Drug-Induced Liver Injury - Diagnosis and Treatment

Introduction

Tigecycline belongs to the glycylcycline class of antibiotics. It shows a broad-spectrum activity and acts against drug-resistant gram-positive organisms. The U.S. Food and Drug Administration approved it in 2005. Currently, It is used for the treatment of community-spread pneumonia and infections of the skin, tissues, and abdomen. The dose of Tigecycline is 50 mg intravenously after a 100 mg loading dose every 12 hours.

The common side effects reported with Tigecycline therapy include nausea, vomiting, and diarrhea, which may lead to the discontinuation of therapy. Other less frequently occurring adverse effects are increased alkaline phosphatase, total bilirubin concentration, prothrombin time, and pancreatitis. In 2010, the Food and Drug Administration suggested that Tigecycline has a higher mortality rate than other antibiotics. However, high mortality is associated with lower success rates rather than the adverse effects of the drugs.

What Are the Symptoms and Signs of Liver Disease?

Patients with mild liver disease may exhibit few or no symptoms. Those with more serious conditions may develop nonspecific or specific symptoms. Nonspecific symptoms, which can occur in various disorders, include:

• Loss of appetite.

• Fatigue.

• Vague abdominal pain.

• Weakness.

Specific symptoms and signs of liver disease include:

• Yellowing of the skin (jaundice) is caused by the accumulation of bilirubin in the blood.

• Itching.

• Easy bruising.

Severe, advanced liver disease with cirrhosis can lead to symptoms and signs specific to cirrhosis, including:

• Fluid accumulation in the abdomen (ascites) and legs (edema) is due to increased pressure in the liver's blood vessels.

• Gastrointestinal bleeding due to varices (enlarged blood vessels in the esophagus or stomach).

• Mental confusion or coma (hepatic encephalopathy) is caused by increased ammonia levels.

• Increased susceptibility to bacterial infections.

• Kidney failure.

Why Is Tigecycline Prescribed?

Tigecycline injections are used for the treatment of infections like:

• Community-acquired pneumonia.

• Skin infections.

• Infections of the abdomen.

Tigecycline is not used to treat pneumonia in people on a ventilator or people with foot infections who have diabetes.

Does Tigecycline Cause Injury to the Liver?

Tigecycline can cause mild, transient aminotransferase level elevations in 2-5% of patients. Rare cases of significant hepatic dysfunction, cholestasis, and jaundice have been reported, often linked to multiorgan failure and sepsis rather than drug-induced hepatotoxicity.

How Does Tigecycline Cause Liver Injury?

The reason why the serum enzyme elevates during Tigecycline intravenous therapy is still unknown. Intravenous Tigecycline therapy given in high doses causes severe direct hepatic injury, including microvesicular steatosis, lactic acidosis, and hepatic failure. This can be due to direct mitochondrial injury, similar to Reye's syndrome.

A minimal amount of metabolism takes place in the liver, and Tigecycline is excreted as it is in the bile, feces, and urine; therefore, it does not cause any liver injury.

How Is the Duration of Tigecycline Treatment Associated With the Risk of Liver Injury?

The mechanism by which Tigecycline produces cholestatic liver injury is not clear. Tigecycline will increase hepatic fatty acid uptake and can induce steatosis. It has also been reported that the various tetracycline derivatives could lead to extensive microvesicular steatosis of the liver by inhibiting mitochondrial respiration. The side effects are observed more frequently in the high-dose group than in the approved-dose group.

It has been reported that the pharmacokinetics of Tigecycline in serum have a long half-life and a large volume of distribution. The excretion of unchanged Tigecycline through feces is the primary route of elimination that can be related to biliary passage function. Tigecycline accumulated in vivo after high dose application on a slow metabolism, and then it may activate immune-mediated bile duct injury with hyperbilirubinemia and markedly increased alkaline phosphatase.

A high dose of Tigecycline treatment is one of the factors leading to the occurrence of adverse side effects. Consequently, it is suggested that liver function and bilirubin indicators should be closely monitored in patients receiving Tigecycline, especially if high doses and prolonged therapy are given. Therefore, maintaining diligent monitoring and keen insight is required. Doctors should pay particular attention to a high maintenance dose and prolonged Tigecycline dosage, as well as the associated use of drugs causing hepatotoxicity.

How to Diagnose Drug-Induced Liver Injury (DILI)?

The drug-induced liver injury occurs when serum alanine transaminase is five times more elevated than the upper limit of normal (ULN) or alkaline phosphatase elevation is two times the upper limit of normal. The alanine transaminase level reaches the upper limit of normal thrice, with the elevation of bilirubin twice more excellent high as the upper limit of normal.

Hepatitis types of liver injury are defined by using the R-value (R = ALT ULN/ALP ULN).

If R ≥ 5 indicates hepatocellular injury, while R < 2 indicates cholestatic injury, an R-value between two and five suggests a mixed type of injury.

How to Treat Drug-Induced Liver Injury?

• In the case of Tigecycline, no dose adjustment is required in patients with mild to moderate hepatic impairment. However, in patients with severe hepatic impairment, aminotransferase elevations that rise above five times the upper limit of normal or are accompanied by jaundice or symptoms should have Tigecycline stopped, or the dosage of Tigecycline should be altered to 25 mg every 12 hours.

• Once a drug-induced liver injury is suspected in a patient, the drug taken by the patient should first be monitored. At the same time, it should also be discontinued if no positive results are obtained by monitoring the dosage. It is highly important to assess the severity of the cholestatic liver injury. Ursodeoxycholic acid (UDCA) and S-adenosyl-L-methionine are widely used for cholestatic liver injury.

• Patients with liver cirrhosis should be monitored during Tigecycline therapy for evidence of severe hepatic dysfunction. Patients on intravenous Tigecycline who develop sucrose-sensitivity to hepatic injury among the various tetracyclines are not known, but switching to another class of antibiotics would be more appropriate than changing to another tetracycline-like agent in patients who develop evidence of liver injury while receiving Tigecycline.

Conclusion

Tigecycline treats community-spread pneumonia and skin, tissue, and abdomen infections. The dose of Tigecycline is 50 mg intravenously after a 100 mg loading dose every 12 hours. The mechanism that causes liver injury could be related to the pharmacokinetics and esterification of Tigecycline. The high dose of Tigecycline treatment is one of the factors leading to the occurrence of adverse side effects. A high mortality rate is associated with lower success rates rather than the adverse effects of the drugs.

Consequently, it is suggested that indicators, both liver function and bilirubin, should be monitored properly in patients receiving Tigecycline, especially if high doses and prolonged therapy are required.