2 Liver PhysiologyWhat are LFT’sRole of LFT’s in investigation of Liver DiseaseInvestigation of abnormal LFTCase studies
3 Major functions of liver Carbohydrate MetabolismFat MetabolismProtein MetabolismHormone MetabolismRemoval of endogenous and exogenous wasteproductsStorageMetabolism and excretion of bilirubin
4 Liver Physiology6 segments, each with own branch of hepatic artery, portal vein andbile ductMetabolic activity occurs within parenchymal cells.80% of organ massRemarkable reserve and Ig functional reserve
6 What are LFT’s? No standard LFT profile Basildon use – -Total protein - Albumin- Total Bilirubin- Alkaline phosphatase (ALP)- Alanine aminotransferase (ALT)Do standard ‘LFT’ assess liver capacity to performnormal function
7 What are LFT’s? Other biochemical LFT options Total protein Conjugated bilirubinGamma glutamyl transferase (GGT)Aspartate aminotransferase (AST)
8 Normal Ranges Total Protein 60 – 80g/l Total Bilirubin <20µmol/l ALT 5 – 40IU/lALP 30 – 130IU/lAlbumin – 50g/l
9 Laboratory Investigations DiagnosisPrognosisMonitoringScreeningNo single lab test currently exists which:Provides answers to the aboveProvides a quantitative assessment of functioning liver capacityUse of combination of standard LFT’s and serial monitoring enhances clinical utility
10 Aminotransferase ALT and AST Intracellular enzymes ↑ plasma enzymes activity due to leakage from damaged or necrotic hepatocytesNot liver specific – wide tissue distribution, heart, musclePlasma activities of AST and ALT are sensitive indicators of hepatocyte damage due to toxins and viruses but are not specific for liver pathology
11 AST- 2 genetically distinct isoenzymes exist;mitochondrial AST (80%) and cystolic AST (20%)- Mild tissue injury results in predominately cystolicreleaseALT- cystolic enzymes- shows greater liver specificity than AST- Majority of liver disease ALT elevated to agreater degree
12 Abnormal ALT in asymptomatic patients Is it abnormal?Alcohol abuse (GT useful)DrugsAntibiotics - penicillins, ciprofloxacin etc.AED’s - phenytoin, carbamazepineStatinsNSAID’sSulphonylureas - glipizideHerbs, homeopathic Rx - ephedra, sennaDrugs of abuse - steroids, cocaine, MDMA, glues
13 Abnormal ALT in asymptomatic patients Chronic hepatitishepatitis C, BAutoimmune hepatitisraised globulin (80%) on electrophoresisauto-antibody tests (ANA)Haemochromatosistransferrin saturation (>45%)Coeliac diseaseWilson’s disease (<40 yrs)caeruloplasmin (85%), Kaiser-Fleischer ringsAlpha1-antitrypsin deficiency
14 Alkaline Phosphatase Membrane bound enzyme Family of isoenzymes and isoformsPresent in many tissues
15 Alkaline PhosphatasePlasma ALP levels are increased further by the solubilisation of membrane bound enzyme due to the detergent action of bile acidsPlasma ALP is a sensitive indicator of Choleostasis but is non-specific for liver pathology
16 Alkaline PhosphataseProduced by the biliary tract at all levels from the canalculi to the mucosa of the gall bladderInvolved in metabolic transport across cell membraneObstruction to bile flow or secretion results in enzyme induction with increased mucosal synthesis of ALP
17 Alkaline Phosphatase Liver or bone? (pregnancy, adolescence) GT useful to exclude liverAge related changesincrease (particularly women) between 40 and 65 yrsIf persistent raised ALP of liver originPrimary biliary cirrhosisanti-mitochrondrial antibodiesUltrasonography
18 GT – Gamma Glutamyl Transferase Membrane bound, wide tissue distribution; liver, kidney and pancreasElevated plasma activity results from solubilisation of bound enzyme by bile salts, cell necrosis and altered membrane permeabilitySlightly more sensitive than ALP in Obstructive Liver Disease
19 GTSynthesis induced by drugs such as DPH, BARBS, Tricyclics and ETOH in absence of liver pathologySensitive indicator of liver disease but will differ hepatocellular from choleostatic diseaseAn increase GT activity can confirm an increase ALP activity as being liver in origin
20 GT Very sensitive for hepatobiliary disease Poor specificity pancreatic disease, AMI, renal failure, diabetes, COPD, alcoholismAlcohol abuse – poor markerReported sensitivity %Best used to evaluate rises in other LFT’s
21 Albumin Index of hepatic synthetic function Low ALB often accompanies chronic liver diseaseMay not indicate reduced synthesis
22 AlbuminPlasma ALB also affected by nutritional stasis, leakage into ascites, renal losses and dilation due to fluid retentionProthrombin better indicator as shorter ½ lifeNormal ALB is good indicator of adequate synthetic function in chronic liver disease
23 Bilirubin Specific for liver dysfunction Assessment of hepatic anion transportInsensitive due to large hepatic functional reserveNormally 92% of bili unconjugatedRaised bili due to increased production, impaired metabolism or reduced excretion
24 BilirubinPlasma bilirubin levels >50µmol/l detected clinically as jaundicedBilirubinuria is always conjugated and is always pathological
25 Typical patterns of abnormalities of simple LFT in various liver diseases. Condition Acute Chronic Cirrhosis Choleostasis MalignancyHepatitis Hepatitis orTest InfiltrationBilirubin N to ↑↑ N to ↑ N to ↑ ↑ to ↑↑↑ NAminotransferase ↑↑↑ ↑ N to ↑ N to ↑ N to ↑Alkaline Phosphatase N to ↑↑ N§ N to ↑↑ ↑↑↑ ↑↑Albumin N N to ↓ N to ↓ N N to ↓-Globulins N ↑ ↑ N NProthrombin Time N to ↑* N to ↑ N to ↑* N to↑† NN = Normal*Not corrected by parental Vitamin K§ May be increased if Cirrhosis present†Corrected by parental Vitamin K
26 Miscellaneous tests of Liver Disease Plasma Bile Acids – highly specific indicator of hepatic anion transport, technically demandingImmunoglobulins – Generally increased in chronic disease. IgM greatly increased in Primary biliary cirrhosis. IgG in autoimmune chronic active hepatitisα-fetoprotein – Increased in 70% of primary hepatocellular carcinomas
27 Role of LFT’s in the Investigation of Liver Disease A )DiagnosisPoor diagnostic toolNon-specific, cannot quantitate extent of liver damageImaging, Clinical history and histology betterCheap, non-invasive, automated, can direct further investigation
28 Role of LFT’s in the Investigation of Liver Disease Surgical v’s non-surgical jaundiceRaised Bilirubin in range 20 – 100µmol/l with other LFT’s normalHaemolytic jaundice or Gilberts rather than extrahepatic biliary dysfunction
29 Role of LFT’s in the Investigation of Liver Disease Hepatocellular v’s CholeostasisRaised Bili, ALP and GT with normal or slightly raised ALTIndicates Choleostasis (but cannot distinguish intra from extrahepatic)
30 Typical Biochemical Changes during Acute Hepatitis Role of LFT’s in the Investigation of Liver Disease B) Monitoring – Main role of LFTTypical Biochemical Changesduring Acute HepatitisPre – ictericIctericPlasma bilirubinPlasma aminotransferasePlasma alkaline phosphataseUrinary bilirubinUrinary urobilogenN/↑↑↑↑N↑↑↑absentTypical biochemical changes during acute hepatitis
31 Role of LFT’s in the Investigation of Liver Disease Causes of Acute Viral hepatitisPre icteric – ALT/AST raised; other LFT normalIcteric – AST/ALT peak; 6 – 100 ULNNormally ALT>ASTAST>ALT poor prognosisALP normal/slightly raised (unless choleostatic element).
32 Role of LFT’s in the Investigation of Liver Disease Enzyme levels can be expected to return to normal in about 5 weeksPersistently raised levels (3 x ULN) could indicate chronic persistent hepatitisSudden reduction in aminotransferase activity bad sign indicating fulminant liver function
33 Role of LFT’s in the Investigation of Liver Disease Neonatal raised BilirubinNeed accurate measure of Bilirubin at critical levels (age, weight and ALB dependant)Phototherapy > 200µmol/lExchange transfusion >3
34 Role of LFT’s in the Investigation of Liver Disease Autoimmune Chronic Hepatitis Therapy - Successful immunosuppressant indicated by reduced AST activity. Relapse indicated by raised ALP activity Post-op Obstructive Jaundice - Clearance of obstructive jaundiced followed by serial bilirubin measurement
35 Role of LFT’s in the Investigation of Liver Disease Cirrhosis - No reliable test for compensated cirrhosis - Procollagen Type III peptide. Non-invasive marker for fibrosis but it is non-specific
36 Role of LFT’s in the Investigation of Liver Disease Alcoholic Liver DiseaseGT induced by ETOHIf raised as a result ETOH intake may never return to normalLiver TransplantStd LFT used to monitor rejectionRaised Bilbirubin increased when rejection occurs
37 Role of LFT’s in the Investigation of Liver Disease C) PrognosisLimited rolePre-transplant assessment of end stage liver diseasePrimary Biliary Cirrhosis- raised bili .....poor sign......<2yr survival bili >120µmol/lFulminant hepatic failure- bili >300µmol/l, poor prognostic sign
38 New Generation LFT Need cheap, reliable, convenient test: ‘accurately diagnose liver pathology’‘provide a quantitative assessment of functional hepatic mass’
39 New Generation LFTQuantitative LFT but are complex and limited to specific centresAminopyrine Breath Test, measures Cyto P450 (dependent demethylation of Carbon 14 labelled aminopyrine to Carbon Dioxide)Indocyanine green clearance – asses hepatic blood flow and hepatocellular activity.
40 New Generation LFTHepatocellular damage – glutathione-5-transferase, molecule sensitive to AST/ALT. Evenly distributed throughout liver, half-life 90 minutes, early marker of liver injuryCholeostasis – CA19-9, Increased serum level due to biliary clearance
41 Investigation of abnormal LFTs Causes of liver disease
42 Liver Pathology Hepatitis – Inflammation and cell damage Toxins, metabolites, infections, autoantibodiesCirrhosis – fibrosis infiltration, shrinkageTumours (Carcinoma)Primary or Secondary metastasesObstruction (Choleostasis)- failure of secretion of bilee.g. Chronic hepatitis cirrhosis yearsGold Std – Imaging and endoscopy
43 Hepatitis Viral or toxic Acute or chronic Viral Agents: Hep A B C (D + E) CMV, EBVToxic Agents: Paracetamol, AlcoholAcute Disease: < 6 months durationChronic Disease: > 6 months with non resolution of acute
44 Outcome of HepatitisMajority of hepatitis cases result in complete resolutionMinority will develop fulmanant hepatic failureAll forms of acute hepatitis may develop into chronicdisease except Hep AChronic hepatitis may be classified by histology- Chronic persistent hepatitis (benign)Chronic acute hepatitis (histological distinct)Chronic disease can progress to Cirrhosis, can progress toCarcinoma
45 Case History 1A 20 year old student developed a flu-like illness with a loss of appetite, nausea and pain in the right hypochondrium.On examination, the liver was just palpable and was tender.Two weeks later he developed jaundice, his urine became darker in colour and his stool became pale.
46 Case History -1 Investigations Serum: bilirubin 38µmol/l 230µmol/l on presentation one week laterSerum:bilirubin 38µmol/l 230µmol/lalbumin 40g/l g/lAST U/l 365U/lALP 70IU/l 150IU/lGGT 60U/l 135U/lUrine:bilirubin positive positiveurobilinogen positive negative
47 CirrhosisAetiology – autoimmune, chronic viral, alcohol Inherited, metabolic disease or Primary cirrhosisDiagnosed by demonstration of fibrous and architectural disruption in biopsy specimenIrreversibleNo symptoms whilst compensated due to functional reserveSymptoms manifest after decompensation – haematemesis, ascites, portal hypertension, encephalopathy, coma
48 Case History 2A middle aged female was admitted to hospital following a haematemesis. Endscopy revealed the presence of oesophageal varices.The only biochemical abnormality was an elevated GGT (245IU/L). The patient was told to abstain from alcohol.She was admitted one year later, jaundiced, drowsy and with clinical signs of liver disease.
49 Case History - 2Investigations Serum: Albumin 25g/l Bilirubin 260µmol/l ALP 315U/l AST 134U/l GGT 360U/l
50 Hepatocellular Carcinoma (HCC) Only 2% of all Cancers in the UKSignificant problem worldwide (Hep B, C; Haemachromatosis)80% due to Cirrhosis5yr Survival rate – 15%Imaging used to identify tumour, biopsyInappropriate and surgical resection is only treatment
51 Case History 3 A elderly woman, weight loss and constipation. She has lost approx 8kg in weight in 2 months and had lost her appetite .She had previously opened her bowels daily but had recently had several days between movements and had passed a small amount on each occasion.On examination she was anaemic and had obviously lost weight .The liver was enlarged and had an irregular edge, a mass was palpable in the right iliac fossa
52 Case History – 3 Serum: Albumin 30g/l ALP 314U/l Bilirubin, AST and GGT normalStool Occult Blood positiveA barium enema revealed a carcinoma of the caecum; an isotopic liver scan showed multiple filing defects characteristic of tumour deposits
53 CholeostasisIntrahepatic – Bile secretion from the hepatocytes into the canaliculi is impairedExtrahepatic - due to obstruction to the flow of performed bile through the biliary tractSymptoms; Pruritis, jaundice, pale stools and dark urineIntra – due to viral hep/ drugs – chlorpromazine or toxins – ETOHInflammation of the biliary tract (Cholangitis)Autoimmune disease – Primary biliary cirrhosis (destruction of bile duct due by lymphatic invasion leading to cirrhosisCFExtra – biliary stones/ inflamation of biliary tract
54 Case History 4 A 40 yr old women presented with jaundice. There was no history of contact with hepatitis, recent foreign travel, injections or transfusions.She did not drink alcohol. She had been well in the past but had suffered pruritus during the past 18months.
55 Case Study - 4Investigations Serum: Total Protein 85g/l Albumin 28g/l Bilirubin 340µmol/l ALP 522U/l AST 98U/l GGT 242U/l
56 Gilbert’s Syndrome – inherited disorder of bilirubin metabolism Asymptomatic, episodes of raised bilirubinEspecially if fasting, tired, other illnessCommon, up to 5% - male > femaleHyperbilirubinaemia <100 umol/lAll other biochemical LFT’s normalUnconjugated hyperbilirubinaemiaProlonged fasting (45hrs): 2-3 fold increaseNicotinic acid (I.v. 50mg): 2-3 fold increase
57 Case History - 5A medical student recovering from an attack of influenza was noticed to be slightly jaundiced. Worried that he might have hepatitis, the student had some blood taken for biochemical tests.
58 Case Study – 5Serum Bilirubin 60umol/l ALP 74 U/l AST 35 U/l Hb 16g/dl Retics 1% Urine bilirubin Neg
59 Inherited disorder of bilirubin metabolism Include; Crigler-Najjar Dublin-Johnson Rotor
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