Understanding liver test abnormalities Emmanuel Tsochatzis Royal Free Hospital and UCL London, UK Quality in Endoscopy: ERCP, Munich 2011 Do not interpret on their own • History • Clinical examination • Laboratory findings • Imaging Quality in Endoscopy: ERCP, Munich 2011 Liver function tests • Interpretation must be performed within the context of the patient’s risk factors, symptoms, concomitant conditions, medications, and physical findings • Rarely provide specific Dx, but rather suggest a general category of liver disease • Differing laboratories differing normal values Quality in Endoscopy: ERCP, Munich 2011 Normal Laboratory Values Normal Abnormal 2 SD normal values = mean ± 2SD of normal population Quality in Endoscopy: ERCP, Munich 2011 LFT abnormalities classification • Hepatocellular injury (AST, ALT) • Cholestatic injury (ALP, γGT, bilirubin) • Infiltration (ALP, γGT, occasionally bilirubin) • Synthetic function (albumin, INR) Albumin, INR, bilirubin – also used as prognostic factors (Child-Pugh, MELD, UKELD) Quality in Endoscopy: ERCP, Munich 2011 Aminotransferases ALT AST catalyze transfer amino groups to form pyruvic acid catalyze transfer amino groups to form oxaloacetate cytosol (20%) and mitochondria (80%), predominantly periportal hepatocytes cytosol T1/2 12-22 hr T1/2 37- 47 hr. liver, cardiac muscle, skeletal low concentration in other muscle, kidneys, brain, tissues – more specific for liver pancreas, lungs, leucocytes, and disease than AST RBC Quality in Endoscopy: ERCP, Munich 2011 Aminotranferases • Level of transaminase elevation • Predominant AST elevation • Rate of transaminase decline Quality in Endoscopy: ERCP, Munich 2011 Level of elevation • >15 times : acute hepatic injury 5-15 times : less useful <5 times : chronic hepatic injury Quality in Endoscopy: ERCP, Munich 2011 ALT and AST > 15 times • Acute viral hepatitis (AE, herpes) • Medications/toxins • Ischaemic hepatitis • Acute bile duct obstruction • Autoimmune hepatitis • Wilson’s disease • Acute Budd-Chiari syndrome • Hepatic artery ligation • Heat stroke AST predominate : medication/toxin, ischemic >75 times : ischemic, toxic, viral (less common) Quality in Endoscopy: ERCP, Munich 2011 AST/ALT ratio <1 : majority of liver disease (usually 0.8) >2 : extrahepatic source alcoholic hepatitis ischemic and toxin acute Wilson’s disease : haemolysis lymphoma cirrhosis >4 : fulminant Wilson’s disease Quality in Endoscopy: ERCP, Munich 2011 Rate of transaminase decline rapid • ischaemic • short half life drug • acute biliary tract obstruction • fulminant hepatitis slow • acute viral hepatitis • long half life drug • AIH • metabolic disease (decline is ominous if ↑INR) Quality in Endoscopy: ERCP, Munich 2011 Unexpected ALT elevation • Muscle disease/injury (CPK, aldolase) • Thyroid dysfunction (TSH) • Coeliac sprue (anti-endomysial antibody) Quality in Endoscopy: ERCP, Munich 2011 Alkaline phosphatase • Of cytosolic origin in the liver • Present in placenta, ileal mucosa, kidney, bone • Half life = 3 days • Elevated in 3d trimester of pregnancy • Blood types O and B: can have elevated ALP after fatty meal due to influx of intestinal ALP • Liver origin: elevated GGT Bone origin: normal GGT Quality in Endoscopy: ERCP, Munich 2011 Alkaline phosphatase Physiologic Pathologic • >60 yr. • intrahepatic • child and adolescent • extrahepatic • pregnancy • blood group O • post meal (fatty meal) Quality in Endoscopy: ERCP, Munich 2011 Infiltrative diseases modest (up to 3x) rise in aminotransferases, and up to 20x rise in ALP, bilirubin N-5x • • • • • • • • TB Fungal infection HCC Lymphoma Metastatic malignancy Amyloidosis Sarcoidosis Other granulomatous diseases Quality in Endoscopy: ERCP, Munich 2011 Infiltrative diseases Cancer, granulomatous disease, amyloidosis, Hodgkin’s Disproportionate ↑ of ALP, ggt compared to bilirubin Sarcoidosis, tuberculosis Two most common that produce jaundice Quality in Endoscopy: ERCP, Munich 2011 γ-glutamyltransferase (GGT) • catalyzed transfer of γ-glutamyl groups of peptides to other amino acid • abundant in liver, kidney, pancreas, intestine, and prostate, spleen, heart, brain but not in bone • T1/2 – 7-10 days – 28 days in alcohol-associated liver injury Quality in Endoscopy: ERCP, Munich 2011 γ-glutamyltransferase (GGT) • Increase – alcohol (even without liver disease) – drug • anticonvulsant (CBZ, phenytoin, and barbiturate), warfarin – almost all type of liver diseases – COPD, renal failure, DM, hyperthyroidism, RA, AMI, pancreatic disease Quality in Endoscopy: ERCP, Munich 2011 Isolated unconjugated hyperbilirubinemia IDB fraction > 85% of total bilirubin 1. increased production : • hemolysis chronic hemolysis-not sustained increase of bilirubin >5 mg/dl in normal hepatic function • • • ineffective erythropoiesis : folate, IDA drug : rifampicin, ribavirin, probenecid resolution of hematoma 2. defects in hepatic uptake/conjugation • • Gilbert’s syndrome Crigler-Najjar syndrome Quality in Endoscopy: ERCP, Munich 2011 Gilbert’s syndrome • benign, unconjugated hyperbilirubinemia with otherwise normal liver chemistries • up to 5% of normal population • polymorphism in TATA box of gene encoding bilirubin UDP-GT impaired ability to conjugate bilirubin • prominent in fasting state, systemic illnesses, haemolysis, some medications Quality in Endoscopy: ERCP, Munich 2011 Gilbert’s syndrome • Dx : – asymptomatic, healthy – mild unconjugated hyperbilirubinemia (<4 mg/dl) with otherwise normal liver chemistries test – exclusion medications and hemolysis Quality in Endoscopy: ERCP, Munich 2011 Conjugated hyperbilirubinemia • DB > 50% of total bilirubin • Can’t differentiate obstruction and parenchymal disease • Delta fraction – CB tightly bound to albumin – tendency of hyperbilirubinemia to resolve more slowly than other biochemical tests Quality in Endoscopy: ERCP, Munich 2011 Diagnostic approach in elevated serum bilirubin Quality in Endoscopy: ERCP, Munich 2011 Common pitfalls Quality in Endoscopy: ERCP, Munich 2011 Ischaemic hepatitis • low-flow hemodynamic state – hypotension, sepsis, cardiac arrhythmia, MI, HF, hemorrhage, extensive burns, severe trauma, heat stroke • hypotension often not documented • usually subclinical Quality in Endoscopy: ERCP, Munich 2011 Ischaemic hepatitis • sudden and massive (>2000) elevation of liver enzymes, tend to decrease rapidly and return normal within 1 wk. • mild and transient elevation of bilirubin (80% < 2 mg/dl) and ALP • extreme elevation LDH (>5000), ALT/LDH < 1.5 • rare acute liver failure • Rx and prognosis - underlying disease Quality in Endoscopy: ERCP, Munich 2011 Acute biliary obstruction • aminotransferase peak early and decline rapidly over 2472 hr. with Abx despite unresolved obstruction • after aminotransferase decrease, bilirubin and ALP increase • ALP – de novo synthesis, initial levels normal • 25% of patients with AST > 10X Quality in Endoscopy: ERCP, Munich 2011 Alcoholic hepatitis • History of alcohol consumption • Systemic symptoms / SIRS • Transaminases DO NOT exceed 300 IU/dl • AST/ALT >1 in 92%, >2 in 70% - pyridoxine deficiency - mitochondrial injury • GGT/ALP > 2.5 Quality in Endoscopy: ERCP, Munich 2011 NAFLD • Fatty liver present in 20-30% of general population • Usually associated with features of metabolic syndrome • Rarely ALT > 4 ULN • ALT>AST (DDx from ALD) • ALP and GGT raised less often than transaminases • ↑ferritin in 40% • Liver biopsy and alcohol exclusion essential for diagnosis Quality in Endoscopy: ERCP, Munich 2011 Case • 43 y old male, asymptomatic • Referred for abnormal liver tests • BMI 28 kg/m2, glucose intolerance • ALT 192, AST 110, ALP 420, GGT 1265 • Liver screen negative • US mild steatosis Quality in Endoscopy: ERCP, Munich 2011 Quality in Endoscopy: ERCP, Munich 2011 Acute hepatitis – subfulminant Hepatocellular or cholestatic pattern Gallbladder wall thickening due to inflamed liver Quality in Endoscopy: ERCP, Munich 2011 Biliary complications post-LT • 6-32% of all transplants • 1/3 in 1st month • Strictures - Anastomotic - Non-anastomotic ischaemic type (ITBL) • DDx from acute/chronic rejection • Check hepatic artery •Jaundice a late feature – non specific ↑LFT Quality in Endoscopy: ERCP, Munich 2011 Quality in Endoscopy: ERCP, Munich 2011 Liver chemistry tests • Interpret within specific context • normal may have abnormal tests • normal value not ensure that patient is free of liver disease • level of abnormality does not reflect severity but may help in DDx • decrease in the value does not mean improvement • limitation in sensitivity and specificity Quality in Endoscopy: ERCP, Munich 2011 Quality in Endoscopy: ERCP, Munich 2011