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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: February 2, 2018.



Fluorouracil (5-FU) is a pyrimidine analogue used as an antineoplastic agent to treat multiple solid tumors including colon, rectal, breast, gastric, pancreatic, ovarian, bladder and liver cancer. Fluorouracil is associated with a low rate of transient serum aminotransferase elevations during therapy and has been implicated in rare cases of clinically apparent acute liver injury.


Fluorouracil (floo" oh ure' a sil) is a fluoropyrimidine that has antineoplastic action against several solid tumors including breast and colon cancers. Fluorouracil is believed to block thymidylate synthase and decrease production of thymidylate, a necessary precursor of DNA. This action interferes with the synthesis of DNA, RNA and protein and blocks cell division. Fluorouracil was approved for use as an anticancer agent in the United States in 1962 and is currently used as an important component of several anticancer drug regimens. Fluorouracil is typically combined with leucovorin (folinic acid) which also inhibits thymidylate synthase, thus enhancing the effects of fluorouracil. Current indications for fluorouracil with leucovorin include palliative therapy of advanced breast, bladder, colon, rectum, liver, pancreas and stomach cancer. Fluorouracil is available in various sized vials of 50 mg/mL generically and under several brand names including Adrucil and Carac. The typical recommended dose is 12 mg/kg given intravenously daily for 4 days and, if tolerated, again on days 6, 8 and 12 as a part of 30 day cycles of chemotherapy. In addition, fluorouracil has been used as a continuous hepatic arterial infusion in management of hepatic metastases from colorectal and other cancers. Fluorouracil is also available topically in creams and solutions for therapy of actinic keratoses and basal cell cancers. Common side effects of intravenous therapy include bone marrow suppression, fatigue, weakness, headache, dizziness, insomnia, paresthesias, abdominal pain, constipation, diarrhea, dyspepsia, nausea, stomatitis, rash, and hand-foot syndrome.


Several forms of hepatotoxicity have been associated with fluorouracil therapy. Serum aminotransferase elevations occur in up to 70% of patients treated with cyclic courses of fluorouracil, the rate of abnormalities being partially dose related. The aminotransferase elevations are usually transient and mild, are not commonly above 5 times the upper limit of normal and rarely associated with symptoms. The elevations may be associated with hepatic steatosis, which can be demonstrated by hepatic imaging and has been confirmed by liver biopsies that show variable degrees of macrovesicular steatosis and portal inflammation. The injury rarely leads to clinically apparent liver injury. Isolated case reports of clinically apparent acute liver injury with jaundice attributed to fluorouracil have been published, but such cases are rare and the relatedness to fluorouracil remains unclear. Intrahepatic artery infusion of fluorouracil is also associated with serum aminotransferase elevations or chemical hepatitis (in 5% to 7% of cases) and in biliary abnormalities, but it rarely causes biliary strictures or the sclerosing cholangitis-like syndrome that is common with floxuridine (FUDR) treatment. In systematic reviews of the literature, biliary strictures suggestive of sclerosing cholangitis have occurred in <1% of patients treated with hepatic arterial infusions of fluorouracil as compared to 5% to 12% of those given floxuridine. Infusions of fluorouracil can also result in marked shrinkage of metastatic tumors in the liver and partial atrophy of the noninvolved liver, resulting in an irregular lobular appearance suggestive of cirrhosis.

A separate and distinct syndrome associated with fluorouracil therapy is the rapid development of coma with hyperammonemia, lactic acid elevations and respiratory alkalosis that occurs most frequently with continuous infusions of high doses of fluorouracil. The onset is generally within 1 to 2 days of starting infusions and is marked by progressive confusion and stupor followed by coma. Standard liver tests such as ALT, AST, alkaline phosphatase and bilirubin are usually normal, but plasma ammonia levels are high (generally >250 μg/dL) and accompanied by varying degrees of respiratory alkalosis, elevations in serum lactate and azotemia. Infectious complications are common, but most patients recover rapidly with hydration and supportive care. Patients who develop this syndrome can later tolerate lower doses of fluorouracil, but recurrences have been reported. The mortality rate is approximately 10%, most deaths being due to sepsis rather than hepatic failure. The cause of the syndrome is not known, but it is associated with higher doses of chemotherapy. This syndrome has not been reliably linked to other pyrimidine analogues such as capecitabine.

Likelihood score: A (well known cause of clinically apparent liver injury).

Mechanism of Injury

While severe hepatotoxicity from fluorouracil may be rare, when it occurs it is likely due to direct or intrinsic hepatotoxicity. The injury may be caused by inhibition of thymidylate synthase. In addition, fluorouracil is extensively metabolized in the liver via the microsomal enzyme system, and production of a toxic intermediate may trigger liver injury. The hyperammonemic coma that occurs with high dose infusions of fluorouracil is likely due to inhibition of mitochondrial function, which may be particularly clinically manifest in persons with an underlying, inherited but subclinical mitochondrial enzyme defect. However, fluorouracil readily crosses the blood-brain barrier and some of the toxicity may be due to a direct effect on the central nervous system.

Outcome and Management

The severity of the liver injury linked to fluorouracil therapy is generally mild. Fluorouracil has not been linked to cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome. There is no information on cross sensitivity to hepatic injury between fluorouracil and other pyrimidine analogues.

Drug Class: Antineoplastic Agents

Other Drugs in the Subclass, Pyrimidine Analogues: Azacitidine, Capecitabine, Cytarabine, Decitabine, Floxuridine, Gemcitabine, Trifluridine/Tipracil


Case 1. Hyperammonemic coma due to fluorouracil.

[Modified from: Advani PP, Fakih MG. 5-FU-induced hyperammonemic encephalopathy in a case of metastatic rectal adenocarcinoid successfully rechallenged with the fluoropyrimidine analog, capecitabine. Anticancer Res 2011; 31: 335-8. PubMed Citation]

A 70 year old woman with metastatic colorectal cancer developed confusion and coma 2 days after a second course of fluorouracil, leucovorin and bevacizumab. She had been treated in the previous year with combination chemotherapy, including fluorouracil (2 g/m2), folinic acid, oxaliplatin and bevacizumab as 46 hour continuous infusions every 2 weeks. Because of gastrointestinal toxicity, the chemotherapy was discontinued, but repeat imaging suggested disease progression and she was restarted on fluorouracil, folinic acid and bevacizumab. Two days after finishing the second cycle of this modified regimen, she developed nausea, vomiting, weakness, diarrhea and confusion. Her mental status deteriorated and she developed coma. She had no known history of liver or neurologic disease. Her other medications included atenolol, hydrochlorothiazide, omeprazole, dexamethasone, warfarin, aprepitant and multivitamins. Laboratory tests showed normal complete blood counts and electrolytes. The serum bilirubin was 0.6 mg/dL, ALT 50 U/L, AST 54 U/L and alkaline phosphatase 79 U/L (all within the normal range). Serum ammonia, however, was markedly elevated at 203 μmol/L (normal 11-51). Computerized tomography of the head was normal. She was treated with supportive care and serum ammonia levels fell into the normal range within 24 hours. She improved clinically and was discharged. In follow up, fluorouracil and leucovorin were stopped and she was treated with capecitabine and bevacizumab. She had no recurrence of symptoms and plasma ammonia levels remained normal on multiple occasions.

Key Points

Medication:Fluorouracil (2.4 g/m2 daily as 46 hour infusions)
Latency:3-4 days
Recovery:Complete within 24 to 48 hours
Other medications:Leucovorin, bevacizumab, atenolol, hydrochlorothiazide, omeprazole, warfarin, multivitamins


An elderly woman with advanced, metastatic colorectal cancer developed hyperammonemic coma within a few days of starting a second cycle of fluorouracil with leucovorin and bevacizumab. Although she had metastatic liver disease, all liver tests were normal. Lactic acid levels and arterial blood gases were not reported. As in other cases of hyperammonemic coma due to fluorouracil, however, recovery was rapid even with simple supportive therapy including hydration and monitoring. In many instances, there is recurrence if fluorouracil is restarted. This report was important in that capecitabine (a prodrug of fluorouracil) therapy was not associated with recurrence. The cause of the hyperammonemia is unknown, but it is likely from the liver rather than brain, and is probably due to direct inhibition of mitochondrial function and urea cycle enzyme activity by the pyrimidine analogue. Dehydration may play an accessory role in this syndrome.



Fluorouracil – Generic, Adrucil®, Carac®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Fluorouracil 51-21-8 C4-H3-F-N2-O2
Fluorouracil Chemical Structure


References updated: 02 February 2018

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    (Among 156 patients with metastatic colorectal cancer undergoing chemotherapy with folinic acid, fluorouracil and irinotecan [FOLFIRI], ALT, AST and Alk P elevations were frequent in a "mixed" pattern causing delay in courses in 16%, decrease in doses in 8% and discontinuation in 2%).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. PubMed Citation. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 49 [5.5%] were attributed to antineoplastic agents, but none to use of fluorouracil).
  • Kusano M, Honda M, Okabayashi K, Akimaru K, Kino S, Tsuji Y, Watanabe M, et al. Randomized controlled Phase III study comparing hepatic arterial infusion with systemic chemotherapy after curative resection for liver metastasis of colorectal carcinoma: JFMC 29-0003. J Cancer Res Ther 2017; 13: 84-90. [PubMed: 28508838]
    (Among 91 patients with metastatic colorectal cancer who received fluorouracil intravenously or by intrahepatic arterial infusion, adverse event rates were similar, but rates of treatment interruption and discontinuation were higher with the direct hepatic artery infusions; no mention of ALT elevations or hepatotoxicity).
  • Guo JH, Zhang HY, Gao S, Zhang PJ, Li XT, Chen H, Wang XD, et al. Hepatic artery infusion with raltitrexed or 5-fluorouracil for colorectal cancer liver metastasis. World J Gastroenterol 2017; 23: 1406-11. [PMC free article: PMC5330825] [PubMed: 28293087]
    (Among 24 patients with metastatic colorectal cancer treated with intraarterial fluorouracil and oxaliplatin, median survival was 15 months and enzyme elevations occurred in 79%, which were above 5 times ULN in 29%).


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