Endocrine Flashcards
HLA genes in T1DM
Account up to 90% of T1DM patients (uptodate)
- DR3-DQ2
- DR4-DQ8
HLA-associated disease in T1DM
- Autoimmune thyroid disease (1 in 5)
- Coeliac disease (1 in 12)
- Pernicious anaemia (1 in 25)
- Others: vitiligo, Addison’s (polyglandular autimmune syndrome type 2), RA, autoimmune hepatitis
- ITP
Pathophysiology of type 1 diabetes
Genetic predisposition (MHC, Ins) + environemntal modifiers –> development of autoantibodies + autoreactive T cells to insulin –> beta cell injury –> insulin deficiency
Environmental risk factors for T1DM
- Maternal enteroviral infection
- Older maternal age
- Enteroviral infection
- Infant weight gain
- Overweight or increased high velocity
- Puberty
- Insulin resistance
- Psychological stress
Environmental protective factors for T1DM
- Higher maternal vitamin D or concentrations in late pregnancy
- Higher omega-3 fatty acids
Antibodies associated with T1DM
- Pro-insulin - sens 40%, sepc 90%
- GAD - sens 72%, sepc 99.3%
- IA-2 (tyrosine phosphatase) - sens 62%, sepc 96%
- ZnT8 - sens 65-80%, spec 98-99%
Beta-cell specific antigens in T1DM
Insulin and ZnT8
Risk of microvascular complications in T1DM
From highest to lowest
Retinopathy > Nephropathy > Neuropathy > Microalbuminuria
In DCCT trial, what subgroups did not demonstrate benefit with intensive therapy?
- Pts with recurrent hypoglycaemia
- Pts with macrovascular complications
- Young children
Examples of ultra short acting insulin (0-4hrs)
Lispro insulin (Humalog)
Aspart insulin (NR, Fiasp)
Glulisine (Apidra)
Examples of short acting insulin (0-6 hrs)
Actrapid
Humulin
Examples of intermediate acting insulin (0-14 hrs)
Isophane (Protaphane, Humulin NPH)
Examples of long acting insulin (24 hours)
Glargine insulin, Detemir insulin (Optisulin/Lantus, Toujeo, Levemir)
Examples of ultra long acting insulin (72 hours)
Degludec (Ryzodeg)
Pharmacokinetic benefits of CSII over MDI
- Reduced variation in absorption
- Eliminates most of SC insulin depot
- Predictable absorption
- Stimulates normal pancreatic function
Clinical benefits of CSII over MDI
- Reduced HbA1c
- Reduced severe hypoglycaemia
- Improved QoL
Disadvantages of CSII over MDI
- Expensive
- Major complications - site infection, DKA (dislodgement of cannula)
Patient selection in pancreas and islet transplantation
- Usually patients with recurrent, severe hypoglycaemia with unawareness
Outcomes of pancreas and islet transplantation
- Reduced hypoglycaemia with improved HbA1c
- Reduced insulin dose/frequency of injections
- Insulin independence
- Improved QoL
Diagnostic criteria for LADA
- Adult (30-75 yrs)
- Diabetes
- Evidence of islet autoimmunity (GAD Ab > 5 units)
- Period of insulin independence (has received diet and antidiabetic therapy)
“Distinguishing” clinical features of LADA over T2DM
Usually age < 50
Acute symptoms
BMI < 25
Personal history or FHx of autoimmunity
Importance of detecting AI diabetes in adults
- Avoidance of SGLT2 inhibitors –> risk of ketoacidosis
- Alteration and/or escalation of oral hypoglycaemic drug treatment
- Early commencement of insulin
- Screening for AI conditions
Pathophysiology of T2DM
Peripheral insulin resistance occurs from genetic + environmental factors
- Central obesity –> increased FFA –> impaired insulin dependent glucose uptake in hepatocytes, myocytes and adipocytes
- Increased serine kinase activity in fat and skeletal muscle cells –> phosphorylation of IRS-1 –> decreased affinity of IRS-1 for PI3K –> decreased GLUT4 channel expression –> decreased cellular glucose uptake
Pancreatic β cell dysfunction: accumulation of pro-amylin (islet amyloid polypeptide) in the pancreas → decreased endogenous insulin production
Progression:
Insulin resistance initially compensated by increased insulin and amylin secretion
As insulin resistance progresses, insulin secretion capacity decreases
Usually presents with isolated postprandial hyperglycaemia before progressing to fasting hyperglycaemia too
Physiology of insulin secretion
Characterised by rapid first-phase insulin response (minutes), then a delayed second phase insulin response (plateaus at 2-3 hours)
Loss of first phase insulin response occurs in DM –> post glucose challenge or postprandial hyperglycaemia
Physiology of insulin signally
Insulin reacts with insulin receptors to allow glucose to enter cell through glucose transports (i.e. GLUT4)
Activation of IRS through insulin receptors leads to:
- Cell growth/differentiation via MAP kinase
- Lipid synthesis via PI-3 kinase
- Protein metabolism via Akt
Hypotheses of insulin resistance
Inflammation: increased adipocyte –> increase inflammatory markers –> acts through JNK –> inhibition of IRS-1 –> dysregulation of glucose
Lipid overload: increased fatty acyl CoA –> B oxidation of muscle cell and inhibition of IRS-1 (via accumulation of DAGs) causing glucose dysregulation
Metabolic contributors to hyperglycaemia in T2DM
- Decreased insulin secretion
- Decreased incretin effect
- Increased lipolysis
- Increased glucose reabsorption
- Decreased glucose uptake
- Neurotransmitter dysfunction
- Increased hepatic glucose production
- Increased glucagon secretion
Diabetic medications working on incretin pathway
DPP-4 inhibitors (-gliptan)
GLP1 receptor agonists (-glutide)
MOA of SGLT2 inhibitors
Increases glucose reabsorption in kidneys in proximal tubule
How much glucose goes through kidneys in a day?
(180L/day)(900mg/L) = 162g/day
MOA and benefit of finerenone in diabetic nephropathy
Nonsteroidal mineralocorticoid receptor antagonist
Reduced risk of nephropathy progression
Approved for eGFR > 25, macroalbuminuria (+ in combination with SGLT2 inhibitor)
Findings of UKPDS substudy
MF initiated in newly diagnosed pts with T2DM is associated with reduction in risk of MI
Findings of STENO-2
Multifactorial intervention targeting glycaemia, BP, dyslipidaemia, reduces CV death and microvascular endpoints in T2DM with microalbuminuria
Studies demonstrating empagliflozin benefits
EMPA-REG
EMPEROR
EMPA-REG OUTCOME
Associated with reduced death via reduction in heart failure in patients with T2DM and CVD, and in HFrEF and HFpEF
Studies demonstrating GLP1 agonist
SUSTAIN 6
HARMONY
REWIND
GLP1 agonist shown to reduce CV events but not CV death in patients with T2DM and comorbidities
MOA of tirzepatide
Dual receptor GLP1/GIP receptor agonist
MOA of Icodec
Weekly insulin analougueM
MOA of retatrutide
Triple GIP/GLP-1/glucagon receptor agonist
Hormones increased and reduced from adipose tissue
Increased:
Visfatin
Resistin
Leptin
FGF-21
RBP-4
Cortisol
Reduced:
Adiponectin
Cytokines released by adipose tissue
TNF-alpha
IL-1B
IL-6
PAI-1
MCP-1
Effects of leptin and adiponectin
Leptin - inhibits hunger
Adiponectin - increases hunger
Gut hormones that inhibit satiety
PYY
Oxyntomodulin
PP
CCK
GLP-1
Amylin
Insulin
Leptin
Pancreas specific - pancreatic polypeptide
Gut hormones that stimulate satiety and hunger
Ghrelin
ILP5
Effect on leptin as BMI reduces
Leptin reduces –> increase in appetite
Pharmacological treatment for obesity
- Phentermine - sympathomimetic amine, affects DA and NA
- Topiramate - monosaccharide AED
- Orlistat - intestinal lipase inhibitor
- Bupropion/naltrexone - combined NA/DA reuptake inhibitor + opioid receptor antagonist
- Liraglutide - GLP1 receptor agonist
Pathophysiology of congenital adrenal hyperplasia
21-hydroxylase deficiency –> reduction in aldosterone and cortisol –> salt losing adrenal crisis
Loss of cortisol –> increase in ACTH –> hyperpigmentation and adrenal enlargement
Increase in adrenal steroid precursors –> increase in adrenal androgens (DHEAS, androstendione) –> increase in testosterone
Important investigation for CAH
17-OH progesterone
- increased in response to deficiency in 21-hydroxylase
Difference between non-classical CAH and classical
More mild form of classical CAH
Presents in female with precocious pubarche and androgen excess
Check 17-OH progesterone level in follicular phase –> may be normal otherwise
Other deficiencies in CAH
11β-hydroxylase deficiency
17α-hydroxylase deficiency
Factors that change plasma cortisol binding globulin concentration
Increased:
- Pregnancy
- Oestrogen administration
- Hyperthyroidism
Decreased:
- Inflammation/acute illness
- Hypothyroidism
- Protein deficiency
- Diminished synthetic capability
- CBG gene mutations
Causes of primary adrenal insufficiency
- Autoimmune adrenalitis - Associated with other autoimmune endocrinopathies
- Infectious adrenalitis - mycobacteria, viruses (CMV, HIV, HSV) , fungi (PJP)
- Adrenal hemorrhage
- Sepsis: especially meningococcal sepsis (endotoxic shock) → hemorrhagic necrosis (Waterhouse-Friderichsen syndrome)
- Disseminated intravascular coagulation (DIC)
- Anticoagulation: especially heparin (heparin-induced thrombocytopenia)
- Venous thromboembolism, especially in antiphospholipid syndrome (APS)
- Adrenal tumor (most commonly pheochromocytoma) → intratumoral bleeding
- (Short-term) steroid usage
- Trauma (mostly blunt trauma, can also occur postoperatively)
- Tumors (adrenocortical tumors, lymphomas, metastatic carcinoma)
- Amyloidosis
- Hemochromatosis
- BL Adrenalectomy
- Cortisol synthesis inhibitors (e.g., rifampin, fluconazole, phenytoin, ketoconazole): drug-induced adrenal insufficiency
- Checkpoint inhibitors
- 21β-hydroxylase
- Vitamin B5 deficiency
Causes of secondary and tertiary adrenal insuffiency
Secondary: decreased ACTH production
- sudden discontinuation of chronic GC therapy
- Hypopituitarism
- Can be caused by checkpoint inhibitors, CTLA4 inhibitor
Tertiary: decreased CRH production
- Sudden discontinuation of chronic glucocorticoid therapy.
- Rarer causes include hypothalamic dysfunction (e.g., due to trauma, mass, hemorrhage, or anorexia)
Diagnosis of adrenal insufficiency
Early morning cortisol
Short synacthen test
- cortisol > 550 excludes adrenal failure unless recent pituitary damage (i.e. haemorrhage, surgery)
Insulin tolerance test (gold standard of ACTH/GH reserved)
Pathophysiology of autoimmune polyglandular syndrome
Type 1: Deficiency in AIRE gene –> autoreactive T cells dysregulation –> AI endocrine diseases
Most commonly - Primary adrenal insufficiency, Hypoparathyroidism, Chronic mucocutaneous candidiasis, Ectodermal dystrophy of skin, nails, and dental enamel
Type 2: Associated with HLA-DR3 and/or HLA-DR4
Results in primary adrenal insufficiency with thyroid autoimmuend isease and/or T1DM
Presentation and diagnosis of adrenoleukodystrophy
X-linked recessive
Cerebral ALD
- childhood presentation
- dementia, blindness, adriplegia
Adrenomyeloneuropathy
- spasticity, distal polyneuropathy
- young men
Diagnosis via elevated very long chain fatty acids
Action of glucocorticoids
Hyperglycaemia
Muscle catabolism
Fat deposition
Anti-inflammatory
Bone catabolism
Hypertension
Definition of Cushing’s syndrome
GC excess
Definition of Cushing’s disease
ACTH producing pituitary adenoma
Diagnosis of Cushing’s
Confirm diagnosis - cortisol
Determine if ACTH independent or dependent (i.e. Cushing’s disease) - ACTH
If confirming Cushing’s disease - determine if pituitary or ectopic - MRI pituitary, BIPSS, CT pan scan, PET
Hyperaldosteronism diagnosis findings
Primary hyperaldosteronism - low renin, high aldosterone (bilateral adrenal hyperplasia, Conn, familial hyperaldosteronism)
Secondary hyperaldosteronism - high renin, high aldosterone (renal artery stenosis, diuretics, Bartter and Gitelman’s)
Causes of mineralocorticoid excess and ARR diagnosis
Low renin, low aldosterone
Exogenous mineralocorticoid
Cushing’s syndrome
Licorice
CAH/11b hydroxylase deficiency
Liddle’s
Medications that have minimal effects on aldosterone levels
Verapamil SR
Hydralazine
Prazosin
Drugs to avoid in ARR testing
Increase in ARR
- B adrenergic blockers
- a2 agonists i.e. clonidine, a-methyldopa
- NSAIDs
- Ca blockers (DHPs)
Decrease in ARR
- Diuretics
ACEi/ARBs
Diagnosis of primary aldosteronism
Hypokalaemia, aldosterone excess, HTN
Elevated ARR
Saline infusion - confirm inadequate aldosterone suppression
Adrenal CT
Adrenal vein sampling
Treatment of primary aldosteronism
Unilateral - unilateral laparoscopic adrenalectomy > medical therapy i.e. spironolactone
Bilateral - medical therapy > unilateral laparoscopic adrenalectomy
Clinical presentation of phaechromocytoma
Headache
Palpitations
Sweating
Tremor
Nausea
Low BMI
Tachycardia
Diagnosis of phaeochromocytoma
Plasma free metanephrines
Genetic testing
Imaging CT/PET scan - heterogenous, large, HU > 30
Treatment of phaeochromocytoma
Surgery with alpha blockade (BP < 130/80) +/- beta blockade if tachyarrhythmia
Effects of beta blocker prior to alpha blockade in phaeochromocytoma
Beta-blockers cancel out the vasodilatory effect of peripheral beta-2 adrenoceptors, potentially leading to unopposed alpha-adrenoceptor stimulation and thereby causing vasoconstriction and increased blood pressure.
Causes of hypogonadism
Primary (LH/FSH high)
- Klinefelter syndrome
- Cryptochidism
- Myotonic dystrophy
- Irradiation, chemotherapy
- Trauma
- Orchitis
- Advanced age
- ESKD
Secondary (LH/FSH low to normal)
- Pituitary/hypothalamic tumour, trauma, surgery, diasease
- Iron overload
- Kallman syndrome, IHH
- Hyperprolactinoma
- Opioids
- GC excess
- Anabolic steroids
- Chronic illness
- Mulnutrition, obesity
- GnRH agonists
Clues for organic hypogonadism
Young age
Borderline obesity
Low comorbid burden
Gynaecomastia, borderline low testicular volume
End organ deficits
Low testosterone (not responding to weight loss), low LH, mildly raised prolactin (pituitary stalk effect)
Effects of LH and FSH on hypogonadism
LH –> Leydig LH-R –> testosterone
FSH –> Sertoli cell FSH-R –> spermatogenesis
Thyroid specific genes that regulated by TSH signal
Sodium iodide symporter
Thyroid peroxidase
Thyroglobulin
Pathophysiology of Grave’s disease
Genetic disposition (HLA DR3 + HLA B8) + autoimmunity + triggers
T cell mediated autoimmune process –> mediated by stimulating TSHr autoantibody, by product of CD4+
Clinical features of Grave’s disease
Diffuse goitre + ophthalmopathy + hyperthyroidism
Diagnosis of Graves disease
Thyroid receptor antibodies + TPO Ab
Tc99 scan
Management of Grave’s disease
- Thionamides (carbimazoles or PTU) –> rash, altered LFTs, neutropenia, pANCA vasculitis
- Iodine ablation - first line in non pregnant with small goiters
- Surgery - carries risk of parathyroid injury and cause hypothyroidism
Approach to thionamide therapy to Graves’
Titrate dose to TSH or “block/replace”
Treat for at least 12-18 months
50% chance of long term remission
Most relapses occur within 6 months of drug cessation
PTU vs carbimazole
PTU
- blocks conversion from T4 to T3
- Associated with fulminant inflammatory hepatitis
- Safer in first trimester
Carbimazole
- No effect on deiodinase
- Increased risk of aplastic cutis, omphalocele and other birth defects
Pathophysiology of Graves’ ophthalmopathy/orbitopathy
Activated B and T cells infiltrate retro-orbital space targeting orbital fibroblasts → cytokine release (e.g. TNF-α, IFN-γ) → local inflammatory response → fibroblast proliferation and differentiation to adipocytes → production of hyaluronic acid and GAGs and increased amount of adipocytes → increase in the volume of intraorbital fat and muscle tissues → exophthalmos, lid retraction, disturbances in ocular motility (causing diplopia)
Clinical features of Graves’ ophthalmopathy
Painful feeling behind globe
Pain with eye movements
Redness of eyelids
Redness of conjunctiva
Swelling of eyelids
Chemosis
Swollen caruncle
Increase in proptosis > 2mm
Decreased eye movements > 5’ any direction
Decreased VA
Familial hypokalaemic periodic paralysis associated with Graves’
Due to transient severe hypokalaemia
Occurs after high carb meals or severe exercise
Seen in Asian people
Effects of pregnancy on thyroid
BHCG and TSH share common alpha subunit, thus both activate TSH receptor –> mild TSH suppression and occasional thyrotoxicosis
Should test thyroid antibodies and subclinical hypothyroidism –> receive thyroxine therapy
Treatment of hypothyroid women in pregnancy
Treat thyroxine dose by ~1.3x to cover increased requirement in first trimester
Presentation of toxic nodules
Usually presents with thyrotoxicosis
DUe to activating somatic TSHr mutation
Clinical features and diagnosis of thyroiditis
Usually asymptomatic
May present with transient thyrotoxicosis
Signs of hypothyroidism in late stages of Hashimoto’s
Low uptake on Tc99 scan
Causes of thyroiditis
Idiopathic
Post pregnancy
Hashimoto’s
Amiodarone
Immune checkpoint inhibitors
Lithium
Effects of amiodarone on thyroid
- Hypothyroidism - interference of T4 synthesis and action
- Thyrotoxicosis - due to iodine load (type 1) and/or thyroiditis (type 2)
Iodine effect on thyroid
“Wolff-Chaikoff” effect - reduction in thyroid hormone in response to large amounts of iodine
“Jod-Basedow” effect - opposite effect where there is increase in thyroid hormone response, escaping the physiologic negative feedback mechanism of the Wolf-Chaikoff effect –> may reflect an autoimmune response
Lithium effect on thyroid
Inhibits T4 production and secretion resulting in hypothyroidism
Can also cause transient thyroiditis
Immune checkpoint inhibitors that may cause thyroid issues
Anti-CTLA4 i.e. ipilimumab, tremilimumab:
- Hypophysitis and central hypothyroidism
- Thyroiditis
Anti-PD1 i.e. nivolumab, pembrolizumab
- Thyroiditis
- Central hypothyroidism
Effect of alemtuzumab on thyroid
Anti-CD52
Graves’ disease is common
Thyroiditis can also occur in rare circumstances
Drugs that can affect thyroid
Iodine
Lithium
Immune checkpoint inhibitors i.e anti CTLA4, anti PD-1
Anti-CD52 inhibitors
TKI inhibitors –> hypothyroidsm
Bexarotene (RXR agonists) –> central hypothyroidism
Indication for treatment of subclinical hypothroidism
Definitely treat:
- TSH > 10 or symptoms of hypoT4
- preconception or early pregnancy
Consider thyroxine if:
- Age < 65
- Heart failure
- TPO or Tg antibody positive
- Dyslipidaemia
Indication of investigation and treatment of subclinical hyperthyroidism
- TSH < 0.1
- Symptoms of thyrotoxicosis
- Co-existing AF or OP
Most common thyroid carcinoma
Follicular carcinoma
Monitor with thyroglobulin
Most severe thyroid carcinoma
Medullary carcinoma
Monitor with calcitonin
Risk factors for thyroid follicular cell carcinoma
- Previous neck radiation
- FHx
- Rapid growth
- Very firm or hard nodule
- Fixation of nodule to adjacent structures
- Paralysis of vocal cords
- Regional lymphadenopathy
- Distant metastases
- PET incidentaloma
Suspicious features of thyroid docules
Irregular borders
Microcalcifications
Hypoechogenicity
Management of follicular thyroid cancer after surgery
TSH suppression after surgery unless low risk
TSH-stimulated radioiodine if intermediate/high risk
Measure serum thyroglobulin to monitor for recurrence
Systemic radioiodine and/or kinase based therapies for recurrent or metastatic disease
Genetic drivers of papillary thyroid carcinoma
BRAF V600E
RTX fusions - RET > NTRK > others
RAS - NRAS > HRAS> KRAS
Pathophysiology of medullary thyroid cancer
C-cell hyperplasia resulting in carcinoma, causing secretion in calcitonin
Associated with RET proto-oncogene (MEN2B)
MEN2A characteristics
Phaeochromocytoma
Hyperparathyroidism
Medullary thyroid carcinoma
Hirschsprung’s disease
Cutaneous lichen amyloidosis
MEN2B characteristics
Mucosal neuromas
Marfanoid body habitus
Medullary carcinoma
Phaeochromocytoma
Management of medullary thyroid carcinoma
Prophylactic thyroidectomy < 20 yrs recommended if RET mutation carrier
Assess for MENII before surgery
Total thyroidectomy
RET oncogene sequencing and family screening
Measure calcitonin
Anterior pituitary hormone deficiency diagnosis
ACTH
- insulin tolerance –> cortisol response to stress
- Synacthen test (may be falsely abnormal) –> for primary adrenal insufficiency
TSH
- TSH AND fT4 and/or T3
- treat with thyroxine with aim to normal fT4 and ft3
LH/FSH
- low testosterone or amenorrhoea
GH
- insulin tolerance test or glucagon stimulation test
- IGF-1 (though may be normal)
Prolactin
- low serum prolactin
- treatment unnecessary
Diagnosis of hormone secreting pituitary tumour
Prolactinoma
- Elevated prolactin level
Acromegaly
- Serum IGF-1
- Oral glucose tolerance test
Cushing’s disease
- 24 hour urinary free cortisol measurement
- midnight salivary cortisol measurement, high dose dexamethasone suppression test (failure to suppress), corticotropin measurement
Thyrotropin-secreting tumour
- Serum thyrotropin measurement
- free t4 measurement
Approach to pituitary mass
Review endocrine function
Assess significant mass effect
- VF defect (bitemporal hemianopia, CNII)
- Oculomotor palsy (CNIII, IV, or VI)
- Imaging showing cavernous sinus invasion or mass abutting optic chiasm
Management of non-secreting pituitary adenoma
Microadenoma (<10mm)
- Observe if no compressive mass effect
- Follow up with MRI and reassess if symptomatic
Macroadenoma (>10mm)
- Transsphenoidal surgery
- Annual MRI to monitor for mass persistence or recurrence)
- Pituitary reserve testing every 6 months for 2 years
- Hormone replacement as required
Effects of non functional pituitary adenoma
Most stain for FSH
May cause mass effect and anterior pituitary failure
Prolactin elevated due to stalk pressure
Clinical features of prolactinoma
Hypogonadism (infertility, amenorrhoea)
Breast tenderness and discharge
High serum prolactin
Approach to prolactinoma
Exclude hypothyroidism (TRH stimulates release of prolactin)
Exclude drugs
Perform MRI pituitary to confirm diagnosis
Commence dopamine agonist to normalise prolactin
Dopamine agonists for prolactinoma
Bromocriptine daily
Cabergoline weekly
Side effects of dopamine agonist
Hypersexuality
Compulsive buying
Punding
Common causes of hyperprolactinaemia
Pregnancy/lactation
Hypothyroidism
Metoclopramide
Neuroleptics
Stress
Pituitary stalk pressure
Opioids
Pregnancy effect on pituitary
Pituitary size increases in pregnancy due to lactotroph hyperplasia
Management of prolactinomas in patients planning pregnancy
Microadenoma –> discontinue DA and periodic VA examination during pregnancy
Macroadenoma –> surgery prior to pregnancy or bromocriptine if vision compromise
Ensure bromocriptine sensitivity prior to pregnancy
Steroids or surgery during pregnancy if vision compromise or adenoma haemorrhage
Postpartum MRI after 6 weeks
Hypercortisolism with low ACTH
Exogenous steroid
Adrenal tumour
Hypercortisolism with high or normal ACTH
Failed suppression to high dose dexamethasone –> Ectopic source
Investigate with CT pan scan or PET
If adequate suppression –> likely Cushing’s disease, pituitary source
Investigate with bilateral sampling of inferior petrous sinus
Differentiating between pituitary vs peripheral ACTH
Desmopressin stimulating test
CRH testing
ACTH and cortisol increase –> pituitary
ACTH and cortisol don’t increase –> ectopic source
Dexamethasone suppression test
Adequate suppression –> Cushing disease
No suppression –> ectopic source
Treatment of Cushing’s disease
Osilodrostat (best) - targets 11B hydroxylase
Metyrapone - targets 11B hydroxlase, often used in pregnancy
Ketoconazole - preferred over metyrapone for non-pregnant women
Avoid mitotane for women in future pregnancy
Common cause of ectopic ACTH
Due to SCLC or lung carcinoid
Cause of ectopic CRH
Carcinoid
Small cell carcinoma
Medullary thyroid carcinoma
Acromegaly diagnosis and treatment
Elevation of IGF-1 with clinical features (acral enlargement, diabetes, OA, sleep apnoea and HTN)
Prolactin elevated if co-secretory tumour
Surgery - first line treatment
Somatostatin receptor 2/5 agonist (octreotide, lanretoide)
After surgery, if IGF-1 elevated - normalise with dopamine agonist first then octreotide or lancreotide, then pegvisomant
Pegvisomant MOA
GH receptor antagonist
Daily SC injection, funded if IGF-1 elevated despite somatostatin analogue
Comorbidities of acromegaly
Thyroid cancer is most common cancer
Increased risk of colon cancer
Joint damage
Cardiovascular disease more likely
Glucose intolerance
TSHoma clinical features and diagnosis
Thyrotoxicosis with elevated fT4 and/or fT3 and non-suppressed TSH
Due to TSH secreting pituitary tumour
Causes of DI
Central
- Head injury/surgical injury to posterior pituitary
- Hypophysitis
- Infiltrating lesions - craniopharyngioma, germinoma, histiocytosis, TB, sarcoid
- Familial (ADH gene mtuation)
Nephrogenic
- Lithium
- Familial (vasopressin receptor or aquaporin gene mutation)
Genes causing familial pituitary tumours
MEN1
p27 - cyclin dependent kinase
AIP - young onset tumours, particularly GH secreting
PPKAR1A - Carney syndrome - spotty skin pigmentation, myxomas, and testicular, adrenal and/or pituitary adenomas or hyperplasia
Pituitary apoplexy causes
Sudden pituitary haemorrhage
Postpartum haemorrhage - Sheehan’s syndrome
Trauma
Enlarging adenoma
Clinical features of pituitary apoplexy
Frontal headache
Neuropraxias
Approach to pituitary apoplexy
Hormones including prolactin
IV steroid replacement
Imaging
Surgery if indicated
Diagnosis of diabetes insipidus
Water deprivation test aiming to induce pOsM > 300 to assess if uOsm > 500-600mmol/L
Hypertonic saline infusion to induce Na > 150 to assess if plasma copeptin 4.9pmol/l
Mechanism of osteoblast
Makes new bone
Mineralises collagen
Mechanism of osteocyte
Mechanosensor
Secretion of FGF23 and sclerostin
Types of bone
Cortical bone - dense outer shell of compact bone, turnover rate of 2-3% per year
Trabecular bone - sponge like network of delicate platelets of bone
Role of RANK ligand
Mediator of osteoclast formation, function and survival
Role of OPG
Decoy receptor that prevents RANK ligand binding to RANK, thus inhibiting osteoclast formation/function/survival
Osteoporosis pathophysiology
Excessive remodelling –> structural deterioration –> increased skeletal fragility –> increased fracture risk
Definition of osteoporosis
BMD score < -2.5
Minimal trauma fracture
Occurrence of osteoporotic fractures
Radiographical vertebral > wrist fracture (in younger) and hip fracture (in older)
Risk factors for osteoporosis
Previous fragility fractures > 50 yrs
Age at menopause
Intercurrent illness affecting bones or falls risk i.e. DM, RA, coeliac, thyroid/parathyroid
Steroids
Smoking
EtOH
FHx
Undeweight
Use of Z score
<-2 may be useful in identifying patients with underlying accelerated causes of bone loss
Secondary causes of bone loss
Hypogonadism
Vitamin D deficiency
Hyperthyroidism
Hyperparathyroidism
Coeliac disease
Multiple myeloma
Drugs - corticosteroids, AEDs, GnRH agonists, aromatase inhibitors
Chronic diseases
MOA of bisphosphonates
Prevents osteoclasts from resorbing bones
MOA of SERMS/estrogen
Change RANK-L/OPG ratio to inhibit osteovlast formation
Binds to estrogen receptor
MOA of Denosumab
Binds to RANK-L and inhibitors it
MOA of anabolic therapy i.e. teriparatide
Binds to G protein coupled receptor and stimulates PTH to promote bone formation
MOA of romosozumab
Monoclonal antibody against sclerostin
Acts by increasing bone formation and reducing bone resorption
Osteomalacia pathophysiology
Deficiency of mineralised bone
- Calcipenic rickets
↓ Calcium → ↑ PTH levels → ↓ phosphate → impaired bone mineralization - Phosphopenic rickets: ↓ phosphate → impaired bone mineralization
- Direct inhibition of mineralization → impaired bone mineralization
Osteomalacia presentation
Bone pain
Fractures (usually stress-type)
Myopathy (waddling gait)
Elevated ALP
Causes of osteomalacia
Vitamin D and calcium deficiency
- Nutritional
- Malabsorption
- Liver disease
- Renal disease
- Nephrotic syndrome
- AEDs
- Genetic causes (VDR, CYP27B1, 25-hydroxylase)
Hypophosphataemia
- Fanconi syndrome
- Tumour induced
- Genetic cause
Iron deficiency and FGF23
Iron deficiency increases FGF23 transcription
IV iron replacement prevents FGF23 cleavage
Thus iron transfusion results in increase phosphaturia –> hypophosphataemia
Genetic cause of hypophosphataemia
X-linked hypophosphataemia (XLH)
Autosomal dominant - FGF23
Autosomal recessive type 1 - DMP1
Type 2 - ENPP1
Type 3 - FAM20c
Clinical features of HLX
Short stature
Osteomalacia
Pseudofractures
Osteoarthritis
Enthesopathies
Spinal stenosis
Poor dentition
Hearing loss
Paget’s disease pathophysiology
Increased osteoclast activity
Increased bone turnover
Thickening and weakening of affected bone
Bone overgrowth
Clinical manifestations of Paget’s disease
Bone pain
Bone deformity
OA of adjacent joints
Fractures
Spinal stenosis
Indication of treatment for Paget’s disease
Bone pain
Involvement of petrous temporal bone
Nerve or spinal cord compression
Cardiac failure
Involvement of critical bone
Involvement of skull
Cosmetic change
Bending of femor or tibia
Therapy of Paget’s disease
Bisphosphonates
Calcitonin
Analgesia
Surgery
Causes of hypercalcaemia
PTH-dependent
- Primary or tertiary hyperparathyroidism
- Abnormality of calcium-sensing receptor (FHH, autoimmune hyperclcaemia)
- Medications: lithium, thiazide diuretics, calcitriol, calcium carbonate and antacids
PTH-independent
- Cancer
- Excess calcitriol (sarcoidosis or other granulomatous disease)
- Excess GI calcium absorption (milk-alkali syndrome)
- Endocrine disorders (thyrotoxicosis, phaechromocytoma, cortisol deficiency, VIPoma)
- Immobilisation
