Hello, my name is Oren Fix, and I'm from Swedish Medical Center in Seattle, Washington. 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 Hepatocellular Injury. During this talk, I will discuss the common etiologies and evaluation of acute AST and ALT elevation, identify the alarm signs that indicate when a patient with acute AST and ALT elevation should be hospitalized or urgently referred, and define acute or fulminant liver failure. At the conclusion of the program, you should be able to list common etiologies of acute AST and ALT elevation, outline the evaluation of acute AST and ALT elevation, identify the alarm signs that indicate when a patient with acute AST and ALT elevation should be hospitalized or urgently referred to a specialist, and define acute or fulminant liver failure. When faced with a patient with acute AST or ALT elevation, you should consider the most common etiologies of drugs or toxins, viral, and ischemia. You should also consider autoimmune hepatitis, Wilson disease, and acute biliary obstruction. When considering drugs or toxins, alcohol is one of the most common etiologies, but in this case, the AST is less than 300 units per liter. Acetaminophen is one of the most common causes of acute liver injury, as are NSAIDs, antibiotics, anti-epileptics, antituberculosis drugs, herbal, nutritional, dietary supplements, and mushrooms. It is important to always ask patients about non-prescribed over-the-counter medications as well as herbal, nutritional, and dietary supplements because they often do not consider these as medications. Viral causes of acute AST and ALT elevation include hepatitis A through E, Epstein-Barr virus, herpes viruses, cytomegalovirus, and adenovirus. And ischemic causes include shock liver or ischemic hepatopathy, and the Bug Chiari syndrome or hepatic vein obstruction. It's also important to be aware of etiologies that do not cause acute AST and ALT elevations. Causes such as non-alcoholic fatty liver disease, hemochromatosis, or other forms of iron overload, primary sclerosine cholangitis, primary biliary cholangitis, formerly known as primary biliary cirrhosis, and alpha-1 antitrypsin deficiency. Acute AST and ALT elevations can be categorized from mild to moderate to marked with mild elevations less than 200 units per liter, moderate 200 to 600 units per liter, and marked over 600 units per liter. They can also be described in terms of the AST to ALT ratio. For example, greater than two to one, which is common in alcoholic hepatitis, and less than one, which is common in viral hepatitis and fatty liver disease. Alarm signs include elevations in bilirubin or INR and or mental status changes associated with marked hepatocellular injury. One of the reasons for categorizing the magnitude of the aminotransferase elevations is that this magnitude can point toward as an etiology. For example, some of the highest AST and ALT elevations are seen in ischemic or toxic liver injury, followed by acute viral hepatitis and autoimmune hepatitis. More chronic liver diseases, such as alcoholic liver disease, chronic hepatitis, and cirrhosis tend to have the lower range of AST and ALT elevations. It is important to note, however, that the magnitude of the elevation in AST and ALT does not always correlate with disease severity. When evaluating a patient for possible drug or toxin-induced injury, it's important to obtain a thorough medication history, including current and medications given or taken in the past six months. It's very important to ask about over-the-counter medications, herbal, nutritional, or dietary supplements because often patients do not consider these to be medications. It's also important to ask about a history of foraging or ingesting wild mushrooms. When evaluating a patient for possible viral hepatitis, ask about risk factors for viral hepatitis, such as travel history, ingestion of raw or uncooked food, such as shellfish, pig, or venison meat, sexual practices, drug use, tattoos, and occupational exposure. When evaluating a patient for alcohol-induced injury, ask about a thorough alcohol history, including excess use and or recent binging. Ask about right upper quadrant pain, fever, jaundice, and look for leukocytosis. An AST to ALT ratio of greater than 2 to 1, especially when GGT is greater than 2 times the upper limit of normal, is highly suggestive of alcohol hepatitis. But AST is generally less than 300 units per liter. An AST greater than 1,000 units per liter is not caused by alcohol alone, and this is a common misconception. Be sure to look for a concomitant cause of acute hepatocellular injury when the AST is this high. Alcohol hepatitis can occur weeks after the last drink, and often serum and urine alcohol levels may be negative on presentation. Patients often minimize or even deny drinking. When evaluating a patient for ischemic liver injury, ask about a history of arrhythmias or syncope, look for evidence of hypotension or shock, including hemorrhagic and septic shock, look for signs of fever or infection, and a history of recent surgery. When evaluating a patient with acute AST and ALT elevation, on physical exam, look for jaundice, hepatomegaly, abdominal tenderness, any alteration of mental status, and the presence of asterixis. For laboratory testing, first-line tests in all patients include the labs in the box on the left. PT, INR, toxicology screen, viral serologies, autoantibodies, and acetaminophen level. Also consider seruloplasmin in the proper patient population. All patients should have a Doppler ultrasound. In patients with acute liver failure, prognostic tests include ammonia, arterial blood gas, lactate, and phosphorus. First-line viral serologic tests are shown in this slide, and these include anti-hepatitis A IgM, hepatitis B surface antigen, anti-hepatitis B core IgM, hepatitis B DNA, anti-hepatitis C, and hepatitis C RNA. Second-line testing in selected patients include anti-hepatitis E IgM and PCRs for Epstein-Barr, herpes simplex virus, and cytomegalovirus. Second-line testing should be sent when first-line tests are unrevealing, but can also be sent with first-line tests in the inpatient setting or with marked acute AST and ALT elevations when time is of the essence. First-line autoantibody testing in all patients should include anti-nuclear antibody, anti-smooth muscle antibody, and gamma globulins or serum protein electrophoresis. It is very important to be aware of alarm signs in the setting of acute AST and ALT elevation. A patient with the following signs should be hospitalized, prolonged PT-INR, altered mental status and or asterixis, unable to tolerate oral fluids, the presence of the systemic inflammatory response syndrome or SIRS, and an unreliable patient, one who cannot get labs drawn frequently or be seen in clinic often. If these alarm signs are not present, the patient can often be managed as an outpatient, but it will be necessary to monitor liver biochemistries and PT and INR frequently, often twice a week. The patient should be seen in clinic often, sometimes once a week, and one should obtain a liver biopsy when noninvasive evaluation is unrevealing, especially if the patient is not improving. It is reasonable, however, to hospitalize a patient with marked acute AST and ALT elevation even if alarm signs are absent. Acute or fulminant liver failure is defined as all of the following. Acute hepatocellular injury, coagulopathy, defined as an INR at least one and a half or greater, altered mental status and or asterixis, and no known preexisting liver disease. The terms fulminant and subfulminant are out of favor, and acute liver failure is the preferred term now. The most common etiology of acute liver failure is acetaminophen, which is responsible for almost half of all cases of acute liver failure in the United States. One should also consider other drugs or toxins, viral ischemia, autoimmune hepatitis, and Wilson's disease. Patients with acute liver failure are often critically ill and should be admitted to the intensive care unit. They require urgent consultation with the liver transplant service or transfer to a liver transplant program. And death occurs from multi-organ system failure, cerebral edema or herniation, and infection. While waiting for transfer to a transplant program or to an intensive care setting, the practitioner could send etiology-specific labs, obtain a Doppler ultrasound, start an acetylcysteine, which should be considered even if acetaminophen overdose is not suspected, and intubate the patient if uptunded, for example, with grade 3-4 encephalopathy. Case 1. This is an 18-year-old woman who was binge drinking on New Year's Eve and seemed tired or hungover on New Year's Day. Of course, this was not suspicious. Even on January 2nd, she had nausea, vomiting, abdominal pain, and seemed moody and sleepy, and this did not arouse too much attention. However, on January 3rd, she became confused, disoriented, agitated, and was talking to objects. Her past medical history includes asthma and depression. Her medications include albuterol and minocycline. Her social history includes being a binge drinker who also smokes marijuana. She lives with her parents. On exam, she was uptunded, confused. She had abdominal tenderness, asterixis. She was not noted to be jaundiced. On laboratory examination, her total bilirubin was 2.4, AST 10,299, ALT 10,651, alkaline phosphatase 199, INR 7.2, lactate 5.8, ammonia 152, and phosphorus 0.5. On serological examination, her anti-hepatitis A IgM was not reactive, hepatitis B surface antigen was negative, anti-hepatitis B core IgM was negative, anti-hepatitis C was negative, anti-nuclear antibody was negative, acetaminophen level was undetectable, and her Doppler ultrasound was normal with patent hepatic and portal veins. The patient was diagnosed with acute liver failure based on the presence of a markedly elevated ALT and AST, a coagulopathy, and an altered mental status. The level of her aminotransferase elevation rules out alcohol as a cause of liver failure where AST is usually less than 300 units per liter. Intentional acetaminophen overdose was suspected due to her history of depression and alcohol intoxication. The rapid time course and the pattern of lab abnormalities strongly suggest acetaminophen toxicity based on the markedly elevated AST and ALT, the minimal elevation of bilirubin and the very high INR, all typical patterns of acetaminophen toxicity. It's extremely important to note that the acetaminophen level is often negative and should never be used to rule out the diagnosis of acetaminophen hepatotoxicity. The patient was treated with IV and acetylcysteine or NAC for suspected acetaminophen overdose. The NAC was stopped when her INR was less than 2, her AST was less than 1,000, and her altered mental status resolved, and the patient fortunately recovered with supportive care. Important points for case one are the following, acetaminophen level is often negative and should never be used to rule out the diagnosis of acetaminophen overdose. A high degree of suspicion is needed to make the diagnosis. When in doubt, start NAC. Studies show that up to 20% of indeterminate cases of acute liver failure are related to acetaminophen. NAC is most effective when started early but can still improve survival even when started over 48 hours after ingestion. And with aggressive supportive care, acetaminophen-induced acute liver failure has a relatively high rate of spontaneous survival. That is, liver transplantation is not commonly required. Case two. This is a 37-year-old woman who presents with a two-day history of subjective fevers, nausea, vomiting, and abdominal pain. Jaundice was noted by her mother. She is taking aspirin but no recent acetaminophen use. She is not currently sexually active, and she denies recent alcohol use. Past medical history is significant for hypothyroidism. Her current medications include levothyroxine and aspirin. On exam, she is jaundiced, ill-appearing. She has a pedomegaly, a diffusely tender abdomen, no asterixis, and no cutaneous stigmata of chronic liver disease. On laboratory evaluation, her total bilirubin is 15.3 with a direct bilirubin of 12.2. Her AST is 253, ALT 42, alkaline phosphatase 227, albumin 3.3, PT 12.7 seconds, INR 1.2, white blood cell count 20.1, hemoglobin 10.6, platelet count 314, alcohol level 0.17%. Her ultrasound shows an echogenic liver and hepatomegaly. When confronted with the positive serum alcohol results, she admitted to drinking a fifth of vodka daily for the past five days. Her presentation was consistent with acute alcohol hepatitis based on the following features, fever, abdominal pain, jaundice, hepatomegaly, leukocytosis, cholestasis, moderate AST elevation, AST to ALT ratio greater than 2 to 1, and elevated alkaline phosphatase. Her discriminant function was 18.5. Over 32 is considered severe with a high mortality, and this is the threshold where systemic corticosteroids are often considered. The patient was managed with supportive care, including nutritional support, and she recovered spontaneously. Important points for case two include the following. Alcohol hepatitis is usually an acute on chronic liver injury, and most patients already have cirrhosis. Patients often minimize or deny drinking, so a high degree of suspicion is necessary to make the diagnosis. And keep in mind that alcohol hepatitis can occur weeks after the last drink. Case three. This is a 50-year-old Japanese woman with stage 2 breast cancer treated with doxorubicin and cyclophosphamide. Her initial ALT was 23, but while undergoing chemotherapy, her ALT rose to 42 and then to 103. A drug-induced liver injury was suspected. Her INR was 1, she had no jaundice, she had normal mental status, and she was followed closely as an outpatient. However, with time, her liver tests started to worsen. On day one, she had a bilirubin of 0.5, AST 92, ALT 103, and INR 1. On day two, her total bilirubin was 0.9, AST 1596, ALT 2120, and INR 1.3. And by day three, her total bilirubin had risen to 1.7, AST was 3542, ALT 3758, and INR was 2, and she was admitted to the hospital. Her IgM anti-hepatitis A was negative, anti-hepatitis B surface was negative, anti-hepatitis B core was positive. Her hepatitis B surface antigen was also positive. Anti-hepatitis C antibody was negative, anti-nuclear antibody was negative, and abdominal ultrasound was normal with patent hepatic and portal veins. After being admitted to the hospital, her liver tests continued to worsen. On day four, her bilirubin was 3, AST 3949, ALT 4092, and INR 2.4, and at this point, she became confused. By day eight, her bilirubin was 17.5, AST was over 7,000, ALT over 4,000, and INR was 10.1. Her hepatitis B DNA returned at greater than 1 billion international units per milliliter. Therefore, chemotherapy-induced reactivation of chronic hepatitis B was confirmed, but despite treatment with tenofovir, she did not improve. Her liver transplantation, unfortunately, could not be considered because of her active breast cancer, and she died of multisystem organ failure, including acute kidney injury and respiratory failure. Important points for case three are the following. Acute liver failure is diagnosed when there is an acute epitocellular injury, coagulopathy, altered mental status, and no known preexisting liver disease. That asterisk is there because hepatitis B reactivation is a minor exception to this last requirement. The presence of alarm signs such as elevations in bilirubin or INR, especially with mental status changes, requires immediate hospitalization. Hepatitis B reactivation in the setting of chemotherapy is preventable if prophylactic antiviral therapy is started at the onset of chemotherapy. And acute liver failure due to drug-induced liver injury other than acetaminophen is associated with a relatively poor prognosis, and patients often do not recover without liver transplantation. To summarize, common etiologies of acute AST and ALT elevation include drugs or toxins, viruses, and ischemia, but also consider autoimmune hepatitis, Wilson's disease, and acute biliary obstruction. The evaluation of acute AST and ALT elevation includes a history focused on the common etiologies and physical exam looking for jaundice, hepatomegaly, abdominal tenderness, altered mental status and asterixis, and laboratory testing, both first and second line. Alarm signs that indicate when a patient with acute AST and ALT elevation should be hospitalized or urgently referred include prolonged PT-INR, altered mental status and or asterixis, inability to tolerate oral fluids, SIRS, or an unreliable patient. Acute liver failure is defined as the presence of all the following, acute hepatocellular injury, coagulopathy, altered mental status and or asterixis, and absence of preexisting liver disease. 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.

acute hepatocellular injury

elevated AST and ALT levels

alcohol hepatitis

acute liver failure

early detection

Fundamentals of Liver Disease