Malabsorption of thyroxine has been described in patients treated with drugs that modify an acidic environment. We determined whether there is an increased need for thyroxine in patients with euthyroid multinodular goiter and impaired secretion of gastric acid. We assessed the dose of thyroxine required to obtain a low level of thyrotropin (0.05 to 0.20 mU per liter) in 248 patients with multinodular goiter. Of these 248 patients, 53 also had Helicobacter pylori–related gastritis and 60 had atrophic gastritis of the body of the stomach (31 with evidence of H. pylori infection and 29 without such evidence). The reference group comprised 135 patients with multinodular goiter and no gastric disorders. In addition, variation in the level of serum thyrotropin was prospectively studied in 11 patients treated with thyroxine before and after H. pylori infection and both before and during treatment with omeprazole in 10 patients treated with thyroxine who had gastroesophageal reflux. The daily requirement of thyroxine was higher (by 22 to 34 percent) in patients with H. pylori–related gastritis, atrophic gastritis, or both conditions than in the reference group. In prospective studies, the occurrence of H. pylori infection in the 11 patients treated with thyroxine led to an increase in the level of serum thyrotropin (P=0.002), an effect that was nearly reversed on eradication of H. pylori infection. In a similar way, omeprazole treatment was associated with an increase in the level of serum thyrotropin in all 10 patients treated with thyroxine, an effect that was reversed by an increase in the thyroxine dose by 37 percent. Patients with impaired acid secretion require an increased dose of thyroxine, suggesting that normal gastric acid secretion is necessary for effective absorption of oral thyroxine.

Levothyroxine, a largely prescribed drug with a narrow therapeutic index, is often a lifelong treatment. The therapeutic efficacy of thyroxine may be marred by behavioral, pharmacologic and pathologic issues acting as interfering factors. Despite a continuous search for an optimal thyroxine treatment, a significant number of patients fail to show a complete chemical and/or clinical response to this reference dose of thyroxine. Gastrointestinal malabsorption of oral thyroxine represents an emerging cause of refractory hypothyroidism and may be more frequent than previously reputed. In this review article we aimed at examining the pharmacologic features of thyroxine preparations and their linkage with the intestinal absorption of the hormone. We have stressed the major biochemical and pharmacologic characteristics of thyroxine and its interaction with the putative transporter at the intestinal level. We have examined the interfering role of nutrients, foods, and drugs on thyroxine absorption at gastric and intestinal level. The impact of gastrointestinal disorders on thyroxine treatment efficacy has been also analyzed, in keeping with the site of action and the interfering mechanisms. Based on the evidence obtained from the literature, we also propose a schematic diagnostic workup for the most frequent and, often hidden, gastrointestinal diseases impairing thyroxine absorption.

THE ASSOCIATION between autoimmune thyroid disease (AITD) and various other autoimmune diseases was first suggested in the early 1960s.^1-4 Indeed, the term thyrogastric autoimmunity or disease has been used to define the prevalence of thyroid autoantibodies^3,5-7 and/or overt AITD in patients with pernicious anemia (PA),⁸ which, in turn, was improperly used as synonymous with atrophic gastritis.⁹ More recently, the association between AITD and PA has been included in type IIIb polyglandular autoimmune disease.¹⁰ However, atrophic gastritis is represented by more than one distinct pathophysiological and clinical entity, which may precede the onset of PA by several years.^9,11,12 In particular, atrophic body gastritis (ABG), formerly known as type A, represents a chronic, symptomless gastritis of the fundic mucosa, which often has an autoimmune pathogenesis,¹² is involved in gastric carcinogenesis,¹³ and is closely related to the appearance of microcytic anemia^4,14 and PA.^8,9 To our knowledge, ABG has not yet been directly characterized in patients with AITD, and its prevalence may be substantially different from that previously assessed only by indirect evidence (ie, the presence of antiparietal cell antibodies [APCAb] and/or PA).^3,5-8,15 Furthermore, the prevalence of AITD, namely, lymphocytic thyroiditis, in its subclinical form appears to have increased during the past 10 years, probably because of the availability of more sensitive diagnostic tools.^16,17

The term ‘thyrogastric syndrome’ defines the association between autoimmune thyroid disease and chronic autoimmune gastritis and it was firstly described in the early 1960s. More recently, this association has been included in polyglandular autoimmune syndrome type IIIb (PAS IIIb), in which autoimmune thyroiditis represents the pivotal disorder. Hashimoto’s thyroiditis is the most frequent autoimmune disease and it has been reported to be associated to gastric disorders in 10 to 40% of patients while about 40% of patients with autoimmune gastritis also present Hashimoto’s thyroiditis. Some intriguing similarities have been described about the pathogenic mechanism of these two disorders, involving a complex interaction among genetic, embryological, immunologic and environmental factors. Chronic autoimmune gastritis is characterized by a partial or total disappearance of parietal cells implying the impairment of both hydrochloric acid and intrinsic factor production. The clinical outcome of this gastric damage is the occurrence of a hypochlorhydric-dependent iron-deficient anemia, followed by pernicious anemia concomitant with the progression to a severe gastric atrophy. Malabsorption of levothyroxine may occur as well. We have briefly summarized in this minireview the most recent achievements on this peculiar association of diseases that, in the last years, has been increasingly diagnosed.