A case of severe hepatotoxicity induced by cisplatin and 5-fluorouracil

Abstract

Severe hepatotoxicity from combination chemotherapy with cisplatin and 5-fluorouracil is a rare adverse effect. In this case report, we present a case with severe hepatotoxicity immediately following chemotherapy with cisplatin and 5-fluorouracil. This female patient had previously been treated with this combination with no hepatotoxicity. The elevated liver enzymes quickly normalized after chemotherapy was stopped. There were no specific changes in liver imaging. As hepatotoxicity occurred after repeated administration of cisplatin, we suggest that this hepatotoxicity might represent a case of allergic hepatitis caused by cisplatin. Severe hepatotoxicity should be watched for with repeated administration of cisplatin.

Introduction

Treatment modalities for esophageal cancers include endoscopic submucosal dissection, esophagectomy, radiotherapy, chemoradiotherapy, chemotherapy, and best supportive care [1]. Chemotherapy is used for locally advanced esophageal cancer preceding surgery or for advanced esophageal cancer with distant metastasis [2, 3]. Cisplatin (CDDP) with 5-fluorouracil (5-FU) is often used as a standard chemotherapeutic regimen. Although this regimen sometimes causes mild hepatotoxicity, no severe hepatotoxicity has been reported [4].

Here, we report a very rare case of severe liver damage, possibly allergic hepatitis induced by CDDP + 5FU therapy.

Case report

A 59-year-old woman was referred to hospital with complaints of chest and pharyngeal discomfort. She had a past history of ovarian cancer treated by surgery and 13 cycles of adjuvant chemotherapy with a combination of paclitaxel and carboplatin. Cancer of the esophagogastric junction was found, classified as stage III (cT3N1M0) based on upper gastrointestinal endoscopy and computed tomography (CT). She received two cycles of neoadjuvant chemotherapy (NAC), with the combination of 5-FU (continuous infusion of 5-FU, 800 mg/m²/day on days 1–5) and CDDP (CDDP, 80 mg/m² on day 1), resulting in a partial response. No liver toxicity was observed during chemotherapy. She underwent esophagectomy after NAC. We will present the pathological image at that time (Fig. 1).

Fig. 1.

Pathology of esophageal cancer

After 1 year of follow-up, she received 66 Gy radiotherapy because of a relapse in one mediastinal lymph node. However, other suspicious lymph node metastases were detected by positron emission tomography–CT after radiotherapy. She was re-admitted to hospital and combination chemotherapy comprising 5-FU (days 1–5) and CDDP (day 1) was resumed, as with her NAC. Laboratory data acquired before chemotherapy showed normal values (Table1, Fig. 2).

Table 1.

Changes in blood count and biochemical test values

Day	Before chemotherapy	2	3	5	8	26
WBC (/μL) (3300–8600/μL)	3050	3080	7390	3290	2460	1580
Neutrophils (%) (38–71%)	77.4	84.8	89.6	78.7	70.4	67.8
Eosinophils (%) (7.3%)	2.3	0	0	0.3	2.4	2.5
Platelets × 104 (/μL) (15.8–34.8 × 104/μL)	15.1	14.4	16.3	13.2	17.4	13
CRP (mg/dL) (0.14 mg/dL)	0.8	0.11	–	–	–	0.2
AST (U/L) (13–30 U/L)	30	1193	280	50	21	24
ALT (U/L) (7–23 U/L)	25	778	434	202	102	23
ALP (U/L) (106–322 U/L)	309	493	435	335	342	306
γ-GT (U/L) (9–32 U/L)	19	87	72	60	61	29
Total bilirubin (mg/dL) (0.4–1.5 mg/dL)	0.5	0.9	0.8	0.6	0.6	0.5
Creatinine (mg/dL) (0.46–0.79 mg/dL)	0.54	0.47	0.49	0.47	0.49	0.53
BUN (mg/dL) (8–20 mg/dL)	8	11	18	8	8	10
NH3 (µg/dL) (12–66 µg/dL)	–	–	49	–	–	–

Values in the parentheses refer to the hospital reference value

Fig. 2.

Changes in AST and ALT levels after chemotherapy

On day 2, she complained of malaise and her consciousness was impaired (I-1 on the Japan coma scale) on the morning round. Blood tests on day 2 showed grade 4 dramatic elevation of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (1193 and 778 IU/L, respectively,) (Fig. 2) [5]. In contrast, other hepatic laboratory values including the serum alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (γ-GT), albumin, and total bilirubin were in the normal range (Fig. 2) (Table 1). Serum ammonia on day 3 was 43 µg/dl, within the normal range. Although HBc antibody testing was positive, HBV reactivation was not observed. In addition, abdominal ultrasound examination showed no significant findings. Other laboratory tests were also in the normal range as shown in Table 1. Chemotherapy was discontinued on day 2 because of the marked AST and ALT elevation. As there was no HBV reactivation, liver imaging was normal, and there was a history of previous carboplatin and CDDP administration, she was diagnosed as having possible allergic hepatitis induced by CDDP.

She was treated with corticosteroids (dexamethasone sodium phosphate, 8 mg on day 2, 4 mg on days 3 and 4) and monoammonium glycyrrhizinate from days 2–8. Elevated serum AST and ALT values rapidly improved (Fig. 2), in parallel with improvement in her performance status over time. No other allergic reaction was observed during and after chemotherapy.

She was discharged on day 8 based on improvements in her hepatic laboratory data.

Discussion

In this case report, we presented a case of severe hepatotoxicity immediately following CDDP + 5FU infusion, although no liver damage was observed with previous combination chemotherapy using CDDP + 5-FU.

The combination of CDDP and 5-FU is widely used, mainly for gastrointestinal tumors like esophageal cancer [1]. Although this combination often causes hepatotoxicity, none of the clinical trials of the combination of CDDP and 5-FU reported liver toxicity over grade 3 [2–4, 6, 7]. By inhibiting thymidylate synthase, 5-FU inhibits DNA synthesis, thus showing antitumor effects. Elevation of the liver enzymes AST and ALT occurs in up to 70% of patient treated with 5-FU [8]. This elevation is usually mild and transient, and may be associated with hepatic steatosis [9]. Severe hepatotoxicity from 5-FU is rare. One patient died due to severe liver damage 4 days after starting intravenous infusion of 5-FU [10]. Autopsy showed massive centrilobular necrosis due to an unknown mechanism. Continuous, high-dose infusions of 5-FU also cause hyperammonemia in some patients without elevation of liver enzymes [11]. However, our case showed mildly impaired consciousness, without hyperammonemia.

Common side effects of CDDP include, nausea, vomiting, nephrotoxicity, electrolyte imbalance, and neuropathy. CDDP has been reported to be associated with infrequent liver enzyme elevation [12]. This elevation was usually mild, transient, and asymptomatic, as with 5-FU.

Severe adverse effects of CDDP were reported in cancer patients with xeroderma pigmentosum (XP) [13]. Adverse effects in XP patients included grade 4 liver enzyme elevation as with our case. However, this liver enzyme elevation could be attributed to impaired DNA repair, the genetic defect present in XP patients. Searching the literature, we found another case report of lethal hepatotoxicity following 5-FU + CDDP therapy. This case was a homozygous carrier of the T variant of the MTHFR gene that encodes methylenetetrahydrofolate reductase. Methylenetetrahydrofolate reductase is important for chemical reactions that involve forms of the vitamin folate, and was reported to be associated with 5-FU toxicity [14]. These two cases had genetic defects associated with anti-cancer drugs. These genetic defects could not be relevant to our case, who showed no severe toxicity from prior combination chemotherapy using CDDP + 5-FU.

Our case underwent repeated platinum-based chemotherapy including CDDP + 5-FU and carboplatin + paclitaxel before her episode of severe hepatotoxicity. We can thus exclude an inherited reason for severe hepatotoxicity. Hypersensitivity reactions have been widely recognized in patients receiving platinum compounds [15]. Symptoms of hypersensitivity include cardiovascular, respiratory, and skin reactions, but not liver enzyme elevation. Drug-induced allergic hepatitis is a rare, liver-specific inflammatory reaction due to hypersensitivity to specific medications such as antiretrovirals [16, 17]. Our case received repeated platinum-containing chemotherapy and presented with grade 4 AST and ALT elevation alone, and rapid improvement following corticosteroid treatment. Regarding crossover hypersensitivity of carboplatin and CDDP, many cases have been reported regardless of the administration sequence [18, 19]. Since prompt improvement of liver injury and repeated administration of platinum, severe liver injury in this case should be related with hypersensitivity caused by multiple doses of platinum.

Although we have no direct evidence of allergic hepatitis, we suggest that severe hepatotoxicity in our case might have been caused by allergic hepatitis due to CDDP.

In conclusion, we have presented a case of severe hepatotoxicity from combination chemotherapy with CDDP and 5-FU, despite the absence of hepatotoxicity during previous CDDP + 5-FU chemotherapy. We should be aware that repeated treatment with platinum may cause severe hepatotoxicity.

Funding

None.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.