Thyroxine and treatment of hypothyroidism: seven decades of experience.

Hypothyroidism is one of the most common endocrine disorders, affecting as much as 10% of the global population. There is a rich cultural milieu of treatment history and interventions dating as far back as 2 millennia. Chinese cretins were treated with sheep thyroid in the 6th century. In 1890, transplanted animal thyroid tissue resulted in a prompt clinical response in a myxedematous patient, and in 1891 injections of sheep thyroid were reported. One year later, the oral administration of fresh sheep thyroid glands was noted to be effective. Within a few years, the danger of over-dosage with extracts was recognized and dosing guidance indicated a low dose start and gradual increase as required based on symptoms. Orally ingested extracts became widespread and by 1914 thyroxine had been crystallized. In 1927, thyroxine, was synthesized as an acid, limiting oral absorption. Finally a sodium salt of thyroxine was introduced in 1949. These synthetic preparations were then made available for clinical use. Prior to 1970, extracts and combination therapy with synthetic LT4 and LT3 were standard replacement until the peripheral deiodinase-mediated T4 to T3 conversion documented the endogenous generation of T3 from LT4 in athyreotic subjects. This resulted in advocacy for patients previously treated with combinations and desiccated thyroid be transitioned to L-thyroxine monotherapy. The determination of the optimal dose has evolved such that now a general recommendation for replacement dosage of LT4 is 1.6-1.7 mcg/kg/day. Thyroid hormone extracts were established prior to the FDA's establishment in 1906, and when the Food, Drug, and Cosmetic act of 1938 enhanced the FDA's regulatory authority. In 1997, FDA declared LT4 products to be new drugs subject to regulation and quickly a pharmacokinetic process to determine interchangeability among approved LT4 products ensued. Differences in bioavailability of 12.5% or more may be considered therapeutically equivalent and therefore such products interchangeable. To assure refill to refill consistency, all levothyroxine sodium products now meet a 95-105% potency specification throughout their labeled shelf-lives. Seventy years after Kendall's great achievement in isolating thyroxine, we have thyroxine products with precise amounts of synthetic hormone that meet demanding regulations to assure high product quality, predictable bioavailability given its narrow therapeutic range, and now are left with potential variance in the therapeutic efficacy among different preparations.

BISPHOSPHONATES FOR THE TREATMENT OF CALCITRIOL-INDUCED HYPERCALCEMIA.

OBJECTIVE: Calcitriol excess is a less common cause of hypercalcemia than hyperparathyroidism. Hypercalcemia due to calcitriol excess is usually managed acutely with intravenous (IV) fluid administration and dietary calcium restriction. Steroids and ketoconazole are second-line agents. There is evidence supporting the role of bone resorption in the genesis of hypercalcemia in vitamin D intoxication and for a rapid response of hypercalcemia to treatment with bisphosphonates. We seek to demonstrate the utility of bisphosphonates in calcitriol-induced hypercalcemia (CIH). METHODS: We present the case of a patient with recurrent CIH from a follicular lymphoma who achieved normalization and subsequent stabilization of serum calcium levels following bisphosphonate administration. RESULTS: A 77-year-old woman with a history of non-small cell lung cancer was admitted with dry mouth, polyuria, weight loss, and fatigue. She was found to have a calcium level of 14.7 mg/dL (normal range is 8.5 to 10.2 mg/dL), 25-hydroxyvitamin D of 47 ng/mL (normal range is 30 to 60 ng/mL), 1,25-dihydroxyvitamin D of 89 pg/mL (normal range is 18 to 72 pg/mL), and parathyroid hormone of 19 pg/mL (normal range is 15 to 65 pg/mL), which recurred despite treatment with IV fluids and strict low-calcium diet. She received 5 mg of IV zoledronic acid and normocalcemia was maintained thereafter, without any diagnosis-specific treatment for >3 months. Positron emission tomography with computed tomography eventually showed new innumerable foci of increased uptake in the skeleton and lymph node biopsy revealed grade 3A follicular lymphoma. CONCLUSION: The first choice for CIH is treating the underlying cause. Bisphosphonates are, however, useful until a diagnosis is made, as they may be safer than steroids and can provide rapid relief even with a single treatment with minimal side effects.

An easy miss: aortic dissection in a 'healthy' male.

Aortic dissection is an uncommon cause of chest discomfort that can be rapidly fatal without early diagnosis and prompt treatment. In this report, we present a man with no risk factors who presented with chest discomfort not typical of a dissection, absent pulse and blood pressure differential and a normal chest radiograph. He eventually was diagnosed with an extensive Type-A aortic dissection. We discuss diagnostic clues, classification of aortic dissection and possible treatment options.