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Phase 2A > Endocrinology > Flashcards

Endocrinology Flashcards

1
Q

what are endocrine glands?

A

ductless glands of the endocrine system that secrete their products directly into the blood

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2
Q

what are exocrine glands?

A
  • glands that secrete substances onto an epithelial surface by way of a duct
  • e.g. sweat, salivary, mammary, ceruminous, lacrimal, sebaceous, mucous, pancreas
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3
Q

what are types of hormone action?

A
  • endocrine (cell targets distant cell through bloodstream)
  • paracrine (cell targets adjacent/nearby cell)
  • autocrine (cell targets itself)
  • holocrine (rupture of plasma membrane, destroying cell and secretion of product into lumen)
  • merocrine (secretions excreted via exocytosis into duct)
  • apocrine (apical portion of cell pinches off and becomes extracellular vesicle)
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4
Q

what are characteristics of water-soluble hormones?

A
  • unbound transport
  • bind to surface receptor
  • short half-life
  • fast clearance
  • e.g. peptides, monoamines
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5
Q

what are characteristics of fat-soluble hormones?

A
  • protein bound
  • diffuse into cell
  • long half-life
  • slow clearance
  • e.g. thyroid hormone, steroids
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6
Q

what are are characteristics of peptide hormones? what is the structure, storage, release, clearance like?

A
  • vary in length
  • linear or ring structures
  • two chains and may bind to carbohydrates
  • stored in secretory granules
  • hydrophilic
  • released in pulses or bursts
  • cleared by tissue or circulating enzymes
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7
Q

what catalyses the formation of L-tyrosine from L-phenylalanine?

A

phenylalanine hydroxylase

- 6-BH4 affects this

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8
Q

what catalyses the formation of L-dopa from L-tyrosine?

A

tyrosine hydroxylase

- 6-BH4 affects this

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9
Q

what catalyses the formation of dopamine from L-dopa?

A

L-aromatic amino acid decarboxylase

- pyridoxal phosphate affects this

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10
Q

what catalyses the formation of norepinephrine from dopamine?

A

dopamine-beta-hydroxylase

- ascorbate affects this

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11
Q

what catalyses the formation of epinephrine from norepinephrine?

A

phenylethanolamine-N-methyltransferase

  • S-adenosyl methionine affects this
  • site of cortisol potentiation
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12
Q

what can be produced from norepinephrine? what catalyses this?

A

norepinephrine -> normetanephrines

- catalysed by catechol-O-methyltransferase

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13
Q

what can be produced from epinephrine? what catalyses this?

A

epinephrine -> metanephrines

- catalysed by catechol-O-methyltransferase

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14
Q

what can be produced from normetanephrines and metanephrines? what catalyses this?

A

vanillylmandelic acid

- catalysed by monoamine oxidase A

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15
Q

what is the pathway of cortisol synthesis?

A

cholesterol -> pregnenolone -> progesterone -> 17-hydroprogesterone -> 11-deoxycortisol -> cortisol

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16
Q

what is the pathway of estriol production?

A

cholesterol -> pregnenolone -> 17-hydroxypregnenolone -> DHEA -> androstenedione -> testosterone/estrone -> estradiol/16alpha-hydroxysterone -> estriol

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17
Q

what enzyme catalyses the formation of 17-hydroxypregnenolone from pregnenolone?

A

17 alpha-hydroxylase

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18
Q

what enzyme catalyses the formation of 17-hydroxyprogesterone from progesterone?

A

17alpha-hydroxylase

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19
Q

what enzyme catalyses the formation of 11-deoxycortisol from 17-hydroxyprogesterone?

A

21-hydroxylase

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20
Q

what enzyme catalyses the formation of cortisol from 11-deoxycortisol?

A

11beta-hydroxylase

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21
Q

what enzyme catalyses the formation of estradiol from testosterone?

A

aromatase

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22
Q

what enzyme catalyses the formation of estrone from androstenedione?

A

aromatase

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23
Q

what enzyme catalyses the formation of testosterone from androstenedione?

A

17beta-hydroxysteroid dehydrogenase

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24
Q

what enzyme catalyses the formation of dihydrotestosterone from testosterone?

A

5alpha-reductase

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25
Q

what is humoral-stimulated hormone release?

A

hormone release caused by altered levels of certain critical ions or nutrients

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26
Q

what is hormone receptor downregulation?

A

hormone secreted in large quantities causes down regulation of its target receptors

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27
Q

what is synergism?

A

combined effects of two hormones amplified

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28
Q

what is hormone antagonism?

A

one hormone opposes other hormone

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29
Q

what is negative feedback?

A

a product feeds back to decrease its own production

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30
Q

what is positive feedback?

A

a product feeds back to increase its own production

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31
Q

what produces vasopressin/ADH?

A

supraoptic nucleus in the hypothalamus

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32
Q

what controls vasopressin release?

A
  • caffeine and alcohol inhibit its release
  • nausea, vomiting, stress, exercise stimulate its release
  • increased osmolality and decreased blood volume stimulate its release
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33
Q

what is oxytocin? what produces it?

A
  • stimulates myoepithelial cells (mammary glands), leading to suckling and milk ejection
  • stimulates the uterus and cervical dilation, leading to labour and uterine contractions
  • produced by paraventricular nucleus in the hypothalamus
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34
Q

what hormones are released by the anterior pituitary?

A
  • thyroid stimulating hormone
  • growth hormone
  • adrenocorticotropic hormone
  • luteinising hormone
  • melanocyte stimulating hormone
  • prolactin
  • follicle stimulating horone
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35
Q

what are the direct actions of growth hormones?

A
  • metabolic, anti-insulin
  • fat metabolism -> increased fat breakdown and release
  • carbohydrate metabolism -> increased blood glucose and other anti-insulin effects
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36
Q

what are the indirect actions of growth hormone?

A
  • growth promoting
  • production of insulin-like growth factors
  • increased cartilage formation and skeletal growth
  • increased protein synthesis and cell growth and proliferation
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37
Q

what is the function/action of thyroid hormone?

A
  • accelerates food metabolism
  • increases protein synthesis
  • stimulation of carbohydrate metabolism
  • enhances fat metabolism
  • increase in ventilation rate
  • increase in cardiac output and heart rate
  • brain development during foetal life and postnatal development
  • growth rate accelerated
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38
Q

what is the short-term stress response?

A
  • increased HR
  • increased BP
  • bronchioles dilate
  • liver converts glycogen to glucose and releases glucose to blood
  • blood flow changes, reducing digestive system activity and urine output
  • metabolic rate increases
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39
Q

what is the long term stress response?

A
  • kidneys retain sodium and water
  • blood volume and blood pressure rise
  • proteins and fats converted to glucose or broken down for energy
  • blood glucose increases
  • immune system suppressesd
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40
Q

what are some other hormones?

A
  • atrial natriuretic peptide
  • insulin-like growth factor I
  • erythropoietin
  • gastrin, secretin
  • prostanoids, nitric oxide, endothelin
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41
Q

what is BMI?

A

body mass index = weight/(height)^2

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42
Q

what are the different ranges of BMI?

A

underweight: <18.5
normal: 18.5-24.9
overweight: 25.0-29.9
obese: 30.0-39.9
morbidly obese: >40

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43
Q

what are some complications of obesity? what fat is this usually caused by?

A

usually abdominal (visceral) rather than subcutaneous fat

  • type 2 diabetes
  • hypertension
  • coronary artery disease
  • stroke
  • osteoarthritis
  • obstructive sleep apnoea
  • carcinoma of the breast, endometrium, prostate and colon
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44
Q

what is the role of the hypothalamus in appetite regulation?

A
  • lateral hypothalamus (hunger centre)

- ventromedial hypothalamic nucleus (satiety centre)

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45
Q

what are central controllers of appetite?

A

increase

  • NPY
  • MCH
  • AgRP
  • orexin
  • endocannabinoid

decrease

  • alpha-MSH
  • CART
  • GLP-1
  • serotonin
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46
Q

what are central controllers of appetite?

A
  • psychological factors
  • neural afferents (vagal)
  • gut peptides: CCK, ghrelin, PYY
  • metabolites: glucose and ketones
  • hormones: leptin, insulin, cortisol
  • cultural factors
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47
Q

what are peripheral factors affecting appetite regulation?

A

leptin and insulin

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48
Q

what are gut factors affecting appetite regulation?

A
  • ghrelin
  • PYY3-36
  • glucagon like peptide 1
  • CCK
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49
Q

what are factors from central areas of the hypothalamus affecting appetite regulation?

A 
NPY (arcuate nucleus)
POMC - alpha MSH (acuate nucleus)
agouti related peptide (arcuate nucleus)
MC3 and MC4 receptors (paraventricular nucleus)
serotonin
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50
Q

how does leptin affect the brain?

A
  • leptin inhibits NPY/agouti related peptide (in arcuate nucleus) which affects PVN and LHA/PFA
  • leptin stimulates pro-opiomelanocortin/cocaine and amphetamine regulated transcript which affects LHA/PFA and PVN
  • decreased fat cell mass -> decreased leptin/insulin expression -> decreased leptin/insulin action in hypothalamus
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51
Q

what are the responses to satiety signals (from the adipose tissue)?

A
  • catabolic pathways activate nucleus tractus solitarius (NTS)
  • anabolic pathways inhibit nucleus tractus solitarius (NTS)
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52
Q

what are characteristics of leptin?

A
  • Greek ‘leptos’ - thin
  • binds to leptin receptor
  • switches off appetite and is immunostimulatory
  • blood levels increase after meal and decrease after fasting
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53
Q

what is decreased leptin/insulin action in hypothalamus on the arcuate nucleus?

A
  • activates NPY/AgRP neuron and increases NPY/AgRP expression, which blocks binding of alpha-MSH to melanocortin receptors leading to decreased activity of pathways, leading to increased food intake (obesity)
  • inhibits POMC neuron and decreases alpha-MSH expression and release
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54
Q

what is peptide YY? what is its action and effects?

A
  • 36 amino acids
  • structurally similar to NPY
  • binds NPY receptors
  • secreted by neuroendocrine cells in ileum, pancreas and colon in response to food
  • inhibits gastric motility
  • reduces appetite
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55
Q

what is cholecystokinin? what are its actions and effects?

A
  • receptors in pyloric sphincter
  • delays gastric emptying, gall bladder contraction, insulin release
  • increases satiety
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56
Q

what is ghrelin? what are its actions and effects?

A
  • 28 aa
  • expressed in stomach
  • stimulates growth hormone release and appetite
  • blood levels high when fasting, fall on re-feeding
  • levels lower after gastric bypass surgery
  • used in anorexia/cachexia
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57
Q

what are some melanocortin receptors?

A

MCR1 - melanocytes; skin pigmentation
MCR2 - adrenal; adrenal cortex, steroid production
MCR3/4 - brain, signalling of satiety
MCR5 - skin

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58
Q

what are the consequences of POMC deficiency?

A

no MCR1 - pale skin
no MCR2 - adrenal insufficiency
no MCR3/4 - hyperphagia and obesity

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59
Q

what are the actions of leptin and insulin? what is their net effect?

A
  1. stimulate POMC/CART neurons -> increased CART and alpha-MSH levels
  2. inhibits NPY/AgRP neurons -> decreased NPY and AgRP

net effect: increased satiety and decreased appetite

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60
Q

what are the actions of ghrelin? what is its net effect?

A

stimulates NPY/AgRP -> increased NPY/AgRP secretion

net effect: increased appetite

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61
Q

what is the action of PYY3-36? what is its net effect?

A
  • homolog of NPY
  • binds to an inhibitory receptor on NPY/AgRP -> decreased secretion of NPY and AgRP

net effect: decreased appetite

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62
Q

what is AMPK?

A

5’ AMP activated protein kinase
- plays a role in cellular energy homeostasis, to activate glucose and fatty acid uptake and oxidation when cellular energy is low

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63
Q

what activates AMPK in the fasted state?

A
  • decreased glucose (GLUT3)
  • decreased insulin (IR)
  • increased ghrelin (GR)
  • decreased leptin (LR)
  • decreased alpha-MSH (MCR)
  • increased AgRP (MCR)
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64
Q

what deactivates AMPK in the fed state?

A
  • increased glucose (GLUT3)
  • increased insulin (IR)
  • decreased ghrelin (GR)
  • increased leptin (LR)
  • increased alpha-MSH (MCR)
  • decreased AgRP (MCR)
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65
Q

what is the central metabolic signal that mediates energy metabolism in fed and fasted states? what are its levels like?

A

malonyl CoA

  • fasted state: decreased levels
  • fed state: increased levels
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66
Q

what is the epidemiology of hypercalcaemia and hypocalcaemia?

A
  • hypercalcaemia is much more common than hypocalcaemia
  • mild asymptomatic hypercalcaemia occurs in 1 in 1000 of the population
  • incidence of 25-30 per 100000 population
  • occurs mainly in elderly females
  • usually due to primary hyperparathyroidism
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67
Q

what is the structure of parathyroid hormone (PTH)?

A
  • 84 amino acids
  • derived from a 115 residue preprohormone
  • secreted from the chief cells of the parathyroid glands
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68
Q

how does PTH levels change with calcium? how is this detected?

A
  • PTH levels rise as serum ionised calcium falls
  • this is detected by specific G protein coupled calcium-sensing receptors on the plasma membrane of the parathyroid cells
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69
Q

what are the actions of PTH?

A

all serve to increase plasma calcium by:

  • increasing osteoclastic resorption of bone (occurring rapidly)
  • increasing intestinal absorption of calcium (slow response)
  • increasing synthesis of 1,25-dihydroxy-cholecalciferol
  • increasing renal tubular reabsorption of calcium
  • increasing excretion of phosphate
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70
Q

what are the major causes of hypercalcaemia?

A
  • excessive PTH secretion
  • malignant disease; low PTH levels (myeloma, bone deposits, osteoclastic tumour factors, PTH secretion)
  • excess action of vitamin D
  • excessive calcium intake (milk-alkali syndrome)
  • other endocrine disease (thyrotoxicosis, Addison’s)
  • drugs (thiazide diuretics, vitamin D analogues, lithium administration, vitamin A)
  • micellaneous (long-term immobility, familial hypocalciuric hypercalcaemia)
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71
Q

what can cause excessive PTH secretion?

A
  • primary hyperparathyroidism, adenoma, hyperplasia or carcinoma
  • tertiary hyperparathyroidism
  • ectopic PTH secretion (very rare)
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72
Q

what can cause excess vitamin D?

A
  • iatrogenic or self-administered excess
  • granulomatous diseases, e.g. sarcoidosis, TB
  • lymphoma
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73
Q

what are some causes of primary hyperparathyroidism?

A
  • unknown causes
  • monoclonal adenoma
  • multiple adenomas/hyperplasia
  • MENtype1 or familial hypocalciuric hypercalcaemia
  • inactivation of some tumour suppressor genes
  • cancer
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74
Q

what are some causes of secondary hyperparathyroidism? what is it?

A

occurs when the parathyroid glands become enlarged and release too much PTH

  • severe calcium deficiency
  • severe vitamin D deficiency
  • chronic kidney failure
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75
Q

what is tertiary hyperparathyroidism? what is it caused by?

A
  • development of apparently autonomous parathyroid hyperplasia after long-standing secondary hyperparathyroidism, most often in renal failure
  • plasma calcium and phosphate are both raised
  • parathyroidectomy is necessary
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76
Q

what are some symptoms and signs of hypercalcaemia?

A
  • tiredness, malaise, dehydration and depression
  • renal colic from stones
  • polyuria or nocturia, haematuria and hypertension
  • polyuria due to the effect of hypercalcaemia on renal tubules, reducing their concentration ability
  • bone pain (affects mainly cortical bone)
  • bones cysts and locally destructive brown tumours
  • pain
  • chrondocalcinosis and ectopic calcification
  • corneal calcification
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77
Q

what defines mild and severe hypercalcaemia?

A

mild: adjusted calcium <3mmol/L
severe: >3mmol/L

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78
Q

what are the common tumours associated with hypercalcaemia?

A

bronchus, breast, myeloma, oesophagus, thyroid, prostate, lymphoma, renal cell carcinoma

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79
Q

what investigations are done to detect PTH levels?

A

several fasting serum calcium and phosphate samples should be done

  • serum PTH
  • hyperchloraemic acidosis
  • renal function (usually normal, measured as baseline)
  • 24-hour urinary calcium or single calcium creatinine
  • elevated serum alkaline phosphatase
  • protein electrophoresis/immunofixation (to exclude myeloma)
  • serum TSH (to exclude hyperthyroidism)
  • 0900 hours cortisol and/or ACTH test (to exclude Addisons disease)
  • serum ACE (diagnosis of sarcoidosis)
  • hydrocortisone suppression test
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80
Q

what are the actions of parathyroid hormone?

A

kidney

  • increased Ca2+ reabsorption
  • decreased phosphate reabsorption
  • increased 1alpha-hydroxylation of 25-OH vitamin D

bone

  • increased bone remodelling
  • bone resporption -> bone formation

GI tract

  • no direct effect
  • increased Ca2+ absorption because of increased 1,25-dihydroxy-cholecalciferol
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81
Q

what is the relationship between serum calcium and PTH?

A

normal: equal
low Ca2+: low Ca2+ and raised PTH
high Ca2+: high Ca2+ and low PTH

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82
Q

how is corrected calcium calculated?

A

corrected calcium = total serum calcium + 0.02*(40 - serum albumin)

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83
Q

what are consequences of hypocalcaemia?

A
  • parasthesia
  • muscule spasm: hands and feet, larynx, premature labour
  • seizures
  • basal ganglia calcification
  • cataracts
  • ECG abnormalitites: long QT interval
  • Chvostek’s sign
  • Trousseau’s sign
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84
Q

how do you test for the Chvostek’s sign?

A
  • tap over the facial nerve
  • look for spasm of facial muscles
  • sign of neuromuscular irritability
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85
Q

how do you test for Trousseau’s sign?

A
  • inflate the blood pressure cuff to 20mmHg above systolic for 5 minutes
  • in hypocalcaemia, there is flexion of the wrist and metacarpophalangeal joints, extension of DIP and PIP joints and adduction of fingers
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86
Q

what are the causes of hypocalcaemia?

A
  • vitamin D deficiency (no gut absorption of Ca2+ and Pi)
  • undermineralised bone
  • hypoparathyroidism
  • renal disease
  • cancer
  • hungry bone syndrome
  • Fanconi syndrome
  • radiation exposure
  • metabolic disorder
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87
Q

what are some syndromes associated with hypoparathyroidism?

A
  • Di George
  • HDR
  • Kenney-Caffey
  • Sanjad-Sakati
  • Kearns-Sayre
  • blomstrand chondrodysplasia
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88
Q

what does Di George syndrome lead to? what is it associated with?

A

developmental abnormality of third and fourth branchial pouches

  • hypoparathyroidism
  • thymic aplasia
  • immunodeficiency
  • cardiac defects
  • cleft palate
  • abnormal facies
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89
Q

what are some causes of hypoparathyroidism?

A
  • neck surgery
  • autoimmune disease
  • hereditary hypoparathyroidism
  • low magnesium
  • radiation to face/neck
  • haemochromatosis
  • Wilson’s disease
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90
Q

what are effects of decreased PTH? what does this lead to?

A
  • decreased renal calcium reabsorption -> increased relative calcium excretion -> decreased serum calcium
  • increased renal phosphate reabsorption -> increased serum phosphate -> decreased formation of 1,25(OH)2D
  • decreased bone resorption -> decreased serum calcium
  • decreased formation of 1,25(OH)2D -> decreased intestinal calcium absorption -> decreased serum calcium
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91
Q

what is associated with pseudohypoparathyroidism?

A
  • short stature
  • obesity
  • round facies
  • mild learning difficulties
  • subcutaneous ossification
  • short fourth metacarpals
  • other hormone resistance
  • resistance to PTH
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92
Q

what is associated with pseudopseudohypoparathyroidism?

A
  • short stature
  • obesity
  • round facies
  • mild learning difficulties
  • subcutaneous ossification
  • short fourth metacarpals
  • other hormone resistance

normal calcium metabolism

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93
Q

what is the regulation of carbohydrate metabolism in non-diabetic humans in the fasting state?

A
  • all glucose comes from the liver (and some from the kidney)
  • glucose delivered to insulin independent tissues, brain and erythrocytes
  • insulin levels are low
  • muscle uses FFA for fuel
  • some processes are very sensitive to insulin, even low insulin levels prevent unrestrained breakdown of fat
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94
Q

what is the regulation of carbohydrate metabolism in non-diabetic humans in the fed state?

A

after feeding (post prandial) - physiological need to dispose of a nutrient load

  • rising glucose (5-10 mins after eating) stimulates insulin secretion and suppresses glucagon
  • 40% of ingested glucose goes to liver and 60% to periphery, mostly muscle
  • ingested glucose helps to replenish glycogen stores both in liver and muscle
  • high insulin and glucose levels suppress lipolysis and levels of NEFA or FFA fall
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95
Q

what is the site of insulin and glucagon secretion?

A
  • endocrine pancreas

- Islets of Langerhans

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96
Q

what is the microstructure of the islets of Langerhans? what do they secrete?

A
  • duct and pancreatic acini on the periphery
  • red blood cells
  • islets of Langerhans: alpha cells, beta cells, delta cells, epsilon cells, PP cells
  • alpha cells: glucagon
  • beta cells: insulin and amylin
  • delta cells: somatostatin
  • epsilon cells: ghrelin
  • PP cells: pancreatic polypeptide
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97
Q

what is insulin’s action in muscle and fat cells?

A
  1. insulin binds to the insulin receptor on muscle and fat cells
  2. intrasignalling cascade
  3. intracellular GLUT4 vesicle mobilisation to plasma membrane
  4. GLUT4 vesicle integration into plasma membrane
  5. glucose entry into cell via GLUT4
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98
Q

what are the effects of insulin?

A
  • decreased glycogenolysis
  • decreased gluconeogenesis
  • increases glucose uptake into insulin sensitive tissues (muscle, fat)
  • supresses lipolysis and breakdown of muscle
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99
Q

what are the effects of glucagon?

A
  • increased glycogenolysis
  • increased gluconeogenesis
  • reduces peripheral glucose uptake
  • stimulates peripheral release of gluconeogenic precursors (glycerol, AAs) by lipolysis and muscle glycogenolysis and breakdown
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100
Q

what are some types of diabetes?

A
  • type 1
  • type 2: includes gestational and medication induced diabetes
  • maturity onset diabetes of youth (MODY), aka monozygotic diabetes
  • pancreatic diabetes
  • endocrine diabetes (acromegaly/Cushings)
  • malnutrition related diabetes
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101
Q

what is the definition of diabetes?

A
  • symptoms and random plasma glucose > 11mmol/l
  • fasting plasma glucose > 7mmol/l
  • no symptoms - GTT (75g glucose) fasting >7 or 2h value > 11mmol/l (repeated on 2 occasions)
  • HbA1c of 48mmol/mol (6.5%)
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102
Q

what is the pathogenesis of type 1 diabetes?

A
  • an insulin deficiency disease characterised by loss of beta cells due to autoimmune destruction
  • beta cells express antigens of HLA perhaps in response to an environmental event
  • activates a chronic cell mediated immune response leading to chronic ‘insulitis’
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103
Q

what does failure of insulin secretion lead to?

A
  • continued breakdown of liver glycogen
  • unrestrained lipolysis and skeletal muscle breakdown
  • inappropriate increase in hepatic glucose output and suppression of peripheral glucose uptake
  • rising glucose concentration leads to increased urinary glucose losses as renal threshold (10mM) is exceeded
  • reduced insulin leads to fat breakdown and formation of glycerol (a gluconeogenic precursor) and FFA
  • ketogenesis is exquistely sensitive to insulin
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104
Q

what does failure to treat with insulin lead to?

A
  • increase in circulating glucagon (loss of local increases in insulin within the islets leads to removal of inhibition of glucagon release), further increasing glucose
  • perceived stress leads to increased cortisol and adrenaline
  • progressive catabolic state and increased levels of ketones
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105
Q

what is the activity of FFA in diabetes mellitus?

A
  • impair glucose uptake
  • are transported to the liver, providing energy for gluconeogenesis
  • are oxidised to form ketone bodies (beta hydroxy butyrate, acetoacetate and acetone)
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106
Q

what are features of ketoacidosis in diabetes mellitus?

A
  • absence of insulin and rising counterregulatory hormones leads to increasing hyperglycaemia and rising ketones
  • glucose and ketones escape in the urine but lead to an osmotic diuresis and falling circulating blood volume
  • ketones cause anorexia and vomiting
  • vicious circle of increasing dehydration, hyperglycaemia and increasing acidosis eventually lead to circulatory collapse and death
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107
Q

what is the pathophysiology of type 2 diabetes?

A

genes and environment -> impaired insulin secretion and insulin resistance -> impaired glucose tolerance -> type 2 diabetes -> progressive hyperglycaemia and high FFA

progressive hyperglycaemia and high FFA -> insulin resistance and impaired insulin secretion

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108
Q

what does impaired insulin action in type 2 diabetes lead to?

A
  • reduced muscle and fat uptake after eating
  • failure to suppress lipolysis and high circulating FFAs
  • abnormally high glucose output after a meal
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109
Q

what can even low levels of insulin do in type 2 diabetes?

A
  • even low levels of insulin prevent catabolism and ketogenesis
  • profound muscle breakdown and gluconeogenesis are restrained
  • ketone production is rarely excessive
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110
Q

what is the pathogenesis of type 1 diabetes?

A

one defect: absent insulin secretion

  • > no hepatic insulin effect
  • > no muscle/fat insulin effect
  • unrestrained glucose + ketone production, more glucose enters the blood
  • impaired glucose clearance + muscle/fat breakdown, less glucose enters peripheral tissues

hyperglycaemia + raised plasma ketones -> glycosuria/ketonuria

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111
Q

what is the pathogenesis of type 2 diabetes?

A

two defects
impaired insulin secretion
-> hepatic insulin resistance
-> muscle/fat insulin resistance

  • excessive glucose production, more glucose enters bloodstream
  • impaired glucose clearance, less glucose enters peripheral tissues

hyperglycaemia -> glucosuria

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112
Q

what is the pathophysiology of type 2 diabetes, in summary?

A

insulin resistance and impaired insulin secretion due to a combination of genetic predisposition and environmental factors (obesity and lack of physical activity)

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113
Q

why doesn’t diabetic ketoacidosis occur in type 2 diabetes?

A
  • it is rare because the low insulin levels are sufficient to suppress catabolism and prevent ketogenesis
  • can occur if hormones e.g. adrenaline rise to high levels (e.g. during an MI)
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114
Q

why does insulin secretion become impaired in type 2 diabetes?

A
  • genetic predisposition (i.e. abnormalities of insulin secretion in first degree relatives)
  • deposition of peptides within the beta cell (amilyn)
  • glucotoxicity hyperglycaemia inhibits insulin secretion
  • main factor is probably lipid deposition in the pancreatic islets which prevents normal function
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115
Q

what are basal insulins available for T1DM and T2DM?

A
  • NPH insulin
  • insulin glargine (100 and 300 U/ml)
  • insulin detemir
  • insulin degludec
  • lente insulin series
  • pumped insulin
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116
Q

what are prandial/meal-time insulins available for T1DM and T2DM?

A
  • insulin lispro
  • insulin glulisine
  • EDTA/citrate human insulin
  • faster acting insulin aspart
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117
Q

what are characteristics of modern insulin therapy in T1D?

A
  • separation of basal from bolus insulin to mimic physiology
  • pre-meal rapid acting boluses adjusted according to pre-meal glucose and carbohydrate content of food to cover meals
  • basal insulin should control blood glucose inbetween meals and during night
  • basal insulin is adjusted to maintain fasting blood glucose between 5-7 mmol/L
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118
Q

what are the differences between T1DM and T2DM?

A

T1DM

  • autoimmune condition (beta-cell damage) with genetic component
  • profound insulin deficiency

T2DM

  • insulin resistance
  • impaired insulin secretion and progressive beta-cell damage but initially continued insulin secretion
  • excessive hepatic glucose output
  • increased counter-regulatory hormones including glucagon
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119
Q

what are characteristics of insulin use in T2DM?

A
  • many people with T2DM need insulin; esp. later or in individuals with poor glycaemic control on other medications
  • basal insulin is initiated followed by addition of a prandial insulin where necessary
  • premix insulins also available
  • long-acting basal insulin analogues associated with lower risk of symptomatic, overall and nocturnal hypoglycaemia
  • prandial insulins mimic meal-time insulin secretion and their faster action allows for greater flexibility at mealtimes
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120
Q

what are the pharmacokinetics of human basal insulin (NPH)?

A
  • human basal (intermediate-acting)
  • 90 minutes onset
  • 2-4 hours peak action
  • up to 24 hours duration
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121
Q

what are the pharmacokinetics of basal analogues (Detemir/Glargine U100)

A
  • basal analogue
  • steady state onset after 1-2 days
  • N/A peak action
  • up to 24 hours duration
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122
Q

what are the pharmacokinetics of rapid acting analogues (insulin aspart, insulin lispro, insulin glulisine)?

A
  • human short acting
  • 10-20 minutes onset
  • 30-90 minutes peak action
  • up to 2-5 hours duration
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123
Q

what are the pharmacokinetics of human premixed 70/30 insulin (mixtard, humulin M3)?

A
  • human premixed 70/30
  • 30 minutes onset
  • 2-8 hours peak action
  • up to 24 hours duration
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124
Q

what is an example of human basal insulin?

A

NPH (neutral protamine hagedorn)

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125
Q

what are examples of basal analogues of insulin?

A

Detemir/Glargine U100

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126
Q

what are examples of rapid-acting analogues of insulin?

A

insulin aspart, insulin lispro, insulin glulisine

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127
Q

what are examples of human premixed 70/30 insulin?

A

mixtard, humulin M3

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128
Q

what are the different insulin approaches in type 2 diabetes?

A
  • once daily basal insulin
  • twice daily mix-insulin
  • basal-bolus therapy
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129
Q

what are advantages of basal insulin in type 2 diabetes?

A
  • simple for the patient, adjusts insulin themselves, based on fasting glucose measurements
  • carries on with oral therapy
  • less risk of hypoglycaemia at night
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130
Q

what are disadvantages of basal insulin in type 2 diabetes?

A
  • doesn’t cover meals

- best used with long acting insulin analogues which are considered expensive

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131
Q

what are advantages of premixed insulin?

A
  • both basal and prandial components in a single insulin preparation
  • can cover insulin requirements through most of the day
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132
Q

what are disadvantages of premixed insulin?

A
  • not physiological
  • requires consistent meal and exercise pattern
  • cannot separately titrate individual insulin components
  • risk for nocturnal hypoglycaemia
  • risk for fasting hyperglycaemia if basal component does not last long enough
  • often requires accepting higher HbA1c goal of <7.5% or <8%
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133
Q

when do many T2DMs begin insulin therapy?

A

with HbA1c levels of >9%

- earlier

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134
Q

what are the definitions of hypoglycaemia and recent limitations?

A

low plasma glucose causing impaired brain function (neuroglycopenia) 3mmol/l

  • mild: self treated
  • severe: requiring help for recovery

hypoglycaemia: 3.9mmol/L

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135
Q

what is level 1 in the new classification of hypoglycaemia?

A

alert value

- plasma glucose <3.9mmol/l (70mg/dl) and no symptoms

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136
Q

what is level 2 in the new classification of hypoglycaemia?

A

serious biochemical

- plasma glucose <3.0mmol/l (55mg/dl)

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137
Q

what is non severe vs severe symptomatic hypoglycaemia?

A

non-severe: patient has symptoms but can self-treat and cognitive function is mildly impaired

severe: patient has impaired cognitive function sufficient to require external help to recover (level 3 of new classification)

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138
Q

what are symptoms that develop in hypoglycaemia?

A
  • trembling
  • palpitations
  • sweating
  • anxiety
  • hunger
  • difficulty concentrating
  • confusion
  • weakness
  • drowsiness, dizziness
  • vision changes
  • difficulty speaking
  • nausea
  • headache
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139
Q

what are some protective mechanisms against severe hypoglycaemia?

A
  • inhibition of endogenous insulin secretion (4.6 mmol/l)
  • counter-regulatory hormones: glucagon and adrenaline
  • symptom onset (autonomic-neuroglycopenic) (3.2-3 mmol/L)
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140
Q

what are some consequences of hypoglycaemia?

A
  • widespread EEG changes (3.0 mmol/L)
  • neurophysiological dysfunction (2.6 mmol/L)
  • cognitive dysfunction; inability to perform complex tasks (3.0-2.4 mmol/L)
  • severe neuroglycopenia; reduced consciousness, convulsions, coma (<1.5mmol/L)
  • seizures, coma
  • cognitive dysfunction
  • accidents in employment
  • prevents desirable glucose targets
  • fear
  • quality of life
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141
Q

what are risk factors for severe hypoglycaemia in T1DM?

A
  • history of severe episodes
  • HbA1c <6.5% (48 mmol/mol)
  • long duration of diabetes
  • renal impairment
  • impaired awareness of hypoglycaemia
  • extremes of age
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142
Q

what are risk factors for severe hypoglycaemia in T2DM? (on insulin or sulphonylureas)

A
  • advancing age
  • cognitive impairment
  • depression
  • aggressive treatment of glycaemia
  • impaired awareness of hypoglycaemia
  • duration of multiple daily injection insulin therapy
  • renal impairment and other comorbidities
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143
Q

what are established risk factors for severe hypoglycaemia?

A
  • low HbA1c; high pre-treatment HbA1c in T2DM
  • long duration of diabetes
  • a history of previous hypoglyaemia
  • impaired awareness of hypoglycaemia
  • recent episodes of severe hypoglycaemia
  • daily insulin dosage >0.85 U/kg/day
  • physically active
  • impaired renal function
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144
Q

what are hypoglycaemia and glucose targets in T2DM?

A
  • aim for lowest HbA1c not associated with frequent hypoglycaemia
  • HbA1c <7.0% (53 mmol/mol) is usually appropriate for recent-onset disease
  • may be appropriate to relax targets (severe complications, advanced co-morbidities, cognitive impairment, limited life expectancy, unacceptable hypoglycaemia from stringent control)
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145
Q

what are the less stringent targets in the frail elderly?

A

HbA1c <7.5%, <8% and <8.5%

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146
Q

how is medication adjusted to prevent hypoglycaemia?

A
  • if on an SU (for T2DM), revise dose or consider changing to another drug class
  • if on basal-bolus insulin, check BG before each meal every day
  • ensure medication is dosed correctly
  • consider insulin adjustments:
    regular/soluble insulin -> rapid acting insulin
    NPH/isophane -> insulin analogues
    adjusting insulin in relation to exercise
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147
Q

what is the treatment of hypoglycaemia?

A
  1. recognise symptoms so they can be treated as soon as they occur
  2. confirm the need for treatment if possible (BG <3.9 mmol/l is the alert value)
  3. treat with 15g fast acting carbohydrate to relieve symptoms
  4. retest in 15 minutes to ensure BG >4.0 mmol/l and retreat if needed
  5. eat a long-acting carbohydrate to prevent recurrence of symptoms
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148
Q

how is imaging used in investigations of disorders of calcium metabolism?

A
  • abdominal x-rays may show renal calculi or nephrocalcinosis
  • high definition hand x-rays can show subperiosteal erosions in the middle or terminal phalanges
  • DXA bone density scan is useful in detecting bone effects in asymptomatic people with hyperparathyroidism in whom conservative management is planned
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149
Q

what are methods of imaging used in investigations of disorders of calcium metabolism?

A
  • ultrasound, which, although insensitive for small tumours, is simple and safe
  • high resolution CT scan or MRI (more sensitive)
  • radioisotope scanning using 99Tc-sestamibi, which is 90% sensitive in detecting adenomas
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150
Q

what is the medical management of primary hyperparathyroidism?

A
  • no effective medical therapies atm
  • high fluid intake should be maintained, a high calcium or vitamin D intake avoided and exercise encouraged
  • new therapeutic agents targeting calcium-sensing receptors (e.g. cinacalcet) are of proven value in parathyroid carcinoma and in dialysis patients and used in primary hyperparathyroidism where surgical intervention is contraindicated
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151
Q

when is surgery indicated in primary hyperparathyroidism?

A
  • people with renal stones or impaired renal function
  • bone involvement or marked reduction in cortical bone density
  • unequivocal marked hyerglycaemia
  • uncommon younger patient, below 50 years
  • previous episode of severe acute hypercalcaemia
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152
Q

what does acute severe hypercalcaemia present as? when is immediate treatment mandatory?

A
  • dehydration
  • nausea and vomiting
  • nocturia and polyuria
  • drowsiness and altered consciousness
  • serum Ca2+ is over 3 mmol/L and sometimes as high as 5 mmol/L
  • immediate treatment is mandatory if the patient is seriously ill or if the Ca2+ is above 3.5 mmol/L
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153
Q

what is the treatment of acute severe hypercalcaemia?

A
  • rehydrate
  • IV bisphosphonates
  • prednisolone (30-60mg daily may be effective)
  • calcitonin (200 units IV 6hourly has short lived action and is little used)
  • oral phosphate (sodium cellulose phosphate 5g TDS; produces diarrhoea)
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154
Q

how is rehydration used in treatment of acute severe hypercalcaemia?

A
  • at least 4-6L of 0.9% saline on day 1, and 3-4L for several days thereafter
  • central venous pressure (CVP) may need to be monitored to control the hydration rate
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155
Q

how are IV bisphosphonates used in treatment of acute severe hypercalcaemia?

A
  • used for hypercalcaemia of malignancy or of undiagnosed cause
  • pamidronate is preferred (60-90mg as an IV infusion in 0.9% saline or glucose over 2-4 hours, or if less urgent, over 2-4 days)
  • levels fall after 24-72 hours, lasting for about 2 weeks
  • zoledronate is an alternative
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156
Q

what are complications of parathyroid surgery?

A
  • postop hypocalcaemia
  • bleeding and recurrent laryngeal nerve palsies (<1%)
  • vocal cord function
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157
Q

what is involved in postoperative care for parathyroid surgery?

A

treatment for hypocalcaemia (more common in patients who have significant bone disease and/or vitamin D deficiency)

  • pre-treating with alfacalcidol 2 um daily from 2 days postop for 10-14 days
  • routine vitamin D replacement (preferably without calcium) is indicated if deficiency is diagnosed
  • Chvostek and Trousseau signs monitored
  • biochemistry monitored
  • plasma calcium measurements are performed daily until stable
  • oral or IV calcium given temporarily
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158
Q

what is familial hypocalciuric hypercalcaemia? what are levels like?

A
  • uncommon
  • autosomal dominant
  • usually asymptomatic
  • demonstrates increased renal reabsorption of calcium despite hypercalcaemia
  • PTH levels are normal or slightly raised and urinary calcium is low
  • loss of function mutations in the gene on the long arm of chromosome 3 encoding for calcium-ion-sensing GPCR in the kidney and parathyroid gland
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159
Q

how is familial hypocalciuric hypercalcaemia treated? how is the diagnosis differentiated from hyperparathyroidism?

A
  • detected by genetic analysis
  • parathyroid surgery is not indicated as course appears benign
  • diagnosis can be differentiated from hyperparathyroidism in an isolated case by the calcium creatinine ratio in blood and urine
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160
Q

what are causes of hypoparathyroidism?

A
  • increased phosphate levels (CKD, phosphate therapy)
  • hypoparathyroidism (surgery, DiGeorge’s, idiopathic, severe hypomagnesaemia)
  • vitamin D deficiency (osteomalacia/rickets, vitamin D resistance)
  • resistance to PTH (pseudohypoparathyroidism)
  • drugs (calcitonin and bisphosphonates)
  • miscellaneous (acute pancreatitis, citrated blood transfusion, low albumin, malabsorption)
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161
Q

what often accompanies idiopathic hypoparathyroidism?

A
  • rare autoimmune disorder

- vitiligo, cutaneous candidiasis, other autoimmune disease

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162
Q

what is DiGeorge’s syndrome?

A

familial condition in which the hypoparathyroidism is associated with intellectual impairment, cataracts and calcified basal ganglia, and occasionally with specific autoimmune disease

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163
Q

what is pseudohypoparathyroidism? what is it associated with?

A
  • syndrome of end-organ resistance to PTH owing to a mutation in the Gsalpha-protein (GNAS1) which is coupled to the PTH receptor
  • variable degrees of resistance involving other G-protein linked hormone receptors may also be seen (TSH, LH, FSH)
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164
Q

what is pseudo-pseudohypoparathyroidism?

A
  • phenotypic defects of pseudohypoparathyroidism
  • without any abnormalities of calcium metabolism
  • may share same gene defect as individuals with pseudohypoparathyroidism and be in the same families
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165
Q

what are clinical features/presentations of hypoparathyroidism?

A
  • neuromuscular irritability and neuropsychiatric manifestations
  • paraesthesiae, circumoral numbness, cramps, anxiety and tetany are followed by convulsions, laryngeal stridor, dystonia and psychosis
  • Chvostek’s sign: gentle tapping over the facial nerve causes twitching of the ipsilateral facial muscles
  • Trousseau’s sign: inflation of the sphygmomanometer cuff above systolic pressure for 3 min induces tetanic spasm of the fingers and wrist
  • severe hypocalcaemia may cause papilloedema and frequently a prolonged QT interval on the ECG
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166
Q

what are investigations used to detect hypocalcaemia?

A
  • low serum calcium (after correction for any albumin abnormality)
  • clinical history and picture
  • serum and urine creatinine (for renal disease)
  • PTH levels in serum (absent or inappropriately low in hypoparathyroidism, high in other causes of hypocalcaemia)
  • parathyroid antibodies (present in idiopathic hypoparathyroidism)
  • 25-hydroxy vitamin D serum level (low in vitamin D deficiency)
  • magnesium level (severe hypomagnasaemia results in functional hypoparathyroidism which is reversed by magnesium replacement)
  • x-rays of metacarpals showing short 4th metacarpals occurring in pseudohypoparathyroidism
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167
Q

what is the treatment of hypocalcaemia?

A
  • cholecalciferol in vitamin D deficiency
  • alpha-hydroxylated derivatives of vitamin D may be preferred for their shorter half life, especially in renal disease as the others require renal hydroxylation
  • daily maintenance doses are 0.25-2ug for allfacalcidol
  • plasma calcium must be monitored for hypercalcaemia
  • oral calcium supplements may be used in early stages of treatment
  • severe hypocalcaemia presenting as an emergency may require replacement with IV calcium gluconate
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168
Q

what are causes of tetany in alkalosis?

A
  • hyperventilation
  • excess antacid therapy
  • persistent vomiting
  • hypochloraemic alkalosis e.g. primary hyperaldosteronism
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169
Q

what is diabetes mellitus?

A

a syndrome of chronic hyperglycaemia due to relative insulin deficiency, resistance or both

  • affects more than 220 million worldwide
  • will affect 440 million by the year
  • complications result in reduced life expectancy and major health costs (including coronary artery disease, peripheral vascular disease and stroke and microvascular damage causing diabetic retinopathy and nephropathy, and neuropathy)
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170
Q

what are features of insulin structure and secretion? what is it coded by? what is it metabolised by?

A
  • involved in storage and controlled release within the body of the chemical energy available from food
  • coded for on chromosome 11
  • synthesised in beta cells of pancreatic iselts
  • enters portal circulation and is carried to the liver
  • about 50% is extracted and degraded in the liver and kidneys
  • C peptide is only partially extracted by the liver and is mainly degraded by the kidneys
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171
Q

what are usual blood glucose levels?

A
  • blood glucose levels are closely regulated in health
  • around 3.5-8.0 mmol/L (63-144 mg/dL)
  • stay similar despite food, fasting and exercise
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172
Q

what is the main organ involved in glucose homeostasis?

A
  • liver absorbs and stores glucose (as glycogen) in the post-absorptive state and releases it into circulation between meals to match the rate of glucose utilization by peripheral tissues
  • combines 3-carbon molecules derived from breakdown of fat (glycerol), muscle glycogen (lactate) and protein (e.g. alanine) into the 6-carbon glucose molecule by gluconeogenesis
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173
Q

how is glucose produced? what is it derived from?

A
  • about 200g of glucose is produced and utilised each day

- more than 90% is derived from liver glycogen and hepatic gluconeogenesis, and the remainder from renal gluconeogenesis

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174
Q

what is the glucose requirement for the body?

A

1 mg/kg bodyweight per minute, or 100g daily in a 70kg man

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175
Q

what happens to glucose that’s taken up by the muscle?

A

stored as glycogen or metabolised to lactate or CO2 and water

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176
Q

what happens to glucose that’s taken up by fat?

A
  • source of energy
  • substrate for TG synthesis
  • lipolysis releases fatty acids from triglyceride together with glycerol, a substrate for hepatic gluconeogenesis
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177
Q

how is insulin synthesised and secreted?

A
  • ribosomes manufacture pre-proinsulin from insulin mRNA
  • hydrophobic pre portion of the pre-proinsulin allows it to transfer to the Golgi apparatus, and is enzymatically cleaved off
  • proinsulin is parcelled into secretory granules in the Golgi
  • pass towards membrane and are stored before release
  • proinsulin molecule folds back onto itself and is stabilised by disulphide bonds
  • biochemically inert peptide, connecting (C) peptide splits off from proinsulin, leaving insulin as two linked peptide chains
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178
Q

what are the two different pathways of insulin secretion by the beta cell?

A

regulated pathway: releases equimolar quantities of insulin and C-peptide

constitutive pathway: small amount of insulin is secreted by the beta cell directly. bypasses the secretory granules

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179
Q

what are local forces regulating insulin secretion from beta cells?

A
  1. glucose enters the beta cell via the GLUT-2 transporter protein
  2. metabolism of glucose within the beta cell generates ATP
  3. ADP/ATP binds to SUR1 (regulatory subunit)
  4. ATP closes potassium channels in the cell membrane
  5. closure of potassium channels predisposes to membrane depolarisation, allowing calcium ions to enter the cell; if a sulfonylurea binds to its receptor this also closes potassium channels
  6. rise in intracellular calcium triggers activation of calcium-dependent phospholipid protein kinase, which leads to fusion of the granules and exocytosis
  7. this secretes insulin
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180
Q

what is the role of GLUT-1?

A

enables basal non-insulin-stimulated glucose uptake into many cells

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181
Q

what is the role of GLUT-2?

A

transports glucose into beta cell, a prerequisite for glucose sensing, and is also present in renal tubules and hepatocytes

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182
Q

what is the role of GLUT-3?

A

enables non-insulin-mediated glucose uptake into brain neurones and placenta

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183
Q

what is the role of GLUT-4?

A

enables much of the peripheral action of insulin. glucose is taken up into muscle and adipose tissue cells following stimulation of the insulin receptor

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184
Q

what is the structure and function of the insulin receptor?

A
  • glycoprotein (400 kDa)
  • coded for on the short arm of chromosome 19
  • on cell membrane
  • dimer with two alpha subunits which include the binding sites for insulin, and two beta subunits, which traverse the cell membrane
  • when insulin binds to the alpha subunits it induces a conformational change in the beta subunits, which activates tyrosine kinase and initiation of a cascade response
  • leads to migration of GLUT-4 to cell surface and increased transport of glucose into the cell
  • insulin receptor complex is internalised, insulin is degraded and the receptor is recycled
  • insulin signal pathway leads to effects on protein metabolism, effects on growth, effects on lipid metabolism and translocation of GLUT-4 vesicle to cell membrane
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185
Q

what are diseases of the exocrine pancreas that can cause diabetes?

A
  • pancreatitis
  • trauma/pancreatectomy
  • neoplasia
  • CF
  • haematochromatosis
  • fibrocalculous pancreatopathy
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186
Q

what are endocrinopathies that can cause diabetes?

A
  • acromegaly
  • Cushing’s syndrome
  • glucagonoma
  • phaeochromocytoma
  • hyperthyroidism
  • somatostatinoma
  • aldosteronoma
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187
Q

what are drugs and chemicals that can cause diabetes?

A
  • vacor (pyrinuron)
  • pentamidine
  • nicotinic acid
  • beta blockers
  • thyroid hormone
  • diazoxide
  • beta adrenergic agonists
  • thiazides
  • phenytoin
  • alpha interferon
  • protease inhibitors
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188
Q

what are immunosuppressive agents that can cause diabetes?

A
  • glucocorticoids
  • ciclosporin
  • tacrolimus
  • sirolimus
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189
Q

what are anti psychotic agents that can cause diabetes?

A
  • clozapine

- olanzapine

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190
Q

what are infections that can cause diabetes?

A
  • congenital rubella

- cytomegalovirus

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191
Q

what are uncommon forms of immune-mediated diabetes?

A
  • stiff person syndrome

- anti-insulin receptor antibodies

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192
Q

what are other genetic syndromes sometimes associated with diabetes?

A
  • Down’s
  • Friedreich’s ataxia
  • Huntington’s chorea
  • Klinefelter’s syndrome
  • Laurence-Moon-Biedl syndrome
  • myotonic dystrophy
  • porphyria
  • Prader-Willi syndrome
  • Turner’s syndrome
  • Wolfram’s syndrome
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193
Q

what are characteristics of type 1 diabetes, including hereditary factors, pathogenesis, clinical features, epidemiology?

A
  • younger age (<30)
  • lean weight
  • symptom duration of weeks
  • northern/European people have higher risk
  • seasonal onset
  • HLA-DR3 or DR4 in >90%
  • autoimmune disease
  • ketonuria
  • clinical: insulin deficiency, ketoacidosis, always need insulin
  • C-peptide disappears
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194
Q

what are characteristics of type 2 diabetes, including hereditary factors, pathogenesis, clinical features, epidemiology?

A
  • older (>30)
  • overweight
  • symptom duration of months/years
  • Asian, African, Polynesian and American-Indian have higher risk
  • no seasonal onset
  • no HLA links
  • no immune disturbance
  • no ketonuria
  • clinical: partial insulin deficiency initially, hyperosmolar state, need insulin when beta cells fail over time
  • C-peptide persists
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195
Q

how can the HLA system cause diabetes?

A
  • chromosome 6
  • 90% of patients carry HLA-DR3-DQ2, HLA-DR4-DQ8 or both, compared to 35% of the background population
  • all DQB1 alleles with an aspartic acid at residue 57 confers neutral to protective effects with the strongest effect from DQB1*0602 (DQ6), while DQB1 alleles with an alanine at the same position (DQ2 and DQ8) confer strong susceptibility
  • HLA DR3-DQ2/HLA DR4-DQ8 heterozygotes have an increased risk of disease
  • some HLA class I alleles modify the risk conferred by class II susceptibility genes
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196
Q

what are genes or gene regions other than the HLA system that can cause diabetes?

A
  • more than 50 non-HLA genes or gene regions influence risk
  • gene encoding insulin (INS) on chromosome 11
  • cytotoxic T-lymphocyte-associated protein-4 (CTLA4) gene
  • lymphoid-specific protein tyrosine phosphatase (PTPN22) gene
  • IL-2R alpha-subunit of the IL-2 receptor complex locus (IL2RA)
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197
Q

what are some islet cell autoantibodies (ICA)?

A
  • GAD65 (glutamic acid decarboxylase)
  • IA-2/ICA512 (protein tyrosine phosphatase)
  • insulin
  • cation transporter ZnT8
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198
Q

what is insulitis?

A

infiltration of pancreatic islets by mononuclear cells

- resembles that in other autoimmune diseases e.g. thyroiditis

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199
Q

what are environmental factors affecting type 1 diabetes?

A
  • incidence of childhood diabetes is rising across Europe by 2-3% each year
  • islet autoantibodies appear in the first few years of life
  • exposure to dietary constituents, enteroviruses e.g. Coxsackie B4 and relative deficiency of vitamin D may play a role
  • cleaner environment with less early stimulation of the immune system may increase susceptibility
  • atopic/allergic conditions and more rapid weight gain leading to insulin resistance may accelerate clinical onset
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200
Q

what is pre-type 1 diabetes and how can type 1 be prevented?

A
  • children who test positive for 2+ autoantibodies have a >80% risk of progression to diabetes, and the risk approaches 100% in those who lose their first phase insulin response to IV glucose and/or develop glucose intolerance
  • intervention before clinical onset of diabetes has been unsuccessful
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201
Q

what factors affect onset of type 2 diabetes?

A
  • increasing age
  • ethnicity
  • family history
  • in poor countries, it’s a disease of the rich, and in rich countries, a disease of the poor
  • stress of pregnancy, drug treatment or intercurrent illness may accelerate onset
  • more prevalent in South Asian, African, Caribbean people
  • those of Middle Eastern and Hispanic American origin living western lifestyles have risk
  • obesity increases the risk of type 2 80-100 fold
  • sedentary/western lifestyle
  • insulin resistance
  • metabolic syndrome
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202
Q

what is metabolic syndrome? what are the criteria for its diagnosis?

A
  • type 2 diabetes is associated with central obesity, hypertension, hypertriglyceridaemia, decreased HDL-cholesterol, disturbed haemostatic variables and modest increases in pro-inflammatory markers
  • insulin resistance and increased cardiovascular risk is associated with these variables
  • criteria: increased waist circumference (or BMI >30) plus two of the following: diabetes (or fasting glucose >6.0 mmol/L), hypertension, raised TGs or low HDL cholesterol
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203
Q

what are genetic components of type 2 diabetes?

A
  • transcription factor-7-like (TCF7-L2) most common variant in Europeans; increased risk of 35%; modulates pancreatic islet cell function
  • KCNQ1 (potassium voltage gated channel) in Asians; increased risk of 10-20%
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204
Q

what are early and late environmental factors affecting type 2 diabetes?

A
  • low weight at birth and at 12 months is linked to glucose intolerance later in life, esp. in overweight/obese
  • poor nutrition early in life impairs beta-cell development and function, predisposing to diabetes
  • low birthweight also predisposes to heart disease and hypertension
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205
Q

how does inflammation affect type 2 diabetes?

A
  • subclinical inflammatory changes are characteristic of both type 2 diabetes and obesity
  • in diabetes, high sensitivity C-reactive protein levels are modestly elevated in association with raised fibrinogen and increased plasminogen activator inhibitor-1 (PAI-1)
  • CRP levels contribute to cardiovascular risk
  • circulating levels of pro-inflammatory cytokines TNF-alpha and IL-6 are elevated in diabetes and obesity
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206
Q

how do abnormalities of insulin secretion and action affect type 2 diabetes?

A
  • some degree of beta-cell dysfunction is necessary
  • insulin binds normally to its receptor
  • insulin resistance is associated with central obesity and accumulation of intracellular TG in muscle and liver, and many have NAFLD
  • patients retain up to 50% of their beta cell mass at time of diagnosis
  • show islet amyloid deposition at autopsy, derived from amylin or islet amyloid polypeptide, which is cosecreted with insulin
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207
Q

what is the Starling curve of the pancreas in type 2 diabetes?

A
  • circulating insulin levels are higher than healthy people following diagnosis
  • tend to rise further
  • decline after months or years due to secretory failure

insulin deficiency relative to increased demand leads to hypersecretion of insulin by a depleted beta-cell mass and progression towards absolute insulin deficiency requiring insulin therapy

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208
Q

how can beta cells be affected by excess glucose?

A

glucotoxicity: hyperglycaemia and lipid excess are toxic to beta cells; this results in further beta-cell loss and further deterioration of glucose homeostasis

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209
Q

what are rare forms of type 2 diabetes?

A
  • insulin receptor mutations (obesity, insulin resistance, hyperandrogenism, acanthosis nigricans)
  • maternally inherited diabetes and deafness
  • Wolfram’s syndrome
  • severe obesity and diabetes (Alstroems, Bardet-Biedl, Prader-Willi, reinitis pigmentosa, mental insufficiency, neurological disorders)
  • disorders of intracellular insulin signalling (Leprechaunism, Rabson-Mendenhall, pseudoacromegaly, lipodistrophy)
  • genetic defects of beta cell function
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210
Q

what are features of MIDD?

A
  • mutation in mitochondrial DNA
  • diabetes onset before age 40
  • variable deafness
  • neuromuscular and cardiac problems
  • pigmented retinopathy
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211
Q

what is Wolfram’s syndrome?

A

DIDMOAD - diabetes insipidus, diabetes mellitus, optic atrophy and deafness

  • recessively inherited
  • mutation in the transmembrane gene, WFS1
  • insulin-requiring diabetes and optic atrophy in the first decade
  • diabetes insipidus and sensorineural deafness in teh second decade progressing to multiple neurological problems
  • few live beyond middle age
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212
Q

what are features of HNF-4a as a cause of beta-cell dysfunction?

A
  • 20q
  • 5% of all cases
  • teens/30s onset
  • progressive hyperglycaemia
  • frequent microvascular complication
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213
Q

what are features of glucokinase as a cause of beta-cell dysfunction?

A
  • 7p
  • 15% of all cases
  • present from birth
  • little deterioration with age
  • rare microvascular complications
  • reduced birthweight
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214
Q

what are features of HNF-1a as a cause of beta-cell dysfunction?

A
  • 12q
  • 70% of all cases
  • teens/20s onset
  • progressive hyperglycaemia
  • frequent microvascular complications
  • sensitivity to sulfonylureas
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215
Q

what are features of IPF-1 as a cause of beta-cell dysfunction?

A
  • 13q
  • <1% of all cases
  • teens/30s onset
  • progression unclear
  • pancreatic agenesis in homozygotes
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216
Q

what are features of HNF-1b as a cause of beta-cell dysfunction?

A
  • 17q
  • 2% of all cases
  • teens/20s onset
  • progression unclear
  • renal cysts, proteinuria, CKD
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217
Q

what is TNDM?

A

transient neonatal diabetes mellitus

  • occurs soon after birth
  • resolves at a median of 12 weeks
  • 50% of cases relapse later in life
  • most have an abnormal imprinting of the ZAC and HYMAI genes on chromosome 6q
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218
Q

what is the cause of PNDM?

A

permanent neonatal diabetes mellitus

- mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the beta-cell potassium-ATP channel

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219
Q

what is the acute presentation of diabetes?

A

young people often present with a 2-6 week history and report:

  • polyuria: due to osmotic diuresis that results when blood glucose levels exceed the renal threshold
  • thirst: due to loss of fluid and electrolytes
  • weight loss: due to fluid depletion and the accelerated breakdown of fat and muscle secondary insulin deficiency

ketonuria is often present in young people and may progress to ketoacidosis

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220
Q

what is the subacute presentation of diabetes?

A
  • clinical onset may be over several months or years, esp. in older patients
  • thirst, polyuria and weight loss are present
  • lack of energy, visual blurring (glucose-induced changes in refraction) or pruitus vulvae or balanitis due to Candida
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221
Q

what are complications of diabetes as the presenting feature?

A
  • staphylococcal skin infections
  • retinopathy noted during a visit to the optician
  • polyneuropathy causing tingling and numbness in the feet
  • erectile dysfunction
  • arterial disease, resulting in MI or peripheral gangrene
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222
Q

how can asymptomatic diabetes be detected?

A
  • glycosuria or raised BP on routine examination
  • glycosuria indicates need for further investigations
  • 1% of the population have renal glycosuria
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223
Q

what can be results of physical examination in diabetes?

A
  • evidence of weight loss and dehydration
  • breath smells of ketones
  • older patients may have complications
  • retinopathy is diagnostic of diabetes
  • physical signs of an illness causing secondary diabetes
  • may have acanthosis nigricans
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224
Q

what are the WHO diagnostic criteria for diabetes?

A
  • fasting plasma glucose >7.0 mmol/L (126 mg/dL)
  • random plasma glucose >11.1 mmol/L (200 mg/dL)
  • one abnormal lab value is diagnostic in symptomatic individuals; two values for asymptomatic people
  • HbA1c >6.5 (48 mmol/mol)
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225
Q

what are the WHO criteria for the glucose tolerance test for fasting and 2hrs after glucose conditions?

A

normal

f: <7.0 mmol/L
2hrs: <7.8 mmol/L

impaired glucose tolerance

f: <7.0 mmol/L
2hrs: 7.8-11.0 mmol/L

diabetes mellitus

f: >7.0 mmol/L
2hrs: >11.1 mmol/L

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226
Q

what is HbA1c?

A

haemoglobin A1c
- integrated measure of prevailing blood glucose over several weeks
>6.5% (48 mmol/mol) is diagnostic of diabetes
5.7-6.4% (39-46 mmol/mol) is increased risk of diabetes

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227
Q

what is recommended for food for diabetics?

A
  • low in sugar (not sugar free)
  • high in starchy carbohydrate (esp. foods with low glycaemic index) i.e. slower absorption
  • high in fibre
  • low in fat (esp. saturated fat)
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228
Q

what is the action of biguanide (metformin)?

A
  • used in diabetes
  • activates AMP-kinase, which is involved in regulation of cellular energy metabolism
  • reduces the rate of gluconeogenesis, and hence hepatic glucose output, to increase insulin sensitivity
  • doesn’t induce hypoglycaemia, doesn’t affect weight gain and doesn’t affect insulin secretion
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229
Q

what adverse effects of biguanide (metformin)?

A
  • anorexia
  • epigastric discomfort
  • diarrhoea
  • prohibits its use in 5-10% of patients
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230
Q

what is the action of sulfonylureas?

A
  • diabetes
  • act on beta cell to promote insulin secretion in response to glucose and other secretagogues
  • ineffective in patients without a functional beta-cell mass, and are usually avoided in pregnancy
  • bind to sulfonylurea receptor which closes ATP-sensitive potassium channels and leads to depolarisation
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231
Q

what are advantages and disadvantages of sulfonylureas?

A
  • cheap
  • more effective than other agents in achieving short term (1-3 years) glucose control
  • effect wears off as the beta cell mass declines
  • may hasten beta cell apoptosis and promote weight gain
  • best avoided in the overweight
  • can cause potentially fatal hypoglycaemia
  • long half lives
  • avoided in liver disease and renal impairment
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232
Q

what are the most commonly used sulfonylureas for diabetes?

A
  • tolbutamide
  • glibenclamide
  • glipizide and glimepiride
  • gliclazide
  • chlorpropamide
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233
Q

what are properties of tolbutamide (sulfonylurea used in diabetes)?

A
  • lower maximal efficacy than other sulfonylureas
  • short half life; preferable in elderly
  • largely metabolised by liver; can use in renal impairment
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234
Q

what are properties of glibenclamide (sulfonylurea used in diabetes)?

A
  • long biological half-life
  • severe hypoglycaemia
  • do not use in elderly
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235
Q

what are properties of glipizide and glimepiride (sulfonylureas used in diabetes)?

A
  • active metabolites

- renal excretion; avoid in renal impairment

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236
Q

what are properties of chlorpropamide (sulfonylurea used in diabetes)?

A
  • very long biological half-life
  • renal excretion - avoid in renal impairment
  • 1-2% develop inappropriate ADH-like syndrome
  • facial flush with alcohol
  • very inexpensive - major issue for developing countries
  • can produce fatal hypoglycaemia
  • not recommended in the elderly
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237
Q

what is the action of meglitinides (in diabetes)?

A
  • e.g. repaglinide and nateglinide
  • insulin secretagogues
  • the non-sulfonylurea moiety of glibenclamide
  • act via closure of K+-ATP channel in beta cells
  • short acting agents that promote insulin secretion in response to meals
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238
Q

what is the action of thiazolidinediones?

A
  • known as the glitazones
  • reduce insulin resistance by interaction with peroxisome proliferator-activated receptor-gamma (PPAR-gamma); this regulates large numbers of genes including those in lipid metabolism and insulin action
  • potentiate the effect of endogenous or injected insulin
  • binds to nuclear receptors mainly found in fat cells
  • act indirectly via the glucose-fatty acid cycle, lowering free fatty acid levels and thus promoting glucose consumption by muscle
  • reduce hepatic glucose production (synergistic with metformin) and enhance peripheral glucose uptake
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239
Q

what are the uses of thiazolidinediones?

A
  • troglitazone and rosiglitazone have been withdrawn for safety reasons (liver failure and increased CV risk)
  • pioglitazone is only remaining agent

unwanted effects of pioglitazone

  • weight gain of 5-6kg
  • fluid retention and heart failure
  • mild anaemia and osteoporosis resulting in peripheral bone fractures
  • increased risk of bladder cancer
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240
Q

what is the action of dipeptidyl peptidase-4 (DPP4) inhibitors?

A
  • enhance the incretin effect
  • enzyme dipeptidyl peptidase 4 rapidly inactivates GLP-1 as this is released into circulation
  • potentiates the effect of endogenous GLP-1 secretion
  • lower blood glucose and are weight neutral
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241
Q

what are the currently available dipeptidyl peptidase 4 inhibitors? when are they most effective?

A
  • linagliptin
  • saxagliptin
  • sitagliptin
  • vildagliptin

most effective in early stages of type 2 diabetes when insulin secretion is relatively preserved. currently recommended for second-line use in combination with metformin or a sulfonylurea

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242
Q

what are adverse effects of dipeptidyl peptidase 4 inhibitors?

A

adverse effects are uncommon

  • nausea
  • acute pancreatitis
  • short term safety record is good
  • it’s widely distributed in the body
  • long-term consequences of inhibition of this enzyme in other tissues is not known
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243
Q

what is the incretin effect?

A

the insulin response to oral glucose is greater than the response to IV glucose

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244
Q

what is the incretin effect caused by?

A

two intestinal peptide hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) have a potentiating effect on pancreatic secretion of insulin

  • GIP causes 30% and GLP-1 70% of the incretin effect
  • both hormones have short half-lives in the circulation, being degraded by DPP4
  • diminished in T2DM
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245
Q

where are glucose-dependent insulinotropic peptide and glucagon-like peptide 1 secreted from?

A
  • GIP is secreted from the K cells in the duodenum

- GLP-1 is secreted from the L cells of the ileum in response to food

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246
Q

what is the action of GLP-1 agonists?

A
  • exenatide and liraglutide are long-acting analogues of GLP-1, which enhance the incretin effect
  • promote insulin release, inhibit glucagon release, reduce appetite and delay gastric emptying
  • blunt the post-prandial rise in plasma glucose and promote weight loss
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247
Q

what are advantages and disadvantages of GLP-1 agonists?

A
  • main disadvantage is the need for subcutaneous injection (twice daily for exenatide and once daily for liraglutide)
  • main advantage is improving glucose control while inducing useful weight reduction
  • work well in 70% but have little benefit in 30%
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248
Q

what are side effects of GLP-1 agonists?

A

nausea, acute pancreatitis and acute kidney injury

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249
Q

how are short-acting insulins used to treat diabetes?

A
  • insulin derived from beef or pig pancreas have been replaced by biosynthetic human insulin
  • short-acting insulins are used for pre-meal injection in multiple dose regimens, for continuous IV infusion in labour or in medical emergencies, and in patients using insulin pumps
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250
Q

how is human insulin absorbed?

A
  • slowly, reaching a peak 60-90 min after subcutaneous injection and its action tends to persist after meals, predisposing to hypoglycaemia
  • absorption is delayed because soluble insulin is in the form of stable hexamers (six insulin molecules around a zinc core) and needs to dissociate to monomers and dimers before it can enter circulation
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251
Q

why is absorption of human insulin delayed?

A
  • soluble insulin is in the form of stable hexamers (six insulin molecules around a zinc core)
  • needs to dissociate to monomers or dimers before it can enter the circulation
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252
Q

what are the actions of insulin analogues?

A
  • short acting insulin analogues have been engineered to dissociate more rapidly following injection without altering the biological effect
  • insulin analogues e.g. rapid acting insulins (insulin lispro, insulin aspart and insulin glulisine) enter the circulation more rapidly than human soluble insulin and disappear more rapidly
  • short-acting analogues have little effect upon overall glucose control
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253
Q

what are some rapid acting insulins?

A

insulin lispro, insulin aspart and insulin glulisine

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254
Q

how can the action of human insulin be prolonged?

A

by addition of zinc or protamine derived from fish sperm

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255
Q

what are examples of intermediate and longer-acting insulins?

A
  • NPH (isophane insulin)
  • insulin glargine
  • insulin detemir
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256
Q

what is the use of NPH as an intermediate and longer-acting insulin?

A
  • can be premixed with soluble insulin to form stable mixtures (biphasic insulins)
  • combination of 30% soluble with 70% NPH is most widely used
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257
Q

what is the action of insulin glargine?

A
  • long acting insulin
    soluble in the vial as a slightly acidic (pH 4) solution, but precipitates at subcutaneous pH, thus prolonging its duration of action
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258
Q

what is the action of insulin detemir?

A
  • long acting insulin
    has a fatty acid tail, which allows it to bind to serum albumin, and its slow dissociation from the bound state prolongs its duration of action
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259
Q

what is the structure of human insulin?

A

A chain and B chain connected by disulphide bridges

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260
Q

what is lispro?

A

a genetically engineered rapidly acting insulin analogue created by reversing the order of the amino acids proline and lysine in positions 28 and 29 of the B chain

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261
Q

what is insulin aspart?

A

similar analogue to lispro created by replacing proline at position 28 of the B chain with an aspartic acid residue

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262
Q

what is insulin glargine?

A

a genetically engineered long-acting insulin created by replacing asparagine in position 21 of the A chain with a glycine residue and adding two arginines to the end of the the B chain

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263
Q

what is insulin detemir?

A

discards threonine in position 30 of the B chain and adds a fatty acyl chain to lysine in position B29

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264
Q

what are stages of T2DM treatment?

A

stage 1: lifestyle changes and metformin

stage 2: add sulphonylurea, basal insulin, consider adding DPP4 inhibitor or glitazone

stage 3: change from SU to basal insulin or add DPP4 inhibitor, add mealtime short-acting SU or intensity insulin to basal insulin, change to basal insulin from DPP4 inhibitor or glitazone or add remaining DPP4 inhibitor or glitazone

stage 4: further intensify treatment or switch to insulin

progress to further step if HbA1c >53mmol/mol

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265
Q

what are types of insulin regimen in type 2 diabetes?

A
  • an intermediate insulin given at night with metformin during the day
  • multidose insulin regimens
  • metformin is a useful adjunct
  • addition of a morning dose of insulin may be needed to control postprandial hyperglycaemia
  • twice daily injections of pre-mixed soluble and isophane insulins
  • more aggressive treatment e.g. multiple injections or continuous infusion pumps
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266
Q

why is ideal control in insulin therapy difficult to achieve?

A
  • low first-pass metabolism in subcutaneous injection compared to secreted insulin
  • subcutaneous soluble insulin takes 60-90 min to achieve peak plasma levels, so the onset and offset of action are too slow
  • absorption of subcutaneous insulin insulin into the circulation is variable
  • basal insulin levels are constant in normal people, but injected insulin peaks and declines in diabetics, with swings in metabolic control
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267
Q

when should insulin analogues be used?

A
  • hypoglycaemia between meals and particularly at night is the limiting factor for patients on multiple injection regimens
  • more expensive rapid-acting insulin analogues are a substitute for soluble insulin
  • analogues reduce frequency of nocturnal hypoglycaemia
  • used on convenience, as patients can inject before meals
  • analogues can reduce high or erratic morning blood sugar readings
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268
Q

what should be done to adjust insulin dosage according to blood glucose results before breakfast?

A

persistently too high: increase evening long-acting insulin

persistently too low: reduce evening long-acting insulin

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269
Q

what should be done to adjust insulin dosage according to blood glucose results before lunch?

A

persistently too high: increase morning short-acting insulin

persistently too low: reduce morning short-acting insulin or increase mid-morning snack

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270
Q

what should be done to adjust insulin dosage according to blood glucose results before evening meal?

A

persistently too high: increase morning long-acting insulin or lunch short-acting insulin

persistently too low: reduce morning long-acting insulin or lunch short-acting insulin or increase mid-afternoon snack

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271
Q

what should be done to adjust insulin dosage according to blood glucose results before bed?

A

persistently too high: increase evening short-acting insulin

persistently too low: reduce evening short-acting insulin

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272
Q

what are the times of greatest risk for hypoglycaemia episodes?

A
  • before meals
  • during the night
  • during exercise
  • irregular eating habits, unusual exertion and alcohol excess may precipitate episodes
  • other cases are just due to variation in insulin absorption
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273
Q

what are symptoms of hypoglycaemia during insulin treatment?

A
  • develop when blood glucose level falls below 3 mmol/L
  • develop over a few minutes
  • adrenergic features of sweating, tremor and a pounding heartbeat
  • all patients with type 1 have intermittent hypoglycaemia
  • one in three go into a coma at some point
  • pallor and a cold sweat
  • hypoglycaemic unawareness: lose warning symptoms; risk of central nervous dysfunction
  • pale, drowsy, detached
  • clumsy, inappropriate, irritable or aggressive behaviour
  • hypoglycaemic coma
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274
Q

what is nocturnal hypoglycaemia?

A
  • basal insulin requirements fall during the night but increase from 4am, when injected insulin levels are falling
  • patients may wake with high glucose levels, but find that injecting more insulin at night increases the risk of hypoglycaemia in the morning
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275
Q

how can nocturnal hypoglycaemia be reduced?

A
  • regular bedtime snack
  • patients taking twice-daily mixed insulin can separate their evening dose and take the intermediate insulin at bedtime rather than dinner
  • reducing dose of soluble insulin before dinner, as this will persist into the night
  • changing to a rapid-acting insulin analogue, with long-lasting analogue at night
  • changing to an infusion pump programmed to deliver lower doses at night
276
Q

what should patients be given in mild hypoglycaemia?

A
  • rapidly absorbed carbohydrate relieves the early symptoms
  • glucose or sweets
  • liquid form
277
Q

what is the treatment of severe hypoglycaemia?

A
  • unconscious patients should be given IM glucagon or IV glucose followed by a flush of 0.9% saline to preserve the vein
  • glucagon mobilises hepatic glycogen; works almost as rapidly as glucose
  • glucagon doesn’t work when liver glycogen levels are low, e.g. after a prolonged fast
  • oral glucose given to replenish glycogen once patient revives
278
Q

what are the ideal target goals of risk factors for diabetic patients?

A 
HbA1c: <7% (53 mmol/mol)
BP: 130/80
total cholesterol: <4 mmol/L
LDL: <2
HDL: >1.1
TGs: <1.7
279
Q

what are the reasonable but not ideal goals of risk factors for diabetic patients?

A 
HbA1c: <8% (64 mmol/mol) 
BP: 140/80
total cholesterol: <5 mmol/L
LDL: <3
HDL: >0.8
TGs: <2
280
Q

what is checked at least once a year for diabetic patients?

A
  • biochemical assessment of metabolic control
  • measure bodyweight
  • measure BP
  • measure plasma lipids
  • measure visual acuity
  • examine state of retina
  • test urine for proteinuria/microalbuminuria
  • test blood for renal function (creatinine, eGFR)
  • check condition of feet, pulses and neurology
  • review CV risk factors
  • review self-monitoring and injection techniques
  • review eating habits
281
Q

what is ketonuria?

A
  • detectable ketone levels in the urine

- occurs in fasted non-diabetics and may be found in well-controlled patients

282
Q

what is ketosis?

A

elevated plasma ketone levels in the absence of acidosis

283
Q

what is diabetic ketoacidosis?

A

a metabolic emergency where hyperglycaemia is associated with a metabolic acidosis due to greatly raised (>5 mmol/L) ketone levels

284
Q

what is hyperosmolar hyperglycaemic state?

A

a metabolic emergency where uncontrolled hyperglycaemia induces a hyperosmolar state in the absence of significant ketosis

285
Q

what is lactic acidosis?

A

a metabolic emergency where elevated lactic acid levels induce a metabolic acidosis

  • rare in diabetic patients
  • associated with biguanide therapy
286
Q

when is diabetic ketoacidosis usually seen?

A

hallmark of type 1 diabetes

  • previously undiagnosed diabetes (10%)
  • interruption of insulin therapy (15%)
  • stress of intercurrent illness (30%)
287
Q

why does dehydration occur during ketoacidosis?

A

increased glucose -> hyperglycaemia and glycosuria > osmotic diuresis -> fluid and electrolyte depletion -> renal hypoperfusion -> impaired excretion of ketones and hydrogen ions

increased ketones -> acidosis -> vomiting -> fluid and electrolyte depletion -> renal hypoperfusion -> impaired excretion of ketones and hydrogen ions

kidney becomes less able to compensate for the acidosis

288
Q

what is the process of ketogenesis?

A

triglycerides from adipose tissue -> FFA(plasma) -> FFA(hepatocyte) -> fatty acyl carnitine -> acetyl CoA(in mitochondrion) -> acetoacetate -> acetone and beta-hydroxybutyrate

289
Q

what ketones are formed in ketogenesis?

A
  • acetoacetate
  • acetone
  • beta-hydroxybutyrate
290
Q

what is the pathogenesis of ketoacidosis?

A
  • state of uncontrolled catabolism associated with insulin deficiency
  • counter regulatory hormone excess and fluid depletion
  • absence of insulin -> hepatic glucose production increased -> reduced peripheral uptake -> osmotic diuresis, loss of fluid and electrolytes and dehydration
  • rapid lipolysis -> increased FFA levels
  • accumulation of ketone bodies produces a metabolic acidosis
  • respiratory compensation for acidosis -> hyperventilation
  • impaired renal excretion of hydrogen ions and ketones due to dehydration
  • as pH falls below 7 (H+ conc > 100 nmol/L), enzyme systems may fail
291
Q

what are clinical features of ketoacidosis?

A
  • prostration
  • hyperventilation
  • nausea
  • vomiting
  • abdominal pain
  • confusion and stupor
  • coma (5%)
  • dehydration, eyeball lax to pressure
  • smell of ketones on breath
  • dry skin
  • subnormal body temp
292
Q

what is the diagnosis of diabetic ketoacidosis?

A
  • hyperglycaemia: measure blood glucose
  • ketonaemia: test plasm with Ketostix. finger prick sample for beta-hydroxybutyrate
  • ketonuria: measure urine ketone levels where plasma ketone measurements are unavailable
  • metabolic acidosis
  • blood and urine culture
  • cardiac enzymes
  • CXR
  • ECG
  • catheterisation if no urine passed after 3 hours of hydration
  • if conscious, nasogastric tube
  • antibiotics if infection
293
Q

what are the obs values of diabetic ketoacidosis?

A
  • pulse >100 bpm or <60
  • systolic BP <90mmHg
  • Glasgow Coma Score <12 or abnormal AVPU
  • sats <92% on air
294
Q

what are blood features of diabetic ketoacidosis?

A
  • blood ketones >6 mmol/L
  • bicarbonate <12 mmol/L
  • venous/arterial pH <7.1
  • hypokalaemia on admission <3.5 mmol/L
295
Q

what should be done immediately in diabetic ketoacidosis?

A
  1. assess
  2. send bloods to lab
  3. set up IV infusion

blood glucose

  • measure baseline and hourly initially
  • aim for fall of 3-6 mmol/L per hour

urea and electrolytes

  • do baseline and hourly until 6 hours, then at 12 hours and at 24 hours
  • add potassium when K+ <3.5 mmol/L. give 20 mmol/h in infusion. 10 mmol/h when K+ = 3.5-5 mmol

FBC
blood gases: 0, 2, 6 hours
creatinine: at 0, 6, 12, 24 hours
bicarbonate: at 0, 1, 2, 3, 6, 12, 24 hours

296
Q

what is phase 1 of diabetic ketoacidosis management?

A
  • admit to level 2 HDU
  • insulin: soluble insulin by infusion or IM
  • fluid and electrolyte replacement: IV 0.9% NaCl with 20 mmol KCL/L
  • adjust KCl conc depending on results of regular blood K+ measurement
  • if BP below 80, give 500 mL 0.9% NaCl over 15min
    if pH below 7 give 500ml of sodium bicarb 1.26% plus 10 mmol KCl
297
Q

what is phase 2 of diabetic ketoacidosis management?

A

insulin and glucose

  • when blood glucose falls to 10-12 mmol/L, change infusion fluid to 1L 5% glucose and 20 mmol KCl 6 hourly
  • continue insulin with dose adjusted according to hourly glucose test results
298
Q

what is phase 3 of diabetic ketoacidosis management?

A

when stable and able to eat and drink normally, transfer to QDS subcutaneous insulin

299
Q

what are special measures for diabetic ketoacidosis management?

A
  • broad-spectrum antibiotic if infection likely
  • bladder catheter if no urine passed in 2 hrs
  • nasogastric tube if drowsy
  • consider CVP pressure monitoring if shocked or if previous cardiac or renal impairment
  • give SC prophylactic LMW heparin
300
Q

what is subsequent management of diabetic ketoacidosis?

A
  • monitor glucose hourly for 8 hrs
  • monitor electrolytes 2 hourly for 8 hours
  • adjust K+ replacement according to results
301
Q

what are the principles of management of diabetic ketoacidosis?

A
  • replace fluid losses (with 0.9% saline)
  • replace electrolyte losses (with K+)
  • restore acid-base balance
  • replace the deficient insulin
  • monitor blood glucose closely
  • seek the underlying cause
302
Q

what are precipitating factors for hyperosmolar hyperglycaemic state?

A
  • consumption of glucose rich fluids
  • concurrent medication e.g. thiazide diuretics or steroids
  • intercurrent illness
303
Q

what are investigations and treatment of hyperosmolar hyperglycaemic state?

A
  • plasma osmolality is usually extremely high
  • extremely sensitive to insulin
  • glucose conc may plummet
  • can cause cerebral damage
  • infuse insulin at 3 U/hour for first 2-3 hours, increasing to 6 U/hour if falling too slowly
  • 0.9% saline
  • low molecular weight heparin to counter increased risk of thromboembolic complications
304
Q

how can lactic acidosis occur in diabetes?

A
  • biguanide therapy
  • low risk in patients on metformin
  • large anion gap (<17 mmol/L)
  • usually without significant hyperglycaemia or ketosis
  • treatment is rehydration and infusion of isotonic 1.26% bicarbonate
  • mortality 50%
305
Q

what are macrovascular complications of diabetes?

A
  • stoke
  • MI
  • coronary artery disease
  • atherosclerosis
  • amputation of limbs for gangrene
306
Q

what are microvascular complications of diabetes?

A

affected sites: retina, renal glomerulus, nerve sheaths

  • diabetic retinopathy, nephropathy and neuropathy
  • cataracts
  • peripheral retina
  • macular oedema/damage
307
Q

what are examples of autonomic neuropathy that can occur in diabetes?

A
  • gustatory sweating
  • cardiac denervation
  • postural hypotension
  • gastroparesis
  • diarrhoea
  • atonic bladder/erectile dysfunction
  • arteriovenous shunting
308
Q

what are examples of somatic neuropathy that can occur in diabetes?

A
  • ocular palsies
  • carpal tunnel syndrome
  • small muscle wasting
  • amyotrophy
  • painful neuropathy
  • neuropathic foot
309
Q

what are distinguishing features of ischaemia in the diabetic foot?

A
  • claudication and rest pain
  • dependent rubor and trophic changes
  • cold and pulseless
  • painful ulceration in heels and toes
310
Q

what are distinguishing features of neuropathy in the diabetic foot?

A
  • usually painless, sometimes painful neuropathy
  • high arch, clawing of toes, no trophic changes
    palpation: warm, bounding pulses
  • painless, plantar ulceration
311
Q

what are the functions of the hypothalamus?

A
  • has vital centres for appetite, thirst, thermal regulation and sleeping/waking
  • integrates neural and endocrine inputs to control release of pituitary hormones
  • role in circadian rhythm, menstrual cyclicity and responses to stress, exercise and mood
312
Q

what do pathological conditions of the anterior pituitary cause?

A
  • most hormones secreted by it are under positive control by the hypothalamic releasing hormones apart from prolactin
  • prolactin is under tonic inhibition by dopamine
  • conditions interrupt the flow of hormones between the hypothalamus and pituitary gland and cause deficiency of most hormones but oversecretion of prolactin
313
Q

what is the function of the posterior pituitary?

A
  • connected to specific hypothalamic nuclei
  • acts as a storage organ
  • ADH and oxytocin are synthesised in the supraoptic and paraventricular nuclei in the anterior hypothalamus
  • stored in the posterior pituitary
314
Q

what are characteristics of growth hormone-releasing hormone (GHRH)?

A 
source: hypothalamus
site of action: pituitary
hormone structure: 44 AA
receptor: membrane; 7TM
post-receptor activity: Gproteins and cAMP
315
Q

what are characteristics of somatostatin?

A

source: hypothalamus
site of action: pituitary
hormone structure: cyclic peptide, 14 or 28 AA
receptor: membrane; 7TM, SST2 + SST5
post-receptor activity: G proteins, inhibit cAMP

316
Q

what are characteristics of growth hormone?

A 
source: pituitary
site of action: liver and other tissues
hormone structure: 191 AA
receptor: transmembrane, dimerised, GHR
post-receptor activity: JAK2, STAT
317
Q

what are characteristics of insulin-like growth factor 1 (IGF-1)?

A

source: liver and locally elsewhere
site of action: many tissues
hormone structure: peptide; 70 AA, 3 disulphide bridges
receptor: transmembrane, IGFR, 2alpha and 2beta subunits
post-receptor activity: receptor tyrosine kinase

318
Q

what are characteristics of thyrotropin releasing hormone (TRH)?

A 
source: hypothalamus
site of action: pituitary
hormone structure: peptide; 3 AA
receptor: membrane; 7TM, TRHR
post-receptor activity: G proteins, PLC/IP3
319
Q

what are characteristics of thyroid stimulating hormone (TSH)?

A

source: pituitary
site of action: thyroid
hormone structure: glycoprotein; alpha and beta subunits
receptor: membrane; 7TM, TSHR
post-receptor activity: G proteins, cAMP/PLC/IP3

320
Q

what are the characteristics of thyroxine and triiodothyronine (T4 and T3)?

A

source: thyroid
site of action: all tissues
hormone structure: thyronines - 4/3 iodine atoms
receptor: nuclear; TR-alpha and beta
post-receptor activity: transcription, TRE/RXR

321
Q

what are characteristics of gonadotropin-releasing hormone (GnRH; LHRH)?

A 
source: hypothalamus
site of action: pituitary
hormone structure: peptide; 10 AA
receptor: membrane, 7TM, GnRH-R1
post-receptor activity: G proteins, PLC/IP3
322
Q

what are characteristics of luteinising hormone (LH)?

A 
source: pituitary
site of action: gonad
hormone structure: glycoprotein; alpha and beta subunits
receptor: membrane, 7TM, LHhCGR
post-receptor activity: G proteins, cAMP
323
Q

what are characteristics of follicle-stimulating hormone (FSH)?

A 
source: pituitary
site of action: gonad
hormone structure: glycoprotein; alpha adn beta subunits
receptor: membrane, 7TM FSHR
post-receptor activity: G proteins, cAMP
324
Q

what are characteristics of oestradiol?

A

source: ovary
site of action: uterus, breast, bone, vascular
hormone structure: steroid ring
receptor: nuclear, ER alpha and beta (ESR1/ESR2)
post-receptor activity: homo/hetero dimer, ERE, transcription

325
Q

what are characteristics of testosterone?

A 
source: testis
site of action: many tissue
hormone structure: steroid ring
receptor: nuclear, AR (NR3C4)
post-receptor activity: dimer, ARE, transcription
326
Q

what are characteristics of inhibin and activin?

A

source: gonad
site of action: pituitary - hypothalamus
hormone structure: peptide dimers, alpha and beta subunits
receptor: transmembrane, dimerised
post-receptor activity: phosphorylation by receptor

327
Q

what are characteristics of dopamine?

A 
source: hypothalamus
site of action: pituitary
hormone structure: amine
receptor: membrane, 7TM, D2 receptor
post-receptor activity: G proteins, inhibit cAMP
328
Q

what are characteristics of prolactin?

A

source: pituitary
site of action: breast, other tissues
hormone structure: peptide, 199AA
receptor: transmembrane, PRLR, class 1 cytokine
post-receptor activity: JAK2 and other pathways

329
Q

what are characteristics of corticotrophin releasing hormone (CRH)?

A 
source: hypothalamus
site of action: pituitary 
hormone structure: peptide, 41AA
receptor: membrane, 7TM, CRF1
post-receptor activity: G proteins, cAMP
330
Q

what are characteristics of adrenocorticotrophic hormone (ACTH)?

A 
source: pituitary
site of action: adrenal 
hormone structure: peptide, 39 AA
receptor: membrane, 7TM ACTHR (MCR2)
post-receptor activity: G proteins, cAMP
331
Q

what are characteristics of cortisol?

A 
source: adrenal
site of action: all tissues
hormone structure: steroid ring
receptor: nuclear, GRalpha
post-receptor activity: transcription, GRE
332
Q

what are characteristics of vasopressin (ADH) affeecting the kidney?

A 
source: hypothalamus -> pituitary
site of action: kidney
hormone structure: peptide, 9AA
receptor: membrane, 7TM, AVPR2
post-receptor activity: G proteins, cAMP, aquaporin 2
333
Q

what are characteristics of vasopressin (ADH) affeecting the vasculature?

A 
source: hypothalamus -> pituitary
site of action: vascular
hormone structure: peptide 9AA
receptor: membrane, 7TM, AVPR1A
post-receptor activity: G proteins, PLC/IP3
334
Q

what are characteristics of vasopressin (ADH) affeecting the pituitary?

A

source: hypothalamus -> portal veins
site of action: pituitary (ACTH secretion)
hormone structure: peptide, 9AA
receptor: membrane, AVPR1B
post-receptor activity: G proteins, PLC/IP3

335
Q

what are characteristics of oxytocin?

A 
source: hypothalamus -> pituitary
site of action: uterus and breast
hormone structure: peptide, 9AA
receptor: membrene, 7TM, OXTR
post-receptor activity: G proteins
336
Q

how do pituitary space-occupying lesions and tumours cause problems?

A
  • local effects of a tumour
  • excess hormone secretion
  • result of inadequate production of hormone by the remaining normal pituitary, i.e. hypopituitarism
337
Q

how can a possible pituitary/hypothalamic tumour cause symptoms?

A
  • pressure on the visual pathways, with field defects and visual loss (most common)
  • pressure of the cavernous sinus, with II, IV and VI cranial nerve lesions
  • bony structures and the meninges surrounding the fossa, causing headache
  • hypothalamic centres: altered appetite, obesity, thirst, somnolence/wakefulness or precocious puberty
  • infiltration of the ventricles, causing interruption of CSF flow leading to hydrocephalus
  • infiltration of the sphenoid sinus with invasion causing CSF rhinorrhoea
338
Q

what are methods of investigation for pituitary space-occupying lesions and tumours?

A

MRI and visual field testing

339
Q

what are common defects of the visual fields caused by pituitary space-occupying lesions and tumours?

A

temporal quadrantanopia and bitemporal hemianopia

340
Q

what are types of hormonal excess caused by pituitary adenomas?

A
  • prolactin excess (prolacinoma or hyperprolactinaemia): histologically, they are chromophobe adenomas
  • GH excess (acromegaly or gigantism): somatotroph adenomas, usually acidophil, sometimes due to specific G protein mutations
  • excess ACTH secretion (Cushing’s disease of Nelson’s syndrome): corticotroph adenomas, usually basophil
341
Q

what are the usual sizes and clinical presentations of prolactinomas?

A

most <10 mm (microprolactinoma)
- galactorrhoea, amenorrhoea, hypogonadism, erectile dysfunction

some >10 mm (macroprolactinoma)
- as above plus headaches, visual field defects and hypopituitarism

342
Q

how is a pituitary/hypothalamic tumour removed or controlled?

A

surgery

  • trans-sphenoidal route is usually treatment of choice
  • very large tumours are sometimes removed via open transcranial (usually transfrontal) route

radiotherapy

  • by conventional linear accelerator or newer stereotactic techniques
  • usually employed when surgery is impracticable or incomplete
  • controls but rarely abolishes tumour mass
  • conventional regimen is a dose of 45 Gy, given as 20-25 fractions via three fields

medical therapy

  • somatostatin analogues and/or dopamine agonists may cause shrinkage of tumour
  • growth hormone receptor antagonist
343
Q

what are other differential diagnoses for pituitary or hypothalamic masses?

A

pituitary adenomas are the most common mass lesion of the pituitary (90%)

  • craniopharyngioma
  • uncommon tumours
  • hypophysitis and other inflammatory masses
  • other lesions
344
Q

what is craniopharyngioma?

A
  • 1-2%
  • cystic hypothalamic tumour, often calcified
  • arises from Rathke’s pouch
  • often mimics an intrinsic pituitary lesion
  • most common pituitary tumour in children
345
Q

what are some uncommon tumours that can be differentially diagnosed as pituitary or hypothalamic masses?

A
  • meningiomas
  • gliomas
  • chondromas
  • germinomas
  • pinealomas
  • primary pituitary carcinomas are very rare
  • prolactin and ACTH secreting tumours may require chemotherapy
  • secondary deposits
346
Q

what is hypopituitarism?

A
  • deficiency of hypothalamic releasing hormones or of pituitary trophic hormones
  • can be selective or multiple
  • isolated deficiencies of all pituitary hormones are seen
347
Q

what is affected in hypopituitarism?

A
  • multiple deficiencies of hormones result from tumour growth or other destructive lesions
  • progressive loss of anterior pituitary function
  • GH and gonadotropins are first affected
  • hyperprolactinaemia occurs early due to loss of tonic inhibitory control by dopamine
  • TSH and ACTH are last to be affected
348
Q

what is panhypopituitarism?

A
  • deficiency of all anterior pituitary hormones
  • caused by pituitary tumours, surgery or radiotherapy
  • vasopressin and oxytocin secretion will be affected only if the hypothalamus is involved in a tumour or a suprasellar extension of a pituitary lesion, or an infiltrative/infalmmatory process
  • posterior pituitary deficiency is rare in uncomplicated pituitary adenoma
349
Q

what are some causes of hypopituitarism?

A
  • congenital (isolated deficiency of pituitary hormones e.g. Kallmann’s syndrome, POUF1 (PIT-1), PROP1, HESX1 mutations)
  • infective (basal meningitis, encephalitis, syphilis)
  • vascular (pituitary apoplexy, Sheehan’s syndrome, carotid artery aneurysms)
  • immunological (hypophysitis, antibodies)
  • neoplastic (pituitary tumours, brain tumours, lymphoma, metastases)
  • trauma (skull fracture, surgery, perinatal)
  • infiltrative (sarcoidosis, Langerhans’, hereditary haemochromatosis)
  • miscellaneous (radiation, fibrosis, chemo, empty sella, anorexia)
  • genetic (PROP1 and POU1F1 mutations prevent differentiation of anterior pituitary cells)
350
Q

what are clinical features of hypopituitarism?

A
  • secondary hypothyroidism and adrenal failure both lead to tiredness and general malaise
  • hypothyroidism causes weight gain, slowness of thought and action, dry skin and cold intolerance
  • hypoadrenalism causes mild hypotension, hyponatraemia and ultimately cardiovascular collapse during severe intercurrent stressful illness
  • gonadotrophin leads to loss of libido, loss of secondary sexual hair, amenorrhoea and erectile dysfunction
  • hyperprolactinaemia may cause galactorrhoea and hypogonadism
  • weight may increase or decrease
  • longstanding panhypopituitarism gives the classic picture of pallor with hairlessness
351
Q

what are syndromes related to hypopituitarism?

A
  • Kallman’s syndrome
  • septo-optic dysplasia
  • Sheehan’s syndrome
  • pituitary apoplexy
  • empty sella syndrome
352
Q

what is Kallman’s syndrome?

A
  • isolated gonadotrophin deficiency
  • arises due to mutations in the KAL1 gene located on the short arm of the X chromosome
  • characterised by anosmia, which has a role in development of the olfactory system and migration of GnRH secreting neurones
353
Q

what is septo-optic dysplasia?

A
  • rare congenital syndrome
  • associated with mutations in the HESX1 gene
  • presents in childhood with a clinical triad of midline forebrain abnormalities, optic nerve hypoplasia and hypopituitarism
354
Q

what is Sheehan’s syndrome?

A
  • due to pituitary infarction following postpartum haemorrhage
  • rare in developed countries
355
Q

what is pituitary apoplexy?

A
  • pituitary tumour enlarged rapidly due to infarction or haemorrhage
  • severe headache, double vision and sudden severe visual loss, sometimes followed by acute life-threatening hypopituitarism
  • can be managed with hormone replacement and close monitoring of vision
356
Q

what is the empty sella syndrome?

A
  • empty sella is sometimes reported on pituitary imaging
  • may be due to a defect in the diaphragma and extension of the subarachnoid space (cisternal herniation) or may follow spontaneous infarction or regression of a pituitary tumour
  • all or most of the sella turcica is devoid of apparent pituitary tissue
  • pituitary function is usually normal
357
Q

what are basal investigations for the HP-ovarian axis?

A

pituitary hormones: LH and FSH
end-organ product/function: oestradiol, progesterone (day 21 of cycle)
other tests: ovarian ultrasound, LHRH test

358
Q

what are basal investigations for the HP-testicular axis?

A

pituitary hormone: LH, FSH
end-organ product/function: testosterone
other tests: sperm count, LHRH test

359
Q

what are basal investigations for the growth axis?

A

pituitary hormone: GH
end-organ product/functionL IGF-1, IGF-BP3
common dynamic tests: insulin tolerance test, glucagon test
other tests: GH response to sleep, exercise or arginine infusion, GHRH test

360
Q

what are basal investigations for the prolactin axis?

A

pituitary hormone: prolactin

end-organ product/function: prolactin

361
Q

what are basal investigations for the HP-thyroid axis?

A

pituitary hormone: TSH
end-organ product/function: free T4, T3
other tests: TRH test

362
Q

what are basal investigations for the HP-adrenal axis?

A

pituitary/hormone: ACTH
end-organ product/function: cortisol
common dynamic tests: insulin tolerance tests, short ACTH (tetracosactide) stimulation test
other tests: glucagon test, CRH test, metyrapone test

363
Q

what are basal investigations for the thirst and osmoregulation axis?

A

end-organ product/function: plasma/urine osmolality
common dynamic tests: water deprivation test
other tests: hypertonic saline infusion

364
Q

what is the procedure for the insulin tolerance test?

A
  • exclude cardiovascular disease (ECG), epilepsy or unexplained blackouts; exclude severe untreated hypopituitarism
  • IV hydrocortisone and glucose available for emergency
  • overnight fast, begin at 8/9
  • soluble insulin, 0.15 U/kg, IV at time 0
  • glucose, cortisol and GH levels at 0, 30, 45, 60, 90, 120 min
365
Q

what is the normal response to an insulin tolerance test?

A
  • cortisol rises above 550 nmol/L
  • GH rises above 7 ng/L (severe deficiency = <3 ng/L)
  • glucose must be <2.2 mmol/L to achieve adequate stress response
366
Q

what are usual replacement therapies for hypopituitarism for the adrenal axis?

A
  • hydrocotisone 15-40 mg daily (starting dose 10mg on rising/5mg lunchtime/5mg evening)
  • normally no need for mineralocorticoid replacement
367
Q

what is the usual replacement therapy for hypopituitarism for the thyroid axis?

A

levothyroxine 100-150 um daily

368
Q

what are the usual replacement therapies for hypopituitarism for the gonadal axis?

A

male: testosterone IM, orally, transdermally or implant
female: cyclical oestrogen/proestrogen orally or as patch
fertility: HCG plus FSH (purified or recombinant) or pulsatile GnRH to produce testicular development, spermatogenesis or ovulation

  • prevents long term problems related to deficiency (e.g. osteoporosis)
369
Q

what are usual replacement therapies for hypopituitarism for the growth axis?

A
  • recombinant human GH used routinely to achieve normal growth in children
  • also advocated for replacement therapy in adults where GH has effects on muscle mass and wellbeing
370
Q

what are usual replacement therapies for hypopituitarism for the thirst axis?

A
  • desmopressin 10-20 um one to three times daily by nasal spray or orally 100-200 um three times daily
  • carbamazepine, thiazides and chlorproamide are sometimes used in mild diabetes insipidus
371
Q

what are usual replacement therapies for hypopituitarism for the breast axis?

A

dopamine agonist (e.g. cabergoline, 500um)

372
Q

what is acromegaly and gigantism? what is it caused by?

A
  • growth hormone stimulates skeletal and soft tissue growth
  • excess produces gigantism in children and acromedaly in adults
  • due to a GH secreting pituitary tumour (somatotroph adenoma)
  • hyperplasia due to ectopic GHRH excess is very rare
373
Q

what is the incidence of acromegaly and gigantism?

A
  • 3-4 million per year

- 50-80 million world wide

374
Q

what are symptoms of acromegaly?

A
  • change in appearance
  • increased size of hands/feet
  • headaches
  • excessive sweating
  • visual detioration
  • tiredness
  • weight gain
  • amenorrhoea or oligomenorrhoea
  • galactorrhoea
  • impotence or poor libido
  • deep voice
  • goitre
  • breathlessness
  • pain/tingling in hand
  • polyuria/polydipsia
  • muscular weakness
  • joint pains
  • arthralgias
  • hypogonadal symptoms
375
Q

what are signs of acromegaly?

A
  • prominent supraorbital ridge
  • prognathism
  • interdental separation
  • large tongue
  • hirsutism
  • thick greasy skin
  • spade-like hands and feet
  • tight rings
  • carpal tunnel syndrome
  • colonic polyps
  • visual field defects
  • galactorrhoea
  • hypertension
  • oedema
  • heart failure
  • arthropathy
  • proximal myopathy
  • glycosuria
  • arthralgias
  • maxillofacial changes
  • acral englargement
376
Q

what are investigations of acromegaly and gigantism?

A
  • GH levels (normal levels <0.5ug/L)
  • glucose tolerance test (acromegalics fail to suppress GH below 0.3 ug/L)
  • IGF-1 levels (almost always raised in acromegaly)
  • visual field examination
  • MRI scan (reveals pituitary adenoma)
  • pituitary function (partial or complete anterior hypopituitarism is common)
  • prolactin (mild to moderate hyperprolactinaemia in 30% of patients; adenoma may secrete both GH and prolactin)
377
Q

how can untreated acromegaly cause death?

A
  • heart failure
  • coronary artery disease
  • hypertension-related causes
  • neoplasia (esp. large bowel tumours)
378
Q

what are the goals of acromegaly treatment?

A
  • to achieve a mean growth hormone level below 2.5 ug/L
  • normal IGF1
  • may be discordance between GH and IFG1 levels
  • hypopituitarism should be corrected when present
  • concurrent diabetes and hypertension should be treated conventionally
379
Q

how can acromegaly be treated?

A
  • surgery
  • pituitary radiotherapy
  • medical therapy (somatostatin receptor agonists, dopamine agonists, growth hormone antagonists)
380
Q

how is surgery used to treat acromegaly?

A

trans-sphenoidal surgery is appropriate first-line therapy

  • results in remission in 60-90% of cases with pituitary microadenoma, and 50% for macroadenoma
  • high preop GH and IGF1 levels are poor prognostic markers of surgical care
  • surgical success rates are variable and dependent on experience

transfrontal surgery rarely required except for massive macroadenomas
- 10% recurrence rate

381
Q

how is pituitary radiotherapy used to treat acromegaly?

A
  • external radiotherapy usually used after surgery fails to normal GH levels rather than as primary therapy
  • combined with medium-term treatment with somatostatin analogue, dopamine agonist or GH antagonist due to slow biochemical response to radiotherapy
  • stereotactic radiotherapy sometimes used
382
Q

what are the three targets of medical therapy for acromegaly?

A

three receptor targets

  • pituitary somatostatin receptors
  • dopamine (D2) receptors
  • growth hormone receptors in the periphery
383
Q

how are somatostatin receptor agonists used for treatment of acromegaly?

A
  • octretide and lanreotide are synthetic analogues of somatostatin that selectively act on receptor subtypes SST2 and SST5
  • receptor subtypes are highly expressed in GH-secreting tumours
  • reduce GH and IGF levels in most patients
384
Q

what is the administration and side effects of somatostatin receptor analogues?

A
  • administered as monthly depot injections
  • generally well tolerated
  • increased incidence of gallstones
  • expensive
385
Q

how are dopamine agonists used for treatment of acromegaly?

A
  • act on D2 receptors
  • given to shrink tumours prior to therapy or to control symptoms and persisting GH secretion
  • most effective in mixed GH producing (somatotroph) and prolactin producing (mammotroph) tumours
386
Q

what are doses for dopamine agonists for acromegaly?

A
  • bromocriptine 10-60 mg daily
  • cabergoline 0.5 mg daily
  • given alone they reduce GH to safe levels in a minority of cases
  • useful for mild residual disease or in combination with somatostatin analogues
387
Q

how are growth hormone antagonists used for acromegaly?

A
  • pegvisomant is a genetically modified analogue of GH
  • GH receptor antagonist which binds to and prevents dimerisation of the GH receptor
  • does not lower GH levels or reduce tumour size
  • does normalise IGF1 levels in 90% of patients
388
Q

how are growth hormone antagonists administered?

A
  • given by daily injection
  • main role is treatment of patients in whom GH and IGF levels cannot be reduced to safe levels with somatostatin analogues alone, surgery or radiotherapy
389
Q

what is the control and actions of prolactin?

A
  • prolactin is mainly controlled by tonic inhibition by hypothalamic dopamine
  • prolactin stimulates lactation and inhibits hypothalamic GnRH secretion and gonadal actions of LH
390
Q

what is prolactin? what are its actions?

A
  • large peptide secreted in the pituitary
  • acts via a transmembrane receptor stimulating JAK2 and other pathways
  • stimulates milk secretion but not breast tissue development
  • inhibits gonadal activity
  • decreases GnRH pulsatility at the hypothalamic level
  • blocks the action of LH on the ovary or testis, producing hypogonadism even when the pituitary gonadal axis itself is intact
391
Q

what inhibits/stimulate prolactin?

A
  • tonic dopamine inhibition

- factors, e.g. TRH that increase prolactin secretion, are probably of less relevance

392
Q

when does physiological hyperprolactinaemia occur?

A
  • pregnancy
  • lactation
  • severe stress
  • sleep
  • coitus
393
Q

what prolactin levels may be physiological and asymptomatic?

A

400-600 mU/L

394
Q

what prolactin levels imply a prolactin-secreting tumour?

A

above 5000 mU/L

395
Q

what are some causes of hyperprolactinaemia?

A
  • prolactinoma
  • co secretion of prolactin in tumours causing acromegaly
  • stalk compression due to pituitary adenomas and other pituitary masses
  • PCOS
  • primary hypothyroidism
  • idiopathic hyperprolactinaemia
  • rarer causes: oestrogen therapy, renal failure, liver failure, post-ictal state, chest wall injury
  • dopamine agonist drugs
  • other antiemetics and opiates
396
Q

what are clinical features of hyperprolactinaemia?

A

stimulates milk production in breast and inhibits GnRH and gonadotropin secretion

  • galactorrhoea, spontaneous or expressible (60% of cases)
  • oligomenorrhoea or amenorrhoea
  • decreased libido
  • decreased potency in men
  • subfertility
  • oestrogen/androgen deficiency
  • delayed or arrested puberty
  • mild gynaecomastia in men
  • headaches and visual field defects if pituitary tumour present
  • infertility
397
Q

how is hyperprolactinaemia investigated?

A
  • confirmed by repeated measurement

- if no clinical features, macroprolactinaemia should be considered

398
Q

what is macroprolactinaemia?

A
  • higher molecular weight complex of prolactin bound to IgG
  • physiologically inactive but occurs in small proportion of normal people
  • can lead to unneccessary treatment
399
Q

how can macroprolactinaemia be diagnosed?

A

in laboratory by precipitation of IgG with polyethylene glycol, after which prolactin levels will be normal on testing

400
Q

what tests are done for hyperprolactinaemia after physiological and drug causes have been excluded?

A
  • visual fields should be checked
  • primary hypothyroidism must be excluded as this can cause it
  • anterior pituitary function should be assessed if any evidence of hypopituitarism or radiological evidence of a pituitary tumour
  • MRI of the pituitary if any clinical features, or when prolactin is above 1000 mU/L
401
Q

what prolactin levels suggest prolactinoma?

A

prolactin helps determine whether the mass is a prolactinoma or a non-functioning pituitary tumour causing stalk-disconnection hyperprolactinaemia

  • above 5000 mU/L in presence of macroadenoma
  • above 2000 mU/L in presence of a microadenoma
402
Q

what is a macroprolactinoma?

A

a pituitary tumour above 10mm diameter

403
Q

what is a microprolactinoma?

A

smaller pituitary tumours (less than 10mm diameter)

404
Q

what is the hook effect?

A

very large prolactinomas can be associated with such high serum prolactin levels that some assays give an artefactual falsely low results
- can be excluded by serial dilutions of the serum sample

405
Q

what is treatment of hyperprolactinaemia?

A

usually treated to avoid the long-term effects of oestrogen or testosterone deficiency

exceptions: minor elevations (400-1000 mU/L) with preservation of normal menstruation and post menopausal people with microprolactinomas who are not taking oestrogen replacement

406
Q

what is the medical treatment for hyperprolactinaemia/prolactinoma?

A

dopamine agonist

  • cabergoline
  • bromocriptine
  • quinagolide
407
Q

how is cabergoline used to treat hyperprolactinaemia?

A
  • 500ug once or twice a week judged on clinical response and prolactin levels
  • best tolerated and longest-acting drug and is the first drug of choice
408
Q

how is bromocriptine used to treat hyperprolactinaemia? what is its dosage and side effects?

A
  • longest established therapy
  • preferred if pregnancy is planned
  • initial dose should be small (1mg), taken with food and increased to 2.5mg two or three times daily
  • side effects include nausea and vomiting, dizziness and syncope, constipation and cold peripheries
409
Q

how is quinagolide used to treat hyperprolactinaemia?

A

75-150ug once daily

410
Q

how is trans-sphenoidal surgery used to treat hyperprolactinaemia?

A
  • may restore normoprolactinaemia in people with microadenoma
  • rarely completely successful with macroadenomas and risks damage to normal pituitary function
  • prolactin should be measured before surgery on any mass in the pituitary region
411
Q

how is radiotherapy used to treat hyperprolactinaemia?

A
  • usually controls adenoma growth
  • slowly effective in lowering prolactin
  • causes progressive hypopituitarism
  • may be used after medical tumour shrinkage or after surgery in larger tumours
412
Q

what is the pituitary-thyroid axis?

A

hypothalamus releases TRH -> pituitary releases TSH which acts on the thyroid -> thyroid releases T4 and T3 which has negative feedback on the hypothalamus and pituitary

413
Q

what is the pituitary-gonadal axis?

A
  • GnRH released from the hypothalamus
  • GnRH travels down anterior pituitary via the hypophyseal portal system and binds to receptors on adenohypophysis -> LH and FSH produced
  • FSH has positive effect on Sertoli cells/ovaries; Sertoli cell produces inhibin which has negative feedback on FSH
  • LH stimulates Leydig cell, which produces testosterone, which negatively affects GnRH
414
Q

what is the hypothalamic-pituitary-adrenal axis?

A
  • hypothalamus releases CRH
  • CRH stimulates anterior pituitary to produce ACTH
  • ACTH stimulates the adrenal cortex to produce cortisol
  • cortisol has negative feedback effect on the anterior pituitary and hypothalamus
415
Q

what is the GH/IGF-1 axis?

A
  • hypothalamus releases GHRH and somatostatin
  • GHRH positively stimulates the pituitary to produce GH
  • somatostatin negatively inhibits the pituitary from producing GH
  • GH causes the liver to release IGF-1
  • IGF-1 has an inhibitory effect on the hypothalamus
416
Q

what effect does dopamine have on prolactin secretion?

A

inhibitory

417
Q

what are hypothalamic hormones that regulate pituitary hormones?

A
  • GHRH and somatostatin (growth hormone)
  • GnRH (LH and FSH)
  • CRH (ACTH)
  • TRH (TSH)
  • dopamine (prolactin
418
Q

what are diseases of the pituitary gland?

A
  • benign pituitary adenoma
  • craniopharyngioma
  • trauma
  • apoplexy/Sheehans
  • sarcoid/TB
419
Q

what do pituitary tumours cause?

A

pressure on local structure e.g. optic nerves
- bitemporal hemianopia

pressure on normal pituitary
- hypopituitarism

functioning tumour

  • prolactinoma
  • acromegaly
  • Cushing’s disease
420
Q

what are types of functioning pituitary tumours?

A

prolactinomas, acromegaly and Cushing’s disease

421
Q

what are local upward symptoms of a pituitary tumour and of hypopituitarism?

A

headaches

  • stretching of dura by tumour
  • hydrocephalus (rare)

visual field defects
- nasal retinal fibres compressed by tumour

visual

422
Q

what are local sideways symptoms of a pituitary tumour and of hypopituitarism?

A

cranial nerve palsies and temporal lobe epilepsy

- lateral extension of tumour

423
Q

what are local downward symptoms of a pituitary tumour and of hypopituitarism?

A

CSF rhinorrhoea

- downward extension of tumour

424
Q

what are characteristics of the hypopituitary man?

A

pale, no body hair, central obesity

425
Q

what is the definition of Cushing’s syndrome?

A

chronic, excessive and inappropriate elevated levels of circulating plasma glucocorticoids (cortisol)

426
Q

what is the involvement of ACTH and cortisol in the hypothalamic-pituitary-adrenal axis?

A
  • ACTH produced by pituitary, pituitary tumour, ectopic tumour or synthetic ACTH stimulates the adrenal gland to secrete cortisol
  • cortisol is produced by the stimulated adrenal gland and an adrenal tumour
  • cortisol has a negative feedback on the pituitary and the hypothalamus (CRH)
  • exogenous steroid has a negative feedback on the pituitary and hypothalamus (CRH)
427
Q

what effect does exogenous steroid have on the HPA axis?

A

negative feedback effect on the pituitary gland and the hypothalamus (CRH)

428
Q

what is the HPA axis like in Cushing’s syndrome?

A
  • increased ACTH production (Cushing’s disease)
  • ectopic ACTH secretion
  • primary adrenal disease
429
Q

what are ACTH-dependent causes of Cushing’s syndrome?

A
  • Cushing’s disease (pituitary-dependent)
  • ectopic ACTH syndrome/producing tumours
  • unknown source of ACTH
  • ACTH administration
430
Q

what are ACTH-independent causes of Cushing’s syndrome?

A
  • adrenal adenoma
  • adrenal carcinoma
  • macronodular hyperplasia (AIMAH)
  • primary pigmented nodular adrenal disease (PPNAD)
  • McCune Albright syndrome
  • glucocorticoid administration
  • alcohol-induced pseudo-Cushing’s syndrome
431
Q

what is the physical appearance of Cushing’s syndrome?

A
  • moon face
  • hirsutism
  • facial plethora
  • acne
  • thinned scalp hair
432
Q

what are clinical features of Cushing’s syndrome?

A
  • carbohydrate metabolism (IGT, diabetes)
  • electrolyte disturbance (sodium retention, hypertension, hypokalaemia)
  • immune suppression (susceptibility to infection)
  • central effects (malaise, depression, psychoses)
  • suppressed gonadal function (oligo/amenorrhoea, impotence, loss of libido)
  • obesity
  • facial plethora
  • rounded face
  • thin skin
  • decreased linear growth
  • hirsutism
  • easy bruising
  • weakness
  • osteopaenia
  • nephrolithiasis
  • pigmentation (only with ACTH-dependent causes)
  • cushingoid appearance
433
Q

what are clinical features of Cushing’s syndrome that are most discriminating of it vs e.g. PCOS or obesity?

A

those associated with protein wasting

  • thin skin
  • decreased linear growth
  • easy bruising
  • weakness
434
Q

what is the two step process of diagnosis of Cushing’s syndrome?

A
  1. confirmation

2. differential diagnosis of the cause; investigation of cause, in major referral centre

435
Q

what are screening tests used for Cushing’s syndrome?

A
  • 24-hour urinary free cortisol measurements
  • 48-hour low dose dexamethasone suppression tests
  • circadian rhythm; late night/midnight serum or salivary cortisol

no single test is perfect
repeated tests may be needed to avoid missing mild or periodic/cyclical disease

436
Q

what are results of the screening tests that would indicate Cushing’s syndrome?

A
  • elevated urinary free cortisol (three 24 hour collections)
  • serum cortisol >50nM (1.8ug/dl) on dexamethasone-suppression testing
  • plasma midnight cortisol; sleeping >50nM (1.8ug/dl); awake > 207nmol/l (7.5ug/dl)
  • elevated late night salivary cortisol
  • circadian rhythm: high midnight cortisol levels >100 nmol/L; 0900 values may be normal
437
Q

how is an ACTH-independent Cushing’s syndrome confirmed?

A

measure plasma ACTH

- <5pg/ml on more than 2 occasions

438
Q

how is an ACTH-dependent Cushing’s syndrome confirmed?

A

measure plasma ACTH

- >15pg/ml

439
Q

how is an ACTH-independent Cushing’s syndrome further investigated and what can the results be?

A

adrenal imaging with CT

  • > adrenal lesion
  • > no adrenal lesion

adrenal lesion

  • adenoma
  • carcinoma
  • AIMAH

no adrenal lesion

  • PPNAD
  • exogenous glucocorticoid
440
Q

how is ACTH-dependent Cushing’s syndrome further investigated and what can the results be?

A

pituitary MRI and CRH test:

  • adenoma >6mm AND
  • positive CRH response AND
  • suppression on dexamethasone

small or no adenoma on MRI and CRH test/inconclusive -> BIPSS

positive ACTH gradient or all three of above -> Cushing’s disease

no ACTH gradient -> CT/MRI thorax and abdomen; somatostatin scintigraphy -> ectopic ACTH?

441
Q

when is medical management used for Cushing’s syndrome?

A

adrenal blockage

- preparation for surgery, not usually a long-term solution

442
Q

when is surgical management used for Cushing’s syndrome?

A

Cushing’s syndrome

  • transsphenoidal surgery
  • bilateral adrenalectomy; risk of Nelson’s

ectopic
- remove source

adrenal adenoma/carcinoma
- adrenalectomy

PPNAD
- adrenalectomy

AIMAH
- adrenalectomy/block aberrant receptors

443
Q

when is radiotherapy used to manage Cushing’s syndrome?

A

Cushing’s disease

- adjuvant (primary) therapy

444
Q

what is the epidemiology of acromegaly?

A
  • incidence of 3.3 per million
  • prevalence of 58 per million
  • mean age at diagnosis is 44 years
  • mean duration of symptoms is 8 years
445
Q

what are comorbidities of acromegaly?

A
  • hypertension and heart disease
  • sleep apnea
  • insulin-resistant diabetes
  • arthritis
  • cerebrovascular events and headache
446
Q

what is the impact of acromegaly on survival?

A

life expectancy decreased by average of 10 years

  • lowest decrease in all acromegaly
  • medium decrease in acromegaly and diabetes
  • highest decrease in acromegaly and cardiac disease
447
Q

what are criteria for exclusion of acromegaly?

A

excluded if: random GH <0.4 ng/ml and normal IGF-1

if either abnormal proceed to: 75gm glucose tolerance test

acromegaly excluded if: IGF1 normal and GTT nadir GH <1ng/ml

448
Q

what are some objectives of therapy in acromegaly?

A
  • restoration of basal GH and IGF1 to normal levels
  • relief of symptoms
  • reversal of visual and soft tissue changes
  • prevention of further skeletal deformity
  • normalisation of pituitary function
449
Q

what are the determinants of success of surgery for acromegaly?

A

microadenoma <1cm; surgical cure rate ~90%
macroadenoma >1cm; surgical cure rate <50%

determinants

  • size of tumour
  • the surgeon
450
Q

what are complications of pituitary surgery?

A
  • anaesthetic complications
  • carotid artery injury
  • CNS injury
  • haemorrhage
  • loss of vision
  • opthalmoplegia
  • meningitis
  • nasal septum perforation
  • post op epistaxis/sinusitis
  • hypopituitarism
  • DI
  • death
451
Q

what are types of radiotherapy used for acromegaly?

A
  • conventional (multi-fractional)
  • sterotactic (single fraction; less radiation to surrounding tissues; proton beam)
  • gamma knife
  • LINAC
  • proton beam
452
Q

what are determinants of efficacy of radiotherapy?

A
  • GH level

- tumour extension

453
Q

what are some disadvantages of conventional radiotherapy for acromegaly?

A
  • delayed response
  • hypopituitarism
  • rare secondary tumours
  • rare visual defects
454
Q

what are goals of dopamine agonists for acromegaly?

A
  • control GH
  • control IGF1
  • improve well being
455
Q

what are advantages and disadvantages of dopamine agonists for acromegaly?

A

advantages

  • no hypopituitarism
  • oral administration
  • rapid onset

disadvantages

  • relatively ineffective
  • side effects
456
Q

what are some examples of somatostatin analogues?

A
  • human somatostatins
  • ocreotide
  • lanreotide
457
Q

what are characteristics of human somatostatin/lanreotide for acromegaly?

A
  • amino acids essential for receptor binding
  • inhibit multitude of hormones
  • half life of 3 minutes
  • rebound
  • binds all 5 receptor subtypes
458
Q

what are characteristics of octreotide for acromegaly?

A
  • more specific
  • half life of 100 minutes
  • no rebound
459
Q

what are the goals of somatostatin analogues for acromegaly?

A
  • control GH
  • control IGF1
  • clinical improvement
460
Q

what is the control exerted by somatostatin analogues in acromegaly?

A
  • IGF1 controlled 65%
  • GH controlled 60%
  • tumour shrinkage
461
Q

what are determinants of efficacy for somatostatin analogues in acromegaly?

A
  • GH level
  • tumour size
  • SMS receptor expression
462
Q

what are disadvantages of somatostatin analogues in acromegaly?

A
  • injectable

- side effects

463
Q

what is Pegvisomant? what are its characteristics?

A
  • GH analogue
  • 191 amino acids
  • 9 amino acid substitutions
  • 4-5 PEG moieties
  • molecular weight 42-46000 D
  • half life >70 hours
  • subcutaneous administration
  • > serum GH cannot be used as a disease marker
  • > cross-reacts in GH assays
464
Q

what is the epidemiology of prolactinoma?

A
  • incidence 10 per 100000
  • women > men
  • prevalence 90 per 100000
465
Q

what is a prolactinoma?

A

benign lactrotroph cell tumour (adenoma) of the pituitary gland that produces prolactin

466
Q

what are the local effects of a macroprolactinoma?

A
  • headache
  • visual field defect (bitemporal hemianopia)
  • CSF leak (rare)
467
Q

what are symptoms of Cushing’s syndrome?

A
  • weight gain (central)
  • change of appearance
  • depression
  • insomnia
  • amenorrhoea/oligomenorrhoea
  • poor libido
  • thin skin/easy bruising
  • hair growth/acne
  • muscular weakness
  • growth arrest in children
  • back pain
  • polyuria/polydipsia
  • psychosis

old photos may be useful

468
Q

what are signs of Cushing’s syndrome?

A
  • moon face
  • plethora
  • depression/psychosis
  • acne
  • hirsutism
  • frontal balding (female)
  • thin skin
  • bruising
  • poor wound healing
  • pigmentation
  • skin infections
  • hypertension
  • osteoporosis
  • pathological features (esp. vertebrae and ribs)
  • kyphosis
  • buffalo hump (dorsal fat pad)
  • central obesity
  • striae (purple or red)
  • rib fractures
  • oedema
  • proximal myopathy
  • proximal muscle wasting
  • glycosuria
469
Q

what is Cushing’s disease?

A

increased circulating ACTH from the pituitary

- causes 65% of cases of Cushing’s syndrome

470
Q

what is ACTH dependent Cushing’s syndrome?

A

ectopic, non-pituitary ACTH producing tumour elsewhere in the body

  • causes 10% of Cushing’s syndrome cases
  • causes consequent glucocorticoid excess
471
Q

what is non-ACTH dependent Cushing’s syndrome?

A

primary excess of endogenous cortisol secretion (25% of cases) by an adrenal tumour or nodular hyperplasia

  • subsequent physiological suppression of ACTH
  • rare cases are due to aberrant expression of receptors for other hormones in adrenal cortical cells
472
Q

what are other tests that can be done if any clinical suspicion of Cushing’s remains after preliminary tests?

A

insulin stress test, desmopressin stimulation test and CRH test

473
Q

what are biochemical and radiological procedures for differential diagnosis of causes of Cushing’s syndrome?

A
  • plasma ACTH levels (low or undetectable ACTH levels, <10ng/L, on two or more occasions indicates non-ACTH-dependent disease)
  • adrenal CT or MRI scan
  • pituitary MRI
  • plasma potassium levels (hypokalaemia is common with ectopic ACTH secretion)
  • high-dose dexamethasone test
  • CRH test
  • chest xray
474
Q

how can Cushing’s syndrome cause death?

A

hypertension, MI, infection, heart failure

475
Q

what is the pharmacological treatment of Cushing’s syndrome?

A

successful treatment with a normal biochemical profile should lead to reversal of clinical features

  • cortisol hypersecretion should be controlled before surgery or radiotherapy
  • metyrapone (11beta-hydroxylase blocker), given in doses of 750mg to 4g daily in 3-4 divided doses
  • ketoconazole given 200mg TDS
  • plasma cortisol should be reduced during the day to 150-300nmol/L
  • aminoglutethimide and trilostane (reversibly inhibits 3-hydroxysteroid dehydrogenase/5-5,4 isomers) are sometimes used
476
Q

what is the treatment of Cushing’s disease? what is Cushing’s disease?

A

pituitary-dependent hyperadrenalism

  • transphenoidial removal of the tumour (remission in 75-80% of cases)
  • external pituitary irradiation (slow acting, 50-60% effective, stereotactic radiotherapy may be useful)
  • medical therapy (e.g. bromocriptine, cabergoline, cyproheptadine, STS analogues are rarely effective)
  • bilateral adrenalectomy (effective last resort; can be performed laparoscopically)
477
Q

what is the treatment for adrenal adenomas?

A
  • should be resected after achievement of clinical remission with metyrapone or ketoconazole
  • contralaeral adrenal suppression may last for a year or more
478
Q

what is the treatment for adrenal carcinomas?

A
  • highly aggressive with a poor prognosis
  • if no widespread metastases, tumour bulk should be reduced surgically
  • mitotane (adrenolytic drug) may inhibit growth of tumour and prolong survival, though it can cause nausea and ataxia
479
Q

what is the treatment of tumours secreting ACTH ectopically?

A
  • should be removed if possible

- chemotherapy/radiotherapy may be used

480
Q

what is Nelson’s syndrome?

A

increased pigmentation (because of high levels of ACTH) associated with an enlarging pituitary tumour

  • occurs in 20% of cases after bilateral adrenalectomy for Cushing’s disease
  • rare now that adrenalectomy is an uncommon primary treatment
  • incidence may be reduced by pituitary radiotherapy soon after adrenalectomy
  • may be treated by pituitary surgery/radiotherapy
481
Q

what are examples of pituitary adenomas secreting other pituitary hormones?

A
  • may rarely secrete TSH (and cause thyrotoxicosis); TSHomas
  • > leads to the unusual biochemical pattern of elevated fT4 levels with normal or high circulating TSH levels
  • FSH and LH secreting pituitary tumours may cause elevated sex steroids; extremely rare
482
Q

what is the protocol, measure, normal test results and use of overnight Dexamethasone (for Cushing’s)?

A

overnight: take 1mg when going to bed at 2300hrs
- measure: plasma cortisol at 0900hrs next morning
- normal test result/positive suppression: plasma cortisol <100nmol/L
- use and explanation: outpatient screening test; some false positives

483
Q

what is the protocol, measure, normal test results and use of low-dose Dexamethasone suppression test for diagnosing Cushing’s syndrome?

A
  • test and protocol: 0.5mg 6-hourly; 8 doses from 0900 on day 0
  • measure: plasma cortisol at 0900hrs on days 0 and +2
  • normal test result/positive suppression: plasma cortisol <50nmol/L on second sample
  • use and explanation: for diagnosis of Cushing’s
484
Q

what is the protocol, measure, normal test results and use of high-dose Dexamethasone suppression test used in differential diagnosis of Cushing’s syndromes?

A
  • test and protocol: 2mg 6-hourly; 8 doses from 0900hrs on day 0
  • measure: plasma cortisol at 0900hrs on days 0 and +2
  • normal test result/positive suppression: plasma cortisol on day +2 less than 50% of that on day 0 suggests pituitary-dependent disease
  • use and explanation: differential diagnosis
485
Q

what is the anatomy of the thyroid gland?

A
  • two lateral lobes connected by an isthmus
  • closely attached to the thyroid cartilage and the upper end of the trachea
  • embryologically, it originates from the base of the tongue and descends to the middle of the neck
  • rich blood supply from superior and inferior thyroid arteries
486
Q

what is the histology of the thyroid gland?

A
  • follicles lined by cuboidal epithelial cells
  • inside the follicles is colloid (iodinated glycoprotein thyroglobulin) which is synthesised by follicular cells
  • each follicle is surrounded by basement membrane
  • parafollicular cells are between follicular cells
  • parafollicular cells contain calcitonin-secreting C cells
487
Q

what is colloid?

A
  • is inside thyroid follicles
  • iodinated glycoprotein thyroglobulin
  • synthesised by follicular cells
488
Q

what do parafollicular cells contain?

A

calcitonin-secreting C cells

489
Q

what does the thyroid gland synthesise?

A
  • triiodothyronin (T3) which acts at the cellular level

- L-thyroxine (T4) which is a prohormone

490
Q

what are T3 and T4?

A

T3: triiodothyronin; acts at the cellular level

T4: L-thyroxine; prohomone

491
Q

what are T3 and T4 derived from?

A

inorganic iodide is trapped by the thyroid by an enzyme-dependent system, oxidised and incorporated into the glycoprotein thyroglobulin to from mono- and diiodotyrosine and then T4 and T3

492
Q

how much T3 and T4 are produced? what happends to T4?

A
  • more T4 than T3 is produced
  • T4 is converted in some peripheral tissues (liver, kidney and muscles) to T3 by 5’-monodeiodination
  • alternative 3’-monodeiodination yields the inactive reverse T3 (rT3)
493
Q

how and when is reverse T3 (rT3) produced?

A

3’-monodeiodination

- occurs particularly in severe non-thyroidal illness

494
Q

how is T4 converted into T3?

A

by 5’-monodeiodination

- T3 is more active

495
Q

what is the transport of T4 and T3?

A
  • in plasma, more than 99% of all T4 and T3 is bound to hormone binding proteins (thyroxine-binding globulin, TBG; thyroid-binding prealbumin, TBPA; albumin)
  • only free hormone can act in the target tissues
  • T3 binds to specific nuclear receptors
496
Q

how is the HPT axis controlled?

A
  • thyrotropin releasing hormone (TRH) from the hypothalamus stimulates the pituitary to secrete TSH
  • TSH stimulates growth and activity of thyroid follicular cells via the G-protein coupled TSH membrane receptor
  • T3 and T4 exert negative feedback on the hypothalamus
497
Q

what does T3 bind to? what does this cause?

A

binds to the thyroid hormone nuclear receptor (TR) on target organ cells to cause modified gene transcription

  • TRalpha and TRbeta
  • TRalpha knock out mice show poor growth, bradycardia and hypothermia
  • TR beta knock out mice show thyroid hyperplasia and high T4 levels in presence of inappropriately normal circulating TSH; thyroid hormone resistance?
498
Q

what do TRalpha and TRbeta knock out mice show?

A
  • TRalpha knock out mice show poor growth, bradycardia and hypothermia
  • TR beta knock out mice show thyroid hyperplasia and high T4 levels in presence of inappropriately normal circulating TSH; thyroid hormone resistance?
499
Q

what is the recommended daily intake of iodine? what can dietary supplementation be?

A
  • at least 140ug per day
  • supplementation of salt and bread has reduced number of areas where endemic goitre still occurs
  • dietary iodine deficiency is a major cause of thyroid disease, as it’s an essential requirement for thyroid disease
500
Q

what are the physiological effects of thyroid hormone on the CVS, bone, respiratory system, GI system, blood, neuromuscular function, carbohydrate metabolism, lipid metabolism and SNS?

A

CVS: increases heart rate and cardiac output

bone: increases bone turnover and resorption

respiratory system: maintains normal hypoxic and hypercapnic drive in respiratory centre

GI system: increases gut motility

blood: increases red blood cell 2,3-BPG, facilitating oxygen release to tissues

neuromuscular function: increases speed of muscle contraction and relaxation and muscle protein turnover

carbohydrate metabolism: increases hepatic gluconeogenesis/glycolysis and intestinal glucose absorption

lipid metabolism: increases lipolysis and cholesterol synthesis and degradation

SNS: increases catecholamine sensitivity and beta-adrenergic receptors in heart, skeletal muscle, adipose cells and lymphocytes; decreases cardiac alpha-adrenergic receptors

501
Q

what is required from the blood for thyroid hormone synthesis?

A

inorganic iodide

502
Q

what are steps involved in thyroid hormone synthesis?

A
  1. inorganic iodide is transferred from the blood into the follicular cell by Na+/I- symporter
  2. iodide is transferred from the follicular cell to the colloid by the iodide transporter, pendrin
  3. thyroperoxidase oxidises two I- to form I2
  4. thyroperoxidase iodinates the tyrosyl residues of the thyroglobulin within the colloid
  5. iodinated thyroglobulin binds megalin for endocytosis back into the cell
  6. TSH binding stimulates endocytosis of the colloid
  7. endocytosed vesicles fuse with lysosomes of follicular cell
503
Q

how is iodine transported into the follicular cell from the blood?

A

by the Na+/I- symporter

  • transports two sodium ions across the BM with one iodide ion
  • secondary active transporter
  • utilises the concentration gradient of Na+ to move I- against its gradient
504
Q

how is iodide moved across the apical membrane into the colloid of the thyroid follicle?

A

pendrin; an anion exchange protein

505
Q

how and why is iodide converted to iodine during thyroid hormone synthesis?

A
  • thyroperoxidase oxidises two I- to form I2
  • iodide is non-reactive
  • only the more reactive iodine is needed for the next step
506
Q

what are actions of thyroperoxidase in thyroid hormone synthesis?

A
  • oxidises two I- to form I2 (iodine)

- iodinates tyrosyl residues of the thyroglobulin within the colloid (synthesised in the ER of the follicular cell)

507
Q

how is iodinated thyroglobulin endocytosed back into the follicular cell?

A

binds megalin

508
Q

what is thyroglobulin?

A
  • a 660kDa, dimeric protein produced by the follicular thyroid cells
  • accounts for half of the protein content of the thyroid gland
  • contains 100-120 tyrosine residues; <20 are iodinated by thyroperoxidase
509
Q

how are MIT and DIT produced?

A
  • monoiodotyrosine is produced by tyrosine residues in thyroglobulin being iodinated on their phenol rings at one position ortho to the phenolic hydroxyl group by thyroperoxidase
  • DIT is produced by the same process above except at both positions ortho to the phenolic hydroxyl group
510
Q

what produces peptidic triiodothyronine (T3)?

A

peptidic MIT + peptidic DIT

- catalysed by thyroperoxidase

511
Q

what produces peptidic thyroxine (T4)?

A

2 peptidic DIT2 -> peptidic thyroxine

- catalysed by thyroperoxidase

512
Q

what produces rT3?

A

peptidic DIT + peptidic MIT -> reverse peptidic triiodothyronine

  • catalysed by thyroperoxidase
  • paired in reverse order
513
Q

how do thyroid hormones cross the follicular cell membrane towards the blood vessels?

A
  • unknown mechanism

- may be monocarboxylate transporter (MCT) 8 and 10 play major roles

514
Q

what proportion of thyroid hormones are protein bound vs free in the blood?

A

> 99% protein bound

<1% free

515
Q

what are thyroid functioning tests?

A
  • TSH measurements

- TRH test

516
Q

what can TSH measurements tell us about thyroid function?

A
  • TSH levels can discriminate between hyperthyroidism, hypothyroidism and euthyroidism (normal thyroid gland function)
  • except hypopituitarism and the sick euthyroid syndrome where low levels occur with low or normal T4 and T3 levels
  • most sensitive
  • accurate diagnosis requires at least 2 tests
517
Q

what can TRH tests tell us about thyroid function?

A
  • rendered almost obsolete by modern sensitive TSH assays except for investigation of hypothalamic-pituitary dysfunction
  • TRH (protirelin) may be used to differentiate between thyroid hormone resistance and TSHoma in context of fT4 and TSH levels
  • after TRH administration there is a rise in TSH in thyroid hormone resistance
  • in TSHoma there is a flat response due to continued autonomous TSH secretion which doesn’t respond to TRH
518
Q

what are TSH levels like in thyrotoxicosis, primary hypothyroidism, TSH deficiency, T3 toxicosis and compensated euthyroidism?

A

normal values: 0.3-3.5mU/L

  • thyrotoxicosis: suppressed (<0.05mU/L)
  • primary hypothyroidism: increased (>10mU/L)
  • TSH deficiency: low-normal or subnormal
  • T3 toxicosis: suppressed (<0.05mU/L)
  • compensated euthyroidism: slightly increased (5-10mU/L)
519
Q

what are free T4 levels like in thyrotoxicosis, primary hypothyroidism, TSH deficiency, T3 toxicosis and compensated euthyroidism?

A

normal values: 10-25pmol/L

  • thyrotoxicosis: increased
  • primary hypothyroidism: low/low-normal
  • TSH deficiency: low/low-normal
  • T3 toxicosis: normal
  • compensated euthyroidism: normal
520
Q

what are free T3 levels like in thyrotoxicosis, primary hypothyroidism, TSH deficiency, T3 toxicosis and compensated euthyroidism?

A

normal levels 3.5-7.5pmol/L

  • thyrotoxicosis: increased
  • primary hypothyroidism: normal or low
  • TSH deficiency: normal or low
  • T3 toxicosis: increased
  • compensated euthyroidism: normal
521
Q

what are causes of hypothyroidism?

A
  • primary disease of thyroid
  • secondary (to hypothalamic-pituitary disease)
  • peripheral resistance to thyroid hormone
522
Q

what are primary diseases of the thyroid that cause hypothyroidism?

A

congenital

  • agenesis
  • ectopic thyroid remnants

defects of hormone synthesis

  • iodine deficiency
  • dyshormonogenesis
  • antithyroid drugs
  • other drugs (e.g. lithium, amiodarone, interferon)

autoimmune

  • atrophic thyroiditis
  • Hashimoto’s thyroiditis
  • postpartum thyroiditis

infective
- post-subacute thyroiditis

post surgery/irradiation

  • radioactive iodine therapy
  • external neck irradiation

infiltration
- tumour

523
Q

what can cause defects of thyroid hormone synthesis?

A
  • iodine deficiency
  • dyshormonogenesis
  • antithyroid drugs
  • other drugs (e.g. lithium, amiodarone, interferon)
524
Q

what situations can cause problems in interpretation of thyroid function tests?

A
  • serious acute or chronic illness
  • pregnancy and oral contraceptives
  • drugs
525
Q

how is thyroid function affected in serious acute or chronic illness?

A
  • reduced concentration and affinity of binding proteins
  • decreased peripheral conversion of T4 to T3 with more rT3
  • reduced hypothalamic-pituitary TSH production
  • systemically ill patients can have a low total and free T4 and T3 with a normal or low basal TSH (sick euthyroid syndrome)
  • levels are mildly below normal and may be mediated by interleukins IL-1 and IL-6
526
Q

what may mediate T4 and T3 levels in serious acute or chronic illness?

A

IL-1 and IL-6

527
Q

how are thyroid levels affected by pregnancy and oral contraceptives?

A
  • greatly increased TBG levels
  • thus high-normal total T4
  • free T4 is usually normal
  • normal ranges for free T4 and TSH alter with normal physiological changes during pregnancy
  • TSH is often slightly suppressed in the first trimester
528
Q

how are thyroid levels affected by drugs?

A
  • amiodarone decreases T4 to T3 conversion and free T4 levels may be above normal in a euthyroid patient
  • amiodarone may induce both hyper- and hypothyroidism
  • many drugs affect thyroid function by interfering with protein binding
529
Q

what is the role of antithyroid antibodies?

A

serum antibodies to the thyroid are common and may be either destructive or stimulating; they may co-exist in the same patient

530
Q

what is the action of destructive antibodies against the thyroid?

A
  • directed against the microsomes or against thyroglobulin
  • antigen for the thyroid microsomal antibodies is the thyroid peroxidase (TPO) enzyme
  • TPO antibodies are found in up to 20% of the normal population
  • only 10-20% of these develop overt hypothyroidism
531
Q

what is the antigen for the thyroid microsomal antibodies?

A

thyroid peroxidase (TPO) enzyme

532
Q

what is the action of stimulating antibodies for the thyroid?

A

TSH receptor IgG antibodies (TRAb) typically stimulate, but may block, the receptor

533
Q

how can TSH receptor IgG antibodies (TRAb) be measured?

A
  • by inhibition of binding of TSH to its receptors (TSH-binding inhibitory immunoglobin, TBII)
  • by demonstrating that they stimulate the release of cAMP (thyroid-stimulating immunoglobulin/antibody TSI, TSAb)
534
Q

what is the epidemiology of hypothyroidism?

A
  • primary hypothyroidism is one of the most common endocrine conditions with an overall UK prevalence of over 2% in women, under 0.1% in men
  • lifetime prevalence for an individual is higher: 9% for women and 1% for men with a mean age at diagnosis of about 60 years
  • world prevalence of subclinical hypothyroidism varies from 1% to 10%
535
Q

what are autoimmune causes of hypothyroidism?

A
  • atrophic (autoimmune) hypothyroidism
  • Hashimoto’s thyroiditis
  • postpartum thyroiditis
  • focal thyroiditis and positive TPO and thyroglobulin antibodies
  • Graves’ disease
536
Q

what is atropic (autoimmune) hypothyroidism?

A
  • most common cause of hypothyroidism
  • associated with antithyroid autoantibodies leading to lymphoid infiltration of the gland and eventually atrophy and fibrosis
  • 6x more common in females; incidence increases with age
  • associated with other autoimmune disease, e.g. pernicious anaemia, vitiligo and other deficiencies
537
Q

what is Hashimoto’s thyroiditis?

A
  • more common in women and in late middle age
  • produces atrophic changes with regeneration, leading to goitre formation
  • gland is usually firm and rubbery but may range from soft to hard
  • TPO antibodies are present, often in high titres (>100IU/L_
  • patients may be hypothyroid or euthyroid, and go through an initial toxic phase, Hashi-toxicity
  • levothyroxine therapy may shrink the goitre
538
Q

what is postpartum thyroiditis?

A
  • transient after pregnancy
  • may cause hyper/hypothyroidism or the two sequentially
  • results from modifications to immune system in pregnancy
  • histologically is a lymphocytic thyroiditis
  • self-limiting, but may proceed to permanent hypothyroidism
  • may be diagnosed as postnatal depression
539
Q

how does iodine deficiency affect thyroid function?

A
  • still exists in some areas as endemic goitre
  • iodine is required for thyroid hormone synthesis
  • patients may be euthyroid or hypothyroid depending on severity of deficiency
  • borderline hypothyroidism -> TSH stimulation and thyroid enlargement in the face of continuing iodine deficiency
540
Q

where is iodine deficiency common?

A

Netherlands, Western Pacific, India, South East Asia, Russia and parts of Africa

541
Q

what are some efforts to prevent iodine deficiency?

A

providing iodine in salt

542
Q

what is dyshormonogenesis?

A
  • rare
  • due to genetic defects in the synthesis of thyroid hormones
  • patients develop hypothyroidism with a goitre
  • a particular familial form is associated with sensorineural deafness due to a deletion mutation in chromosome 7, causing a defect in pendrin (Pendred’s syndrome)
543
Q

what is Pendred’s syndrome?

A
  • genetic condition
  • associated with sensorineural deafness
  • deletion mutation in chromosome 7
  • causes a defect in transporter pendrin, which has a role in thyroid hormone synthesis
544
Q

what are symptoms of hypothyroidism?

A
  • tiredness/malaise
  • weight gain
  • anorexia
  • cold intolerance
  • poor memory
  • change in appearance
  • depression
  • poor libido
  • goitre
  • puffy eyes
  • dry, brittle unmanageable hair
  • dry coarse skin
  • arthralgia
  • myalgia
  • muscle weakness/stiffness
  • constipation
  • menorrhagia or oligomenorrhoea
  • psychosis
  • coma
  • deafness
545
Q

what are sings of hypothyroidism?

A
  • mental slowness
  • psychosis/dementia
  • ataxia
  • poverty of movement
  • deafness
  • periorbital oedema
  • deep voice
  • peaches and cream complexion
  • dry thin hair
  • loss of eyebrows
  • dry skin
  • mild obesity
  • hypertension
  • hypothermia
  • heart failure
  • bradycardia
  • pericardial effusion
  • myotonia
  • muscular hypertrophy
  • proximal myopathy
  • slow-raising reflexes
  • cold peripheries
  • carpal tunnel syndrome
  • oedema
  • anaemia
546
Q

what is myxoedema?

A

accumulation of mucopolysaccharide in subcutaneous tissues; occurs in hypothyroidism

547
Q

what is the classical picture of hypothyroidism?

A

slow, dry-haired, thick-skinned, deep-voiced patient with weight gain, cold intolerance, bradycardia and constipation

548
Q

when may special difficulties occur in diagnosis of hypothyroidism?

A
  • children with hypothyroidism may not show classic features but often have slow growth velocity, poor school performance and sometimes arrest of pubertal development
  • young women with hypothyroidism may not show obvious signs; should be excluded in oligomenorrhoea/amenorrhoea, menorrhagia, infertility or hyperprolactinaemia
  • the elderly show clinical features that are difficult to differentiate from normal ageing
549
Q

how is primary hypothyroidism investigated?

A
  • serum TSH
  • anaemia
  • increased serum aspartate transferase levels (from muscle/liver)
  • increased serum creatine kinase levels
  • hypercholesterolaemia and hypertrigliceridaemia
  • hyponatraemia due to increased ADH and impaired free water clearance
550
Q

what is serum TSH like in primary hypothyroidism?

A
  • high TSH confirms it

- low free T4 confirms hypothyroid state

551
Q

what replacement therapy is used in hypothyroidism?

A

levothyroxine (thyroxine/T4)

  • given for life
  • starting dose depends on severity of deficiency, age and fitness of patient
  • 100ug daily for young and fit
  • 50ug for small, old or frail
552
Q

what is borderline hypothyroidism/compensated euthyroidism?

A
  • low normal serum T4 levels and slightly raised TSH levels

- if after surgery or radioactive iodine therapy, it is compensatory

553
Q

what is the treatment of borderline hypothyroidism/compensated euthyroidism?

A
  • treatment with levothyroxine when TSH is consistently above 10mU/L, or when symptoms, antibodies or lipid abnormalities are present
  • where TSH is only marginally raised, tests should be repeated 3-6 months later
554
Q

what is myxoedema coma?

A
  • severe hypothyroidism may present with confusion/coma
  • hypothermia often present, cardiac failure, pericardial effusions, hypoventilation, hypoglycaemia and hyponatraemia
  • mortality was 50%
555
Q

what is treatment for myxoedema coma?

A
  • T3 orally and IV in doses of 2.5-5ug every 8hrs
  • large IV doses shouldn’t be used
  • oxygen
  • monitoring of CO and pressures
  • gradual rewarming
  • hydrocortisone 100mg IV 8hrly
  • glucose infusion to prevent hypoglycaemia
556
Q

what is myxoedema madness?

A
  • depression is commmon in hypothyroidism
  • may become demented or psychotic, with delusions
  • may occur shortly after starting T4 replacement
557
Q

how is congenital hypothyroidism screened for?

A
  • incidence is 1 in 3500 births
  • untreated it produces permanent neurological and intellectual damage (cretinism)
  • blood spot, as in the Guthrie test, detecting a high TSH level is efficient and cost-effective
  • cretinism prevented if T4 started within first few months
558
Q

how is hypothyroidism in the elderly screened for?

A
  • low pick-up rate
  • controversial, not currently recommended
  • patients who have had thyroid surgery or received radioiodine should have regular tests, and those receiving lithium or amidarone therapy
559
Q

what are common causes of hyperthyroidism?

A
  • Graves’ disease (autoimmune)
  • toxic multinodular goitre
  • solitary toxic nodule/adenoma
560
Q

what are uncommon causes of hyperthyroidism?

A
  • acute thyroiditis (viral e.g. de Quervain’s, autoimmune, post-irradiation, postpartum)
  • gestational thyrotoxicosis (HCG stimulated)
  • neonatal thyrotoxicosis (maternal thyroid antibodies)
  • exogenous iodine
  • drugs; amiodarone
  • thyrotoxicosis factitia (secret T4 consumption)
561
Q

what are rare causes of hyperthyroidism?

A
  • TSH-secreting pituitary tumours
  • metastatic differentiated thyroid carcinoma
  • HCG producing tumours
  • hyperfunctioning ovarian teratoma (struma ovarii)
562
Q

how can Graves’ disease cause hyperthyroidism?

A
  • most common cause
  • serum IgG antibodies bind to TSH receptors in the thyroid, stimulating thyroid hormone production
  • TSHR-Ab are specific for Graves’
563
Q

what are genetic associations of Graves’ disease?

A
  • HLA-B8, DR3 and DR2
  • 40% concordance rate in MZ twins and 5% DZ
  • weak association with cytotoxic T lymphocyte-associated antigen 4, HLA-DRB08 and DRB30202 on chromosome 6
564
Q

what may initiate the pathogenesis of Graves’ disease?

A
  • Yersinia enterocolitica, E. coli and other Gram-negatives contain TSH binding sites
  • may be an infection in a genetically susceptible indivisuals
565
Q

what other diseases/problems is Graves’ disease associated with?

A
  • thyroid eye disease
  • Graves’ dermopathy is rare
  • lymphadenopathy and splenomegaly
  • other autoimmune disorders
566
Q

what are features of de Quervain’s thyroiditis?

A
  • transient hyperthyroidism from an acute inflammatory process, probably viral in origin
  • toxicosis, fever, malaise, pain in neck, tachycardia and local thyroid tenderness
  • thyroid function test show initital hyperthyroidism, erythrocyte sedimentation rate and plasma viscosity are raised
  • thyroid uptake scans show suppression in acute phase
  • hypothyroidism may follow after few weeks
  • treatment of acute phase is aspirin, and short-term prednisolone in symptomatic cases
567
Q

what is amiodarone? what can it cause?

A 
class III antiarrythmic drug
- causes type I and type II AIT
568
Q

what is type I amiodarone-induced thyrotoxicosis?

A
  • caused by amiodarone
  • associated with pre-existing Graves’ disease or multinodular goitre
  • hyperthyroidism is probably triggered by high iodine content of amiodarone
  • may be higher T4;T3 ratios than usual
  • low iodine areas
  • iodine induced excess
  • thyroid hormone release
  • Jode-Basedow phenomenon
569
Q

what is type II AIT?

A
  • not associated with previous thyroid disease
  • may be due to direct effect of drug on follicular cells leading to a destructive thyroiditis with release of T4 and T3
  • may be associated with a hypothyroid phase months after presentation
  • amiodarone inhibits deiodination fo T4 to T3; may be higher T4;T3 ratios than usual
  • normal thyroid
  • destructive
570
Q

what is pretibial myxoedema?

A

infiltration of the skin on the shin

571
Q

what is thyroid acropachy?

A
  • rare

- clubbing, swollen fingers and periosteal new bone formation

572
Q

what are symptoms of hyperthyroidism?

A
  • weight loss
  • increased appetite
  • irritability/behaviour change
  • restlessness
  • malaise
  • stiffness
  • muscle weakness
  • tremor
  • choreoathetosis
  • breathlessness
  • palpitation
  • heat intolerance
  • itching
  • thirst
  • vomiting
  • diarrhoea
  • eye complaints
  • goitre
  • oligomenorrhoea
  • loss of libido
  • gynaecomastia
  • onycholysis
  • tall stature
  • sweating
573
Q

what are signs of hyperthyroidism?

A
  • tremor
  • hyperkinesis
  • psychosis
  • proximal myopathy
  • proximal muscle wasting
  • onchyolysis
  • palmar erythema
  • tachycardia or AF
  • full pulse
  • warm vasodilated peripheries
  • systolic hypertension
  • cardiac failure
  • exophthalmos
  • lid lag and stare
  • conjunctival oedema
  • opthalmoplegia
  • periorbital oedema
  • goitre, bruit
  • weight loss
574
Q

what are investigations for hyperthyroidism?

A

primary hyperthyroidism

  • serum TSH suppressed (<0.05mU/L)
  • raised free T4 and T3

secondary hypothyroidism

  • raised free T4 and T3
  • inappropriately high TSH
  • thyroid peroxidase and thyroglobulin, TRAb antibodies are present in Graves’
  • isotope uptake scan
575
Q

what different types of treatment are used in hyperthyroidism?

A
  • antithyroid drugs (course or long-term)
  • radioiodine 131I
  • surgery (partial, subtotal thyroidectomy)
576
Q

what antithyroid drugs are used in hyperthyroidism? how do they work?

A
  • carbimazole and propylthiouracil (UK)
  • thiamazole/methimazole (USA)
  • inhibit formation of thyroid hormones and suppress immune function
  • decrease synthesis of new thyroid hormone
  • PTU inhibits conversion T4 -> T3
  • do not treat underlying cause of hyperthyroidism but immune modifying effects are seen (decrease IL-6) and reduction in antibody titres
577
Q

what is the dosage and side effects of carbimazole (for hyperthyroidism)?

A
  • 20-40mg daily, 8hrly or single dose
  • rash, nausea, vomiting, arthralgia, agranulocytosis, jaundice
  • active metabolite is thiamazole (methimazole)
  • mild immunosuppressive activity
578
Q

what is the dosage and side effects of proplthiouracil (for hyperthyroidism)?

A
  • 100-200mg, 8hrly
  • rash, nausea, vomiting, agranulocytosis
  • blocks conversion of T4 to T3
579
Q

what is the dosage and side effects of proanolol (beta blocker for symptomatic control of hyperthyroidism)?

A
  • 40-80mg every 6-8hrs
  • avoid in asthma
  • use agents without intrinsic sympathomimetic activity as receptors highly sensitive
580
Q

what is the gradual dose titration regimen for hyperthyroidism?

A
  1. start carbimazole 2-40mg daily
  2. review after 4-6 weeks and reduce dose of carbimazole, depending on clinical state and fT4/fT3 levels. TSH levels may be suppressed for months
  3. when clinically and biochemically euthyroid, stop beta-blockers
  4. review thyroid function regularly during treatment course
  5. reduce carbimaozle if fT4 falls below or TSH rises above normal
  6. increase carbimazole if fT4 or fT3 are above normal
  7. stop treatment at end of course if patient is euthyroid on 5mg daily carbimazole
581
Q

what is the block and replace regiment for hyperthyroidism?

A
  • full doses of antithyroid drugs are given to suppress thyroid completely
  • thyroid activity is replaced with 100ug of levothyroxine daily once euthyroid
  • continued for 18 months
  • avoids over- or undertreatment
  • contraindicated in pregnancy
582
Q

how is radioactive iodine used in hyperthyroidism?

A
  • iodine given in empirical dose (200-550MBq) due to variable uptake and radiosensitivity of the gland
  • accumulates in the gland and destroys it by local radiation
  • takes months
  • should be euthyroid before
  • stop drugs 4 days before, not recommence until 3 days after
  • long term surveillance
  • eye problems and neck pain
583
Q

when should surgery be used to treat hyperthyroidism?

A
  • only in patients who have previously been euthyroid
  • stop drug 10-14 days before
  • give potassium iodide 60mg TDS to reduce vascularity of the gland
  • experienced surgeons
584
Q

what are complications of thyroidectomy?

A
  • early postop bleeding causing tracheal compression and asphyxia
  • laryngeal nerve palsy (1%)
  • transient hypocalcaemia (10%)
  • reduced thyroid function
585
Q

what is thyroid crisis/storm?

A
  • rare
  • mortality 10%
  • rapid deterioration of hyperthyroidism
  • hyperpyrexia, severe tachycardia, extreme restlessness, cardiac failure, liver dysfunction
  • precipitated by stress, infection, surgery in unprepared patient, radioiodine therapy
586
Q

what is treatment of thyroid crisis/storm?

A
  • propranolol in full doses
  • potassium iodide
  • antithyroid drugs
  • corticosteroids
  • supportive measures
  • control of cardiac failure and tachycardia
587
Q

what are indications for surgery or radioiodine in hyperthyroidism?

A
  • patient choice
  • persistent drug side effects
  • poor compliance with drug therapy
  • recurrent hyperthyroidism after drugs
588
Q

what are indications for surgery in hyperthyroidism?

A

large goitre, unlikely to remit after antithyroid drugs

589
Q

what is goitre?

A

a swelling of the neck resulting from enlargement of the thyroid gland

590
Q

how does hyperthyroidism affect pregnancy?

A
  • high level of HCG is a weak stimulator of the TSH receptor

- causes suppressed TSH with elevated fT4/fT3 in first trimester, associated with hyperemesis gravidarum

591
Q

how does hyperthyroidism affect neonatal life?

A
  • TSI crosses placenta to stimulate fetal thyroid
  • carbimazole and PTU cross placenta
  • T4 crosses poorly
  • smallest does of PTU is used
  • fetal heart rate above 16/minute suggest hyperthyroidism
592
Q

what is thyroid hormone resistance caused by?

A
  • inherited condition caused by an abnormality of the thyroid hormone receptor
  • mutations to TRbeta lead to higher levels being needed
  • normal feedback control mechanisms lead to high levels of T4 with normal TSH to maintain euthyroid state
593
Q

what are the consequences of thyroid hormone resistance?

A
  1. tests appear abnormal even when euthyroid and not needing treatment
  2. different tissues contain different receptors, thus different levels of hormones to maintain euthyroidism may be needed in different places
594
Q

what is the pathophysiology of dysthyroid eye disease/ophthalamic Graves’ disease?

A
  • due to specific immune response causing retro-orbital inflammation
  • swelling and oedema of extraocular muscles leads to limited movement and proptosis
  • increased pressure on optic nerve may cause optic atrophy
  • histology shows focal oedema and GAG deposition, then fibrosis
  • TSH receptor antibodies are seen in the serum
  • more common and severe in smokers
595
Q

what is the model of the initiation of thyrotopin-receptor autoimmunity in Graves’ opthalmopathy and its consequences?

A
  1. thyrotrophin receptor internalised and degraded by APC that present thyrotophin-receptor peptides, in association with MHCII, to T helper cells
  2. helper cells become activated, interact with autoreactive B cells through CD154-CD40 bridges, and secrete IL-1 and INF-gamma
  3. these cytokines induce differentiation of B cells into plasma cells that secrete anti-thyrotrophin-receptor antibodies
  4. antibodies recognise thyrotrophin receptor on orbital fibroblasts and initiate tissue changes, with IFN-gamma and TNF
  5. antibodies stimulate thyrotrophin receptor on thyroid follicular cells, leading to hyperplasia and increased production of T3 and T4
596
Q

what internalises and degrades the thyrotropin receptor?

A

APC that present thyrotropin-receptor peptides, in association with MHCII antigens, to helper T cells

597
Q

what happens to helper T cells in Graves’ opthalmopathy?

A
  • become activated
  • interact with autoreactive B cells through CD154-CD40 bridges
  • secrete IL-2 and IFN-gamma
598
Q

what is the action of IL-2 and IFN-gamma in Graves’ opthalmopathy?

A
  • induce the differentiation of B cells into plasma cells

- plasma cells secrete anti-thyrotrophin-receptor antibodies

599
Q

what initiates the tissue changes characteristic of Graves’ opthalmopathy?

A
  • anti-thyrotrophin-receptor antibodies recognise the thyrotrophin receptor on orbital fibroblasts
  • these antibodies, with the secreted type 1 helper T cytokines IFN-gamma and TNF, initiate tissue changes
  • stimulate thyrotropin receptor on thyroid follicular epithelial cells, leading to hyperplasia and increased production of T3 and T4
600
Q

what are clinical features of thyroid eye disease?

A
  • high proportion of people with Graves’ disease notice soreness, painful watering or prominence of the eyes
  • more severe proptosis occurs in some cases
  • limitation, discomfort of eye movement and visual impairment due to optic nerve compression are uncommen
  • corneal damage may occur
  • periorbital oedema and conjunctival oedema and inflammation
601
Q

what is treatment of thyroid eye disease?

A
  • stopping smoking
  • treatment may be local or systemic, and always requires liason between specialist endocrinologist and ophthalmologists
  • methylcellulose or hypromellose eyedrops (aid lubrication and improve comfort)
  • sleeping upright
  • eyelids taped to ensure closure at night
  • systemic steroids (prednisolone 30-120mg daily; reduce inflammation)
  • surgical decompression of the orbit
  • lid surgery (protects cornea if lids cannot be closed)
  • corrective eye muscle surgery
  • irradiation of the orbits (20Gy in divided doses; improves inflammation and ocular motility but not proptosis)
  • immunomodulatory agents
602
Q

what are characteristics of goitres?

A
  • 9% of population
  • noticed as cosmetic defect by family/friends
  • painless
  • pain and discomfort in acute varieties
  • large goitres can produce dysphagia and difficulty in breathing; oesophageal or tracheal compression
  • puberty/pregnancy may cause diffuse increase in size
603
Q

what should be noted on examination of a goitre?

A
  • size, shape, consistency and mobility of gland
  • if the lower margin can be demarcated (implying absence of retrosternal extension)
  • bruit may be present
  • associated lymph nodes should be found
  • tracheal position determined
  • medications/exposure to radiation
604
Q

what can cause pain in a goitre?

A

thyroiditis, bleeding into a cyst, thyroid tumour

605
Q

what are diffuse causes of goitre?

A
  • physiological (puberty, pregnancy)
  • Graves’ disease
  • Hashimoto’s disease
  • acute thyroiditis (de Quervain’s)
  • iodine deficiency (endemic goitre)
  • dyshormonogenesis
  • goitrogens (e.g. sulfonylureas)
606
Q

what are types of nodular goitre?

A
  • multinodular goitre
  • solitary nodular
  • fibrotic (Reidal’s thyroiditis)
  • cysts
607
Q

what are tumours that cause goitre?

A
  • adenomas
  • carcinomas
  • lymphomas
608
Q

what are miscellaneous causes of goitre?

A
  • sarcoidosis

- tuberculosis

609
Q

what are types of diffuse goitre?

A
  • simple
  • autoimmune
  • thyroiditis
  • iodine deficiency
  • dyshormonogenesis
  • goitrogens
610
Q

what are characteristics of a simple goitre?

A
  • smooth and soft
  • no clear cause found for enlargement
  • associated with thyroid growth-stimulating antibodies
611
Q

what are characteristics of goitre in autoimmune thyroid disease?

A
  • firm diffuse goitre of variable size
  • bruit often present in thyrotoxicosis
  • Hashimoto’s thyroiditis and thyrotoxicosis
612
Q

what are characteristics of goitre in thyroiditis?

A
  • acute tenderness in diffuse swelling, with severe pain

- may produce transient clinical hyperthyroidism with an increase in serum T4

613
Q

what are characteristics of multinodular goitre?

A
  • most common
  • patient usually euthyroid but may be hyperthyroid or borderline with suppressed TSH levels but normal free T4 and T3
  • most common cause of tracheal/oesophageal compression and can cause laryngeal nerve palsy
  • readily apparent clinically
  • small nodules in glands which are clinically diffusely enlarged and associated with autoimmune thyroid disease
614
Q

what are characteristics of solitary nodular goitre?

A
  • difficult problem of diagnosis
  • malignancy should be concern
  • often cystic or benign
  • challenge is to identify small minority of malignant nodules, which require surgery, from the majority of benign nodules
  • history of rapid enlargement, associated lymph nodes or pain may suggest aggressive malignancy
  • risk factors for malignancy are previous irradiation, iodine deficiency and familial cases
615
Q

what are characteristics of fibrotic goitre (Riedel’s thyroiditis)?

A
  • rare
  • woody gland
  • associated with other midline fibrosis
  • hard to distinguish from carcinoma, being irregular and hard
  • systemic symptoms of inflammation and elevation in inflammatory markers
  • IgG4 related disease
616
Q

what are indications for surgical intervention in euthyroid goitre?

A
  • possibility of malignancy
  • pressure symptoms on trachea or oesophagus
  • cosmetic reasons
617
Q

what are types of thyroid malignancy and their frequency?

A
  • papillary (70%)
  • follicular (20%)
  • anaplasic (<5%)
  • lymphoma (2%)
  • medullary cell (5%)
618
Q

what is the behaviour, spread and prognosis of papillary thyroid carcinoma?

A
  • young people
  • local, sometimes lung/bone secondaries
  • good prognosis, esp. in young
619
Q

what is the behaviour, spread and prognosis of follicular thyroid carcinoma?

A
  • most common in women
  • metastases to lung/bone
  • good prognosis if resectible
620
Q

what is the behaviour, spread and prognosis of anaplastic thyroid carcinoma?

A
  • aggressive
  • locally invasive
  • very poor prognosis
621
Q

what is the behaviour, spread and prognosis of lymphoma of thyroid?

A
  • variable behaviour

- sometimes responsive to radiotherapy

622
Q

what is the behaviour, spread and prognosis of medullary cell carcinoma of the thyroid?

A
  • often familial
  • local and metastases
  • poor prognosis, but indolent course
623
Q

what is medullary carcinoma?

A

neuroendocrine tumour of the calcitonin-producing C cells of the thyroid

  • prophylactic thyroidectomy
  • total thyroidectomy and wide lymph node clearance
  • local invasion/metastasis is frequent
  • responds poorly to treatment
624
Q

what is the genetic aspect of medullary carcinoma?

A
  • often associated with multiple endocrine neoplasia type 2
  • 25% have a mutation of the RET proto-oncogene
  • people with MEN2 mutations are advised to have a prophylactic thyroidectomy as early as 5 to prevent development of MTC
625
Q

why are autoimmune thyroid diseases important?

A
  • first autoimmune diseases to be described
  • 2% of women will get Graves’ disease or autoimmune hypothyroidism (5-10 times the frequency in men)
  • 5% will have postpartum thyroiditis and up to 20% have positive thyroid antibodies
  • associated with other serious autoimmune disorders
626
Q

what are thyroid autoantibodies and when are they found?

A
  • thyroglobulin and thyroid peroxidase (TPO) antibodies found in almost all patients with autoimmune hypothyroidism
  • present in 75% of Graves’ patients
  • low levels present in healthy individuals at risk of thyroid or other autoimmune disease
627
Q

what is the mechanism of thyroid cell destruction?

A
  • cytotoxic (CD8+) T cell mediated
  • thyroglobulin and TPO antibodies may cause secondary damage, but alone have no effect
  • uncommonly, antibodies against the TSH-receptor may block the effects of TSH
628
Q

what are TSH-R antibodies?

A

TSH receptor antibodies

  • originally called long acting thyroid stimulators (LATS)
  • now called thyroid stimulating antibodies
  • cause of Graves’ disease
  • some TSH-R antibodies don’t stimulate the receptor; may block the effects of TSH - these (rarely) can cause hypothyroidism
629
Q

what causes Graves’ disease?

A

TSH receptor antibodies (thyroid stimulating antibodies)

630
Q

how do antibodies cause hyperthyroidism and hypothyroidism?

A

stimulating TSAb (stimulating) -> hyperthyroidism (Graves’ disease)

blocking TSBAb (blocking) -> hypothyroidism (myxoedema)

631
Q

what is predisposition to thyroid autoimmunity?

A
  • genetic and environmental factors in varying proportion
  • being female is a bigger risk factor, and onset of disease is common postpartum
  • HLA-DR3 and other immunoregulatory genes contribute (25% MZ concordant)
  • environmental factors including stress, high iodine intake, smoking
632
Q

what are genetic predispositions to thyroid autoimmunity?

A 
HLA
target organ
T cell response
immunoglobin
cytokine
633
Q

what are environmental predispositions to thyroid autoimmunity?

A

diet, infection, drugs, toxins, stress

634
Q

what are endogenous predispositions to thyroid autoimmunity?

A

sex hormones, glucocorticoids, prolactin, birthweight, pregnancy

635
Q

how does autoimmune activity change in pregnancy and the postpartum period?

A

decreases in pregnancy and increases in the postpartum period (autoimmune thyroiditis and Graves’ thyrotoxicosis)

636
Q

what are autoimmune diseases associated with thyroid autimmunity?

A
  • T1DM
  • Addison’s disease
  • pernicious anaemia
  • vitiligo
  • alopecia areata
  • coeliac disease/dermatitis herpetiformis
  • chronic active hepatitis
  • rheumatoid arthritis/SLE/Sjorgren’s syndrome
  • mysathenia gravis (Graves’)
637
Q

what are characteristics of thyroid associated ophthalmopathy?

A
  • present in most Graves’ and some autoimmune hypothyroidism patients
  • swelling in extraocular muscles
  • most likely due to an autoantigen in the extraocular muscle that cross reacts with, or is identical to, a thyroid autoantigen
  • current favourite candidate is the TSH receptor
638
Q

what processes occur in the preadipocyte fibroblasts in thyroid associated ophthalmopathy?

A
  • TSH-R specific T cells bind to TSH-R cells on preadipocyte fibroblast
  • TSH-R stimulating antibody binds to TSH-R
  • leads to adipogenesis -> muscle swelling -> proptosis, peiorbital edema, diplopia, optic neuropathy
639
Q

what processes occur in preadipocyte fibroblasts/intact extraocular muscle cells?

A
  • cytokines (IFN-gamma, TNF, IL-1) act on preadipocyte fibroblast
  • preadipocyte fibroblast releases GAG -> water trapping -> edema and muscle swelling -> proptosis, peiorbital edema, diplopia, optic neuropathy
640
Q

what is sporadic non-toxic goitre?

A
  • commonest endocrine disorder
  • 8.6% prevalence thyroid enlargement
  • euthyroid
  • goitre: diffuse, multinodular, solitary nodule, dominant nodule
  • differentiate benign from malignant
641
Q

what are the mechanisms for hyperthyroidism?

A
  1. overproduction of thyroid hormone
  2. leakage of preformed hormone from thyroid
  3. ingestion of excess thyroid hormone
642
Q

what is the definition of hyperthyroidism?

A

excess of thyroid hormones in the blood

643
Q

what are causes of hyperthyroidism?

A
  • congenital (neonatal) hyperthyroidism
  • non autoimmune hereditary hyperthyroidism
  • subacute thyroiditis
  • silent thyroiditis
  • postpartum thyroiditis
  • iodine induced hyperthyroidism
  • hyperemesis gravidarum
  • molar pregnancy (hCG)
  • thyrotoxicosis factitia
  • metastatic differentiated thyroid Ca2+
  • struma ovarii
  • pituitary resistance to thyroid hormone
  • pituitary adenoma (TSHoma)
644
Q

what causes drug induced hyperthyroidism?

A

iodine, amiodarone, lithium, radiocontrast agents

645
Q

what are Graves’-specific clinical signs with hyperthyroidism?

A
  • diffuse goitre
  • thyroid eye disease (infiltrative)
  • pretibial myxoedema
  • acropachy
646
Q

what are investigations of hyperthyroidism?

A
  • thyroid function tests to confirm biochemical hyperthyroidism
  • diagnosis of underlying cause is important because treatment varies
  • clinical history, physical signs usually sufficient for diagnosis
  • supporting investigations
647
Q

what are disadvantages of antithyroid drugs?

A
  • remission rates 30-50%
  • no definite way to predict remission/relapse for an individual patient

poor prognostic factors:

  • severe biochemical hyperthyroidism
  • large goitre
  • TRAb +ve at end of course of ATD
  • male sex
  • young age of disease onset
648
Q

what are common and less common side effects of thionamides?

A

common: rash

less common:

  • arthralgia
  • hepatitis
  • neuritis
  • thrombocytopenia
  • vasculitis

usually occur within first few months and resolve after stopping drug

649
Q

what are features of agranulocytosis as a side effect of thionamides?

A
  • most serious side effect
  • occurs in 0.1 to 0.2%
  • manifests as sore throat, fever, mouth ulcers
  • must warn patients before starting ATD
  • stop if patient develops symptoms and check FBC
650
Q

what are characteristics of 131I (thyroid therapy)?

A
  • one of 2 isotopes of I (127I stable)
  • ideal for ablation
  • emits large beta particles of moderate energy
  • beta particles non-penetrating and deliver 90% of energy within a 1-2mm zone to follicular cells
  • some gamma ray emission
  • half life 8.1 days
651
Q

how does radioiodine therapy work for hyperthyroidism?

A
  • emission of beta particles results in ionization of thyroid cells
  • direct damage to DNA and enzymes
  • indirect damage via free radicals
652
Q

what are early effects of 131I?

A
  • necrosis of follicular cells
  • vascular occlusion
  • occur over weeks to months
653
Q

what are long-term effects of 131I?

A
  • shorter cell survival
  • impaired replication of cells
  • atrophy and fibrosis
  • chronic inflammation resembling Hashimoto’s
  • late hypothyroidism
654
Q

what is surgery for hyperthyroidism?

A
  • near total thyroidectomy for Graves’ disease and multi nodular goitre
  • near total thyroidectomy/lobectomy for toxic adenoma
655
Q

what are the three types of hypothyroidism?

A

primary (>99%)

  • absence/dysfunction of thyroid gland
  • most cases due to Hashimoto’s thyroidits

secondary/tertiary
- pituitary/hypothalamic dysfunction

656
Q

what are causes of primary hypothyroidism?

A
  • Hashimoto’s thyroiditis
  • 131I therapy
  • thyroidectomy
  • postpartum thyroiditis
  • drugs
  • thyroiditides
  • iodine deficiency
  • thyroid hormone resistance
657
Q

what are causes of secondary/tertiary hypothyroidism?

A

pituitary disease, hypothalamic disease

658
Q

what are drug causes of hypothyroidism?

A
  • iodine, inorganic or organic (iodide, iodinated contrast agents, amiodarone)
  • lithium
  • thionamides
  • interferon-alpha
659
Q

what are causes of neonatal hypothyroidism?

A

thyroid agenesis, thyroid ectopia, thyroid dyshormonogenesis

660
Q

what are causes of hypothyroidism in the child?

A

resistance to thyroid hormone, isolated TSH deficiency

661
Q

what is the investigation of primary hypothyroidism?

A
  • increased TSH (most sensitive marker)
  • usually decreased free T4 and T3
  • T4/T3 may be low normal in mild hypothyroidism
  • positive tire of TPO antibodies in Hashimoto’s
662
Q

what is the investigation of secondary/tertiary hypothyroidism?

A

TSH inappropriately low for reduced T4/T3 levels

663
Q

what is the treatment of hypothyroidism?

A
  • synthetic L-thyroxine (T4)

- older treatments: dessicated thyroid (pig and beef extracts)

664
Q

how is treatment monitored in primary hypothyroidism?

A
  • dose titrated until TSH normalises

- T4 half-life is long; check levels 6-8 weeks after dose adjustment

665
Q

how is treatment monitored in secondary/tertiary hypothyroidism?

A
  • TSH will always be low

- T4 is monitored

666
Q

what drugs increase or decrease thyroid hormone secretion?

A

iodide, amiodarone, lithium

667
Q

what drugs decrease TSH secretion?

A

dopamine and dopaminergic agonists, glucocorticoids, cytokines, octreotide

668
Q

what drugs increase metabolism of T4?

A

rifampin, phenytoin, carbamazepine, barbituates

669
Q

what drugs decrease thyroidal synthesis?

A

carbimazole, propylthiouracil, lithium

670
Q

what drugs impair T4 to T3 conversion?

A

beta-blockers, glucocorticoids, amiodarone, propylthiouracil, radiocontrast dyes

671
Q

what drugs displace T4/T3 from plasma proteins?

A

furosemide, NSAIDs, mefenamic acid, carbamazepine, beta-blockers

672
Q

what drugs increase thyroxine-binding globulin (TBG), total T3, total T4?

A

estrogens, tamoxifen, heroin, methadone, raloxifene

673
Q

what drugs impair absorption of thyroxine?

A

cholestyramine, aluminum hydroxide, ferrous sulfate, sucralfate, calcium carbonate, protein pump inhibitors

674
Q

what drugs alter autoimmunity of the thyroid?

A

interleukin-1, interferon-alpha, interferon-beta, TNF-alpha

675
Q

what drugs modify thyroid hormone action?

A

amiodarone

676
Q

what effects can drugs have on the thyroid and its function?

A
  • increase or decrease thyroid hormone secretion
  • decrease TSH secretion
  • increase hepatic metabolism of T4
  • decrease thyroidal synthesis
  • impair T4 to T3 conversion
  • displacement of T4/T3 from plasma proteins
  • increase TBG and total T3/T4
  • impair absorption of thyroxine
  • autoimmunity altered
  • modify thyroid hormone action
677
Q

what are characteristics of amiodarone and its function?

A
  • dirty drug
  • potent anti-arrhythmic (AF)
  • 37% iodine by weight
  • 200mg tablet; 75mg iodide
  • lipid soluble
  • long elimination and half-life
  • 14-18% get abnormalities
  • AIT or AIH
678
Q

what are characteristics of amiodarone induced hypothyroidism (AIH)?

A
  • susceptibility
  • inhibitory effect on thyroid hormone synthesis
  • inability of gland to escape Wolf-Chaikoff effect
  • accelerate Hashimoto’s trend
  • reduction in thyroid hormone synthesis
  • downregulation of peripheral receptors
679
Q

what is the action of ipilimumab (and Nivolumab)?

A
  • recently recommended by NICE for advanced melanoma
  • mode of action: monoclonal antibody, activates immune system by inhibiting CTLA-4 which normally downregulates immune system
  • target CTLA-4; keeps T cell active to destroy cancer cells
680
Q

what is ipilimumab hypophysitis (IH)?

A

inflammation of the pituitary gland induced by ipilimumab

  • can occur as early as 4 weeks after
  • median 11 weeks
  • most remain on glucocorticoids
  • males>females
  • more frequent with increased usage given overall survival benefit
  • strategies for early detection
681
Q

what are symptoms of hypoparathyroidism?

A
  • tingling/burning in fingertips, toes, lips
  • muscle aches/cramps
  • twitching of muscles
  • fatigue
  • painful menstrual periods
  • patchy hair loss
  • dry, coarse skin
  • brittle nails
  • depression/anxiety
682
Q

what are symptoms of hyperparathyroidism?

A
  • osteoporosis
  • kidney stones
  • excess urination
  • abdominal pain
  • tiring easily
  • depression/forgetfulness
  • bone and joint pain
  • nausea, vomiting, loss of appetite
683
Q

what are the calcium, PTH and phosphate levels like in primary hyperparathryoidism?

A
  • calcium increased
  • PTH increased
  • phosphate decreased
684
Q

what are the calcium, PTH and phosphate levels like in hypoparathyroidism?

A
  • calcium decreased
  • PTH decreased
  • phosphate increased
685
Q

what are the calcium, PTH and phosphate levels like in pseudohypoparathyroidism?

A
  • calcium decreased
  • PTH increased
  • phosphate increased
686
Q

what are the calcium, PTH and phosphate levels like in pseudopseudohypoparathyroidism?

A
  • calcium normal or decreased
  • PTH normal
  • phosphate normal or increased

Phase 2A (28 decks)

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