Drug-Induced Liver Injury Caused by Capecitabine: A Case Report and a Literature Review

Chemotherapy is a backbone in the treatment of metastatic breast cancer and most patients will receive chemotherapy at some point during their disease course. When starting a new treatment, the choice of drug relies on HER-2 status, estrogen receptor status, and other factors such as age and performance status. With chemotherapy, there is not one specific chemotherapeutic drug that is considered first-line therapy, as it depends on numerous factors such as previous treatment, toxicity, performance status, comorbidity, and patient preference. One of the widely used drugs in the treatment of metastatic breast cancer is Capecitabine. Capecitabine is usually well-tolerated and can also be used in the treatment of vulnerable/fragile patients. Presented in this article is an uncommon reaction in a typical breast cancer patient receiving Capecitabine who developed an unforeseen severe acute liver injury, followed by a review of the literature concerning severe liver toxicity due to treatment with Capecitabine.

A 63-year-old female, initially diagnosed in 2015 with invasive ductal carcinoma in the right breast, had a tumor which was ER positive and HER-2 normal. She was treated with mastectomy and received adjuvant treatment with Epirubicin, Cyclophosphamide, and Docetaxel but received only 3 courses due to severe side effects. She then had standard radiotherapy and started adjuvant Letrozole treatment in 2016, which was discontinued in 2017 due to adverse effects. The patient had a relapse of her breast cancer in 2019 with metastasis to the lungs and pleurae. The patient then began treatment with Letrozole and Ribociclib. Unfortunately, already after 3 months, CT scans showed progression of the disease. Subsequently, the patient started Capecitabine treatment, however, in a reduced dose due to previous toxicity to anticancer drugs. She received the first cycle of Capecitabine, and when she came for the appointment for the second cycle, she presented with elevated levels of lactate dehydrogenase of 298 U/L (105–205 U/L) and alanine aminotransferase (ALT) of 360 U/L (10–45 U/L). The second cycle of Capecitabine was consequently canceled due to the elevated liver enzymes. At this stage, the patient presented no symptoms other than mild discomfort and achiness under the right curvature. In the following 8 weeks, the liver enzyme levels continued to increase to a maximum of lactate dehydrogenase 376 U/I and ALT 1,217 U/I. Furthermore, bilirubin levels increased to a maximum of bilirubin at 67 μmol/L (5–25 μmol/L) and alkaline phosphatase of 302 U/I (35–105 U/L). At this time, the performance status of the patient was noticeably and severely declining, and several additional new symptoms occurred including nausea, increased fatigue, and discolored urine and stool. The declining performance status and evolving symptoms showed a manifest acute hepatitis. The clinical regression of the patient still progressed after the patient stopped Capecitabine intake, and the symptoms were not alleviated until approximately 2 months later. Several diagnostic tests were performed including testing for viral hepatitis, EBV, and CMV which were all negative, and blood tests containing immunoglobulins, smooth muscle antibody, and mitochondrial antibody, which were also within normal range. A mutation in the dihydropyrimidine dehydrogenase (DPYD) gene was also considered as this mutation has been found to lead to a significant increase in the toxicity due to Capecitabine. A gene sequencing test was performed that ruled out the presence of this mutation.

Additionally, an ultrasound of the bile ducts was performed to rule out bile duct obstruction as a cause of the elevation of enzyme levels. However, there were no pathological findings at the ultrasound examination. Furthermore, a contrast enhanced CT scan was performed to rule out hepatic or portal vein thrombosis which showed no pathological findings. Of note, the patient had no alcohol use, nor did she receive other medications that could have led to liver function abnormalities. A liver biopsy was then performed, and the pathological report was consistent with acute drug-induced liver injury (DILI) – toxic hepatitis. The Roussel Uclaf Causality Assessment Method (RUCAM) is a method used to assess the association between a certain drug and liver injury [1]. This patient had a RUCAM score of 7 implying that the patient falls into the “probable” category meaning that this liver injury could be caused by Capecitabine treatment. Furthermore, the patient had a Naranjo score of 6 which again implies that this liver injury and its association to Capecitabine falls into the “probable” category [2].

Within 2–3 months after the Capecitabine dose was administered, the condition of the patient slowly improved, and the enzyme levels spontaneously started to decrease, ultimately reaching normal levels. Afterward, the patient restarted chemotherapy with the drug Eribulin in a reduced dose which was well-tolerated with no complications and with no signs of liver toxicity. This treatment was continued for 12 cycles after which the patient started treatment with Paclitaxel instead due to progression of the disease.

Capecitabine is an orally administered chemotherapeutic prodrug that will be converted to the active metabolite Fluorouracil (FU) primarily in the liver and in the tumor cells. In the liver, Capecitabine converts to 5′-deoxy-5-fluorocytidine (5′-DFCR) after which it converts to 5′-deoxy-5′-fluorouridine (5′-DFUR) by the enzyme cytidine deaminase. Once converted to 5′-DFUR in the liver, it is further metabolized with the help of thymidine phosphorylase to 5-FU in both tumor cells and normal cells [3]. After conversion to FU, it further metabolizes to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP) in both tumor and normal cells. The mechanism of these two active metabolites is the inhibition of the DNA, RNA, and protein synthesis by reducing thymidine production and competing with uridine triphosphate, thereby decelerating tumor growth [3]. For 5-FU to be effectively metabolized and cleared, DPYD plays an important role as a key enzyme in clearing the drug. A mutation in the gene coding for DPYD will result in increased accumulation of the drug and subsequently increased toxicity [4].

Capecitabine has an antineoplastic effect once converted to 5-FU and is primarily used for the treatment of metastatic breast and colorectal cancer [5]. It is absorbed in the gastrointestinal tract with the highest plasma concentration of fluorouracil and Capecitabine after 1.5–2 h. The drug has an elimination half-life of 45–60 min and is almost exclusively excreted in the urine [5].

Capecitabine has several side effects. The most frequently seen are diarrhea, nausea, vomiting, reduced appetite, abdominal pain, stomatitis, fatigue, and hand-foot syndrome [6]. Less frequently observed side effect is moderate hepatic impairment in the form of moderately elevated bilirubin, and/or other liver function test abnormalities without clinical signs of hepatitis. Additionally, other less frequently observed side effects include anemia, neutropenia, headache, fever, weight loss, hyperbilirubinemia, conjunctivitis, back pain, alopecia, dyspnea, and dryness of mouth [6].

Rarely seen side effects in patients receiving Capecitabine treatment include angina pectoris, arrhythmias, myocardial ischemia, ear pain, ascites, blurred vision, allergic reactions, bone pain, diabetes mellitus, vaginal bleeding, pneumothorax, pancytopenia, hydronephrosis, and hematuria [6]. Several reports have shown that patients with DPYD deficiency tend to develop more severe toxic adverse effects compared to those with normal levels of the enzyme [4, 6]. Additionally, other unusual side effects documented in case reports include a 40-year-old woman receiving Capecitabine and Oxaliplatin and developing acute pancreatitis, a 45-year-old woman receiving Capecitabine and developing swelling around eyes and lips, hyperpigmentation and muscle weakness, and finally, two breast cancer patients with metastatic disease developing Capecitabine-induced ileitis [4, 7, 8].

For this report, a literature search was performed based on the Pubmed database. References were identified by searching for records dating back to the year 2000. Only reports in English language were included. Initially, the following terms were used: “Capecitabine,” “liver injury,” “liver toxicity,” “hepatitis” and “toxic hepatitis.” The reference lists in the identified reports were hand-sorted to supplement the first search. Additionally, new searches were made to find articles covering broader subjects by using search words “Drug-induced,” “toxicity,” “chemotherapy,” and “Side effects.” This new search was made to ensure that no relevant studies were overlooked as the first search yielded only few results, Figure 1. Of the results from the searches “Capecitabine induced liver injury” and “Chemotherapy-induced liver toxicity,” some articles were excluded if the studies included patients with liver metastases or if the chemotherapeutic drug in question in fact was not Capecitabine or 5-Fluorouracil either as monotherapy or in combination with another drug. The reason for this was that patients with liver metastases could have an affected liver function due to the metastatic involvement, while if the patients received other chemotherapeutic drugs the effect of the individual drug could not be estimated. While liver metastasis does not rule out development of DILI and might contribute to it, the aim of this case report was to investigate DILI in patients without liver metastasis receiving Capecitabine. This left us with five reports which could be included in our review, descripting a total of 43 patients (shown in Table 1) [9‒13]. The studies reported only mild to moderate hepatic injury after Capecitabine treatment including hepatic steatosis and moderately elevated liver enzyme levels as a response to Capecitabine.

The case presented here is an unusual case of a patient experiencing severe liver toxicity and clinical signs of severe hepatitis due to Capecitabine treatment. The patient had no adverse effects from Capecitabine other than the observed severe liver toxicity. Other explanations for this severe liver toxicity were ruled out and the diagnosis of DILI was confirmed by liver biopsy. In the literature, only a few case reports are found that present moderate liver toxicity with an increase in ALT, aspartate aminotransferase, bilirubin, and alkaline phosphatase, although none of these cases reported liver affection as critical as seen in our case. The literature indicates that other chemotherapeutic agents tend to increase liver enzyme levels as well as affect the structure of the liver. Drugs such as Methotrexate have been shown to be associated with an increased risk of liver injury but mainly as hepatic steatosis [14]. 5-FU has been associated with the development of fatty liver. However, in this case, a biopsy showed DILI with no signs of hepatic steatosis. Additionally, several diagnostic tests were performed, including a negative gene sequencing test for a DPYD-mutation, to rule out other causes. Ultimately, the biopsy confirmed the diagnosis of idiosyncratic DILI without other pathological findings. When reviewing the literature, no similar cases of a severe acute reaction to Capecitabine have been reported. It is important to emphasize that there are different types of DILI which include hepatocellular, cholestatic, and mixed pattern. The patient in this case was affected by a mixed pattern DILI, which may not always be the case depending on the class of medication in question. DILI can be further classified into type A and B. Type A is dependent on the dose whereas type B is dose independent. Concerning the patient in this case report, the type of DILI was dose independent meaning the patient developed a type B reaction. Different classes of medication, other than cytostatic drugs, can result in DILI as is seen in a case report concerning antibiotic-induced liver injury [15].

This case stands out in comparison to other cases of Capecitabine associated liver injury, as there is not only a severe increase in liver enzyme levels, a biopsy-verified DILI, as well as a critically affected patient with clinical symptoms of DILI. The fact that the patient did not show other adverse effects from Capecitabine contributes to the rarity of this case, as most patients with hepatic injury caused by chemotherapy have other side effects along with the liver injury. This case report aims to bring attention to an unusual acute liver injury due to Capecitabine treatment. It emphasizes the importance of monitoring the liver enzyme levels of patients receiving Capecitabine as the toxicity seen in our case could have led to a fatal outcome. This rare reaction to Capecitabine could also be misinterpreted as a sign of progression that would prevent the patient from receiving the necessary acute care. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000529866).

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Ethical approval is not required for this study in accordance with local and national guidelines.

The authors have no conflicts of interest to declare.

The manuscript was not funded.

Miriam Hussein and Anders Bonde Jensen have contributed equally to this article.

As this is a case report the data provided in the article originate from the patient’s electronic medical journal which is not accessible for public use. The data that support the findings of this case report are not available on legal and ethical grounds. All data that support the findings of this study are included in this article. Further inquiries can be directed to the corresponding author.