Endocrine Flashcards
(152 cards)
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
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)
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
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
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
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
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
8
Q
How is T1DM managed?
A
- Insulin replacement therapy
- Glucose/Ketone monitoring
- CHO counting and education
- Supported self-management
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
10
Q
What is the function of insulin?
A
- Increases cellular glucose uptake
- Stimulates glycogenesis, enourages DNA synthesis and promotes GH release
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
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
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
14
Q
Define T2DM
A
Chronic, progressive metabolic disorder characterised by hyperglycaemia, insulin resistance and partial insulin deficiency
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
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
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
18
Q
What are the symptoms of T2DM?
A
- Polyuria
- Polydipsia
- Polyphagia
- Glycosuria
- Fatigue
- Weight loss
- Blurred vision or wounds taking longer to heal
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
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
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
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
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
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
25
How does symptom control balance with adverse effects of metformin?
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)
26
What is the class, action and indication of gliclazide?
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
27
How does symptom control balance with adverse effects of Gliclazide?
Symptom control:
- High efficacy
Adverse effects:
- Main: Hypoglycaemia
- Also; rashes, nausea, vomiting
- No CV benefit; Weight gain; Hypoglycaemic risk; caution in CKD
28
What is the class, indication and action of Exanatide?
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
29
How does symptom control balance adverse effects of Exanatide?
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
30
What is the class, indication and action of a 'gliptin'?
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
31
How does symptom control balance adverse effects of a 'gliptin'?
Symptom control:
- Moderate efficacy; Low hypoglycaemic risk; Well tolerated
Adverse effects:
- Weight neutral; No CV benefit; Reduce dose in CKD
32
What is the class, indication and action of a -flozin?
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
33
How does symptom control balance adverse effects of a -flozin?
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
34
What is the class, indication and action of thiazolidinediones?
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
35
How does symptom control balance adverse effects of thiazolidinedione?
Symptom control:
- Moderate efficacy, CV benefit, low hypo risk
Adverse effects:
- Weight gain; fluid retention; fractures
* Side effects outweigh prognosis benefit therefore rarely used*
36
What prescribing considerations are needed with T2DM medication in the elderly
- Polypharmacy: risk of drug interactions
- Increased risk of adverse events
- Inc. likelihood of hypoglycaemia
37
What prescribing considerations are necessary for T2DM medication in renal disease?
- 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)
38
What prescribing considerations are necessary for T2DM medication in heart failure?
- 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
39
What is the action and indication for insulin?
What are the types of insulin?
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
40
How does symptom control balance with adverse effects of insulin?
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
41
What hormone(s) is/are released from the anterior pituitary?
- **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
42
What hormone(s) is/are produced by the hypothalmus?
- **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
**TRH** (thyrotropin releasing hormone): to ant/ pituitary to stimulate TSH release
**GnRH** (gonadotropin releasing hormone): to ant. pituitary to release LH and FSH
43
What stimulates prolactin release and which pituitary gland is it released from?
- Stimulated by suckling
- Released from anterior pituitary
44
What hormones are released by the posterior pituitary?
- 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*
45
Where is the thyroid gland found?
What is the histology of the thyroid?
- 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
46
What are the general processes involving thyroglobulin in the thyroid?
- 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)
47
Describe the feedback loop involving the thyroid
- 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
48
Compare the production of T3 and T4
- 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
49
What is the function of thyroid hormones?
- Increased metabolism
- Growth and development
- Increased catecholamine effect (fight or flight): stimulates HR, raises BP
50
Define hypothyroidism
- When the thyroid produces abnormally low levels of thyroid hormones ie. underactive thyroid
51
What are the causes of hypothyroidism?
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
52
What is the clinical importance of hypothyroidism if there is a pituitary pattern in TFTs?
- 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)
53
What are the signs and symptoms of hypothyroidism
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
54
What investigations are carried out when determining thyroid function?
- TSH levels
- Free T3/T4 levels
- Autoantibodies: thyroid peroxisomal antibody (TPO) and TSH receptor antibodies
- TSH receptor antibodies are diagnostic for Graves' disease
55
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?
- Hashimoto's: autoimmune destructive thyroiditis
56
What is the treatment for hypothyroidism?
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
57
What is destructive thyroiditis?
What is thyrotoxicosis?
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
58
What are the complications of undiagnosed hypothyroidism at birth?
- Pre-eclampsia
- Stillbirth
- Miscarriage
- Low birth weight
59
What effect does undiagnosed hypothyroidism in a mother have on a developing foetus?
How is hypothyroidism investigated in neonates?
- Coarse facial features
- Macroglossia (large tongue)
- Developmental delay
- Goitre
- Cool and dry skin
Investigation: heel prick screening test in 1st week after birth
60
Define hyperthyroidism
Abnormal overproduction of thyroid hormones (T3/T4) ie. overactive thyroid
61
What is the aetiology of hyperthyroidism?
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
What are the causes of Graves' disease?
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
What are the signs and symptoms of hyperthyroidism?
- 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
What results on investigation would suggest hyperthyroidism?
- 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
What is the class, action and indication of levothyroxine?
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
What is the treatment for hyperthyroidism?
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
What is the class, action and indication of carbimazole?
What is the main adverse effect and what pharmacokinetic information is useful to know?
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
How does amiodarone cause thyroid disease?
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
What drug can cause thyroid disease?
Amiodarone (for supraventricular or ventricular tachycardias) due to high iodine content
70
What is the classification for amiodarone thyroid disease?
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
What is the clinical relevance of autoantibodies in thyroid disease?
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
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?
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
What investigations are necessary for determining nodules and tumours in the thyroid gland?
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
What is a hot nodule?
How is it diagnosed?
- 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
What are the 4 main types of thyroid carcinoma?
What are the main RFs for each?
- Papillary: most common, usually women \<40yr
- Follicular: middle aged, usually women
- Anaplastic: rarest but most serious, \>60yrs
- Medullary: familial
76
How are thyroid carcinomas investigated?
- 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
What are the treatment options for a thyroid carcinoma?
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
Describe the anatomy of the adrenal gland and where the production of hormones take place
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
What area of the adrenal gland is associated with the renin-angiotensin system?
What regulates the renin-angiotensin system?
- Concerned with the zona glomerulosa
- Main regulator of aldosterone release: renin in response to low BP
80
Explain the renin-angiotensin system
- 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
What is the function of aldosterone?
What regulates its release?
- 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
Where is cortisol produced?
How is release regulated?
ie. what is the axis?
- 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
What is the function of cortisol?
'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
What types of hormones are those produces from the adrenal gland?
What do they start as?
Which have a diurnal rhythm?
- Cortisol: glucocorticoid, aldosterone: mineralocorticoid, Androgens: sex steroids
- They all start as cholesterol
- Cortisol and androgens have a diurnal rhythm
85
Differentiate Cushing's Syndrome and Cushing's Disease
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
What are the causes of Cushing's Syndrome?
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
What are the clinical features of Cushing's syndrome?
- **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
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?
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
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?
2. 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
How is Cushing's syndrome treated?
- **Treat the cause**
Steroid use: gradually reduce and stop steroids
Tumour: surgery, radiotherapy, drugs to reduce effect of cortisol
91
What is adrenal insufficiency?
What are the main causes of primary adrenal insufficiency
- Inadequate adrenocortical function
- Deficiency in both cortisol and aldosterone
- Main causes of **primary** adrenal insufficiency: Addison's disease and autoimmune destruction
92
What is the clinical presentation of adrenal insufficiency
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
Patient presents with weight loss, fatigue, postural hypotension and salt cravings. You suspect adrenal insufficiency. What investigations do you do?
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
How do you treat Addison's disease?
Hormone replacement therapy
- Hydrocortisone (corticosteroid) to replace cortisol
- Fludrocortisone to replace aldosterone
95
What is the class, indication and action of hydrocortisone?
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
What are the functions of mineralocorticoids?
- Increased resorption of water
- Increased resorption of sodium
- Increased renal secretion of potassium
97
Define congenital adrenal hyperplasia (CAH)
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
What is the pathophysiology of congenital adrenal hyperplasia (CAH)?
- 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
What are the clinical features of Congenital Adrenal Hyperplasia (CAH)?
How is CAH diagnosed?
What is the treatment?
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
What is essential/primary hypertension?
Hypertension with no known cause
101
What is secondary hypertension and what are the RFs for developing it?
Secondary hypertension: hypertension caused by another disorder eg. renal disease
RFs:
- Young (\<40yrs), resistant/severe hypertension
102
What is primary aldosteronism?
The overproduction of aldosterone from adrenal gland cortex
- Related to overactivity of zona glomerulosa and overproduction of aldosterone
103
What clinical picture would be seen in a patient with primary aldosteronism?
- Hypertension
- Young (\<40)
- Hypokalaemia
104
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?
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
What is the management for primary aldosteronism?
Surgical
- Only for unilateral adrenal adenoma
- Unilateral laparoscopic adrenalectomy
- Cures hypokalaemia and hypertension
Medical
- Use MR antagonist (spironolactone)
106
Define a phaeochromocytoma
A rare tumour of the adrenal **medulla** that produces adrenaline and noradrenaline
107
What are the signs and symptoms of a phaeochromocytoma?
- Hypertension
- **Episodes** of headache, nausea, vomiting, pallor, sweating, tremor, anxiety, chest/abdo pain, palpatations
- Crises last 15 minutes
- Often well between crises
108
What is the treatment for phaeochromocytomas?
Initially: alpha-blocker
- Doxazosin
- Aim for SBP \<120mmHg if possible
Then, beta-blocker if tachycardic
- Bisoprolol
Encourage salt intake
109
What is an adrenal incidentaloma?
What are the different types?
Incidentally discovered / unsuspected adrenal lesion discovered through diagnostic imaging for an unrelated condition, without prior suspicion of tumour/disease
Types: malignant or functional
110
How is a malignant adrenal incidentaloma determined?
What functional adrenal incidentaloma's could be found?
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
Outline the normal anatomy of the male reproductive system (just where spermatogenesis occurs)
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
Outline the regulation of hormone release in the male reproduce system
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
Outline the functions of the male gonad
- testosterone production (leydig cells)
- fertility (spermatogenesis with help of sertoli and leydig cells)
114
Outline testosterone transport in the blood in males
- circulates bound to SHBG and some albumin
- free testosterone is active
- it is activated to the more potent form (dihydrotestosterone) in target tissues
115
What are the effects on testosterone on the body?
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
Define hypogonadism
- 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
Outline the clinical features of male hypogonadism in children and adults
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
How is endocrine function investigated?
- 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
How do you investigate for hypogonadism?
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
Differentiate between hypogonadotrophic hypogonadism and primary gonadal failure
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
List 3 causes of hypogonadotropic hypogonadism
- non-functioning pituitary tumour
- pituitary surgery
- head injury
- Kallmann's syndrome: isolated LH and FSH deficiency
- Cerebellar ataxia
- Genetic syndromes
122
What would results of
Testosterone
LH and FSH
be for a patient with hypogonadotrophic hypogonadism?
What investigations would you do next?
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
What is Kallmann's Syndrome?
How is acquired?
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
How would Kallmann's syndrome present in childhood, adolescence and adulthood?
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
What would test results of
testosterone
LH/FSH
Prolactin
be in a patient with primary gonadal failure?
Testosterone: low
LH/FSH: normal or high (ant. pituitary trying to stimulate testosterone release)
Prolactin: normal
126
List 3 causes of primary gonadal failure
- 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
What is Klinefelter's syndrome?
What is the pathology
= 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
List 3 phenotypes of Klinefelter's syndrome
- delayed puberty
- suboptimal genital development
- reduced secondary sexual characteristics
- persistent gynaecomastia
- azoospermia (infertility)
- behavioural issues / learning difficulties
129
How is Klinefelter's syndrome managed?
- Androgen replacement
- Fertility counselling
- Psychological support
130
outline the management of hypogonadism
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
Outline the phases of menstruation and the hormone regulation of the female reproductive system
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
Define amenorrhoea
The absence of a menstrual period
133
Differentiate between primary and secondary amenorrhoea
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
List 3 causes of primary amenorrhoea
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
List 3 causes of secondary amenorrhoea
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
Define hirsutism
Excess hair growth in a male pattern due to increased androgens and increased skin sensitivity to androgens
137
List three causes of hirsutism
Ovarian:
- PCOS
- androgen secreting tumour
Adrenal:
- congenital adrenal hyperplasia (CAH)
- Andorgen secreting tumour
Idiopathic
138
Define polycystic ovarian syndrome (PCOS)
- Chronic oligo- and/or anovulation
- Clinical and/or biochemical signs of hyperandrogenism
139
Outline the presentation of PCOS
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
What abnormalities are seen on an ultrasound of a patient with PCOS
Ovarian cysts
- 20-25% of women of reproductive age have polycystic ovaries ie. ovarian cysts are common and not always pathological
141
Outline the pathophysiology of polycystic ovarian syndrome
**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
What investigations are important for a patient with suspected PCOS?
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
What does an elevated DHEA-S in a women suggest and why?
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
How do you determine if the location of androgen excess is adrenal or ovarian?
Measure DHEA-S: sig elevated if adrenal pathology as more DHEA-S is produced here
145
What management options are available for polycystic ovarian syndrome?
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
What is a neuroendocrine tumour (NET)?
What is a neuroendocrine cell?
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
List 3 types of neuroendocrine tumours
- Carcinoid tumours: can occur in GI tract, lungs, thymus
- Pancreatic NETs
- Phaeochromocytoma: tumour of the adrenal cortex and release or noradrenaline and adrenaline
148
Define hypoglycaemia
In diabetics: biochemical threshold of plasma glucose \<4mmol/l
In non-diabetics: biochemical threshold of plasma glucose \<3mmol/l
149
Outline the clinical presentation of hypoglycaemia
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
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
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
List 3 causes of spontaneous hypoglycaemia
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
List the clinical features seen with cortisol excess
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
