What is Toxic Hepatitis?

Overview

The liver is one of the organs in the body where metabolism and breakdown of different drugs occur. This makes the liver the most susceptible organ to possible injuries from drugs and other substances.^1,3 Gastrointestinal organs (stomach and small and large intestine) send approximately 75% of blood to the liver and spleen.² 

Hepatotoxicity (or toxic hepatitis) is considered a rare form of liver disease. It is usually difficult to diagnose because of the lack of information about its pathogenicity which is directly related to the mechanism of the development of the disease. 

Toxic hepatitis is a form of inflammation of the liver which occurs as an adverse effect of the inaccurate consumption of specific substances or medications.² 

Several mechanisms can lead to either hepatic injury or increase the severity of the damage process. Liver damage can be due to impact on liver cells (hepatocellular), decreased bile flow (cholestatic), or mixed. Most drug metabolism occurs through activation of the hepatic cytochrome enzyme called p-450 which interacts with some organelles such as mitochondria causing liver cell dysfunction. This increases the production of oxidants and the accumulation of bile acid resulting in severe damage. 

In addition, liver damage takes place through different immune mechanisms (the body’s protective mechanisms) and ends up causing severe liver toxicity. This in turn releases an excessive amount of oxidants that, in turn, injure liver cells. 

Causes of toxic hepatitis

There are several causes of liver failure including the following: paracetamol toxicity, hepatic ischaemia, viral and autoimmune hepatitis, and drug-induced liver injury from prescription drugs and herbal and dietary supplements.^1,4 

Many drug types contribute to drug-induced liver injury including the following:

• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Anti-infective drugs (anti-tubercular drugs)
• Anti-cancer drugs
• Hormonal drugs
• Immunosuppressive agents, sedative and neuropsychiatric drugs
• Acetaminophen (common causative agent leading to drug-induced liver injury)
• Antibiotics (most commonly causes liver toxicity with amoxicillin-clavulanate stands out as the most common drug in this class) 
• Herbal drugs and supplements cause a variety of symptoms, but their usage remains under-reported

Signs and symptoms of toxic hepatitis

Signs and symptoms of toxic hepatitis include:

• Fatigue
• Decreased appetite
• Sensitivity to fatty and oily food 
• Epigastric pain and discomfort and tender liver
• Jaundice
• Light coloured faeces 
• Fever
• Rash & itching
• Joints’ pain

Management and treatment for toxic hepatitis

The first step in the management of toxic hepatitis is identifying the cause and protecting the liver from further damaging effects, especially from disturbed functions of liver enzymes. This involves discontinuing the causing agent and at the same time, the use of a reverse agent drug is considered one of the main lines of treatment for toxic hepatitis. There are many drugs and reversing agents that can be used to reverse the action of certain agents that cause toxic hepatitis, for instance, N-acetylcysteine can be used to reverse the effect of acetaminophen drugs, while carnitine has been proposed as a reverse agent for valproate. 

Glucocorticoids are used as reverse agents for immune-mediated drug-induced liver injury. In the case of mushroom toxicity, medications like silymarin together with benzylpenicillin can be used to reverse the damaging effects on liver cells.⁶ It’s recommended to follow up and monitor the symptoms until they have been resolved and restored to normal levels.

Even though all those antidotes help counteract the effects of other drugs currently available, there are no reverse agents used frequently. However, N-acetylcysteine is considered the main drug that reverses the toxicity of acetaminophen, the main component of paracetamol.⁵ Hospitalisation is advised in advanced cases of liver toxicity and the severe cases, liver transplantation may be required.

Diagnosis of toxic hepatitis

As a preliminary step for achieving a proper diagnosis, a differential diagnosis should be performed to exclude other forms of liver disease through further clinical, pathological and analytical investigations. The International Serious Adverse Events Consortium (iSAEC) suggested the following guidelines to follow while investigating toxic hepatitis.

• It can be diagnosed through multiple laboratory liver tests that might show liver enzyme elevation. Those tests and enzymes that need to be investigated include alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin
• The AST and bilirubin levels can determine the prognosis of toxic hepatitis cases and can help in the identification of the cases that can be fixed through liver transplantation thus preventing death
• Patients who have allergic symptoms should have eosinophilia autoantibodies tests done as well
• Chronic drug-induced liver injury can present with different manifestations including chronic hepatitis, liver fibrosis, and cirrhosis^7,8 
• Elevated serum bilirubin, low albumin, and blood coagulation defects signify severe liver damage

Risk factors

Different risk factors can increase the chances of toxic hepatitis such as:⁹

• Age
• Gender
• The stage of disease (toxicity)
• Nutritional status
• History of other liver diseases
• History of infection with hepatitis
• Acetylation status 
• High alcohol intake

For instance, children are at an increased risk of liver toxicity caused by valproate and are more prone to Reye syndrome in case of aspirin consumption. However, older patients are more susceptible to the risk of toxicity when consuming drugs such as amoxicillin-clavulanate.

Complications

• Acute respiratory failure: It is characterised by not getting enough oxygen to the lungs, with incomplete removal of CO₂ resulting in impaired gas exchange which may lead to hypoxia
• Acute liver failure: Impairment of liver function which leads to fatigue, nausea, loss of appetite, discomfort and diarrhoea. Drug-induced liver injury can cause chronic liver disease and the risk usually increases with cholestatic or mixed type compared to hepatocellular type
• Acute renal failure: Reduction in kidney function as a result of elevated levels of serum creatinine 
• Severe metabolic acidosis: Elevated acid production and decreased production of acids simultaneously from the kidneys leading to decreased pH of blood (lower than 7.35)

FAQs

How can I prevent toxic hepatitis?

It is crucial to educate patients about the adverse effects of different drugs or long-term medications that can directly cause toxic hepatitis. Moreover, physicians and medical professionals should take a brief medical history of the patients to be able to discuss the drugs that can cause further liver injury before taking any supplements such as herbal, dietary or over-the-counter medications.

How common is toxic hepatitis?

In the USA & Europe, drug-induced liver injury is the most common cause of toxic hepatitis with up to 50% fatality rate.^10,11 In addition, it has been reported that drug-induced liver injury is a rare occurrence with an incidence of about 14-19 per 100,000 people.¹⁰ However, there is no evidence about the exact percentage of drug-induced hepatic injury cases.

When should I see a doctor?

Patients who are following long-term treatment with a drug that can potentially cause liver damage are advised to consult a clinician as early as they start the treatment. However, not all patients follow those guidelines and may suffer from advanced and severe hepatic injury and inflammation. Therefore, some patients may require admission to intensive or advanced care. 

Most patients who experience drug-induced hepatic failure have a prognosis according to evidence-based research. While some patients try to treat themselves by stopping the drugs immediately after experiencing side effects, they may still suffer prolonged cholestasis which may last for approximately 3 to 12 months after withdrawal of the causative drug. Therefore, patients are advised to consult their physician if they notice any of the previously stated symptoms especially if they are following prolonged medication courses. This is because this may dramatically lead to poor prognosis after causing increased bile secretion and developing ‘vanishing bile duct syndrome’ and cholestatic cirrhosis. 

Summary

Hepatotoxicity (or toxic hepatitis) is considered a rare form of liver disease. It can be due to various causes including drug toxicity, hepatitis, or hepatic ischaemia. This condition can be diagnosed by multiple laboratory liver function tests measuring liver enzymes and parameters like albumin and bilirubin. Management of this condition includes identifying the causative agent and starting treatment accordingly. If not treated appropriately, this can lead to conditions like respiratory, liver, kidney failure and metabolic acidosis.

Currently, multiple improvements in management have resulted in lower mortality rates. Liver transplantation has been suggested as the line of treatment for more advanced and severe cases of toxic hepatitis. However, enhancement of the medical management of those cases is recommended to be able to save more lives.