Acute hepatitis is a general diagnosis referring to any of a wide variety of conditions causing acute inflammation or injury to hepatocytes, resulting in elevation of liver biochemical lab tests. Hepatitis is classified as acute if it resolves in less than six months, and if abnormal findings last greater than six months, it classifies as chronic hepatitis. The term is common when referring to hepatitis from a viral etiology (acute viral hepatitis) but acute hepatitis can result from a wide variety of etiologies including drugs (drug-induced hepatitis), alcohol (alcoholic hepatitis), immunologic (autoimmune hepatitis) or conditions where the liver is secondarily affected such as biliary tract dysfunction (cholestatic hepatitis), pregnancy-related liver dysfunction, shock or metastatic malignancy.
This activity will focus on acute conditions that primarily affect hepatocytes.
There is a long list of possible etiologies for acute hepatitis and acute exacerbations of chronic hepatitis. In general, the causes of acute hepatitis and acute liver failure are the same with infectious causes and drug-induced liver injury being the two largest groups. Below is a list of common causes for acute hepatitis and acute liver failure.
Infectious causes include:
Toxin or substance-related causes include:
Immunologic or inflammatory conditions
Metabolic or hereditary
Ischemic and Vascular
The epidemiology of all of the possible causes of acute hepatitis is beyond the scope of this review. There is some reporting data for specific conditions causing acute hepatitis, particularly the hepatotropic viral hepatitis A (HAV), B (HBV), C (HCV), D (HDV), and E (HEV). Other conditions causing acute hepatitis are likely under-reported such as non-hepatotropic viral infections, drug-induced liver injury (DILI), auto-immune diseases, etc. Also, there are some data related to conditions progressing to acute liver failure. Based on reported data, viral and drug-induced liver injury are the most common causes of acute hepatitis and acute liver failure.
Generally, the rates of viral hepatitis are low in high-income regions and high in resource-poor regions.
Hepatitis A virus (HAV) has decreased by 95% since the introduction of the hepatitis A vaccine in 1995. The past five years have seen a small increase in cases mostly from isolated food-related outbreaks, persons who use drugs, and the homeless population. Like HAV, cases of acute HBV have decreased significantly since the introduction of the vaccine in 1990. Currently, the age group 40 and older have the highest rate of acute hepatitis B, related to the risk factors of injection drug use, multiple sex partners, and lack of prior vaccination. Hepatitis C has been steadily increasing since 2010, particularly in the 20 to 40 age group, thought to be secondary to injection drug use related to the opioid crisis and improved surveillance.
Worldwide, the World Health Organization estimates that 1 in 3 people have been infected with either HBV or HCV. In high endemic areas, HAV has infected more than 90% of children by age 10. Again the majority of cases are in low-income regions.
The most serious complication of acute hepatitis is acute liver failure; this is a rare condition and reported data frequently comes from liver transplant centers. These centers might select for a sicker patient population and under-report patients who spontaneously recover or lack access to these specialized centers. Given those limitations, the epidemiology of acute liver failure varies in different countries. In the UK, US, and Australia, drug-induced liver failure from acetaminophen (paracetamol) causes 39 to 50% of cases, while the hepatotropic viruses cause between 7 to 15% of cases. Globally, hepatitis A, B, and E probably cause most cases of acute liver failure reported as 50% of cases in Japan, 68% of cases in India, and 91% of cases in Bangladesh.
A liver biopsy can be helpful to determine the etiology of acute hepatitis (discussed in the Evaluation section). Acute hepatitis from acetaminophen overdose might show central-to-central bridging necrosis, and minimal inflammatory cell infiltrates. Hepatitis secondary to viral infections might show intranuclear viral inclusions and surrounding neutrophils. Autoimmune hepatitis might show bridging necrosis, and lymphoplasmacytic infiltrates. Alcohol misuse-related injury might show diffuse microvesicular steatosis, Mallory bodies, fibrosis, or cirrhosis. In hemochromatosis, biopsy sample would show iron accumulation with hepatocellular hemosiderin pigment. Finally, in Wilson disease, the samples would show increased hepatic copper concentrations.
The clinical course and presenting symptoms of acute hepatitis vary widely from asymptomatic elevated liver biochemical blood tests to signs and symptoms suggesting acute liver failure with jaundice and encephalopathy. The clinical presentation depends on the etiology, co-morbidities, pre-existing liver disease, and individual patient characteristics.
To help narrow possible etiologies, it is crucial to take a detailed history. This history should include a time course of the illness, travel history, and assessing for high-risk activities like IV drug use, alcohol consumption, sexual contact history, blood-product transfusions, or recent mushroom ingestion.
Medication history should include not only prescription medications but also a detailed accounting of over-the-counter medications, which should include questions about substances that might contain acetaminophen (paracetamol), such as cold/cough medications, as well as vitamins and herbal/nutritional supplements.
In the cases of acute viral hepatitis, common symptoms include fever, malaise, fatigue, loss of appetite, vomiting, diarrhea, and abdominal pain. Patients may notice yellowing of the sclera (icterus) or yellowing of the skin (jaundice), prompting them to seek medical evaluation. Patients might report dark-colored urine, from rising levels of direct bilirubin and light-colored stools.
Physical exam should access not only for icterus and jaundice but other signs of liver disease such as caput medusae, spider nevi, palmar erythema, ascites, Dupuytren contracture, gynecomastia, and hepatic encephalopathy.
If the patient progresses to acute liver failure, additional symptoms might include drowsiness, cognitive impairment, seizures, abnormal bleeding, hypotension, and other manifestations related to multiple organ failure.
When evaluating patients, it is helpful to determine if the clinical course indicates acute hepatitis (liver biochemical test abnormalities present less than six months) versus chronic hepatitis (abnormalities present greater than six months). Laboratory tests associated with the liver include AST, ALT, alkaline phosphatase, GGT, bilirubin, ammonia, PT/INR, and albumin. Abnormalities in specific tests suggest hepatocellular injury or abnormal function of liver metabolism and synthesis. Which tests are abnormal, and the degree of abnormality can help determine the severity of illness and help narrow the possible etiologies.
The American College of Gastroenterology has published guidelines for the evaluation of patients with abnormal liver tests. The initial approach depends on the degree of elevation of the ALT and AST. For patients with mild elevations (less the 5x the upper limit of normal), they recommend complete blood count, platelet count, AST, ALT, alkaline phosphatase, total bilirubin, albumin, PT/INR, Hepatitis A IgM Antibody, Hepatitis B Surface Antigen, Hepatitis B Core Antibody (IgM), Hepatitis B Surface Antibody and Hepatitis C Antibody, and iron panel (serum iron, total iron-binding capacity, serum transferrin saturation and serum ferritin). Plus, they recommend an abdominal ultrasound. For patients with severe (>15 times the upper limit of normal) or massive (ALT over 10000 U/L) elevations, they recommend adding Ebstein-Barr virus, cytomegalovirus, ceruloplasmin (Wilson disease), autoimmune markers (antinuclear antibodies, anti-smooth muscle antibodies, Anti-liver/kidney microsomal antibodies, IgG), serum drug panel (including acetaminophen) and urine toxicology. Also, add Doppler abdominal ultrasound looking for vascular occlusion, eg. Budd-Chiari syndrome.
If patients are presenting acutely symptomatic and ill-appearing, it is essential to remember that the liver test abnormalities might be part of a multiorgan process, and patients might need other tests such as pregnancy tests, blood gases, lactic acid, blood culture, lipase, etc. to find the primary etiology.
An abdominal ultrasound is the best initial imaging test, especially for patients with lab abnormalities suggesting cholestasis. Biliary dilatation suggests extrahepatic causes of cholestasis (gallstones or masses), while no dilatation suggests intrahepatic causes of cholestasis like drug toxicity, primary biliary cholangitis, primary sclerosing cholangitis, etc.).
Liver biopsy is indicated to assist with diagnosis, prognosis (staging), and/or developing treatment plans. Diagnostically, biopsies help in patients with atypical clinical features, coexisting liver diseases, abnormal liver tests of unknown etiology, fever of unknown origin, or abnormalities on imaging studies of uncertain etiology. Prognostically, biopsies help determine where patients might be in the natural course of known parenchymal liver diseases. Examples include Hepatitis B, Hepatitis C, Hemochromatosis, autoimmune hepatitis, and Wilson's Disease. Finally, specific treatment planning can take place after biopsy results identify specific diagnoses. For example, steroids in some cases of autoimmune hepatitis. Liver biopsy methods include percutaneous biopsy, fine-needle aspiration biopsy, transjugular (transvenous) biopsy, and laparoscopic biopsy.
In most cases, if patients are minimally symptomatic, have mild liver enzyme elevations, and normal synthetic function, then they can be followed with repeat testing in about three months. If levels remain high, further testing is needed, which might include biopsy and referral to a specialist.
Hepatitis A and E are the most common causes of acute viral hepatitis and are generally self-limited, resolving in 2 to 4 weeks. Patients need supportive care, including fluids, antiemetics, and symptomatic treatment. Patients should avoid alcohol and other potentially hepatotoxic medications and supplements but otherwise can continue with their usual medications. They should also receive education about reducing the risk of transmission of infection to others.
Although a rare condition, ill-appearing patients with findings of acute hepatitis should have screening for acute liver failure looking for any degree of hepatic encephalopathy and coagulopathy (INR greater than 1.5). These patients need more aggressive monitoring and treatment, including fluid resuscitation, monitoring for hypoglycemia, hypokalemia, hypomagnesemia, hypophosphatemia, bleeding, and worsening encephalopathy. These patients will need ICU admission and likely transfer to a liver transplant center. There are several criteria scoring tools (e.g., King's College Criteria) to help determine the need for a liver transplant.
Because acetaminophen (paracetamol) hepatotoxicity is a common cause of acute hepatitis and acute liver failure, it needs to be considered in all patients with acute hepatitis. Treatment with N-acetylcysteine is the recommended course in all patients with acute liver failure except ischemic hepatitis, with or without evidence of acetaminophen overdose.
N-Acetylcysteine - can be given oral or IV:
There is a broad differential diagnosis for patients presenting with malaise, fever, nausea, vomiting, loss of appetite, abdominal pain, and abnormal liver tests. Differential diagnoses include conditions that directedly injury hepatocytes but should also include conditions causing secondary injury from extrahepatic or nonhepatic etiologies. These secondary conditions might include choledocholithiasis, biliary or pancreatic malignancies, liver metastasis, sepsis, systemic hypotension, hepatic artery thrombosis, congestive heart failure, etc.
The prognosis for patients with acute hepatitis depends on the etiology. The reader can investigate specific etiologies for details related to specific prognoses.
Although rare, the most serious complication of acute hepatitis is progression to acute liver failure (ALF). Key findings in acute liver failure include acute liver injury with a two- to three times elevation of aminotransferases, along with hyperbilirubinemia and jaundice, plus coagulopathy with INR over 1.5 and any degree of hepatic encephalopathy in patients without prior liver disease and less than 26-week duration. As with acute hepatitis, there are multiple causes of ALF.
Whether a patient progresses from acute hepatitis to acute liver failure depends on the etiology. It's estimated less than 1% of patients with acute hepatitis A and about 1% of patients with acute hepatitis B will progress to acute liver failure, Between 20 to 40% of patients in developing countries, have acute hepatitis E as the cause for ALF. About 69% of patients with acute, severe autoimmune hepatitis progress to ALF, and about 2% of ALF results from Wilson disease.
In the US and much of Europe, acute liver failure is most often secondary to acetaminophen (paracetamol) hepatotoxicity or idiosyncratic drug reactions, causing 40 to 50% of cases. In low-resource countries, viral infections are the most common cause. Approximately 45 to 55% of all patients with ALF recover spontaneously, and about 25% receive a liver transplant to aid recovery, leaving about a 25% mortality.
The specific cause of acute liver failure is an important predictor for spontaneous recovery. Approximately 75% of patients spontaneously recover from acetaminophen (paracetamol) induced failure, but only about 40% spontaneously recover from other causes.
Patients with acute liver failure should be considered for liver transplant and transferred to transplant centers. There are several prognostic screening tools for ALF and the need for emergent liver transplantation. Two of the more common guidelines are the King's College Criteria and the Model for End-Stage Liver Disease (MELD) Score. Readers can find the details for these guidelines in the StatPearls section on Acute Liver Failure and Hepatic Failure.
Vaccinations for both hepatitis A virus and hepatitis B virus have been available since the 1990s and have decreased the incidence when widely used. Hepatitis A virus gets transferred by fecal-oral contamination, and improved food handling, water purification, and improved hygiene will reduce the risk of spreading infection. For hepatitis B and C risk, of infection can be decreased by avoiding IV drug use and safe sex practices.
Accidently toxic ingestion of acetaminophen by children is reducible with child-resistant packaging. Also, in adults, unintentional toxic ingestion can be reduced with education about the many non-prescription products which contain acetaminophen.
For stable minimally symptomatic patients, if an etiology for acute hepatitis is not determined initially, then they need follow-up to monitor for the normalization of the liver tests or further evaluation if the abnormal test results continue.
Keys to remember and avoid in patients with acute hepatitis:
Because acute hepatitis has a large number of etiologies, it requires an interprofessional, collaborative team approach to diagnose and manage appropriately. Patients might present on the spectrum from asymptomatic with incidental abnormal liver biochemical test results to critically ill with acute liver failure. Acute evaluation and initial management might start with primary care physicians, emergency physicians, or advance practice providers. Depending on the etiology and the severity of the illness, other specialists might need to be involved in the care team, including pharmacists, nursing staff, toxicologists, gastroenterologists, hepatologists, infectious disease specialists, immunologists, general surgeons, transplant surgeons, intensive care teams or liver transplant centers. [Level 2]
Also, for some patients, it might be necessary to include mental health (overdose), public health (infectious hepatitis), or substance abuse professionals (IV drug misuse).
A pharmacist should thoroughly review the patient's medication profile and history, checking for hepatotoxic agents, and dosing of drugs that can lead it hepatic issues, reporting concerns to the team. They will also have involvement in any pharmaceutic interventions (e.g., NAC, ensuring that dosing and interactions are safe. In acute care situations, nursing will assist with patient intake, administering medication, and monitoring treatment progress and being alert to signs of adverse drug effects or regression of the patient's condition. These are but a few examples of how interprofessional teamwork can improve patient outcomes. [Level 5]
For a patient presenting with acute liver injury from acetaminophen (paracetamol), treatment with N-acetylcysteine improves outcome. [Level 2]
In patients with drug-induced liver injury and coagulopathy, treatment with N-acetylcysteine is indicated even if acetaminophen (paracetamol) levels are negative. [Level 2]
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