Thank you so much, Jill, great to see you again. Good morning, everyone. The support for this course or the support that this course has received is just been fantastic. It's been absolutely wonderful. We had a terrific first day. Today we're going to start with a series of talks on liver disease. And I'm happy to kick it off myself. So here we go with the first one, which is evaluation of abnormal liver tests. And the reason why I retitled it abnormal liver tests instead of liver function tests, is that you're going to see that many times when we use the term liver function tests. It's actually a misnomer. What we're talking about is liver tests. Some of them are liver function tests and others are a different type of liver test that doesn't test for liver function. So here we go. I have nothing to disclose. So the objectives today are to define liver tests to describe and categorize different types of liver tests, 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. Here's our first polling question. ALT, or alanine aminotransferase, is A, a liver function test? B, a liver injury test? C, a cholestatic liver enzyme? Or D, a liver synthetic test? Which one is it? So it's a liver injury test. Doesn't tell you anything about liver function, really. It's not a cholestatic enzyme and it's not a synthetic test either. All right, so we're proving the value of some of these questions. All right, the next one is question two. Alkaline phosphatase is A, specific to the liver? B, specific to the bile duct? C, can rise only in bile duct obstruction? Or D, can rise in any cholestatic process? Which one is it? You're smart. I hope I can teach you something today. I sure am going to try. Bilirubin is A, a cholestatic liver enzyme? B, a breakdown product of hemoglobin? C, an aminotransferase? Or D, a liver synthetic test? That's right. That's great. It's not an enzyme. It's a breakdown product of the hemoglobin that's in your red blood cells. Okay. GGT and 5' nucleotides are A, used primarily to detect liver injury? B, are liver enzymes used to help determine the source of an elevated alkphos? C, are always ordered together with alkphos? Or D, are liver synthetic tests? All right. You guys are great. You're great, and you're awake on a Saturday morning. God bless you. Okay, enough questions for now. You did fantastically. So first, liver tests are more than numbers, right? I mean, there's all kinds of liver disorders that we need to diagnose and treat, whether that's viral hepatitis, non-alcoholic steatohepatitis, or fatty liver disease, alcohol hepatitis, or cirrhosis, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis. By the way, those are two of Andrea's favorite diseases. Fatty liver of pregnancy, HELP, DILI, drug-induced liver injury, alpha-1 antitrypsin deficiency. There are all sorts of disorders that we all see and have to manage, and liver tests can be indispensable in both helping with diagnosis and treatment. These tests can tell us all kinds of things. These tests can tell us whether the liver's injured, how well the liver's functioning in terms of its ability to synthesize proteins, including clotting factors, the ability to conjugate and transport bilirubin, which we said is a breakdown product of your red blood cells, which your body's got to get rid of, right? There is a list of commonly used liver tests, and they're not all liver function tests, and they're not all enzymes either, and it's important to understand which one is what because each one tells you something different, or you wouldn't be using all of them. If one or two of them told you everything, then you wouldn't need a bunch of them, right? So there's AST, there's ALT, there's ALP, which we frequently call ALKFOS, alkaline phosphatase. Those three are enzymes, as is GGTP and 5'-nucleotidase. Those five are enzymes. Bilirubin is not an enzyme. It's a chemical, and we said it's a breakdown product, a pigment in your red blood cells. When that hemoglobin's broken down, one of the pigment byproducts is bilirubin, and it can be measured, and your liver cells transport it out to the bile duct, and so it can tell you something about how well your liver is doing in that function. And then the prothrombin time tells you what's going on with the clotting factors that the liver makes. So the nomenclature is very important because you've got to know what you're talking about, otherwise you can't communicate with other caregivers about liver disease. Liver tests is the most general term. It's the most all-encompassing. Every one of those moieties that I talked about just now, everything on that list is a liver test. The liver injury tests are a subgroup. The liver synthetic function tests, or the liver function tests, are yet another subgroup. And in a Venn diagram, overlapping fashion, some of them are liver enzymes, and some are not enzymes, but other types of chemicals that are not catalyzing proteins, which is what the definition of enzymes is, as you remember from biochemistry. Liver function tests is a rather specific subgroup of the above. The liver injury tests are AST and ALT. Those two enzymes are already made and stored and ready to release by the hepatocytes, the liver cells. And so when the liver is goosed because it's inflamed or it's injured, it can secrete these already made enzymes right into the bloodstream, and so they go up pretty quickly. And because they reflect liver injury rapidly and almost immediately, they're called liver injury tests. So AST and ALT, those two aminotransferases, should be referred to as liver injury tests and not liver function tests. Liver synthetic function tests, abbreviated liver function tests, are albumin and PT or INR, because those are proteins that are synthesized by your liver. If they're low, then it might be because your liver isn't healthy enough to be making them in the proper amounts. Liver enzymes, well, first, to be a liver enzyme, they actually have to be enzymes, and we said that prothrombin and bilirubin are not enzymes, so they couldn't be liver enzymes. The liver enzymes are AST, ALT, ALKFOS, GGT, and 5'-Nucleotidase. The liver function tests, the ones that tell you something about how well the liver is functioning and making stuff or actively using energy to secrete stuff, are albumin, PT or INR, and bilirubin. The cholestatic liver tests, the liver tests that tell you something about whether the liver is either transporting bilirubin properly or whether that transported bilirubin in the form of bile is getting down the ductules and the bile ducts properly, or if the bile duct system is obstructed. Those tests are ALKFOS and GGT and 5'-Nucleotidase, those three being enzymes, and bilirubin, which is not an enzyme but is a chemical. Cholestatic liver enzymes, so we just said to be a liver enzyme, they have to be enzymes. That's a subgroup of that list of four that doesn't include bilirubin because we just said bilirubin is not an enzyme. So it's a cholestatic liver test, but it's not a cholestatic liver enzyme. So to talk about this over and over, which I do so that you don't forget it, the liver enzymes or aminotransferases and cholestatic enzymes, or liver injury tests and cholestatic enzymes, and the liver chemistries, which is yet another moniker, include the liver synthetic chemistries, the actual liver synthetic function tests of albumin and PTINR and bilirubin. Those are chemistries. They're chemicals. They're not enzymes. So there's a lot of confusion and frank misnomers because LFTs is often misused because AST and ALT aren't liver function tests. They're liver injury tests, so you shouldn't call them LFTs. They're LITs. Liver enzymes can be misused because bilirubin ain't an enzyme, so it can't be a liver enzyme. However, it is a liver test that reflects liver function in the form of transport of bilirubin across the cell membrane of the hepatocyte. Transaminase and transaminase are not even words. You hear people say, hey, the LFTs are elevated. They've got a transaminitis. Nope, they don't because that's not a word. Neither is transaminase. The proper word is aminotransferase, and if something's elevated, say exactly which tests are elevated. Don't say there's a transaminitis. There are patterns of abnormality of liver tests, and this is really important in the work that you do. If there's liver injury, look to the AST and the ALT, which are the LITs, to be elevated out of proportion to ALKFOS. Now, the cholestatic liver enzymes may be elevated, but if there's liver injury, the aminotransferases are going to be elevated out of proportion to how much the cholestatic liver enzymes, such as ALKFOS, GGT, or 5' are going to be elevated. Liver function compromise, which usually means bilirubin transport and protein production as the surrogate markers, are going to show a low bilirubin and or an elevated PTINR and or an elevated bilirubin. Cholestasis, which is a word for saying basically that the biliary system, including the transport of bilirubin across the liver cell membrane, is not normal. That can be due to lack of transport or to blockage of the bile duct system from the root of the tree trunk of the bile duct all the way to the tip-top branches up inside the liver. In this situation, the ALKFOS and, of course, the GGT and 5' nucleotides will be elevated out of proportion to the liver injury tests, which are AST and ALT. However, because, like I told you, AST and ALT are already made and ready to eat, so to speak, inside the liver cell, ready to be released immediately, those are actually going to rise earlier in biliary obstruction than the ALKFOS. But given time, ultimately, the ALKFOS and or bilirubin will be elevated out of proportion to the liver injury tests. GGT and 5' nucleotides basically tell you the same thing as the ALKFOS. However, because ALKFOS can also be produced by bone and other tissues, just because the ALKFOS is up doesn't necessarily mean that it's because of biliary obstruction or lack of proper bilirubin transport. If you don't know, you can either fractionate the ALKFOS to make sure that the elevated ALKFOS is the liver fraction of ALKFOS and not bone, or a lot of times it's a lot quicker and easier to also order a GGT or a 5'. And if those are elevated, that's pretty much a surrogate marker that's good enough to tell you that that elevated ALKFOS is from the liver and not bone. Now, other common patterns of abnormality. Ultra-high liver enzyme elevations suggest ischemic injury or shock liver. Very high liver injury tests, acute hepatitis. Very high liver injury tests with an elevated PTINR and encephalopathy, acute liver failure. Moderate elevations of aminotransferases with an AST to ALT ratio over 2 to 1 in the right setting, that suggests alcohol toxicity to the liver. Usually, moderate elevations of aminotransferases with ALT greater than AST, typically rising before ALKFOS and bilirubin, are suggestive of biliary obstruction, like we said a minute ago. Now, a clinical approach to the abnormal liver enzymes always, like with every other disease process, involves a history and physical, which come first. That's what probably prompted you to get the liver tests in the first place. The history and the symptoms are going to give you a lot of direction. Acuity versus chronicity can narrow it up. Past medical history, pregnancy, medication, social history, including substance use, family history, allergies, and intolerances are going to wrap that up, along with a work history, toxin exposure history, travel history, and drug and substance abuse, whether we're talking about prescription stuff or the illicit ones. There are a number of questions you can ask during the history. I think, as healthcare professionals, you already know what these are, but I've listed them for you and won't insult you by going through them below by below. With the physical look for jaundice and scleral icterus, which is yellowing of the whites of your eyes, it's usually something you can pick up if you're experienced with a bilirubin of around three or even a little lower. In fluorescent lights, you can often detect it at around two and a half. There may be evidence of pruritus, which is itching all over. That is suggestive of cholestasis, even if the bilirubin's not elevated. Look for portal hypertensive stigmata, like ascites in the belly, fluid in the belly that weeps off the liver in portal hypertension. If they have ascites and jaundice, is that from cirrhosis or is that from metastatic disease? If they have an enlarged liver or a tender liver edge, do they have hepatitis? A liver mass, right upper quadrant tenderness or a Murphy's sign suggests cholangitis or cholecystitis. We talked about this briefly before. AST and ALT elevated out of proportion to cholestatic tests is a patecellular injury. The history will direct your potential etiologies, and I've listed some ideas about workup. Cholestatic tests out of proportion to AST and ALT is a cholestatic liver test elevation pattern. Usually start with some noninvasive imaging, like an ultrasound probably followed by an MRI if that's indicated, and a need for liver biopsy is determined by the above. Let's do a case. A 64-year-old man's witness collapsing while walking for exercise in a city park. EMS was nearby and found him to be pulseless and v-fib. He was immediately resuscitated and transported to the hospital. Blood work drawn on admission demonstrates an AST and ALT that are sky high, an alkfoss of only 150, a bilirubin that's 1.4, and an albumin that's 3.9. The liver enzyme abnormalities here are most consistent with A, acute viral hepatitis C, B, acute cholangitis from an obstructing bile duct stone, C, ischemic cholang, I'm sorry, ischemic hepatopathy or shock liver, D, venoclusive disease, or E, alcohol hepatitis. Which one is it? It's ischemic hepatopathy or shock liver. We said that the liver injury tests were way elevated out of proportion to everything else, and this guy was in shock, in pulseless v-fib, so this is shock liver. Management includes A, viral hepatitis serologies, B, ERCP, C, treating the underlying condition, D, liver biopsy, E, alcohol cessation, and behavioral modification. This is shock liver, right? We need to get his heart pumping. If you can get blood back to the liver, the liver's going to be okay, so the answer is C. 32-year-old woman presents with right upper quadrant abdominal pain and chill. She's experienced this intermittently over the past two months. She says she drinks a beer or a glass of wine on most evenings, denies drug use, no prescription meds, takes only acetaminophen for her pain, and her urine's been clear. She's never had surgery, weight stable, three-month-old daughter, adopted two-year-old son. Man, I threw all kinds of stuff in this. She works in a liquor store and bartends on occasion. She's got a touch of a fever, stable vitals, otherwise mild right upper quadrant tenderness with a negative Murphy's sign. She doesn't look particularly ill, but she looks tired, and she started exercising again. All right, blood work demonstrates ALT and AST look pretty normal. The ALKFOS a little bit elevated. Bilirubin's a little bit elevated. Albumin looks normal. The INR is normal. The white blood cell count is up a little bit with a left shift. So, she's got a fever, right? She's got pain and tenderness, and she's got a white count elevation. So, is this viral hepatitis C? Is it HELP syndrome? She's not pregnant now. Is it acute hepatitis from alcohol? Yes, she bartends and drinks, but does that cause a fever and a left shift and a high white count? I don't think that's usually the case. Acute fatty liver of pregnancy, not pregnant, right? So, I threw all that alcohol stuff in there to trick you. This is actually acute cholangitis from a bile duct stone. You can have other stuff and still have that. Best management includes viral hepatitis serologies, empiric antibiotics and a liver biopsy, empiric antibiotics and urgent ERCP, empiric antibiotics, right upper quadrant ultrasound and a surgical consultation. Or is it E, alcohol cessation? We just said this wasn't alcohol, right? She doesn't need a liver biopsy. It's not a liver problem. And we don't need hepatitis serologies. We don't even need an urgent ERCP. Put her on antibiotics. Get a surgical consultation because she's going to need a cholecystectomy. And depending on the surgeon, they may be able to clear that bile duct while they're taking the gallbladder out and obviate the need for an ERCP. So, you don't need an urgent ERCP. Get the surgical consult first. One more case. 20-year-old man brought to the ED by his frat brothers. He was drinking at a keg party four days ago, slipped and hit his head on his shoulder on a brick walkway, but was able to continue partying by taking Tylenol regularly around the clock. It says he takes a double dose of Tylenol to keep the pain in check, and he's done well with that. Thank goodness. After all, it is rush week, so he's been required to attend nightly keg parties with the Rushies, including tonight. His fraternity brothers think he's intermittently, mildly confused, though. Blood work. AST's 1,700. ALT's 2,100. Alk-Fos is 302. Billy is 5. His albumin's 3.6, and his INR is elevated. These are consistent with what? Acute drug-induced liver injury from alcohol, acute liver injury from Tylenol, ischemic hepatopathy or shock liver from his fall, cirrhosis from alcohol, or Gilbert's syndrome. That, folks, is Tylenol toxicity exacerbated by all that alcohol consumption. That's really dangerous stuff. Does he need to be in the hospital and get viral serologies, hospital, and by antibiotics and liver biopsy, hospital, antibiotics, ERCP? Does he need Tylenol and ethanol levels, toxicology, screen, et cetera, et cetera? Of course he needs that. We said that this is Tylenol toxicity. This guy's going to lose his liver, possibly, if we don't jump on him right away. And even if we jump on him right away, he could still need a liver transplant. He's encephalopathic. That's probably why he's confused. That's a bad sign. He needs to be in a liver unit with a full evaluation in the intensive care unit. Practice pearls, folks. Most liver test abnormalities require workup. History and physical exam can narrow and focus the direction of workup. Acute versus chronic, hepatocellular versus cholestatic, viral versus toxic, autoimmune travel, et cetera. Patterns of liver enzyme abnormality combined with clinical presentation direct the next steps in testing, whether that's laboratory imaging or endoscopic. Understanding what each liver assay tests for and how it reflects liver injury or function is key to interpreting the nature of the underlying pathology and how to investigate and manage going forward. Remember that additional investigation typically involves a combination of viral serologies, autoimmune markers, autoimmune or rather immunoglobulins, metabolic enzyme assays, iron studies, genetic tests, and imaging. I thank you very much.

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