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1 Pathology Course CHEMICAL PATHOLOGY Tom Marjot Kindly sponsored by:

2 I used….. Oxford handbook – chemistry and micro Robbins for histopath and haem ‘Clinical Chemistry’ Caution about exam and the normal ranges

3 Coming up… Calcium, phosphate, bones Kidney stones Water and electrolytes Pituitary Thyroid Make links within path and between path and specialities.

4 CALCIUM, PHOSPHATE, BONES Only 7 diagnoses to choose from 1.Malignancy 2.Hyperparathyroidism 3.Osteomalacia 4.Pagets 5.Osteoporosis 6.Familial hypocaluric hypercalcaemia 7.Others p13

5 DIAGNOSIS? Why these? Treatment? PATIENT 1

6 DIAGNOSIS? PATIENT 2

7 PATIENT 2 - CONTINUED

8 Calcium mmol/L Controlled by two hormones, PTH and activated vitamin D PTH has a more powerful effect – Reabsorption of Ca 2+ from BONE – Reabsorption of Ca 2+ from KIDNEYS – Excretion of Phosphate from kidney – Increases renal 1-alpha hydroxylation of vitamin D 1,25(OH) 2 D only causes reabsorption of Ca 2+ from GIT (NB calcitonin – reduces Calcium, marker for medullary Thyroid Ca)

9 to Zero “If in the presence of hypercalcaemia PTH is not reduced to zero then diagnosis is PRIMARY HYPERPARATHYROIDISM” - A benign hypersecreting adenoma

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12 Hypercalcaemia in malignancy Often in very advanced disease Due to – boney metastasis – PHrP “parathyroid hormone related peptide” Squamous cell lung carcinoma  PTrH

13 SECONDARY HYPERPARATHYROIDISM

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15 Vascular calcification Renal vascular lesions are frequently characterised by heavily calcified plaques, rather than traditional lipid-rich atheroma

16 SECONDARY HYPERPARATHYROIDISM TERTIARY

17 Vitamin D deficiency  low/normal calcium, slightly raised PTH but never enough to cause hypercalcaemia

18 OSTEOPOROSIS : All biochemistry is normal. Diagnosis via DEXA scanning PAGETS DISEASE : defined by +++ increase in ALP, NB risk of osteosarcoma

19 Raised ALP and normal calcium Raised ALP and raised Calcium Raised ALP and low calcium Pagets Healing fractures Boney mets Hyperparathyr oidism Osteomalacia Renal failure ALKALINE PHOSPHATASE A rise in alkaline phosphatase can be caused by each one of the following except: A.Pregnancy B.Pagets disease C.Healing fractures D.Hypoparathyroidism E.Osteomalacia NB: Myeloma has normal ALP

20 OSTEOSARCOMA Highly malignant 60% at knee Peak in adolescence Look for ‘codmans triangle’ EWINGS SARCOMA Highly malignant Long bones & pelvis Peak in adolescence “small round cells” Onion skinning of periosteum Stains for CD99 (MIC2) t(11,22) Cytoplasm stains positive for ALKALINE PHOSPHATASE Acid phosphatase?

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22 Vitamin D deficiency Will trigger a PTH response to try and increase calcium but never enough to cause HYPERcalcaemia Vit D deficiency not a cause of hypercalcaemia

23 Hyp o parathyroidism Much rarer than hyperparathyroidism Congential or acquired Congenital; absence of Parathyroid glands (DiGeorges syndrome) Acquired: -post thyroid surgery (temporary or permanent) -Autoimmune -Magnesium deficiency (alcoholics) Receptor resistance to parathyroid hormone  pseudo-hypoparathyroidism

24 DiGeroges T cell B cell ??? T CELL

25 High forehead Low set, abnormally folded ears cleft palate, small mouth and jaw Hypocalcaemia T cell lymphopenia Complex congenital heart disease Oesophageal atresia DiGeorge syndrome Developmental defect of 3rd/4th pharyngeal pouch 75% sporadic Deletion at 22q11 Probably involves TBX1 Normal numbers B cells Reduced numbers T cells Homeostatic proliferation with age Immune function improves with age

26 CATCH 22 CARDIAC – ESPECIALLY TETRALOGY ABNORMAL FACIES THYMIC APLASIA CLEFT PALATE HYPOPARATHYROIDISM / HYPOCALCAEMIA 22 – 22q

27 Lymphoid progenitors Stem cells Pre-T cells Failure of lymphocyte precursors : Severe combined immune deficiency (X-linked SCID) Failure of thymic development : DiGeorge syndrome Failure of expression of HLA molecules: Bare lymphocyte syndromes Failure of signalling, cytokine production and effector functions: IFNgamma deficiency, IL12 deficiency S C I D C LASS SWITCHING I FNgamma D iGeorge

28 CALCIUM, PHOSPHATE, BONES Only 6 diagnoses to choose from 1.Malignancy 2.Hyperparathyroidism 3.Osteomalacia 4.Pagets 5.Osteoporosis 6.Familial hypocaluric hypercalcaemia 7. Others

29 Steroids Hyperthyroidism Alcohol and smoking Thin (BMI<22) Testosterone ↓ (prostate cancer treatment) Early menopause Renal failure Erosive Rheumatoid arthritis Diet - malabsorption Osteoporosis:

30 Familial Hypocaluric Hypercalcaemia Consider this diagnosis in … Asymptomatic hypercalcaemia Young patient Known family history Low urinary calcium <200mg/day Due to loss of function mutations in calcium sensing receptor in kidney  increased reabsorption Completely benign

31 Others A 30-year old man has recently developed a cough, and shortness of breath on exertion. Chest X-ray shows bilateral hilar lymphadenopathy. Routine blood tests show a calcium of 2.8mmol/l SARCOIDOSIS Granulomatous conditions, epitheloid cells (macrophages) can ectopically 1-alpha hydroxylate vitamin D. PATH GRANULOMAS: PBC, Sarcoid, TB, Leprosy, Histoplasmosis, Cryptococcus, Crohns

32 Renal stones A.Calcium oxalate B.Ammonium magnesium phosphate C.Cysteine D.Xanthine E.Urate A 26 year old woman develops severe right flank pain radiating to the groin. She has recently been treated for a urinary tract infection. Urinary MC&S confirmed the presence of ureaplasma urilyticum

33 Renal stones A.Calcium phosphate B.Ammonium magnesium phosphate C.Cysteine D.Xanthine E.Urate A 26 year old woman develops severe right flank pain radiating to the groin. She has just undergone aggressive combination chemotherapy for treatment of a Burkitt lymphoma. Chronic – Gout Acute – tumour lysis syndrome T(8,14) C-myc

34 OSTEOSARCOMA Highly malignant 60% at knee Peak in adolescence Look for ‘codmans triangle’ EWINGS SARCOMA Highly malignant Long bones & pelvis Peak in adolescence “small round cells” Onion skinning of periosteum Stains for CD99 (MIC2) t(11,22) Cytoplasm stains positive for ALKALINE PHOSPHATASE

35 WATER AND ELECTROLYTES

36 ASIADH BDiabetes insipidus CDiabetes mellitus DPsychogenic polydipsia EPrimary hyperparathyroidism FSarcoidosis GAmyloidosis HAddison’s disease IVitamin D deficiency A 25 year old man complains of thirst & polyuria. Investigations: Na 151mmol/l, K 4.0mmol/l, Urea 7.1mmol/l, Creatinine 115umol/l, low urine osmolality, Glucose 4.3mmol/l ( ), Calcium 2.4mmol/l ( ), Phosphate 0.9mmol/l ( ). A 25 year old man complains of thirst & polyuria. Investigations: Na 129mmol/l, K 3.7mmol/l, Urea 4.2mmol/l, Creatinine 90umol/l, low urine osmolality, Glucose 4.6mmol/l, Calcium 2.38mmol/l, Phosphate 1.0mmol/l. A 40 year old woman complains of thirst & polyuria. Investigations: Na 145mmol/l, K 4.0mmol/l, Urea 6.2mmol/l, Creatinine 100umol/l, Urine specific gravity 1.030, Glucose 4.5mmol/l, Calcium 2.91mmol/l, Phosphate 0.4mmol/l.

37 ASIADH BDiabetes insipidus CDiabetes mellitus DPsychogenic polydipsia EPrimary hyperparathyroidism FSarcoidosis GAmyloidosis HAddison’s disease IVitamin D deficiency A 25 year old man complains of thirst & polyuria and suffering from bipolar. Investigations: Na 151mmol/l, K 4.0mmol/l, Urea 7.1mmol/l, Cr 115umol/l, low urine osmolality, Glucose 4.3mmol/l ( ), Calcium 2.4mmol/l, Phosphate 0.9mmol/l ( ).

38 ASIADH BDiabetes insipidus CDiabetes mellitus DPsychogenic polydipsia EPrimary hyperparathyroidism FSarcoidosis GAmyloidosis HAddison’s disease IVitamin D deficiency A 25 year old man complains of thirst & polyuria. Investigations: Na 129mmol/l, K 3.7mmol/l, Urea 4.2mmol/l, Creatinine 90umol/l, low urine osmolality, Glucose 4.6mmol/l, Calcium 2.38mmol/l, Phosphate 1.0mmol/l ( ).

39 DIABETES INSIPIDUS Cannot produce a concentrated urine due to: a deficiency of antidiuretic hormone (ADH) or renal resistance to ADH High concentrated plasma (high osmolality) Hypernatraemia in presence of very dilute urine (+polyuria and polydipsia) PSYCHOGENIC POLYDIPSIA Excessive water drinking in absence of physiologic stimuli Hyponatraemia in presence of dilute urine (+polyuria and polydipsia)

40 Diagnosis: 8hr fluid deprivation test Normal: Urine concentration ↑ >600mOsmol/kg Primary polydipsia: Urine concentrates > mOsmol/kg Cranial DI: urine concentrates only after giving desmopressin Nephrogenic DI: zero concentration urine after desmopressin

41 ASIADH BDiabetes insipidus CDiabetes mellitus DPsychogenic polydipsia EPrimary hyperparathyroidism FSarcoidosis GAmyloidosis HAddison’s disease IVitamin D deficiency A 40 year old woman complains of thirst & polyuria. Investigations: Na 145mmol/l, K 4.0mmol/l, Urea 6.2mmol/l, Creatinine 100umol/l, Urine specific gravity 1.030, Glucose 4.5mmol/l, Calcium 2.91mmol/l, Phosphate 0.4mmol/l ( ).

42 Calcium mmol/L PTH has a more powerful effect 1.Reabsorption of Ca 2+ from BONE 2.Reabsorption of Ca 2+ from KIDNEYS 3.Excretion of Phosphate from kidney 4.Increases renal 1-alpha hydroxylation of vitamin D 1,25(OH) 2 D only causes reabsorption of Ca 2+ from GIT

43 Water, sodium and potassium Water never actively transported anywhere in the body Moves depending on change in solute content of a fluid compartment Solute content of EXTRACELLULAR FLUID = osmolality NB osmolarity and osmolality are basically the same Tiny difference in the technology used to measure solute concentrations 2(Na + + K + ) + Urea + Glucose NR: mosmol/l

44 2(Na + +K + ) + Urea + Glucose NR: mosmol/l Even slight loss of water (in water deprivation)  will increase osmolality and result in movement of H2O from ICF to ECF  Stimulate thirst centres in hypothalamus  VASOPRESSIN RELEASE ICF ECF Osm >295 p4

45 Osmolar gap Measured Osmolality – Calculated Osmolality Should be roughly equal (<10) Significant discrepancy provides indirect evidence that extra osmotically active species are present in plasma. Ethanol, methanol & ethylene glycol

46 Hyperosmolar non-ketotic coma 2(Na + +K + ) + Urea + Glucose In a patient with hyperosmolar non ketotic coma. TRUE OR FALSE 1.Heparin in a useful treatment 2.The prognosis is worse than in DKA 3.The patients diabetes can subsequently be controlled by diet alone 4.The degree on unconciousness is most closely associated with plasma osmolality 5.Very large amounts of insulin are required T T T F T

47 Hyponatraemia Sodium concentration relies on both sodium and water in the plasma Low concentration does not necessarily imply sodium depletion Diagnosis relies on asking 2x questions 1 – what is the osmolality 2 – what is the fluid status of the patient (clinically)

48 Hyponatraemia Measure osmolality Increased or normal Decreased Hyperglycaemia Mannitol Hypertonic IV infusion Lipaemia Hyperproteinaemia Isotonic IV infusion True hyponatraemia 1/ “What is the osmolality?” 2(Na + +K + ) + Urea + Glucose

49 True Hyponatraemia Assess ECF volume Not dehydrated 1/ “What is the volume status?” Dehydrated Urinary sodium >20mmol/L <20mmol/L Sodium lost via kidneys Addisons Diuretics Sodium lost elsewhere D+V Burns Overloaded CCF Cirrhosis Renal failure Euvolaemic SIADH ++ Urine osmolality eg >500mmol

50 Scenario 89 year old woman bought to A and E having suffered two brief fits at home. She is currently drowsy but has no headache. Husband states she has never been to hospital but that her GP has just started her on an antihypertensive. She has reduced skin turgor and no focal neurology. Thiazide diuretics => ↓Na

51 Which of the following is not caused by thiazide diuretics? A.Hyponatraemia B.Hypokalaemia C.Hypocalcaemia D.Gout E.Insulin resistance F.Hyperlipidaemia Hypercalcaemia

52 THIAZIDES. 4 hyper 2 hypos HYPO Hyponataemia Hypokalaemia HYPER Hypercalcaemia (↓calcium excretion, therefore Rx recurrent stones) Hyperuricaemia  gout Hyperlipidaemia Hyperglycaemia

53 SIADH True Hyponatremia Euvolaemic No Renal, Adrenal, cardiac disease Not on Drugs (eg Diuretics) U. Na > 20 +  U. Osmo Not dehydrated Euvolaemic SIADH ++ Urine osmolality eg >500mmol

54 You get phoned about this patients potassium 5.7mmol/l Which one of the following would not explain this result? A.Delay in transport to the laboratory B.Losartan therapy C.Addisons disease D.Acute renal failure E.Conns syndrome

55 Aldosterone Increases  ↓K + Conns syndrome Decreases  ↑ K + Addisons ACEI and ARBs Potassium-sparing dieuretics

56 Caution should always be exercised when combining diuretics. However, which one of the following combinations is always contraindicated? A.Metolozone + bumetanide B.Bendroflumethiazide + furosemide C.Amiloride + spironolactone D.Bendroflumethiazide + triamterene E.Spironolactone + furosemide

57 NB that cortisol at high levels has mineralocorticoid effects Mineralocorticoid = aldosterone 67 year old Long term smoker with 1 month history of haemoptysis admitted to hospital for investigation. On examination you notice significant abdominal striae, a proximal myopathy and he is quite confused. ECG shows inverted T waves and large PR interval. 1.Hypokalaemia 2.? Cushingoid symptoms 3.Lung cancer Small cell lung cancer can produce ectopic ACTH ACTH  ++ Cortisol  Cushings syndrome High cortisol has aldosterone-like effects  Hypokalaemia

58 Aldosterone continued… 1.Complete pituitary failure (no ACTH) 2.Congenital adrenal hyperplasia (no cortisol or aldosterone) Emergency treatment is always HYDROCORTISONE. – Glucocorticoid (cortisol) effects and Mineralcorticoid (aldosterone) effects.

59 Pituitary failure Use combined pituitary function test (CPFT) – triple bolus test Administer 1.Gonadotrophin releasing hormone 2.Insulin 3.Thyrotrophin releasing hormone 1.Measure LH and FSH 2.Measure cortisol and growth hormone 3.Measure prolactin and TSH

60 Thyroid Disease When to think about thyroid disease… Atrial Fibrillation Hyperlipidaemia Diabetes Mellitus Certain Drugs - Amiodarone 25% biochemical. 5% clinical hypoT - Lithium 6x higher Downs, Turners, Addisons

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62 LITHIUM Monitor thyroid function every 6 months Renal function should be monitored at baseline and every 6 months 0.4–1 mmol/litre. >1.5 fatal Antagonises ADH Therefore inability to concentrate urine  dehydration and acute kidney injury Caution with diuretics Tremor, ataxia, nystagmus and polydipsia.

63 TFTs ↑TSH ↓T4HYPOTHYROIDISM ↓TSH ↑T4HYPERTHYROIDISM ↑TSH ↔T4SUBCLINICAL HYPOTHYROIDISM TREATED HYPOTHYROIDISM ↓TSH ↔T4 SUBCLINCIAL HYPERTHYROIDISM

64 SUBCLINICAL THYROID DISEASE “compensated disease” Cardiovascular risk factor Hypercholesterolaemia Recheck TFTs, recheck history Treat TSH>10, +ve autoantibodies, other AI disease

65 BE CAREFUL WITH THYROID TERMINOLOGY 1 – Marker for papillary and follicular thyroid cancer 2 – Binds 5% of circulating T4 3 – Binds 80% circulating 4 – Inhibits thyroperoxidase 5- Upregulates thyroperoxidase 6- beta-hCG cross reacts with this mollecules receptor 7- Levels predict the rate of conversion of subclinical hypothyroidism to thyroid disease A Thyroglobulin B Thyroxine C Triiodothyronine D TSH E Thyroid-binding globulin F Thyroperoxidase G Anti-TPO antibodies H Thionamide I Tyrosine J Albumin K Thyroid binding pre-albumin

66 Colloid with Thyroglobulin Capillary lumen iodide I-I- T 4 T 3 I2I2 Thyroid peroxidase MIT DIT TIT rTIT T4 Proteolytic enzymes

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68 Thyoid in pregnancy Interesting things to think about Prevalent in young women Increased demand (hypermetabolic), increased hcg, loss of iodine through placenta and urine Both hyper and hypo affect the baby PTU and methimazole. PTU 1 st trimester Meth afterwards Postpartum thyroiditis ; common 9%.

69 Causes of hyperthyroidism Graves’ disease 40-60% Toxic multinodular goitre 30-50% Single toxic adenoma 5% Subacute thyroiditis Postpartum thyroiditis Silent thyroiditis (immune and amiodarone) Factitious thyroiditis TSH induced Thyroid cancer induced Trophoblastic tumour and Struma ovarii High uptake Low uptake

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