Endocrinology Flashcards
1
Q
What is Sheehan’s syndrome?
A
Post-partum hypopituitarism secondary to hypotension (due to post-partum haemorrhage). Partly due to the fact that the adenohypophysis enlarges during pregnancy due to lactotroph hyperplasia, so diminished blood supply due to PPH causes pituitary infarction.
2
Q
Give symptoms of Sheehan’s syndrome.
A
Lethargy, anorexia, weight loss, failure of lactation and failure to resume menses. However, these are all relatively common symptoms post-partum meaning diagnosis is often delayed.
3
Q
What is pituitary apoplexy?
A
Intra-pituitary haemorrhage or (less commonly) infarction. Sever sudden onset headache, with bitemporal hemianopia due to pressure on optic chiasm.
4
Q
Why is a dynamic pituitary test necessary to assess plasma levels of adenohypophyseal hormones?
A
Because interpretations of a single plasma reading are limited due to natural fluctuations in levels of circulating hormones. E.g. cortisol is undetectable at certain points of the day, T4 has a half-life of 6 days, FSH/LH is cyclical and ACTH is pulsatile.
5
Q
What is given in a dynamic pituitary function test?
A
TRH - causes TSH release.
GnRH to stimulate FSH & LH release.
Insulin to induce hypoglycaemia (<2.2mM) acting as a stressor to induce the release of GH and ACTH.
6
Q
What can we use to replace each of the adenohypophyseal hormones? What should me monitor to check levels?
A
Hydrocortisone to replace ACTH. Monitor serum cortisol.
Thyroxine to replace TSH. Monitor serum free T4.
HRT (E2 + progestogen) to replace LH/FSH in women. Monitor symptom improvements.
Testosterone to replace LH/FSH in men. Monitor serum testosterone and symptom improvements.
GH to replace GH
7
Q
Give signs of somatotrophin deficiency in adults.
A
Reduced lean mass, increased adiposity, increased waist: hip ratio, reduced muscle strength and bulk, reduced exercise performance, reduced HDL-cholesterol and raised LDL-cholesterol.
8
Q
Why is hypersecretion of adenohypophyseal hormones often associated with bitemporal hemianopia?
A
Due to suprasella tumour compressing optic chiasm.
9
Q
What does an excess in each of the anterior pituitary hormones cause?
A
ACTH: Cushing's DISEASE (pituitary tumour). TSH: thyrotoxicosis. LH/FSH: precocious puberty in children Prolactin: hyperprolactinaemia. GH: gigantism, acromegaly.
10
Q
Give physiological and pathological causes of hyperprolactinaemia.
A
Physiological: pregnancy, breast-feeding.
Pathological: prolactinoma.
11
Q
What drugs can be used to treat hyperprolactinaemia?
A
D2 receptor agonists which bind to D2 receptors on lactotrophs and inhibit prolactin secretion.
Examples = bromocriptine; cabergoline.
12
Q
How does excess growth hormone lead to diabetes mellitus?
A
GH leads to increased endogenous glucose production, leading to reduced muscle glucose uptake. This increased insulin production increases insulin resistance, so glucose tolerance is impaired and diabetes mellitus ensues.
13
Q
Give symptoms of acromegaly.
A
Obstructive sleep apnoea, hypertension, cardiomyopathy, hyperhidrosis, enlarged tongue.
Prolactin also often high (secondary hypogonadism and associated symptoms).
14
Q
How is acromegaly treated?
A
Surgical resection of tumour. Somatostatin analogues may be given pre-surgery to reduce GH secretion and tumour size - making removal easier.
15
Q
What sort of change in shape of osmoreceptors leads to INCREASED osmoreceptor firing?
A
SHRINKAGE (since the EC fluid must have a higher osmolarity than the cell)
16
Q
Give causes of acquired cranial diabetes insipidus.
A
Traumatic brain injury, pituitary surgery, pituitary tumours, TB.
17
Q
What can cause nephrogenic diabetes insipidus?
A
Certain drugs, such as lithium toxicity.
18
Q
Give symptoms of diabetes insipidus.
A
Large volumes of urine (polyuria), dilute urine (hypo-osmolar), thirst (polydipsia), dehydration (if no access to water).
NO HYPERGLYCAEMIA.
19
Q
What biochemistry of the blood would you expect to find in a patient suffering diabetes insipidus?
A
HYPERnatraemia
Raised urea
Raised plasma osmolality.
20
Q
What biochemistry of the blood would you expect to find in a patient suffering psychogenic polydipsia?
A
Mild HYPOnatraemia
LOW plasma osmolality
21
Q
What is desmopressin?
A
A selective vasopressin receptor peptidergic agonist (selective for V2). Mimics vasopressin and results in a decrease in urine volume and concentration.
22
Q
How would you differentiate between cranial and nephrogenic diabetes insipidus diagnostically?
A
Using a fluid deprivation test.
Neither group can concentrate their urine when deprived of fluid, however upon the administration of DDAVP, central DI sufferers can concentrate their urine. Nephrogenic DI sufferers cannot.
MUST STOP IF LOSE >3% OF BODY WEIGHT
23
Q
What is syndrome of inappropriate ADH (SIADH)?
A
The plasma vasopressin concentration is inappropriately high for the existing plasma osmolality.
24
Q
Give 2 ways in which SIADH causes hyponatraemia.
A
Increased circulating vasopressin leads to increased water reabsorption from the collecting ducts. This causes an expansion of the ECF volume, leading to hyponatraemia.
Increased water reabsorption also increases the volume of the blood, stretching the atria and causing ANP release. ANP induces natriuresis, leading to hyponatraemia.
25
Give signs of SIADH
Significantly raised urine osmolality.
Decreased urine volume.
Decreased Na+ concentration in the blood.
26
Give symptoms of SIADH.
Can be symptomless.
If p(Na+) falls below 120mM: generalised weakness, poor mental function and nausea ensue.
If it falls below 110mM, confusion leading to a coma and ultimately death can occur.
27
What does demeclocycline do?
It is a V2receptor antagonist, which inhibits AQ2 synthesis. Thus prevents water reabsorption, causing AQUARESIS (not diuresis as electrolytes are still reabsorbed).
28
How would you treat SIADH?
Immediately fluid restrict and administer drugs such as demeclocycline which counter the effects of excess vasopressin. If a tumour, resect.
29
How would you decide the dose of levothyroxine to give to someone with primary hypothyroidism?
Use TSH as a guidance marker - aim to suppress TSH into the reference range with the dose of TSH.
30
How would you decide the dose of levothyroxine to give to someone with secondary hypothyroidism?
Can't use TSH due to adenohypophyseal failure. Aim for fT4 (free T4) to be in the middle of the reference range.
31
What complications may arise from giving T3 (liothyronine) or a combination T3/T4 therapy?
Toxicity: palpitations, tremor, anxiety etc.
32
What %s of T3 and T4 are bound (mainly to TBG)?
99.97% of T4 is bound (0.03% is free), 99.70% of T3 is bound (0.3% is free).
33
Give the 3 symptoms caused by the antibodies in Graves' disease.
Smooth goitre/ overactive thyroid gland due to antibody which binds to TSH receptor on follicular cells.
Exophthalmos due to antibody which binds to muscle behind eye.
Pretibial myxoedema due to stimulation of growth of soft tissues of shin.
34
What is Plummer's disease?
A cause of hyperthyroidism (not of immune origin). Due to benign adenoma that is overactive at making thyroxine.
Toxic nodular goitre.
35
What effects does thyroxine have on the sympathetic nervous system?
It sensitises B-adrenoceptors to ambient levels of adrenaline and noradrenaline. Thus there's apparent sympathetic activation.
Symptoms: tachycardia, palpitations, tremor in hands, lid lag, diarrhoea, sweating, heat intolerance, weight loss despite increased appetite.
36
What is thyroid storm?
Hyperthyroidism PLUS 2 or more of the following:
Hyperpyrexia (extremely high fever) >41 degrees.
Accelerated tachycardia/ cardial failure
Delirium/ frank psychosis.
Hepatocellular dysfunction; jaundice
Most common in patients with underlying Grave's disease. Probably results from acute elevation of catecholamines (infection, surgery, cessation of meds, stress).
37
What is propylthiouracil (PTU)?
A thionamide which inhibits the thyroid peroxidase enzyme, hence inhibiting T3/T4 production. May also suppress antibody production in Grave's and reduce the conversion of T4 to T3 in peripheral tissues.
38
Why is propranolol, a non-selective B-blocker, given alongside thionamides to treat hyperthyroidism?
Because thionamides take weeks to exert clinical effects (due to stores of T3/4 in the colloids (biochemical effects do take place after hours). Propranolol gives much faster relief of symptoms.
39
How does iodide (for example potassium iodide) work as a therapy for hyperthyroidism?
Due to the WOLFF-CHAIKOFF EFFECT. Iodide prevents iodination of thyroglobulin.
40
Why is iodide a useful treatment for surgery preparation?
Since within 10-14 days of first administering iodide, the vascularity and size of the gland is reduced.
41
How does radioiodine (I-131) work in treating hyperthyroidism?
The radioiodine accumulates in the colloid, emits B particles which destroy follicular cells.
Radioactive t1/2 is 8 days; radioactivity negligible after 2 months (avoid close contract with small children - contra-indicated by pregnancy and breast-feeding.
42
What are the causes of Cushing's syndrome?
Pituitary adenoma (Cushing's disease); excess steroid usage; ectopic ACTH (e.g. from lung cancer); adrenal adenoma secreting cortisol.
43
What would you expect to happen in a normal patient during a low dose dexamethasone suppression test?
You'd expect cortisol production to decrease.
44
How does treatment using metyrapone cause unwanted salt retention and hypertension?
Metyrapone arrests steroid synthesis at the 11-deoxycortisol stage (by inhibiting 11B-hydroxylase) in the zona fasciculata and reticularis. This causes 11-deoxycorticosterone to accumulate in the zona glomerulosa (which has aldosterone-like activity).
45
How can Cushing's be treated surgically?
Dependent upon aetiology:
Pituitary resection.
Bilateral adrenalectomy.
Unilateral adrenalectomy (for an adrenal mass).
46
Why might eplerenone be favoured over spironolactone as an MR antagonist?
Spironolactone isn't very specific: it binds to progesterone receptors to cause menstrual irregularities and inhibits androgen receptors to cause gynaecomastia in men. Eplerenone has a similar affinity for the MR, yet is more specific.
47
What are phaeochromocytomas?
Tumours of the adrenal medulla (secrete catecholamines; A, NA).
48
Give symptoms of Addison's.
Postural hypotension, increased pigmentation and patches of vitiligo (loss of pigmentation - strong indicator of autoimmune cause), hypotension.
49
How would you investigate and diagnose Addison's disease?
Perform a blood test: biochemical indicators are low sodium, high potassium, low cortisol at 9am; high ACTH.
Synacthen test: would expect a rise in cortisol after the administration of synthetic ACTH: otherwise is an indicator of Addison's.
Adrenal autoantibody blood test.
50
Give symptoms of Cushing's.
Abdominal weight gain (centripetal obesity), plethoric face, hypertension, proximal myopathy, abdominal striae, hirsutism, thin skin, bruising.
Patient appears cushingoid.
51
What investigations would you perform to reach a diagnosis of Cushing's syndrome?
24-hour urine free cortisol collection.
Low dose dexamethasone suppression test.
Midnight/sleeping cortisol - expected to be low but would be high in cushingoid patients.
52
What is congenital adrenal hyperplasia?
Born with non-functioning cortex enzymes. Most commonly 21-hydroxylase. Can be deficiency (partial) or absence (complete).
53
How would a neonate present with congenital adrenal hyperplasia resulting in 21-hydroxylase absence (CAH)?
Present with salt-losing addisonian crisis. Before birth (in utero), foetus gets steroid across the placenta. Girls might have ambiguous genitalia (virilised by adrenal testosterone).
54
How do people with partial 21-hydroxylase deficiency present and why?
Deficient cortisol and aldosterone, but excess sex steroid and testosterone due to high ACTH (no negative feedback). Leads to hirsutism and virilisation in girls and precocious puberty in boys due to adrenal testosterone.
55
Why does 11-hydroxylase deficiency lead to hypertension and hypokalaemia?
Because 11-deoxycorticosterone builds-up in the zona glomerulosa. 11-deoxycorticosterone behaves like aldosterone, so despite there being an aldosterone deficiency, there is an excess of mineralcorticosteroids.
56
Describe 17-hydroxylase deficiency.
Deficiency of both cortisol and sex steroids. Excess 11-deoxycorticosterone and aldosterone (mineralocorticois). Leads to hypertension, hypokalaemia and symptoms associated with glucuocorticoid and sex steroid deficiencies.
57
Give 4 aldosterone release triggers
Aldosterone release stimulated by angiotensin II. Triggered by hyperkalaemia, hyponatraemia, reduction in renal blood flow and B1-adrenoceptor stimulation.
58
Which regions of the adrenal cortex produce which corticosteroids?
```
Sex steroids (androgens, oestrogens) are produced in the zona reticularis.
Glucocorticoids (cortisol) are produced in the zona fasciculata.
Mineralocorticoids (aldosterone) are produced in the zona glomerulosa.
```
59
Compare, briefly, the glucocorticoid and mineralocorticoid receptor (GR and MR).
GR: wide distribution, selective for glucocorticoids however low affinity for cortisol.
MR: discrete distribution (kidney), do not distinguish between aldosterone and cortisol, high affinity for cortisol.
60
In Cushing's syndrome, why may you get excessive stimulation of mineralocorticoid receptors, leading to hypokalaemia and hypernatraemia?
Normally, cortisol is converted to an inactive form, cortisone, by 11b-hydroxysteroid dehydrogenase 2 (11bhsd2) in the kidneys. In Cushing's, this enzyme is overwhelmed due to excessive amounts of cortisol, leading to stimulation of the MR receptor.
61
What is fludrocortisone?
An aldosterone analogue, used as an aldosterone substitute in Addison's disease. It binds to the mineralocorticoid receptor. Given orally.
62
What is hydrocortisone?
A glucocorticoid with mineralocorticoid activity at high doses (hence it binds to both receptors). It has a duration of 8 hours. Given orally: may be given parenterally (intravenous or intramuscularly).
63
What is dexamethasone?
A synthetic glucocorticoid with NO mineralocorticoid activity. Hence, it binds exclusively to the glucocorticoid receptor. It has a duration of 40 hours. Can be administered orally or parenterally.
64
What is prednisolone?
A glucocorticoid with weak mineralocorticoid activity (binds to glucocorticoid receptor / mineralocorticoid receptor weakly).
65
What would you give to treat primary adrenocortical failure (Addison's)?
Hydrocortisone and fludrocortisone to replace lack of cortisol and aldosterone.
66
What would you give to treat secondary adrenocortical failure (ACTH deficiency)?
Lack of cortisol but aldosterone is normal (aldosterone secretions determined by angiotensin II) hence give HYDROCORTISONE ONLY.
67
How would you treat someone in Addisonian crisis (acute adrenocortical failure)?
Give i.v. 0.9% NaCl to rehydrate patient.
High dose hydrocortisone - i.v. infusion or i.m. every 6 hours. At high doses, hydrocortisone has mineralocorticoid effect (overwhelms 11B-hsd 2) so replaces aldosterone too.
Give 5% dextrose if hypoglycaemic.
68
What are the objectives of treating congenital adrenal hyperplasia (CAH) and how are these realised?
Replace cortisol and suppress ACTH production (in turn suppressing the excessive androgen production). This is realised by giving dexamethasone 1/day, pm or hydrocortisone 2/3 a day.
Replace aldosterone - realised by giving fludrocortisone.
69
Why should glucocorticoid doses be increased in times of stress, such as minor illnesses?
Cortisol is the stress hormone. People with adrenal failure can't regulate their cortisol production, so their dose needs to be adjusted to help them deal with stresses.
Normal cortisol production in around 20mg a day. In stress, this can rise by up to 10 times.
70
Getting doses right is tricky. How can you tell in a woman suffering adrenocortical failure if the prescribed glucocorticoid dose is too high or low.
If the GC dose is too high, the patient appears CUSHINGOID.
| If it's too low, ACTH will rise causing excess androgen production, leading to hirsutism,
71
Give symptoms of phaeochromocytomas.
Hypertension in young people; episodic severe hypertension (can cause MI or stroke); high adrenaline can cause VF and possibly death.
72
What is the precursor of aldosterone which behaves like aldosterone causing hypertension and hypokalaemia in 11-hydroxylase deficiency?
11-deoxycorticosterone.
73
Contrast expected blood levels of LH, FSH and testosterone/oestradiol for primary gonadal failure and hypothalamic/pituitary disease.
Primary gonadal failure: high LH & FSH, low testosterone/oestradiol.
Hypothalamic/pituitary disorder: low LH/FSH, low testosterone and oestradiol.
74
Give symptoms of hypogonadism in males.
Loss of libido, impotence (inability to achieve erection/orgasm), decreased muscle bulk, osteoporosis, small testes.
75
What is the cause of hypogonadism in Kallmann syndrome?
Hypothalamic failure (fails to produce GnRH).
76
Upon finding a male's LH, FSH and testosterone were all low, how would you proceed?
MRI the pituitary.
77
Define azoospermia and oligospermia.
Azoospermia is the absence of sperm in the ejaculate.
| Oligospermia is a reduced number of sperm in the ejaculate.
78
What are the effects of testosterone in adulthood and why won't it restore fertility?
All male patients are given replacement testosterone, but to restore fertility LH and FSH are needed - the gonadotrophins are needed for proper spermatogenesis. Testosterone given to male adults will increase lean body mass, muscle size and strength, induce bone formation and increase mass (in young men) and increase libido and potency.
79
How is testosterone converted to other important sex steroids and on which nuclear receptors do the products act?
Converted to dihydrotestosterone (DHT) by 5A reductase. Acts on androgen receptor (AR).
Converted to 17B-oestradiol by aromatase - which acts via the oestrogen receptor (ER).
80
Give causes of amenorrhoea.
Pregnancy/ lactation, hyperprolactinaemia, ovarian insufficiency (including Turner's syndrome), gonadotrophin failure, androgen excess, underweight.
81
What investigations could you perform to find the cause of amenorrhoea?
Pregnancy test; LH, FSH and E2 levels; prolactin levels; androgens; chromosomal analysis (X0), ultrasound scan of ovaries/uterus.
82
What signs are diagnostic of PCOS?
Need 2 of the following: polycystic ovaries on ultrasound; oligo/anovulation; clinical / biochemical androgen excess.
83
What are the symptoms of PCOS?
Hirsutism, menstrual cycle disturbances, increased weight.
84
What is clomiphene and what condition is it used to treat?
Clomiphene is a fertility drug, which is anti-oestrogenic and binds to oestrogen receptors in the hypothalamus blocking the normal negative feedback, resulting in an increase in the secretion of GnRH and gonadotrophins.
85
What effects does prolactin have on the hypothalamo-pituitary axis?
It inhibits GnRH secretion by the hypothalamus and inhibits LH's actions on the ovary/testis - leading to infertility.
86
What causes hyperprolactinaemia?
Dopamine antagonist drugs (anti-emetics and anti-psychotics) which decrease dopamine's inhibitory effects.
Prolactinoma.
Stalk compression due to pituitary adenoma (prevents dopamine inhibiting prolactin).
Hypothyroidism, as this leads to an increase in TRH which stimulates prolactin secretion.
87
What treatments are used in patients with prolactinomas?
Treat the cause.
Stop taking dopamine antagonist drugs.
Take dopamine agonists (bromocriptine, cabergoline).
Dopamine agonist therapy should reduce the size of a prolactinoma: surgery is rarely warranted.
88
Give some presentation characteristics which may lead to ambiguity in diagnosing either type 1 or type 2 DM.
T1DM may arise after decades of life (latent autoimmune diabetes in adults (LADA))
T2DM may arise in childhood.
Occasionally, diabetic ketoacidosis is a feature of T2DM.
Monogenic diabetes can present phenotypically as either type.
89
Describe how T1DM can be modelled as a relapse-remitting disease.
It shows step-wise non-linear decline in B-cell mass over time, with a cyclic immunological response. Increases in the number of autoreactive effector T-cells are controlled by increases in the number of regulatory t-cells, however disequilibrium can occur over time so the number of effector T-cells surpasses regulation. This results in an acute decline in pancreatic islet function.
90
Give classic signs and symptoms of a presenting type 1 diabetic.
Signs: dehydration, cachexia (abnormally low weight associated with chronic disease), hyperventilation, smell of ketones, glycosuria, ketonuria.
Symptoms: polyuria, nocturia, polydipsia, blurring of vision, thrush, weight loss, fatigue.
91
What most clearly distinguishes between T1DM and T2DM?
T1DM associated with ketoacidosis (proteolysis) as in T2DM there is still sufficient insulin to suppress ketogenesis (and proteolysis).
T1DM presents with ketonuria.
92
What dietary changes would you recommend to someone with type 1 diabetes?
```
Reduce calories as fat.
Reduce refined carbohydrate.
Increase complex carbohydrates.
Increase soluble fibre.
Balance distribution of food over the course of the day.
```
93
How do we mimic physiological insulin release in the treatment of T1DM?
Short-acting human insulin/insulin analogue taken with meals.
Long-acting insulin analogue provides background insulin levels.
Insulin pump delivers pre-programmed basal rates alongside a bolus for meals.
94
What is the limitation of an insulin pump?
It doesn't measure glucose levels so there is no completion of the feedback loop.
95
Why are hypoglycaemic episodes major causes of anxiety in patients and families?
Scary. Most mental processes impaired below 3mmol/l and consciousness impaired below 2mmol/l. May have long-term impacts on brain. Can cause arrhythmia and death.
96
What is meant by the term hypoglycaemic unawareness.
Where recurrent hypos in a diabetic leads to a gradual desensitisation to symptoms and eventually results in loss of warning signs.
97
What are common causes of hypos?
Unaccustomed exercise, missed meals, inadequate snacks, alcohol, inappropriate insulin regime.
98
What are the signs and symptoms of a hypo?
Palpitations, tremors, sweating, pallor/ cold extremities, anxiety, drowsiness, confusion, altered behaviour, coma/
99
How do you treat a patient suffering a hypo?
Feed them: give sugar and complex carbs.
| In consciousness impaired, opt for a parenteral route. Give I.V. dextrose (10%) and I.M glucagon.
100
How does insulin deficiency lead to hyperglycaemia?
Insulin deficiency allows lipolysis to go unabated (insulin decreases lipolysis), resulting in glycerol production (for gluconeogenesis in liver). Proteolysis also isn't inhibited, allowing the breakdown of protein to amino acids, again a substrate for gluconeogenesis in the liver. Lack of inhibition of gluconeogenesis and glycogenolysis increases HGO.
Insulin deficiency also means glucose in circulation is unable to enter tissues, especially muscles, as no GLUT 4 channels are activated. So the glucose produced by the liver stays in the blood.
101
Explain how insulin deficiency leads to ketoacidosis.
Insulin deficiency allows lipolysis to continue unabated, resulting in fatty acid production with travels to the liver.
Insulin normally acts on mitochondrial membrane to prevent ketogenesis. In its absence, acetoacetate and 3-hydroxybutyrate (ketone bodies) are produced (which are acidic).
In non-diabetics, this is a normal response to low blood sugar so the brain has an energy supply.
ABNORMAL when present in conjunction with hyperglycaemia.
102
Which type of diabetes have twin-studies shown to have a stronger genetic factor?
T2DM.
103
Briefly describe T2DM.
Not ketosis prone, not mild, often involves weight, lipids and BP which may be presenting features.
104
Describe MODY.
An autosomal dominant inherited type of diabetes with multiple hereditary forms. Positive FH.
Results in ineffective pancreatic B-cell insulin production. Mutations of transcription factor genes and/or glucokinase genes.
Not associated with obesity.
105
Describe the genetic factors behind "regular" T2DM
May always have limited resistance.
Obesity/ fatty acids in adulthood definitely progress the disease.
Mitogenic changes and metabolic dyslipidaemia cause macrovascular disease which may develop before B-cell failure.
Eventually insulin deficiency may become absolute in which case insulin is given - but still T2DM!
106
What is the association between obesity and T2DM and why is central/omental obesity particularly important?
Obesity is more than a precipitant: 80% of T2DM sufferers are obese.
Fatty acids and adipocytokines are important. Central obesity is important since the adipocytes drain to the portal vein - so the adipocytokines have more of an effect on the liver.
107
Why is weight gain a common side-effect of diabetes treatments and which first-line treatment is NOT associated with weight gain?
Metformin is NOT associated with weight gain.
| Treatment usually results in the cessation of glycosuria, so the excess glucose (energy) is not excreted.
108
What dietary advice would you give to someone with T2DM?
Control total calories and increase exercise.
Reduce refined carbs
Increase complex cards
Reduce fat as a proportion of calories.
Increase unsaturated fat as a proportion of fat.
Increase soluble fibre.
Address salt.
109
What issues are there to control in T2DM?
Weight, dyslipidaemia, glycaemia, BP.
110
What is orlistat?
A GI lipase inhibitor. Treatment of weight limited.
111
What is metformin?
A safe and effective insulin sensitiser. Used in overweight patients where diet alone has not succeeded.
Reduces resistance: reducing HGO and increasing peripheral glucose disposal.
112
What are sulphonylureas?
Drugs which stimulate the B-cells to produce insulin. They skip the glucose metabolism and directly inhibit ATP sensitive K+ channels - resulting in insulin release.
Cause weight gain and hence are used in lean patients.
113
What is acarbose?
An a-glucosidase inhibitor, which prolongs absorption of oligosaccharides, allowing insulin to cope following defective first phase release. SE = flatus.
114
What are thiazolidinediones?
Peroxisome proliferator-activated receptor-gamma agonists (PPAR-y). They are insulin-sensitisers (mainly peripheral).
They modify adipocyte differentiation so weight gain is peripheral not central. Improve glycaemia and lipids.
115
What are exenatide and liraglutide?
GLP-1 agonists (which increase insulin secretion, suppress glucagon production and cause weight loss).
116
What are gliptins?
DPP-4 inhibitors, which increase the half-life of endogenous GLP-1. They have an anti-glucagon effect.
Unlike GLP-1 agonists, they have a neutral effect on weight.
117
What is empagliflozin?
A SGLT2 inhibitor which inhibits the Na-Glu transporter on the proximal convoluted tubules and as such increases glycosuria.
118
Other than drugs addressing hyperglycaemia, what other treatments may be beneficial in type 2 diabetics?
Control BP
Possibly a gastric bypass.
Statins to treat dyslipidaemia.
119
What are the 3 pathologies associated with MICROVASCULAR disease and why are they important'?
Retinopathy: the main cause of visual loss in diabetes and the main cause of blindness in people of working age.
Nephropathy
Neuropathy: diabetes is the most common cause of neuropathy and therefore lower limb amputations.
120
Describe the stages of retinopathy.
Background diabetic retinopathy: hard exudates (lipid, cheese colour), microaneurysms (dots), blot haemorrhages.
Pre-proliferative diabetic retinopathy: cotton wool sports (soft exudates) representing retinal ischaemia.
Proliferative diabetic retinopathy: visible new vessels, on disc or elsewhere.
121
What is maculopathy?
A subtype of background retinopathy where the hard exudates are near the macula. This can threaten direct vision.
122
How is retinopathy managed?
Background retinopathy: improve glucose management and warn patients the signs are there.
Pre-proliferative: general ischaemia. If left, new vessels WILL grow. Pan-retinal photocoagulation. Laser beams prevent vessel formation.
Proliferative: also needs pan-retinal photocoagulation.
Maculopathy: a grid of photocoagulation.
The aim is to prevent the formation of new vessels which may bleed and affect vision.
123
Describe diabetic nephropathy.
Patients usually hypertensive. Progressively increasing proteinuria. Progressively deteriorating kidney function.
124
How is diabetic nephropathy monitored and treated?
Monitored using a dipstick to test proteinuria. Measures microalbumin.
Intervention: control diabetes and BP, inhibit RAAS, e.g. by using an ARB.
125
How does diabetes cause neuropathy?
The vasa nervorum (small vessels supplying nerves) become blocked.
126
Why is diabetic neuropathy a particular problem for the feet?
The longest nerves supply the feet. More common in tall people. Loss of sensation. Danger is that patients will not sense an injury to the foot, e.g. stepping on a nail.
127
What is the difference between a diabetic 3rd nerve palsy and one caused by compression?
In both cases, the eye is down and out.
In diabetes, since the outer parasympathetic fibres don't easily lose their blood supply, the pupil still responds to light.
In the case of compression, the pupil is fixed in a dilated position.
128
What is autonomic neuropathy?
Loss of autonomic nerves to GI tract, bladder and CVS.
Leads to dysphagia, delayed gastric emptying, constipation and diarrhoea, postural hypotension. Case repots of sudden cardiac death.
129
What is radiculopathy?
Pain over spinal nerves. Usually affects a dermatome on chest or abdominal wall.
130
What are the main features of diabetic MACROVASCULAR disease?
Early widespread atherosclerosis, ischaemic heart disease, cerebrovascular disease, peripheral vascular disease.
131
What is metabolic syndrome?
An increased waist circumference (>102cm in men, >88cm in women) plus 2 or more of the following:
fasting glucose >6mmol/l, HDL <1.0mmol/l in men, <1.3 in women and hypertension (>135/80), urine microalbumin.
All facets of metabolic syndrome are associated with macrovascular disease.
132
What is the main difference between microvascular disease and macrovascular disease?
Microvascular disease causes morbidity.
Macrovascular disease is a systemic disease, commonly present in multiple arterial beds, which causes MORTALITY and morbidity.
133
Briefly describe the problems associated with each of the features of macrovascular disease.
IHD: the major cause of morbidity and mortality in diabetes. The mechanisms are similar with or without diabetes.
Cerebrovascular disease: earlier and more widespread
Peripheral vascular resistance: contributes to diabetic foot problems with neuropathy.
Renal artery stenosis: may contribute to hypertension and renal failure.
134
How do we treat macrovascular disease?
Treatment targeted to hyperglycaemia alone has minor effect on increased risk of CVD. Prevention of macrovascular disease requires aggressive management of multiple risk factors.
135
What are the modifiable and non-modifiable risk factors of macrovascular disease?
Modifiable: dyslipidaemia, high BP, smoking, diabetes.
| Non-modifiable: age, sex (male), low birth weight, genes.
136
Describe a neuropathic foot.
Numb, warm, dry, palpable foot pulses, ulcers at points of high pressure loading.
137
Describe an ischaemic foot.
Cold, pulseless, ulcers at foot margins.
138
Describe a neuro-ischaemic foot.
Numb, cold, dry, pulseless, ulcers at points of high pressure loading and foot margins.
139
How do you manage diabetic feet?
Control diabetes, inspect feet daily, have feet measured when buying shoes, inspect inside of shoes for foreign objects, cut nails straight across, care with heat, never walk barefoot.
140
How do you manage foot ulceration?
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Relieve the pressure (e.g. bed rest).
Antibiotics, possibly long-term
Debridement
Revascularisation (angioplasty, arterial bypass surgery).
Amputation.
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141
Give 2 hormones involved in short term appetite regulation.
Ghrelin, released by cells in the stomach, increases appetite. (Stimulates NPY/Agrp and inhibits POMC). Rises before a meal.
PYY3-36, released by ileum and colon L-cells, decreases appetite. Released post-prandially.
142
Explain how the stimulation of POMC and Agrp receptors regulated appetite.
POMC stimulation produces a-MSH which binds to MC4R in the paraventricular nucleus and decreases appetite.
Agrp releases Agrp which is an antagonist of MC4R, increasing appetite.
143
What is special about the arcuate nucleus in the hypothalamus that allows it to integrate peripheral and central feeding signals?
It has an incomplete blood brain barrier, allowing peripheral hormones to cross.
144
What is meant by leptin being a "hormone of absence"
It is an anti-starvation hormone rather than an anti-obesity hormone. The presence of leptin tells the brain that one has sufficient fat reserves, but high leptin has little effect.
Absence has profound effects: hyperphagia, lowered energy expenditure, sterility.
145
How does leptin regulate appetite?
It circulates in levels proportional to the body's body fat levels. It activates POMC and inhibits NPY/Agrp neurones to DECREASE appetite.
146
Why is leptin ineffective as a weight loss drug?
Most people have high leptin, leading to leptin resistance.
| Useful for a small population of children who have leptin deficiency - as they haven't developed resistance.
147
What is GLP-1?
A gut hormone derived from the preproglucagon gene which is released post-prandially. It is a well-characterised incretin, which lowers blood glucose by stimulating insulin, and suppressing appetite and glucagon.
148
Give 3 types of satiety action.
Post-prandial - reducing food intake following a meal.
Chronic - gut disease, chronic elevation suppresses appetite.
Acute nausea - toxin ingestion - acutely very high levels.
149
How does Ca2+ regulate PTH secretion?
Binds to receptors on parathyroid cells.
150
What is the name given to Vit D3 and D2 and how are they derived?
Vit D3 is cholecalciferol and is derived from the UVB conversion of 7-dehydrocholesterol in the skin.
Vit D2 is ergocalciferol and is from the diet.
151
What converts 25-hydroxy cholecalciferol to calcitriol (1,25-dihydroxy cholecalciferol) ?
Renal 1a-hydroxylase (stimulated by PTH).
152
What does calcitriol do?
Increases Ca2+ maintenance in bone by stimulating osteoblast activity.
Increases Ca2+ and PO43- absorption in gut
Increases Ca2+ reabsorption in kidneys.
Increases PO43- secretion in kidneys.
Negatively feedbacks on PTH.
153
What are causes of vitamin D deficiency?
Malabsorption or dietary insufficiency (decreased ergocalciferol).
Lack of UVB light.
Liver disease, renal disease (lack of 25 OH-D3 and 1a-hydroxylase respectively).
Receptor defects.
154
How do Ca2+ levels affect AP generatability?
AP generation requires Na+ influx across cell membrane,
Hypercalcaemia = Ca2+ blocks Na+ influx, so less membrane excitability.
Hypocalcaemia = Ca2+ enables greater Na+ influx, so more membrane excitability.
155
What signs are associated with hypocalcaemia?
Convulsions, arrhythmias, tetany, paraesthesia (numbness, e.g. hands, mouth, feet, lips).
"CATs go numb".
156
What is Chvostek's sign?
Tap the facial nerve just below zygomatic arch.
| Positive response = twitching of facial muscles (irritability due to hypocalcaemia).
157
What is Trousseau's sign?
Inflation of BP cuff for several minutes induces carpopedal spasms. Neuromuscular irritability due to hypocalcaemia.
158
What are the causes of hypocalcaemia?
Vit D deficiency, low PTH levels, PTH resistance, renal failure.
159
What signs are associated with hypercalcaemia?
"Stones, abdominal moans and psychic groans".
Stones - renal effects. Polyuria and thirst, nephrocalcinosis, renal colic, renal failure.
Abdominal moans - GI effects. Anorexia, nausea, dyspepsia, constipation, pancreatitis.
Psychic groans - CNS effects. Fatigue, depression, impaired concentration, altered mentation, coma.
160
What happens in primary hyperparathyroidism?
Raised Ca2+ and PTH.
NO negative feedback.
Autonomous PTH secretion despite hypercalcaemia.
Low phosphate (PTH inhibits renal Na+/Po43- co-transporter).
161
Describe hypercalcaemia of malignancy.
Tumours/ metastases secrete a PTH-like peptide.
| PTH is low, but calcium is high, since the peptide has PTH-like effects.
162
Describe secondary hyperparathyroidism.
Low calcium, high PTH.
PTH levels are appropriate.
Renal failure.
163
Describe the effects and findings of vit D deficiency.
Lack of mineralisation of bone, leading to rickets in children and osteomalacia in adults.
Plasma 25-hydroxy cholecalciferol usually low
Plasma Ca2+ low (may be normal if secondary hyperparathyroidism developed)
Plasma PO43- low
PTH high (secondary hyperparathyroidism)
164
How do we replace calcitriol in patients with vit D deficiencies?
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Give 25(OH) D3 in patients with normal renal function.
Give alphacalcidol in patients with renal failure (1a-hyroxycholecalciferol - an active metabolite of calcitriol).
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165
How much seminal fluid (semen) and how many sperm are present in a typical ejaculation?
15-120 million spermatozoa per ml.
| 2-5ml of seminal fluid.
166
How many sperm reach an ovum?
1/ million.
| 1/100 sperm in ejaculate enters the cervix. 1/ 10,000 in cervix reaches ovum.
167
Which organs contribute to the formation of seminal fluid?
Small contribution from epididymis/ testis.
| Mainly from seminal vesicles, prostate and bulbourethral glands.
168
Describe capacitation.
The process of sperm achieving fertilising capability in the female reproductive tract.
1. Loss of glycoprotein 'coat'
2. Change in surface membrane characteristics
3. Development of whiplash movements of tail.
This takes place in the ionic and proteolytic environment of fallopian tubes. It is oestrogen and Ca2+ dependent.
169
How does a spermatozoon penetrate the zona pellucida of an ovum?
Binds to ZP3 (sperm receptor).
Ca2+ influx into sperm/ stimulated by progesterone.
Release of hyaluronidase and proteolytic enzymes (from acrosome).
Leads to penetration of zona pellucida.
170
How is polyspermy prevented?
By the triggering of the cortical reaction. Fertilisation induces cortical granules to release molecules which degrade the zona pellucida (e.g. ZP3), preventing further sperm from binding.
171
Describe what happens at implantation.
Attachment phase: outer trophoblast cells contact uterine epithelium. Leukaemia inhibitory factor (LIF) from endometrial secretory glands stimulates adhesion of blastocyst to endometrial cells.
Decidualisation phase: changes in underlying uterine stromal tissue. Requires progesterone domination.
172
Describe endometrial changes after implantation.
Glandular epithelial secretion.
Growth of capillaries.
Glycogen accumulation
Increased vascular permeability.
173
Describe changes in hormone levels in pregnancy.
Progesterone and oestrogen produced in corpus luteum in first 40 days (stimulated by hCG action on LH receptors), after which placenta starts to take over.
Maternal and foetal DHEAs converted to oestrogen.
Increased ACTH, adrenal steroids, prolactin, IGF-1, iodothyronines (hCG can stimulate thyroid), PTH.
Decreased gonadotrophins (LH, FSH), pituitary GH, TSH.
174
What role does oxytocin play in parturition?
Uterine contraction and cervical dilation.
| Also milk ejection
175
Describe lactation.
Suckling stimulates hypothalamus. Prolactin from adenohypophysis stimulates milk synthesis. Oxytocin from neurohypophysis stimulates milk ejection.
176
Describe the roles of osteoblasts and osteoclasts in bone remodelling - a dynamic process.
Osteoblasts synthesise osteoid (unmineralised bone) and participate in mineralisation (calcification of osteoid).
Osteoclasts release lysosomal enzymes which breakdown bone (bone resorption).
Osteoblasts stimulate osteoclasts. They express RANKL on their surface, which binds to RANK-R on osteoclast precursors, producing activated osteoclasts resulting in bone resorption. Osteoblasts express receptors for PTH and calcitriol, thus regulate the balance between bone formation and resorption.
177
Summarise the organic and inorganic components of bone.
99% of the body's calcium is stored as bone.
The organic component of bone - osteoid - is unmineralised bone and comprises 35% of the bone's mass (95% of which is type I collagen fibres).
The inorganic component of bone - calcium hydroxyapatite - fills the space between collagen fibres and comprise 65% of the mass of the bone.
178
What is the difference between lamellar and woven bone?
Cortical and trabecular bone are lamellar: the collagen fibrils are laid down in alternating orientations.
Cortical bone is hard, trabecular is spongy.
Woven bone is disorganised and weaker.
179
What happens in vitamin D deficiency?
Vitamin D deficiency leads to inadequate mineralisation of newly formed bone matrix (osteoid).
In children, it leads to rickets. The cartilage of epiphysial growth plates and bone are affected. Leads to skeletal abnormalities and pain and growth retardation.
In adults, it leads to osteomalacia (after epiphysial closure). Leads to skeletal pain, increased fracture risk and proximal myopathy.
180
In terms of calcium regulation, what happens in renal failure?
In decreased renal function, calcitriol levels decrease due to reduced 1a-hydroxylase. This leads to reduced Ca2+ reabsorption. There is also less PO43- excretion, leading to an increase in plasma PO43- concentration. PO43- binds to and sequesters Ca2+ - leading to both hypocalcaemia and vascular calcification.
Hypocalcaemia leads to reduced bone mineralisation.
Hypocalcaemia leads to increased PTH. Leads to increased bone resorption.
This leads to osteitis fibrosa cystica.
181
What is osteitis fibrosa cystica?
A rare hyperparathyorid bone disease.
Results in excess osteoclastic bone resorption, secondary to elevated PTH.
Leads to "brown tumours" - radiolucent bone lesions.
182
How is hyperphosphatemia treated? What causes it?
Caused by vitamin D toxicosis, or excess alphacalcidol.
Low phosphate diet. Phosphate binders, which reduced GI phosphate absorption.
Parathyroidectomy.
183
Describe osteoporosis
Osteoporosis is not painful: lends to fractures.
Fewer trabeculae.
Post-menopausal women at risk, due to oestrogen deficiency.
Bone mineral density (BMD) >2.5 SDs below the average value for young healthy adults (T-score of -2.5 or lower).
BMD predicts future fracture risk.
Measured by DEXA scan (dual energy X-ray absorptiometry). Measures femoral neck and lumbar spine.
Mineral (Ca2+) contents of bone measured, the more mineral, the greater the bone density.
184
Compare osteomalacia and osteoporosis.
Osteomalacia - vit D deficiency, leading to inadequately mineralised bones. Low Vit D, low Ca2+, high PTH, painful and predisposes to fractures.
Osteoporosis - bone resorption exceeds formation, decreased bone MASS, serum biochemistry normal, diagnosis via DEXA scan. Also predisposition to fracture.
185
What are the risk factors for osteoporosis?
Oestrogen deficiency in post-menopausal women.
Osteoblast senescence in men and women (age-related).
Hypogonadism in young men and women.
Endocrine conditions (Cushing's, hyperthyroidism, primary hyperparathyroidism).
186
Describe why HRT is given and problems with it.
HRT given to reduce osteoporosis risk as it has anti-resorptive effects on skeleton, preventing bone loss.
Women with an intact uterus need additional progesterone to prevent endometrial hyperplasia.
Use limited due to increased risk of breast cancer and venous thromboembolism.
187
What is the first-line treatment in osteoporosis?
Bisphosphonates. They bind avidly to hydroxyapatite and are ingested by osteoclasts.
They impair the ability of osteoclasts to reabsorb bone.
Decrease osteoclast progenitor development and promote apoptosis of osteoclasts. Net effect is reduced bone turnover.
188
What are the worries associated with giving bisphosphonates to young people.
They accumulate at sites of bone mineralisation and remain part of bone until it is resorbed, which can be years later. Problems with malignancy.
189
What is denosumab?
A human monoclonal antibody with binds to RANKL, inhibiting osteoclast formation and activity. Hence inhibit osteoclast-mediated bone resorption.
2nd line to bisphosphonates for osteoporosis treatment.
190
What is teriparatide?
A recombinant PTH fragment - increases formation and resorption but formation outweighs resorption.
3rd line treatment for osteoporosis.
191
What is Paget's disease?
Accelerated, localised but disorganised bone remodelling.
Excess bone resorption (osteoclastic overactivity) followed by a compensatory increase in bone formation (osteoblasts).
New bone formed = woven bone which is mechanically weaker and structurally disorganised.
Leads to bone frailty, bone hypertrophy and deformity.
192
Why do bones affected by Paget's disease feel warm?
They have increased vascularity.
193
How is Paget's disease diagnosed?
Plasma Ca2+ normal, plasma alkaline phosphatase usually increased.
Plain X-rays = lytic lesions, thickened, enlarged, deformed bones (later).
Radionucleotide bone scans demonstrate extent of skeletal involvement.
Bisphosphonates used in treatment to reduce bony pain and disease activity.
