PSH Clinical Guidelines Statement 2017 Interpreting Liver Function Tests Dr. Asad A Chaudhry Consultant Hepatologist, Chaudhry Hospital, Gujranwala, Pakistan. Liver function tests (LFTs) generally refer to bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT). Most labs also report total protein, albumin and globulin in the panel of LFTs. Most LFTs do not measure liver function. These tests are liver chemistries and tests of liver synthetic and metabolic function. There are other non-liver tests, which are utilized to estimate hepatic fibrosis and mortality in patients with advanced liver disease. Liver Chemistries Reflect Injury to the Liver Tests assessing liver function Tests assessing hepatic metabolism Non-Liver function tests Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Alkaline phosphatase (ALP) Gamma glutamyl transferase (GGT) 5 nucleotidase Albumin INR (Factor VII) Total bilirubin Direct and indirect bilirubin Platelet count Serum Creatinine LIVER TRANSAMINASES Transaminases are enzymes that convert amino acids to alpha-keto acids. There are several transaminases in liver: Of these, Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are measured to assess the presence of cellular injury. ALT is a cytoplasmic enzyme, while AST is based in mitochondria. Injury to hepatocyte releases ALT into serum in higher concentrations than AST. ALT is generally higher than AST in all forms of chronic liver disease except those which selectively injures the mitochondria which is commonly seen in patients with alcohol induced hepatitis or nonalcoholic steatohepatitis (NASH). Several studies have attempted to define the true upper limit of normal for ALT. The subjects included in these studies had normal body weight and no medical illness. In this population, the upper normal limit for serum ALT (defined as two standard deviations above the mean) was approximately 19 for females and 30 for males. Page 1 of 5
Although ALT is generally higher than AST in most forms of chronic liver disease the ratio of these enzymes is affected by the degree of fibrosis. As fibrosis increases AST generally becomes greater than ALT and the AST: ALT is > 1 in about 80% of the patients with liver cirrhosis. AST is also found in tissues other than liver namely muscle, kidney and brain. Injury to the above cause a rise in AST without affecting the ALT. Liver disease as a cause of elevated transaminases is unlikely where ratio of AST/ALT exceeds five, especially when ALT is normal. AST and ALT generally comes from liver though there may be other causes of origin of these enzymes. AST ALT Liver Yes Yes Skeletal Muscles Yes Small amounts Heart Yes No Brain Yes No Kidney Yes No ALKALINE PHOSPHATASE (ALP) ALP is an enzyme found in many cell types. Its function is to remove a phosphate group from phosphorulated substrates such as phospholipids and sugars. In the liver, it is located on the canalicular membrane of the hepatocyte and is believed to be involved in the transport of phospholipids into bile. ALP is not present in the bile duct cells. Serum ALP rises whenever there is bile duct injury or obstruction. Non-liver ALP: The most common sites of ALP production apart from liver include bone, intestine, kidney and placenta. Certain types of tumors as ovarian and lung adenocarcinoma also secrete ALP. Isolated elevations in serum ALP may therefore not always reflect injury to the liver or biliary tree. Placental ALP increases during third trimester and immediate post-partum. Paget s disease of bone is associated with very high ALP. Bone ALP is also affected by age. Rapid bone growth in children and adolescents cause elevations in ALP. The total ALP starts to decline in early 20 s but starts to increase in the elderly reflecting osteoporosis. Fractionating the ALP can differentiate liver or non-liver ALP. Unfortunately, the total ALP often reflects a mixture of ALP from these different organs and fractionations typically yields a result that is difficult to decipher. Measurements of alternate liver enzyme, which is also affected in cholestatic liver disease, is helpful in this situation. The 2 most common enzymes, which are measured, include gamma glutamyl transferase (GGT) and 5 nucleotidase. Cholestasis of Liver: Page 2 of 5
The term cholestasis refers to a pathophysiologic process in which there is injury to or obstruction of the biliary ductal system. Biochemically, patients are referred to as having cholestasis when the ALP is elevated. Cholestatic liver diseases can be divided into 2 groups Obstructive Jaundice Intrahepatic cholestasis Obstructive Jaundice Intrahepatic Cholestasis ALP Elevated Elevated Bilirubin Elevated Normal or elevated Large Bile Ducts Dilated Normal Small Bile Ducts Proliferation Normal-Abnormal Histology Bile Lakes Bilirubic stasis Intrahepatic Cholestasis: It is characterized by elevation in ALP with either a normal or elevated bilirubin but a normal biliary ductal system. Causes of Intrahepatic Cholestasis: 1. Medications NSAID s, H2 blockers, PPI, Phenytoin or other anti-epileptics, oral hypoglycemic agents, lipid lowering drugs, anti-fungal agents, sulfonamides, erythromycin, antidepressants, anti-psychotic medicines 2. Infiltrative Disorders Five disease, which infiltrate the liver all present as intrahepatic cholestasis. These include sarcoidosis, tuberculosis, amyloidosis, lymphoma and hepatic metastasis. Infiltrating tumors such as oat cell carcinoma and sometimes infiltrating HCC may also present as pure cholestasis. 3. Alcoholic hepatitis 4. Benign recurrent cholestasis COAGULATION FACTORS AS LFTs Liver is the site of synthesis of most coagulation factors. These include I, II, V, VII, IX, X, XII and XIII. The formation of factors II, VII, IX and X is dependent upon gammacarboxylation. This reaction requires vitamin K as a co-factor. The prothrombin time (PT) is measure of the time taken to convert prothrombin to thrombin. Factor VII is a necessary step in the process. The half-life of factor VII is only 6 hours and as a result PT represents the most sensitive test of acute hepatic dysfunction. A number of different factors may cause a prolongation of PT; BILIRUBIN Inadequate dietary intake of vitamin K Cholestasis Intrinsic Hepatocellular Dysfunction Bilirubin is a breakdown product of heme. The heme is initially cleaved by heme-oxygenase into biliverdin, which is subsequently converted to bilirubin. Unconjugated bilirubin is insoluble in an aqueous environment and Page 3 of 5
must be bound to albumin in the circulation. Unconjugated bilirubin is actively transported into hepatocyte. Within the hepatocyte bilirubin is conjugated by the enzyme UDPglucuronosyl transferase into a bilirubindiglucoronide. The conjugated bilirubin is water soluble and excreted in bile. Hyperbilirubinemia is seen: 1. Excessive bilirubin production Commonly observed in hemolytic conditions. Also observed in patients who suffer from significant intraabdominal bleeding or bleeding into a limb. As the clot breaks down large amounts of unconjugated bilirubin are released in the circulation 2. Decreased hepatic conjugation genetic alterations in the UDPglucuronosyl transferase enzyme lead to either absent or a reduced rate by which bilirubin is conjugated. Certain medications inhibit this enzyme. Both can lead to impaired conjugation of bilirubin and jaundice. 3. Inherited disorders of bilirubin conjugation two main categories: a. Unconjugated hyperbilirubinemia: Crigler- Najjar Syndrome Type I, Crigler-Najjar Syndrome Type II, Gilbert s Syndrome b. Conjugated hyperbilirubinemia: Disorders of secretion of conjugated bilirubin into bile Rotor s Syndrome, Dubin Johnson syndrome NON-LIVER TESTS TO ASSESS LIVER FUNCTION Platelet Count Platelet count declines with advancing fibrosis. This is secondary to reduction in synthesis of thrombopoietin by the liver and increased sequestration of platelets by spleen due to splenomegaly caused by portal hypertension. A single most common cause of thrombocytopenia in the absence of blood disorder is liver cirrhosis especially in a patient with chronic liver disease. A platelet count of < 125 is one of the most sensitive test for identification of patients with liver cirrhosis Serum Creatinine Serum creatinine is an important measure of liver function in patients with advanced cirrhosis. It is incorporated in MELD score to predict 30-day mortality in patients with cirrhosis and carries more weight in the calculation than either bilirubin or platelet count. A rising creatinine in a cirrhotic patient increases MELD score exponentially and is associated with extremely poor prognosis. Page 4 of 5
REFERENCES 1. Mitchell L. Shiffman. Approach to Abnormal liver tests. Annual postgraduate course syllabus, American College of Gastroenterology 2012:65-68 2. Lee TH, Kim WR, Poterucha JJ. Evaluation of elevated liver enzymes. Clin Liver Dis 2012 May;16:183-98. 3. Prati D, Taioli E. Zanella A. et al. Updated definitions of heathy ranges of serum alanine aminotransferase levels. Ann Internal Med 2002;137:1-10 4. Siddique A. Kowdley KV. Approach to a patient with elevated serum alkaline phosphatase. Clin Liver Dis 2012;16:199-229. 5. Krier M, Ahmed A. The asymptomatic outpatient with abnormal liver function tests. Clin Liver dis 2009;13:167-77. Page 5 of 5