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Endocrine Flashcards

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1
Q

HLA genes in T1DM

A

Account up to 90% of T1DM patients (uptodate)
- DR3-DQ2
- DR4-DQ8

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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
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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

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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
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5
Q

Environmental protective factors for T1DM

A
  • Higher maternal vitamin D or concentrations in late pregnancy
  • Higher omega-3 fatty acids
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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%
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7
Q

Beta-cell specific antigens in T1DM

A

Insulin and ZnT8

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8
Q

Risk of microvascular complications in T1DM

A

From highest to lowest
Retinopathy > Nephropathy > Neuropathy > Microalbuminuria

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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
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10
Q

Examples of ultra short acting insulin (0-4hrs)

A

Lispro insulin (Humalog)
Aspart insulin (NR, Fiasp)
Glulisine (Apidra)

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11
Q

Examples of short acting insulin (0-6 hrs)

A

Actrapid
Humulin

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12
Q

Examples of intermediate acting insulin (0-14 hrs)

A

Isophane (Protaphane, Humulin NPH)

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13
Q

Examples of long acting insulin (24 hours)

A

Glargine insulin, Detemir insulin (Optisulin/Lantus, Toujeo, Levemir)

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14
Q

Examples of ultra long acting insulin (72 hours)

A

Degludec (Ryzodeg)

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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
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16
Q

Clinical benefits of CSII over MDI

A
  • Reduced HbA1c
  • Reduced severe hypoglycaemia
  • Improved QoL
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17
Q

Disadvantages of CSII over MDI

A
  • Expensive
  • Major complications - site infection, DKA (dislodgement of cannula)
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18
Q

Patient selection in pancreas and islet transplantation

A
  • Usually patients with recurrent, severe hypoglycaemia with unawareness
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19
Q

Outcomes of pancreas and islet transplantation

A
  • Reduced hypoglycaemia with improved HbA1c
  • Reduced insulin dose/frequency of injections
  • Insulin independence
  • Improved QoL
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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)
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21
Q

“Distinguishing” clinical features of LADA over T2DM

A

Usually age < 50
Acute symptoms
BMI < 25
Personal history or FHx of autoimmunity

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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
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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

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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

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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
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MOA of anabolic therapy i.e. teriparatide
Binds to G protein coupled receptor and stimulates PTH to promote bone formation
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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
150
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
152
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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