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1

What is the significance of the thyroid C-Cell?

1. Produces calcitonin which inhibits Ca2+ absorption, inhibits osteoclasts, and inhibits renal reabsorption Ca+
2. Main cell in thyroid medullary Ca

**Calcitonin is like an 'anti-PTH' EXCEPT, that like PTH, it also inhibits renal tubular reabsorption.

2

Describe the steps involved in thyroid hormone synthesis.

1. Albumin-bound iodide gets taken up and extracted by the NIS (Na+/Iodide symporter) on the basal surface of the follicle cell and stored at the apical surface of the cell.
2. TSHr is activated by TSH resulting in follicular release of Thyroglobulin (Tg) into the colloid, along with Iodine (Io) (via Pendrin transporter).
3. Thyroid peroxidase (TPO) catalyses a reaction resulting in the binding of Tg and Io.
4. The Tg-Io complex is taken back up into the follicular cell where it is processed by the lysosome into T3 and T4
5. T3 and T4 are released out the basal membrane into the bloodstream where it feeds back on TSH and TRH respectively.

3

1. What is the mechanism of Amiodarone hypothyroidism?
2. Where and in who is it a problem?
3. How do you manage it?
4. How do you monitor it?

1. Loss of escape from the Wolff-Chaikoff effect in autoimmune thyroiditis resulting in iodine-driven hypothyroidism
2. Iodine-replete countries, women, and when anti-TPO positive.
3. Levothyroxine, continue amiodarone
4. Monitor TSH - T4 will be elvated regardless due to suppression of deiodinase.

4

What is the difference between Amiodarone-Induced Thyrotoxicosis (AIT) Types 1 and 2?

Type 1: Activation and increased production (Graves, MNG)

Type 2: Destruction and excess release (acute thyroiditis due to thyroid gland destruction and stored hormone release)

5

1. What is the mechanism of Amiodarone-Induced Thyrotoxicosis Type 1?
2. What imaging would you do? What would it show?
3. How do you treat it? How does it work?

1. Increased iodine leads to hyperthyroidism from excessive hormone synthesis (Jod-Basedow effect)
2. Colour flow Doppler U/S: Increased vascularity. Thyroid scintiscan is not useful due to high levels of endogenous iodine which inhibits tracer uptake. Decreased or normal uptake however may favour type 1 AIT.
3. Carbimazole: prevents TPO from iodinating thyroglobulin à decreased T3 and T4 production . Cease amiodarone (unless it’s really needed, it has a long T1/2)

6

1. What is the mechanism of Amiodarone-Induced Thyrotoxicosis Type 2?
2. What characterises AIT Type 2?
3. How do you image it and what does it show?
4. How do you treat it?

1. Drug-induced lysosomal activation → destructive thyroiditis with histiocyte (tissue macrophage) accumulation in the thyroid → release of pre-formed T3 and T4
2. No intrinsic thyroid abnormality, incidence increases with amiodarone dose.
3. Colour flow Doppler: Decreased vascularity
4. Prednisone 40-50mg daily, and cease amiodarone (unless you really need it!)

7

What is the Wolff-Chaikoff effect?

Hypothyroidism due to high iodine load.

8

What is the Jod-Basedown effect?

Excess iodine causes hyperthyroidism in pre-existing thyroid disease

9

What is the difference between thyrotoxicosis and hyperthyroidism?

Thyrotoxicosis is defined as the state of thyroid hormone excess and is not synonymous with hyperthyroidism, which is the result of excessive thyroid function.

10

How do you tell if a patient likely has Type 1 or Type 2 AIT when presenting with a mixed-picture Amiodarine-induced thyrotoxicosis?

A rapid response (reduction in thyroid hormone levels) to combined treatment (pred AND carbimazole) suggests Type 2 AIT. Steroids work faster and pre-existing hormone will be depleted while carbimazole has rapid-antithyroid effect but takes longer on levels due to stored pre-existing hormone which is still being replenished.

11

What is the management of Graves Disease?

1. Beta-blockers - control adrenergic effects
- propranolol 0.25mg-0.5mg/kg 3-4 times per day
- start as soon as dx made - don't wait for uptake scan

2. Thionamides ('imazoles and PTU)
- Methimazole / Carbimazole (prodrug of Methimazole) is preferred
- longer acting
- once daily dosing
- more rapid efficacy
- Less side effects (agranulocytosis, deranged LFTs)
- Teratogenic in first trimester
- PTU
- 1st trimester

Goal: rapid euthyroidism in 3-8 weeks
Need baseline bloods: FBC and LFTs - C/I if neutropaenic, deranged LFTs
Titrate dose to size of goitre and severity of hyperthyroidism
Not curative for most

3. Radioactive iodine ablation
- only once euthyroid
- C/I if pregnant/severe opthalmopathy (can use concurrent steroids if mild)
- Hormone stores must be depleted prior - otherwise destructive release --> thyrotoxicosis
- main SE: hypothyroidism
- Curative

4. Surgery
- big or obstructive goitre
- opthalmopathy
- pregnancy (preferably be six months prior to avoid use of thionamides
- suspicion of malignancy or hyperparathyroidism

12

Outline the how the renin-angiotensin system works.

What are the effects of angiotensin 2?

RAAS - it’s job is to restore normovolaemia.

Macula densa (JGA) detects low chloride concentration in the tubule, baroreceptors in the afferent arteriole detects decreased perfusion pressure.

Renin is then secreted from the glomerulus and JGA, resulting in the production of AT1 (renin is the substrate), followed by conversion to ATII, catalysed by ACE (mainly present in the lung).

AT2 effects (all except vasoconstriction via AT1 receptors):  
• Systemic vasoconstriction of vascular smooth muscle (via AT2 receptors) 
• Na+ reabsorption (early proximal tubule)
• Aldosterone secretion from the adrenal cortex resulting in Na+ reabsorption in the cortical collecting tubule
* Catecholamine release
• Maintenance of GFR via afferent + efferent arterioles with the help of thromboxane A2 (a vasoconstrictor) and local prostaglandins (vasodilators).  This happens in response to a drop in systemic pressure, by constricting the efferent arteriole and opening up the afferent, the net result is maintenance of renal perfusion.

13

What is the medical management of BPH?  How do the drugs work?


Management options
watchful waiting
medication: alpha-1 antagonists, 5 alpha-reductase inhibitors. The use of combination therapy was supported by the Medical Therapy Of Prostatic Symptoms (MTOPS) trial
surgery: transurethral resection of prostate (TURP)

Alpha-1 antagonists e.g. tamsulosin, alfuzosin
decrease smooth muscle tone (prostate and bladder)
considered first-line, improve symptoms in around 70% of men
adverse effects: dizziness, postural hypotension, dry mouth, depression

5 alpha-reductase inhibitors e.g. finasteride
block the conversion of testosterone to dihydrotestosterone (DHT), which is known to induce BPH
unlike alpha-1 antagonists causes a reduction in prostate volume and hence may slow disease progression. This however takes time and symptoms may not improve for 6 months. They may also decrease PSA concentrations by up to 50%
adverse effects: erectile dysfunction, reduced libido, ejaculation problems, gynaecomastia

14

What are the electrolyte abnormalities in Addison's disease and how do you establish the diagnosis?


In a patient with suspected Addison's disease the definite investigation is a ACTH stimulation test (short Synacthen test). Plasma cortisol is measured before and 30 minutes after giving Synacthen 250ug IM. Adrenal autoantibodies such as anti-21-hydroxylase may also be demonstrated

Associated electrolyte abnormalities
hyperkalaemia
hypercalcemia

hyponatraemia
hypoglycaemia

metabolic acidosis


15

How do you test for coeliac disease?


NICE issued guidelines on the investigation of coeliac disease in 2009. If patients are already taking a gluten-free diet they should be asked, if possible, to reintroduce gluten for at least 6 weeks prior to testing.

Immunology
tissue transglutaminase (TTG) antibodies (IgA) are first-choice according to NICE
endomyseal antibody (IgA)
anti-gliadin antibody (IgA or IgG) tests are not recommended by NICE
anti-casein antibodies are also found in some patients

Jejunal biopsy
villous atrophy
crypt hyperplasia
increase in intraepithelial lymphocytes
lamina propria infiltration with lymphocytes

16

What does the adrenal medulla secrete?

The adrenal medulla secretes virtually all the adrenaline in the body as well as secreting small amounts of noradrenaline. It essentially represents an enlarged and specialised sympathetic ganglion

17

What does the B3 receptor do?

Enhancement of lipolysis in adipose tissue.
Thermogenesis in skeletal muscle

18

What does the insulin receptor do?

1.  TKI
2.  Increases glut-4 transporter molecules on outer membrane of tissues ie muscle and fat
3.  Influx of glucose, glycogen synthesis, glycolysis, FFA synthesis
4.  Mutations are rare.

19

Name three points about leptin

1.  Appetite suppressant
2.  Precursor is alpha-melanocyte stimulating hormone which acts in the hypothalamus
3.  Increased in obese people.

20

What is C-peptide and why is it important?

1.  Fragment of proinsulin that is removed to create insulin.
2.  Distinguishes between established Type 1 & MODY diabetes (C-Peptide will be low as not producing), and type 2 diabetes/obesity (high due to insulin resistance)
3.  Measured instead of insulin because it can be measured while someone is receiving insulin injections, and due to the liver metabolising insulin quite variably in the portal circulation.

21

Which one of the following is the most common biochemical association of obesity? 
A. Mutation of the insulin receptor. 

B. Reduced serum leptin. 
C. Mutation of the β3-adrenergic receptor. 

D. Raised serum C-peptide. 

E. Raised blood glucose. 


D

22

Which diseases cause hypokalemia with hypertension?

Cushing's syndrome
Conn's syndrome (primary hyperaldosteronism)
Liddle's syndrome
11-beta hydroxylase deficiency*
Renovascular hypertension

*21-hydroxylase deficiency, which accounts for 90% of congenital adrenal hyperplasia cases, is not associated with hypertension

23

Which diseases cause hypokalaemia without hypertension?

diuretics
GI loss (e.g. Diarrhoea, vomiting)
renal tubular acidosis (type 1 and 2**)
Bartter's syndrome
Gitelman syndrome

24

Describe Polymorphic eruption of pregnancy

- pruritic non-blistering condition associated with last trimester
- lesions often first appear in abdominal striae
- management depends on severity: emollients, mild potency topical steroids and oral steroids may be used

25

Describe Pemphigoid gestationis

- pruritic blistering lesions
- often develop in peri-umbilical region, later spreading to the trunk, back, buttocks and arms
- usually presents 2nd or 3rd trimester and is rarely seen in the first pregnancy
oral corticosteroids are usually required

26

Which lipid profiles are associated with an increased risk of coronary artery disease?

High levels of LDL

High triglycerides with low HDL

27

Which one of the following best describes the association between hyperinsulinaemia (insulin resistance) and coronary heart disease? 
The relationship is: 

A. independent of total cholesterol. 

B. confined to subjects with low HDL (high density lipoprotein) cholesterol. 

C. confined to obese individuals. 

D. confined to hypertensive subjects only. 

E. confined to diabetic subjects only. 


A.  The dyslipidaemia associated is usually hypertriglyceridaemia and low HDL.  This is more important than total cholesterol.

28

What is the basic pathogenesis of type 1 and 2 diabetes?

Type 1
 - deficiency of insulin secretion
 - elevated plasma glucagon
 - due to autoimmune pancreatic B-islet cell destruction
 - prone to ketoacidosis

Type 2
 - combination of insulin resistance and inadequate secretion to compensate

29

What is the major cause of Type 1 DM?
When does it occur?

- Immune mediated Type 1A in over 95% of cases

- Idiopathic in <5% (type 1b)

- peak incidence before school age and again around puberty

30

What is the influence of genetics on type 1 diabetes?

- 1/3 due to genes, 2/3 to environmental factors
- 95% are either HLA-DR3 or DR4 positive
- HLA-DQ genes more specific - HLADQB1*0302 is found in Type 1 patients, while HLADQB*0602 is found in controls.
- 10% of genetic risk found at 5' polymorphic region of the insulin gene - affects the expression of the insulin gene in the thymus resulting in depletion of specific T-lymphocytes.