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  1. Recommended Reading Lecture Notes in Clinical Biochemistry 7th Edition G Beckett, S Walker, P Rae, P Ashby (Blackwell publishing) Clinical Chemistry 6th Edition W J Marshall, S K Bangert (Pubslished by Mosby) An illustrated Colour text - Clinical Biochmeistry 3rd edition Alan Gaw et al (Churchill Livingston) Handbook of Clinical biochmeistry 1st Edition R Swaminathan (Oxford University Press) Clinical Chemistry in diagnosis and treatment Philip Mayne (Edward Arnold) A Guide to Diagnostic Clinical Chemistry 3rd Edition Walmsely & White (Blackwell)

  2. Clinical Biochemistry of Liver Disease Dr Vivion Crowley Consultant Chemical Pathologist St James’s Hospital

  3. Illustrative case History • 75 yr old female presented to her GP • C/O dyspepsia and “back “ pain • Background hx: • Breast Ca – Rx with mastectomy, Tamoxifen • Variegate Porphyria • Type 2 Diabetes mellitus • Subclinical Hypothyroidism • GP requested Liver Function Tests (Liver Profile)

  4. Albumin 43 (34-48) g/L Total Bilirubin 7 (0 – 21) umol/L Alkaline Phosphatase 67 (35 -104) IU/L GGT 93 (5 – 36) IU/L Alanaine transaminase (ALT) 40 (6 – 31) IU/L

  5. In view of abnormal LFTs the GP ordered further investigations • Anti Smooth Muscle abs - neg • Anti Mitochondrial abs - neg • Alpha-1 Antitrypsin 1.5 (0.9 – 2.0) g/L • Caeuroloplasmin 26.2 (20 – 60) mg/dl • Transferrrin Saturation 34% (15 – 45) % • PT 14.8 (11.5 – 15.0) s • APTT 30.4 s (25 – 35) s

  6. GP requested imaging studies in view of negative blood tests Ultrasound of abdomen and pelvis • Liver • Diffuse inhomogenous somewhat echogenic texture • No focal lesion • Bile ducts not dilated CT scan of abdomen • Liver • Normal size • Subcapsular surface of the liver has a nodular outline • Liver texture has a diffuse slightly coarse appearance • Appearances consistent with Cirrhosis

  7. Learning Point • The only indicator for the presence of underlying cirrhosis in this patient were her mildly abnormal LFTs

  8. What are the functions of the liver? • Key role in intermediary metabolism • e.g. gluconeogenesis, glycolysis, ketogeneis, lipid synthesis • Protein synthesis – including many plasma proteins and blood • clotting factors • Bile secretion and role in digestion • Primary site of xenobiotic detoxification -drug and toxin metabolism • Ureagenesis - ? Role in acid-base balance

  9. What are Liver Function Tests (LFTs) • Total Bilirubin • Conjugated vs. Unconjugated • Anion transport • Alkaline Phosphatase (ALP) • -Reference range varies with age – higher in childhood • and adolescence • Isoenzymes e.g. bone, liver, intestine, malignancy • Bile flow • Gamma-glutamyl transferase (GGT) • -Sensitive indicator of liver disorder • -Cholestasis • -Induced by many drugs and toxins e.g. C2H5OH, • pheytoin, barbiturates, ? statins

  10. Transaminases • -Alanine aminotransferase (ALT) • -Aspartate aminotransferease (AST) • -ALT is more liver specific • -AST is also found in cardiac and skeletal muscle • -Hepatocellular integrity • Albumin • - Plasma transport protein • Assesses Protein synthesis in liver • Prothrombin time • Extrinsic pathway of coagulation • Reflects protein synthetic function

  11. What role do LFTs in clinical management ? • Detecting the presence of liver disease • Indicating the broad diagnostic category of the liver disease • Monitoring treatment

  12. Specialised Liver-related tests • Viral Hepatitis Screen – A, B, C etc. • Autoimmune Heaptitis screen – AMA, ASMA, • Serum protein electrophoresis • α1- antitrypsin • α fetoprotein (AFP) • Transferrin Saturation/Ferritin/HFE Genotyping • Caeruloplasmin, Plasma/Urine Copper • Ultrasound scan, CT, MRI • Biopsy

  13. Clinical History • C2H5OH Hx • Family Hx – Haemochromatosis, Wilson Disease, • Drug Hx – What medication is the patient taking? • Travel Hx – Recent travel, Blood transfusions

  14. Bilirubin production and metabolism UDP Glucoronosyl transferase

  15. Hyperbilirubinaemia • Jaundice evident with Bilirubin levels 35-70μmol/L • Normally 95% of plasma bilirubin is unconjugated • Conjugated – Hepatic/posthepatic • (Bilirubinuria) • Hepatocellular diseases • Cholestatic diseases • Dubin-Johnson** • Rotor’s syndrome** • Unconjugated - prehepatic • *(No bilirubinuria) • Haemolyis • Resolving haematoma • Gilbert’s Syndrome • Crigler-Najjar syndrome *Except in Nephrotic syndrome **Benign congenital conjugated hyeprbilirubinaemia

  16. Gilbert’s Syndrome • Present in 5% of the population • Males > females • Genetic origin • – insertion of TA in promoter region of UGT-1Agene • Exacerbated by fasting and illness • Confirm conjugated hyperbilirubinaemia • Rule out haemolysis FBC, Reticulocyte count • Rule out underlying liver disease -

  17. Causes of neonatal jaundice Unconjugated bilirubin level > 300μmol/L may be associated with Kernicterus (brain damage due to uptake of unconjugated bilirubin)

  18. Patterns of LFTs • Hepatocellular • Predominant elevation in AST/ALT – • Cholestatic • Predominant elevation in ALP with GGT ± Bilirubin • Mixed • Elevation in both AST/ALT, and ALP/GGT ± Bilirubin

  19. Causes of a Hepatocellular Pattern of LFTs • Marked elevations in ALT/AST > x5 URL • (patient likely to be symptomatic) • Viral hepatitis • Ischaemic hepatitis • Autoimmune hepatitis • Drug/toxins e.g. alcoholic hepatitis • Mild/Moderate elevations in ALT/AST < x5 URL • (patient may be asymptomatic) • Chronic Hepatitis • ALD • NAFLD/NASH – associated with obesity, T2DM, Hyerlipidaemia • Metabolic liver disease - HH, WD, A1AT • Drugs • Autoimmune LD

  20. Approach to an asymptomatic patient with elevated ALT/AST Elevated AST/ALT Repeat test ? Muscle problem Still Elevated Normal Check CK Elevated Normal Likely Liver Aetiology Viral serology AI hepatitis screen Fe/TIBC/Ferritin/HFE genotyping Caeuruloplasmin if < 40 yr A1AT Coeliac screen Drug Hx etc Ultrasound scan MRI/CT Bx

  21. Causes of a Cholestatic Pattern of LFTs Elevated ALP and GGT ± Bilirubin, relative to transaminases • Extrahepatic • (Bilirubin elevated) • Cholelithiasis (CBD) • Malignancy – HOP, • Primary sclerosing cholangitis • Intrahepatic • (Bilirubin not elevated) • Medications • TPN • Sepsis • Postoperative • PBC • Alcoholic hepatitis • Liver mets • Pregnancy-related • CCF GGT is useful in differentiating Liver as a cause of elevated ALP

  22. An approach to the patient with isolated elevation in ALP Elevated ALP Normal What is GGT? Elevated ?bone, placenta, Intestine etc. US/CT/MRI No abnormality Biliary dilation Focal mass Consider other causes Medications PBC -AMA Specialised investigations

  23. Other LFTs • Serum ammonia • used for investigation of hepatic encephalopathy • -lacks sensitivity and specificity • -useful for investigation of urea cycle disorders • Serum LDH • -included in LFTs in SJH • -5 isoenzymes – heart, erythrocytes, skel mus, liver, others • -not specific for liver - ? role in ischaemia-related abnormal LFTs • -useful in monitoring certain malignancies e.g. B-cell lymphoma • - “not really a LFT”

  24. Reference Ranges for LFTs Biochemistry Department, St James’s Hopsital * NB: Reference Range is age related

  25. Case 1 24 yr old male Insurance medical showed abnormal LFTs ? Cause What further tests are indicated? What is the most likely cause of raised Bilirubin?

  26. Case 2 • 35 yr old female with a 4/52 hx of • malaise, anorexia, upr abdominal pain, ?haematuria • O/E Icteric What further investigations are indicated? What fraction of her bilirubin is elevated and how does this impact on her “haematuria”?

  27. Case 3 You are phoned about the following results and asked to comment on the ALP which appears to be elavated? Pt is a 17 yr old male – clinical details “still growing” What is the likely cause for the elevated ALP? Which isoenzyme is increased?

  28. Case 4 • 48yr old female is attending a lipid-clinic • polygenic hypercholesterolaemia • On atorvastatin 20mg/d for 2 years • C/o tired fatigue, malaise LFTs measured 6/12 previously were normal What further investigations would you perform? What is the differential diagnosis?

  29. Case 5 • 37 yr old male is referred to a lipid clinic with ? Mixed hyperlipidaemia • (Chol 7.0 Trigs 5.2) • BMI 35, WC=120cm • Normotensive • Otherwise clinically well What further investigations would you suggest and why?

  30. Case 6: Background • Phonecall from a GP regarding LFTs • 72yr old female with discomfort in R hypochondrium • No other hx of note • Not on medications • No C2H5OH

  31. Case 6: LFTs

  32. Case 6: Further investigations • Mixed cholestatic and hepatocellular liver disease • Fe, TIBC, TS% - all normal • Hepatic Antibody screen – negative • Ultrasound of Upr Abdomen recommended • Gallstones diagnosed

  33. Case 7: Background • 47 yr old male • Hx – malaise and ?icterus (confirmed in sclera) • No recent hx C2H5OH excess or medication

  34. Case 7: Dx • Predominant hepatitic picture • Resolving to cholestatic LFTs • Probable acute viral hepatitis

  35. Case 8 • 24 yr old male • Vague hx of feeling unwell, also wt loss >7Kg • ? Eating disorder/psychiatric illness

  36. Case 8: Further Investigations • FBC and Reticuloctye count – normal • Viral Hep screen – normal • Hep antibody screen – normal • U/S – normal • Biochmeical Dx: • -unconjugated Hyeprbilirubinaemia (Gilbert’s syndrome) • -confirmed by genetics

  37. Case 9: Why the elevated LFTs? • 52 yr old male • No medical hx of note • Not on regular medications • Non-specific hx • Routine Bloods done by GP • “Family Hx IHD” written on request form

  38. Case 9: Results • Fasting Lipid and Glucose – unremarkable • AST = 243, LDH = 1525 (230-450) • GGT = 85 (10-55) other LFTs normal • GP surprised at the raised AST • ? Further investigations

  39. Case 9: Further Investigations • ALT = 50 (7-35) • CK 1191 (29-195) • CK-MBmass = 132 (<12) • CK-MB fractionation 10% (<6%)

  40. Case 9: Dx • GP practice contacted: • -Informed by Registrar that results were of concern • -needed to be communicated to GP • -1day later Consultant phoned to see if action had been taken • -Pt contacted and advised to present to A/E SJH • Troponin T = 3.25 (<0.01) • Acute Coronary Syndrome (Acute MI) • PTCA and stenting performed

  41. Paracetamol Overdose • Hepatic necrosis observed within 36-72 hours • Accumulation of breakdown product NAPQI

  42. Early diagnosis and treatment of paracetamol OD is essential • Ideally before 12 hours post ingestion • N-acetylcysteine (Parvolex) is an effective agent

  43. Iron Overload Syndromes • Primary: • Hereditary Haemochromatosis (HH) • Secondary: • Non HH Cirrhosis • Ineffective erythropoiesis – sideroblastic anaemia, Thalassaemia • Multiple transfusions • Bantu siderosis • Porphyria Cutanea Tarda (PCT)

  44. Hereditary Haemochromatosis • Autosomal recessive • Mutations in HFE gene • C282Y • H63D • 93% associated with homozygosity C282Y + • 6% associated with compound heterozygosity C282Y + H63D • 1% No mutations identified

  45. Clinical presentation of HH • Males > females • Usually in middle age • Clinical presentation caused by iron accumulation in • Liver – fatty change Cirrhosis • Pancreas – Diabetes • Heart – dilated cardiomyopathy • Joints – arthropathy • Pituitary – secondary hypogonadism (males > females0 • Testses – primary hypogonadism (rarer) • Parathyroid - hypocalceamia

  46. Diagnosis of HH • Increased Transferrin Saturation (Plasma Fe/TIBC) • 55% - genotype • 45-55% - may consider genotype • Increased Ferritin • HFE genotype • Liver Biopsy • Liver Iron content

  47. Figure A H63D C282Y 1 2 3 1 2 3 • Homozygous mutant • Heterozygous • Wild type (normal) • Homozygous mutant • Heterozygous • Wild type (normal)

  48. Case Example : Haemochromatosis 51yr old male HFE genotype C282Y homozygous –Hereditary Haemochromatosis

  49. Wilson disease • Autosomal recessive • Associated with mutations in ATP7B • (Cu transporting P type ATPase) • Clinical presentation – Children and adults usually < 40 years • CNS – extrapyramidal system, Kayser-Fleischer rings in cornea • Liver – fatty liver, cirrhosis,acute fulminant hepatic failure • Kidney, Haemolytic anaemia • Dx: • Low plasma caeruloplasmin • Increased Urinary Cu excretion (Penicillamine Challenge Test) • Liver Bx – measure Cu content