Cystic Fibrosis as a Cause of Malabsorption and Increased Requirement of Levothyroxine

Dear Editor:

Malabsorption is a cause of suboptimal treatment with levothyroxine (LT4) in hypothyroid patients and it should always be suspected when thyrotropin (TSH) remains high despite an adequate weight-related drug dosage (1). Cystic fibrosis (CF), an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, is well known to cause malabsorption of nutrients and drugs (2), but there is little evidence of an increased need for LT4 in these patients.

Here we report two patients (no. 1, a 44-year-old female; no. 2, a 39-year-old male), affected by postsurgical hypothyroidism, who were unable to reach adequate TSH levels despite a daily LT4 dosage largely exceeding their weight-estimated substitution dose, even after multiple increases (up to ∼5.0 μg/[kg·day]). They correctly took their LT4 tablets in the morning after overnight fasting, almost one hour before coffee and meals, and did not take any interfering medications. With the suspicion of malabsorption, both patients underwent an acute loading absorption test. After LT4 load, thyroxine (T4) and free thyroxine (fT4) values remained below the lower reference range limit in patient no. 1; in patient no. 2, T4 levels remained in the lower part of the reference range, whereas a slight increase of fT4 toward normal levels, but under a 2.5-fold cutoff, was observed, thus confirming true malabsorption in both subjects (Table 1). A liquid LT4 formulation was initiated in both patients, at progressively lower daily doses (down to ∼2.0 μg/[kg·day]), reaching stable target TSH ranges in subsequent evaluations.

The two patients we describe here represent an example of impaired LT4 absorption due to CF in adulthood. In the early 1990s, Depasse et al. reported the case of a male newborn with congenital hypothyroidism and CF, in whom impaired pancreatic secretion and transit abnormalities resulted in decreased absorption of LT4, which was partially overcome by the administration of pancreatic enzymes, even if the LT4 doses required to normalize TSH and fT4 were higher than usual (3). The increased LT4 requirement associated with CF may be due to the combination of pancreatic insufficiency, reduced biliary salt production, abnormalities in intestinal transit, and chronic intestinal inflammation (2). CF can cause malabsorption of different degrees in relation to the severity of the disease, as demonstrated in these two patients. Indeed, patient no. 1, who suffered from more advanced disease with malnutrition, pancreatic, and biliary insufficiency, displayed a more severe defect in LT4 absorption than patient no. 2. In patient no. 1, however, administration of pancreatic enzymes did not improve LT4 absorption, a finding that contrasts with the report of Depasse et al. (3). As illustrated here, the LT4 absorption test can be a useful tool to confirm malabsorption, potentially leading to adjustments in the therapeutic approach. In our patients, a liquid oral LT4 formulation has been able to attenuate the problem of the impaired LT4 absorption, and it may present a valuable alternative in CF patients permitting to reach target TSH levels that were difficult to achieve with the conventional tablet formulation, as reported in other conditions (4).