FEMALE SPEAKER: Welcome to Mayo Clinic COVID-19 Expert Insights and Strategies. The following activity is supported in part by an independent medical education grant from Pfizer Inc and is in accordance with ACCME guidelines.

AMANDA CHANEY: Hi. Thanks for joining me today. I'm Amanda Chaney. I'm a nurse practitioner at Mayo Clinic in Jacksonville, Florida in the transplant department, hepatology. I'm going to bring you another lecture on the COVID-19 Expert Lecture Series. This one is regarding abnormal liver profiles and Liver Function Testing and how do we approach that. Here are some disclosures that I have. So we're going to talk a little bit about some reasons why there could be abnormal LFTs in patients. We're going to talk spotting the why and what's that process look like, and then, when to refer.

First, we want to talk a little bit about the liver's function and what does it do. I gotta admit, when I first started in hepatology and liver transplant, I was pretty clueless about what the liver did, which is a lot. We wanted to talk a little bit about the synthesis of what it produces. So it produces proteins like albumin. It produces clotting factors, fibrinogen, prothrombin. There is metabolism of nutrients, so amino acids, cholesterol, fat, and glucose.

And then there's detoxification of substances, so whatever medications you consume, it's going to be detoxified within the liver. And ammonia is converted from its toxic form of NH3 over to urea in the liver and then excreted out through the urine. And if the liver is impaired, and that's not happening, then the ammonia can cross the blood brain barrier and lead to confusion and more problems. And so definitely a very important function that the liver does.

It also aids in immune response. So the Kupffer cells are activated within the liver. And then digestion, it helps with digestion. It creates about a liter of bile a day, which seems like an enormous amount. Bile salts are critical for fat soluble vitamin absorption. And so if the patient has a biliary disease, or if they have longstanding malnutrition or cirrhosis, it's very typical that these patients will have impairment of those fat-soluble vitamins [INAUDIBLE] so Vitamin A, vitamin E, vitamin K, all of those are impaired. And then fat/cholesterol absorption occurs in the liver as well.

When we think about liver function tests, liver biochemical tests is really the more appropriate term. These are the ones that we think about. So alk phos, ALT, AST, bilirubins-- total and direct-- Protime or INR, GGT, 5-nucleotidase, as well as the LDH level. For the purposes of this lecture, we're going to really focus in on these five studies.

When we think about testing and figuring out what's going on the liver, we can break it up into hepatocellular and cholestatic testing. The cholestatic testing is really looking more at the biliary core process. And so alkaline phosphatase would be one of those in the grouping of cholestatic.

Normal is anywhere from 30 to 115. If there is an isolated elevation in the alk phos, then you can get a GGT to see is it more from the liver, is it more from bone, and that can guide some of your differentials. A fractionated ALP can be done as well, which also can do the same and guide you into which direction this is happening.

When we think about bilirubin, bilirubin is the direct breakdown from heme. So if there is an isolated bilirubin elevation, you want to think about biliary disease as well as a problem going on with the breakdown of heme and breakdown of the hemoglobin. And so definitely, if this is isolated, and there's more of a direct hyperbilirubinemia, you could do a hemolytic screen to further look into that.

Albumin is a protein that is synthesized in the liver, and so it's very common to be low in patients who have longstanding cirrhosis and/or malnutrition or cancer. And so definitely, we can look at that as a part of the whole picture when thinking about liver disease.

One of the best liver function tests is truly an INR. So when we know that the INR is high, that is really a good indicative sign of poor function on the liver's part. It could be a sign of vitamin K deficiency, which again can happen in a patient who has bilirubin problems or has malnutrition or prolonged cancer or prolonged jaundice.

And you can figure out whether or not that's going on or not if you give them a bolus dose of vitamin K, so 10 milligrams sub q for three doses. And if the INR gets better following that bolus, then it's probably a relation to vitamin K deficiency. If it doesn't get better, then it's indicative of more core liver functioning.

So it can be really confusing. So normal levels don't always mean that the patient's liver is good. Some patients with liver injuries, particularly longstanding chronic hepatitis, will have normal labs. And then some patients with normal labs may have liver injury. And it may make you feel really frustrated and like you're studying for an exam, and you're never going to get it right. [CHUCKLES] So what you have to do is look at the patient and look at the different results.

So there are some abnormal liver testing, and when that happens, and it frequently happens for patients in the outpatient and in the inpatient setting-- it could be a mixed picture-- a lot of times, a patient's going to be completely asymptomatic and walking and talking and doing just fine. So you want to know if this is an acute thing going on, so in between a month and six months, or is this more of a chronic issue. And so you can divide it into that categorization.

Hepatocellular/cholestatic disease, if that's the picture that's going on-- so if it's a viral hepatitis, if it's alcohol hepatitis, those patients are going to have elevations of not more than 10 times the normal range. For a patient who has primary hepatocellular disease-- so this is talking about patients who have acetaminophen toxicity, acute liver failure for unknown etiology, or patients who have a trauma where they all the sudden don't have any blood flow to the liver-- those liver cells are actually dying, and the enzymes within those liver cells are released in very high amounts.

And so those lead to elevations that are 25 times the normal range. And so we're talking about the transaminases, the ALT, AST are in the thousands. And so that's how you can differentiate a little bit between more of the acute abnormalities that are super, super high versus those who may be in the more 100 ranges.

We're going to talk a little bit about a case study. So this is an actual patient. She was super sweet. Mrs. S, she was a pleasant 55-year-old lady, and she went to the emergency room for a one week history of itching and yellowing of the skin. She had gone to work the day before, and a friend of hers at work said, oh, my gosh, you are so yellow. And not only would it kind of give her a bit of a complex, but she thought that she should come to the ER and have that evaluated.

She had been diagnosed by her PCP with some chronic bronchitis about two weeks before, and she was started on Bactrim DS twice a day for 14 days. And so far she's completed seven days of that treatment. She reports really feeling fatigued, nauseous, and they actually did in the ER a right upper quadrant ultrasound because of abdominal pain she was having. She denies any history of liver disease. She denies any alcohol consumption. She does have a medical history significant for obesity, for diabetes on metformin. She's on Synthroid for hypothyroidism. And she has known chronic bronchitis.

This is her physical exam. So blood pressure is pretty good. Her heart rate's 90. Respiration rate is 24. And she has a little bit of a temp. It's 38.2. She is very yellow. She appears very jaundiced and with scleral icterus. And she complains of severe itching and so badly where she has scrapes on her arm from just excoriating her skin because she's scratching so much because she's itching so bad. She also has a mild maculopapular rash to the chest and the back, and it started the day that she came to the emergency room.

This is what her labs look like. So remember, total bilirubin is anywhere from 0 to 1, right? And so on her labs it's 12. Her alk phos is 250. Her ALT is 75. AST is 42. Her INR is 1.2. CBC is normal. And her renal profile is normal. So no evidence of any thrombocytopenia, no evidence of anemia. Specifically looking at the kidney function, no electrolyte imbalances, and creatinine is normal.

Her ultrasound showed fatty infiltrate of the liver consistent with fatty liver disease, patent vasculature-- so all the vessels in the liver, portal vein, hepatic artery, all that's flowing well. And there is some presence of gallstones. So what do you do? Do you A, admit her to the hospital? Do you, B, repeat a liver panel? Do you, C, send her for blood cultures and a lactic acid? Do you, D, send her for viral hepatitis studies? Do you, E, stop the antibiotic? Or do you, F, do all of the above? And what we did was do F, all of the above.

We're going to go back to her in a few minutes, but we're going to talk through some of this abnormal liver testing. So when I was first starting in hepatology one of my wise preceptor physician mentors said, it's really not that hard. You can break it up into four findings, disease, infection, drugs, or pregnancy. And so I have taken that to heart, and I like to categorize things and keep things very organized in my brain. And so this helped me a lot to think about this very organized and strategically.

This is a really good table that I have found very useful when talking about abnormal liver testing, and it's adapted from the American Association for the Study of Liver Disease who actually have some great resources on that website to help with some of these understanding liver disease specific things.

So when we're looking at liver injury tests, those are going to be the alk phos as well as the transaminases, which is the ALT, AST. And like I mentioned before, those get really, really high in hepatocellular injury. Though the alk phos is more of a cholestatic picture. And so thinking about something wrong with the bile ducts or something going on biliary system-wise, that would be really, really elevated in a cholestatic problem.

And then we break it into the function of the liver. So the true function of the liver is using the INR. That's one of the best ones. And so if it's long and does not correct with vitamin K, then that's more liver cell hepatocellular injury. If it corrects with vitamin K, that's probably because of the deficiency because it's not working with the fat soluble vitamins. And so that will correct with vitamin K.

Total and direct bilirubins can be really, really high in either disease, whether it's just hepatocellular or with cholestasis. And then albumin is going to be low, very low, in patients who have malnutrition or have chronic liver disease. So again, take this table and make it your own, but it really helped me to kind of put it all into very structured pieces.

So we mentioned that the patient with moderate elevation of those transaminases. And so we're talking about in the high 50s, 60s, 70s, up to the mid-100s maybe, those are going to be more your viral hepatitis patients, fatty liver, alcohol disease. But really, really high elevations looking at in the 1,000 range, those are patients who have a toxic hepatitis. So I've seen this once with a patient who had an acute hepatitis B. I've seen it once for a patient has had an acute hepatitis A. Most of the time, those acute phases are more self-limiting and symptomatic treatment versus needing to come into the hospital for a transplant evaluation, but it can happen.

And then, patients who have ischemic or shock livers, so thinking about a trauma, specifically a car accident or some sort of trauma that had a shock to the liver where there wasn't any blood flow for a period of time. Patients who have elevated bilirubin, so that's that more cholestatic picture, the bilirubin gets into the skin, into the dermis, and it causes severe itching.

And there are some ways to treat that. Some patients with severe hyperbilirubinemia like thinking in the 50s or 60s ranges sometimes are really, really difficult to control their pruritus. There is some school of thought out there that plasmapheresis or those sorts of measures, drastic but can be done to help with some of the symptoms of that.

And so that can happen with medication. It can happen with alcohol disease. I've seen a few cases where a patient was on an herbal medication, and they had an acute elevation of their bilirubin levels. And viral hepatitis can have sometimes an elevation in the bilirubins as well.

Particularly for biliary disease, we're talking about primary sclerosing cholangitis our primary biliary cirrhosis, those are very commonly known reasons why a patient could have a very, very high bilirubin level. And I crossed out abnormal LFTs because we really want to think about this more as abnormal liver testing versus LFTs because not all of these are true function tests.

This is another depiction of the school of thought that I was bringing to you earlier. Looking at the more in the 100 range is going to be chronic hepatitis, alcohol, and then, we get to autoimmune, that can be into the 1,000 range, but not really much higher than that. Acute viral hepatitis can be in the 1,000 range. Ischemic or toxic liver injury like acetaminophen toxicity, those can be very, very high.

So what are your steps for your evaluation? So as always, you want to get a really good history and a base for differential diagnosis on what you find on your labs, what you find on your imaging studies. We definitely need to know whether this is an acute process versus a chronic process. And then if the patient does have chronic liver disease, and they have cirrhosis, we need to know if they are compensated, or if they are decompensated. And then, we'll go into a little bit of complications of liver disease.

So as far as history, you want to know alcohol consumption, if they have any risk for viral hepatitis, travel outside of the country, or any blood transfusions prior to 1992. There's a lot in the history that can be gained to kind of guide you on your differential where you're going to go.

Medication-- so I mentioned before herbal medications are not benign, and so I think it's really important to get a full history of all the medications a patient could be taking. Looking at physical exam findings-- so does the patient have ascites or they have muscle wasting? Do they have temporal wasting? Are they yellow? Do they have any scleral icterus? Do they have any venous protuberances on their belly because of the ascites or caput medusae? There is some palmar erythema that can happen in the patient with chronic liver disease.

And then risk factors, you want to know do they have any risk factors for cardiovascular disease? Do they have any co-morbidities of diabetes or any sort of inflammatory bowel disease that could lead you to more of an autoimmune picture? So all of these pieces are really important to talk to the patient about, talk to their caregivers. See if there's anything that guides you into the direction of where this abnormal testing could have come from.

So I'm going to ask you, why do you think Mrs. S had hyperbilirubinemia? Do you think it was, A, because of viral hepatitis? Do you think it was, B, because of a drug reaction from her antibiotic? Do you think it was, C, from fatty liver disease? Or do you think it was, D, from a cholestatic disease?

And the answer is actually B. She actually had hyperbilirubinemia because of a drug reaction because of that antibiotic. So what is your next step in reading this. Do you, A, stop the Bactrim? Do you, B, an urgent referral to an expert for a transplant evaluation? Do you, C, consult infectious disease? Or do you, D, start her on Ursodiol?

So your immediate next step is going to be to stop the antibiotic. She actually was seen at an outside emergency room, and because her liver enzymes were so high and her bilirubins were so high, she was sent to our ER for transfer. And so we accept her, and we did an urgent evaluation for a transplant in the hospital just in case the bilirubins didn't respond and didn't improve. But thankfully, they did.

So we're going to talk to us a minute about drug-induced liver injuries. So when we think about drug-induced liver injury, we've seen it a lot in antibiotics, especially sulfa medications that a patient was on to contribute to hyperbilirubinemia. It can be because of acetaminophen. It can be because of NSAIDS.

And then I've had another patient who was on some weight loss supplements with his wife, and he wanted to support her and help her with her weight loss journey, and he ended up having an acute elevation in his liver enzymes as well as the bilirubins and needed transferred to our center for an urgent transplant evaluation.

And that was the only thing that we could find. We did viral hepatitis studies. We did all the other studies in the book and could not find anything that caused, but we took away that piece of the equation, and eventually, his labs got better. And his wife was fine. She didn't have any problem with the weight loss supplement. But those supplements and just anything a patient puts in their body is definitely important to review in the history to get a very well rounded, clear picture of what's going on.

So this talk is in the lecture series of COVID-19. So what about patients with COVID-19? So in this paper, there are some medications that are being tested for patients who have moderate to severe COVID symptoms, and these medications, antibiotics and antivirals, do cause some elevated liver enzymes and abnormal liver labs. And so it's really important to know that and to take the whole picture into consideration. Any new medication could be blamed for this sort of reaction.

And so this paper-- I'll guide you back to this paper, but it was a really good one that was put out by the International Association for the Study of Liver Disease. And it had a great table in it that shows which medications specifically can be related to abnormal liver profiles and labs.

So in the evaluation piece, you want to stop anything that could be possibly hepatotoxic. Consider drug to drug interactions definitely for patients who are older and who are on a lot of medications, or even the post-transplant setting, patients are on a ton of medications. Consider drug to drug interactions. Like I said, antibiotics are to be blamed frequently.

Thinking about additional lab tests that you want to get-- so we want to rule out other causes of liver disease. So get those viral hepatitis studies. Iron studies rule out hemochromatosis. Alcohol screen, toxic screen, any sort of steroids or anything else that be a cause for that as well as autoimmune markers to rule out any autoimmune disease. And then your first step for imaging is always going to be an ultrasound.

So the usual patient is going to be completely asymptomatic. We're going to have mildly elevated transaminases. Their blood test workup, all the other labs that you've gotten are completely normal and negative. And so your differential is pretty standard thinking about is it medications, is it from disease, or is it from-- pregnancy you usually can rule out, especially an area who is an older population and who are men. You can rule that out pretty easily.

And so in your differential a lot of times this is from alcohol, hepatitis alcohol related disease, fatty liver disease, or from medication, from the drug interaction. For patients with alcohol injury, the typical board question is that their AST to ALT ratio is 2 to 1, and there's an elevation in the GGT. AST is usually less than 300. So it's high, but it's less than that 300 number.

So what are our recommendations? So typically, we like to trend it. We like to see what happens. So if there's no hepatic decompensation, no significant lab findings. You did the work up and nothing else is coming back positive so there's nothing to treat. Lifestyle modifications-- tell the patient not to drink alcohol. You don't want to add any more insult to injury. So if the liver is already irritated, you don't want to get more irritated with more things to detoxify.

Weight loss, if the patient does have a need for that, then definitely that is one of the mainstay of treatment for fatty liver disease. And so we want to advise them on that, maybe consult with a nutritionist and see what their recommendations are for some guidance on some good food choices.

And then controlling the diabetes-- so again, you don't want to add more insult to injury, and you want to control if there is any insulin resistance or any sort of issue with that. And you want to have that under good control so that the liver doesn't have to work harder.

There is repeat testing that's recommended in six months or so, and if they're still elevated, then you can go ahead and get a consult with a specialist to see what else could be done or what other imaging you should consider. For patients who have viral hepatitis, hepatitis A and B typically clear on its own. If it doesn't and hepatitis B particularly, then antivirals could be recommended depending on the case.

If the iron studies are abnormal that you got, then a patient could have a history, a genetic profile consistent with hemochromatosis. So consider that testing. Stopping all iron supplements because again, you don't want to add more problems to that, and alcohol consumption, and then liver biopsy if there are ongoing abnormalities.

For a patient with an abnormal alk phos only, then we could get GGT testing. We could do a fractionated ALT, and then a history, physical exam. If the GGT testing is abnormal, then that can point you in the direction of getting more studies, so an AMA and an ultrasound specifically looking at an autoimmune piece. And then liver biopsy if there's ongoing abnormalities. We have seen this, an isolated AST elevation, particularly in marathon runners or really strenuous exercisers, and it's related to muscle injury. So that is a possibility for that patient.

So what do you do if there is biliary ductal dilitation? So this is the cholestatic picture. There's on ultrasound had picked up something that was concerning for ductal dilitation in the bile duct. We would recommend AMA testing, so looking for PSC, PVC, sort of picture as well as ERCP. That's one of the best things to do to visualize what's going on in the bile ducts.

If there's strictures, if there's specific tightness that's going on in those bile ducts they can place a stent in that and open it up. Possibly, sometimes patients need external drainage if the internal drainage does not work. We want to keep those ducts open. If they do get strictured and tight and block from drainage, those patients can become septic very fast. And so we definitely want to identify that soon and quick and get them the proper treatment.

If there's abnormal bilirubin levels, again, we talked about this a little bit earlier, getting hemolytic testing to see if the bilirubin is being broken down appropriately. And again, if the conjugated bilirubin is elevated along with other abnormalities on the liver profile, then further imaging and testing could be done.

So again, when we think about this, we think about it in a kind of cellular in the liver injury piece, and then in the cholestatic piece, we're looking more at the bile duct piece. So if it's acute, it could lead us down the differential for hepatocellular injury, of viral hepatitis, or drug or toxin. If it's cholestatic injury, then it could be drug-induced or could be from a bowel duct obstruction.

And so the questions to ask yourself in that acute phase is, number one, if it's more hepatocellular, is there evidence of liver failure? And if your answer is yes, then the patient probably needs to be hospitalized and see a specialist. If your answer is yes for the cholestatic picture, then again, admission and further workup with a specialist to see if they have cholangitis. If they do, get it corrected sooner rather than later because if you don't, then this patient could get very sick and have sepsis and septic shock.

On the chronic side, again, hepatocellular injury more for alcohol, fatty liver disease, viral hepatitis. And cholestatic, is there evidence of primary biliary cirrhosis? Is there evidence of drug-induced injury? So the question to ask yourself in the chronic phase is is this cirrhosis? For the yes, is it compensated or is it decompensated?

And we're going to talk about when to phone a friend. So when you get that expert consultation, you really are asking why is this patient-- I've done the initial workup. I've gotten a really great history, but six months later, they still have persistent LFTs. This is the time when you go ahead and get that evaluation. And liver biopsy can be done, but it should only be done by a trained expert. It does come with its risks, bleeding, bowel perforation, infection. And so definitely want to do it in a place where they do a lot of them, they do them well, and by a clinician who knows what they're doing.

So we talked a little bit about cirrhosis. This is kind of my world in transplant work where I live, and there's about 5 million people in the United States living with liver disease, and cirrhosis as the 8th most common cause of death in the United States. Complications result in significant morbidity and mortality.

And so I talked briefly about the compensated versus decompensated. If the patient has compensated cirrhosis, they could be walking, talking, doing just fine until they move to that decompensated stage. And so what does that mean? Complications of cirrhosis include SBP, so spontaneous bacterial peritonitis, hepatorenal syndrome, ascites, esophageal varices with bleeding, portal hypertension. These are just to name a few. But if a patient develops any one of those, they have successfully or unsuccessfully moved from compensated to a decompensated cirrhotic. And that's when we need to do a transplant evaluation.

So how sick are these patients with cirrhosis? So we evaluated that two ways. The first was back in the '60s. The Child Pugh Score was created, and it was used to estimate the severity of illness. It took into consideration the total bilirubin, the INR, the albumin, and then the presence of ascites and encephalopathy. Patients with a Child Pugh A Score, they had a pretty good survival in one to two years. But as we get to more of the C score, these are the more decompensated cirrhosis patients. At two years, they have a 35% survival.

In the 2000s, Dr. Weisner sought to do the 2.0 version of the calculation for cirrhotics and see how bad the cirrhosis was, and if they could figure out a way to put patients on a priority on the wait list for transplant where the sickest person gets the transplant, not just by their wait time of how long they're waiting on the list.

So he took into consideration the total bilirubin, the INR, and the creatinine. Puts it in a calculation, and you pop out a number, and it ranges from 9 to 40. So 9 is too early for transplant where 40 is a patient who's in urgent need for transplant. So those are the patients who are, if they're listed for transplant, those are higher on the list. And it is used by the United Network for Organ Sharing to prioritize the wait list.

A little bit later, the sodium was added to the calculation, and it's now called the MELD-Sodium Score, and what was found in the evidence and literature was that the patients who had cirrhosis and who had decompensated liver disease who also had hyponatremia, those patients had a higher risk of death and were definitely sicker. And so that's the reason why they added the sodium into the calculation. For those who are hyponatremic are sicker, and they need to be prioritized at a higher level for transplant.

This is another slide of that table that we mentioned earlier. And again, just you can take that into consideration with these patients. And so liver injury in a COVID world, so what exactly does that mean? And this is adapted from that article that I led you to earlier.

So a patient could have ALT and AST elevation with some of the antiviral medications. This would seem to happen more often in patients who are older, who are of male gender, and who have diabetes mellitus and hypertension. So again, thinking about patients who have liver disease, who have metabolic syndrome, these patients typically are sicker with COVID-19. And then, the medication that you're giving them can cause isolated transaminases elevation as well.

It's important to note that patients with COVID-19 who have tested positive, about 2 to 11% of them have underlying chronic liver disease, and that many patients with COVID-19 have developed some sort of degree of hepatic dysfunction. And so again, something really important for us to be mindful of. Mortality was about 0 to 2% in our latest current literature for patients with chronic liver disease.

With that, I want to thank you for joining me and for listening to this lecture. I hope it was helpful for you. This is my contact information if you have any questions or anything that I can answer of research for you that you were wondering about. And with that, I thank you very much.