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S2D: The Symptom to Diagnosis Podcast - Episode 17: Jaundice or Abnormal Liver Enzymes
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S2D: The Symptom to Diagnosis Podcast - Episode 17: Jaundice or Abnormal Liver Enzymes
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Language: EN.
Segment:0 .
[upbeat intro music]
DR. CIFU: I'm Adam Cifu.
DR. STERN: [chuckles] And I'm still Scott Stern.
DR. CIFU: And this is S2D, the Symptom to Diagnosis podcast. What are we doing today, Scott?
DR. STERN: Well, if memory serves me correctly we're doing jaundice and abnormal liver enzymes.
DR. CIFU: Another one of those classic medicine differential diagnoses, right?
DR. STERN: Absolutely.
DR. CIFU: Actually, I've got a story about this one. Are you ready?
DR. STERN: [chuckles] Oh God, go ahead.
DR. CIFU: So this goes back to when I was a third year medical student.
DR. STERN: Okay.
DR. CIFU: We had like a little clerkship group with our clerkship director. I won't give the year of this, but it was a long time ago. And I remember the clerkship director asked me for differential diagnosis of abnormal liver function tests. Okay? And I gave a differential diagnosis and I named like, I don't know, 12, 15 things, I was so impressed with myself. And the young clerkship director looked at me and said, "Huh, if you can give me 10 more, maybe you'll get a residency spot." [both chuckle] - [Dr. Stern] Oh my God.
DR. CIFU: So anyway, that has stuck with me.
DR. STERN: That reminds me of I was once in medical school the person who was running our class on disease I now run, who's a biochemist, asked me to graph out the pathway of bilirubin metabolism. And I must have looked like a complete idiot. I'm like, are you serious? [chuckles] Well, I now know that, but I didn't at the time.
DR. CIFU: [chuckles] Oh God. Okay. So you're the expert of the day. Do you have a case to present to me?
DR. STERN: I do. So actually, I remember this very well because it wasn't all that long ago, maybe two years ago and a woman came in to see me who was 65 years old and she said, "I'm really having a problem doctor Stern, can you help me?" And I said, "Sure." And she goes, "Well, I don't know what's going on. I'm really, really itchy. And the other thing I've noticed is my stools don't look right, they're really light, and it looks like my skin is kind of yellow."
DR. CIFU: [chuckles] So she served you a differential diagnosis on a platter.
DR. STERN: On a platter it was.
DR. CIFU: Is that all you're going to give to me?
DR. STERN: I think that's plenty actually, but go ahead.
DR. CIFU: Okay. So I guess what I would start with is I'm going to pull way back. Okay? And I'm going to say, jaundice. You should not jump right into this is jaundice or just not jump into yellow skin equals jaundice. Right? We all have stories about carotenemia and things like that. My daughter when she was little ate just carrots and sweet potatoes and had an orange hue to her.
DR. STERN: So wait, you got to tell them how to distinguish that before you go on. So you know that--
DR. CIFU: So I would say scleral icterus, right?
DR. STERN: Right, exactly.
DR. CIFU: And so this person I'll assume that her sclera are a little bit icteric but also she's got itchy skin which speaks for hyperbilirubinemia and she's got pale stool as well. So I guess the one other question I might ask with what you've told me so far is, has she noticed any difference in her urine?
DR. STERN: Her urine is dark.
DR. CIFU: Her urine is dark. Okay. So the kind of classic differential diagnosis, right? For jaundice, or we could even say for abnormal liver function tests but we'll say, abnormal liver function tests and then jaundice, would be is this conjugated hyperbilirubinemia or unconjugated hyperbilirubinemia? You've sort of told me that it's conjugated hyperbilirubinemia because she's got dark urine.
DR. CIFU: And that means that it's not just unconjugated bilirubin which doesn't get filtered by the kidneys, I guess, because it's bound to albumin--
DR. STERN: Right.
DR. CIFU: You're the expert here. Okay.
DR. STERN: Right.
DR. CIFU: So this has to be conjugated hyperbilirubinemia and then the next step in that differential diagnosis is to say, is this an intrahepatic obstruction or is this an extrahepatic obstruction, right? This kind of reeks to me of an extrahepatic obstruction given that we're hearing dark stools as well--
DR. STERN: Light stools.
DR. CIFU: Sorry, light stools as well, because basically nothing's getting through, where if it's intrahepatic, I generally think of people, they've got an overload of the conjugated bilirubin but they're still spilling some into the stool. So that makes me worried that she's got an anatomic obstruction and that could be just about anything. Right? I think about bile duct disease, certainly benign or malignant, benign stuff: stricture, stones, malignant: basically, horrible stuff, right?
DR. CIFU: Pancreatic cancer, cholangiocarcinoma. And so I'd like to hear more about her, which will probably put me off but I'd like to hear about medications, past medical history. I'm certainly going to ask for labs and I'm probably going to ask for an ultrasound to see what her right-upper quadrant looks like.
DR. STERN: Great. So otherwise she's been pretty healthy in the past. She is a smoker but otherwise had not really had any significant problems. I had the same thought you did. It was painless which made me more worried.
DR. CIFU: Sure.
DR. STERN: Why do you say "sure"? Tell me.
DR. CIFU: Well, I mean, I think painless jaundice is classic for pancreatic cancer. Smoking raises your risk for pancreatic cancer, though I mean, that doesn't raise it enough that it's like lung cancer. So that would make me more concerned. I guess, sitting in the room with her, I'd ask her-- I was going to say some of the fun questions about pancreatic cancer but that sounds sort of awful but, you know, migratory thrombophlebitis, has this woman had any superficial thrombophlebitis recently, depression?
DR. CIFU: I actually learned just re-reading some stuff before this podcast, I don't know if this data's any good or not but there's a lot of depression sort of occurring in the months before a diagnosis of pancreatic cancer--
DR. STERN: Which is really interesting, right?
DR. CIFU: Which is really interesting.
DR. STERN: Yeah. So she didn't have that, but literally she told me this one line and I've never walked out of a room after one line and thought, well, that's pancreatic cancer--
DR. CIFU: Yeah.
DR. STERN: --because like you said, if it was a stone in the common bile duct, more often than not they have some pain with it. Her LFTs showed pretty much what we might expect, her CBC was unremarkable, her bilirubin was 8.5, her alk phos was quite high at 280, her AST and ALT were only minimally elevated at 55 and 50.
DR. CIFU: Yeah.
DR. STERN: So--
DR. CIFU: Yeah, it's interesting. I think the right answer is a right-upper quadrant ultrasound at this point. But to be honest with you, I mean I'm so suspicious of this, of what's going on here, that I might go right to the better test, I might say-- and these days, you know we can get these tests so quickly that I could probably get an ultrasound today, I could probably get an MRCP in the next two days.
DR. STERN: Yeah.
DR. CIFU: So I might go right to that.
DR. STERN: And actually as we'll come to later the MRCP is the better test. Even the CT scan is not that great at the common bile duct. So an MRCP is the test of choice and I was pretty sure we were going to see a pancreatic carcinoma. Fortunately, what we saw was a mass at the ampulla of Vater.
DR. CIFU: Huh. Okay.
DR. STERN: And she was then referred to one of our surgical colleagues.
DR. CIFU: Right. So maybe we'll stop there.
DR. STERN: Okay.
DR. CIFU: That could be good
DR. CIFU: or it could be terrible, but we'll find out. So your job now is to tell me about some of the really key points, we usually do five key points about diagnosing abnormal liver function tests or jaundice and you want to start off?
DR. STERN: So, I mean the first step in anybody who looks jaundiced is to distinguish whether it's conjugated hyperbilirubinemia which is called direct bilirubin, or whether it's unconjugated hyperbilirubinemia. That can be done with a simple blood test, although as you've alluded to an astute clinician can also look at the urine and tell because unconjugated bilirubin is tightly bound to albumin, as you said, and albumin is too big to be filtered at the glomerulus.
DR. STERN: So unconjugated bilirubin does not show up in the urine and those patients typically have normal colored urine. Additionally, most of the patients who have unconjugated hyperbilirubinemia are not associated with marked elevations in bilirubin, hemolysis doesn't typically give you a bilirubin above five, nor does Gilbert's, the other common cause of unconjugated hyperbilirubinemia. And so typically those patients have subtle scleral icterus but they're not orange like pumpkins, frankly.
DR. CIFU: Right.
DR. STERN: And so often,
DR. STERN: right in the room, you'll have a good sense of whether someone has conjugated hyperbilirubinemia or unconjugated. And as I said, unconjugated hyperbilirubinemia is most commonly Gilbert's or hemolysis. There are other things that can do it as we'll talk about later, but that's certainly the first point.
DR. CIFU: I think you might be soft today because I think you may have insinuated that I am an astute clinician.
DR. STERN: I'll come back and correct that later. [chuckles] Okay. All right. So, you know, the next point is what do you do then when it's conjugated hyperbilirubinemia and really--
DR. CIFU: So you've sort of said, unconjugated, generally a pretty simple differential diagnosis. So you're going to kind of dive into conjugated.
DR. STERN: I am, exactly.
DR. CIFU: Okay.
DR. STERN: Right. I should mention that severe end-stage liver failure can cause unconjugated hyperbilirubinemia but that's normally obvious. Now conjugated hyperbilirubinemia is more complicated. And basically, I like to break it down into two big groups and that is hepatocellular disease a.k.a. some form of hepatitis, or some obstruction and that obstruction can be intrahepatic or extrahepatic. And actually simple blood tests can help with this. So most of the hepatocellular diseases, hepatitis cause marked increases in the AST and ALT much more than alk phos, because as those liver cells die, they release AST and ALT and as they die, what happens is the architecture of the liver gets disrupted.
DR. STERN: And so the bilirubin that was already conjugated, this used to confuse me as a student, the bilirubin has already been conjugated, it is in those bile ducts but as those cells die that line the bile ducts that conjugated bilirubin leaks out and now goes into the central circulation.
DR. CIFU: Right. There's a potential to get confused because you do have hepatocellular injury and you might think that you've injured so many hepatocytes that you're no longer conjugating bilirubin at all but I guess, you know, the liver is a big organ, the liver's conjugating capacity is enormous, that even a really sick liver still conjugates bilirubin.
DR. STERN: Right. And the way we define it is over 50%--
DR. CIFU: Right.
DR. STERN: --is conjugated
DR. STERN: then we're going to call it conjugated. So they will have increases in the unconjugated bilirubin but usually it's still more than 50% conjugated. Although again, if the liver is completely failed--
DR. CIFU: Right.
DR. STERN: --it's unconjugated.
DR. STERN: So hepatitis, to recoup, will cause elevations in the ALT and AST more than alk phos, whereas obstruction which can be intrahepatic or extrahepatic causes alk phos elevations more than AST and ALT. So those blood tests are often really helpful.
DR. CIFU: Good. And intrahepatic cholestasis, I feel like that's getting into the weeds a little bit because very often when people think about cholestatic jaundice, they immediately go to sort of macroscopic obstruction of the biliary tree, but you have to recognize that that portion of the differential diagnosis includes a lot of intrahepatic and it's worth looking at the antibiotics, you know-- [chuckles]
DR. STERN: Right.
DR. CIFU: --looking at the medications which cause that because we see that all the time with really sick people in the hospital.
DR. STERN: Right and also things that metastasize to the liver can cause this, as you know lots of nodules in the liver can do the same. It looks biochemically like an extrahepatic obstruction but the common bile duct is normal because it's the tiny bile ducts that are getting blocked up, right?
DR. CIFU: Lots of little tiny bile ducts getting blocked. I think you're up to point three.
DR. STERN: So once we get to the point where someone looks like they have an obstructive pattern the alk phos and the GGT is elevated then simply you need to image those bile ducts, and there's a variety of tests, ultrasound, CT or MRCP, and as we already discussed, MRCP clearly gives you the best definition of those. And so that's very helpful if the bile ducts are dilated, you have an extrahepatic obstruction and if they're not, you've got some intrahepatic cause.
DR. CIFU: Right. And I think we've already talked enough about the testing, but it really-- This is where the test you choose depends not only on your differential diagnosis, but the severity of illness of the patient, of where you are, how rapidly you need evaluation. Right? So if you're in the emergency room with someone who you think has cholangitis or is coming in with cholecystitis say, you know, boy just slap an ultrasound on that person.
DR. CIFU: Right? And you've got a test which has given you a ton of information while if you're with a fairly well person, at least well in the short term, like you're a person in clinic, maybe you have the luxury of getting the best test first.
DR. STERN: You know, I think that's a clinical pearl worth saying and I'm going to say it now because we didn't-- [both chuckle]
DR. STERN: --we weren't planning on saying it which is really jaundice and fever is a different animal.
DR. CIFU: Yeah.
DR. STERN: So jaundice and fever can be hepatitis, but your point about cholangitis, ascending cholangitis, is really important because those people are life-threateningly sick and the amount of bacteria that ascends into the liver and cause high grades or bacteremia is frightful. As a matter of fact, the fastest blood culture that ever returned positive I ever saw was somebody in cholangitis. So I think when you see fever and jaundice, you need to jump all over that and be treating those people while you're figuring it out because that's really terrifying.
DR. CIFU: Well, it's one of the few diseases that for me, and any pathologist who's listening to this podcast, I'm not sure why anybody would--
DR. STERN: [chuckles]
DR. CIFU: --would probably have a complete fit over this, but when I see cholangitis, I really think back to the histology of the liver, and I just think of the pus backing up into the sinusoids and recognizing like, that is going straight into the bloodstream.
DR. STERN: Absolutely, right.
DR. CIFU: We should, you know-- we're on podcast 17 here and we have, I don't know, somewhere 25 to 30 like classic symptoms that we're going to cover--
DR. STERN: Right.
DR. CIFU: --and we've no idea
DR. CIFU: what the future holds beyond that. I guess we never have any idea what the future holds, but as you say, jaundice and fever, rash and fever, it'd be interesting kind of combinations of presentations--
DR. STERN: Oh that'd be fun, combination day.
DR. CIFU: Yeah. Maybe sometime this summer.
DR. STERN: All right. So the fourth point is having broken it down into groups now of hepatocellular diseases and then intra- and extrahepatic obstruction, we can really kind of focus the differential diagnosis. And so, let's just recoup that for everyone to be clear. So unconjugated hyperbilirubinemia is normally Gilbert's, hemolysis or severe liver failure; conjugated with hepatocellular picture usually some form of hepatitis.
DR. STERN: Now the most common thing that we see in the clinic every day is minimal elevations in ALT and AST due to non-alcoholic fatty liver disease. But all the things when they're more marked, viral hepatitis, alcoholic hepatitis are definitely is one and two, and then there's autoimmune hepatitis, drug-induced hepatitis, ischemia in the very sick patient, typically in the ICU and cirrhosis, and then a variety of obscure things that I thought were common as a medical student.
DR. STERN: I remember having a patient as a medical student where I thought Wilson's was number one on the differential. And I'm pretty sure Wilson's is never number one on the differential. And then the conjugated and obstructive patterns if it's extrahepatic, thinking stones and tumors primarily and if it's intrahepatic obstructive pattern thinking, and I've seen this many times, infiltrative tumors whether it's colon cancer or lymphoma or something of that sort, primary biliary cirrhosis and then cirrhosis, toxins and sepsis.
DR. CIFU: Good. One thing I would say, and I know you know this, since this is what we do all the time, but those people in the clinic with minimally elevated liver function tests certainly non-alcoholic steatohepatitis, NASH whatever we want to call it, is very common. The other things, you know, to really think about with that group, Hepatitis C commonly presented like that in the past, now that we're screening people I feel like we see less of that. Alcohol, right?
DR. STERN: Right.
DR. CIFU: Even the people who are just having two, three drinks a night you'll certainly see that, and acetaminophen use, right?
DR. STERN: Right.
DR. CIFU: There'll be people who are using a lot of Tylenol, I've had people surprisingly who are training for a 10 K who come in with abnormal liver function tests just because they're going through three or four grams of Tylenol.
DR. STERN: Well, that's a really good point. And that we're going to come back to later because it's often accidental. But I think that you're right about that. And the Hep C, you're right. As you know the liver tests can fluctuate between normal and not, so simply repeating it later and finding it's normal, doesn't release you from the obligation of having made sure it wasn't Hep C because it can still be doing damage.
DR. STERN: So I think that's important. I'm not always sure what to tell the person who's having one or two drinks, whose ALT and AST is 40, what do you do with that?
DR. CIFU: I'll tell you what I do with that.
DR. STERN: What do you do with that?
DR. CIFU: I think that we accept, what? Up to three times the upper limit of normal for statins. And I think it's a whole lot more pleasurable to have a drink or two at night--
DR. STERN: [chuckles]
DR. CIFU: And so I tell people, look if I'm going to accept it for statins, I'm going to accept it for a beer.
DR. STERN: So if I'm having one beer a night, it's one times normal and I can have two beers a night, it's two times, all right, we'll let that one go. [chuckles]
DR. CIFU: I'm certainly not going to talk about your--
DR. STERN: Well, we can talk about my margarita use but that's a separate podcast. Well, that's what we could do! What-- Nevermind. All right. So the fifth key point is what happens when it's just the alkaline phosphatase that's elevated and it's worth remembering that alkaline phosphatase also comes from bone, and we certainly have had patients who present with metastatic boney disease, where that's the first clue.
DR. STERN: And so if the alk phos is elevated, I usually get a GGT, if the GGT is also elevated I'm more concerned that it's coming from the liver and I'm going to image the liver. Whereas if the alk phos alone is elevated and the GGT is normal, I'm often going to do a bone scan.
DR. CIFU: Good. And maybe just to pitch for the more benign causes of isolated elevated bone alk phos. Right? You certainly see that with Paget's disease, you see that with primary hypercalcemia. So there's a whole differential that goes with that too. And I think you're right, I mean we all fear that, Oh my God, is this person presenting with metastatic boney disease? That's coming to my attention first with isolated elevated alk phos that we see. Fortunately, most of the time it's something more benign and explainable but you're certainly right.
DR. CIFU: You can't blow that off.
DR. STERN: The other thing I'd mention while we're on alk phos is that you don't get the marked elevations in alk phos that you get in ALT and AST. The ranges vary from hospital to hospital but if you say the average upper limit of normal is 150, an alk phos of 300 would really make my eyes pop.
DR. CIFU: Yeah.
DR. STERN: Whereas we get ALT and AST elevations all the time that are in that range.
DR. CIFU: Right, right. Good point. Good point. So why don't we get back to the case? So I feel like we did a lot of it.
DR. STERN: We did.
DR. CIFU: So we were at the stage, she's in your office, we talked about all the lab tests and-- Oh, yes! So she's got the mass at the ampulla of Vater. So I guess this could be basically anything, right? It could be of an intestinal origin, right? So she could just have duodenal polyps, she could have a duodenal cancer. I've actually seen someone with metastatic melanoma to that area of the duodenum presenting as jaundice in someone who had melanoma 10 years before,
DR. STERN: Wow, that's scary. I mean, you don't want melanoma, there's a take-home pearl.
DR. CIFU: And then I guess it could be cholangiocarcinoma, sort of at the very end of the bile duct, but what happened? I assume that you went after that with an ERCP?
DR. STERN: So she went to ERCP and it looked malignant and she went to surgery and she actually had I didn't even know this was a thing, but she had cancer of the ampulla of Vater, there was simply adenomatous tissue there and it was malignant. The good news for her is the prognosis for that's much better than for pancreatic carcinoma, 50% cure rate, whereas for a pancreatic carcinoma it's nowhere near that high. And so it's been several years now.
DR. STERN: She had some complications postoperatively but she's done well and so, so far, no recurrence.
DR. CIFU: That's good news. Did she have a Whipple for that?
DR. STERN: Yeah, she did.
DR. CIFU: So you loose a lot. Okay. Wow. That's a great case. Very interesting and happy she did well.
DR. STERN: Right.
DR. CIFU: Okay. So fingerprints. Scott, you got a fingerprint?
DR. STERN: I do. So a palpable spleen, people can have splenomegaly and not be able to feel it, but if you can feel it, it's truly significant for splenomegaly with a likelihood ratio of eight.
DR. CIFU: Nobody can have splenomegaly that I can't feel. [both laugh]
DR. STERN: I would like to differ with that, but okay, fine.
DR. CIFU: I'll just add to that, just so I have something to say in fingerprints, that that's not true for a palpable liver edge, meaning that a palpable liver edge can be normal. So if you feel a liver edge, you might want to do other things, to scratch out the liver maybe, do liver function tests, but that - unlike splenomegaly - that doesn't mean that the liver is abnormal.
DR. STERN: Right, because the liver can be lying low, like COPDers often have enlarged lungs and then a low liver.
DR. CIFU: Great point. I would actually say for people who are just kind of getting good at the physical exam that when you're seeing someone who's got COPD really interesting things to do with them is one, measure diaphragmatic excursion, tap out those people's lung and then have them take a really deep breath measure how far their diaphragm goes, it's often very small. Recognize where their heart has shifted, you often hear their heart best in the epigastrium. And then I agree, you can almost always feel liver edge in those people, you get really good at feeling what does the edge of a liver feel like.
DR. STERN: Yeah. Now it does seem to me that you're almost only going to see it to like one or two fingerbreadths. I started seeing people who are three or four fingerbreadths, it's almost always pathological.
DR. CIFU: Right, yeah. I don't know the test characteristics on that but I think that's definitely true. I sort of feel like, at this point I kind of know what a normal liver edge feels like. And I kind of know what like, hmm, that's probably not good.
DR. STERN: I didn't present you a patient who I saw once, I'm going to go on an aside here, who came into my office and I'd never met him before. And I said, "What's wrong?" And he says, "I don't feel well." And I said, "What's wrong?" And he goes, "I don't feel well." I said, "Well, what sort of symptoms are you having?" And he goes, "I don't feel well." I'm like, "Oh my goodness." So I finally asked him to take his shirt off.
DR. STERN: And as he takes his shirt off, across the room, I see a mass in his belly--
DR. CIFU: Wow.
DR. STERN: --across the room.
DR. STERN: And when I went to examine him I couldn't even tell what it was, it went all the way into his pelvis and across the midline, and it turned out it was his liver--
DR. CIFU: Wow.
DR. STERN: --from Budd-Chiari.
DR. CIFU: Wow.
DR. STERN: And it went all the way through his belly.
DR. CIFU: Interesting.
DR. STERN: Yeah.
DR. STERN: Anyway, I thought it'd be nice today to give you that one.
DR. CIFU: You're like chatty Scotty today.
DR. STERN: I am chatty Scotty.
DR. CIFU: Okay, common misconceptions.
DR. STERN: Okay, so--
DR. STERN: Are you trying to tell me to be quiet? All right. So we've talked about the first one which is hemolysis and Gilbert's, they can cause mild jaundice, but not marked jaundice. So I did have this patient with sickle cell anemia that presented in a very interesting way which gets to this color of urine, where he was quite jaundiced when I saw him and I walked into the room and also noticed that his urine was quite dark in color which proved that he had conjugated hyperbilirubinemia.
DR. STERN: And it actually had been assumed prior to that that it was unconjugated hyperbilirubinemia from his hemolysis, but just looking at his urinal was a clue that something else was going on. And in fact, he'd formed a bilirubin stone in his gallbladder and was obstructing his common bile duct causing jaundice from it.
DR. CIFU: That's another very interesting, very instructive case, let's say. I think the one thing I might-- I agree with you about hemolysis not causing marked jaundice. I think we probably have to differentiate or define what marked jaundice is, right? Because it's true when you take care of people with sickle cell anemia in the hospital, they're jaundiced, right?
DR. STERN: Right.
DR. CIFU: But it is true when people, when you see people with a bili of 18 or 20 it's really a completely different look. And that's really no matter what color skin they have--
DR. STERN: Right.
DR. CIFU: Maybe my common misconception, and again, we sort of touched on this, we actually definitely touched on this, is that jaundice is always associated with dark urine, right? So dark urine does mean that there's conjugated hyperbilirubinemia, unconjugated bilirubin cannot be filtered. And I would say, as we mentioned not all dark urine is conjugated hyperbilirubinemia, right? There are lots of other things that make the urine change crazy colors, and people are not great at telling you perfectly that like this is root beer urine.
DR. CIFU: You know, this is cranberry urine--
DR. STERN: Right, right.
DR. CIFU: --and this is ice tea urine or I guess maybe just tea colored urine. So, you know, hemoglobinuria, myoglobinuria, methemoglobinuria, I guess methemoglobinemia, you know, those generally we think of as being, I guess redder urines, there are things that make the urine brown. Actually, I wish I had the website, there is a terrific UCSF website which has like urine colors but the things I think about that make urine really brown, so some foods, Fava beans, aloe, antimalarials especially those which cause hemolysis, porphyria and glomerulonephritis actually, if you have glomerulonephritis with dysmorphic red cells, that can really cause brownish urine.
DR. STERN: So you ever seen porphyria?
DR. CIFU: [chuckles] Once.
DR. STERN: Really?
DR. CIFU: Yes.
DR. CIFU: Actually from-- I saw it via a loved one of mine who's a dermatologist who will show up on this podcast at some point, patient with porphyria in clinic that I got there.
DR. STERN: And what do you cook, Fava beans? I've never had Fava beans. What do you eat them in?
DR. CIFU: You are showing who's Italian in this conversation--
DR. STERN: Yes.
DR. CIFU: --and who is not.
DR. STERN: Yes, yes.
DR. CIFU: I'll make you some someday.
DR. STERN: All right, deal. All right. So should we go to pet peeves?
DR. CIFU: Pet peeves, go crazy.
DR. STERN: All right. So my first pet peeve is one of the things that causes jaundice is obviously a stone in the common bile duct. And so when we see a patient like that, we know to image it. But many patients who have symptomatic biliary tract disease and cholecystitis also have stones in their common bile duct, and we need to look for those preoperatively. So any patient who has an elevated even if they're not jaundiced, but if their liver enzymes are elevated or they've had pancreatitis or they have a dilated common bile duct any of those things, not more than one, any of those things should make us look at the common bile duct before we go taking out their gallbladder.
DR. CIFU: Sounds great, sounds great. And for me, one word: transaminitis.
DR. STERN: You don't like that word?
DR. CIFU: God! Just don't say that to me.
DR. STERN: [chuckles] Why?
DR. CIFU: You have an inflammation of your transaminases? It's the stupidest thing in the world.
DR. STERN: [chuckles]
DR. CIFU: It's like nails on the blackboard, makes me grit my teeth, oh, I can't stand it. And it's like a measure of what kind of a mood I am in, because if I'm kind of chill and relaxed and it's the beginning of rounds, I'll just sit and listen to it, let it go. If it's at the ends of rounds or I'm a little bit edgy--
DR. STERN: Well, what do you think of all the verbs that we've developed? Like we're going to cath them or we've, you know-- We could do another podcast on words we don't like.
DR. CIFU: I've written an article about that.
DR. STERN: You have, have you?
DR. CIFU: [chuckles] Yeah.
DR. STERN: All right.
DR. CIFU: Let's go on.
DR. STERN: Clinical pearls. So I like to think of bodily fluids as the colors of life.
DR. CIFU: [giggles]
DR. STERN: [chuckles] So colors of life, if your urine's dark, think about bilirubin in the urine. If the stool is light actually it's light because bile is not getting to that. And for those of you who are biochemists what happens is, the bilirubin that gets excreted into the bowel is turned by bacteria into stercobilin and that's what makes your stool brown which is why when you have diarrhea and the bile moves quickly, it's still yellow.
DR. STERN: So in case any biochemists quiz you, you're now ready.
DR. CIFU: Okay. And you can have greener stool with really rapid transport--
DR. STERN: There you go.
DR. CIFU: --for the same reason.
DR. CIFU: I don't want to get too much into this, but you know you don't have to get crazy about like, I want to look at all the colors, but at least when you're rounding on people and the patient is unlucky enough to have a Foley catheter and maybe you're lucky enough that they do, take a look at the urine--
DR. STERN: Take a look.
DR. CIFU: --you may learn something.
DR. CIFU: We certainly do it with pleural fluid that we see lying around, sputum that we see next to the bed, sometimes helps you. Okay. My clinical pearl. So you sort of dissed [chuckles] the differential diagnosis--
DR. STERN: I did.
DR. CIFU: --of unconjugated hyperbilirubinemia and I have to say, I sort of agree. It's not that interesting, it's mostly hemolysis and it might be acute hemolysis of unknown cause that you need to work up, it might be dysarthria paresis that you know from the minute they walk in that this is someone with sickle cell anemia and a pain crisis, but do think of some other things that are around there. So extravasation of blood, people can get unconjugated hyperbilirubinemia from just like a huge, I don't know, retroperitoneal bleed or a complication of a cardiac catheterization as they begin to metabolize that, break that down.
DR. CIFU: Impaired uptake of unconjugated bilirubin, so you mentioned sepsis, heart failure, drugs, I think rifampin is probably the classic. So just make that differential diagnosis a little more complicated than you gave it credit for.
DR. STERN: [chuckles] Fair enough. My next one is you always have to keep in mind Tylenol. We alluded to this earlier, Tylenol is one of those things that if you're going to intervene, you need to intervene early because if you do it early, you can save the liver, if you do it too late, you're looking at liver transplant. So any patient presents with increased LFTs of any type with any sort of psychiatric manifestation, any sort of overdose, you really need to be putting that at the top of your differential because it has such specific treatment early.
DR. CIFU: Right and it's especially important, I think, because of the fact that we toss this piece of data around a lot that half of all acetaminophen intoxications are accidental. I think those breakdown into real accidental, you know, I'm taking Tylenol because I'm having pain and maybe I'm also drinking or maybe my liver function isn't perfect to begin with. And then there are the people who are sort of acting out and they're like I'm going to have a suicide attempt as a cry for help, but I'm going to do it with Tylenol because pssh--
DR. STERN: Right.
DR. CIFU: --and that can be just an absolute tragedy because - not that a suicide that was meant to be is not a tragedy - but it can be people who really don't want to hurt themselves who end up doing horrible injury to themselves.
DR. STERN: All right. So I guess the next one will be on alcoholic liver disease. So when we see the AST much greater than the ALT, we think about liver disease, my understanding is because often they have a pyridoxine deficiency and they can actually synthesize ALT very well. But in any case, 70 to 80% of patients with alcoholic liver injury have levels of greater than two of AST to ALT and levels of more than three are even more specific, so--
DR. CIFU: Right.
DR. STERN: --something to remember.
DR. CIFU: That three to one is something that I take away that like when I see that ratio and I ask the person if they drink and they say no, I am like, come on.
DR. STERN: Right.
DR. CIFU: [chuckles] You know.
DR. CIFU: I feel like I'm throwing out some maybe iffy data on this podcast--
DR. STERN: [chuckles]
DR. CIFU: --because I'm usually really careful about this but this is something that I've just seen in so many places and I've never really looked in great depth at where this comes from, but it's the whole thing about depression being the first symptom of pancreatic cancer. And a lot of this is obviously retrospective and it's people who were probably depressed at the time because they have pancreatic cancer but people have quoted as high as 45% of people, which I can't believe.
DR. CIFU: But I have to say, if I had a middle-aged patient who came to me who had never had issues with depression or mental health, who all of a sudden at age 60 becomes depressed, I would at least think about that. Probably not to the point that I would be doing an MRCP but probably to the point that I'd be examining them and checking LFTs.
DR. STERN: Interesting.
DR. CIFU: You're scoffing.
DR. STERN: Well, no, no. [both chuckle] I'm just wondering, I've never done that. So I'm wondering what I would do with that but it's worth a thought.
DR. CIFU: Maybe you've learned something from me.
DR. STERN: Well, I wouldn't go that far.
DR. CIFU: [chuckles]
DR. STERN: So my last one is detecting jaundice. So, you know, it's very hard in patients of color to look at skin sometimes and detect mild jaundice. So then we often look at the sclera but the more pigmented your skin is, the more likely you are to have conjunctival staining from melanin which can make the sclera dark and hard to see whether or not it's really yellow. So one technique I learned early on was if you lift someone's eyelids and ask them to look at the floor you actually can see the sclera of their eye that's always covered by their upper lid that doesn't get conjunctival pigmentation on it, and it's a good way to look for scleral icterus in people who have dark skin.
DR. CIFU: Right. And this is generally looking at mild hyperbilirubinemia, right?
DR. STERN: Right.
DR. CIFU: Because the sclera starts becoming icteric like two to three, right?
DR. STERN: That's right.
DR. CIFU: So it's very low levels that you're not going to really see in anybody's skin. I find the most sensitive places for me, sclera as you said, sort of superior sclera are the best, under the tongue helps me, as long as you've got a really bright light to look there--
DR. STERN: Okay.
DR. CIFU: --and palms is the other thing. And I always like palms because I can act as a control. Right? So for looking for anemia, looking for icterus I can put my hand up next to the patient and that helps quite a bit. So we hope you found this episode of S2D, the Symptom to Diagnosis podcast useful and a bit enjoyable. If you like listening to us, please rate us on iTunes, we've heard that's important, or maybe not. Don't rate us, just give us five stars.
DR. STERN: [chuckles]
DR. CIFU: If you want to chat, tweet at me @adamcifu. And as a reminder, our textbook, Symptoms to Diagnosis: An Evidence-Based Guide takes a much deeper dive into how to think about and reason through the diagnosis of medical presentations. The book is available in print through all the usual places on your mobile device and also available and fully searchable via the Access Medicine website available worldwide from McGraw Hill. A reminder that the cases that we discuss are drawn from our clinical experiences but, because protecting patient privacy is part of our oath, we never discuss actual patients and most cases are composites.
DR. CIFU: The music for the S2D podcast is courtesy of Dr. Maylyn Martinez.
DR. STERN: Thank you.
DR. CIFU: Thank you. [upbeat outro music]
Segment:0 .
[upbeat intro music]
DR. CIFU: I'm Adam Cifu.
DR. STERN: [chuckles] And I'm still Scott Stern.
DR. CIFU: And this is S2D, the Symptom to Diagnosis podcast. What are we doing today, Scott?
DR. STERN: Well, if memory serves me correctly we're doing jaundice and abnormal liver enzymes.
DR. CIFU: Another one of those classic medicine differential diagnoses, right?
DR. STERN: Absolutely.
DR. CIFU: Actually, I've got a story about this one. Are you ready?
DR. STERN: [chuckles] Oh God, go ahead.
DR. CIFU: So this goes back to when I was a third year medical student.
DR. STERN: Okay.
DR. CIFU: We had like a little clerkship group with our clerkship director. I won't give the year of this, but it was a long time ago. And I remember the clerkship director asked me for differential diagnosis of abnormal liver function tests. Okay? And I gave a differential diagnosis and I named like, I don't know, 12, 15 things, I was so impressed with myself. And the young clerkship director looked at me and said, "Huh, if you can give me 10 more, maybe you'll get a residency spot." [both chuckle] - [Dr. Stern] Oh my God.
DR. CIFU: So anyway, that has stuck with me.
DR. STERN: That reminds me of I was once in medical school the person who was running our class on disease I now run, who's a biochemist, asked me to graph out the pathway of bilirubin metabolism. And I must have looked like a complete idiot. I'm like, are you serious? [chuckles] Well, I now know that, but I didn't at the time.
DR. CIFU: [chuckles] Oh God. Okay. So you're the expert of the day. Do you have a case to present to me?
DR. STERN: I do. So actually, I remember this very well because it wasn't all that long ago, maybe two years ago and a woman came in to see me who was 65 years old and she said, "I'm really having a problem doctor Stern, can you help me?" And I said, "Sure." And she goes, "Well, I don't know what's going on. I'm really, really itchy. And the other thing I've noticed is my stools don't look right, they're really light, and it looks like my skin is kind of yellow."
DR. CIFU: [chuckles] So she served you a differential diagnosis on a platter.
DR. STERN: On a platter it was.
DR. CIFU: Is that all you're going to give to me?
DR. STERN: I think that's plenty actually, but go ahead.
DR. CIFU: Okay. So I guess what I would start with is I'm going to pull way back. Okay? And I'm going to say, jaundice. You should not jump right into this is jaundice or just not jump into yellow skin equals jaundice. Right? We all have stories about carotenemia and things like that. My daughter when she was little ate just carrots and sweet potatoes and had an orange hue to her.
DR. STERN: So wait, you got to tell them how to distinguish that before you go on. So you know that--
DR. CIFU: So I would say scleral icterus, right?
DR. STERN: Right, exactly.
DR. CIFU: And so this person I'll assume that her sclera are a little bit icteric but also she's got itchy skin which speaks for hyperbilirubinemia and she's got pale stool as well. So I guess the one other question I might ask with what you've told me so far is, has she noticed any difference in her urine?
DR. STERN: Her urine is dark.
DR. CIFU: Her urine is dark. Okay. So the kind of classic differential diagnosis, right? For jaundice, or we could even say for abnormal liver function tests but we'll say, abnormal liver function tests and then jaundice, would be is this conjugated hyperbilirubinemia or unconjugated hyperbilirubinemia? You've sort of told me that it's conjugated hyperbilirubinemia because she's got dark urine.
DR. CIFU: And that means that it's not just unconjugated bilirubin which doesn't get filtered by the kidneys, I guess, because it's bound to albumin--
DR. STERN: Right.
DR. CIFU: You're the expert here. Okay.
DR. STERN: Right.
DR. CIFU: So this has to be conjugated hyperbilirubinemia and then the next step in that differential diagnosis is to say, is this an intrahepatic obstruction or is this an extrahepatic obstruction, right? This kind of reeks to me of an extrahepatic obstruction given that we're hearing dark stools as well--
DR. STERN: Light stools.
DR. CIFU: Sorry, light stools as well, because basically nothing's getting through, where if it's intrahepatic, I generally think of people, they've got an overload of the conjugated bilirubin but they're still spilling some into the stool. So that makes me worried that she's got an anatomic obstruction and that could be just about anything. Right? I think about bile duct disease, certainly benign or malignant, benign stuff: stricture, stones, malignant: basically, horrible stuff, right?
DR. CIFU: Pancreatic cancer, cholangiocarcinoma. And so I'd like to hear more about her, which will probably put me off but I'd like to hear about medications, past medical history. I'm certainly going to ask for labs and I'm probably going to ask for an ultrasound to see what her right-upper quadrant looks like.
DR. STERN: Great. So otherwise she's been pretty healthy in the past. She is a smoker but otherwise had not really had any significant problems. I had the same thought you did. It was painless which made me more worried.
DR. CIFU: Sure.
DR. STERN: Why do you say "sure"? Tell me.
DR. CIFU: Well, I mean, I think painless jaundice is classic for pancreatic cancer. Smoking raises your risk for pancreatic cancer, though I mean, that doesn't raise it enough that it's like lung cancer. So that would make me more concerned. I guess, sitting in the room with her, I'd ask her-- I was going to say some of the fun questions about pancreatic cancer but that sounds sort of awful but, you know, migratory thrombophlebitis, has this woman had any superficial thrombophlebitis recently, depression?
DR. CIFU: I actually learned just re-reading some stuff before this podcast, I don't know if this data's any good or not but there's a lot of depression sort of occurring in the months before a diagnosis of pancreatic cancer--
DR. STERN: Which is really interesting, right?
DR. CIFU: Which is really interesting.
DR. STERN: Yeah. So she didn't have that, but literally she told me this one line and I've never walked out of a room after one line and thought, well, that's pancreatic cancer--
DR. CIFU: Yeah.
DR. STERN: --because like you said, if it was a stone in the common bile duct, more often than not they have some pain with it. Her LFTs showed pretty much what we might expect, her CBC was unremarkable, her bilirubin was 8.5, her alk phos was quite high at 280, her AST and ALT were only minimally elevated at 55 and 50.
DR. CIFU: Yeah.
DR. STERN: So--
DR. CIFU: Yeah, it's interesting. I think the right answer is a right-upper quadrant ultrasound at this point. But to be honest with you, I mean I'm so suspicious of this, of what's going on here, that I might go right to the better test, I might say-- and these days, you know we can get these tests so quickly that I could probably get an ultrasound today, I could probably get an MRCP in the next two days.
DR. STERN: Yeah.
DR. CIFU: So I might go right to that.
DR. STERN: And actually as we'll come to later the MRCP is the better test. Even the CT scan is not that great at the common bile duct. So an MRCP is the test of choice and I was pretty sure we were going to see a pancreatic carcinoma. Fortunately, what we saw was a mass at the ampulla of Vater.
DR. CIFU: Huh. Okay.
DR. STERN: And she was then referred to one of our surgical colleagues.
DR. CIFU: Right. So maybe we'll stop there.
DR. STERN: Okay.
DR. CIFU: That could be good
DR. CIFU: or it could be terrible, but we'll find out. So your job now is to tell me about some of the really key points, we usually do five key points about diagnosing abnormal liver function tests or jaundice and you want to start off?
DR. STERN: So, I mean the first step in anybody who looks jaundiced is to distinguish whether it's conjugated hyperbilirubinemia which is called direct bilirubin, or whether it's unconjugated hyperbilirubinemia. That can be done with a simple blood test, although as you've alluded to an astute clinician can also look at the urine and tell because unconjugated bilirubin is tightly bound to albumin, as you said, and albumin is too big to be filtered at the glomerulus.
DR. STERN: So unconjugated bilirubin does not show up in the urine and those patients typically have normal colored urine. Additionally, most of the patients who have unconjugated hyperbilirubinemia are not associated with marked elevations in bilirubin, hemolysis doesn't typically give you a bilirubin above five, nor does Gilbert's, the other common cause of unconjugated hyperbilirubinemia. And so typically those patients have subtle scleral icterus but they're not orange like pumpkins, frankly.
DR. CIFU: Right.
DR. STERN: And so often,
DR. STERN: right in the room, you'll have a good sense of whether someone has conjugated hyperbilirubinemia or unconjugated. And as I said, unconjugated hyperbilirubinemia is most commonly Gilbert's or hemolysis. There are other things that can do it as we'll talk about later, but that's certainly the first point.
DR. CIFU: I think you might be soft today because I think you may have insinuated that I am an astute clinician.
DR. STERN: I'll come back and correct that later. [chuckles] Okay. All right. So, you know, the next point is what do you do then when it's conjugated hyperbilirubinemia and really--
DR. CIFU: So you've sort of said, unconjugated, generally a pretty simple differential diagnosis. So you're going to kind of dive into conjugated.
DR. STERN: I am, exactly.
DR. CIFU: Okay.
DR. STERN: Right. I should mention that severe end-stage liver failure can cause unconjugated hyperbilirubinemia but that's normally obvious. Now conjugated hyperbilirubinemia is more complicated. And basically, I like to break it down into two big groups and that is hepatocellular disease a.k.a. some form of hepatitis, or some obstruction and that obstruction can be intrahepatic or extrahepatic. And actually simple blood tests can help with this. So most of the hepatocellular diseases, hepatitis cause marked increases in the AST and ALT much more than alk phos, because as those liver cells die, they release AST and ALT and as they die, what happens is the architecture of the liver gets disrupted.
DR. STERN: And so the bilirubin that was already conjugated, this used to confuse me as a student, the bilirubin has already been conjugated, it is in those bile ducts but as those cells die that line the bile ducts that conjugated bilirubin leaks out and now goes into the central circulation.
DR. CIFU: Right. There's a potential to get confused because you do have hepatocellular injury and you might think that you've injured so many hepatocytes that you're no longer conjugating bilirubin at all but I guess, you know, the liver is a big organ, the liver's conjugating capacity is enormous, that even a really sick liver still conjugates bilirubin.
DR. STERN: Right. And the way we define it is over 50%--
DR. CIFU: Right.
DR. STERN: --is conjugated
DR. STERN: then we're going to call it conjugated. So they will have increases in the unconjugated bilirubin but usually it's still more than 50% conjugated. Although again, if the liver is completely failed--
DR. CIFU: Right.
DR. STERN: --it's unconjugated.
DR. STERN: So hepatitis, to recoup, will cause elevations in the ALT and AST more than alk phos, whereas obstruction which can be intrahepatic or extrahepatic causes alk phos elevations more than AST and ALT. So those blood tests are often really helpful.
DR. CIFU: Good. And intrahepatic cholestasis, I feel like that's getting into the weeds a little bit because very often when people think about cholestatic jaundice, they immediately go to sort of macroscopic obstruction of the biliary tree, but you have to recognize that that portion of the differential diagnosis includes a lot of intrahepatic and it's worth looking at the antibiotics, you know-- [chuckles]
DR. STERN: Right.
DR. CIFU: --looking at the medications which cause that because we see that all the time with really sick people in the hospital.
DR. STERN: Right and also things that metastasize to the liver can cause this, as you know lots of nodules in the liver can do the same. It looks biochemically like an extrahepatic obstruction but the common bile duct is normal because it's the tiny bile ducts that are getting blocked up, right?
DR. CIFU: Lots of little tiny bile ducts getting blocked. I think you're up to point three.
DR. STERN: So once we get to the point where someone looks like they have an obstructive pattern the alk phos and the GGT is elevated then simply you need to image those bile ducts, and there's a variety of tests, ultrasound, CT or MRCP, and as we already discussed, MRCP clearly gives you the best definition of those. And so that's very helpful if the bile ducts are dilated, you have an extrahepatic obstruction and if they're not, you've got some intrahepatic cause.
DR. CIFU: Right. And I think we've already talked enough about the testing, but it really-- This is where the test you choose depends not only on your differential diagnosis, but the severity of illness of the patient, of where you are, how rapidly you need evaluation. Right? So if you're in the emergency room with someone who you think has cholangitis or is coming in with cholecystitis say, you know, boy just slap an ultrasound on that person.
DR. CIFU: Right? And you've got a test which has given you a ton of information while if you're with a fairly well person, at least well in the short term, like you're a person in clinic, maybe you have the luxury of getting the best test first.
DR. STERN: You know, I think that's a clinical pearl worth saying and I'm going to say it now because we didn't-- [both chuckle]
DR. STERN: --we weren't planning on saying it which is really jaundice and fever is a different animal.
DR. CIFU: Yeah.
DR. STERN: So jaundice and fever can be hepatitis, but your point about cholangitis, ascending cholangitis, is really important because those people are life-threateningly sick and the amount of bacteria that ascends into the liver and cause high grades or bacteremia is frightful. As a matter of fact, the fastest blood culture that ever returned positive I ever saw was somebody in cholangitis. So I think when you see fever and jaundice, you need to jump all over that and be treating those people while you're figuring it out because that's really terrifying.
DR. CIFU: Well, it's one of the few diseases that for me, and any pathologist who's listening to this podcast, I'm not sure why anybody would--
DR. STERN: [chuckles]
DR. CIFU: --would probably have a complete fit over this, but when I see cholangitis, I really think back to the histology of the liver, and I just think of the pus backing up into the sinusoids and recognizing like, that is going straight into the bloodstream.
DR. STERN: Absolutely, right.
DR. CIFU: We should, you know-- we're on podcast 17 here and we have, I don't know, somewhere 25 to 30 like classic symptoms that we're going to cover--
DR. STERN: Right.
DR. CIFU: --and we've no idea
DR. CIFU: what the future holds beyond that. I guess we never have any idea what the future holds, but as you say, jaundice and fever, rash and fever, it'd be interesting kind of combinations of presentations--
DR. STERN: Oh that'd be fun, combination day.
DR. CIFU: Yeah. Maybe sometime this summer.
DR. STERN: All right. So the fourth point is having broken it down into groups now of hepatocellular diseases and then intra- and extrahepatic obstruction, we can really kind of focus the differential diagnosis. And so, let's just recoup that for everyone to be clear. So unconjugated hyperbilirubinemia is normally Gilbert's, hemolysis or severe liver failure; conjugated with hepatocellular picture usually some form of hepatitis.
DR. STERN: Now the most common thing that we see in the clinic every day is minimal elevations in ALT and AST due to non-alcoholic fatty liver disease. But all the things when they're more marked, viral hepatitis, alcoholic hepatitis are definitely is one and two, and then there's autoimmune hepatitis, drug-induced hepatitis, ischemia in the very sick patient, typically in the ICU and cirrhosis, and then a variety of obscure things that I thought were common as a medical student.
DR. STERN: I remember having a patient as a medical student where I thought Wilson's was number one on the differential. And I'm pretty sure Wilson's is never number one on the differential. And then the conjugated and obstructive patterns if it's extrahepatic, thinking stones and tumors primarily and if it's intrahepatic obstructive pattern thinking, and I've seen this many times, infiltrative tumors whether it's colon cancer or lymphoma or something of that sort, primary biliary cirrhosis and then cirrhosis, toxins and sepsis.
DR. CIFU: Good. One thing I would say, and I know you know this, since this is what we do all the time, but those people in the clinic with minimally elevated liver function tests certainly non-alcoholic steatohepatitis, NASH whatever we want to call it, is very common. The other things, you know, to really think about with that group, Hepatitis C commonly presented like that in the past, now that we're screening people I feel like we see less of that. Alcohol, right?
DR. STERN: Right.
DR. CIFU: Even the people who are just having two, three drinks a night you'll certainly see that, and acetaminophen use, right?
DR. STERN: Right.
DR. CIFU: There'll be people who are using a lot of Tylenol, I've had people surprisingly who are training for a 10 K who come in with abnormal liver function tests just because they're going through three or four grams of Tylenol.
DR. STERN: Well, that's a really good point. And that we're going to come back to later because it's often accidental. But I think that you're right about that. And the Hep C, you're right. As you know the liver tests can fluctuate between normal and not, so simply repeating it later and finding it's normal, doesn't release you from the obligation of having made sure it wasn't Hep C because it can still be doing damage.
DR. STERN: So I think that's important. I'm not always sure what to tell the person who's having one or two drinks, whose ALT and AST is 40, what do you do with that?
DR. CIFU: I'll tell you what I do with that.
DR. STERN: What do you do with that?
DR. CIFU: I think that we accept, what? Up to three times the upper limit of normal for statins. And I think it's a whole lot more pleasurable to have a drink or two at night--
DR. STERN: [chuckles]
DR. CIFU: And so I tell people, look if I'm going to accept it for statins, I'm going to accept it for a beer.
DR. STERN: So if I'm having one beer a night, it's one times normal and I can have two beers a night, it's two times, all right, we'll let that one go. [chuckles]
DR. CIFU: I'm certainly not going to talk about your--
DR. STERN: Well, we can talk about my margarita use but that's a separate podcast. Well, that's what we could do! What-- Nevermind. All right. So the fifth key point is what happens when it's just the alkaline phosphatase that's elevated and it's worth remembering that alkaline phosphatase also comes from bone, and we certainly have had patients who present with metastatic boney disease, where that's the first clue.
DR. STERN: And so if the alk phos is elevated, I usually get a GGT, if the GGT is also elevated I'm more concerned that it's coming from the liver and I'm going to image the liver. Whereas if the alk phos alone is elevated and the GGT is normal, I'm often going to do a bone scan.
DR. CIFU: Good. And maybe just to pitch for the more benign causes of isolated elevated bone alk phos. Right? You certainly see that with Paget's disease, you see that with primary hypercalcemia. So there's a whole differential that goes with that too. And I think you're right, I mean we all fear that, Oh my God, is this person presenting with metastatic boney disease? That's coming to my attention first with isolated elevated alk phos that we see. Fortunately, most of the time it's something more benign and explainable but you're certainly right.
DR. CIFU: You can't blow that off.
DR. STERN: The other thing I'd mention while we're on alk phos is that you don't get the marked elevations in alk phos that you get in ALT and AST. The ranges vary from hospital to hospital but if you say the average upper limit of normal is 150, an alk phos of 300 would really make my eyes pop.
DR. CIFU: Yeah.
DR. STERN: Whereas we get ALT and AST elevations all the time that are in that range.
DR. CIFU: Right, right. Good point. Good point. So why don't we get back to the case? So I feel like we did a lot of it.
DR. STERN: We did.
DR. CIFU: So we were at the stage, she's in your office, we talked about all the lab tests and-- Oh, yes! So she's got the mass at the ampulla of Vater. So I guess this could be basically anything, right? It could be of an intestinal origin, right? So she could just have duodenal polyps, she could have a duodenal cancer. I've actually seen someone with metastatic melanoma to that area of the duodenum presenting as jaundice in someone who had melanoma 10 years before,
DR. STERN: Wow, that's scary. I mean, you don't want melanoma, there's a take-home pearl.
DR. CIFU: And then I guess it could be cholangiocarcinoma, sort of at the very end of the bile duct, but what happened? I assume that you went after that with an ERCP?
DR. STERN: So she went to ERCP and it looked malignant and she went to surgery and she actually had I didn't even know this was a thing, but she had cancer of the ampulla of Vater, there was simply adenomatous tissue there and it was malignant. The good news for her is the prognosis for that's much better than for pancreatic carcinoma, 50% cure rate, whereas for a pancreatic carcinoma it's nowhere near that high. And so it's been several years now.
DR. STERN: She had some complications postoperatively but she's done well and so, so far, no recurrence.
DR. CIFU: That's good news. Did she have a Whipple for that?
DR. STERN: Yeah, she did.
DR. CIFU: So you loose a lot. Okay. Wow. That's a great case. Very interesting and happy she did well.
DR. STERN: Right.
DR. CIFU: Okay. So fingerprints. Scott, you got a fingerprint?
DR. STERN: I do. So a palpable spleen, people can have splenomegaly and not be able to feel it, but if you can feel it, it's truly significant for splenomegaly with a likelihood ratio of eight.
DR. CIFU: Nobody can have splenomegaly that I can't feel. [both laugh]
DR. STERN: I would like to differ with that, but okay, fine.
DR. CIFU: I'll just add to that, just so I have something to say in fingerprints, that that's not true for a palpable liver edge, meaning that a palpable liver edge can be normal. So if you feel a liver edge, you might want to do other things, to scratch out the liver maybe, do liver function tests, but that - unlike splenomegaly - that doesn't mean that the liver is abnormal.
DR. STERN: Right, because the liver can be lying low, like COPDers often have enlarged lungs and then a low liver.
DR. CIFU: Great point. I would actually say for people who are just kind of getting good at the physical exam that when you're seeing someone who's got COPD really interesting things to do with them is one, measure diaphragmatic excursion, tap out those people's lung and then have them take a really deep breath measure how far their diaphragm goes, it's often very small. Recognize where their heart has shifted, you often hear their heart best in the epigastrium. And then I agree, you can almost always feel liver edge in those people, you get really good at feeling what does the edge of a liver feel like.
DR. STERN: Yeah. Now it does seem to me that you're almost only going to see it to like one or two fingerbreadths. I started seeing people who are three or four fingerbreadths, it's almost always pathological.
DR. CIFU: Right, yeah. I don't know the test characteristics on that but I think that's definitely true. I sort of feel like, at this point I kind of know what a normal liver edge feels like. And I kind of know what like, hmm, that's probably not good.
DR. STERN: I didn't present you a patient who I saw once, I'm going to go on an aside here, who came into my office and I'd never met him before. And I said, "What's wrong?" And he says, "I don't feel well." And I said, "What's wrong?" And he goes, "I don't feel well." I said, "Well, what sort of symptoms are you having?" And he goes, "I don't feel well." I'm like, "Oh my goodness." So I finally asked him to take his shirt off.
DR. STERN: And as he takes his shirt off, across the room, I see a mass in his belly--
DR. CIFU: Wow.
DR. STERN: --across the room.
DR. STERN: And when I went to examine him I couldn't even tell what it was, it went all the way into his pelvis and across the midline, and it turned out it was his liver--
DR. CIFU: Wow.
DR. STERN: --from Budd-Chiari.
DR. CIFU: Wow.
DR. STERN: And it went all the way through his belly.
DR. CIFU: Interesting.
DR. STERN: Yeah.
DR. STERN: Anyway, I thought it'd be nice today to give you that one.
DR. CIFU: You're like chatty Scotty today.
DR. STERN: I am chatty Scotty.
DR. CIFU: Okay, common misconceptions.
DR. STERN: Okay, so--
DR. STERN: Are you trying to tell me to be quiet? All right. So we've talked about the first one which is hemolysis and Gilbert's, they can cause mild jaundice, but not marked jaundice. So I did have this patient with sickle cell anemia that presented in a very interesting way which gets to this color of urine, where he was quite jaundiced when I saw him and I walked into the room and also noticed that his urine was quite dark in color which proved that he had conjugated hyperbilirubinemia.
DR. STERN: And it actually had been assumed prior to that that it was unconjugated hyperbilirubinemia from his hemolysis, but just looking at his urinal was a clue that something else was going on. And in fact, he'd formed a bilirubin stone in his gallbladder and was obstructing his common bile duct causing jaundice from it.
DR. CIFU: That's another very interesting, very instructive case, let's say. I think the one thing I might-- I agree with you about hemolysis not causing marked jaundice. I think we probably have to differentiate or define what marked jaundice is, right? Because it's true when you take care of people with sickle cell anemia in the hospital, they're jaundiced, right?
DR. STERN: Right.
DR. CIFU: But it is true when people, when you see people with a bili of 18 or 20 it's really a completely different look. And that's really no matter what color skin they have--
DR. STERN: Right.
DR. CIFU: Maybe my common misconception, and again, we sort of touched on this, we actually definitely touched on this, is that jaundice is always associated with dark urine, right? So dark urine does mean that there's conjugated hyperbilirubinemia, unconjugated bilirubin cannot be filtered. And I would say, as we mentioned not all dark urine is conjugated hyperbilirubinemia, right? There are lots of other things that make the urine change crazy colors, and people are not great at telling you perfectly that like this is root beer urine.
DR. CIFU: You know, this is cranberry urine--
DR. STERN: Right, right.
DR. CIFU: --and this is ice tea urine or I guess maybe just tea colored urine. So, you know, hemoglobinuria, myoglobinuria, methemoglobinuria, I guess methemoglobinemia, you know, those generally we think of as being, I guess redder urines, there are things that make the urine brown. Actually, I wish I had the website, there is a terrific UCSF website which has like urine colors but the things I think about that make urine really brown, so some foods, Fava beans, aloe, antimalarials especially those which cause hemolysis, porphyria and glomerulonephritis actually, if you have glomerulonephritis with dysmorphic red cells, that can really cause brownish urine.
DR. STERN: So you ever seen porphyria?
DR. CIFU: [chuckles] Once.
DR. STERN: Really?
DR. CIFU: Yes.
DR. CIFU: Actually from-- I saw it via a loved one of mine who's a dermatologist who will show up on this podcast at some point, patient with porphyria in clinic that I got there.
DR. STERN: And what do you cook, Fava beans? I've never had Fava beans. What do you eat them in?
DR. CIFU: You are showing who's Italian in this conversation--
DR. STERN: Yes.
DR. CIFU: --and who is not.
DR. STERN: Yes, yes.
DR. CIFU: I'll make you some someday.
DR. STERN: All right, deal. All right. So should we go to pet peeves?
DR. CIFU: Pet peeves, go crazy.
DR. STERN: All right. So my first pet peeve is one of the things that causes jaundice is obviously a stone in the common bile duct. And so when we see a patient like that, we know to image it. But many patients who have symptomatic biliary tract disease and cholecystitis also have stones in their common bile duct, and we need to look for those preoperatively. So any patient who has an elevated even if they're not jaundiced, but if their liver enzymes are elevated or they've had pancreatitis or they have a dilated common bile duct any of those things, not more than one, any of those things should make us look at the common bile duct before we go taking out their gallbladder.
DR. CIFU: Sounds great, sounds great. And for me, one word: transaminitis.
DR. STERN: You don't like that word?
DR. CIFU: God! Just don't say that to me.
DR. STERN: [chuckles] Why?
DR. CIFU: You have an inflammation of your transaminases? It's the stupidest thing in the world.
DR. STERN: [chuckles]
DR. CIFU: It's like nails on the blackboard, makes me grit my teeth, oh, I can't stand it. And it's like a measure of what kind of a mood I am in, because if I'm kind of chill and relaxed and it's the beginning of rounds, I'll just sit and listen to it, let it go. If it's at the ends of rounds or I'm a little bit edgy--
DR. STERN: Well, what do you think of all the verbs that we've developed? Like we're going to cath them or we've, you know-- We could do another podcast on words we don't like.
DR. CIFU: I've written an article about that.
DR. STERN: You have, have you?
DR. CIFU: [chuckles] Yeah.
DR. STERN: All right.
DR. CIFU: Let's go on.
DR. STERN: Clinical pearls. So I like to think of bodily fluids as the colors of life.
DR. CIFU: [giggles]
DR. STERN: [chuckles] So colors of life, if your urine's dark, think about bilirubin in the urine. If the stool is light actually it's light because bile is not getting to that. And for those of you who are biochemists what happens is, the bilirubin that gets excreted into the bowel is turned by bacteria into stercobilin and that's what makes your stool brown which is why when you have diarrhea and the bile moves quickly, it's still yellow.
DR. STERN: So in case any biochemists quiz you, you're now ready.
DR. CIFU: Okay. And you can have greener stool with really rapid transport--
DR. STERN: There you go.
DR. CIFU: --for the same reason.
DR. CIFU: I don't want to get too much into this, but you know you don't have to get crazy about like, I want to look at all the colors, but at least when you're rounding on people and the patient is unlucky enough to have a Foley catheter and maybe you're lucky enough that they do, take a look at the urine--
DR. STERN: Take a look.
DR. CIFU: --you may learn something.
DR. CIFU: We certainly do it with pleural fluid that we see lying around, sputum that we see next to the bed, sometimes helps you. Okay. My clinical pearl. So you sort of dissed [chuckles] the differential diagnosis--
DR. STERN: I did.
DR. CIFU: --of unconjugated hyperbilirubinemia and I have to say, I sort of agree. It's not that interesting, it's mostly hemolysis and it might be acute hemolysis of unknown cause that you need to work up, it might be dysarthria paresis that you know from the minute they walk in that this is someone with sickle cell anemia and a pain crisis, but do think of some other things that are around there. So extravasation of blood, people can get unconjugated hyperbilirubinemia from just like a huge, I don't know, retroperitoneal bleed or a complication of a cardiac catheterization as they begin to metabolize that, break that down.
DR. CIFU: Impaired uptake of unconjugated bilirubin, so you mentioned sepsis, heart failure, drugs, I think rifampin is probably the classic. So just make that differential diagnosis a little more complicated than you gave it credit for.
DR. STERN: [chuckles] Fair enough. My next one is you always have to keep in mind Tylenol. We alluded to this earlier, Tylenol is one of those things that if you're going to intervene, you need to intervene early because if you do it early, you can save the liver, if you do it too late, you're looking at liver transplant. So any patient presents with increased LFTs of any type with any sort of psychiatric manifestation, any sort of overdose, you really need to be putting that at the top of your differential because it has such specific treatment early.
DR. CIFU: Right and it's especially important, I think, because of the fact that we toss this piece of data around a lot that half of all acetaminophen intoxications are accidental. I think those breakdown into real accidental, you know, I'm taking Tylenol because I'm having pain and maybe I'm also drinking or maybe my liver function isn't perfect to begin with. And then there are the people who are sort of acting out and they're like I'm going to have a suicide attempt as a cry for help, but I'm going to do it with Tylenol because pssh--
DR. STERN: Right.
DR. CIFU: --and that can be just an absolute tragedy because - not that a suicide that was meant to be is not a tragedy - but it can be people who really don't want to hurt themselves who end up doing horrible injury to themselves.
DR. STERN: All right. So I guess the next one will be on alcoholic liver disease. So when we see the AST much greater than the ALT, we think about liver disease, my understanding is because often they have a pyridoxine deficiency and they can actually synthesize ALT very well. But in any case, 70 to 80% of patients with alcoholic liver injury have levels of greater than two of AST to ALT and levels of more than three are even more specific, so--
DR. CIFU: Right.
DR. STERN: --something to remember.
DR. CIFU: That three to one is something that I take away that like when I see that ratio and I ask the person if they drink and they say no, I am like, come on.
DR. STERN: Right.
DR. CIFU: [chuckles] You know.
DR. CIFU: I feel like I'm throwing out some maybe iffy data on this podcast--
DR. STERN: [chuckles]
DR. CIFU: --because I'm usually really careful about this but this is something that I've just seen in so many places and I've never really looked in great depth at where this comes from, but it's the whole thing about depression being the first symptom of pancreatic cancer. And a lot of this is obviously retrospective and it's people who were probably depressed at the time because they have pancreatic cancer but people have quoted as high as 45% of people, which I can't believe.
DR. CIFU: But I have to say, if I had a middle-aged patient who came to me who had never had issues with depression or mental health, who all of a sudden at age 60 becomes depressed, I would at least think about that. Probably not to the point that I would be doing an MRCP but probably to the point that I'd be examining them and checking LFTs.
DR. STERN: Interesting.
DR. CIFU: You're scoffing.
DR. STERN: Well, no, no. [both chuckle] I'm just wondering, I've never done that. So I'm wondering what I would do with that but it's worth a thought.
DR. CIFU: Maybe you've learned something from me.
DR. STERN: Well, I wouldn't go that far.
DR. CIFU: [chuckles]
DR. STERN: So my last one is detecting jaundice. So, you know, it's very hard in patients of color to look at skin sometimes and detect mild jaundice. So then we often look at the sclera but the more pigmented your skin is, the more likely you are to have conjunctival staining from melanin which can make the sclera dark and hard to see whether or not it's really yellow. So one technique I learned early on was if you lift someone's eyelids and ask them to look at the floor you actually can see the sclera of their eye that's always covered by their upper lid that doesn't get conjunctival pigmentation on it, and it's a good way to look for scleral icterus in people who have dark skin.
DR. CIFU: Right. And this is generally looking at mild hyperbilirubinemia, right?
DR. STERN: Right.
DR. CIFU: Because the sclera starts becoming icteric like two to three, right?
DR. STERN: That's right.
DR. CIFU: So it's very low levels that you're not going to really see in anybody's skin. I find the most sensitive places for me, sclera as you said, sort of superior sclera are the best, under the tongue helps me, as long as you've got a really bright light to look there--
DR. STERN: Okay.
DR. CIFU: --and palms is the other thing. And I always like palms because I can act as a control. Right? So for looking for anemia, looking for icterus I can put my hand up next to the patient and that helps quite a bit. So we hope you found this episode of S2D, the Symptom to Diagnosis podcast useful and a bit enjoyable. If you like listening to us, please rate us on iTunes, we've heard that's important, or maybe not. Don't rate us, just give us five stars.
DR. STERN: [chuckles]
DR. CIFU: If you want to chat, tweet at me @adamcifu. And as a reminder, our textbook, Symptoms to Diagnosis: An Evidence-Based Guide takes a much deeper dive into how to think about and reason through the diagnosis of medical presentations. The book is available in print through all the usual places on your mobile device and also available and fully searchable via the Access Medicine website available worldwide from McGraw Hill. A reminder that the cases that we discuss are drawn from our clinical experiences but, because protecting patient privacy is part of our oath, we never discuss actual patients and most cases are composites.
DR. CIFU: The music for the S2D podcast is courtesy of Dr. Maylyn Martinez.
DR. STERN: Thank you.
DR. CIFU: Thank you. [upbeat outro music]
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