During this 20-25 minute pre-recorded lecture, Dr. Jawad Ahmad discusses the topic of abnormal LFTs and jaundice. This in-depth review will provide an update on this topic for your clinical practice as well as supplement your learning for the ABIM Gastroenterology and Hepatology boards. CME pre-requiste of live Q & A webinar, 8th Annual Mount Sinai Intensive Board Review in Gastroenterology & Hepatology on Oct 13. Hello everybody. My name is joe Arda marred and I'm going to be presenting abnormal LFTs and jaundice as part of the Mount Sinai intensive review in gastroenterology and hepatology. I have no disclosures. So let's start with a question. This is a 19 year old man who was referred to the liver clinic for abnormal liver tests. He comes with his mom who really feels this is related to his drinking because he's been mixing with the wrong crowd at school and in fact he's been expelled Due to his behavior and poor great on exam. He's a little overweight with a bmi of 29, looks a bit disheveled, nervous but on exam of his abdomen. Really you don't find any evidence of chronic liver disease. And his laboratory studies have shown for you LT of 87 s. t. 163. Total bilirubin mildly elevated but mainly indirect alkali foster tater 32 iron are 1.4. So the question is what statement is the most likely to be true? A mom is right, he's drinking. Be mom is wrong. This is an auto so more dominant genetic disease. C the indirect hyper bilirubin Neemia is due to Gilbert's syndrome. D this disease has a very uniform presentation of course. E this disease is fatal without treatment. So I'll give you a second. The correct answer is e this disease is fatal without treatment because this is Wilson disease. Now board questions are written by people like us and they have to make it relatively straightforward. What that means is they typically will give you clues at least in the case based questions in the stem of the question. I can almost guarantee that Wilson will be on the G. I. Liver boards because it's an easy disease to ask questions about. And there are some pearls that you should remember. In general the S. T. Is going to be created in the vault. The alkaline phosphate days is usually very low in Wilson disease. If they're going to ask you a question, usually they're going to have someone with some anemia because it's associate with the Coombs negative hemolytic anemia and the serial plasma will be low. But it isn't always especially if the patient is so erotic. And the important point about Wilson is that even though it's a rare disease, remember it can present in lots of different ways. So a mild abnormal liver tests all the way to acute liver failure. It's fatal without treatment. It's got neuropsychiatric symptoms and the Kaiser fleischer ring. The famous thing that most textbooks show is almost universal if you have evidence of neurological symptoms. It's also some more receptive. And there are extra hepatic manifestations such as the fanconi anemia renal tubular acidosis. Our property in a variety of other things. So just be aware of it because it's an easy thing to ask questions about. Although not a disease are going to see very commonly liver tests or liver function test really remember our liver injury test there markers of the liver being injured as opposed to it functioning. However, the nomenclature is such that we continue calling them normal LFT LFTs. Normal LFTs are based on normal populations. What that means is that what we're using today are cut offs that are probably a bit too high Because when you look at healthy blood donors who are not overweight using in Haines type data, the upper limit normal really should be 30 in a man in 20 and a woman for the A. L. T. And A. S. T. Remember. This should increase with age, the upper limit of normal and it's associated with the degree of trunk all fat and therefore your BMI. However, if you were to change the range it would probably lead to increased evaluation for diseases that really are very mild such as fatty liver disease. And I've listed some references there that you can read at your leisure. When we look at alkaline phosphate days remember it can come from liver and less frequently bone but it's also uh found from the intestine and from placenta. So pregnant ladies can have an elevated alkaline phosphate taste In the old days we would fraction eight alkaline foster days. Now you can use an elevated GT to distinguish that it's coming from the liver. Remember increases with age particularly women. G. T. Is found in lots of places. Um And when you see it elevated and it's a liver source. Remember this is very uh non specific. It's very sensitive to any liver damage. And we use it as a rough indicator perhaps of alcohol. But it can go up with really any uh liver damage. And that's why it's usually not part of the hepatic function panel macro enzymes do exist. So macro A. S. T. For instance. And so you should consider that if the A. S. T. Is for instance 10 or 15 times greater than the L. T. In the absence of alcohol. So remember mild elevations, abilities are very common. I'm really not that significant. So you should repeat it first off and using N. Haynes data. If you re check ma be elevated liver tests about a third of the time when you re check it, it'll be normal. So it's always worth rechecking. And this is a relatively old data. But I think that's actually very good advice. Let's go to another question. This is a 62 year old gentleman is referred to your liver clinic for abnormal liver test based on routine screening. Uh He's overweight. He's got evidence of the metabolic syndrome but he's also got a history of drinking. His medications are listed including Lipitor metformin. And listen to people examination is essentially normal and his liver test has shown there lt of 86 asd of 55 alkaline fossil fuels. GT and tell the world Ruben all normal. The primary care doctor has performed an additional work up is hepatitis C. Antibody is positive. A and a is positive at one in 40 and the ferret in is 4 50 which is mildly elevated. So the question is what is not an appropriate next test? Hepatitis C. RNA B. S. M. A. And quantitative immunoglobulins. See doing a liver biopsy, D abdominal imaging or E. And H. F. E. Gino type. So the answer is c liver biopsy that would not be an appropriate test to do at this stage. All the others are appropriate to varying degrees. So you check the hepatitis C. RNA and it's negative is Pepsi Reiber is positive and that confirms prior exposure is Hfts wild type. So he doesn't have at least for the things that we test for. He doesn't have genetic hemochromatosis and his s. Emma. And quantitative immunoglobulins are normal. So remember A. And a and elevated ferreting can be seen in patients with Nash. Here's his abdominal imaging is an ultrasound there on the left hand side and it shows an eca genic liver. And if you were to do a liver biopsy, this is what you would see on the right there's evidence of uh severe stenosis. So the Liberace pop full of fat. I always think it's a good idea to try and categorize lft abnormalities. So there's one system that I've shown here. So there's a paracel yeller cola, static or mixed, particularly interested in drug induced liver injury and that's what we use to define the injury at the end of the talk. I'll also mention some cases where you can get isolated hyper bilirubin Neemia really without elevation of liver test. Not that these are things that we would see very commonly in an adult practice. But these are again, easy things to ask questions about. So it's something that I think it's worth knowing. So a lot of cellular LFT abnormalities really are LT and S. T. So remember this can be chronic and can fluctuate remember. You should ensure that it's all coming from the liver, particularly the is very elevated as we know that this can be coming from other sources and the degree of elevation will help you with the differential diagnosis. The ratio of A. S. T. To LT is helpful. So we are all aware of alcohol and it's very important to review the medication list again, for the board purposes. This is an easy thing to ask questions on. So prescription medicines, but also over the counter medicines, herbal medicines and recreational medicines and then look for clues in the stem of the question. Is there evidence of alcohol? Are their risk factors for fatty liver diseases? Have been travel, are their context? Any kind of peculiar hobbies all of these can be useful in the stem of the question. So, I've given you a little table here of para celular ab abnormal LFTs and the things to look out for. So chronic viral hepatitis for instance will give you usually mildly elevated A. S. T. R. LT and usually not very high alcohol. The ratio of S. T. Two LT is almost universal. I'm trying to think back. I can't remember an alcoholic that I haven't seen where the enzymes are elevated with the A. S. T. And LT wasn't greater than at least 2 to 1 fatty liver disease. Usually same as viral hepatitis, mildly elevated trans emanated. Really. Is it very very elevated? Remember? But acute viral hepatitis or toxic injury? Well we'll give you very high enzymes with or without jaundice and autoimmune can do somewhat similar cirrhosis. Remember the the enzymes can be normal. Uh The ratio may not actually help you in that situation because cirrhosis the A. S. T. Two L. T. Can kind of reverse viral hepatitis we think of as being greater than S. T. But in cirrhosis that actually can be reversed metabolic typically gives you mild elevation or sometimes normal LFTs. So the work up for mildly elevated STL. T. Really should be pretty standard. So you do viral markers of hepatitis B. Hepatitis C. Which I've listed there. So that's a core antibody surface antibody and surface antigen and that's part of the panel and hepatitis C antibody and you would check RNA or DNA if the serology is positive metabolic studies. Iron studies and iron saturation of ferreting are the initial test for hemochromatosis and I think my colleague dr odin will be talking about metabolic liver disease. Autoimmune disease. Remember especially if it's a woman, a middle aged woman A. N. A. S. M. A quantitative immunoglobulins of the initial test. And I always think it's worthwhile getting imaging on anybody with mark the elevated liver test and I would usually start with an ultrasound liver box. He would not be first line. So let's move on to another question. This is a 42 year old lady referred for unexplained elevated liver tests for about six months. She looks well. She's got some irritable bowel types symptoms loose stool and bloating. She denies alcohol or drugs or exam is normal. The studies have shown their LT of 100 ste 122 alkaline for stays 73. Total bilirubin is .9. She's mildly anemic m. c. d. 78. The hepatitis B and C. Serology. Czar negative and her autoimmune markers are also negative. You do an ultrasound, it's normal. So question three years which of the following tests or procedures will be most helpful in making a diagnosis. Liver biopsy, colonoscopy, endoscopy and biopsy, hepatitis C. RNA or iron studies. So I'll give you a second correct answer is endoscopy and biopsy and I use this case to illustrate that systemic diseases can also present with abnormal liver enzymes. Here's the endoscopy and the biopsy. And she had celiac antibodies checked which will markedly positive and all her biochemical abnormalities normalized after six months of being on the gluten free celiac diet. So there was no need for a liver biopsy. It's going to question for 36 year old ladies referred for unexplained elevated liver tests for about two months. She's lost weight, she feels weak, tired having some difficulty getting out of bed, no alcohol or drugs. When you examine her, she is pretty wasted. And A. B. M. I. Is 17. Lab studies have shown their A. L. T. 4 22. A. S. T. 3 98. How can I? First days 111. Total bilirubin is one Hemoglobin is 13. Hepatitis b. c. and autoimmune serology is negative. And our imaging shows a normal looking liver on ultrasound question for is which of the following test or procedure will be helpful in making a diagnosis in this particular patient. So liver biopsy iron studies hepatitis a antibody cP can al delays or brain M. R. I. I'll give you a second. The correct answer is C. P. K. And al delays. Because this lady is also suffering from a systemic disease that can present with abnormal liver enzymes. So we talked about before that the work up for mildly elevated enzymes. But in the situation where a lot of those tests are negative and particularly if the patient has some ever other evidence of something else going on. So for the first patient had some gi symptoms and had this micro citic anemia. The second patient really seemed to have some sort of neurological muscular issue. So thyroid disease, muscle disorders, adrenal insufficiency and some Gi disorders such as celiac can cause mildly abnormal liver test. So it's something to think about uh kind of in the second stage after everything else that you checked initially comes back negative. So uh these are things also are easy to ask questions about. So something to uh something worth considering. People have asked me and I've looked it up. I really can't explain why the liver enzymes are elevated in celiac disease. Really kind of somewhat poorly understood. Although it's very obvious that the enzymes get better when you treat the celiac disease. Similar things with thyroid disease and the muscle disorders. The mechanism really are unclear. Another question. 30 year old african american man referred because of abnormal liver test. He has has some abdominal fullness. You're in his dark, he's been itching for about a month not taking any medicines really. No other medical issues. No weight loss denies any drugs. You examine him. He's got mild victories. His liver and spleen are enlarged. No cities labs are shown their bilirubin of 2.5 alkaline phosphates. 400 GT 2 58 L. T. Of 53 And A. S. T. of 69. So the question is which of the following statements is the most accurate. The magnitude of the alkaline fosters elevation helps you to distinguish between intra and extra Paddick disease. An MRI mrcB would not be helpful and Emma will be very helpful, absence ability, ductile dilation excludes extra Paddick disease a liver biopsy may be necessary to make a diagnosis. So again, read the question carefully because it says what's the most accurate Because some of these may be true but really may not be as accurate as some of the others. So the answer is actually e a liver biopsy may be necessary to make a diagnosis. So again, think back to the question and the stem here's his cT scan. So you see liver and spleen are enlarged and liver biopsy shows non cash creating granulomas. So this is sarcoidosis that really leads us to coalesce static LFTs so they really reflect how can I force stage. You don't necessarily need to be joined us for this. The GT confirms its deliver source, it can be intra or extra paddocks and the degree of elevation really doesn't help you. An ultrasound would be initial test but cT or MRI depending on where you're at and the ease of access balloon dilation implies extra Paddick obstruction. But remember just because you don't have, it doesn't mean that you can't have diseases where there is obstruction to the extra padded ducks such as PSC. So M. R. C. P. Can be more helpful in that situation and the lack of balloon dilation negative blood test usually mean that you got to do a liver biopsy as was the case here. Remember when you do get a patient with cool, aesthetic LFTs. You need to do a thorough check of what medicines they're taking. So again, classically a jaundiced patient with mildly elevated liver enzymes. Anabolic steroids is something to think about it, particularly as a young man imaging as we talked about and laboratory tests. Am a yes. If it was a middle aged lady but not in a young african american gentleman you would check here but it wouldn't be something that you would be really concerned about in terms of primary biliary cholangitis. While test yes, you should do um atypical viruses maybe less so. And in the hospitalized patient we really have to think about if the patient is septic or if the patient is on TPN. Very classic question for for the board's TPN and liver enzyme abnormalities. So I've listed some of the causes of color status here, which you can read at your leisure. And it's a very long list. So let's do another question. This is question 6, 24 year old hispanic lady comes with vague abdominal discomfort, nausea and vomiting a little confused and joined us for about two days. No drugs, alcohol travel. She's in a relationship with one other person but admits to having unprotected intercourse. You examine her. She's jaundiced her right up according is tender liver edges, just about palpable and she has a mild liver flap or asterix this lab work has shown their total bilirubin of 3.6 S. T. 11,000 lt of 6000 Alkaline phosphate is very mildly elevated in an iron are 4 7. So concerning question is which of the following statements is true. Initial important initial tests should include a hepatitis A I G. M. Antibody hepatitis B surface antigen and hepatitis B Core antibody GM. The 2-1 ratio suggests alcoholic hepatitis of the belt. A normal cerebral plasma and excludes Wilson disease, pregnancy related liver failure is likely. A liver biopsy is usually necessary to make a diagnosis. Just think about that for a second, the answer is a initial test should include viral markers. So particularly for acute hepatitis A, which is the I G. M antibody and the core I G. M. For acute hepatitis B or sometimes reactivation of hepatitis B. The others really are not true. So this is uh if you want to classify it and a pad of cellular pattern with jaundice, she's got acute liver failure, She had evidence of encephalopathy and an elevated iron are the differential here is going to be wide. Could be toxic viral indeterminant. So just some things to think about serial plasma remember is an acute phase reactant and a normal level in acute liver failure doesn't necessarily mean that this is not Wilson disease. This is not going to be alcohol usually doesn't present like this. And the trans emanates is are far too elevated for alcoholic hepatitis. Remember for liver injury and I think dr Kushner is going to be talking about liver injury in pregnancy. The really bad things in pregnancy occurred in the third trimester and this lady is not in the third trimester of pregnancy. Liver biopsy is usually not required an acute liver failure very occasionally we would do it and it would be risky. And for viral hepatitis as we talked about the I. G. M. Is the important one for acute viral hepatitis. And again, I've listed here some potential causes of para celular liver enzyme abnormalities with jaundice. So you can peruse at your leisure the work up, because we talked about, remember for toxic, you would do a settlement fin level, you would do a urine tox screen the viral test we already talked about as well as the autoimmune and Wilson disease vascular yeah, particularly if it's a lady coming or even a man with tender happen omega, you would want to do a Doppler because remember, but chiari syndrome could present a little bit like this. Um, and if there's indeterminant, then you have to consider other tests including liver biopsy. Question seven, A 28 year old man is, is referred for elevated bilirubin level. He's a pharmaceutical rep. His only symptom is he gets occasional dark urine he denies any medications, alcohol or smoking exam is normal. Lab has shown there his liver enzymes are actually normal. Outman is also normal, but it's total bilirubin is mildly elevated and it's all unconscious gated or indirect. So the question is which of the following statements is true. This is a disorder that is not genetically inherited. It affects both sexes sexes equally. The bit of Ruben rises after a high fat meal. A liver party can confirm the diagnosis. The primary defect is in conjugation of bilirubin too, laconic acid mediated via UdP glucose. I'll transfer, raise bit of a mouthful. So I'll give you a second. The answer is e I'm sure everyone is aware of what this was. But the question didn't ask you, what's the diagnosis. It ask you things that hopefully you you're aware of. So remember, this is gilbert syndrome. Let's do another question. And then we'll talk about both. So this question 8 47 old ladies seen for several weeks of malaise and jaundiced her urine is dark, she has intense itching, she's lost weight, no medications, alcohol or smoking. She had a similar episode several years ago that resolves spontaneously. You examine her, she's got solar electricity, but really nothing else of note. You do imaging and her MRI is normal. You do lab work and it's shown their bilirubin is eight mainly conjugated LT and sp are essentially normal alkaline phosphate of 376 album and it's normal. Iron Ore is normal. Which of the following is the most likely diagnosis PSC Brick, which is benign recurrent paddock color stasis, p thick to Dubin johnson syndrome or p thick three. I'll give you a second. So the answer is Brick. This was a real case that I saw. Um and I use this just to go through bilirubin metabolism. Remember isolated hyper bilirubin India's ask things that kid the pediatrician c uh we occasionally see them remember bilirubin formed by the breakdown of him. So 80% of that comes from hemoglobin. So therefore Hamal Asus or ineffective. Aretha processes can lead to an elevated bilirubin. It's mainly uncontradicted in plasma because not soluble in water and bound to albumin. So therefore an isolated hybrid room anemia could be due to overproduction of bilirubin or because of impaired uptake or conjugation or maybe excretion. So in initial step is to fractionated, so direct versus indirect or conjugated versus uncomplicated. The bigger room then is taken up by the parasites of facilitated diffusion process. It can move either way and it is a concentration gradient. The conjugation or glue colonization occurs in the entire plasma, ridiculous catalyzed by this udP enzyme group. And the ugt one. A one is the important Aiso form because of all the disease is essentially related to deficiency in that. So your bowel syndrome, the pediatric diseases of krill and that Najar. Um and it's also affected by breast milk. So occasionally mayonnaise can be uh join us because because of this once it's conjugated, the active transport occurs across the canonical membrane and then it's excreted mediated by several organic and iron transporters. Most important is m. r. p. two affected by a quiet and genetic diseases and buy drugs as well as pregnancy. So bilirubin installed is almost all conjugated and therefore water soluble. Uh The conjugated bilirubin can undergo anthropogenic recirculation because the bacteria then converted into Euro by limitations uh which also can be uh undergo and traumatic recirculation. So again I've given you some tables here of some of the features uh the cradle in a jar our pediatric disease. But I remember from my boards that this is fair game for the board. So something uh to remember Jobbers is also um recessive. It's 2-1 male to female elevation. Remember the bilirubin goes up after fasting not with a fat meal and the mutation is in that enzyme. As we talked about the box it would be normal Crigler Najjar. Both of them are also some more recessive. One is less severe than the other. Remember the less severe one responds to PHENobarbital Dubin, johnson wrote to al adil and pacific are listed there. Brick is at the bottom there multiple mutations. It's a benign disease. P thick I think it's worth remembering because again this can come up on the board or just remember that uh I think three is the one where you get a lot of stone disease and pacific to is the one that's got bad color stasis in a high risk of liver cancer. So therefore needs a transplant. The first one is also a bilas disease. And that gives you a severe cold stasis and needs transplant too, and I think.