Hypothyroid patients on optimal replacement but with persisting symptoms continue to be a challenge for their treating physicians. This commentary is based on a substantial clinical experience with this subpopulation.

With the focus on laboratory tests to achieve a diagnosis, aspects of the traditional clinical examination have been overlooked. In particular the routine testing of tendon reflexes has lapsed. A delay in the relaxation phase of tendon reflexes (hypothyroid hyporeflexia), once known as a positive Woltman’s sign, has long been the hallmark sign of overt hypothyroidism. The majority will do well when treated with appropriate thyroxine replacement.

This sign is also positive in those patients on thyroxine (T4) with normal T4 and Thyrotropin (TSH) levels if they have symptomatic intracellular Triiodothyronine (T3) deficiency. These patients will respond promptly to combination therapy (T4+T3). This subgroup accounts for more than half of the thyroxine-dissatisfied population. They should be described as having T3-hypothyroidism.

The remaining symptomatic patients with normal reflexes have unrelated conditions. A small clearly defined subgroup with autoimmune symptoms and very high anti-Thyroperoxidase (anti-TPO) antibodies (>10 times the upper limit of normal) will respond to total thyroidectomy with a marked improvement that is maintained for 3-5 years. They can be categorised as having TPO-toxic hypothyroidism.

Many patients can have persistent symptoms because of psycho-social issues and the burden of having a chronic disease. They have in-denial-hypothyroidism. There are very rare cases of thyroxine allergy.

This nomenclature should assist physicians in their diagnosis and management of the several subgroups of patients on thyroxine with persistent symptoms.