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Recommended Reading Lecture Notes in Clinical Biochemistry 7 th Edition G Beckett, S Walker, P Rae, P Ashby (Blackwell publishing) Clinical Chemistry 6.

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Presentation on theme: "Recommended Reading Lecture Notes in Clinical Biochemistry 7 th Edition G Beckett, S Walker, P Rae, P Ashby (Blackwell publishing) Clinical Chemistry 6."— Presentation transcript:

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

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

3 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) Illustrative case History

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 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 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 GP requested imaging studies in view of negative blood tests

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 Unconjugated - prehepatic *(No bilirubinuria) Haemolyis Resolving haematoma Gilbert’s Syndrome Crigler-Najjar syndrome Conjugated – Hepatic/posthepatic (Bilirubinuria) Hepatocellular diseases Cholestatic diseases Dubin-Johnson** Rotor’s syndrome** *Except in Nephrotic syndrome **Benign congenital conjugated hyeprbilirubinaemia

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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 Normal Still Elevated 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 ? Muscle problem

22 Causes of a Cholestatic Pattern of LFTs Elevated ALP and GGT ± Bilirubin, relative to transaminases Intrahepatic (Bilirubin not elevated) Medications TPN Sepsis Postoperative PBC Alcoholic hepatitis Liver mets Pregnancy-related CCF Extrahepatic (Bilirubin elevated) Cholelithiasis (CBD) Malignancy – HOP, Primary sclerosing cholangitis 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 What is GGT? Normal ?bone, placenta, Intestine etc. Elevated US/CT/MRI Biliary dilation Focal mass No abnormality Medications PBC -AMA Consider other causes 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 g/L Bilirubin <17 umol/L ALP* IU/L* AST 7-40 IU/L ALT 7-35 IU/L GGT10-55 IU/L * NB: Reference Range is age related

26 24 yr old male Insurance medical showed abnormal LFTs ? Cause Albumin42 (35-50 g/L) Bilirubin38 (<17 umol/L) ALP98 ( IU/L) AST30 (7-40 IU/L) ALT28 (7-35 IU/L) GGT37 (10-55 IU/L) What further tests are indicated? What is the most likely cause of raised Bilirubin? Case 1

27 35 yr old female with a 4/52 hx of -malaise, anorexia, upr abdominal pain, ?haematuria -O/E Icteric Alb35 Bilirubin126 ALP250 (40-120) AST1459 ALT2009 GGT331 What further investigations are indicated? What fraction of her bilirubin is elevated and how does this impact on her “haematuria”? Case 2

28 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” Alb46 Bilirubin12 ALP220 (40-120) AST20 ALT20 GGT9 What is the likely cause for the elevated ALP? Which isoenzyme is increased? Case 3

29 48yr old female is attending a lipid-clinic -polygenic hypercholesterolaemia -On atorvastatin 20mg/d for 2 years -C/o tired fatigue, malaise Alb42 TBilirubin8 ALP250 (40-120) AST38 ALT26 GGT220 LFTs measured 6/12 previously were normal What further investigations would you perform? What is the differential diagnosis? Case 4

30 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 Glucose6.8 mmol/L Alb38 TBili15 ALP82 AST58 ALT72 GGT67 (<55) What further investigations would you suggest and why? Case 5

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 28/43/5 Alb (35-50)39 Tbili (3-17)106 AST (7-40) ALT (7-35)95 Alk Phos (40-120) GGT (5-40) LDH ( ) 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 47 yr old male Hx – malaise and ?icterus (confirmed in sclera) No recent hx C2H5OH excess or medication 6/512/5 Alb4543 TBili Alk Phos GGT AST34475 ALT707

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

36 Case 8 24 yr old male -Vague hx of feeling unwell, also wt loss >7Kg -? Eating disorder/psychiatric illness 7/34/4 Alb5150 Tbili (3-17)9348 Conj Bili9 Alk Phos7484 GGT1418 AST2523

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 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 Homozygous mutant 2.Heterozygous 3.Wild type (normal) 1.Homozygous mutant 2.Heterozygous 3.Wild type (normal)

49 Case Example : Haemochromatosis 51yr old male Total protein71 Total Bilirubin14 Alk Phos82 GGT39 AST44 ALT92 Serum Fe38 TIBC41 Transferrin sat93% Ferritin1,316 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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