Correspondence

Hepatotoxicity of Saccharin

N Engl J Med 1994; 331:134-135July 14, 1994

Article

To the Editor:

Saccharin is not known to alter liver function1-4. We report on a patient who had elevated serum concentrations of liver enzymes after the oral administration of three different drugs, of which saccharin was the only common constituent. Reexposure to pure saccharin supported its role in the pathogenesis of liver damage in this patient.

A 70-year-old woman being evaluated for chronic fatigue was found to have increased levels of serum aspartate aminotransferase (306 U per liter), alanine aminotransferase (247 U per liter), γ-glutamyltransferase (1000 U per liter), and alkaline phosphatase (478 U per liter). The patient had taken 1 mg of lorazepam daily for one year for chronic anxiety but said that she did not abuse alcohol. During the preceding two weeks, she had taken an oral solution of dihydroergocristine because of occasional dizziness and vertigo. Tests for hepatitis B and C infection and for autoimmune diseases were negative, as was an ultrasonographic examination of the liver.

The dihydroergocristine was discontinued, and her serum liver-enzyme concentrations declined (Figure 1Figure 1Serum Liver-Enzyme Concentrations in a Woman after Exposure to Saccharin.) but then increased again when she resumed dihydroergocristine therapy. The medication was again discontinued, and an oral solution of chlordemethyldiazepam was prescribed. Her serum liver-enzyme concentrations increased again. Since the only constituent that the two medications have in common is a sweetener (sodium saccharin), the patient was asked not to take any drug or food containing saccharin.

After the patient's serum liver-enzyme values had returned to normal (except for γ-glutamyltransferase) and after we obtained institutional approval for the study and the consent of the patient, she was given 12.5 mg of pure sodium saccharin daily for five days. Her serum liver-enzyme concentrations rose again after a week, reaching a peak one month later. The close temporal relation between the administration of saccharin-containing drugs and hepatic dysfunction, as well as its recurrence after rechallenge, indicates that saccharin caused the patient's hepatic dysfunction5.

The pathogenesis of saccharin hepatotoxicity in this patient is obscure. Symptoms or signs suggestive of hypersensitivity were absent. Saccharin is not metabolized in vivo, being eliminated in an almost unmodified form (and almost exclusively) in the urine,2 and it does not accumulate in the liver2. The small amount of saccharin (never exceeding 16 mg daily) taken by our patient underscores the idiosyncratic nature of the reaction.

Francesco Negro, M.D.
Alessandra Mondardini, M.D.
Franco Palmas, M.D.
Molinette Hospital, 10126 Torino, Italy

5 References

1. 1

   Arnold DL. Toxicology of saccharin. Fundam Appl Toxicol 1984;4:674-685
   CrossRef | Medline

2. 2

   Saccharin: current statusFood Chem Toxicol 1985;23:417-546
   CrossRef | Web of Science | Medline

3. 3

   Kumar A, Weatherly MR, Beaman DC. Sweeteners, flavorings, and dyes in antibiotic preparations. Pediatrics 1992;87:352-360
   Web of Science

4. 4

   Golightly LK, Smolinske SS, Bennett ML, Sutherland EW III, Rumack BH. Pharmaceutical excipients: adverse effects associated with `inactive' ingredients in drug products. Med Toxicol Adverse Drug Exp 1988;3:209-240
   Medline

5. 5

   Benichou C. Criteria of drug-induced liver disorders: report of an international consensus meeting. J Hepatol 1990;11:272-276
   CrossRef | Web of Science | Medline

Citing Articles (3)

Citing Articles

1. 1

   Christina R. Whitehouse, Joseph Boullata, Linda A. Mccauley. (2008) The Potential Toxicity of Artificial Sweeteners. AAOHN Journal 56:6, 251-259
   CrossRef

2. 2

   Romain Gloro, Isabelle Hourmand-Ollivier, Brigitte Mosquet, Laurent Mosquet, Pierre Rousselot, Ephrem Salam??, Marie-Astrid Piquet, Th??ng Dao. (2005) Fulminant hepatitis during self-medication with hydroalcoholic extract of green tea. European Journal of Gastroenterology & Hepatology 17:10, 1135-1137
   CrossRef

3. 3

   &NA;. (1994) Saccharin causes liver dysfunction. Reactions Weekly &NA;:511, 2
   CrossRef