And now it's my pleasure to welcome Andrea Gossard, who is my valued and stellar colleague. She's going to review case studies and liver disease. I would like for you to know that Andrea is a certified nurse practitioner, clinical associate in gastroenterology and hepatology, and she is also an associate professor of medicine at Mayo Clinic, the mothership in Rochester, Minnesota. Her clinical and research interests include autoimmune liver and biliary tract disease, including PSC, PBC, and autoimmune hepatitis. In addition to her clinical practice, Andrea is actively engaged in leadership of nurse practitioner and physician assistant practice within her department, the Midwest Regional Practice, and Mayo Clinic Enterprise. Andrea, the audience is yours. Take it away. Thank you so much, Dr. Martin, and good morning. It's a pleasure to be here this morning to talk with you about case studies in liver disease. And I would like to thank the course directors for the invitation to be part of this terrific program. I'm excited to work through cases over the next several minutes and then to regroup with Dr. Martin as we talk about some complications that you may see in the setting of liver disease. So I have no disclosures. So we will start with case study number one. And this is obviously on the heels of Dr. Martin's exceptional talk. You're likely to know exactly where we're heading with each of these. But this is a 54-year-old woman who was referred for elevated liver tests, again, not elevated liver function studies, found during routine blood work. In this case, her AST is mildly elevated at 108 with a more significant elevation of the ALT and even more elevation of her alkaline phosphatase. Importantly, her bilirubin levels are normal. Clinically, she describes fatigue with mild intermittent pruritus. As with any case where you're seeing elevated liver tests, we typically would recommend rechecking them to make sure that they are quote unquote real, that they're something that persists over a period of time. As you may know, many people will have intermittent elevations of their liver tests for a variety of reasons. But not so commonly is that necessarily due to chronic liver disease. For instance, a viral infection, or to Dr. Martin's case, excess Tylenol use. Many things can drive up the enzymes. But if they persist, it's important to evaluate for underlying liver disease. In this case, the elevations did persist. So an ultrasound was performed and revealed some coarsening to the hepatic architecture. Importantly, there was no evidence of a liver mass or hepatoma, and there was no splenomegaly or abdominal fluid. Blood tests for viral hepatitis, iron overload syndromes were unrevealing. A fiber scan was performed and revealed no excess hepatic steatosis or fat and no fibrosis. So fiber scans are, of course, being performed much more commonly today than in the past. These are a nice noninvasive way to assess for hepatic fat and fibrosis, oftentimes done in the office, even point of care. We're starting to see more and more of these used for evaluating hepatic steatosis that can improve over time or worsen over time. So they've become a very helpful tool. With this particular case, the anti-mitochondrial antibody was found to be positive. So with an elevated alkaline phosphatase or liver enzyme profile that is cholestatic, so to speak, with the ALK-PFAS more significantly elevated than the aminotransferase levels, coupled with a positive anti-mitochondrial antibody, in this case, about 95% of the time, you're quite accurate with the diagnosis of primary biliary cholangitis. So this is a disease, of course, of the biliary tree, the microscopic bile ducts, with a prevalence of 29 per 100,000 patients. The vast majority of people diagnosed with PBC are female. Again, liver enzymes elevated in a cholestatic profile with that alkaline phosphatase, more elevated when you look at respect or in relationship to the upper limit of normal than the ALT and AST. And the vast majority of patients will have a positive anti-mitochondrial antibody. Now the fifth bullet I have is compatible histology. So in general, if you have a woman, 40s, 50s, with an elevated alkaline phosphatase level and a positive anti-mitochondrial antibody, you can feel confident in that diagnosis of primary biliary cholangitis and a liver biopsy wouldn't be indicated. In the setting of an anti-mitochondrial antibody negative situation, then sometimes we will think about a liver biopsy to make the diagnosis of AMA negative PBC. So that's where the histology may come into play. But in general, the vast majority of patients diagnosed with PBC do not need a liver biopsy to establish the diagnosis. Clinical presentation. So fatigue is definitely the most common complaint. But as we all know, as clinicians, fatigue is something that can be described in a variety of settings that isn't very specific to PBC. I would estimate that 30 to 60% of the patients that I see for primary biliary cholangitis do describe fatigue. Paritis is another issue that's quite common. And the way that patients will describe it is it's a sense of itching or almost a tingling sensation under the skin that they feel the need to scratch. Most patients will describe kind of that all over sensation. So it's not usually focal paritis, but more diffuse widespread paritis. Patients will also tell me that this will wake them from sleep or they'll wake up with excoriations from scratching. So we know the paritis can be pervasive and really impact their quality of life. And thankfully, we have some good therapies for that. Some patients with primary biliary cholangitis will actually present with advanced fibrosis. So it was unbeknownst to them they even had a liver condition and they've already got well established fibrosis at the time of presentation. And then of course, many are entirely asymptomatic and it was simply discovered by liver tests that were checked and found to be elevated. The elevations persisting over time and then further evaluation with that anti mitochondrial antibody. In general, primary biliary cholangitis has a long natural history. So for the majority of patients, this is something they're likely to die with not from. That said, for some patients, as I'd mentioned, we may see well established fibrosis at the time of diagnosis. And that really kind of resets that timeline because now you're managing complications of advanced stage liver disease. There is effective treatment for most patients with primary biliary cholangitis and we'll discuss that. It's also not uncommon to have other autoimmune conditions. The most common other autoimmune condition that we see is thyroid dysfunction, which I would estimate is around 30% of patients. Also, we may have, although there may not be a family member with PBC necessarily, there are oftentimes stories within the family of other people who have autoimmune conditions. So we'll see this sort of constellation effective of patients with this condition may have a mother and an aunt with thyroid dysfunction, someone who has rheumatoid arthritis, renounce phenomenon, even multiple sclerosis. So we know that other autoimmune conditions are not uncommon within the family. And that can sometimes kind of help if you're wondering, is this the right diagnosis? Management options for primary biliary cholangitis include those listed here. Ursa deoxycholic acid was a therapy that was originally approved by the FDA for gallstones in the 80s. And then the approval for use in primary biliary cholangitis came in the late 90s after clinical trials that were performed at Mayo Clinic. Ursa deoxycholic acid is, to be frank, a very effective therapy for most patients with PBC. It's a weight-based dose, 13 to 15 milligrams per kilogram per day, typically in two divided doses. Of course, if the patient has very low body weight, then sometimes a single dose of 750 or even 900 milligrams per day is acceptable. For the majority of patients, this will lead to improvement in the alkaline phosphatase level. In April of 2016, a second agent received FDA approval, and that was obeticholic acid, or Ocalava as a trade name. When it was originally approved, it was recommended you use 5 to 10 milligrams per day, and oftentimes as an adjunct therapy to Ursa deoxycholic acid or as a substitute therapy if Ursa was not able to be used for one reason or another. In May of 2021, due to post-marketing experience, they did adjust the prescription recommendations, and it is ill-advised to use in the setting of advanced fibrosis. Originally, it was suggested you could use 5 milligrams per week in this setting, but for many, they just avoid it altogether if evidence of advanced fibrosis is seen. Again, that's where your fiber scan is beneficial, or if you happen to use MR, MR elastography is beneficial to ensure you know the stage of disease before you think about initiating obeticholic acid. In my experience, about a third of patients who are provided obeticholic acid will have trouble with itching from the therapy, but again, we do have options for managing that. Phenofibrate is a product that's available for use of treatment for lipid disorders in the U.S. In Europe, a product called bizofibrate was used as an adjunct therapy as part of treatment for primary biliary cholangitis and found to provide benefits, so we don't have bizofibrate in the U.S., we have phenofibrate. Oftentimes, that's prescribed at a dose of 160 milligrams per day, but again, adjunct to ursodeoxycholic acid, or as I mentioned here, even triple therapy may be something that will be recommended in the future. In general, this seems to be well tolerated. You do need to monitor their kidney function along with their liver enzymes, of course, to evaluate for improvement. And then, of course, the clinical trial landscape continues as we look for other therapies. There are several things in the queue that we will hope to have information on within the next few years. Prognostic studies have been beneficial in creating these different tools. I can tell you that in a practice where primarily what I see is cholestatic liver disease, we don't use these commonly, but in general, you have multiple options available that you could use to provide patients' estimations regarding prognosis. So, back to our case. Patient has now returned as part of a one-year follow-up visit and has new complaints of increasing fatigue, right upper quadrant pain, and generalized aches. You obtain updated lab work and notice a shift in the biochemistries. So, again, drawing from Dr. Martin's excellent talk, you see that this patient is much more hepatitic than cholestatic with that ALT that is now 10 times the upper limit of normal. Slightly more modest, but yet still concerning elevation of the AST and definitely less elevation of that alkaline phosphatase. So, your treatment for the PVC looks like it's perhaps provided some benefit, but the liver enzyme elevations are up. And particularly concerning, now this patient has an elevated total belly ribbon. So, you proceed with additional laboratory work, and you find that this patient has, again, more profound elevations of the immunotransferase levels. The additional laboratory work revealed a double of the gamma globulin. So, normal level is typically 1.6, and in this case, 3.2 or higher would be something of concern. And autoantibodies were found to be positive. So the most common autoantibody positivity is this type one autoimmune hepatitis where it's the anti-nuclear antibody. And autoimmune hepatitis is something where in general, you would be thinking about that, again, hepatitic liver enzyme profile, the additional studies to help corroborate the diagnosis and probably a liver biopsy to confirm those histologic changes. So autoimmune hepatitis has a prevalence of 17 per 100,000, so again, uncommon, far more commonly in women than in men and may affect children with the pediatric form oftentimes being type two autoimmune hepatitis. Autoimmune hepatitis in the setting of PBC as an overlap syndrome is uncommon, but can and does happen. I see cases of this probably at least one per month. Clinical presentation in general, the increase in fatigue, which again is a difficult symptom to really narrow down what might be contributing, could be thyroid dysfunction, could be just normal stress or life, deconditioning. There are lots of things that go into the perception of fatigue, but the arthralgias is something that we don't commonly see in the setting of PBC that I would say is pretty consistent amongst our patients who develop autoimmune hepatitis overlap. They may also have right upper quadrant pain, and that in my mind is oftentimes related to the degree of ALT and AST elevation with that inflammation in the liver contributing to that sense of an ache or right upper quadrant fullness. That's something that we don't typically see in PBC that is a bit more common in autoimmune hepatitis. As is the case here, they may be jaundiced, and oftentimes this is insidious, and all of a sudden they've developed jaundice in the setting of PBC, and so you do have to look for this overlap syndrome. And thankfully, the therapy tends to be quite good at improving the situation, but that can be kind of a startle, obviously a startling symptom for patients with chronic liver disease. Nausea, loss of appetite, fluid retention, and then of course some have no idea their liver enzymes are elevated. I have a patient like this right now. The enzymes went up into the 500 range, and he states he's feeling the best he's ever felt. So they certainly can be asymptomatic with these marked changes in their enzymes. So I mentioned autoimmune hepatitis typically would warrant a liver biopsy. Oftentimes what we will be looking for is interface hepatitis. There may be evidence of fibrosis on the biopsy. Again, we would look to see how much of this is reversible once they are on effective therapy. So the key is to continue to follow these patients after they're treated. Prompt therapy with corticosteroids improves survival significantly, as is seen here. 10-year life expectancy for treated patients with and without cirrhosis is quite similar. Life expectancy for patients in clinical remission is similar to that of the normal population. So we definitely have patients who we can get into full clinical remission that can remain in remission even off therapy for decades. So the key is, again, continuing to follow because relapse does occur and is regrettably not uncommon. Even up to 2 3rds of patients will relapse once tapered off entirely. So management, prednisone was first described as treatment in the 1960s. Typically, use of azathioprine as a steroid sparing agent is added. We use that more commonly than 6-MP. Budesonide and mycophenolate mofetile are also used. I had mentioned yesterday, I was at the LiverConnect meeting just recently, and budesonide is something that's gaining traction even as first-line therapy. But for now, prednisone is typically a first-line approach. Management is quite dependent on response to treatment, meaning that patients need to be monitored with respect to their liver enzyme levels to ensure that you do taper carefully to ensure that they do not have relapse in the midst of a taper. So I will oftentimes drag this out over very slow withdrawal over weeks to months as we taper patients down to a lowest dose possible in order to keep the disease in remission. And then, of course, ongoing surveillance is appropriate just because we do see relapse and we'll want to catch that promptly. So continued monitoring of their liver enzymes is key. So switching gears to the other sort of half of the types of patients that I see, this is a 24-year-old man referred for elevated liver enzymes. Blood work performed while monitoring his therapy for chronic ulcerative colitis revealed the following profile. So mild elevations of the AST and ALT with more marked elevation of the alkaline phosphatase and concerningly, a total bilirubin of 2.9 with direct of 1.6. Again, this patient notes fatigue, pruritus, but also describes dark urine that doesn't seem to get better when he's adequately hydrated. Primary sclerosis and cholangitis is a condition that occurs in perhaps five out of every 100,000 patients. Elevated liver enzymes typically in a cholestatic profile. Positive PENCA. So we use this, but to be frank, we typically don't need it to make the diagnosis. So I think it's an okay test to add, but I don't think it's particularly necessary. But most importantly, these patients, the diagnosis is made with cholangiography. So we do have access to MR cholangiography at our institution, and that is quite helpful in confirming the diagnosis. Liver biopsies are rarely helpful and typically not needed in this setting, because once again, we would expect the diagnosis to be evident and based on the MRCP. This is an image of a 3D recreation of the biliary tree, mostly noting the intraepodic effect. But yeah, and I apologize, I'm not able to really show exactly, but you can see the sort of dilation of the intraepodic ducts where they look much more plump and then others where they're much more narrow. So that kind of dilation is not uncommon and is as a result of downstream bile duct narrowing due to the thickened walls that develop in the setting of PSC. And I have three of these images to look at just for comparison purposes, because the disease is heterogeneous. We can see many different sort of displays of how the disease can impact the biliary tree with this beading effect that you can appreciate if you look carefully kind of in those right ducts, some of those are more narrowed with areas where there's more contrast showing. So you kind of get a bit of that pearl necklace effect. And then the extraepodic duct draining the liver on this image, you can see some narrowing here as well. And then the last one, again, just different ways that the 3D recreations are performed, but you can see sort of some ducts are more uniform and others have that dilation and kind of plump effect that is not a common in the setting of PSC. So PSC far more common in men than in women, median age 41 years, I will say I have many, many 20 somethings despite that median age. And the vast majority will have inflammatory bowel disease. Now, most of these patients, the inflammatory bowel disease is chronic ulcerative colitis but we do see Crohn's disease and there are some, I work closely with my IBD colleagues on these patients and there are some who have really features of both and we'll identify that as PSC associated inflammatory bowel disease. Patients can be entirely asymptomatic. They can also present with symptoms. I wouldn't say that they commonly present with bacterial cholangitis, it can happen, but most of the time we'll detect it before it gets to that point. And then many times they're being imaged for inflammatory bowel disease evaluation and that's where the first evidence of bile duct abnormalities are seen and then they're referred to the clinic that I practice in where we sort of take it from there with more dedicated MR imaging. PSC has a variable natural history. I see new consults every Monday, oftentimes from around the country and regrettably if they've done a literature search or looked at Google, they come in very unnerved by what's out there. In general, most patients are going to do well, but there is the concern about progression to liver transplant, which thankfully is a life-saving opportunity. There is a risk of cholangiocorsonoma, which is estimated at 12% over the lifetime of a patient with PSC, but that's why we screen regularly because that risk is there. Thankfully today we have options with liver transplantation for some patients who develop cholangiocorsonoma. That was not an option when I first started with this practice some 20 years ago. So it is something that we want to continue to monitor to detect these early so that we can have opportunity to intervene. Regrettably, there's still no FDA approved therapy despite multiple, multiple studies. Ursa deoxycholic acid had a lot of interest early on based on the information from primary biliary cholangitis. However, it has been disappointing. That said, there are some patients who respond. I would estimate 20% of patients will have biochemical improvement with Ursa deoxycholic acid. It's an indolent or benign therapy. It really has very few side effects. And so it is something to think about, but it has not been shown to improve the natural history of the disease. Oral vancomycin receives a lot of attention largely based on clinical trials that came out of Stanford. However, we have yet to prove that this is a beneficial therapy in the setting of PSC. There is a multi-site trial going on in the U.S. right now. So hopefully we'll have that answer within a short time. And then of course, clinical trials continue to be entertained in order for us to find an effective therapy. Importantly, routine ERCP is not supported. So sometimes patients will come and have been advised they should have this conducted every six to 12 months just to open up the biliary tree. There's not good data to support that. So we do not take that approach. We reserve ERCP for patients who are symptomatic or we have reason to go in to obtain samples based on imaging or blood test results, particularly the CA-19-9. Surveillance for cholangiocarcinoma is appropriate. Again, that lifetime risk is estimated at 12%. So MR cholangiography coupled with a carbohydrate antigen 19-9, that's the blood test, is what we use for surveillance. If advanced fibrosis, then we also need to monitor for hepatocellular carcinoma with imaging every six months. Although these are not common tumors in the setting of PSC, having cirrhosis does increase their risk of developing them. So screening is appropriate. There is a prognostic tool that's available created by my colleague, Dr. John Eaton. And this is beneficial, provides a 10-year estimation of decompensation. Again, we'll sometimes use this in clinical practice if patients like to take a look at what their risk is down the road. And then overlap syndromes, as I had suggested earlier, these occur perhaps in 10% of cases. Most common is the primary biliary cirrhosis and autoimmune hepatitis. We do see autoimmune hepatitis complicate primary sclerosing cholangitis, but that's not as common. And then it's been infrequent, but we can sometimes see clinical features of both PBC and PSC. And again, we manage these conditions respective to the individual condition. So PBC would be treated for PBC and autoimmune hepatitis with the appropriate AIH therapy. So practice pearls, there are three main categories of autoimmune liver disease based on clinical serologic and histologic findings, and those are listed there. Therapeutic management of each condition is distinct. If evidence of advanced fibrosis, then HCC surveillance is needed along with monitoring for the development of esophageal varices, portal hypertension, and monitoring for progression and decompensation, which would include following for fluid retention and managing that as needed. Of course, GI bleeding and hepatic encephalopathy. And with that, thank you for your attention. Thank you.

liver disease

case studies

primary biliary cholangitis

PBC

primary sclerosing cholangitis

PSC