Hello, I'm Stuart Amatow, and I'm so disappointed I can't be there with everyone. Mildly symptomatic COVID kept me from coming, but let me start off by thanking Dr. Wani, Dr. Lightdale, and the ASU committee for inviting me to give you a talk on filiary disease diagnosis and management. Here are my disclosures and my learning objectives. Let's get into this. Filiary disease may present with incidental findings and or signs or symptoms. Some examples of incidental findings include abnormal liver studies, some of which you can see patterns with, such as an isolated alkaline phosphatase, suggestive of HIV cholangiopathy, or an extremely high T. billy, suggestive of malignancy rather than simple stone disease. Abnormal imaging can be suggestive and or diagnostic of stones, as well as diagnostic of stricture. In fact, you could see a stricture with dilated enteropatics and think cholangiocarcinoma. Signs or symptoms include abdominal pain, which may be suggestive of biliary colic, and this is going to be based on frequency, timing, and triggers. And then there's jaundice, so elevated T. billy. In the young, you think of choledocal cyst or primary sclerosine cholangitis. In those from Eastern Asia, you might think of some regionality disease associations, such as recurrent pyogenic cholangitis, painless weight loss. In the adults, you think of malignancy. Here are some details about biliary stone biochemistry. The majority of stones in the United States are cholesterol. They are supersaturated cholesterol from such things as gallbladder dysmotility, as seen in pregnant women, secondary to high progesterone. Also seen with obesity, estrogen, hyperlipidemia, ileal disease, such as with Crohn's, and with lipid-lowering medications. Black pigment stones are the next most common, secondary to hemolysis, frequently seen in cirrhotics, those with cystic fibrosis, and again with distal ileal disease. And they're composed of oxidized calcium bilirubinate. The least common in the United States, but more common in East Asia, are brown pigment stones. These are non-oxidized calcium bilirubinate, and many times are involved with bacterial parasite infections and or prior manipulation, including cholecystectomy. While cholelithiasis refers to stones within the gallbladder, choledocalithiasis refers to stones within the common duct. Now these stones can be formed in one of two ways. The more common way, or secondary, is what we think of most of the time, which are stones passing from the gallbladder. This is what we see most typically in Western countries. And of note, without cholecystectomy, despite sphincterotomy, cholelithiasis can become symptomatic with issues in upwards of 20% to 40% of patients that do not get a cholecystectomy. Now less common are primary stones, or primary cholelithiasis, as seen with cystic fibrosis, perianpillary diverticula, or choledocalysis. And this is when the stones form from stasis within the duct. We can think of choledocalithiasis as uncomplicated, which can be symptomatic or asymptomatic, or complicated, as seen with acute pancreatitis, acute cholangitis, or secondary biliary cirrhosis. So let's jump into some cases. You're presented with a 70-year-old individual with abdominal pain. This patient had similar episodes in the past that's resolved. Slightly greater than 4, alkaline foster taste, mildly elevated, ASD-ALT in the 5 to 600s. The patient has normal lipase, elevated INR, and a white blood cell count of 30,000. Right upper quadrant ultrasound demonstrates a dilated common bile duct, seen on the left, as well as gallbladder stones with no evidence of cholecystitis. The patient becomes hypotensive and confused. The type of things you might be asked are, what's the next step, and what's going on? You immediately think that this is cholangitis with biliary obstruction, but the next step is resuscitation, as well as reversing the INR, if possible. After that, and when the patient's stable, you move towards an urgent DRCP, as delays can result in poor outcome. You want to think about Raynaud's Pentad in this situation of fever, jaundice, pain, change in mental status, and hypotension. If you can't reverse, you can always place a pancreatic ductal stent, as well as a biliary stent, without sphincterotomy, with or without stone extraction to allow for decompression. Percutaneous approach is only appropriate if ERCP is not feasible or is failed. And you should think about gallstone formation in individuals with increased risks, younger females, those on TPN, those on oral contraceptive, or those with Crohn's. Now, at times, you'll be asked when to do an ERCP in relationship to a cholecystectomy. You should do an ERCP first, with a delayed cholecystectomy, when a obstructing stone is seen clearly on imaging. Or, there are very strong predictors for obstructing cholecystectomy, such as a bili greater than four, ascending cholangitis, of course, once the patient is stabilized, but within 24 hours. And again, you may delay cholecystectomy. Or, with suspected gallstone acute pancreatitis. These are folks you definitely want to do within 24 hours. And you may delay cholecystectomy until such time as some of the inflammation is resolved. You may consider doing a cholecystectomy with an intraoperative cholangiogram, or an upfront ERCP with tandem cholecystectomy to follow in individuals that have a strong predictor of obstructing choledoblithiasis without any complications, such as a dilated CBD with the stone seen in the gallbladder, and a bili rubin of less than four, but elevated from normal. In individuals with none of these findings, you'd consider doing a cholecystectomy alone. With any suspicion, the surgeon can do an intraoperative cholangiogram. Individuals that have indeterminate findings, you can always consider doing an MRCP or an EUS prior to any interventions. And it should be noted that the sensitivity and the quality of an MRCP is essentially equivalent to an endoscopic ultrasound. How about some other gallbladder entities? Well, there's gallbladder polyps, or non-mobile stones. 5% of adults have these, and they can be in the form of cholesterol, inflammatory, adenomyoma, adenoma, adenoparsinoma. They're difficult to distinguish between, so you do surveillance by radical quadrant ultrasound until there's rapid growth or growth above 10 millimeters, and then you'll recommend a cholecystectomy. Now, increased risk of badness or cancer can happen with greater age, gallstones, lower polyp number actually is an increased risk, and primary sclerosine cholangitis. There's also porcelain gallbladder. It's mostly asymptomatic and incidental finding. You typically need an abdominal CT to exclude a synchronous mass. And this is seen as a rim of calcification on plain film. Now, there is a greater risk of malignancy with segmental deposits of calcium rather than a complete rim as shown in the panels A and B. Now, interestingly, I was taught that you get a cholecystectomy, but this has changed as of late. You don't always have to get a cholecystectomy as it's not always cancer, and it's typically not, and so they recommend surveillance rather than cholecystectomy if it's a straightforward porcelain gallbladder. Now, let's move on to biliary strictures, and what you see here is a near-complete differential for this entity. You can read through this on your own and we'll cover most of these in the remaining portion of this lecture. I show here an example of biliary strictures, actually, multiple strictures involving bifurcations and primary insertions, and this is suggestive of malignancy, but a picture alone doesn't always give the diagnosis, and so you have to get history, you have to look at the biochemical profile, and then, of course, do imaging and a time sampling to make the diagnosis. To be complete, here are some other biliary diseases, some of which we'll touch upon. There's congenital diseases such as cystic fibrosis and biliary atresia, biliary cysts, choledocal cysts, and Corollis disease, and cholecystitis. There's a role for ERCP and or EUS transluminal drainage in individuals who are nonsurgical candidates. Here we show cannulation of the gallbladder and subsequent deployment of a double pigtail stent to facilitate gallbladder drainage in individuals with cirrhosis and nonsurgical candidate. Let's jump into some more cases. Here you're presented with a patient that appears to have peritonitis postcholestectomy. Essentially, they had an uncomplicated laparoscopic cholestectomy three days back. They returned, however, a progressive abdominal pain, guarding, and tenderness on exam. All liver studies were normal, as was a lipase, white cell blood count was elevated, and cross-sectional imaging revealed immature fluid collection. You're asked what the next step is. Now, you've got to be careful here. Of course, this is a bile leak, but the next step is not in the ERCP. Rather, you'd prefer to have percutaneous drainage of the collection to control the leak, but also to avoid significant infection and contamination from the ERCP. Once the drain is in, intervention by ERCP is not that urgent. Of note, 95% of individuals with simple leaks will resolve following a sphincterotomy or a cut of the ampulla with a placement of a plastic stent. Now, transsection injuries can be difficult to manage endoscopically, and right posterior stricture should be noted that these may lead to atrophy of part of the lobe, recurrent cholangitis, and may ultimately require resection. So, those patients should be followed closely. Now, it also should be noted that stents do not need to bridge the defect, as seen when we managed ductal luschka. Essentially, what we're doing is placing a stent and doing the sphincterotomy to allow a path of least resistance for bile to flow into the duodenum and not into the defect. Here, we're given a 22-year-old with postprandial right upper quadrant pain. Cross-sectional CT imaging and EGD were normal. Empirical cystectomy was without effect. Liver studies were variably mildly elevated. However, ultimately, an MRCP was obtained and demonstrated this, which ultimately suggested that this diagnosis was PSC. Now, with PSC, the next steps are not always an ERCP, but definitively, a colonoscopy with biopsies. ERCP should be done primarily only with dominant strictures or concerns of malignancy, so for sampling and or for intermittent dilation in individuals who are acutely jaundiced. So, some key concepts with primary sclerosine cholangitis. You want to do a colonoscopy regardless of symptoms. If UC is found, you need to do that colonoscopy surveillance every year, given the high risk of malignancy, which is three times higher than IBD alone in these individuals that have overlapped disease. Therefore, you may consider a colectomy. You really want to be judicious when placing stents, maybe only with progressive jaundice or cholangitis. We typically tend to only dilate unless we see frank pus in individuals, then we'll place stents at times. There's no clear drug therapies for PSC. Urso-deoxycholic acid have been given to improve biochemical profile. Some individuals are given standing macromycin or other antibiotics if they have recurrent episodes of infection. And you don't want to sample any related masses by endoscopic ultrasound or by percutaneous biopsies. This goes for most liver lesions as there's concern for seeding. And ideally, you want to find some adjacent nodes, sample those by US or sample introductively with brushing or with cholangioscopy and biopsies. You can follow an individual's CA-19-9. And after ERCPs or other interventions with individuals who don't drain well, you typically want to give post-procedural antibiotics. This segues nicely into our next patient, who's a 78-year-old with jaundice and itching, has no pain, no significant medical history, but has weight loss, malaise, T-billy of greater than 15, and an alkaline phosphatase of three times normal. The referring provider did their correct next steps landing on non-invasive imaging, including an MRI MRCP shown here as a reconstruction. The way I would interpret this is diffuse intrahepatic dilation with possible left lobe atrophy, all secondary to complex stricturing of the bifurcation. Leading me to think that this is cholangiocarcinoma. While the next step is ERCP in this case, it's only because we had an MRCP up front to provide a roadmap and allow us to know which sectors we should decompress. Here, I'd probably target the right anterior, right posterior, and potentially avoid the left, which may be atrophic. T-billy greater than 10 without pain, especially, should be considered to be a malignancy rather than something benign like stone disease. Patients may present with liver dysfunction, and that tends to be a bad prognostic sign. Again, you want to sample from within the duct and not outside of the duct to within the duct to avoid theoretical seeding. We'll talk about sampling in just a bit. 20% of patients with cholangiocarcinoma will present with malignancies not involving the primary biliary tree. These folks present with pain, weight loss, alkaline phosphatase elevations alone, and are typically managed by our hepatologist, transplant hepatologist. Should note that there's emerging data for palliative local regional RFA or radiofrequency ablation, which we could do by ERCP. This involves coagulative necrosis with a subacute immune response and has been shown to increase survival time and performance. Now, we show here another individual with complex stricturing at the bifurcation who ultimately needed three sectors drained, including the left, the right anterior, and the right posterior, with complex metal stents shown in that bottom right panel. You should be aware of the business classification of high-liver tumors. This may be discussed in another lecture. However, when it involves only the common duct, that's type 1. When it involves the common duct and the bifurcation, type 2. Common duct bifurcation extending into the right lobe, 3A, extending into the left lobe, 3B, and extending into both primaries, that's bismuth type 4. Now, as we know, tissue is always the issue. I know it's cholangiocarcinoma, you know it's cholangiocarcinoma, even the oncologist knows, but they won't treat until we have a tissue diagnosis. Therefore, how do we get tissue? Well, we can do it by brushing, which is during ERCP, we pass a brush over the wire, we collect fluid and we send that for cytology. We can do it by biopsy, which is fluoroscopically guided biopsy, or we could do it by cholangioscopy directed biopsy. Now, all of these things have various sensitivities associated with them. Brushing is the least sensitive. Fluoroscopic biopsies are slightly better, but we potentially tend to not actually sample the stricture because it's fluoroscopically guided. And then lastly, we have the option with the highest sensitivity, which is cholangioscopy. As you see in the top left of the images, there's a daughter scope, which goes through the working channel of the duodenoscope. And then we can actually visualize the stricture within the duct, which is that top middle panel. We then can pass a biopsy forcep, a mini spy bite forcep that's called, through that working channel of that daughter scope in biopsy directly what we believe to be the malignant area. Here we see from like changes at the stricture, not more of a benign picture, but more of a malignant picture with high vascularity. There's also fluorescent in situ hybridization, typically reserved for primary sclerosine cholangitis as a guide to suggest the potential for malignancy, but is now being used more and more in helping with the diagnosis of cholangiocarcinoma. It involves polysomy or the gains of loci. And again, it's suggested they're not diagnostic of cholangio and will prompt you to sample further. Now, what you see in the right side of the panel is samples of brushings in cytology, ranging from benign to the middle, which is atypical to the bottom, which is malignant, where you see larger nuclei, overlapping cells, larger cells, et cetera. And also to mention that CA-19-9, it can be followed, but usually you get that after the patient's been decompressed, but a rising CA-19-9 of 129 has a reasonable sensitivity and specificity. Let's do another case presentation. Here we got a 30-year-old with abdominal pain and diarrhea. Now of note, the patient's an immigrant from Southern Africa, has no fever, no jaundice, and a near isolated significant elevation of alkaline phosphatase. MRCP demonstrates a distal common bile duct stricture. With this information, you should be thinking AIDS cholangiopathy. So some key concepts. Frequently, there are multifocal strictures, unlike this case presentation. And most frequently, this is associated with secondary sclerosine cholangitis due to progression of AIDS cholangiopathy. Typically, this is only seen in folks that are untreated with HIV. CD4 counts less than 100. The intervention is ERCP with sphincterotomy. You can brush and biopsy to ensure you're not missing a malignancy, but you could also send for infectious disease studies, CMV, crypto, microsporidia, AFB, and culture, with crypto being the most common. Stool and blood tests are also helpful, and of course, antiretroviral therapy is the ultimate goal. You could add on ursodeoxycholic acid. How about we talk about a 30-year-old from a different part of the world, this time with fevers and jaundice, and immigrating from East Asia. Patient presents with right upper quadrant pain, ability to remember greater than four, as well as mild to moderate elevations of other liver studies. Imaging demonstrates intra and extrahepatic dilation with profound dilation with one lobe and stones, shown here. And the circle is actually highlighting a large stone. So with this information, you should be thinking recurrent pyogenic cholangitis. So here's some of the key concepts. It's actually quite prevalent, up to 30 to 50%. That's what the data says. I double-checked it, and this is in East Asia. It requires TDS-ERCP and cholangioscopy for intrapathic brownstone clearance. And it can be tricky if those stones are above strictures, and you'll have to use something called lithotripsy, potentially, to break those stones up and remove. It's thought to be associated with parasites. Clonibrus is a common cause. There is a risk of abscess and cholangiocarcinoma with these folks. And therefore, if you're not successful rather quickly with ERCP, and or you believe you're successful and the patient continues to have fevers, usually refer to our liver surgeons for consideration of hepatic resection. And this is, again, individuals that have atrophic lobes or recurrent disease despite best efforts with the ERCP. Now let's change gears and talk about a 20-year-old woman with dictaric sclera, abdominal pain, and elevated lipase. She's had three episodes of idiopathic pancreatitis in the past, but no complaints of pain or any other symptoms outside of these events. Her bilirubin today is five or over five, and her other liver studies are essentially normal. Right epiclogen ultrasound demonstrates both intra- and extra-hepatic dilation, and both CT and MRI MRCP demonstrate a distal-type common duct stenosis and diffusely thickened pancreas with the narrow duct, shown here on both MRI and CT. Now, in this situation, you should be thinking autoimmune pancreatitis with the key concept of being a sausage-shaped pancreas with a featureless border and a narrow, essentially normal main duct. Now, inflammatory structures such as with the bile duct here outside of an acute event are mostly unlikely or uncommon outside of the development of chronic pancreatitis. The diagnosis involves a combination of imaging, histology, and for one of the subtypes, serology, with an IgG for two times the upper limit of normal. Now, histology can be tricky. You'll be biopsying an ambula, which has risks, or the pancreas by fine-needle biopsy utilizing EUS, which also has risks and both have poor sensitivity. You can really drive home the diagnosis by treating with the glucocorticoid trial, because you get near-immediate resolution, but you have to do that after excluding other diagnoses, in particular, cancer. Now, there are two subtypes of autoimmune pancreatitis. There's type one. That's the one that we kind of think about more, which is IgG4-related disease. It can involve multiple organs, such as the liver. And then the more common, type two, it's typically limited to the pancreas. You probably hear about this in other lectures, but associated with IBD, younger individuals, and involves a granulocyte epithelial lesion of the duct. And now, this disease entity may also ultimately result in pancreatic atrophy. All right, what about this one? A 68-year-old male with a new diagnosis of PSC. Seems uncommon, it's possible, but the patient has jaundice and abdominal pain, and an MRCP that demonstrates multifocal biliary strictures. And it's also noted that they have a normal pancreas. So what's the next step? Well, serum IgG4. And why? Because it's not PSC. This case is actually an example of IgG4 sclerosing cholangitis. And so here's some of the key concepts. Well, you have an elevated serum IgG4, five times the upper limit of normal. And while it's rare, it spares the pancreas. So type one AIP can involve both. And it's crucial to discern from PSC, because you can treat this. Steroid therapy, you taper and you get a response. Rituximab's another option. You monitor for symptoms. You can follow IgG4, IgE, and complement. And it's usually diagnosed by liver biopsy, where you get this lymphoplasmicytic tissues with IgG4 plasma cells. And what it's showing on that imaging is the inflammatory reaction, but a preserved ductal cell architecture. Now, how about this two-year-old I consulted on that had an enlarged liver in normal liver studies? On MRI, MRCP shown here, there was multifocal segmental dilation of large atriopatics, but no symptoms, no pain, no itching. And this is a diagnosis of imaging. And this is Corolla's disease, or type five colodopal cysts. That's an autosomal recessive disease. It's frequently associated with autosomal recessive polycystic kidney disease. The duct lining's abnormal, ulcerated and hyperplastic on biopsy. The syndrome is associated with fibrosis and an increased risk of cholangiocarcinoma thought secondary to biliary stasis. It may present with portal hypertension. And if the portal hypertension becomes complicated and or there's recurrent infections may ultimately lead to a need for transplant. Alkaline phosphatase and direct bilia are often elevated and treatment is supported. Antibiotics, fat soluble vitamins for the cholestasis and beta blockers for the portal hypertension. ERCP is reserved for stones and or obstruction only. And at times you may have to use cholangioscopy or VHL for intra-hepatic stone. How about the other colodopal or biliary cysts? Well, we tend to think about these within the Todani classification. We just talked about type five. The other four are shown here. Type one being a fusiform dilation of the common duct and being the most common. Type two being a bile duct that are particularly quite rare. Type three being a saccular dilation within the duodenal wall, also known as a colodopal seal. And we'll talk about that in a second. And type four being either a combination of cystic dilations and a multifocal arrangement of intra and extra hepatics or just extra hepatic. Some key concepts, quite rare, one in a hundred thousand, more common in Asia, maybe upwards of one in a thousand and more common in females or males. It's thought that stasis increases the risk of cholangiocarcinoma, giving an upwards of 30% lifetime risk. And therefore we want to either survey these or refer them to our surgeons for resection. With the exception of type three, a colodopal seal. Now this may present with pancreatitis and is managed completely by ERCP. Now the ERCP can be tricky, which is a whole nother topic, but it actually can be cured with ERCP. The others again, either need surgery or observation. Type three is associated with anomalous pancreatic biliary junction. And this results in pancreatic juice getting into the biliary tree and it has an increased risk of malignancies, in particular gallbladder cancer. So you should refer these individuals for cholecystectomy if they have an APBJ. Frequently presented in the young as painless jaundice, maybe even a palpable mass. And the diagnosis can't be done by ERCP. With equivocal findings, you can move on to an EUS and with obstruction or a type three, you do an ERCP. Now how about this 50 year old with a history of orthotopic liver transplant presenting with fevers and jaundice? Now he was transplanted for cirrhosis in the setting of PSC, but his transplant was only 10 weeks ago. And he's presenting with mild liver study elevations. Doppler ultrasound was normal. Liver biopsy was without rejection, prompting an MRI MRCP, which suggested an asthmatic stenosis. That led to ERCP for management with this panel showing stenosis between the donor and recipient duct. And this next panel showing that it's not always as simple as a stricture. Sometimes you can have other complications related to that stricture, such as this really large stone that required multiple sessions of ERCP and cholangioscopy to manage as well as the stricture. Some key concepts, biliary disease is relatively common with DCD and living donor transplants. More common in living donor, it could be that they have multiple anastomosis typically. You can think of them as anastomotic or non-anastomotic. Anastomotic being local ischemia and they tend to occur early and relatively common. Non-anastomotic etiologies include hepatic artery thrombosis and stenosis or overall ischemic time during transplant. Could be also immune related as with rejection. Again, the pathway is Doppler ultrasound, MRCP, liver biopsy, and reserving ERCP only when there's a target. You sometimes have to think about the etiology of the cirrhosis as to what could be causing the abnormal numbers or abnormal presentation. In this case, it was too soon for PSC to have occurred. This typically occurs within months to years. And that gets you to also think about the timing of the complications with it being acute or distant, both being rejection, acute being ischemia, and also distant being PSC as mentioned. Now, how about this 42-year-old woman who presents with increased, mainly isolated alkaline phosphatase fatigue and itching? Now, she has a history of hypertriglyceridemia. She's known to have hepatomegaly. She's found to have excoriations and hyperpigmentation of the skin, and she has elevated AMA and ANA titers. Now, liver biopsy is performed and significant inflammation is found around the bile duct. This is primary biliary cholangitis, also known previously as primary biliary cirrhosis. It's rare, typically found in young women, and it involves a T lymphocyte-mediated attack on small ducts leading to destruction and disappearance. This results in cholestasis, cirrhosis, and liver failure. It's associated with Sjogren's, thyroid disease. Diagnosis is through some titers, alkaline phosphatase, but ultimately the biopsy helps understand the progression of the disease. This is the one disease, ursodeoxycholic acid is actually efficacious, and it has an impact on outcomes. Thenofibrate is second-line therapy, and it can actually improve the ursodeoxycholic acid response. Endoscopy is reserved for varices, et cetera, but not really an ERCP type of disease. Now, I'm essentially over time, but if they let this run, let's review some high-yield random pearls. Diagnostic imaging should be used for diagnostic evaluation, while ERCP should be reserved for targeted intervention. So get an MRI, EUS, retroviral ultrasound to try to find something that you can intervene upon, and then maybe do an ERCP. And that's because ERCP can result in complications such as cholecystitis, pancreatitis, perforation, bleeding. There's no role for ERCP in hemobilia, with the exception of maybe clearing a clot. If you have a gallbladder fistula with bowel obstruction, the diagnosis likely is bouvaraise. You could consider an upper endoscopy to fragment that stone. Someone that has right upper quadrant pain with normal imaging and normal liver studies may deserve an EUS, but certainly not an ERCP. Functional disease that results with no target leading to an ERCP has a high risk of complications such as pancreatitis. Moreover, manometry is no longer utilized outside of IRB-approved research studies. ERCP in patients with functional biliary pain alone, 15 to 30% result in post-procedural pancreatitis. Again, we don't have time to review these at this moment, but I wanted to make sure that you had in one lecture all of the biliary disorders for your review. It's my honor to go to work every day and work next to Marty Freeman, Sean Mallory, Guru Trikonathan, and Nabil Azeem. Again, I'm profoundly disappointed that I couldn't be there in person to share this lecture with you. I hope to be able to join for the panel discussion, and thank you for your attention.

biliary disease

choledocholithiasis

cholangitis

ERCP

gallbladder polyps

biliary strictures

primary sclerosing cholangitis