Acute hepatitis is a term used to describe a wide variety of conditions characterized by acute inflammation of the hepatic parenchyma or injury to hepatocytes resulting in elevated liver function indices. In general, hepatitis is classified as acute or chronic based on the duration of the inflammation and insult to the hepatic parenchyma. If the period of inflammation or hepatocellular injury lasts for less than six months, characterized by normalization of the liver function tests, it is called acute hepatitis. In contrast, if the inflammation or hepatocellular injury persists beyond six months, it is termed chronic hepatitis.  The most common infectious cause of acute hepatitis is due to a viral infection(acute viral hepatitis). Nevertheless, acute hepatitis can result from a wide variety of noninfectious causes as well that include but not limited to are drugs (drug-induced hepatitis), alcohol (alcoholic hepatitis), immunologic (autoimmune hepatitis, primary biliary cholangitis) or as a result of indirect insult secondary to biliary tract dysfunction (cholestatic hepatitis), pregnancy-related liver dysfunction, shock or metastatic disease.
Acute hepatic inflammation can be caused by many infectious and noninfectious causes, of which the most common causes are secondary to a viral infection or drug-induced liver injury. Below is a list of common causes for acute hepatitis and acute liver failure.
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. 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 areas. The incidence of Hepatitis A virus (HAV) has significantly decreased by approximately 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 affected more than 90% of children by age 10. Again the majority of cases are in low-income regions.
The most severe complication of acute hepatitis is acute liver failure requiring liver transplantation and rarely occurs with data being reported only from liver transplant centers. These centers might select a sicker patient population and under-report patients who spontaneously recover or lack access to these specialized centers. Given these 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.
The histopathology of acute hepatitis is determined by the underlying etiology causing the hepatocellular injury. Acute hepatitis secondary to acetaminophen overdose demonstrates characteristic histological features such as central to central bridging necrosis and minimal inflammatory cell infiltrates. The histopathology features of acute hepatitis secondary to viral infections usually show intranuclear viral inclusions and surrounding neutrophils. Classical historical features of autoimmune hepatitis demonstrate portal inflammation and interface hepatitis formally known as piecemeal necrosis which is essentially the presence of portal inflammatory cells between the portal and liver parenchyma. Diffuse microvesicular steatosis, Mallory bodies, fibrosis, or cirrhosis of the typical findings seen in alcohol-related liver injury.Iron accumulation with hepatocellular hemosiderin pigment and increase hepatic copper concentrations and liver biopsy samples are the classical histopathological findings in patients with hereditary hemochromatosis and Wilson's disease respectively. The microscopic changes in PSC and PBC are not pathognomonic for the condition. PBC is characterized by classical findings of florid duct lesion which is essentially granulomatous and lymphocytic portal inflammation centered around the interlobular bile ducts. The presence of concentric rings of fibrosis known as onion skin fibrosis is the hallmark historical features of PSC.
The clinical presentation of acute hepatitis depends on the underlying etiology. It can clinically manifest with various clinical signs and symptoms, ranging from asymptomatic elevated liver function tests to acute liver failure requiring liver transplantation. Hence, ascertaining the etiology of acute hepatitis is of utmost importance in its clinical management, making it very crucial to obtain a detailed history that should include the duration of the presenting illness, travel history, and assessing for high-risk activities like IV drug use, alcohol consumption, sexual history, prior blood-product transfusion history, or recent food intake. It is also imperative that drug history include not only recent or current prescription medications but also over-the-counter medications, acetaminophen (paracetamol), common cough/cold medications that contain acetaminophen, multivitamins and herbal/nutritional supplements.
Patients with acute viral hepatitis commonly present with symptoms such as fever, malaise, fatigue, loss of appetite, vomiting, diarrhea, and abdominal pain. Patients may also report yellowish discoloration of their sclera (icterus) and /or skin (jaundice), dark-colored urine, and light-colored stools.
Depending on the underlying etiology, physical exam findings can range from the presence of icterus and jaundice to signs of acute encephalopathy, seizures, bleeding diathesis, hypotension, and other manifestations related to multiple organ failure. Signs of chronic liver disease such as caput medusae, spider nevi, palmar erythema, ascites, Dupuytren contracture, gynecomastia, and hepatic encephalopathy can be seen in patients presenting with acute on chronic liver disease.
When evaluating patients with acute hepatitis, it is very important to distinguish between acute hepatitis and chronic hepatitis. The biochemical tests such as AST, ALT, alkaline phosphatase, GGT, lactate dehydrogenase, bilirubin, PT/INR, and albumin determine the normal functioning of the liver and any abnormalities in these tests is indicative of injury to the hepatocytes from infectious and noninfectious causes as outlined above. The possible etiology and severity of the hepatocellular injury can be determined based on the abnormality of one or more of these biochemical tests that are involved in the performance of a specific liver function. Also, it is very important to maintain suspicion for an extrahepatic process that could be contributing to abnormal liver function tests such as pregnancy, lactic acidosis, sepsis, and cardiac dysfunction.
Markers of hepatocyte metabolic/catabolic activities
Markers suggestive hepatocellular injury
Markers of liver injury secondary to cholestasis
Markers of synthetic function
Although liver function tests give an initial idea about the possible etiology and severity of the underlying hepatocellular injury, further evaluation with specific diagnostic tests are recommended to ascertain the etiology of acute hepatitis. Based on the guidelines published by the American College of Gastroenterology(ACG) for the evaluation of patients with abnormal liver function tests.The initial approach depends on the degree of elevation of the ALT and AST.
The management of acute hepatitis depends on the specific etiological factor implicated in the acute injury to the hepatocytes. Hepatitis A and E are the most common infectious causes of acute hepatitis and usually have a self-limited clinical course, resolving in 2 to 4 weeks with supportive treatment that includes IV fluids, antiemetics, and symptomatic treatment. Patients should avoid the use of alcohol and other potentially hepatotoxic medications and over the counter supplements but otherwise. They should also receive education about reducing the risk of transmission of infection to others.
Acute acetaminophen ingestion is a common noninfectious cause of acute hepatitis leading to acute liver failure and needs to be considered in all patients presenting with signs and symptoms of acute liver failure. Prompt treatment with N-acetylcysteine should be initiated as early as possible after obtaining an initial history and acetaminophen testing. N-acetylcysteine can be administered orally or IV based on the clinical scenario as mentioned below.
Treatment with N-acetylcysteine is also recommended for all patients with acute liver failure except ischemic hepatitis, with or without evidence of acetaminophen overdose..The majority of the patient's with minimal symptoms and abnormal liver function tests and normal liver synthetic function can be evaluated as an outpatient or referred to hepatology. In patients with persistently elevated liver function with no clear identification of a specific etiology, further evaluation with a liver biopsy is warranted. Infrequently, patients with acute hepatitis associated with acute liver failure characterized by hepatic encephalopathy and coagulopathy (INR greater than 1.5) should be discussed with and evaluated by the hepatology team for possible transfer to the nearest liver transplant center. There are several criteria scoring tools (e.g., King's College Criteria) to help determine the need for referral for liver transplantation.
Besides evaluating for the aforementioned causes of acute hepatitis caused by direct injury to the hepatocytes, other conditions causing secondary injury from extrahepatic or nonhepatic etiologies should also be considered on the differential diagnosis which includes choledocholithiasis, biliary or pancreatic malignancies, liver metastases, sepsis, systemic hypotension, hepatic artery thrombosis, congestive heart failure, etc.``
Prognosis of acute hepatitis depends on the etiology causing direct injury to the hepatocytes. Timely identification of the etiological agent causing acute hepatitis and the specific management is extremely important to reduce morbidity and mortality.
Although rare, the most serious complication of acute hepatitis is progression to acute liver failure (ALF) which is characterized by 2-3 times increase in serum transaminases, hyperbilirubinemia, coagulopathy, and rapid onset of hepatic encephalopathy in patients without any prior liver disease. The progression from acute hepatitis to acute liver failure depends on the underlying etiology. It is estimated that less than 1% of patients with acute hepatitis A and about 1% of patients with acute hepatitis B will progress to ALF. In contrast, 20 to 40% of patients with acute hepatitis E progress to ALF in developing countries. 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 hepatotoxicity or idiosyncratic drug reactions contributing approximately 40 to 50% of ALF cases. In low-resource countries, viral infections are the most common cause of ALF. Approximately 45 to 55% of patients with ALF recover spontaneously, and about 25% need a referral for a liver transplant, and the rest 25% succumb.
The specific etiology of acute liver failure is also an essential 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 should be promptly transferred to transplant centers. There are several prognostic screening tools for ALF and the assessment for emergent liver transplantation. Two of the most common risk scores used to assess for transplant evaluation are the King's College Criteria and the Model for End-Stage Liver Disease (MELD) Score.
Vaccinations for both hepatitis A virus and hepatitis B virus have been available since the 1990s and have significantly decreased the incidence of these infections. 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. The risk of contracting hepatitis B and hepatitis C infection can be decreased by avoiding IV drug use and safe sex practices.
Accidently toxic ingestion of acetaminophen by children can be reduced with safe storage practices out of reach from children and utilizing packaging that utilize childproof safety precautions. 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:
Given the exhaustive conditions that can cause acute hepatitis, the management of this clinical condition requires an interprofessional, collaborative team approach that would aid in making a timely diagnosis resulting in appropriate management. Clinical presentation of acute hepatitis in patients can range from being asymptomatic with incidental abnormal liver biochemical test results to being critically ill with signs concerning for acute liver failure. In clinical practice, acute hepatitis is primarily encountered by primary care physicians, emergency medicine physicians, and internists. Depending on the etiology and the severity, other specialists may need to be involved in the care team, including gastroenterologists, hepatologists, pharmacists, nursing staff, toxicologists, infectious disease specialists, transplant surgeons, intensive care teams, or liver transplant centers.In some instances of acute hepatitis caused by drug overdose or drug abuse, the involvement of behavioral health experts and substance abuse professionals is imperative. Clinical pharmacists should thoroughly review the patient's medication profile and assist with appropriate drug dosing to prevent further insult from hepatotoxicity from drugs and drug-drug interactions.
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