Table of Contents PatternsLiver enzymesBilirubinFunctional liver testsOther testsFurther investigations to find causeSome non-hepatic causes of deranged LFTsTry some scenarios Patterns Acute hepatitic picture: ALT/AST in 1000s, ALP mildly raised Chronic hepatitic picture: ALT/AST in 100s Cholestatic (obstructive) picture: ALP significantly raised, ALT/AST mildly raised, ↑bilirubin Alcoholic: ↑γGT, ↑mean corpuscular volume, AST/ALT mildly elevated (AST>ALT), ↑bilirubin in acute alcoholic hepatitis (may be disproportionate to ALT/AST) Cirrhosis/chronic liver disease: liver enzymes may be normal, ↓albumin, ↑coagulation tests Liver enzymes Enzymes leak from damaged liver cells and therefore they reflect liver injury (not function). Aminotransferases – alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ALT sources: specific to liver AST sources: liver, heart, skeletal muscle, kidneys, pancreas Marked increase (>1000): Toxin-/drug-induced hepatitis (e.g. paracetamol) Acute viral hepatitis (Hep A/B/E, EBV, CMV) Liver ischaemia Modest increase (300-500): chronic viral/alcoholic/autoimmune hepatitis, biliary obstruction Mild increase (<300): cirrhosis, non-alcoholic fatty liver disease, hepatocellular carcinoma, haemochromatosis/Wilson’s, cardiac Ratio of ALT:AST ALT>AST: chronic liver disease AST>ALT: + in established cirrhosis, ++ in alcoholic liver disease Alkaline phosphatase (ALP) Main sources: biliary ducts, bone (Paget’s disease, bony metastasis, fractures, osteomalacia, renal bone disease) Lesser sources: placenta (pregnancy), small intestine (fatty meals), kidneys (chronic kidney disease) Isoenzyme analysis can confirm Marked increase (>4x normal): cholestasis (e.g. gallstones, pancreatic cancer, primary biliary cholangitis, primary sclerosing cholangitis, drugs, strictures) Moderate increase (<3x normal): hepatitis, cirrhosis, infiltration (e.g. hepatocellular carcinoma, liver abscess etc.) Gamma-glutamyltransferase (γGT) Mirrors ALP so can be used to confirm if a rise in ALP is of hepatic origin Raised with alcohol abuse and enzyme-inducing drugs Bilirubin Bilirubin Extravascular haemolysis results in breakdown of Hb → globulin (further broken down into amino acids) + haem (further broken down into bilirubin). This unconjugated bilirubin is then conjugated by the liver so it can be excreted in bile. In advanced liver disease, the liver retains its ability to conjugate bilirubin, but it cannot excrete it. Normal bilirubin values (µmol/L)Total ≤20Indirect (unconjugated) ≤15Direct (conjugated) ≤5 Unconjugated hyperbilirubinaemia: increased ‘indirect’ bilirubin (unconjugated = indirect) Increased red blood cell breakdown (haemolytic anaemia) Impaired hepatic uptake (drugs, heart failure) Impaired conjugation (Gilbert’s syndrome, physiological neonatal jaundice) Mixed hyperbilirubinaemia Hepatocellular dysfunction (liver disease) Conjugated hyperbilirubinaemia: increased Functional liver tests Albumin Albumin makes up more than half of the total protein in the blood. The remainder is made up by globulins (other blood proteins) which include α1-globulins (α1-antitrypsin), α2-globulins (α2-macroglobulin, haptoglobin), β-globulins (complement, transferrin), and γ-globulins (immunoglobulins). Albumin is synthesised by the liver and has a half-life of around 20 days. Hence, changes in levels happen over weeks. ↓albumin + ↓total protein = cirrhosis, nephrotic syndrome, chronic inflammation, protein-losing enteropathy, alcoholism, protein malnutrition/malabsorption ↓albumin + normal total protein = infection (albumin is a negative acute phase protein) ↓albumin + ↑ total protein = myeloma, Waldenström’s Prothrombin time/INR PT/INR depend on clotting factors and fibrinogen which are synthesised by the liver. Some clotting factors have short half-lives (e.g. 6-8 hours) so changes can occur rapidly. Raised PT/INR: liver disease (with impaired function), vitamin K deficiency, consumptive coagulopathy (e.g. disseminated intravascular coagulation) Other tests FBC clues Anaemia = GI bleeding Macrocytosis = alcohol Thrombocytopenia = effect of alcohol on bone marrow, hypersplenism, liver cirrhosis or disseminated intravascular coagulation Further investigations to find cause Blood tests Viral Viral hepatitides: hepatitis A IgM, hepatitis B surface antigen, hepatitis C IgG, hepatitis E IgM CMV serology EBV serology Autoimmune liver screen Anti-smooth muscle (autoimmune hepatitis type 1) Anti-mitochondrial (primary biliary cholangitis) Anti-liver-kidney microsomal (autoimmune hepatitis type 2, hepatitis C/D, drug-induced hepatitis) Antinuclear (autoimmune hepatitis type 1, SLE) Tumour markers – if cirrhosis/weight loss α- fetoprotein (hepatocellular carcinoma) Infiltrative Ferritin and transferrin saturation (haemochromatosis) – but be aware ferritin is also an acute phase protein Serum copper and caeruloplasmin ± 24-hour urinary copper (Wilson’s disease) Fasting glucose and lipids (fatty liver disease) Metabolic α1-antitrypsin (α1-antitrypsin deficiency) Immunoglobulins and protein electrophoresis (IgM raised in primary biliary cholangitis, IgA raised in alcoholic liver disease, IgG raised in autoimmune hepatitis) Tissue transglutaminase antibody (coeliac disease) Toxins Paracetamol level (paracetamol overdose) Imaging Abdominal ultrasound: first line imaging (quick and cheap) that is useful for determining liver texture, size and presence of any gallstones or cholecystitis Abdominal CT: can confirm pancreatitis or tumour Elastography: grades liver fibrosis in chronic liver disease non-invasively Magnetic resonance cholangiopancreatography: to look for duct disease/stones if ultrasound normal Procedures Ascitic tap: if ascites present Liver biopsy (CT-guided usually, but done trans-jugular if there is ascites or coagulopathy) Some non-hepatic causes of deranged LFTs In addition to any described above: Drugs Hepatitis: tuberculosis antibiotics (rifampicin/isoniazid/pyrazinamide), sodium valproate, methotrexate, methyldopa, amiodarone, statins, paracetamol, phenytoin, ketoconazole/fluconazole, nitrofurantoin, sulfonylureas/sulfonamides Cholestasis: co-amoxiclav (may be delayed/severe), clarithromycin/erythromycin, carbamazepine, chlorpromazine, contraceptives, flucloxacillin, sulfonylureas/sulfonamides Right heart failure Sepsis Coeliac disease Haemolysis Hyperthyroidism Right lower lobe pneumonia Try some scenarios Find the normal lab values here. A 17 year old student presents with a fever and sore throat. He has cervical lymphadenopathy. His full blood count shows a lymphocytosis. Liver function tests reveal: ALT 1020, ALP 130, Bilirubin 27, Albumin 36. Which pattern of LFT derangement is present? Oops! This section is restricted to members. Which further tests would you consider? Oops! This section is restricted to members. What is the likely diagnosis? Oops! This section is restricted to members. How would you manage the patient? Oops! This section is restricted to members. A 20 year old female with severe depression and bipolar disorder presented to the acute medical unit after a paracetamol overdose. Her paracetamol level is checked and is over the treatment line. Her ALT is 62 but her other liver function tests are normal. Which treatment would you administer? Oops! This section is restricted to members. Which two specific blood tests are the most important to check at the end of the infusion? Oops! This section is restricted to members. If the patient refused the treatment and tried to leave, what would you do? She seems to understand the risks of the decision. Oops! This section is restricted to members. A 54 year old who drinks 1L vodka daily, presents with vomiting. On examination, he seems to be tremulous and is confused. He has large volume ascites. His blood tests are taken and his liver function tests are as follows: ALT 122, ALP 22, Bilirubin 120, Albumin 22. His coagulation test reveals: INR 3.0. His renal function test reveals: Na+ 128, K+ 4, Ur 6, Cr 190. What do you think is going on? Oops! This section is restricted to members. What is your initial management? Oops! This section is restricted to members. An ascitic fluid aspirate is taken and the ascitic white cell count is raised. What are you concerned about and what additional treatments would you administer? Oops! This section is restricted to members.