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Chemical Pathology

Chemical Pathology. Dr Swathikan Chidambaram, MBBS BSc (Hons) Academic Foundation Doctor, Oxford. General Tips and Resources. Study material Lectures Pathology Guide Questions Past paper questions Meeran’s questions – quizzes, in-lecture questions

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Chemical Pathology

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  1. Chemical Pathology Dr Swathikan Chidambaram, MBBS BSc (Hons) Academic Foundation Doctor, Oxford

  2. General Tips and Resources • Study material • Lectures • Pathology Guide • Questions • Past paper questions • Meeran’s questions – quizzes, in-lecture questions • Pathbase - https://candidate.speedexam.net/signin.aspx?site=pathbase • Pathology SBAs by Sukhpreet Singh Dubb • References for chemical pathology • Clinical Chemistry by Marshall and Bangert

  3. Overview • Calcium • Acid Base • LFTs • Diabetes • Other endocrine disorders • Porphyrias

  4. Calcium physiology • Basics • Calcium • 99% in bone. 1 % remainder. • Free (“ionised”) ~50% - biologically active • Protein-bound ~40% - albumin* • Complexed ~10% - citrate / phosphate

  5. Calcium physiology Parathyroid hormone Calcitonin Increase serum calcium Decrease serum phosphate Decrease serum calcium Increase serum phosphate Bone resorption by osteoclasts (via osteoblasts)* Increased Ca reabsorption in gut Less bone reabsorption by osteoclasts Decreased Ca reabsorption in gut Less PO4 reabsorption at PCT More Ca reabsorption at DCT Decreased Ca reabsorption at DCT Calcitriol

  6. Calcium pathology • Osteoporosis • Osteomalacia • Paget’s disease • Parathyroid bone disease • Renal osteodystrophy • Malignancy • Familial hypocalciurichypercalcaemia

  7. Hypercalcemia • False – always repeat sample • If repeat sample shows hypercalcemia, the next best test is PTH level*. • True • Primary • Secondary • Tertiary

  8. Repeat it! • Causes of erroneously high Ca: • Drip arm (Calcium gluconate infusion) • Cuffed sample (raised albumin, normal urea) • Dehydration (raised albumin and urea) • Albumin • High albumin -> artificially elevated calcium; look at corrected calcium instead

  9. Primary Hyperparathyroidism • Adenoma – commonest cause* • Hyperplasia • (Carcinoma) • Other cause of raised/inappropriate normal PTH • Familial hypocalciurichypercalcaemia • Malignancy -> High calcium and low phosphate, LOW PTH* • If you suspect primary hyperPTH -> suspect MEN 1 and 2a syndrome* Calcium ALP PTH Phosphate

  10. Treatment • Fluids -> fluids -> fluids • Surgical removal of affected glands • Cinacalcet – activates CaSr protein -> lower serum calcium

  11. Hyperparathyroidism Calcium • Secondary • Vitamin D deficiency • Renal failure • Tertiary • ESRF - develops hypercalcaemia • Post transplant – to diff from primary hypercalcemia • Low phosphate PTH Phosphate ALP Calcium Phosphate Calcium ALP PTH Phosphate Calcium ALP PTH Phosphate

  12. If the PTH is low? • Malignancy • Rarer • Sarcoid (+other granulomatous disorders) • Vitamin D excess • Thyrotoxicosis • Milk-alkali syndrome • Thiazide diuretics (mild) • Hypoadrenalism

  13. Case 1 • 51 year old women under investigation following recurrent renal calculi and constipation • Ca: 3.0 (2.2-2.6) • Phosphate 0.70 (0.8-1.4) • Other electrolytes normal • Next test(s)?

  14. PTH • PTH: 6 (2-7) • Normal PTH • Diagnosis?

  15. Hypocalcaemia • Causes: • DiGeorge Syndrome, Surgical removal - no PTH • Vit D deficiency - no calcitriol • Magnesium deficiency - reduced PTH release • Pseudohypoparathyroidism - PTH resistance • Pesudo-pseudohypoPTH - normal biochem with clinical findings • Cases

  16. Case 3 • 79-year-old lady admitted following and fall, found to have #NOF • Calcium – 2.2 (2.2-2.6) • Phosphate – 0.8 (0.8-1.4) • Next test(s)?

  17. Case 3 • 79-year-old lady admitted following and fall, found to have #NOF • Calcium – 2.0 (2.2-2.6) • Phosphate – 0.8 (0.8-1.4) • Next test(s)? • Vit D – 30 (60-105nmol/L)

  18. Case 4 • 7 year old child with cleft palate has the following findings • Calcium – 1.6 (2.2-2.6) • Phosphate – 2.5 (0.8-1.4) • ALP – 20(30-150)

  19. Other situations • Paget’s disease: isolated increase in ALP* • Symptoms: bone pain, deafness, heart failure, saber tibia • Osteoporosis: all normal* • Symptoms: fractures • DEXA scan: below -2.5 (osteoporosis) vs -2.5 to -1 (osteopenia) vs >-1 (normal) • Bisphosphonates and vitamin D

  20. Hypoglycemia • Whipple’s triad. Actual number varies with patient. • Causes • Insulinoma, sulphonylurea abuse, factitious insulin • Treatment – consciousness, intact swallow • Oral glucose* • Glucagon – refractory hypoglycemia*

  21. Insulin + C-peptide • Both low • Appropriate response (stress response) • Trauma, fasting, critical illness, liver failure • Rarely non-islet cell tumour hypoglycaemia • Insulin high + normal/low C-peptide • Iatrogenic or factitious insulin • Rarely autoimmune conditions • Both high • Sulphonylurea, quinine, pentamidine • Insulinoma – think MEN syndromes High plasma glucose detected by B islet cells GLUT2 channels B-islet cells secrete preproinsulin -> proinsulin -> exocytosis of insulin + C-peptide in equal amounts Plasma glucose levels fall

  22. Question • Type 1 diabetic with hypoglycaemia • Insulin – low • C-peptide – low • Insulinoma • Factitious insulin • Fasting • Sulphonylurea • Non-islet cell tumour hypoglycaemia

  23. Question • Type 1 diabetic with hypoglycaemia • Insulin – high • C-peptide – low • Insulinoma • Factitious insulin • Fasting • Sulphonylurea • Non-islet cell tumour hypoglycaemia

  24. Question • Type 2 diabetic with hypoglycaemia • Insulin – High • C-peptide – High • Insulinoma • Factitious insulin • Fasting • Sulphonylurea • Non-islet cell tumour hypoglycaemia

  25. DKA • Usually in T1DM • Rarely can occur in T2DM • Omitted insulin or increased requirement e.g. infection, trauma, acute illness • DM diagnosis, pH<7.35, ketones >3M, T1DM • HONK: normal pH, no ketones, high osmolality, T2DM

  26. DKA • First step in management? • Crystalloid fluid - rehydration • Insulin – drive glucose into cells • Potassium – insulin drives K into cells • Bicarbonate – if needed, correct alkalosis • Dextrose – rebound hypoglycemia from insulin

  27. HONK/HNK • Only in T2DM • Extreme dehydration, and plasma osmolality > 320mOsm • Insulin still present in small amounts -> no ketosis • Fluids • Insulin • Potassium • ± Heparin/LMWH

  28. Liver • Function • Enzymes • Serology

  29. Functions of the liver: • Metabolism of • Fat • Gluconeogenesis • Protein • Synthesis of coag. Factors • Hormone metabolism • Drugs • Bilirubin • Storage • Glycogen

  30. Markers of function • Clotting - INR (APTT); synthesis of all but factor 7 • Albumin (negative acute phase protein) • Bilirubin

  31. Markers of liver cell damage • NOT specific to the liver • ALT is more specific than AST • Hepatitis • ↑ AST + ALT • Alcoholic – AST:ALT = >2:1 • Viral – AST:ALT = <1:1 • Cholestasis • ↑ ALP • ↑ GGT • Chronic alcohol use • ↑ GGT • ALP: other sources e.g. bone, prostate, placenta, kidney, GI tract • ALT • AST • ALP • GGT • Bilirubin

  32. Case • 50 year old man present to A&E with abdominal pain and jaundice • LFTs • ALP – 300 • Bilirubin – 40 • AST – 95 • ALT – 105 • First imaging test? Bilirubin: 3-17μmol/L ALP: 30-150 AST: 5-35 ALT: 5-35

  33. What do they mean? • HBsAg: acuteinfection • HBeAg: marker of chronicinfection • HbcAg: chronicinfection • Anti-HBs: immunityaftervaccinationoracuteinfection • Vaccinehasonlysurfaceantigen • Anti-HBcIgG: lifelong marker of past acuteorchronicinfection

  34. Hepatitis • 24 year old gentleman returns from a year of travelling, feeling generally unwell. • Hep B surface antigen: negative • Hep B surface antibody: positive • Hep B core antibody (IgG): negative • Hep B core antibody (IgM): negative • Past infection • Acute infection • Chronic infection • Immunised • None of the above

  35. Hepatitis • 24 year old gentleman returns from a year of travelling, feeling generally unwell. • Hep B surface antigen: positive • Hep B surface antibody: negative • Hep B core antibody (IgG): negative • Hep B core antibody (IgM): positive • Past infection • Acute infection • Chronic infection • Immunised • None of the above

  36. Questions • 60 year old male with known gallstones, presents with jaundice • ALP – 400, ALT – 600 • ALP – 500, ALT – 20 • ALP – 500, ALT – 120 • ALP – 40, ALT – 600 • ALP – 40, ALT – 30 Bilirubin: 3-17μmol/L ALP: 30-150 AST: 5-35 ALT: 5-35

  37. Questions • 24 year old male presents following an overdose of paracetamol • ALP – 400, ALT – 600 • ALP – 500, ALT – 20 • ALP – 500, ALT – 120 • ALP – 40, ALT – 600 • ALP – 40, ALT – 30 Bilirubin: 3-17μmol/L ALP: 30-150 AST: 5-35 ALT: 5-35

  38. Questions • Asymptomatic 24 year old male with bilirubin of 40. His cousin has the same condition • ALP – 400, ALT – 600 • ALP – 500, ALT – 20 • ALP – 500, ALT – 120 • ALP – 40, ALT – 600 • ALP – 40, ALT – 30 Bilirubin: 3-17μmol/L ALP: 30-150 AST: 5-35 ALT: 5-35

  39. Questions • 50 year old male, presents with jaundice, ALP 700, ALT – 200. USS shows no evidence of gallstones, no biliary tree dilatation • Next test(s)? Bilirubin: 3-17μmol/L ALP: 30-150 AST: 5-35 ALT: 5-35

  40. Acid-Base Physiology pH: 7.35-7.45 pO2: >10.6 kPa PCO2: 4.7-6.0 kPa Base Excess: ±2 mmol/L Bicarb: 24-30 • Look at pH -> determine acidosis/alkalosis • Look at CO2 -> determine if respiratory problem • Look at HCO3 -> determine if metabolic problem • Check for compensation • Partial if pH is not normal range. Complete if pH in normal range. Primary renal disturbance -> respiratory compensation Primary respiratory disturbance -> renal compensation

  41. Blood gases pH: 7.35-7.45 pO2: >10.6 kPa PCO2: 4.7-6.0 kPa Base Excess: ±2 mmol/L Bicarb: 24-30 • pO2 – 8 • pCO2 – 8 • pH – 7.24 • Bicarb - 25 • Lung injury/dysfunction • COPD • Aspiration • Fibrosis • Decreased ventilation • Neuromuscular disease • Anaesthetics/sedatives Respiratory acidosis

  42. Blood gases • PO2 – 11 • PCO2 – 5.6 • pH – 7.3 • Bicarb - 12 pH: 7.35-7.45 pO2: >10.6 kPa PCO2: 4.7-6.0 kPa Base Excess: ±2 mmol/L Bicarb: 24-30 • Increased H+ formation • Lactic acidosis • DKA • Decreased H+ excretion • Renal tubular acidosis (type 1 and 4) • Renal failure • Loss of bicarb • Diarrhoea • Ileostomy • Fistulae • Renal tubular acidosis (type 2) Metabolic acidosis

  43. Blood gases • PO2 – 11 • PCO2 – 3 • pH – 7.5 • Bicarb - 25 pH: 7.35-7.45 pO2: >10.6 kPa PCO2: 4.7-6.0 kPa Base Excess: ±2 mmol/L Bicarb: 24-30 • Increased ventilation • Anxiety/panic attack • PE • Severe anaemia • Respiratory stimulants (e.g. salicylates) Respiratory alkalosis

  44. Blood gases • PO2 – 11 • PCO2 – 4.8 • pH – 7.48 • Bicarb - 35 pH: 7.35-7.45 pO2: >10.6 kPa PCO2: 4.7-6.0 kPa Base Excess: ±2 mmol/L Bicarb: 24-30 • Vomiting • Pyloric stenosis • Hypokalemia • Inadequate intake • Increased excretion • Mineralocorticoid excess Metabolic alkalosis

  45. Acid-Base Physiology Reference: Costanzo, Physiology 6th Edition 2017

  46. Calculate the anion gap • Young woman admitted to A&E, drowsy, unable to give any history. Her friend is with her and says she was completely well yesterday and has no medical problems. pO2 - 11 pH – 7.50 pCO2 – 2.0 Bicarb – 12 pH: 7.35-7.45 pO2: >10.6 kPa PCO2: 4.7-6.0 kPa Base Excess: ±2 mmol/L Bicarb: 24-30 Respiratory alkalosis with metabolic compensation OR Mixed respiratory alkalosis with metabolic acidosis

  47. Calculate the anion gap Na - 140 K – 4.5 Cl – 106 Bicarb – 12 Glucose – 5.0 Urea – 8

  48. Calculate the anion gap • Anion gap = Cations – anions = (Na + K) – (HCO3 + Cl) • 140+4.5 – (106+12) = 26.5 Normal range – 14-18 KULT • Ketones • Uraemia • Lactate • Toxins • Methanol • Ethylene glycol • Aspirin

  49. Porphyria • 7 disorders • Neurovisceral • AIP • Skin • CEP • EPP - photosensitivity • PCT • NV + Skin • HCP • VP ALA synthase is the rate limiting step*

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