What is Drug-Induced Hepatotoxicity?
Drug-induced liver injury (DILI) is a reaction that can occur quickly or develop over time when the liver is exposed to certain natural or synthetic substances. This condition can be categorized based on how it shows its symptoms, how it affects the liver, or via the results of a liver biopsy. Determining the true number of cases is tough, but it’s known to be the top cause of sudden liver failure in the U.S. Drug-induced liver damage usually occurs in two ways: directly related to the dosage of the drug (intrinsic) or in a more unpredictable manner (idiosyncratic).
In many cases, DILI will show no symptoms. However, the most common sign is the yellowing of the skin and eyes, known as jaundice. Specific lab tests can diagnose this condition by detecting elevated levels of certain enzymes in the liver. In liver cell injury, aminotransferases levels rise, while in bile duct injury, a different enzyme alkaline phosphatase (ALP) increases. Although a liver biopsy is not always needed to confirm diagnosis, it can help rule out other health problems related to the liver. The first step in treating drug-induced liver injury is to stop using the drug that caused it. Usually, the chances of recovering are quite good once the drug use is stopped.
What Causes Drug-Induced Hepatotoxicity?
Certain factors can increase the risk of drug-induced liver injury (DILI), like being a woman, being older, and having a higher body mass index (BMI). It’s known that over 1000 medications and herbal compounds can cause liver damage. You can find these listed in an online database called LiverTox, managed by the National Institute of Diabetes, Digestive, and Kidney Diseases.
Among the common causes of this condition are medications like acetaminophen, whereas aspirin, tetracycline, and vitamin A cause it less frequently.
There are also some drugs and substances which can induce DILI in an unpredictable manner, including:
* Antibiotics (accounting for 45.4% of cases): the most common is amoxicillin-clavulanate, but others like ciprofloxacin and sulfamethoxazole-trimethoprim, as well as isoniazid (INH), can also cause it.
* Nonsteroidal anti-inflammatory drugs (NSAIDs), widely used to reduce inflammation and pain.
* Herbal and dietary supplements (16.1% of cases): among them green tea extract, anabolic steroids, or multi-ingredient nutritional supplements.
* Heart related drugs (10% of cases): this includes statins, used for cholesterol management, and amiodarone.
* Central nervous system agents: here are medications for mental health disorders like valproate and phenytoin.
* Cancer-fighting drugs: such as tyrosine kinase inhibitors, tumor necrosis factor inhibitors, alpha inhibitors, and methotrexate.
Risk Factors and Frequency for Drug-Induced Hepatotoxicity
Determining the exact number of Drug-Induced Liver Injury (DILI) cases is tricky because it’s often underreported and there are different ways to diagnose it. Still, in the United States and around the globe, less than 15 to 20 people out of 100,000 get DILI each year. Even though it’s the most frequent cause of sudden (acute) liver failure in the US, accounting for 13%-16% of cases, it’s relatively rare compared to other causes of liver damage. DILI is more common in women (59%) than men, which may be due to different hormones and how certain medicines affect the body. It also seems to affect more people over 50, perhaps because they’re likely to take more prescription drugs.
Signs and Symptoms of Drug-Induced Hepatotoxicity
Drug-induced liver injury (DILI) is a condition that can cause a variety of symptoms and sometimes, a person may not display any symptoms at all. The most common symptoms include yellowing of the skin (jaundice), weakness, stomach pain, dark stools or urine, nausea, and itching. This condition can also lead to acute or chronic liver failure, making it tough to distinguish from other liver conditions. Sometimes, if there’s an immune reaction due to the injury, symptoms may be accompanied by fever, rashes, increased eosinophils (a type of white blood cell), and a severe skin condition called Stevens-Johnson syndrome. Notably, symptoms usually show up between three and six months after taking the harmful medicine, making a detailed medicine history important.
- Yellowing of the skin (jaundice)
- Weakness
- Stomach pain
- Dark stools or urine
- Nausea
- Itching
- Acute or chronic liver failure (sometimes)
- Fever, rashes and increased eosinophils (cases of immune-mediated injury)
- Stevens-Johnson syndrome (rare)
During a physical examination, doctors may look for signs such as yellow skin (jaundice), tenderness in the upper right area of the stomach, and sometimes an enlarged liver, commonly seen when the liver damage has led to chronic liver disease.
Testing for Drug-Induced Hepatotoxicity
Diagnosing drug-induced liver injury (DILI) starts by looking at the patient’s medical history, the medicine they’re taking, and by ruling out any pre-existing liver disease. As there are no specific tests for DILI, doctors have to be very vigilant.
Your doctor may need to conduct some tests to help with the diagnosis. These tests could measure levels of various compounds in your blood such as alanine aminotransferase (ALT), aspartate transferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), total bilirubin, albumin, and prothrombin time. They might also check your complete blood count, electrolytes, viral infections, and autoantibodies.
Based on these tests, different types of liver injuries can be identified. For instance, if the liver cells themselves are damaged, levels of transaminases (i.e., ALT and AST) in your blood may be three times higher than normal. Conversely, if the injury is cholestatic, which means it’s affecting the flow of bile, alkaline phosphatase levels could be three times the normal limit.
Doctors may also use imaging studies such as abdominal ultrasounds or MRI scans, particularly if the bile flow is blocked. Although liver biopsy isn’t typically necessary for diagnosis, it could be helpful in ruling out other potential liver diseases.
Currently, research is also being conducted on potential biomarkers, such as micro-RNAs, that may help in diagnosing DILI or predicting its progression. Apart from this, some rating systems have been designed to help diagnose DILI objectively. One of these, the Roussel Uclaf Causality Assessment (RUCAM), takes into account risk factors, liver enzyme levels, potential offending drugs, and other potential causes to determine the probability of DILI.
Treatment Options for Drug-Induced Hepatotoxicity
The best way to treat drug-induced liver damage is to stop taking the drug that’s causing the problem. There are some specific treatments available for certain types of liver damage. For instance, if the liver damage is due to an overdose of the painkiller acetaminophen, a medication called N-acetyl-cysteine (NAC) is used. NAC helps to detoxify the harmful substances produced by the drug. Another treatment is L-carnitine, which is used for an overdose of the drug valproic acid.
Glucocorticoid therapy, a type of steroid treatment, is sometimes used, but its role is limited. It’s often used if the liver damage resembles that of autoimmune hepatitis, an inflammatory liver disease.
There are also treatments for the symptoms of drug-induced liver damage. For example, bile acid sequestrants can be used to treat a type of liver damage characterized by the build-up of bile, and antihistamines can treat itching, a common symptom of liver damage.
Patients with signs of worsening liver damage or acute liver failure, a serious condition that can occur in response to certain drugs, need to be admitted to the hospital. Anyone suspected of having acute liver failure might need to consider a liver transplant because this condition can be life-threatening.
Finally, it’s crucial to report any cases of drug-induced liver damage to regulatory bodies responsible for drug safety. This helps to determine if a particular drug is too risky to keep on the market.
What else can Drug-Induced Hepatotoxicity be?
Diagnosing DILI, which stands for drug-induced liver injury, can be quite difficult. This is because it can closely resemble other conditions that have to do with the liver. Some of these liver diseases include:
- Various forms of viral hepatitis (A, B, C, E)
- Conditions caused by viruses such as cytomegalovirus (CMV), or Epstein-Barr
- Ischemic hepatitis, which happens when the liver doesn’t get enough blood or oxygen
- Autoimmune hepatitis, where the body’s immune system attacks the liver
- Hemochromatosis, which is a build-up of iron in the body
- Wilson disease, a rare disorder that causes copper to accumulate in the liver
- Non-alcoholic fatty liver disease (NAFLD), a condition related to excess fat in the liver
- Alcoholic hepatitis, inflammation of the liver caused by drinking alcohol
- Gilbert syndrome, a harmless genetic liver disorder
It could also be mistaken for biliary disease conditions like:
- Cholangitis, an infection of the bile duct
- Choledocholithiasis, which involves stones in the bile duct
- Primary biliary cirrhosis and primary sclerosing cholangitis, progressive diseases that damage the bile ducts
In addition, DILI can also resemble different kinds of cancers, such as liver cancer, lymphoma, or malignancies related to the pancreas and bile ducts.
What to expect with Drug-Induced Hepatotoxicity
Most patients tend to recover well once the drug causing the issue is stopped, with about 90% bouncing back. “Hy’s law” is used to predict the risk of mortality. It considers things like ALT/AST levels (liver enzymes) being more than three times the usual upper limit, and total bilirubin (a substance the liver produces) being up to two times the regular upper limit, without having an obstruction or any other explanation for these levels.
This risk is higher in individuals aged 65 and above, though death rates do not vary. A type of liver damage, called hepatocellular injury, has a slightly higher risk of leading to death or the need for a liver transplant, compared to another type called cholestatic injury.
About 10% of patients eventually need a liver transplant. After receiving a transplant, the survival rate is 66%.
Possible Complications When Diagnosed with Drug-Induced Hepatotoxicity
There’s a 17% chance that the condition may progress to chronic liver disease. This is most commonly seen in patients who have a long-term cholestatic injury, a condition called vanishing duct syndrome. It’s also worth noting that acute liver failure is more frequently caused by damage to liver cells rather than a cholestatic injury.
Preventing Drug-Induced Hepatotoxicity
Preventing drug-induced liver injury (DILI) can start by teaching patients about their medications. This includes understanding over-the-counter drugs, prescription drugs, and herbal and dietary supplements. If patients experience signs of liver damage or acute liver failure, they should seek further medical evaluation immediately.
