Endocrinology Flashcards

Question

Prognosis for hyperthyroidism

Answer 1

Prognosis depends on the underlying cause and severity. Patients may well become hypothyroid during the course of their management and require levothyroxine to achieve a euthyroid status.

Answer 2

Graves’ disease is the most common cause of hyperthyroidism worldwide. It is an autoimmune induced excess production of thyroid hormone

Answer 3

- This is the MOST COMMON CAUSE of hyperthyroidism (2/3rds of cases) - More common in FEMALES than males - Typically presents at 40-60yrs (appears earlier if maternal family history)

Answer 4

- 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 5

- Family history - Female - Autoimmune disease - Stress - High iodine intake - Radiation - Tobacco use

Answer 6

Involves anti-TSH antibodies causing increased thyroid hormone production through stimulation of the TSH receptor. Of note, anti-TSH antibodies react with orbital antigens in fat and connective tissue, causing retro-orbital inflammation which leads to thyroid eye disease.

Answer 7

- Thyroid acropachy - clubbing, swollen fingers and periosteal bone formation - Thyroid bruit - continuous sound heard over thyroid mass - Pretibial myxoedema - raised, purple-red symmetrical skin lesions over the anterolateral aspects of the shin - Eye signs - Exophthalmos - protruding eye - Ophthalmoplegia - paralysis or weakness of eye muscles

Answer 8

TFT's: raised T3 and T4, reduced TSH. All other aspects of investigation and management are the same as generic hyperthyroidism

Answer 9

- 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 10

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

Answer 11

- 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 12

- 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 13

Also known as a ‘thyroid storm’, a thyrotoxic crisis is a life-threatening complication of hyperthyroidism and is most commonly seen in patients with Graves’ disease or toxic multinodular goitre.

Answer 14

It is classified as an endocrine emergency and it often occurs secondary to a precipitating factor such as infection or trauma in patients with known hyperthyroidism. However, it may also be the first manifestation of undiagnosed hyperthyroidism.

Answer 15

- Hyperpyrexia: often > 40°C - Tachycardia: often > 140 BPM, with or without atrial fibrillation - Reduced GCS - consciousness

Answer 16

- Nausea and vomiting - Diarrhoea - Abdominal pain - Jaundice - Confusion, delirium or coma

Answer 17

- TFTs: elevated T3 and T4 levels, suppressed TSH levels - ECG: tachycardia; may demonstrate atrial fibrillation - Blood glucose: perform in all patients with reduced consciousness

Answer 18

- Conservative: IV fluids, NG tube insertion (if vomiting), tepid sponging, paracetamol, ITU admission - Antithyroid drugs: propylthiouracil is generally preferred, but carbimazole is an alternative - Corticosteroid: IV hydrocortisone or methylprednisolone - Beta-blocker: propranolol PO, or IV over 10 minutes - Oral iodine: Lugol’s iodine is offered > 1 hour after propylthiouracil (some trusts advise giving it at 4 hours) - blocks the peripheral conversion of T4 to T3 - Sedation: if required, use chlorpromazine - Plasma exchange or thyroidectomy: in refractory patients

Answer 19

Even if promptly treated, it has a mortality of 10-20%

Answer 20

Hypothyroidism is a common endocrine condition caused by a deficiency in thyroid hormone. Hypothyroidism is a pathological state reflecting a reduction in circulating T3 and T4. Hypothyroidism is classified as primary, secondary and congenital. 95% of cases are primary, with secondary and congenital causes being rare.

Answer 21

- It is estimated that the prevalence of any cause of hypothyroidism is 1-2%, with Hashimoto’s thyroiditis being the most common cause in the developed world. Iodine deficiency is the most common cause worldwide. - Female gender: 5-8x more likely to develop than men - Middle-aged: peak age is 30-50 years old in Hashimoto’s thyroiditis

Answer 22

Hashimoto’s thyroiditis: commonest cause in the developed world - Autoimmune process associated with HLA-DR5 and anti-TPO antibodies, which act as competitive inhibitors for the enzyme - Associated with other autoimmune conditions e.g. type 1 diabetes and Addisons disease - Diffuse painless goitre and can experience a transient thyrotoxic state known as hashitoxicosis - 5-10x more common in women - Increased risk of Non-Hodgkin lymphoma

Answer 23

- Follows a viral prodrome and can also present with a transient thyrotoxic state - Painful goitre with raised inflammatory markers. Usually self-limiting

Answer 24

- Autoimmune with most patients developing thyrotoxicosis within the first 6 months of birth, with subsequent hypothyroidism - Most patients’ thyroid function normalises by 12 months

Answer 25

- Hard non-tender thyroid goitre due to fibrous tissue - Causes a painless goitre

Answer 26

- Commonest cause worldwide, due to dietary deficiency - Uncommon in the developed world due to iodine-fortified salt and foods

Answer 27

After treatment for hyperthyroidism e.g. Graves’ disease, patients can experience long term hypothyroidism and require levothyroxine replacement

Answer 28

- 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) - Lithium - Anti-thyroid drugs e.g. carbimazole

Answer 29

- Often due to compression from a pituitary tumour (e.g. adenoma), but may occur following surgery/radiation or vascular pathology (e.g. pituitary apoplexy) - Rarely, it may be due to hypothalamic pathology, e.g. a tumour - Drugs: cocaine, steroids and dopamine all inhibit TSH secretion

Answer 30

- Family history - History of autoimmunity - Genetic disorders: Turner and Down syndrome - Chest or neck irradiation - Thyroidectomy or radioiodine

Answer 31

Hypothyroidism is a pathological state reflecting a reduction in circulating T3 and T4. 95% of cases are primary, with secondary causes being rare. Primary hypothyroidism is due to pathology affecting the thyroid gland itself, such as an autoimmune disorder (e.g. Hashimoto’s thyroiditis) or iodine deficiency. Secondary hypothyroidism is usually due to pathology affecting the pituitary gland (e.g. pituitary apoplexy) or a tumour compressing the pituitary gland. It may also be caused by hypothalamic disorders and certain drugs. Congenital hypothyroidism occurs due to an absent or poorly developed thyroid gland (dysgenesis), or one that has properly developed but cannot produce thyroid hormone (dyshormonogenesis).

Answer 32

- Dermatological: hair loss, loss of lateral aspect of the eyebrows (Queen Anne's sign), dry and cold skin, coarse hair - Bradycardia - Goitre - Decreased deep tendon reflexes - Carpal tunnel syndrome - Hoarse voice

Answer 33

- Myxoedema - seen in autoimmune hypothyroidism - Fluid retention - oedema, pleural effusions, ascites - Weight gain - Cold intolerance - Lethargy - Dry skin - Constipation - Menorrhagia: followed later by oligomenorrhoea and amenorrhoea

Answer 34

Thyroid function tests (TFTs) - decreased T3/T4 and increased TSH in primary disease. Increased TSH and normal T4 in subclinical Decreased or normal TSH and decreased T4 signals Secondary hypothyroidism

Answer 35

Antibodies: Anti-TPO is associated with Hashimoto's thyroiditis in 95% of cases, also look for Anti-TPO, Anti-thyroglobulin Inflammatory markers: raised in De Quervains thyroiditis

Answer 36

- Ultrasound: not routinely carried out but may be useful if there is a goitre or focal nodule and malignancy is suspected in patients with normal thyroid function - Radionuclide scan: not routinely carried out. Uses a small dose of a radioactive chemical (isotope) called a tracer that can detect cancer, trauma, infection or other disorders. - Fasting lipids: hypothyroidism is associated with hypercholesterolemia - Serum glucose and HbA1c: hypothyroidism is associated with hypoglycaemia. Also, Hashimoto's thyroiditis is associated with T1DM - FBC and serum B12 level: autoimmune thyroid disease is associated with a higher risk of pernicious anaemia - Coeliac serology: to assess for coeliac disease if autoimmune thyroid disease is suspected. Thyroid disease is more common in patients with coeliac disease.

Answer 37

The aims of treatment are to resolve signs and symptoms and to maintain serum TSH and FT4 levels within or close to the normal reference range (0.5-2.5 mU/L). All patients with secondary hypothyroidism require urgent referral to an endocrinologist.

Answer 38

- Levothyroxine (T4): offer with regular review of symptoms and TSH every 3 months. Once TSH is stable (on 2 occasions at least 6 months apart), review TSH annually - T4 starting dose: 50-100 mcg OD for most patients - Lower T4 starting dose: 25 mcg OD titrated slowly if > 50 years, severe hypothyroidism or a history of ischaemic heart disease - Advise that symptoms may lag behind treatment changes for several weeks or months - Review dose every 8-12 weeks when dose is changed - Interactions: iron and calcium carbonate reduce levothyroxine absorption so should be given ≥ 4 hours apart

Answer 39

- If TFTs are abnormal, advise delaying conception and using contraception until stabilised on levothyroxine - Inform the woman that there is an increased demand for levothyroxine in pregnancy, with the dose usually increased by at least 25-50 mcg and aiming for a low-normal TSH - Post-partum thyroiditis: the hypothyroid state may require levothyroxine, with most patients’ thyroid function normalising by 12 months of the birth

Answer 40

- Cardiovascular: hypercholesterolaemia is associated with ischaemic heart disease - Neurological: carpal tunnel syndrome, peripheral neuropathy, proximal myopathy - Myxoedema coma: rare but potentially fatal outcome of untreated/undertreated hypothyroidism. Presents with confusion, hypothermia, hypoglycaemia, hypoventilation, and hypotension - Thyroid lymphoma: patients with Hashimoto's thyroiditis are at increased risk of lymphoma, usually diffuse large B cell lymphomas - Thyroxine side-effects - Hyperthyroidism - Atrial fibrillation - Osteoporosis - Angina

Answer 41

Hypothyroidism, if well managed with levothyroxine, will not present any issues for the individual and euthyroid status can be achieved. However, if left untreated, hypothyroidism slowly develops and worsens and predisposes to the above complications.

Answer 42

The most common cause of hypothyroidism in the West. Antithyroid antibodies is the cause for this type of hypothyroidism

Answer 43

- It is estimated to affect between 0.5% and 2% of the population. - More common in FEMALES than males - Incidence increases with age

Answer 44

- Female sex - Associated with other autoimmune disease e.g. T1DM - Associations with Turner's and Down's syndrome

Answer 45

Autoimmune inflammation of thyroid gland. This is associated with anti thyroid peroxidase (TP) antibodies and anti-thyroglobulin antibodies. There may also be anti-TSH receptor antibodies leading to degeneration of thyroid gland. (Thyroid peroxidase converts iodide into iodine and is essential for thyroid hormone production. As is thyroglobulin) It exists in two forms: - Goitrous: characterised by a firm and rubbery goitre - Atrophic: characterised by an atrophic gland Initially it causes goitre, after which there is atrophy of the thyroid gland

Answer 46

Cancers of the thyroid gland: Four types account for more than 98% of thyroid malignancies: papillary, follicular, anaplastic, and medullary.

Answer 47

- Thyroid cancer is the most common endocrinological malignancy - Not generally common, but are responsible for 400 deaths annually in the UK - More common in women than men, generally - Most likely to be diagnosed between the ages of 45 to 54 years.

Answer 48

- Palpable thyroid nodule in most cases - Occasionally (5%) they present with cervical lymphadenopathy or with lung, cerebral, hepatic or bone metastases - Thyroid gland may increase in size, become hard and may be irregular in shape - Tracheal deviation - Neck enlargement - Dysphagia - Hoarseness of voice - Dyspnoea

Answer 49

- Fine needle biopsy - To distinguish between benign or malignant nodules - TFTs - To check if hyperthyroid or hypothyroid (TSH, T3 & T4) - needs to be treated before carcinoma surgery - Ultrasound of neck - Can differentiate between benign or malignant - Laryngoscopy - paralysed vocal cord is highly suggestive of malignancy

Answer 50

- Most frequent (around 80%) - F>M - Peak incidence 30s-50s

Answer 51

- These cancers are derived from the follicular cells - they secrete thyroglobulin and take up radioiodine - They can spread via lymphatic invasion to cervical nodes and neck - They are slow growing

Answer 52

- Radiation exposure - Mutation RET and BRAF

Answer 53

- Lobectomy (or total thyroidectomy with lymph node removal) - High risk patients may receive radioiodine to catch the cancer that may not have been resected - TSH suppression with thyroid hormone replacement *(TSH is a growth factor for the cancer)*

Answer 54

Associated with best prognosis (10 year survival >95%)

Answer 55

- 10% of thyroid cancers - F>M - Peak in 40s-60s

Answer 56

- Derived from follicular cells - secretes thyroglobulin and takes up radioiodine - Hurthle cells (a subtype of follicular cells) seen - Early metastases - Can spread via vascular invasion: locally invasive, invades thyroid capsule - Distal spread more common than papillary

Answer 57

Mutations in RAS

Answer 58

- Lobectomy (or total thyroidectomy with lymph node removal) - High risk patients may receive radioiodine to catch the cancer that may not have been resected - TSH suppression with thyroid hormone replacement

Answer 59

- More aggressive than papillary

Answer 60

- 5% of thyroid cancers - Sporadic (80%) - F>M, peak in 40s-60s - Familial (20%) - F:M, peak onset at early age

Answer 61

- Derived from para-follicular cells (aka C-Cells responsible for calcitonin production) - do not secrete thyroglobulin and does not take up radioiodine - Associated with early metastasis

Answer 62

- Family with MEN 2A and 2B - Mutation in RET

Answer 63

- Lobectomy (maybe total thyroidectomy with lymph node removal) - Thyroid hormone replacement for normal TSH (no TSH suppression)

Answer 64

More aggressive than follicular

Answer 65

- 3% of thyroid cancers - M>F - Peak in 60s to 80s

Answer 66

- Also known as undifferentiated carcinoma due to poor differentiation - Very aggressive - Spread: infiltrative to local structures, soft tissue of neck, widespread metastases, early mortality

Answer 67

- Does not respond to radioactive iodine - If possible a total thyroidectomy is done - Combined chemotherapy and radiation - may be palliative

Answer 68

Worst prognosis

Answer 69

- Generally a B cell-type non-Hodgkin's lymphoma. It generally arises in the setting of pre-existing Hashimoto's thyroiditis. - Management - Primary thyroid lymphoma is treated with a combination of radiation and chemotherapy. The most common chemotherapy regimen is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone).

Answer 70

- Goitre - Benign thyroid nodule

Answer 71

- Airway obstruction - Surgery related: - Hypoparathyroidism - Recurrent laryngeal nerve damage - Bleeding - TSH suppression related: - Atrial fibrillation - Bone mineral loss - Radioiodine related: - Secondary tumours - Dryness of mouth

Answer 72

Cushing syndrome is the clinical manifestation of pathological hypercortisolism from any cause.

Answer 73

- Cushing’s syndrome is uncommon, with an estimated 1-10 cases per million in the population - It most commonly affects people aged 20 to 50 years - Occurs 3 times more commonly in women than in men

Answer 74

- Iatrogenic - due to exogenous steroid use - Cushing's disease - a pituitary adenoma secreting excess ACTH - Primary disease - e.g. adrenal adenoma or adrenal hyperplasia - secreting excess cortisol - Paraneoplastic Cushing's- cancer producing ectopic ACTH e.g. from small cell lung cancer or neuroendocrine tumours - Carney complex - a genetic disorder with multiple benign tumours, e.g. cardiac myxoma - Micronodular adrenal dysplasia - rare cause

Answer 75

- Long term steroid use - Pituitary adenoma - Adrenal adenoma - Small cell lung cancer - Neuroendocrine tumours

Answer 76

- Hypertension - Moon face - Buffalo hump - Central adiposity - Violaceous striae - Muscle wasting and proximal myopathy - Ecchymoses and fragile skin - Acne

Answer 77

- Bloating and weight gain - Mood change - Tiredness - Easy bruising - Increase susceptibility - Menstrual irregularity - Reduced libido

Answer 78

After excluding exogenous glucocorticoid use, the first step is to confirm hypercortisolism which can be done with any of the following: - 24-hour urinary free cortisol - Overnight dexamethasone suppression test: most sensitive; shows failure of cortisol suppression - Low dose dexamethasone suppression test: shows failure of cortisol suppression - Late-night salivary cortisol - helps to demonstrate a loss of the normal circadian pattern.

Answer 79

- 24-hour urinary free cortisol - Overnight dexamethasone suppression test

Answer 80

Once hypercortisolism is confirmed, the source must be localised: - 9am ACTH: - If elevated: suggests an ACTH-dependent cause and warrants a high dose dexamethasone suppression test - If low: suggests an ACTH-independent cause and warrants a CT adrenals to look for adrenal pathology - High dose dexamethasone suppression test (DST): suppression of cortisol occurs in Cushing’s disease (pituitary adenoma), but not in an ectopic ACTH source

Answer 81

If a DST is inconclusive: - CRH stimulation test: - Pituitary source: cortisol rises - Ectopic or adrenal source: no change in cortisol - Petrosal sinus sampling of ACTH: to differentiate between pituitary and ectopic ACTH source Final localisation tests: - MRI pituitary: if Cushing’s disease (pituitary adenoma) is suspected - CT chest, abdomen and pelvis: if an ectopic source is suspected

Answer 82

- Obesity - Metabolic syndrome

Answer 83

ACTH-dependent causes: - Cushing’s disease (pituitary adenoma): first-line treatment is with trans-sphenoidal resection of the pituitary. There is a role for medical therapy (e.g. glucocorticoid antagonists) or radiotherapy if surgery fails - Ectopic ACTH source: treatment of underlying cancer ACTH-independent causes: - Iatrogenic: review the need for medication and try weaning if possible - Adrenal tumour: tumour resection or adrenalectomy - Unilateral adrenal adenoma Unilateral adrenalectomy offers curative therapy. Where available the laparoscopic approach is generally preferred to open surgery. Following surgery patients will need a tapering course of exogenous steroids for a period of time as their endogenous CRH and ACTH will be suppressed. - Bilateral adrenal hyperplasia In patients with overt Cushing's bilateral adrenalectomy may be offered. Following this patients require replacement of glucocorticoids and mineralocorticoids. - Adrenal carcinoma Following appropriate staging resection is the mainstay of management. Adjuvant chemotherapy, radiotherapy or mitotane may be given.

Answer 84

Recurrence of adrenocorticotrophic hormone-dependent Cushing syndrome is common, with at least a 5% to 26% risk of recurrence at 5 years. Patients who have achieved remission should be screened periodically (every 6-12 months) for recurrence of disease.

Answer 85

Complications associated with action of cortisol - - Osteoporosis - Increased susceptibility to infection - Diabetes mellitus - Hypertension Treatment related - - Hypopituitarism - Adrenal insufficiency - Nelson syndrome after bilateral adrenalectomy - enlarged pituitary, development of adenomas. - Hypothyroidism - Growth hormone deficiency - Hypogonadism

Answer 86

The prognosis depends on the underlying cause. Adrenal adenomas and pituitary microadenomas are associated with a favourable outcome. Those with adrenal carcinomas have poor outcomes. The prognosis in ectopic ACTH production depends on the underlying malignancy, but many are aggressive and grow rapidly.

Answer 87

- Cushingoid features and abnormal cortisol levels but not associated with HPA pathology - Common causes include alcohol excess, severe depression, obesity, pregnancy - Results in a false positive dexamethasone suppression test and 24h urinary free cortisol - Differentiated using an insulin stress test

Answer 88

Dexamethasone should, in the healthy patient, send negative feedback to the pituitary and hypothalamus resulting in ↓ ACTH and thus reduced cortisol. - 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

Answer 89

Growth hormone (GH) is secreted in a pulsatile fashion under the control of two hypothalamic hormones: - Growth hormone releasing hormone (GHRH) stimulates GH secretion - Somatostatin (SST) inhibits GH secretion GH is also inhibited by high glucose and dopamine Ghrelin (synthesised in the stomach) also stimulates release of GH

Answer 90

- Indirectly through the induction of insulin-like growth factor (IGF-1), which is synthesised in the liver and other tissues - Directly on tissues such as the liver, muscle, bone or fat to induce metabolic changes

Answer 91

Acromegaly is a condition caused by an excess of growth hormone (GH) most commonly related to a pituitary adenoma.

Answer 92

Gigantism refers to excess GH production before fusion of the epiphyses of the long bones

Answer 93

- Acromegaly is a rare disease with a prevalence of < 0.1% - Acromegaly is often recognised in middle-aged men or women but can occur at any age. - The disease is equally distributed between both sexes.

Answer 94

- Pituitary adenomas account for > 90% of cases of acromegaly. - Other causes of acromegaly are very rare. They are related to excess secretion of GHRH or GH: - Ectopic release of GH: May be seen in neuroendocrine tumours. - Ectopic release of GHRH: Related to tumours including carcinoid and small cell lung cancer. - Excess hypothalamic release of GHRH: Related to hypothalamic tumours.

Answer 95

- MEN-1: pituitary adenomas, primary hyperparathyroidism, and pancreatic neuroendocrine tumours; MEN-1 is present in 6% of cases - McCune-Albright syndrome

Answer 96

Acromegaly describes a state of excessive growth hormone (GH) production. A pituitary somatotroph adenoma is responsible in over 95% of cases, but acromegaly can rarely occur due to ectopic secretion from a GHRH or GH producing-tumour, such as a pancreatic tumour. Excessive GH causes soft-tissue growth resulting in the classical appearance seen in the disease. Additionally, if sufficiently large, a pituitary adenoma can cause bitemporal hemianopia, and significant compression can lead to panhypopituitarism.

Answer 97

- Bitemporal hemianopia: due to compression of optic chiasm by pituitary tumour - Facial features: - Prominent jaw and supra-orbital ridge - Coarse facial appearance - Prognathism: protrusion of the lower jaw - Splaying of teeth - Macroglossia: large tongue - Spade like hands - Sweaty palms and oily skin - Hypertension - Organomegaly

Answer 98

- Visual disturbance - Headaches - Obstructive sleep apnoea - Rings and shoes are tight - Polyuria and polydispia due to T2DM - Tingling in hands: carpal tunnel sydrome - Hyperprolactinaemia: raised prolactin seen in over 20% of cases - features include galactorrhea, dysmenorrhoea, hypogonadism, decreased libido and infertility.

Answer 99

- Serum insulin-like growth factor 1 (IGF-1): elevated in acromegaly - As per Endocrine Society guidelines, this is the first-line investigation for suspected acromegaly and, if elevated or inconclusive, an OGTT should be conducted to confirm the diagnosis; also used for monitoring - Oral glucose tolerance test (OGTT): - Physiologically, a glucose load should cause suppression of GH - In acromegaly, there is failure of GH suppression 2 hours post 75g glucose load (lack of suppression of GH to < 1 μg/L)

Answer 100

Pituitary MRI, Visual field tests, check pituitary hormone secretions for other hormones, CT other parts of body if ectopic suspected, GHRH levels check as will be elevated in hypothalamic cause

Answer 101

Acromegaloidism or pseudo-acromegaly

Answer 102

Surgery: trans-sphenoidal resection of the pituitary. Surgery is first-line as acromegaly can have significant systemic complications

Answer 103

- Medical: for patients unsuitable for surgery or if there are persistent symptoms after surgery - Dopamine agonists: used in mild disease; cabergoline is first-line (bromocriptine is an alternative) and has 30% efficacy - Somatostatin analogues: used in moderate to severe disease to directly inhibit GH release (e.g. octreotide); has an efficacy of 35-60% - GH antagonist: pegvisomant is also used in severe disease but, in reality, is often avoided due to cost; once-daily subcutaneous injection. Very effective and reduces IGF-1 in up to 95% of patients, but does not reduce tumour size so surgery is still required

Answer 104

Radiotherapy: reserved for patients who have failed medical and surgical treatment, or in elderly patients unsuitable for surgery

Answer 105

Patients with acromegaly will require lifelong monitoring of growth hormone and insulin-like growth factor 1 (IGF-1) levels. Once the initial treatment interventions (surgical, medical, and radiotherapy, as required) have remediated or significantly improved the disease state, regular monitoring of disease-related parameters is recommended. Medical complications of acromegaly also require ongoing monitoring and treatment e.g. regular screening for colorectal cancer

Answer 106

Cardiomyopathy, heart failure, hypertension, obstructive sleep apnoea, carpel tunnel, T2DM, Colorectal cancer, organ dysfunction, arthritis

Answer 107

The aim of treatment is biochemical normalisation of IGF-1 and random serum GH levels. Surgical treatment is curative, however, patients still need regular monitoring of GH and IGF-1 levels with life expectancy near normal in treated disease. Acromegaly appears to be associated with an increased mortality. Much of this risk is related to the obstructive sleep apnea and cardiovascular complications. Studies have reported average survival reduction of up to 10 years in patients with acromegaly.

Answer 108

Late puberty, tall for age, reduced gonadal development

Answer 109

Primary: independant of RAAS, known as Conn's syndrome Secondary: dependant on RAAS Both result in increased sodium retention and therefore water retention (increased BP)

Answer 110

- Primary hyperaldosteronism was originally thought to be rare, with a prevalence of <1%, but recent evidence suggests that it may be more common than initially thought. - Common in middle-aged adults

Answer 111

- Primary hyperaldosteronism Describes adrenal dysfunction causing raised aldosterone levels with decreased renin levels due to negative feedback from sodium retention. Causes include: - Adrenal hyperplasia: idiopathic bilateral hyperplasia is the most common cause (⅔), can also be unilateral - Adrenal adenoma: classically termed Conn’s syndrome - Adrenal carcinoma: extremely rare - Familial hyperaldosteronism: rare Secondary hyperaldosteronism Describes inappropriate activation of the RAAS, therefore patients have raised aldosterone and raised renin levels. Causes include: - Renal artery stenosis - Heart Failure: arterial hypovolemia due to reduced oncotic pressure causes reduced renal perfusion

Answer 112

- Family history of early onset hypertension - Family history of primary hyperaldosteronism

Answer 113

Aldosterone is a mineralocorticoid and its role involves renal excretion of potassium and acid, as well as sodium reabsorption. The renin-angiotensin-aldosterone system (RAS) is activated in cases of hypovolemia and hyponatraemia and leads to increased aldosterone levels with subsequent salt and water retention. Classically, the disease presents as refractory hypertension, hypokalaemia, and metabolic alkalosis. Hypernatraemia may or may not be seen.

Answer 114

- Refractory hypertension - Hypokalaemia - increased K+ secretion by kidneys - Metabolic alkalosis - increased H+ secretion by kidneys

Answer 115

- Lethargy - Mood disturbance - Paresthesia and muscle cramps - Polyuria and nocturia

Answer 116

Aldosterone/renin ratio: first-line diagnostic test. Will show high aldosterone, with low renin in cases of primary hyperaldosteronism and high aldosterone and high renin in cases of secondary hyperaldosteronism. CT imaging should be performed if there is a raised ratio.

Answer 117

- Serum U&Es: hypokalaemia and hypernatraemia may be seen - Patients may have normal sodium levels due to the ‘aldosterone-escape’ mechanism - Water is absorbed alongside sodium which increases the hydrostatic pressure within peri-tubular capillaries causing sodium to leak back into the tubule - Blood gas - to look for alkalosis - High-resolution CT abdomen: useful to exclude carcinoma; if CT suggests an adenoma or hyperplasia, perform bilateral adrenal venous sampling - Adrenal venous sampling: to determine if there is unilateral or bilateral disease, and if the mass is functional - Adrenal vein sampling measures the amount of corticosteroid secreted from each adrenal gland - In a non-functional mass, imaging will show an abnormality but corticosteroid levels will be normal; removal would not be necessary in this instance - In cases of secondary hyperaldosteronism - doppler/ CT angio/ MRA to look for renal artery stenosis

Answer 118

- Other forms of hypertension e.g. - Essential hypertension - Secondary hypertension - Liddle syndrome

Answer 119

- Laparoscopic adrenalectomy: for unilateral adrenal hyperplasia or adenoma - Spironolactone: for bilateral adrenal hyperplasia or adenoma; spironolactone is an aldosterone antagonist

Answer 120

- In unilateral disease where surgery is inappropriate, treat with spironolactone - ENaC inhibitor: Amiloride, a potassium-sparing diuretic, may be used if aldosterone antagonists are not tolerated.

Answer 121

In secondary hyperaldosteronism - percutaneous renal artery angioplasty to resolve the renal artery stenosis

Answer 122

- Patients who have undergone unilateral adrenalectomy - BP, plasma electrolytes, and aldosterone and renin levels should be monitored every 6 to 12 months for clinical and biochemical evidence of recurrence (if cured postoperatively) or worsening (if improved but not cured) of PA. - Patients receiving aldosterone medications - Electrolytes and renal function should be monitored regularly (e.g., every 3 to 6 months), watching for development of hyperkalaemia, hyponatraemia, and uraemia. CT of the adrenals should be performed annually at first and, if no nodular growth is seen, every 3 to 4 years, indefinitely. - Patients with familial hyperaldosteronism type I (FH-I) - Hypertension is readily controlled by administering glucocorticoids in low doses. Control can be assessed by clinic, home, and ambulatory BP monitoring, and by periodic (e.g., yearly) echocardiography.

Answer 123

- Secondary to long-standing hypertension: ischaemic heart disease, stroke, hypertensive nephropathy and chronic kidney disease - Iatrogenic - hyperkalaemia

Answer 124

Patients with primary hyperaldosteronism have increased mortality and cardiovascular morbidity compared to age and sex-matched controls. Surgical management leads to a cure in 50% of patients and the rest will have improvement of symptoms and blood pressure.

Answer 125

- Pituitary adenomas are the third most common intra-cranial neoplasms in adults, accounting for about 10% of all intra-cranial tumours. - The prevalence of pituitary adenoma varies from 19 to 28 cases per 100,000 in the UK - Prevalence increases with age - there is a peak in incidence between the ages of 30 to 60 years

Answer 126

- MEN-1 - Carney complex - Familial isolated pituitary adenomas - rare

Answer 127

Usually macroadenomas and can secrete a variety of hormones depending on the cell of origin A number of cell lines may be affected: - Mammotrophs: Results in hyperprolactinaemia caused by a prolactinoma. - Somatotrophs: Acromegaly occurs due to excess growth hormone. - Corticotrophs: Results in the release of excess cortisol (Cushing's syndrome) through excess production of ACTH.

Answer 128

Symptoms will vary depending on cells affected and mass effects of the tumour Prolactinoma - Galactorrhoea - Irregular menses - Lack of libido - Erectile dysfunction Cushing's related symptoms Acromegaly related symptoms Compressive effects - Headache - Visual disturbances - bitemporal hemianopia - Palsy of cranial nerves III, IV, VI - Diabetes insipidus - May even present as hypopituitarism

Answer 129

*Those with a known family history (first and second-degree relatives) may be screened. Screening tends to be annual, typically from the ages of 5 to 65 (and may continue after this time, but less frequently).* - Hormonal tests - - Prolactinoma: raised prolactin - Acromegaly: raised IGF-1 and failure of growth hormone suppression following oral glucose tolerance test - Other: the remaining hormones should also be screened as mass effect can lead to hypopituitarism. - Imaging - - MRI is 1st line - PET-CT - CT - DNA testing - MEN1: mutation testing should be offered to patients and their relatives

Answer 130

- Rathke's cleft cyst: an abnormal fluid-filled (cyst) sac that usually is found between the anterior and posterior pituitary glands. - Craniopharyngioma: a rare type of noncancerous (benign) brain tumor that begins near the brain's pituitary gland and can affect the function of the pituitary gland and other nearby structures in the brain. - Meningioma: a tumor that forms on membranes that cover the brain and spinal cord just inside the skull. - Hypophysitis: a rare condition which involves the acute or chronic inflammation of the pituitary gland or pituitary stalk. - Infection

Answer 131

Functioning tumours - Prolactinomas: first-line management is with dopamine agonists such as bromocriptine - Acromegaly/ Cushing's: transsphenoidal resection is first-line Non-functioning tumours - Surgical resection: conducted when mass effect is observed

Answer 132

Patients with clinically non-functional pituitary adenomas (CNFPAs) generally have a good prognosis. The 10-year progression-free survival for pituitary adenoma is 80% to 94%. Micro-adenomas do well with observation. Macro-adenomas have a propensity to grow, and even when diagnosed as asymptomatic, need very close monitoring. Patients with CNFPAs may be at increased risk of death, especially secondary to cardiovascular disease. Patients with pituitary adenomas have been shown to have a lower quality of life (QoL) before and after pituitary surgery compared with people without pituitary adenomas.

Answer 133

Addison’s disease (primary adrenal insufficiency) is caused by destruction or dysfunction of the adrenal cortex. Results in mineralocorticoid (aldosterone), glucocorticoid (cortisol) and gonadocorticoid (androgens) deficiency

Answer 134

- In Europe, the overall prevalence has increased from 40-70 cases per million in the 1960s to more than 140 cases per million in developed countries. - More common in women

Answer 135

- Autoimmune adrenalitis - most common in western world. Autoantibodies target the adrenal gland and the enzymes involved in steroid synthesis. One of the main targets for autoimmune destruction is the enzyme 21-hydroxylase. - Infection - TB (most common worldwide), HIV, Meningococcal infection - Congenital cause - congenital adrenal hyperplasia causes impaired cortisol synthesis - Medication - Long term steroid use (causes reduced ACTH via negative feedback) - Etomidate, Mitotane, Aminoglutethimide (reduce cortisol production) - drugs usually used to treat Cushing's syndrome - Rare causes - Adrenal hemorrhage/ infarction - Malignant invasion - Infiltration of adrenal glands - Hemochromatosis - Amyloidosis

Answer 136

- Female gender - Autoimmune conditions - Autoimmune polyendocrinopathy syndrome - Adrenal haemorrhage - Warfarin which may predispose to adrenal haemorrhage - TB - HIV

Answer 137

Addison’s disease refers to chronic primary adrenal insufficiency (hypoadrenalism) resulting in reduced adrenocortical hormones, including mineralocorticoids (zona glomerulosa), glucocorticoids (zona fasciculata), and androgens (zona reticularis). Corticosteroids (glucocorticoids and mineralocorticoids) are involved in renal excretion of potassium and acid as well as sodium reabsorption. Hence, adrenal insufficiency results in a metabolic acidosis coupled with hyperkalaemia and hyponatraemia. In developed countries, such as the UK, most cases (80%) are caused by autoimmune destruction of the adrenal glands. These patients are at risk of developing other autoimmune conditions such as vitiligo or thyroid disease, and on occasion, forms part of an autoimmune polyendocrinopathy syndrome (APS). Due to there not being any negative feedback, there are higher levels of CRH and ACTH.

Answer 138

- Hyperpigmentation (caused by increased levels of ACTH) - especially in palmar creases and buccal mucosa - Vitiligo - due to loss of androgens - Loss of pubic hair in women - Hypotension and postural drop - Associated autoimmune conditions - Tachycardia

Answer 139

- Lethargy and generalised weakness - Loss of libido - Nausea and vomiting - Cachexia - weight loss and muscle wasting - Dehydration - Salt-cravings - Collapse and shock (Addisonian crisis)

Answer 140

8 - 9 am cortisol: NICE suggests using this first-line in primary care - <100 nmol/L: highly suggestive of Addison’s; NICE advise admission to hospital - 100 - 500 nmol/L: refer the patient for an ACTH stimulation test - >500 nmol/L: Addison’s is unlikely; this result would be expected in normal people

Answer 141

ACTH stimulation test (short Synacthen test): Plasma cortisol is measured before and 30 minutes after giving Synacthen 250μg IM (ACTH analogue) - Failure of an adequate rise in cortisol post-Synacthen (with peak cortisol levels < 500 nmol/L at 1 hour) suggests Addison’s disease

Answer 142

- 8 am ACTH: increased due to loss of negative feedback from cortisol - Adrenal antibodies: anti-21-hydroxylase suggests autoimmune aetiology - U&Es: mineralocorticoid deficiency causes hyponatraemia and hyperkalaemia - Aldosterone/renin ratio: decreased in Addison’s disease due to reduction in mineralocorticoid production - CT adrenal: atrophied glands in Addison’s disease; can also identify if malignancy is the cause

Answer 143

- Haemochromatosis due to hyperpigmentation - Hyperthyroidism due to weight loss and tachycardia - Anorexia nervosa due to weight loss

Answer 144

Corticosteroid replacement: - Hydrocortisone in 2-3 doses divided throughout the day with a total dose of 20-30 mg for glucocorticoid replacement. Dose divisions vary in shift-workers with different sleep cycles; the largest dose is always given upon waking - Fludrocortisone is recommended once daily for mineralocorticoid replacement (50-300 micrograms)

Answer 145

- Androgen replacement - mainly in women - Patient education: - Patients should be advised regarding medication compliance and not missing doses - Advise patients to wear a MedicAlert bracelet or carry steroid cards in case of an Addisonian crisis - Advise patients to double their glucocorticoid dose (hydrocortisone) if they develop an intercurrent illness - When travelling, patients should take extra medication plus an emergency hydrocortisone injection kit

Answer 146

Patients should be evaluated annually to judge adequacy of glucocorticoid and mineralocorticoid replacement. Dose can be adjusted depending on presentation of patients at review. Monitoring also key due to complications associated with Addison's disease.

Answer 147

- Secondary Cushings due to excess hormone replacement - Osteopenia and osteoporosis - Secondary hypertension - Addisonian crisis - drop in glucocorticoid levels usually due to non-compliance with medication

Answer 148

Addison’s disease is a lifelong illness. 40% of patients will experience an adrenal crisis. Overall, the mean age at death is 75.7 years (for females) and 64.8 years (for males), which is 3.2 and 11.2 years less than the estimated life expectancy.

Answer 149

Addisonian crisis, also known as an adrenal crisis, is a state of acute insufficiency of adrenocortical hormones. It most often occurs on a background of established Addison’s disease due to precipitating factors such as poor medication compliance, infection, trauma, surgery, and myocardial infarction.

Answer 150

In those with Addison’s disease, 40% of patients will experience one crisis

Answer 151

- Steroid withdrawal: any patient on long term steroids should not abruptly withdraw their medication - Severe dehydration - Sepsis or surgery: resulting in acute exacerbation of pre-existing adrenal insufficiency (e.g. Addison’s disease) - Meningococcal infection: meningococcal sepsis can lead to adrenal haemorrhage (Waterhouse-Friderichsen syndrome)

Answer 152

Drop in level of corticosteroids. Corticosteroids (glucocorticoids and mineralocorticoids) are involved in renal excretion of potassium and acid as well as sodium reabsorption. Hence, adrenal insufficiency results in a metabolic acidosis coupled with hyperkalaemia and hyponatraemia. In a crisis, there is also accompanying haemodynamic instability due to sodium and, therefore, fluid loss.

Answer 153

- Hypotension - Hypovolemic shock - Reduced GCS - consciousness - Confusion - Pyrexia - increased temperature

Answer 154

- Nausea and vomiting - Abdo pain - Trigger e.g. infection or MI

Answer 155

- 12-lead ECG: hyperkalaemic changes include flat P waves, short QT interval, broad QRS, ST depression, and tented T waves - VBG: can be conducted quickly and will reveal metabolic acidosis with hyponatraemia and hyperkalaemia. Patients may also be hypoglycaemic - U&E’s: hyponatraemia and hyperkalaemia; acute kidney injury may be present due to hypovolaemia causing pre-renal injury - FBC and CRP: leukocytosis and raised inflammatory markers may suggest an underlying infection as the precipitant - TFTs: hypothyroid states may mimic an Addisonian picture

Answer 156

- IV fluids: for resuscitation (e.g. normal saline); consider dextrose if hypoglycaemic - Corticosteroid: hydrocortisone 100 mg IV (IM is an alternative) and a further dose 6 hours later may be given. Oral replacement usually starts after 24 hours, with a reduction to maintenance over 3-4 days - Fludrocortisone is not required in the acute stage as hydrocortisone exerts an effect at the mineralocorticoid receptor - Treat the underlying cause e.g. infection

Answer 157

There are poor outcomes if treatment is delayed, with a risk of death due to hypovolaemic shock. Mortality is almost 100% if untreated

Answer 158

Secondary adrenal insufficiency is adrenal hypofunction due to a lack of adrenocorticotropic hormone (ACTH). Adrenal suppression refers to decreased cortisol production as a result of negative feedback on the hypothalamic-pituitary-adrenal axis, caused by excess glucocorticoids. The consequence is decreased production of both corticotropin-releasing hormone from the hypothalamus and adrenocorticotropic hormone from the pituitary gland, leading to a decrease in serum cortisol levels.

Answer 159

- Iatrogenic - commonest cause. Due to long term steroid use leading to suppression of the HPA axis - Hypothalamic pituitary disease - resulting in reduced ACTH production - Removal of pituitary tumour - the remaining ACTH-secreting cells in the pituitary gland may be sluggish in their recovery, resulting in a period of adrenal suppression

Answer 160

- Decreased levels of ACTH resulting in decreased glucocorticoid (CORTISOL) - Mineralocorticoid production remains intact

Answer 161

Similar presentation to Addison's disease. However, no hyperpigmentation as there is no excess ACTH

Answer 162

Same as with Addison's disease - ACTH levels are low and mineralocorticoid production is intact in secondary hypoadrenalism - can be used to differentiate from Addison’s

Answer 163

- Adrenals will recover if long-term steroids are slowly weaned off - but this is a long and difficult process - ORAL HYDROCORTISONE - replacement of glucocorticoids

Answer 164

Adrenal insufficiency secondary to corticosteroid treatment has a generally good prognosis. Time to recovery depends on dose and/or potency of glucocorticoid used and treatment length. Signs and symptoms of Cushing's syndrome will disappear with time as the inciting medication is stopped.

Answer 165

Antidiuretic hormone (ADH) is produced by the magnocellular neurons in the paraventricular and supraoptic nuclei of the hypothalamus. It is stored and released by the posterior pituitary in response to rising plasma osmolality or decreasing blood volume. It may also be referred to as arginine vasopressin (AVP) or simply vasopressin. ADH acts on the distal convoluted tubule and collecting duct to increase water reabsorption independent of sodium. ADH stimulates the insertion of aquaporin-2 channels onto the luminal membrane, allowing the free entry of water. ADH also causes vasoconstriction of arterioles.

Answer 166

The syndrome of inappropriate anti-diuretic hormone (SIADH) results from excess ADH secretion. ADH excess, as the name suggests, results in reduced diuresis - water excretion and urinary output are reduced. This leads to an increase in total body water and hyponatraemia.

Answer 167

- Hyponatraemia is the most common electrolyte disorder encountered in clinical practice - The prevalence of hyponatraemia in the community is around 8% and increases with age (approximately 12% in people aged 75 or older)

Answer 168

- Neurological - Meningitis, encephalitis or cerebral abscess - Intracranial haemorrhage, e.g. subarachnoid or subdural haemorrhage - Stroke - Trauma - Malignancy - Small cell carcinoma of the lung most commonly - Other cancers, e.g. breast cancer, and head and neck tumours, are rarer causes - Infections - Pneumonia - Tuberculosis - HIV - Endocrine - Hypothyroidism - Hypopituitarism - Drugs (remember mnemonic CARDISH - chemo, antidepressants, recreational drugs, diuretics, inhibitors e.g. ACEI & SSRIs, sulfonylurea, hormones e.g. desmopressin)** - SSRIs and TCAs - Proton pump inhibitors - Carbamazepine - Cyclophosphamide - Sulfonylureas (glimepiride and glipizide)

Answer 169

- Age >50 - Pulmonary conditions - Malignancy - Medicine associated with SIADH induction - CNS disorder

Answer 170

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) describes increased antidiuretic hormone (ADH) release from the posterior pituitary or an ectopic source. ADH is responsible for free water reabsorption by acting on the collecting ducts of the kidney, resulting in water retention by increased insertion of aquaporin 2, but not the reabsorption of solutes. This increases blood volume and decreases serum osmolarity. Increased ADH results in increased free water retention, subsequent dilution of the blood and a decrease in solutes in the blood. Increase in blood volume leads to stretching of heart muscle and release of ANP and BNP(natriuretic peptide). This inhibits renin release and activity, and therefore the RAAS system. This promotes natriuresis (excretion of sodium). This leads to sodium and water excretion, which promotes further ADH activity. This cycle continues. Overtime, the kidneys will adapt. The number of aquaporin channels will decrease to compensate for the amount of ADH present. This will now lead to diuresis as well as natriuresis. This is why there is there is a euvolaemic state rather than a hypervolaemic state, coupled with hyponatraemia. Overall, patients will have high urine Na+ levels and low serum Na+ levels. They will be euvolaemic due to compensatory mechanisms.

Answer 171

Hyponatraemic and euvolaemic (no features of hyper- or hypovolaemia)

Answer 172

Mild (130-135 mmol/L): - Nausea, vomiting, headache, lethargy, anorexia Moderate (125-129 mmol/L): - Weakness, muscle aches, confusion, ataxia, asterixis Severe (< 125 mmol/L): - Reduced consciousness, seizures, myoclonus, respiratory arrest

Answer 173

There is no single test that conclusively diagnoses SIADH. Instead, diagnosis relies upon suggestive biochemistry results and the clinical context. Blood tests Renal function: gives a serum sodium that confirms hyponatraemia. May also show a low serum urea consistent with mild volume expansion. Serum osmolality: a low serum osmolality is seen, less than 280 mOsm/kg. Urinary tests Urinary osmolality: a high urine osmalality is seen, greater than 100 mOsm/kg. Urine sodium: typically a high urinary sodium is seen, greater than >40 mmol/L.

Answer 174

- **Low plasma osmolality**: < 275 mOsm/kg - **High urine osmolality**: > 100 mOsm/kg - **High urine sodium**: > 30 mmol/L - **Clinical euvolaemia** - **Exclusion of glucocorticoid deficiency or hypothyroidism** (rare)

Answer 175

Treat underlying cause - Acute management: <48 hrs onset Acute hyponatraemia must be treated urgently due to the risk of cerebral oedema and herniation - Hypertonic (3%) saline is preferred - slow infusion to avoid complications - Furosemide (diuretic) - in patients who have fluid overload. Causes an increase in water, Na+, Ka+ and Cl- excretion. (Note: KCl should be replaced) Chronic management: - Correction should not occur too quickly and aim for a maximum increase in 10 mmol/L per day - Mild to moderate asymptomatic cases: fluid restriction to increase Na+ conc - Fluid restriction may not be used in SIADH secondary to subarachnoid haemorrhage as it risks lowering blood pressure which may cause cerebral vasospasm and infarction. - Severe or symptomatic cases: guidelines differ but demeclocycline or tolvaptan may be considered - Demeclocycline, a tetracycline antibiotic, causes an iatrogenic nephrogenic diabetes insipidus through the inhibition of ADH. Though historically popular it is rarely used today. - A newer class of drugs termed vaptans (e.g. tolvaptan) are now more commonly used. These ADH receptor antagonists are effective but expensive agents.

Answer 176

- Cerebral oedema: hyponatraemia lowers the osmolality of the blood causing an osmotic shift of water into brain tissue with subsequent oedema and risk of herniation - Central pontine myelinolysis: rapid correction of sodium can cause osmotic demyelination, particularly in chronic hyponatraemia (slow correction is vital) - Manifests as tremors, dysarthria, quadriplegia, ophthalmoplegia, seizures and extrapyramidal symptoms - May result in ‘locked-in syndrome’, where patients are awake but unable to verbally communicate or move - Diagnosis is confirmed with MRI

Answer 177

If the underlying cause is found and treated successfully, SIADH typically resolves. If the underlying condition persists, SIADH is difficult to manage, secondary to difficulty complying with necessary fluid restriction or medicines.

Answer 178

Potassium homeostasis is multifactorial and depends on intake, absorption, distribution, and excretion. Important hormonal factors that reduce serum potassium include insulin (causes an intracellular shift of potassium), adrenaline (beta-receptor stimulation causes intracellular shift), and aldosterone (promotes potassium excretion).

Answer 179

A serum level >5.5 mmol/L is considered to be hyperkalaemia A serum level > 6.5mmol/L = MEDICAL EMERGENCY!

Answer 180

- Decreased excretion: - Acute kidney injury (AKI) or oliguric renal failure (where there is very small amount of urine produced) - COMMON - Drugs: - Potassium-sparing diuretics e.g. spironolactone - COMMON - ACE inhibitors (interfere with RAAS) e.g. ramipril - COMMON - NSAIDs - COMMON - Ciclosporin - Heparin - Beta-antagonists: inhibit cellular entry of potassium - Digoxin: inhibitor of Na+/K+ ATPase causing reduced cellular entry of potassium - Addison’s disease - reduced aldosterone causes reduced potassium excretion - Redistribution of K+ - intracellular to extracellular: - Diabetic ketoacidosis - insulin resistance - insulin controls Na+/K+ pump - pumping sodium out of cell in exchange for K+. With insulin resistance, the K+ leaves the cell. - Metabolic acidosis - to compensate H+ is pumped into cell from the blood, in exchange of K+ - Tissue necrosis or lysis - Rhabdomyolysis - muscle breakdown releases potassium - Death of muscle fibres and release of their contents, including K+, into bloodstream caused by a traumatic CRUSH INJURY e.g. from a car accident or building collapse - Tumour lysis syndrome - Severe burns - Increased load: - Potassium chloride - Transfusion of stored blood

Answer 181

- The amount K+ in the blood determines the excitability of nerve and muscle cells, including skeletal muscle, smooth muscle and cardiac muscle - When K+ levels in the blood rise - this reduces the difference in electrical potential between cardiac myocytes and outside of the cells meaning the threshold for action potential is significantly decreased resulting in increased abnormal action potential and thus abnormal heart rhythms that can result in ventricular fibrillation and cardiac arrest - In smooth muscle it can cause cramping - due to depolarisation and contraction - In skeletal muscle it can cause weakness and flaccid paralysis - resting potential is too high, which means muscle can't repolarise and then contract again - In cardiac muscle it can cause arrhythmias or even cardiac arrest

Answer 182

- Tachycardia (arrhythmia) - Fast irregular pulse - ECG differences - tall tented T waves, small P waves, wide QRS

Answer 183

- Muscle weakness - Lightheadedness - Muscle cramps - Paresthesia (tingling in skin) - Palpitations - Chest pain

Answer 184

- 12-lead ECG: hyperkalaemic changes include flat P waves, short QT interval, broad QRS, ST depression, and tented T waves - U&Es: confirm high serum potassium levels - Lithium heparin sample: rule out pseudohyperkalaemia. This is where thrombus formation and haemolysis within a normal EDTA tube can cause a falsely elevated potassium concentration; e.g. when the tourniquet is too tight or blood is left sitting too long - VBG: check for acidosis which may be causing the hyperkalaemia

Answer 185

- Could be artefactual - repeat tests if pt has no symptoms - Haemolysis e.g. from vigorous venepuncture or due to K+ release from abnormal RBCs in some blood disorders e.g. leukaemia - Contamination with K+ EDTA anticoagulant in FBC bottles - Thrombocythaemia (increased platelets) - K+ leaks out of platelets during clotting - DKA - Hyperosmolar hyperglycaemic state - Chronic kidney disease

Answer 186

If there are signs of myocardial hyperexcitability and serum levels > 6.5mmmol/L - Cardiac membrane protection: if ECG changes are present, 10ml of 10% IV calcium gluconate or calcium chloride should be given immediately. If ECG changes are not present this should not be given, regardless of the serum concentration - Calcium protects the cardiac membrane but its effects are short-lived and may need repeating after 5 minutes if ECG changes persist (repeat ECGs are required) - It does not lower potassium concentration - Potassium reduction: - Insulin/dextrose infusion: causes an intracellular shift of potassium; the dose is 10 units actrapid with 50 ml of 50% glucose over 15 mins - Nebulised salbutamol: causes an intracellular shift of potassium

Answer 187

- Treat underlying cause - Review medication - Can give polystyrene sulfonate resin (calcium resonium) which binds K+ in the gut and thus reduces absorption

Answer 188

- Haemodialysis: removes potassium from the body - Enema - if vomiting prevents calcium resonium administration

Answer 189

Cardiac arrhythmias and arrest: severe hyperkalaemia is associated with broadening of the QRS complex and can cause potentially life-threatening ventricular tachycardia or ventricular fibrillation, and subsequent cardiac arrest

Answer 190

The prognosis of patients with hyperkalaemia ultimately depends on the underlying cause. Untreated moderate and severe hyperkalaemia is associated with the development of potentially life-threatening arrhythmias so must be treated expediently.

Answer 191

Potassium is an essential body cation, which has a normal plasma concentration of 3.5-5.5 mmol/L. Hypokalaemia is defined as a plasma potassium concentration < 3.5 mmol/L. Hypokalaemia can be further divided as follows: - **Mild:** 3.0-3.4 mmol/L - **Moderate:** 2.5-2.9 mmol/L - **Severe:** < 2.5 mmol/L or symptomatic

Answer 192

- Hypokalaemia is a common electrolyte abnormality in secondary care affecting up to 20% of inpatients. - Potassium concentration is highly variable depending on age, sex, ethnicity and socioeconomic status.

Answer 193

- Inadequate intake - Eating disorders: bulimia, anorexia nervosa, alcoholism - Poor diet - Systemic illness and dental problems - Inadequate potassium in feed or fluid replacement (IVF, NG feed, TPN) - Increased excretion - Renal tubular failure - Diuretics (thiazide-like & loop) - Mineralocorticoid excess e.g. - Cushing's syndrome - Conn's syndrome - Nephrotic syndrome - leaky kidneys resulting in increased aldosterone secretion and thus K+ loss - Steroid use causing mineralocorticoid excess - Genetic causes include: **Bartter’s syndrome:** Refers to a group of autosomal recessive conditions characterised by hypokalaemia, alkalosis, and hypotension or normotension, related to genetic variants in genes encoding proteins in the loop of Henle. **Gitelman’s syndrome:** Is an autosomal recessive condition characterised by hypokalaemia, hypomagnesaemia, alkalosis, and hypotension or normotension, related to a genetic variant in a gene encoding the thiazide-sensitive sodium chloride transporter. **Liddle’s syndrome:** Is an autosomal recessive condition characterised by hypokalaemia and hypertension, related to genetic variants in genes encoding the subunits of the epithelial sodium channel. - Gastrointestinal: diarrhoea, vomiting, pyloric stenosis, villous adenoma, laxative abuse - Skin: burns, erythroderma, hyperhidrosis - Shift from extracellular to intracellular K+ - Alkalosis - H+ moves out of cell and is swapped for K+ as a compensatory mechanism - Insulin excess - Na+/K+ pump, more K+ moves into cell - Activation of beta-adrenergic receptors (e.g. salbutamol) enhance movement of K+ intracellularly.

Answer 194

K+ key for maintaining resting cell membrane potential Low levels of K+ can affect smooth, skeletal and cardiac muscles due to diminished contraction - Cardiac - arrhythmias and cardiac arrest - Smooth muscle - constipation - Skeletal muscle - weakness, cramps and flaccid paralysis - Respiratory muscles - respiratory depression

Answer 195

- Arrhythmias - Muscle paralysis and rhabdomyolysis (severe) - Hypotonia - decreased muscle tone - Hypoflexia - muscles less responsive to stimuli

Answer 196

- Fatigue - Generalised weakness - Light headedness - Muscle cramps and pain - Tetany - Palpitations - Constipation

Answer 197

The diagnosis of hypokalaemia is based on a laboratory sample of plasma potassium: - **Mild:** 3.0-3.4 mmol/L - **Moderate:** 2.5-2.9 mmol/L - **Severe:** < 2.5 mmol/L or symptomatic

Answer 198

- ECG - Prolonged PR, ST segment depression, flattening of T wave, U wave present - Urine osmolality - Urinary electrolytes (sodium & potassium) - Full blood count - U&Es, bone profile, magnesium - VBG/ABG (can assess acid/base, bicarbonate & chloride) - CK (creatinine kinase) - sign of muscle damage

Answer 199

- Treat underlying cause - Review medication - If taking a diuretic, replace with a potassium sparing diuretic - Other electrolyte abnormalities, magnesium in particular, should be identified and replaced. Hypokalaemia difficult to treat until Mg2+ levels have been normalised. - Potassium replacement - - Oral route preferred - e.g. SANDO-K (potassium chloride with potassium bicarbonate), two tablets, three times a day for mild hypokalaemia and two tablets, four times a day for moderate hypokalaemia.

Answer 200

- IV replacement with 40 mmol of KCL in 1 litre of normal saline. The maximal rate on a normal ward is 10 mmol of potassium an hour. A repeat blood test should be sent after each bag of replacement. - In rare cases it may be necessary to give more concentrated replacement (e.g. 40 mmol KCL in 500ml of normal saline or 10 mmol KCL in 100 mls of normal saline) or more rapid replacement. This should only be done under the guidance of a senior physician in compliance with local guidelines, normally in an HDU/ITU setting. - Do not give K+ if oliguric - Never give K+ as a fast stat bolus dose

Answer 201

Cardiac - arrhythmias and cardiac arrest

Answer 202

Diabetes insipidus (DI) is a metabolic disorder characterised by an absolute or relative inability to concentrate urine, resulting in the production of large quantities of dilute urine. It is due to the patient's inability to make ADH or respond to ADH. This leads to polydipsia, polyuria, and hypotonic urine.

Answer 203

- DI is uncommon, although the exact prevalence is difficult to estimate. - There are no differences in prevalence between sexes or among ethnic groups. - Inherited causes for both central and nephrogenic DI account for less than 10% of all cases.

Answer 204

- Nephrogenic - pathology affecting the kidney - Drugs e.g. Lithium, Demeclocycline - Genetic - AVR2 gene X chromosome - Intrinsic kidney disease - Post-obstructive uropathy - urine can't flow due to obstruction and so refluxes back into kidney - Electrolyte imbalances - mainly hypokalaemia and hypercalcaemia - Cranial - ADH not produced or secreted - Idiopathic - Congenital defects in ADH gene - Brain tumours - Head injuries - Brain malformations - Hypophysitis - Hypophysectomy - Infections e.g. meningitis, encephalitis, TB - Infiltration e.g. sarcoidosis - Brain surgery - Radiotherapy

Answer 205

- Pituitary surgery - Craniopharyngioma - Brain injury - Congenital pituitary abnormalities - Medication e.g. lithium - Autoimmune disease - some cases linked to antibodies against ADH secreting cells - Family history - CNS infections - Pregnancy - associated with a number of changes in salt and water regulation. A transient central DI may develop as a consequence of a decreased osmotic threshold for thirst and ADH release, and a decrease in plasma osmolality. Also associated with increase in metabolic clearance of ADH.

Answer 206

- Central DI results from any condition that impairs the production, transportation, or release of ADH. - Nephrogenic DI results from conditions that impair the renal collecting ducts' ability to respond to ADH. Both central and nephrogenic DI are characterised by impaired renal water re-absorption, resulting in the production of excessive, hypotonic (dilute) urine (polyuria). This is accompanied by significant thirst and increased drinking (polydipsia), as central osmo-sensing and peripheral baro-sensing drive central thirst and thirst-dependent behaviours to maintain circulating volume and osmolar status.

Answer 207

- Postural hypotension - Hypernatraemia

Answer 208

- Polyuria - Polydipsia - Dehydration

Answer 209

- **U&E** - hypernatraemia found - **Serum glucose** - exclude DM - **Urine osmolality** - low urine osmolality found - **Serum osmolality** - high serum osmolality found - **Water deprivation test (desmopressin suppression test)** - avoid taking fluid or foods 8 hrs before test. Then urine osmolality is measured followed by giving desmopressin. 8 hrs later urine osmolality is measured again. Allows us to differentiate between cranial and nephrogenic diabetes insipidus - Cranial - ADH not being made but kidney's still able to respond. So when desmopressin is given, urine osmolality should increase. In nephrogenic causes, desmopressin will not have an effect on urine osmolality after synthetic desmopressin administration.`

Answer 210

Water deprivation test (desmopressin suppression test)

Answer 211

MRI - for cranial DI. Test anterior pituitary function.

Answer 212

- Primary polydipsia - normal ADH, but excessive thirst and excessive urine production. In the water deprivation test, patient's with primary polydipsia will already have high urine osmolality prior to desmopressin administration. - Diabetes mellitus - due to polyuria and polydipsia - Hypercalcaemia

Answer 213

- Correct underlying cause - Mild cases can be managed conservatively e.g. low sodium diet - **Desmopressin** - Used in **cranial DI** to replace ADH - Can be used in nephrogenic DI at very high doses. This needs monitoring - **Thiazide diuretic e.g. Bendroflumethiazide for nephrogenic DI** - will produce a mild hypovolaemia which will encourage the kidneys to take up more Na+ and water in the proximal tubule, thereby offsetting water losses

Answer 214

NSAIDs - can be used in nephrogenic DI. Prostaglandins locally inhibit ADH action. NSAID's lower urine volume and plasma Na+ by inhibiting prostaglandin synthase.

Answer 215

- Urgent plasma U&E, serum and urine osmolality - IV fluid to keep up with urine output. If severe hypernatraemia, do not lower Na+ rapidly. Risk of cerebral oedema with rapid correction! - IM desmopressin

Answer 216

Patients require regular follow-up with monitoring of serum electrolytes to assess sodium status. For patients with central DI, follow-up imaging is recommended if initial scans were unable to detect pathology, as pituitary, para-pituitary, or stalk lesions may not manifest on initial scanning. In patients with nephrogenic DI for whom polyuria is significant, bladder dysfunction may develop. If unrecognised, this may lead to renal impairment. These patients need periodic renal and bladder ultrasonography and regular assessment of serum creatinine.

Answer 217

Outcome and outlook depend on the underlying aetiology, type of DI, and associated comorbidities. - While DI is often a lifelong condition, central DI following pituitary surgery or traumatic brain injury may be transient. - Nephrogenic DI secondary to hypercalcaemia or hypokalaemia commonly resolves following treatment of the underlying electrolyte disorder. While nephrogenic DI secondary to medication may resolve following agent discontinuation, this is often not the case in those with nephrogenic DI secondary to lithium. - DI developing in pregnancy typically resolves following delivery.

Answer 218

**Parathyroid hormone:** Changes in the body’s levels of extracellular calcium are detected by the calcium-sensing receptor in parathyroid cells. There are four parathyroid glands situated in four corners of the thyroid gland. The parathyroid glands, specifically the chief cells in the glands, produce parathyroid hormone in response to hypocalcaemia (low blood calcium). The parathyroid hormone causes: - The bones to release calcium - The kidneys to reabsorb more calcium so it's not lost in the urine (as well as excrete more phosphate) - The kidneys to synthesise calcitriol/ active Vitamin D. Active Vitamin D then goes on to cause the gastrointestinal tract to increase calcium absorption.

Answer 219

Hypercalcemia refers to a higher than normal calcium levels in the blood, generally over 10.5 mg/dL.

Answer 220

- **Acidosis:** promotes less binding between albumin and calcium. This causes less bound calcium and more free ionised calcium - **Osteoclastic bone resorption due to:** - **Hyperparathyroidism** - **Malignant tumours:** secrete parathyroid hormone-related protein or PTHrP, a hormone that mimics the effect of parathyroid hormone which stimulates the osteoclasts and cause osteoblasts to die - **Excess vitamin D:** increased calcium absorption from GI tract - **Sarcoidosis:** due to the uncontrolled synthesis of 1,25-dihydroxyvitamin D3 by macrophages - **Thyrotoxicosis:** thyroid hormones known to cause bone resorption - **Milk-alkali syndrome:** ingestion of large amounts of calcium and absorbable alkali, with resulting hypercalcemia. - **Medications** - Thiazide diuretics increases calcium reabsorption in the distal tubule of the kidney - Lithium - **Familial benign hypocalciuric hypercalcaemia:** defect in calcium sensing receptor

Answer 221

High levels of ionised calcium affect a variety of cellular processes, in particular, electrically active neurons. With high levels of extracellular calcium, voltage-gated sodium channels are less likely to open up, which makes it harder to reach depolarisation, and makes the neuron less excitable. - This causes slower or absent reflexes - The sluggish firing of neurons also leads to slower muscle contraction, which causes constipation and generalised muscle weakness. - In the central nervous system, hypercalcaemia causes confusion, hallucinations, and stupor. Too much calcium in the blood causes hypercalciuria. This leads to a loss of excess fluid in the kidneys causing an individual to get dehydrated.

Answer 222

- Abdominal pain - Vomiting - Constipation - Dehydration - Polydipsia - Polyuria - Absent reflexes - Muscle weakness - Weight loss - Depression - Confusion - Hallucinations - Stupor - Hypertension - Pyrexia

Answer 223

- Bloods: high calcium. Also check parathyroid hormone, vitamin D, albumin, phosphorus, and magnesium levels. - In malignancy, there is low albumin, low chloride, alkalosis, low potassium, high phosphate, high ALP - Hyperparathyroidism: high PTH - 24 hr urinary Ca2+ excretion: raised - Electocardiogram: tachycardia, AV block, shortening of the QT interval, and sometimes in the precordial leads the appearance of an J wave - Imaging - Chest X-ray - Isotope bone scan

Answer 224

Hyperalbuminaemia (pseudohypocalcaemia): causes there to be a higher concentration of protein-bound calcium, while free ionised calcium concentrations stay the same. This can occur when individuals are dehydrated, concentrating albumin.

Answer 225

- Increase urinary calcium excretion - **Rehydration:** increases filtering of Ca2+ - **Loop diuretics:** inhibit calcium reabsorption in the loop of Henle - Decrease calcium absorption from GI tract - **Glucocorticoids** - Prevention of bone resorption - **Biphosphonates** - **Calcitonin** - **Chemotherapy** may help in malignancy

Answer 226

- Kidney stones: due to dehydration combined with hypercalciuria - Renal failure - Ectopic calcification e.g. cornea - Cardiac arrest

Answer 227

Hypocalcemia refers to lower than normal calcium levels in the blood, generally less than 8.5 mg/dL.

Answer 228

With increased phosphate: - Chronic kidney disease: lack of reabsorption of Ca2+, lack of active vitamin D - Hypoparathyroidism: e.g. due to removal of or autoimmune destruction PT glands, DiGeorge syndrome - Pseudohypoparathyroidism - Acute rhabdomyolysis: large numbers of cells die and release phosphate. The phosphate binds to the ionised calcium and forms calcium phosphate, making it insoluble and effectively decreasing the total amount in blood. - Hypomagnesaemia: magnesium is needed for PTH secretion With normal or low phosphate: - Vitamin D deficiency: leads to less Ca2+ absorption from GI tract - Osteomalacia - Acute pancreatitis: free fatty acids end up binding to ionised calcium, which is insoluble and precipitates. - Over-hydration - Respiratory alkalosis: high pH (alkalosis) causes more binding between albumin and calcium, which results in less free ionised calcium

Answer 229

Low levels of ionised calcium affect a variety of cellular processes e.g. - With low levels of extracellular calcium, voltage-gated sodium channels are less stable and more likely to open up, which allows the cell to depolarise more easily, and makes the neurone more excitable. This can trigger tetany.

Answer 230

**SPASMODIC:** - Spasms (Trousseau's sign): blood pressure cuff occludes the brachial artery, and that pressure on the nerve is enough to make it fire, which results in a muscle spasm that makes the wrist and metacarpophalangeal joints flex. - Perioral numbness/ paraesthesiae - Anxious, irritable, irrational - Seizures - Muscle tone increases: colic, wheeze and dysphagia - Orientation impaired and confusion - Dermatitis - Impetigo herpetiformis (severe pustular psoriasis occurring in pregnancy) - Chvosteks sign (facial muscles twitch after the facial nerve is lightly finger tapped); choreoathetosis, cataract (if chronic hypocalcaemia), cardiomyopathy

Answer 231

- **Bloods:** low calcium. Also check for parathyroid hormone, vitamin D, albumin, phosphorus, and magnesium levels. - **Electrocardiogram:** may show prolonged QT, prolonged ST segment, and arrhythmias e.g. torsade de pointes and atrial fibrillation.

Answer 232

Hypoalbuminaemia (pseudohypocalcaemia): there is a loss of bound calcium but free ionised levels remain the same

Answer 233

- **Calcium supplements** e.g. calcium gluconate - **Vitamin D supplementation** e.g. alfacalcidol, if appropriate - If alkalosis, **correct alkalosis**

Answer 234

Hyperparathyroidism refers to a condition where there is an overproduction of parathyroid hormone.

Answer 235

Caused by uncontrolled parathyroid hormone produced directly by a tumour of the parathyroid glands (independent of calcium levels). This leads to hypercalcaemia. Most often, primary hyperparathyroidism is caused by a single parathyroid adenoma which happens either because of a genetic mutation in a single cell or because of an inherited disorder e.g. multiple endocrine neoplasia. Rarely, primary hyperparathyroidism is caused by hyperplasia or by a parathyroid carcinoma.

Answer 236

Insufficient vitamin D or chronic renal failure leads to low absorption of calcium from the intestines, kidneys and bones. This causes hypocalcaemia. This is usually due to kidney issues as the kidney can't filter out the phosphate or make active vitamin D. The parathyroid glands reacts to the low serum calcium by excreting more parathyroid hormone. Over time the total number of cells in the parathyroid glands increase as they respond to the increased need to produce parathyroid hormone. The glands become more bulky. The serum calcium level will be low or normal but the parathyroid hormone will be high.

Answer 237

This happen when secondary hyperparathyroidism continues for a long period of time. It leads to hyperplasia of the glands. The baseline level of parathyroid hormone increases dramatically. Then when the cause of the secondary hyperparathyroidism is treated the parathyroid hormone level remains inappropriately high. This high level of parathyroid hormone in the absence of the previous pathology leads to high absorption of calcium in the intestines, kidneys and bones and causes hypercalcaemia.

Answer 238

Hypercalcaemia: - Excess calcium makes neurons less excitable, which leads to slower muscle contractions, and diminishes neuron firing in the central nervous system. Hypercalciuria: - This is because there is just too much calcium to be reabsorbed by the kidneys. Excess loss of calcium in urine can lead to dehydration.

Answer 239

‘Stones, thrones, bones, groans, and psychiatric overtones’ - Stones: **kidney stones or gallstones** - Thrones: refers to the toilet, **polyuria** that results from impaired sodium and water reabsorption. - Bones: **bone pain** - Groans: refers to symptoms of **constipation, nausea and vomiting** - Psychiatric overtones: **depressed mood, fatigue, psychosis and confusion**

Answer 240

Bloods: high levels of parathyroid hormone; testing for blood levels of calcium, phosphate, and vitamin D to confirm the type of hyperparathyroidism. - 24 hr urinary calcium: raised - ALP: raised from bone activity

Answer 241

Imaging e.g. - DEXA scan for osteoporosis - Can show osteitis fibrosa cystica

Answer 242

Malignant hyperparathyroidism: parathyroid related protein produced by some squamous cell lung cancers, breast and renal cell carcinomas. This can mimic PTH and lead to hypercalcaemia.

Answer 243

- If mild, increase fluid intake, avoid thiazides and high Ca2+ intake - Surgical removal of the tumour - Calcimimetics: drugs that imitate the action of calcium by attaching to the calcium-sensing receptors on parathyroid cells

Answer 244

- Correcting the vitamin D deficiency - Phosphate binders - Renal transplant to treat renal failure - Sometimes parathyroidectomy

Answer 245

Surgical removal of parathyroid tissue

Answer 246

- Secondary hyperparathyroidism can cause: - Renal osteodystrophy: bone resorption - Secondary and tertiary hyperparathyroidism can cause: - Calcification in blood vessels and soft tissues: the high levels of phosphate cause it to stick to any available calcium, forming bone-like crystals. - Bone resorption: - Bone fractures - Osteoporosis - Osteopenia - Nephrolithiasis - Iatrogenic - Hypoparathyroidism - Recurrent laryngeal nerve damage

Answer 247

Hypoparathyroidism refers to a condition where there is an underproduction of parathyroid hormone.

Answer 248

- Autoimmune polyendocrine syndrome type 1: destroys parathyroid glands. - DiGeorge syndrome:*a deletion on the 22q11 part of the chromosome that causes a variety of immune and cardiac defects as well as parathyroid glands that can’t produce enough parathyroid hormone. - Autosomal-dominant hypoparathyroidism: a mutation in the parathyroid cell’s calcium-sensing receptor. Secondary: - Removal of parathyroid gland during surgery - Hypomagnesium: magnesium is needed for PTH secretion

Answer 249

Low levels of parathyroid hormone lead to hypocalcaemia and hyperphosphatemia. This makes neurons more excitable, which can trigger tetany. Other symptoms include paresthesia - numbness or tingling of hands, feet, and around the mouth, changes in cardiac output, and calcification in places like the basal ganglia or the lens of the eye. The spontaneous firing of neurons leads to Chvostek's sign: facial muscles twitch after the facial nerve is lightly tapped. It also can cause Trousseau's sign: a blood pressure cuff occludes the brachial artery, and that pressure on the nerve is enough to make it fire, which results in a muscle spasm that makes the wrist and metacarpophalangeal joints flex.

Answer 250

- **Chvostek's sign** - **Trousseau's sign** - **Arrhythmias**

Answer 251

- **Tetany** - **Paresthesia** - **Seizures**

Answer 252

- Bloods: low PTH, low calcium, low vitamin D, high phosphate. - Electrocardiogram: may show prolonged QT, prolonged ST segment, and arrhythmias e.g. torsade de pointes and atrial fibrillation.

Answer 253

- Pseudohypoparathyroidism type 1A (Albright hereditary osteodystrophy): the kidneys and bones don’t respond to parathyroid hormone because of a defect in their parathyroid hormone receptor. Presents with: short metacarpals, round face, short stature, calcified basal ganglia. Low calcium, high phospate.

Answer 254

- Calcium and vitamin D supplements - Recombinant human parathyroid hormone

Answer 255

If the hypocalcaemia and hyperphosphatemia are severe, this can lead to life-threatening complications e.g. severe seizures and cardiac arrhythmias.

Answer 256

- In the gastrointestinal tract, serotonin increases motility and peristalsis - In the vasculature, platelets take up the serotonin and later use it to constrict blood vessels, particularly after injury - In the connective tissue of the heart, it stimulates fibroblasts which make lots of collagen.

Answer 257

Carcinoid tumour refers to a tumour of the neuroendocrine cells, resulting in excessive release of certain hormones.

Answer 258

**Carcinoid tumour:** Neuroendocrine cells mutate and divide uncontrollably, leading to a carcinoid tumour. Most of the time this occurs in the gastrointestinal tract. The cancerous neuroendocrine cells produce and secreting large amounts of hormones. Tumours can secrete: Bradykinin, tachykinin, serotonin, substance P, VIP, gastrin, insulin, glucagon, ACTH, parathyroid and thyroid hormones. Counterintuitively, they also express more somatostatin receptors on their surface. Carcinoid tumours tend to be slow growing. Common primary sites include: Appendix, small or large intestines, rectum, stomach, pancreas, liver, lungs, ovaries, testis, and the thymus. Sometimes tumours can metastasise. A common site for this is the liver. **Carcinoid syndrome:** Associated with hepatic involvement. Carcinoid syndrome occurs when there is a buildup of hormones produced by the neuroendocrine cells as the liver is no longer able to metabolise them. - Increased histamine and bradykinin: can cause vasodilation leading to flushing - Increased histamine: can cause itching - Increased serotonin: can cause thickening of fibrosis, particularly in the heart valves leading to heart dysfunction, like tricuspid regurgitation and pulmonary stenosis; and bronchoconstriction leading to asthma, shortness of breath, and wheezing. Also reduces the amount of tryptophan available to the body to make niacin, vitamin B3. Reduced levels of niacin can cause pellagra, a disease which causes symptoms like inflamed skin and mental confusion.

Answer 259

- Diarrhoea - Shortness of breath - Flushing - Itching - Hepatic metastases: may cause RUQ pain Symptoms are worsened by alcohol and stress: stimulate the neuroendocrine cells.

Answer 260

- 24 hr urine 5-hydroxyindoleacetic acid: show increased levels - Chest X-ray/ chest or pelvis MRI/ CT: to identify location - Plasma chromogranin A: reflects tumour mass - Ostreoscan: injected radiolabelled somatostatin analogue, octreotide, to bind to the increased number of somatostatin receptors on tumour cells.

Answer 261

- Decreasing emotional stress and alcohol consumption - Somatostatin analogues: e.g. octreotide, inhibit hormone release - Surgical resection - Debulking embolisation or radiofrequency ablation of hepatic metastases can help with symptoms

Answer 262

- GI tumours can cause: appendicitis, intussusception, or obstruction - Carcinoid crisis: tumour outgrow blood supply or is handled too much during surgery. This causes mediators to flood out causing life-threatening vasodilation, hypotension, tachycardia, bronchoconstriction and hyperglycaemia. Treated with high dose octreotide, supportive measurements and management of fluid balance.

Answer 263

5-8 years survival. 3 years if metastases present 80% of tumours metastasise!

Answer 264

Phaeochromocytoma is a rare tumour (usually benign) arising from chromaffin cells in the adrenal medulla resulting in the overproduction of catecholamines **Rule of 10s:** - 10% extra-adrenal (paraganglioma): the most common extra-adrenal site is the organ of Zuckerkandl located at the bifurcation of the aorta. - 10% bilateral - 10% malignant - 10% familial

Answer 265

- The typical presentation is between 30-50 years of age - Phaeochromocytomas are rare and account for only 0.05% of hypertensive individuals

Answer 266

- MEN 2A: phaeochromocytoma, medullary thyroid cancer, primary hyperparathyroidism - MEN 2B: phaeochromocytoma, medullary thyroid cancer, marfanoid habitus, mucosal neuromas - Von-Hippel-Lindau syndrome: phaeochromocytoma, renal cell carcinoma, cerebellar hemangioblastoma - Neurofibromatosis 1: phaeochromocytoma and skin changes, e.g. café-au lait spots and neurofibromas Triggers include: - Stress - Physical exertion - Certain foods that contain tyramine

Answer 267

- Adrenaline is produced by the “chromaffin cells” in the adrenal medulla of the adrenal glands. A phaeochromocytoma is a tumour of the chromaffin cells that secretes unregulated and excessive amounts of catecholamines. - Adrenaline is a “catecholamine” hormone and neurotransmitter that stimulates the sympathetic nervous system and is responsible for the “fight or flight” response. In patients with a phaeochromocytoma the adrenaline tends to be secreted in bursts giving periods of worse symptoms followed by more settled periods. - Phaeochromocytoma's typically form in one of the adrenal glands, but rarely can be in both and sometimes can even develop in other parts of the body where chromaffin cells are found like the carotid arteries in the neck, the bladder, and the abdominal aorta. If they arise from an extra-adrenal source, they are referred to as a paraganglioma. - In approximately 10% of cases, phaeochromocytoma is associated with familial conditions such as: - **MEN 2:** caused by a mutation in the RET gene, a protooncogene - **Neurofibromatosis 1:** caused by a mutation in the gene NF1 that encodes for a tumour suppressor protein called neurofibromin - **Von-Hippel-Lindau disease:** a mutation in the VHL gene which codes for the von Hippel-Lindau tumour suppressor protein.

Answer 268

- **Hypertension:** present in 90% of cases and usually refractory to treatment - **Tachycardia** - **Paroxysmal atrial fibrillation** - **Hypertensive retinopathy**

Answer 269

Episodic headaches, palpitations, anxiety, sweating

Answer 270

- 24 hr urinary metanephrine collection: metanephrine is a breakdown product of catecholamines, urinary and serum metanephrines are the first-line investigation; will both be elevated (97% sensitivity) - Plasma-free metanephrines - CT abdomen and pelvis: if there is biochemical evidence of a phaeochromocytoma, then CT imaging can be performed to look at the adrenals

Answer 271

- PET scan: used if metastatic disease is suspected and is generally preferred over scintigraphy - I-123 MIBG scintigraphy: radionucleotide incorporates itself into the phaeochromocytoma so helps localise metastatic tissue if suspected - Chromogranin A: may be used in combination with 24 hr urinary metanephrine collection for follow-up

Answer 272

- **Peri-operative:** initial alpha blockade (e.g. phenoxybenzamine) **followed by** beta-blockade (e.g. propranolol) - **Alpha-blockade** must be offered for at least 7-14 days pre-operatively to allow for blood pressure and heart rate normalisation - **Beta-blockade** is usually required for additional blood pressure control and management of tachyarrhythmias - Commencing a beta-blocker **before** an alpha-blocker can lead to unopposed alpha stimulation, subsequent vasoconstriction and a hypertensive crisis - **Surgical:** definitive management with laparoscopic adrenalectomy

Answer 273

Medical: patients not suitable for surgery should be treated with long term anti-hypertensive agents

Answer 274

- Hypertensive crisis: patients can present with severe hypertension and evidence of end-organ damage e.g. cerebral haemorrhage, encephalopathy, arrhythmias, myocardial infarction, and renal failure. Requires IV anti-hypertensive therapy e.g. labetalol - Metastatic spread: commonly to lymph nodes, liver, bones, and lungs.

Answer 275

Generally associated with an excellent prognosis. Localised phaeochromocytomas have a 95% 5-year survival rate

Endocrinology Flashcards

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