaired free water excretion)
• CK: mildly raised (myopathy)
• Cortisol: check before starting levothyroxine if secondary hypothyroidism suspected (risk of adrenal crisis if coexistent hypoadrenalism)

Levothyroxine Replacement

• Standard dose: 1.6 μg/kg/day (typically 50-150 μg OD)
• Starting dose: 50-100 μg OD in young, healthy adults
• Elderly/cardiac disease: start 25 μg OD; increase by 25 μg every 4-6 weeks (rapid replacement may precipitate angina/MI/AF)
• Take on empty stomach, 30-60 minutes before breakfast (consistent timing)
• Target TSH: within reference range (0.4-4.5 mU/L); check 6-8 weeks after dose change
• Once stable: annual TFT

Drug Interactions

• Absorption reduced by: calcium, iron, PPIs, cholestyramine (take ≥4 hours apart)
• Increased requirement: pregnancy (increase by ~25-50%), oestrogen (OCP, HRT)

Subclinical Hypothyroidism

• TSH >10 mU/L: treat with levothyroxine
• TSH 4.5-10: treat if symptomatic, positive anti-TPO, or planning pregnancy; otherwise monitor

Pregnancy

• Increased levothyroxine requirement (~25-50% increase); check TFTs every 4 weeks in first half
• TSH target: <2.5 mU/L in first trimester (some guidelines)

Referral Criteria

• Endocrinology: suspected central hypothyroidism, difficulty achieving target TSH, pregnancy with complex thyroid disease
• Suspected thyroid lymphoma (rapid goitre growth in Hashimoto)

Excellent with levothyroxine replacement. Normal life expectancy when adequately treated. Over-replacement (suppressed TSH): risk of AF, osteoporosis (especially in postmenopausal women). Under-replacement: persistent symptoms, cardiovascular risk (hyperlipidaemia). Subclinical hypothyroidism: ~2-5% per year progress to overt hypothyroidism (higher if anti-TPO positive).

Causes of Hypothyroidism

Levothyroxine Dose Adjustment Guide

Key Facts

Graves disease is the commonest cause of hyperthyroidism. First-line treatment is antithyroid drugs for 12-18 months. Relapse rate after ATD is ~50%. Radioiodine is the definitive treatment. Agranulocytosis requires immediate ATD cessation.

Epidemiology

Prevalence ~0.5-2%. F:M 5-10:1. Graves: peak age 30-50 years. Toxic MNG: older patients. Thyrotoxicosis factitia: intentional/accidental thyroxine ingestion.

Aetiology

Toxic multinodular goitre: autonomous nodules; often elderly; gradual onset. Toxic adenoma: single autonomous nodule.

Pathophysiology

Excess thyroid hormone increases basal metabolic rate, oxygen consumption, heat production, and sympathetic activity. Effects: cardiac - tachycardia, AF, high-output cardiac failure; musculoskeletal - myopathy, osteoporosis; GI - increased motility; CNS - anxiety, tremor, hyperreflexia.

Symptoms

• Weight loss (despite increased appetite)
• Heat intolerance, sweating
• Palpitations (sinus tachycardia, AF)
• Tremor (fine), anxiety, irritability, insomnia
• Diarrhoea/increased stool frequency
• Proximal muscle weakness
• Menstrual irregularity (oligomenorrhoea)

Signs

• Tachycardia, AF
• Fine tremor, warm moist palms
• Goitre (diffuse in Graves; nodular in MNG)
• Lid lag, lid retraction (any cause of thyrotoxicosis)
• Hyperreflexia

Graves-Specific Features

• Graves orbitopathy: proptosis (exophthalmos), periorbital oedema, conjunctival injection, diplopia (EOM restriction), optic neuropathy (sight-threatening)
• Pretibial myxoedema: waxy plaques on shins
• Thyroid acropachy: digital clubbing (rare)

Red Flags

• AF with thyrotoxicosis → rate control + anticoagulation
• Thyroid storm (see separate topic)
• Graves orbitopathy with visual loss → urgent ophthalmology
• Agranulocytosis on ATDs: sore throat/fever → STOP ATD, urgent FBC

TFTs

• TSH: suppressed (<0.1 mU/L)
• Free T4: raised; free T3: raised (T3 thyrotoxicosis if T4 normal)

Autoantibodies

• TRAb (TSH receptor antibodies): positive in >95% of Graves; highly specific
• Anti-TPO: positive in ~75% of Graves (less specific)

Imaging

• Thyroid uptake scan (technetium-99m/¹²³I): diffuse increased uptake = Graves; patchy = MNG; single hot nodule = toxic adenoma; low/absent uptake = thyroiditis, factitia
• USS thyroid: nodule assessment; Doppler for vascularity

Bloods

• FBC: baseline before ATDs
• LFTs: baseline (ATDs can cause hepatotoxicity)
• ESR: raised in subacute thyroiditis

Other

• ECG: AF, tachycardia
• DEXA: if osteoporosis suspected (prolonged thyrotoxicosis)

Antithyroid Drugs (First-Line - NICE CKS)

• Carbimazole 20-40mg/day initially; two approaches:
  • Titration: start high, reduce to maintenance (5-15mg/day) based on TFTs
  • Block-and-replace: high-dose carbimazole (40mg/day) + levothyroxine 100-150μg/day
• Duration: 12-18 months then withdraw; remission in ~50% (Graves)
• Propylthiouracil (PTU) 200-400mg/day: reserved for first trimester pregnancy (carbimazole teratogenic - aplasia cutis) or carbimazole intolerance
• Side effects: rash (~5%), arthralgia, GI; agranulocytosis (~0.2-0.5%) - warn patient: sore throat/fever → STOP drug, urgent FBC

Beta-Blockers (Symptom Control)

• Propranolol 40-80mg TDS: controls palpitations, tremor, anxiety while ATDs take effect (2-6 weeks for ATD onset); also inhibits T4→T3 conversion

Radioiodine (¹³¹I)

• Definitive treatment; commonly used for relapse after ATDs, toxic MNG
• Contraindicated: pregnancy/breastfeeding, active moderate-severe Graves orbitopathy
• Most become hypothyroid → lifelong levothyroxine
• Avoid close contact with children/pregnant women for ~3 weeks after treatment

Thyroidectomy

• Total thyroidectomy: large goitre with compressive symptoms, suspected malignancy, severe Graves orbitopathy (radioiodine may worsen), patient preference
• Risks: recurrent laryngeal nerve injury (hoarseness ~1%), hypoparathyroidism (~1-2%), hypothyroidism (expected after total)
• Render euthyroid with ATDs pre-operatively + Lugol iodine (10 days pre-op to reduce thyroid vascularity)

Graves Orbitopathy

• Mild: lubricants, selenium 100μg BD (EUGOGO trial)
• Moderate-severe: IV methylprednisolone pulses, orbital radiotherapy
• Sight-threatening (optic neuropathy): urgent IV steroids ± surgical decompression
• Teprotumumab (anti-IGF-1R): emerging therapy

Referral Criteria

• Endocrinology: all new thyrotoxicosis for diagnosis and management
• Ophthalmology: Graves orbitopathy
• Surgery: large goitre, compression, malignancy suspected

Graves: ~50% remission after 12-18 months ATDs; ~50% relapse. Radioiodine: >90% cure but most become hypothyroid. Surgery: >95% cure; hypothyroidism expected. Toxic MNG/adenoma: rarely remit spontaneously; radioiodine or surgery usually needed. Untreated thyrotoxicosis: risk of AF, heart failure, osteoporosis, thyroid storm. Graves orbitopathy: ~5% develop sight-threatening disease.

Causes of Thyrotoxicosis

Block-and-Replace vs Titration

Key Facts

Graves disease is the commonest autoimmune cause of hyperthyroidism. TRAb is both diagnostic and pathogenic. Management involves ATDs, radioiodine, or surgery depending on clinical context. Graves orbitopathy requires specialist management.

Epidemiology

Prevalence ~0.5-1%. F:M 5-10:1. Peak age 30-50 years. Lifetime risk ~3% in women. More common in smokers (especially orbitopathy).

Aetiology

Autoimmune: genetic (HLA-DR3, CTLA-4 polymorphisms) + environmental triggers (stress, smoking, pregnancy, infection, iodine excess). TRAb stimulate TSH receptors on thyroid follicular cells → unregulated thyroid hormone production and gland enlargement.

Pathophysiology

Thyrotoxicosis Features

• As per hyperthyroidism: weight loss, tremor, palpitations, heat intolerance, diarrhoea
• Diffuse, smooth, non-tender goitre (may have bruit due to increased vascularity)

Graves-Specific Features

• Orbitopathy (~25-50%): proptosis, periorbital oedema, conjunctival injection/chemosis, EOM restriction (inferior rectus most commonly → diplopia on upgaze), lid retraction, lagophthalmos, optic neuropathy (rare but sight-threatening)
• Pretibial myxoedema (~1-5%): raised waxy plaques/nodules on anterior shins; peau d'orange appearance
• Thyroid acropachy (<1%): digital clubbing, periosteal reaction
• Thyroid dermopathy: localised or generalised

Red Flags

• Severe proptosis with corneal exposure → ophthalmology
• Thyroid storm features → emergency

TFTs

• Suppressed TSH, raised free T4 ± free T3

TRAb

• Positive in >95% - diagnostic; also useful for: relapse prediction (high TRAb at ATD cessation → higher relapse risk), neonatal Graves risk (check in 3rd trimester), distinguishing Graves from thyroiditis

Uptake Scan

• Diffuse increased uptake (confirms Graves vs thyroiditis/toxic nodule)

Orbital Assessment

• CT/MRI orbits: if moderate-severe orbitopathy; shows enlarged EOM (especially inferior and medial rectus), orbital fat expansion
• CAS (Clinical Activity Score): grades activity of orbitopathy

Bloods

• FBC, LFTs: baseline before ATDs

Antithyroid Drugs

• Carbimazole: first-line; 20-40mg/day initially; titration or block-and-replace; 12-18 months
• PTU: first trimester pregnancy only
• Warn: agranulocytosis risk

Radioiodine

• For relapse or as first-line definitive therapy; single dose; most become hypothyroid
• Avoid in active moderate-severe orbitopathy (may worsen - give steroid cover: prednisolone 0.3-0.5mg/kg for 3 months)

Surgery

• Total thyroidectomy: large goitre, compression, moderate-severe active orbitopathy, patient preference

Orbitopathy (EUGOGO Guidelines)

• Mild: lubricants, selenium 100μg BD × 6 months
• Moderate-severe active: IV methylprednisolone pulses (500mg weekly × 6, then 250mg weekly × 6)
• Sight-threatening: emergency IV steroids; surgical decompression
• Teprotumumab (anti-IGF-1R): clinical trials show proptosis reduction
• All patients: stop smoking (strongest modifiable risk factor)

Pregnancy

• ATDs cross placenta; carbimazole teratogenic in first trimester → use PTU first trimester, then switch to carbimazole

Referral Criteria

• Endocrinology: all Graves disease
• Ophthalmology: orbitopathy (even mild)
• Surgery: if thyroidectomy indicated

~50% remission after 12-18 months ATDs (lower if: large goitre, high TRAb at cessation, T3-predominant, young age, male, smoker). Radioiodine: >90% cure; hypothyroidism in ~80% at 1 year. Surgery: >95% cure; hypothyroidism expected. Orbitopathy: ~90% mild/self-limiting; ~5% sight-threatening. Neonatal Graves (transient): resolves as maternal TRAb clears (weeks-months).

Graves Disease - Unique Features vs Other Thyrotoxicosis

Clinical Activity Score (CAS) for Graves Orbitopathy

Key Facts

Most thyroid nodules are benign. Systematic evaluation with USS grading and FNA cytology identifies the ~5% that are malignant. The BTA guidelines provide a clear pathway for investigation.

Epidemiology

Palpable nodules ~5% of population. USS-detected nodules ~50% (especially in women, elderly). ~5% of thyroid nodules are malignant.

Aetiology

Benign: colloid nodules (most common), follicular adenoma, cysts, Hashimoto nodule. Malignant: papillary (~80%), follicular (~10%), medullary (~5%), anaplastic (~2%), lymphoma.

Pathophysiology

Most nodules represent focal thyroid hyperplasia, colloid accumulation, or benign neoplasia. Malignant transformation involves genetic mutations: RET/PTC rearrangements (papillary), RAS mutations, BRAF V600E (papillary - associated with poorer prognosis), PAX8-PPARγ (follicular).

Presentation

• Often asymptomatic - found incidentally on imaging or examination
• Neck swelling (patient or clinician finds lump)
• Compressive symptoms (large goitre): dysphagia, dyspnoea, hoarseness (recurrent laryngeal nerve)

Features Suggesting Malignancy

• Hard, fixed, non-tender nodule
• Rapid growth
• Cervical lymphadenopathy
• Hoarseness (recurrent laryngeal nerve involvement)
• Family history of thyroid cancer or MEN2
• History of neck irradiation
• Age <20 or >60
• Male sex (higher proportion malignant)

Red Flags

• Rapidly enlarging nodule → anaplastic carcinoma or lymphoma
• Hoarseness + thyroid mass → malignancy involving RLN
• Compressive symptoms → urgent assessment

TFTs

• If TSH normal/raised → USS

Thyroid USS + BTA U-Classification

• U1: normal
• U2: benign (isoechoic, halo, spongiform cyst)
• U3: indeterminate/equivocal
• U4: suspicious (solid hypoechoic, lobulated)
• U5: malignant (solid hypoechoic, irregular margins, microcalcifications, taller-than-wide, nodal metastasis)
• FNA indicated: U3 (if >1 cm), U4, U5

Fine Needle Aspiration Cytology

• Thy classification (RCPath):
  • Thy1: non-diagnostic → repeat FNA
  • Thy2: benign → monitor
  • Thy3a: neoplasm possible → repeat FNA or surveillance
  • Thy3f: follicular neoplasm → diagnostic lobectomy (cannot distinguish adenoma from carcinoma on FNA)
  • Thy4: suspicious of malignancy → surgery
  • Thy5: malignant → surgery

Other

• Calcitonin: if medullary thyroid cancer suspected (MTC) or family history of MEN2
• Molecular testing: BRAF, RAS, RET/PTC - increasingly used for Thy3 nodules to guide management

Benign (Thy2, U2)

• Reassurance; follow-up USS at 3-6 months, then annually for 3-5 years
• Repeat FNA if growing

Indeterminate (Thy3)

• Thy3a: repeat FNA or surveillance USS
• Thy3f: diagnostic lobectomy (histological assessment needed to distinguish follicular adenoma from carcinoma)

Suspicious/Malignant (Thy4/5)

• Thyroidectomy: total thyroidectomy for confirmed malignancy (see thyroid cancer)
• MDT discussion: thyroid cancer MDT

Observation

• Small benign nodules: monitor with USS
• Growing benign nodule: repeat FNA or surgery

Referral Criteria

• 2WW (NICE NG12): unexplained thyroid lump in a child or adult (palpable thyroid nodule)
• Endocrine surgery: U3-5 or Thy3-5

~95% of thyroid nodules are benign. Benign nodules on FNA: <3% false-negative rate. Follicular neoplasm (Thy3f): ~20-30% are malignant on final histology. Most thyroid cancers (especially papillary) have excellent prognosis (>95% 10-year survival). Anaplastic thyroid cancer: very poor prognosis (median survival ~6 months).

BTA U-Classification and Action

Thy Classification and Management

Key Facts

Differentiated thyroid cancer (papillary and follicular) has an excellent prognosis with appropriate treatment. Medullary thyroid cancer requires specific management and genetic screening for MEN2. Anaplastic thyroid cancer is one of the most aggressive human malignancies.

Epidemiology

~3,500/year in UK. F:M 3:1. Peak age 30-50 (papillary), 40-60 (follicular), >60 (anaplastic). Incidence increasing (~5%/year - largely due to incidental detection by imaging).

Aetiology

Papillary: radiation exposure (childhood neck irradiation, nuclear accidents), iodine sufficiency. Follicular: iodine deficiency. Medullary: sporadic (75%) or familial MEN2 (25%). Anaplastic: may arise from de-differentiation of long-standing papillary/follicular cancer.

Pathophysiology

Differentiated (Papillary/Follicular)

• Thyroid nodule (often asymptomatic; found incidentally or on examination)
• Cervical lymphadenopathy (especially papillary)
• Hoarseness (RLN involvement - advanced)
• Dysphagia, dyspnoea (compression - late)
• Bone pain, pathological fracture (follicular - distant metastasis)

Medullary

• Thyroid nodule
• Diarrhoea (calcitonin effect - ~30%)
• Flushing
• Family history of MEN2 (phaeochromocytoma, hyperparathyroidism)

Anaplastic

• Rapidly enlarging hard thyroid mass in elderly
• Compressive symptoms: stridor, dysphagia, hoarseness
• Widely invasive at presentation

Red Flags

• Rapidly growing thyroid mass → anaplastic or lymphoma
• Hoarseness → RLN invasion
• Family history of MEN2 or thyroid cancer → genetic screening

Pre-Operative

• FNA cytology: Thy4/5 confirms suspected/confirmed malignancy
• USS neck: assess nodule and cervical lymph nodes
• Calcitonin: if medullary thyroid cancer suspected
• CEA: elevated in MTC
• Genetic testing: RET proto-oncogene if MTC (MEN2 screening)

Post-Operative

• Thyroglobulin (Tg): tumour marker for differentiated thyroid cancer (should be undetectable after total thyroidectomy + RAI)
• Anti-Tg antibodies: may interfere with Tg assay
• Whole-body radioiodine scan: post-ablation; identifies residual/metastatic disease
• Neck USS: surveillance for recurrence
• Calcitonin: monitoring for MTC recurrence

Differentiated (Papillary/Follicular)

1. Total thyroidectomy ± central compartment lymph node dissection
2. Radioactive iodine (¹³¹I) ablation: destroy residual thyroid tissue and micrometastases; given 4-6 weeks post-surgery
3. TSH suppression: levothyroxine at doses to suppress TSH (0.1-0.5 mU/L for high-risk; 0.5-2.0 for low-risk) - TSH stimulates differentiated thyroid cancer growth
4. Thyroglobulin monitoring: every 6-12 months; rising Tg suggests recurrence
5. Neck USS surveillance: annually for 5-10 years

Medullary

• Total thyroidectomy + central and bilateral lateral lymph node dissection
• NO role for radioiodine (C cells do not take up iodine)
• Calcitonin and CEA monitoring
• RET genetic testing: if positive → screen family for MEN2
• Phaeochromocytoma screening: MUST exclude before thyroid surgery in MEN2
• Targeted therapy (vandetanib, cabozantinib) for advanced disease

Anaplastic

• Very poor prognosis; often unresectable at diagnosis
• Palliative: external beam radiotherapy ± chemotherapy (doxorubicin)
• Tracheostomy may be needed for airway compromise
• Targeted therapy (dabrafenib + trametinib if BRAF V600E positive)

Referral Criteria

• Thyroid cancer MDT: all suspected/confirmed thyroid cancer
• Endocrine surgery: thyroidectomy
• Clinical genetics: MTC (RET testing, MEN2 screening)
• Nuclear medicine: radioiodine ablation

Papillary: 10-year survival >95%; excellent even with lymph node metastasis. Follicular: 10-year survival ~90%; worse if distant metastasis. Medullary: 10-year survival ~75%; worse if MEN2B variant. Anaplastic: median survival ~6 months; one of the most lethal cancers. Recurrence of differentiated thyroid cancer: ~10-30% at 10 years; most recurrences are treatable. Thyroglobulin is an excellent tumour marker for monitoring.

Thyroid Cancer Types Comparison

MEN2 Syndromes

Key Facts

Thyroiditis encompasses several inflammatory conditions with different aetiologies but a common pattern of transient thyroid hormone release. The uptake scan showing low uptake is key to distinguishing thyroiditis from other causes of thyrotoxicosis.

Epidemiology

Subacute thyroiditis: incidence ~5 per 100,000/year; F:M 3:1; peak age 30-50. Postpartum thyroiditis: ~5-10% of postpartum women. Hashimoto: commonest cause of hypothyroidism (covered separately).

Aetiology

Subacute: presumed viral (often post-URTI; coxsackievirus, adenovirus, mumps). HLA-B35 association. Postpartum/silent: autoimmune (anti-TPO positive). Drug-induced: amiodarone (type 2), checkpoint inhibitors, lithium.

Pathophysiology

Subacute (de Quervain) Thyroiditis

• Painful, tender, firm thyroid (often unilateral initially, migrating)
• Systemic: fever, malaise, myalgia
• Thyrotoxic phase (weeks 1-4): palpitations, weight loss, tremor
• Hypothyroid phase (weeks 4-12): fatigue, weight gain
• Recovery phase: euthyroid by 3-6 months (~95% recover fully)
• Preceded by viral URTI in 2-8 weeks

Postpartum Thyroiditis

• 1-6 months postpartum: transient thyrotoxicosis (often mild, may be missed)
• 3-12 months postpartum: hypothyroid phase (more symptomatic; fatigue, depression, weight gain)
• ~80% recover; ~20% develop permanent hypothyroidism
• Associated with anti-TPO antibodies

Red Flags

• Severe pain unresponsive to NSAIDs → consider acute suppurative thyroiditis (rare, bacterial)
• Thyrotoxicosis misdiagnosed as Graves → antithyroid drugs are ineffective and inappropriate

Bloods

• TFTs: thyrotoxic phase (suppressed TSH, raised T4/T3); hypothyroid phase (raised TSH, low T4)
• ESR/CRP: markedly raised in subacute thyroiditis (ESR often >50)
• Anti-TPO: positive in postpartum/silent thyroiditis; may be positive in subacute
• TRAb: negative (distinguishes from Graves)

Imaging

• Thyroid uptake scan: low/absent uptake in thyrotoxic phase - KEY diagnostic feature (vs diffuse high uptake in Graves)
• USS thyroid: diffuse hypoechogenicity; may show focal areas of inflammation

Subacute Thyroiditis

• Thyrotoxic phase: beta-blockers (propranolol 40-80mg TDS) for symptom control; NO antithyroid drugs
• Pain: NSAIDs (ibuprofen 400mg TDS, naproxen 500mg BD); if insufficient: prednisolone 30-40mg/day, taper over 4-8 weeks
• Hypothyroid phase: levothyroxine if symptomatic (temporary - reassess at 6-12 months)
• Recovery: most euthyroid by 3-6 months; ~5% develop permanent hypothyroidism

Postpartum Thyroiditis

• Thyrotoxic phase: beta-blockers if symptomatic; NO antithyroid drugs
• Hypothyroid phase: levothyroxine if symptomatic or planning pregnancy (may be temporary)
• Monitoring: TFTs every 4-8 weeks during active phases
• Long-term: annual TFTs (20% develop permanent hypothyroidism)

Referral Criteria

• Endocrinology: diagnostic uncertainty, severe thyroiditis, recurrent episodes

Subacute thyroiditis: self-limiting; ~95% recover full thyroid function by 6-12 months; ~5% permanent hypothyroidism; recurrence rare (~2%). Postpartum thyroiditis: ~80% recover; ~20% permanent hypothyroidism (higher if anti-TPO positive, higher titres). Postpartum thyroiditis recurs in ~70% of subsequent pregnancies.

Thyroiditis - Typical Triphasic Course

Thyroid Uptake Scan Patterns

Key Facts

Thyroid storm is a clinical diagnosis based on the Burch-Wartofsky scale. Multi-modal treatment must be started immediately. The order of drug administration matters - give ATD before iodine.

Epidemiology

Rare: <2% of thyrotoxic patients. More common in Graves disease. Mortality ~10-30% even with treatment (higher in elderly, delayed treatment).

Aetiology

Almost always occurs on a background of uncontrolled/poorly treated hyperthyroidism with an acute precipitant: infection, surgery, trauma, DKA, MI, iodinated contrast, radioiodine, drug withdrawal.

Pathophysiology

Cardinal Features

• Fever: high (>38.5°C, often >40°C); diaphoresis
• Cardiovascular: severe tachycardia (>140 bpm), AF, high-output heart failure, hypotension/shock
• CNS: agitation, delirium, psychosis, seizures, coma
• GI: nausea, vomiting, diarrhoea, abdominal pain, jaundice (hepatic dysfunction - ominous sign)

Burch-Wartofsky Point Scale

• Temperature, CNS effects, GI/hepatic, cardiovascular (HR, HF, AF) scored

• 45 points = highly suggestive of thyroid storm

Red Flags

• Multi-organ failure
• Jaundice/hepatic dysfunction (poor prognostic sign)
• Coma
• Cardiovascular collapse

Immediate

• TFTs: suppressed TSH, markedly elevated T4/T3 (but may not be dramatically different from uncomplicated thyrotoxicosis)
• FBC, U&Es, LFTs, coagulation, glucose, calcium
• Blood cultures, urine cultures, CXR: identify precipitant
• ECG: tachycardia, AF
• ABG: metabolic/respiratory alkalosis or mixed

Burch-Wartofsky Scoring

• Clinical scoring system to support diagnosis

Emergency Multi-Modal Treatment (Simultaneous)

1. Antithyroid drugs (block new hormone synthesis):

   • PTU 200mg QDS PO/NG preferred (also blocks peripheral T4→T3 conversion)
   • Alternative: carbimazole 20-40mg QDS PO/NG

2. Iodine (blocks thyroid hormone release - give ≥1 HOUR after ATD):

   • Lugol iodine 5-10 drops TDS PO/NG
   • Or potassium iodide 60mg TDS

3. Beta-blockers (rate control + T4→T3 block):

   • Propranolol 40-80mg QDS PO or 1-5mg IV slowly
   • Esmolol infusion if IV needed and cardiac monitoring available

4. Corticosteroids (reduces T4→T3 conversion, treats relative adrenal insufficiency):

   • IV hydrocortisone 100mg QDS or IV dexamethasone 2mg QDS

5. Supportive:

   • IV fluids, cooling measures (tepid sponging, fans; AVOID aspirin - displaces T4 from binding proteins)
   • Paracetamol for fever
   • Treat precipitant (antibiotics if infection)
   • Cardiac monitoring, ITU admission
   • Cholestyramine 4g QDS: may help by binding thyroid hormone in GI tract

Definitive Treatment

• Once stabilised: plan definitive treatment (radioiodine or thyroidectomy after euthyroid state achieved)

Referral Criteria

• ITU: all suspected thyroid storm
• Endocrinology: urgent consultation
• Surgery: if thyroidectomy needed as definitive treatment

Mortality ~10-30% even with treatment. Prompt recognition and multi-modal treatment improve survival. Poor prognostic factors: older age, coma, jaundice/hepatic failure, cardiovascular collapse, delayed treatment. With modern ICU care and aggressive treatment, outcomes are improving. Survivors require definitive treatment of underlying thyrotoxicosis.

Thyroid Storm Treatment - Order of Administration

Burch-Wartofsky Point Scale (Simplified)

Key Facts

Myxoedema coma is a medical emergency with very high mortality. Early recognition and treatment with IV thyroid hormones and hydrocortisone are essential. It almost always has a precipitant.

Epidemiology

Very rare. More common in elderly women, winter months, long-standing untreated hypothyroidism.

Aetiology

Severe untreated or undertreated hypothyroidism + acute precipitant. Precipitants: infection (UTI, pneumonia - commonest), cold exposure, sedatives/anaesthetics, MI, stroke, trauma, GI haemorrhage, non-adherence to levothyroxine.

Pathophysiology

Cardinal Features

• Hypothermia (<35°C, may be <30°C; standard thermometers may not register)

• Bradycardia and hypotension
• Hypoventilation: respiratory failure with CO₂ retention

Other Features

• Non-pitting oedema (face, hands - myxoedema)
• Dry, cool, pale skin
• Hyponatraemia (dilutional - impaired free water excretion)
• Hypoglycaemia
• Pleural/pericardial effusions
• Ileus, constipation, urinary retention

Red Flags

• Hypothermia + altered consciousness in patient with known hypothyroidism or thyroidectomy scar → myxoedema coma
• Respiratory failure → may need mechanical ventilation
• Cardiovascular collapse

Immediate

• TFTs: very high TSH, very low T4 (primary); or low TSH + low T4 (secondary/central)
• U&Es: hyponatraemia (common and significant)
• Blood glucose: hypoglycaemia
• ABG: hypoxia, hypercapnia (CO₂ retention), respiratory acidosis
• Cortisol: assess for coexistent adrenal insufficiency (before steroid administration)
• FBC, CRP, blood cultures: infection screen
• CXR: pleural effusion, pneumonia
• ECG: bradycardia, low voltage, prolonged QT
• Core temperature (low-reading thermometer)

Emergency Treatment (ITU)

1. IV hydrocortisone 100mg STAT (give BEFORE levothyroxine - prevents adrenal crisis); then 50-100mg TDS until adrenal function clarified
2. IV levothyroxine: loading dose 300-500μg IV slowly, then 50-100μg IV daily
3. IV liothyronine (T3): 10-20μg IV then 10μg TDS; consider in severe/refractory cases (more rapid onset than T4)
4. Supportive:
   • Passive rewarming ONLY (warm blankets, warm room); AVOID active rewarming (causes vasodilatation → cardiovascular collapse)
   • IV fluids (cautious - fluid overload risk; correct hyponatraemia with fluid restriction if mild; hypertonic saline if severe/symptomatic)
   • Glucose replacement if hypoglycaemic
   • Mechanical ventilation if respiratory failure
   • Vasopressors if persistent hypotension (noradrenaline)
5. Treat precipitant: antibiotics if infection suspected (even without fever - hypothermia masks pyrexia)

Referral Criteria

• All myxoedema coma: ITU admission
• Endocrinology: urgent consultation

Mortality ~25-60% (higher in elderly, delayed treatment, severe hypothermia, cardiovascular collapse, sepsis). Factors predicting poor outcome: severe hypothermia (<32°C), GCS <8, advanced age, APACHE II score, sepsis. Early recognition and treatment significantly improve survival. Survivors require long-term levothyroxine with adherence support.

Myxoedema Coma - Treatment Priorities

Why Hydrocortisone BEFORE Levothyroxine?

• Thyroid hormone replacement increases cortisol metabolism
• If patient has coexistent adrenal insufficiency (common in polyglandular autoimmune syndrome or central hypothyroidism), giving thyroxine alone may precipitate adrenal crisis
• Always assume adrenal insufficiency until proven otherwise

Key Facts

Cushing syndrome has multiple causes requiring systematic biochemical confirmation and localisation. Untreated cortisol excess significantly increases cardiovascular risk and mortality. Transsphenoidal surgery is first-line for Cushing disease.

Epidemiology

Endogenous Cushing syndrome: incidence ~2-3 per million/year. Cushing disease: F:M 3:1. Ectopic ACTH: M > F (SCLC, carcinoid). Iatrogenic Cushing: very common with chronic steroid use.

Aetiology

ACTH-dependent (80%): Cushing disease (pituitary adenoma - 70%), ectopic ACTH secretion (SCLC, bronchial carcinoid, thymic carcinoid, phaeochromocytoma - 15%). ACTH-independent (20%): adrenal adenoma (~10%), adrenal carcinoma (~5%), bilateral adrenal hyperplasia (BMAH, PPNAD), exogenous steroids.

Pathophysiology

Chronic cortisol excess affects virtually every organ system: metabolic syndrome (insulin resistance, central adiposity, dyslipidaemia), protein catabolism (proximal myopathy, skin thinning, striae, osteoporosis), immune suppression, psychiatric effects (depression, psychosis), mineralocorticoid effects (hypertension, hypokalaemia in ectopic ACTH).

Classic Features

• Central (truncal) obesity: redistribution of fat to trunk, face (moon face), dorsocervical (buffalo hump), supraclavicular fat pads
• Purple striae: >1 cm wide; abdomen, thighs, breasts (NOT simple stretch marks)
• Proximal myopathy: difficulty rising from chair, climbing stairs
• Easy bruising: thin fragile skin
• Facial plethora: reddened round face
• Hirsutism, acne: androgen excess (adrenal)

Metabolic

• Hypertension (~80%), diabetes/impaired glucose tolerance (~50%), dyslipidaemia
• Osteoporosis, pathological fractures (vertebral)

Psychiatric

• Depression (~50-70%), anxiety, insomnia, irritability, psychosis (~10%)
• Cognitive impairment

Other

• Menstrual irregularity, reduced libido, erectile dysfunction
• Recurrent infections (immunosuppression)
• Poor wound healing

Features Suggesting Ectopic ACTH

• Hypokalaemia (prominent mineralocorticoid effect)
• Rapid onset
• Hyperpigmentation (very high ACTH)
• Weight loss (underlying malignancy)

Red Flags

• Severe hypokalaemia + rapid-onset Cushing features → ectopic ACTH (SCLC)
• Adrenal mass + virilisation → adrenal carcinoma
• Children: growth arrest + weight gain → consider Cushing

Step 1: Confirm Cortisol Excess (≥2 Abnormal Tests)

• 24-hour urinary free cortisol (UFC): ×2 (raised - >3× ULN highly suggestive)
• Overnight dexamethasone suppression test (ONDST): 1mg dexamethasone at 11pm → 9am cortisol; failure to suppress (<50 nmol/L) = positive
• Late-night salivary cortisol: ×2 (elevated - loss of normal diurnal variation)

Step 2: Determine ACTH Dependence

Step 3: Localise Source

ACTH-dependent:

• Pituitary MRI: microadenoma visible in ~60% of Cushing disease
• High-dose dexamethasone suppression test: 2mg QDS × 48 hours; cortisol suppression >50% suggests pituitary (not ectopic)
• CRH test: ACTH/cortisol rise suggests pituitary origin
• Inferior petrosal sinus sampling (IPSS): gold standard to distinguish pituitary from ectopic; central:peripheral ACTH ratio >2:1 (>3:1 after CRH) = pituitary

ACTH-independent:

• Adrenal CT/MRI: adenoma, carcinoma, bilateral hyperplasia

Other

• U&Es (hypokalaemia), glucose/HbA1c, lipids, DEXA (osteoporosis)
• If ectopic suspected: CT chest/abdomen (SCLC, carcinoid), octreotide scan

Exogenous Cushing

• Taper corticosteroids gradually (do NOT stop abruptly - adrenal crisis risk)
• Use steroid-sparing agents where possible

Cushing Disease (Pituitary)

• First-line: transsphenoidal pituitary surgery (TSS); cure rate ~65-90% for microadenomas
• Second-line: repeat surgery, pituitary radiotherapy (conventional or stereotactic)
• Medical: metyrapone 250mg-6g/day (11β-hydroxylase inhibitor), ketoconazole 200-1200mg/day (steroidogenesis inhibitor), osilodrostat (11β-hydroxylase inhibitor - NICE), pasireotide (somatostatin analogue - reduces ACTH)
• Bilateral adrenalectomy: last resort; cures hypercortisolism but requires lifelong replacement; risk of Nelson syndrome (pituitary tumour growth → hyperpigmentation)

Adrenal Tumour

• Adrenalectomy: laparoscopic for adenoma; open for carcinoma
• Adrenal carcinoma: mitotane ± chemotherapy (EDP-mitotane)

Ectopic ACTH

• Treat underlying tumour (surgery, chemotherapy)
• Medical cortisol control: metyrapone, ketoconazole
• Bilateral adrenalectomy if source not resectable

Perioperative

• Hydrocortisone replacement post-operatively (adrenal suppression from chronic cortisol excess; may take 6-18 months for HPA axis recovery)
• DEXA scan and treat osteoporosis
• Cardiovascular risk factor management

Referral Criteria

• Endocrinology: all suspected Cushing syndrome
• Neurosurgery: Cushing disease
• Endocrine/adrenal surgery: adrenal tumours
• Oncology: ectopic ACTH

Untreated Cushing syndrome: significantly increased mortality (cardiovascular, infection). 5-year mortality ~50% without treatment. With successful treatment: mortality normalises over years but cardiovascular risk remains elevated. Cushing disease: ~65-90% cure after first TSS; ~25% recurrence at 10 years. Adrenal adenoma: excellent prognosis after adrenalectomy. Adrenal carcinoma: poor prognosis (5-year survival ~35-50%). Ectopic ACTH: depends on underlying tumour.

Cushing Syndrome - Diagnostic Algorithm

Cushing Syndrome vs Cushing Disease

Key Facts

Addison disease is rare but potentially fatal if undiagnosed. Hyperpigmentation is the distinguishing feature from secondary adrenal insufficiency. All patients need sick-day rules education and emergency hydrocortisone.

Epidemiology

Prevalence ~100-140 per million. F:M 2:1. Peak diagnosis age 30-50 years.

Aetiology

UK: autoimmune (~80%), TB (~10-15%), other (metastases, haemorrhage, infiltrative, drugs). Autoimmune polyendocrine syndrome type 1 (APS-1): Addison + chronic mucocutaneous candidiasis + hypoparathyroidism (AIRE gene mutation). APS-2 (more common): Addison + autoimmune thyroid disease ± T1DM.

Pathophysiology

Symptoms

• Fatigue, weakness (universal)
• Weight loss, anorexia
• Nausea, vomiting, abdominal pain
• Dizziness, postural hypotension
• Salt craving (aldosterone deficiency)
• Myalgia, arthralgia
• Depression

Signs

• Hyperpigmentation: palmar creases, buccal mucosa, scars, nipples, skin folds, sun-exposed areas (ACTH excess - NOT present in secondary adrenal insufficiency)
• Postural hypotension (systolic drop >20 mmHg)
• Weight loss
• Vitiligo (associated autoimmune condition)

Biochemical Features

• Hyponatraemia (~90%), hyperkalaemia (~65%), hypoglycaemia
• Mildly raised urea (dehydration), raised calcium (sometimes)
• Eosinophilia, lymphocytosis

Red Flags

• Acute collapse with hypotension, hyponatraemia, hyperkalaemia → adrenal crisis (see separate topic)
• Unexplained hyperpigmentation with fatigue and weight loss → urgent Synacthen test

Definitive

• Short Synacthen test: IM/IV Synacthen 250μg; measure cortisol at 0 and 30 minutes; peak cortisol <450 nmol/L = adrenal insufficiency; baseline cortisol <100 nmol/L highly suggestive
• 9am cortisol: screening; <100 nmol/L = likely insufficient; >450 nmol/L = likely sufficient; intermediate → SST needed

Confirm Primary vs Secondary

• ACTH level: HIGH in Addison (primary); LOW/normal in secondary
• Renin and aldosterone: renin HIGH, aldosterone LOW in Addison (not affected in secondary)

Aetiology

• Adrenal antibodies (21-hydroxylase antibodies): positive in ~90% of autoimmune Addison

• Very long chain fatty acids (VLCFA): young men → adrenoleukodystrophy

Associated Conditions

• TFTs (autoimmune thyroid), HbA1c (T1DM), B12 (pernicious anaemia), coeliac screen

Glucocorticoid Replacement

• Hydrocortisone 15-25 mg/day in divided doses: e.g., 10mg on waking, 5mg midday, 5mg late afternoon (mimics circadian rhythm)
• Alternatively: prednisolone 3-5 mg/day in 1-2 doses
• Monitor: clinical wellbeing, weight, BP; avoid over-replacement (Cushingoid features, osteoporosis)

Mineralocorticoid Replacement

• Fludrocortisone 50-200μg OD
• Monitor: postural BP, electrolytes, renin (aim for high-normal renin)

DHEA (Optional)

• DHEA 25-50mg OD: consider in women with persistent low mood/fatigue despite adequate cortisol replacement

Sick-Day Rules (Essential)

• Minor illness (cold, fever): DOUBLE hydrocortisone dose
• Vomiting/unable to take oral: IM hydrocortisone 100mg
• Major surgery/trauma: IV hydrocortisone 100mg QDS
• Carry steroid emergency card, MedicAlert bracelet, emergency IM hydrocortisone injection kit

Patient Education

• Never stop steroids abruptly
• Inform all healthcare providers (dentist, surgeon, anaesthetist)
• Annual flu vaccination

Referral Criteria

• Endocrinology: all patients with new Addison disease
• Screen for associated autoimmune conditions

With adequate replacement therapy, life expectancy approaches normal. Mortality risk ~2× population rate (mainly from adrenal crisis, cardiovascular disease, infection). Adrenal crisis: mortality ~0.5 per 100 patient-years. Risk factors for poor outcomes: inadequate replacement, delayed diagnosis, poor sick-day rule adherence. Quality of life often impaired despite adequate biochemical replacement.

Primary vs Secondary Adrenal Insufficiency

Autoimmune Polyendocrine Syndromes

Key Facts

Adrenal crisis is a medical emergency requiring immediate hydrocortisone. The most common scenario is a patient with known adrenal insufficiency who becomes unwell and does not increase their steroid dose. Prevention through sick-day rule education is critical.

Epidemiology

~5-10 episodes per 100 patient-years in patients with known adrenal insufficiency. Mortality per crisis ~6%. Higher risk: primary adrenal insufficiency (Addison), concomitant diabetes, elderly.

Aetiology

Acute cortisol deficiency in the context of physiological stress. Causes: non-adherence to sick-day rules (commonest), abrupt corticosteroid withdrawal after prolonged use (>3 weeks of prednisolone ≥7.5mg/day), bilateral adrenal haemorrhage/infarction, pituitary apoplexy, first presentation of undiagnosed Addison disease.

Pathophysiology

Symptoms

• Severe weakness, fatigue
• Nausea, vomiting, abdominal pain (may mimic acute abdomen)
• Confusion, drowsiness → coma
• Muscle cramps

Signs

• Profound hypotension/shock: refractory to IV fluids and vasopressors without steroids
• Tachycardia
• Dehydration
• Hypothermia (or fever if infection precipitant)
• Hyperpigmentation (if chronic Addison)

Biochemistry

• Hyponatraemia, hyperkalaemia (primary AI)
• Hypoglycaemia
• Raised urea (dehydration)
• Hypercalcaemia (sometimes)

Red Flags

• Hypotension not responding to fluids/vasopressors → ALWAYS consider adrenal crisis
• Patient wearing MedicAlert bracelet with reduced consciousness
• Collapse in patient on long-term steroids who has recently stopped

Immediate (Before Giving Steroids if Possible)

• Random cortisol: <100 nmol/L during acute illness virtually diagnostic; <250 nmol/L highly suggestive
• ACTH: high = primary; low = secondary (send simultaneously)
• U&Es: Na⁺, K⁺, renal function
• Blood glucose
• Blood gas: metabolic acidosis
• FBC, CRP, blood cultures, lactate: identify infection
• ECG: hyperkalaemia changes

Do NOT delay treatment for investigation results

Emergency Treatment

1. IV/IM hydrocortisone 100mg STAT (IM if no IV access - ambulance crews can give this)
2. IV 0.9% NaCl: rapid fluid resuscitation (1L stat then guided by response)
3. Continuous IV hydrocortisone: 50mg QDS IV or 200mg/24h continuous infusion
4. IV dextrose if hypoglycaemic
5. Treat precipitant: antibiotics if infection; DO NOT wait for culture results
6. Monitor: continuous cardiac monitoring (hyperkalaemia risk), hourly BP, glucose, fluid balance

Subsequent Management

• Once stable and eating: convert to oral hydrocortisone (double usual dose initially, then taper to maintenance over 2-3 days)
• Add fludrocortisone when IV hydrocortisone dose <50mg/day (high-dose hydrocortisone has sufficient mineralocorticoid activity)
• Investigate cause if new presentation

Prevention (Critical)

• Sick-day rules education: double dose for illness; IM injection if vomiting
• Steroid emergency card + MedicAlert
• Emergency IM hydrocortisone kit: train patient and family
• Gradual steroid withdrawal: in patients on long-term exogenous steroids (>3 weeks at ≥7.5mg prednisolone)

With prompt treatment, recovery from adrenal crisis is usually rapid (hours to days). Mortality ~6% per crisis episode. Recurrence common: ~50% of patients with adrenal insufficiency experience at least one crisis. Most crises are preventable with adequate sick-day rule education and emergency preparedness. Delayed treatment significantly worsens outcome.

Adrenal Crisis - Key Steps

Steroid Withdrawal Risk

Key Facts

Phaeochromocytoma is rare but potentially fatal if undiagnosed. The key clinical challenge is diagnosis - consider in any patient with episodic symptoms or resistant hypertension. Alpha-blockade before surgery is mandatory to prevent life-threatening perioperative complications.

Epidemiology

Incidence ~2-8 per million/year. Peak age 30-50 years. ~0.2-0.6% of hypertensive patients. ~5% of incidentally discovered adrenal masses.

Aetiology

~60-70% sporadic. ~30-40% hereditary: MEN2A/2B (RET mutation), Von Hippel-Lindau (VHL mutation), SDH mutations (SDHA/B/C/D - paraganglioma syndromes), NF1. All patients with phaeochromocytoma should have genetic testing.

Pathophysiology

Excessive catecholamine secretion (noradrenaline predominantly in adrenal; noradrenaline in extra-adrenal paraganglioma) → episodic or sustained hypertension, tachycardia, vasoconstriction. Catecholamines metabolised to metanephrines (normetanephrine, metanephrine) - these are more stable and better for biochemical diagnosis.

Classic Triad (Episodic - Minutes to Hours)

• Headache (severe, pounding)
• Sweating (profuse diaphoresis)
• Palpitations (tachycardia)
• ± Anxiety, tremor, pallor (NOT flushing)

Hypertension

• Paroxysmal (~50%): dramatic BP spikes (>200/120 mmHg) with intervening normotension
• Sustained (~50%): with or without paroxysms
• Resistant hypertension: uncontrolled despite ≥3 antihypertensives

Other

• Weight loss
• Hyperglycaemia (catecholamine-mediated glycogenolysis)
• Postural hypotension (paradoxical - chronic vasoconstriction → reduced plasma volume)
• Cardiomyopathy (catecholamine-induced - Takotsubo-like)

Red Flags

• Hypertensive crisis triggered by anaesthesia, surgery, drugs (beta-blockers without alpha-cover, metoclopramide, TCAs)
• Adrenal incidentaloma → always check metanephrines
• Family history of MEN2, VHL, SDH mutations

Biochemical

• Plasma free metanephrines: most sensitive test (~97%); normetanephrine and metanephrine; sample after 30 minutes supine rest
• 24-hour urine metanephrines and catecholamines: alternative; high specificity
• Chromogranin A: elevated (non-specific)

Imaging (After Biochemical Confirmation)

• CT/MRI adrenals: localise tumour; typically >3 cm, high signal on T2 MRI, enhancing
• ¹²³I-MIBG scintigraphy: functional imaging; confirms catecholamine-producing tumour; detects extra-adrenal/metastatic disease
• ⁶⁸Ga-DOTATATE PET/CT: superior for SDH-related paragangliomas and metastatic disease
• ¹⁸F-FDG PET/CT: for suspected metastatic disease

Genetic Testing

• All patients: screen for RET (MEN2), VHL, SDHB/C/D, NF1
• SDHB mutations: highest malignancy risk (~30-70%)

Other

• Blood glucose (hyperglycaemia), calcium/PTH (MEN2A → hyperparathyroidism)
• If MEN2: calcitonin (medullary thyroid cancer)

Pre-Operative Preparation (Essential)

1. Alpha-blockade first: phenoxybenzamine 10mg BD (titrate to 1-2mg/kg/day; target BP <130/80 seated, >90 mmHg standing) or doxazosin 2-16mg/day; start ≥10-14 days before surgery
2. Liberal salt and fluid intake: expand plasma volume (counteract chronic vasoconstriction-induced hypovolaemia)
3. Beta-blocker ONLY after adequate alpha-blockade (usually 2-3 days pre-op): propranolol 20-40mg TDS or atenolol - for tachycardia control

Surgery

• Laparoscopic adrenalectomy: curative for benign localised disease (>90%)
• Perioperative: close BP monitoring; IV phentolamine for hypertensive crisis; volume replacement for post-resection hypotension

Post-Operative

• Monitor for hypotension (loss of catecholamine drive) and hypoglycaemia
• Check metanephrines at 2-4 weeks → should normalise
• Annual biochemical surveillance lifelong (10% recurrence)

Malignant/Metastatic

• ¹³¹I-MIBG therapy (therapeutic radioiodine)
• Chemotherapy: cyclophosphamide/vincristine/dacarbazine (CVD)
• Targeted therapies: sunitinib

Referral Criteria

• Endocrinology/endocrine surgery: all confirmed phaeochromocytoma
• Clinical genetics: all patients (genetic testing)
• Oncology: metastatic disease

Benign phaeochromocytoma: >90% cure rate with surgery. 5-year survival after surgery ~95%. Malignant phaeochromocytoma (~10-15%): 5-year survival ~50%. SDHB mutations: highest malignancy risk. Annual surveillance essential - recurrence rate ~10%. Untreated: risk of hypertensive crisis, stroke, MI, death. Paraganglioma: higher malignancy rate than adrenal phaeochromocytoma.

Hereditary Phaeochromocytoma Syndromes

Alpha-Blockade Protocol

Key Facts

Primary hyperaldosteronism is underdiagnosed. It should be screened for in all patients with resistant hypertension, hypokalaemia, or adrenal incidentaloma. The distinction between unilateral and bilateral disease is critical as it determines surgical vs medical management.

Epidemiology

~5-10% of hypertensive patients. Previously thought rare - now recognised as common due to improved screening. F:M 2:1 for adenoma.

Aetiology

Bilateral adrenal hyperplasia (~60%), aldosterone-producing adenoma (~35%), unilateral adrenal hyperplasia (~2%), adrenal carcinoma (<1%), familial hyperaldosteronism (type I - glucocorticoid-remediable).

Pathophysiology

Hypertension

• Often severe or resistant (uncontrolled on ≥3 drugs including a diuretic)
• Young onset hypertension (<40 years)

Hypokalaemia (Only ~30%)

• Muscle weakness, cramps
• Polyuria, polydipsia (nephrogenic DI from hypokalaemia)
• Cardiac arrhythmias (severe)

Metabolic

• Metabolic alkalosis
• Mild hypernatraemia

Other

• Fatigue
• Headache
• Glucose intolerance

Red Flags

• Severe hypokalaemia (<3.0 mmol/L) with hypertension → strong suspicion
• Resistant hypertension in young patient
• Adrenal incidentaloma + hypertension → always screen

Screening

• Aldosterone:Renin Ratio (ARR): raised aldosterone with suppressed renin
• Standardised conditions: morning sample, seated for 15 minutes; ideally stop interfering drugs (spironolactone ≥6 weeks, ACEi/ARB ≥2 weeks); use non-interfering antihypertensives (verapamil, doxazosin)
• Raised ARR in the context of hypokalaemia is very suggestive

Confirmatory

• Saline infusion test: IV 2L 0.9% NaCl over 4 hours; post-infusion aldosterone >240 pmol/L = failure to suppress = confirmed PA
• Alternative: oral sodium loading test, fludrocortisone suppression test

Subtype Differentiation

• CT adrenals: adenoma vs bilateral hyperplasia (NB: CT can be misleading - non-functioning adenomas are common)
• Adrenal venous sampling (AVS): gold standard for lateralisation; aldosterone lateralisation ratio >4:1 = unilateral disease

Other

• U&Es (K⁺), VBG (metabolic alkalosis)
• Genetic testing: if age <20 or family history (glucocorticoid-remediable aldosteronism)

Unilateral Disease (Adenoma/Unilateral Hyperplasia)

• Laparoscopic adrenalectomy: curative for BP in ~50%; cures hypokalaemia in >95%
• Pre-operative: correct hypokalaemia; spironolactone 4-6 weeks pre-op

Bilateral Disease (Bilateral Hyperplasia)

• Spironolactone 25-100 mg OD: first-line; MRA; reduces BP and corrects K⁺
• Side effects: gynaecomastia, breast tenderness, menstrual irregularity (anti-androgen effects)
• Eplerenone 50-100 mg BD: selective MRA; fewer anti-androgen side effects; alternative if spironolactone not tolerated
• Add other antihypertensives as needed (amiloride 10-20mg/day as alternative K⁺-sparing)

Monitoring

• BP, U&Es regularly
• Annual renal function, potassium

Referral Criteria

• Endocrinology: all confirmed/suspected PA
• Interventional radiology: AVS
• Endocrine surgery: unilateral disease

Unilateral adenoma: adrenalectomy cures hypokalaemia in >95% and hypertension in ~50% (remainder have improved BP control on fewer medications). Bilateral hyperplasia: good BP and K⁺ control with spironolactone; lifelong treatment needed. Primary hyperaldosteronism confers additional cardiovascular risk beyond that expected from BP alone (aldosterone-mediated cardiac/vascular fibrosis). Treatment reduces this excess risk.

Causes of Secondary Hypertension - Screening Indications for PA

Spironolactone vs Eplerenone

Key Facts

CAH is the commonest cause of ambiguous genitalia in 46,XX neonates and the commonest adrenal cause of virilisation. The key management challenge is balancing adequate cortisol replacement to suppress androgen excess without causing growth retardation from glucocorticoid excess.

Epidemiology

Classic CAH: ~1 in 15,000. Non-classic: ~1 in 200-1,000 (commoner in certain ethnic groups - Ashkenazi Jewish, Hispanic, Italian). Carrier frequency ~1 in 60.

Aetiology

Pathophysiology

Classic Salt-Wasting (~75% of Classic CAH)

• 46,XX neonates: ambiguous genitalia (clitoromegaly, labial fusion, urogenital sinus) - most common presentation
• 46,XY neonates: normal genitalia; may present with salt-wasting crisis at 1-3 weeks (vomiting, dehydration, shock, hyperkalaemia, hyponatraemia)
• Salt-wasting crisis: medical emergency

Classic Simple Virilising

• 46,XX: ambiguous genitalia at birth (milder than salt-wasting) or progressive virilisation
• 46,XY: premature adrenarche, accelerated growth, advanced bone age; short adult height
• Both sexes: precocious puberty (peripheral)

Non-Classic (Late-Onset)

• Presents in adolescence/adulthood (especially females)
• Hirsutism, acne, menstrual irregularity, subfertility
• Often misdiagnosed as PCOS
• Males may be asymptomatic

Red Flags

• Ambiguous genitalia in neonate → urgent endocrinology (karyotype, 17-OHP)
• Neonatal collapse with hyperkalaemia/hyponatraemia → salt-wasting crisis

Biochemical

• 17-hydroxyprogesterone (17-OHP): markedly elevated in classic CAH (>300 nmol/L neonatal; >30 nmol/L in non-classic); mildly elevated in non-classic (may need ACTH stimulation test)
• ACTH stimulation test: 250μg Synacthen; measure 17-OHP at 0 and 60 minutes; exaggerated 17-OHP rise confirms CAH
• Serum cortisol: low or inappropriately normal
• Electrolytes: hyponatraemia, hyperkalaemia (salt-wasters)
• Renin: elevated (salt-wasters)
• Androgens: elevated androstenedione, testosterone

Genetics

• CYP21A2 gene sequencing: confirms diagnosis, genotype-phenotype correlation, carrier testing, prenatal diagnosis

Imaging

• Pelvic USS: in neonates with ambiguous genitalia (uterus present?)
• Bone age X-ray: advanced in virilising forms
• Adrenal CT/MRI: not routine (may show bilateral hyperplasia)

Glucocorticoid Replacement

• Children: hydrocortisone 10-15 mg/m²/day in 3 divided doses (lowest effective dose to suppress androgens while allowing normal growth)
• Adults: hydrocortisone 15-25 mg/day or prednisolone 2.5-5 mg/day or dexamethasone 0.25-0.5 mg ON (dexamethasone most potent at suppressing ACTH/androgens but higher SE risk)

Mineralocorticoid (Salt-Wasters)

• Fludrocortisone 50-200 μg OD
• Sodium chloride supplementation in infancy

Sick-Day Rules

• Double/triple hydrocortisone dose during illness
• IM hydrocortisone if vomiting
• Steroid emergency card + MedicAlert

Monitoring

• 17-OHP, androstenedione, testosterone (target: normal range - not over-suppressed)
• Growth velocity, bone age (annually in children)
• Avoid over-treatment (Cushingoid features, growth suppression) and under-treatment (androgen excess, advanced bone age, virilisation)

Surgical

• Feminising genitoplasty for severely virilised 46,XX: timing controversial; MDT decision with family

Non-Classic CAH

• May not need glucocorticoids if asymptomatic
• Hydrocortisone or low-dose dexamethasone if symptomatic (hirsutism, subfertility)
• OCP for menstrual regulation and anti-androgen effect

Referral Criteria

• Paediatric endocrinology: all neonatal/childhood cases
• Adult endocrinology: transition, non-classic CAH
• DSD MDT: ambiguous genitalia

With appropriate treatment, most patients with classic CAH lead normal lives. Final adult height: often reduced by 1-2 SD despite treatment (advanced bone age, glucocorticoid effects). Fertility: reduced in classic CAH women (~60-80% pregnancy rate with good management); men generally fertile. Non-classic CAH: excellent prognosis; subfertility treatable. Testicular adrenal rest tumours: may develop in undertreated males (ACTH-driven - respond to increased glucocorticoid dose).

CAH Subtypes

Classic vs Non-Classic CAH

Key Facts

Acromegaly is insidious - average delay from symptom onset to diagnosis is ~7-10 years. Early diagnosis and normalisation of GH/IGF-1 are essential to prevent irreversible complications. Comparing old photographs is a useful diagnostic clue.

Epidemiology

Prevalence ~60-70 per million. Incidence ~3-4 per million/year. Mean age at diagnosis ~40-50 years. Equal sex distribution.

Aetiology

GH-secreting pituitary adenoma (>95%): sporadic mostly; ~5% familial (MEN1, familial isolated pituitary adenoma - AIP mutations, Carney complex). Ectopic GHRH (<5%): bronchial/pancreatic carcinoid.

Pathophysiology

Slow-Onset Features (Compare Old Photos)

• Hands: spade-like, increased ring/glove size, doughy palms
• Feet: increased shoe size
• Face: prognathism (jaw protrusion), frontal bossing, increased interdental spacing, macroglossia, coarsened features, thickened skin
• Sweating (excess), oily skin
• Headache
• Deepened voice (vocal cord thickening)
• Arthralgia (large joint osteoarthropathy)

Complications

• Cardiovascular: LVH, cardiomyopathy, hypertension (~40%), heart failure
• Metabolic: diabetes mellitus (~25%), impaired glucose tolerance (~40%)
• Respiratory: obstructive sleep apnoea (~50%)
• Colonic: polyps → increased colorectal cancer risk (colonoscopy at diagnosis, then 3-5 yearly)
• Musculoskeletal: arthropathy, carpal tunnel syndrome, spinal stenosis
• Visual: bitemporal hemianopia (macroadenoma)
• Hypopituitarism: from tumour compression

Red Flags

• Visual field defect → urgent pituitary MRI
• Heart failure in young patient → consider acromegaly
• Pituitary apoplexy: sudden headache, visual loss, meningism

Screening

• Serum IGF-1: elevated (age and sex-adjusted); correlates with GH secretion; single best screening test

Confirmatory

• Oral glucose tolerance test (OGTT) with GH: 75g glucose load; GH measured at 0, 30, 60, 90, 120 minutes; GH fails to suppress below 1 μg/L (or <0.4 μg/L with newer assays) = diagnostic

Imaging

• Pituitary MRI (gadolinium-enhanced): localise/size adenoma; assess chiasmal compression

Complications Assessment

• Visual fields: formal perimetry
• Echocardiogram: LVH, cardiomyopathy
• Sleep study: OSA
• Colonoscopy: polyps/CRC screening
• HbA1c, OGTT: diabetes
• Pituitary function tests: full anterior pituitary hormones (LH/FSH, testosterone/oestradiol, TSH/T4, cortisol, prolactin)
• Calcium/PTH: if MEN1 suspected

First-Line: Transsphenoidal Surgery

• Transsphenoidal pituitary adenomectomy: cure rate ~60-80% (microadenoma), ~40-60% (macroadenoma)
• Post-operative: check GH/IGF-1 at 6-12 weeks; OGTT for biochemical remission

Medical Therapy

Somatostatin analogues (first-line medical):

• Octreotide LAR 20-30mg IM monthly; lanreotide 60-120mg SC monthly
• Normalise IGF-1 in ~50-60%; reduce tumour size in ~30-50%
• Side effects: GI (diarrhoea, steatorrhoea), gallstones (~20%), glucose intolerance

GH receptor antagonist:

• Pegvisomant 10-30mg SC daily: normalises IGF-1 in ~90%; does not reduce tumour size; monitor LFTs

Dopamine agonist:

• Cabergoline 0.5-3mg/week: effective in ~10-20% (mainly if co-secretion of prolactin)

Radiotherapy

• Stereotactic radiosurgery or fractionated RT: for residual/recurrent disease after surgery
• Slow onset of effect (years); risk of hypopituitarism (~50% at 10 years)

Monitoring

• GH and IGF-1: 3-6 monthly until stable, then annually
• Pituitary MRI: annually until stable
• Complication screening: ongoing

Referral Criteria

• Endocrinology: all suspected/confirmed acromegaly
• Neurosurgery: transsphenoidal surgery
• Ophthalmology: visual field assessment

Untreated: 2-3× increased mortality (cardiovascular disease is leading cause). If GH and IGF-1 normalised: mortality approaches normal population. Biochemical remission with surgery: ~60-80% microadenoma, ~40-60% macroadenoma. Many complications are reversible with treatment (soft tissue changes, diabetes, OSA, cardiac function). Skeletal changes and arthropathy are often irreversible. Average 7-10 year diagnostic delay.

Acromegaly Complications Screening

Treatment Algorithm

Key Facts

Prolactinomas are uniquely among pituitary adenomas managed medically first-line. Dopamine agonists are highly effective at both normalising prolactin and reducing tumour size. Surgery is rarely needed.

Epidemiology

Prevalence ~50 per 100,000. Commonest pituitary tumour (~40%). F:M for microprolactinoma ~20:1; macroprolactinoma ~1:1. Peak diagnosis age 20-50.

Aetiology

Sporadic (vast majority). Familial: MEN1 (pituitary adenoma + parathyroid + pancreatic tumour). AIP mutations (familial isolated pituitary adenoma). Lactotroph-specific: somatic mutations in transcription factors.

Pathophysiology

Women (Usually Microprolactinoma)

• Galactorrhoea (~80%)
• Amenorrhoea/oligomenorrhoea (~90%)
• Infertility (anovulation)
• Reduced libido
• Vaginal dryness

Men (Often Macroprolactinoma - Later Diagnosis)

• Reduced libido, erectile dysfunction
• Infertility (low sperm count)
• Galactorrhoea (uncommon in men - ~20%)
• Gynaecomastia
• Mass effects (macroprolactinoma): headache, bitemporal hemianopia, cranial nerve palsies
• Hypopituitarism (compression of normal pituitary)

Red Flags

• Visual field defect → urgent MRI and visual fields
• Pituitary apoplexy: sudden severe headache, visual loss, meningism, hypopituitarism
• Giant prolactinoma (>4cm, PRL >10,000): more aggressive, may invade cavernous sinus

Biochemical

• Serum prolactin: microprolactinoma typically 1000-5000 mU/L; macroprolactinoma often >5000 mU/L
• PRL >5000: almost certainly prolactinoma
• PRL 1000-2000: could be stalk effect, drugs, or microprolactinoma
• Hook effect: if large pituitary mass with 'normal' PRL → request serial dilutions
• Macroprolactin screen: PEG precipitation - to exclude macroprolactinaemia (asymptomatic, no treatment needed)

Pituitary Function

• LH, FSH, oestradiol/testosterone (hypogonadism)
• TSH, free T4 (exclude hypothyroidism + assess pituitary function)
• Cortisol (9am), IGF-1

Imaging

• Pituitary MRI (gadolinium-enhanced): size, extension, cavernous sinus invasion
• Visual fields: formal perimetry if macroadenoma/chiasmal compression

Other

• DEXA: if chronic hypogonadism (osteoporosis risk)
• Pregnancy test: in women of childbearing age

First-Line: Dopamine Agonists

• Cabergoline 0.25mg twice weekly initially; titrate to 0.5-1mg twice weekly (max 4.5mg/week); preferred - more effective, fewer SE, twice-weekly dosing
• Bromocriptine 1.25mg OD initially; titrate to 2.5-7.5mg BD; more SE (nausea, postural hypotension)
• Response: PRL normalisation in ~80-90%; tumour shrinkage in ~80% (may be dramatic - check MRI at 3-6 months)
• Side effects: nausea (take with food), dizziness, postural hypotension, fatigue; high-dose cabergoline (Parkinson doses) - cardiac valve fibrosis (not significant at prolactinoma doses)

Duration

• Continue for ≥2 years; then consider withdrawal if: PRL normal, tumour significantly shrunk or not visible on MRI, no immediate fertility plans
• ~30% recurrence after withdrawal; monitor PRL 3-monthly for 1 year, then annually

Surgery (Transsphenoidal)

• Indications: dopamine agonist intolerance/resistance (rare), patient preference, CSF leak, pituitary apoplexy
• Cure rate: ~70-80% microadenoma, ~30-40% macroadenoma

Radiotherapy

• Rarely needed; for aggressive/resistant tumours

Pregnancy

• Stop cabergoline once pregnant (most microprolactinomas remain stable)
• Bromocriptine preferred if DA needed during pregnancy (more safety data)
• Macroprolactinoma: higher risk of expansion during pregnancy; close monitoring (visual fields, symptoms)

Referral Criteria

• Endocrinology: all confirmed prolactinomas
• Neurosurgery: if surgery indicated
• Ophthalmology: visual field assessment for macroadenoma

Microprolactinoma: excellent; DA normalises PRL in ~80-90%; many shrink or resolve. Macroprolactinoma: DA highly effective; visual field improvement in >80%. Recurrence after DA withdrawal: ~30%. Surgery: cure rates lower for macroadenoma. Fertility: restored in majority with DA treatment. Long-term: osteoporosis risk if hypogonadism untreated. Malignant prolactinoma: extremely rare.

PRL Level and Diagnosis

Cabergoline vs Bromocriptine