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Dept of Endocrinology, Niguarda Hospital, Milan, Italy
CORRESPONDENCE:
To the Editor:
The article by Abramowicz et al. 1 should show the first case of primary pulmonary hypertension (PPH) associated with the use of amfepramone (diethylpropion), an anorectic drug, and BMPR2 mutation. In my opinion, the relationship between amfepramone and the rise of PPH in this case is unproven.
BMPR2 mutation is related to PPH without use of anorectics. Autosomal dominant germline mutations in BMPR2 have been identified in 
55% of familial cases and in 25% of patients with negative family history 2.
There are three different types of anorectic drugs: fenfluramines (fenfluramine and dexfenfluramine), serotonin releasers; noradrenergic agents (i.e. amfepramone), noradrenaline releasers; and sibutramine, a noradrenaline and serotonin reuptake inhibitor 3.
It is true that BMPR2 mutations combined with exposure to fenfluramine derivatives increase the risk of developing PPH, but the mechanisms of the lesions, with any probability, are associated with the serotoninergic pathway 4–6. Amfepramone is a noradrenaline releaser and not a serotonin stimulant.
However, after Abenhaim et al. 7 showed a correlation between anorectics and PPH, a second much larger study was performed in the USA 8. This study showed that: 1) only the use of fenfluramines for 
6 months remained associated with the diagnosis of PPH; and 2) when only recent users of fenfluramines (i.e. those using them in the 6 months preceding diagnosis) were counted as exposed, the associated adjusted odds ratios from the logistic regression that reflected the directions of associations were higher.
Therefore: 1) Abramowicz's patient had a mutation, which could, per se, cause PPH; 2) there are no data that amfepramone causes PPH; 3) a direct relationship between noradrenergic pathway and PPH has never been supposed; 4) the exposure to anorectic drug was too short; and 5) the period between amfepramone use and the onset of symptoms is too long.
Considering this case, if we use the common algorithms for the assessment of adverse drug reactions 9–11, the result is unlikely. It is very difficult to be able to suppose that the use of amfepramone could have any relationship, even indirectly, in the rise of primary pulmonary hypertension.
References
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