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Phase 3 > Endocrine > Flashcards

Endocrine Flashcards

1
Q

Define type 1 diabetes

A

A metabolic, autoimmune disorder of multiple aetiology characterised by hyperglycaemia with disturbance of carbohydrate, protein and fat metabolism, resulting from defects in insulin secretion, insulin action or both

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2
Q

What is the aetiology of T1 diabetes?

A
  • Combination of genetic and environmental factors
  • Genetic: HLA-DR3 and HLA-DR4
  • Environmental RFs: viral infection, Vit. D infection, cows milk, obesity
  • This leads to autoimmune destruction of Islet of Langerhan B-cells in the pancreas
  • Type IV hypersensitivity (cell-mediated immune response)
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3
Q

What is the clinical presentation of T1DM?

A
  • Polyuria: frequent passing of large amounts of urine
  • Polydipsia: excessive thirst
  • Polyphagia: excessive eating/appetite
  • Glycosuria: glucose in urine
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4
Q

What is the pathogenesis of T1DM?

A
  • Autoimmune destruction of the insulin-producing B-cells in Islets of Langerhans in pancreas
  • Presence of Islet cell antibodies causing accumulation of lymphocytic infiltration and destruction of B-cells
  • Type IV hypersensitivity (cell-mediated immune response targeting Islet of Langerhan B-cells)
  • As B-cell mass declines, insulin secretion also declines until insufficient insulin to maintain normal blood glucose
  • Insulin is needed for glucose to enter cells, so if it can’t, it remains in the blood causing hyperglycaemia
  • Symptoms appear after 90% of B-cells are destroyed (hyperglycaemia)
  • Severe insulin deficiency
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5
Q

What is the WHO diagnostic criteria for Diabetes?

A

Fasting Plasma Glucose

  • Normal: <7 Diabetes: >7

Random/2-hr Plasma Glucose

Normal: <7.8 Diabetes: >11.1

  • One abnormal value is diagnostic if symptomatic
  • 2 abnormal values is diagnostic if asymptomatic

HbA1c: average glucose over 2-3 months

  • Normal: <42mmol/mol
  • Pre-diabetic: 42-47mmol/mol
  • Diabetic: >48mmol/mol or 6.5%
  • Primary test for T2DM, not for T1DM
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6
Q

What is HbA1c and what are the pitfalls to using this value?

A
  • This is haemoglobin bound to glucose
  • The value represents average plasma glucose over 2-3 months
  • Primary test for T2DM and can be used in conjunction with other tests for T1DM

Pitfall: it doesn’t respond quickly to changes in glucose levels

  • Removal of the pancreas would result in diabetes but HbA1c would be normal
  • T1DM can develop rapidly (esp. in children), so HbA1c may be misleading
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7
Q

How is T1DM diagnosed?

A

Plasma glucose: Fasting >7, 2-hr >11.1

  • One abnormal value with symptoms or 2 abnormal values if asymptomatic on separate occassions

Symptoms

  • Polyuria, polydipsia, polyphagia, glycosuria

PLASMA Ketone testing +/- bicarbonate

  • 0.6-1.5mmol/l: indicates development of a problem
  • >1.5mmol/l in presence of hyperglycaemia indicates high risk of DKA

Pancreatic/Islet cell autoantibodies (GAD ab)

  • Associated with autoimmune process associated with T1DM

C-Peptide Testing

  • C-peptide secreted in equimolar concentrations to insulin
  • Marker of endogenous insulin secretion
  • Differentiates between T1 and T2: will be low in T1 and normal/high in T2
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8
Q

How is T1DM managed?

A

- Insulin replacement therapy

  • Glucose/Ketone monitoring
  • CHO counting and education
  • Supported self-management
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9
Q

What are the main types of insulin replacement used for T1DM?

What are the target glucose levels?

A

Basal bolus:

  • Long-acting insulin analogue in morning with short-acting analogue taken at mealtimes
  • More flexibility with mealtimes, content of meals and structure of day (work/exercise) howevere more injections

BM Fixed regime:

  • Mixture of short-acting and inter-mediate acting taken twice daily (breakfast and dinner)
  • Very structured (only 2 injections) but much less flexibility with day
  • At some points, there’ll be excess insulin and there’s a risk of hypoglycaemia

target glucose level: HbA1c <53mmol/l

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10
Q

What is the function of insulin?

A
  • Increases cellular glucose uptake
  • Stimulates glycogenesis, enourages DNA synthesis and promotes GH release
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11
Q

What education is required for newly diagnosed T1DM patients?

A
  • Insulin administration
  • Glucose/Ketone monitoring
  • Sick dat rules: may need more insulin when ill, and never stop long-acting insulin
  • Detection and management of hypoglycaemia
  • Driving regulations
  • Exercise and diet (esp alcohol)
  • Micro and macrovascular complications
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12
Q

Compare T1DM and T2DM

A

T1DM: immune pathogenesis and severe insulin deficiency

T2DM: combination of insulin resistance and partial insulin deficiency

Age - T1DM: <35, T2DM: >35

Weight: T1 lean, T2 obese/overweight

Symptom duration: T1 weeks, T2 months/years

Seasonal onset: T1 yes, T2 no

Hereditary: T1 HLA-DR3/4, T2 none

Pathogenesis: T1 autoimmune, T2 no immune disturbance

Ketonuria/aemia/Acidosis: T1 common, T2 uncommon

Clinical:

  • T1 insulin deficiency +/- ketoacidosis, dependent on insulin
  • T2 partial insulin deficiency +/- hyperosmolar state, may need insulin

Biochem:

  • T1: C-peptide negative, usually GAD ab +ve
  • T2: C-peptide elevated, GAD ab -ve
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13
Q

Briedly describe the less common types of diabetes and how they might be distinguished from each other

A

LADA (Latent Autoimmune Diabetes of the Adult)

  • Slow burner T1DM ie. develops later on, will have autoantibodies
  • Not absolute insulin deficiency

Pancreatic Diabetes

  • Caused by mutation of a single gene ie. monogenic
  • Other aetiology: pancreatectomy, pancreatitis
  • Also have loss of alpha cells (produce glucagon) therefore higher risk of hypoglycaemia
  • Main features: <25yrs, familial
  • Managed by diet, oral antihyperglycaemic agents, insulin

MODY (Maturity Onset Diabetes of the Young)

  • Mongenic
  • Features: <25yrs, normal weight
  • Normal C-peptide and -ve autoantibodies
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14
Q

Define T2DM

A

Chronic, progressive metabolic disorder characterised by hyperglycaemia, insulin resistance and partial insulin deficiency

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15
Q

What is the pathogenesis for T2DM?

A
  • Combination of insulin resistance and partial insulin deficiency
  • With a high-glucose diet, the body is able to maintain normal glycaemia by producing more insulin
  • The body then develops insluin resistance leading to impaired glucsoe tolerance in a hyperinsulinaemic state
  • Insulin production increases until eventually pancreas can’t accomodate from hyperinsulinaemia (with regards to insulin resistance)
  • Therefore, insulin levels fall to develop partial insulin deficiency, the threshold for diabetes
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16
Q

What are the early and late signs of hypoglycaemia?

A

Early:

  • Hunger, tingling lips, palpatations
  • sweating, fatigue, dizziness, shaking/trembling
  • Irritable, pale

Late:

  • Weakness, blurred vision
  • Difficulty concentrating, confusion
  • Seem drunk (slurred speech, unusual behaviour)
  • Seizures, syncope
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17
Q

What are the risk factors for T2DM?

A
  • >40yrs (or >25 for South Asian population)
  • 1st degree relative with T2DM
  • Overweight or obese
  • South Asian, Chinese, African carribean or black African origin
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18
Q

What are the symptoms of T2DM?

A
  • Polyuria
  • Polydipsia
  • Polyphagia
  • Glycosuria
  • Fatigue
  • Weight loss
  • Blurred vision or wounds taking longer to heal
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19
Q

How is T2DM diagnosed?

A

HbA1c

  • A result of <6.5% / 48mmol/l

General DM diagnosis includes fasting plasma glucose >7.0 and 2-hr post feeding plasma glucose >11.1

  • One of these with symptoms diagnostic
  • Need both and on two separate occassions to be diagnostic if asymptomatic
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20
Q

What are the goals for treatment in T2DM?

A
  • Reducing rates of microvascular complications ie. complications affecting small blood vessels: Retinopathy, nephropathy, neuropathy, foot disease
  • Cardiovascular safety: minimum requirement
  • Reducing rates of macrovascular complications: MI, stroke, HF, peripheral vascular disease
  • Prescribe treatment that is in favour of improving outcome (prognosis): need to balance symptom control and prognosis with side effects and adherence
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21
Q

What are the complications of T2DM?

A

Microvascular complications:

  • Retinopathy: glaucoma, cataracts
  • Nephropathy: inc. BP and overworked by inc. glucocse
  • Neuropathy: pain +/or numbness
  • Diabetic foot: undetected foot wounds lead to infections and gangrene
  • Impaired wound healing, impaired bision

Macrovascular complications:

  • Heart: MI, HF
  • Brain: stroke, cerebrovascular disease, cognitive impairment
  • Extremeties: peripheral vascular disease
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22
Q

What are the biomedical targets for treatment of T2DM?

A

HbA1c: around 7% (individualised) eg. patient with hypoglycaemic unawareness may have a target of 8/8.5%

BP: <130/80

  • ACEi (ramipril) or ARB, calcium channel blocker, thiazide diuretic

Cholesterol: statin if >40yrs

Normal body weight / weight reduction

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23
Q

List the treatment ladder for T2DM

A

Very first line: lifestyle modifications (diet and exercise) especially if early on and aymptomatic

1st line (1 agent): metformin or sulphonylureas (SU, Gliclazide)

2nd line (2 agents): add SU (gliclazide), SGLT-2 inhibitor (flozin), DPP-4 inhibitor (gliptin) or glitazone

3rd line (3 agents): add SU, SGLT-2 inhibitor, DPP-4 inhibitor or glitazone OR injectable therapy (GLP-1 agonist or insulin)

4th line (4 agents): add another from the list above

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24
Q

What is the class, indication and action of metformin?

A

Class: Biguanide

Indication: T2DM alonside exercise and diet

  • Metabolic and reproductive abnormalities associated with polycystic ovarian syndrome

Action:

  • Increases the activity of AMP-dependent protein kinase (AMPK)
  • This inhibits gluconeogenesis (hepatic glucose production)
  • Reduces insulin resistance
  • Increases peripheral insulin sensitivity in mucle, increasing glucose uptake and utilisation
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25
Q

How does symptom control balance with adverse effects of metformin?

A

Symptom control:

  • Moderate efficiacy; Weight reduction; Low hypoglycaemic risk; CV benefit

Adverse effects:

  • GI (diarrhoea, vomiting, nausea), lack of appetite
  • Not recommended in renal failure (eGFR <30)
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26
Q

What is the class, action and indication of gliclazide?

A

Class: Sulphonylurea (SU)

Indication: T2DM alongside exercise and diet

Action:

  • Stimulates ß-cells of the pancreas to produce more insulin
  • Increases cellular glucose uptake and glycogenesis (reduces gluconeogenesis)
  • Short acting
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27
Q

How does symptom control balance with adverse effects of Gliclazide?

A

Symptom control:

  • High efficacy

Adverse effects:

  • Main: Hypoglycaemia
  • Also; rashes, nausea, vomiting
  • No CV benefit; Weight gain; Hypoglycaemic risk; caution in CKD
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28
Q

What is the class, indication and action of Exanatide?

A

Class: GLP-1 agonist

Indication: T2DM (in association with excess weight)

Action:

  • GLP-1 is an endogenous incretin secreted after meals (in response to oral glucose) to increase insulin secretion
  • Act on B cells to increase insulin release, A-cells to reduce glucagon secretion and the brain to increase satiety
  • GLP-1 agonists increase insulin secretion, decreases glucagon secretion and reduces hunger
  • Lowers glucose alone, but when given in combo with metformin, SU and/or insulin, can improve glucose control
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29
Q

How does symptom control balance adverse effects of Exanatide?

A

Symptom control:

  • High efficacy; CV benefit; Low hypoglyaemic risk; Weight loss
  • Lowers glucose alone, but when given in combo with metformin, SU and/or insulin, can improve glucose control

Adverse effects:

  • Main: GI (nausea, vomiting, diarrhoea)
  • Injected; GI side effects; uncertain safety of pancreas
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30
Q

What is the class, indication and action of a ‘gliptin’?

A

Class: DPP-4 inhibitor

Indication: T2DM

Action:

  • Inhibit DPP-4 which breaks down endogenous incretins (GLP-1) which increase glucose-mediated insulin secretion and suppress glucagon secretion (a cells of pancreas)
  • DPP-4 rapidly degrade GLP-1 (glucagon-like peptide)
  • DPP-4 inhibitors prolong action/enhance effects of endogenous incretins, enhancing the first-phase of insulin response
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31
Q

How does symptom control balance adverse effects of a ‘gliptin’?

A

Symptom control:

  • Moderate efficacy; Low hypoglycaemic risk; Well tolerated

Adverse effects:

  • Weight neutral; No CV benefit; Reduce dose in CKD
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32
Q

What is the class, indication and action of a -flozin?

A

Class: SGLT-2 inhibitor

Indication: T2DM

Action:

  • Inhibit SGLT-2 (Sodium-Glucose co-Transporter 2) in proximal convoluted tubule of the kidney
  • This decreases renal reabsorption of glucose
  • Loss efficacy in those with renal impairment
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33
Q

How does symptom control balance adverse effects of a -flozin?

A

Symptom control:

  • Moderate efficacy; CV benefit; Renal benefit; Weight loss; Low hypoglycaemic risk

Adverse effects:

  • Main: Risk of GU infection
  • Small risk of hypovolaemia; don’t start if eGFR <60
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34
Q

What is the class, indication and action of thiazolidinediones?

A

Class: Glitazone

Indication: T2DM

Action:

  • Increases insulin sensitivity by actings as ligands for the nuclear hormone receptor PPARy
  • PPARy found predominantly in adipose tissue but also pancreatic B-cells, muscle and liver
  • Increases sensitivity of fat, muscle and liver to endogenous and exogenous insulin
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35
Q

How does symptom control balance adverse effects of thiazolidinedione?

A

Symptom control:

  • Moderate efficacy, CV benefit, low hypo risk

Adverse effects:

  • Weight gain; fluid retention; fractures
  • Side effects outweigh prognosis benefit therefore rarely used*
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36
Q

What prescribing considerations are needed with T2DM medication in the elderly

A
  • Polypharmacy: risk of drug interactions
  • Increased risk of adverse events
  • Inc. likelihood of hypoglycaemia
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37
Q

What prescribing considerations are necessary for T2DM medication in renal disease?

A
  • Stop metformin when eGFR <30
  • Caution with SU as inc. risk of hypoglycaemia
  • Dose reduction required with GLP-1 agonists and DPP-4 inhibitors
  • SGLT-2 inhibitors less effective at glucose lowering in CKD (eGFR <60)
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38
Q

What prescribing considerations are necessary for T2DM medication in heart failure?

A
  • Metformin can be used in chronic HF, but withhold during acute episodes of failure
  • Stop/ Don’t start Glitazone
  • Flozins (SGLT-2 inhibitors) reduce hospitalisation for HF with and without diabetes
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39
Q

What is the action and indication for insulin?

What are the types of insulin?

A

Indications:

  • T1DM, T2DM, hyperkalaemia (in conjunction with dextrose)

Action:

  • Insulin increases cellular uptake of glucose
  • Stimulates glycogenesis, promotes DNA synthesis and promotes release of growth hormones (GH)
  • Liver: Reduces gluconeogenesis
  • Skeletal muscle: increased glucose uptake and utilisation
  • Adipose tissue: decreased lipolysis

Types:

  • Novorapid: short acting
  • Glargine: long acting
  • Humalog mix: intermediate and fast acting
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40
Q

How does symptom control balance with adverse effects of insulin?

A

Symptom control:

  • High efficacy

Adverse effects:

  • Main: hypoglycaemia
  • Injected; No CV benefit; Weight gain; Highest hypoglycaemic risk
  • Other: sweats/shakes/tachycardia/fatigue (symptoms of hypoglycaemia) and oedema
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41
Q

What hormone(s) is/are released from the anterior pituitary?

A
  • GH (Growth hormone): liver and other tissues
  • ACTH (Adrenocorticotropic hormone): to adrenals for corticosteroid release
  • TSH (Thyroid Stimulating Hormone): to thyroid for T3/T4 release
  • LH (Luteinising Hormone) and FSH (Follicle stimulating hormone: to ovaries (oestrogen, progesterone and inhibin) or testes (inhibin and testosterone)
  • Prolactin: milk production
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42
Q

What hormone(s) is/are produced by the hypothalmus?

A
  • GHRH (Growth hormone releasing hormone) and somatostatin: GHRH stimulates GH release from anterior pituriary whereas somatostatin inhibits GH release
  • CRH (corticotropin-releasing hormone): to ant. pituitary to stimulate ACTH release

TR​H (thyrotropin releasing hormone): to ant/ pituitary to stimulate TSH release

GnRH (gonadotropin releasing hormone): to ant. pituitary to release LH and FSH

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43
Q

What stimulates prolactin release and which pituitary gland is it released from?

A
  • Stimulated by suckling
  • Released from anterior pituitary
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44
Q

What hormones are released by the posterior pituitary?

A
  • ADH/Vasopressin: to kidney to reduce blood volume
  • Oxytocin: to uterus to cause contractions
  • These are both produced in the hypothalamus but stored in the posterior pituitary*
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45
Q

Where is the thyroid gland found?

What is the histology of the thyroid?

A
  • Found in the neck, spanning between C5 and T1
  • Divided into two glands with a central isthmus to connect the two

Histology:

  • Thyroid follicles surrounded by a single layer of epithelial cells
  • Follciles are full of colloid: gel-like substance rich in thyroglobulin and iodine
  • Colloid and nodules
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46
Q

What are the general processes involving thyroglobulin in the thyroid?

A
  • There’s an iodide-dependant sodium co-transporter in the thyroid and ribosomal formation of thyroglobulin
  • This is exocytosed, oxidated, iodinated and conjugated
  • These processes result in formation of triiodothyronine (T3) and thyroxine (T4)
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47
Q

Describe the feedback loop involving the thyroid

A
  • Hypothalamus releases TRH, stimulating the anterior pituitary to release TSH
  • This stimulates the thyroid to release T3 and T4
  • If there’s not enough T3/T4, the pituitary gland will produce more TSH (elevation in TSH) as hypothalamus releases more TRH
  • If there are high T3 and T4 levels, they will negatively feedback to hypothalamus and ant. pituitary to inhibit production of TRH and TSH
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48
Q

Compare the production of T3 and T4

A
  • More T4 is produced from the thyroid however T3 is more potent
  • All cells have the deiodinase enzyme that converts T4 to active T3
  • In the context of low thyroid hormone levels, more T3 will be produced from the thyroid
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49
Q

What is the function of thyroid hormones?

A
  • Increased metabolism
  • Growth and development
  • Increased catecholamine effect (fight or flight): stimulates HR, raises BP
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50
Q

Define hypothyroidism

A
  • When the thyroid produces abnormally low levels of thyroid hormones ie. underactive thyroid
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51
Q

What are the causes of hypothyroidism?

A

Pituitary: hypopituitarism

Thyroid:

  • Thyroidectomy
  • Post-radioactive iodine ablation
  • Autoimmune: thyroiditis (Hastimoto’s) or blocking TSH receptor antibodies
  • Can be secondary to an overactive thyroid

Inborn errors: congenital hypothyroidism

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52
Q

What is the clinical importance of hypothyroidism if there is a pituitary pattern in TFTs?

A
  • Thyrotrophs are the toughest pituitary cells, the weakest being somatotrophs
  • Want to check the other axis involving the thyroid
  • Especially want to check cortisol levels (adrenal axis, removes free water): if thyroxine is replaced first while being cortisol deficient - will get cardiac failure and cardiac arrest)
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53
Q

What are the signs and symptoms of hypothyroidism

A

Tired, Weak, Dry skin

  • Cold intolerance, Bradycardia
  • Menorrhagia (heavy/prolonged periods)
  • Goitre (swollen thyroid gland),
  • Hair loss, Poor concentration, Constipation
  • Weight gain and poor appetite
  • Paraesthesia (abnormal sensations, tingling)
  • Oedema Loss of libido Depression
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54
Q

What investigations are carried out when determining thyroid function?

A
  • TSH levels
  • Free T3/T4 levels
  • Autoantibodies: thyroid peroxisomal antibody (TPO) and TSH receptor antibodies
  • TSH receptor antibodies are diagnostic for Graves’ disease
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55
Q

Patient has 4 month history of

  • fatigue, puffy ankles, gained 6kg and constipated

O/E: 54bpm, peripheral oedema and moderate goitre

Investgations: elevated TSH, undetectable free T4 and +ve thyroid peroxisomal antibodies

What would be the diagnosis?

A
  • Hashimoto’s: autoimmune destructive thyroiditis
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56
Q

What is the treatment for hypothyroidism?

A

Thyroxine replacement therapy: levothyroxine

  • Most are on this alone and they still have the deiodinase enzymes
  • If someone is on thyroxine and T4 has normalised but TSH is still high (in context of thyroid problem): think about poor compliance or inability to absorb thyroxine
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57
Q

What is destructive thyroiditis?

What is thyrotoxicosis?

A

Thyroiditis: inflammation of the thyroid gland which can cause either hypo- or hypothyroidism

  • Destructive thyroiditis: causes hypothyroidism (if autoimmune = Hastimoto’s)

Thyrotoxicosis: excess thyroid hormone

  • Autoimmune thyrotoxicosis: Graves’ Disease
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58
Q

What are the complications of undiagnosed hypothyroidism at birth?

A
  • Pre-eclampsia
  • Stillbirth
  • Miscarriage
  • Low birth weight
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59
Q

What effect does undiagnosed hypothyroidism in a mother have on a developing foetus?

How is hypothyroidism investigated in neonates?

A
  • Coarse facial features
  • Macroglossia (large tongue)
  • Developmental delay
  • Goitre
  • Cool and dry skin

Investigation: heel prick screening test in 1st week after birth

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60
Q

Define hyperthyroidism

A

Abnormal overproduction of thyroid hormones (T3/T4) ie. overactive thyroid

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61
Q

What is the aetiology of hyperthyroidism?

A

Pituitary:

  • Pituitary adenoma
  • Other hormones acting as TSH eg. HCG (when pregnant, levels of HCG are elevated and looks similar to TSH) - transient gestational thyrotoxicosis

Thyroid:

  • Autoimmune: acute thyroiditis, activating TSH receptor antibodies (Graves’ disease - autoimmune thyrotoxicosis)
  • Thyroid adenoma
62
Q

What are the causes of Graves’ disease?

A

Genetic and environmental causes

  • Genetic: HLA, thyroid receptor
  • Environmental: tobacco smoke, iodine

(Smoking is associated with thyroid eye disease and Graves’ disease)

  • Immune modulating therapy eg. interferon
63
Q

What are the signs and symptoms of hyperthyroidism?

A
  • Exophthalmos and opthalmoplegia
  • Goitre
  • Bruit (only in Graves’ disease)
  • Tachycardia, angina, AF
  • Systolic hypertension
  • Oligo/Amenorrhoea
  • Heat intolerence and excessive sweating
  • Sweaty, tremulous warm hands
  • Proximal myopathy
  • Weight loss and inc. appetite
  • Anxious, irritable
  • Fast, fine tremour
64
Q

What results on investigation would suggest hyperthyroidism?

A
  • Correlating signs and symptoms
  • T4 would be high
  • Thyroid problem: low TSH (due to negative feedback)
  • Pituitary problem or above: high TSH
  • Bruit with TSH receptor antibodies: Graves’ disease
  • If antibodies are negative: do uptake scan to determine antibody negative Graves’ disease or nodular thyroid disease
65
Q

What is the class, action and indication of levothyroxine?

A

Class: synthetic thyroid hormone

Indication: hypothyroidism

Action:

  • Thyroxine increases metabolic rate of all tissues
  • Acts like T4 and gets converted to T3 in the liver and kidney
  • Maintains brain function, food metabolism and body temperature among other things
66
Q

What is the treatment for hyperthyroidism?

A

Either supportive and symptomatic or treat the cause

Propanolol: Beta-blocker

  • Reduces anxiety and sweats
  • Crosses blood brain barrier

Carbimazole: Thionamide

  • Anti-thyroid medication
  • Targets the iodination stage to block thyroxine production
  • If pregnant, swap for propylthiouracil (thionamide)

Radioactive iodine

67
Q

What is the class, action and indication of carbimazole?

What is the main adverse effect and what pharmacokinetic information is useful to know?

A

Class: Thionamide

Indication: Hyperthyroidism, thyrotoxicosis, preparation for thyroid surgery

Action:

  • Reduces the activity of the peroxidase enzyme needed for thyroid hormone production (iodination)
  • May also reduce peripheral ocnversion of T4 to T3
  • Pro-drug

Main adverse effect: crosses the placenta therefore not safe for pregnancy (use propylthiouracil)

Pharmacokinetic: takes several weeks to work therefore often co-prescribed with a beta-blocker to reduce side effects

68
Q

How does amiodarone cause thyroid disease?

A

It has a very high iodine content, and patients will therefore consume much more iodine than the daily requirements

  • This can cause hyper- or hypothyroidism
69
Q

What drug can cause thyroid disease?

A

Amiodarone (for supraventricular or ventricular tachycardias) due to high iodine content

70
Q

What is the classification for amiodarone thyroid disease?

A

Type 1: autoimmune thyrotoxicosis

  • Will also have pre-existing antibodies
  • Excess thyroid hormones
  • Treatment: high-dose carbimazole

Type 2: destructive thyroiditis

  • Due to Jod Basedow effect (iodine-induced hyperthyroidism)
  • Treatment: glucocorticoids
71
Q

What is the clinical relevance of autoantibodies in thyroid disease?

A

Thyroid peroxisomal antibodies (TPO)

  • Can be +ve in a patient but may not develop into thyroid disease
  • TSH receptor antibodies: diagnostic for Graves’ disease
72
Q

What condition is thyroid eye disease seen in?

How do you determine thyroid eye disease?

What is the major complication of thyroid eye disease aand how is it treated?

A

Exophthalmos: anterior protrusion of the eyeball out of the orbit

  • Bilateral in Graves’ disease

When looking in eyes, shouldn’t see sclera above or below the pupil

  • Sclera seen above: lid lag
  • Sclera seen below: exophthalmos

Major complication: corneal ulceration

  • Wear protective glasses, tape eyelids shut at night
  • Eye drops
  • If there are changes in colour vision: ophthalmology emergency (indicates compression on optic nerve by swollen extraocular muscles - need steroids
73
Q

What investigations are necessary for determining nodules and tumours in the thyroid gland?

A

TFTs: TSH and free T4

Imaging:

  • Ultrasuons scan: helps determine presence of nodules and can use to guide fine needle aspiration or biopsy
  • Uptake scan: small defined black ring would be a hot nodule, multinodular goitre would be white with multiple black spots (black is radiolabelled iodine)

Fine needle biopsy and aspiration

74
Q

What is a hot nodule?

How is it diagnosed?

A
  • Nodules that produce excess thyroid hormone
  • Uptake scan: They take up large amounts of radioactive iodine relative to the rest of the thyroid gland
75
Q

What are the 4 main types of thyroid carcinoma?

What are the main RFs for each?

A
  • Papillary: most common, usually women <40yr
  • Follicular: middle aged, usually women
  • Anaplastic: rarest but most serious, >60yrs
  • Medullary: familial
76
Q

How are thyroid carcinomas investigated?

A
  • Clinical presentation: firm, growing lump, difficulty swallowing/breathing
  • Thyroid Function Tests (blood test): could show underactive/overactive thyroid rather than carcinome
  • Ultrasound scan: if lump seen, biopsy
  • Biopsy: diagnostic

If cancer is confirmed: MRI or CT to check for metastatic spread

77
Q

What are the treatment options for a thyroid carcinoma?

A

Treatment: surgery followed by therapeutic radioiodine

  • A thyroidectomy: removal of all or part of the thyroid gland
  • Radioactive iodine treatment: swallow radioactive iodine substance that’s absorbed by the remaining cancerous cells and kills them
  • Will be on levothyroxine (thyroid hormone replacement) for rest of life
  • External radiotherapy if radioiodine is unsuitable
78
Q

Describe the anatomy of the adrenal gland and where the production of hormones take place

A

Out cortex and inner medulla

Adrenal cortex: produces adrenal steroid hormones

  • Zona Glomerulosa: Aldosterone (salt)
  • Zona Fasciculata: Cortisol (sugar)
  • Zona Reticularis: Androgens (sex)
  • Different layers are relayed to expression of steroidogenic enzymes. All steroid hormones start as cholesterol*

Adrenal medulla:

  • Chromograffin cells: catecholamines (ie. adrenaline and noradrenaline)
79
Q

What area of the adrenal gland is associated with the renin-angiotensin system?

What regulates the renin-angiotensin system?

A
  • Concerned with the zona glomerulosa
  • Main regulator of aldosterone release: renin in response to low BP
80
Q

Explain the renin-angiotensin system

A
  • Renin released from kidney in response to low blood pressure
  • This causes production of angiotensin I from angiotensinogen (from liver)
  • ACE (lungs) converts angiotensin I to angiotensin II
  • Causes direct (vasoconstriction) and indirect (aldosterone) methods of BP elevation
  • Aldosterone: acts on kidneys to stimulate reabsorption of sodium and water
81
Q

What is the function of aldosterone?

What regulates its release?

A
  • Opens Na channels in the kidney allowing reabsorption of salt therefore water with obligate loss of potassium to keep neutral electrical balance
  • Regulated by renin release
82
Q

Where is cortisol produced?

How is release regulated?

ie. what is the axis?

A
  • Produced in the Zona Fasciciulata in the cortex of the adrenal glands
  • Regulated by the hypothalamus

Hypothalamus-pituitary-adrenal axis

  • Hypothalamus stimulated to release CRH in response to stress, illness and time of day (diurnal)
  • Stimulates the ant. pituitary to release ACTH which stimulates adrenals to release cortisol
83
Q

What is the function of cortisol?

A

‘Stress hormone’

  • Most cells have cortisol receptors therefore cortisol affects many body functions
  • Adipose: promotes fat breakdown
  • Bone: reduces bone formation
  • Liver: gluconeogenesis (inc. blood glucose)
  • Muscle: decreases amino acid uptake by muscle
  • Pancreas: cortisol counteracts insulin (inc. blood glucose)
  • CNS: heightened memory and attention, decreases serotonin and decreases sensitivity to pain
  • Controlling affect on salt and water balance: Inc. blood pressure
  • Reduces inflammation
84
Q

What types of hormones are those produces from the adrenal gland?

What do they start as?

Which have a diurnal rhythm?

A
  • Cortisol: glucocorticoid, aldosterone: mineralocorticoid, Androgens: sex steroids
  • They all start as cholesterol
  • Cortisol and androgens have a diurnal rhythm
85
Q

Differentiate Cushing’s Syndrome and Cushing’s Disease

A

Cushing’s Syndrome: the set of characteristics caused by excess cortisol production by the adrenal glands

Cushing’s Disease: when excess cortisol production is caused by excess ACTH production from an anterior pituitary adenoma

86
Q

What are the causes of Cushing’s Syndrome?

A

ACTH dependent ie. a high ACTH stimulating cortisol release

  • Pituitary adenoma producing ACTH
  • Cushing’s disease
  • Ectopic ACTH (would be worried about malignancy)
  • Ectopic CRH (rare)

ACTH independent ie. a low ACTH due to negative feedback

  • Adrenal adenoma
  • Adrenal carcinoma
  • Nodular hyperplasia
  • Steroid medication
87
Q

What are the clinical features of Cushing’s syndrome?

A
  • Hirsutism, proximal myopathy (wasting), plethora, hypertension, easy bruising and striae
  • Moon face
  • Weight gain/obesity
  • Increased abdominal fat
  • Tendancy to hyperglycaemia
  • Inc. risk of infection and poor wound healing
  • Depression/low mood or euphoria
  • Osteoporosis
88
Q

If someone presented with hirsutism, weight gain, plethora, easy bruising and HTN, and you suspected cortisol excess, what investigations would you do to diagnose Cushing’s syndrome?

A
  1. Screen for Cushing’s syndrome - ie. elevated cortisol
    - 24hr urinary free cortisol
    - early morning urine cortisol:creatinine ratio x3
    - dexamethosone suppression test: dex. is similar to cortisol and supresses ACTH therefore plasma cortisol levels should be undetectable. Low dose to diagnose and high dose to determine cause. Overnight or low dose test over 48hrs
    - late night salivary cortisol: normal would be undetectable or low
89
Q

A patient presenting with hirsutism, weight gain, plethora, easy bruising and HTN. Suspected cortisol excess.

Dexamethasone suppression test: cortisol levels remain high

What investigations are carried out next?

A
  1. Localise the cortisol source

Plasma ACTH: low in adrenal source

High dose dexamethasone suppression test

  • Cortisol will suppress to <50% if pituitary cause
  • 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 tumours
90
Q

How is Cushing’s syndrome treated?

A
  • Treat the cause

Steroid use: gradually reduce and stop steroids

Tumour: surgery, radiotherapy, drugs to reduce effect of cortisol

91
Q

What is adrenal insufficiency?

What are the main causes of primary adrenal insufficiency

A
  • Inadequate adrenocortical function
  • Deficiency in both cortisol and aldosterone
  • Main causes of primary adrenal insufficiency: Addison’s disease and autoimmune destruction
92
Q

What is the clinical presentation of adrenal insufficiency

A

Cortisol and aldosterone deficiency (also destruction of the glomerulus)

Cortisol

  • Anorexia, weight loss
  • Fatigue, legarthy
  • Dizziness, hypotension and postural hypotension
  • Syncope
  • Abdominal pain, vomiting, diarrhoea
  • Muscle joint pain
  • Craving salt, hair loss
  • Hypoglycaemia

Elevated ACTH (when pituitary trying to stimulate adrenal cortex): causes skin pigmentation

Aldosterone

  • Electrolyte abnormalities
93
Q

Patient presents with weight loss, fatigue, postural hypotension and salt cravings. You suspect adrenal insufficiency. What investigations do you do?

A

Biochemistry:

  • Low serum Na, raised serum K due to aldosterone deficiency
  • Hypoglycaemia due to cortisol deficiency

Short synacthen test:

  • Measure plasma cortisol before and 30mins after IV ACTH injection
  • Normal: baseline >250, post ACTH >480
  • With adrenal insufficiency: would not elevate this much

ACTH levels

  • Sig. elevated w/ adrenal insufficiency (no neg feedback)

Renin/Aldosterone levels

  • High renin, low aldosterone with adrenal insufficiency

Adrenal autoantibodies

94
Q

How do you treat Addison’s disease?

A

Hormone replacement therapy

  • Hydrocortisone (corticosteroid) to replace cortisol
  • Fludrocortisone to replace aldosterone
95
Q

What is the class, indication and action of hydrocortisone?

A

Class: corticosteroid (glucocorticoid)

Indication:

  • replacement therapy for adrenal insufficiency
  • post-transplantation for immunosuppression
  • Exacerbations of inflammatory conditions eg. excema, RA, IBD
  • Acute asthma

Action:

  • Binds to glucocorticoid receptors, up-regulating the activity of anti-inflammatory mediators and down-regulating the activity of pro-inflammatory mediators
  • Provides immunosuppression
96
Q

What are the functions of mineralocorticoids?

A
  • Increased resorption of water
  • Increased resorption of sodium
  • Increased renal secretion of potassium
97
Q

Define congenital adrenal hyperplasia (CAH)

A

A group of inherited, autosomal recessive disorders characterised by deficiency in one or more of the enzymes in the cortex of the adrenal glands

ie. disorder of the cortex

- Leads to overproduction of androgens

98
Q

What is the pathophysiology of congenital adrenal hyperplasia (CAH)?

A
  • All adrenal steroid hormones start as cholesterol
  • The pathway depends on enzymatic stepwise progression to the final product
  • In CAH, there’s a genetic disorder leading to defect in one of these enzymes: usually full 21-hydroxylase deficiency
  • Therefore, no progression to the final profect
  • Absolute deficiency of these coumpounds will present in childhood in the neonate period with cortisol and aldosterone deficiency
  • There will be ACTH stimulation due to lack of cortisol, but do to enzyme deficiency, there will be a build up of progesterone and DHEA with no cortisol or aldosterone production
  • Ie. overproduction of androgens and deficiency of cortisol and aldosterone
99
Q

What are the clinical features of Congenital Adrenal Hyperplasia (CAH)?

How is CAH diagnosed?

What is the treatment?

A

Female: ambiguous genitalia (excess DHEA and progesterone)

Boys: adrenal crisis (hypotension, hyponatraemia), early virilsation (masculinisation)

Diagnosis: synacthen test with 17OH porgesterone to see if there is a further rise in 17OHP

Treatment: mineralocorticoid (fludrocortisone) and glucocorticoid (hydrocortisone) replacement

100
Q

What is essential/primary hypertension?

A

Hypertension with no known cause

101
Q

What is secondary hypertension and what are the RFs for developing it?

A

Secondary hypertension: hypertension caused by another disorder eg. renal disease

RFs:

  • Young (<40yrs), resistant/severe hypertension
102
Q

What is primary aldosteronism?

A

The overproduction of aldosterone from adrenal gland cortex

  • Related to overactivity of zona glomerulosa and overproduction of aldosterone
103
Q

What clinical picture would be seen in a patient with primary aldosteronism?

A
  • Hypertension
  • Young (<40)
  • Hypokalaemia
104
Q

34yr old patient presents with hypertension

  • 1-yr history of HTN
  • No other PMH, no regular medication
  • BP: 168/98mmHg
  • Renal function normal but low plasma K

What do you suspect this to be and how would you investigate?

A

Suspicion: Primary aldosteronism due to young age, HTN and hypokalaemia

Investigations:

Test renin and aldosterone levels

  • Aldosterone: elevated, Renin: low

Aldosterone-Renin Ratio (ARR): best screening tool

  • Can determine is aldosterone production is autonomous (working independently from RAS) or whether it’s normal for the patient’s physiological state
  • If increased, consider further confirmation testing
  • Problem: renin and aldosterone are interfered by a lot of factors therefor stop all medications if possible (esp. B-blockers and MR antagonists which suppress renin)

If ARR elevated: saline suppression test

  • 2l saline over 4hrs, should not produce aldosterone as don’t need to retain more salt/water ie. suppresses aldosterone
  • 4hr aldosterone >27: highly suspicious

Hypokalaemia in <50%

105
Q

What is the management for primary aldosteronism?

A

Surgical

  • Only for unilateral adrenal adenoma
  • Unilateral laparoscopic adrenalectomy
  • Cures hypokalaemia and hypertension

Medical

  • Use MR antagonist (spironolactone)
106
Q

Define a phaeochromocytoma

A

A rare tumour of the adrenal medulla that produces adrenaline and noradrenaline

107
Q

What are the signs and symptoms of a phaeochromocytoma?

A
  • Hypertension
  • Episodes of headache, nausea, vomiting, pallor, sweating, tremor, anxiety, chest/abdo pain, palpatations
  • Crises last 15 minutes
  • Often well between crises
108
Q

What is the treatment for phaeochromocytomas?

A

Initially: alpha-blocker

  • Doxazosin
  • Aim for SBP <120mmHg if possible

Then, beta-blocker if tachycardic

  • Bisoprolol

Encourage salt intake

109
Q

What is an adrenal incidentaloma?

What are the different types?

A

Incidentally discovered / unsuspected adrenal lesion discovered through diagnostic imaging for an unrelated condition, without prior suspicion of tumour/disease

Types: malignant or functional

110
Q

How is a malignant adrenal incidentaloma determined?

What functional adrenal incidentaloma’s could be found?

A

Imaging characteristics: size <4cm

Low Housfield Units on non-contrast CT (density indication): <10HU

Dynamic scan: adenoma wash out

Functional adrenal incidentalomas:

  • aldosterone, cortisol, androgens, catecholamines
111
Q

Outline the normal anatomy of the male reproductive system (just where spermatogenesis occurs)

A

Bulk of the testes = seminiferous tubules

  • This is where sperm are formed and allow sperm to mature

Sertoli cells: found within seminiferous tubules

  • provide nutrients to the developing sperm cells and contribute to the blood-testis barrier

Leidig cells: sit outside the seminiferous tubules

  • produce testosterone

The basement membrane and sertoli cells maintain the blood-testis barrier to prevent the immune system attacking the sperm

  • sperm form from base of seminiferous tubules toward the lumun

Seminiferous tubules - straight tubules - rete testis - efferent ducts - epididymis - vas deferens

112
Q

Outline the regulation of hormone release in the male reproduce system

A

Hypothalamus releases GnRH in response to oestrogen and testosterone levels

  • This stimulates the anterior pituitary to release gonadotrophs (FSH and LH)
  • FSH acts on sertoli cells to facilitate spermatogenesis
  • LH acts on leydig cells to release testosterone, which further stimulates sertoli cells

Negative feedback:

  • sertoli cells secrete inhibin which negatively feedback to the anterior pituitary
  • Leydig cells are releasing testosterone that regulates both FSH and LH release from ant. pituitary and GnRH release from the hypothalamus
113
Q

Outline the functions of the male gonad

A
  • testosterone production (leydig cells)
  • fertility (spermatogenesis with help of sertoli and leydig cells)
114
Q

Outline testosterone transport in the blood in males

A
  • circulates bound to SHBG and some albumin
  • free testosterone is active
  • it is activated to the more potent form (dihydrotestosterone) in target tissues
115
Q

What are the effects on testosterone on the body?

A

Growth:

  • sex organ
  • skeletal muscle
  • epiphyseal plates (fuse in response to oestrogen)
  • larynx growth (deeper voice)
  • secondary characteristics

Other effects:

  • erythropoiesis, behaviour

Fertility:

  • libido, erectile function and spematogenesis

Adult:

  • muscle mass, bone mass, body shape
  • mood, libido
116
Q

Define hypogonadism

A
  • A condition in which decreased production of gonadal hormones leads to below-normal function of the gonads and retardation of sexual growth and development in children
117
Q

Outline the clinical features of male hypogonadism in children and adults

A

Children:

  • slow growth in teens with no pubertal growth spurt
  • small testes and phallus
  • lack of secondary sexual development

Adults:

  • depression/low mood
  • poor libido and erectile problems
  • azoospermia (infertility)
  • poor muscle bulk/power, poor energy
  • sparse body/facial hair and gynaecomastia
  • shortning and narrowing phallus
  • small testes and abnormal consistency
118
Q

How is endocrine function investigated?

A
  • height
  • weight
  • history: growth (look at family growth charts), what age did they enter puberty, sexual history (do they have kids, is the problem condition/long-standing, DH, SH, FH
  • Examination: looking for secondary sexual characteristics and use of orchidometer to assess stage of development of the testes (measures their volume)
119
Q

How do you investigate for hypogonadism?

A

Sex steroid deficiency

  • Testosterone: key hormone for determining hypogonadism. T has a carcadian rhythm so early morning testosterone is usually tested. can measure free or total testosterone and SHBG
  • LH/FSH: help determine possible pituitary cause

Fertility:

  • semen analysis (1-3 days after last ejaculation)
  • should have 2-5ml, 20x106 sperm/ml, 50% progressive motility, >30% normal morphology
120
Q

Differentiate between hypogonadotrophic hypogonadism and primary gonadal failure

A

Hypogonadotrophic hypogonadism:

  • A clinical syndrome in which there is gonadal failure due to lack of pituitary gonadotrophin (LH and FSH) production
  • Either a hypothalamic problem (absence or lack of GnRH) or pituitary problem

Primary Gonadal Failure:

  • testicular problem
121
Q

List 3 causes of hypogonadotropic hypogonadism

A
  • non-functioning pituitary tumour
  • pituitary surgery
  • head injury
  • Kallmann’s syndrome: isolated LH and FSH deficiency
  • Cerebellar ataxia
  • Genetic syndromes
122
Q

What would results of

Testosterone

LH and FSH

be for a patient with hypogonadotrophic hypogonadism?

What investigations would you do next?

A

Testosterone: low

LH and FSH: low LH +/- FSH

if concerned about the pituitary, measure the other pituitary hormones (don’t want to miss pituitary tumour, for example)

low cortisol

low IGF-1/GH

TSH

Na

raised prolactin: if a patient has a prolactinoma, they’ll produce breast milk. Prolactin suppresses LH and FSH

123
Q

What is Kallmann’s Syndrome?

How is acquired?

A

A condition causing hypogonadotrophic hypogonadism due to a deficiency of GnRH

  • Familial with variable penetration, usually X-linked
  • Failure of cell migration of GnRH cells to the hypothalamus from the olfactory placode
  • Associated with aplasia of the olfactory lobes giving rise to lack of smell
124
Q

How would Kallmann’s syndrome present in childhood, adolescence and adulthood?

A

Childhood:

  • poor growth
  • undescended testes (cryptorchidism)

Adolescence (commonly presents here due to lack of sexual development):

  • poor growth
  • delayed/absent puberty features
  • small testes and micropenis

Adulthood:

  • slow, but adequate growth
  • small testes and phallus
  • hypogonadal features (low testosterone)
125
Q

What would test results of

testosterone

LH/FSH

Prolactin

be in a patient with primary gonadal failure?

A

Testosterone: low

LH/FSH: normal or high (ant. pituitary trying to stimulate testosterone release)

Prolactin: normal

126
Q

List 3 causes of primary gonadal failure

A
  • Klinefelter’s syndrome
  • Seminiferous tubule failure: can be caused by trauma, chemo, radiotherapy, multisystem disorders eg. amyloidosis, sarcoidosis, haemachromatosis
  • Adult leydig cell failure: can be caused by trauma, chemo, radiotherapy, multisystem disorders
  • Cryptorchidism
  • complex genetic syndromes
127
Q

What is Klinefelter’s syndrome?

What is the pathology

A

= A condition in males who have XXY sex chromosomes rather than XY

Pathology:

  • leydig cells don’t function properly and seminiferous tubules begin to regress
  • therefore less testosterone is made and inc. LH/FSH secreted (ant. pituitary trying to stimulate T release)
  • slightly more oestrogen produced
128
Q

List 3 phenotypes of Klinefelter’s syndrome

A
  • delayed puberty
  • suboptimal genital development
  • reduced secondary sexual characteristics
  • persistent gynaecomastia
  • azoospermia (infertility)
  • behavioural issues / learning difficulties
129
Q

How is Klinefelter’s syndrome managed?

A
  • Androgen replacement
  • Fertility counselling
  • Psychological support
130
Q

outline the management of hypogonadism

A

Androgen replacement therapy

  • helps maintain normal levels of circulating testosterone
  • bone and muscle mass to normal levels, improves libido, improves erectile function
  • oral, IM or topical
  • side effects: mood issues, acne, sweating, gynaecomastia
  • will not achieve high enough intra-testicular levels so if patient wants fertility, need to stop ART and start ferility treatment

Fertility treatment

  • injectable hCG
  • recombinant LH
  • FSH/GnRH pumps: overstimulates the pituitary
131
Q

Outline the phases of menstruation and the hormone regulation of the female reproductive system

A

Phases:

Ovary: follicular (day 0-14) and luteal (day 14-28)

Endometrium: mensus (day 0 to 4/7), proliferative (day 4/7 to 14) and secretory (day 14-28)

Regulation:

Hypothalamus releases GnRH stimulating the anterior pituitary to release FSH and LH

  • FSH stimulates granulosa cells (in follicule) to secrete oestrogen (supports development of oocytes and follicles)
  • Oestrogen at high levels is a negative feedback to the ant. pituitary and hypothalamus
  • Oestrogen and very high levels is a positive feedback to stimulate LH and FSH surge: ovulation and formation of corpus luteum

LH stimulates theca cells (of corpus luteum) to secrete progesterone, inhibit and oestrogen

  • Progesterone is used for endometrium development and inhibits LH and FSH secretion
  • Inhibin inhibits FSH and LH to a lesser extent
  • Oestrogen inhibits LH and FSH
132
Q

Define amenorrhoea

A

The absence of a menstrual period

133
Q

Differentiate between primary and secondary amenorrhoea

A

Primary: menstrual periods have never begun (from age 16)

Secondary: the absence of menstrual periods for 3 consecutive cycles or a time period more than 6 months in a women who was previously menstruating

134
Q

List 3 causes of primary amenorrhoea

A

Genitourinary abnormalities

  • Absence of the uterus, cervix or vagina

Chromosomal abnormalities

  • Turner’s syndrome (female carrying only one X chromosome)

Secondary hypogonadism ie. pituitary/hypothalmic cause

  • Kallmann’s syndrome (failure of GnRH neurons in the hypothalamus to develop)
  • Pituitary disease
  • Hypothalamic amenorrhoea: low BMI, stress, illness (external factors)
135
Q

List 3 causes of secondary amenorrhoea

A

Uterine: Ashermans syndrome (uterine adhesions)

Ovarian:

  • Polycystic Ovarian syndrome (PCOS)
  • premature ovarian failure (ovaries stop working before 40yrs): can be autoimmune or due to turner’s syndrome

Pituitary:

  • prolactinoma
  • non-functioning pituitary (inhibiting pituitary gland fxn) or functioning (prolactinoma) tumour

Hypothalamic:

  • external stressors: stress, weight loss, opiates

Other:

  • Phsyiological: pregnancy, lactation
  • Iatrogenic: OCP
  • thyroid dysfunction
  • hyperandrogenism eg. Cushing’s, CAH
136
Q

Define hirsutism

A

Excess hair growth in a male pattern due to increased androgens and increased skin sensitivity to androgens

137
Q

List three causes of hirsutism

A

Ovarian:

  • PCOS
  • androgen secreting tumour

Adrenal:

  • congenital adrenal hyperplasia (CAH)
  • Andorgen secreting tumour

Idiopathic

138
Q

Define polycystic ovarian syndrome (PCOS)

A
  • Chronic oligo- and/or anovulation
  • Clinical and/or biochemical signs of hyperandrogenism
139
Q

Outline the presentation of PCOS

A

Classic presentation: symptoms of anovulation

  • amenorrhoea or oligomenorrhoea
  • irregular cycles

Associated with: symptoms of hyperandrogenism

  • hirsutism, acne and alopecia

Spectrum of presentation varies:

  • anovulatory women without hirsutism
  • Hirsute women with mainly regular cycles

Usually presents during adolescence

Associated with metabolic abnormalities and inc. risk of T2DM

140
Q

What abnormalities are seen on an ultrasound of a patient with PCOS

A

Ovarian cysts

  • 20-25% of women of reproductive age have polycystic ovaries ie. ovarian cysts are common and not always pathological
141
Q

Outline the pathophysiology of polycystic ovarian syndrome

A

Gonadotrophins

  • Increased LH conc.: supports ovarian theca cell development therefore increased ovarian androgen production
  • Decreased FSH: low constant levels result in continuous stimulation of follciles without ovulation (no FSH surge) hence driving the polycystic ovarian pattern with anovulation
  • Reduced FSH also decreases conversion of androgens to oestrogens in granulosa cells

Androgens

  • increased levels of testosterone and androstenedione
  • inc. androgen production from theca cells under influence of LH
  • disordered enzyme action: ovarian enzyme expression (inc. ovarian androgen production) and inc. in peripheral conversion (androstenedione and T peripherally converted to DHT)
  • Decreased SHBG: therefore more free testosterone (biologically active). If elevated T and SHBG then may not be pathological

Insulin resistance

  • reduced insulin sensitivity in women with PCOS
  • sensitivity falls with inc. BMI therefore overweight women are more symptomatic
142
Q

What investigations are important for a patient with suspected PCOS?

A

Confirm hormone profile:

  • testosterone
  • androstenedione
  • DHEA-S (only slightly elevated)
  • SHBG
  • FSH/LH

If hormone profile consistent with PCOS, assess for other features

  • T2DM
  • Abnormal lipids
143
Q

What does an elevated DHEA-S in a women suggest and why?

A

Both the adrenal gland and ovary produce androgen compounts

  • the main discriminating androgen for determining the location of androgen excess: DHEA-S
  • Sig. elevation of DHEA-S suggests adrenal pathology
144
Q

How do you determine if the location of androgen excess is adrenal or ovarian?

A

Measure DHEA-S: sig elevated if adrenal pathology as more DHEA-S is produced here

145
Q

What management options are available for polycystic ovarian syndrome?

A

Aims:

  • weight loss and lifestyle intervention
  • insulin sensitisers ie. Metformin

Metformin:

  • for obese and non-obese, improves insulin sensitivity
  • leads to reduced LH levels and raised SHBG and so a fall in free testosterone

OCP to help regularity of periods

146
Q

What is a neuroendocrine tumour (NET)?

What is a neuroendocrine cell?

A

A rare tumour that can develop in many different organs and affects cells that release hormones into the blood stream

(Neuroendocrine cells: receive neuronal input and respond by releasing hormones into the bloodstream)

147
Q

List 3 types of neuroendocrine tumours

A
  • Carcinoid tumours: can occur in GI tract, lungs, thymus
  • Pancreatic NETs
  • Phaeochromocytoma: tumour of the adrenal cortex and release or noradrenaline and adrenaline
148
Q

Define hypoglycaemia

A

In diabetics: biochemical threshold of plasma glucose <4mmol/l

In non-diabetics: biochemical threshold of plasma glucose <3mmol/l

149
Q

Outline the clinical presentation of hypoglycaemia

A

Autonomic Symptoms:

  • Sweating, palpatation, pallor, tremor, nausea, irritability, hunger

Neuroglycopenic Symptoms:

  • slured speech, incoordination, weakness, dizziness, vision impairment, headache, seizures, coma

Whipple’s Triad:

  • symptoms of hypoglycaemia
  • low plasma glucose concentration
  • relief of symptoms after plasma glucose level is raised
150
Q

Patient with symptoms of hypoglycaemia lasting 30-60 minutes, 2 episodes 2 years apart

  • stable weight
  • family history of T2DM

Outline the diagostic pathway for this patient

A

Endocrine Society Diagnostic Approach

  • need to determine if patient is ill/medicated or seemingly well
  • Ill/Medicated: check drugs, critical illness (eg. hepatic/renal/cardiac failure, sepsis), hormone deficiency eg. cortisol, non-islet cell tumour
  • Seemingly well: endogenous hyperinsulinism (insulinoma, functional islet-cell disorders, insulin autoimmune hypoglycaemia eg. ab to insulin/insulin receptor)

Baseline Investigations

  • U&Es, LFT, TFTs
  • HbA1c and synacthen test

If all normal: 72-hour fast

  • provoke homeostatic response that keeps glucose conc from falling to concs that’s cause symptoms in absence of food
  • complete when: plasma glucose <2.5mmol/l, 72hrs have past or plasma glucose <3 with Whipple’s triad
  • once complete, measure insulin (should be undetectable). if detectable: suggests insulin excess. Can also measure C-peptide that’s released alongside insulin from the pancreas ie indicates endogenous insulin
  • if C-peptide is detectable, check for drugs that stimulate insulin release ie. SUs or gliclazide

Biochem before imaging to prevent incidentalomas

  • CT/MRI of abdomen or pancreas
  • EUS
151
Q

List 3 causes of spontaneous hypoglycaemia

A

Pancreatic:

  • insulinoma

Non-islet cell tumour hypoglycaemia:

  • metastatic cancer, lymphoma, myeloma, leukaemia

Autoimmune hypoglycaemia:

  • AI insulin syndrome, anti-insulin receptor

Drug induced:

  • insulin, sulphonylureas, beta blockers

Toxins: alcohol

Organ failure

  • severe liver failure, ESRF and renal dialysis

Endocrine disease:

  • hypopituitarism, adrenal failure, hypothyroidism

Miscellaneous:

  • sepsis, starvation, anorexia nervosa, severe excessive exercise
152
Q

List the clinical features seen with cortisol excess

A

Ie. Cushing’s syndrome

Face: moon face, plethora, acne and hirsutism, alopecia

Weight gain: truncal obesity

Skin: thin, fragile, striae, bruising

Limbs: proximal myopathy

Reproductive: amenorrhoea, low libido and erectile dysfunction

Associated: HTN, impaired glucose tolerance, reduced bone mineral density, vascular disease, susceptibility to infection

Phase 3 (12 decks)

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