Unusual causes of hyperthyrotropinemia and differential diagnosis of primary hypothyroidism: a revised diagnostic flow-chart.

The clinical consequences of primary hypothyroidism include cardiovascular morbidity, increased mortality and poor quality of life, therefore guidelines endorsed by several Scientific Societies recommend measuring circulating TSH in patients at risk. The assessment of serum TSH levels is also deemed to be the most robust and accurate biomarker during the management of replacement therapy in patients with a previous diagnosis of primary hypothyroidism. In line with a reflex TSH laboratory strategy, free T4 is measured only if the TSH falls outside specific cut-offs, in order to streamline investigations and save unjustified costs. This serum TSH-based approach to both diagnosis and monitoring has been widely accepted by several national and local health services, nevertheless false negative or positive TSH testing may occur leading to inappropriate management or treatment. This review aims to describe several infrequent causes of increased circulating TSH, including analytical interference, resistance to TSH, consumptive hypothyroidism, and refractoriness to levothyroxine replacement treatment. We propose a clinical flow-chart to aid correct recognition of these various conditions, that represent important potential pitfalls in the diagnosis and treatment of primary hypothyroidism.