What to know about drugs and liver damage

What is drug-induced liver injury?

DILI is the technical term for liver damage that results from toxins within drugs. The condition can be a temporary or long-term response to the toxins, and the compounds containing the toxic substances can be either naturally occurring or artificially manufactured.

DILI can be intrinsic or idiosyncratic. Intrinsic means that the injury depends on the dosage, which makes it easier to predict and avoid. There is also a short latency period, meaning that there is not much time between taking the drug and experiencing the condition.

Idiosyncratic DILI is harder to control. It has a long latency period, as the condition tends to begin 1–2 weeks after taking the drug. Idiosyncratic cases tend to depend more on individual risk factors than factors relating to the drug itself, which makes them difficult to predict.

DILI is the most common cause of acute liver failure in the United States.

Which drugs can cause liver damage?

The National Institute of Diabetes and Digestive and Kidney Diseases keeps a searchable database called LiverTox, which lists the medicines and herbal compounds that can damage the liver.

There are more than 1,000 types that can cause damage. These include prescription and nonprescription medications and selected dietary and herbal supplements.

The table below gives some examples of these drugs.

Herbal and dietary supplements are responsible for 20% of DILI cases, while antibiotics account for 45.4% of idiosyncratic cases.

Paracetamol, also known as acetaminophen, causes the highest number of intrinsic DILI cases. This is because when the liver metabolizes the drug, it can cause too many reactive metabolites to build up, leading to cell and bodily tissue death.

Symptoms

The duration of the symptoms of DILI varies. Some cases are acute, with the condition being only temporary, while others are chronic, meaning that it lasts for an extended period. However, people typically develop signs and symptoms within 3–6 months of taking the drug.

The type and extent of the symptoms can also differ, with many people not experiencing any symptoms.

For those who do, the most common symptom is jaundice, which causes the eyes to appear yellow and the skin to look green-yellow due to too much bilirubin collecting in the cells.

Other common symptoms include:

• weakness
• abdominal pain
• dark stool
• dark urine
• nausea
• pruritis, which is the term for itchy skin

Causes

The primary cause of DILI is whichever drug has injured the liver, but the process varies depending on whether the condition is intrinsic or idiosyncratic.

When the condition is intrinsic, the dosage of a drug is the leading cause.

The cause of idiosyncratic DILI is a combination of risk factors that relate to the drug, the individual, and the environment.

Risk factors

The level of risk varies according to the drug. However, additional factors can dictate the severity of DILI. This is particularly the case with idiosyncratic DILI, although risk factors can also contribute to intrinsic DILI.

According to a 2020 study, the main risk factors fall under genetic and environmental categories. Genetic factors are unique to the individual and may include the following:

• mutation within an enzyme called the cytochrome P450 enzyme
• genetic expression in transport proteins
• genetic expression in nuclear receptors
• changes to the levels of immune components

Environmental factors are more general and can include:

• older age
• female sex
• nutritional status
• alcohol intake
• pregnancy
• high body mass index (BMI)
• inflammation
• pre-existing conditions
• the particular combination of drugs
• any previous reactions to drugs

Alterations in gut microbiota are also a key risk factor, as they affect the function of the immune system and how the body metabolizes drugs.

The risk does not depend on these factors independently. The area requires more research, but studies suggest that the risk comes from how the drug, individual, and environmental factors combine and interact.

Diagnosis

DILI can be difficult to diagnose, as many people do not experience symptoms. When symptoms do occur, the condition appears similar to other disorders relating to the liver and nearby organs.

The condition is particularly challenging to diagnose when the cause is a herbal or dietary supplement. This is because people are less likely to be aware of toxic substances within the compound, and it is harder to establish a link between the cause and condition.

Doctors may use different criteria when making a diagnosis. There are currently no tests available for diagnosing DILI specifically, so the process of elimination plays a large role in the diagnosis. However, certain biomarkers within the body may support a diagnosis. These include glutamate dehydrogenase and keratin-18.

A healthcare professional will generally begin a diagnosis by evaluating a person’s medical history, including any pre-existing liver conditions and their history of drug use, and establishing when the condition started and how it has progressed. The next steps will depend on the outcome of this stage, but the doctor is likely to conduct blood tests.

A doctor may also request a liver biopsy. This will not determine whether a person has DILI, but they can use the results to rule out other potential causes of the symptoms.

Treatment

If a doctor suspects that a person has DILI, they will recommend immediately stopping the use of the drug likely responsible for the damage.

The doctor may also remove the drug causing the condition from the person’s system. Two types of drugs have specific compounds that people can take as treatment measures:

• N-acetyl-cysteine (NAC) for reducing acetaminophen toxicity
• L-carnitine for reducing valproic acid toxicity

Treatment plans also depend on how the liver responds to the toxins. A doctor may prescribe glucocorticoid therapy if the liver damage presents as autoimmune hepatitis.

Additionally, treatment will involve treating the direct symptoms of liver damage.

In severe cases, particularly when the cause is idiosyncratic DILI, a person may require a liver transplant.

Prevention

A key preventive measure is to understand a drug’s effects before taking it. If people are aware of the possible effects, they are more likely to identify them and link them back to the drug.

People should always speak with a doctor before taking any new medications or herbal or dietary supplements.

Doctors may sometimes use the following compounds to prevent liver injury from drugs.

• Rapamycin: This compound induces autophagy, which is the body’s way of cleaning out damaged cells and producing new, healthier cells.
• Chloroquine: This compound inhibits autophagy.
• 3-methyladenine: This compound also inhibits autophagy.

Autophagy is the mechanism that enables cells to respond to stress. By controlling this process, scientists hope to reduce or prevent DILI.

Summary

The liver is responsible for metabolizing drugs, and, as a result, the organ has high exposure to toxins that may occur within them. More than 1,000 drugs and herbal compounds can cause liver damage.

DILI can be intrinsic, meaning that it results from too high a dosage, or idiosyncratic, which occurs due to a combination of risk factors.

Currently, no specific tests are available for diagnosing DILI, so doctors may use different diagnostic criteria when confirming the condition.