Chemical PathologyNotes

Fluid Balance

- ⅔ INTRACELLULAR

- ⅓ EXTRACELLULAR

Electrolytes

Cations

  • Intracellular = K+ (3.5 - 5)
  • Extracellular = Na+ (135 - 145)

Anions

  • Intracellular = protein and phosphate
  • Extracellular = Cl- and HCO3- (22 -26)

Osmolality

“Total number of solute particles in solvent”(280-295 mosmol/l)

Calculated Plasma osmolality = 2([Na+] +[K+]) + urea +glucose

Osmolar Gap(<10) = Measured osmolality – calculated osmolality

Anion Gap (~ 18 mmol) = Na + K - Cl - Bicarbonate

Key controllers of ECF

Extra-renal System

  • Stimulated by:
  • Osmoreceptors
  • Baroreceptors (low volume)
  • Action by:
  • Thirst
  • Anti-diuretic hormone from posterior pituitary
  • ANF (reduced sensitivity of osmoreceptors, RAA antagonism)

Intra-renal System

  • Stimulated by:
  • Reduced renal perfusion
  • Action by:
  • Renin-angiotensin-aldosterone system (positive)
  • ANF (negative)

Too much fluid

  • Increased intake (rarely a problem)
  • Increased/inappropriate sodium reabsorption
  • Cardiac failure
  • Nephrotic syndrome
  • Reduced excretion
  • Renal failure
  • Nephritic syndrome

Too little fluid

  • Inadequate intake (during illness)
  • Distribution problem
  • Sepsis
  • 3rd spacing
  • Excess loss
  • Fluids (gut, kidneys, skin, respiratory)
  • Blood (internal vs. external)

Sx

  • Confusion/coma
  • Cool hands
  • Cap. Refill
  • Tachycardia
  • Tachypnoea
  • BP/postural drop
  • JVP
  • Sunken eyes
  • Dry mouth
  • Lungs clear
  • Urine output (< 30ml/hr)
  • No oedema

Tx

Types / Contents
CRYSTALLOIDS
- electrolytes in water / Normal saline / 154 mmol Na+ in 1L
Dextrose saline / 30 mmol/l Na+ + 40g dextrose
5% dextrose / 50g dextrose in IL
Hartmannʼs / Anions + Cations + Ca + lactate
COLLOIDS
- fluids with high molecular
weight molecules / Natural (e.g. blood, albumin)
Synthetic (e.g. Gelofusin, Haemaccel) / Dextran compounds

Electrolyte Disorders

Hyponatraemia

  • Na+ < 135 mmol/l

Serum sodium(mmol/l) / Features
130-135 / Asymptomatic
125-130 / MILD - N/V, mild disorientation
115-125 / MODERATE - confusional state
<115 / SEVERE - seizures/coma
Hypovolaemia / Normovolaemia / Hypervolaemia
Cause / Renal / Non-renal / Renal / Non-renal
Adrenalfailure
(Addisons)
Diuretics / Vomiting Diarrhoea
Skin loss / SIADH / ARF/CRF / Cardiac Failure
Cirrhosis
Nephrotic syndrome
Inappropriate IV fluid
U. Na+(mmol/l) / >20 / <10 / >20 / >20 / <10

Syndrome of Inappropriate ADH

  • Malignancy
  • Small cell malignancies (lung, pancreas, lymphoma)
  • Lung pathology
  • TB, pneumonia, abscess
  • CNS pathology
  • Infections, bleeds
  • Drugs (carbamezapine, chlorpropramide, cyclophosphamide, ectasy (MDMA))

Sx

  • ↓ [Na]
  • Euvolaemia
  • ↓osmolality
  • ↑urinary [Na]
  • No other cause (diagnosis of exclusion)

Hypernatraemia

  • Insufficient fluid intake
  • Water loss increased relative to sodium loss
  • DI (low urine osmolality)
  • Osmotic diuresis (high urine osmolality)
  • Primary aldosteronism

Hypokalaemia

  • Reduced intake (rare)
  • Cellular uptake
  • Insulin, alkalosis
  • Increased loss (common)
  • Gut (diarrhoea, vomiting, fistulae)
  • Kidneys (↑mineralocorticoid, diuretics, RTA 1 & 2)

Sx:

  • Generally asymptomatic
  • Muscle weakness
  • Reduced gut motility
  • Cardiac arrhythmias

Hyperkalaemia

  • Increased intake (rare)
  • Cellular loss
  • Acidosis, severe haemolysis/rhabdomyolysis
  • Decreased loss
  • Renal failure
  • Decreased mineralocorticoids (RTA 4)
  • Potassium sparing diuretics + NSAIDs + ACEi

Sx:

  • Cardiac arrest
  • Muscle weakness
  • Paraesthesiae

Tx

  • Stabilise the myocardium
  • 10ml 10% calcium gluconate
  • Drive K into the cells
  • 10u insulin + 50ml 50% dextrose
  • Salbutamol
  • Mop up K
  • Calcium resonium, haemofiltration

Calcium

  • Serum calcium: 2.2-2.6 mmol/l

Hypocalcaemia

Ca < 2.2 mmol/l

Causes:

  • Parathyroid removal
  • Vit. D deficiency
  • Renal disease

Diagnosis

  • U&Es - ? Renal disease
  • Serum PTH

Clinical features:

  • Asymptomatic
  • Perioralparaesthesia
  • Trousseau’s sign,
  • Chvostek’s sign
  • Prolonged QT
  • Cataract (chronic)

Treatment

  • Mild
  • Calcium supplements
  • In renal failure
  • Alphacalcidol
  • Severe
  • Calcium gluconate infusion

Hypercalcaemia

Ca > 2.6mmol/l

Causes:

  • 1° Hyperparathyroidism
  • Myeloma
  • Bony mets
  • PTH-related protein
  • Granulomatous disease (TB, sarcoid)
  • Vit. D intoxication
  • Diuretic therapy
  • Tertiary hyperparathyroidism
  • Milk-alkali syndrome

Sx:

  • Asymptomatic
  • Osteitisfibrosacystica
  • Nephrogenic DI (thirst, polyuria etc)
  • Renal stones
  • Abdominal symptoms (vomit, constipation, pain)
  • Weakness
  • Fatigue
  • Confusion

Treatment

3.5 = MEDICAL EMERGENCY

  • Fluids (0.9% normal saline) - promote diuresis
  • Bisphosphonate- inhibit further bone resorption
  • Others: surgery, steroid for sarcoid

Acid-base balance

Normal range
pH / 7.35 - 7.45
pCO2 / 4.5 - 6
pO2 / 11-14
HCO- / 22 - 26
Base excess / -2 to +2

Metabolic Acidosis

↑[H+]= pCO2

↓[HCO-]

Respiratory Acidosis

↑[H+]= ↑pCO2

[HCO-]

Metabolic Alkalosis

↓[H+]= pCO2

↑[HCO-]

Respiratory Alkalosis

↓[H+]= ↓pCO2

[HCO-]

Hydrogen ions are buffered by:

BicarbonateH++HCO3- ↔ H2CO3

HaemoglobinH+ + Hb- ↔ HHb

Phosphate H++HPO4- ↔ H2PO4

Renal Function Tests

GFR

  • “Volume of unit plasma that can be completely cleared of marker substance per unit time.”
  • Normal = 60 - 120 ml/min
  • Varies considerably (1ml/min per year)

Urine Microscopy

  • White blood cells
  • Infection
  • Sterile pyuria - partially treated UTI or stone/tumour
  • Bacteria
  • Infection
  • Hyaline casts (normal mucoprotein)
  • Healthy
  • Red cell casts
  • Glomerulonephritis/severe tubular damage
  • White cell casts
  • Pyelonephritis/glomerulonephritis
  • Crystals
  • Calcium oxalate (75%) - spikey and radio-opaque [metabolic/idiopathic]
  • Triple phosphate (17%) - large, radio-opaque may form staghorn calculus[proteusUTIs]
  • Uric acid (5%) - smooth, brown, radio-lucent [hyperuricaemia]
  • Hydroxyapatite(1%)
  • Cysteine(1%) - yellow, crystalline, semi-opaqe[renal tubular defects, cystinuria]

Liver Function Tests

Test / Normal Values / Abnormalities
Bilirubin (total) / 5 – 17 mol/L
Direct Bilirubin (conjugated) / < 5 umol/L
Alkaline phosphatase / 35 – 130 iu/L / ↑ with choleostasis
Aspartatetransaminase / 5 – 40 iu/L / ↑when hepatocytes die (ischaemia, toxins, viruses)
Alaninetransaminase / 5 – 40 iu/L
Albumin / 35 – 50 g/L / ↓in sepsis, malnutrition, chronic LD
-glutamyl transpeptidase / 10 – 48 iu/L / ↑ with ETOH & phenytoin
Albumin / 35 – 50 g/L
-globulin / 5 – 15 g/L
Prothrombin time / 12-16 seconds

Congenital Syndromes

Condition / Inheritance / Deficiency / Presentation
Crigler- Najjar / AR / Bilirubin metabolism (UGT1A1) / Hyperbilirubinaemia
+/- Kernicterus
Gilbert’s / Variable / ↓glucoronyltransferase activity / ↑bilirubin
N. liver chemistry
Dubin-Johnson / AR / Defective anionic conjugate transfer / Asymptomatic/no abnormal LFTs
Rotor (D-J subtype) / AR / Unknown / ↑Urine coproporphyrin
Unpigmented liver

Uric acid metabolism

  • Plasma concentrations.
  • Men 0.12 – 0.42 mmol/l
  • Women 0.12 – 0.36 mmol/l

Gout

  • Monosodium urate crystals
  • Men>women

Clinical features

  • Exquisite pain
  • Red, hot and swollen joint
  • 1st MTP joint is classical

Diagnosis

  • Negatively birefringent crystals

Treatment

  • NSAIDS are the first line treatment acutely
  • Colchicine lowers urate levels
  • Allopurinol for chronic episodes

Pseudogout

  • Pyrophosphate crystals
  • Self limiting 1 – 3 weeks
  • Positively brefringent crystals

Endocrine Investigations

Condition / Causes / Diagnosis
Cushing’s Syndrome (↑Cortisol) / Pituitary (Micro/macroadenoma)
Adrenals (Adenoma/carcinoma)
Malignancy
Exogenous steroids / Midnight plasma cortisol
Low dose DEXA test
Salivary cortisol
Urinary free cortisol
Conn’s Syndrome (↑Aldosterone) / “Hyperfunction of aldosterone secreting cells”
Adenoma, carcinoma, hyperplasia / Plasma aldosterone↑
Plasma renin↓
Addison’s Disease (↓Cortisol) / Short Synacthen test
Thyroid Disease / TSH
T3
+/- thyroid autoantibodies

Protein Markers

Protein / Function / Information
CRP / Acute phase protein / Peaks at 48h
α-1 anti-trypsin / Prevents neutrophilelastase activation / ↓ in emphesema & cirrhosis
Transferrin / Plasma Fe Transport
Caeruloplasmin / Contains Cu
Mops-up superoxide radicals / Deficiency in Wilson’s disease
Ferritin / ↓ in IDA,
↑ in Fe overload & acute inflammation
Haptoglobin / ↓ in haemolysis
β2-microglobulin / MHC Class I component

Nutrition

Fat Soluble Vitamins

Deficiency / Excess / Test
A Retinol / Colour Blindness / Exfoliation Hepatitis / Serum
D Cholecalciferol / Osteomalacia/rickets / Hyper-calcaemia / Serum
E Tocopherol / Anaemia/neuropathy
?malignancy/IHD / Serum
K Phytomenadione / Defectiveclotting / PT

Water Soluble Vitamins

Deficiency / Excess / Test
B1 Thiamin / Beri-Beri, Neuropathy
Wernicke Syndrome / RBCtransketolase
B2 Riboflavin / Glossitis / RBC glutathionereductase
B6 Pyridoxine / Dermatitis/Anaemia / Neuropathy / RBC ASTactivation
B12 Cobalamin / Pernicious anaemia / Serum B12
C ascorbate / Scurvy / Renal stones / Plasma
Folate / MegaloblasticAnaemia
Neural tube defect / RBC, folate
Niacin / Pellagra

Trace Elements

Deficiency / Excess / Test
Iron / Hypochromic Anaemia / Haemochromatosis / FBC, Fe, Ferritin,
Iodine / Goitre Hypothyroid / TFT
Zinc / Dermatitis
Copper / Anaemia / Wilson’s / Cu, Caeroplasmin
Fluoride / Dental caries / Flourosis

Metabolic Disorders

Disorder(s) / Examples / Defect / Clinical characteristics
Amino acid disorders / Autosomal recessive defect in metabolism of single amino acid / PKU (↑ phenylalanine)
Homocystinuria (↑ / Failure to thrive
Seizures
Musty skin odour
Organic acidurias / Defective late metabolism ofsingle amino acid (usually
branched) / Methylmalonicacidaemia, Propionicacidaemia, Isovalericacidaemia, Maple syrup urine disease / Developmental delay
Organic acids in urine sample
Urea cycle defects / Deficiency of an enzyme involvedin the urea cycle → build up of
ammonia / 6 disorderse.g. arginaemia, citrullinemia / Encephalopathy
Irreversible neurological damage
Carbohydrate disorders / Alteration of carbohydratecycling in the cell / Lactose intolerance
Gycogen storage disorders / Hypoglycaemia
Lactic acidosis
Cataract formation
Liver/kidney problems
Peroxisomal disease / Disorders of lipid metabolismwhere there are empty cellpersoxisomes / Zellweger syndrome / Hypotonia
Seizures
Mitochondrial disease / Mutations in mitochondrial DNA.
Most serious when affectsmuscle, brain. / Mitocondrialmyopathies
e.g. diabetes mellitus anddeafness, Leber’s hereditaryoptic neuropathy / Lots
Lysosomal storage disorders / Various defects in lysosomalfunction that lead toaccumulation of toxicsubstances / Gauncher’s disease
Niemann-Pick disease
Tay-Sachs disease / Present late (adulthood)