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Chemical Pathology 1 Dr Nicole James, BSc (Hons), MBBS (Dist.) Foundation Year 2 Doctor, Royal Berkshire Hospital NHS Trust 6 April 2023 Content 1. Sodium and fluid balance 2. Potassium 3. Calcium 4. Acid-base balance 5. Liver function tests Content 1. Sodium and fluid balance 2. Potassium 3. Calcium 4. Acid-base balance 5. Liver function tests Osmolality vs Osmolarity Osmolality = mOsm/kg of solvent • More accurate • Measured by automated lab machine OsmolaRity = mOsm/litRe of solvent • More practical • Calculated from blood tests Osmolar gap Calculated osmolality = 2 (Na + K) + glucose + urea = 275 – 295 mOsmol/kg Measured osmolality – calculated osmolality > 10mOsmol/kg Caused by other substances that are not part of the equation: • Alcohol: methanol, ethanol • Sugars: mannitol, sorbitol • Lipids: hypertriglyceridaemia • Proteins: hypergammaglobulinaemia Take home message 1 In practice, we are not bothered about the difference between osmolality and osmolarity. Sodium is the largest contributor to plasma osmolality. 2 (Na + K) + glucose + urea CPQ 1 Rank the expected calculated osmolality in patients with each of the following outcomes, with 1 being the highest osmolality and 5 being the lowest. Diabetes insipidus Diabetic ketoacidosis Hyperosmolar hyperglycaemic state Pneumonia SIADH CPQ 1 Rank the expected calculated osmolality in patients with each of the following outcomes, with 1 being the highest osmolality and 5 being the lowest. 1. Hyperosmolar hyperglycaemic state 2. Diabetic ketoacidosis 3. Diabetes insipidus 4. Pneumonia 5. SIADH Sodium regulation: Blood volume Increased blood volume à atrial stretch à increased release of atrial natriuretic peptide (ANP) Decreasing release of: • Aldosterone (adrenal cortex) • ADH (hypothalamus) • Renin (kidney) Hence decreasing sodium concentration and blood volume Sodium regulation: Osmolality High osmolality à thirst + ADH release à decrease sodium concentration Low osmolality à ADH suppression à increase sodium concentration Conflict in role of ADH in maintaining blood volume (increase if low) and osmolality (decrease if low) – volume more important Hyponatraemia Step 1 – Check plasma osmolality to exclude pseudohyponatraemia (low sodium with normal/high plasma osmolality) • Normal osmolality – high lipids, proteins • High osmolality – high sugars, alcohols True hyponatraemia Low sodium with low plasma osmolality All states of hyponatraemia are due to relative excess of water True hyponatraemia Step 2 – Assess volume status • BP, HR, CRT • Leg oedema • Pulmonary oedema Hypovolaemic hyponatraemia Hypovolaemic (low total body water) – appropriately high ADH Step 3 – Check urinary sodium for cause • If < 20 mmol/L = extra-renal loss (vomiting, diarrhoea, burns) • If > 20 mmol/L = renal loss (renal disease, diuretics, cerebral salt wasting) Management – treat underlying cause, IV 0.9% NaCl or slow IV hypertonic 3% NaCl Hypervolaemic hyponatraemia Hypervolaemic (high total body water) but low “effective arterial blood volume” • Reduced cardiac output: CCF • Increased peripheral arterial vasodilation: cirrhosis Step 3 – Check urinary sodium for cause • If < 20 mmol/L = CCF, cirrhosis, nephrotic syndrome • If > 20 mmol/L = CKD Management – treat underlying cause, fluid restrict Euvolaemic hyponatraemia Increased total body water relative to sodium Step 3 – Check urinary sodium for cause • If < 20 mmol/L = psychogenic polydipsia, tea and toast diet • If > 20 mmol/L = hypothyroidism, adrenal insufficiency, SIADH Management – treat underlying cause, fluid restrict, demeclocycline or tolvaptan for resistant SIADH Diagnosing SIADH Causes – brain, lung, pills Diagnosis of exclusion – check TFTs and cortisol levels first Diagnostic criteria • Low plasma sodium (< 135) • Low plasma osmolality (< 270) • High urinary sodium (> 20) • High urinary osmolality (> 100) • No adrenal/thyroid/renal dysfunctionHyponatraemia Take home message 2 Hyponatraemia is a water problem (low serum osmolality). Assess volume status and urinary sodium to distinguish between causes of hyponatraemia. SIADH is a diagnosis of exclusion. Hypernatraemia High sodium = high osmolality Assess volume status • Hypovolaemia – osmotic diuresis, diarrhoea, burns • Hypervolaemia – hypertonic 3% NaCl, hyperaldosteronism • Euvolaemia – diabetes insipidus Management – oral intake of water, slow IV 5% dextrose (1L/6hr) guided by urine output and plasma sodium Diabetes insipidus Central (lack of ADH) • Causes – pituitary surgery, irradiation, tumour, trauma • Management – desmopressin Nephrogenic (ADH resistance) • Causes – electrolyte disturbances (hypokalaemia, hypercalcaemia), drugs (lithium, demeclocycline) • Management – thiazides Diabetes insipidus Key investigations • Serum glucose – to exclude DM • Serum potassium – to exclude hypokalaemia • Serum calcium – to exclude hypercalcaemia • Plasma and urine osmolality • Water deprivation test Water deprivation test Urine concentrates after restriction = normal or primary polydipsia Urine concentrates after desmopressin = central DI Urine remains dilute after desmopressin = nephrogenic DI Diagnostic criteria for DI – despite raised plasma osmolality, urine is dilute with a urine:plasma osmolality of < 2:1 VSA 1 A 65 year old gentleman who is a long-term smoker presented with a 2-month history of cough, shortness of breath and weight loss. His examination is unremarkable. His investigation results are as follows: Na 128, K 4.0, adjusted Ca 2.4, urinary sodium 40, normal TSH and cortisol level. His CXR report is pending. What is the next best step in investigation? VSA 1 A 65 year old gentleman who is a long-term smoker presented with a 2-month history of cough, shortness of breath and weight loss. His examination is unremarkable. His investigation results are as follows: Na 128, K 4.0, adjusted Ca 2.4, urinary sodium 40, normal TSH and cortisol level. His CXR report is pending. What is the next best step in investigation? Paired serum and urine osmolalities Take home message 3 Hypernatraemia always means high osmolality. Diabetes insipidus is excluded if urine:plasma osmolality ratio is > 2:1. Content 1. Sodium and fluid balance 2. Potassium 3. Vitamin D and calcium 4. Acid-base balance 5. Liver function tests Hypokalaemia Key features – muscle weakness, cramps, hypotonia ECG features – flattened/inverted T wave, prominent U wave, prolonged PR interval, ST depression Causes – increased loss, increased cellular influx, decreased intake Hypokalaemia Increased potassium loss • GI loss – diarrhoea, vomiting, high output stoma • Renal loss – Conn’s syndrome, diuretics, congenital defects (Bartter and Gitelman syndromes) Increased cellular influx – insulin, beta agonists, refeeding syndrome, metabolic alkalosis In all cases – cause metabolic alkalosis • If acidosis – consider renal tubular acidosis, partially treated DKA Hypokalaemia Key investigations • Serum magnesium – correct if low • Aldosterone:renin ratio (if concomitant high BP) Management • Mild to moderate (2.5 – 3.5 mmol/L) – Oral Sando-K • Severe (< 2.5 mmol/L) – 10 mmol/hour IV KCl, continuous ECG monitoring • Daily U&Es in all cases Hyperkalaemia ECG features – tall tented T wave, small P wave, widened QRS, prolonged PR interval, sine wave Causes – artefact, iatrogenic, reduced excretion, increased cellular release Hyperkalaemia Artefact – haemolysis Iatrogenic – massive blood transfusion, excessive K+ therapy Reduced excretion – renal disease, aldosterone deficiency, drugs (potassium-sparing diuretics, ACEi, ARB) Increased cellular release – metabolic acidosis, tissue breakdown Hyperkalaemia Key investigations • Renal function – urea, creatinine, eGFR • Cortisol level or short SynACTHen test • Creatine kinase Management – treat if ECG changes or K+ > 6.5 mmol/L • IV calcium gluconate • IV insulin with dextrose • Consider: salbutamol, potassium binders, dialysis Take home message 4 If potassium is low, remember to check magnesium level. If potassium is unexpectedly high, repeat blood test before treating. SBA 1 A 50 year old gentleman with known hypertension attends an annual review at his GP. He takes ramipril 10mg OD. His BP is 138/78. He is asymptomatic and feels well. His blood test results are as follows: Na 139, K 6.8, urea 5.0, Cr 90, eGFR 88. What is the most appropriate immediate action? A. Add indapamide B. Advise low potassium diet C. Change ramipril to amlodipine D. Reduce dose of ramipril E. Repeat urea and electrolytes SBA 1 A 50 year old gentleman with known hypertension attends an annual review at his GP. He takes ramipril 10mg OD. His BP is 138/78. He is asymptomatic and feels well. His blood test results are as follows: Na 139, K 6.8, urea 5.0, Cr 90, eGFR 88. What is the most appropriate immediate action? A. Add indapamide B. Advise low potassium diet C. Change ramipril to amlodipine D. Reduce dose of ramipril E. Repeat urea and electrolytes VSA 2 A patient has had hypertension at a young age and the following blood test results on his U&Es: Na 147, K 3.2, urea 5.0, Cr 70. What is the next best investigation to confirm the likely diagnosis? VSA 2 A patient has had hypertension at a young age and the following blood test results on his U&Es: Na 147, K 3.2, urea 5.0, Cr 70. What is the next best investigation to confirm the likely diagnosis? Aldosterone:renin ratio Content 1. Sodium and fluid balance 2. Potassium and renal physiology 3. Vitamin D and calcium 4. Acid-base balance 5. Liver function tests Calcium homeostasis Bone – 99% Serum – 1% • Free, ionised, biologically active – 50% • Bound to albumin – 40% • Complexed with citrate/phosphate – 10% Calcium homeostasis Parathyroid hormone Calcitonin Increase serum calcium Decrease serum phosphate Decrease serum calcium Increase serum phosphate Bone resorption by osteoclasts (via Increased Ca Less bone reabsorption in gut Decreased Ca osteoblasts)* reabsorption by reabsorption in gut osteoclasts Less PO4 reabsorption at PCT More Ca reabsorption at DCT Decreased Ca reabsorption at DCT Calcitriol Hypocalcaemia Symptoms/signs – paraesthesia (peri-oral), arrhythmia (long QT), convulsions, tetany (Trousseau’s sign), spasm (Chvostek’s sign) Causes • Hypoparathyroidism – DiGeorge (primary), post- thyroidectomy (secondary), low magnesium • Vitamin D deficiency Hypocalcaemia Investigations – ECG (bedside), bloods (Mg, phosphate, PTH level, ALP), imaging (consider DEXA if # history) Management • Mild (> 1.9 mmol/L, no Sx) – Oral calcium, vitamin D supplement • Severe (< 1.9 mmol/L, Sx present) – IV calcium gluconate Hypercalcaemia Symptoms/signs – renal stones, bone pain, abdominal pain, constipation, polyuria/dipsia, depression Causes • Low PTH – malignancy (PTHrP, bony mets, multiple myeloma), hyperthyroidism, hypoadrenalism, sarcoidosis, thiazides, vitamin D excess • Raised PTH – primary and tertiary hyperparathyroidism »How to differentiate – late-stage CKD in tertiary »Suspect MEN1 and 2a syndrome if primary Hypercalcaemia Investigations – myeloma screen, TFTs, cortisol level Management • Acute: IV 0.9% NaCl +/- diuretics • Medical: Bisphosphonates (malignant hypercalcaemia), cinacalcet • Surgical: Parathyroidectomy if parathyroid adenoma Other conditions Paget’s disease – abnormal bone remodelling • Isolated raised ALP Osteoporosis – reduced bone density • Normal Ca, phosphate, PTH CPQ 2 Rank the plasma calcium concentration in the following conditions, with 1 bring the lowest and 5 being the highest. Primary hyperparathyroidism Secondary hyperparathyroidism Osteoporosis Osteomalacia Parathyroid carcinoma CPQ 2 Rank the plasma calcium concentration in the following conditions, with 1 bring the lowest and 5 being the highest. 1. Osteomalacia 2. Secondary hyperparathyroidism 3. Osteoporosis 4. Primary hyperparathyroidism 5. Parathyroid carcinoma VSA 3 Which enzyme is raised in Paget’s disease and osteomalacia and is caused by osteoblast activation? VSA 3 Which enzyme is raised in Paget’s disease and osteomalacia and is caused by osteoblast activation? Alkaline phosphatase (ALP) Take home message 5 The commonest cause of hypercalcaemia in the community is a parathyroid adenoma. Management of hypercalcaemia in the acute setting is fluids, fluids, fluids. Commonest cancers that can metastasise to the bone are prostate, breast, lung. Content 1. Sodium and fluid balance 2. Potassium and renal physiology 3. Vitamin D and calcium 4. Acid-base balance 5. Liver function tests Interpreting blood gases Step 1 – What is the pH? Step 2 – Is carbon dioxide driving the change? • Acidosis, raised = respiratory • Alkalosis, low = respiratory • Alkalosis, raised = compensation for metabolic alkalosis • Acidosis, low = compensation for metabolic acidosis Step 3 – Is bicarbonate driving the change? Step 4 – Is there compensation? pH 7.35-7.45 • pH within normal range = complete PCO 4.7-6.0 kPa Base excess ±2 mmol/L • pH outside normal range = partial Bicarbonate 24-30Interpreting blood gases pH 7.35-7.45 pO >10.6 kPa PCO 4.7-6.0 kPa 2 Base excess ±2 mmol/L Bicarbonate 24-30Interpreting blood gases pH 7.35-7.45 pO >10.6 kPa PCO 4.7-6.0 kPa 2 Base excess ±2 mmol/L Bicarbonate 24-30Interpreting blood gases pH 7.35-7.45 pO >10.6 kPa PCO 4.7-6.0 kPa 2 Base excess ±2 mmol/L Bicarbonate 24-30 Anion gap Useful for differentiating between equivocal gas results. Example: 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. pH – 7.50 pCO2 – 2.0 Respiratory alkalosis with metabolic compensation pO2 – 11 OR Bicarbonate – 12 Mixed respiratory alkalosis with metabolic acidosis Anion gap Anion gap = Cations – anions = (Na + K) – (HCO3 + Cl) Normal = 14 – 18 mmol/L If raised, think about presence of exogenous substances. Take home message 6 Always check the source of the blood gas – arterial or venous. Always check level of oxygenation – will affect interpretation blood gas values. Content 1. Sodium and fluid balance 2. Potassium and renal physiology 3. Vitamin D and calcium 4. Acid-base balance 5. Liver function tests Liver function tests Markers of function • Clotting – PT/INR • Albumin • Bilirubin Markers of damage • Bilirubin • ALT, AST • GGT • ALP Jaundice Prehepatic – haemolytic anaemia, ineffective erythropoiesis • Key – absent conjugated bilirubin, absent urine bilirubin Hepatic – hepatocellular dysfunction, impaired conjugation, impaired bilirubin uptake Post-hepatic (obstruction) – stones, pancreatic cancer • Key – dark urine (raised urobilinogen), pale stool (low stercobilinogen) Raised ALT and AST Raised AST:ALT > 2:1 – alcoholic hepatitis Raised AST:ALT < 1:1 – viral hepatitis ALT/AST in the 1000s – acute viral hepatitis, ischaemic hit, toxins Raised bilirubin Unconjugated • Increased haemolysis – extravascular (spherocytosis), intravascular (haemoglobinuria) • Impaired hepatic uptake – drugs (contrast, rifampicin) • Impaired conjugation – Gilbert’s syndrome (deficiency of UDP- glucuronyl transferase), Crigler-Najjar syndrome (absolute deficiency) Conjugated • Hepatocellular dysfunction – congenital, infections, toxins, autoimmune, neoplasm, vascular • Decreased hepatic excretion – congenital (Dubin-Johnson, Rotor syndrome) Raised ALP Other sources of ALP – bone, placenta, GI tract, kidney, prostate Isolated raised ALP • Physiological – pregnancy, childhood (growth spurt) • Pathological Raised GGT and ALP • Obstructive (cholestasis) – gallstones, drugs (co- amoxiclav, OCP, sulphonylurea) • Alcoholic hepatitis Deranged LFTs AST/ALT Clotting Albumin ALP/GGT Cirrhosis Normal INR raised Low Normal (Raised in (Raised in acute acute decompensation) decompensati on) Acute liver Raised + + INR raised May be Raised ++ failure normal Cholestasis Raised + Normal Normal Raised ++ Alcohol Raised + Unaffected Unaffected Raised ++ [Mainly abuse GGT] Take home message 7 The best marker of liver function in acute liver injury is prothrombin time. If a patient has raised ALP, check GGT to ensure it is a biliary source. Resources Revision • Pathology Course Lecture Slides • MedEd Path Guide • MedEd Lecture Series Practice questions • Past paper questions • MedGEMS – for VSA (https://medgems.marstonhillier.com) • SBAs and EMQs in Clinical Pathology by Sukhpreet Singh Dubb • Blackboard quizzes Thank you for your attention. Questions? Email: nicole.james@royalberkshire.nhs.uk Please fill in feedback.