Hello, my name is Cynthia Levy and I'm from the Division of Hepatology at the University of Miami. If you have any questions, please do not hesitate to click on the button, ask the forum, where common issues regarding liver diseases are discussed. The title of my module is Chronic Cholestatic Injury. During this talk, I will discuss the concept of chronic cholestasis, how do we diagnose it, what are the most common causes, is this intra-hepatic or extra-hepatic, and finally how do we investigate a patient with chronic cholestasis. These are my disclosures. At the conclusion of the program, you should be able to recognize the presence of chronic cholestasis, conduct the initial diagnostic evaluation to determine the cause of chronic cholestasis, differentiate intra-hepatic and extra-hepatic causes of chronic cholestasis, and recognize clinical scenarios of chronic cholestatic injury in which a referral to gastroenterology may be warranted. In this cartoon, we illustrate the anatomic relationship between the liver and biliary tree and the small bowel and pancreas. Importantly, you can see the distinction between intra-hepatic biliary tree and extra-hepatic bile ducts. This will become important when determining the etiology of chronic cholestatic injury. Chronic cholestasis is arbitrarily defined as impaired bioflow persisting for more than six months. It may be of insidious onset developing over several years, and biochemically, it is characterized by the presence of persistent elevation of serum alkaline phosphatase. The most common causes of chronic cholestasis are drug-induced liver injury, or DILI, and primary biliary cholangitis, previously known as primary biliary cirrhosis. We should also consider primary sclerosing cholangitis, sarcoidosis, liver allograft rejection, graft-versus-host disease, opportunistic viral cholangitis, and secondary causes of sclerosing cholangitis. The first thing we will do in this diagnostic process of evaluation of a patient with chronic cholestasis is to determine if the cause is intra-hepatic or extra-hepatic. Among intra-hepatic causes, the most common are drug-induced liver injury, primary biliary cholangitis, and primary sclerosing cholangitis. And we should also consider infiltrative liver disease, such as sarcoidosis, tuberculosis, amyloidosis, lymphoma, and abscess. Total parenteral nutrition, stethohepatitis, ischemic cholangiopathy, sickle cell disease, graft rejection, and metastatic disease can also cause intra-hepatic cholestasis. Among extra-hepatic causes, the most common will be primary sclerosing cholangitis or secondary sclerosing cholangitis, such as that due to IgG4-related disease, ischemic cholangiopathy, chronic pancreatitis, or complications from extensive manipulation of the biliary tree. Alternatively, we should also consider cholangiocarcinoma or other malignant obstruction, anastomotic strictures, and infectious etiologies, such as Ascaries, liver flukes, and AIDS cholangiopathy. With that differential diagnosis in mind, how do we investigate chronic cholestasis? The first thing that we need to do now is a very thorough history and physical exam, followed by specific labs and imaging tests. Through the history, we'll find that most patients are actually asymptomatic. However, some will have itching or fatigue, which are the most common symptoms in cholestatic liver diseases. Alarm signs are jaundice, weight loss, choluria, A. coli, icitis, or gastrointestinal hemorrhage. Those are signs of more advanced liver disease or even malignancy and should prompt referral to a specialist. On the physical exam, we can find skin hyperpigmentation, xanthomas, especially on the extensor surfaces, or xanthelasmas, these fat deposits around the inner corner of the eyelid, usually associated with hyperlipidemia. Alarm signs on the physical exam would be those related to decompensated cirrhosis, such as icitis, presence of asterixes, and this should prompt, again, referral to a specialist. As far as laboratory tests, the serum liver chemistry is indicative of cholestasis, or serum alkaline phosphatase, 5-nucleotidase, and gamma glutamyl transferase, or GGT. Please note that hyperlipidemia is not indicative of cholestasis, as it may be elevated due to overproduction, impaired uptake, conjugation excretion, or regurgitation from damaged hepatocytes or bioducts. Once you find the chronically elevated alkaline phosphatase, it is important to determine the origin of that enzyme. As you have learned in the abnormal liver test module, alkaline phosphatase can originate from the liver, bone, intestines, or placenta. If there is concomitant elevation of AST and or ALT, then this alkaline phosphatase is likely from hepatobiliary origin. However, if this is an isolated elevation of alkaline phosphatase, it could be useful to check GGT and 5-nucleotidase. When both of these are normal, we should investigate non-hepatic sources of alkaline phosphatase. Alternatively, if GGT or 5-nucleotidase are elevated, then again, alkaline phosphatase would likely be of hepatobiliary origin. Once you have determined that the alkaline phosphatase is of hepatobiliary origin, the initial step to differentiate intrahepatic versus extrahepatic cholestasis is obtaining a Radoper quadrant ultrasound. The ultrasound may show dilated or irregular bile ducts and these findings could prompt further investigation, perhaps with MRCP or ERCP. It's important to realize, however, that an ultrasound may not detect subtle changes of early primary sclerosing cholangitis. You should order an MRCP if there is a high index of suspicion for extrahepatic cholestasis. These images show examples of typical findings of classic primary sclerosing cholangitis, also called large duct PSC. On the left, we have MRCP and on the right, we have ERCP, which is obtained by endoscopy. You will note multifocal strictures and dilatations by both techniques. The arrows will point to the areas of these strictures and dilatations, forming sometimes a color of beads, as shown in this ERCP. On this slide, we show a picture obtained through an endoscopic ultrasound, or EUS, showing a pancreatic mass causing obstruction or better compression of the common bile duct, which is now dilated. Going back to our algorithm for evaluation of elevated alkaline phosphatase of hepatobiliary origin, once we perform the right upper quadrant ultrasound, if this is completely normal and we don't have a high index of suspicion for extrahepatic biliary disease, then we should continue with serologic evaluation. On the other hand, if the ultrasound showed abnormalities and we have confirmed those with MRCP or ERCP, we can now establish an extrahepatic origin for a chronic cholestasis. Proceeding with serologic evaluation, the most important test will be an anti-mitochondrial antibody, or AMA. When that test is positive in the presence of chronic cholestasis, it's highly suggestive of a diagnosis of primary biliary cholangitis, or PBC. If that test is negative, however, we will need to proceed with a liver biopsy to complete our diagnostic evaluation. We can also consider doing a liver biopsy when our ultrasound shows parenchymal abnormalities that are non-specific and need further confirmation or evaluation. A liver biopsy will be indicated and very useful in the following scenarios, AMA negative primary biliary cholangitis, infiltrative and granulomatous diseases, small duct PSC, and drug-induced liver injury. Approximately 90% of all cases of PSC are the so-called classic PSC, or large duct PSC, in which you have the chronic elevation of alkaline phosphatase and cholangiographic evidence of multifocal stricturing and dilatations. However, in about 10% of the cases, the cholangiogram will be completely normal and diagnosis will be made by histology. In the picture below, we show a typical case of primary biliary cholangitis. In the center, there is a distorted bile duct, which is being attacked and infiltrated with a mononuclear infiltrate. This is a very florid, inflammatory infiltrate consisting of lymphocytes, plasma cells, macrophages, histiocytes, and thus called florid duct lesion. This biopsy is an example of granulomatous disease. You can see multiple granulomas and this is a case of sarcoidosis. Those are non-caseating granulomas seen in the parenchyma. In the next liver biopsy, we see an infiltrative process. We can observe infiltration of the liver with this amorphous, waxy, pink material, which represents amyloid deposition. So this is a case of hepatic amyloidosis. Amyloidosis will affect the liver in 60-90% of the cases and the clinical manifestation will be hepatomegaly and chronic elevation of alkaline phosphatase. I want you to pay particular attention to drug-induced liver injury as a cause of chronic cholestasis because it is fairly common. Drug-induced liver injury may appear weeks after stopping the drug. A typical example is that with amoxicillin clavulanate. I also want you to be familiar with a fantastic resource called Liver Talks and the website is available for you through this link. Here you can search for any publication related to hepatotoxicity with any drug or even herbal compounds. Now, there are several types of drug-induced chronic cholestasis. So a drug can cause chronic cholestasis alone or bland cholestasis. Cholestasis can be mixed with hepatitis and the cholestasis can indeed persist long after hepatitis resolves. We can have vanishing bile duct syndrome or a form of secondary sclerosing cholangitis. This is an incomplete list of agents causing intrahepatic or extrahepatic chronic cholestasis. The list is fairly long. Please note commonly used medications including several antibiotics, NSAIDs, sex hormones that are listed here. Vanishing bile duct syndrome is a condition caused by progressive destruction of segments of the biliary tree. More than 40 drugs have been implicated, more commonly chlorpromazine, oxypenicillins, and erythromycin. This may evolve into biliary cirrhosis and resolution, when it occurs, may take more than two years. Treatment with urthodeoxycholic acid may be helpful, however, this remains unproven. Here we show an example of chlorpromazine-induced vanishing bile duct syndrome. This patient had severe duct opinion cholestasis due to chlorpromazine use. You can see on the top panels extensive fibrosis, marked fibrosis, and in the bottom panel we will see the marked absence of bile ducts, intrahepatic cholestasis, and there is also iron overload in the Kupfer cells. Now that you have diagnosed chronic cholestasis and you have an idea about the diagnosis, the specific etiology, it is important to know how to manage chronic cholestatic injury. The first thing here is to look for evidence of advanced fibrosis or cirrhosis, or for platelets below 150,000. If that's the case, we should proceed with surveillance for hepatocellular carcinoma and screening for esophageal varices. We should also determine if this patient is a liver transplant candidate. You will note that I added in this purple box that a platelet count below 150,000 should serve as an indication to proceed with screening for esophageal varices. This is because in cholestatic liver diseases, we may see development of portal hypertension prior to appearance of cirrhosis and what we call pre-cirrhotic portal hypertension. Now if your patient does not meet those criteria, then we can continue monitoring symptoms and liver biochemistries at regular intervals. At this point, I want to bring your attention back to alarm signs, which should prompt referral to specialists. The presence of any evidence of portal hypertension, such as ascites, variceal hemorrhage, encephalopathy, jaundice, and thrombocytopenia should prompt referral. In addition, if the presence of cirrhosis is unclear with the methods available, we should consider referral to a specialist for a liver biopsy. We have now completed discussion on diagnosis and management of chronic cholestatic injury. Let's review a couple of cases to solidify this knowledge. The first case is a 54-year-old woman who saw a primary care physician for her annual visit. She complains of mild intermittent itching and fatigue. The patient has never had any surgery and her only medications are calcium and vitamin D. Her physical exam is unremarkable. After reviewing the tests below, what is the next step in the diagnostic process? Her laboratory tests from January 2015 showed an alkaline phosphatase of 426, an AST of 40, ALT 54, and total bilirubin of 1. In August, her alkaline phosphatase was 398, AST 39, ALT 58, and total bilirubin of 1.1. An ultrasound has already been performed showing normal liver, gallbladder, and spleen. As we discussed, the first step in her evaluation once we documented chronic cholestasis, and in this case, this is evidenced by an alkaline phosphatase that has been elevated for more than six months, the first step is to obtain an ultrasound to rule out extrahepatic cause for this chronic cholestasis. Her ultrasound was normal. So now we have an alkaline phosphatase that is three to four times elevated chronically in a middle-aged woman who also has pruritus and fatigue. There's no evidence of biliary obstruction. So the next step is serologic evaluation, and the most important test is, again, the antimyotocondrial antibody. In her case, that test was positive with a titer of 1 to 320. This is a high titer, and therefore, in this case, diagnostic of primary biliary cholangitis, PBC. A liver biopsy is not mandatory in this case. We now will start the standard of care therapy, which is ursodeoxycholic acid at a dose of 13 to 15 milligrams per kilo per day. We will monitor her response by following serum alkaline phosphatase levels. If her alkaline phosphatase doesn't drop below 1.5 to 2 times upper limit of normal after 6 to 12 months of therapy, this patient should be referred to a gastroenterologist. We should also consider using a non-invasive test to assess fibrosis, such as transient telestography. And we will always monitor for indirect evidence of advanced liver disease, such as a decreased platelet count, the presence of splenomegaly, or stigmata of chronic liver disease. As recommended by guidelines, we should obtain a baseline bone densitometry to screen for osteoporosis. The key points for this case are that in the setting of chronic cholestasis, first step in evaluation is to rule out biliary obstruction with an imaging test. Once we have established that the cause of cholestasis is intrahepatic, look through her medication list to rule out drug-induced liver injury. In this case, she was not taking anything, and check an AMA status. In the absence of other identifiable cause, a positive AMA in a patient with chronic cholestasis is diagnostic of PBC. PBC affects one woman for every 1,000 women over the age of 40. Pruritus and fatigue are the most common symptoms in PBC. We'll move on to case number two. We now have a 34-year-old African-American male coming in for follow-up. He had been complaining of chronic diarrhea with blood and associated with abdominal cramps, on and off for the past year. We referred him to a local gastroenterologist who performed a colonoscopy and diagnosed him with pan-ulcerative colitis. He was started on mezalamine four months ago and reports resolution of the bloody diarrhea, although he complains of occasional radical quadrant discomfort and intermittent itching. On routine laboratory tests, you note the following, AST 80, ALT 101, alkaline phosphatase 580, total bilirubin 1.3, hemoglobin 11.8, platelets 213. Comparing to your previous notes, there has been mild worsening over the past four to six months. His alkaline phosphatase was previously 398 and the total bilirubin was 0.8. So how do we work up this case? We have a young male with inflammatory bowel disease, chronic cholestasis as evidenced by an alkaline phosphatase approximately five times upper limit of normal, and who is complaining of itching. This is concerning for primary sclerosing cholangitis. We now perform an ultrasound and it shows only somewhat irregular bile ducts. Of note, we could also find thickening of the wall of extrahepatic bile ducts or changes in the gallbladder. On the other hand, ultrasound could be normal, but given your high level of suspicion and already some changes in this ultrasound, you now proceed with an MRI with MRCP and this showed multifocal strictures conforming your diagnosis of primary sclerosing cholangitis. Unfortunately, there is no available medical therapy for PSC and the role of ursodoxycolic acid is unclear. You should refer to a gastroenterologist for long-term management and we will consider clinical trial participation depending on the center. In the long term, we should watch for acute cholangitis, which usually manifests with right upper quadrant pain, jaundice, and fever. We'll treat this patient symptomatically and recommend annual colonoscopy with biopsies due to an increased risk of colon cancer in patients with PSC and ulcerative colitis. We will also recommend annual cross-sectional imaging of the liver to survey for cholangiocarcinoma and gallbladder polyps. Again, as for primary biliary cholangitis, we should obtain a baseline bond encetometry to screen for osteoporosis. The important points in this case are that a chronically elevated alkaline phosphatase and itching, again, indicate a cholestatic process. Approximately 4% of all patients with inflammatory bowel disease develop PSC. Most will have ulcerative colitis, but patients with Crohn's disease and indeterminate colitis can also develop PSC. Conversely, up to 80% of patients with PSC have inflammatory bowel disease. Two-thirds of patients with PSC are males. One should have a high index of suspicion for PSC in this young male with ulcerative colitis who has evidence of chronic cholestasis. Ultrasound showed irregular bile ducts. However, it could have been normal. The next step is to pursue an MRCP to confirm diagnosis and evaluate the extent of disease. Patients with PSC are at high risk for malignancy, cholangiocarcinoma, gallbladder cancer, and colon cancer. In summary, chronic cholestasis is characterized by an elevation of serum alkaline phosphatase persisting beyond 6 months. Initial evaluation includes confirmation of hepatobiliary origin of alkaline phosphatase. Chronic cholestasis may be intra-hepatic or extra-hepatic in origin. Cross-sectional imaging is required to exclude extra-hepatic etiologies such as PSC. Common causes of intra-hepatic cholestasis are drug-induced liver injury, PBC, and infiltrative diseases. In general, patients with chronic cholestasis should be referred to a gastroenterologist for expert management. I hope you have enjoyed this presentation and I invite you to access additional content on liver learning on this topic or any other related topics at your leisure. Thank you.

chronic cholestatic injury

diagnosis

serum alkaline phosphatase

primary biliary cholangitis

Fundamentals of Liver Disease