EndocrinologyTier 1Disease (DEADMAN)

Glucocorticoid therapy complications

Description

Iatrogenic Cushing syndrome + immunosuppression + HPA suppression, occurring together and dose-dependently
Almost all complications are dose x duration; cumulative dose predicts most, but fracture and hyperglycaemia track current dose

By system

System	Complication
Bone	Osteoporosis and fracture, osteonecrosis (dose-related, can follow short high-dose courses)
Metabolic	Steroid diabetes, weight gain and central adiposity, dyslipidaemia, hypertension, hypokalaemia
Muscle	Proximal myopathy - painless, CK normal
Skin	Thin skin, purpura, striae, poor healing, acne, hirsutism
Eye	Posterior subcapsular cataract, glaucoma, central serous chorioretinopathy
GI	Peptic ulcer only in combination with NSAIDs, pancreatitis
Neuropsychiatric	Insomnia, irritability, emotional lability, mania, depression, psychosis
Infection	Bacterial, PJP, reactivation of TB, HBV, strongyloides
Endocrine	Adrenal suppression -> crisis on withdrawal or stress
Vascular	Withdrawal-independent excess CV events at high dose

Equivalent doses

Hydrocortisone 20 mg = prednis(ol)one 5 mg = methylprednisolone 4 mg = dexamethasone 0.75 mg
Dexamethasone has no mineralocorticoid activity and a long biological half-life -> most HPA suppression per anti-inflammatory unit

Epidemiology

~1-3% of the population on oral glucocorticoids at any time; higher over 70y
30-50% of long-term users sustain a fracture
Steroid diabetes in ~10-30% of those on prolonged therapy
Commonest cause of Cushing syndrome overall, and of secondary osteoporosis

Aetiopathogenesis

Bone - the mechanism explains the treatment

dec osteoblastogenesis + inc osteoblast and osteocyte apoptosis -> *bone formation falls* (dominant effect)
Early transient inc osteoclast survival (inc RANKL, dec OPG) -> a burst of resorption in the first months
Secondary: dec intestinal Ca absorption + inc renal Ca loss -> inc PTH; hypogonadism; myopathy -> falls
Pattern: cancellous bone first (vertebrae, ribs, proximal femur)
- ~6-12% loss in year 1, then ~3%/yr
*Fractures occur at a higher BMD than in postmenopausal osteoporosis* - the bone is qualitatively worse, so BMD under-reads the risk
-> an antiresorptive alone is mechanistically incomplete - it does not restore formation

Other mechanisms

Fibroblast inhibition -> skin atrophy, striae, bruising, impaired wound healing
Immunosuppression is predominantly of cell-mediated immunity (T cells, macrophage function, cytokine transcription)
- Neutrophilia is demargination, not activation - the neutrophils work less well despite the higher count
Protein catabolism -> type II fibre atrophy -> proximal myopathy
Hepatic gluconeogenesis + peripheral insulin resistance -> post-prandial-predominant hyperglycaemia
Crosses the blood-brain barrier -> mood, sleep and psychosis
HPA suppression: exogenous cortisol suppresses CRH/ACTH -> adrenal atrophy; recovery of the axis takes months

Diagnosis

Assessing anyone on long-term steroid

Indication, current dose, cumulative dose, duration
Is the underlying disease actually controlled?
Has a steroid-sparing agent been considered?
Which complications are already present, and which are being screened for?

Screening

BP, weight/waist, HbA1c and fasting glucose (and a post-prandial glucose - fasting alone misses steroid diabetes)
BMD by DEXA at baseline and 1-2 yearly; vertebral fracture assessment or lateral spine imaging (most vertebral fractures are silent)
Lipids; ophthalmology review for cataract and IOP
Vitamin D, calcium
Before starting: TB (IGRA), HBV serology, strongyloides serology in at-risk patients

Suspected adrenal suppression

Assume it in anyone on >prednisolone 5 mg/day for >3-4 weeks, any dose at night, or repeated courses
09:00 cortisol taken >=24h after the last dose (omit that morning's dose); short Synacthen if equivocal
Prednisolone cross-reacts in some cortisol assays - use hydrocortisone or dexamethasone cover when testing

Steroid myopathy vs disease flare

Myopathy: painless, proximal, normal CK, normal inflammatory markers, improves on dose reduction
Myositis flare: painful, raised CK, worsens on reduction

Management

1. Minimise exposure - the only intervention that fixes everything

Lowest effective dose, shortest duration, single morning dose
Steroid-sparing agent early: methotrexate, azathioprine, MMF, biologics, or the disease-specific agent
Alternate-day dosing where the disease allows
Consider topical/inhaled/local injection routes

2. Bone protection

Start with the first prescription if long-term therapy is anticipated - do not wait for a DEXA
Calcium ~1000-1300 mg/day (diet preferred) + vitamin D; weight-bearing exercise; cease smoking; limit alcohol; treat hypogonadism
Who to treat pharmacologically
- AU/PBS: prednisolone >=7.5 mg/day for >=3 months with T-score <=-1.5, or any prior minimal-trauma fracture
- ACR: risk-stratified - treat all high and very-high risk, consider in moderate risk
Agent choice
- Very high risk -> anabolic first (teriparatide, abaloparatide, romosozumab), then lock in with an antiresorptive
  - Teriparatide beats alendronate for vertebral fracture in GIOP - it targets the actual defect
- High/moderate risk -> oral or IV bisphosphonate, or denosumab
- *Never stop denosumab without transitioning to a bisphosphonate - rebound vertebral fractures*
Reassess when the glucocorticoid stops; fracture risk falls back within ~1 year

3. Glycaemia

Screen before and during; check post-prandial or afternoon glucose
Prednisolone morning dosing -> hyperglycaemia peaks midday-evening -> morning intermediate-acting insulin (isophane) or a mealtime-weighted regimen matches the profile
Do not stop insulin when the steroid stops abruptly without a plan - hypoglycaemia

4. Gastrointestinal

Steroid alone is not an ulcer risk - the risk is the NSAID combination
Avoid concurrent NSAIDs; PPI if NSAID, anticoagulant or prior ulcer

5. Infection

PJP prophylaxis: trimethoprim-sulfamethoxazole when prednisolone >=20 mg/day for >=4 weeks, especially with a second immunosuppressant or lymphopenia
Vaccinate before starting where possible; live vaccines contraindicated at immunosuppressive doses
Ivermectin for strongyloides if seropositive; antiviral prophylaxis if HBsAg or anti-HBc positive
Fever and inflammatory markers are blunted - a normal CRP does not exclude sepsis

6. Withdrawal and stress dosing

Never stop abruptly after >3-4 weeks of suppressive dosing
Taper to physiological (~prednisolone 5 mg) reasonably quickly, then slowly; test the axis before stopping
Sick day rules: double the dose for intercurrent illness; parenteral hydrocortisone for vomiting, surgery or trauma
Medical alert bracelet and a written emergency plan
Steroid withdrawal syndrome - arthralgia, lethargy, malaise with normal cortisol - not adrenal insufficiency, but the taper needs to slow

7. Other

Ophthalmology review; BP and lipid management; sleep hygiene; warn about mood change and psychosis and treat early
Weight and diet advice at initiation

Associations

Underlying disease amplifies risk - RA, PMR, IBD, COPD, transplant, vasculitis
Risk factors for GIOP: age 60-80 (~26x the vertebral fracture risk of age 18-31), low BMI, prior fracture, low BMD, smoking, high alcohol, high dose and long duration
Osteonecrosis of the femoral head - can follow even short high-dose courses; also SLE, alcohol, sickle cell
Cushingoid habitus, hypokalaemic alkalosis at very high doses or with fludrocortisone
Interaction: CYP3A4 inhibitors (ritonavir, itraconazole) raise steroid exposure dramatically - iatrogenic Cushing from inhaled or intra-articular steroid

Natural history & complications

Bone loss is fastest in the first 3-6 months - so is the fracture excess, which appears within 3 months of starting
Fracture risk returns towards baseline within ~1 year of cessation
Cataract, osteonecrosis and skin atrophy are irreversible; myopathy, glycaemia, weight and mood largely reverse
HPA axis recovery: weeks to 12+ months depending on dose and duration; ACTH recovers before cortisol
Adrenal crisis on withdrawal or intercurrent illness is the main preventable cause of death in this group
Long-term users carry excess cardiovascular and infectious mortality independent of the underlying disease

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