Endocrine Flashcards
What are the inhibitory hypothalamic hormones, and what do they inhibit?
Somatostatin: Growth Hormone and TSH release
Dopamine: Prolactin release
Aldosterone
Mineralocorticoid, synthesised in zona glomerulosa
Released stimulated by Angiotensin II in response to hypotension and hyponatraemia
Target: DCT + collecting ducts → upregulated NaK pumps + ENaC channels, Hydrogen ion secretion
Cortisol
Glucocorticoid, synthesiased in zona fasciculata
Release stimulated by: ACTH in response to stress and hypoglycaemia
Androgens
SHEA produced in Zona reticularis, precursor to other steroids, particularly testosterone (converted in Leydig cells), and Oestradiol
Catecholamines
Adrenaline and Noradrenaline
Synthesised in adrenal medulla, not steroid hormones and not cholesterol based
Structures at risk in cavernous sinus syndrome
CN III, IV, V1, V2, VI
Carotid Artery
Most effective method of weight loss in obesity
Bariatric surgery
Criteria for metabolic syndrome
3 of the 5:
- Increased waist circumference
- Wait: hip ratio used
- Males >0.9
- Females >0.85
- Hypertension
- Triglycerides >1.7
- HDL <1.0
- Impaired glucose tolerance/insulin resistance
Key features of MEN1
- Primary hyperparathyroidism due to parathyroid adenoma -> severe hypercalcaemia
- Pancreatic tumours
- Pituitary adenomas, mostly prolactinoma
(3 Ps: Parathyroid, Pancreas, Pituitary)
Key features of MEN 2A
- Medullary Thyroid Carcinoma
- Pheochromocytoma
- Primary hyperparathyroidism
Key Features of MEN 2B
- Medullary thyroid carcinoma
- Multiple neurinomas
- ## Marfinoid Habitus
Gold standard management for BPH
TURP
Metabolites of Testosterone
5-alpha-reductase: Produces dihydrotestosterone, key for external genitalia formation, prostate development, hair follicles
Aromatase: produces oestradiol, acts on bone and brain and key for epihyseal fusion, bone mass, verbal memory
Most common congenital cause of primary hypogonadism?
Klinefelter Syndrome
Karyotype 47, XXY or Mosaic 46 XY
Small firm testes, infertility, learning difficulties
How are LH and FSH results interpreted in hypogonadism (i.e. low Testosterone)?
LH + FSH raised: Primary Hypogonadism
LH + FSH low: Secondary Hypogonadism, functional hypothalamic disorder
Congenital Causes of Secondary Hypogonadism
Kallmann’s Syndrome: associated with anosmia
Prader Willi
Contraindication to Testosterone Replacement Therapy
Hormone responsive tumours: prostate cancer, breast cancer
Key side effects of Testosterone Replacement
Erythrocytosis
Prostatic enlargement
Detection of subclinical prostate cancer
Acne
Gynaecomastia
Male pattern baldness
Worsening of heart failure
Transient worsening of OSA
Infertility due to reduced spermatogenesis
What are the Rotterdam Criteria for PCOS?
Need two of the three, with other endocrinological conditions excluded
- Oligo-ovulation and/or anovulation
- Hyperandrogenism (Acne, alopecia, hirsutism)
- Enlarged and/or polycystic ovary on ultrasound (volume ≥10ml and/or multiple cystic follicles in one or both ovaries)
PCOS Management
- Weight loss most effective - restores ovulation, increases insulin sensitivity, increased SHBG (reducing testosterone)
- COCP → increased SHBG, reduces free androgens
- Androgen blockade (i.e. Spiro)
- Letrozole and Clomiphene can be used for induction of ovulation
Gold standard test to distinguish central and nephrogenic Diabetes Insipidus?
Fluid deprivation test
- No change in urine output = DI
- Desmopressin given:
- Urine output drops: central DI
- Urine output unchanged: nephrogenic
What is Copeptin?
Prohormone for vasopressin.
Give patient hypertonic saline, which should drive rise in ADH to retain water and thus copeptin rises. In central DI, ADH not released, Copeptin level will be low.
Can do arginine stimulated copeptin level if serum sodium is normal, and then if very low indicates central DI
Key drug cause of Diabetes Insipidus?
Lithium
Management of Diabetes Insipidus
Central: Desmopressin, treat cause
Nephrogenic: Desmopressin doesn’t work. Need to remove cause
Differentiate Psychogenic Polydipsia and Diabetes Insipidus
Psychogenic Polydipsia:
- Low sodium, normal glucose
- Low plasma osmolality
- Dilute urine with low osmol <100
- Low urine sodium <10
Diabetes Insipidus
- High plasma osmolality
- Low urine osmolality <300
- Normal or high urine sodium
(So essentially in psychogenic polydipsia the kidney is trying to retain fluid, retaining sodium)
What is the gold standard diagnostic testing for Acromegaly?
OGTT is gold standard, but best test now is IGF-1 → elevated = diagnostic
Primary treatment for Acromegaly?
Surgical resection is first line, 80% success rate. IGF-1 levels for surveillance post op.
Somatostatin analogues such as Octreotide if levels high post op or can’t have surgery. Reduced GH release → reduce systemic symptoms and also reduce size of adenoma improving mass effect.
RTx also for recurrence post op
What is a key rare complication of Pegvisomant used for Acromegaly? Why does this occur?
Can cause tumour enlargement. This is because it doesn’t target the tumour directly, but instead prevents the excess GH from binding to its target. Also means GH levels/ IGF-1 levels remain high.
Second line agent after Octreotide. GH receptor antagonist.
HLA and Type 1 Diabetes
High Risk: DR3, DR4
Protective: DR2
Auto antibodies in Type 1 Diabetes Mellitus
Glutamic Acid Decarboxylase
Insulinoma Associated Ab
Proinsulin
Zinc Transport
Latent Autoimmune Diabetes of Adulthood
Subtype of T1DM
Initially responds to oral agents as Beta cells not yet depleted
Criteria:
- Age of onset ≥30
- Positive titre for a least one T1DM autoantibody
- Not treated with insulin within the first 6 months
Which other autoimmune disease is most closely associated with Type 1 Diabetes?
Autoimmune thyroid disease (27%)
Coeliac Disease (12%)
Key benefit of using closed loop system for T1DM?
Key benefit is lowering risk of severe hypoglycaemia. Also small HbA1c benefit
Benefits and Adverse Effects of intensive insulin therapy?
Reduces microvascular complications, particularly retinopathy and nephropathy.
Increases risk of severe hypoglycaemia and weight gain.
Benefits greater, and adverse effects lessened by insulin analogues compared to human insulin.
Estimation of Insulin requirements
0.5U/kg/day
Half given as basal
Half split through day as bolus doses, guided by patient
Insulin carbohydrate ratio and insulin sensitivity factor
ICR: grams or carbs/unit of insulin (around 500/total daily insulin)
ISF: effect 1U rapid acting insulin will have over a couple of hours (around 100/total daily insulin requirement)
SGLT2i in Type 1 Diabetes Mellitus
Not approved in Australia, but:
- reduce HbA1c
- Body weight reduction
- Lower daily insulin requirement
- Lower SBP
- Increased risk of ketosis
Metformin and Type 1 Diabetes
Small reduction in weight and lipids
No effect on HbA1c
Benefits of continuous glucose monitoring
Reduced time in hypoglycaemia without compromising HbA1c
Improve time in target range
Improve HbA1c
Benefits of Continuous SC insulin Infusion
Reduced hypoglycaemic events without increasing HbA1c
Improves Hb1c
Reduced hospitalisation for hypoglycaemia and ketoacidosis
Reduced work absenteeism
Improved QOL
Neurogenic/Autonomic Hypoglycaemia symptoms
Adrenergic: Palpitations, tremor, anxiety/arousal, pallor
Cholinergic: Sweating, hunger, paraesthesia
Occur at BGL <4
Neuroglycopaenic Hypoglycaemia symptoms
Cognitive impairment
Behaviour change
Psychomotor abnormalities
Seizures
Coma
Occur with BGL <3
Risk Factors for hypoglycaemia unawareness
Increasing age and long diabetes duration
Aggressive glycaemic control
Frequent hypoglycaemia
Autonomic neuropathy
Medications, e.g. beta blockers
Diagnosis of HHS
Serum BGL >30
Serum Osmolality >320
Dehydration
pH >7.3
Low ketones (<3)
Altered level of consciousness
Diabetic Neuropathy
Microangiopathy of vasonervorum causes nerve ischaemia
Length dependent sensory > motor neuropathy
Paraesthesia most common symtpom
Don’t forget autonomic neuropathy
Earliest manifestation of diabetic microvascular disease?
Retinopathy
Non Proliferative Diabetic Retinopathy
Subclinical, normal vision.
Microaneurysms, dilated venules, flame haemorrhages, cotton wool exudates, macular oedema
Proliferative Diabetic Retinopathy
Small vessel damage → reduced blood flow → VEGF release → neovascularisation → new vessels fragile and prone to rupture
Extensive neovascularisation
Retinal ischaemia
Fibrosis
Vitreal haemorrhage
Retinal detachment
Management: laser photocoagulation, intravitreal anti-VEGF (Bevacizumab)
Risk Factors for recurrence of diabetic ulcers
Loss of vibration (No. 1)
Preulcerative lesions
Peripheral arterial disease
Previous ulcer
Osteomyelitis
High GDS
Glucose transporters
GLUT2 brings glucose into beta cells which drives Insulin release
GLUT4 brings glucose into peripheral cells
Mature Onset Diabetes of the Young
Autosomal Dominant hereditary form of DM.
MODY3: most common and most severe, due to mutations of hepatocyte nuclear transcription factor 1. Treat with Sulphonylurea
MODY2: second most common, due to mutation of glucokinase. Mild hyperglycaemia, minimal treatment needed.
What is the first change seen in type 2 diabetes/impaired glucose tolerance?
Loss of first phase insulin secretion → post prandial hyperglycaemia
Treatment targets in Type 2 Diabetes
General <7.0%
New onset aim <6.0%
Reduction improves microvascular outcomes
Intensive control <6.5% increases mortality
SGLT2 Inhibitors
Block glucose reabsorption in proximal convoluted tubule. Low risk of hypoglycaemia, but have risk of euglycaemic ketoacidosis and UTIs. Contraindicated in renal impairment (Empa <30, Dapa <25)
Benefits.
Reduced HbA1c
Weight loss
Reduced blood pressure
Reduced MACE
Reduced HF hospitalisation, Empa reduced HF mortality and all cause mortality
Renoprotective
Metformin
Inhibit hepatic gluconeogenesis, no risk of hypo, modest weight decrease.
First line unless contraindicated. Severe renal impairment is key contraindication.
Risk of lactic acidosis, GI side effects. Hold when unwell
Sulfonylurea
Bind to ATP sensitive K channels on Beta cells → calcium influx → insulin secretion. High risk of hypoglycaemia which rises with age and renal/hepatic impairment.
Lead to weight gain. Contraindicated in hypoglycaemia and pregnancy as well as CrCl <15.
Not used much now. Gliclazide key example.
DPP4 Inhibitors
Inhibit DPP4 → reduced GLP-1 breakdown → Increased glucose dependent insulin secretion, slowed gastric emptying, inhibition of glucagon release, reduced appetite.
No risk of hypo with monotherapy. Contraindicated in renal impairment, and can worsen CCF (esp Saxagliptin). Linagliptin can be used in any CrCl.
End in “gliptin”
GLP-1 Agonists
Increase GLP-1 activity which increases glucose dependent insulin secretion, slowed gastric emptying, reduced glucagon release, reduced appetite, reduced hepatic steatosis.
Minimal hypoglycaemia risk, marked decrease in weight.
Mortality benefit for Liraglitide. Others reduce MACE and stroke risk. Semaglutide slows CKD progression.
Contraindicated in renal impairment, CrCl <30 (<15 for Dulaglutide)
Insulinoma
Insulin secreting neuroendocrine tumour of the beta cells, most common neuroendocrine tumour and most common cause of endogenous hyperinsulinism. Mostly benign.
5% part of MEN1. Present with sympathetic symptoms then neuroglycopaenic symptoms. High C peptide and proinsulin.
Tumour resection for localised disease. Octreotide can work while awaiting surgery.
Features of Thyroid Nodules concerning for malignancy
Hypoechoic
Height greater than width
Irregular margins
Calcification
Increased vascularity
Size >10mm
Workup for thyroid nodule
TFTs to ensure euthyroid
Ultrasound then done
Tc-99 scan can be done to further assess risk. Hot nodules typically benign, cold nodules concerning for malignancy
Biopsy lesions >10mm with high risk features and all >20mm
Thyroid Follicular Adenoma
Most common type of thyroid adenoma. 10-15% malignant but can’t tell on FNA so need to excise. If surgical excisional biopsy shows cancer then completion thyroidectomy + adjuvant therapy indicated
Monitoring thyroid cancers for response to therapy and recurrence
Medullary: Calcitonin
Follicular and Papillary: Thyroglobulin
Thyroid Cancer Subtypes
Papillary (80%): young females, good prognosis
Follicular (10%)
Medullary (5%): part of MEN2
Anaplastic (1%): Worst prognosis
Management of Papillary thyroid cancer
<1cm: Hemi or total thyroidectomy followed by surveillance
>1cm: Total thyroidectomy, radioactive iodine treatment with TSH stimulation, annual screening (USS, Thyroglobulin)
Mechanisms of Amiodarone thyroid toxicity
Type 1: increased thyroid synthesis due to excessive iodine (from the Amiodarone), responds to antithyroid drugs, occurs early in course of treatment
Type 2: Due to direct thyrocyte toxicity leading to inflammation. Typically self limiting, not responsive to antithyroid drugs. Responsive to steroids. More common
Colour doppler reduced in type 2, as it Sestamibi scan/
When in doubt use both steroids and ATDs
Benefit of Propranolol in Thyrotoxicosis
Slows heart rate like other beta blockers, but also reduces peripheral conversion of T4 to T3.
Indications for Radioactive Iodine in Hyperthyroidism
Second line after antithyroid medications.
Indicated in failed medical therapy or patients with contraindications to medical therapy
Hashimoto Thyroiditis Pathology/Pathophysiology
Antibodies to thyroid peroxidase drive CD8 T lymphocyte and Th1 lymphocyte response leading to thyroid gland destruction.
Lymphocytic infiltrates, plasma cells, new germinal follicles, colloid atrophy present in histology. Collagen deposition is a marker of longstanding disease.
What other Autoimmune conditions are associated with Hashimoto Thyroiditis?
Coeliac Disease
Type 1 Diabetes Mellitus
Vitiligo
Most common cause of hypothyroidism worldwide?
Iodine deficiency
Testing for Iodine Deficiency
Negative autoantibodies
High TSH, low T3/T4
24 hour urinary iodine post oral iodine loading will be low (as iodine is retained rather than excreted)
Complications of Iodine supplementation
Excessive replacement: hyperthyroidism (Jod-Basedow effect)
Wolff-Chiakoff effect: worsening of hypothyroidism initially due to transient downregulation of iodine uptake in follicular cells due to sudden rise in iodine concentration.
Threshold to treat subclinical hypothyroidism
TSH >10
What peripheral tissues can convert T4 to T3?
Liver
Kidneys
Skeletal muscle
Drug Causes of Graves’s Disease
Alemtuzumab (Humanised anti CD52)
Anti-retroviral therapy
Drugs that can influence TFT results
Amiodarone (High TSH, high T4, low T3)
Carbamazepine (low T4 and T3)
Enoxaparin (High T4 and T3)
Heparin (High T4 and T3)
Phenytoin (Low T3)
Biotin (High T4, low TSH)
Lithium and thyroid function
Causes hypothyroidism with goitre.
Due to reduced pinocytosis which impairs thyroglobulin release. Accumulates in cells and results in goitre formation.
Not linked to therapeutic range/dose. More common in women, prolonged use, TPO antibodies.
Common causes of impaired Thyroxine absorption
PPI
Antacid
Calcium carbonate
Alcohol
Soy
Milk
Features of a Pituitary Microadenoma
<1cm in diameter
Monoclonal
Majority are non functioning
<5% enlarge
Hypodense after gadolinium, due to reduced blood supply
Features and assessment of Pituitary Macroadenoma
> 1cm in diameter
To assess for function: Prolactin, TSH, fT4, Urinary Free Cortisol, IGF-1
Assess visual fields for mass effect
What does visual field defect indicate in assessment of pituitary adenoma?
Macroadenoma
What is the most likely aetiology of a pituitary mass that causes diabetes insipidus?
Metastasis - mets mainly spread to the posterior pituitary, so DI is classic of metastatic spread to the pituitary
Order of hormonal loss in hypopituitarism
GH, LH, FSH, TSH, ACTH
Craniopharyngioma
Embryonic remnants of Rathke’s pouch
BRAF V600E mutation
Mostly in kids, but make up 1% of adult intracranial tumours
Often calcified, with cystic component
Key mutations in Congenital Hypopituitarism
HesX-1
Pit-1 (GH, TSH, Prolactin)
Prop-1(Low GH, TSH, prolactin, FSH)
Pituitary Apoplexy
Generally due to haemorrhage. Don’t bleed into normal pituitary
Can mimic SAH
Need to give steroid as acute ACTH deficiency can be life threatening
Key indication for surgery is visual impairment
Radiotherapy and Pituitary function
Usually quite delayed, minimal in first 3 years
GH deficiency common, almost all at 5 years post
Then LH/FSH, ACTH, TSH
Lymphocytic Hypophysitis
Key cause of primary hypophysitis
More common in women, and particularly during pregnancy or post partum.
ACTH deficiency most commonly
Most common cause of immunotherapy related hypophysitis, and details
CTLA-4 (Ipilimumab)
(Some pituitary cells express CTLA-4)
ACTH most affected (ACTH only in PD1, total anterior pituitary in CTLA-4)
Visual field defects rare
DI is rare
What is the key receptor present on Pituitary Adenomas that allows treatment?
Somatostatin receptor
SST2: Octreotide (GH)
SST5: Likely to respond to Pasireotide (ACTH, GH)
D2: Dopamine agonist
Management of non functioning Pituitary Adenomas (PitNETs)
Asymptomatic don’t need anything acute if non functioning and vision normal
Transphenoidal pituitary surgery indicated if there are visual problems or enlarging
30% will regrow post surgery (more likely if silent corticotroph)
Post op RTx if regrowing post surgery
Medical therapy doesn’t work well for mass effect (doesn’t shrink tumour)
Why does compression of the pituitary stalk lead to hyperprolactinaemia?
Compression of stalk → reduced dopamine flow to pituitary → reduced inhibition of prolactin secretion → hyperprolactinaemia
What do the findings of a repeat MRI for a pituitary incidentaloma indicate?
If no growth on repeat MRI at 1 year, and remains non functioning, no further monitoring required
If any chiasmal compression or hypopituitarism
What is the key complication of pasireotide?
Reduces insulin and incretin levels → hyperglycaemia in 33%
GLP agonists particularly effective in managing this
What marker suggest poor response to Octreotide
High Ki-67 index
Assessment of adult GH deficiency
IGF-1 is useful but not diagnostic, can be normal despite deficiency.
The more other hormones are deficient, the more likely GH is to be deficient (3 deficient = 96% chance GH deficient)
Stimulation testing: Glucagon response <3 (<1 if obese) diagnostic
Impact of oral GH supplementation
Reduced cholesterol, improved cardiac function, improved quality of life, reduced body fat, improved insulin sensitivity.
No impact on cancer risk
Can increase conversion of cortisol to inactive form → may need glucocorticoid replacement
Oral oestrogens (e.g. women taking the pill) are relatively resistant to oral GH
Key spurious and physiologic causes of hyperprolactinaemia (Things to rule out)
Macroprolactinaemia (prolactin bound together by Ig, increases half life in circulation)
Pregnancy
Drugs: Metoclopramide, Domperidone, Fluoxetine, Verapamil, Oestrogens
If no clinical sequelae, not pregnant and not on any causative drugs, check macroprolactin levels.
Who do women present earlier with hyperprolactinaemia?
Women present earlier as menstrual cycle far more sensitive than testicular axis to changes in prolactin levels, and thus develop symptoms earlier.
Thus if men do present they typically present with a macroadenoma
What intermediary hormone/signalling molecule is inhibited in hyperprolactinaemia?
Kisspeptin - inhibited by prolactin and thus reduces the usual pulsatile GnRH secretion → bloackade of oestrogen induced LH surge.
Reduced gonadal steroid production results.
Which pituitary tumour is most common in MEN1, and what proportion of these tumours are part of MEN1 when they do occur?
Prolactinoma
10% of prolactinomas are part of MEN1
Management of Prolactinaemia
Dopamine agonism key
Bind to D2 receptor → increased dopamine → reduced prolactin synthesis and release
Normalise prolactin levels and shrink tumour
Cabergoline: more specific to D2 receptor than bromocriptine
Can cause valvular heart fisease, so need TTE if higher doses
Impulse control disorder is significant issue, need to screen
Tumour shrinkage occurs within days so often can avoid surgery evenin in patients with visual field defects
20% can remain in remission after discontinuation of Cabergoline
What electrolyte imbalances can mimic nephrogenic DI?
Hypercalcaemia and hypokalaemia can down regulate AQP2 channels → clinical picture similar to nephrogenic DI
What additional activity does PTU have over Carbimazole?
Also reduces peripheral conversion of T4 to T3
Which patients are most likely to go into remission with medical therapy for Graves Disease?
> 40 years old
Mild disease (fT4 <40)
Low TRAB levels (<3x ULM)
No goitre
Key risk factors for PTU that mean Carbimazole is preferred
Hepatotoxicity can be fulminant with PTU
PTU can also induce an ANCA positive, Lupus like vasculitis
Only times PTU us preferred: 1st trimester pregnancy, Thyroid storm
Carbimazole can cause pancreatitis
What is the key contraindication to Radioiodine therapy for Graves Disease?
Active Graves orbitopathy - radioactive iodine still stimulates TSH receptors, leading to worsening of gravers ophthalmopathy
What is an additional therapy that can improve mild Graves Orbitopathy?
Selenium 100mcg BD
Other treatment for severe disease:
- IV Methylprednisolone
- Cyclosporin, RTX, Toci
How does non toxic goitre progress?
Initially due to combination of genetic and environmental factors, typically relating to low iodine intake. Initially causes diffuse hyperplasia, but over time somatic mutations lead to focal epithelial proliferation and formation of nodules. These nodules may become hyper functioning (toxic) nodules which are autonomous → hyperthyroidism
Management of Toxic Nodule Goitre and Toxic Adenoma (and post treatment outcomes)
Radioactive Iodine is treatment of choice, works very well
Rates of post op hypothyroidism are low because the remainder of the thyroid doesn’t take up the iodine due t low TSH
Conditions that don’t show any uptake on Thyroid Scintigraphy
Thyroiditis, exogenous thyroid hormone excess, Iodine exposure
Thyroiditis
Inflammation leads to release of thyroid hormone stores. No overproduction of thyroid hormones
Wolff Chaikoff Effect
Expected response post iodine load - transient reduction in thyroid hormone production due to downregulation of sodium iodine transporter
Euthyroid state returns within 24-48hr
Jod-Basedow Phenomenon
Pathological response to exogenously administered iodine.
Occurs in patients with impaired thyroid autoregulation
Results in thyrotoxicosis as thyroid can take up iodine autonomously
Drug induced thyroid disorders
Alemtuzumab: reconstitution syndrome → Graves
ICI: Graves
TKI: Hypothyroidism
When to treat subclinical hypothyroidism
Pregnancy
<70 years of age and TSH >10
All other situations unclear
Should send TPO antibodies - 60-80% actually have undiagnosed Hashimoto’s
Subclinical Hyperthyroidism
Mild: TSH 0.1-0.4; Severe <0.1
Increases risk of cardiac mortality and AF as well as fracture risk
Treat if: TSH <0.1, also consider when mild if >65 or known cardiac disease
What occurs in sick euthyroid?
Impaired peripheral conversion of thyroxine, and reduced TSH, so everything usually low initially
No treatment required, no evidence of benefit for thyroid replacement. Just repeat once well
Why are higher doses of thyroxine needed during pregnancy?
Some increased demand, but also higher thyroid binding globulin, meaning more needed to saturate this and have normal functional free thyroid hormone
Leading cause of mortality in Myxoedema coma?
Respiratory failure
Leading cause of adrenal insufficiency?
Autoimmune Adrenalitis >90%
Key HLA: DR3-DQ2, DR4-DQ8
Driven by CD8+ T cells, reacting against 21-hydroxylase
60% is autoimmune polyendocrine syndrome
AIRE gene mutation
Accompanied by hypoparathyroidism, candidiasis (type 1)
Autoimmune thyroid disease and T1DM (type 2)
Adrenal insufficiency + Neurological features
Adrenoleukodystrophy
Why is TSH high in adrenal insufficiency?
Loss of cortisol’s inhibitory effect
Testing for Adrenal Insufficiency
Normal Synacthen, high ACTH, low Aldosterone, high renin, low DHEAS, 21-hydroxylase antibodies,
Ab negative: check VLCFA in males, image adrenal for mets, TB, lymphoma, APLS Ab
Critical Illness Corticosteroid Insufficiency
Prolonged high cortisol, plus opioids and possibly steroid use lead to significant suppression of ACTH.
Over time response blunted, can’t then stimulate cortisol release
Clinical diagnosis, no good testds
Key investigation for Congenital Adrenal Hyperplasia
17-hydroxyprogesterone
Mutation of CYP21A2 gene, leading to 21-hydroxylase deficiency
Loss of cortisol and if severe aldosterone
Can be salt wasting, and need mineralocorticoid replacement to manage this
Primary Hyperaldosteronism
Most common cause of secondary hypertension
Increasess risk of: stroke, MI, CCF, AF, renal impairment
Mx: Adrenalectomy for unilateral hyperaldosteronissm. MRA for bilateral forms
Majority is bilateral hyperplasia
Only 25% have hypokalaemia. If present need to correct before doing aldosterone:renin ratio, as hypokalaemia suppresses aldosterone production
Aldosterone:renin ratio and impact of different medications
Raised ratio = hyperaldosteronism
Stop diuretics and spiro 6 weeks before testing
Others 2-4 weeks prior
Beta blockers: decrease renin (can cause false positive)
ACEi: drop Aldosterone, increase Renin (false negative)
Diuretics: increase renin (false negative)
DHP CCB: decrease aldo, increase renin (false negative)
So all cause false negatives except beta blockers
Agents to use: non DHP CCB, Prazosin, Hydralazine, moxonidine
Confirmatory testing for hyperaldosteronism
ARR has poor specificity, so confirmatory testing important
Can skip if: hypokalaemia, undetectable plasma renin, plasam aldo >550
IV Saline test → Aldosterone >171
Captopril test: Aldosterone drops, renin rises, ARR reduced
Then do CT: if unilateral adenoma and patient <35, presume functioning. Can identify carcinomas, and find hyperplasia which just needs medical mnagement.
Adrenal venous sampling otherwise - gold standard for subtyping
Familial Hyperaldosteronism
Rare, but type 1 can be treated with dex, so important to be aware of
Check if PA in very young patient
CYP11B1, CYP11B2
Target for medical management of bilateral adrenal hyperplasia
Not used for secretory adenoma (Surgery better, though no mortality benefit).
Aim for normal BP, normal K, normal plasma renin
Predominant type of adenoma when found incidentally
Non functioning (75%)
Of remaining functional, cortisol producing most common
Adrenal mass and metastasis
Only time biopsy is indicated (once phaeo excluded)
An adrenal mass found in a patient with history of malignancy will be a met in 20% of cases
Management of suspicious adrenal lesion
Adrenalectomy usually
Can do biopsy if high likelihood of met
Confounders when testing metanephrines
TCAs, SNRI, MAOI, Levodopa, Methyldopa, CCB, Beta blockers, labetalol, Caffeine, Paracetamol, Mesalazine, Sulfasalazine
If not >3x ULN with these medicatiosn avoided, do Clonidine suppression test
Normetanephrine vs metanephrine
Normetanephrine higher when lesion is extra-adrenal. i.e. Paraganglioma
Management of phaeochromocytoma
Surgery, but need to control hormones first to avoid haemodynamic instability.
Give alpha blockade before beta blockade, but do give both
To prevent unopposed alpha activity which can cause circulatory collapse
Metastatic disease: chemotherapy or radiotherapy options
Mutations in Phaeochromocytoma
SDHB, SDHD, VHL, RET, NF1
Plus associated with MEN-2
Benefit of 1mg overnight dex suppression test
High NPV, useful in shift workers, best test for cortisol secreting adrenal adenomas.
When to do 24hr urinary free cortisol
Pregnancy, on OCP, on Carbamazepine, Malabsorption
Highly specific test for Cushing’s Disease
Desmopressin test: ACTH secreting adenomas express vasopressin V1b receptors, prodsucing an increase in plasma ACTH concentration after desmopressin injection
Next steps once Cushing’s Syndrome confirmed
ACTH:
High → image pituitary → inferior petrosal sinus sampling
Low → image adrenals
Can do CRH levels, Desmopressin test, etc. if MRI pituitary shows large mass, to confirm this is the cause
Location of ectopic ACTH producing NETs
Neck and Chest mostly
Management and Recurrence of Cushing’s Syndrome causes
Cushing’s Disease: pituitary surgery → repeat surgery or medical therapy or radiotherapy
Ectopic Cushing’s: surgery if possible
Adrenal adenoma: Adrenalectomy, unusual to recur unless carcinoma → poor prognosis
Pathophysiology of PCOS and blood test results
ABnormality of GnRH pulsatile release → Increased LH release → raised LH/FSH ratio
Insulin resistance due to obesity
Ovulatory dysfunction → hyperandrogenism, follicular arrest
Low oestrogen, high testosterone is result
Bloods: Raised testosterone, low SHBG, raised DHEAS, raised LH/FSH ratio, elevated AMH (this isn’t in diagnostic criteria)
OGTT is best test in PCOS for diabetes
What to exclude when trying to diagnose PCOS
CAH: 17OH progesterone (<6 = excluded)
Hyperprolactinaemia
Cushing’s Syndrome, 24h UST, DST
Acromegaly: IGF-1
Hypothyroidism
Androgen secreting tumours: imaging
Most effective means to induce ovulation in PCOS
Letrozole (i.e. Aromatase Inhibitor)
Functional Hypothalamic Amenorrhoea
Absence of menses due to stress, weight loss, xercise
No identifiable anatomic/organic cause
Under or normal weight
GnRH pulsatility suppressed → high cortisol, low/N TSH, low T3, low IGF-1, low leptin, low FSH, low LH, low oestrogen
Low bone density
FGFR1 most common gene associated with risk
Need to exclude pregnancy
Check prolactin and pituitary function
Provera challenge to exclude PCOS (get withdrawal bleed if PCOS), no bleed with FHA
Weight gain is key management
Calcium and Vit D for Osteoporosis
Primary Ovarian Insufficiency
Essentially menopause early, <40 years of age
Diagnosis: raised FSH in menopausal range (usually >40) on ≥2 occasions
Most cases idiopathic/unknown, but can be induced by chemo, radiotherapy, Fragile X, autoimmune (autoimmune polyendocrine syndrome 1 and 2)
Tests: raised FSH, low oestradiol, FMR-1 for Fragile X,
Management: HRT, donor oocytes for fertility
Spontaneous pregnancy can occur
46XY Complete Gonadal Dysgenesis
Essentially should be male based on karyotype, but SRY gene on Y chromosome not working → female phenotype, but ovaries don’t develop properly as need both X chromosomes for this → have female external genitalia but only gonadal streak
Leads to primary amenorrhoea
Gonadal streaks need to be removed
High FSH and LH
Low Oestradiol
Normal testosterone
Management: HRT → development of secondary female sex characteristics, remove streak gonads, assisted reproduction
Complete Androgen Insensitivity Syndrome
Female external genitalia, but no internal structures as mullerian inhibitory factor present to block this. Testis present → tesotsterone aromatased → normal breast development
46XY karyotype, normal or high testosterone, LH normal or high
Turner Syndrome
1:2500 live female births
Loss of whole or part of X chromosome → 45X most common karyotype
Short stature
90% have ovarian failure
Oocytes lost rapidly, all lost by puberty → infertile
Bicuspid aortic valve (16%), Coarctation of aorta (11%)
30% hypothyroidism
Hypertension
SNHL
Renal tract abnormalities
Diabetes
Give GH, HRT
Use of HRT in Menopause
Is risk of breast cancer with long term use, as well as cardiovascular disease
If used in patients <60 without history of CVD, Breast rCa, VTE → risks minimised
Generally can use safely if within 10 years of menopause
Need E and P to prevent endometrial cancer
SSRIs can be useful
Kallman Syndrome
Hypogonadotrophic hypogonadism + anosmia
Men
ANOS1 or KAL1 X lnked recessive
GnRH and Olfactory neurons don’t work properly
Presents at puberty
Check for renal agenesis, SNHL
lfactory bulkb/tract absent on MRI
HRT with testosterone → induced puvberty
Induction spermatogenesis
Can recover spontaneously
Klinefelter Syndrome
47XXY, or 46XY/47XXY mosaic
Tall, feminized physique, mild IQ impairment, poor beard growth, bresst development
Raised FSH and LH, low testosterone
Associated with T2DM, Osteoporosis, Thyroid disease, ILD, Breast cancer
Mx: Testosterone, increased risk of chromosomal abnormalities in offspring
What needs to be excluded prior to commencing testosterone replacement for male hypogonadism?
Other risks
Prostate Cancer
Doesn’t increase risk of cardiovascular disease, but can cause polycythaemia
Phases of Menstrual Cycle
Median length 28 days
Follicular phase: 1st day of menses to ovulation. Oestradiol levels secreted by developing follicles → stimulates LH surge → ovulation
Ovulation
Luteal phase: corpus luteum formed post ovulation, secretes progesterone which stimulates endometrial growth
Key hormone for diagnosis of CAH (and hormone deficient)
Test 17-OH progesterone
But 21 hydroxylase is what’s lost → prevents conversion of 17-OH progesterone into cortisol and progesterone into aldosterone in most severely affected patients
Steroid replacement for management
In what form is the majority of calcium in the body?
Ionised
Calcium reabsorption
Passive paracellular reabsorption in PT and TAL (90%)
- Calcium sensing receptor regulates calcium absorption in TAL
- This reabsorption is tied to Mg reabsorption
Active reabsorption in DCT (10%) - mediated by PTH
Familial Hypocalciuric Hypercalcaemia
Inactivating mutation of Calcium Sensing Receptor → doesn’t stop calcium reabsorption (in kidneys), doesn’t turn of PTH production (in parathyroids)
Leads to mild-moderate PTH dependent hypercalcaemia
AD inheritance. CaSR gene, G alpha 11 gene
Key for diagnosis: Inappropriately low urinary calcium excretion
Hypermagnesaemia common
Doesn’t cause kidney stones or osteoporosis another key differentiator
PTH action on kidney
Stimulates transcellular calcium reabsorption in DCT
Phosphate excretion in PT
Stimulates 1-alpha-hydroxylase → 1,25 Vit D synthesis
FGF23
Key regulator of phosphate levels
Levels rise when phosphate rises, blocking PT reabsorption, and downregulates bone resorption
Decreases PTH synthesis
Release stimulates by: PTH, phosphate levels, 1,25 Vit D
What cells produce PTH?
Parathyroid chief cells
Benefits of Parathyroidectomy
Reduced fracture risk
Reduced kidney stones
Slows progression of CKD
Indications: Renal involvement key, CRCl <60, nephrolithiasis, nephrocalcinosis
Routine imaging for parathyroids
Ultrasound and Technetium 99 sestamibi to identify location of nodes and any enlargement
Non operative options for management of hyperparathyroidism
Bisphosphonates if only issue is reduced BMD. Improves BMD as much as PTx
Cinacalcet for those unfit for surgery with severe/symptomatic hypercalcaemia. Doesn’t improve BMD. Stimulates CaSR.
Romosozumab mechanism and other detail
Inhibits sclerostin → increased bone formation, reduced resorption
Contraindicated with history of MI/Stroke
Used only when people have very poor BMD despite being on another antiresoprtive agent and still having fractures
Osteoblasts
Form bone, can be inhibited by high PTH levels
ALso make hydroxyappatite, important for bone mineralisation
Osteocytes
Osteoblasts initially, that get trapped in cortical bone and then become osteocytes
At baseline secrete sclerostin, inhibiting bone formation (i.e. block Osteoblast activity). With mechanical stress to bone, sclerostin production stops → bone remodelling to respond to stress
Produce RANKL which stimulates osteoclastogenesis and increases bone resorporption
Osteoclast
Bone resorption
Formation and activation stimulated by osteoblasts/osteoclasts via RANKL
RANKL activity stimulated by PTH and Vitamin D
RANK on osteoclasts precurors stimulated.
Osteoprotegerin is a soluble decoy receptor for RANKL, so increased level blocks osteoclast activation (Denosumab mimics this)
Oral calcium and peak bone mass
Small benefit
Who to treat for osteoporosis
T score < -2.5
Fracture of hip or vertebra regardless of T score
Osteopaenia at femoral neck or total hip with 10 year FRAX risk ≥3% or MOF risk ≥20%
Osteopaenia with other fragility fractures (wrist, pelvis, proximal humerus)
Role of Trabecular Bone Score
Assess actual microstructure of the bone, can adjust FRAX probability of fracture
Role of Z score in Osteoporosis
For assessment of secondary causes of osteoporosis, by comparing to expected for age: If within 2 SD of expected, unlikely to have secondary osteoporosis
Role of bone turnover markers and bisphosphonate use
Crosslaps (CTX) should be low when on bisphosphonates
Should be used to monitor effect
Can use CTX, ALP, P1NP to monitor for wearing off of effect during bone holiday
Which patients should receive calcium and Vitamin D supplements
Those on bisphosphonates, and those in RACF. Plus Vit D for those who are deficient in community, and calcium for those without adequatedietary calcium. But if levels normal, not required.
Bisphosphonate mechanism
Inhibit osteoclast activity by inducing osteoclast apoptosis
When to repeat DEXA post antiresorptive commencement
Need to wait at least 2-3 years, otherwise won’t necessarily have seen benefit
Compare fractures related to bisphosphonate (atypical femoral fractures) and fractures related to osteomalacia
Bsiphosphonate fractures begin at lateral cortex
Osteomalacia medial cortex
Denosumab side effects
Osteonecrosis of jaw, atypical femoral fracture
Cellulitis and Eczema are classic issues
Rapid loss of BMD if stopped without replacement
Key serious risk of Teriparatide
Osteosarcoma
Physiologic function of Sclerostin
Binds to Wnt to block Osteoblast formation -> reduced bone formation
Mechanism of Romosozumab
Inhibits sclerostin activity -> stimulates bone formation, inhibits bone resorption
Possible increase in cardiovascular risk
Used in patients with severe osteoporosis, still having fractures despite antiresorptive therapy
Reduces risk of vertebral and hip fractures
Mechanism of steroid induced osteoporosis
Glucocorticoids inihibit osteoblastogenesis and also damage osteocytes -> reduced bone formation, and reduced remodelling in response to mechanical stress = poor quality bone
So someone on steroids will have lower bone quality and strength than someone not on steroid with same BMD
Who to treat for steroid related osteoporosis?
Previous fracture OR age >70 OR Prednisolone dose >7.5mg/day
If not previous fracture, age <70 or Pred dose <7.5mg/day, then treat if T score < -2.5, FRAX MOF >20% or Hip Fracture >3%
Bisphosphonates first line, but Denosumab and Teriparatide also work
Role of testosterone replacement in hypogonadism for osteoporosis
Testosterone treatment doesn’t lower incidence of fracture compared to placebo
When to use calcium citrate over calcium carbonate?
When patient is on a PPI. Carbonate required stomach acid to assist with absorption and should be taken with food.
Vitamin D and calcium absorption
Vitamin D promotes active transcellular absorption via TRPV channels in proximal small intestine
Paget’s Disease of the Bone
Consider with isolated ALP rise
Only treat if symptomatic or in high risk location
Waist circumference cut offs
Men: 102cm
Women 88cm
Basal Metabolic Rate and obesity
Rising as weight increases, not decreasing. Makes up 50-70% of total daily energy expenditure
Leptin
Secreted by white adipose tissue
Low leptin drives appetite
Overweight individuals are resistant to Leptin, so body thinks it has low levels
Ghrelin
Orexogenic - released during fasting to stimulate appetite
Released by Oxyntic glands in fundus and body of stomach
Increases with fasting
Increases gastric emptying
GLP-1
Anorexigenic - released post prandially and induce satiety
Secreted by enteroendocrine L cells
Release stimulated by presence of food in small intestine
Stimulates insulin release, decreases gastric emptying and increases beta cell mass
CCK
Anorexigenic - released post prandially and induce satiety
Secreted by Intestinal I cells when fat and protein in duodenum
Also stimulates gall bladder contraction, slows gastric emptying and promotes pancreatic enzyme secretion
Pancreatic Polypeptide
Anorexigenic - released post prandially and induce satiety
Secreted by pancreatic F cells in presence of food, particularly high protein content
Regulates pancreatic exocrine secretion, modules gastric acid release and GI motility
Neurohormonal mechanisms and bariatric surgery
Key mechanism for effect - essentially get food into small intestine earlier = earlier release of satiety hormones
