Homeostasis

A Comprehensive Guide to Renal, Endocrinology and Urology

Dr Niccole Ranaei

Hypothalamic-pituitary axis

• Affects three systems– Adrenal– Thyroid– Gonadal

• Anterior pituitary releases:– LH– FSH– Growth hormone (GH)– Prolactin– TSH – ACTH

• Pituitary pituitary releases:– Vasopressin (ADH)– Oxytocin

Hypothalamic pituitary adrenal axis

Cortisol• Released from zona

fasciculata of adrenal cortex in response to stress and low glucose

• It increases blood glucose (gluconeogenesis)

• Suppresses immune system• Aids metabolism of fats,

proteins and carbs

Hypothalamic pituitary gonadal axis

Hypothalamic pituitary thyroid axis

Pituitary tumours• Almost always benign adenomas

1. Chromophobe – 70%. Many non-secretary. Some cause hypopituitarism. Half produce prolactin, few produce ACTH/GH

2. Acidophil – 15%. Secrete GH or prolactin3. Basophil – 15%. Secrete ACTH.

Disease classification• Prolactin only 🡪 prolactinoma• GH only 🡪 acromegaly• ACTH only 🡪 Cushing’s disease

Features of local pressure• Headache• Visual field defects (bilateral temporal hemianopia due to compression of the optic chiasm)• Palsy of CN 3, 4, 6 (pressure or invasion of the cavernous sinus)• Also diabetes insipidus

Craniopharyngioma• Not strictly a pituitary tumour• Originates from Rathke’s pouch, so is situated between pituitary and the 3rd ventricle floor• Rare but the commonest childhood intracranial tumour• Over 50% present in childhood with growth failure• Adults may present with amenorrhoea, decreased libido, hypothalamic symptoms (e.g. DI, hyperphagia,

sleep disturbance) or tumour mass effect

Acromegaly

• Due to increased GH secretion• GH functions: growth, increases Calcium, increases muscle mass, increases glucose (so GH low when glucose high)• Cause: 99% pituitary tumours or hyperplasia e.g. via ectopic GH-releasing hormone from a carcinoid tumour• 5% associated with MEN1 syndrome• GH stimulate bone and soft tissue growth through increased secretion of insulin-like growth factor-1 (IGF-1)

Clinical presentation• Acroparaesthesia (burning/tingling of the extremeties)• Amenorrhoea, decreased libido• Headache• Increased sweating• Snoring• Arthralgia, backache

Complications• May present with CCF or ketoacidosis • Impaired glucose tolerance (40%). 15% have diabetes • Vascular: hypertension, left ventricular hypertrophy (±dilatation/CCF), cardiomyopathy, arrhythmias.• Increased risk of ischaemic heart disease and stroke• Neoplasia: increased colon cancer risk• Subfertility is common

Investigations • Glucose, calcium and phosphate (raised)• GH levels (don’t rely on random GH as secretion is pulsatile, may be normal in between). GH is also raised in stress, pregnancy, puberty and sleep

– Normally GH secretion inhibited by high glucose, but not in acromegaly– If basal GH is >0.4 and/or IGF-1 is raised, an oral glucose tolerance test is needed (OGTT)– If the lowest GH value is >1, acromegaly is confirmed.

• MRI of pituitary fossa• Look for hypopituitarism • Visual fields and acuity• ECG, Echo.

Management• 1st line: Tumour excision (trans-sphenoidal surgery)• 2nd line: If surgery fails to correct GH/IGF-1 hypersecretion, try somatostatin analogues (SSA) ± radiotherapy. E.g. octreotide or lanreotide • 3rd line: The GH antagonist pegvisomant is used if resistant or intolerant to SSA. It suppresses IGF-1 to normal in 90%• Radiotherapy if unsuited to surgery or therapy

Signs of acromegaly• Increased growth of hands

and feet• Coarsening of face, wide

nose• Big supraorbital ridges• Macroglossia (big tongue)• Widely spaced teeth• Puffy lips, lids and skin • Scalp folds• Skin darkening• Acanthosis nigrans• Obstructive sleep apnoea• Carpal tunnel (50%)

Hyperprolactinaemia

• Commonest hormonal disturbance of pituitary• Presents earlier in women (menstrual disturbance) but later in men (e.g. with erectile dysfunction ± mass effects)• Prolactin stimulates lactation• Raised levels leads to hypogonadism, infertility and osteoporosis, by inhibiting secretion of gonadotropin releasing hormone

(therefore reduced LH/FSH, testosterone or oestrogen)• Prolactin is secreted from the anterior pitutary and release is inhibited by Dopamine produced in the hypothalamus

Causes of hyperprolactinaemia1. Excess production from the pituitary e.g. prolactinoma2. Disinhibition, by compression of the pituitary stalk, reducing local dopamine levels 3. Use of dopamine antagonist• Physiological: pregnancy, breastfeeding, stress • Drugs (most common cause): metoclopramide, haloperidol, a-methyldopa, oestrogens, ecstasy/MDMA, antypsychotics (a

reason for ‘non-compliance’. Sustained hyperprolactinaemia 🡪 reduced libido, sexual dysfunction etc)• Diseases:

– Prolactinoma (micro/macro adenoma)– Stalk damage: pituitary adenomas, surgery, trauma– Hypothalamic disease: craniopharyngioma, other tumours– Others: hypothyroidism (due to raised TRH), chronic renal failure

Clinical presentation• Females: amenorrhoea or oligomenorrhoea, infertility, galactorrhoea, decreased libido, increased weight, dry vagina• Males: erectile dysfunction, decreased facial hair, galactorrhoea• May present late with osteoporosis or local pressure effects from the tumour• Macroprolactinomas may compress the optic disc 🡪 reduced acuity, diplopia, ophthalmoplegia, visual field loss

Management• 1st line: Dopamine agonists (Bromocriptine or cabergoline). SE: nausea, depression, postural hypotension• 2nd line: Surgery (trans-sphenoidal) may be considered if intolerant of DA agonists. High success rate but risks of

permanent hormone deficiency and prolactinoma recurrence

Diabetes Insipidus• Passage of large volumes of dilute urine due to impaired water resorption by the kidney

Cause

• Cranial DI: Due to reduced ADH (vasopression) secretion the posterior pituitary. Causes:– Idiopathic (50%)– Congenital defects in ADH gene– Tumour (may present with DI and hypopituitarism) – craniopharyngioma, metastases, pituitary tumour– Trauma: may be temporary – Hypophysectomy (post pituitary gland removal)– Autoimmune hypophysitis– Infiltration: sarcoidosis etc. – Vascular: haemorrhage– Infection: meningoencphalitis

Clinical presentation

• Polyuria• Polydipsia• Dehydration• Symptoms of hypernatraemia (lethargy, thirst, weakness, irritability, confusion, coma and fits)

Investigations

• U&E• Calcium• Glucose (exclude DM)• Serum and urine osmolalities. Estimate= 2x(Na+K) + urea +glucose. Normal is 285-295 mOsmol and urien can be concentrated to more than twice this

– Significant DI excluded is urine to plasma osmolality ratio is more than 2:1

Management

• Cranial DI: – Find the cause – MRI head. – Test anterior pituitary function– Give desmopressin (synthetic ADH analogue)

• Nephrogenic DI:– Treat the cause– If it persists, try bendroflumethiazide

Nephrogenic DI: impaired response of the kidney to ADH. Causes:• Inherited• Metabolic: low potassium, high calcium• Drugs: lithium, demeclocycline• Chronic renal disease• Post-obstructive uropathy

Diagnosis of Diabetes Insipidus

The water deprivation test: • Purpose is to see if kidneys persist in producing dilute urine despite

dehydration– Stage 1: Fluid deprivation for 8 hours. Empty bladder, then no drinks and only

dry food. Weight hourly.– If >3% weight lost during test, order urgent serum osmolality. If f >300mOsm,

proceed to next stage, if not, continue test– Stage 2: differentiate cranial from nephrogenic DI. Proceed if urine still dilute

(>600mOsm). Give Desmopressin. Water can be drunk now– Measure urine osmolality hourly for the next 4 hours– Interpretation:

• Normal if urine osmolality >600mOsm In Stage 1 U:P ratio >2. (normal concentrating ability)

• Primary polydipsia: urine concentrates, but less than normal e.g. >400-600mOSm/kg• Cranial DI: urine osmolality increases to >600mOsm after desmopressin• Nephrogrenic DI: no increase in urine osmolality after desmopressin

Thyroid• The hypothalamus secretes TRH (thyrotropin-releasing hormoen) that stimulates TSH (thyroid stimulating hormone) from the anterior pituitary• TSH increases produciton of Thyroxine (T4) and triiodothyronine (T3) from the thyoid, which exert a negative feedback on TSH production• The thyroid produces mainly T4, which is 5x less active than T3• 85% of T3 is formed from peripheral conversion of T4• Most T3 and T4 in plasma is protein bound (thyroxine-binding globulin – TBG). • The unbound portion is the active part • Thyroid hormone abnormalities are usually due to problems with the thyroid gland itself and rarely caused by the hypothalamus/anterior pituitary

Basic tests

• Free T3 and T4 more useful than total, as total is affected by TBG• Total T3 and T4 are raised when TBG is raised (and vice versa)• TBG is raised in pregnancy, oestrogen therapy (HRT, oral contraceptives) and hepatitis• TBG is low in nephrotic syndrome and malnutrition (both from protein loss), drugs, chronic liver disease and acromegaly.

If hyperthyroidism suspected

• Ask for T3, T4 and TSH• In hyperthyroidism, all will have LOW TSH (except the rare TSH secreting pituitary adenoma)• Most have raised T4 (but only 1% have raised T3)

If hypothyroidism suspected

• Ask for only T4 and TSH (T3 adds no extra information)• TSH varies through the day (troughs at 2pm)

Other investigations

• Thyroid autoantibodies – may be increased in autoimmune thyroid disease: Hasimoto’s or Grave’s• TSH receptor antibody – may be raised in Grave’s (useful in pregnancy)• Serum thyroglobulin – useful in monitoring the treatment of carcinoma and in detection of facticious (self medicated) hyperthyroidism where it is low• Ultrasound• Isotope scan – useful for determining cause of hyperthyroidism and to detect retrosternal goitre

Interpretation of thyroid function testsHigh TSH, low T4 hypothyroidism

High TSH, normal T4 Treated hypothyroidism or subclinical hypothyroidism

High TSH, high T4 TSH secreting tumour or thyroid hormone resistance

Low TSH, raised T4 and low T3 Slow conversion of T4 to T3 (deiodinase deficiency, euthyroid thyroxinaemia)

Low TSH, normal T4/T3 Sublinical hyperthyroidism

Low TSH, Low T4 Central hypothyroidism (hypothalamic or pituitary disease)

Low TSH, Low T4, Low T3 Sick euthyroidism or pituitary disease

Normal TSH, abnormal T4 Consider changes to TBG, assay interference, amiordarone or pituitary TSH tumour

Hyperthyroidism/thyrotoxicosis• Usually from gland dysfunction

Causes• Grave’s disease: (2/3) females 9:1. Typical age 40-69 (younger if maternal family history)

– Due to circulating IgG autoantibodies binding to and activationg G-protein coupled thyrotropin receptors which cause smooth thyroid enlargement and increased hormone production (esp T3)

– Triggers: stress, infection, child birth– Associated with other autoimmune diseases: Type 1 Diabetes, vitiligo, Addison’s

• Toxic multinodular goitre – seen in the elderly and iodine deficient areas. There are nodules that secrete thyroid hormones– Control thyrotoxicosis with drugs first and then radioiodine.

• Toxic adenoma – there is a solitary nodule producing T3 and T4. On isotope scan, the nodule is ‘hot’ and the rest of the gland is suppressed. – Treat with radioiodine

• Ectopic thyroid tissue – metastatic follicular thyroid cancer, choriocarcinoma or struma ovarri: ovarian teratoma with thyroid tissue• Exogenous: iodine excess e.g. food contamination, contrast medi, levothyroxine excess causes raised T4 and low T3 (and low thyroglobulin)• Others:

1. Subacute de Quervain’s thyroiditis: self-limiting post-viral with painful goitre, fever ± raised ESR. Low isotope uptake on scan. Give NSAIDs2. Drugs: amiodarone, lithium (hypothyroidism more common)3. Post partum4. TB (rare)

Clinical presentation• Diahorroea• Weight loss, increased appetite (if very increased, paradoxical weight gain in 10%)• Over-active, sweats, heat intolerance • Palpitations, tremor, irritability, labile emotions• Oligomenorrhoea ± infertility• Rarely psychosis, chorea, panic, itch, alopecia, urticaria• Signs: pulse fast/irregular, warm moist skin, fine tremor, palmar erythema, thin hair, lid lag, lid retraction, possible goitre, thyroid nodules or bruit

depending on the cause• Signs of Grave’s disease:

1. Eye disease: exophthalmos, ophthalmoplegia2. Pretibial myxoedema: oedematous swellings above lateral malleoli (paradoxical name)3. Thyroid acropachy: extreme manifestation, with clubbing, painful finger and toe swelling, and periosteal reaction in limb bones

Investigations• TSH low (suppressed)• T4 and T3 raised• There may be mild normocytic anaemia, mild neutropenia (in Graves’)• ESR, calcium and LFT raised • Also: check thyroid autoantibodies, isotope scan (if cause unclear, to detect nodular disease or subacute thyroiditis)• If opthalmopathy, test visual fields, acuity and eye movements

Management of hyperthyroidism

1. Drugs– β blockers e.g. propanolol for rapid control of symptoms– Antithyroid: 2 strategies (equally effective)

• Titration: e.g. carbimazole and reduce according to TFT’s every 1-2 months• Block replace: carbimazole + thyroxine simultaneously (less risk of iatrogenic hypothyroidism)• About 50% of Grave’s will relapse, and then need radioiodine/surgery• Carbimazole SE: agranulocytosis (🡪 sepsis. Rare)

2. Radioiodine (131I)– most become hypothyroid post treatment– CI: pregnancy, lactation– Caution in active hyperthyroidism as risk of thyroid storm

3. Surgery (thyroidectomy)– Carries risk of damage to recurrent laryngeal nerve (hoarse voice) and hypoparathyroidism– Patients may become hypo/hyperthyroid

Complications of hyperthyroidism• Heart failure (thyrotoxic cardiomyopathy, increased in the elderly)• Angina• AF (see in 10-25%, control hyperthyroidism and warfarinize if no CI)• Osteoporosis, ophthalmopathy, gynaecomastia• Thyroid storm

Thyroid eye disease • Seen in 25-50% of those with Grave’s• Main risk factor is smoking• Eye disease may not correlate with eye disease and the patient can be euthyroid/hypo/hyperthyroid at presentation• May be the first presenting sign of Grave’s and can also be worsened by treatment, typically with radioiodine (usually

transient)• Retro-orbital inflammation and lymphocyte infiltration results in swelling of the orbit

Clinical presentation• Eye discomfort, grittiness, increased tear production, photophobia, diplopia, reduced acuity, afferent pupillary defect (may

mean optic nerve compression 🡪 urgent)• Exophthalmos (appearance of protruding eyes)• Proptosis (eyes protrude beyond the orbit (look from above))• Conjunctival oedema• Corneal ulceration, papilloedema, loss of colour vision• Ophthalmoplegia (esp of upward gaze) occurs due to muscle swelling/fibrosis

Management• Symptomatic treatment e.g. artificial tears, sunglasses• Severe: high dose steroids (IV methylprednisolone) decreasing according to Sx• Surgical decompression for severe sight-threatening disease or for cosmetic reasons

Hypothyroidism (myxoedema)• If treated, prognosis is excellent, if not it can be disastrous (e.g. heart disease/dementia)

Autoimmune causes of primary hypothyroidism

• Primary atrophic hypothyroidism (females 6:1). Common. Diffuse lymphocytic infiltration of the thyroid, leading to atrophy 🡪 no goitre• Hashimoto’s thyroiditis: Goitre due to lymphocytic and plasma cell infiltration. Commoner in women 60-70y. Rarely initial period of hyperthyroid (Hasitoxicosis).

Autoantibody titres are very high

• 🡪 both seen with other autoimmune diseases: type 1 DM, Addison’s and PA (psoriatic arthritis?)• Other causes

– Iodine deficiency (world wide chief cause)– Post-thyroidectomy or radioiodine treatment– Drug induced: anti-thyroid drugs, amiodarone, lithium, iodine– Subacute thyroiditis: temporary hypothyroidism after hyperthyroid phase

• Secondary hypothyroidism: Not enough TSH (due to hypopituitarism – very rare)• Associations: Down’s/Turner’s syndromes, cystic fibrosis, primary biliary cirrhosis, ovarian hyperstimulation• Pregnancy problem: Eclampsia, anaemia, prematurity, low birthweight, stillbirth, PPH

Clinical presentation

• Tired, sleepy, lethargic, low mood, cold-disliking, weight gain, constipation, menorrhagia• Hoarse voice, loss of memory/cognition, dementia, myalgia, cramps, weakness• Signs – BRADYCARDIC (this is pretty loose…)

– Reflexes react slowly– Ataxia (cerebellar)– Dry thin hair/skin– Yawning/drowsy/coma– Cold hands ± low temperature– Ascites ± non-pitting oedema (lids/hands/feet) ± pericardial or pleural effusion– Round puffy face/double chin/obese– Defeated demeanor– Immobile ± ileus– CCF– Also: neuropathy, myopathy, goitre (some causes)

Investigations• Raised TSH, low T4• In rare secondary hypothyroidism: low TSH (due to lack

from pituitary) , and low T4• Cholesterol and triglycerides raised• Macrocytosis (high MCV) and less often normochromic

anaemia

Treatment• Levothyroxine • Once normal, check TSH annually

Goitre1. Is the thyroid smooth or nodular?2. Is the patient eu/hypo/hyperthyroid?

Smooth, non-toxic goitre• Endemic (iodine deficiency), congenital, goitrogens, thyroiditis, physiological, inflammatory, Hashimoto’s/Riedel’s thyroiditis• Colloid goitres are late hyperplastic gotres where follicular tissues invaded by colloid

Smooth, toxic goitre• Grave’s disease, De Quervain’s thyroiditis

Multinodular colloid goitre• Most common type in the UK• 50% of people presenting with a single nodule actually have a multinodular goitre• Usually euthyroid but hyperthyroidism may develop• Hypothyroidism/malignancy are rare

Toxic multinodular goitre• The same as non-toxic multinodular goitre on examination but patient is hyperthyroid• Plummer’s disease is hyperthyroidism with single toxic nodule which may present in the background of a suppressed

multinodular goitre

Single thyroid lump• 10% malignant• Cyst• Adenoma• Discrete nodule in a multi-nodular goitre

Thyroid cancer

1. Papillary (60%)– Often in the young– Spread: nodes and lung– Rx: total thyroidectomy to remove non-obvious tumour ± node excision ± radioiodine to ablate residual cells– Give thyroxine to suppress TSH– Prognosis: better if young and female

2. Follicular (

MEN 1/ MEN 2

• In MEN syndromes there are functioning hormone-producing tumours in multiple organs • Autosomal dominant• MEN 1 (the P’s). Mutation in MEN-1 gene (tumour suppressor gene) for Menin protein

– Parathyroid hyperplasia/adenoma (95%, most have hypercalcaemia)– Pancreas endocrine tumours (70%) – gastrinoma or insulinoma or rarely somatostatinoma (DM +

steatorrhoea + gallstones/cholangitis), VIPoma or glucagonomas.– Pituitary prolactinoma (50%) or GH secreting tumour (Acromegaly)– Adrenal and arcinoid tumours also related

• MEN 2a (TAP - the glands)– Thyroid – medullary thyroid carcinoma (see in 100%)– Adrenal – phaeochromocytoma (50%, usually benign and bilateral)– Parathyroid hyperplasia (80% but less than 20% have hypercalcaemia)

• MEN 2b– Similar features to 2a but also:– Mucosal neuromas (bumps on lips, cheeks, tongue, glottis, eyelids and visible corneal nerves)– Marfanoid appearance– But no hyperparathyroidism

• Mutation in MEN 2a/b is the ret proto-oncogene, a receptor tyrosine kinase.

Thyroid disease and pregnancyNormal changes in pregnancy

• Normal pregnancy mimics hyperthyroidism • TBG and T4 increase to maintain free T4 levels• High levels of HCG mimic TSH• TSH may fall below normal in 1st trimester (suppressed by HCG)• The best thyroid tests in pregnancy are free T4, free T3 and TSH

Pre pregnancy hyperthyroidism

• Fertility is reduced by hyperthyroidism• Manage with antithyroid drugs, radioactive iodine (CI in pregnancy and breast feeding, avoid pregnancy for 4 months after use) or surgery

Hyperthyroidism in pregnancy

• Usually Grave’s disease • Increased risk of prematurity, foetal loss and maybe malformations• Severity often falls in pregnancy• Transient exacerbations may occurs (1st trimester and post partum)• 1st line: Propylthiouracil (keep dose as low as possible)• If can’t be controlled with drugs, partial thyroidectomy in 2nd trimester • Note: labour, delivery, surgery and anaesthesia can precipitate a thyroid storm (fever, tachycardia, changed mental state – agitation, psychosis and coma) 🡪 urgent treatment).

Hypothyroidism

• Associated with relative infertility, miscarriage, stillbirth, premature labour and abnormality• Optimize T4 preconception• Increase levothyroxine by 30% as soon as patient knows they’re pregnant

Post-partum thyroiditis (5%)

• Hyperthyroidism followed by hypothyroidisms (4 months post partum)• The hyperthyroid phase is normally self-limiting requiring no treatment (B blockers would be sufficient if needed)• Monitor for hypothyroid phase for >6 months and treat if symptomatic• 95% have thyroid antiperoxidase antibodies• Hypothyroidism may be associated with post partum depression, so check thyroid status of women with postpartum depression

Neonatal thyrotoxicosis

• Seen in 1% of babies with past Grave’s disease• Signs: foetal tachycardia (>160) in late pregnancy ± intrauterine growth restriction

Calcium homeostasis

• The concentration of calcium is regulated by the action of PTH (parathyroid hormone) and vitamin D on the kidneys, bones and GI tract

• PTH increases serum calcium by stimulation of calcium reabsorption and activation of vitamin D in the kidney, and increasing calcium release from bone

• The most active form of vitamin D (1,25-hydroxyvitamin D) increases intestinal calcium absorption

• Total plasma calcium is normally 2.2-2.6 mmol/L• Usually only 40% of total plasma calcium is ionized and physiologically

relevant; the remainder is bound to albumin and thus unavailable to tissues

• Routine analytical methods measure total plasma calcium and this must be corrected for the serum albumin concentration (add or subtract 0.02 mmol/L for every 1g/L by which the simultaneous albumin lies below or above 40g/L)

HypercalcaemiaCauses

• 90% - primary hyperparathyroidism or malignancy (e.g. from bone mets, myeloma or PTHrP)• Other causes: sarcoidosis, vit D intoxication, thyrotoxicosis, lithium, tertiary hyperparathyroidism, milk-alkali syndrome and familial benign hypocalciuric

hypercalcaemia (rare)

• HIV can cause both hyper/hypo calcaemia

Clinical presentation

• ‘Bones, stones, groans and psychic moans’• Abdomial pain, vomiting, constipation, polyuria, polydipsia, depression, anorexia, weight loss, tiredness, weakness, hypertension, confusion, pyrexia, renal stones,

renal failure, ectopic calcification (e.g. cornea), cardiac arrest

• ECG: reduced QT interval

Investigations

• The main distinction is malignancy vs primary hyperparathyroidism• Pointers to malignancy

– Albumin low– Cl- low, K+ low (K+ high in other causes of hypercalcaemia)– Alklalosis – PO

43- high, alk phos high

• Pointers to hyperparathyroidism– PTH high– K+ low

• FBC• Protein electrophoresis (for myeloma)• CXR, isotope bone scan (for bone mets)• 24h urinary Ca2+ excretion (for familial hypocalciuric hypercalcaemia)• TSH to exclude hyperthyroidism• Hydrocortisone suppression test: hydrocortisone 40mg orally 3x daily for 10d leads to suppression of plasma calcium in sarcoidois, vit D mediated hypercalcaemia

and some malignancies

Management

• Acute hyeprcalcaemia– Diagnose and treat underlying cause. If Ca >3.5mmol/L and symptomatic:– Correct dehydration (if present with IV 0.9% saline)– Bisphosphonates (prevents bone resorption by inhibiting osteoclast activity (e.g. pamidronate). SE: flu like Sx, low phosphate, bone pain, N&V– Further management: Chemotherapy (in malignancy), steroids (in sarcoidosis)

Parathyroid

• PTH normally secreted in response to low Ca2+ levels by 4 parathyroid glands, posterior to the thyroid

• The glands are controlled by –ve feedback via Ca2+ levels

• PTH acts on:– Increasing osteoclast activity releasing Ca2+ and PO

43- from

bones– Increases Ca2+ and decreases PO

43- resorption in the kidney

– Active 1,25 dihydroxy-vitamin D3 production is increased– Overall effect: increases Ca2+ and decreases PO

43-

HyperparathyroidismPrimary

• 80% solitary adenoma• 20% hyperplasia of all glands• 85) and parathyroidectomy

Tertiary

• The development of apparently autonomous parathyroid hyperplasia after longstanding secondary hyperparathyroidism, most often seen in renal disease

– Raised Calcium. VERY raised PTH (unlimited by feedback control)

Malignant

• Parathyroid-related protein (PTHrP) is produced by some squamous cell lung cancers, breast and renal cell carcinomas• This mimics PTH resulting in raised calcium (but PTH is low, as PTHrP is not detected in the assaay)

So remember: 🡪Only primary and tertiary hyperparathyroidism cause hypercalcaemia

raised

Very raised

HypocalcaemiaCauses• With raised PO

43-

– Chronic kidney disease (most common cause – inadequate vit D production and renal phosphate retention)– Hypoparathyroidism (including thyroid or parathyroid surgery)– Pseudohypoparathyroidism– Acute rhabdomyolysis – Vit D deficiency– Hypomagensia

• With low or normal PO4

3- – Osteomalacia (raised alk phos)– Acute pancreatitis – Over-hydration– Respiratory alkalosis (total calcium is normal but ionized calcium is low due to high pH 🡪 symptomatic)

Clinical presentation ‘SPASMODIC’• Spasms (carpopedal spasms = Trosseau’s sign)• Perioral paraesthesiae• Anxious, irritable, irrational• Seizures• Muscle tone increased in smooth muscle – hence colic, wheeze and dysphagia• Orientation impaired (time, place and person) and confusion• Dermatitis (e.g. atopic/exfoliative)• Impetigo herpetiformis (hypocalcaemia and pustules in pregnancy – rare and serious)• Chvostek’s sign (corner of mouth twitches when CN7 is tapped over parotid), choreoathetosis, cataract, cardiomyopathy (long

QT interval on ECG)

Management• Mild: give calcium daily with daily calcium levels • In chronic kidney disease: Alfacalcidol (vit D analogue)• Severe symptoms: give 10% calcium gluconate IV over 30 mins and repeat as necessary. Correct any respiratory alkalosis

Hypocalcaemia

Trousseau’s signChvostek’s sign

Osteomalacia• In osteomalacia there is a normal amount of bone but its mineral content is low (there is excess uncalcified osteoid and cartilage)• This is the reverse osteoporosis in which mineralization is unchanged, but there is overall bone loss• Rickets is the result if this process during the period of bone growth, osteomalacia is the result if it occurs after fusion of the epiphyses

Causes

• Vit D deficiency – due to malabsorption, poor diet or lack of sunlight• Renal osteodystrophy – renal failure leads to 1,25-dihydrxy-cholecalciferol deficiency• Drug induced – anticonvulsants may induce liver enzymes, leading to an increased breakdown of 25-hydroxy-vitamin D• Vit D resistance – a number of inherited diseases in which osteomalacia responds to very high doses of vit D• Liver disease – due to reduced hydroxylation of vit D to 25-hydroxycholecalciferol and malabsorption of vit D e.g. in cirrhosis• Tumour-induced osteomalacia – oncogenic hypophosphataemia: mediated by raised tumour production of phosphatonin fibroblast growth factor 23 which causes

hyperphosphaturia. Reduced serum PO4

3- often causes myalgia and weakness

Clinical presentation

• Rickets: growth retardation, hypotonia, apathy in infants.– Once walking: knock/kneed, bow legged and deformities of the metaphyseal-epiphyseal junction (e.g. the rachitic rosary)– Features of hypocalcaemia are often mild– Children with rickets are ill

• Osteomalacia: bone pain and tenderness, fractures (esp femoral neck), proximal myopathy (waddling gait), due to low phosphate and vit D deficiency

Investigations

• Calcium (mildly low – but may be severe), low PO4

3-

• Alk phos (high), PTH (high)• 25(OH)-vitamin D (low) except in vit D resistance • In renal failure 1,25 (OH)

2 vitamin D is low

• Biopsy: bone biopsy shows incomplete mineralization. Muscle biopsy (if proximal myopathy) is normal• Xray:

– Osteomalacia 🡪 loss of cortical bone, also apparently partial fractures without displacement may be seen (Looser’s zones)– Rickets 🡪 cupped, ragged metaphyseal surfaces

Management

• In dietary insufficiency, give vitamin D e.g. as one Calcium D3 Forte• In malabsorption or hepatic disease, give vit D3 (ergocalciferol) or parenteral calcium (monthly)• In renal disease or vit D resistance, give alfacalcidol or calcitriol (1,25-dihydroxy-vitamin D3) (both can cause dangerous hypercalcaemia)• Monitor plasma calcium weekly initially and if N&V

Osteomalacia/Rickets

‘Rachitic Rosary’

Paget’s disease of bone• Also called osteitis deformans• Increased bone turnover associated with increased number of osteoblasts and osteoclasts• Resultant re-modelling, bone enlargement, deformity and weakness• Rare in 40% of skeleton involved) and osteosarcoma

Investigations• X ray: localized enlargement of bone. Patchy cortical thickening with sclerosis, osteolysis and deformity.

Commonly axial skeleton, long bones and skull• Bone scan: ‘hot spots’• Ca2+ and PO

43- normal. Alk phos very raised.

Management• Analgesia• If analgesia fails, alendronte may be tried to reduce pain/deformity

Adrenal cortex

• The adrenal cortex produces steroids:1. Glucocorticoids – e.g. cortisol – which affect

carbohydrate, lipid and protein metabolism

2. Mineralcorticoids – e.g. aldosterone – which control sodium and potassium balance

3. Androgens – sex hormones – which have a weak effect until peripheral conversion to testosterone and dihydrotestosterone

Cushing’s syndrome • Clinical state due to chronic glucocorticoid excess (cortisol) and loss of the normal feedback mechanisms fo the hypothalamo-pituitary-adrenal axis and loss of circadian rhythm of cortisol secretion (normally

highest on waking)

• The chief cause is oral steroids• Endogenous causes are rare: 80% due to high ACTH of these a pituitary adenoma (Cushing’s disease) is the commonest cause

ACTH dependent causes (high ACTH)

• Cushing’s disease – bilateral adrenal hyperplasia from an ACTH-secreting pituitary adenoma.– Peak age 30-50 years– Low dose dexamethasone test leads to no change in plasma cortisol, but 8mg (high dose) may be enough to more than halve morning cortisol (as in normals)

• Ectopic ACTH production – esp small cell lung cancer and carcinoid tumours– Specific features: pigmentation (due to v high ACTH), hypokalaemic metabolic alkalosis (v high ACTH leads to mineralcorticoid activity), weight loss, hyperglycaemia– Classical signs of Cushing’s are often absent– Dexamethasone even in 8mg high dose fails to suppress cortisol production

ACTH independent causes (low ACTH due to –ve feedback)

• Adrenal adenoma/cancer – may cause abdo pain ± virilization in females. Because the tumour is autonomous, dexamethasone in any dose will not suppress cortisol• Adrenal nodular hyperplasia – no dose of dexamethasone will suppress cortisol• Iatrogenic – pharmacological doses of steroids (common)• Rarely: Carney complex. McCune-Albright syndrome

Clinical presentation

• Weight gain• Mood change (depression, lethargy, irritability, psychosis)• Proximal weakness• Gonadal dysfunction (irregular menses, hirsutism, erectile dysfunction)• Acne• Recurrent Achilles tendon rupture• Occasionally virilization in females• Signs: central obesity, plethoric, moon face, buffalo neck lump, supraclavicular fat distribution, skin and muscle atrophy, bruises, purple abdominal striae, osteoporosis, hypertension, infection prone, poor

healing

• Signs of the cause e.g. abdo mass

Investigations

• Random plasma cortisols are misleading, as illness, time of day and stress (e.g. venepuncture) influences results• MRI detects only 70% of pituitary tumours causing Cushing’s (many are too small) • 1st line Overnight dexamethasone suppression test

Management (depends on cause)

• Cushing’s disease: Removal of pituitary adenoma• Adrenal adenoma/carcinoma: adrenalectomy: ‘cures adenoma’s but rarely cures cancers. Radiotherapy/adrenolytic drugs follow if carcinoma• Ectopic ACTH: surgery if tumour is located and hasn’t spread.

– Metyrapone, ketoconazole and fluconazole reduced cortisol secretion pre-op of if awaiting effects of radiation• Prognosis: untreated Cushing’s has increased vascular mortality. Treated, prognosis is good (but myopathy, menstrual irregularity, hypertension and DM often remain)

Investigating Cushing’s syndrome• First, confirm the diagnosis (a raised plasma cortisol) then localize the source on the basis of lab testing

1st line- overnight dexamethasone suppression test• Good outpatient test• Give dex 1mg overnight• Do serum cortisol at 8am

– If normal, this high dose of steroid causes –ve feedback, so ACTH and cortisol LOW– In Cushing’s, no cortisol suppression– False + (pseudo-Cushing’s’) are seen in depression, obesity and alcohol excess and inducers of liver enzymes (phenytoin, phenobarbital,

rifampicin)• 24h urinary free cortisol is an alternative

2nd line tests • If above abnormal: 48h dexamethasone suppression test • Give dex for 2 days• Measure cortisol at 0 and 48h

– Again, in Cushing’s syndrome, there is failure to suppress cortisol• Midnight cortisol

– Require admission (unless salivary cortisol used)– Often inaccurate due to difficulties in measurement– Normal circadian rhythm (cortisol lowest at midnight, highest early morning) is lost in Cushing’s– Midnight blood, via a cannula during sleep, shows cortisol HIGH in Cushing’s

Localization tests – where is the lesion?• If the above are +ve• Plasma ACTH:

– If ACTH is undetectable, an adrenal tumour is likely 🡪 CT adrenal glands– If ACTH is detectable, distinguish a pituitary cause from ectopic ACTH production with a high dose dexamethasone suppression test

• High-dose dexamethasone suppression test – Complete or partial suppression indicates Cushing’s as the pituitary retains some feedback control– An ectopic source is not under feedback control

Addison’s• Primary adrenal insufficiency (= Addison’s disease) is rare but can be fatal. • Secondary adrenal insufficiency= most common cause is iatrogenic (long standing steroid therapy leading to suppression)• Destruction of the adrenal cortex leads to glucocorticoid (cortisol) and mineralocorticoid (aldosterone) deficiency • Anyone on prednisolone for long enough to suppress the pituitary-adrenal axis, or who has overwhelming sepsis, or has metastatic cancer may suddenly develop adrenal insufficiency

with deadly hypovolaemic shock

Cause:

• 80% due to autoimmunity in the UK• Others: TB (commonest cause world), adrenal mets (e.g. from lung, breast, renal cancer), lymphoma, opportunistic infections in HIV (e.g. CMV), adrenal haemorrhage

(Waterhouse-Friederichsen syndrome, antiphospholipid syndrome, SLE), congenital (late-onset congenital adrenal hyperplasia)

Clinical presentation

• Often diagnosed late • Lean, tanned, tired, tearful ± weakness, anorexia, dizzy, faints, flu-like myalgias/arthralgias• Mood: depression, psychosis, low self-esteem• GI: N&V, abdo pain, diarrhoea/constipation (think of Addison’s in all with unexplained abdo pain or vomiting)• Pigmented palmar creases and buccal mucosa (high ACTH, cross-reacts with melanin receptors)• Postural hypotension• Vitiligo• Signs of critical deterioration: shock (hypotension, tachycardia), fever and coma

Investigations

• Low Na, high K (due to low mineralcorticoid)• Low glucose (due to low cortisol)• Also: uraemia, high calcium, eosinophilia, anaemia• Short ACTH stimulation test (Synacthen test): do plasma cortisol before and 30 mins after tetracosactide (Synacthen)

– Addison’s is excluded if 2nd cortisol >550nmol/L

• ACTH: in Addison’s, 9am ACTH is high (inappropriately high). It is low in secondary causes • 21-hydroxylase adrenal autoantibodies: +ve in autoimmune disease in >80%• Plasma renin and aldosterone: To assess mineralocorticoid status • AXR/CXR: any past TB e.g. upper lung fibrosis or adrenal calcification

Management

• Replace steroids: – Hydrocortisone daily. Avoid giving late (may cause insomnia) – to replace cortisol– Flucrocortisone daily – to replace aldosterone

Addisonian crisis Clinical presentation

• Tachycardia• Vasoconstriction• Postural hypotension• Oliguria• Weak• Confused• Comatose • Often (but not always) in a patient with known Addison’s (e.g. when oral steroid has not been increased to cover stress such as pneumonia) or

someone on long-term steroid who has forgotten their tablets

• Remember bilateral adrenal haemorrhage (e.g. meningococcaemia) as a cause

Precipitating factors

• Infection, trauma, surgery

Management (if suspected treat before biochemical results)

• Take blood for cortisol and ACTH if possible • Hydrocortisone sodium succinate IV stat• IV fluids e.g. saline• Monitor blood glucose: the danger is hypoglycaemia • Blood, urine, sputum for culture, then antibiotics (e.g. cefuroxime)

Continuing treatment

• Glucose IV may be needed if hypoglycaemic• Continue IV fluids, more slowly as guided by clinical state. Correct U&E imbalance• Continue hydrocortisone sodium succinate• Change to oral steroids after 72h• Fludrocortisone may be needed if the cause is adrenal disease: ask an expert• Search for (and vigorously treat) the underlying cause. Get endocrinological help

Congenital Adrenal Hyperplasia

• Increased secretion of androgenic hormones due to deficiency of 21-hydroxylase, 11-hydroxylase or 3b-hydroxysteroid dehydrogenase.

• Cortisol is inadequately produced, and the consequent rise in adrenocorticotrophic hormone leads to adrenal hyperplasia and overproduction of androgenic cortisol precursors

• CAH is a leading cause of male pseudohermaphroditism

Clinical presentation• Vomiting, dehydration and amibiguous genitalia• Girls may be masculinized • Boys may be normal at birth, but have precocious puberty or ambiguous genitalia

(low androgens in 17-hydroxylase deficiency) or incomplete masculinization (hypospadias with cryptorchidism from low 13b-hydroxysteroid dehydrogenase)

Investigations• Hyponatraemia (with paradoxically high urine sodium)• Hyperkalaemia• High plasma 17-hydroxyprogesterone in 90%

Hypogonadism• Hypogonadism is failure of testes to produce testosterone, sperm or both• Features: small testes, reduced libido, erectile dysfunction, loss of pubic hair, reduced muscle

bulk, increased fat, gynaecomastia, osteoporosis, low mood.

• If prepubertal: incomplete puberty, eunuchoid body, reduced secondary sex characteristics

Causes

• Primary hypogonadism – is due to testicular failure e.g. from:– Local trauma, torsion, chemo/irradtiation– Post orchitis e.g. mumps, HIV, brucellosis, leprosy– Renal failure, liver cirrhosis or alcohol excess (toxic to Leydig cells)– Chromosomal abnormalities e.g Klinefelters (47XXY) – delayed sexual development, small testes and

gynaecomastia

• Hypogonadism secondary to: – Reduced LH/FSH e.g. from:

• Hypopituitarism• Kallman’s syndrome – isolated GnRH deficiency, often with anosmia and colour blindness• Systemic illness (e.g. COPD, HIV, DM• Prader-Willi syndrome

Management

• If total testosterone

Hirsutism• Is common (10%) and usually benign• It implies hair growth in women, in the male pattern

Causes• Familiar• Idiopathic• Due to increased androgen production by the ovary (e.g. PCOS, ovarian

cancer), the adrenal glang (e.g. late onset CAH, Cushing’s or adrenal cancer) or drugs (e.g. steroids)

PCOS• Causes secondary oligo-/amenorrhoea, infertility, obesity, acne and

hirsutism• Blood tests: increased testosterone, low sex hormone binding globulin,

high LH:FSH ratio, TSH, lipids. • Metformin may restore cycles and fertility and helps insulin resistance• Management: metformin, healthy eating, clomifene is used for

infertility

Diabetes• Results from lack or reduced effectiveness of endogenous insulin.

Type 1 DM

• Usually juvenile onset but may occur at nay age• Cause: insulin deficiency from autoimmune destruction of insulin secreting pancreatic β cells• Patients must have insulin, and are prone to ketoacidosis and weight loss • Associated with other autoimmune diseases

Type 2 DM

• Mainly due to changes in lifestyle• Higher prevalence occurs in Asians, men and the elderly• Most are >40 years• Cause: decreased insulin secretion ± increased insulin resistance• Associated with obesity, lack of exercise, calorie and alcohol excess• >80% concordance in identical twins• Typically progresses from a preliminary phase of impaired glucose tolerance or impaired fasting glucose (This is unique window for lifestyle intervention)

Diagnosis (WHO criteria)

• Symptoms of hyperglycaemia (e.g. polyuria, polydipsia, unexplained weight loss, visual blurring, genital thrush, lethargy) AND raised venous glucose detected once– Fasting >7mmol/L or random >11.1 mmol OR

• Raised venous glucose on 2 separate occasions – fasting >7, random >11.1, or oral glucose tolerance test (OGTT) 2h value >11.1

Features that suggest DM type 1

• Weight loss, persistent hyperglycaemia despite diet and medications, presence of autoantibodies (islet cell antibodies and anti-glutamic acid decarboxylase antibodies), ketonuria on urine dipstick

Other causes of DM

• Steroids, anti HIV drugs, newer antipsychotics , thiazides• Pancreatic: pancreatitis, surgery (where >90% of pancreas is removed), trauma, pancreatic destruction (cystic fibrosis), pancreatic cancer• Cushing’s disease, acromegaly, phaeochromocytoma, hyperthyroidism, pregnancy• Others: acanthosis nigricans, congenital lipodystrophy, glycogen storage diseases.

Managing diabetes • MDT approach• Educate/negotiate on target HbA1c (e.g. 6.5%)• Lifestyle modifications:

– Exercise, diet (low in saturated fats/sugars, high in starch carbs, moderate protein)– Smoking cessation– Foot care– Pre-conception advise

• Drugs– Start a statin and control BP– Type 1: insulin – many different types/modulations/regimes

• Fingerprick glucoses before a meal inform about long acting insulin doses. After a meal for short acting insulin doses. • Regimes: BD – twice daily by pen. Or QDS before meals ultra-fast insulin + bedtime long acting analogue (useful for adjusting doses with size of meals or

exercise)

– Type 2• Start a biguanide (Metformin) at once to increase insulin sensitivity and help weight. SE: N&V, abdo pain NOT hypoglycaemia• If HbA1c >7% 16 weeks later, add a sulfonylurea (e.g. gliclazide) to increase insulin secretion. Causes weight gain, sitagliptin good alternative. • Insulin may be needed just before or after main meals • Sulfonylurea receptor binders (nateglinide) increased b-cell insulin release• Glucagon like peptide analogues e.g. exenatide • A-glucosidase inhibitors – acarbose

Monitoring glucose cortisol1. Fingerprick glucose if type 1 DM (and some type 2)2. Glycated haemoglobin (HbA1c) relates to mean glucose level over previous 8 weeks. Targets are negotiable e.g. 6.5-7.4%

(depends on patients wish and arterial risk e.g. past MI or stroke)3. Be sure to ask about hypoglycaemic attacks (and whether symptomatic). Hypoglycaemic awareness may dimish if control too

tight or with time in type 1 DM.

Insulin dosing during intercurrent illnesses e.g. influenza• Illness often increases insulin requirements despite reduced food intake• Maintain calorie intake e.g. using milk• Check blood glucose >4 x daily and look for ketonuria• Increase insulin dose if glucose rising• Admit if vomiting, dehydrated, ketotic, a child or pregnant

Complications of Diabetes

• Injection sites: infection or lipohypertrophy – advise on rotating sites of injection• Vascular disease

– Chief cause of death. MI x4 more common and more likely to be ‘silent’– Stroke x2 more common– Address other risk factors: diet, smoking, hypertension– Suggest a statin for all

• Nephropathy– Microalbuminuria is when urine dipstick is –ve for protein but the urine albumin:creatinine ratio (UCR) is >3

reflecting early renal disease and increased vascular disease and increased vascular risk– Can give a2a blocker – candesartan (reduces albumin excretion by 60%) or ACE-I

• Diabetic retinopathy– Blindness is preventable– Arrange annual fundoscopy or retinal photography for all – Refer to ophthalmologist is pre-proliferative changes or if any uncertainty at or near the macula– Pre-symptomatic screening enables laser photocoagulation to be used– Background retinopathy: microaneurysms (dots), haemorrhages (blots) and hard exudates (lipid deposits)– Pre-proliferative retinopathy: cotton wool spots (e.g. infarcts), haemorrhages, venous bleeding. These are signs

of retinal ischaemia– Proliferative retinopathy: new vessels form. Needs urgent referral. – Maculopathy: (hard to see in early stages). Suspect if fall in acuity. Prompt laser, intravitreal steroids or

anti-angiogenic agents may be needed in macular oedema• Cataracts• Rubeosis iridis: new vessels on iris: occurs late and may lead to glucoma• Metabolic complications e.g. DKA• Diabetic feet: neuropathy, ischaemia, foot ulceration• Neuropathy

Diabetic ketoacidosisClinical presentation

• Gradual drowsiness, vomiting and dehydration in type 1 (very rarely type 2)• Do glucose in all those with unexplained vomiting, abdo pain, polyuria, polydipsia, lethargy, anorexia, ketotic breath, dehydration, coma or deep

breathing (sighing ‘Kussmaul’ hyperventilation)

• Triggers: infection e.g. UTI, surgery, MI, pancreatitis, chemotherapy, antipsychotics, wrong insulin dose/non-compliance Diagnosis

• Requires acidosis (pH 20 mmol, if so, give soluble insulin• Tests: blodo glucose, U&E, HCO3-, osmolality, blood gases, FBC, blood culture. Urine: ketones, MSU. CXR• NG tube only if N&V/unconscious• Insulin: give via a pump• Check GCS, glucose, U&E and HCO3- regularly• Continue fluid replacement, K+ replacement• Find and treat infection• Give LMWH until mobile

Fluid replacement

• Give IL of 0.9% saline stat. Then typically 1L, over the next hour, 1L over 2h, IL over 4h, then 1L over 6h – adjusted according to urine output• Use 5% dextrose when blood glucose 65y or with CCF need less saline more cautiously

Potassium replacement

• Total body potassium is invariably low, and plasma K+ falls as K+ enters cells with treatment• Don’t add K+ to 1st bag. Start adding K+ when urine flows at >30ml

Complications

• Cerebral oedema, aspiration pneumonia, hypokalaemia, hypomagnesaemia, hypophosphataemia, thromboembolism

Other diabetic emergenciesHypoglycaemic coma• Usually rapid onset• May be preceded by odd behaviour e.g. aggression, sweating, tachycardia, seizures• Management: give 20-30mg dextrose IV (200-300ml of 10% dextrose). Expect prompt recovery.• Glucagon is nearly as rapid as dextrose but will not work in drunk patients• Once conscious, give sugary drinks and a meal

Hyperglycaemic hyperosmolar non-ketotic (HONK) coma• Typically those with DM type 2 are at risk of this• History is longer (e.g. 1 week) with marked dehydration and glucose >35mmol/L• Acidosis is absent as there as been no switch to ketone metabolism• Patient is often old, and presenting for the 1st time• Osmolality is >340mOsm/kg• Occlusive events are a danger (focal CNS signs, chorea, DIC, leg ischaemia/rhabdomyolosis)• DVT risk – fully heparinize • Rehydrate with 0.9% saline (9L over 48h) e.g. at half the rate used in ketoacidosis • Replace K+ when urine starts to flow • Wait 1h before giving insulin as it may not be needed, avoid changes to avoid pontine myelinolysis • Look for the cause e.g. MI, drugs, bowel infarct

Hyperlactataemia• A rare but serious complication of DM with metformin use or septicaemia• Blood lactate >5mmol/L• Seek expert help. Give oxygen. • Treat sepsis vigorously, optimise tissue perfusion

The kidneyWater, K+ and H+ excretion here

Common renal symptoms

Dysuria (pain on micturition)

• UTI• Uretheritis or cystitis (bladder inflammation)• Chlamydia or gonorrhoea

Polyuria (excessive urine output of >2.5-3L in 24h)

• Need to differentiate from nocturia or frequency, these are not the same thing

• Polydipsia (excessive thirst leading to increased fluid intake >3L)

• Solute diuresis (e.g. hyperglycaemia with glycosuria)• Diabetes Insipidus • Chronic Kidney Disease

Nocturia

• Most often due to drinking before bed• Men over 50 years = prostate enlargement

Oliguria (low urine output)

• Acute Kidney Injury (if maintained over several hours)• Urinary tract obstruction• May be physiological – in pts with hypotension/hypovolaemia• Anuria (no urine) – suggests bilateral ureteric/bladder outflow

obstruction

Haematuria • May arise from anywhere in the renal tract. Can be

macro/microscopic • May happen after viral disease or vigorous exercise • Renal causes: neoplasia, glomerulonephritis (often

IgA nephropathy), polycystic kidney, pyelonephritis and trauma

• Extra-renal causes: calculi, infection (cystitis, prostatitis, urethritis), neoplasia (bladder, prostate, urethra), trauma (e.g. from catheter)

• Haematuria + dysuria 🡪 usually a UTI

Pain• Loin/flank pain occurs in

• kidney infections (acute pyelonephritis)• upper urinary tract obstruction• occlusion of the renal artery due to

thrombosis in situ or emboli• Chronic renal pain occurs in cystic renal disease and

renal tumours• Acute severe pain radiating from the flank to the

iliac fossa and testes or labium is typically ureteric colic 🡪 calculus

Glomerulopathies

• The presence of some form of glomerular disease, as opposed to tubulointerstitial or vascular disease, is usually suspected from the history and from one or more of the following urinary findings:– Haematuria (particularly if the red cells are abnormally shaped/distorted

e.g. dysmorphic)– Red cell casts– Proteinuria (which may be in the nephrotic range)

• Glomerulopathies can be classified as they related to 4 major glomerular syndromes1. Nephrotic syndrome – massive proteinuria, hypoalbuminaemia,

lipiduria and hyperlipidaemia2. Acute glomerulonephritis (acute nephritic syndrome): abrupt onset of

haematuria with casts or dysmorphic red cells, non-nephrotic range proteinuria, oedema, hypertension and transient renal impairment

3. Rapidly progressive glomerulonephritis: features of acute nephritis, focal necrosis with or without crescents and rapidly progressive renal failure over weeks

4. Asymptomatic haematuria, proteinuria (or both): usually incidental dipstick findings and may be an early indicator of renal disease

Glomerulonephritis (GMN)• GN is a common cause of end-stage renal failure in adults, along with diabetes and

hypertension.• They are a group of disorders where damage to the glomerular filtration apparatus causes

a leak of protein ± blood into the urine, depending on the disease • Patients may be asymptomatic, or present with haematuria (microcytic ± red cell casts),

proteinuria, renal failure or hypertension• Will present as a nephrotic or nephritic picture

Investigations• Bloods: FBC, U&E, LFT, ESR, CRP, immunoglobulins, electrophoresis, C3, C4,

autoantibodies (ANA, ANCA, anti-dsDAN, anti-GMB), blood culture, ASOT, HbsAg, anti-HCV• Urine: RBC casts, MC&S, Bence-Jones protein• 24 hour urine: protein• CXR, renal ultrasound ± renal biopsy• Quantify proteinuria (urine PCR) – protein/creatinine ratio

General management• Keep BP

Glomerulonephritis

Nephritic

IgA

ANCA

Anti-GBM

Proliferative GlomerulonephritisLupus

Nephrotic

Minimal change

Focal Segmental Glomerulosclerosis

Membranous nephropathy

Acute nephritis (nephritic syndrome)IgA nephropathy (Berger’s disease) 40-50%• Commonest GN in the developed world• Micro/macro haematuria ± proteinuria• Mesangial IgA (+ IgG and C3) on biopsy• Presentation: young boy with episodic frank haematuria, occurring a few days after URTI e.g. pharyngitis• Recovery often rapid between attacks• Increased IgA due to infection, then forming deposits in mesangial cells• Rx: control BP, ACE/ARB, steroids, immunosuppression unclear.

ANCA +• Small vessel vasculitis• cANCA – proteinase 3, Wegner’s• pANCA – myeloperoxidase, micropolyangitis

Anti-GBM disease aka Goodpasture’s syndrome• Development of auto-antibodies to type IV collagen (essential component of GBM but also in lungs 🡪 occasional haemoptysis)• Young males most commonly• Macroscopic haematuria, progressing rapidly to oliguria• Renal failure may occur within days of onset of symptoms• Rx: plasma exchange, corticosteroids ± cytotoxics

Membranous proliferative• Chief cause post-streptococcal GN, occurring 1-12 weeks after a sore throat or skin infection • Renal biopsy: inflammatory reaction affecting mesangial and endothelial cells. IgG and C3 deposits. • Serology: raised ASOT, low C3• Treatment is supportive. >95% recover renal function

Henoch-Schonlein purpura (HSP)• A systemic variant of IgA nephropathy, causing a small vessel vasculitis• Purpuric rash on extensor surfaces (typically legs), polyarthritis, scrotal and scalp swelling, abdo pain and nephritis

Nephrotic syndrome• There is massively increased filtration of macromolecules across the glomerular capillary wall due to structural and functional abnormalities of the glomerular

podocytes

Cause

• Adults: – Membranous nephropathy 20-30% – usually idiopathic but also drugs (e.g. gold, penicillamine, NSAIDs), autoimmune disease (e.g. SLE), neoplasia (carcinoma of lung, colon,

stomach, breast), infections (e.g. hep) and others (e.g. sickle cell)• IgG and C3 deposition along the glomerular basement membrane• Risk of renal vein thrombosis • Biopsy: thickened GBM. • IgG and C3 deposits • 40% spontaneous remission• Rx: if renal function getting worse 🡪 steroids or cyclophosphamide

– Focal segmental glomerulosclerosis – unknown aetiology. • Common cause of nephrotic syndrome in black people

• Children:– Minimal-change nephropathy – most common in boys

Inherited: AD Polycystic kidney disease

• Common (1/1000)• Multiple cysts develop throughout both kidneys• Cysts increase in size with advancing age• Leads to renal enlargement and the progressive destruction of normal kidney tissue, with gradual loss of kidney function• Most cases due to PKD1 gene mutation (short arm chr16), which codes for polycystin 1 (protein) – an integral membrane

protein which regulates tubal and vascular development in kidneys

Clinical presentation• Presents at any age after 2nd decade• Acute loin pain due to cyst haemorrhage or infection or urinary tract formation (uric acid calculi more commonly)• Abdo discomfort caused by renal enlargement• Hypertension • Progressive renal impairment• End-stage renal failure develops in 50% by 50-60 years• Liver cysts (usually clinically insignificant). Rarely cysts in pancreas, spleen, ovary.• Subarachnoid haeomorrhage – intracranial aneurysms more common• Mitral valve prolapse in 20%

Investigations• Clinical examination – large irregular kidneys, hypertension and possibly hepatomegaly• Ultrasound – for definitive diagnosis

Management• None to slow down progression• Blood pressure should be carefully controlled and disease progression monitored by serial measurements of serum

creatinine• Many will eventually need renal replacement by dialysis ± transplant

Inherited: Alport’s

• 85% X linked. Mutations in COL4A5 gene (encodes the a5 chain of type IV collagen)

Clinical presentation• Haematuria• Proteinuria • Progressive renal insufficiency• Systemic manifestations: sensorineural deafness and ocular

defects (e.g. lenticonus: bulging of lens capsule seen on slit-lamp)

Management• Treat as for renal failure.

Interstitial disease: Tubulointerstitial nephritis

• Primary injury to the renal tubules and interstitium resulting in decreased renal function

Acute tubulointerstitial nephritis• Normally due to an allergic drug reaction• Most commonly drugs of the penicillin family and NSAIDs• Infections (e.g. strep) are a less common cause• Immune disorders e.g. SLE • Presentation: fever, eosinophilia and eosinophiluria, normal or only mildly raised urine protein

excretion, hypertension and acute kidney injury (AKI)– Systemic Sx: fever, rash, arthalgia

• Renal biopsy: intense interstitial cellular infiltrate and variable tubular necrosis • Management: withdraw offending drug. Treat any underlying infection. Treat AKI. High dose steroids

(pred)• Most make good recovery.

Chronic tubulointerstitial nephritis • Results from many disorders• Cause: chronic pyelonephritis often with reflux nephropathy, sickle cell disease, lead or cadmium

intoxication• Extensive fibrosis and tubular loss on renal biopsy• Patients present with chronic renal failure e.g. proteinuria, polyuria or uraemia

Systemic diseases affecting the kidney

• Diabetes• Polyarteritis• Hypertension• Haemolytic uraemic syndrome• Atheroma• HSP, amyloid• Myeloma• systemic sclerosis, SLE.

Acute renal failure

Definition• A significant deterioration in renal function occurring over hours or days, clinically manifesting as an abrupt and sustained rise

in serum urea and creatinine• It might be asymptomatic, but oliguria (80%1. Pre-renal (40-70%): due to renal hypoperfusion e.g. hypovolaemia, sepsis (causing systemic vasodilation), CCF, cirrhosis,

renal artery stenosis, NSAIDs or ACE-i (these interfere in renal blood flow)2. Intrinsic (10-50%) – ATN is damage to the renal tubular cells, caused by ischaemia (with causes of renal hypoperfusion as

above) or nephrotoxins (often due to drugs such as aminoglycosides, amphotericin b, tetracyclines), radiological contrast agents, uric acid crystals, haemoglobinuria (in rhabdomyolysis) or myeloma

3. Others: vascular (vasculitis, TTP, GN, interstitial nephritis etc.)

Investigations• Blood tests: U&E (beware of hyperkalaemia), FBC, clotting, LFT, CJ, ESR, CRP, blood cultures• If cause unclear: serum immunoglobulins, electrophoresis, complement levels (C3/4), autoantibodies (ANA, ANCA,

anti-dsDNA, anti-GBM) and ASOT• Urine dipstick• Microscopy for RBC, WBC, crystals and casts• CXR: pulmonary oedema?• ECG: signs of hyperkalaemia• Renal ultrasound: renal size or obstruction

Assessment of ARF

1. Is the renal failure acute or chronic? Suspect chronic if:– History of co-morbidity e.g. DM, hypertension, long duration of Sx, previously

abnormal blood tests, small kidneys on US with high echogenicity. – The presence of anaemia, hypocalcaemia or high phosphate may not help to

distinguish but ABSENCE suggests acute

2. Is there urinary tract obstruction?– Should always be considered as a cause of ARF because it is reversible and prompt

treatment prevents permanent renal damage– Should be suspected in pts with a single functioning kidney or in those with Hx of

renal stones, BPH or previous pelvic/retroperitoneal surgery– Examine for a palpable bladder, pelvic or abdo masses or an enlarged prostate – Complete anuria suggests renal tract obstruction and is unusual in ARF– Renal US best way to detect dilatation of the renal pelvis and calyces, although

obstruction may be present without dilatation esp in cancer

3. Is there a rare cause of ARF?– E.g. glomerulonephritis– These are usually associated with haematuria or proteinuria, and warrant urgent

renal referral for consideration of a renal biopsy and treatment

Acute renal failure: managing complications

Hyperkalamia• May cause arrhythmias or cardiac arrest• ECG changes:

– Tall, tented ‘T’ waves– Small or absent p wave– Increased PR interval– Widened QRS complex – ‘sine wave’ pattern– Asystole

Management• IV calcium gluconate until ECG improves – cardioprotective • IV insulin + glucose (stimulates cellular reuptake of potassium)• Salbutamol nebs. Consider calcium resonium to bind K+ in gut• Haemodialysis or haemofiltration required if anuric

Pulmonary oedema• High flow oxygen by face mask• Venous vasodilator e.g. morphine (+metoclopramide)• Furesemide• If no response, urgent haemodialysis• Consider CPAP• Consider venesection if patient in ‘extremis’• Maybe IV nitrates

Chronic renal failure• Kidney damage for >3 months based on findings of abnormal structure/function OR GFR3 months with or without evidence of kidney damage• Classification is based on GFR/evidence of renal damage • End-stage renal failure (ESRF)= GFR60, recurrent UTIs, urinary obstruction or a systemic illness that affects the kidneys

Investigations

• Hb (low – normochromic normocytic anaemia), ESR, U&E (raised urea and creatinine)• Glucose (DM)• Hypocalcaemia• Hyperphosphataemia• High alk phos (renal osteodystrophy)• Hyperparathyroidism• Urine: M&C, dipstick, 24h urinary protein• Imaging: renal ultrasound (size is usually small) but may be normal or large with DM, polycystic kidney disease and others• CXR: cardiomegaly, pleural/pericardial effusion or pulmonary oedema• Bone x ray: may show osteodystrophy• Renal biopsy if cause unclear and there are normal sized kidneys

Chronic renal failure managementRefer early to a nephrologist

Treat reversible causes: relieve obstruction, stop nephrotoxic drugs, deal with hypercalcaemia and cardiovascular risk

Lifestyle advice

• CKD patients should take exercise, achieve a health weight and stop smoking• Match dietary and fluid intake with excretion• Na+ restriction: helps control BP and prevent oedema• A moderate protein diet is recommended – thought to slow down progression of disease but beware or protein-calorie malnutrition• K+ restriction: only if hyperkalaemia • HCO

3- supplements to correct acidosis

Hypertension

• Even a small BP drop may save significant renal function• Target BP is

Renal bone disease: osteodystrophy

• Umbrella term for various forms of bone disease that develop in CKD i.e. – osteomalacia– osteoporosis– secondary and tertiary hyperparathyroidism– osteosclerosis

• Renal phosphate retention and impaired production of 1,25-dihydroxyvitamin D (the active hormonal form of vitamin D) lead to a fall in serum calcium concentration

• This leads to compensatory increased in PTH secretion• A sustained excess of PTH results in skeletal decalcification

Management

• Treat if hyperparathyroidism if present• PO

43- rises in chronic renal failure, which increases PTH further, and also precipitates in the

kidney and vasculature

• Restrict dietary PO4

3- (milk, cheese, eggs)

• Give binders e.g. Calchicew to bind PO4

3- in the gut to decrease its absorption

• Vit D analogues (e.g. alfacalcidol) and Calcium supplements reduce bone disease and hyperparathyroidism (secondary and tertiary)

Dehydration

Biochemistry• Raised urea (disproportionate relative to small rise in creatinine)• Raised albumin (also useful to plot change in patient’s condition)• Raised haematocrit (PCV)

Presentation• Tachycardia• Postural drop in BP (low BP is a late sign of hypovolaemia)• Reduced capillary refill time• Reduced urine output• Cool peripheries • Dry mucous membranes• Reduced skin turgor • Sunken eyes

Fluid overload• Raised JVP• Pitting oedema of the sacrum, ankles or even legs and abdomen• Tachypnoea • Bibasal crepitations • Pulmonary oedema on CXR

Acute management of pulmonary oedema (heart failure)• Oxygen• IV access• ECG• Diamorphine• Furosemide IV• GTN spray• Nitrate infusion e.g. isosorbide dinitrate• If worsening: further furosemide• Consider ventilation e.g. invasive or CPAP• If systemic BP

Hyperkalaemia• Plasma potassium >6.5mmol/L is an emergency and required urgent treatment • The worry is of myocardial hyperexcitability leading to VF and cardiac arrest

Causes

• Oliguric renal failure • K+ sparing diuretics (e.g. spironolactone and amiloride)• Rhabdomyolysis • Metabolic acidosis (diabetes)• Excess K+ therapy• Addison’s disease • Massive blood transfusion• Burns• Drugs e.g. ACE-I, suxamethonium• Artefactual result

Concerning signs/symptoms

• Fast irregular pulse• Chest pain• Weakness/light-headedness• Palpitations• ECG: tall tented T waves, small p waves, a wide QRS and VF

Non-urgent treatment• Treat the underlying cause, review medications• Polystyrene sulfonate resin (e.g. Calcium

resonium) binds K+ in the gut• If there is evidence of myocardial hyperexcitablity

or K+>6.5mmol/L, get senior assistance and treat as an emergency

Emergency treatment• IV Calcium gluconate – repeat as necessary• Insulin + glucose • Nebulized salbutamol • Calcium resonium • Dialysis

Hypokalaemia• If K+ 2.5 and no Sx): give oral K+ supplements. Review K+ after 3 days• If severe (

HypernatraemiaCauses – usually due to water loss in excess of sodium ions• Fluid loss without water replacement (e.g. diarrhoea, vomit, burns)• Incorrect IV fluid replacement (excessive saline)• Diabetes insipidus (suspect if large urine volume. This may follow head injury or CNS

surgery, especially pituitary)• Osmotic diuresis (for diabetic coma)• Primary aldosteronism. Suspect if hypertensive, low K+ and alkalosis (raised HCO

3-)

Clinical presentation• Lethargy• Thirst• Weakness, irritability, confusion• Coma and fits

Management• Give water orally if possible• If not, give dextrose 5% IV slowly guided by urine output and plasma sodium• Use 0.9% saline if hypovolaemic, since this causes less marked fluid shifts and is

hypotonic in a hypertonic patient• Avoid hypertonic solutions

Hyponatraemia

• Plasma Na+ concentration depends on the amount of both Na+ and water in the plasma• Hyponatraemia therefore does not necessarily imply Na+ depletion• Assessing fluid status is the key to diagnosis (see next slide)

Causes – see next slide Iatrogenic hyponatraemia• Happens when 5% dextrose is infused continuously without adding 0.9% saline (the dextrose is quickly

used, rendering the gluid hypotonic and causing hyponatraemia)

Clinical presentation• Anorexia, nausea and malaise initially • Then: headache, irritability, confusion, weakness, reduced GCS and seizures• Hyponatraemia also increases the risk of falls in the elderly

Management• Correct the underlying cause, never base treatment on Na+ concentration alone• Replace Na+ and water at the same rate they were lost:

– In asymptomatic chronic hyponatraemia: fluid resuscitaiton is often sufficient, although demeclocycline (ADH antagonist) may be required

– If hypervolaemic (cirrhosis, CSF) treat the underlying disorder first – In acute/symptomatic hyponatraemia or if dehydrated: cautious rehydration with 0.9% saline may be given,

but do not correct changes rapidly as central pontine myelinolysis may occur. – Consider adding furosemide when not hypovolaemic to avoid fluid overload – Vasopressor receptor antaognists (‘vaptans’ e.g. conivaptan) promote water excretion without loss of

electrolytes– In emergency (seizures, coma): get help. Consider hypertonic saline (e.g. 1.8% saline) ± furosemide

Hyponatraemia: SIADH

• Syndrome of Inappropriate ADH secretion• An important, but over-diagnosed cause of hyponatraemia• The diagnosis required:

– Concentrated urine (Na+> 20mmol and osmolality >500mOsm) – PLUS hyponatraemia OR low plasma osmolality– The absence of hypovolaemia, oedema or diuretics

Causes• Malignancy: lung small-cell, pancreas, prostate, thymus or lymphoma• CNS disorders: meningoencephalitis, abscess, stroke, subarachnoid or subdural haemorrhage, head

injury, neurosurgery, GBS, vasculitis or SLE• Chest disease: TB, pneumonia, abscess, aspergillosis, small-cell lung cancer• Endocrine disease: hypothyroidism (not true SIADH but perhaps due to excess ADH release from

carotid sinus baroreceptors triggered by reduced cardiac output• Drugs: opiates, psychotropics, SSRIs, cytotoxics • Other: acute intermittent porphyria, trauma, major abdo or thoracic surgery, symptomatic HIV

Management• Treat the cause and restrict fluid• Consider salt ± loop diuretic if severe• Demeclocyline is used rarely• Vasopressin receptor antagonists (‘vaptans’) being used more often

Urinary tract obstruction• Urinary tract may be obstructed at any point between the kidney and the urethral meatus resulting in dilatation of the tract proximal to the obstruction• Dilatation of the renal pelvis= hydronephrosis• Eventually there is compression and thinning of the renal parenchyma with a decrease in the size of the kidney

Cause

• Prostate obstruction (hypertrophy or tumour)• Gynaecological cancer• Calculi • Others: clots, congenital abnormalities of urinary tract, ureteric/urethral stricture, neuropathic bladder.

Clinical presentation

• Upper urinary tract obstruction– Dull ache in the flank or loin which may be provoked by an increase in urine volume e.g. high fluid intake or diurectics– Complete anuria is strongly suggestive of complete bilateral obstruction or complete obstruction of a single functioning kidney– Partial obstruction 🡪 polyuria as a result of tubular damage and impairment of concentrating mechanisms

• Bladder outlet obstruction– Hesitancy, poor stream, terminal dribbling and a sense of incomplete emptying– Retention with overflow characterized by the frequent passage of small quantities of urine– Infection commonly occurs and may precipitate acute retention of urine

• Depending on the site of obstruction an enlarged bladder or hydronephrotic kidney may be felt on examination • Pelvic (for malignancy) and rectal examination (for prostate enlargement) essential for diagnosis

Investigations

• Ultrasound– Excretion urography identifies site of obstruction and shows a characteristic appearance (a delayed nephrogram)

• Radionucleotide studies: no value in acute obstruction but may help in long standing obstruction• Retrograde/antegrade pyelography, cystoscopy and pressure-flow studies during bladder filling and voiding

Management

• Surgery if persistent (elimination of obstruction 🡪 massive diuresis)• In some cases definitive relief of obstruction is not possible and urinary diversion may be required – e.g. indwelling urethral catheter, stent or ileal

conduit

Prostate cancer• 2nd commonest male malignancy • Incidence rises with age. 80% in men >80s• Associations:

– High testosterone– Family history

• Most are adenocarcinomas arising in peripheral prostate • Spread may be local (seminal vesicles, bladder, rectum) via lymph• May spread further via blood e.g. bone (sclerotic bony lesions)

Clinical presentation• Asymptomatic or nocturia• Hesitancy, poor stream, terminal dribbling or obstruction• Weight loss ± bone pain suggests mets• PR examination: may show hard, irregular prostate

Investigations• PSA (normal in 30% of small cancers)• Transrectal ultrasound + biopsy• Bone x-rays• Bone scan• CT/MRI (MRI for staging)

Management• Local disease: radical prostatectomy (+immediate goserelin if node +, widely used regimen), radiotherapy or watchful

waiting with PSA monitoring (depends on age and clinical status of patient)• Brachytherapy for local disease (being assessed in trials)• Metastatic disease: hormonal drugs may give benefit for 1-2 years. Gonadotrophin-releasing analogues e.g. 12 weekly

goserelin• Symptomatic relief: analgesia, treat hypercalcaemia, radiotherapy for bone mets/spinal cord compression• Prognosis: 10% die in 6 months, 10% live >10 years

Epididymo-orchitis

Causes• Chlamydia, E.coli, mumps, gonorrhoea, TB

Clinical presentation• Sudden onset tender swelling• Dysuria• Sweats/fever

Investigations• Urine sample (1st catch may be more helpful than MSU)• Urethral discharge sample• Consider STI screen

Management• If 35 years – associated with UTI commonly, so try ciprofloxacin• Also analgesia, bed rest, scrotal support and drainage of any abscesses

Testicular torsion

If in any doubt, surgery is required

Clinical presentation• Sudden onset pain in one testis, which makes walking uncomfortable• Pain in the abdomen• N&V• Signs: inflammation of one testis – it is tender, hot and swollen. Testis may lie high and transversely. • Torsion may occur at any age but is most common at 11-30 years old• With intermittent torsion the pain may have passed on presentation, but if it was severe, and the lie is

horizontal, prophylactic fixing may be wise

DD: the main one is epididymo-orchitis – but with this the patient tends to be older, there may be symptoms of urinary infectin and more gradual onset of pain. Also consider trauma, tumour and an acute hydrocele

Investigations• Doppler ultrasound (may demonstrate lack of blood flow to testis) • Isotope scan may be useful• DO NOT DELAY SURGICAL EXPLORATION FOR INVESTIGATIONS

Management• Ask consent for possible orchiectomy + bilateral fixation (orchidopexy) (need to fix both)

Testicular cancer• Commonest cancer in males 15-44• Types

– Seminoma (30-65 years)– Teratoma (20-30 years)– Tumours of Sertoli cells (🡪 oestrogens)– Tumours of Leydig cells (🡪 androgens)– Lymphoma

• 10% of malignancies occur in undescended testes, even after orchidopexy• 5% have tumour in the other testis• Risk factors: undescended testis, infant hernia, infertility

Clinical presentation

• Typically painless testicular lump, noticed after trauma/infection• May also present with haematospermia, secondary hydrocele, pain• SOB (lung mets), abdominal mass (enlarged lymph nodes) • Effects of secreted hormones

Staging

1. No evidence of metastases

2. Infradiaphragmatic node involvement (spread via the para-aortic nodes NOT inguinal nodes)

3. Supradiaphragmatic node involvement

4. Lung involvemnt (haematogenous)

Investigations

• CXR• CT• Excision biopsy• A-fetoprotein and b-HCG are useful tumour markers and help monitor treatment (check before + after treatment)

Management

• Surgery: Orchidectomy• Chemotherapy/radiotherapy• Seminomas are very radioesensitive (Stage 1 seminomas: orchidectomy + radiotherapy cures 95%)• 5 year survival >90% in all groups)

Bladder cancer• Adenocarcinomas and squamous cell carcinomas rare in the west • 80% confined to bladder mucosa and only 20% penetrate muscle (increasing 5yr mortality to 50%)

Associations• Smoking• Aromatic amines (rubber industry)• Chronic cystitis• Schistomiasis (squamous cell carcinoma)• Pelvic irradiation

Clinical presentation• Painless haematuria• Recurrent UTIs• Voiding irritability• Tumour spreads to liver and lungs

Investigations• Urine: microscopy/cystology (cancers may cause sterile pyuria)• IVU (intravenous urogram) may show ± ureteric involvement• Cystoscopy with biopsy is diagnostic• Bimanual exploration under anaesthetic helps assess spread• CT/MRI or lymphangiography may show involved pelvic nodes

Management• Confined to bladder only (80%): diathermy via transurethral cystoscopy/transurethral resection of bladder tumour

(TURBT). Potentially chemotherapy (mitomycin C). 5 year survival 95%• Muscle involvement: radical cystectomy is gold standard. Radiotherapy gives worse survival rate than surgery but preserves

the bladder. • Invasion beyond bladder: Usually palliative chemo/radiotherapy. Chronic catheterization and urinary diversions help to

relieve pain.

Renal tumours• Renal cell carcinoma – 90% of all renal cancers• Mean age 55 years. Male 2:1• 15% of haemodialysis patients develop RCA

Clinical presentation• 50% incidental finding• Haematuria• Loin pain• Abdo mass• Anorexia, malaise, weight loss• Rarely, invasion of left renal vein compresses left testicular vein causing a varicocele • Spread may be direct (renal vein) via lymph • Spread may be distant via blood to bone, liver and lung

Investigations• Hypertension (due to renin secretion)• Blood: FBC (polycythaemia (high RBC) from EPO secretion), ESR, U&E, ALP (bony mets)• Urine: RBCs, cytology• Imaging: Ultrasound, CT/MRI (including 3D), renal angiography, IVU (filling defect ± calcification), CXR

(‘canon ball’ mets)

Management• Radical nephrectomy ± chemotherapy• Prognosis: 5 year survival 45%

Renal calculi (nephrolithiasis)• Consist of crystal aggregates • Stones form in collecting ducts and may be deposited anywhere from the renal pelvis to the urethra though classically at the pelviureteric junction, pelvic prim and

vesicoureteric junction

• Common. Lifetime incidence 15%. Peak 20-40• Male 3:1

Types

• Calcium oxidate (75%)• Magnesium ammonium phosphate (Struvite. 10-20%)• Also: urate, hydroxyapatite, brushite and cystine

Clinical presentation

• May be asymptomatic or…• Renal colic: excruciating spasms ‘loin to groin’ (or genitals/inner thigh), often with N&V. Often cannot lie still (differentiates from peritonitis)

– Renal obstruction: felt in the loin, between rib 12 and the lateral edge of lumbar muscles– Obstruction of mid-ureter: may mimic appendicitis/diverticulitis– Obstruction of lower-ureter: bladder irritability and pain in scrotum, penile tip or labia majora– Obstruction in bladder/urethra: pelvic pain, dysuria, strangury (desire but inabilty to void) ± interrupted flow

• UTI: can co-exist (increased risk if voiding impaired)• Haematuria• Proteinuria• Sterile pyuria • Anuria

Investigations

• FBC, U&E, Ca2+, PO4

3- , glucose, bicarbonate, urate

• Urine dipstick: usually +ve for blood (90%)• MSU: MC&S• Further tests for cause: urine pH, 24h urine (for calcium, urate, oxalate etc.). • Stone biochemistry• Imaging:

– KUB XR (kidney, ureters and bladder). 80% of stones visible – IVU– Spiral non-contrast CT (better than IVU)

Management• Analgesia (e.g. diclofenac) + IV fluids• Antibiotics (e.g. cefuroxime) if infection• Stones 5mm/pain not resolving:

• Medical expulsive therapy: nifedepine or a-blockers (tamsulosin) ± prednisolone (start at presentation)

• Most pass within 48h after this• If not: ESWL (electric shock lithotripsy)• If large, multiple or complex🡪 PCNL (percutaneous

nephrolithotomy – keyhole surgery)

UTI• Uncomplicated – normal renal tract • Complicated

– Abnormal renal/GU tract– Voiding difficulty/outflow obstruction– Poor renal function– Impaired host defences– Virulent organism e.g. staph aureas

• Recurrent UTI: further infection with a new organism• Relapse: further infection with the same organism• Organisms:

– Ecoli (70% in community but 41% in hospital)– Also: staph saprophyticus, proteus mirabilis

Risk factors:

• Female sex, sexual intercourse, exposure to spermicide (in women, by diaphragm or condoms)• Pregnancy (common but normally asymptomatic, until serious pyelonephritis, premature delivery (± fetal death), so do routine dipstix in pregnancy• Menopause• Poor host defense (immunosuppresion, diabetes)• Urinary tract: obstruction, stones, catheter, malformation

Clinical presentation

• Acute pyelonephritis: high fever, rigors, vomiting, loin pain and tenderness, oliguria (if acute renal failure)• Cystitis: frequency, dysuria, urgency, strangury, haematuria, suprapubic pain• Prostatitis: flu-like symptoms, low backache, few urinary symptoms, swollen or tender prostate on PR• Signs: fever, abdo pain or loin tenderness, foul-smelling urine. Ocassionally distended bladder and enlarged prostate

Investigations

• If symptomatic, dipstick the urine. Treat emperically if nitrites or leucocytes are +ve while awaiting sensitivities on MSU• If –ve dipstick, consider sending an MSU for lab MC&S to confirm this• Send a lab MSU anyway if male, a child, pregnant, immunosuppressed or ill • Ultrasound or IVU/cystoscopy: if child, men or failure to response to treatment, recurrent UTI (>2/year), pyelonephritis, unusual organism, persistent haematuria

UTI: management

🡪 Non pregnant women with asymptomatic bacteruria should not be treatedAdult, non-pregnant women• Lower UTI:

– Trimethoprim or nitrofurantoin 3 days sufficient – 2nd line: co-amoxiclav

• Upper UTI: – Take a urine culture– Cefuroxime IV then oral 7d course (or ciprofloxacin for 7 days if not severe)– Avoid nitrofurantoin– Resistance to trimethoprim also very common

Adult, pregnant women (NICE)• Treat any bacteruria regardless of symptoms• Nitrofurantoin is recommended over trimethoprim• Others: amoxicillin, trimethoprim (give folic acid), cefelexin

Adult men• Treat any bacteruria regardless of symptoms• Nitrofurantoin or trimethoprim 7 days

Urinary retentionAcute retention

• Bladder usually tender, containing about 600ml• Causes:

– Prostate obstruction (usual cause in men)– Urethral strictures– Anticholinergics – ‘holding’– Alcohol– Constipation– Post op (pain/inflammation/anaesthetics)– Infection – Neurological (cauda equina syndrome)– Carcinoma

• Investigations: MSU, U&E, FBC, and PSA. Renal ultrasound if renal impairment• Management

– Catheterize and try a prostate procedure– If in clot retention, will require 3 way catheter and bladder washout– After e.g. 7 days, trial without catheter may work (esp if 12)• Institute definite treatment promptly• Intermittent self-catheterization is sometimes required

Biochemistry – some major disease patterns

Abnormal kidney function: 2 major pictures1. Low GFR –

– High: urea, creatinine, K+, H+, urate, PO4

3-, anion gap– Low: Ca2+, HCO

3-,

– Causes: early acute oliguric renal failure, CKD– In CKD also: low Hb, high PTH and renal bone disease

2. Tubular dysfunction– High: H+– Low: K+, urate, PO

43-, HCO

3-

– Normal creatinine and urea– Others: polyuria with urinary glucose, amino acids, proteins (lysozyme, b2-microglobulin) or phosphate– Causes: recovery from acute renal failure, hypercalcaemia, hyerpuricaemia, myeloma, pyelonephritis, hypokalaemia, Wilson’s disease, galactomsaemia and heavy metal poisoning

Thiazide and loop diuretics • High: K+, HCO

3-, urea

• Low: Na+

Hepatocellular disease • High: bilirubin, AST, alk phos (slightly), clotting times• Low: albumin

Cholestasis • High: bilirubin,AST • Very high: GGT, alk phos

Addison’s disease • High: K+• Low: Na+

Cushing’s syndrome• May show low K+, high HCO

3-, Na +

Conn’s syndrome• High: HCO

3-

• Low: K+• Na+ normal or high (also hypetension)

Diabetes inspidius• High: Na+, plasma osmolality• Low: urine osmolality

SIADH• Low: Na+, plasma osmolality• Normal or low urea and creatinine• High: urine osmolality, urine Na+