Endocrinology - Alison's Flashcards

Question

What is an insulin receptor and what is it's role?

Answer 1

A glycoprotein, coded for on the short arm of chromosome 19, which straddles the cell membranes of many cells -insulin binds = activation of tyrosine kinase and initiation of a cascade response = migration of the GLUT-4 transporter to the cell surface and increased transport of glucose into the cell

Answer 2

-Pancreatic pathology e.g. total pancreatectomy, chronic pancreatitis, haemochromatosis -Endocrine disease e.g. acromegaly and Cushing’s disease -Drug induced -Maturity onset diabetes of youth (MODY): Autosomal dominant form of type 2 diabetes - single gene defect altering beta cell function Tends to present <25 yrs with a positive family history

Answer 3

- Thiazide diuretics - Beta-blockers - Immunosuppressives e.g. ciclosporin and tacrolimus (used in UC and skin) - Thyroid hormone - Corticosteroids

Answer 4

Cardiovascular problems - 70% Chronic kidney disease - 10% Infections - 6% Directly related to hyperglycaemia

Answer 5

- Atherosclerosis - so more likley to have stroke, ischaemic heart disease, peripheral vascular disease etc - Peripheral vascular disease - Affects distal vessels. 15-40 times more likely to have lower limb amputation. Symptoms include intermittent claudication and rest pain

Answer 6

- Retinopathy - Nephropathy - Neuropathy Manifest 10-20 years after diagnosis in young patients

Answer 7

- Microaneurysms (seen as tiny red dots) form due to poorly controlled diabetes causing intramural pericyte death and thickening of the basement membrane. - Haemorrhages (seen as blots) form due to breach of the microaneurysms causing leakage of fluid into the retina which is cleared by veins but leaves behind protein and lipid deposits causing hard exudates (yellowish deposists)

Answer 8

- Early detection and treatment can reduce risk of blindness - Theres a National eye screening program - Laser therapy, it doesn't improve sight but stabilises deterioration and prevents progression, but risks include loss of night vision and the loss of peripheral vision

Answer 9

- Thickening of basement membrane to glomerular damage due to poor glycaemic control leads to microalbuminuria - this gives an early warning sign of an impending renal problem. - May induce transient nephrotic syndrome - May progress to end stage kidney disease and require dialysis and transplant

Answer 10

This is undetectable by conventional dipstick - result shows negative for protein. But urine albumin:creatinine ratio > 3 will indicate microalbuminuria

Answer 11

Treat BP aggressively with ACE inhibitors or angiotensin receptor blockers

Answer 12

Commonest form is distal symmetrical neuropathy

Answer 13

- Pain - Allodynia, paraesthesia, burning pain (worse at night) - Autonomic - Postural hypotension, Gatsroparesis, Diarrhoea, Constipation, Incontinence, Erectile dysfunction - Insensitivity - ‘Glove and stocking’ sensory loss, can lead to foot ulceration, infection, amputations and falls - Diabetic amyotrophy - painful asymmetrical wasting of quadriceps, diminished knee reflex - Mononeuritis - Isolated palsies mainly to extraoccular muscles (III and VI). There’s a characteristic feature of diabetic CN III lesion of sparing of the pupillomotor fibres so there is a retained pupillary reflex

Answer 14

Treatment - Good glycaemic control | Management - Foot screening, teach patients to care for feet and check daily

Answer 15

Poorly controlled diabetes impairs the function of leucocytes

Answer 16

Disease of insulin deﬁciency usually caused by autoimmune destruction of beta cells of the pancreas

Answer 17

- A ‘slow burning’ variant with slower progression to insulin deﬁciency occurs in later life - May be difﬁcult to differentiate from type 2 diabetes (which also presents in later life) - clinical clues include; leaner build, rapid progression to insulin therapy following an initial response to other therapies and the presence of circulating islet autoantibodies)

Answer 18

Autoimmune - Auto-antibodies forming against insulin and islet beta cells - Insulitis Idiopathic Genetic susceptibility - HLA-DR3-DQ2 or HLA-DR4-DQ8

Answer 19

- Results from autoimmune destruction by autoantibodies of the pancreatic insulin-secreting Beta cells in the Islets of Langerhans - Causing insulin deﬁciency and thus the continued breakdown of liver glycogen (producing glucose and ketones) leading to glycosuria and ketonuria as more glucose is in the blood - In skeletal muscle and fats there is impaired glucose clearance - Eventual complete Beta cell destruction results in the absence of serum C-peptide - Present VERY LATE often with only 10% of beta cells remaining

Answer 20

In skeletal muscle and fats there is impaired glucose clearance: Blood glucose is increased - when it reaches 10mmol/L body can no longer absorb glucose - you become thirsty and get polyuria (as body attempts to remove excess glucose)

Answer 21

- Reduced supply of glucose (since there will be a signiﬁcant decline in circulating insulin) and an increase in fatty acid oxidation (due to an increase in circulating glucagon) - The increased production of Acetyl-CoA leads to ketone body production that exceeds the ability of peripheral tissues to oxidise them. Ketone bodies are relatively strong acids (pH 3.5), and their increase lowers the pH of blood - IMPAIRS THE ABILITY OF HAEMOGLOBIN TO BIND TO OXYGEN - note if a patient is in diabetic ketoacidosis, the excess ketones in the blood will result in their BREATH SMELLING OF PEAR DROPS (KETONES)

Answer 22

-Northern European - especially Finnish -Family history - HLA-DR3-DQ2 or HLA-DR4-DQ8 in > 90% -Associated with other autoimmune disease: Autoimmune thyroid Coeliac disease Addison’s disease (excess cortisol) Pernicious anaemia -Environmental factors: Dietary constituents Enteroviruses such as Coxsackie B4 Vitamin D deﬁciency Cleaner environment may increase type 1 susceptibility

Answer 23

- Typically manifests in childhood, reaching a peak incidence around the time of puberty - but can present at any age - Usually younger - < 30yrs - Patient is usually lean - Increased in those of Northern European ancestry, especially in Finland - Incidence is increasing in most populations - particularly children

Answer 24

Results from a combination of insulin resistance and less severe insulin deﬁciency

Answer 25

- Decreased insulin secretion +/- increased insulin resistance - Associated with obesity, lack of exercise, calorie and alcohol excess - No immune disturbance - No HLA disturbance but there is a stronger genetic link - Polygenic disorder - More common in MALES than females

Answer 26

Central obesity, hypertension, hypertriglyceridaemia, a decreases high-density lipoprotein (HDL) cholesterol, disturbed homeostatic variables and modest increases in a number of pro-inﬂammatory markers -accumulation of intracellular triglycerides in muscle and liver and a high proportion have non-alcoholic fatty liver disease

Answer 27

- Insulin binds normally to its receptor on the surface of cells in DMT2 just like in healthy people - thus insulin resistance develops post-receptor - At the time of diagnosis the Beta cell mass is reduced to about 50% of normal - Almost all patient show amyloid deposition in the islets of the pancreas at autopsy derived from a peptide known as amylin or islet amyloid polypeptide which is co-secreted with insulin - Levels are higher due to increased glucose production from the liver (due to the inadequate suppression of gluconeogenesis) and reduced glucose uptake by peripheral tissues (insulin resistance) - Hyperglycaemia and lipid excess are toxic to beta cells (glucotoxicity) and this is thought to result in further beta cell loss and further deterioration or glucose homeostasis - It typically progresses from a preliminary phase of impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) - this is a UNIQUE WINDOW FOR LIFESTYLE INTERVENTION to prevent FULL DMT2 progression

Answer 28

Fasting plasma glucose < 7mmol/L - Oral glucose tolerance of 2hrs glucose > 7.8mmol/L but < 11mmol/L

Answer 29

Fasting plasma glucose > 6.1mmol/L but < 7mmol/L

Answer 30

-Family history - genetics -Increasing age -Obesity and poor exercise - can trigger DMT2 in genetically susceptible individuals -Ethnicity - Middle Eastern, South-east Asian and Western paciﬁc -Environment: There is an association between low weight (as a result of poor nutrition) at birth and at 12 months of age with glucose intolerance later in life Thought to be caused because poor-nutrition early in life impairs beta cell development and function - predisposing to diabetes later in life Low birth weight has also been shown to predispose to heart disease and hypertension

Answer 31

- Common is all populations enjoying an afﬂuent lifestyle - has increased in incidence due to the ageing population and increasing obesity in the Western world - Older - usually >30 yrs of age - but teenagers are starting to get it - Often overweight around the abdomen - More prevalent in South Asian, African and Caribbean ancestry - Middle eastern and Hispanic Americans also more at risk - Hypertension is present in 50% of patients with DMT2 and a higher proportion of African and Caribbean patients

Answer 32

- type 1 tend to be leaner and present with more marked polydipsia, polyuria, weight loss and ketosis - type 2 the patient tends to be overweight in the abdominal area and also presents with polydipsia, polyuria and weight loss and ketosis (only when very advanced with absolute insulin deﬁciency) but less marked

Answer 33

-Ketonuria is often present in young people and may progress to ketoacidosis if these early symptoms are not recognised and treated: Occur primarily in DMT1 and very advanced DMT2 (i.e. when there is absolute insulin deﬁciency) -Patients may have breath smelling of ketones (pear-drops) -Evidence of weight loss and dehydration may be present -Older patients may present with established complications and the presence of the characteristic retinopathy is DIAGNOSTIC in diabetes -Patients with severe insulin resistance (i.e. DMT2) may have acanthosis nigricans - characterised by blackish pigmentation at the nape of the neck and in the axillae

Answer 34

2-6week history -Polyuria and nocturia: Since glucose draws water into the urine by osmosis - not enough glucose can be reabsorbed as kidneys have reached the renal maximum reabsorptive capacity This results in high levels of glucose in tubule urine and thus lots of water resulting in polyuria and nocturia -Polydipsia (thirst): Due to the loss of ﬂuid and electrolytes from excess glucose and thus water being in the urine -Weight loss: Due to ﬂuid depletion and the accelerated breakdown of fat and muscle secondary to insulin deﬁciency

Answer 35

- Onset may be over several months or years, particularly in older patients - Polyuria, polydipsia and weight loss are typically present but tend to be less marked - Patients may complain of such symptoms as lack of energy, visual blurring (due to glucose-induce changes in refraction) or pruritus vulvae or balantis that is due to Candida infection

Answer 36

- In these individuals, the only symptoms detected may just by glycosuria and raised blood glucose with no other symptoms of ill-health - More common in older people, who have a raised renal threshold for glucose - When present, glycosuria is NOT DIAGNOSTIC for diabetes but indicates the need for further investigations

Answer 37

-Random plasma glucose -Fasting plasma glucose For both tests one abnormal value is DIAGNOSTIC in symptomatic individuals Two abnormal values are required in asymptomatic individuals For borderline cases: -Oral glucose tolerance tests (OGTT) -Haemoglobin A1c: -Screen urine for microalbuminuria - to asses for kidney disease FBC, U&Es, liver biochemistry, fasting blood sample for cholesterol and triglycerides Raised blood pH to look for metabolic acidosis (high H+ and low HCO3-, due to ketoacidosis) - seen in DMT1 and advanced DMT2

Answer 38

-Fasting > 7mmol/L = DIABETES DIAGNOSIS -2 hrs after glucose > 11.1 mmol/L = DIABETES DIAGNOSIS -Can also detect impaired glucose tolerance (IGT) - a risk factor for future diabetes and cardiovascular disease: Fasting < 7mmol/L 2 hrs after glucose 7.8-11.0mmol/L

Answer 39

- Measures amount of glycated haemoglobin - thus tells us blood glucose concentration - HbA1c > 6.5% normal (48mmol/mol) = DIABETES DIAGNOSIS

Answer 40

> 11.1mmol/L = DIABETES DIAGNOSIS

Answer 41

> 7mmol/L = DIABETES DIAGNOSIS

Answer 42

- Staphylococcal skin infection - Retinopathy found during visit to optician - Polyneuropathy causing tingling and numbness in the feet - Erectile dysfunction - Arterial disease resulting in MI or peripheral gangrene

Answer 43

-MDT approach -Educate patient on disease and risks -Maintain lean weight, stop smoking and take care of feet (to reduce gangrene risk) -Encourage regular physical activity and reduction in bodyweight in the obese - both of which improve glycaemic control in DMT2 -Good glycemic control with good diet: Low in sugar High in starchy carbohydrates with low glycaemic index e.g. pasta High in ﬁbre Low in fat

Answer 44

- Treatment of hypertension with ACE-inhibitors e.g. RAMIPRIL - Treatment of hyperlipidaemia with statins e.g. SIMVASTATIN - risk factors for long term complication

Answer 45

-Insulin is always indicated in a patient who has been in ketoacidosis and is usually required in lean patients who present under the age of 40 -For good control is it VITAL to educate to self-adjust doses -Ensure they: Can phone for support (24/7 nurse) Can modify diet wisely and avoid binge drinking Partner can abort hypoglycaemia e.g. sugary drinks -Synthetic (recombinant) human insulin is used and administered via SUBCUTANEOUS INJECTION into abdomen, thighs or upper arm -Change injection site to prevent areas of lipohypertrophy (fatty lumps)

Answer 46

- Short acting (soluble insulins) - Short acting insulin analogues - Long acting insulin

Answer 47

Start working within 30-60 minutes and last for 4-6 hours Given 15-30 minutes before meals in patients on multiple dose regimens and by continuous IV infusion in labour, during medical emergencies, at the time of surgery and in patients using insulin pumps

Answer 48

Human insulin analogies (insulin aspart, insulin lispro, insulin glulisine) have a fast onset and a short duration that the soluble insulin but overall DO NOT IMPROVE DIABETIC CONTROL Have a reduced carry-over effect compared to soluble insulin and are used with the evening meal in patients who are prone to nocturnal hypoglycaemia

Answer 49

- Insulin premixed with retarding agents (either protamine or zinc) precipitate crystals - Can be intermediate (12-24 hrs) or long-acting (more than 24hrs) - The protamine insulins are also known as isophane or NPH insulins - The zinc insulins are also known as lente insulins - Insulin glargine is a structurally modiﬁed insulin that precipitates in tissues and is then slowly released from the injection site

Answer 50

Hypoglycaemia - most common (also caused by SULFONYLUREA) Injection site - lipohypertrophy Insulin resistance - mild and associated with obesity Weight gain - insulin makes people feel hungry

Answer 51

- Lifestyle & dietary changes are ESSENTIAL! - Dietary factors e.g. low sugar, high in starch carbohydrates with low glycaemic index e.g. pasta, high in ﬁbre, low in fat (esp. sat. fat) - Nutrient load should be spread throughout the day (three main meals with snacks in between and at bedtime) - which reduces swings in blood glucose - Blood pressure control e.g. RAMIPRIL - Hyperlipidaemia control e.g. STATINS - Exercise - Weight loss if obese - associated with improved diabetic control - Can give ORLISTAT in obesity which is an intestinal lipase inhibitor and reduces the absorption of fat from the diet - it promotes weight loss

Answer 52

-Used in association with diet & lifestyle changes when this alone has failed to control hyperglycaemia -Initially give a biguanide eg Metformin -If HbA1c > 53mmol/L 16 weeks later then add a sulfonylurea e.g. ORAL GLICLAZIDE: -If at 6 months the HbA1c > 57mmol/L consider adding: Insulin, glitazone, sulfonylurea receptor binding, GLP

Answer 53

-Reduces rate of gluconeogenesis in the liver -Increases cells sensitivity to insulin -Helps with weight issues -Reduces CVS risk in diabetes S/E; anorexia, diarrhoea, nausea, abdominal pain, NOT HYPOGLYCAEMIA -Contraindicated in heart failure, liver disease or renal disease, since can induce lactic acidosis

Answer 54

-Promotes insulin secretion -These are ineffective in patients without a functional beta-cell mass -Avoided in pregnancy -Effect wears off as beta-cell mass declines S/E; hypoglycaemia (must monitor glucose), promote weight gain (so best avoided in the overweight!!) -Should be used with care in people with liver disease and those with renal impairment should use sulfonylurea’s primarily excreted by the liver -The safest drug in the very elderly is ORAL TOLBUTAMIDE since it has a very short duration of action

Answer 55

Previously undiagnosed diabetes Interruption of insulin therapy The stress of intercurrent illness e.g. surgery or infection

Answer 56

- insulin deficiency = uncontrolled catabolism - high circulating glucose = osmotic diuresis by kidnets and dehydration & loss of electrolytes - plasma osmolality rises and renal perfusion falls - peripheral lipolysis = more FFAs broken into Acetyl-CoA turned into ketones - high ketones = metabolic acidosis - vomit = more loss - rep compensation = hyperventilation - pH drops = enzymes less efficient - stress hormones accelarate process - fatal if untreated

Answer 57

- Stopping insulin therapy - Infection e.g. UTI - Surgery - MI - Pancreatitis - Undiagnosed diabetes

Answer 58

- Pear drop breath - The excess ketones are excreted in the urine but also appear in the breath, producing a distinctive smell (pear drops) - Kussmaul’s respiration (deep rapid breathing) may be present - sign of respiratory compensation by hyperventilating - Some disturbance of consciousness is common but only 5% present with coma - Body temperature is often subnormal even in the presence of infection

Answer 59

- Vomiting - which exacerbates fluid and electrolyte loss, causing profound dehydration - Eyes are sunken, tissue turgor is reduced and the tongue is dry - in severe cases of dehydration - Gradual drowsiness, vomiting and dehydration in type 1 diabetic (very rarely in type 2 diabetic) - A few patients have abdominal pain - which is so severe it can sometimes be confused for a surgical acute abdomen

Answer 60

-Hyperglycaemia - blood glucose > 11mmol/L -Raised plasma ketones > 3mmol/L - measured using a ﬁnger prick sample and near--patient meter that measure ----Beta-hydroxybutyrate (major ketone) -Acidaemia - blood pH < 7.3 -Metabolic acidosis with bicarbonate < 15mmol/L -Urine stick testing shows heavy glycosuria and ketonuria -Urea and creatinine are often raised as a result of dehydration -Total body K+ is low as a result of osmotic diuresis - but serum K+ is often raised due to the absence of insulin which allows K+ to shift out of cells -FBC may show raised white cell count even in the absence of infection Blood cultures, CXR and urine microscopy and culture to look for infection -ECG and cardiac enzymes to look for MI

Answer 61

-Immediate ABC mangement -Replace the ﬂuid loss with 0.9% saline -Restore electrolyte loss (K+) -Restore acid-base balance over 24hrs - normally done by kidneys once circulating volume has been restored -Replace the deﬁcient insulin: Give insulin + glucose (to prevent hypoglycaemia) which both inhibit gluconeogenesis and thus ketone production -Monitor blood glucose closely -Therapy can lead to a shift of K+ into cells resulting in hypokalaemia so treat this -Complications of management: Hypotension - increase circulating volume with saline to treat this Coma - insert naso-gastric tube to prevent aspiration Cerebral oedema - from rapid lowering of blood glucose and thus osmolality of blood Hypothermia -Late complications include pneumonia and deep-vein thrombosis (DVT) - occur especially in comatose or elderly patient

Answer 62

- This is a life-threatening emergency characterised by marked hyperglycaemia, hyperosmolality and mild or no ketosis - This is the metabolic emergency characteristic of uncontrolled type 2 diabetes mellitus

Answer 63

Endogenous insulin levels are reduced but are still sufﬁcient to inhibit hepatic ketogenesis but insufﬁcient to inhibit hepatic glucose production

Answer 64

- Infection - most common precipitating cause - particularly pneumonia - Consumption of glucose rich ﬂuids - Concurrent mediation such as thiazide diuretics or steroids

Answer 65

Patients present in middle or later life often with previously undiagnosed diabetes

Answer 66

-Severe dehydration (secondary to osmotic diuresis) -Decreased level of consciousness - which is directly related to the elevation of plasma osmolality -Hyperglycaemia -Hyperosmolality - which may predispose to stroke, MI or arterial insufﬁciency of the lower limbs -No ketones in blood or urine Stupor or coma -Bicarbonate is NOT LOWERED

Answer 67

- Hyperglycaemia - blood glucose > 11mmol/L - Urine stick testing shows heavy glycosuria - Plasma osmolality is extremely high - Total body K+ is low as a result of osmotic diuresis - but serum K+ is often raised due to the absence of insulin which allows K+ to shift out of cells

Answer 68

- These patients are more sensitive to insulin so give a lower rate of infusion - Fluid replacement with 0.9% saline - Low molecular weight heparin e.g. SC ENOXAPARIN to reduce risk of thromboembolism, MI, stroke and arterial thrombosis which patient is at increased risk of due to hyperosmolality - Restore electrolyte loss (K+) - Risk of cerebral oedema - from rapid lowering of blood glucose (with insulin - that they are extremely sensitive to) and thus osmolality of blood

Answer 69

Deﬁned as plasma glucose < 3mmol/L

Answer 70

-In diabetics: Due to insulin or sulphonylurea treatment - commonest cause: E.g. with increased activity, missed meal, accidental or nonaccidental overdose -In non-diabetics - EXPLAIN: Ex -Exogenous drugs - insulin, oral hypoglycaemic, alcohol binge with no food P - Pituitary insufﬁciency L - Liver failure A - Addison’s disease I - Islets cell tumour (insulinoma) & immune hypoglycaemia N - Non-pancreatic neoplasm e.g. ﬁbrosarcomas and haemangiopericytomas

Answer 71

Autonomic: Sweating, anxiety, hunger, tremor, palpitations, dizziness Neuroglycopenic: Confusion, drowsiness, visual trouble, seizures, coma Rarely there are focal symptoms such as transient hemiplegia, mutism, personality change, restlessness and incoherence

Answer 72

-Fingerpick blood during attack (on ﬁlter-paper at home) - and then can be sent for analysis -Take drug history and exclude liver failure -Bloods - glucose, insulin, C-peptide, plasma ketones -If hypoglycaemic hyperinsulinaemia: -Due to insulinoma, sulfonylurea or insulin injection (no C-peptide in serum) or congenital -If low insulin, no excess ketones: -Due to non-pancreatic neoplasms or anti-insulin receptor antibodies -If low insulin, increased ketones: Alcohol, pituitary insufﬁciency, Addison’s disease

Answer 73

- If episodes are often then advise many small high-starch meals - In diabetics re-educate on insulin use and safety!! Pharmacological - Oral sugar and long-acting starch e.g. toast - If cannot swallow then give 50% Glucose IV - Or IM Glucagon if no IV access

Answer 74

• Recurrent laryngeal nerve • Superior laryngeal nerve • Parathyroid glands • Trachea • Common carotid artery • Internal jugular vein

Answer 75

Triiodothyronine = more active

Answer 76

Thyroxine = less active than T3 but more is produced

Answer 77

- Iodine cotransported with Na+ into follicular cells (iodine trapping). Na pumped back out Na+/K+/ATPases - iodine transported into colloid (protein rich core) - Oxidised into iodine - Binds to tyrosine residues using thyroid peroxidase - monoiodotyrosine = 1 iodine T1 - diiodotyrosine = 2 iodine T2 - When stimulated they are cleaved: T1 + T2 = T3, T2 + T2 = T4 - TSH stimulates movement of T3 & T4 - iodated + lysosomes = proteolysis = T3 & T4 released

Answer 78

- Grave's disease - Toxic multiodular goitre - solitary toxic adenoma - De Quervains' thyroiditis - Drug induced

Answer 79

- Serum IgG antibodies, speciﬁc for Graves’ disease, known as TSH receptor stimulating antibodies (TSHR-Ab) bind to TSH receptors in the thyroid - Thereby stimulating thyroid hormone production (T3 & T4) - essentially they behave like TSH - Resulting in excess secretion of thyroid hormones and hyperplasia of thyroid follicular cells resulting in hyperthyroidism and diffuse goitre - Persistent high levels predict a relapse when drug treatment is stopped - Similar auto antigen can also result in retro-orbital inﬂammation - graves opthalmopathy

Answer 80

- Nodules that secrete thyroid hormones - Seen in elderly and in iodine-deﬁcient areas - Commonly occurs in older women and drug therapy rarely produces prolonged remission

Answer 81

Cause of about 5% of cases of hyperthyroidism | Prolonged remission is rarely induced by drug therapy

Answer 82

Transient hyperthyroidism sometimes results from acute inﬂammation of the thyroid gland, probably due to viral infection Typical for there to be globally reduced uptake on technetium thyroid scan Usually accompanied by fever, malaise and pain in the neck Treat with aspirin and only give prednisolone for severely symptomatic cases

Answer 83

AMIODARONE - anti-arrhythmic drug: Can cause both hyperthyroidism (due to the high iodine content of amiodarone) and hypothyroidism (since it also inhibits the conversion of T4 to T3) Iodine Lithium

Answer 84

- Female - Genetic - HLA-B8, DR3 and DR2 - E. coli and other gram-NEGATIVE organisms contain TSH-binding sites so may initiate pathogenesis via ‘molecular mimicry’ - Smoking - Stress - High iodine intake - Autoimmune disease: - Vitiligo (pale white patches -on skin) - Addison’s disease - Pernicious anaemia - Myasthenia gravis - Type 1 DM

Answer 85

- Graves occurs more commonly in females typically between the ages of 40-60 - Other causes of hyperthyroidism again mainly occurs in women but between the ages of 20-40

Answer 86

- Results in retro-orbital inﬂammation and swelling of the extrocular muscles - Eye discomfort, grittiness, increased tear production, photophobia, diplopia, reduced acuity - Exophthalmos - appearance of protruding eye and proptosis - eye protrudes beyond orbit - Conjunctival oedema - Corneal ulceration - Ophthalmoplegia - paralysis of eye muscles - Graves dermopathy - only in -Graves (Rare) - Pretibial myxoedema which is raised, purple-red symmetrical skin lesions over the anterolateral aspects of the shin - Thyroid acropachy - clubbing, swollen ﬁngers and periosteal bone formation

Answer 87

- Hands - Palmar erythema, warm moist skin and ﬁne tremor - Diffuse goitre - Lid lag & ‘stare’ - can occur in any hyperthyroidism - Hyperkinesis - muscle spasm - Warm - vasodilator peripheries - Proximal myopathy & muscle wasting - Lymphadenopathy and splenomegaly can occur

Answer 88

- Palpitations - Diarrhoea - Weight loss & increased appetite - Oligomenorrhea (infrequent periods) +/- infertility - Heat intolerance i.e. sweating a lot - will be wearing fewer clothes than normal - Irritability/behavioural change - Anxiety Elderly: - Atrial ﬁbrillation - Other tachycardias and/or heart failure Children: - Excessive height or excessive growth rate - Behavioural problems like hyperactivity

Answer 89

Usually no other differentials would fit the presentation, sometimes milds cases just need to differentiated from anxiety

Answer 90

-Thyroid function tests (TFTs): Serum TSH is suppressed: Due to negative feedback produced by hyperthyroidism T4 & T3 raised - DIAGNOSTIC: -T4 is almost always raised -T3 is more sensitive In secondary hyperthyroidism e.g. pituitary resistance or pituitary secreting adenoma - TSH will be very elevated and not suppressed since the fundamental problem is with the pituitary -Thyroid peroxidase (TPO) and thyroglobulin antibodies - Present in 80% of Graves’ but are all found in normal hyperthyroidism -Ultrasound of thyroid - Helps to differentiate Graves’ from toxic adenoma Graves’ speciﬁc tests: - TSH receptor stimulating antibodies (TSHR-Ab) raised - DIAGNOSTIC of GRAVES’ - Mild neutropenia - Eyes are examined via CT/MRI of orbit (For Graves)

Answer 91

-Thyroid crisis or thyroid storm:MEDICAL EMERGENCY! Rare, life threatening condition in which there is a rapid deterioration of thyrotoxicosis (RAPID T4 INCREASE) Features include hyperpyrexia, tachycardia, extreme restlessness and eventually delirium, coma and death Usually precipitated by stress, infection, surgery or radioactive iodine therapy in an unprepared patient Treated with LARGE DOSES of: ORAL CARBIMAZOLE ORAL PROPRANOLOL ORAL POTASSIUM IODIDE (to block acutely the release of thyroid hormone from gland) IV HYDROCORTISONE (to inhibits peripheral conversion of T4 to T3)

Answer 92

- Conservative treatment includes smoking cessation and sunglasses - Treated with IV Methylprednisolone and surgical decompression or eyelid surgery

Answer 93

- Beta-blockers eg. propanalol - Anti-thyroid drugs - Radioactive iodine

Answer 94

-PROPYLTHIOURACIL (PTU) stops the conversion of T4 to T3 -ORAL CARBIMAZOLE which blocks thyroid hormone biosynthesis and also has immunosuppressive effects (which will affect Graves’ disease process) -2 strategies: --Titration e.g. ORAL CARBIMAZOLE for 4 wks then reduce doses according to thyroid function tests (TFTs; TSH, T3 & T4) --Block-replace therapy e.g. ORAL CARBIMAZOLE + THYROXINE (T4) which has less risk of developing hypothyroidism -Half of those with Graves’ relapse on discontinuation of drug treatment after 2 yrs -Main side effect is AGRANULOCYTOSIS - results in a severely low white blood cell count (leukopenia) - most commonly neutropenia: If they get sore throat, mouth ulcers and fevers then STOP DRUG ASAP -Other S/E; rash (common), arthralgia, hepatitis and vasculitis (in bold less common)

Answer 95

- RADIOACTIVE I(131) is given - Contraindicated in pregnancy and breast feeding - Can be given to all ages - Stop antithyroid drugs 4 days before giving iodine - Iodine is essential for thyroid hormone production so is readily taken up by the thyroid gland - Here it accumulates and results in local irradiation and tissue damage with return to normal thyroid function over 4-12 weeks - S/E; discomfort in the neck and hyperthyroidism initially

Answer 96

- Indicated for those with large goitre, poor response to drugs and have drug side-effects - Subtotal thyroidectomy only in those who have been rendered euthyroid (normal functioning thyroid gland) - Total thyroidectomy only in those with large goitre or suspicion of malignancy (toxic adenoma) in a nodule and also for Graves’ - Stop antithyroid drugs 10-14 days before and give potassium iodide to reduce vascularity of the gland - Patients become hypothyroid

Answer 97

Tracheal compression from postoperative bleeding - Laryngeal nerve palsy resulting in hoarse voice - Transient hypocalcaemia - due to removal of parathyroid gland too

Answer 98

Underactivity of the thyroid gland may be primary, from disease of the thyroid gland, or much less commonly, secondary to hypothalamic or pituitary disease (secondary hypothyroidism)

Answer 99

- The most common cause of hypothyroidism - Associated with antithyroid autoantibodies leading to lymphoid inﬁltration of the gland and eventual atrophy and ﬁbrosis - since there is atrophy there is NO GOITRE - Associated with other autoimmune disease e.g. pernicious anaemia and vitiligo

Answer 100

- Form of autoimmune hypothyroidism - Most common in middle age & in women aged 60-70yrs - Produces atrophic changes & regeneration = GOITRE FORMATION due to lymphocytic and plasma cell inﬁltration - Gland is usually ﬁrm and rubbery but may range from soft to hard - Thyroid peroxidase = enzyme essential for the production and storage of thyroid hormone - Thyroid peroxidase antibodies (TPO-Ab) are present in HIGH TITRES - Patients may be hypothyroid or euthyroid (normal thyroid function) - LEVOTHYROXINE THERAPY may shrink the goitre, even when the patient is not hypothyroid

Answer 101

- Usually a transient phenomenon observed following pregnancy - May cause hyperthyroidism, hypothyroidism or the two sequentially - Thought to result from modiﬁcations to the immune system necessary in pregnancy and histologically is a lymphocytes thyroiditis (AUTOIMMUNE) - Normally self-limiting but when conventional antibodies are found there is a high chance of this proceeding to permanent hypothyroidism - Can be misdiagnosed as postpartum depression - why TFTs are essential!

Answer 102

- Thyroidectomy - for treatment of hyperthyroidism or goitre - Radioactive iodine treatment or external neck irradiation for head and neck cancer

Answer 103

- Carbimazole - Lithium - Amiodarone: Can cause both hyperthyroidism (due to the high iodine content of amiodarone) and hypothyroidism (since it also inhibits the conversion of T4 to T3) - Interferon

Answer 104

- Dietary iodine deﬁciency - results in goitre - Patients are euthyroid or hypothyroid, depending on the severity of iodine deﬁciency - Mechanism is thought to be borderline hypothyroidism leading to TSH stimulation and thyroid enlargement in the face of continuing iodine deﬁciency - Iodine deﬁciency is a problem in the Netherlands, Wester paciﬁc, India, SE Asia, Russia and part of Africa

Answer 105

- Autoimmune hypothyroidism is associated with other autoimmune disease e.g. DMT1, Addisons’, pernicious anaemia - Associated with Turner’s (only affects females, only have one X chromosome as opposed to the normal XX) & Down’s (trisomy 21) syndrome, cystic ﬁbrosis, primary biliary cirrhosis and ovarian hyper-stimulation

Answer 106

- Worldwide = iodine deﬁciency - The most common cause of primary hypothyroidism in areas with no iodine deﬁciency is autoimmune/atrophic hypothyroidism - More common in FEMALES than males - Incidence increases with age

Answer 107

BRADYCARDIC - Reﬂexes relax slowly - best seen on achilles with them kneeling on a chair - Ataxia (cerebellar) - Dry, thin hair/skin - Yawning/drowsy/coma - Cold hands +/- temperature drop - Ascites - Round puffy face - Defeated demeanour - Immobile +/- Ileus (temporary arrest of intestinal peristalsis) - Congestive cardiac failure

Answer 108

- Hoarse voice - Goitre - Constipation - Cold intolerant - Weight gain - Menorrhagia - Myalgia, weakness - Tired, low mood, dementia - Myxoedema - accumulation of mucopolysaccharide in SC tissue

Answer 109

May not show the classic features but often have a slow growth velocity, poor school performance and sometimes an arrest in puberty

Answer 110

May not show obvious signs. Hypothyroidism should be excluded in all people with oligomenorrhea/ amenorrhoea, menorrhagia, infertility or hyperprolactinaemia

Answer 111

Hard to differentiate clinical features from normal ageing - should exclude hypothyroidism in those with cognitive impairment

Answer 112

- THyroid function tests (TFTs) - Thyroid antibodies and organ specific antibodies - Blood tests

Answer 113

- Serum TSH high (conﬁrm primary hypothyroidism) - increases in an attempt to make thyroid work again - -In secondary hypothyroidism the TSH is inappropriately low for the low T4/T3 - since issues is in the pituitary - Serum free T4 low - DIAGNOSTIC for HYPOTHYROID STATE

Answer 114

TPO-Ab (Thyroid peroxidase antibody)

Answer 115

- Anaemia: - -Usually normochromic and normocytic - -May be macrocytic (sometimes due to pernicious anaemia) - -Or microcytic (in women, due to menorrhagia or undiagnosed coeliac disease) - Raised serum aspartate transferase levels from muscle and/or liver - Increase serum creatinine kinase levels associated with myopathy - Hypercholesterolaemia - Hyponatraemia due to an increase in ADH and impaired free water clearance

Answer 116

Lifelong thyroid hormone replacement e.g. ORAL LEVOTHYROXINE (T4) - -In patients with ischaemic heart disease use with caution and start on lower dose - -Aim is normal TSH conc. which will be achieved by levothyroxine - but don’t give too much so as to completely suppress TSH as this carries risk of AF and osteoporosis Monitoring treatment: - Primary hypothyroidism: - -Dose is titrated until TSH normalises - -Check T4 levels 6-8 weeks after dose adjustment - Secondary hypothyroidism: - -TSH will always be low - -T4 is monitored

Answer 117

Myxoedema coma: - Severe hypothyroidism (REDUCED T4) that may rarely present with confusion and coma - particularly in elderly - Typical features include hypothermia, cardiac failure, hypoventilation, hypoglycaemia and hyponatraemia - MEDICAL EMERGENCY and given IV/ORAL T3 & glucose infusion as well as gradual rewarming

Answer 118

``` Papillary (70%): Follicular (20%): Anaplastic (<5%): Lymphoma (2%) Medullary cell (5%) ```

Answer 119

70% of thyroid carcinomas - Most common, well differentiated - Young people, local spread and good prognosis - Arise from thyroid epithelium

Answer 120

20% of thyroid carcinomas - Middle age, spread to lung/bone, usually good prognosis - Well differentiated, arise from thyroid epithelium

Answer 121

<5% of thyroid carcinomas - Very undifferentiated and arise from thyroid epithelium - Aggressive, local spread but poor prognosis

Answer 122

5% of thyroid carcinomas Arise from calcitonin C cells of thyroid gland

Answer 123

-Minimally active hormonally -Over 90% secrete thyroglobulin which can be used as a tumour marker after thyroid ablation -Carcinomas derived from thyroid epithelium may be: Differentiated - papillary or follicular Undifferentiated - anaplastic

Answer 124

-Radiation

Answer 125

- Not common, but are responsible for 400 deaths annually in the UK - More common in FEMALES than male

Answer 126

- Thyroid nodule - Present in 90% - Cervical lymphadenopathy - May also metastasis to lung, cerebral, hepatic or bone metastases - If thyroid gland increases in size, becomes hard and is irregular in shape - think carcinoma

Answer 127

Dysphagia or hoarseness of voice - due to tumour compression on surrounding structures i.e. oesophagus and laryngeal nerve

Answer 128

- Fine needle aspiration cytology biopsy - To distinguish between benign or malignant nodules - Blood test - to check TFTs (TSH, T4 & T3) - To check if hyperthyroid or hypothyroid - needs to be treated before carcinoma surgery - Ultrasound of thyroid - Can differentiate between benign or malignant

Answer 129

- Thyroid LOVES iodine = readily take up radioactive iodine which in turn will locally irradiate and destroy cancer - providing very little radiation damage to other surrounding structures - Lots of LEVOTHYROXINE (T4) to keep TSH reduced as this is a growth factor for the cancer! - Chemotherapy = reduce risk of spread & treats micro-metastases that have been undetected - Papillary and follicular carcinomas: - -Total thyroidectomy - -Ablative radioactive iodine - Anaplastic carcinomas and lymphomas: - -DO NOT responde to radioactive iodine - -External radiotherapy provides brief respite - mainly palliative - Medullary carcinoma: - -Thyroidectomy and lymph node removal

Answer 130

General term which refers to chronic excessive and inappropriate elevated levels of circulating CORTISOL whatever the cause - Alcohol excess mimics this

Answer 131

Speciﬁcally refers to excess glucocorticoids resulting from inappropriate ACTH (adrenocorticotrophic hormone) secretion from the pituitary due to tumour

Answer 132

Cortisol is released from the zona fasciculata of the adrenal cortex

Answer 133

- Increased carbohydrate and protein catabolism (breakdown) - Increased deposition of fat and glycogen - Na+ retention - Increased renal K+ loss - Diminished host response to infection

Answer 134

According to circadian rhythm & in stress - Highest at 7/9am - Lowest at mignight

Answer 135

- Oral steroids VERY COMMON - Spontaneous endogenous = rare - -80% = raised ACTH, most common is pituitary adenoma (Cushing's disease) -Alcohol, depression, obesity, pregnance = high cortisol

Answer 136

- Cushing’s disease - most common ACTH-dependent cause: - -Bilateral adrenal hyperplasia from an ACTH-secreting pituitary adenoma (benign) (usually a microadenoma) - -Equal prevalence in both men and women - -Peak age is 30-50 yrs Ectopic ACTH production: - -a ACTH producing tumour elsewhere - -Especially small cell lung cancer and carcinoid tumours ACTH treatment for e.g. asthma

Answer 137

(↓ ACTH due to negative feedback from raised cortisol): - Adrenal adenoma (benign)/cancer - tumour of the adrenal that releases cortisol - Iatrogenic such as administration of a glucocorticoid e.g. PREDNISOLONE -Excess cortisol can either result from excess ACTH which in turn stimulates excess cortisol release or from neoplasms in the adrenals which in turn stimulate the zona fasciculata to release more cortisol

Answer 138

- Obese - central fat distribution - Plethoric complexion (ruddy and swollen) with moon face - Mood - depression, lethargy, irritable, psychosis - proximal weakness - gonadal dysfunction - Protein catabolic effect of cortisol - muscle atrphy, thin skin, purple striae on abdomen - Acne - High BP - children not grow up, just out - infections - osteoporosis - hyperglycaemia

Answer 139

Pseudo-Cushing’s syndrome - caused by alcohol excess, resolves after 1-3 weeks of alcohol abstinence

Answer 140

- Drug history STEROIDS - Random plasma cortisol - 1st line test - 2nd line test

Answer 141

If high then proceed to 1st line test | May mislead as illness, time of day and stress (e.g. due to venepuncture) will inﬂuence results

Answer 142

- Dexamethasone should, in the healthy patient, send negative feedback to the pituitary and hypothalamus resulting in ↓ ACTH and thus reduced cortisol - Overnight dexamethasone suppression test: - -Oral dexamethasone 1mg at 00:00 - -Measure serum cortisol at 8AM - -Normally there will be cortisol suppression < 50nmol/L - -In Cushing’s syndrome there will be no suppression Urine free cortisol over 24hrs is an alternative: -Take > 2 measurements (cortisol is bound to corticosteroid binding globulin, when capacity is reached then will spill out to urine)

Answer 143

If there's no supression - Perform 48hr dexamethasone supression test - If above +ve, do plasmsa ACTH -If ACTH = 0 = adrenal tumour likely = CT/MRI/adrenal vein sampling -If ACTH detectable = ectopic production = high dose dexamethason suppression/corticotropin releasing hormone test -If test shows that cortisol doesn't respond to CRH then look for ectopic source of ACTH - IV contract CT, MRI, CXR

Answer 144

Stop steroids

Answer 145

-Surgical selective removal of pituitary adenoma - trans-sphenoidal approach Bilateral adrenalectomy (remove both adrenal glands): - If source unlocatable or recurrence post-op - Complication: Nelson’s syndrome: - Increase skin pigmentation due to signiﬁcantly increased ACTH from an enlarging pituitary tumour as the adrenalectomy will remove the negative feedback - Will respond to pituitary radiotherapy

Answer 146

Adrenalectomy

Answer 147

Adrenalectomy (doesn’t cure cancer) so radiotherapy and adrenolytic drugs e.g. MITOTANE

Answer 148

- Surgery if tumour is located and hasn’t spread - Drugs that inhibit cortisone synthesis e.g. METYRAPONE, KETOCONAZOLE and FLUCONAZOLE are used pre-op or if awaiting effects of radiation