Beyond the Gut: thyroxine malabsorption, pharmacokinetics, and delivery

Refractory primary hypothyroidism is defined by persistently elevated thyroid-stimulating hormone despite supraphysiological oral levothyroxine dosing. The distinction between true malabsorption and pseudomalabsorption (nonadherence) is critical for management planning. In 2023, Quiroz-Aldave et al proposed a comprehensive framework for the evaluation and management of refractory primary hypothyroidism, while Liu et al provided an updated overview of both conventional and novel levothyroxine formulations. This mini-review synthesizes recent evidence published since 2023 and presents 2 illustrative cases managed within our clinical service. A PubMed search identified 41 relevant publications, including case reports, pharmacological studies, and clinical investigations. Case 1, a young woman with congenital hypothyroidism, demonstrated adequate intestinal absorption on a supervised levothyroxine absorption test, with subsequent findings supporting pseudomalabsorption. Recent studies have validated rapid absorption protocols (2-3 hours), offering feasible and cost-effective alternatives to conventional prolonged protocols. Case 2, a man with papillary thyroid carcinoma and end-stage renal failure, exhibited impaired gastrointestinal absorption confirmed by absorption testing. Management required escalation to parenteral therapy, with subcutaneous levothyroxine ultimately achieving biochemical stability. Importantly, no standardized absorption test exists for off-label intramuscular or subcutaneous administration; pharmacokinetic principles, particularly area under the curve calculations, may help estimate absorption readiness in these contexts. Emerging literature highlights gastrointestinal, surgical, and pharmacologic contributors to true malabsorption, as well as the superiority of liquid formulations in selected contexts. Subcutaneous administration is gaining interest as a tolerable, patient-friendly alternative to intramuscular dosing, although safety and pharmacokinetic validation of parenteral T4 remain necessary. Novel formulations under development may further optimize therapeutic options.