Case 9 Flashcards

Question

does any or how much iodinated tyrosine in the thyroglobulin remains as MIT and DIT and never becomes thyroxine?

Answer 1

• These free tyrosine molecules area also released into the cytoplasm of the thyroid cells when thyroglobulin is digested. 1. However, they are not secreted into the blood. 2. Instead, their iodine is cleaved from them by a deiodinase enzyme and the iodine and tyrosine are available again for recycling within the gland for forming additional thyroid hormones.

Answer 2

because of failure of this recycling process.

Answer 3

Even though most of the thyroid hormone that is secreted into the blood is T4, about 50% of this deiodinates into T3 once it reaches the tissue.

Answer 4

99% of them bind to plasma proteins for transport to tissues.

Answer 5

 Thyroxine-binding globulin (mainly)  Thyroxine-binding prealbumin (much less)  Albumin (much less)

Answer 6

• The thyroid hormones have a high affinity to the plasma-binding proteins. • This means that these hormones are released to the tissue cells slowly. • Thyroxine has a much higher affinity than T3.  Half of thyroxine is released to tissue cells every 6 days.  Half of T3 is released to tissue cells every 1 day.

Answer 7

* On entering the cells, the thyroid hormones bind to intracellular proteins. * Thyroxine binds more strongly than T3. * In this way, the thyroid hormones are stored in the target cells themselves, and are used slowly over a period of days or weeks.

Answer 8

 Thyroid hormones have a slow onset and long duration of action.  Thyroxine has a half-life of 15 days (as shown in the graph).  Most of the latency and prolonged period of action of these hormones are caused by their high affinity for binding to the plasma and intracellular proteins, followed by their slow release.

Answer 9

 Increase in transcription of genes.  Increased cellular metabolic activity.  Increased growth.  Increased metabolism of carbohydrates and fats.  Increases need for vitamins by increasing enzymes in the body.  Increases blood flow, cardiac output, heart rate, heart strength.  Increased respiration.  Increased GI motility.  Increased CNS excitation, which can lead to muscle tremors.  Increased tiredness.  Maintains normal sex function.

Answer 10

• Thyroid hormones activate nuclear transcription of large numbers of genes. 1. This increases the synthesis of Therefore, in all cells of the body, great numbers of protein enzymes, structural proteins, transport proteins, and other substances are synthesised. 2. The net result is generalised increase in functional activity throughout the body.

Answer 11

 Thyroxine is deioditnated to T3.  Intracellular thyroid hormone receptors have a very high affinity for T3.  T3 binds to nuclear thyroid hormone receptors.  The thyroid hormone receptor usually forms a heterodimer with retinoid X receptor (RXR) on the DNA. (This means that the receptor joins together with RXR).  On binding with thyroid hormone, the receptors become activated and initiate the transcription process.  This leads to the formation of different types of mRNA and subsequent the RNA translation on the ribosomes to form hundreds of new intracellular proteins. - The variety of synthesis of proteins allows for the other aforementioned effects of thyroid hormone.

Answer 12

* Thyroid hormones increase the metabolic activity of most body tissues. * The basal metabolic rate can increase to 60-100% above normal when large quantities of the hormones are secreted.

Answer 13

1. Utilisation of food for energy 2. Protein synthesis/catabolism 3. Growth rate 4. Other endocrine glands

Answer 14

* T3/T4 causes an increase in the size and number of mitochondria. * Also, the total membrane surface area of the mitochondria also increases in proportion to the increased metabolic rate. * This results in increased ATP production and cellular function.

Answer 15

* T3/T4 increase the activity of the enzyme Na+/K+ ATPase. * This increases the rate of transport of both Na+ and K+ ions. * Because this process uses energy and increases the amount of heat produced in the body, it is a mechanism by which thyroid hormone increases the body’s metabolic rate.

Answer 16

• Thyroid hormones promote growth in growing children. 1. In hypothyroid, the rate of growth is greatly reduced. 2. In hyperthyroid, excessive skeletal growth often occurs.  This causes the child to become considerably taller at an earlier age.  However, bones also mature more rapidly and the epiphyses close at an early age.  Therefore, the duration of growth and eventual height of the adult may actually be shortened. * Thyroid hormone also promotes growth and development of the brain both during foetal life and for the first few years of postnatal life. * If the foetus does not secrete sufficient quantities of TH, growth and maturation of the brain before birth and afterward are greatly retarded, and the brain remains smaller.

Answer 17

• TH stimulates almost all aspects of carbohydrate metabolism including: 1. Rapid uptake of glucose by cells. 2. Enhanced glycolysis. 3. Enhanced gluconeogenesis. 4. Increased absorption rate from GI tract. 5. Increased insulin secretion with its resultant secondary effects on carbohydrate metabolism. • These effects result from the overall increase in cellular metabolic enzymes caused by the increased gene transcription and subsequent enzyme synthesis caused by thyroid hormones.

Answer 18

• All aspects of fat metabolism are enhanced under the influence of TH. 1. In particular, lipids are mobilised rapidly from the fat tissue, which decreases the fat stores of the body to a greater extent than almost any other tissue element, leading to a loss in weight. 2. This also increases the free fatty acid concentration in the plasma and greatly accelerates the oxidation of free fatty acids by the cells. 3. The oxidation of fatty acids results in the formation of acetyl-CoA, which can then enter the citric acid cycle, causing increased release of energy.

Answer 19

• Even though thyroid hormones increase free fatty acids, they decrease the plasma concentrations of: 1. Cholesterol 2. Phospholipids 3. Triglycerides • Decreased thyroid secretion greatly increases the plasma concentrations of these molecules, causing excessive deposition of fat in the liver. • Mechanism of Action:  The decrease in plasma cholesterol concentration is caused by increase rate of cholesterol secretion in the bile and consequent loss in the faeces.  A possible mechanism for the increased cholesterol secretion is that thyroid hormone induces increased numbers of low-density lipoprotein receptors on the liver cells, leading to rapid removal of low-density lipoproteins from the plasma by the liver and subsequent secretion of cholesterol in these lipoproteins by the liver cells

Answer 20

• Vitamins are essential parts of some enzymes and coenzymes. • TH increases quantities of bodily enzymes so it causes increased need for vitamins. - Therefore, a relative vitamin deficiency can occur when excess TH is secreted.

Answer 21

- increased blood flow and cardiac output - increased HR - increase heart strength - normal arterial pressure

Answer 22

• Increased metabolism in the tissues causes more rapid utilisation of oxygen than normal and release of greater than normal quantities of metabolic end products from the tissues 1. These effects cause vasodilation in most body tissues, thus increasing blood flow • The rate of blood flow in the skin increases because of the increased need for heat elimination from the body. 1. As a consequence of the increased blood flow, cardiac output also increases.

Answer 23

* TH has a direct effect on the excitability of the heart, thus increasing the heart rate. * This effect is important because the HR is one of the sensitive physical signs that clinicians use in determining whether a patient has excessive or diminished TH production.

Answer 24

• When TH is increased, the heart muscle strength becomes depressed because of long-term excessive protein catabolism.

Answer 25

• The mean arterial pressure remains normal after administration of TH. • Due to increased blood flow through the tissues between heartbeats, the pulse pressure is often increased. 1. Therefore, systolic pressure elevates in hyperthyroidism. 2. Diastolic pressure decreases.

Answer 26

* The increased rate of metabolism increases the utilisation of oxygen and formation of carbon dioxide. * These effects activate all the mechanisms that increase the rate and depth of respiration.

Answer 27

• In addition to increased appetite and food intake, TH increases both: 1. The rates of secretion of digestive juices 2. The motility of the GI tract • Hyperthyroidism often results in diarrhoea. • Hypothyroidism can cause constipation.

Answer 28

* Generally, TH increases the rapidity of cerebration. * Hyperthyroidism leads to extreme nervousness and many psychoneurotic tendencies such as: 1. Anxiety complexes 2. Extreme worry 3. Paranoia

Answer 29

* Slight increase in TH makes muscles react with vigour. * Excessive increase in TH causes the muscles to become weakened because of excess protein catabolism. * Lack of TH causes the muscles to become sluggish, and they relax slowly after contraction.

Answer 30

a fine muscle tremor

Answer 31

* This tremor is caused by increased reactivity of the neuronal synapses in the areas of the spinal cord that control muscle tone. * The tremor is an important means for assessing the degree of thyroid hormone effect on the CNS.

Answer 32

• Due to the exhausting effect of TH on muscles and CNS, hyperthyroid subjects feel constantly tired because of the excitable effects of TH on synapses.

Answer 33

• Increased TH increases the rates of secretion of endocrine glands, but it also increases the need of the tissues for the hormones. 1. E.g. Increased thyroxine secretion increases the rate of glucose metabolism everywhere in the body. 2. This causes a corresponding need for increased insulin secretion by the pancreas.

Answer 34

* Normal TH allows for normal sexual function to occur * In men: 1. Lack of TH – loss of libido 2. Excess TH – impotence • In women: 1. Lack of TH – loss of libido, menorrhagia and polymenorrhoea/sometimes even amenorrhoea  (excessive and frequent menstrual bleeding/irregular periods) 2. Excess TH – oligomenorrhoea (greatly reduced bleeding) • The action of TH on the gonads is due to the effects of metabolic activities combined with excitatory and inhibitory feedback effects operating through the anterior pituitary hormones that control the sexual functions.

Answer 35

• To maintain normal levels of metabolic activity in the body, the right amount of TH must be secreted at all times: - Specific feedback mechanisms operate through the hypothalamus and anterior pituitary gland to control the rate of thyroid secretion.

Answer 36

• TSH (thyrotropin) is a glycoprotein secreted by the anterior pituitary gland. • This hormone increases the secretion of T4 and T3 by thyroid gland. • Its specific effects on the thyroid are as follows: 1. Increased proteolysis of thyroglobulin that is stored in the follicles, with resultant release of the TH into the circulation. 2. Increased activity of the iodide pump, which increases the rate of “iodide trapping” 3. Increased iodination of tyrosine to form the TH. 4. Increased size and increased secretory activity of the thyroid cells. 5. Increased number of thyroid cells + a change from cuboidal to columnar cells and much infolding of the thyroid epithelium into the follicles. • In summary, TSH increases all the known secretory activities of the thyroid glandular cells - The most important early effect (30mins) being proteolysis of thyroglobulin to release T3 + T4 followed by the rest (hours-days).

Answer 37

1. TSH binds with TSH receptors on the basal membrane surfaces of the thyroid cell. 2. This activates adenylyl cyclase in the membrane, which increases the formation of cAMP inside the cell. 3. Finally, the cAMP acts as a 2nd messenger to activate protein kinase which causes multiple phosphorylations throughout the cell. • The result is both an immediate increase in secretion of TH and prolonged growth of the thyroid glandular tissue itself

Answer 38

• Anterior pituitary secretion of TSH is controlled by a hypothalamic hormone, thyrotropin-releasing hormone (TRH): 1. This is secreted by nerve endings in the median eminence of the hypothalamus. 2. From the median eminence, the TRH is then transported to the anterior pituitary by way of the hypothalamic-hypophysial portal blood. • TRH directly affects the anterior pituitary gland cells to increase their output of TSH.

Answer 39

1. First to bind with TRH receptors in the pituitary cell membrane. 2. This, in turn, activates the phospholipase second messenger system inside the pituitary cells to produce large amounts of phospholipase C. 3. This is followed by a cascade of other second messengers, including calcium ions and diacyl glycerol. 4. Eventually, this leads to TSH release.

Answer 40

• Increased thyroid hormones in the body fluids decreases secretion of: 1. TRH by the hypothalamus 2. TSH by the anterior pituitary

Answer 41

a peptide hormone secreted by the thyroid gland

Answer 42

decreases plasma calcium concentration

Answer 43

in the C cells, lying in the interstitial fluid between the follicles of the thyroid gland.

Answer 44

increased plasma calcium concentration

Answer 45

parathyroid hormone

Answer 46

• Calcitonin decreases blood calcium ion concentration rapidly in two ways: 1. Immediate effect - decrease the absorptive activities of the osteoclasts thus shifting the balance in favour of deposition of calcium in the exchangeable bone calcium salts. 2. Prolonged effect - decrease the formation of new osteoclasts.

Answer 47

* Calcitonin has a weak effect on plasma calcium concentration. * This is because any initial reduction of the calcium ion concentration caused by calcitonin leads within hours to a powerful stimulation of PTH secretion, which almost overrides the calcitonin effect. • Calcitonin also has minor effects of calcium handling in the kidneys and intestines.

Answer 48

• Parathyroid hormone (PTH) controls extracellular calcium and phosphate concentrations by regulating:  Intestinal reabsorption  Renal excretion  Exchange of these ions between the extracellular fluid and bone

Answer 49

* Excess activity of the parathyroid gland (increased release of PTH) causes rapid absorption of calcium salts from the bones, resulting in hypercalcemia in the extracellular fluid. * Hypo-function of this gland causes hypocalcaemia.

Answer 50

1. Rapid phase – this begins in minutes and increases progressively for several hours  This results from activation of osteocytes to promote calcium and phosphate absorption. 2. Slow phase – this requires several days/weeks  It results from proliferation of the osteoclasts, followed by greatly increased osteoclastic reabsorption of the bone itself.

Answer 51

the over-activity of the thyroid gland.

Answer 52

a hyper-metabolic state caused by elevated circulating levels of free T3 and T4, caused by hyperthyroidism.

Answer 53

* Hyperthyroidism can be primary or secondary. * Primary hyperthyroidism is when the pathology is within the thyroid gland. * Secondary hyperthyroidism is when the thyroid gland is stimulated by excessive TSH in the circulation. * Secondary hyperthyroidism is rare. The pathology is usually at the site of the pituitary gland.

Answer 54

TSH-secreting pituitary adenoma (rare).

Answer 55

• The most common causes of thyrotoxicosis are also associated with hyperfunction of the gland and include the following: 1. Diffuse hyperplasia of the thyroid associated with Graves’ disease (85% of cases) 2. Multinodular goitre 3. Toxic adenoma of the thyroid 4. Thyroiditis

Answer 56

Prevalence • 400/100,000 persons • Lifetime risk of 1% in men and up to 2% in women. • 60-80% of cases are due to Graves' disease with a peak onset at 20-50 years. • Remainder of cases are due to nodular thyroid disease that appears later in life. • Affects females more than males (ratio 9:1) Incidence • 0.77/1,000 annually in women • 0.14/1,000 annually in men • In England the incidence of Graves' disease has been reported as 0.5/1,000/year

Answer 57

* Family history – genetic susceptibility * High iodine intake * Smoking * Toxic multi-nodular goitre * Childbirth * Highly active antiretroviral therapy (HAART)

Answer 58

to the hypermetabolic state induced by excess TH and to over-activity of the sympathetic nervous system (i.e. an increase in the β-adrenergic tone).

Answer 59

• Most common cause of endogenous hyperthyroidism. • It is characterised by a triad of clinical findings: 1. Hyperthyroidism due to diffuse, hyperfunctional enlargement of the thyroid 2. Infiltrative ophthalmopathy with resultant exophthalmos (protrusion of eyeball)  This is an autoimmune inflammatory response affecting the orbit, leading to bulging eyes. 3. Pretibial myxoedema – this is localised, infiltrative dermopathy, which is present in a minority of patients.  Red, swollen skin, usually on the shins and tops of feet.  Texture of the skin is similar to that of an orange peel.

Answer 60

• Graves’ disease has a peak incidence between ages 20-40. • Women are affected 10 times more than men. • This disorder is said to be present in 1.5-2% of women. • Genetic factors are important in the aetiology of Graves’ disease 1. There is a concordance rate in monozygotic twins of 30-40% 2. This is less than 5% among dizygotic individuals

Answer 61

* In Graves’ disease, the body produces antibodies to the TSH-receptor (TSHr). * Antibodies to thyroglobulin, T3 and T4 may also be produced. * These antibodies can bind to TSHr and chronically stimulate them. * This result of chronic stimulation is an abnormally high production of T3 and T4. * This, in turn causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goitre.

Answer 62

1. Thyroid-Stimulating Immunoglobulins (TSI): - These antibodies, mainly IgG, act as long-acting thyroid stimulants, activating the cells in a longer and slower way than TSH. - They bind to the TSHr and mimic the action of TSH, increasing the release of TH.  Individuals with Graves’ disease have detectable levels of this autoantibody.  TSI are relatively specific for Graves’ disease, in contrast to thyroglobulin and thyroid peroxidase antibodies. 2. Thyroid Growth-Stimulating Immunoglobulins (TGI): - These antibodies bind directly to the TSHr and have been implicated in the growth of thyroid follicular epithelium. 3. TSH/Thyrotropin-Binding Inhibitor Immunoglobulins (TBII): - These anti-TSH receptor antibodies prevent TSH from binding normally to its receptor on thyroid epithelial cells.  Some forms of TBII mimic the action of TSH, resulting in the stimulation of thyroid epithelial cell activity.  Other forms may not stimulate the thyroid gland, but will prevent TSI and TSH from binding to and stimulating the receptor. These patients will experience hypothyroidism.

Answer 63

• Autoimmunity also plays a role in the development of the infiltrative ophthalmopathy that is characteristic of Graves’ disease. • In Graves ophthalmopathy, the volume of the retro-orbital connective tissues and extra-ocular muscles is increased for several reasons including: 1. T-cell infiltration of the retro-orbital space. 2. Inflammatory oedema and swelling of extra-ocular muscles. 3. Accumulation of extracellular matrix components, specifically hydrophilic glycosaminoglycans such as hyaluronic acid and chondroitin sulfate. 4. Increased numbers of adipocytes (fatty infiltration). • These changes displace the eyeball forward (bulging eyes) and can interfere with the function of the extra-ocular muscles.

Answer 64

* Orbital pre-adipocyte fibroblasts express the TSHr and thus become targets of an autoimmune attack. * T-cells reactive against these fibroblasts secrete cytokines, which stimulate fibroblast proliferation and synthesis of extracellular matrix proteins (glycosaminoglycans) and increase surface TSHr expression, perpetuating the autoimmune response. * The result is progressive infiltration of the retro-orbital space and ophthalmopathy.

Answer 65

* The thyroid gland is usually symmetrically enlarged because of diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells. * Parenchyma has a soft, meaty appearance resembling normal muscle. * Histologically, the follicular epithelial cells in untreated cases are tall and more crowded than usual.

Answer 66

the under-activity of the thyroid gland.

Answer 67

* Hypothyroidism is caused by inadequate function of the thyroid gland (primary hypothyroidism) or by not enough stimulation by TSH (central hypothyroidism). * Primary hypothyroidism is 1000x more common than central hypothyroidism.

Answer 68

1. Iron deficiency is the most common cause of primary hypothyroidism and endemic goitre worldwide. 2. Hashimoto’s Thyroiditis in places with sufficient dietary iodine. 3. After treatment of hyperthyroidism – usually after radioiodine treatment.

Answer 69

* The earliest biochemical abnormality is an increase in serum TSH concentration with normal serum T4 and T3 concentrations (subclinical hypothyroidism). * This is followed by a decrease in serum T4, causing symptoms - require treatment (overt hypothyroidism). * Hypothyroidism results from insufficient secretion of TH and can be due to a variety of abnormalities; the severest form is myxoedema (cutaneous and dermal oedema).

Answer 70

• Hypothyroidism increases with age – most common around 60 years of age. • Autoimmune hypothyroidism (Hashimoto’s) is more common in Japan. Incidence • Overt form = 2% women and 0.2% men. • Subclinical form = 6-8% women and 3% men. • 2.5% of pregnant women develop hypothyroidism.

Answer 71

* Hashimoto thyroiditis is the most common cause of hypothyroidism in areas of the world where iodine levels are sufficient. * This disease describes patients with goitre and intense lymphocytic infiltration of the thyroid. * It is characterised by gradual thyroid failure due to autoimmune destruction of the thyroid. • Hashimoto thyroiditis has a strong genetic component. 1. Concordance of the disease is in 40% in monozygotic twins, 2. Circulating anti-thyroid antibodies are present in approximately 50% of asymptomatic siblings of Hashimoto patients.

Answer 72

* This disorder is most prevalent between 45-65 years. * It is more common in women than in men. * Female predominance is 10:1 - 20:1 * Although it is primarily a disease of older women, it can occur in children and is a major cause of non-endemic goitre in the paediatric population.

Answer 73

* In Hashimoto thyroiditis, there are various antibodies against thyroid peroxidase, thyroglobulin and TSH receptors. * Induction of thyroid autoimmunity is accompanied by a progressive depletion of thyrocytes by apoptosis and replacement of the thyroid parenchyma by mononuclear cell infiltration and fibrosis

Answer 74

1. CD8+ cytotoxic T cell-mediated cell death of thyrocytes. 2. Cytokine-mediated cell death: Excessive T-cell activation leads to the production of TH1 inflammatory cytokines such as interferon-γ in the thyroid gland, with resultant recruitment and activation of macrophages and damage to follicles 3. Antibody-dependent cell-mediated cytotoxicity - anti-thyroglobulin, and anti-thyroid peroxidase antibodies

Answer 75

• This is enlargement of the entire gland without producing nodularity. • Formation of Goitre:  Low iodine levels  Decreased synthesis and secretion of TH  Compensatory increase in TSH  Follicular cell hypertrophy and hyperplasia  Growth and enlargement of thyroid gland (goitre) • Increasing dietary iodine supplementation has decreased the frequency and severity of goitre.

Answer 76

Radioiodine

Answer 77

• The isotope used is 131I (usually as the sodium salt). • Given orally, it is taken up and processed by the thyroid in the same way as the stable form of iodide. • Eventually, it becomes incorporated into thyroglobulin. • The isotope emits both β radiation and ϒ rays: 1. The ϒ rays pass through the tissue without causing damage. 2. The β particles have a short range - absorbed by the tissue and exert a powerful cytotoxic action, resulting in destruction of the cells of the thyroid follicles. • 131I has a half-life of 8 days.  So, by 2 months its radioactivity has effectively disappeared.  Due to the emission of gamma rays, people are advised to keep their distance from patients on radioiodine. * Hypothyroidism will eventually occur after treatment with radioiodine, particularly in patients with Graves' disease – thyroxine can be given to treat this. * There is a theoretical risk of developing thyroid cancer.

Answer 78

• These are drugs that supress thyroid secretion. • The substances involved in the suppression include:  Thiyocyanate Ions – decrease iodide trapping  Propylthiouracil (PTU)/Carbimazole/Methimazole – block peroxidase and iodination of tyrosine  High concentrations of inorganic iodides - • They have different mechanisms to block thyroid secretion.

Answer 79

• These decrease iodide trapping by causing competitive inhibition of Na+/I- symporter when administered in high concentrations. • However, a problem with this drug is that even though no TH is produced, the deficiency in TH in the plasma sends a positive feedback to the APG to increase TSH production.  As a result, there is overgrowth and goitre formation of the thyroid without adequate TH production.

Answer 80

• These compounds decrease TH formation from iodides and tyrosine. • The mechanism involves:  Partly blocking the peroxidase enzyme that is required for iodination of tyrosine.  Partly blocking the coupling of two iodinated tyrosines to formT4 or T3. • However, a goitre can form due to the feedback system.

Answer 81

* When iodides are present in the blood in high concentration, most activities of the thyroid gland are decreased. * The effect is to reduce the rate of iodide trapping, so that the rate of iodination of tyrosine to form thyroid hormones is also decreased. * Because iodides in high concentrations decrease all phases of thyroid activity, they slightly decrease the size of the thyroid gland and especially decrease its blood supply. * For this reason, iodides are frequently administered to patients for 2 to 3 weeks before surgical removal of the thyroid gland to decrease the necessary amount of surgery, especially to decrease the amount of bleeding.

Answer 82

* This drug is part of a group of drugs, known as thioureylene, which also comprise of methimazole and propylthiouracil. * They all have anti-thyroid activity.

Answer 83

• Thioureylenes decrease the output of TH from the gland. • They also cause a gradual reduction in: 1. Signs and symptoms of thyrotoxicosis, 2. Basal metabolic rate 3. Pulse rate returning to normal over a period of 3-4 weeks • They inhibit the iodination of tyrosyl residues in thyroglobulin. • It is thought that they inhibit the thyroperoxidase-catalysed oxidation reactions by acting as substrates for the peroxidase-iodinium complex, thus competitively inhibiting the interaction with tyrosine. • Propylthiouracil has the additional effect of reducing the deiodination of T4 to T3 in peripheral tissues.

Answer 84

* Thioureylenes are given orally. * Carbimazole is rapidly converted to methimazole, which is distributed throughout the body water. * It has a plasma half-life of 6-15 hours * An average dose of carbimazole produces more than 90% inhibition of thyroid incorporation of iodine within 12 hours. * Propylthiouracil acts more rapidly because of its additional effect as an inhibitor of the peripheral conversion of T4 to T3. * Both methimazole and propylthiouracil cross the placenta and also appear in the milk. * After degradation, the metabolites are excreted in the urine.

Answer 85

• The most important unwanted effect is granulocytopenia (decrease in granulocytes). • This is relatively rare, having an incidence of 0.1-1.2%.  It is reversible on cessation of treatment. • Rashes are more common (2-25%). • Other symptoms include:  Headaches  Nausea  Jaundice  Pain in joints

Answer 86

• Another way of treating hyperthyroidism is administering iodine. • Iodine is converted in vivo to iodide (I-), which temporarily inhibits the release of TH. • When high doses of iodine are given to thyrotoxic patients there is inhibition of the secretion of TH.  Over a period of 10-14 days, there is marked reduction in vascularity of the gland, which becomes smaller and firmer. • Iodine is given orally in a solution with potassium iodide. • The mechanism of action is not entirely clear; it may inhibit iodination of thyroglobulin, possibly by reducing the H2O2 generation that is necessary for this process. • It could also be that an increase in iodide ions, causes a negative feedback in TSH. • This method is mainly used: 1. In preparation of patients for surgical resection of the gland. 2. As part of severe thyrotoxic treatment. • Allergic reactions are possible when this method is used.

Answer 87

* These are used to treat the symptoms of heart failure. * They are also used to treat congestive heart failure and in the management of cardiac arrhythmias, protecting the heart from a second heart attack (myocardial infarction). * As β-adrenergic receptor antagonists, they diminish the effects of adrenaline and other stress hormones. ``` • Other uses for beta-blockers include:  Hypertension  Tachycardia  Dysrhythmias  Tremor  Agitation ```

Answer 88

* There are 3 main types of β receptors - β1, β2 and β3: * β1 – mainly in heart and kidneys * β2 – lungs, GIT, liver, uterus, vascular smooth muscle, skeletal muscle * β3 – adipocytes

Answer 89

• Stimulation of β1 receptors by adrenaline/noradrenaline induces a positive chronotropic and inotropic effect, thus increasing cardiac conduction velocity and automaticity • The increase in cardiac output is by:  Increasing the HR in the SA node  Increasing the atrial muscle contractility  Increasing the contractility and the automacity of ventricular cardiac muscle  Increasing the conduction and automacity of AV nodes • Stimulation of β1 receptors in kidneys causes renin release.

Answer 90

 Smooth muscle relaxation/ bronchodilation  Induces tremor in skeletal muscle  Increases glycogenolysis in the liver and skeletal muscle

Answer 91

induces lipolysis.

Answer 92

• β-blockers inhibit these normal adrenaline/noradrenaline mediated sympathetic actions, but have minimal effect on resting subjects.

Answer 93

* Beta-blockers are β1- β2 receptor antagonists. * Reduce HR, thus giving the left ventricle more time to fill up * REDUCE BP!!! by decreasing the contractility, thus putting less load on the heart.

Answer 94

• Nausea; diarrohea; bronchospasm and dyspnea (if β2 receptor antagonists used); bradycardia; hypertension; heart failure; fatigue; dizziness. • Other adverse effects include the following:  Blockade of β1, especially at macula densa, inhibits renin release - Thus decreasing release of aldosterone - This causes hyponatremia (low Na+) and hyperkalaemia (high K+)  Blockade of β2 receptors can cause hypoglycaemia as β2 adrenoreceptors normally stimulate glycogenolysis (hepatic glycogen breakdown) and pancreatic release of glucagon - These work together to increase plasma glucose - Therefore, blocking β2 receptors lowers plasma glucose

Answer 95

* This specifically is a non-selective β-blocker - It blocks both β1 and β2. * It is not an anti-thyroid agent but it’s useful for decreasing many of the signs and symptoms of hyperthyroidism: 1. Tachycardia 2. Dysrhythmias 3. Tremor 4. Agitation 5. Anxiety • They are used in hyperthyroid patients during the initial treatment period while the thioureylenes or radioiodine take effect. • They are also used as part of the treatment of acute hyperthyroid crisis. (Uncommon medical emergency caused by an exacerbation of hyperthyroidism characterised by decompensation of one or more organ systems in people with untreated or poorly treated hyperthyroidism) • Adverse side effects include: 1. Insomnia and nightmares due to the lipophilic state of this beta-blocker so there is high penetration across the BBB 2. GI tract disturbances

Answer 96

``` • Haemoglobin concentration 13g/dl  Normal:  Men = 14.0-17.5 (mean 15.7) g/dL  Women = 12.3-15.3 (mean 13.8) g/dL  Reason = none; normal in patient ```

Answer 97

``` • Haematocrit concentration 0.4  (This is the volume of RBCs in blood)  Normal:  Male = 40.7-50.3%  Female = 36.1-44.3%  Reason = none; normal in patient ```

Answer 98

• Leucocyte count 4.0x109/l with 40% lymphocytes  Normal:  1.5 – 4.0x109/l  Reason = normal in patient but very baseline due to the chronic stress

Answer 99

 Normal = shouldn’t be too high or too low; 0.4-4.5 |  Reason = this is due to the increased T4 levels which cause a negative feedback to the APG to stop producing TSH

Answer 100

 Normal = uptake between 15-25% |  Reason = due to hyperthyroidism, the patient had an increased uptake

Answer 101

• A measure of relative size based on the mass and height of an individual • The BMI for a person is defined as their body mass (in kg) divided by the square of their height (metres)  The value universally being given in units of kg/m2 • There are a wide variety of contexts where the BMI of an individual can be used as a simple method to assess how much the recorded body weight departs from what is healthy or desirable for a person of that height • Once the BMI score is worked out, a scale can be used to categorise what the score actually shows in terms of health of the individual with that specific height and mass * A low BMI can lead to a risk of developing problems such as nutritional deficiency and osteoporosis * A high BMI can lead to risks of developing heart disease, high blood pressure, stroke and diabetes

Answer 102

1. Zona Glomerulosa – mineralocorticoids (e.g. aldosterone) 2. Zona Fasciculosa – glucocorticoids (e.g. cortisol) 3. Zona Reticulosa – sex steroid precursors (e.g. androstenedione)

Answer 103

 The three layers of the adrenal cortex comprise of different enzymes, thus allowing them to produce different hormones.  Cholesterol is used to form all of the adrenal cortex hormones.

Answer 104

1. Zona Glomerulosa –Early action of the HSD3B2 enzyme steers away from sex steroid precursors to aldosterone or cortisol. 2. Zona Fasciculosa – this contains the CYP11B2 enzyme, thus allowing for the production of cortisol. 3. Zona Reticulosa – this contains the CYP17A1 enzyme, thus allowing for the production of sex steroid precursors (andostenedione)

Answer 105

1. Overproduction of hormones  Zona Glomerulosa – mineralocorticoid excess (Conn Syndrome)  Zona Fasciculosa – glucocorticoid excess (Cushing Syndrome)  Zona Reticulosa – excess sex steroid precursors  Mixed overproduction is indicative of (rare) adrenocortical cancer.  Medulla – excess catecholamine secretion (Phaeochromocytoma tumour) 2. Under-production of hormones  ‘Primary’ – the entire cortex is affected (Addison Disease/ TB/ HIV)  ‘Secondary’ - hypopituitarism, loss of ACTH

Answer 106

Hyperaldosteronism/ Conn Syndrome: • This is the overproduction of adrenal cortical hormones. • Symptoms include: hypertension, hypokalaemia, weakness, lethargy • Diagnosis:  Looking for inappropriate aldosterone secretion (test negative feedback loop)  Screening test: aldosterone/renin ratio (in Conn syndrome, this will be higher than normal) • Treatment:  Adrenalectomy  Mineralcorticoid receptor antagonists

Answer 107

• This is excessive endogenous cortisol secretion. (can be exogenous) • It is characterised clinically and biochemically by:  Features of glucocorticoid excess.  Loss of circadian rhythm to cortisol secretion.  Disruption of negative feedback loop.

Answer 108

 Benign pituitary adenoma (Cushing’s Syndrome characterised by this tumour is called Cushing’s Disease)  Adrenal hyperplasia  Benign/ malignant tumour of the adrenal gland  Ectopic ACTH secreting tumour  Long-term use of glucocorticoid medication (e.g. prednisolone)

Answer 109

 Round face with purplish plethora  Central obesity (face and trunk mainly, arms are skinny)  Diabetes  Hypertension

Answer 110

 Loss of circadian rhythm  Cortisol levels raised in urine – not very good test (poor sensitivity and specificity)  Low dose dexthamethasone suppression test (give this overnight, in the morning the levels of cortisol should be suppressed)  Exclude pseudo-Cushing syndrome (clinical features of Cushing Syndrome, which disappear when underlying cause is resolved (alcohol, depression))

Answer 111

 Benign pituitary adenoma - trans-sphenoidal hypophysectomy  Adrenal hyperplasia - adrenalectomy  Benign/ malignant tumour of the adrenal gland - adrenalectomy  Ectopic ACTH secreting tumour – palliative care, surgery, chemotherapy  Long-term use of glucocorticoid medication (e.g. prednisolone) – stop the use of this medication

Answer 112

Hypoadrenalism/ Addison Disease • This is the under-production of glucocorticoids and mineralocorticoids. ``` • Primary Causes:  Tuberculosis/ AIDs  Autoimmune – this is called Addison Disease • Secondary Causes:  Pituitary insufficiency (ACTH low) ```

Answer 113

 Weakness and tiredness  Darkened areas of skin (pigmentation) – due to loss of negative feedback  Hypotensive, Hyperkalaemic patient (major sign)

Answer 114

 ACTH stimulation test (Short synacthen test) – stimulate ACTH secretion and measure cortisol level after 30 mins. In hypoadrnalism, the cortisol level

Answer 115

 Hydrocortisone – this medication is given life-long. |  May need mineralocorticoid replacement (fludrocortisone)

Answer 116

Hypothalamus -> TRH -> anterior pituitary (thyrotroph) -> TSH -> thyroid -> T4 -> T3 - T3 -> inhibits anterior pituitary gland - T3 -> inhibits hypothalamus

Answer 117

Thyroid hormone distinct for the fact that it contains iodine TSH -> receptor -> cAMP -> intracellular effects -> thyroglobulin and TPO (thyroid peroxidase) biosynthesis & packaging -> out of apical membrane into colloid  Thyroglobulin+I- (storage of thyroid hormone – means thyroid gland has quite a lot of thyroid hormone) (in colloid) - ‘organification’ (active TPO)  Thyroglobulin-containing thyroid hormone -> (back into cell) -> thyroglobulin degradation -> I- -> Pendrin -> I- (out of cell into colloid) and -> T4, T3 -> into capillary

Answer 118

effective at suppressing the synthesis and secretion of thyroid hormones: - Carbimazole - Methimazole (active metabolite of carbimazole; used in USA) - Propylthiouracil (PTU)

Answer 119

Iodination of tyrosine -> thyroxine Thyroxine -> reverse T3 (if you take iodine from middle of molecule of) Thyroxine -> T3 (if you take iodine from end of molecule of) Reverse-T3 -> T3 (if you take iodine from end of molecule of) - T4 has 2 choices, it either converts to T3 or rT3 - The more rT3 you make, the more hypothyroid you are - T4 = inactive storage - T3 = active hormone - Reverse T3 = blocks T3 - If you take too much T3, available T4 will convert to rT3 because there is already more than enough T3

Answer 120

- Thyroid gland makes about 80% T4 and 20% T3 - T3 is the most active of the hormones - T4 -> T3 (rarely ever a problem with this conversion, therefore it’s T4 that you replace instead of T3, even though T3 is the active hormone) - Half-life of T4 is much longer so you only have to give it once per day - Half-life of T3 is much shorter so you have to give it three times per day = less compliance

Answer 121

fT4 (free T4) -> T4 -> rT3 T4 -> T3 -> T3 in nucleus -> binds to TR (thyroid hormone receptor) -> mRNA -> protein (T3 action) fT3 -> T3 -> T2 - Turning on and off genes = slow effect - ‘fight or flight’ e.g. adrenaline = quick acting hormones

Answer 122

in liver and kidney

Answer 123

- t1/2 T3 in circulation is 1-3 days; t1/2 T4 in circulation is 5-7 days; T3 has to be given tds, T4 is given once daily

Answer 124

- Sequential iodination of tyrosine - Thyroid hormone is stored - T4 – produced entirely by thyroid; T3 (active form) – peripheral T4 mono-deiodination (liver and kidney), metabolically active; reverse T3 – biologically inactive - t1/2 T3 in circulation is 1-3 days; t1/2 T4 in circulation is 5-7 days; T3 has to be given tds, T4 is given once daily - TR acts in nucleus on gene expression, therefore thyroid hormone effects are slow - HPT axis regulated according to the principles of negative feedback; for primary thyroid disorders, TSH indicates thyroid status, a ‘biomarker’

Answer 125

Graves' disease = hyperthyroidism | Hashimoto disease = hypothyroidism

Answer 126

- classic Hashimoto (goitrous) | - atrophic (non-goitrous) (the autoimmune response has killed it all)

Answer 127

- in reality, a mix of antibody mediated/T cell-mediated - TPO, TSHR, Tg auto-antibodies Anti-TPO, anti-Tg (antithyroglobulin), TBII (TSH receptor-blocking antibodies) (this last to lesser extent)

Answer 128

- amiodarone - iodides (high concentrations suppress TH release) - lithium

Answer 129

- Congenital (1:5000 neonates, paediatrics) (blood test soon after birth – important for brain development) - TTF1, PAX8, Pendred syndrome, NIS

Answer 130

Secondary/tertiary: hypopituitarism/hypothalamic - Pituitary adenoma, congenital deficiency, irradiation - (sarcoid, infection)

Answer 131

- Insidious - Weight gain - Cold intolerance, particularly at extremities - Fatigue, lethargy - Depression - Mentally slowed, dull expressionless face (N.B. myxoedema coma) - Coarse skin, ‘puffy’, (possible carpal tunnel syndrome) - Dry, brittle, thinning hair - Hoarse voice - Constipation, faecal loading, ‘megacolon’ - Menstrual disturbance o menorrhagia, oligo/amenorrhoea - Muscle stiffness, cramps, slow-relaxing reflexes - Generalised weakness and paraesthesias - Cerebellar ataxia - Bradycardia, possible cardiomegaly and pericardial effusion - Macroglossia (congenital) - Loose outer third of your eyebrows - Thickening of skin

Answer 132

arises from autoimmune destruction of the parietal cell, loss of intrinsic factor secretion and consequently, vitamin B12 deficiency (macrocytic)) – destruction of parietal cells in stomach

Answer 133

- Investigation o Blood test (TFTs – thyroid function tests) o Normochromic normocytic anaemia o Macrocytosis, mixed dyslipidaemia - Consider other autoimmune endocrinopathies o Adrenal, ovary, T1DM, (pernicious anaemia, vitiligo) - No need for ultrasound scan (or autoantibody measurement?)

Answer 134

Once daily thyroxine, lifelong, usually 100 mcg; young, rapid start; elderly, gentle increment Goal: normalise TSH, repeat blood tests after 4-6 weeks - If thyroid gland isn’t producing thyroid hormone as should, TSH goes up – you diagnose primary hypothyroidism by a raised serum TSH • fT4↓; fT3↓; TSH↑ (> 2 x upper limit) (if you leave it for longer and don’t go doctor straight away, TSH level with keep increasing): treat with thyroxine • fT4 →; fT3 →; TSH → : normal, never treat with thyroxine (the broad, vague symptoms seen on other side are due to something else) • fT4 →; fT3 →; TSH↑: compensated response + symptoms, treat with thyroxine no symptoms, could wait & repeat test, subclinical hypothyroidism • fT4↓; fT3↓; TSH ↓ (if pituitary gland destroyed) or → : consider potential pituitary disease / sick euthyroid syndrome

Answer 135

- major cause of goitre and hypothyroidism world-wide | - 7% of world population (0% Japan) (80% Andes, Zaire)

Answer 136

Thyrotoxicosis i.e. excess circulating thyroid hormone - Not necessarily hyperthyroidism - Sometimes virus will irritate the thyroid and the thyroid dumps all of its stores out into the circulation -> transient thyrotoxicosis - Then thyroid hormone levels go low - So, a period of ‘hyperthyroidism’ followed by hypothyroidism

Answer 137

thyrotoxicosis

Answer 138

- Graves’ Disease (autoimmune, other associated features) - Toxic nodule (possibly part of MNG (multinodular goitre), no other features) - (Pituitary adenoma or thyroid hormone resistance syndrome) - Transient - viral (e.g. Coxsackie, ECHO) followed by hypothyroidism, ‘De Quervain subacute thyroiditis’ - Pharmacological (thyroid hormone)

Answer 139

- The biggest of the nodules becomes autonomous - As if that nodule gone death - When all the signals and hormones are telling it to stop producing thyroid hormone, it continues pumping out the hormone - Patient becomes thyrotoxic - Nodule will never go away - Graves’ disease will come and go - Important to discriminate between the two causes

Answer 140

Commonest to less usual: - Irritability, nervousness - Hyperactivity - Heat intolerance, sweating - Palpitations - Weight loss - Dyspnoea - Fatigue, weakness - Increased appetite - Increased bowel frequency - Altered mood - Insomnia - Oligo/amenorrhoea - Hair loss

Answer 141

- Inspection (clothing, weight, hair loss, eye disease, obvious goitre, ask patient to swallow) - Hands (warm moist palms, fine tremor, palmar erythema, onycholysis, pulse rate and rhythm) - Palpation (is it painful? tender, size, texture, nodular / diffuse, mobile; lymphadenopathy) - Percussion (retrosternal goitre) - Auscultation (bruit – if you hear this it’s graves’ disease – thyroid already very vascular and if there’s increased activity, there’s increased blood flow to thyroid -> can make a wooshing sound) - Extra findings (hyperreflexia, muscle weakness, congestive cardiac failure) - Graves-specific (thyroid orbitopathy, pretibial myxoedema, vitiligo) - Integrate clinical thyroid status - hyperthyroid - euthyroid - hypothyroid Two examinations: thyroid and thyroid-status of this patient If it’s thyroid cancer, it’s not a symmetrical growth, there may be lymph nodes to feel Muscles swell up which pushes eye forward, also a bit of lid retraction, double vision (may be struggling to abduct one of eyes)

Answer 142

o (transient thyroiditis) o Graves’ Disease o Toxic nodule (part of multinodular goitre) o Pituitary adenoma o Thyroid hormone resistance syndrome o Thyroid function test • fT4 ↑; fT3 ↑; TSH ↓ • fT4 → ; fT3 → ; TSH ↓ : sub-clinical hyperthyroidism (where you have low levels of TSH but normal levels of T3 and T4) o Thyroid auto-antibodies (stimulatory, mimic TSH)

Answer 143

- Ultrasound (see nodules) o Increased echogenicity: homogenous (Graves) or heterogeneous (MNG) - Uptake scan (low dose radioiodine or other radionuclide) (outline thyroid) o Homogeneous or isolated ‘hot nodule’ (hotspot for nodule)

Answer 144

o Block thyroid hormonogenesis  Thionamide: Carbimazole or propylthiouracil (use PTU if trying for pregnancy)  Goal: restore normal thyroid hormone levels; in time TSH should normalise  Definitive treatment options (radioiodine or surgery; radioiodine is very useful for toxic nodule – won’t go away)

Answer 145

T1DM, Addison’s disease, vitiligo, pernicious anaemia, alopecia areata, myasthenia gravis, coeliac disease

Answer 146

- Waxing and waning inflammatory autoimmune stimulation of the thyroid - 20’s-40’s - More ‘aggressive’ in children and males - All of the previous symptoms and signs (thyroid bruit) and o Thyroid eye disease/Graves orbitopathy (people can lose their sight) o Pretibial myxoedema

Answer 147

o Carbimazole (immunosuppressive; N.B. agranulocytosis) o Carbimazole + thyroxine o Beta blockers for symptomatic relief o Monitor thyroid function test o Trial off treatment o 1/3 ‘cure’; 1/3 relapse sometime; 1/3 relapse soon

Answer 148

GRAVES’ ORBITOPATHY/THYROID EYE DISEASE - Inflammation of the extraocular muscles, causing increased retro-orbital pressure o Proptosis or optic nerve damage, diplopia, corneal ulceration - Usually associated with thyroid upset, but can be entirely separate - Higher frequency and worse outcome with cigarette smoking - Radioiodine aggravates - Treated with artificial tears, immunosuppression, debatable effects of radiotherapy - Ultimately ‘burns itself out’ Unilateral thyroid eye disease – could be tumour – important differential diagnosis Bilateral = systemic disorder

Answer 149

- 0.2% pregnancies, why treat? o Spontaneous abortion o Premature labour o Small birth weight o Congestive cardiac failure o Pre-eclampsia - Exacerbated in early pregnancy / ameliorated in later pregnancy o hCG also stimulates the thyroid (normal fT4/fT3, low TSH is normal in pregnancy) - Not radioiodine o Fetal thyroid present at 8-10 weeks gestation - Not beta blockers o fetal bradycardia, hypoglycaemia, respiratory depression, IUGR - Surgery if intolerant of thionamide/agranulocytosis FOETAL HYPERTHYROIDISM - 1% Graves’ pregnancies generate fetal hyperthyroidism, placental crossing of TSHR stimulating Abs - Fetal heart rate >160 bpm, goitre, advanced neonatal bone age, craniosynostosis - Even if maternal thyroidectomy, might still have lots of antibodies, measure at start of second trimester? o If >5 fold normal, significant risk of fetal hyperthyroidism, can be treated by maternal thionamide

Answer 150

Zona glomerulosa = nests of cells – more tightly packed together Zona fasciculata = cells more in columns Zona reticularis = net-like – cells more spread out and diffuse

Answer 151

- Adrenocortical hormones are steroids - Steroids are built on the back bone of cholesterol - Testicles and ovaries produce hormones that are also based on steroids - Glucocorticoids = ‘gluco’ because has an effect on regulating sugar - they’re used for their immunomodulatory, anti-inflammatory effects in rheumatoid arthritis - Zona glomerulosa has the complement of enzymes that take you from cholesterol -> aldosterone - Zona fasciculata and reticularis that have the complement of enzymes that shunt you over towards cortisol - And in particular in the zona reticularis, you also get androstenediones (sex steroid precursors)

Answer 152

(circadian rhythm + stress) -> hypothalamus -> CRH -> anterior pituitary (corticotroph) -> ACTH -> adrenal cortex -> cortisol  Cortisol -> inhibits anterior pituitary  Cortisol -> inhibits hypothalamus Peripheral tissues: Cortisol -> (HSD11B2) -> cortisone -> (HSD11B1) -> cortisol

Answer 153

- Over-production—the site reflects hormone excess o Glomerulosa: mineralocorticoid excess (aldosterone) (increase blood pressure, increase Na+ reabsorption, decrease K+) (Conn syndrome) o Fasciculata: glucocorticoid excess (too much cortisol) (Cushing syndrome) o Reticularis: excess sex steroid precursors (+ cortisol / tumour) - Under-production o Primary: the entire cortex is affected (Addison disease, TB / HIV) o Secondary: hypopituitarism, loss of ACTH (i.e. aldosterone secretion preserved) (ACTH causes release of cortisol) - Disordered production o Congenital adrenal hyperplasia - Incidentalomas (asymptomatic adrenal tumour that is discovered on imaging test which was ordered to evaluate a problem that is unrelated to adrenal disease)

Answer 154

- Classically thought to be rare: incidence 0.1-1.0 new cases/100 000 o Perhaps 2% of T2DM clinics? Subtle glucocorticoid disturbance - Excessive, inappropriate endogenous cortisol secretion characterized clinically and biochemically by: o Features of glucocorticoid excess o Loss of circadian rhythm to cortisol secretion o Disruption of negative feedback loop

Answer 155

Glucagon, adrenaline, noradrenaline, cortisol, growth hormone (acromegaly)

Answer 156

- Moon face with purplish plethora - Central obesity, buffalo hump - Weight Gain - Hypertension - Depression/ psychosis - Diabetes mellitus - Hypogonadism - Susceptibility to infection - Malaise - Osteoporosis - Easy bruising - Striae - Proximal myopathy - Poor wound healing - Purple stretch marks - Acanthosis nigricans (AN) – darkness particularly under armpit – sign of insulin resistance - Hirsuties (heavy growth of hair, often in abnormal distribution) - Acne - Symptoms overlapping with PCOS

Answer 157

Cortisol, like glucagon, epinephrine and growth hormone, can be thought of as antagonistic to insulin: Cortisol tends to increase blood glucose levels by: - Promoting gluconeogenesis - Raising hepatic glucose output - Inhibiting glucose uptake by muscle and fat Other effects: - Lipolysis from adipose tissue - Protein catabolism to release amino acids

Answer 158

It’s the hormone that wakes you up in the morning – levels are high in the morning – when it declines that’s why you start to feel tired You can have excess cortisol or just abnormal levels at different times

Answer 159

You can have excess cortisol or just abnormal levels at different times 1. Loss of circadian rhythm - Random cortisol is no use – levels change throughout day - Measure bedtime/midnight serum or salivary cortisol levels 2. Measure 24-hour urinary free cortisol - Cortisol washes over from circulation to urine – if you have too much in circulation you get more going over into urine 3. If overactivity is suspected; try to supress it - Measure cortisol after low dose of dexamethasone (potent, synthetic glucocorticoid – pronounced anti-inflammatory properties) - 1 mg overnight or 0.5 mg QID for 8 doses - Following 9 am cortisol should be suppressed (less than 50 nmol/L = haven’t got Cushing syndrome) - Potent glucocorticoid -> switch of ACTH -> decrease cortisol -> cortisol levels should be low 4. Exclude pseudo-Cushing syndrome - Clinical features of Cushing Syndrome, which disappears when the underlying cause is resolved - Common causes alcohol, depression

Answer 160

- Most common is patient on respiratory ward – e.g. prednisolone (99%, obvious) – muscle wasting, paper thin skin, easy bruising - Corticotroph tumour ‘Cushing disease’ (not syndrome) (68%) – tumour in pituitary gland that makes too much ACTH - Cushing syndrome = too much of the hormone (cortisol), Cushing disease = when comes from pituitary gland from a corticotrophadenoma - Ectopic ACTH-secreting tumour (15%) – tumour in chest – nasty tumour – patient looks like they’ve got cancer - Adrenocortical tumour (17%)

Answer 161

Scenario 1: adrenal tumour - ACTH undetectable/suppressed – low levels that are constantly there? INFERIOR PETROSAL SINUS SAMPLE -> sample blood -> look at levels of ACTH – tells you that there’s massive amounts coming from the petrosal sinus TRANS-SPHENOIDAL SURGERY - Cut a little window at pituitary fossa - Pick away at tumour in pituitary gland - Huge pituitary tumour – may not be making hormones but if hits optic chiasma -> bitemporal hemianopia Scenario 2: distinguishing between ACTH-dependent causes 1. Low-dose dexamethasone suppression test Diagnoses Cushing syndrome 2. High-dose dexamethasone suppression test Localises Cushing syndrome 2 mg QID (i.e. 6 hourly) for 8 doses ending at midnight Corticotroph tumour: >50 % suppression of following 9 a.m. cortisol Ectopic ACTH: <50 % suppression of following 9 a.m. cortisol

Answer 162

Untreated life expectancy <5 years - Medical - Block production of cortisol (metyrapone, ketoconazole, mitotane) - Pituitary tumours - trans-sphenoidal hypophysectomy +/- Radiotherapy - 20-50% may be not permanently cured - may require bilateral adrenalectomy - Ectopic ACTH - usually palliative, surgery, DXT / chemotherapy - Adrenal tumours - adrenalectomy (can live off one adrenal gland)

Answer 163

HYPOADRENALISM - Rare – 0.8 cases per 100,000 - Primary causes - Tuberculosis / AIDS - Addison disease / autoimmune (T1DM, thyroid disease, PA, vitiligo) - Metastatic tumour - Lymphoma - Intra-adrenal haemorrhage or infarction - Bilateral adrenalectomy - Secondary hypoadrenalism comes from pituitary insufficiency - In this country = autoimmune most common - Worldwide = infection – TB or AIDS most common

Answer 164

cortisol and aldosterone

Answer 165

- Non-specific - Tiredness - Weakness - Nausea & vomiting - GI disturbance - Abdominal pain - Weight loss - Postural hypotension (supine and erect BP) - Dizziness - Fainting - May present in circulatory failure (‘crisis’) - Hypoglycaemia (due to low cortisol) - Hypotensive, hyperkalaemic patient - Pigmentation (loss of negative feedback) (unusual places for pigmentation because you’ve got too much MSH (melanocyte-stimulating hormone), as a by-product of ACTH because not enough cortisol - Other autoimmune disorder (e.g. vitiligo)

Answer 166

- If under-activity is suspected; try to stimulate it - Short synacthen test o Give ACTH i.v. / i.m. and measure cortisol 30 minutes later o If less than 550 nmol/L, it is inadequate

Answer 167

``` - Treat with hydrocortisone lifelong o 10 mg on waking, 5 mg mid-afternoon o Double in significant illness (e.g ‘flu’) - Steroid alert bracelet - Steroid card - May need mineralocorticoid replacement o Fludrocortisone (100 mcg) ```

Answer 168

o Adrenal cortex  Conn syndrome o Adrenal medulla  Phaeochromocytoma Clinically, endocrine hypertension falls into the minority that is not ‘essential hypertension’ - hypertension caused by demonstrable hormone excess, which is cured upon normalising circulating levels (or action) of the hormone - these patients tend to be younger, therefore also remember: - renal artery stenosis - coarctation of the aorta

Answer 169

(and all in excess can elevate it) - Angiotensin II - Aldosterone - Cortisol - Epinephrine (adrenaline) / norepinephrine (noradrenaline) - Calcium / PTH - Growth hormone

Answer 170

Aldosterone is the body’s major mineralocorticoid: - It promotes sodium resorption from the urine and potassium excretion - It increases blood pressure In turn, aldosterone biosynthesis is regulated primarily by: - The renin-angiotensin system (forming a negative feedback loop) (angiotensin stimulates the release of aldosterone from the adrenal cortex and ADH/vasopressin from the hypothalamus) - Serum potassium concentration

Answer 171

Decrease extracellular fluid volume -> juxtaglomerular cells -> renin -> increase conversion of angiotensinogen -> angiotensin I -> angiotensin II -> adrenal cortex Potassium -> adrenal cortex Adrenocorticotrophin -> adrenal cortex Adrenal cortex -> aldosterone -> increase sodium (and water) resorption -> increase extracellular fluid volume Sodium and water resorption -> (distal convoluted tubule: Na+/K+-ATPase exchanger therefore sodium resorption = potassium excretion) -> increase potassium -> adrenal cortex Westernised diet: high salt intake = shrivelled zona glomerulosa - Juxtaglomerular cells on the afferent arteriole - Macula densa in the distal tubule

Answer 172

Aliskiren = direct renin inhibitor – used in essential (primary) hypertension ACE inhibitors = angiotensin-converting enzyme Eplerenone, Spironolactone = aldosterone antagonist

Answer 173

``` CONN SYNDROME/PRIMARY MINERALOCORTICOID EXCESS Primary hyperaldosteronism - Causes hypertension, ~2% of all patients with hypertension - Peak incidence 30-50 years of age - Female: male ratio 2:1 - Symptoms few - high index of suspicion - Hypokalaemia, weakness, lethargy - Headaches due to hypertension ```

Answer 174

- Vomiting (metabolic alkalosis) - Diarrhoea or other fluid loss from the lower bowel - Insulin therapy (insulin activates Na+/K+-ATPase in many cells) - Diuretic use - Rare causes include renal tubular acidosis and Bartter syndrome

Answer 175

YOUNG PERSON/SEVERE HYPERTENSION/HIGH SODIUM/LOW POTASSIUM Diagnosis: - Looking for inappropriate aldosterone secretion - Exploitation of the negative feedback loop - Ensure adequate salt intake, replace potassium into the normal range - Stop other anti-hypertensives (especially diuretics and beta-blockers) HT + hypokalaemia or severe hypertension in young person  Measure serum aldosterone/renin ratio ->low/normal = essential hypertension, secondary aldosteronism (renal artery stenosis, CCF) -> high -> possible Conn syndrome - Confirmatory testing (salt loading, erect and supine aldosterone/renin ratios, fludrocortisone suppression test)  Non-suppressed aldosterone -> Conn syndrome -> high resolution computed tomography/MRI  Suppressed aldosterone -> essential hypertension High-resolution CT/MRI  Unilateral adenoma – contralateral gland normal -> probable aldosterone-producing adenoma (benign) (Conn tumour) -> adrenalectomy (very occasionally, Conns syndrome is caused by a cancerous tumour in the adrenal gland)  Bilateral micro- or macronodular disease -> medical management (e.g. spironolactone or eplerenone) (this isn’t Conn’s syndrome – Conns is normally a tumour I think)

Answer 176

- Aldosterone acts on the mineralocorticoid receptor (MR) in the distal convoluted tubule - Spironolactone and eplerenone are MR antagonists - they bind onto receptors on principal and alpha-intercalated cells

Answer 177

rare tumour of adrenal gland tissue -> it results in release of too much epinephrine and norepinephrine

Answer 178

- Catecholamines - Epinephrine (adrenaline) - Norepinephrine (noradrenaline) - Stored in cell cytoplasm - Released in response to nervous stimuli - Rapidly metabolised in liver, kidney & nerve endings - Clinically - Underactive: no syndrome - Overactive: a tumour called phaeochromocytoma Tyrosine -> DOPA -> dopamine -> norepinephrine -> epinephrine and others

Answer 179

- Act via a & b receptors - Brain o Causes alertness, anxiety, agitation - Eyes o Pupil dilation - Liver  glycogenolysis - Lungs o Bronchodilation - Pancreas  Glucagon, decrease Insulin - Kidney  Renin release - Adipose  lipolysis - Skin  Sweating - Heart & cardiovascular o HR, force of contraction, vasoconstriction & vasodilation - Muscle  contraction  protein breakdown

Answer 180

- 10% malignant - 10% multiple - 10% extra-adrenal - May form part of MEN2 and other hereditary tumour syndromes o Diagnosis  Plasma & urinary catecholamines: 24 hr urine collection - DDx (Conn’s, renal artery stenosis, coarctation of the aorta) - Episodic release - Imaging o MRI o CT o Uptake - Treatment o Surgery o Administration of a-blocker (phenoxybenzamine) & b-blocker (propranolol) The triad of classical symptoms in phaeochromocytoma (adrenal medulla over-production): - Hypertension - Throbbing bilateral headaches - Palpitations

Answer 181

- MEN2 (multiple endocrine neoplasia) (type a: thyroid medullary carcinoma, phaeochromocytoma) (type b: as above plus musosal neuromas) - Von Hippel Lindau syndrome - Von Recklinghausen neurofibromatosis