Acute Hepatitis

Etiology

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[10][11][12].

Infectious causes:

• Hepatotropic viruses:
• Hepatitis A Virus(HAV)
• Hepatitis B Virus (HBV)
• Hepatitis C Virus (HCV)
• Hepatitis D Virus (HDV)
• Hepatitis E Virus (HEV)
• Nonhepatotropic virus:
• Epstein-Barr virus (EBV)
• Cytomegalovirus (CMV)
• Herpes simplex virus (HSV)
• Coxsackievirus
• Adenovirus
• Dengue virus
• Coronavirus-19(COVID-19)
• Bacteria, fungi, and parasites

Toxin or substance-related causes include:

• Alcohol-related: fatty liver disease, acute alcoholic hepatitis, or alcoholic cirrhosis
• Drugs and toxins
• Dose-dependent, e.g. acetaminophen (paracetamol)
• Non-dose-dependent, e.g., idiosyncratic drug reaction most commonly related to antibiotics and anticonvulsants but also statins, NSAIDs, herbal/nutritional supplements
• Other toxins, e.g., mushroom (Amanita phalloides), herbal and dietary supplements, carbon tetrachloride, sea anemone sting  

Immunologic or inflammatory conditions

• Autoimmune hepatitis
• Biliary disease such as primary biliary cholangitis or primary sclerosing cholangitis.

Metabolic or hereditary

• Nonalcoholic fatty liver disease
• Hemochromatosis
• Wilson's disease

Pregnancy-related 

• Preeclampsia
• Acute fatty liver of pregnancy
• HELLP syndrome

Ischemic and Vascular

• Cardiogenic/Distributive shock
• Hypotension
• Heatstroke
• Cocaine, methamphetamine, ephedrine
• Acute Budd-Chiari syndrome
• Sinusoidal obstruction syndrome

Miscellaneous

• Acute fatty liver of pregnancy
• Malignancy
• Eclampsia
• HELLP syndrome
• Reye' syndrome
• Primary graft non-function after liver transplantation

Epidemiology

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 [10][12][13].

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[14].

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[13].

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[15][16][17]. 

Histopathology

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[10]. Diffuse microvesicular steatosis, Mallory bodies, fibrosis, or cirrhosis of the typical findings seen in alcohol-related liver injury[18].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[19]. 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[20].

History and Physical

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[5][12]. 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.  

Evaluation

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[1][2][3]. 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

• Elevated serum bilirubin: Synthesized primarily in the reticuloendothelial cells from the breakdown of heme-containing proteins. It can be abnormally increased in liver diseases secondary to impaired uptake, impaired conjugation, or secondary to leak from damaged hepatocytes or bile ducts.

• Elevated ammonia: increase because the liver fails to metabolize ammonia. 

Markers suggestive hepatocellular injury

• Elevation of serum transaminases such as aminotransferases, aspartate aminotransferase (AST), also called serum glutamic-oxaloacetic transaminase (SGOT), and alanine aminotransferase (ALT), also called serum glutamic pyruvic transaminase (SGPT) is suggestive of hepatocellular injury.
  • Marked elevations greater than five times the upper limit of normal or greater than 500 IU/L is suggestive of extensive hepatocellular injury. It is commonly encountered in acute hepatitis, drug-induced liver injury such as acetaminophen overdose, profound ischemia to the liver, hepatic necrosis, or cases of severe autoimmune hepatitis.
  • Milder elevations are considered less than five times the upper limit of normal or less than 500 IU/L and can result from a variety of liver injuries or disorders. Some of these disorders can overlap with acute causes but often are associated with more chronic hepatitis or nonhepatic causes, examples of which include smoldering inflammation from autoimmune disorders, hemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency, alcoholic liver disease, nonalcoholic fatty liver disease, and drug-induced liver injury.

Markers of liver injury secondary to cholestasis 

• Elevation in alkaline phosphatase (AP) and gamma-glutamyl transferase (GGT) reflect underlying cholestasis secondary to the liver's impaired ability to secrete bile, which can be secondary to various intra-hepatic or extrahepatic causes. Common causes include choledocholithiasis, malignancy, primary biliary cirrhosis, or primary sclerosing cholangitis.

Markers of synthetic function 

• Elevated Prothrombin time (PT): This occurs when liver injury results in decreased synthetic function of the vitamin K-dependent coagulation factors (II, VII, IX, X). Prolongation of the international normalized ratio (INR) more than 1.5 is considered a poor prognostic sign and a key component to make a diagnosis of acute liver failure [15]. Prolongation of PT/INR occurs within hours to days of liver injury, making it a better marker than albumin to determine the liver's synthetic function.

• Decreased albumin: This is not specific to liver injury, and its utility in the diagnosis of acute hepatitis is limited. These tests can become abnormal in a matter of days, making this a better marker for acute liver dysfunction than albumin. 

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[21].The initial approach depends on the degree of elevation of the ALT and AST. 

• Mild elevation in serum transaminases ( <5 times the upper limit of normal): ACG guidelines recommend checking a complete blood count, AST, ALT, alkaline phosphatase, total bilirubin, albumin, PT/INR, comprehensive hepatitis panel that includes 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) and imaging with an abdominal ultrasound examination.

• Severe elevation in serum transaminases (>15 times the upper limit of normal) or massive (ALT over 10000 U/L) elevations: ACG guidelines recommend checking for Ebstein-Barr virus(EBV), cytomegalovirus(CMV), ceruloplasmin, autoimmune markers (antinuclear antibodies, anti-smooth muscle antibodies, Anti-liver/kidney microsomal antibodies, IgG), drug panel test that includes acetaminophen, and urine toxicology. Guidelines also recommend the performance of a sonographic Doppler study of the hepatic vein, portal vein, and hepatic artery to rule out vascular occlusion, eg. Budd-Chiari syndrome.  

• Imaging: Abdominal ultrasound examination is the best initial choice of imaging study in patient's presenting with lab abnormalities suggestive of cholestasis. Findings of biliary dilatation are suggestive of extrahepatic causes of cholestasis (gallstones or masses), while the absence of biliary ductal dilatation suggests intrahepatic causes of cholestasis such as drug-induced liver injury, PBC and PSC[21]. 

• Liver biopsy: Although not routinely performed, liver biopsy is indicated if the diagnosis is not clear such as patients presenting with atypical clinical features, coexistent chronic liver disease, inconclusive extensive biochemical workup, fever of unknown origin and abnormalities on imaging studies of uncertain etiology. The commonly performed methods of liver biopsy include percutaneous, CT/ US-guided, transjugular (transvenous), and Endoscopic Ultrasound(EUS) guided biopsies[21][22].

Treatment / Management

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[4]. 

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.

• 72-hour oral protocol -  N-acetylcysteine oral: 140 mg/kg orally as a loading dose, followed by 70 mg/kg every 4 hours for a total of 17 doses
• 20 hour IV protocol - N-acetylcysteine IV: 150 mg/kg intravenously over 60 minutes as a loading dose, followed by 50 mg/kg over 4 hours (12.5 mg/k/ per hour for 4 hrs), then 100 mg/kg over 16 hours (6.25 mg/kg per hour for 16 hours)

Treatment with N-acetylcysteine is also recommended for all patients with acute liver failure except ischemic hepatitis, with or without evidence of acetaminophen overdose.[11][12][15].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[2][3][21]. 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[10][11][12].(A1)

Differential Diagnosis

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[2][12].``

Prognosis

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.

Complications

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[12][15][16]. 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.[10]

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[12]. 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[10]. 

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[11].

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[12].