Lactose intolerance is not the cause of gastrointestinal adverse effects in beta thalassemia patients treated with deferasirox
Authors: Idit Pazgal, Marius Brown, Tsachi Tsadok Perets, Yaron Niv, Eliezer Rachmilewitz, Pinhas Stark
Journal: American Journal of Hematology (2014)

To the Editor: Survival of transfusion dependent beta thalassemia patients has improved significantly over the past few decades as better treatment became available. However, systemic iron overload continues to be the main contributor to severe morbidity and early mortality, and consequently, iron chelation remains an essential treatment in these patients 1. Deferasirox (Exjade®, DFX), taken orally once daily is the most common iron chelator in use in many countries worldwide 1, 2. However, significant gastrointestinal (GI) adverse effects (AEs), including abdominal discomfort, flatulence, pain, vomiting, and diarrhea, resulting from unknown etiology, are associated with DFX treatment, consequently resulting in low compliance and treatment discontinuation 1, 2. Lactose monohydrate, widely used in the manufacturing process of pharmaceutical products 3, is an active ingredient of DFX (1.1 mg lactose: 1.0 mg DFX) 4. We have evaluated whether lactose intolerance is the cause of GI AEs associated with DFX treatment. The study included 21 patients with transfusion dependent beta thalassemia (10 males, 11 females, age 22–51 years), who are or were treated with DFX (patients with well-defined pathology in the GI tract, other than AEs attributed to DFX, were excluded from the study). DFX dose range was 23.3–51.0 mg/kg body weight/day. The actual amount of DFX consumed daily was between 1,000 and 3,000 mg, and accordingly, the daily amount of lactose ingestion was between 1,100 and 3,300 mg, equivalent to the lactose content found in up to 2-oz cup of milk 5, 6 (Table 1). The study was approved by the hospital local Helsinki committee. After obtaining a signed informed consent, patients filled a brief questionnaire regarding any GIT AEs related to the consumption of DFX, and/or dairy food and drink, and underwent the lactose hydrogen breath test (LHBT) which is considered to be the most reliable, noninvasive technique for conformation of the diagnosis of lactose deficiency 7-10. After an overnight fast, patients were given 50 g of lactose in 200-ml water solution. Breath samples were obtained before and 30, 60, 90, 120, 150, and 180 min after the ingestion of lactose. An increase of >20 PPM in breath hydrogen concentration was considered diagnostic for lactase deficiency. A positive LHBT is considered diagnostic for lactose malabsorption, and a positive LHBT associated with GI AEs after the ingestion of lactose load is considered diagnostic for lactose intolerance 7, 9, 10. Clinical and laboratory data were analyzed for any possible association between lactase deficiency, lactose intolerance, and DFX-induced GI AEs. Twelve patients (57.1%) had a negative LBHT. Among them, five (41.7%) had experienced clinical signs or symptoms of GI AEs, while seven (58.3%) had no clinical signs or symptoms. Nine patients (42.9%) had a positive LBHT. Among them, three (33.3%) had experienced clinical signs or symptoms of GI AEs, while six (66.7%) had no clinical signs or symptoms (Fig. 1). LHBT and GI symptoms in multi transfused beta thalassemia patients treated with Deferasirox (P values NS). Using Chi-Square test and Fisher's exact test for count data, any association between LBHT results and clinical GI signs and symptoms were insignificant (P values 0.43–1.00). According to the drug monograph, DFX-associated GI AEs were reported by 26% of the patients, mainly nausea, vomiting, diarrhea or abdominal pain 4. These AEs are usually transient, dose-dependent, mostly mild to moderate, and resolve despite treatment continuation. It is widely assumed that in the presence of lactase deficiency the administration of a drug such as DFX that contains a significant amount of lactose can be the reason for the development of significant GI AEs. It is recommended that patients with severe lactase deficiency should not take this drug. However, it has been reported that there is no direct association between lactose intolerance due to lactase deficiency and clinical signs and symptoms of lactose malabsorption 5, 6. The results of the study are in line with the conclusions of the NIH consensus development conference on lactose intolerance and health, that is, there is no relationship between lactose malabsorption due to lactase deficiency and clinical signs of lactose intolerance 6, and clearly indicate that GI signs and symptoms associated with DFX treatment are not due to lactose intolerance, and therefore their etiology still unknown and remain to be explored. Idit Pazgal,1 Marius Brown,2 Tsachi Tsadok Perets,2 Yaron Niv,2 Eliezer Rachmilewitz,1 and Pinhas Stark1 1Comprehensive Center of Thalassemia, Hemoglobinopathies and Rare Anemias, Institute of Hematology; 2Institute of Gastroenterology & Liver Diseases; Beilinson Hospital, Rabin Medical Center, Petah Tikva & Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel