Liver Toxicity

What is Liver Toxicity?

Drug-induced liver injury (DILI) is a key factor causing problems with the liver. This condition can result in a variety of symptoms–from mild ones that may go unnoticed, such as asymptomatic transaminitis (an elevation in certain liver enzymes that doesn’t cause any symptoms), to more serious ones like acute or chronic hepatitis (short-term or long-term liver inflammation), cholestasis (a condition where the flow of bile from the liver is slowed or stopped), and in severe cases, liver failure.

DILI can be triggered by various prescription drugs, along with herbal and dietary supplements. It often results in the drug or supplement causing the issue being pulled from the market to prevent further cases.

What Causes Liver Toxicity?

Taking certain types of medication can lead to drug-induced liver injury. These can be numerous, including things like nonsteroidal anti-inflammatory drugs (commonly known as NSAIDs), anti-infection drugs (such as those used to treat tuberculosis), drugs used to treat cancer, hormonal medicines, drugs that suppress your immune system, and medicines used to calm you down or treat mental health conditions.

The drug that is most frequently linked to problems with the liver is called acetaminophen. Antibiotics are also often linked to liver damage, with a specific one called amoxicillin-clavulanate being the most common culprit.

Additionally, herbal supplements can also cause a range of symptoms related to liver damage, but their use often goes unreported.

If you’d like more information on drug-induced liver injury, the NIH LiverTox website is a good online resource. It provides comprehensive information about liver injuries that can be caused by prescribed medicines and dietary and herbal supplements.

Risk Factors and Frequency for Liver Toxicity

Drug-induced liver injury is a leading cause of acute liver failure in the United States and Europe. It accounts for between 20% and 40% of all extreme liver failures. This injury can happen quite rarely, with reports suggesting it occurs in just 1 out of every 10,000 to 100,000 individuals. However, the total number of cases is hard to pinpoint because a lot of them go unreported or are missed. It’s also challenging to definitively attribute liver damage to a specific drug as there are no universally agreed-upon guidelines for assessing drug-induced liver injury.

The Drug-Induced Liver Injury Network has been set up in the United States since 2003 to gain a better understanding of this issue. They collect and analyze data from suspected cases to understand the causes and risk factors, as well as the outcomes of drug-induced liver injuries.

Several risk factors contribute to an increased likelihood of drug-induced liver injury. These include old age, being female, chronic alcoholism, and pregnancy.
In some cases, these factors are linked to a higher risk from specific drugs rather than all drugs. Children are more likely to have liver toxicity from valproate, and aspirin has been linked to increased risk of Reye syndrome in children.
As people age, there’s a higher risk of toxicity when taking drugs like amoxicillin-clavulanate.
Certain types of human leukocyte antigen (HLA) have been identified as risk factors for drug-induced liver injury.

Signs and Symptoms of Liver Toxicity

Patients with specific health issues can experience a range of symptoms. Some people may feel tired, have a reduced appetite, dislike fatty food, and feel discomfort in the upper belly area along with having a tender liver. People with the cholestatic type of this condition may display symptoms like developing a yellowish skin color known as jaundice, having light-colored poop, and feeling itchiness. Occasionally, they might manifest allergic reactions including fever, skin rashes, and joint aches.

Fatigue
Decreased appetite
Aversion to oily food
Discomfort in the upper belly area
Tender liver
Jaundice (for the cholestatic type)
Light-colored poop (for the cholestatic type)
Itchiness (for the cholestatic type)
Fever (occasionally)
Skin rash (occasionally)
Joint aches (occasionally)

Testing for Liver Toxicity

Drug-induced liver injury can usually cause mild to moderate increases in liver tests, but in rare circumstances, it can be deadly. It can cause an increase in liver enzymes, which are proteins that speed up certain chemical reactions in the body. These can include alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin. It’s crucial to highlight that there’s no individual test that can accurately predict drug-induced liver injury.

In some patients, drug-induced liver injury may cause an allergic reaction leading to eosinophilia (an increase in the number of a specific type of white blood cells known as eosinophils) and elevated autoantibodies (proteins produced by the immune system that mistakenly attack one’s own cells and tissues).

In its chronic form, drug-induced liver injury can reveal different signs including persistent liver inflammation (hepatitis), liver fibrosis (scarring), or cirrhosis (late-stage of scarring). Taking note of increased total bilirubin levels (a yellowish substance in the blood), decreased albumin levels (a protein made by the liver), and faults in blood coagulation (clotting) are essential signs of severe liver damage. Furthermore, the drug-induced liver injury that affects liver cells causes a more pronounced increase in ALT compared to ALP. On the other hand, if it hinders the flow of bile, the increase in ALP may surpass that of ALT.

In 2011, the International Serious Adverse Events Consortium (iSAEC) suggested changes to the biochemical criteria for identifying drug-induced liver injury. They recommended considering this condition if any of the following results are met:

Alanine transferase is greater than or equal to 5 times the normal upper limit
Alkaline Phosphatase is greater than or equal to 2 times the normal upper limit, particularly in patients with raised 5′-nucleotidase or GGT, and no elevation related to bone diseases
Alanine transferase is greater than or equal to 3 times the normal upper limit and total bilirubin is greater than or equal to 2 times the normal upper limit

This guidance was provided to avoid unwarranted discontinuation of medications. However, it can sometimes be challenging to confidently determine if the liver injury is caused by a drug or worsening of existing liver damage. Typically, a rise in liver tests is attributed to drug-induced liver injury when there’s a prior record of drug use, when stopping the drug improves the liver injury, when re-administering the drug triggers the injury again, and when there are known cases of the drug causing liver injury in other patients.

Treatment Options for Liver Toxicity

If a medication is causing harm to your liver, the first step is to stop taking that medication. N-acetylcysteine is an antidote for acetaminophen poisoning – this is when too much of the painkiller acetaminophen has been taken and it’s causing damage to the liver. This antidote has also been found to help people survive other kinds of sudden severe liver failure not caused by acetaminophen. Carnitine, a substance produced by the body, has been used to treat liver damage caused by valproate, a medication often used to treat epilepsy and bipolar disorder.

Although steroids have been suggested as a possible treatment for liver injury, they aren’t well studied in this area. Currently, glucocorticoids, a type of steroid, are used for liver injury caused by the body’s immune response to a drug. Silymarin, a substance found in milk thistle, has been used alone or in combination with benzylpenicillin, an antibiotic, to treat liver injury caused by poisonous mushrooms, but we need more research to understand how effective these treatments are.

Ursodeoxycholic acid, a type of bile acid, could be tried in patients with cholestasis, a condition where bile isn’t able to flow from the liver to the gut. Antihistamines, often used to treat allergies, could be used for itching, a common symptom in liver diseases. Patients should continue to have check-ups until their symptoms have completely gone and blood tests show that their liver is working normally again.

Diagnosing drug-induced liver injury can be tricky because it can resemble any kind of liver disease. It’s important to rule out other possible causes to make a correct diagnosis. Usually, drug-induced liver injury is noted when there’s an increase in certain liver tests, which could point to a variety of issues.

Healthcare providers should consider and rule out all the causes of conditions that are similar to hepatitis. These include:

Viral hepatitis
Alcohol-related liver disease
Non-alcoholic fatty liver disease
Autoimmune hepatitis

When evaluating a patient, they should also take into account causes of cholestasis, which is a condition where the flow of bile from the liver is reduced or blocked. The causes they should consider include:

Biliary obstruction (blockage in the tubes that carry bile from the liver)
Primary biliary cirrhosis (a slow progressive destruction of the bile ducts in the liver)
Primary sclerosing cholangitis (a disease of the bile ducts that causes inflammation and scarring, leading to blockage)

What to expect with Liver Toxicity

Most people who experience drug-induced liver damage end up recovering. However, some people might continue to experience cholestasis – a condition where the flow of bile from the liver slows down or stops – even after they stop taking the medicine that caused the problem. Usually, this condition gets better within 3 to 12 months after stopping the medicine, but some people may have a longer recovery period. In some extreme cases, they might develop conditions like vanishing bile duct syndrome or cholestatic cirrhosis, both of which can seriously damage the liver and have a poor prognosis, or a higher chance of a negative outcome.

The levels of AST (a type of protein enzyme) and bilirubin (a pigment produced by the liver) in the body can give us an idea of how likely it is that a patient might die or need a liver transplant.

Drug-induced liver damage can cause long-term liver disease and the risk of this happening usually increases if the damage causes cholestasis or a mix of conditions, compared to if it specifically affects the liver cells (hepatocellular type).

Possible Complications When Diagnosed with Liver Toxicity

Sudden breathing problems
Sudden liver failure
Sudden kidney failure
Severe imbalance of acidity in the body

Preventing Liver Toxicity

Many natural remedies like herbal supplements, food-based supplements, and other drugs that you can buy without a prescription can sometimes harm the liver. This can cause problems, and it’s especially risky for people who already have liver disease. If you’re thinking about starting any kind of herbal or dietary supplement, it’s critical to talk with your usual healthcare provider first. Also, remember to review any existing medications you’re taking with your doctor. This helps to check if the new supplements might mix badly with your current medicines, which could result in severe liver damage.

Frequently asked questions

Liver toxicity, also known as drug-induced liver injury (DILI), is a condition where the liver is damaged due to the use of certain drugs or supplements. It can cause a range of symptoms, from mild ones that may go unnoticed to more serious ones like liver inflammation, cholestasis, and in severe cases, liver failure.

Liver toxicity occurs in just 1 out of every 10,000 to 100,000 individuals.

Signs and symptoms of liver toxicity include: - Fatigue - Decreased appetite - Aversion to oily food - Discomfort in the upper belly area - Tender liver - Jaundice (for the cholestatic type) - Light-colored poop (for the cholestatic type) - Itchiness (for the cholestatic type) - Fever (occasionally) - Skin rash (occasionally) - Joint aches (occasionally)

Taking certain types of medication, including nonsteroidal anti-inflammatory drugs (NSAIDs), anti-infection drugs, drugs used to treat cancer, hormonal medicines, drugs that suppress the immune system, and medicines used to calm you down or treat mental health conditions, can lead to drug-induced liver injury. Additionally, herbal supplements can also cause liver damage. Several risk factors, such as old age, being female, chronic alcoholism, and pregnancy, contribute to an increased likelihood of drug-induced liver injury. Certain types of human leukocyte antigen (HLA) have also been identified as risk factors.

The conditions that a doctor needs to rule out when diagnosing Liver Toxicity are: - Viral hepatitis - Alcohol-related liver disease - Non-alcoholic fatty liver disease - Autoimmune hepatitis - Biliary obstruction (blockage in the tubes that carry bile from the liver) - Primary biliary cirrhosis (a slow progressive destruction of the bile ducts in the liver) - Primary sclerosing cholangitis (a disease of the bile ducts that causes inflammation and scarring, leading to blockage)

The types of tests that may be ordered to diagnose liver toxicity include: - Liver enzyme tests: These tests measure the levels of liver enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT). Elevated levels of these enzymes can indicate liver damage. - Total bilirubin test: This test measures the levels of bilirubin, a yellowish substance in the blood. Increased levels of bilirubin can be a sign of severe liver damage. - Eosinophilia test: This test measures the levels of eosinophils, a type of white blood cell. An increase in eosinophils may indicate an allergic reaction associated with drug-induced liver injury. - Autoantibody test: This test detects the presence of autoantibodies, which are proteins produced by the immune system that mistakenly attack the body's own cells and tissues. Elevated levels of autoantibodies may be seen in drug-induced liver injury. - Blood coagulation test: This test evaluates the blood's ability to clot. Abnormalities in blood coagulation can be a sign of severe liver damage. - Imaging tests: Imaging tests such as ultrasound, CT scan, or MRI may be ordered to assess the structure and function of the liver. It's important to note that there is no individual test that can accurately predict drug-induced liver injury, and the diagnosis is usually made based on a combination of clinical evaluation, medical history, and laboratory tests.

Liver toxicity can be treated by stopping the medication that is causing harm to the liver. In cases of acetaminophen poisoning, N-acetylcysteine is used as an antidote. It has also been found to help people with sudden severe liver failure not caused by acetaminophen. Carnitine has been used to treat liver damage caused by valproate. Glucocorticoids are currently used for liver injury caused by the body's immune response to a drug. Silymarin, found in milk thistle, has been used to treat liver injury caused by poisonous mushrooms, but more research is needed. Ursodeoxycholic acid can be tried in patients with cholestasis, and antihistamines can be used for itching. Regular check-ups and blood tests are important until symptoms have completely resolved and the liver is functioning normally again.

The prognosis for liver toxicity caused by drug-induced liver injury varies depending on the severity of the damage. Most people who experience drug-induced liver damage recover fully, but some may continue to experience cholestasis even after stopping the medication. In extreme cases, conditions like vanishing bile duct syndrome or cholestatic cirrhosis can occur, which can seriously damage the liver and have a poor prognosis. The levels of certain enzymes and pigments in the body can help determine the likelihood of death or the need for a liver transplant.

A hepatologist or a gastroenterologist.