Endocrine Flashcards
1
Q
HLA genes in T1DM
A
Account up to 90% of T1DM patients (uptodate)
- DR3-DQ2
- DR4-DQ8
2
Q
HLA-associated disease in T1DM
A
- 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
3
Q
Pathophysiology of type 1 diabetes
A
Genetic predisposition (MHC, Ins) + environemntal modifiers –> development of autoantibodies + autoreactive T cells to insulin –> beta cell injury –> insulin deficiency
4
Q
Environmental risk factors for T1DM
A
- Maternal enteroviral infection
- Older maternal age
- Enteroviral infection
- Infant weight gain
- Overweight or increased high velocity
- Puberty
- Insulin resistance
- Psychological stress
5
Q
Environmental protective factors for T1DM
A
- Higher maternal vitamin D or concentrations in late pregnancy
- Higher omega-3 fatty acids
6
Q
Antibodies associated with T1DM
A
- 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%
7
Q
Beta-cell specific antigens in T1DM
A
Insulin and ZnT8
8
Q
Risk of microvascular complications in T1DM
A
From highest to lowest
Retinopathy > Nephropathy > Neuropathy > Microalbuminuria
9
Q
In DCCT trial, what subgroups did not demonstrate benefit with intensive therapy?
A
- Pts with recurrent hypoglycaemia
- Pts with macrovascular complications
- Young children
10
Q
Examples of ultra short acting insulin (0-4hrs)
A
Lispro insulin (Humalog)
Aspart insulin (NR, Fiasp)
Glulisine (Apidra)
11
Q
Examples of short acting insulin (0-6 hrs)
A
Actrapid
Humulin
12
Q
Examples of intermediate acting insulin (0-14 hrs)
A
Isophane (Protaphane, Humulin NPH)
13
Q
Examples of long acting insulin (24 hours)
A
Glargine insulin, Detemir insulin (Optisulin/Lantus, Toujeo, Levemir)
14
Q
Examples of ultra long acting insulin (72 hours)
A
Degludec (Ryzodeg)
15
Q
Pharmacokinetic benefits of CSII over MDI
A
- Reduced variation in absorption
- Eliminates most of SC insulin depot
- Predictable absorption
- Stimulates normal pancreatic function
16
Q
Clinical benefits of CSII over MDI
A
- Reduced HbA1c
- Reduced severe hypoglycaemia
- Improved QoL
17
Q
Disadvantages of CSII over MDI
A
- Expensive
- Major complications - site infection, DKA (dislodgement of cannula)
18
Q
Patient selection in pancreas and islet transplantation
A
- Usually patients with recurrent, severe hypoglycaemia with unawareness
19
Q
Outcomes of pancreas and islet transplantation
A
- Reduced hypoglycaemia with improved HbA1c
- Reduced insulin dose/frequency of injections
- Insulin independence
- Improved QoL
20
Q
Diagnostic criteria for LADA
A
- Adult (30-75 yrs)
- Diabetes
- Evidence of islet autoimmunity (GAD Ab > 5 units)
- Period of insulin independence (has received diet and antidiabetic therapy)
21
Q
“Distinguishing” clinical features of LADA over T2DM
A
Usually age < 50
Acute symptoms
BMI < 25
Personal history or FHx of autoimmunity
22
Q
Importance of detecting AI diabetes in adults
A
- Avoidance of SGLT2 inhibitors –> risk of ketoacidosis
- Alteration and/or escalation of oral hypoglycaemic drug treatment
- Early commencement of insulin
- Screening for AI conditions
23
Q
Pathophysiology of T2DM
A
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
24
Q
Physiology of insulin secretion
A
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
25
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
26
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
27
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
28
Diabetic medications working on incretin pathway
DPP-4 inhibitors (-gliptan)
GLP1 receptor agonists (-glutide)
29
MOA of SGLT2 inhibitors
Increases glucose reabsorption in kidneys in proximal tubule
30
How much glucose goes through kidneys in a day?
(180L/day)(900mg/L) = 162g/day
31
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)
32
Findings of UKPDS substudy
MF initiated in newly diagnosed pts with T2DM is associated with reduction in risk of MI
33
Findings of STENO-2
Multifactorial intervention targeting glycaemia, BP, dyslipidaemia, reduces CV death and microvascular endpoints in T2DM with microalbuminuria
34
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
35
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
36
MOA of tirzepatide
Dual receptor GLP1/GIP receptor agonist
37
MOA of Icodec
Weekly insulin analougueM
38
MOA of retatrutide
Triple GIP/GLP-1/glucagon receptor agonist
39
Hormones increased and reduced from adipose tissue
Increased:
Visfatin
Resistin
Leptin
FGF-21
RBP-4
Cortisol
Reduced:
Adiponectin
40
Cytokines released by adipose tissue
TNF-alpha
IL-1B
IL-6
PAI-1
MCP-1
41
Effects of leptin and adiponectin
Leptin - inhibits hunger
Adiponectin - increases hunger
41
Gut hormones that inhibit satiety
PYY
Oxyntomodulin
PP
CCK
GLP-1
Amylin
Insulin
Leptin
Pancreas specific - pancreatic polypeptide
42
Gut hormones that stimulate satiety and hunger
Ghrelin
ILP5
43
Effect on leptin as BMI reduces
Leptin reduces --> increase in appetite
44
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
45
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
46
Important investigation for CAH
17-OH progesterone
- increased in response to deficiency in 21-hydroxylase
47
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
48
Other deficiencies in CAH
11β-hydroxylase deficiency
17α-hydroxylase deficiency
49
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
50
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
51
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)
52
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)
53
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
54
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
55
Action of glucocorticoids
Hyperglycaemia
Muscle catabolism
Fat deposition
Anti-inflammatory
Bone catabolism
Hypertension
56
Definition of Cushing's syndrome
GC excess
57
Definition of Cushing's disease
ACTH producing pituitary adenoma
58
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
59
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)
60
Causes of mineralocorticoid excess and ARR diagnosis
Low renin, low aldosterone
Exogenous mineralocorticoid
Cushing's syndrome
Licorice
CAH/11b hydroxylase deficiency
Liddle's
61
Medications that have minimal effects on aldosterone levels
Verapamil SR
Hydralazine
Prazosin
62
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
63
Diagnosis of primary aldosteronism
Hypokalaemia, aldosterone excess, HTN
Elevated ARR
Saline infusion - confirm inadequate aldosterone suppression
Adrenal CT
Adrenal vein sampling
64
Treatment of primary aldosteronism
Unilateral - unilateral laparoscopic adrenalectomy > medical therapy i.e. spironolactone
Bilateral - medical therapy > unilateral laparoscopic adrenalectomy
65
Clinical presentation of phaechromocytoma
Headache
Palpitations
Sweating
Tremor
Nausea
Low BMI
Tachycardia
66
Diagnosis of phaeochromocytoma
Plasma free metanephrines
Genetic testing
Imaging CT/PET scan - heterogenous, large, HU > 30
67
Treatment of phaeochromocytoma
Surgery with alpha blockade (BP < 130/80) +/- beta blockade if tachyarrhythmia
68
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.
69
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
70
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)
71
Effects of LH and FSH on hypogonadism
LH --> Leydig LH-R --> testosterone
FSH --> Sertoli cell FSH-R --> spermatogenesis
72
Thyroid specific genes that regulated by TSH signal
Sodium iodide symporter
Thyroid peroxidase
Thyroglobulin
73
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+
74
Clinical features of Grave's disease
Diffuse goitre + ophthalmopathy + hyperthyroidism
75
Diagnosis of Graves disease
Thyroid receptor antibodies + TPO Ab
Tc99 scan
76
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
77
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
78
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
79
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)
80
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
81
Familial hypokalaemic periodic paralysis associated with Graves'
Due to transient severe hypokalaemia
Occurs after high carb meals or severe exercise
Seen in Asian people
82
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
83
Treatment of hypothyroid women in pregnancy
Treat thyroxine dose by ~1.3x to cover increased requirement in first trimester
84
Presentation of toxic nodules
Usually presents with thyrotoxicosis
DUe to activating somatic TSHr mutation
85
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
86
Causes of thyroiditis
Idiopathic
Post pregnancy
Hashimoto's
Amiodarone
Immune checkpoint inhibitors
Lithium
87
Effects of amiodarone on thyroid
- Hypothyroidism - interference of T4 synthesis and action
- Thyrotoxicosis - due to iodine load (type 1) and/or thyroiditis (type 2)
88
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
89
Lithium effect on thyroid
Inhibits T4 production and secretion resulting in hypothyroidism
Can also cause transient thyroiditis
90
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
91
Effect of alemtuzumab on thyroid
Anti-CD52
Graves' disease is common
Thyroiditis can also occur in rare circumstances
92
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
93
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
94
Indication of investigation and treatment of subclinical hyperthyroidism
- TSH < 0.1
- Symptoms of thyrotoxicosis
- Co-existing AF or OP
95
Most common thyroid carcinoma
Follicular carcinoma
Monitor with thyroglobulin
96
Most severe thyroid carcinoma
Medullary carcinoma
Monitor with calcitonin
97
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
98
Suspicious features of thyroid docules
Irregular borders
Microcalcifications
Hypoechogenicity
99
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
100
Genetic drivers of papillary thyroid carcinoma
BRAF V600E
RTX fusions - RET > NTRK > others
RAS - NRAS > HRAS> KRAS
101
Pathophysiology of medullary thyroid cancer
C-cell hyperplasia resulting in carcinoma, causing secretion in calcitonin
Associated with RET proto-oncogene (MEN2B)
102
MEN2A characteristics
Phaeochromocytoma
Hyperparathyroidism
Medullary thyroid carcinoma
Hirschsprung's disease
Cutaneous lichen amyloidosis
103
MEN2B characteristics
Mucosal neuromas
Marfanoid body habitus
Medullary carcinoma
Phaeochromocytoma
104
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
105
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
106
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
107
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
108
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
109
Effects of non functional pituitary adenoma
Most stain for FSH
May cause mass effect and anterior pituitary failure
Prolactin elevated due to stalk pressure
110
Clinical features of prolactinoma
Hypogonadism (infertility, amenorrhoea)
Breast tenderness and discharge
High serum prolactin
111
Approach to prolactinoma
Exclude hypothyroidism (TRH stimulates release of prolactin)
Exclude drugs
Perform MRI pituitary to confirm diagnosis
Commence dopamine agonist to normalise prolactin
112
Dopamine agonists for prolactinoma
Bromocriptine daily
Cabergoline weekly
113
Side effects of dopamine agonist
Hypersexuality
Compulsive buying
Punding
114
Common causes of hyperprolactinaemia
Pregnancy/lactation
Hypothyroidism
Metoclopramide
Neuroleptics
Stress
Pituitary stalk pressure
Opioids
115
Pregnancy effect on pituitary
Pituitary size increases in pregnancy due to lactotroph hyperplasia
116
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
117
Hypercortisolism with low ACTH
Exogenous steroid
Adrenal tumour
118
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
119
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
120
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
121
Common cause of ectopic ACTH
Due to SCLC or lung carcinoid
122
Cause of ectopic CRH
Carcinoid
Small cell carcinoma
Medullary thyroid carcinoma
123
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
124
Pegvisomant MOA
GH receptor antagonist
Daily SC injection, funded if IGF-1 elevated despite somatostatin analogue
125
Comorbidities of acromegaly
Thyroid cancer is most common cancer
Increased risk of colon cancer
Joint damage
Cardiovascular disease more likely
Glucose intolerance
126
TSHoma clinical features and diagnosis
Thyrotoxicosis with elevated fT4 and/or fT3 and non-suppressed TSH
Due to TSH secreting pituitary tumour
127
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)
128
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
129
Pituitary apoplexy causes
Sudden pituitary haemorrhage
Postpartum haemorrhage - Sheehan's syndrome
Trauma
Enlarging adenoma
130
Clinical features of pituitary apoplexy
Frontal headache
Neuropraxias
131
Approach to pituitary apoplexy
Hormones including prolactin
IV steroid replacement
Imaging
Surgery if indicated
132
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
133
Mechanism of osteoblast
Makes new bone
Mineralises collagen
134
Mechanism of osteocyte
Mechanosensor
Secretion of FGF23 and sclerostin
135
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
136
Role of RANK ligand
Mediator of osteoclast formation, function and survival
137
Role of OPG
Decoy receptor that prevents RANK ligand binding to RANK, thus inhibiting osteoclast formation/function/survival
138
Osteoporosis pathophysiology
Excessive remodelling --> structural deterioration --> increased skeletal fragility --> increased fracture risk
139
Definition of osteoporosis
BMD score < -2.5
Minimal trauma fracture
140
Occurrence of osteoporotic fractures
Radiographical vertebral > wrist fracture (in younger) and hip fracture (in older)
141
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
142
Use of Z score
<-2 may be useful in identifying patients with underlying accelerated causes of bone loss
143
Secondary causes of bone loss
Hypogonadism
Vitamin D deficiency
Hyperthyroidism
Hyperparathyroidism
Coeliac disease
Multiple myeloma
Drugs - corticosteroids, AEDs, GnRH agonists, aromatase inhibitors
Chronic diseases
144
MOA of bisphosphonates
Prevents osteoclasts from resorbing bones
145
MOA of SERMS/estrogen
Change RANK-L/OPG ratio to inhibit osteovlast formation
Binds to estrogen receptor
146
MOA of Denosumab
Binds to RANK-L and inhibitors it
147
MOA of anabolic therapy i.e. teriparatide
Binds to G protein coupled receptor and stimulates PTH to promote bone formation
148
MOA of romosozumab
Monoclonal antibody against sclerostin
Acts by increasing bone formation and reducing bone resorption
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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
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Osteomalacia presentation
Bone pain
Fractures (usually stress-type)
Myopathy (waddling gait)
Elevated ALP
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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
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Iron deficiency and FGF23
Iron deficiency increases FGF23 transcription
IV iron replacement prevents FGF23 cleavage
Thus iron transfusion results in increase phosphaturia --> hypophosphataemia
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Genetic cause of hypophosphataemia
X-linked hypophosphataemia (XLH)
Autosomal dominant - FGF23
Autosomal recessive type 1 - DMP1
Type 2 - ENPP1
Type 3 - FAM20c
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Clinical features of HLX
Short stature
Osteomalacia
Pseudofractures
Osteoarthritis
Enthesopathies
Spinal stenosis
Poor dentition
Hearing loss
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Paget's disease pathophysiology
Increased osteoclast activity
Increased bone turnover
Thickening and weakening of affected bone
Bone overgrowth
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Clinical manifestations of Paget's disease
Bone pain
Bone deformity
OA of adjacent joints
Fractures
Spinal stenosis
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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
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Therapy of Paget's disease
Bisphosphonates
Calcitonin
Analgesia
Surgery
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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
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