Editor's Note: Cholestatic drug-induced liver injury (DILI) is a drug-induced condition characterized primarily or prominently by intrahepatic cholestasis, featuring clinical, biochemical, and histopathological evidence. It is a relatively common and serious adverse drug reaction that can lead to acute liver failure and even death, affecting the clinical application of medications. In recent years, significant breakthroughs in targeted and immunotherapy for cancer have markedly improved the prognosis and survival of patients with malignancies. However, liver injury caused by antitumor drugs, particularly cholestatic DILI, has become a major clinical concern. Recently, at the 8th International Forum on Drug-Induced Liver Injury and the 9th National Conference on Drug-Induced Liver Injury, Professor Enqiang Chen from West China Hospital of Sichuan University, delivered an outstanding report on cholestatic DILI, which is summarized below for our readers.Introduction: Antitumor Drugs and Liver Injury
Professor Chen began by addressing four liver-related issues of concern to oncologists, using detailed data to reveal that while antitumor drugs effectively target tumor cells, they inevitably cause damage to normal cells, a key cause of DILI. Common culprits include conventional chemotherapy drugs, tyrosine kinase inhibitors (TKIs), and immune checkpoint inhibitors (ICIs). Patients with DILI suffer from impaired liver function, necessitating a reduction in the intensity of antitumor treatment, which not only affects the efficacy of cancer therapy but also overall survival of the patients.
Definition and Diagnosis of Cholestasis Related to Antitumor Drugs
Professor Chen explained that bile production and excretion involve a complex process, including hepatocytes, bile duct cells, bile acid transport proteins, and various cell surface regulatory receptors. Cholestasis results from intra- or extrahepatic causes that impede bile production or flow, leading to the accumulation of substances that should be excreted into the bile (such as conjugated bilirubin, bile acids, cholesterol, and alkaline phosphatase) in the blood.
Cholestasis is categorized into intrahepatic and extrahepatic types based on its location, and into hepatocellular and cholangiocellular types based on cellular damage. Hepatocellular cholestasis is due to functional defects in bile formation within hepatocytes, where inflammatory cytokines impair bile secretion and inhibit bile acid and bilirubin transport proteins, leading to cholestasis. Cholangiocellular cholestasis results from impaired bile secretion or flow within intrahepatic bile ducts. The incidence of hepatocellular cholestasis is approximately 6.7 times that of cholangiocellular cholestasis.
Cholestatic liver disease can present two pathophysiological models: “ascending” or “bottom-up,” where damage starts from bile duct epithelial cells and extends to hepatocytes, and “descending” or “top-down,” where damage begins from hepatocytes and extends to bile duct cells. Antitumor drugs typically cause primary hepatocellular damage, presenting as descending intrahepatic cholestasis.
Early intrahepatic cholestasis usually lacks specific symptoms but can progress to fatigue, poor appetite, nausea, and upper abdominal discomfort. Severe cases may develop generalized itching and jaundice. In liver disease diagnosis, elevated γ-glutamyltransferase (GGT) and alkaline phosphatase (ALP) levels are complementary. ALP is distributed in the liver, bones, intestines, kidneys, and placenta, while serum GGT primarily comes from hepatocytes and bile duct epithelial cells. Concurrent elevation of ALP and GGT indicates damage to hepatocytes and bile duct cells; elevated ALP without GGT suggests non-hepatic disease. Elevated ALP and GGT are early markers of cholestasis and are recommended by Chinese guidelines for diagnosing intrahepatic cholestasis.
Managing Cholestasis Related to Antitumor Drugs
Professor Chen emphasized the importance of identifying and managing cholestasis in oncology patients. Not all cholestasis cases present with jaundice, and conversely, jaundice or hyperbilirubinemia indicates severe cholestasis, but many early-stage cholestasis patients do not exhibit jaundice.
DILI can be categorized based on initial biochemical abnormalities into hepatocellular, cholestatic, and mixed types. Clinicians should follow proper diagnostic documentation for antitumor drug-related liver injury, including diagnosis naming (chemotherapy, targeted, or immune drugs, or traditional Chinese medicine-induced liver injury), clinical type (hepatocellular, cholestatic, or mixed), course (acute or chronic), RUCAM score (highly probable or probable), and severity.
Treatment Goals and Principles
The primary treatment goals for drug-induced liver injury in cancer patients are removing the cause and managing cholestasis. Discontinuing the causative antitumor drug is critical. For asymptomatic cholestasis patients, symptomatic treatment for elevated ALP and GGT can be administered. For ALP elevation, ursodeoxycholic acid or S-adenosylmethionine may be used.
Professor Chen also highlighted the need to manage symptoms like depression and fatigue in patients with drug-induced cholestasis during treatment. Oncologists should proactively monitor cancer patients for early signs of DILI and take appropriate measures to prevent severe liver injury. Patients should undergo comprehensive serum liver biochemistry tests before, during, and after antitumor treatment. Monitoring frequency should be adjusted based on the drug’s hepatotoxic risk, known patient risk factors, and severity and progression of liver injury. Oncologists should carefully assess the benefit/risk ratio based on baseline or ongoing liver biochemistry results to make clinical decisions regarding antitumor therapy.
In conclusion, recognizing and managing cholestatic DILI associated with antitumor drugs is vital for optimizing cancer treatment outcomes and patient survival.
