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Medicine Year 3 > Week 9 - Endocrine > Flashcards

Week 9 - Endocrine Flashcards

1
Q

What biomedical targets should be met in T2DM to prevent complications?

A
  • HbA1c - 7% or individualised
  • BP <130/80 (ACEI or ARB, CCB, thiazide diuretic)
  • Cholesterol - statin if aged >40, <5 once started
  • Normal body weight
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2
Q

How can aldosterone excess be confirmed?

A
  • Stop medications if possible
    • Definitely stop beta blockers and MR antagonists (act on RAS)
    • Alternative drugs include alpha-blockers/verapamil/hydralazine
  • Saline suppression test
    • 2L saline over 4 hours
    • 4h aldosterone >270 pmol/l highly suspicious
  • Subtype identification - adrenal adenoma vs bilateral hyperplasia on CT
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3
Q

Describe the origins of circulating androgens in women

A
  • DHEAS - <5% ovary, >95% adrenal, 0% peripheral conversion
  • Androstenedione - 60% ovary, 35% adrenal, 5% peripheral conversion (from DHEAS)
  • Testosterone - 60% ovary, 5% adrenal, 35% peripheral conversion (from androstenedione)
  • Dihydrotestosterone - 0% ovary, 0% adrenal, 100% peripheral conversion (from androstenedione and testosterone)
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4
Q

At what age does toxic multi-nodular goitre with thyrotoxicosis usually occur

A

>50 y/o

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5
Q

What would typically be seen in terms of clinical features, on examination and investigations in a patient presenting with genetic diabetes?

A
  • Clinical features
    • Well
    • Normal BMI
    • Family history of diabetes
  • Examination
    • Normal
  • Investigations
    • Glucose high
    • HbA1c high
    • K+ normal
    • HCO3 normal (not acidotic)
    • C-peptide elevated
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6
Q

At what age do patients with MODY typically present?

A

<25 years onset

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7
Q

Describe the mechanism of action of thionamides

A
  • Reduce TH synthesis
    • Inhibit iodide oxidation (inhibit thyroid perioxidase)
    • Inhibit iodination of tyrosine
    • Inhibit coupling of DI/MIT
  • Slow effect
  • Propylthiouracil - reduces conversion of T4 to T3, reduces action of T3 acutely
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8
Q

List the symptoms of hypoglycaemia

A

As plasma glucose levels drop hypoglycaemic symptoms develop

  • Autonomic symptoms - sweating, palpitation, pallor, tremor, nausea, irritability, hunger
  • Neuroglycopaenic symptoms - inability to concentrate, confusion, drowsiness, personality change, slurred speech, incoordination, weakness, dizziness, vision impairment, headache, seizures, coma
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9
Q

Compare the typical age of onset in T1DM vs T2DM

A
  • T1DM <35 usually
  • T2DM >35 usually
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10
Q

What could cause hypoglycaemia in a seemingly well patient?

A
  • Endogenous Hyperinsulinism
    • Insulinoma
    • Functional islet-cell disorders (Nesidioblastosis)
      • Noninsulinoma pancreatogenous hypoglycaemia
      • Post gastric bypass hypoglycaemia
    • Insulin Autoimmune hypoglycaemia
      • Antibody to Insulin
      • Antibody to Insulin Receptor
  • Accidental, Surreptitious, Malicious hypoglycaemia
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11
Q

List diseases associated with RET protooncogenes

A
  • Familial medullary thyroid cancer
  • multiple endocrine neoplasia type 2 and 3 (MTC, phaeochromocytoma, primary hyperparathyroidism)
  • Hirschprung’s
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12
Q

What is the differential diagnosis in hypothyroidism?

A
  1. Hypothyroidism
  2. Anaemia
  3. Depression
  4. Hypoadrenalism
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13
Q

Describe the structure of T3/4

A
  • T4 - 2 tyrosine and 4 iodine
  • T3 - 2 tyrosine and 2 iodine
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14
Q

List the endocrine features of MEN1

A
  • Primary hyperparathyroidism
  • Entero-pancreatic tumour
    • Gastrinoma
    • Insulinoma
    • Non-functioning
    • Other - glucagonoma, VIPoma, somatostatinoma
  • Foregut carcinoid
    • Thymic carcinoid
    • Bronchial carcinoid
  • Anterior pituitary adenoma
    • Prolactinoma
    • Other GH + PRL, GH, non-functioning
    • ACTH
  • Adrenal cortical tumour
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15
Q

What are the benefits vs risks of SGLT2 inhibitors (flozins)?

A

Benefits:

  • Moderate efficacy
  • CV benefit (BP and heart failure)
  • Renal benefit (CANA)
  • Weight loss
  • Low hypo risk
  • Reduced CV events

Risks:

  • Risk of GU infections
  • Small risk of hypovolaemia/DKA
  • Do not start if eGFR <60
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16
Q

What could cause hypoglycaemia in a ill/medicated patient?

A
  • Drugs
  • Critical illness
    • Hepatic, renal or cardiac failure
    • Sepsis, including malaria
    • Inanition (prolonged undernutrition)
  • Hormone deficiency
    • Cortisol - can present w/ hypoglycaemia
  • Non-islet cell tumour
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17
Q

What causes hypopituitarism leading to amenorrhoea?

A
  • Pituitary tumour - damage to cells or hormone secreting e.g. prolactinoma
  • Pituitary surgery/radiotherapy
  • Head injury
  • Kallman’s syndrome - isolated LH + FSH deficiency
  • Cerebellar ataxia
  • Genetic syndromes
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18
Q

What is the function of testosterone?

A
  • Growth
    • Sex organs
    • Skeletal muscle
    • Epiphyseal plates
    • Larynx growth - voice deepens
    • Secondary sex characteristics
  • Other effects
    • Erythropoiesis - women have lower haemoglobin than men
    • Behaviour - more aggressive
  • Adult
    • Muscle mass
    • Mood
    • Bone mass
    • Libido
    • Body shape
  • Fertility
    • Libido
    • Erectile function
    • Spermatogenesis
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19
Q

What investigations should be done in hypoglycaemia?

A
  • U&E, LFT, TFT
  • HbA1c
  • Synacthen test
  • 72 hour fast
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20
Q

What are the complications of Grave’s disease?

A
  • Dysthyroid eye disease
  • Dermopathy
  • Thyroid acropachy
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21
Q

61 y/o entertainer, T2D 5 yrs, on metformin 1g bd, Empagliflozin 10mg, BMI 30, HbA1c 64, eGFR>60, smoker, hypertension, H/O IHD & heart failure, wants to look good for radio

Next best step?

A) SU

B) GLP-1a

C) Gliptin

D) Insulin

E) Glitazone

A

SU - gain weight, risk of hypo

GLP - lose weight, CVD risk reduction (if willing to inject)

Insulin - gain weight, no CV risk reduction

Glitazone - can’t use in heart failure

B - GLP-1a

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22
Q

What change occurs in the follicles when they become active?

A

Epithelial cells - Cuboidal/squamous to columnar when active

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23
Q

What features point towards a diagnosis of pancreatic diabetes?

A

History of alcohol excess (abnormal LFTs may be due to alcohol) may predispose to pancreatic pathology, history of acute pancreatitis.

History of exocrine dysfunction would suggest pancreatic pathology (diarrhoea, malabsorption)

Haemochromatosis is a relatively common genetic disease in West of Scotland; Iron deposition can affect a number of organs including pancreas (diabetes), liver (abnormal LFTs), heart (cardiomyopathy).

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24
Q

What are the signs and symptoms of hypothyroidism?

A
  • Symptoms include
    • Tiredness
    • Weight gain
    • Feeling cold - preference for watch
    • Constipation
    • Myalgia
    • Carpal tunnel syndrome
    • Menorrhagia
  • Signs include
    • Excess weight
    • Thick coarse facial features
    • Dry skin
    • Fine, brittle hair
    • Loss of outer eyebrows
    • Delayed relaxation of ankle and other deep tendon reflexes
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25
What plasma glucose values are diagnostic of diabetes?
Plasma glucose (mmol/l) * Fasting * Normal \<5.6 * Impaired glucose tolerance \<7 * Diabetes \>7 * 2 hour * Normal \<7.8 * Impaired glucose tolerance 7.8-11.0 * Diabetes \>11.1
26
What is Grave's disease?
Autoimmune condition, thyroid stimulating antibody
27
Define Addison's disease
* Primary adrenal insufficiency * Autoimmune destruction of adrenal cortex - 90% destroyed before symptomatic, autoantibodies in 70%
28
List the effects of cortisol
* Increased gluconeogenesis * Permissive effect on glucagon * Increased lipolysis in adipose tissue to produce free fatty acids (used for energy or in gluconeogenesis) * Insulin antagonist * Increased skeletal muscle protein breakdown * Memory, learning, mood * Immune suppression
29
What are the types of hypogonadism?
* Dependent on where the problem is * Hypothalamic-pituitary problem - hypogonadotrophic hypogonadism * Testicular problem - primary gonadal failure
30
Give examples of types of neuroendocrine tumours
Carcinoid tumours - GI tract, lungs, thymus etc. Pancreatic NETs Phaeochromocytoma/paraganglioma
31
List causes of hirsutism
* Ovarian * PCOS 95% * Androgen secreting tumour \<1% * Adrenal * Congenital adrenal hypertrophy \<1% * Androgen secreting tumour \<1% * Idiopathic * Normal investigations 3%
32
Define diabetes mellitus
A metabolic disorder of multiple aetiology characterised by chronic hyperglycaemia with disturbances of carbohydrate, protein and fat metabolism resulting from defects in insulin secretion, insulin action, or both.
33
Define goitre
Swelling of the neck due to enlargement of the thyroid - hypothyroid, hyperthyroid or euthyroid with nodular disease
34
What are the potential complications of thyroidectomy?
* Haemorrhage - thyroid is very vascular * Recurrent laryngeal palsy (hoarseness) * Permanent hypocalcaemia (PTH damage) * Hypothyroidism
35
What are the benefits vs risks of metformin?
Benefits: * Moderate efficacy - HbA1c fall by 1% * Weight reduction * Low hypo risk * CV benefit * Extensive experience * Low cost Risks: * GI side effects * Can't be used if eGFR \<30 * Small risk of lactic acidosis
36
What is the differential diagnosis in hyperthyroidism?
1. Grave's w/ thyrotoxicosis 2. Hashimoto's thyroiditis w/ thyrotoxicosis - transient subacute thyrotoxicosis initially 3. Toxic-multi-modular goitre w/ thyrotoxicosis 4. Transient gestational thyrotoxicosis 5. Phaeochromocytoma 6. Carcinoid syndrome 7. Alcohol dependence/withdrawal 8. Substance misuse
37
What is the cause of iatrogenic Cushing's syndrome?
* Prolonged high dose steroid therapy, usually oral (can be inhaled/injected) * In asthma, rheumatoid arthritis, inflammatory bowel disease, transplants etc. * Chronic suppression of ACTH production and adrenal atrophy * Unable to respond to stress/illness - need extra doses when ill * Cannot stop steroid therapy suddenly - gradual withdrawal of steroid therapy if 4-6+ weeks
38
41 y/o, safety inspector, T2DM 7 months, No PMHx, BMI 31, HbA1c 70, asymptomatic, boss has released the hounds. Next best step? A) SU B) Metformin C) Continue lifestyle advice D) Refer to Specialist Clinic E) Another 2nd line agent
* HbA1c higher, 7 months since diagnosis * B - metformin is 1st line drug * Not SU * Would be more beneficial is symptomatic * Risk of more weight gain or hypos (especially with occupation)
39
How should insulin be administered?
* There are a number of different devices to administer insulin - the DSNs usually spend time with patients deciding together the most appropriate * It is important that the correct insulin with the correct device are prescribed after this decision has been made * All staff should remind patients of the importance of rotation of injection sites to avoid lipohypertrophy and consequent erratic insulin administration * Insulin should be given 15-30 mins before meal (depending whether they contain rapid acting analogue insulins or human insulin) * Basal insulin as part of a basal bolus regime can be given at any time of the day
40
What lifestyle measures should be taken in the management of T2DM?
* Diet quality and calorie restriction * Weight watchers * VLCD/DIRECT study - 1/3 remission at 2 years but 2/3 remission with weight loss of 10kg, 6 years duration of T2D * Liquid replacement diet - 800cals per day then reverse dieting * Increased physical activity * First 3 months and then reinforced at each contact
41
List the types of thyroid tumours and the cells from which they originate
* Follicular cell * Benign adenoma * Papillary cancer * Follicular cancer * Anaplastic cancer - poorly differentiated * Thyroid C cell * Medullary cancer
42
Which symptoms distinguish toxic multi-nodular goitre with thyrotoxicosis from Grave's disease with thyrotoxicosis?
Toxic multinodular goitre w/ thyrotoxicosis - CV manifestations tend to occur and patient has obstructive symptoms from the goitre (e.g. dysphagia, dysphonia, dyspnoea)
43
34 y/o woman, T2DM for 1 month, No PMHx, BMI 23, HbA1c 70, eGFR \>60, symptomatic, losing weight fast Next best step? A) SU B) Metformin C) Continue lifestyle advice D) Refer to Specialist Clinic E) Another 2nd line agent
\>35, insulin deficiency, normal BMI, losing weight, acute onset Possible type 1 DM? D - test for autoantibodies, random glucose, ketones, C-peptide
44
Describe insulin regimens used in T1DM
1. Basal bolus * Basal long acting insulin * Bolus short acting at meal times w/ CHOs * Gives flexibility, short acting can works within 15 minutes so can eat/exercise at different times everyday 2. BD mix regimen * Intermediate acting twice per day at breakfast + dinner * Need more rigid eating times * Less injecting required
45
Describe the venous drainage of adrenal glands
* Left adrenal vein, drains to left renal vein * Right adrenal vein, drains to inferior vena cava
46
How can primary and secondary adrenal insufficiency be distinguished?
* Short synacthen test * Primary = low cortisol after ACTH * Secondary = high cortisol after ACTH
47
What activates the renin-angiotensin system?
Activated in response to low BP and/or high plasma potassium
48
Describe the incidence of thyroid cancer in men/women
Incidence of Thyroid Cancer per year: 5. 6/100,000 women = 1958 (230 deaths) 2. 2/100,000 men = 769 (143 deaths)
49
What are the issues with androgen replacement therapy for hypogonadism?
* Side effects - * Mood issues (aggression/behaviour change) * Libido issues * Increased haematocrit * Possible prostate effects - higher risk of prostate cancer? * Acne, sweating * Gynaecomastia - breast cancer * Risk of exposing people in close contact to topical androgens e.g. babies * Drugs of Abuse * Cycling, athletics, baseball * Powerlifting * Complex doping regimens * Masking agents * LH/GnRH * Tamoxifen * Natural supplements - testosterone boosters
50
What is the normal physiological repsonse to low BP?
* Renin production (major regulator of aldosterone production) * Conversion of angiotensin --\> angiotensin I --\> angiotensin II (angiotensin converting enzyme) * Angiotensin II causes direct (vasoconstriction) and indirect (aldosterone) methods of BP elevation * Aldosterone causes increased salt and water retention by the kidneys * Circulating volume restored, BP raised
51
Describe the formation of ACTH
* Peptide hormone formed from cleavage of pro-opiomelanocortin (POMC) in corticotropes in anterior pituitary * Lipotropin (beta endorphin precursor), beta endorphin and metencephalin (opiod peptides - reduce pain, euphoria) and melanocyte stimulating hormone also released
52
Describe the pharmacological treatment of hirsutism
* Ovarian androgen suppression - COCP (Dianette ideal) * Adrenal androgen suppression - corticosteroids * Androgen receptor antagonist - spironolactone, cyproterone acetate (teratogenic) * 5 alpha reductase inhibition - finasteride * Insulin sensitisers - metformin * Topical inhibitors - eflornithin
53
What determines the presentation of neuroendocrine tumours?
* Tumour type * Size and location * Hormone production - functional or non-functional * Presence of metastases * E.g. bowel tumours produce hormones, metabolised in liver (inactivated), metastatic disease to liver bypasses metabolism so hormone excess
54
What causes hypothyroidism?
* Primary - high TSH, low T4 * Autoimmune Hashimoto thyroiditis * Iodine deficiency * Drugs e.g. lithium * Congenital hypothyroidism * Post-radioactive iodine * Post-thyroiditis * Secondary - low TSH, low T4 * Pituitary or hypothalamic disease
55
What are benefits vs risks of insulin therapy?
Benefits: * High efficacy * Extensive experience Risks: * Injected * No CV benefit * Weight gain * Highest hypoglycaemic risk
56
What is Kallman's syndrome?
* Commonest form of isolated gonadotrophin deficiency * Failure of cell migration of GnRH cells to hypothalamus from Olfactory placode * Associated with aplasia/hypoplasia of olfactory lobes - giving anosmia or hyposmia * Also may be associated with deafness, renal agenesis, cleft lip/palate * May have micropenis +/- cryptorchidism
57
How prevalent is PCOS?
* Affects \>5% women of reproductive age * Commonest cause of anovulatory infertility (80%)
58
What would typically be seen in terms of clinical features, on examination and investigation results in a patient presenting with type 1 diabetes?
* Clinical features * Young * Symptoms - thirst, polyuria, polydipsia, weight loss * BMI normal/low * Other autoimmune diseases? * Examination * Thin, dehydrated, tachycardic * Investigation * Glucose high * HbA1c high or normal (acute onset) * K+ high (insulin deficiency) * Bicarbonate low (acidotic) * C-peptide low or undetectable * GAD antibodies positive
59
How are thyroid carcinomas treated?
Surgery and therapeutic radioiodine TSH dependent - suppression of TSH Monitor thyroglobulin (multikinase inhibitors)
60
How is PCOS treated?
* Pharmacological treatment for hirsutism * Calorie restriction and wieght reduction associated with vast improvement in metabolic indices in obese women with PCOS * Diet and lifestyle changes improve ovulation rate and fertility
61
List the types of steroid receptor
* Glucocorticoid receptor - widespread * Minerlocorticoid receptor - distal nephron, salivary glanfs, sweat glands, large intestine
62
What would investigations show in hypogonadotrophic hypogonadism?
* Low testosterone, low LH and FSH +/- * High prolactin * High levels of prolactin suppress FSH/LH (prevent pregnancy while breast feeding) * Low cortisol * Low IGF-1/GH * Low TSH * High Na+
63
List the clinical features of Kallman's syndrome in childhood, adolescence and adulthood
* Childhood * Poor growth * Undescended testes * Adolescence * Poor growth * Small testes * Micropenis * Delayed/absent puberty features * Adult * Slow, but adequate growth * Small testes * Small phallus * Hypogonadal features
64
Describe the arterial supply of the thyroid gland
* Superior and inferior thyroid artery (left and right) * Superior is 1st branch of external carotid - supplies superior and anterior parts * Inferior is branch of thyrocervical trunk, from subclavian artery - supplies posterior and inferior parts
65
80 y/o man, lives alone, mild cognitive impairment, T2D 15 yrs, BMI 27, HbA1c 67, no microvascular complications, CKD 3, osteoporosis, on metformin 1g bd, asymptomatic, wants to answer phone Next best step? A) SU B) Gliptin C) Continue plan D) Flozin E) Glitazone
Don't use SU - can't risk hypoglycaemia in cognitive impairment Gliptin, flozin - can't use in CKD3 Asymptomatic, no complications, risks associated with lowering glucose C - continue plan
66
Describe the epidemiology of T2DM
Prevalence varies remarkably among ethnic groups living in the same environment 39% have at least one parents with the disease Lifetime risk for a first-degree relative is 5-10 times higher than that of age and weight-matched without family history of diabetes Environment explains why prevalence in Pima Indians in Mexico is less than 1/5 that in US Pima Indians (6.9% vs 30%)
67
How is nuclear imaging used in the diagnosis of thyrotoxicosis?
* Thyroid scintigraphy scanning with technetium-99m or iodine-131 is useful when antibody testing negative, a nodule is palpable, or thyrotoxicosis without hyperthyroidism is suspected * Important patterns * Diffuse uptake with suppression of background activity = Grave's * Irregular uptake - multi-nodular goitre * Hot nodule - toxic adenoma * Reduced uptake - thyroiditis e.g. viral
68
List the symptoms/signs of late onset congenital adrenal hyperplasia
Oligomenorrhoea, hirsutism, reduced fertility
69
Describe inheritance of neuroendocrine tumours
* Most sporadic * Can be associated with hereditary tumour syndromes * E.g. MEN type 1, vHL, NF1
70
How does the action of angiotensin II lead to aldosterone release?
* Binds to 7TMD G-coupled receptor * Activates phospholipase C * Hydrolyses PIP2 to IP3 and DAG * IP3 causes stored calcium to be released * Increased calcium activates Ca2+ calmodulin dependent protein kinases (CaMKs), causes StAR transcription, increased cholesterol movement into the mitochondria * Increased aldosterone production
71
How do gonadotrophins contribute to the pathophysiology of PCOS?
* Increased LH concentration * Increased LH receptors in PCOS ovaries * Support ovarian theca cells * Increased ovarian androgen production * Decreased FSH * Low constant levels result in continuous stimulation of follicles without ovulation * Decreased conversion of androgens to oestrogens in granulosa cells
72
What causes hypothyroidism?
* Pituitary * Hypopituitarism * Thyroid * Thyroidectomy * Post radioactive iodine ablation * Autoimmune * Thyroiditis - postpartum * Silent * Hashimoto's - blocking TSH receptor antibodies * Inborn errors * Congenital hypothyroidism
73
What is the effect of primary aldosteronism on aldosterone and renin production?
Overactivity in zona glomerulosa - excess aldosterone production Renin suppressed due to negative feedback - aldosterone not being stimulated by renin
74
How is thyroid hormone release stimulated?
* Thyroid releasing hormone (TRH) secreted by hypothalamus, stimulates thyroid stimulating hormone (TSH) release from the anterior pituitary * TSH binds to G protein coupled receptor on follicular cells, activated cAMP and phospholipase C * cAMP mediates actions - increased Tg iodination, microvilli number and length, endocyotsis of colloid droplets, TH release, iodine influx, cellular metabolism, protein (including Tg) synthesis and DNA synthesis * Increases TH stores, within 1 hours increases TH release
75
What are the risks for hyperthyroidism?
* Autoimmune disease * Female * Pregnancy * Drugs e.g. amidarone
76
List the signs/symptoms of hypothyroidism
* Weight gain * Depression * Lethargy * Constipation * Cold intolerance * Poor concentration * Hoarseness * Menorrhagia * Bradycardia * Dry skin * Coarse, thin hair * Anaemia * Slow relaxing reflexes * May have goitre * Pale, puffy face * Lose lateral 1/3 of eyebrows
77
What is the value of metformin in PCOS treatment?
* In theory * For obese and non-obese - improves insulin sensitivity * Leads to lower LH levels and higher SHBG and hence lower free androgens * May regulate ovulatory function and hence menstruation * Small number of RCT * Significant but modest increase in ovulation rate * Questionable effect on hirsutism (no data on acne) * No effect independent of weight loss * Efficacy and indications for treatment unclear * Insulin sensitizers ineffective for infertility * Metformin in treatment of PCOS * Not useful for treatment of infertility * Not very effective for treatment of hirsutism * May have a place in management of women at high risk of developing diabetes
78
List the effects of aldosterone
* Bind to mineralocorticoid receptors on principle cells of DCT and collecting ducts * Upregulates Na+/K+ ATPase, ENaC, H+/ATPase (intercalated cells), K+ secretion into lumen, SGK-1 (increased Na+/K+ ATPase) * Causes * Increased Na+ reabsorption by the kidneys, therefore increased water reabsorption and an increase in BP * Increased K+ excretion by the kidneys * Increased H+ excretion by the kidneys
79
What is the impact of undiagnosed/treated maternal hypothyroidism on the foetus?
* Neonatal hypothyroidism/cretinism * Coarse facial features * Macroglossia * Large fontanelles * Umbilical hernia * Mottled, cool and dry skin * Developmental delay * Pallor * Myxoedema * Goitre
80
What are the complications associated with Grave's disease?
* Ophthalmology * Dermopathy - free tibial myxoedema * Thyroid acropachy - periostitis of multiple pharyngeal and metacarpal bones
81
What causes secondary adrenal insufficiency?
* Pituitary/hypothalamus tumour/exogenous steroid use (predisolone, dexatriethasone, inhaled corticosteroid) * No skin darkening, no need for fludrocortisone
82
What causes hypertension?
* \>90% hypertension cases there is no known cause (essential/primary) * \<10% cases are secondary to another disorder e.g. renal disease, hormone excess * Secondary cause more likely: * Young * Resistant/severe hypertension * Clinical suspicion
83
How is the production of cortisol regulated?
* Hypothalamus produces cortisol releasing hormone (CRH) in response to time of day, stress, illness * CRH stimulates ACTH production from the anterior pituitary * ACTH stimulates the adrenal cortex to produce cortisol * High cortisol levels have negative feedback effect on anterior pituitary and hypothalamus
84
Describe the inheritance of Kallman's syndrome
* Familial with variable penetration * X-linked - absence of KAL gene (KAL1) * Autosomal dominant (KAL2) * Autosomal recessive (KAL3) * Other genetic causes of IHH exist (e.g. Kisspeptin/GPR54 mutations)
85
How are autoantibodies used in the diagnosis of thyroid disease?
## Footnote Thyroid peroxisomal antibody positive in Hashimoto's thyroiditis and Grave's disease, TSH receptor antibodies positive in Grave's disease only (diagnostic - cause of Grave's)
86
What does plasma ketone level indicate in diabetes?
If high can indicate diabetic ketoacidosis Below 0.6mmol/L - normal, no action required 0.6-1.5mmol/L - indicate the development of a problem that may require medical assistance Above 1.5mmol/L - in the presence of hyperglycaemia indicates high risk of DKA
87
What features point towards a diagnosis of genetic diabetes/MODY?
* Family history is present - multigenerational. Type 2 diabetes is also strongly heritable (approx 80%- 90% concordance with monozygotic twins vs 40% type 1 diabetes monozygotic twins) * Age of onset - \<25 at diagnosis makes genetic diabetes more likely) * Other clinical features that may suggest genetic diabetes is more likely e.g. * Renal disease (HN1B) * Personal or family history of deafness (maternally inherited diabetes and deafness, MIDD) * Sensitivity to sulphonylureas, HNF1A patients often experience hypoglycaemia with standard doses of gliclazide and smaller doses are often effective.
88
Describe the lifetime risk of developing thyroid disease
* Autoimmune thyroiditis * Inflammation up to 27% of women * +ve autoantibodies 10-12% * Hypothyroidism * 1-2% women * 0.1-0.2% men * Subclinical hypothyroidism (slightly low/normal T4, raised TSH) * 10% of women over 55 years * Hyperthyroidism * 0.5-2% * Subclinical hyperthyroidism * 0.1-0.4%
89
What considerations should be made when prescribing T2DM therapies in the elderly?
* Polypharmacy with risk of drug interactions * Increased likelihood of adverse events to drugs * Decrease in eGFR * Increased likelihood of hypoglycaemia * Individualise therapy balancing likely benefit with potential risks
90
What is congenital adrenal hyperplasia?
* Autosomal recessive disorder * Range of genetic disorders relating to defects in steroidogenic genes * Most common - CYP21 (21 alpha hydroxylase)
91
82 y/o man, lives alone, moderate cognitive impairment, T2D 17 yrs, BMI 22, HbA1c 130, no microvascular complications, CKD 3, osteoporosis, on metformin 1g bd, Gliclazide 160 bd, symptomatic Next best step? A) Gliptin B) GLP-1a C) Continue plan D) Insulin E) Glitazone
Gliptin won’t reduce HbA1c, not effective in well established disease Insulin - reduce HbA1c (D) Glitazone - fracture risk
92
How prevalent is Klinefelter's syndrome?
Commonest genetic cause of male hypogonadism (1 in 500 male births)
93
What should be considered when an adrenal incidentaloma is found?
* Malignancy? * Imaging characteristics * Size \<4cm * Low Housfield units on non-contrast CT - \<10HU * Lipid rich * = no further scan * Dynamic scan * Wash out - adenoma rapid wash out * Functional - hormone producing? * Aldosterone * Cortisol * Androgens * Catecholamines
94
How can congenital hypothyroidism be treated in a baby?
Can add thyroxine to breast/formula milk
95
How is T1DM managed?
Insulin replacement Glucose/ketone monitoring CHO counting/structured education Supported self management
96
41 y/o, safety inspector, T2DM 1 month, No PMHx, BMI 31, HbA1c 57, eGFR\>60, asymptomatic, boss not happy as sleeping on the job. Next best step? A) SU B) Metformin C) Lifestyle advice D) Refer to Specialist Clinic E) Another 2nd line agent
* C - lifestyle advice, could control HbA1c with just lifestyle changes * Asymptomatic, low HbA1c, no complications
97
How is an insulinoma managed?
Endocrinologist/radiologist/pancreatic surgeons/oncologists Laparoscopic distal pancreatectomy MEN1 genetics - sometimes incidentalomas
98
Describe the features of LADA
* Age of onset usually \>25 * 0 parents affected * Obesity rare * Insulin treatment variable, usually needed within months - years of diagnosis * Polygenic inheritance * GAD autoantibody positive
99
How can hypoaldosteronism present similarly to hypothyroidism? How can the two be distinguished while taking a history?
* Can present with fatigue and postural hypotension * Ask about any personal or family auto-immune history, any steroid continuing medication or opiate based analgesia
100
Describe the mechanism of action of sulphonylureas
* Bind to SUR1 receptor on cell membrane of pancreatic beta cells, which results in closure of ATP-K+ potassium channels on beta cells, allowing an influx of calcium which results in release of stored insulin * Increased cellular glucose uptake and glycogenesis, reduces gluconeogenesis * Less effective over time - residual insulin used up
101
Describe the location of the thyroid gland
* Anterior neck, C5-T1 * Behind sternohyoid and sternothyroid muscle * Visceral compartment of neck (with trachea, oesophagus and pharynx) - bound by the pre-tracheal fascia
102
What is responsible for growth during infancy, childhood and puberty?
* Infantile - IU growth +/- GH * Childhood - GH and T4 * Pubertal - GH and sex steroids * Chronic disease or malnutrition will affect ability to grow at any age
103
How are islet autoantibodies used in diabetes diagnosis?
Markers of autoimmune process associated with T1DM Present in 80% of T1DM if combination of glutamic acid decarboxylase (GAD) and insulinoma-associated antigen 2 measured (\<1% of MODY) Some patients with phenotype of T2DM have positive antibodies (progress more quickly to insulin deficiency). Most useful 3-5 years from diagnosis (overlap with T2DM/MODY before, especially in obese)
104
Define Cushing's syndrome
* Excess cortisol production * High mortality, rare * More common in women - 20-40 years old
105
Describe the structure and function of the adrenal glands
* Outer cortex, inner medullar * Cortex produces adrenal steroid hormones, three layers * Outermost zona glomerulosa - aldosterone (salt) * Middle zona fasciculata - cortisol (sugar) * Inner reticularis - androgens (sex) * Cortex has layers with distinct functions related to expression of steroidogenic enzymes * All steroids start from cholesterol but expression of specific steroidogenic enzymes leads to synthesis of different hormones and distinction of layers producing different end products * Medulla contains chromagraffin cells which produce catecholamines (adrenaline, noradrenaline etc.)
106
Which investigations should be done in a patient presenting with hypothyroidism?
* Thyroid function tests - TSH, fT4 * Thyroid autoantibodies (Ab) - Thyroid peroxidase (TPO Ab) * \*\*Also consider if felt clinically appropriate: * FBC : Haemoglobin measurement can diagnose anaemia * 9am Cortisol: assess adrenal reserve (hypoadrenalism)
107
How is hyperthyroidism diagnosed?
* Biochemical proof of suppressed TSH and high free thyroid hormone * Anti-TSH receptor/Tg/TPO antibodies * ESR - inflammation * Ultrasound - increased vascularisation of thyroid (Grave's) * Radioactive iodine uptake test with PET scan
108
What factors may contribute to the development of hypoglycaemia in patients with T1DM?
* Correct insulin dispensed? * Incorrect balance between fast acting insulin and carbohydrate at meals * Too much basal insulin * Overused injection sites * Exercise (increases insulin sensitivity) * Early pregnancy
109
What are the benefits vs risks of GLP-1 receptor agonists?
Benefits: * High efficacy * CV benefit * Low hypo risk * Weight loss Risks: * Injected * GI side effects * Uncertain safety re. pancreas - pancreatitis risk?
110
What causes MODY?
1-2% of DM (often unrecognised) Caused by change in a single gene (monogenic), autosomal dominant (50% chance inheriting) 6 genes have been identified accounting for 87% of UK MODY (HNF1-A around 70%) Runs in families from one generation to next
111
What considerations should be made when prescribing T2DM therapies in heart failure?
* May use metformin in chronic heart failure, withhold during acute episodes of failure (tissue hypoperfusion/organ failure stop metformin) * Stop or do not initiate Glitazone * Flozins reduced hospitalisation for heart failure with and without diabetes
112
61 y/o entertainer, T2D 3 yrs, on metformin 1g bd, BMI 32, HbA1c 77, eGFR\>60, smoker, hypertension, H/O IHD, symptomatic, wants to look good on TV Next best step? A) SU B) Gliptin C) Continue plan D) Flozin E) Glitazone
D - flozin Heart disease, lower BP Lose weight Counsel on side effects
113
Describe the structure of the zona fasciculata
* Large cells arranged in cords - spongiocytes (appear empty) * Parallel organisation - fenestrated capillaries run alongside
114
Describe the gross structure of the thyroid gland
* L and R lobes (+ pyramidal lobe sometimes - anatomical variant) - R bigger, joined by isthmus * Weight 15-25g - varies with I2 intake, increases during puberty, pregnancy, lactation * Very vascularised
115
Describe the hypothalamic-pituitary-adrenal axis
* Time of day (circadian), stress or illness stimulate release of corticotrophin releasing hormone (CRH) from the hypothalamus * CRH stimulates adrenocorticotrophic (ACTH) hormone from the anterior pituitary * ACTH stimulates cortisol/androgen release from the adrenal cortex
116
Describe the control of male gonadal function
* Hypothalamus secretes GnRH * GnRH acts on anterior pituitary, stimulates secretion of LH and FSH * LH acts on Leydig cells - produce androgens (testosterone, converted to oestrogen by aromatase) * FSH acts on Sertoli cells to stimulate spermatogenesis * Negative feedback * Testosterone and oestrogen have negative feedback effect on anterior pituitary and hypothalamus * Sertoli cells produce inhibin B, which has a negative feedback effect on the anterior pituitary
117
What are the actions of aldosterone?
* Aldosterone binds to mineralocorticoid receptors in the renal tubule collecting cells * Causes activation of ENaC - sodium and water reabsorption * Consequential potassium excretion to maintain neutral electrical balance
118
What are the risks vs benefits of sulphonylureas?
Benefits: * High efficacy * Extensive experience Risks: * No CV benefit * Weight gain * High hypo risk * Caution in CKD
119
Describe the mechanism of action of insulin
* Increase glucose uptake and utilisation in skeletal muscle * Reduce hepatic glucose output, increase glycogenesis * Decrease lipolysis * Decrease gluconeogenesis
120
What is a phaeochromocytoma? What is a paraganglioma?
* Phaeochromocytoma - tumour of the chromaffin cells of the adrenal medulla * Paraganglioma - neuroendocrine neoplasm outwith the adrenal medulla
121
How is C-peptide used in diabetes diagnosis?
Secreted in equimolar concentrations to insulin Useful marker of endogenous insulin secretion Most useful 3-5 years from diagnosis (overlap with T2DM/MODY before especially in obese) Can be measured in blood or urine (urine C peptide/creatinine ratio)
122
What investigations should be done to determine the source of ACTH dependent cortisol excess?
* MRI pituitary * CT chest/abdo/pelvis * EUS and biopsy * Somatostatin receptor scintigraphy (Octreotide scan) * NET often have somatostatin receptors on surface - radiolabelled isotopes taken up by tumour * Can see if it is NET and any distant spread
123
List the causes of hyperthyroidism
* Pituitary * Pituitary adenoma * Other hormones acting as TSH - HCG * Thyroid * Autoimmune * Graves disease * Thyroiditis acute early phase * Activation TSH receptor antibodies * Thyroid adenoma
124
What is important to consider in hypothyroidism treatment?
* Compliance important - have to take everyday for rest of life * Can give entire quantity for week in one day * Can develop inability to absorb - coeliac or other medications * PPIs - need gastric acid to absorb * Iron - chelates and binds to tablets
125
List the clinical features of Cushing's syndrome
* Weight gain * Hirsutism * Psychiatric - euphoria, sometimes depression or psychotic symptoms and emotional lability * Proximal myopathy * Obesity - truncal/generalised * Plethora- excess of blood, turgescent and reddish complexion * Moon facies * Hypertension * Bruising * Striae (red/purple) * Buffalo hump * Thinning of skin * Thin arms and legs - muscle wasting * Osteoporosis * Tendency to hyperglycaemia * Negative nitrogen balance * Increased appetite * Increased susceptibility to infection * Poor wound healing * Avascular necrosis of the femoral head * Cataracts * Benign intracranial hypertension
126
Where are the adrenal glands located?
In abdomen, superior to kidneys Retroperitoneal
127
How is hypothyroidism treated?
* Levothyroxine * 1.7-2.0 micro g/kg/day on empty stomach * Avoid taking with PPI, ferrous sulphate or calcium - chelate, won't be absorbed (incomplete gastric absorption) * Start low in elderly/cardiac disease - increase HR quickly, could have ischaemic heart disease * Long half-life * Travels bound to protein, metabolised to triiodothyronine (T3) * Goal = normalise symptoms and TSH (normal level is disputed)
128
What would typically be seen in terms of clinical features, on examination and investigations in a patient presenting with type 2 diabetes?
* Clinical features * High BMI * Family history of diabetes * May be symptomatic - tired, polyuria, polydipsia etc. * Examination * Overweight * Acanthosis nigricans? * Investigations * Glucose high * HbA1c high (slow onset) * K+ normal (endogenous insulin production) * HCO3 normal (not acidotic) * C-peptide elevated
129
Give examples of endocrinopathies which can present with elevated glucose
Acromegaly, Cushing's syndrome and thyrotoxicosis
130
How can anaemia present similarly to hypothyroidism? How can the two be distinguished?
* Can present with fatigue, reduced exercise tolerance and feeling cold * Patient may look pale * Full blood count helps confirm diagnosis
131
How is MODY managed?
Managed by diet, OHAs (sensitive), insulin (not always)
132
What causes secondary amenorrhoea?
* Uterine * Asherman's syndrome - uterine adhesions * Ovarian * PCOS * Premature ovarian failure * Pituitary * Pituitary tumour - non-functioning or hyperfunctioning * Prolactinoma most common * Hypothalamic * Weight loss, stress, drugs e.g. opiates
133
What causes late onset congenital adrenal hyperplasia?
* Partial 21 alpha hydroxylase deficiency * Maintain cortisol within normal range * Increased ACTH drive leads to increased 17OPH and adrenal androgens
134
What education should be given to diabetic patients regarding pregnancy?
* Women of reproductive age should be asked about pregnancy planning and contraceptives * Pregnancy in the context of poorly controlled HBA1C is associated with adverse outcomes for both maternal and foetal health * Women with diabetes (both type 1 and type 2) should be encouraged to plan pregnancy for safe outcomes for mother and baby
135
What causes phaeochromocytomas?
* Up to 25% associated w/ genetic condition * Multiple endocrine neoplasia (MEN) * Von Hippel-Lindau (VHL) syndrome * SDHD and SDHB * Neurofibromatosis
136
How does testosterone circulate? In what form is it most active?
* Steroid hormone - intracellular action * Circulates bound to SHBG and albumin * Free testosterone is active * Activated to more potent form in target tissues by 5-alpha reductase
137
List the symptoms of a phaeochromocytoma
Symptoms include episodic sweating, heat intolerance, pallor, feelings of apprehension/anxiety, episodic or sustained hypertension, palpitations, chest pain and dyspnoea
138
Describe the structure of the zona glomerulosa
Clusters of small cells, dark granules, close association with blood vessels
139
What effect can amiodarone have on the thyroid?
* 200mg amiodarone releases approx. 6mg iodine - way more iodine than required in diet = iron overload * Jod Basedow phenomenon - iodine induced hyperthyroidism * Wolff Chaikoff effect - iodine induced hypothyroidism Amiodarone Thyroid Disease * Type 1 - autoimmune thyrotoxicosis * Treatment high dose Carbimazole * Type 2 - destructive thyroiditis * Treatment glucocorticoids
140
Why are symptoms of mineralocorticoid excess seen in cortisol excess (Cushing's syndrome)?
Get symptoms of mineralocorticoid excess (hypertension, low K+, oedema etc.) because normally enzyme in kidney (11 beta-hydroxysteroid dehydrogenase) keeps mineralocorticoid receptors free for aldosterone binding but when cortisol levels are high the MR is overwhelmed and cortisol binds - causes overactivation of receptors and mineralocorticoid effects.
141
What are the clinical features of male hypogonadism in a child/young adult?
* Slow growth in teens * No pubertal growth spurt * Small testes and phallus * Lack of secondary sexual development
142
How are steroid hormones formed?
* All synthesised from cholesterol - taken up from circulation (as LDL through LDL receptors then esterified to free cholesterol) or synthesised de novo from acetyl coA (rate limiting enzyme is HMG coA reductase) * Rate limiting step - cholesterol transported from cytoplasm into mitochondria by steroidogenic acute regulatory protein (StAR)
143
What features point towards a diagnosis of LADA?
* Usually more prominent osmotic features although often not insulin requiring for few years post diagnosis * Obesity is not a predisposing factor but presence of obesity does NOT exclude LADA * May have other autoimmune history/ FH * Auto antibodies (GAD/Islet cell) often present * Can initially be difficult to distinguish from T2DM- often need to observe over tim
144
What education should be given to diabetic patients regarding hypoglycaemia?
* Recognising symptoms (tremor, sweating, palpitations, blurred vision, confusion, drowsiness) * Understand how to treat i.e 15-20g fast acting carbohydrate eg 5-6 dextrose tabs and recheck BG 15-20 mins later * It is important to stress insulin should NOT be withheld (never stop insulin) * Next dose of insulin should be given with appropriate carbohydrate * Patients should be encouraged to look for precipitants and account for them
145
How is PCOS defined?
* Not just ovarian morphology - on ultrasound 20-25% of women of reproductive age have polycystic ovaries * Heterogenous disorder of unclear aetiology * Complex interaction of metabolic, hypothalamic, pituitary, ovarian and adrenal mechanisms * Definitions have varied over years - changes prevalence * Current definition - clinical and/or biochemical signs of hyperandrogenism, oligo- and/or anovulation
146
What should be considered when determining the cause of hypoglycaemia?
1. Whipple's triad present? * Symptoms consistent with hypoglycaemia * Low plasma glucose concentration * Relief of symptoms after plasma glucose level raised 2. Ensure that there is definite (not HBGM) evidence of a low glucose level 3. Do symptoms occur in the fasting or postprandial state * Diagnostic strategy is to replicate conditions in which hypoglycaemia would be expected 4. Take a full past medical history, family history and drug history 5. Ill/medicated individual vs seemingly well individual
147
What causes pancreatic diabetes?
1-2% of DM (often unrecognised) Caused by pancreatectomy, pancreatitis (alcohol excess, gallstones), haemochromatosis (liver disease, cardiomyopathy, pituitary disease), carcinoma, cystic fibrosis Risk of hypos higher than T1DM as loss of alpha cells that produce glucagon
148
Describe the mechanism of action of DDP-4 inhibitors (gliptins)
* Oral glucose stimulates the release of the endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin-releasing polypeptide (GIP) * Stimulate insulin release and inhibit glucagon release resulting in lower blood glucose * Rapidly inactivated by dipeptidyl peptidase-4 (DPP-4) * Inhibit DPP-4 and enhance effects of endogenous incretins (e.g. GLP-1) * Increase glucose-mediated insulin secretion, suppress glucagon secretion
149
What are the clinical features of male hypogonadism in an adult?
* Depression/low mood * Poor libido * Erectile problems * Poor muscle bulk/power * Poor energy * Sparse body/facial hair * Gynaecomastia * Gynoid weight gain * Great head hair * Short phallus * Small testes - abnormal consistency
150
List the clinical features of adrenal insufficiency
* Anorexia, weight loss * Fatigue/lethargy * Dizziness and low BP * Abdominal pain, vomiting, diarrhoea * Skin pigmentation (in palmar creases/buccal mucosa) * Electrolyte abnormalities - aldosterone
151
How is a biphasic mixed insulin regimen carried out?
* Given twice per day * Short acting component in the morning covers breakfast and lunch * Short acting component in the evening covers evening meal and snack before bed * Long acting component of both insulins cover basal insulin requirements * Mealtimes should be at relatively fixed times in order to minimise hypoglycaemia and coincide with peak action of short acting insulin * Dose does not vary and while easier to administer, more difficult to achieve optimal glycaemic control without hypoglycaemia
152
What are the main features of pancreatic diabetes?
* History of cause (sometimes alcohol history), exocrine dysfunction * May have ketones and be acidotic * C peptide low but often detectable * Pancreatic antibodies negative * May require imaging * Managed by SU +/- insulin
153
List the symptoms of thyrotoxicosis
* Weight loss * Increased appetite * Tremor * Oligomenorrhoea * Polyuria * Weakness * Fatigue * Diarrhoea * Insomnia * Anxiety * Change in heat preference - cold not hot
154
What investigations should be done in the diagnosis of PCOS?
* Confirm profile of PCOS * Testosterone * Androstenedione * DHEAS * SHBG * FSH/LH * Assess for other features * Type 2 diabetes * Abnormal lipids * Exclude other pathologies
155
Compare the features of T1DM vs T2DM
* Weight * Lean in T1DM, overweight or obese in T2DM * Duration of symptoms * Weeks in T1DM, months/years in T2DM * Higher risk ethnicity * Northern European in T1DM, Asian, African, Polynesian and Native American in T2DM * Seasonal onset * Yes T1DM, no T2DM * Hereditary * HLA DR3/4 in 90% T1DM, no HLA links in T2DM * Pathogenesis * T1DM autoimmune, no immune disturbance in T2DM * Ketonuria/ketonaemia/acidosis * Common in T1DM, uncommon in T2DM * Clinically * T1DM - insulin deficiency, +/- ketoacidosis, dependent on insulin for survival * T2DM - partial insulin deficiency at presentation, +/- hyperosmolar state, may need insulin * Biochemistry/immunology * T1DM - c-peptide inappropriate/negative, GAD antibody positive * T2DM - c-peptide elevated, GAD antibody usually negative
156
What causes primary gonadal disease?
* Complex genetic syndromes e.g. myotonic dystrophy * Chromosomal defects e.g. Klinefelter's syndrome * Seminiferous tubule failure/adult Leydig cell failure * Trauma e.g. torsion * Chemotherapy * Radiotherapy * Multisystem disorders e.g. haemochromatosis * Cryptorchidism
157
Describe the structure of the zona reticularis
* Smaller cells, haphazard arrangement * Stain darker, less lipids
158
What can cause TFTs to not be in agreement with clinical findings?
In very unwell patients e.g. in ICU a pattern of 'sick euthyroidism' is often seen w/ low TSH levels, low free T3 and sometimes low fT4 levels Tests should be interpreted carefully with consideration of the patient's condition and should be repeated after the patient has recovered
159
What are the goals of therapy in T2DM?
* Reducing rates of microvascular complications * Retinopathy, nephropathy, foot disease (ulceration) * Cardiovascular safety * Minimum requirement of treatments (FDA 2008) * Reducing rates of macrovascular complications * Myocardial infarction, stroke, heart failure, peripheral vascular disease
160
What is the purpose of a 72 hour fast test? What is measured?
* Provoke the homeostatic response that keeps blood glucose concentrations from falling to concentrations that cause symptoms in the absence of food (Glucagon, Adrenaline, GH, Cortisol ) * Complete at plasma glucose at 2.5 mmol/L, 72 hours have elapsed or when plasma glucose is \< 3 if Whipple’s triad previously documented * Measurements * Glucose * Insulin - should be undetectable in hypoglycaemia, detectable means insulin excess * C peptide - measure C-peptide to determine if endogenous insulin excess (C-peptide detectable) or exogenous insulin excess (accidental or deliberate insulin injection - doesn't contain C-peptide) * SU screen - sulphonylureas cause endogenous insulin excess, hypoglycaemia * Beta hydroxybutyrate - ketone body, produced in starvation, if low hypoglycaemia not due to starvation * Insulin antibodies (taken at any time - equivocal) - autoimmune cause * Gut peptides chromagranin A73 (0-60) - tumour marker
161
List the causes of spontaneous hypoglycaemia
* Pancreatic * Insulinoma * Non-insulinoma pancreatogenic hypoglycaemia (NIPH) - nesidioblastosis * Non-Islet cell tumour hypoglycaemia * IFG II secreting tumours (mesenchymal tumours, carcinomas of the liver, stomach and adrenals) * Lymphoma, myeloma, leukaemia * Metastatic cancer * Autoimmune hypoglycaemia * Autoimmune insulin syndrome * Anti-insulin receptor * Reactive hypoglycaemia * Post gastric surgery * Alcohol provoked reactive hypoglycaemia * Drug induced * Insulin * Sulphonylurea * Repaglinide * Salicylates * Quinine * Haloperidol * Beta blockers * Indomethacin * Lithium * Heparin * Trimethoprim * Pentamidine * Disopyramide * Dietary toxins * Alcohol * Mushrooms causing acute liver failure * Organ failure * Severe liver disease * End stage renal disease and renal dialysis * Congestive cardiac failure * Endocrine disease * Hypopituitarism * Adrenal failure * Hypothyroidism * Inborn errors of metabolism * Miscellaneous * Sepsis * Starvation * Anorexia nervosa * Total parenteral nutrition * Severe excessive exercise
162
What considerations should be made when prescribing T2DM therapies in renal disease?
Prevalence of CKD in T2D: * Over 1/3 of people with T2D have impaired kidney function (CKD stage 2-5) Prescribing considerations in renal disease: * Stop metformin when eGFR \<30 * Caution with SUs as increased risk hypoglycaemia * Dose reduction required for some tides and gliptins * SGLT2 inhibitors less effective at glucose lowering in CKD (eGFR \>60) * Renal protection with CANA
163
What education should be given to diabetic patients about sick day rules?
* Never stop insulin * Basal insulin (as part of basal bolus regime) can be continued even if not eating and drinking * However, insulin and carbohydrate are required in order to prevent ketoacidosis therefore patients who are vomiting often require in patient admission for intravenous treatment * Acute illness can potentially increase insulin requirements * Correction doses can be given if patients are on basal bolus regimes, but close monitoring of BMs and urine or capillary ketones are important.
164
Describe the histological layers of the adrenal glands
* Mature adipose tissue surrounds for protection * Fibrous capsule * Zona glomerulosa * Zona fasciculata * Zona reticularis * Medulla
165
Should a patient with suspected diabetes be treated while awaiting investigation results?
Important to exclude DKA first - should be a rapid process Once diabetes confirmed and DKA excluded, treatment would be reasonable Results of investigations not likely to alter short term management plan
166
Describe the structure of the adrenal medulla
* Chromaffin cells, medullary veins, splanchnic nerves * Rounded cords with large secretory cells * Blood from capillaries/sinusoids of cortex and arterioles from capsule
167
Describe glucose targets in T1DM
* Individualised and person * HbA1c \<53mmol/L * Before breakfast 5.5-7mmol/l * Before other meals 4.5-7.5mmol/l * Before bed 6.5-8mmol/l * Aim for glucose to rise \<2mmol/l 2 hours post bolus
168
What are the functions of the testes?
* Testosterone production (Leydig cells) * Spermatogenesis (spermatocytes, Leydig and Sertoli cells)
169
Why can carbimazole not be used in early pregnancy?
Teratogenic - can cause skull defects in 1st trimester
170
When is a radioactive iodine uptake scan used in the diagnosis of thyroid disease?
If antibodies negative but symptomatic/nodular thyroid
171
How does thyroglobulin become converted to active hormone?
* Colloid enveloped by microvilli on cell surface (endocytosis) to form colloid vesicles within cells, fuse with lysosomes * Enzymes in lysosomes break down iodinated thyroglobulin, releasing T3/4 * T3/4 pass across basal cell membrane into capillary (T4\>T3)
172
Compare hypo- and hyperthyroidism
* Hypothyroidism = low TH * More common and more difficult to treat * Hyperthyroidism = excess TH
173
What would typically be seen in terms of clinical features, on examination and investigations in a patient presenting with pancreatic diabetes?
* Clinical features * Symptoms - thirst, polyuria, polydipsia, symptoms of exocrine insufficiency e.g. diarrhoea, malnutrition, weight loss * Low BMI * History of previous alcohol excess/other pancreatic risk factors * Examination * Thin, dehydrated, tachycardic * Investigations * High glucose * HbA1c high/normal (acute onset) * K+ high (insulin deficiency) * Bicarbonate low (acidotic) * C-peptide low or undetectable * Faecal elastase low (pancreatic exocrine insufficiency) * GAD antibodies negative
174
Describe the WHO criteria for diabetes diagnosis
* Fasting plasma glucose of \>7.0 mmol/L * Random plasma glucose of \>11.1 mmol/L * One abnormal value diagnostic if symptomatic * Two abnormal vaueus diagnostic if asymptomatic * HbA1c 6.5% or 48mmol/mol (pitfalls) * Average glucose over 2-3 months - if acute onset can be normal in diabetes * Diabetes should not be diagnosed on the basis of glycosuria or a BM stick * OGTT only required for diagnosis if gestational diabetes mellitus or impaired fasting glycaemia
175
How is the thyroid be examined by palpation?
Feel for thyroid cartilage ('Adam's apple'), below is the isthmus of the thyroid, either side are the L and R lobes of the thyroid Lumps/bumps or palpable thyroid can be normal and is common
176
What aids can be used in the diagnosis of diabetes?
Ketone testing +/- bicarbonate Pancreatic autoantibodies C-peptide testing
177
What investigations should be done in suspected thyroid cancers?
* TFT * Imaging * Fine needle aspiration
178
How is congenital hypothyroidism diagnosed?
Screening (heel-prick) in the first week of life
179
Describe the mechanism of action of steroid hormones
* Diffuse through plasma membrane * Bind to intracellular cytosolic receptor - steroid receptor * Receptor-hormone complex moves into nucleus, binds to glucocorticoid response element (DNA sequence) in 51 flanking region of target genes * Binding causes gene transcription of mRNA sequences, translation produces proteins which modulate the response
180
How is late onset congenital adrenal hyperplasia diagnosed?
Synacthen test with 17 alpha hydroxyprogesterone
181
Which hormones are produced by each part of the adrenal glands?
* Cortex * Zona glomerulosa - mineralocorticoids e.g. aldosterone * Zona fasiculata - glucocorticoids e.g. cortisol * Zona reticularis - adrenal androgens e.g. DHEA, DHEAS * Medulla * Catecholamines - adrenaline, noradrenaline
182
Define hirsutism
Excess hair growth in a male pattern due to increased androgens and increased skin sensitivity to androgens
183
List types of insulin preparations
* Rapid-acting analogue * Short-acting (soluble) * Intermediate acting * Long-acting analogue * Rapid acting analogue-intermediate mixture * Short acting-intermediate mixture
184
What education should be given to diabetic patients regarding driving?
* The DVLA require to be informed when patient commence insulin treatment * There are a number of additional requirements for patients treated with insulin * Check BG before every car journey and every 2 hours if on a long journey * Have capacity to check BG when driving and fast acting carbohydrate to treat hypo if occurs * In event of hypo, move out of drivers seat and treat, only returning to drive 45m after BG returned to normal
185
How is Cushing's syndrome managed?
* Surgical - removal of ACTH source * Transphenoidal pituitary surgery * Laproscopic adrenalectomy * Medical - metyrapone/ketaconazole - inhibit cortisol production, short-term
186
How is a basal bolus insulin regimen carried out?
* Given at least 4 times per day * Basal (long acting) insulin is given once or sometimes twice per day depending on the formulation * Bolus doses of fast acting insulin are given with carbohydrate containing meals * If patients are not eating carbohydrate, bolus doses are not given * If snacks containing significant doses of carbohydrate are taken, patients should take additional bolus insulin * This regime gives greater flexibility regarding mealtimes and carbohydrate ingestion but does require additional input from patient (multiple injections, multiple BG testing).
187
How are thyroid autoantibody tests interpreted?
* Markers of autoimmune thyroid disease * Anti-TPO antibodies present in 45-80% of Grave's disease and 80-95% of Hashimoto's disease/atrophic thyroiditis * Anti-TSH receptor antibodies are the most reliable test for diagnosing Grave's disease (cause Grave's disease)
188
What causes Hashimoto's thyroiditis?
* Autoantibodies against thyroid perioxidase, thyroglobulin and TSH * Activation of CD8+ T cells in response to cell mediated immune response affected by CD4+ T cells - thyrocyte destruction * Type 4 hypersensitivity
189
List the pharmacological treatments of T2DM
1st line: Metformin but sometimes SU 2nd line: Two oral agents (add SU, Flozin, Gliptin, Glitazone) 3rd line: Three agents (add any of the above OR start injectable therapy with GLP-1 agonist or insulin) 4th line: Four agents from list above
190
Describe the aetiology of Grave's disease
* Autoimmune disease - associated diseases in family * Genetic susceptibility (HLA, TG, thyroid receptor) * Environmental - iodine, tobacco smoke * Smoking especially important in pathogenesis of thyroid eye disease, especially in women * Immune modulating treatment - interferon, alemtuzumab (anti CD52 mAb)
191
What features point towards a diagnosis of type 2 diabetes?
Usually occurs in over 40’s Gradual Onset Often few or absent symptoms Typically overweight or obese with features of insulin resistance Family history of diabetes is common
192
What investigations should be done in a patient presenting with hyperthyroidism?
Thyroid function tests - TSH, fT4, tT3 (would expect low TSH, high fT4 and tT3 in hyperthyroidism) Thyroid autoantibodies (Ab): Thyroid receptor (TRAb), Thyroid peroxidase (TPO Ab) Pregnancy test? \*\*Also consider if felt clinically appropriate: FBC / ESR: can be elevated with a thyroiditis 24h urine collection for metanephrines: a negative result helps exclude a phaeochromocytoma 24h urine collection for 5 HIAA: a negative result helps exclude carcinoid syndrome Liver function tests: can be abnormal in alcohol excess Urine toxicology: consider if substance misuse suspected. Nuclear imaging in the diagnosis of thyrotoxicosis Thyroid scintigraphy scanning with technetium-99m or Iodine -131 is useful when antibody testing is negative, a nodule is palpable, or thyrotoxicosis without hyperthyroidism is suspected.
193
List the symptoms of carcinoid syndrome
Symptoms of carcinoid syndrome (serotonin metabolite release): * Flushing * Diarrhoea * Asthma * Right heart valvular lesions
194
What are the signs/symptoms of classical thyrotoxicosis?
* Weight loss * Tremor * Heat imbalance * Diarrhoea * Tachycardia * Hypertension * Palpitations * Sweating
195
How is hyperthyroidism treated?
* Thionamides - carbizamole, propylthiouracil * Carbizamole - drug of choice, absorbed well from gut, converted to methimazole via 1st pass metabolism, half life = 12-15 hours * Propylthiouracil - less active, shorter half-life, higher dose needed - 2nd line or in pregancy * Beta-blockers e.g. propanolol - reduces sympathetic symptoms, no hormonal effect * Potassium iodide - reduced TH released acutely * Radioactive iodine * Surgery - thyroidectomy (partial or total)
196
Describe circulating thyroid hormone
* Free 0.5%, bound 99.5% * Free is active and regulated * Bound is bound to thyroid binding globulin, transthyretin and albumin * T4 converted to T3 by deiodination from outer ring in periphery * Catalysed by selenodiodinase enzymes (D1 in liver, kidney, muscle, D2 in brain, pituitary)
197
What are the functional units of the thyroid gland?
* Follicles - epithelial structures * Single layer of cuboidal epithelium with basement membrane, colloid in centre * Store thyroglobulin (iodinated glycoprotein) - storage form of T3/4
198
How can the cortisol source be identified in Cushing's disease?
* Plasma ACTH * If low then adrenal source * High dose dexamethasone suppression test * If pituitary, cortisol will suppress to \<50% * No response in ectopic ACTH * CRH test * Exaggerated response in pituitary disease * No response in ectopic ACTH * Imaging * Adrenal CT or MRI * Pituitary MRI only detects 50% of ACTH producing pituitary tumours Optimal imaging for ectopic tumours unclear (CT/PET/MRI)
199
List the clinical features of Addison's disease
* Anorexia * Weight loss * Pre-syncope * Low BP (postural hypotension) * Abdominal pain * Vomiting * Diarrhoea * Skin pigmentation
200
How is an adrenal adenoma treated?
Laparoscopic adrenalectomy Short term requirement for hydrocortisone replacement therapy
201
Describe the features of medullary thyroid cancer
3% of total Cancer of parafollicular (calcitonin) producing thyroid cells Familial
202
How is glucose monitoring done in T1DM?
* 4 times per day * Before each meal and before bed * Additionally if feel unwell/hypoglycaemic * Finger prick * 30% now use flash glucose monitoring (Libre) - device just under skin measures interstitial glucose (v close to capillary glucose), scan to give graph of overall trends in glucose levels, no pin prick needed
203
Describe the prevalence of phaeochromocytomas
Rare, 2-8/million cases per year
204
Define adrenal incidentalomas
Incidentally discovered adrenal lesion discovered through diagnostic imaging for unrelated condition, without prior suspicion of tumour/disease Prevalence 0.2-7%
205
How is hypothyroidism managed?
* Thyroid hormone replacement – Levothyroxine usually starting at 50-100mcg (25mcg where there is a concern of ischaemic heart disease) and titrating in 25mcg increments aiming for a normal TSH * There may be a time lag from TSH being in the normal range to clinical improvement
206
How can hypogonadism be treated?
* Androgen replacement therapy * Oral * IM * Topical * Fertility treatment * HCG * Recombinant LH + FSH * GnRH pumps
207
What are the symptoms/signs of a phaeochromocytoma?
* Hypertension (intermittent in 50%) * Episodes of headache, palpitations, pallor and sweating * Also tremor, anxiety, nausea, vomiting, chest or abdo pain * Crises last 15 minutes * Often well between crises
208
Describe the mechanism of action of ACTH
* Binds to 7TMD G protein coupled receptor * Conformational change - adenyl cyclase, increases cAMP, PKA activation, Ca2+ influx * Rapid and long-term actions * Rapid - stimulation of cholesterol delivery to mitochondria * Long-term - transcription of genes coding for steroidogenic enzymes * Increases cortisol/androgen production
209
What are the risk factors for hypothyroidism?
* Female * Age * Genetic predisposition (autoimmune) * Drugs e.g. lithium
210
How is Cushing's syndrome diagnosed?
1. Is cortisol elevated? * Perform two of the following: * 24hr urinary free cortisol * Urine cortisol:creatinine ratio x3 * Dexamethasone suppression test * Either overnight or low dose test over 48 hours * Plasma cortisol should be undetectable in normal circumstances * Late night salivary cortisol 2. ACTH dependent or independent * Measure ACTH * High ACTH - ACTH dependent * Pituitary adenoma (68%) - Cushing's disease * Ectopic ACTH (12%) * Ectopic CRH (\<1%) * Low/normal ACTH - ACTH independent * Adrenal adenoma (10%) * Adrenal carcinoma (8%) * Nodular hyperplasia (1%)
211
Describe the innervation of the adrenal glands
Coeliac plexus and thoracic splanchnic nerves (innervate chromaffin cells)
212
How is Klinefelter's syndrome treated?
Androgen replacement +/- psychological support +/- fertility counselling
213
Define MEN1
Autosomal dominant predisposition to tumours of parathyroid, anterior pituitary and enteropancreatic endocrine cells Clinically defined when \>2 primary MEN1 tumour types occur
214
What education should be given to diabetic patients regarding exercise and alcohol?
* Both can affect BG * Short term increase with alcohol due to carb content followed by BG lowering effect of alcohol * Exercise can have variable effect but most likely to increase insulin sensitivity and increase risk of hypo
215
What is the difference between primary and secondary amenorrhoea?
* Primary - never had a period * Secondary - previously had periods but have stopped for \>6 months
216
Describe the mechanism of action of GLP-1 receptor agonists
* Oral glucose stimulates the release of endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin-releasing polypeptide (GIP) * Stimulate insulin release and inhibit glucagon release resulting in lower blood glucose * Rapidly inactivated by dipeptidyl peptidase-4 (DPP-4) * GLP-1 receptor agonists increase glucose mediated insulin secretion, suppress glucagon secretion * Increase satiety and suppress appetite
217
What investigations should be done in suspected carcinoid syndrome?
Urinary 5-HIAA - elevated Gut peptide profile Cross sectional imaging of chest/abdomen/pelvis Somatostatin receptor scintigraphy (SRS) - localisation/spread
218
Describe the prognosis of phaeochromocytomas
15-20% malignant - 5 year survival \<50% 80-85% benign - recurrence rate \<10% and 5 year survival 96%
219
Which diseases are often associated with Addison's disease?
Other autimmune diseases e.g. T1DM, thyroid, pernicious anaemia
220
List the symptoms of carcinoid syndrome
Flushing, diarrhoea
221
Describe the venous drainage of the thyroid gland
* Superior, middle and inferior thyroid veins - form venous plexus * Supeior and middle drain to internal jugular vein * Inferior drains to brachiocephalic vein
222
What factors can contribute to the development of hyper/hypoglycaemia?
* Administration of insulin * Dose of insulin * Illness * CHO counting * Injection sites * Exercise and alcohol * Early or later pregnancy * Pump failure
223
Describe the process of spermatogenesis
In seminiferous tubules of testes - spermatozoa at basement membrane develop into mature sperm at lumen
224
What is measured in thyroid function tests?
TSH 0.4-5mU/l Free thyroxine (fT4) 9-21pmol/l Total thyroxine (T4) 60-160 nmol/l Free triiodothyronine (fT3) 0.9-2.5pmol/l Total triiodothyronine (T3) 1.2-2.6 nmol/l
225
How do androgens contribute to the pathophysiology of PCOS?
* All synthesised from cholesterol * DHEA, androstenediol, androstenedione, testosterone, dihydrotestosterone elevated in PCOS * Increased androgen production from theca cells of ovary under influence of LH * Disordered enzyme action * Ovarian enzyme expression * Peripheral conversion * Decreased SHBG * Produced in liver, binds testosterone * Only free testosterone is biologically active * Hyperandrogenism * Hyperinsulinaemia
226
Compare cortisol and aldosterone concentration
* High concentration of cortisol compared with aldosterone * Cortisol converted to cortisone (inactive), catalysed by 11 beta-hydroxysteroid dehydrogenase in selected tissues e.g. kidneys to allow aldosterone to function
227
What localising studies can be done in hypoglycaemia?
* Radiology * CT/ MRI abdomen / pancreas l * EUS * Arterial Calcium Stimulation * Distinguishes focal (Insulinoma) from diffuse disease (nesidioblastosis/islet cell hypertrophy) * Used when endogenous hyperinsulinaemic hypoglycaemia & negative imaging. * Injection of calcium gluconate into gastroduodenal, splenic and superior mesenteric artery with sampling of hepatic venous insulin levels (double or tripling of basal insulin concentrations)
228
How is hormone production in the adrenal gland regulated?
* Androgens regulated by ACTH * Glucocorticoids regulated by ACTH * Mineralocorticoids regulated RAS
229
What is the function of the thyroid gland in calcium homeostasis?
* Thyroid C/parafollicular C cells - in follicles and between follicles * Secrete calcitonin - decreases serum Ca2+
230
What would investigations show in primary gonadal disease?
Low testosterone Normal/high LH/FSH Normal prolactin
231
How is insulin administered in T1DM?
* Usually prefilled pens * 10-15% use insulin pump * Insulin sent under skin using wire * Short acting insulin - can quickly adjust basal rate of insulin throughout day (exercise, illness)
232
What is required for male fertility?
Testicular function and erectile function (includes blood flow, nerves etc.) Intact relationship between testes, epididymis, vas deferens, seminal vesicles, prostatic urethra, penile urethra + erectile function
233
Describe the presentation of congenital adrenal hyperplasia in males and females. How is this treated?
* Female * Ambiguous genitalia - increased adrenal androgen production * Not enough cortisol/aldosterone being produced, ACTH produced to try to stimulate production * Adrenal androgens still being produced, excess ACTH causes adrenal androgens to build up * Male * Adrenal crisis (hypotension, hyponatraemia) * Early virilisation (development of male secondary sex characteristics) Treated with mineralocorticoid and glucocorticoid replacement
234
How does radioactive iodine function to treat hyperthyroidism?
* Destroys thyroid tissue by beta emission * May worsen eye disease * Defer conception (at least 4 months), pregnancy = contraindication * Hypothyrodism is main side effect - may be transient
235
Why does skin pigmentation occur in Addison's disease
High levels of ACTH (no negative feedback) - bind to melanocortin 1 receptors on the surface of dermal melanocytes
236
What are other causes of amenorrhoea (besides primary and secondary)?
* Physiological * Pregnancy * Lactation * Iatrogenic * OCP or other hormonal contraceptives * Thyroid dysfunction * Hypothyroid - heavy irregular periods * Hyperthyroid - amenorrhoea * Hyperandrogenism * Cushing's syndrome * CAH * Adrenal or ovarian tumour
237
Describe the mechanism of action of SGLT2 inhibitors (flozins)
Inhibit SGLT2 in the proximal convoluted tubule of the kidney Decreases renal reabsorption of glucose May be useful in many circumstances
238
What are the benefits vs risks of DPP-4 inhibitors?
Benefits: * Low/moderate efficacy * 0.5-1% reduction HbA1c * Low hypo risk * Few adverse events Risks: * Weight neutral * No CV benefit * Reduce dose in CKD
239
Describe the presentation of PCOS
* Classic presentation is with symptoms of * Anovulation (amenorrhoea, oligomenorrhoea, irregular cycles), associated with symptoms of hyperandrogenism (hirsutism, acne, alopecia) * However spectrum of presentation includes anovulatory women without hirsutism and hirsute women with mainly regular cycles * Typically presents during adolescence * Typical endocrine features are raised testosterone and LH * Also associated with metabolic abnormalities and increased risk of type 2 diabetes
240
In which situations is the use of HbA1c in the diagnosis of diabetes not useful?
* Children/ young adults (more likely to have Type 1 which typically has rapid onset * Recent use of medication likely to increase plasma glucose acutely * Acute pancreatic damage * Acute illness (Could be stress hyperglycaemia) * Symptoms have been present for \<2months In this case, diagnosis could be could be “stress hyperglycaemia”, so requires confirmatory testing
241
Give examples of the proposed environmental risk factors for the development of T1DM
* Viral infections, particularly enterovirus infections * Immunisations * Diet, especially exposure to cow's milk at an early age * Higher socioeconomic status * Obesity * Vitamin D deficiency * Perinatal factors such as maternal age, history of preeclampsia, neonatal jaundice and low birth weight (reduced risk)
242
Describe dermopathy in Grave's disease
* Infiltrative dermopathy, waxy discoloured induration of the skin (peau d'orange) * Begins in feet/lower legs, spreads upwards in advanced cases
243
Describe the causes of Cushing's syndrome
* ACTH dependent * Pituitary adenoma (68%) * Ectopic ACTH - carcinoid/oma * Ectopic CRH * ACTH independent * Adrenal adenoma * Adrenal carcinoma * Nodular hyperplasia
244
What causes hyperthyroidism?
* Autoimmune - Grave's disease * Toxic adenoma - benign hormone-producing tumour * Multinodular goitre * Thyroiditis (transient) * Excess administration of thyroxine (? weight loss) - high T4, low TSH
245
Describe the mechanism of action of thiazonlidinediones (glitazones)
* PPAR gamma-receptor agonists * Increase sensitivity of fat muscles, and liver endogenous and exogenous insulin * Decreased lipolysis, increased muscle glucose uptake, reduced hepatic glucose production * Increase transcription of GLUT-4 glucose transporters that directly facilitate glucose uptake
246
How is prescription of T2DM therapies decided?
Need to balance symptom control/prognosis with side effects/adherence to medication - aim of treatment is to prescribe treatment when the balance is in favour of improving outcomes.
247
What is the cause of Klinefelter's syndrome?
XXY (but other sex chromosome variations exist) High LH and FSH but seminiferous tubules regress and Leydig cells do not function normally - high oestrogen in response to FSH/LH
248
Describe the pathogenesis of T2DM
* Chronic, progressive metabolic disorder characterised by hyperglycaemia, insulin resistance and relative impairment of insulin deficiency * Common with a prevalence that rises markedly with increasing levels of obesity * Most likely arises through complex interaction among many genes (polygenic) and environmental factors
249
Describe the general pathophysiology of PCOS
Gonadotrophins + androgens + insulin resistance
250
Describe the embryological origin of the adrenal glands
* Cortex - genital ridge (mesoderm) * Medulla - neural crest (sympathetic nerve system) - ectoderm
251
List older and newer T2DM therapies
* Older * Metformin * SU's * Glitazones * Insulin * Newer * DPP-4 inhibitors - 'gliptins' * GLP-1 receptor agonists - 'tides' * SGLT 2 inhibitors - 'flozins'
252
Describe the arterial supply of the adrenal glands
* Superior adrenal artery - inferior phrenic artery * Middle adrenal artery - abdominal aorta * Inferior adrenal artery - renal arteries
253
Describe the natural progression of subacute thyroiditis with thyrotoxicosis
Thyrotoxicosis is usually transient (approx. 10-20 days) and followed by hypothyroidism (days 30-63)
254
How is hypothyroidism diagnosed?
Measure - free T4, TSH, thyroid autoantibodies
255
Describe Grave's ophthalmopathy
* Swelling in retrobulbar area due to glycosaminoglycan accumulation * Lid retraction/lag and periorbital oedema * Proptosis (protrusion), diplopia, nerve compression * Potentially sight threatening
256
What is the effect of insulin resistance in PCOS?
* Insulin sensitivity decreases with increasing BMI - exacerbated in PCOS * Overweight/obese women with PCOS are more symptomatic * Higher prevalence of oligo/amenorrhoea and hirsutism * Increased insulin in response to glucose load * Increased insulin resistance * Cause vs association * Insulin stimulates theca cells of ovaries * Insulin reduces hepatic production of SHBG * Increased circulating androgens
257
How is primary aldosteronism managed?
* Surgical * Unilateral laparoscopic adrenalectomy * Only if adrenal adenoma * Cure of hypokalaemia * Cures of hypertension in 30-70% cases * Medical * Use MR antagonists (spironolactone or eplerenone)
258
How can the complications of T2DM be prevented?
* Microvascular disease * Glycaemic control * Macrovascular disease * Glycaemic control * Conventional CV risk factors (smoking, BP, cholesterol)
259
To what extent is T1DM passed on genetically in families?
Lifetime risk of developing T1DM * No family history - 0.4% * Offspring of an affected mother - 1-4% * Offspring of an affected father - 3-8% * Offspring with both parents affected - reported as high as 30% * Non-twin sibling of an affected patient - 3-6% * Dizygotic twin - 8% * Monozygotic twin - 30% within 10 years of diagnosis of the first twin and 65% concordance by age 60 years
260
How is an ectopic ACTH producing NET managed?
* Endocrinologist - control cortisol excess and sequelae (diabetes, blood pressure, electrolytes, infection, thrombosis and poor wound healing) * Surgery * Oncologists
261
What is the role of adrenal androgens? How is their production regulated?
* Zona reticularis produces adrenal androgens * In men gonads produce most androgens * Physiological role of adrenal androgens not fully understood - important in some pathological states * Probably under control of ACTH - diurnal rhythm
262
List the features of thyroid eye disease
* Exophthalmos (proptosis) * Risk of corneal ulceration from proptosis * Tape eyelids shut at night? * Wear glasses during treatment * Lid lag * Upper eyelid retraction * Changes in colour vision * Urgent referral to ophthalmology * Compression of optic nerve due to swelling of extra-ocular muscles * Sight threatening
263
What are the benefits vs risks of thiazodinediones (glitazones)?
Benefits: * Moderate efficacy * Probably CV protection * Low hypo risk * Past experience Risks: * Weight gain * Fluid retention - can't use in heart failure * Fractures * Not usually used anymore
264
How is adrenal insufficiency managed?
* Hydrocortisone as cortisol replacement * If unwell IV * Then 15-30mg daily - split dose (oral tablets) * Mimic diurnal rhythm * Fludrocortisone as aldosterone replacement * Monitor BP and plasma K+ * Education - increase dose when unwell * Cannot stop suddenly * Need identification to show long-term steroid treatment
265
How can you test for male hypogonadism?
* Sex steroid deficiency? * Testosterone * Early morning - circadian rhythm (do you get morning erections?) * Free testosterone \>200 * Total testosterone \>16 * SHBG * LH and FSH * Help determine possible pituitary cause * Fertility? * Semen analysis * 1-3 days after last ejaculation * 2-5ml volume * 20 x 10^6 sperm/ml * 50% progressive motility * \>30% normal morphology
266
List the types of diabetes
Multiple distinct and overlapping phenotypes * Type 2 diabetes mellitus - 90% * Type 1 diabetes mellitus - 5% * Pancreatic diabetes mellitus * Maturity onset diabetes of the young (MODY) * Latent autoimmune diabetes in adults (LADA)
267
How are those with T1DM educated on managing their condition?
Should be given education on: * Administration of insulin * Glucose/ketone monitoring * Sick day rules * Hypoglycaemia * Driving regulations e.g. test before driving - 5mmol/L to drive * Exercise and alcohol - alcohol raises blood glucose short term then it falls * Pregnancy - aim for HbA1c \<7% pre-conception for best maternal/baby outcomes * Targets * Complications * CHO Counting: DAFNE = dose adjustment for normal eating Course to give education and advice on managing T1DM and diet Also digital education for children/young people
268
Describe the clinical manifestations of Klinefelter's syndrome
* Wide clinical variation in phenotype due to hormonal response to LH surges * Delayed puberty * Suboptimal genital development * Reduced secondary male sexual characteristics * Persistent gynaecomastia * Azoospermia * Behavioural issues/learning difficulties * Clinically manifests at puberty
269
Describe the synthesis of thyroid hormones
* Need iodine - seawater, fruit, vegetables * Oral iodine converted to iodide in GI tract and absorbed * Iodide transported into follicular cells against chemical gradient on basolateral membrane by sodium iodide transporter (thyroid symporter) - active transport, inhibited by perchlorate * Iodide diffuses to apex, prendrine transports into vesicles at apical membrane * Oxidation of iodide to iodine in vesicles, catalysed by thyroid peroxidase * Binds to tyrosine residues on thyroglobulin = organification * Formatioin of di/mono-iodotyrosine (T3/4), endocytosis of thyroglobulin into cell
270
How is Cushing's syndrome diagnosed?
* Establish cortisol excess * Dexamethasone suppression testing * 24 hr urinary free cortisol * Late night salivary cortisol * Establish course of cortisol excess * Measure ATCH * Undetectable - adrenal scan * Normal/high - CRH stimulation test * No change - CT chest/abdomen/pelvis - ectopic * Exaggerated rise in ACTH - pituitary MRI
271
What causes congenital hypothyroidism?
* Thyroid dysgenesis (85%) * TSH receptor * Dyshormonogenesis * Thyroid peroxidase * Thyroglobulin * Sodium iodide symporter * Pendrin (Pendred syndrome)
272
What is the function of Sertoli cells?
* Blood-testis barrier - protects sperm from immune destruction * Remove damaged spermatocytes * Secrete androgen binding protein - locks testosterone into testes (testosterone levels much higher in testes than peripherally)
273
Describe the mechanism of action of metformin
* Major effect is to suppress hepatic gluconeogenesis, reducing glucose output from liver * Also increases peripheral insulin sensitivity, increasing glucose uptake and utilisation * Increase AMPK activity * Also has cardiovascular protective effects - can't be fully explained
274
What are the actions of the renin-angiotensin system?
Renin leads to production of angiotensin II - direct (vasoconstriction) and indirect (thirst/aldosterone) methods of increasing blood pressure
275
Define adrenal insufficiency
* Inadequate adrenocortical function * Primary insufficiency * Addison's disease - autoimmune (most common) * Autoimmune destruction
276
What is the genetic cause of medullary thyroid cancer?
Mutations of RET protooncogenes
277
Why is propylthiouracil used to treat hyperthyroidism in pregnancy?
Carbimazole (usually drug of choice) has adverse effects on newborns - skin conditions
278
How is colloid produced in thyroid follicles?
* Synthesise glycoprotein * Protein from RER, sugar added in Golgi * Convert iodide to iodine * Iodine + glycoprotein = thyroglobulin
279
Define hyperthyroidism
Thyroid activity resulting in thyrotoxicosis
280
Describe the embryonic origin of the thyroid gland
* Endodermal origin, forms in floor of primitive pharynx near base of tongue (thyroglossal duct) * Moves down through neck (and hyoid bone) to adult anatomical position * Foramen caecum at back of tongue is embryological remnant
281
Compare T3 and T4
* T4 - higher quantity released * Less active, like a prohormone * T3 - more active form, formed by peripheral deiodination of T4
282
How is adrenal insufficiency diagnosed?
* Suspicious biochemistry * Low Na, high K * Hypoglycaemia * Short synacthen test * Measure plasma cortisol before and 30 minutes after IV synthetic ACTH injection * Normal: baseline \>250nmol/l, post ACTH \>480 * ACTH levels * Should be high (cases skin pigmentation) * Renin aldosterone levels * High renin, low aldosterone * Adrenal autoantibodies
283
Describe the gross structure of the adrenal glands
* Endocrine glands (4-6cm, 6-8g) - rich blood supply * Pyramidal * Yellow due to high cholesterol * Outer cortex and inner medulla * Outer cortex - zones, secrete different hormones * Inner medulla - embryologically/histologically distinct
284
How is hypoglycaemia defined?
Patients with diabetes - hypoglycaemia defined by biochemical threshold of plasma glucose less than 4mmol/L In non-DM - documented plasma glucose \<3.0 mmol/L (some protocols lower)
285
What causes primary amenorrhoea?
* Genitourinary abnormalities * Congenital absence of uterus, cervix or vagina * Rokitansky syndrome - uterus absent * Androgen insensitivity syndrome - foetal structures there but don’t develop, resistance to androgens * Chromosomal abnormalities * Turner's syndrome (XO) * Secondary hypogonadism (pituitary/hypothalamic causes) * Kallman's syndrome * Pituitary disease * Hypothalamic amenorrhoea * Low BMI, stress illness
286
Describe the pre-operative treatment of phaeochromocytomas
* Alpha-blockage initially * Phenoxybenzamine or doxazosin * Aim for SBP \<120mmHg if possible * Postural drop * Then beta blocker if tachycardic * Labetalol or bisoprolol * Encourage salt intake
287
Give examples of methods of CHO counting for T1DM
* Only used in basal and bolus regimen * 500 rule: bolus insulin given as a ratio of UNITS to GRAMS of CHO (for example 1 unit for 10g CHO, calculated by 500 divided by total daily amount of insulin) * DAFNE use CHO portion = 10g * This is expressed as 1CP:1 unit, 1.5CP:1 unit, 2 CP: 1 unit * 100 rule - pre-bolus BM correction (to personal target) also given as ratio of units to anticipated drop in glucose (for example 1 unit to drop glucose 3 mmol/l, calculated by 100 divided by total daily amount of insulin)
288
How can depression and hypothyroidism be distinguished?
Explore other symptoms such as appetite, sleep pattern
289
How is Addison's disease diagnosed?
* Biochemistry - low Na+, high K+, hypoglycaemia * Short synacthen test * Measure plasma cortisol before and 30 minutes after ACTH injection * Normal - baseline \>250nmol/L, post-ACTH \>480nmol/L * ACTH level - high * Renin high, aldosterone lw * Adrenal autoantibodies
290
What are neuroendocrine tumours?
Rare tumours Affect cells (neuroendocrine cells) that can release hormones into the bloodstream Can be benign or malignant
291
What is thyroid acropachy?
* Rare * Digital clubbing, swelling of digits and toes - periosteal reaction of extremity bones * Usually with ophthalmopathy and dermopathy
292
Describe key aspects of management of T2DM relating to CV risk - what targets should used and what agents would you consider to achieve these?
* BP lowering * Hypertension in diabetes should be treated aggressively with lifestyle modification and drug therapy * Target diastolic \<80mmHg, target systolic \<130mmHg * Patients with diabetes requiring antihypertensives should be commenced on * An ACE inhibitor (ARB if ACE inhibitor intolerant), or * A calcium channel blocker, or * A thiazide diuretic * Antiplatelet * Good evidence lacking but aspirin is not currently recommended for primary prevention of vascular disease in patients with diabetes * Lipid lowering * Lipid-lowering drug therapy with simvastatin 40mg or atorvastatin 10mg is recommended for primary prevention in patients with type 2 diabetes aged \>40 years regardless of baseline cholesterol on the basis of evidence from large RCTs * Less good evidence for patients under 40 - if they have additional risk factors, lipid lowering therapy should be considered * Once treatment is commenced, target cholesterol should be \<5
293
In treatment of hypopituitarism which hormone must be replaced first?
* Somatotrophs lost first, thyrotrophs last * Cortisol is most important - always replace cortisol first
294
What are the important variables to consider in T2DM management?
* Patient socio-cultural context/preferences/motivation * Age * Duration of diabetes * Complications (macro, micro, hypo awareness) * HbA1c * BP * BMI * Current lifestyle
295
Describe the pathophysiology of autoimmune hypothyroidism
* Infiltration of CD4+ and CD8+ T cells, autoantibodies blocking TSH receptor/attacking thyroid peroxidase/Tg * Progressive destruction of thyroid follicular tissue
296
Describe the clinical features of Cushing's syndrome
* Euphoria (or depression/psychosis) * Hypertension * Buffalo hump * Thinning of skin * Wasting of arm + leg muscles * Easy bruising * Avascular necrosis of femoral head * Increased abdominal fat * Moon face and red cheeks * Cataracts * Striae
297
Why does transient gestational hyperthyroidism occur?
* In pregnancy beta HCG is high, last 13 amino acids are the same as TSH * 13 weeks gestation when HCG is highest - receptors in thyroid recognise HCG as TSH is stimulated to make more thyroid hormone * Causes transient gestational thyrotoxicosis * Treatment - IV fluids, beta blockers, anti-emetics (often accompanied by hyperemesis)
298
What signs would indicate primary aldosteronism?
* Commonest secondary cause of hypertension * Hypokalaemia - present in less than 50% of cases * Aldosterone-renin-ratio (ARR) best screening tool - increased in primary aldosteronism
299
Describe the innervation of the thyroid gland
Sympathetic trunk, doesn't control hormone secretion
300
Describe the action of thyroid hormone
* Nuclear receptors - cytosolic T3 transported to the nucleus, binds to thyroid receptors alpha and beta, proteins synthesised * T3 acts as ligan for TR - transcription factor, alters gene expression * Determinants of brain and somatic development (foetal) * Skeletal (increases in bone tumours), cardiovascular (increases HR), increases metabolic rate
301
What tools are used in diagnosis of suspected male hypogonadism?
* Measurements of height/weight * History * Growth * Family * Sexual * Drug - alcohol, IV drugs, opiates * Social * Examination * Orchidometer - what stage in development are the testes at? * 4-6ml early puberty, 8-10ml mid puberty, 12-15 late puberty
302
Describe the pathogenesis of T1DM
Chronic, progressive metabolic disorder characterised by hyperglycaemia and the absence of insulin secretion Type 1 diabetes results from autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans Occurs in genetically susceptible subjects and is probably triggered by one or more environmental agents
303
How is Grave's disease with thyrotoxicosis managed?
Pharmacological treatment of Graves’ will induce a sustained remission in 40-50% - the remainder will require a further course of treatment or definitive therapy. * Anti thyroid drugs * Beta blockers (e.g. propranolol) can be used to improve symptoms (anxiety, palpitations, sweating etc.) whilst anti-thyroid medication becomes effective. * Carbimazole and Propylthiouracil * PTU reduces T3 and T4 production * They also reduce TSH receptor stimulating antibody levels * Carbimazole is usually used, but PTU used if pregnancy planned or within the first trimester of pregnancy * This is switched to carbimazole in the second trimester if ongoing treatment is required * Patients should always be warned about the symptoms of infections and rashes - fever, mouth ulcers or a sore throat may herald agranulocytosis and hence patients must know to stop treatment and have an urgent FBC checked * There are 2 regimens used: * A reducing regimen where higher doses are started at initiation of treatment (e.g. 40 mg of Carbimazole) then as the patient becomes euthyroid the dose is reduced, maintaining a euthyroid state * Block and Replace – Commence with blocking medication e.g. 40mg of Carbimazole – then when patient is euthyroid add in Thyroxine * Smoother biochemical control, ideal where there is concern of hypothyroidism with thyroid eye disease, avoid in pregnancy * Radioactive Iodine (131I) * Contraindicated in pregnancy, lactation, and in patients with active thyroid eye disease * May be socially unacceptable e.g. to mothers due to the restrictions on prolonged close contact with small children afterwards. * 131I acts slowly – may induce hypothyroidism requiring life long thyroxine therapy, can induce a transient thyroiditis * Treatment of choice for toxic MNG – except large MNG or those with significant retrosternal extension causing obstructive symptoms, who may require surgery, also often used in patients who have remission after a course of medical therapy. * Surgery * Subtotal/total thyroidectomy – Is indicated where 131I is contraindicated or unacceptable to the patient or where there is a large goitre as above * Hypothyroidism, hypocalcaemia, recurrent laryngeal nerve palsy are important considerations. * Generally - following any treatment, patient are monitored regularly by clinical assessment and repeat thyroid function blood tests.
304
List other causes of diabetes
* Genetic defects of beta-cell function * Genetic defects in insulin action * Endocrinopathies * Acromegaly, Cushing's, Phaeochromocytoma * Immunosuppressive agents * Glucocorticoids, tacrolimus, cyclosporin * Anti-psychotics * Clozapine, olanzapine * Genetic syndromes associated with DM * Down's syndrome, Friedrich's ataxia, Turner's syndrome, myotonic dystrophy, Klinefelter's syndrome
305
Define thyrotoxicosis
Thyrotoxicosis = syndrome resulting from excessive free thyroxine (fT4) and/or free triiodothyronine (fT3)
306
Describe the affinity of steroid hormone receptors for steroid hormones
* Mineralocorticoid receptor = aldosterone \> deoxycorticosterone \> corticosterone \> cortisol \> dexamethasone * Glucocorticoid receptor = dexamethasone \> corticosterone \> cortisol = aldosterone

Medicine Year 3 (15 decks)

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