Oral LT4 Research Articles

6668 Myxedema Coma and Takotsubo Cardiomyopathy

Abstract Disclosure: A.M. Skariah: None. S. Jain: None. Background: Takotsubo cardiomyopathy (TCM) also know as broken heart syndrome is a transient decrease in systolic cardiac function in the absence of obstructive CAD. TCM is likely related to hyperadrenergic conditions leading to increased cardiac sensitivity to catecholamine surge leading to cardiomyopathy. TCM is more associated with hyperthyroidism. Case presentation: Patient is an 84-year-old female with PMH of celiac disease,hypertension,prediabetes, and atrial fibrillation s/p cardioversion, on amiodarone. She was brought to the ER after having an unwitnessed fall. She was hypotensive 76/56 mm of Hg, hypothermic 35.5 degree C, HR 90 beats/min; labs significant for hyponatremia, macrocytic anemia, TSH 65.47uIU/ml, FT4 <0.4 ng/dl and mild QTC prolongation of 469ms. Family mentioned history of constipation, progressive weakness, poor oral intake, memory problems and cold sensitivity for a couple of months. Started on 1 pressor, 3 units of PRBC and 2 liters of IVF; BP improved; labs and history suggestive of myxedema coma with myxedema coma Popoveniuc score 85 suggestive of high suspicion for myxedema coma.She had TSH 50.39 uIU/ml and FT4 of 0.4 ng/dl for her memory issues workup 2 months prior to presentation but was not started on medication. Upon admission, started stress dose steroids followed by IV levothyroxine 100 mcg. Not started on LT3 given her old age and atrial fibrillation history. Received additional dose of LT4 100 mcg within few hours. TFT improved with TSH 35 uIU/ml and FT4 1 ng/dl after 2 doses. Later same day, shock worsened, and patient was on 3 pressors along with stress dose of steroids. Cardiology was consulted; recommended an Echocardiogram.Echo was done on day 2; EF 55-60 % with severe hypokinesis of apical myocardium consistent with TCM. Normal echocardiogram studies 4 months ago.Started on weight-based regimen of LT4 75 mcg IV on day 3 and switched to 100 mcg oral when patient tolerated pills.Patient was down to 2 pressors on day 3 and gradually off pressors by day 6. Repeat TFT -showed improvement TSH 12 uIU/ml and FT4 0.7 ng/dl—day 5. Eventually her mentation improved and was discharged on oral LT4. Conclusion: TCM is rare complication of treatment of myxedema coma. Our patient developed shock requiring 1 pressor which unexpectedly worsened to 3 pressors requirement after initial LT4 treatment. High doses of LT4 and LT3 which is part of myxedema coma treatment sensitizes myocardial tissue to catecholamines by increasing expression of beta adrenoreceptors in cardiac myocytes with subsequent ionotropic and chronotropic effects. This may contribute to cardiac stunning and TCM. It’s beneficial to evaluate patients with myxedema coma who develop worsening cardiac status after initiation of high dose of thyroid hormone replacement for TCM. Presentation: 6/2/2024

Morning exercise affects the absorption of oral levothyroxine: a single center pilot study.

Levothyroxine (LT4) is the first-line hormone replacement therapy for hypothyroidism. Several factors which have an influence on oral LT4 absorption have been previously described; however, the influence of exercise on oral LT4 absorption has not been reported, yet. It was aimed to investigate the possible effect of morning exercise, right after LT4 ingestion, on the absorption of LT4 tablets in this study. Patients with primary hypothyroidism who fulfilled the inclusion criteria were offered to participate in a 6-week morning exercise programme and those who agreed to participate were enrolled in our study. Patients were required to have a walk for 30 min with a regular speed right after taking their daily LT4 treatments and start having breakfast the first hour after LT4 intake. Pre- and post-exercise TSH levels were recorded and TSH percentage change was calculated. All patients had decreased TSH levels after the exercise programme. There was a significant decrease in TSH levels (p < 0.001). A significant positive correlation between TSH percentage change and daily dose of LT4 per kg of body weight was also shown. This is the first study which demonstrates the significant positive effect of morning exercise on the absorption of LT4 tablets. In addition to that, it was also found that as the daily dose of LT4 increases, the percentage decrease of TSH level becomes greater.

SAT477 Consumptive Hypothyroidism In A Patient With Plasma Cell Neoplasm

Abstract Disclosure: G. Sidhu: None. I. Madahar: None. A. Haider: None. J. Giordano: None. Introduction: Thyroxine (T4) is converted into metabolically active form triiodothyronine (T3) by deiodinase enzyme 1 &amp; 2 (D1 &amp; D2). Deiodinase 3 converts T4 and T3 into metabolically inactive form reverse T3 (rT3)&amp; di-iodothyronine (T2) . Consumptive hypothyroidism syndrome (CHS) is a very rare form of hypothyroidism seen in patients with neoplasms, which express high levels of D3 enzyme. Case: 68-year-old female withhistory of Multiple Myeloma (MM), POEMS, hyperlipidemia and hypothyroidism was admitted with acute kidney injury, cirrhosis of unclear etiology, large volume ascites and anasarca. She weighed 92 kg on admission. She was complaint with her 50 mcg of levothyroxine and on admission her TSH was 7.14 (N: 0.43-3.55 uIU/ml), Free T4 (FT4): &amp;lt;0.42 (N: 0.7-1.25 ng/dl), total T4 (TT4): 2.6 (N: 4.8-11.7 ug/dl), total T3 (TT3): &amp;lt;20 (N: 80-200 ng/dl). Oral LT4 was switched to IV form due to underlying concerns of malabsorption from anasarca. rT3 was noted to be 40 (N: 8-25 ng/dl). Despite escalated intravenous levothyroxine doses for seven days her FT4, FT3 continued to remain undetectable So her LT4 dose was increased to 75 mcg IV daily initially and eventually to 100 mcg IV daily and 125 mcg daily. On 10th day of hospitalization, after her IV LT4 dose was increased to 200 mcg daily, (almost 2.5 mcg/kg/day) her FT4 levels became detectable, 0.50, rT3: 68 and TT3: &amp;lt;20 and TT4: 3.1. Since her rT3 levels were noted to rise after increasing the dose of LT4, liothyronine (LT3) 5 mcg BID was added to her regimen. PET scan showed small sclerotic bone lesions suspicious for active malignancy. Chromogranin A was elevated 313 (N: &amp;lt;311 ng/ml). IR guided biopsy of scapular sclerotic lesion was done and specimen was sent University of Chicago to measure DI-3 activity in the specimen Pathology results were suggestive of plasma cell neoplasm but unfortunately deiodinase activity could not be quantified. Patient developed hepato-renal syndrome during hospitalization and her family decided to pursue hospice care. Discussion: Critical care illness thyroid disease is also associated with increased DI-3 activity and increases rT3, however T4 and TSH are also low in the setting of critical care illness, and most patient do not require supraphysiologic T4 replacements. The presence of D3 in normal tissues such as the brain &amp; placenta has been hypothesized to protect tissues from the effects of excessive thyroid hormone. However, aberrant expression of the enzyme can lead to severe hypothyroidism from inactivation of both endogenously produced and exogenously administered thyroid hormone. Previously this rare syndrome was described in association with massive hemangiomas in children and in a single case of a hemangioendothelioma in an adult. However case reports in adults have been described in nonvascular tumors who required supraphysiologic doses of levothyroxine prior to the resection of a large malignant solitary fibrous tumor. Presentation Date: Saturday, June 17, 2023

SAT475 Levothyroxine and Liothyronine Treated Myxedema Coma with Irreversible Cardiopulmonary Failure: A Rare Phenomenon

Abstract Disclosure: T. Menon: None. Y. Xie: None. A. Wang: None. Introduction: We describe a case of myxedema coma associated with irreversible cardiogenic shock and the challenges in optimal management. Case Presentation: A previously healthy 23-year-old man with a history of untreated hypothyroidism (TSH 100 uIU/mL six months prior) presented to the hospital for abdominal pain, shortness of breath, and cough. He soon had two cardiac arrests with successful resuscitation and was stabilized via mechanical ventilation and vasopressors. Physical exam showed peripheral and facial edema with mild jaundice. Laboratory results showed elevated creatinine 1.73 (0.5-1.30 mg/dL), AST 440 (10-40 U/L), ALT 353 (10-45 U/L), and total bilirubin 3.6 (0.2-1.2 mg/dL). Thyroid function tests showed TSH 857 (0.27-4.20 uIU/mL), FT4 &amp;lt;0.1 (0.9-1.8 ng/dL), and TT3 &amp;lt; 20 (80-200 ng/dL), and negative thyroglobulin and TPO antibodies. A thyroid ultrasound showed a small thyroid gland. Echocardiogram revealed severe bi-ventricular failure, with an ejection fraction of 10-15%, dilated chambers, pulmonary hypertension, and moderate pericardial effusion. The patient was initiated on VA-ECMO and treated medically for cardiogenic shock. Myxedema coma treatment was started with IV levothyroxine (LT4) 400 mcg, IV Liothyronine (LT3) 10 mcg, and IV hydrocortisone 100 mg every eight hours. The patient subsequently received IV LT4 100 mcg daily and IV LT3 10-30 mcg daily based on levels of daily FT4 and TT3. Hydrocortisone was tapered down as free cortisol levels prior to steroid administration were elevated at 4.6 (0.2-1.8 ug/dL). Despite significant improvements in TSH values (from 857 to 67 uIU/L), FT4 (from &amp;lt;0.1 to 1.2 ng/dL), and TT3 (from &amp;lt; 20 to 60 ng/dL), the patient’s cardiac function did not improve and he underwent successful orthotopic heart transplantation two weeks after initial presentation. A cardiac biopsy demonstrated cardiomegaly with left ventricular hypertrophy, subendocardial fibrosis, and patent arteries, without other etiologies of heart failure. The patient recovered and was discharged on oral LT4 137 mcg daily, LT3 5 mcg twice daily, and prednisone per cardiac transplantation protocol. Discussion: Several cases describe myxedema coma with reversible heart failure in 4 to 5 days with appropriate hypothyroidism treatment. This case, however, describes irreversible cardiomyopathy despite optimal medical therapy, eventually requiring heart transplantation. Because the cardiac myocyte is dependent on plasma T3 due to lack of intracellular deiodinase, T3 administration may improve cardiac function in myxedema coma induced heart failure. Consensus regarding the use, optimal dose, and duration of LT3 in these situations requires further investigation. Conclusion: We report an unusual case of irreversible cardiomyopathy due to myxedema coma in a young, healthy patient, highlighting the need for rapid correction of hypothyroidism with both IV LT4 and LT3. Presentation Date: Saturday, June 17, 2023

RF23 | PSAT258 Comparable Bioavailability of a Novel Levothyroxine Solution taken 10 or 30 minutes prior to a High-Fat, High-Calorie Breakfast

Abstract Levothyroxine (LT4) is the recommended treatment for hypothyroidism and the second most prescribed medication in the US. Several formulations are available, however most patients take LT4 tablets. Evidence suggests that absorption of levothyroxine tablets is decreased when taken with food, especially those rich in soy, iodine, and fiber. In order to avoid erratic absorption of LT4, it is recommended that oral formulations are taken on an empty stomach, 30-60 minutes before breakfast. However, compliance with this recommendation is often difficult for patients with busy schedules or on multiple medications, yet important in patients with conditions that are sensitive to changes in TSH levels such as pregnancy and thyroid cancer.There is evidence that oral liquid LT4 formulations that bypass the gastric dissolution phase of absorption may mitigate this food effect. ThyquidityTM (levothyroxine sodium) oral solution has demonstrated bioequivalence to Synthroid® under fasting conditions and allows individualized dosing flexibility. A bioavailability study was conducted to assess the rate and extent of absorption of the oral LT4 solution (100 mcg /5 mL) administered either 10 or 30 minutes before a standardized high-calorie, high-fat breakfast in an open-label, randomized, single-dose, 2-period, 2-sequence, crossover study. A single 600 μg oral dose of LT4 solution (ThyquidityTM, 30 mL) was administered to healthy adults either 10 or 30 minutes before consuming a 950 kcal, high fat (56%) breakfast in each study period and blood was collected for total (bound and free) T4 for 48 hours after drug administration. Treatment periods were separated by a 40-day wash-out period.The ratios of geometric LS means with corresponding 90% confidence intervals were calculated from the exponential of the difference between the LT4 solution administration 10 and 30 minutes prior to the meal for AUC0-48 and Cmax. An absence of food effect (bioequivalence) would be concluded if the baseline corrected 90% confidence intervals of this ratio fell within 80.00% to 125.00% for Ln-transformed AUC0-48 and Cmax.Forty healthy volunteers participated in the trial, 38 were included in the data analysis. There were no serious adverse events or discontinuations due to AEs. The geometric LS mean ratios of AUC0-48 and Cmax for baseline-adjusted LT4 were 88.74% (84.71-92.95%) and 85.07% (81.1-89.33%) respectively. The corresponding 90% CIs were included within the acceptable range for bioequivalence, indicating the absence of a meaningful difference in LT4 absorption when administering at 10 or 30 minutes before a meal.Based on these results, it may be possible to decrease the interval between the administration of Thyquidity (levothyroxine sodium) oral solution to 10 minutes before breakfast, thus offering patients further dosing flexibility. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:36 p.m. - 12:41 p.m.

RF23 | PSAT259 Comparable Bioavailability of a Novel Levothyroxine Solution when Administered with Coffee

Abstract Levothyroxine (LT4) is the treatment of choice for hypothyroidism and the second most prescribed medication in the United States. Despite its established efficacy and widespread availability, approximately 40% of patients treated with LT4 fail to achieve thyroid stimulating hormone (TSH) levels within the normal range. Current LT4 product guidelines recommend administration in the fasting state 30-60 minutes before breakfast to avoid a food interaction leading to reduced intestinal absorption of LT4. This recommendation may impact compliance, as over 50% of adult Americans drink coffee every day, 65% of which is consumed during breakfast.While the majority of patients receive LT4 tablets, there is evidence that liquid formulations that bypass the gastric dissolution phase may mitigate the interference with coffee. ThyquidityTM (levothyroxine sodium) oral solution has demonstrated bioequivalence to Synthroid® under fasting conditions and allows individualized dosing flexibility in a variety of clinical scenarios. A bioavailability study was conducted to assess the rate and extent of absorption of the oral LT4 solution (100 mcg /5 mL) administered with coffee compared to administration under fasting conditions in an open label, randomized, two-period, two-treatment, two-sequence, crossover, single dose bioavailability study in 40 healthy adults. A single 600 μg oral dose of LT4 solution (ThyquidityTM, 30 mL) was administered 5 minutes before drinking 8 ounces of American coffee (without milk or sweeteners) or under fasting conditions in each study period. Blood samples were collected for total (bound and free) T4 for 48 hours after drug administration. Treatment periods were separated by a 40-day wash-out period.The ratios of geometric LS means with corresponding 90% confidence intervals (CI) were calculated from the exponential of the difference between the LT4 solution administration 5 minutes prior to coffee and administration under fasting condition for AUC0-48 and Cmax. An absence of a food effect would be concluded if the baseline corrected 90% CIs of this ratio fell within 80.00% to 125.00% for Ln-transformed AUC0-48 and Cmax.Forty healthy adults participated in the trial. There were no serious adverse events (AE) or discontinuations due to AEs. The geometric LS mean ratio of AUC0-48 and Cmax for baseline-adjusted LT4 were 93.98% (90.06-98.07%) and 95.99% (92.64- 99.45%) respectively. The corresponding 90% CIs were included within the acceptance range for bioequivalence.This study demonstrated comparable bioavailability of a single oral 600 μg dose of Thyquidity oral solution administered, 5 minutes prior to coffee or under fasting conditions. These results are consistent with earlier evidence that liquid LT4 overcomes the interference from coffee seen with LT4 tablets and may offer additional flexibility for patients. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 1:06 p.m. - 1:11 p.m.

Expert opinion on liquid L-thyroxine usage in hypothyroid patients and new liquid thyroxine formulation - Tirosint SOL [Opinia ekspertów dotycząca stosowania płynnej postaci lewotyroksyny oraz nowego preparatu Tirosint SOL u chorych na niedoczynność tarczycy

Hypothyroidism is a common endocrine disorder affecting 3-15% of the adult population in subclinical form and 0.3-0.8% as overt disease. The mainstay of treatment is replacement monotherapy with levothyroxine (LT4). Currently several oral LT4 formulations including tablets, softgel capsules, and liquid formulations are available. Liquid LT4 is manufactured as LT4 solution in 85% glycerol and 96% ethanol and as LT4 solution in purified water and glycerol. The latest formulation, Tirosint SOL, gained FDA approval in 2017. To evaluate the clinical utility of liquid LT4 we reviewed the literature using three databases: PubMed/MEDLINE, Scopus, and Embase and found 405 articles among which 23 prospective and two retrospective studies were further evaluated. Finally, several case reports on rare clinical conditions were discussed. Our review demonstrated that liquid LT4 was more effective than tablet formulation in patients with malabsorption caused by interfering diseases, drugs, and bariatric surgery. The better pharmacokinetics of liquid LT4 was also confirmed in subjects without malabsorption: patients on replacement or suppressive therapy, who switched from tablet to liquid formulation in equivalent dose, gained better hormonal control, and required less frequent TSH measurements. The drug also appeared effective and easy to handle in patients fed by enteric tube. Liquid LT4 appeared equally effective whenever taken before or during breakfast. The analysis of the drug utility in particular populations including newborns, pregnant women, and the elderly confirmed the high value and safety of liquid LT4. However, in neonates the higher incidence of TSH suppression on liquid in comparison to tablet LT4 therapy was noted, and particular attention to avoid over-treatment must be paid. Concluding: the literature review revealed that liquid LT4 is especially advantageous in patients with malabsorption and the critically ill, but it seems also very promising in common therapy. The lack of alcohol content in the new formulation makes Tirosint SOL especially attractive.

Alternative routes of levothyroxine administration for hypothyroidism

The aim of the article is to present the basics of oral levothyroxine (LT4) absorption, reasons why patients may have persistently elevated serum thyroid stimulation hormone (TSH) levels, and alternative strategies for LT4 dosing. Although oral LT4 tablets are most commonly used for thyroid hormone replacement in patients with hypothyroidism, case studies report that liquid oral LT4, intravenous, intramuscular, and rectal administration of LT4 can successfully treat refractory hypothyroidism. Hypothyroidism is one of the most common endocrine disorders encountered by primary care physicians and endocrinologists. LT4 is one of the most widely prescribed medications in the world and it is the standard of care treatment for hypothyroidism. Generally, hypothyroid patients will be treated with LT4 tablets to be taken orally, and monitoring will occur with routine serum thyroid tests, including TSH concentrations. However, many patients fail to maintain serum TSH levels in the target range while managed on oral LT4 tablets. A subset of these patients would be considered to have poorly controlled hypothyroidism, sometimes termed refractory hypothyroidism. For these patients, optimization of ingestion routines and alternative formulations and routes of administration of LT4 can be considered, including oral liquid, intravenous, intramuscular, and even rectal formulations.

Stability and consistency of compounded oral liquid levothyroxine formulations

ObjectiveWith consideration of the narrow therapeutic index of levothyroxine (LT4), the objective of this study was to investigate the stability and consistency of compounded oral liquid formulations of LT4. MethodsSix pharmacies and 6 student pharmacists provided compounded oral liquid formulations of LT4. Pharmacies used their standard compounding best practice including addition of excipients, labeling, and storage instructions. The student pharmacists were required to have completed all academic compounding training and were provided instructions and materials. All analyses were performed at the Pharmaceutical Education and Research Center, a Food and Drug Administration–registered pharmaceutical sciences laboratory. The compounded products were assayed for percent of labeled strength (%LS) of LT4 on days 3, 6, 13, 20, 27, and 34. Each compounding pharmacy and student pharmacist subsequently prepared a second compounded product sample approximately 30 days later to simulate a refill prescription. ResultsIndividual product assays on days 3, 6, 13, 20, 27, and 34 demonstrated a range in variation of %LS from 12% to 47% (mean 26.5%). Wide variations of %LS of LT4 were observed between compounding sources. The assays for all products on day 3 demonstrated a range for %LS of LT4 from 77% to 113%, and those on day 34 ranged from 30% to 97%. Assay comparison of the original compounded product (month 1) to the refill compounded product (month 2) varied from 1% to 58%. Variations in excipients and flavorings were also present. One sample contained liothyronine and was not used for evaluation. These variations may be secondary to aliquot sampling of a suspension or product degradation. ConclusionCompounded oral liquid LT4 products are unlikely to deliver the precise prescribed dosage and reliable product performance when administered to patients.

Oral Levothyroxine is an Effective Option for Myxedema Coma: A Single-Centre Experience

Introduction: Myxedema coma is an endocrine emergency with a very high mortality rate. As per the American Thyroid Association, initial thyroid hormone replacement for myxedema coma should be intravenous levothyroxine (LT4). However, in India, the availability of intravenous LT4 is limited. Often, crushed LT4 tablets are given through the enteral route when parenteral therapy is unavailable. No data or protocol is available for the administration of oral LT4 in myxedema coma. The aim of this study was to assess the effectiveness of oral LT4 in patients diagnosed with myxedema coma and to formulate a protocol for oral LT4 that can be used to guide the treatment of patients when intravenous LT4 is unavailable. Methods: This retrospective observational study included patients diagnosed with myxedema coma between January 2010 and December 2019. The diagnosis of myxedema coma was based on the diagnostic scoring system for myxedema coma proposed by Popoveniuc et al. [Endocr Pract. 2014 Aug;20(8):808–17]. Dosing of oral LT4 was decided as per our institutional protocol. Results: Fourteen patients (11 males and 3 females) with a median age of 67.5 years (range 11–82) with myxedema coma were included. All patients had central nervous system manifestations, and sepsis was the most common precipitating factor. The median myxedema score was 72.5 (normal ≤25), and the median length of hospital stay was 12 days (range 3–18). The oral LT4 regimen consisted of a loading dose of 300–500 μg, followed by taper over the next 3–5 days. With this regimen, 13 patients survived, and only 1 patient died. Conclusion: Oral LT4 is an effective treatment option for myxedema coma when intravenous LT4 is unavailable.

Levothyroxine Formulations: Pharmacological and Clinical Implications of Generic Substitution.

Oral levothyroxine (LT4) is the standard therapy for patients with hypothyroidism. Oral LT4 is available in several formulations, including tablets, soft gel capsules and oral solution. Multiple brand-name and generic LT4 tablets are available. In the US, the Food and Drug Administration (FDA) has developed a protocol for establishing bioequivalence of LT4 formulations based on serum thyroxine (T4) levels after a single oral dose administered to healthy volunteers. This protocol has been criticized by professional endocrinology associations for using healthy individuals and ignoring serum thyroid-stimulating hormone (TSH) levels. In addition, the protocol did not initially correct for baseline T4 levels, although this was changed in a later version. There are concerns that the FDA’s protocol could allow products with clinically significant differences in bioavailability to be declared therapeutically equivalent and interchangeable. Once a generic LT4 has been shown to be bioequivalent to a brand-name LT4, it may be substituted for that brand-name LT4 with no need for dose adjustment or follow-up therapeutic monitoring. Often, the substitution is made by the pharmacy without the physician’s knowledge. Even small differences between LT4 formulations can cause significant changes in TSH levels. This may be a particular concern in vulnerable populations, including elderly, pregnant, and pediatric patients. Problems that can be encountered when switching between formulations or when original products are reformulated are discussed in this review. These problems include altered efficacy and adverse events, some of which can be caused by excipients. Patients should be maintained on the same LT4 preparation if possible. If the LT4 preparation is changed, TSH levels should be evaluated and, if necessary, the dose of LT4 adjusted.Funding: Merck.Plain Language Summary: Plain language summary available for this article.

Switch from tablet levothyroxine to oral solution resolved reduced absorption by intestinal parasitosis.

SummaryReduced intestinal absorption of levothyroxine (LT4) is the most common cause of failure to achieve an adequate therapeutic target in hypothyroid patients under replacement therapy. We present the case of a 63-year-old woman with autoimmune hypothyroidism previously well-replaced with tablet LT4 who became unexpectedly no more euthyroid. At presentation, the patient reported the onset of acute gastrointestinal symptoms characterized by nausea, loss of appetite, flatulence, abdominal cramps and diarrhea, associated with increase of thyrotropin levels (TSH: 11 mIU/mL). Suspecting a malabsorption disease, a thyroxine solid-to-liquid formulation switch, at the same daily dose, was adopted to reach an optimal therapeutic target despite the gastrointestinal symptoms persistence. Oral LT4 solution normalized thyroid hormones. Further investigations diagnosed giardiasis, and antibiotic therapy was prescribed. This case report is compatible with a malabsorption syndrome caused by an intestinal parasite (Giardia lamblia). The reduced absorption of levothyroxine was resolved by LT4 oral solution.Learning points:The failure to adequately control hypothyroidism with oral levothyroxine is a common clinical problem.Before increasing levothyroxine dose in a patient with hypothyroidism previously well-controlled with LT4 tablets but no more in appropriate therapeutic target, we suggest to investigate non adhesion to LT4 therapy, drug or food interference with levothyroxine absorption, intestinal infection, inflammatory intestinal disease, celiac disease, lactose intolerance, short bowel syndrome after intestinal or bariatric surgery, hepatic cirrhosis and congestive heart failure.LT4 oral solution has a better absorptive profile than the tablet. In hypothyroid patients affected by malabsorption syndrome, switch of replacement therapy from tablet to liquid LT4 should be tested before increasing the dose of LT4.

Levothyroxine Absorption Test in the management of a patient with persistent hypothyroidism

Hypothyroidism refers to the common pathological condition of thyroid hormone deficiency. If untreated, it can lead to serious adverse health effects and ultimately death1 . Synthetic thyroxine has been used to treat hypothyroidism successfully since 19272 . The optimal daily dose of 1.6- 1.8 ug/body weight (kg) per day of levothyroxine (LT4) is an appropriate replacement dose1–3. The absorption of oral LT4 occurs mostly in the jejunum and ileum (60–80% of the ingested dose)3–6. It is maximal when the stomach is empty and takes place within the first 3 hours of ingestion2 . For patients who require larger doses of LT4 than expected, the underlying cause can be challenging to determine2 . Several factors must be considered: low patient compliance, reduced LT4 absorption from interfering dietary factors and medications, or gastrointestinal disorders contributing to malabsorption7 . The most common cause of mal-absorption is poor or non-compliance with oral LT4 treatment by the patient8 . Compliance with treatment is the key to good outcomes in medical care.Medical non-compliance is a major public health problem that imposes a considerable financial burden upon modern healthcare systems and is also a source of ongoing frustration to doctors9 . The concept of pseudo-malabsorption of thyroid hormones was first outlined in 1991 when it was described a factitious disorder due to patient non-compliance with the intention to deceive10. An effective way to distinguish nonadherence from mal-absorption is to perform levothyroxine absorption testing (LAT)5 . This article aims describe the LT4 absorption rapid test in a patient with hypothyroidism, highlighting its importance in the diagnosis of LT4 pseudo-malabsorption.

Thyroid disorders in pregnancy

There are significant changes that occur in the thyroid gland and its function during pregnancy, thus making the assessment of thyroid functions in pregnancy substantially important. Normal pregnancy is associated with an increase in renal iodine excretion, an increase in T4 binding proteins, an increase in thyroid hormone production, and thyroid stimulatory effects of human chorionic gonadotropin (hCG), and the treatment targets are different from women who are not pregnant. Both hypothyroidism and hyperthyroidism are associated with significant impact on the fetomaternal unit and pregnancy outcomes. Evidence appears to support an association between overt thyroid dysfunction and an increased risk of infertility, and there is strong evidence to recommend treatment for overt hypothyroidism in pregnancy. The recommended treatment of maternal hypothyroidism is the administration of oral LT4.

Drug interactions in users of tablet vs. oral liquid levothyroxine formulations: a real-world evidence study in primary care.

Several medications may interact with levothyroxine (LT4) intestinal absorption or metabolism, thus reducing its bioavailability. We investigated the variability of thyroid stimulating hormone (TSH) levels and prescribed daily dosages (PDDs) of LT4 before and during potential drug-drug interactions (DDIs) in users of tablets vs. oral liquid LT4 formulations. By using the Italian general practice Health Search Database (HSD), we retrospectively selected adult patients with at least one LT4 prescription from 2012 to 2015 and at least 1 year of clinical history recorded. The incident prescription of interacting medications (e.g., proton pump inhibitors, calcium or iron salts) was the index date. Analysis was carried out using a self-controlled study design. Overall, 3965 users of LT4 formed the study cohort (84.1% women, mean age 56 ± 16.5 years). TSH variability on the entry date was greater among liquid LT4 users than in those prescribed with tablets as shown by the difference between 75th and 25th centile, which were 3.01 and 3.8, respectively. The incidence rate ratio (IRR) for TSH variability did not differ between groups, before and during exposure to DDIs. In contrast, PDDs less likely increased during the exposure to DDI with oral liquid LT4 compared with tablets (IRR = 0.84; 95% CI: 0.77-0.92), especially in patients with post-surgical hypothyroidism (IRR = 0.75; 95% CI: 0.64-0.85). In clinical practice, the use of oral liquid LT4 is not associated with increased PDDs, compared with tablets formulation, during exposure to DDIs. These results support the need for individualizing LT4 formulation to prescribe, especially in patients with various comorbidities and complex therapeutic regimens.

Excessive Uterine Bleeding in a Non-Compliant Patient With Profound Hypothyroidism: A Case Report and Review of the Literatures

Studies suggest that dysthyroidism is associated with disturbances in female menstruation with hypothyroidism being associated with abnormal uterine bleeding. We report a case of excessive uterine bleeding due to severe hypothyroidism. The patient was a 35-year-old female with a history of papillary thyroid cancer, status post total thyroidectomy and subsequent two times of radioactive iodine treatment for residual thyroid cancer. She presented to emergency room two times in 4 days for persistent heavy vaginal bleeding. Her complete blood count (CBC) upon admission showed hemoglobulin (HgB) of 7.0 g/dL and hematocrit (HCT) of 20.0%. The patient admitted that she had not taken levothyroxine (LT4) for at least 4 weeks. The thyroid function test showed elevated thyroid-stimulating hormone (TSH) level of 74.71 mIU/L and decreased free T4 level of 0.55 ng/dL (reference range is 0.34 - 5.60 mIU/L and 0.58 - 1.64 ng/dL, respectively). The patient was given two units of packed red blood cell transfusion to correct the hemorrhagic anemia and then was given 25 mg of conjugated estrogen (Premarin) intravenously (IV) to control the bleeding. She was discharged on oral medroxyprogesterone acetate (Provera) and LT4 and was asked for regular follow-ups. This is an uncommon but representative case of acute menstrual blood loss anemia caused by profound hypothyroidism. The disturbance of hypothalamus-pituitary-ovarian axis due to the severe hypothyroidism is likely the major etiology for the excessive dysfunctional uterine bleeding. J Med Cases. 2016;7(6):234-238 doi: http://dx.doi.org/10.14740/jmc2502w

Levothyroxine Malabsorption Induced by Diabetic Gastroparesis Exacerbated During Pregnancies: Effect of Intramuscular Levothyroxine Injections and Levothyroxine Soft Gel Capsules

ABSTRACT Objective: We report a case of severe hypothyroidism with levothyroxine (LT4) malabsorption induced by diabetic gastroparesis. This was exacerbated during the patient's 2 pregnancies. Management was improved by intramuscular (IM) LT4) injections and LT4 soft gel capsules. Methods: Case report with literature review. Results: A 23-year-old Hispanic female with type 1 diabetes (DM) and hypothyroidism developed diabetic gastroparesis with unpredictable responses to LT4. She had 2 pregnancies during which her oral LT4 was switched to weekly IM injections of LT4 that maintained her euthyroid state. An LT4 absorption test with 1,000 mcg LT4 revealed reduced LT4 absorption. A gastric emptying scan showed delayed emptying, and endoscopy demonstrated a large amount of residual food in the patient's stomach after an overnight fast. Weekly IM injections of LT4 and LT4 soft gel capsules maintained her euthyroid state after her last pregnancy with a follow-up longer than 1-year. A repeat LT4 absorption test with a 1,000-mcg LT4 soft gel capsule preparation demonstrated improved absorption compared to the initial LT4 absorption test. Conclusion: This may be the first patient described in the literature in whom diabetic gastroparesis was associated with impaired oral LT4 absorption and exacerbation during pregnancies. Our experience with this patient suggests that rational management of this problem may include IM LT4 injections or oral LT4 soft gel capsule administration. Abbreviations: CHF congestive heart failure DM diabetes mellitus IM intramuscular LT4 levothyroxine T4 thyroxine TFTs thyroid function tests TSH thyroid-stimulating hormone

The Clinical Utility of Free Thyroxine in Oral Levothyroxine Absorption Testing

Original absorption studies for levothyroxine (LT4) were validated using total thyroxine (TT4) measurements. Free thyroxine (FT4) has largely supplanted TT4 in clinical practice. The objective of our study was to assess the clinical utility of FT4 in oral LT4 absorption testing. In this retrospective electronic health record analysis, we recorded data of patients who underwent LT4 oral absorption testing between November 2010 and January 2012 because of persistent hypothyroidism despite a greater than anticipated weight-based dose of LT4. Patients included had primary hypothyroidism and an absorption test with assessment of both TT4 and FT4 measured at times 0, 30, 60, 90, 120, 180, 240, 300, and 360 minutes. The test was conducted with 1 mg (five 200-μg tablets) of Synthroid® after an overnight fast by a standard nonisotopic method. A total of 10 patients (3 men/7 women) underwent absorption testing. Prior to testing, the median daily LT4 dose was 250 μg (range, 150 to 350 μg). Three patients were also on liothyronine (10, 20, or 50 μg daily). Based on the calculated amount absorbed, 1 patient demonstrated subnormal absorption, and 9 patients were normal. Median body mass index was 33 kg/m2 (range, 21 to 50 kg/m2). Median calculated absorption was 105% (range, 3.7 to 195.6%). The correlation comparing FT4 and TT4 was 0.88 (95% confidence interval, 0.56 to 0.97; P<.001), a significant correlation. FT4 and TT4 correlated highly, even in patients who were severely hypothyroid; FT4 may be used interchangeably with TT4 as a qualitative assessment of suspected malabsorption using an oral LT4 absorption test.

Comparison Among the Daily Levothyroxine Doses According to the Etiology of Hypothyroidism

Background: The initial doses of levothyroxine (LT4) replacement therapy in patients with hypothyroidism in clinical practice are usually empirical, perhaps because of the lack of data suggesting how much hormone is needed in each patient’s situation. The aim of our study is to evaluate the daily dose of oral LT4 needed to achieve the TSH goals in patients with hypothyroidism caused by different etiologies. Methods: Patients were divided and analyzed according to the etiology of the hypothyroidism. We retrospectively evaluated data from 557 patients (501 women) with hypothyroidism who had normal serum TSH and free T4 (FT4) levels in at least two consecutive appointments in which they were using the same levothyroxine doses. Results: The mean dose of levothyroxine in the total sample was 91.3 ± 37.18 µg/day (1.39 ± 0.63 µg/kg/day). Stratifying by group: central hypothyroidism 53.94 ± 28.07 µg/day (0.82 ± 0.48 µg/kg/day); primary hypothyroidism (no intervention) 81.37 ± 29.84 µg/day (1.25 ± 0.53 µg/kg-day); post radioactive iodine (I 131 ) 97.42 ± 28.32 µ g/day (1.33 ± 0.55 µg/kg/day); post-thyroidectomy for benign causes 102.8 ± 36.96 µg/day (1.54 ± 0.59 µg/kg/day); post-thyroidectomy for thyroid cancer 138.5 ± 35.25 µg/day (2.17 ± 0.58 µg/kg/day). Conclusion: The dose of LT4 required to stabilize the patient varies according to different hypothyroidism etiologies. doi: http://dx.doi.org/10.4021/jem165w

Levothyroxine Absorption in Morbidly Obese Patients Before and After Roux-En-Y Gastric Bypass (RYGB) Surgery

Roux-en-Y gastric bypass (RYGB) modifies the anatomical structure of the upper intestine tract, reduces gastric acid secretion, and may impair LT4 absorption. The aim of this study was to evaluate the LT4 absorption in morbidly obese patients before and after RYGB. Thirty morbidly obese patients were divided in two groups: The NS group included 15 patients before RYGB surgery (BMI = 43.1 ± 4kg/m(2)), and the S group included 15 patients after surgery (BMI = 37.3 ± 4kg/m(2)). Two baseline samples were collected, and 600μg of oral LT4 tablets were administered. Blood samples were collected at 30, 60, 120, 180, 240, 300, and 1440min. Serum-free T4 (FT4), total T4 (TT4), and TSH were measured at each time point. The increase in TT4, FT4, and TSH (ΔTT4, ΔFT4, and ΔTSH) was calculated, subtracting from the baseline mean value. The pharmacokinetics parameters regarding LT4 absorption, maximum ΔTT4, and area under the curve(AUC) of both ΔTT4 and ΔFT4 were significantly higher in the S group compared with the NS group (p < 0.05). It was observed, however, that there was a significant delay in the absorption of LT4 in the S group. Basal serum TSH and leptin levels were higher in the NS group (p = 0.016 and 0.026, respectively), whereas basal serum TT4, FT4, ΔTSH, and the AUC of ΔTSH were similar between groups. In this study, we have demonstrated that Roux-en-Y bypass surgery does not diminish LT4 absorption. A small but significant delayed absorption of LT4, however, was observed in patients after surgery.