Hello, my name is Victor Navarro, and I'm from the Division of Hepatology at the Einstein Medical Center, Philadelphia. 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 Acute Cholestatic Injury. During this talk, I will discuss the pathophysiology, presentation, and management of acute cholestatic liver injury. I have no conflicts with the content of this presentation, and there will be no discussion of any unapproved, off-label, or investigational uses of a product. The learning objectives are listed here. At the conclusion of the program, you should be able to define and recognize cholestasis, differentiate between intrahepatic and extrahepatic cholestasis, conduct an evaluation for acute cholestasis and determine its cause, and determine when acute cholestasis requires urgent intervention. Broadly stated and shown on slide 4, cholestasis refers to a lack of normal bioflow. This can occur at several levels, from the intrahepatic smallest bile ducts, to the larger bile ducts in the perihilar region, to the largest extrahepatic bile ducts that could be affected by surrounding structures, such as the pancreas and the duodenum, are important clinical features of acute cholestasis. The onset is usually within six months of presentation to a clinician. The mechanism can be thought of as being hepatocellular, where there is an impairment of bile conjugation, or ductular, where there is an impairment of bile flow. The clinical presentation is based upon symptoms of cholestasis, an exclusion of non-hepatic causes which can also make the patient appear to be cholestatic through the development of jaundice, and this could include hemolysis and Gilbert syndrome. You'll see listed symptoms of acute cholestasis. Typically, these include jaundice, fatigue and listlessness, pruritus, fever, and occasionally right upper quadrant abdominal pain. Shows those labs which reflect cholestasis. The alkaline phosphatase is typically elevated, but other things can cause elevation in the alkaline phosphatase, and so tests that are confirmatory for a biliary or liver origin of alkaline phosphatase are useful to keep in the armamentarium of the clinician. These include the gamma glutamyl transpeptidase, or GGT, the 5' nucleotidase, which is more specific for cholestasis, and there may also be a coexistence with hyperbilirubinemia, but also a coexistence of the alkaline phosphatase with an elevation in the liver enzymes, the AST, aspartate aminotransferase, and the ALT, alanine aminotransferase. It's important to know that isolated hyperbilirubinemia does not reflect cholestasis. It's mostly indirect. If it is mostly indirect, this is considered Gilbert's or hemolysis as the most likely causes. Isolated direct hyperbilirubinemia can be seen in sepsis or in some congenital diseases such as Dubin-Johnson syndrome. There are several causes of acute cholestatic injury, that is, presentation within six months. The most common are drug-induced, obstruction of the bile ducts, and viral hepatitis, but the clinician must also consider other causes that can present as cholestasis, total perennial nutrition, for example, sepsis, which really isn't an impairment in bile flow, but can cause a patient to present with jaundice, alcohol, infiltration of the liver, jaundice following operations, and the cholestasis of pregnancy. It's important to note that isolated gallbladder disease, for example, acute cholecystitis, does not lead to jaundice and or increased alkaline phosphatase unless a gallstone becomes impacted in the cystic duct or neck of the gallbladder, causing compression of the common duct. This is referred to as Moritzi syndrome. Again, it's important to note that isolated gallbladder disease, such as acute cholecystitis, does not lead to jaundice or increased alkaline phosphatase unless a gallstone becomes impacted in the cystic duct or neck of the gallbladder, causing a compression of the common bile duct, which is referred to as Moritzi syndrome. A Diagnostic Approach to Acute Cholestasis. Typically, the clinician becomes aware of cholestasis by examining the patient and identifying cholestatic symptoms or lab abnormalities for less than six months. The next step is to determine if this might be intrahepatic or extrahepatic cholestasis. Simply stated, intrahepatic cholestasis is associated with normal appearing bile ducts on imaging, and extrahepatic cholestasis is associated with dilated or abnormal bile ducts on imaging. This pictorial gives one the sense of an approach to diagnostic testing. The initial investigation should be the ultrasound, followed by cross-sectional, three-dimensional dynamic imaging, such as with magnetic resonance. The next level in testing is an endoscopic ultrasound or ERCP, endoscopic retrograde cholangiopancreatography. Finally, a liver biopsy is available to the clinician to investigate cholestasis. As stated, an ultrasound is the first diagnostic test in the evaluation of acute cholestasis. This photo gives a pictorial representation of a gallstone within the common bile duct leading to a dilated bile duct, and this indicates the presence of extrahepatic cholestasis. The most common causes of acute extrahepatic cholestasis are another thing to consider. The most common cause is a stone in the common bile duct, or choledocalothiasis, but we must also consider pancreatitis, stricture of the bile ducts, cancer of the bile ducts or pancreas, and also postoperative bile duct injury, for example, after cholecystectomy. The steps in the diagnostic evaluation of acute cholestasis for an extrahepatic cause are listed, and details are given for MR cholangiography. Details are given for MR cholangiography, the acronym being MRCP, and its value as a diagnostic tool in acute cholestasis with an extrahepatic cause. MRCP is a valuable tool to investigate the cause of dilated bile ducts seen on ultrasound. It will exclude extrahepatic causes if the ultrasound does not show bile duct dilatation and an extrahepatic cause is still suspected. An MRCP does not require IV contrast, and conventionally, the MRCP precedes an ERCP, which is, of course, more invasive, and is typically sought in the absence of acute symptoms such as fever or chills. You'll see an example of extrahepatic bile duct obstruction as identified through the MRCP. Dilated ducts are shown as indicated by the arrow, and there is also a darker gallstone evident in the distal bile duct. The value from a diagnostic perspective of endoscopic ultrasound, or EUS, EUS is a useful tool to inspect the ampulla and distal bile duct when the cause of extrahepatic obstruction is unclear. For example, stones and tumors may be sometimes confused, and the EUS can help to discriminate one from the other. In the case of tumor, the EUS can precede the ERCP in the absence of acute symptoms such as fever, chills, or right upper quadrant pain that would necessitate a more invasive intervention urgently. The risk is certainly less than for an ERCP, but it requires a trained endoscopist. There is an example of what is seen during an EUS. The thick yellow arrow indicates a gallstone with shadowing, and the bile duct is also indicated to be dilated. There are details given for ERCP in the diagnostic evaluation of acute cholestasis due to extrahepatic causes. The ERCP is valuable to investigate the cause of dilated bile ducts and to relieve the obstruction through stone removal and possibly stenting. The ERCP should be performed urgently if any of the following are present. Acute cholestasis, bile duct dilation on ultrasound, cholangitis. The ERCP and its value in the diagnostic evaluation of acute cholestasis. The ERCP is valuable to investigate the cause of dilated bile ducts and to relieve an obstruction, for example, through the removal of a stone or placement of a stent. The ERCP should be performed urgently if the following are present. If the patient has acute cholestasis with bile duct dilation on ultrasound or another imaging study, and if there are signs of cholangitis, which include fever, chills, and right upper quadrant abdominal pain. It's important to note that it's an invasive procedure and it has risks. The pancreatitis risk is about 5% and it's operator dependent. There's the possibility of retroperitoneal perforation, about 1% of cases, and there's also the possibility of bleeding after a sphincterotomy, again, about 1%. An ERCP, where a gallstone was evident in the distal duct as indicated by the arrow with mild dilation of the bile ducts. The indications for urgent intervention in a patient with acute extrahepatic cholestasis. These include acute cholangitis, as previously listed. That is the patient with fever or rigors, abdominal pain, particularly in the right upper quadrant and jaundice. A patient with bile duct injury and bile peritonitis, which tends to cause significant pain. Or a patient with gallstone pancreatitis who has an impacted stone. This pictorial gives you a sense of the diagnostic armamentarium available for the patient with acute cholestasis in a progressive format. As previously shown, an ultrasound is the first best test followed by an MRI scan and eventually an EOS and ERCP. These tests are important to exclude extrahepatic causes. However, once extrahepatic causes have been ruled out, the liver biopsy becomes a valuable tool to investigate intrahepatic causes of cholestasis. Pictorially shown is a pictorial to show the causes of acute intrahepatic cholestasis. The bile ducts, as stated previously, can be affected at various levels. At the smallest, ductular level, alcohol, viral hepatitis, drug-induced hepatitis, sepsis, and infiltrative disease with obstruction or impingement of the small bile ducts can occur. Estrogen, pregnancy, and graft versus host disease may also affect the smallest bile ducts or ductules to cause an impairment in bile flow. Of course, in intrahepatic cholestasis, flow through the larger hepatic ducts and common hepatic duct is normal. The causes of acute intrahepatic cholestasis, the most common include drug-induced cholestasis and viral hepatitis, but the clinician must also consider alcohol, infiltrative disease such as lymphomas, and non-malignant diseases such as sarcoidosis. Pregnancy should also be considered. It's important to note that sepsis can be associated with jaundice, but it's frequently referred to as cholestasis of sepsis. This is actually incorrect because there is no impairment of bile flow and the alkaline phosphatase is typically normal in a patient with sepsis-associated jaundice. This is the evaluation for intrahepatic cholestasis. Again, the best first test is the ultrasound and this will demonstrate the absence of bile duct dilation in intrahepatic cholestasis, the MRCP, can confirm the absence of bile duct dilation. There are serological tests also that will help to discern the various causes of intrahepatic cholestasis. These include acute hepatitis A serologies with the IgM, acute hepatitis B serologies with a hepatitis B surface antigen, as well as the IgM anti-HBC. Acute hepatitis C tests will include the combination of an antibody to hepatitis C along with a hepatitis C viral load or RNA. There are other viruses that can present with intrahepatic cholestasis, CMV where the acute titer IgM is available, as well as EBV or the monospot for acute mononucleosis. Antibodies should also be obtained as autoimmune diseases can present with what appears to be intrahepatic cholestasis. This can be judged based upon anti-nuclear antibodies, anti-smooth muscle, anti-mitochondrial antibodies, and an elevation in IgG for immunoglobulins. Drug and alcohol history and levels when appropriate are also obtainable. A liver biopsy is also important in the evaluation of intrahepatic cholestasis. The liver biopsy can be obtained percutaneously or through a catheterization of the hepatic vein. It's indicated to differentiate among causes for liver injury. It also can detect infiltrative processes. The contraindications to percutaneous biopsy include coagulopathy, prolongation of the INR or very low platelets, ascites, and dilation of the intrahepatic ducts, which could, if pierced with a biopsy needle, could lead to infection or bleeding. The risks of a liver biopsy include about one in 1,000 who require transfusion. The risk of death is about one in 10,000. There can also be bile leak with pain, perforation of an adjacent organ. Detail is given to drugs as a cause for acute intrahepatic cholestasis. Cholestasis usually occurs after exposure to certain drugs, and some are known to be associated with this presentation. The symptoms are typical for cholestasis with jaundice, fatigue, malaise, and itching. The lab tests typically show a predominant elevation in the alkaline phosphatase and usually with modest elevations in the ALT and AST. The diagnosis of drug-induced cholestasis results from a careful exclusion of other causes of cholestasis and hepatitis. And the most commonly implicated drugs leading to cholestasis include amoxicillin, clavulanate, estrogens, and anabolic steroids. I refer the learner to the Livertox website, www.livertox.nih.gov, which is a very useful resource in drug injuries. Livertox is a compendium of all prescribed medications and many herbal and dietary supplements, and each drug and supplement has a record which lists what is known of its hepatotoxicity. Viral hepatitis is detailed as a cause of acute intrahepatic cholestasis. Symptoms typically include constitutional symptoms and jaundice. Lab tests typically show an ALT that's slightly greater than the AST. There's an elevated bilirubin, and often, depending upon the cause, there might be the presence of hepatitis A IgM for acute hepatitis A, hepatitis B surface antigen in acute hepatitis B, and hepatitis C RNA in acute hepatitis C. One must also remember that hepatitis E is also a cause of acute viral hepatitis and can be assessed with an antibody. CMV, IgM, and monospot tests are also available. Alcohol is detailed as a cause for acute intrahepatic cholestasis. Typically alcohol is found in association with fatty liver and heavy alcohol intake. The symptoms include jaundice, hepatomegaly, spider nevi, and ascites. The presentation from a biochemical perspective for alcohol injury is rather typical, with an AST that's greater than the ALT in a ratio of 2 to 1, and usually the enzymes do not exceed 2 to 300. The bilirubin tends to be higher than the alkaline phosphatase, and leukocytosis is quite common. The diagnosis of alcohol-induced intrahepatic cholestasis is made by excluding other causes, and the liver biopsy is very helpful because it shows steatosis, acute inflammatory cells, but also characteristic for alcohol injury. Malory's hyaline gives a pictorial of a typical liver biopsy in a patient with acute intrahepatic cholestasis in alcohol, that is, alcoholic hepatitis. There's the appearance of ballooned hepatocytes with Malory's hyaline as indicated at the tip of the arrow. There's also acute inflammation, typically with an abundance of polymorphonuclear cells, and there's also fat or steatosis as indicated by the double arrows. Details infiltration as a cause for acute intrahepatic cholestasis. Although rare, it can occur and can be due to impingement of the bile ducts. Presentation includes hepatomegaly and constitutional symptoms, sometimes vague, such as fever, listlessness, and weight loss. Lab tests include a predominant elevation in the alkaline phosphatase. The diagnosis of infiltrative disease can be suspected based upon abnormal enhancement on imaging, typically dynamic imaging, and the liver biopsy. Common processes that cause this form of acute cholestasis include sarcoidosis, malignancy, and sometimes infection. Histological representation of sarcoidosis, with a non-caseating granuloma, and the liver biopsy. This, typically, is a cause of acute intrahepatic cholestasis. Cholestasis of pregnancy occurs in the second or third trimester and presents as pruritus and jaundice. Lab tests include an elevation in the bilirubin, alkaline phosphatase, and GGT, and, aside from the presentation of cholestasis in a pregnant woman, with no signs of extra hepatic bile duct obstruction, is typically supported by the presence of elevated serum bile acids. It's important to keep in mind that patients who have cholestasis of pregnancy are at increased risk of prematurity and fetal demise, and they're treated with ursodeoxycholic acid. I'd like to go over some cases. This is a 58-year-old man with a history of prostatitis. He was treated with amoxicillin clavulanate for 14 days, and on day 12, he noted the onset of malaise and jaundice. You can see that on day 12, he had an elevation in the alkaline phosphatase, the ALT slightly higher than the AST, and there was an elevation in the direct bilirubin. On day 42, you can see that his alkaline phosphatase climbed, as did the direct bilirubin. Tests for viral hepatitis and autoimmunity were negative, and an ultrasound showed no dilated bile ducts. This is a sample of his liver biopsy. The long yellow arrow shows inflammation within the lobule, and the shorter arrow gives an example of bile staining of his hepatocytes. The patient experienced progressive jaundice, fatigue, indonision, but with minimal pruritus. Of course, his drug was stopped. Symptoms and jaundice peaked at 42 days following the onset of his symptoms, and there was progressive resolution of the jaundice without specific treatment. The patient's bilirubin was normal by day 65 following the onset of his symptoms. Some important points about drug-induced cholestasis. It can have normal alkaline phosphatase at the onset. It can progress after discontinuation of an offending drug, and it can be quite prolonged. In fact, three months of symptoms is not atypical. Resolution is common with cessation of the drug, and the liver biopsy can confirm the diagnosis in the right context, of course, but it's unlikely to change management. Our second case, which is of a 60-year-old female with obesity and diabetes. She reported a one-day history of fever and right upper quadrant pain. An examination showed tenderness on palpation and percussion in the right upper quadrant. Her lab test showed a modest elevation in the alkaline phosphatase of 165. The AST was 348, ALT 589, direct bilirubin 4.5, and there was leukocytosis with a white blood cell count of 24,000. The first test done was an ultrasound, which showed dilated bile ducts, as shown by the arrow, and also a gallstone, which is lighter within the common bile duct. There were also gallstones seen in the gallbladder. Because of her presentation, an ERCP was done, and to the right of your screen, you can see the stones that were extracted from the bile duct. In the bottom panel on the right, you can see the catheter that was used to extract those gallstones from the common bile duct. It shows the course of our patient. On day two, her alkaline phosphatase rose to 450, AST fell to 144, ALT to 130, and her direct bilirubin rose to 41.5, with a white blood cell count of 24,000. On day four, after the ERCP and stone removal, her alkaline phosphatase fell to 265, AST 45, ALT 108, and direct bilirubin fell to 1.3, and her white blood cell count also fell to 13,000. The patient experienced progressive improvement in pain following her ERCP. The liver enzymes normalized by day five after her ERCP, and the white blood cell count was normal, and she was referred for cholecystectomy as an inpatient. Some important points about choledocalothiasis with cholangitis. Acute bile duct obstruction presents early on with increased transaminases, usually with an alkaline phosphatase that's lower than the enzymes. Acute cholangitis should be suspected with the presence of right upper quadrant pain, fever, chills, and leukocytosis. And when there's evidence of obstruction or stone in this setting, that constitutes an indication for an urgent ERCP. Removal of the obstruction leads to rapid clinical and biochemical improvement. So I'd like to summarize for you now some important salient features of acute cholestasis. Cholestasis refers to poor bile flow and can originate from intrahepatic or extrahepatic causes. Ultrasound is the best initial test to differentiate between intra- and extrahepatic cholestasis. Management of extrahepatic cholestasis usually entails correction of an obstructing process on an urgent basis in the presence of cholangitis. Intrahepatic cholestasis is usually diagnosed by exclusion of extrahepatic causes, an accurate history, and sometimes liver biopsy. I hope you have enjoyed this presentation, and I invite you to access additional content on liver learning on this topic and any other related topics at your leisure. Thank you.

Acute Cholestatic Injury

Jaundice

Alkaline Phosphatase

Ultrasound

Cholangitis

Fundamentals of Liver Disease