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APPROACH to ABNORMAL LIVER TESTS Mitchell L Shiffman, MD

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APPROACH to ABNORMAL LIVER TESTS Mitchell L Shiffman, MD APPROACH TO ABNORMAL LIVER TESTS Mitchell L Shiffman, MD Liver Institute of Virginia Bon Secours Health System Richmond and Newport News, VA CATAGORIES OF LIVER FUNCTION TESTS: What are commonly referred to as liver function tests (LFTs) do not actually measure liver function. Liver transaminases and alkaline phosphatase are utilized to assess injury to the liver but can still be normal in patients with liver disease. True liver function tests measure the metabolic and synthetic function of the liver. Other “non-liver” tests can be utilized to estimate hepatic fibrosis and mortality in patients with advanced liver disease. Liver chemistries: Aspartate aminotransferase Reflect injury to the liver Alanine aminotransferase Alkaline phosphatase Gamma glutamyl transferase 5’ nucleotidase Tests which assess liver function Albumin INR (factor 7) Tests which assess hepatic metabolism Total bilirubin Direct and indirect bilirubin Non-Liver function tests Platelet count Serum creatinine LIVER TRANSAMINASES: Transaminases are enzymes that convert amino acids to alpha-keto acids. During this reaction an amino acid is metabolized to its alpha-keto acid by removing the amino group and leaving an alpha-keto group. Alpha-keto-acids are produced from amino acids by the reverse reaction. The liver contains several transaminases. The two that are typically measured to assess for the presence of liver cell injury are alanine aminotransferase (ALT) and aspartate aminotransferase (AST). ALT is a cytoplasmic enzyme. AST is a mitochondrial based enzyme. Injury to liver cells release ALT into serum in higher concentrations than AST. For this reason, ALT is always higher than AST in all forms of chronic liver disease except for those diseases which selectively injure the mitochondria. This most commonly occurs in patients with either alcohol induced liver injury or non-alcoholic steatohepatitis (NASH). What is the normal value for ALT: There is no defined WHO (World Health Organization) normal value for serum ALT. In the past the upper normal for ALT was defined as 2 standard deviations above the mean for that population. However, with the epidemic of HCV, obesity and NAFLD it was noted that the upper normal for serum ALT increased between 1970-2000 in many locations and tertiary care medical centers; especially in those centers that specialized in liver disorders. Several studies have attempted to define the true upper limit of normal for ALT. All of these studies included Liver Function Tests only healthy persons taking no medications and with normal body weight. Patients with a serologic positive test for any liver disorder, persons on any medications and those with an elevated BMI were excluded. Some of these studies were performed on healthy volunteers others were performed on blood donors. In this population the upper normal for serum ALT (defined as two standard deviations above the mean) was approximately 19 for females and 30 for males. African Americans had slightly higher values for ALT then Caucasians. Ratio of AST and ALT: 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 progresses and patients develop cirrhosis the ratio of AST/ALT increases and becomes greater than 1 once cirrhosis has developed. This “rule” is true about 80% of the time can be utilized with other laboratory tests to help determine that a patient with chronic liver disease has developed cirrhosis. ALT is found in high concentrations within the liver and in very low concentrations in other tissues. In contrast, AST is found in many other tissues with high metabolic rates including muscle (skeletal, cardiac and smooth muscle), kidney and brain. Injury to any off these tissues can cause elevations in AST but will not significantly affect ALT. Thus, patients with elevations in serum transaminases where the ratio of AST/ALT exceeds 5 are unlikely to have liver injury, especially if the ALT is normal. Using liver tests to assess hepatic fibrosis: Since the AST/ALT ratio is affected by the degree of fibrosis several fibrosis scoring systems have been developed to estimate hepatic fibrosis and possibly replace liver biopsy. APRI Index: The APRI (aspartate-platelet ratio index) is simple and utilizes only 2 commonly ordered laboratory values; AST and platelet count. The APRI is calculated as follows: APRI = AST/(AST ULN)/(platelet tcount) x 100. Since AST increases and the platelet count declines with increasing fibrosis, increasing fibrosis is associated with a rise in APRI. The positive predictive value for APRI values greater than 1.5 with cirrhosis (Metavir fibrosis stage 4) is about 80%. The positive predictive value for APRI values less than 0.5 with either none or mild fibrosis is also about 80%. Although APRI values between 0.5-1.5 are suggestive of intermediate stages of fibrosis (Metavir stages 2 and 3) the positive predictive value for APRI between this range is only about 60%. FIB-4: The FIB-4 was originally developed in a cohort of patients with HCV and HIV co-infection but has now been applied to several populations including patients with NAFLD. The formula is simple to calculate and utilizes 3 commonly performed laboratory tests and the patient’s age. The FIB-4 is calculated as follows: FIB-4 = ((Age in years) x AST)) / (Platelet count x (ALT/2). Liver Function Tests In general, the higher the value the more likely the patient will have advanced fibrosis or cirrhosis. In patients with chronic HCV values less than 1.45 have a 90% probability for not having advanced fibrosis or cirrhosis; Ishak fibrosis scores 4-6 or Metavir fibrosis score of 3-4. Values greater than 3.25 have a 97% specificity and 65% positive predictive value for having advanced fibrosis or cirrhosis. A Fib-4 of greater than 3.25 has a positive predictive value of about 90% for advanced fibrosis or cirrhosis (Ishak stages 4-6). In patients with non-alcoholic fatty liver/nonalcoholic steatohepatitis values of >2.67 were 90% predictive of advanced fibrosis or cirrhosis and values less than 1.30 were 90% predictive of not having advanced fibrosis or cirrhosis. Cut-off values will vary for other etiologies of liver disease. Fibrosure: Fibrosure is a proprietary laboratory test which utilizes several liver chemistries to arrive at a value which correlates with the degree of fibrosis in patients with chronic HCV. It may be less reliable in patients with NAFD and other forms of chronic liver disease. The chemistries utilized in fibrosure include: alpha-2-macroglobulin, haptoglobin, gamma-GT, age in years, total bilirubin, apo-A1 and sex. The scale extends from 0-1. Values less than 0.1 have an 80% positive predictive value for none-mild fibrosis (Metavir fibrosis stage 0-1). Values greater than 0.8 have a positive predictive value of about 80% for advanced fibrosis or cirrhosis (Metavir fibrosis stage 3-4). The overlap in fibrosis scores, F1-3, for values between these extremes is significant and therefore, Fibroscore values between 0.1-0.8 do not correlate well with any specific stage of fibrosis. Assessing fibrosis with elastography: Elastography is a technique which measures how elastic or stiff the liver is. This can be performed with ultrasound or magnetic resonance. Fibroscan: Fibroscan is a devise which assesses liver stiffness by ultrasound. The Fibroscan devise provides a numerical value for liver stiffness in kilopascals (kPa). The more fibrotic the liver, the more stiff the liver will be in kPa. Fibroscan has been utilized to assess liver fibrosis in many liver disorders. The most data generated has been in patients with HCV. In chronic HCV a liver stiffness value of >12 kPa is about 80% specific for cirrhosis on liver biopsy; and a value of about 4 kPa or less is about 80% specific for none-mild fibrosis. There is significant overlap for values between 4-12 kPa with fibrosis stages F1-F3. In addition, many factors can affect the measurements obtained with Fibroscan. For example, higher values will be obtained after a meal because increased hepatic blood flow increases liver stiffness. Significant amounts of steatosis and severe hepatic inflammation which can be seen in severe autoimmune hepatitis may also lead to higher kPa values. Shearwave ultrasonography: This is another ultrasound technique to measure liver stiffness. This is performed with a special software package incorporated into a standard ultrasound machine. Instead of reporting the data in kPa these instruments report stiffness as mm/sec. The data accumulated to date using shearwave ultrasound to assess liver fibrosis is currently limited. Liver Function Tests Magnetic resonance elastography: Liver stiffness can also be measured by MR. This requires a specialized MR unit, a coil/probe which is placed over the liver for the scan and a specialized software package. The technique is not yet FDA approved, and MR units that can perform scan and analysis are currently limited. Data is just starting to emerge regarding values that are significant. The cost of MR is also significantly greater in the USA than for Ultrasound, Fibroscan or any non-invasive biochemical marker. ALKALINE PHOSPHATASE: Alkaline phosphatase (ALP) is an enzyme that is found in many cell types. Its function is to remove a phosphate group from phosphorulated substrates such as phospholipids and sugars. In the liver, the enzyme is located on the canalicular membrane of the hepatocyte and at this location ALP is believed to be involved with the transport of phospholipids into bile. ALP is not present in bile duct cells. Serum ALP rises when the canalicular membrane is “disrupted”. This causes translocation of ALP from the canalicular membrane to the basal lateral surface of the hepatocyte where it enters the plasma. Differentiating liver from non-liver ALP: The most common organs which produce ALP include the liver, bone, intestine, kidney and placenta.
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