When Is an Indole Not an Indole? To the Editor: An indole is not an indole when it is a naphthalene derivative! We routinely measure 5-hydroxy- indoleacetic acid (5HIAA) by a long- established method using nitroso-

To the Editor: An indole is not an indole when it is a naphthalene derivative! We routinely measure 5-hydroxyindoleacetic acid (5HIAA) by a longestablished method using nitrosonaphthol, as first described by Udenfriend in 1955 [1], but with various modifications to improve specificity [2]. The profession’s elder statesmen may well recall the method of Hanson and Serin [3] using Erlich’s reagent. Although the Udenfriend method is very specific for 5-hydroxyindoles, it is subject to interference, probably the most documented being that from acetaminophen and its metabolites [4]. In our laboratory, all 5HIAA-positive urines are assessed by ultraviolet scanning of the reaction product and comparison with a 5HIAA standard before confirmation by HPLC at a neighboring laboratory. Recently, a urine was received for 5HIAA analysis from a 52-year-old male patient complaining of hot flushes. The result was considerably increased at 442 mmol/24 h, a typical carcinoid value, and created much interest among the staff. However, the ultraviolet spectrum exhibited a lmax of 652 nm compared with the 5HIAA lmax of 632 nm, a red shift of 20 nm, which could easily be missed by the casual observer. The HPLC value for 5HIAA was not increased (19 mmol/24 h). Consequently, a discussion ensued regarding our original value, and the consultant felt that the index of suspicion for carcinoid syndrome was relatively low. This prompted enquiries regarding the patient’s drug history, and it was found that the patient had recently been prescribed nabumetone, a nonsteroidal anti-inflammatory agent [Relafen (Relifex in the UK); SmithKline Beecham]. Nabumetone, 4-6-methoxy-2-naphthyl)-butan-2-one, is a naphthalene derivative that, after first pass through the liver, is metabolized to 3-acetic-6-methoxynaphthalene and further metabolized to 3-acetic-6hydroxynaphthalene before being excreted in the urine [5]. The metabolite structures are similar to 5HIAA (see diagram). After discussion, the consultant, general practitioner, and patient all agreed to withhold Relifex for 1 month, repeat the 5HIAA collection, recommence Relifex, and repeat the 5HIAA analysis 1 month later. The 5HIAA result was normal (25 mmol/ 24 h, measured by the Udenfriend method only) when the patient was not taking the drug and was greatly increased before and after the drugfree period (442 and 387 mmol/24 h, respectively) as measured by the Udenfriend method but not by the HPLC method (19 and 30 mmol/24 h). In conclusion, we think it essential that all positive 5HIAA analyses be confirmed by a specific method such as HPLC.