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Recommended Reading Lecture Notes in Clinical Biochemistry 7th Edition

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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 ( ) 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 (20 – 60) mg/dl Transferrrin Saturation 34% (15 – 45) % PT 14.8 (11.5 – 15.0) s APTT 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 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


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

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

19 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

20 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

21 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 Drug Hx etc Viral serology AI hepatitis screen Fe/TIBC/Ferritin/HFE genotyping Caeuruloplasmin if < 40 yr A1AT Coeliac screen Ultrasound scan MRI/CT Bx

22 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

23 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 Medications Consider other causes PBC -AMA Specialised investigations

24 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”

25 Reference Ranges for LFTs Biochemistry Department, St James’s Hopsital
Albumin 35-50 g/L Bilirubin <17 umol/L ALP* IU/L* AST 7-40 IU/L ALT 7-35 IU/L GGT 10-55 IU/L * NB: Reference Range is age related

26 Case 1 24 yr old male Insurance medical showed abnormal LFTs ? Cause
Albumin 42 (35-50 g/L) Bilirubin 38 (<17 umol/L) ALP 98 ( IU/L) AST 30 (7-40 IU/L) ALT 28 (7-35 IU/L) GGT 37 (10-55 IU/L) What further tests are indicated? What is the most likely cause of raised Bilirubin?

27 Case 2 35 yr old female with a 4/52 hx of
malaise, anorexia, upr abdominal pain, ?haematuria O/E Icteric Alb 35 Bilirubin 126 ALP 250 (40-120) AST 1459 ALT 2009 GGT 331 What further investigations are indicated? What fraction of her bilirubin is elevated and how does this impact on her “haematuria”?

28 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” Alb 46 Bilirubin 12 ALP 220 (40-120) AST 20 ALT GGT 9 What is the likely cause for the elevated ALP? Which isoenzyme is increased?

29 Case 4 48yr old female is attending a lipid-clinic
polygenic hypercholesterolaemia On atorvastatin 20mg/d for 2 years C/o tired fatigue, malaise Alb 42 TBilirubin 8 ALP 250 (40-120) AST 38 ALT 26 GGT 220 LFTs measured 6/12 previously were normal What further investigations would you perform? What is the differential diagnosis?

30 Case 5 Fasting Glucose 6.8 mmol/L Alb 38 TBili 15 ALP 82 AST 58 ALT 72
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 Fasting Glucose 6.8 mmol/L Alb 38 TBili 15 ALP 82 AST 58 ALT 72 GGT 67 (<55) What further investigations would you suggest and why?

31 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

32 Case 6: LFTs 28/4 3/5 Alb (35-50) 39 Tbili (3-17) 10 6 AST (7-40) 113 106 ALT (7-35) 95 Alk Phos (40-120) 352 372 GGT (5-40) 874 930 LDH ( ) 426 495 CK (34-170) 82

33 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

34 Case 7: Background 6/5 12/5 Alb 45 43 TBili 181 242 Alk Phos 454 408
47 yr old male Hx – malaise and ?icterus (confirmed in sclera) No recent hx C2H5OH excess or medication 6/5 12/5 Alb 45 43 TBili 181 242 Alk Phos 454 408 GGT 813 428 AST 344 75 ALT 707

35 Case 7: Dx Predominant hepatitic picture Resolving to cholestatic LFTs Probable acute viral hepatitis

36 Case 8 7/3 4/4 Alb 51 50 Tbili (3-17) 93 48 Conj Bili 9 Alk Phos 74 84
24 yr old male Vague hx of feeling unwell, also wt loss >7Kg ? Eating disorder/psychiatric illness 7/3 4/4 Alb 51 50 Tbili (3-17) 93 48 Conj Bili 9 Alk Phos 74 84 GGT 14 18 AST 25 23

37 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

38 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

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

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

41 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

42 Paracetamol Overdose Hepatic necrosis observed within 36-72 hours
Accumulation of breakdown product NAPQI

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

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

45 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

46 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

47 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

48 Figure A C282Y H63D 1 2 3 1 2 3 Homozygous mutant Heterozygous
Homozygous mutant Heterozygous Wild type (normal) Homozygous mutant Heterozygous Wild type (normal)

49 Case Example : Haemochromatosis Total protein 71 Total Bilirubin 14
51yr old male Total protein 71 Total Bilirubin 14 Alk Phos 82 GGT 39 AST 44 ALT 92 Serum Fe 38 TIBC 41 Transferrin sat 93% Ferritin 1,316 HFE genotype C282Y homozygous –Hereditary Haemochromatosis

50 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

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