Levothyroxine replacement therapy is experiencing worldwide growth, particularly in the United States and Europe, especially among the elderly population [22]. Despite its widespread use, cross-sectional surveys of patients taking levothyroxine have shown that between 40 and 48% are either over-treated or under-treated [9, 10, 23]. Many explanations can be given for this. Firstly, numerous conditions are known to interfere with LT4 absorption by primarily affecting gastric pH, particularly with tablets [21]. In fact, LT4 absorption mainly occurs in the jejunum and ileum [24], and studies on LT4 tablets have shown that its absorption is maximal when the stomach is empty, demonstrating the key role of gastric acidity in this process [15, 21]. Hence, patients with gastrointestinal disorders such as coeliac disease, Helicobacter pylori infection, and atrophic gastritis, or those with jejunoileal bypass surgery, require higher daily doses of LT4 [21]. The same has been shown for food and drugs such as coffee, dietary fiber, proton pump inhibitors, calcium carbonate, and ferrous sulfate supplementation [21]. In agreement, ATA Guidelines suggest taking LT4 in a fasting state in the morning or at bedtime, away from interfering drugs [5].

The therapeutic environment has changed with the advent of novel formulations in recent years. Several studies have demonstrated that novel formulations containing ethanol can circumvent the LT4 malabsorption issue [15]. Moreover, it is well known that patients on therapy with novel formulations have a better quality of life [18], partly due to the possibility of taking the therapy with breakfast [14], which improves adherence. Many drops make an ocean, and the future challenge is represented by tailored therapy. However, we are still far from the possibility of administering the right dosage to the right patient, although the dream is becoming more attainable [6].

Indeed, a novel ethanol-free formulation has been commercialized with a wide range of intermediate dosages, making the administration of effective therapy easier. Taking in account the clinical data suggesting the superiority of e-LT4 compared to tablets [11,12,13, 16, 17, 19, 20, 25,26,27,28], it is reasonable to think the same might apply to ethanol-free LT4 (ef-LT4). However, to the best of our knowledge, no non-inferiority study between e-LT4 and ef-LT4 has been conducted. Indeed, only two studies have compared liquid ethanol-free formulations to tablets with discordant results [29, 30].

Bornikowska et al. showed in a single-site study that taking ef-LT4 provided higher efficacy, a better thyroid hormone profile, and a greater improvement in quality of life [29]. The TSH profile was similar between the two groups (ef-LT4: 1.71 vs. Tablets: 1.64 mlU/L, p = 0.773, respectively), but fT4 levels were higher (15.96 vs. 14.13 pmol/L, p < 0.001, respectively) [29]. Conversely, Markantes et al. in a prospective randomized crossover phase III study showed that ef-LT4 is therapeutically equivalent to tablets [30].

On the contrary, many studies have investigated TSH levels by switching LT4 tablet to e-LT4. The meta-analysis by Virili et al., mainly obtained from studies enrolling patients with known causes leading to LT4 malabsorption, showed that the pooled mean difference of TSH value between tablet LT4 and e-LT4 formulation was −4.23 mIU/L (p < 0.0001) [13]. Based on these data, it is reasonable to speculate that e-LT4 is superior to ef-LT4 in terms of hormonal profile.

Our data, even if obtained in a small set of patients, are the first suggesting that ef-LT4 is less effective than e-LT4 after 6 and 12 months from the switch. The deterioration appears to worsen over time (Fig. 1). If this data were to be validated in larger prospective studies, how can we explain it? In other words, the possible open-label questions are: why might ethanol-free formulations have reduced absorption? Can ethanol play a fundamental role in the absorption of LT4? Indeed, ethanol is a widely used pharmaceutical excipient in oral formulations, serving as a co-solvent that increases the solubility of poorly soluble drugs [31]. Ethanol stimulates gastric acid secretion, increases mucosal and microvascular permeability in the small intestine, and reduces the motility of the small intestine through its direct effect on the muscular intestinal layer and its toxic effect on the vagus nerve [31]. Thus, it is reasonable to think that ethanol can improve LT4 absorption, and it is plausible that the capability to circumvent malabsorption is mediated precisely by ethanol. On the other hand, many patients dislike the presence of ethanol, at least for palatability, because of the taste it imparts, as well evidenced by Guglielmi et al. in 10.7% of patients [18]. This was also the reason why the enrolled patients decided to switch from e-LT4 to ef-LT4. Palatability studies on ef-LT4 are needed.

This study has a few limitations, including its retrospective nature, and the relatively small patient cohort. Nevertheless, the data provide a real-life experience from a tertiary level Thyroid Unit with extensive experience in LT4 treatment, primarily using the liquid formulation [11, 12, 14, 16, 17, 32, 33]. Importantly, the data obtained at 12 months of ef-LT4 treatment confirmed and highlighted the increasing TSH trend. Secondly, we cannot exclude that the TSH increase is due to a thyroiditis worsening reducing the residual function. Long longitudinal studies performed in athyreotic patients are needed to investigate this issue. Finally, during the study period, the shelf life of ef-LT4 and e-LT4 was shortened from 18 months to 5 and 7 months, for a potential instability of the glycerol used in the formulations. However, the producer supplied the pharmacies, which distributed the drug on a limited basis to ensure it was consumed before its expiration date. Therefore, the data we reported should not be affected by this possible bias, as also demonstrated in the control groups.