Hello, my name is Hugo Vargas, and I'm from the Transplantation Center and Divisions of Gastroenterology and Hepatology at the Mayo Clinic in Arizona. If you have any questions, please do not hesitate to click on the button, ask the forum, where common issues regarding liver diseases are discussed. The title of my module is Liver Tests. In this talk, I will discuss the recognition and definition of the differences between liver injury tests and liver function tests, describe the characteristics of hepatocellular, cholestatic and mixed patterns of liver injury tests, identify the main causes and consequences of acute versus chronic liver disease, recognize alarm signs in the pattern of liver tests that would indicate hospitalization or urgent referral to a specialist. I have no relevant financial relationships to disclose. There will be no discussion of any unapproved, off-label or investigational uses of a product during this presentation. At the conclusion of this program, you should be able to recognize and define the difference between liver injury tests and liver function tests, describe the characteristics of hepatocellular, cholestatic and mixed patterns of liver injury tests, identify the main causes and consequences of acute versus chronic liver disease, and recognize alarm signs in the pattern of liver tests that would indicate hospitalization or urgent referral to a specialist. Liver function tests, or LFTs, are commonly utilized terms to represent liver-associated enzymes but not liver function. Thus, this terminology is inaccurate and should be avoided. Liver enzyme abnormalities reflect injury to either hepatocytes or bile duct cells. Therefore, they can be referred to as liver injury tests. Liver function tests reflect liver synthetic function. These are the real LFTs. Liver Injury Tests Liver injury tests can be classified as hepatocellular, cholestatic, or mixed. The hepatocellular liver injury tests consist of two enzymes, alanine aminotransferase, or ALT, and aspartate aminotransferase, or AST. Generally, normals are considered to be below 40 IU per liter. But more specifically, this should be less than 30 for men and less than 19 for women. The cholestatic or biliary liver injury tests include alkaline phosphatase, or ALK-FOS. The normal for this particular enzyme is age-dependent, with high levels during growth periods and pregnancy. Gamma glutamyl transferase and 5' nucleotidase are both indicative of cholestasis in cases of isolated elevated alkaline phosphatase and can be used as confirmatory enzymes. While disease processes can be generally one versus the other types, there are patients who present with a mixed picture of both hepatocellular and cholestatic abnormalities. Classification of liver injury abnormalities can be made based on duration or magnitude of the changes. Generally, acute cases of liver injuries are usually classified if the patient has been ill for greater than a month but less than six months. As the name implies, chronic disease is generally classified as a disease that has been present for more than six months. This again is a very arbitrary decision. The magnitude of the enzyme elevation, particularly with respect to hepatocellular liver injury tests, is important to recognize. Mild cases are those where AST and ALT elevations are less than 200 IU, moderate cases are defined as those between 200 and 600 IU, and severe cases are those where the elevations are greater than 600 IU. While it is not always absolute, as the slide may imply, the magnitude of the elevation can usually be correlated to the liver disease that is causing the injury. This is particularly important in aminotransferase elevations. As you can see from the figure, generally magnitude elevations that are less severe tend to include chronic viral hepatitis, alcoholic liver disease, and cirrhosis, whereas autoimmune hepatitis, acute viral diseases, and ischemic or toxic liver injury can represent very high elevations of the enzymes. When reviewing abnormal liver injury tests, the clinician should always keep in mind several caveats. It is important to recognize that normal values are arbitrary parameters. Some patients with normal liver enzymes may have underlying liver injury, and alternatively, normal individuals who have low probability of liver injury may have elevated liver enzymes. Thus, the clinician should always interpret the results of these enzyme elevations in the context of the clinical presentation. Additionally, elevations of aminotransferases are not exclusively seen in liver disease. If the clinician has ruled out hepatic causes for elevations of aminotransferases, he or she should think about muscle injury as a possibility. Rhabdomyolysis, dermatomyositis, epilepsy, and the presence of abnormal liver injury numbers in patients who are long-distance runners or who exercise intensely should lead them to evaluate the possibility of elevations of creatine phosphokinase or CBK, aldolase, lactate dehydrogenase or LDH in order to rule out muscle disease. Additionally, thyroid disease, celiac disease, anorexia nervosa, and adrenal insufficiency can sometimes present with abnormal liver injury numbers. Let us now turn our attention to serum alkaline phosphatase or ALP, which as we mentioned before is an enzyme that is seen elevated during biliary disorders. This enzyme is not a single enzyme but rather a family of enzymes which can come from the liver, bone, intestine, placenta, or the kidneys and have different clinical implications. Isolated ALP is the hallmark of cholestasis, but in this clinical situation is usually associated with abnormal aminotransferases, GGT, and or 5' nucleotidase. Isolated elevation of ALP may occur in Paget's disease and other non-hepatic disorders. The clinician has as an option the fractionation of ALP as a means to test the source of the enzyme. Unfortunately, the assays used to create the separations are not reliable as there can be overlap between liver and bone fractions. Thus, use of this test is reserved for cases where there is isolated elevation of ALP with normal GGT and 5' nucleotidase. Serum ALP becomes elevated due to increased synthesis regurgitation of hepatic ALP back into the serum and usually retained by elastase can contribute to the elevation of ALP. Generally, elevations less than 4 times upper limit of normal are felt to be nonspecific and deserve observation. Elevations greater than 4 times upper limit of normal are usually associated with cholestasis, either intra-hepatic or extra-hepatic. Serum Gamma Glutamyl Transferase or GGT. This enzyme is usually reserved as a confirmatory test for cholestasis. It's present in cell membranes in many tissues, unfortunately has comparable values in men and women. Newborns have to be carefully considered as their numbers can be higher than for adults in the normal range. Generally, this enzyme does not rise during pregnancy. High GGT values are present in diseases of the liver, biliary tract, and the pancreas and certain medications such as barbiturates, phenytoin, and alcohol can significantly increase the levels of this enzyme. It is very important to note that elevations of GGT are very nonspecific as only one-third of cases of GGT elevations are due to liver disease. Serum 5' nucleotidase. Again, this is an enzyme that can serve as a confirmatory test for cholestasis. It may come from the liver, intestine, brain, heart, blood vessels, and pancreas. Similar to alkaline phosphatase, it is elevated with cholestasis, infiltrative diseases, or space-occupying lesions of the liver. It does not rise during bone disease. Unfortunately, this enzyme doesn't rise in parallel with serum alkaline phosphatase, so if the ALP is elevated and 5' nucleotidase is not, cholestasis is not necessarily ruled out. Liver function tests. As the name implies, liver function tests reflect the liver's synthetic or excretory capacity. Examples of these tests include albumin, with a normal range between 3.8 and 5 grams per deciliter, prothrombin time, or its international normalized ratio, or INR, which should be less than 1, and serum bilirubin, which should be between 0.3 and 0.8 milligrams per deciliter. Let's focus now on albumin as a liver function test. Albumin is the most abundant blood protein and is synthesized by the liver only. Generally, it is preserved in acute liver disease. In the setting of chronic liver disease, low serum albumin is indicative of the presence of cirrhosis, provided there is no loss of protein through the urine or stool. Now let's focus on prothrombin time. Prothrombin time reflects clotting factors that are synthesized by the liver in a vitamin K dependent fashion. Prothrombin time, or its normalized version, INR, are very helpful in the diagnosis of hepatic dysfunction, either acute or chronic. In cholestatic injury or biostasis, intravenous vitamin K administration will correct the abnormality. Remember that vitamin K is liposoluble and needs bile to be absorbed. In hepatocellular injury, since the problem is synthetic dysfunction, IV vitamin K will not correct this abnormality. Lastly, serum bilirubin. Bilirubin reflects the ability of hepatocytes in secreting it into the bile canaliculus. It can therefore be elevated both in hepatocellular injury with poor liver secretory function or in cholestatic injury where there is poor bile flow. In both hepatocellular and cholestatic injury, the direct fraction usually predominates. Indirect hyperbilirubinemia is indicative of the presence of hemolysis or Gilbert syndrome, particularly in the absence of abnormal liver enzymes. Gilbert syndrome is characterized by an indirect hyperbilirubinemia never higher than 6 mg per deciliter. Now let's put together what we have just learned about the different enzymes and the patterns in which they present. As clinicians, we will be presented with both liver injury tests as well as liver function tests. Pattern recognition is very helpful in discerning the process and creating an adequate differential diagnosis. In hepatocellular injury, AST and ALT are predominantly elevated with minimal to no increases in alkaline phosphatase. Albumin can definitely be increased in this setting, as can be the predominant time. And if the injury is chronic, albumin will certainly decrease. On the last column, we can see the changes in cholestasis. Generally, transaminases are not very elevated in this setting, but they can be high. The predominant change is alkaline phosphatase, which is predominantly increased. Alcohol and direct bilirubin can certainly be normal, but generally tend to be increased as well. INR can be prolonged, and it generally can improve with the administration of vitamin K. Generally, albumin does not decrease in the acute phase of cholestasis. When putting a clinical picture together with respect to liver injury, the clinician has to do the following. First establish the duration of abnormalities. Is the change acute or is it chronic? Then a pattern has to be recognized in order to make a good differential diagnosis. And then last but not least, recognition of the prioritization of the workup and treatment of the disease has to be ascertained. Let's talk about acute hepatocellular injury. Generally, most patients with acute hepatocellular injury have either viral hepatitis or a drug-induced disease. We also have to consider the presence of alcohol, although generally AST and ALT are never higher than 400 international units in the setting of alcoholic hepatitis. Ischemia can also present with an acute hepatocellular picture, and generally the transaminases are very high, usually greater than 5,000 international units. Autoimmune liver disease, acute bile obstruction, hepatic vein obstruction, or the Bottichiari syndrome and Wilson's disease can also elevate the hepatocellular injury enzymes. This flow diagram illustrates how one should manage patients with acute hepatocellular injury. Having established the chronicity of the disease, we look at the magnitude of the elevation of the enzymes. If they are greater than 200 international units and are accompanied by encephalopathy or an INR increase above 1.5, consideration should be given to hospitalization in a transplant center as this patient may have ongoing liver failure. If this is not the case, then the magnitude of the elevations should prompt the timing of the evaluation. The magnitude of the enzyme elevation should drive the rate at which the evaluation is performed, but evaluation longitudinally is indicated in both circumstances. During the follow-up period and evaluation, avoidance of alcohol and medications is imperative to ensure that those etiologies are ruled out. Let's turn our attention now to acute cholestatic injury. Commonly, drug-induced disease or bile duct obstruction generally presents in an acute cholestatic pattern. The causes can include viral hepatitis, the use of total parenteral nutrition or TPN, sepsis, chronic use of alcohol, infiltration of the liver by infectious or neoplastic processes, postoperative jaundice, or cholestasis of pregnancy in those specific circumstances. Here's a flow diagram for the management of acute cholestatic injury. It is very important to recognize that a most important step in the evaluation of cholestasis is to evaluate the patency of the biliary tree. Ultrasound is the most economic and effective means to do this in the clinical setting. If bile duct dilatation is noted, and particularly if the patient is presenting with fevers or chills, hospitalization may be prudent to prevent a septic episode from cholangitis. If the presence of sepsis is not suspected, a rapid referral to a GI specialist is indicated in order to instrument the biliary tree and relieve the obstruction. If obstruction is not noted, we need to confirm that the alkaline phosphatase is indeed coming from the liver, then discontinue medications and follow tests to do a workup dependent on persistency of the findings. Let us now consider chronic hepatocellular injury. Most common causes include non-alcoholic or alcoholic steatohepatitis, or viral hepatitis. One also has to consider the presence of autoimmune hepatitis, drug-induced liver disease, Wilson's disease, or alpha-1-atatrypsin deficiency. Rarely, hemochromatosis can give elevations of ASD and ALT. This flow diagram illustrates the management of chronic hepatocellular injury. A most important step in the evaluation of chronic diseases of the liver is the consideration of the presence of cirrhosis. For those who need further details on this matter, please link to the module on cirrhosis management. However, if there is enough evidence at this point, screening tests for hepatocellular carcinoma and portal hypertension, including varices and ascites, should be carried out. The question of whether the patient is a liver transplantation candidate should be asked, and for answers beyond the scope of this module, please link to the cirrhosis transplant module. If, however, there is no clear evidence of cirrhosis and the liver injury number elevations are modest, the patient can be evaluated again in three to six months. If the evaluation renders a much higher elevation of the transaminases, close follow-up in one to three months is appropriate, and the speed with which a workup is completed has to be determined at this juncture. Let us now turn our attention to chronic cholestatic injury. Most common problems include drug-induced disease or primary biliary cholangitis or, as used to be known before, primary biliary cirrhosis. Consider the presence of primary sclerosing cholangitis, sarcoidosis, liver allograft rejection, graft-versus-host disease in the appropriate settings, opportunistic viral cholangitis, or secondary sclerosing or biliary cholangitis. Here is a flow diagram for the management of chronic cholestatic injury. Again, the consideration of the presence of cirrhosis is very important, and again, we invite you to follow the link to the cirrhosis diagnosis module for further details. If the patient appears to have cirrhosis, screening for hepatocellular carcinoma and portal hypertension complications is prudent. Also, the consideration of when to refer the patient to liver transplantation, if appropriate, should be asked at this point. If there is no evidence of cirrhosis, one needs to question the hepatic origin of the elevations of alkaline phosphatase, if appropriate, discontinue medications that could potentially induce cholestasis, and follow up tests and do a workup, as appropriate. This table, hopefully, will help the clinician summarize the most common causes of abnormal liver enzymes and alarm signs. Let's pay attention to the left side of the slide. If we have determined that the injury is predominantly hepatocellular, we then go and focus on the timing of the injury. If it is acute, one should consider the presence of viral hepatitis or drug-induced disease. And carefully evaluate the patient for evidence of liver failure. If the injury, on the other hand, is chronic, the presence of viral hepatitis and steatohepatitis, either alcoholic or non-alcoholic, is important to consider. And again, as always with chronic disease, weigh the possibility that the patient already has cirrhosis and the implication that that carries. On the right-hand side of the slide, we see cholestatic disease. Again, if the injury is acute, one needs to rule out the presence of drug-induced disease and choledocholithiasis or other obstructive causes. If there's evidence of cholangitis, this patient needs to be managed in a hospital setting to avoid the presentation of sepsis. If the disease is more likely to be chronic, one has to also rule out drug-induced disease and take into consideration chronic cholestatic diseases, such as PBC and PSC. And again, as with hepatocellular injury, the evidence for the presence of cirrhosis has to be weighed carefully in order to refer the patient to the right specialist at the right time. Included are a list of references for further reading on these matters. I hope you have enjoyed this presentation and I invite you to access additional content on liver learning on this topic or any other related topics at your leisure. Thank you.

liver tests

Hugo Vargas

Mayo Clinic

liver injury tests

liver function tests

chronic liver diseases

Fundamentals of Liver Disease