Next, it's my pleasure to introduce to you my great friend, our course director and leader, Dr. Joe Vicari. Joe, it's all yours. Thank you, John, and thank you for the kind words. John's presentation is a great segue into a couple case studies that we'll look at in liver disease. I have no disclosures. My objectives are simple, is to give you a focused, practical approach to clinical care on two disease states that are more common than we think of, and I think sometimes overlooked by providers, both physicians and APPs. In general, I want to get you thinking more broadly about some less common liver disease. Once again, our goal is to always think, think, and think some more. We have a 46-year-old white male who came to the clinic with abnormal transaminase, or better stated after that great talk by John, aminotransferases. The AST was 68, the ALT was 78, and he had a normal albumin, platelet count, and bilirubin. He has a history of diabetes, relatively newer in onset. His father had some type of liver disease. He wasn't quite sure, and he's always been thought to be a little more tan, even though he really did not spend much time in the sun. Physical exam was unremarkable, except for the tan skin. What is the most likely cause of his abnormal aminotransferases, diabetes mellitus, family history of liver disease, and this tan skin? What is the most likely cause of his abnormal aminotransferases, diabetes mellitus, family history of liver disease, and tan skin? Is it autoimmune hepatitis, primary biliary cholangitis, hemochromatosis, or hepatitis B? And we'll give you a moment to think about it. Excellent. The majority of you got it correct. This person has hemochromatosis. So that'll be our first case to discuss, and hemochromatosis. Hereditary hemochromatosis is caused by a genetic defect in the HFE gene, and this leads to an increased state of iron overload. The genetic defect is actually an abnormality in a peptide in the liver called hepcidin, and in patients that have hereditary hemochromatosis, there's a low level of hepcidin, or it does not attach appropriately to its receptors, allowing it to do its job. And hepcidin's job is to inhibit iron absorption. So when it doesn't work in this genetic defect, we have an increase in iron absorption. There are four types of mutations that we can see. The most common and the ones that cause disease are the C282Y homozygous state and the C282YH63D mutation, which is a compound heterozygote. And in classic genetics, a compound heterozygote refers to two different mutations at one particular gene. So there's one mutation on each chromosome of the gene. And these are the mutations that can cause hereditary hemochromatosis. Interestingly, hereditary hemochromatosis is one of the most common genetic disorders in individuals of European descent, and it is predominantly a genetic disorder in white people. The homozygosity for 282Y, which is the most common expression of the disease worldwide, occurs in 1 in 150 people to 1 in 300. And in the United States, it occurs about 1 in 300 people. And it's important to know that not all homozygous individuals express the disease. And in those with C282YH63D mutation, they have a very small chance of developing the disease, about 1 to 2%. I have one slide on secondary iron overload. There's not enough time to focus on it. We're focusing on the primary form of iron overload, but causes of secondary iron overload are chronic alcohol use, non-alcoholic fatty liver disease, hepatitis C, some hematologic disorders. They could play a role in people who have some of the more unusual genetic defects that would not get the disease without a secondary form. So just know there is a secondary form. Typical presentation that you may see when a patient comes to the office, and the most common is a mild elevation of the immunotransferases. If patients have symptoms, the most common is weakness and lethargy, so not very specific. They may have a new onset of diabetes, like in my patient that I saw in the clinic. They could present with arthralgias, perhaps knee pain, pain in their fingers and hands. We can see impotence in males as a presentation, and EKG abnormalities. As we'll see, there are cardiac abnormalities as well. And iron overload causes people to be relatively immunocompromised, so they are at risk for some infections. I really like this slide. I think it's a slide that sums up all we need to know about the organ systems involved in some of the presentations. So if you're one that likes to catalog stuff with pictures, I think this is a good one to keep. We could see in the brain, we can get hypopituitarism, which can lead to hypogonadism that's a little more common in men than women, but in women that have it, they may have cessation or irregular menses. There's cardiac injury. We can see a cardiac myopathy due to iron overload, and we can see atrial arrhythmias. The liver is the primary area of injury, so we can see a hepatitis or an aminotransferase abnormality, and we can see any of the stages of fibrosis all the way to cirrhosis with complications of malignancy, which we'll talk about in a moment. The pancreas can be injured, leading to diabetes. We can have joint pains and aches, as we see represented by a radiographic image of the knee and the hand as more common areas where you might have arthralgias and joint injury, and then you see the tan skin or what has classically been described as a person that presents with bronze diabetes. They have this tan look, and they have diabetes. So I really like this slide. It gives us a lot in one slide. There is a cancer risk in patients with hereditary hemochromatosis and is a high cause of mortality in patients that don't get diagnosed or get diagnosed later in their disease. The risk of hepatocellular carcinoma is about 20 to 200 times that of the general population. Like almost every other liver disease, patients that get hepatocellular carcinoma have the precursor of cirrhosis. Previously, we weren't sure if more advanced liver injury like stage 3 fibrosis could put people at risk for cancer in hereditary hemochromatosis, but we now know patients with fibrosis, including stage 3, are not at risk for hepatocellular carcinoma, and there is no increase in risk of hepatocellular carcinoma in first-degree relatives that have the disease but do not have cirrhosis. There's a slight increased risk of cholangiocarcinoma, and some other cancers may be associated with hereditary hemochromatosis. Basic evaluation is simple. If you suspect hemochromatosis, you start by measuring a ferritin. Ferritin processes intracellular iron. If the ferritin is greater than 200 in women, greater than 300 in men, it should start to get you thinking about the diagnosis. Transferrin saturation is where we take the iron and divide it by the TIBC. The value that comes out of that is a percentage, and if it is greater than 45%, we should start thinking about hereditary hemochromatosis. We already commented on the genetics that are important, so once you suspect it, and as we'll see in the next slide, when you confirm it or have a high suspicion, then you should proceed with genetic testing. The role for liver biopsy and MRI is small, and again, we'll cover that in the next slide. Here's another slide I really like. It's from an ACG guideline. I believe the guideline is from 2022. Again, if you like the catalog slides or pictures, this is a great one. So if we start at top, we have a symptomatic person that presents. We have an asymptomatic person that presents with mildly abnormal liver enzymes, so greater than 35 on this scale, and then we have the adult first degree relative of a person with hemochromatosis. In these cases, when we suspect hemochromatosis, we should order the transferrin saturation and the serum ferritin. If the transferrin saturation is less than 45% and the serum ferritin is normal, no further evaluation is needed. However, in the adult first degree relative, genetic testing is important, as we pointed out, because if they have a spouse or a partner and have a child, there could be genetic risks for any children that they may have. Now if the transferrin saturation is greater than 45% in any of these individuals and or there's an elevated serum ferritin, we go ahead with genotyping. If the patient has a C282Y mutation, their homozygous, we then take a look at the serum ferritin. If the serum ferritin is greater than 1000 or there are significantly elevated liver enzymes, then we would want to proceed with liver biopsy because there's a higher risk for cirrhosis in patients with a serum ferritin of 1000. Once we make our final diagnosis from that group, then they go on to therapeutic phlebotomy. If the serum ferritin is less than 1000 and they have normal or only minimal liver enzymes, there's no need for liver biopsy and you proceed to therapeutic phlebotomy. If a patient has, and we'll concentrate here on the compound heterozygote, if they have a C282YH63D mutation, we have to realize that other liver disorders could be at play because the risk of them developing disease is only 1 to 2%. So rule out other liver diseases, rule out secondary sources of iron overload, and then you should quantify the amount of liver iron and it's best done with an MRI with some special software that can calculate a hepatic iron concentration, it's non-invasive. So if the MRI shows an elevated hepatic iron concentration and the serum ferritin is greater than 1000, then they have hemochromatosis and go to phlebotomy. You could also do a liver biopsy in this case. I like this slide. It runs you through the evaluation and treatment. So one again that I would probably catalog as an image. Treatment is very simple. Phlebotomy is very successful in treating patients with hemochromatosis. We start off weekly and then depending on lab values, it can be as often as four times a year or as low as two times a year. We follow these patients with a ferritin and when the ferritin is in the range of 50-100, we know we have effective phlebotomy and we maintain our phlebotomy schedule to maintain those labs and we want to keep the hemoglobin greater than 11. So monitor the hemoglobin, keeping it greater than 11. Chelation therapy, there are a number of options. There's an oral chelator, an infusion chelator, and a subcutaneous injection form of chelation. Chelation should only be used when phlebotomy fails or phlebotomy is not tolerated. There can be some significant side effects with some of the chelation agents. We want to advise patients to limit alcohol because that does increase iron absorption. We want to avoid vitamins with iron, but you do not need to restrict dietary iron. Liver transplant is reserved for those who have a late diagnosis of hemochromatosis, so they have cirrhosis and they have complications. There's very few transplants reported in the literature and those that are reported tend to do well unless they have significant non-liver side effects. For example, they have congestive heart failure from a cardiomyopathy and liver transplant does cure the disease since hepcidin, that peptide I talked about earlier, the majority of it is produced in the liver. So we then go back to the normal state of liver inhibition, excuse me, of iron inhibition after transplant. I'm showing this slide just one more time. I really like it. If you catalog things, I think it really helps you work through this disease and work through it very easily. Non-cirrhotics with treatment, it's very good. Their long-term survival does not differ from the general population. If someone has cirrhosis, then we treat them like everyone else who has cirrhosis. We screen for hepatocellular carcinoma with ultrasound. That is my preferred method. It's inexpensive and helpful. If you're elected to do a CT to screen for hepatocellular carcinoma, I could not argue with you and you may or may not want to use an alpha-feta protein. Literature can go either way and you should screen for varices and we'll hear more about varices in our next talk. Remember about non-hepatic organ damage. Also refer to the appropriate consulting services. Those who may have poorly controlled diabetes, endocrine consult. Those who have cardiomyopathy or cardiac disease, off to a cardiologist. Diabetes does not improve with treatment, but cardiac disease can and the aminotransferase can. Some improve, some don't. Make sure you review those with your patients. We've talked about hepatocellular carcinoma. that's a quick review of hemochromatosis. Let's move on to the next case. And both of these cases are patients that I saw within the last five or six years. So the next patient's a 70-year-old female who is referred for abnormal immunotransferases, has jaundice, has an elevated bilirubin, and an elevated alkaline phosphatase. She has a decreased appetite, fatigue, nausea, and right upper quadrant pain. Her AST was 500, her ALT was 600. The bilirubin was 3.8, ALKFAS 800. And like our previous patient, the INR, albumin, and platelet count were normal. Importantly, and it gets to our point about William Ulster yesterday, the history is so very important. When we make a diagnosis, this may be a clue. Five days ago, she started sulfamethoxazole and trimethoprim for urinary tract infection. What is the most likely cause of her liver injury? Is it Wilson's disease? Drug-induced liver disease? From simethoprim, I had a little tongue twister there, I apologize. Non-alcoholic fatty liver disease or primary sclerosing cholangitis. Excellent, very good. This is drug-induced liver disease or DILI. I picked this case because as you'll see, it occurs more common than we think, and I don't think all of us as providers, physicians and APPs, think about this enough. So I want to make sure we get this on your radar screen and think about, and I think there'll be some numbers that will make a good impression to get you thinking about it. There are three types of injury that can occur in drug-induced liver disease or DILI. There's a direct injury, and this is dose-dependent and predictable. For example, acetaminophen. If any of us humans take a high enough dose of acetaminophen, and if acetaminophen is administered in high enough doses in laboratory animals, we will get drug-induced liver disease, whether it's a mild injury or a severe injury. So direct is dose-dependent and predictable. Then there's idiosyncratic. It's dose-independent and unpredictable. And an example of this would be amoxicillin clabulonate. And there is likely some type of genetic predisposition. There's been some work with alleles, certain alleles and haplotypes. So it's hard to know exactly what part of our immune system may have a role in this. There's no clinical testing available at this time, but this is different. It's dose-independent and unpredictable. And finally, there's indirect injury. And this is due to the biologic action of the drug on the immune system. So not the immune system's immediate response, but this is the drug inducing it on the immune system. And a classic example is nitrofurantoin. So some epidemiology. If you look at some of the original thoughts on incidence and prevalence, it was very hard to determine because obviously we cannot do prospective studies in drug-induced liver disease. So DILI, I think classically, has been thought to occur in about 1 in 10,000 to 1 in 100,000 patients. However, more recently, we have some better information based on retrospective studies and from data obtained from EMRs, from electronic medical records, which has been very helpful. So it's estimated the annual incidence of DILI worldwide is about 14 to 19 people per 100,000. And about 30% of these will present with jaundice. And remember, when we talk about DILI, we're not only talking about prescribed medications, we're talking about herbal and dietary supplements, which in some part of the world, where it's used more frequently and more commonly used, such as Asian countries compared to the United States, we have to think about herbal and dietary supplements due to the diverse nature of our country. DILI is the cause of jaundice in up to 50% of patients with new-onset jaundice. And that statistic opened my eyes a little bit. And DILI accounts for 10% of acute hepatitis. So this slide should get us thinking. When we see patients coming in with a new-onset liver disease, we should make sure we do a thorough medication review, which won't take very long. I'm gonna have a table that will help you have a nice reference for some medications to think about. So what about risk factors? Well, age, sex, race, and ethnicity, really, it's unclear what the impact is as a risk factor on DILI. We do have some trends. As far as age, adults are more likely to get DILI than children. As far as sex, females are more likely to get DILI than males. And in race and ethnicity, it seems that amoxicillin clavulonate is more common in African-Americans than whites. And simethoprim, trimeth... Bactrim, again, the tongue twister, I apologize. Injury from Bactrim is more likely to occur in whites versus African-Americans. And in the United States and abroad, herbal dietary supplements are more likely to occur in Asian populations because it's more widely used in those cultures. Here are some risk factors that are better known. The drug properties. Escalating doses, whether done by the provider or by the patient, is a known risk factor. Shortening the interval dose, so taking the medication more frequently. And this happens a lot, especially with acetaminophen, by the patients without provider oversight. Same thing with escalating doses. That happens sometimes by the individual without provider oversight. And those who are using multiple hepatotoxic drugs. Post-genetic factors can play a role, especially in those that have an underlying risk for autoimmune disease in general. And as we'll see, if there's a medication-induced hypersensitivity reaction, we have to make sure we look at the eosinophil account and our CBC. And other important factors that definitely have a negative impact and they'll include obesity, diabetes mellitus, chronic liver disease, and CKD. Clinical manifestations. There really is not a lot that points us to any specific etiology, but we do know that the most common presentation is acute hepatitis. So in someone that comes in with acute hepatitis, in addition to doing your viral studies, make sure you think about medications. Many patients are asymptomatic. However, we have patients like my patient who really felt quite unwell. She was tired. We could see fever, anorexia, nausea, vomiting, right up a quadrupane and jaundice. Patients with cholestasis can have puritis. And I'm going to mention liver failure a few times because the survival rate in those who have liver failure, for example, in idiosyncratic DILI is as low as 25%. So if you receive a call, and I remember getting a couple of calls from outside hospitals to our hospital. We were not an academic center, but we were a referral center from smaller hospitals in the Northern Illinois area. I had a couple of calls where clearly patients had liver failure from a medication. And since the mortality rate and the survival rate is low, if you think someone has liver failure from a medication, they should be immediately transferred to a tertiary center that has a liver transplant program. These people are sick and can get very sick and go south very quickly. So you need them at the best center, which would be at a tertiary center with a transplant center. And I will repeat that again. Different types of injury we see, hepatocellular injury, disproportionate elevation of aminotransferases. John, you could see I got it right this time. So I was paying attention in your previous talks last year. So disproportionate elevation of aminotransferases compared to ALKFAS. DILI may be normal. It may be elevated. In cholestatic injury, there's a disproportionate elevation of the ALKFAS compared to aminotransferases. DILI may be elevated, and most times it is, but it can be normal. And in those who present with a mixed picture of injury, you get a little bit of each, hepatocellular injury and cholestatic injury. Those with acute DILI, that occurs in less than three months, and those that have chronic DILI have abnormal tests for greater than three months. So we have to think long-term in patients with DILI. Don't just think immediately. We can see it as far out as six months or 180 days. I like this table. This table's from UpToDate. It gets you thinking about what could be the source, what drug could be the source of injury. So if we have hepatocellular injury or hepatitis, the ALT is typically greater than or equal to three times the upper limit of normal. If it's purely cholestasis, the ALKFAS is greater than two times the upper limits of normal, and the aminotransferases are unimpressive. And in mixed, the ALT is greater than or equal to three times normal, and the ALKFAS is greater than equal to two times normal. Now the R value on the right can be very helpful as well, and maybe a little more specific and sensitive. The R value is calculated as follows. You take the ALT and divide it by the upper limits of normal of the ALT. That gives you the numerator. You take the ALKFAS and divide it by the upper limits of normal for ALKFAS. That gives you the denominator. If the value of that equation is greater than or equal to five, it's hepatitis or hepatocellular injury. If the value is less than or equal to two, it's cholestasis. And if it's in between two and five, it's mixed. In my patient, it was 2.4, so she had mixed injury. So at the bottom, you can see how to calculate it. It's very simple, and it can be very helpful. This table is from a paper from the Mayo Clinic a few years ago. I really like it. It shows you your liver test abnormality on the left, hepatocellular, cholestasis, or mixed injury. And it gives you a nice list of medications to run through. If you want to think a little bit more in depth and think about histologic patterns, figure if you need some more help to guide you, the bottom half of the table is also very nice, going through drug-induced autoimmune hepatitis, steatohepatitis, steatosis, and other abnormalities. And other entities. And so this is another one. If you catalog things, this table is very nice to have and to easily reference. The diagnosis of delay is a diagnosis of exclusion. Make sure you test for other liver diseases when appropriate. So if there's a cholestatic pattern, for instance, you may want to check an anti-mitochondrial antibody to make sure you don't have a presentation that may be atypical for primary biliary cholangitis. So think of other liver diseases, viral hepatitis. So diagnosis of exclusion. We need a detailed medical and most important medication history. That will help you make the diagnosis. If patients present with an autoimmune-like presentation, think of a hypersensitivity reaction. Take a look at your eosinophils on the CBC. Those who have moderate to significant elevation of any of their lab values, the immunotransferases, the BILI, the ALKFOS, they might have clinically significant DILI and may need to be hospitalized. For those who have cholestasis, remember to image to make sure we don't get fooled by a common bile duct stone or obstruction or an obstructing process in the biliary tree or pancreas. Liver biopsy has much less of a role in DILI, but if there is confusion, a liver biopsy could help sort out the answer. Management is mostly supportive. Hospitalization for those who need it and ICU setting for those who are sick. Early recognition is very important. We must identify the drug and review it, excuse me, and remove it as soon as possible. There is medicinal therapy for some patients. For instance, those with acetaminophen. You're all familiar with treating acetaminophen toxicity with N-acetyl with NAC. And some experts recommend in any form of drug-induced liver disease, you can make a case to give NAC. It certainly won't hurt, but it may help. So consider giving NAC to anyone with a significant or serious DILI. For hypersensitivity-induced or autoimmune-induced, give glucocorticoids, treat the puritis, serial labs, and those with severe DILI with liver failure, again, these people have a low survival rate. Once you recognize it, get them off to the tertiary center that has a liver transplant program. They are best equipped to take care of those patients. Prognosis overall depends on the type and severity of DILI, but overall, it is very good. I think we've spoken enough about the importance of referring acute liver failure patients. We know that acute liver failure due to acetaminophen that require hemodialysis, they have a worse prognosis. Those with an elevated creatinine at time of presentation or preexisting elevated creatinine and preexisting liver disease have a worse prognosis. Purely cholestatic DILI does better overall than hepatocellular injury from DILI, and cholestatic DILI, as compared to hepatocellular injury, DILI is more likely to develop chronic disease. So my pearls, you're probably tired of hearing me say this, but it's think, think, think when it comes to liver disease and everything we do, specifically with these two diseases, I'd like to see these on your radar screen. You cannot make the diagnosis unless you think about it. Hereditary hemochromatosis and DILI are more common than most providers suspect. In DILI, we can see hepatocellular injury, cholestatic injury, or mixed. In hemochromatosis, physical exam findings are very important if you remember the image of the gentleman that we had showing the different organ systems, very helpful in us making the diagnosis. Once we think about the right diagnosis for hemochromatosis and DILI, we can order the correct tests to establish diagnosis and refer them if needed, if they are sick. The correct diagnosis and correct treatment always leads to better outcomes. And it's our job to provide high quality care for patients. So think, think, think, and you will provide the highest quality care for your patients. Thank you for the time and allowing me to present these cases.

Dr. Joe Vicari

liver disease

hereditary hemochromatosis

genetic testing

therapeutic phlebotomy

drug-induced liver injury (DILI)

supportive care