Dr. Beccari and I are very excited to welcome everybody back today on behalf of the entire faculty. We really enjoyed the interaction between the polls and the questions and answers. For those who weren't here, just a quick review yesterday. We started with onboarding, role of APPs, the art and science of a quality visit and some billing and reimbursement. Our expert faculty then went through some things about endoscopic procedures, and we had some case-based radiology studies. Today we're going to build upon that, and we'll have more case-based studies really focusing on a wide, diverse clinical case scenarios that we'll see in our practice. At the end, we're going to have a roundtable discussion, and so any topics that maybe we didn't have a time to touch on or additional questions that you have, we'll try to answer at that time. Starting us off today is Dr. John Martin, and he'll be talking about the evaluation of abnormal liver function tests. This has always been a very popular topic in this course, certainly by a popular speaker. For those of you who don't know him, Dr. Martin is a full-time practicing gastroenterologist at the Mayo Clinic in Rochester, Minnesota. In addition to his clinical practice, Dr. Martin's interests center endoscopy unit operations and efficiency, technological innovations in endoscopy, and endoscopic training and simulation, and hands-on training and education. He has served numerous ASG committees and previously served on the ASG Governing Board. Dr. Martin also currently serves on the ASG Practice Operations Committee and is certainly very involved in the education and training of APPs. Good morning, Dr. Martin. The audience is yours. Good morning, Sarah, and thank you so much for your very kind introduction. It is wonderful to be back this morning, and we're going to have one heck of a great and fun day learning together, so here we go. We are going to talk for the next few minutes about the evaluation of abnormal liver tests, and I've crossed out function. That's not an error. I've drawn a line through that word for a good reason, and you'll see what that reason is very shortly. So while we call these LFTs, we're going to talk a little bit about the terminology, the different terms for the various liver tests, and how to analyze them. I have no relationships with commercial support to disclose to you. So the objectives of this talk are to define liver tests, to describe and categorize different types of liver tests, to discuss the implications of abnormalities of specific liver tests, to learn the disorders associated with liver test abnormalities, and to determine how to work up patients with liver test abnormalities. Let's start with a few polling questions to wake us up. ALT or alanine aminotransferase is 1. a liver function test, 2. a liver injury test, 3. a cholestatic liver enzyme, or 4. a synthetic liver test. Only one of these is correct. Which one is it? I'm going to go through these one by one, okay? It's not a liver function test, because as you're going to learn soon, ALT is actually not a liver function test, but it's a liver injury test. It's also not a cholestatic liver enzyme, although it is a liver enzyme. It's not a cholestatic one, and it is not a liver synthetic test. The second polling question is alkaline phosphatase, which is sometimes abbreviated ALP, is 1. Specific to the liver, 2. Specific to the bile duct, 3. Can rise only in bile duct obstruction, or 4. Can rise in any cholestatic process. Well, number one is wrong. It's not specific to the liver. Alkphos can be produced by the bone and multiple other organs in the body, and therefore it is not specific to the liver. Although your chemistry department can actually fractionate that alkphos to determine how much of it is liver fraction versus bone fraction. Number two is also incorrect, because I just told you that it's not specific to the liver and it's not specific to the bile duct either, although cholangiocytes, which are the cells that line the bile duct, do have an enzyme that can synthesize alkphos. Number three is also wrong. Bile duct obstruction is absolutely not the only reason that your alkphos can go up. It can go up from a host of reasons related to the biliary tree and the liver, but can also go up for bone reasons and other reasons, like we were just talking about. So it can rise in any cholestatic process. Number four is correct. The other three are wrong. Polling question three, bilirubin 1. Is a cholestatic liver enzyme 2. Is a breakdown product of hemoglobin 3. Is an aminotransferase 4. Is a liver synthetic test. So with this one, number one, it's not a cholestatic liver enzyme. In fact, bilirubin isn't an enzyme at all. It's actually two that's correct. It's a breakdown product of hemoglobin and three is incorrect because it's not an aminotransferase. You know that words that end with ace are enzymes and we just got done saying that bilirubin is not an enzyme. So it's definitely not an aminotransferase. And it is not a liver synthetic test either. So there you go. Bilirubin is a breakdown product of hemoglobin. You knew that. Gamma GT or GGT or GGTP, they all mean the same thing. They're just different abbreviations for the same enzyme. And five prime nucleotide ace. And one of these is correct. They're used primarily to detect liver injury or are liver enzymes used to help determine the source of an elevated alkaline phosphatase level? Or is it three are always ordered together with alkaline phosphatase? Or is it four are liver synthetic tests? Only one is correct. Excellent. You know your hepatology and I'm thrilled to see that. So it's not used, these are not used to detect liver injury. They're not liver injury tests. They are actually cholestatic liver enzymes. And they're used to help you determine if the alkphos is up, whether the alkphos elevation is due to liver alkphos or bone alkphos. So it's kind of a tiebreaker. So you can either fractionate that alkaline phosphatase to determine bone versus liver component or you can order a GGT or a five prime. And if those are elevated along with the alkphos, you can bet that that alkphos elevation is from a liver source. They are frequently ordered together for that tiebreaker purpose. But they're not always ordered together. That's just one of those testology things. If it says always, you know, it's probably not the right answer. And then they're not liver synthetic tests either. They're cholestatic enzymes. But you did awesome on that. Love this stuff, right? So first, liver tests are more than just numbers. They're a tool for you to help figure out why the patient's got a liver problem going on because that's going to help you determine how best to treat it. And look, there are all kinds of things that can go on with the liver that aren't right that you can help control or even cure. There are viral hepatitis A, B, C, D, and E. There's the beginning of your alphabet. There's NASH, which is non-alcoholic steatohepatitis. It's called MASH, metabolic-associated. And there's NAFLD, which is part of that spectrum of fatty liver disease, non-alcoholic fatty liver disease, NAFLD, N-A-F-L-D. There's alcohol-induced hepatitis or cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, often called PBC, primary sclerosing cholangitis, abbreviated PSC. There's acute fatty liver disease of pregnancy, AFLP. There's HELP, DILI, alpha-1 antitrypsin deficiency, acute biliary obstruction, chronic biliary obstruction that can be secondary to a host of processes, including secondary sclerosing cholangitis, secondary biliary cirrhosis, and so on and so forth. So what do these liver tests tell us? They can tell us about liver injury. They can tell us about liver function. And when we talk about liver function in this parlance, we're talking about the ability of the liver cells, the hepatocytes, to synthesize various proteins, including serum proteins, primarily albumin, but also clotting proteins like factor VII and other clotting factors in the blood, as well as the ability to do some heavy lifting that requires a lot of energy, like the ability to conjugate and then transport bilirubin into the biliary system. That's heavy lifting. And so when we talk about liver function, these are the sort of processes we're talking about. So there's liver injury and liver function, and we'll talk in a few minutes about why it's important to understand that concept. Now here is a list of various liver tests, and they're not all liver function tests, and they're not all enzymes either, and it's very, very important to understand that. AST is aspartate aminotransferase, and because it ends with an ace, you know it's an enzyme. ALT is alanine aminotransferase, ALP is alkaline phosphatase. Those are all enzymes. Bilirubin, sometimes nicknamed Billy, can be fractionated into the total fraction that direct the indirect fraction. That's not an enzyme. It's a hemoglobin breakdown product. We just said that. Gamma GTP or GGT is gamma glutamyl transpeptidase or gamma glutamyl transferase. All those terms mean the same thing and refer to that particular cholestatic liver enzyme. Another cholestatic liver enzyme is 5' nucleotidase, which sometimes you'll hear people call 5'. 5' nucleotidase isn't an enzyme, but it is a protein. It's a serum protein in the blood, and it's synthesized by the liver. Protime or prothrombin time, PT or INR, they're all reflecting the same thing, is an element of the clotting cascade and is dependent on clotting factors that the liver produces. So if it takes longer for the blood to clot because your protime is out, it can be a sign of synthetic dysfunction of the liver. So there's different terms here, and they actually mean different things. They do not all mean the same things. And so it's important to understand this confusing nomenclature, and we're going to make it less confusing or not confusing at all right now. Liver tests is the most general and all-encompassing terms. It includes the chemistries and also the enzymes. So if you want to talk about every one of those tests we just mentioned right here, the all-encompassing term is liver tests. Liver injury tests or LITs refers to a subset of liver tests, and liver function tests refers to a different subset of liver tests. Liver enzymes is yet another subset of liver tests, and there's some overlap here. And liver function tests, the most misused term of all, has to do with specific tests within this overall category that reflect liver synthetic and transport functions. Liver injury tests are AST and ALT, and we said that these are enzymes because the full term ends with ASE. These are called liver injury tests because they are synthesized and then already stored in what you can think of as a ready-to-use form in the hepatocyte, the liver cell. So if the liver cell is irritated, inflamed, otherwise injured, because they're already existing and stored in the liver cell, can be immediately released into the bloodstream and measured and found to be elevated. And as a result, they are often called liver injury tests, and they are a type of liver test and they are also a liver enzyme. They are liver injury tests. Liver synthetic function tests are albumin and PT and INR because these reflect the liver's ability to synthesize proteins that they put out into the bloodstream where you can measure them. And if the liver is not synthesizing proteins properly, then these can be low. Liver function tests and liver injury tests are different. Liver enzymes reflect that subset of liver tests, which are actually enzymes. Enzymes are specific proteins that bind to receptors to cause a reaction to happen. And the only liver tests that are enzymes are those that end with ASE, and they are AST, ALT, ALKFOS, GGT, and 5 prime. Liver function tests measure not only synthetic protein synthesis functions of the liver, albumin, and PTINR, but also the liver's function in conjugating and transporting bilirubin from the hepatocyte across the hepatocyte cell membrane into the bloodstream, which we said requires energy and is a heavy lifting thing. These three are liver function tests. So now you know and understand the nomenclature and the different categories of the various liver tests. So now that you know that basis, other categorizations and subcategories include that category that is called cholestatic liver tests, which are a measure of bilirubin not getting out of the liver and the biliary system into the intestine. Those are ALKFOS, GGT, 5 prime nucleotidase, and bilirubin. These are cholestatic liver enzymes because only the first three are enzymes. Bilirubin is not an enzyme. It's a chemistry. But all four of these reflect cholestasis. So only a subset of cholestatic liver tests are enzymes, and it's these first three. Those can be called cholestatic liver enzymes, which is a subset of cholestatic liver tests. So in summary, the liver enzymes are the aminotransferases, AST and ALT, and the cholestatic liver enzymes, ALKFOS, GGT, and 5 prime. Liver chemistries, which are not enzymes, are liver synthetic chemistries, albumin and PTINR, and bilirubin, which can be fractionated to total and direct component. Now let's eliminate some misnomers and confusion. LFTs, that term is often misused because AST and ALT, although some people may refer to them as LFTs, do not reflect liver function. We said that liver function is reflected by synthetic protein synthesis, PTINR and albumin, and bilirubin, because bilirubin also reflects the ability to transport bilirubin properly. Those constitute a measure of liver function, but not AST and ALT. They help you to determine the presence or absence of liver injury. So AST and ALT are liver tests, and they're aminotransferases, and they're liver enzymes, but they're not liver function tests. So it is not correct to call them LFTs. The term liver enzymes can also be misused because people will order a liver enzyme panel, and it will sometimes include bilirubin, which, as you know, isn't an enzyme at all, because it doesn't end in ASE. Bilirubin is sometimes included in the term liver enzyme or LFTs, but neither is correct, because bilirubin is not an enzyme, although its measure can be a reflection of liver function. Furthermore, you may hear the terms transaminase or transaminitis, and those are actually not even proper terms. It's not transaminase, it's aminotransferase, and it's not transaminitis, it's aminotransferase elevation. Use the term aminotransferase, especially if you're talking to hepatologists. They know what's right and what's wrong in their nomenclature. So let's talk a bit about patterns of abnormality. Patterns of liver injury abnormality exist when the AST and the ALT, which are liver injury tests, are elevated out of proportion to cholestatic liver enzyme elevation, namely the elevation of ALKFOS. So if the AST and ALT are more elevated than the ALKFOS is elevated, then you have a liver injury pattern. Liver function compromise, on the other hand, is reflected by a low albumin or an elevated protimer INR. Both of those demonstrate reduced liver function, namely protein synthesis, and or if the bilirubin is elevated, which suggests reduced uptake, conjugation, or transport of bilirubin, presumably by a hepatocyte that's not functioning normally. Cholestasis is reflected by the ALKFOS being elevated out of proportion to the aminotransferases AST and ALT, by the GGT or the 5' being elevated in the setting, of course, of an ALKFOS also being elevated because those are, remember, tiebreakers to help you determine that an ALKFOS elevation is actually coming from the liver and not the bone. Bilirubin typically rises later than ALKFOS and cholestasis, and AST and ALT typically rise earlier than ALKFOS and bilirubin. Why? You know why, because the liver's already synthesized them and they're already stored in the hepatocyte, so they're ready to be released. ALKFOS actually has to be induced, so the biliary tree needs to be obstructed for a while to induce the ALKFOS synthase enzyme to then start producing ALKFOS. And then, when the biliary tree's been obstructed long enough, the bilirubin finally starts to back up into the bloodstream, where you can measure it being elevated, so they usually rise in that order. GGT and 5'—we just talked about that. Other common patterns of abnormality include an ultra-high liver enzyme elevation, which suggests an ischemic injury or an ischemic hit to the liver. Very high liver injury tests frequently harken the arrival of an acute hepatitis. Very high liver injury tests that also include an elevated PTINR and encephalopathy harken the arrival of acute liver failure, whereas moderate elevations of aminotransferases with AST to ALT ratio over 2 to 1 in the right setting are suggestive of alcohol-induced toxicity and injury to the liver. Usually, moderate elevations of aminotransferases with ALT greater than AST, typically rising before ALKFOS and bilirubin, on the other hand, are suggestive of biliary obstruction. Remember, though, history and physical exam come first before labs, and presumably that's what prompted you to order liver tests in the first place. History and symptoms can provide a lot of direction. Acuity versus chronicity can narrow your workup. Past medical history, the pregnancy state, medication, social history, family history, allergies and intolerances, work history, toxin exposure, travel history, drug and substance abuse, whether illicit or not—all of these things provide tremendous direction and help you narrow differential diagnosis. So, you know how to take a history—all of these things here—without going through the entire list for you. You know these things. Don't forget them. Use what you already know. Get a really good history and narrow down and focus that differential diagnosis. On your physical exam, look for jaundice or sclerolicturus, which is often detectable, particularly under fluorescent lights when the bilis 3 or above. The presence of pruritus, severe itching, may be suggestive of cholestasis as a cause. Ascites, other portal hypertensive stigmata like abdominal distension or bulging flanks, shifting dullness, pitting edema, splenomegaly, venous collaterals, or ascites with jaundice. Is there cirrhosis or metastatic disease underlying? An enlarged liver on the abdominal exam or a tender liver edge. Is that hepatitis? Or the presence of a liver mass or right upper quadrant tenderness or remember Murphy's sign? Is that cholecystitis or cholangitis going on? AST and ALT elevated out of proportion to cholestatic liver tests suggest hepatocellular injury, including hepatitis. Remember that history directs these potential etiologies. Cholestatic tests on the other hand, out of proportion to AST and ALT is a cholestatic pattern. There you usually want to start with non-invasive imaging to exclude biliary obstruction, which is typically an ultrasound, which may be followed up by an MRI and an MRCP if that's necessary, as opposed to liver injury patterns, which will make you want to pursue more of a hepatocellular workup with viral serologies, getting an alcohol and other toxin history, and checking other blood work to look for various markers of specific hepatocellular diseases. The need for a liver biopsy is often determined by the results of all of that workup. I think it's worthwhile to work through a case or two. Here's a 64-year-old man who has witnessed collapsing while walking for exercise in a city park. EMS was nearby, thankfully, and found him to be pulseless in V-fib. He was immediately successfully resuscitated and transported to the hospital where blood work was drawn on admission and demonstrated a super high AST of over 2,800, an ALT over 3,000, and an ALKFOS only trivially elevated at 150, and a total bilirubin that was sort of upper limits at normal at 1.4, and an albumin that was essentially normal at 3.9. These liver enzyme abnormalities are most consistent with, is it A, acute viral hepatitis C, B, acute cholangitis from an obstructing bile duct stone, C, ischemic hepatopathy or shock liver from ischemic injury, or is it veno-occlusive disease from chemotherapy, or E, acute alcohol hepatitis. It's ischemic hepatopathy. You may recollect that I mentioned earlier that super high elevations in the aminotransferases are a feature of an ischemic hit to the liver. Management here, does it include viral hepatitis serologies, ERCP, treating underlying cardiac condition and supportive ICU care, a liver biopsy, or alcohol cessation and behavior modification? And the answer, of course, is treating the underlying cardiac condition and supportive ICU care. Here's another case. A 32-year-old woman presents with right upper quadrant abdominal pain and chills. She's experienced this intermittently over the past two months. She says that she drinks a beer or a glass of wine on most evenings, but denies drug use and is on no prescription medications, has taken only acetaminophen for her pain, and her urine's been clear. She's never had surgery. Her weight's stable. She has a three-month-old daughter and an adopted two-year-old son. She works in a liquor store and bartends on occasion. Her exam reveals a mild fever, stable vitals, right upper quadrant tenderness with a negative Murphy's sign. She doesn't look particularly ill, but she appears tired. She started exercising again. Blood work demonstrates AST and ALT, which are mildly elevated, an ALKFOS, which is also mildly elevated, a bilirubin, which is also mildly elevated, an albumin and an INR that are normal, and a white blood cell count that's elevated with a mild left shift. This pattern is most consistent with what? Acute viral hepatitis C? Early acute cholangitis from an obstructing bile duct stone? Is it acute hepatitis from alcohol? Is it HELP? Or is it acute fatty liver of pregnancy? And I would say this is most suggestive of acute cholangitis from an obstructing bile duct stone. The best management here actually includes empiric antibiotics, a right upper quadrant abdominal ultrasound, and surgical consultation because she probably needs her liver or needs her gallbladder out and may need her bile duct cleared. I'm going to let you work through this third case. In the interest of time, you'll be able to see it with its answer in GI leap. So I'm going to whet your appetite by leaving that for you to work through. So practice pearls. Most liver test abnormalities require workup. History and physical can narrow and focus the direction of workup. Acute versus chronic, hepatocellular versus cholestatic, viral versus toxic, autoimmune, travel and so forth. Patterns of liver enzyme abnormality combined with clinical presentation, direct next steps and testing, whether laboratory, imaging or endoscopic. Understanding the what each liver enzyme assay tests for and how it reflects liver injury and function is key to interpreting the nature of the underlying pathology and how to investigate and manage going forward. Additional investigation typically involves a combination of viral serologies, autoimmune markers, immunoglobulins, metabolic enzyme assays, iron studies, genetic tests and imaging. Thank you very much.

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