Thyroxine Absorption Research Articles

P-68 A CHALLENGING CASE OF HYPOTHYROIDISM

Abstract Introduction Hypothyroidism is a common disease. L thyroxine once reached the stomach, undergoes disintegration and dissolution, and the active ingredient must reach the actual site of absorption. Disintegration is highly affected by the type of the formulation, the fasted or fed state, the gastric residence time, and the gastric motor function. The dissolution process consists of the release of solute molecules from the solid phase to the liquid one. Gastric juice pH. food, drugs and H pylori can affect L thyroxine absorption. Clinical Case IAA; A 54 y old female patient, known case of follicular thyroid carcinoma (FTC) since 2013, managed with total thyroidectomy, multiple radioactive iodine doses due to residual tissue. Post operative hypocalcemia that was resolved within a year. She was doing well on L- thyroxine suppressive dose of 200mcg/d. In 2018; she was operated for breast carcinoma, received chemotherapy and tamoxifen tablets. She was doing well on L thyroxine suppressive dose 250 mcg/d taken one hour before breakfast on an empty stomach, and was in complete remission regarding FTC. She lost to follow up for nearly one year. Her investigations: TSH= 39.7 mu/l, FT4= 6 (normal= 6.5-22 pmol/l), hemoglobin= 10.7 g/dl, calcium 8.7 mg/dl (normal= 8.4-10.5mg/dl not on calcium tab), celiac and H pylori serological screening were negative. TSH after 3 months =12.8 mu/l, She denied non compliance, Dose of L- thyroxine increased and gluten free diet was tried and did not work, dose increased to 400mcg/d. She was lost to follow up and came after one year,TSH =80 mu/l. L-thyroxine absorption test was performed; and L thyroxine mal-absorption was confirmed. She was advised to crush L-thyroxine 400 mcg/day and take it with water. TSH after two months was =13, free T4 =14 (normal=6.5-22 pmol/l). Gastroscopy showed pan moderate edematous gastritis and moderate erosive duodenitis. Duodenal biopsy showed chronic inflammation, negative celiac disease or malignancy. Conclusion Thyroid hormone is important for growth of intestinal mucosa. Selective L thyroxine malabsorption in the present case could be related to poor drug compliance and chronically uncontrolled thyroid status lead to intestinal edema and malabsorption. The other explanation was that gastritis caused inability of the stomach to properly dissolve tablet preparations to yield the active ingredient. The good response to crushed L thyroxine, which was a method of giving the drug to infants, suggested L thyroxine malabsorption problem started from the stomach.

7370 Review of the Literature, and Report of a Series of Patients with Lactose Intolerance and Levothyroxine Malabsorption in Treatment with Liquid L-T4

Abstract Disclosure: S. Ferrari: None. A. Patrizio: None. V. Mazzi: None. F. Ragusa: None. C. Botrini: None. G. Elia: None. E. Balestri: None. E. Barozzi: None. L. Rugani: None. F. Bracchitta: None. G. Stoppini: None. G. Frenzilli: None. E. Baldini: None. C. Virili: None. S. Benvenga: None. P. Fallahi: None. A. Antonelli: None. Intolerance to lactose-containing foods is frequent, with a prevalence of 7-20% in Caucasians, and of 80-95% among Native Americans. Therefore, lactose intolerance (LI) issue needs to be taken in account in the management of hypothyroid patients needing large doses of levothyroxine (L-T4) (> 1.7-2 μg/kg/day) to achieve euthyroidism. Indeed, the absorption of oral T4 may be affected in patients with LI, by following a diet containing lactose, whereas it is resulted to be improved with a lactose-free diet. Lactose is often present as a supplementary ingredient in many commercially available drugs, as L-T4 preparations. In susceptible individuals, drugs containing lactose can cause LI symptoms, and lactose in L-T4 preparations could impair thyroxine absorption. Moreover, it has been shown that patients with LI requiring an increased dosage of L-T4 benefit from a treatment with a lactose-free L-T4 formulation. The lactose-free liquid L-T4 formulation is able to circumvent LI malabsorption leading to the normalization of thyroid-stimulating hormone (TSH) in patients with subclinical hypothyroidism, and long term stable TSH levels. Further studies will be needed to evaluate the liquid L-T4 formulation in larger numbers of patients with hypothyroidism and LI. Presentation: 6/3/2024

Serum Copper, Iron, and Total Iron Binding Capacity in Hypothyroidism: A Case Control Study

Background: Thyroid hormone metabolism is linked to iron metabolism. Thyroperoxidase, a key enzyme in the biosynthesis of thyroid hormones, is iron-dependent. Thus, iron deficiency might be the primary cause of hypothyroidism. Copper is another trace element that has been linked to thyroid status. Copper regulates excessive thyroxine (T4) absorption and reduces cell damage during thyroid hormone synthesis. The present study clarified the possible correlations between iron and copper levels as well as total iron binding capacity (TIBC) and triiodothyronine (T3), T4, as well as thyroid-stimulating hormone (TSH) levels in healthy and hypothyroid subjects.Materials and methods: Thirty-five healthy subjects and 35 hypothyroid subjects were included in this study. Serum T3, T4, and TSH levels were measured using the enzyme linked fluorescence assay. Serum iron levels and TIBC were estimated using ferrozine/magnesium carbonate method, while serum copper levels were estimated using colorimetric method.Results: Copper levels were not significantly different between healthy and hypothyroid subjects. Iron and T4 levels were significantly lower in hypothyroid subjects compared with those in healthy subjects, while TIBC and TSH levels were significantly higher. There was no significant correlation between copper levels and T3, T4, and TSH levels.Conclusion: There were inverse correlations between TIBC and T4 as well as iron levels, and there was no significant correlation between copper levels and all thyroid function parameters. Routine examination of iron levels and thyroid function is highly recommended for early diagnosis and therapy of hypothyroidism.Keywords: total iron binding capacity, iron, copper, hypothyroidism

Validity of the Rapid Thyroxine Absorption Test for the Differentiation Between Levothyroxine Non-compliance and Malabsorption in Thyroid-Stimulating Hormone Refractory Hypothyroidism.

Introduction Thyroid-stimulating hormone refractory hypothyroidism is a common problem. This is due to either non-compliance or malabsorption with levothyroxine (LT4). The study aimed to assess the validity of the rapid LT4 absorption test in the differentiation between LT4 malabsorption and non-compliance. Methods A cross-sectional study was done from January to October 2022 at Faiha Specialized Diabetes, Endocrine, and Metabolism Center, in Basrah, Southern Iraq. Twenty-two patients with thyroid-stimulating hormone (TSH) refractory hypothyroidism were evaluated by rapid LT4 absorption test with measurements of TSH before 1000 μg LT4 intake, and free thyroxine (pmol/l) and total thyroxine before (nmol/l) (baseline TT4 and baseline FT4) and two hours after (2-HR TT4 and 2-HR FT4). The findings were compared with the following four-week-long supervised LT4 absorption test results. Results In the rapid LT4 absorption test, patients with (2-HR FT4 minus baseline FT4 ≤1.28 pmol/l (0.1 ng/dl) or 2-HR FT4 minus baseline FT4 1.28-6.43 pmol/l (0.1-0.5 ng/dl) plus 2-HR TT4 minus baseline TT4<72.08 nmol/l (5.6 µg/dl)), eight out of 10 patients were correctly diagnosed with malabsorption. And in those with (2-HR FT4 minus baseline FT4 ≥6.43 (0.5 ng/dl) or 2-HR FT4 minus baseline FT4 1.28-6.43 (0.1-0.5 ng/dl) plus 2-HR TT4 minus baseline TT4≥72.08 (5.6 µg/dl)), 11 out of 12 patients were correctly diagnosed as non-compliant. This criterion showed 88.8% sensitivity, 15.4% specificity, 80% positive predictive value, and 91.6% negative predictive value for diagnosing LT4 malabsorption. Conclusion The rapid LT4 absorption test showed good diagnostic accuracy in differentiating non-compliance from malabsorption when (2-HR FT4 minus baseline FT4) and (2-HR TT4 minus baseline TT4) were used as criteria.

ODP445 If You Can't Beat Them, Join Them: A Therapeutic Strategy for Maintaining Euthyroidism in Non-Compliant Patients

Abstract Levothyroxine (LT4) has been the mainstay therapy for hypothyroidism since synthesized in 1949, and it was depicted to be a daily, usually lifelong, therapy. LT4 may have many interactions with other medications, food, and supplements, for which it should also be taken on an empty stomach, at least thirty minutes before consuming any other product, to achieve adequate absorption. These two characteristics of LT4 therapy are two of the main reasons for patient non-compliance, leading to uncontrolled hypothyroid state shown by abnormal thyroid stimulating hormone (TSH) levels, and associated symptoms. LT4 properties, such as seven-day half-life, as well as increased peripheral conversion to metabolically active T3 by local deiodinase enzyme when there are low T4 levels, provide a scenario where it can be used at longer dosing intervals than the traditional daily dosing. This is the case of a 27-year-old female with past medical history of hypothyroidism on daily replacement therapy with 50mcg of branded LT4, presenting to the endocrinologist for continuation of care. Over the course of visits, patient showed uncontrolled thyroid disease with altered levels of TSH, ranging from 5.4 uIU/mL up to 46.8 uIU/mL (N: 0.45-5. 0 uIU/mL), despite appropriate dose adjustments and frequent TSH and free T4 (FT4) monitoring. Due to persistent clinical and biochemical hypothyroidism requiring dosage increases up to 300mcg, patient was referred for a thyroxine absorption test to rule out LT4 malabsorption versus medication non-compliance. A supervised dose of 812mcg of the same branded LT4 was provided, based on body weight, and TSH, free T3, and free T4 levels were measured before administration and sequentially at 30, 45, 60, 90, 120, 240, and 360 minutes after dose, yielding TSH values ranging from 0.11 uIU/mL to 0.18 uIU/mL, consistent with adequate TSH suppression. Patient admitted to erratic medication ingestion for which a dose of 150 mcg LT4 orally daily was started. TSH levels remained above 9. 0 uIU/mL, for which a trial of complete weekly dosage was offered and accepted by patient. Two months after therapeutic adjustment, patient became both clinically and biochemically euthyroid, with TSH level of 1.35 uIU/mL without any adverse effects from excess hormone intake. Medication non-compliance is an issue every physician must battle with. This case serves as an example of the great impact of individualized modification of LT4 administration to establish a therapeutic regimen that adjusts to each patient's lifestyle while allowing them to remain clinically stable, which is a great benefit for both the patient and the clinician. Although studies already exist in proving the benefits of weekly versus daily therapy in such patients without major risks, further investigation should be conducted, as therapeutic guidelines could potentially change altogether in the future to avoid, or at least reduce, non-compliance consequences. Presentation: No date and time listed

Comparison of supervised rapid thyroxine absorption test in refractory and well-controlled primary hypothyroid patients in a tertiary care center in Sri Lanka and formulation of a prediction model to predict the expected FT4 rise during the test

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Ramadan Fasting and Changes in Thyroid Function in Hypothyroidism: Identifying Patients at Risk.

Background:Ramadan fasting (RF) is associated with major changes in meal times. This can affect thyroxine absorption and thyroid function (TF) in patients with hypothyroidism. We aimed to examine the short- and long-term impact of RF on TF in patients with primary hypothyroidism on levothyroxine.Methods:TF tests in patients with primary hypothyroidism attending an endocrine center in the United Arab Emirates were retrospectively analyzed. The impact of RF on TF, namely serum thyrotropin (TSH) TSH, free thyroxine (fT4) and free triiodothyronine (fT3), was investigated in 481 patients within 3 months before Ramadan (BR), 1–2 weeks (PR1), and 3–6 months (PR2) post-Ramadan. Controlled TF was defined as TSH between 0.45 and 4.5 μIU/mL. Inadequate control was defined as TSH >4.5 μIU/mL. Loss of control was defined as having controlled TF at BR and inadequate control at PR1. Multivariable regression analyses were used to assess the association of baseline TSH, baseline levothyroxine dose, and medication use with loss of thyroid control in Ramadan.Results:TSH increased significantly from a median of 2.0 (0.8–3.7) μIU/mL at BR to 2.9 (1.4–5.6) μIU/mL at PR1 (p < 0.001). This was accompanied by a fall in fT4 and fT3 at PR1 (p < 0.001). 25.5% of patients with previously controlled TF at BR had deterioration in TF at PR1. Sixty-one percent of patients with previously uncontrolled TF at BR remained uncontrolled at PR1. Baseline TSH was significantly associated with loss of thyroid control in Ramadan with an odds ratio (95% confidence interval) of 1.5 (1.17–1.92) (p < 0.001), whereas other variables, including medications known to affect levothyroxine absorption were not associated with loss of control. TSH, fT4, and fT3 levels returned to normal at PR2.Conclusions:RF can negatively affect TF of patients on levothyroxine replacement. Although this effect is modest and transitory in most patients, a significant minority exhibit more pronounced, and clinically relevant changes. The latter includes those with higher TSH BR, and a smaller group whose thyroid disease appears to be particularly affected by the mealtime and lifestyle changes of Ramadan.

Myxoedema coma caused by immunotherapy-related thyroiditis and enteritis.

SummaryThyroid dysfunction is among the most common immune-related adverse reactions associated with immune checkpoint inhibitors. It most commonly manifests as painless thyroiditis followed by permanent hypothyroidism. This usually causes mild toxicity that does not interfere with oncological treatment. In rare instances, however, a life-threatening form of decompensated hypothyroidism called myxoedema coma may develop. We present a case of myxoedema coma in a woman in her sixties who was treated with a combination of CTLA-4 and PD-1 immune checkpoint inhibitors; for stage four malignant melanoma. She became hypothyroid and required thyroxine replacement after an episode of painless thyroiditis. Six months after the initial diagnosis of malignant melanoma, she presented to the emergency department with abdominal pain, profuse diarrhoea, lethargy and confusion. She was drowsy, hypotensive with a BP of 60/40 mmHg, hyponatraemic and hypoglycaemic. Thyroid function tests (TFTs) indicated profound hypothyroidism with a TSH of 19 mIU/L, and undetectable fT3 and fT4, despite the patient being compliant with thyroxine. She was diagnosed with a myxoedema coma caused by immune-related enteritis and subsequent thyroxine malabsorption. The patient was treated with i.v. triiodothyronine (T3) and methylprednisolone in the ICU. While her clinical status improved with T3 replacement, her enteritis was refractory to steroid therapy. A thyroxine absorption test confirmed persistent malabsorption. Attempts to revert to oral thyroxine were unsuccessful. Unfortunately, the patient’s malignant melanoma progressed significantly and she passed away four months later. This is the first reported case of myxoedema coma that resulted from two distinct immune-related adverse reactions, namely painless thyroiditis and enterocolitis.Learning pointsMyxoedema coma, a severe form of decompensated hypothyroidism is a rare immunotherapy-related endocrinopathy.Myxedema coma should be treated with either i.v. triiodothyronine (T3) or i.v. thyroxine (T4).Intravenous glucocorticoids should be co-administered with thyroid hormone replacement to avoid precipitating an adrenal crisis.Thyroid function tests (TFTs) should be monitored closely in individuals with hypothyroidism and diarrhoea due to the risk of thyroxine malabsorption.A thyroxine absorption test can be used to confirm thyroxine malabsorption in individuals with persistent hypothyroidism.

Over-the-counter protein supplement resulting in impaired thyroxine absorption in a hypothyroid patient

SummaryWhey protein is a popular dietary supplement that is claimed to provide multiple health benefits. It has been shown to delay gastric emptying and impair ileal nutrient absorption. Additionally, some of the other additives like papain enzyme, soy lecithin in these protein supplements could interfere with L-thyroxine absorption. There is no evidence in the literature for the effects of protein supplements on L-thyroxine absorption. Herein, we describe a case of a 34-year-old lady who was on endocrinology follow up for primary hypothyroidism with stable thyroid-stimulating hormone (TSH) levels within the normal range while on L-thyroxine with a dose of 125 µg daily for the last 3 years, presenting with mild hypothyroid symptoms and elevated TSH level following a recent introduction of a protein supplement by her physical care adviser. Her treatment adherence and ingestion technique were good throughout, she was not on other medications or herbal remedies, there were no other changes in her food pattern or features suggestive of malabsorption, she was not pregnant, was taking the same L-thyroxine brand and TSH test was done from the routine lab. Since the only factor which could have contributed to the deranged TSH levels was the recent introduction of the whey protein supplement, we advised her to stop the protein supplement while continuing the same dose of L-thyroxine. Her TSH level was repeated in 6 weeks and was found to be normal (1.7 mIU/L). Our case report demonstrates that over-the-counter protein supplements could interfere with L-thyroxine absorption. Therefore, patients on L-thyroxine should be cautious when taking them.Learning pointsOver-the-counter protein supplements could interfere with oral L-thyroxine absorption.The underlying mechanism could be the effect of whey protein by delaying gastric emptying and reduced responsiveness of organic anion transporters in the ileum, and there may be a contribution from other additives like papain and soy lecithin present in these supplements.When there is an elevation of previously stable thyroid-stimulating hormone (TSH) value in a hypothyroid patient on oral L-thyroxine, the patient's assessment should include inquiring for a recent introduction of protein supplement, in the absence of other well-known risk factors.Discontinuation of protein supplement results in normalization of thyroid function tests.Patients on oral L-thyroxine should be cautious when taking over-the-counter protein supplementation.

Thyroxine absorption test protocol for hypothyroid patients on high dose thyroxine replacement

Abstract presented at the Phillippine Nurses UK World Cafe Convention, 24 October 2020

SAT-505 Non-Adherence to Levothyroxine Treatment, a Condition Not to Be Ignored nor Forgotten, Should Be Assessed by Thyroxine Absorption Test

Hypothyroidism due to non-compliance with levothyroxine (LT4) treatment is not infrequent (pseudomalabsorption). It should be considered in patients with persistent severe clinical and biochemical hypothyroidism even after excessive LT4 dose. The diagnosis can be confirmed by LT4 Absorption Test. We present 4 female patients (age range 21-44 years) with suspicion of (pseudo)malabsorption who underwent absorption test (3 patients with autoimmune hypothyroidism and one patient with hypothyroidism after total thyroidectomy due to Graves’ disease). They presented with persistent hypothyroidism (TSH 30 to >100 mU/L) even after gradual increase to excessive LT4 dose (400-700 μg daily). All denied non-compliance; drug and dietary interference with LT4 absorption and nephrotic syndrome were excluded. Two patients with autoimmune hypothyroidism underwent absorption test with their last daily LT4 dose as loading dose (700 and 200 μg) followed by hourly free T4 (fT4) determination for 6 hours, after an overnight fast. In one fT4 remained stable during the test (maximum fT4 increase +10% from baseline levels) indicating true malabsorption. New absorption test with combination of LT4 and ascorbic acid resulted in a fT4 raise +139% and further investigation revealed achlorhydria due to pernicious anaemia. The patient was treated with LT4 400μg x 2, Liothyronine 40μg x 2 and vitamin C in high doses. In the other patient, fT4 rose to maximum +71% from baseline 6 hours after the loading dose intake. She was diagnosed with pseudomalabsorption and became compliant and biochemically euthyroid with 150 μg/day LT4. Another two patients (1 with autoimmune, 1 with hypothyroidism after total thyroidectomy) underwent absorption test with a weight-adjusted weekly fasting LT4 dose (1,6 μg/kg of the body weight X 7) followed by hourly fT4 measurement for 5 hours. Peak fT4 reached a level of +290% and +309% of the baseline fT4 levels, respectively, 3 hours after administration of the dose. Both patients had pseudomalabsorption. They continued to deny non-compliance and were treated with once weekly supervised weight-adjusted LT4 over 6 consecutive weeks, resulting in TSH normalization. Pseudomalabsorption should be ruled out with LT4 absorption test in patients suspected of non-compliance with LT4 treatment, after drug/dietary interference, nephrotic syndrome and intestinal malabsorption are excluded. Different absorption protocols have been suggested with different loading doses (standard or weight-adjusted) and different duration (rapid 2-6 hours, long 5 weeks). An LT4 absorption peak with >70% increase in fT4 levels in 3 hours with a linear increase of fT4 in the first 1-1.5 hour is expected in the rapid test. In the long test normalization of TSH and fT4 is anticipated week 6 (1 week after the final dose). In case the patient remains non-compliant, treatment options include a single supervised weekly LT4 dose.

Efficacy and Safety of Once-Weekly Thyroxine for Thyroxine-Resistant Hypothyroidism.

ContextNoncompliance with thyroxine therapy is the most common cause of poor control of hypothyroidism. An open-label prospective study to compare once-weekly thyroxine (OWT) with standard daily thyroxine (SDT) was undertaken.DesignPatients taking thyroxine doses of >3 μg/kg/d, with or without normalization of TSH, were included and administered directly observed OWT or nonobserved SDT according to patient preference based on their weight for 6 weeks. Furthermore, patients on OWT were advised to continue the same at home without supervision.ResultsTwenty six of 34 patients on OWT and 7 of 18 patients on SDT achieved a TSH <10 μIU/mL (P < 0.05), and 2 patients from the SDT arm were lost to follow-up. During home treatment, 15 of 25 at 12 weeks and 19 of 23 contactable patients at a median follow-up of 25 months maintained TSH below target. Thyroxine absorption test was unable to predict normalization of TSH at 6 weeks of OWT therapy. No adverse events were seen with OWT-treated patients over the 12-week follow-up period. OWT has significantly higher efficacy (OR = 5.1) than SDT for patients with thyroxine-resistant hypothyroidism and is not associated with side effects.ConclusionOWT benefits a majority of patients in the long-term treatment of thyroxine-resistant hypothyroidism, in the real-world setting.

Ulcerative Colitis as a Novel Cause of Increased Need for Levothyroxine.

Background: Thyroxine absorption takes place at the small intestine level and several disorders affecting this intestinal tract lead to thyroxine malabsorption. An increased need for thyroxine has also been observed in gastric disorders due to variations in drug dissolution and/or in its ionization status. Ulcerative colitis (UC) is an inflammatory bowel disease that has been postulated as a potential cause of the increased need for thyroxine, but there is a lack of evidence on this topic. This study is aimed at measuring the thyroxine requirement in hypothyroid patients with UC.Patients and Methods: Among 8,573 patients with thyroid disorders consecutively seen in our referral center from 2010 to 2017, we identified 34 patients with a definite diagnosis of UC. Thirteen of them were hypothyroid (12 F/1 M; median age = 53 years), bearing UC during the remission phase and in need for thyroxine treatment, thus representing the study group. The dose of T4 required by UC patients has been compared to the one observed in 51 similarly treated age- and weight-matched patients, compliant with treatment and clearly devoid of any gastrointestinal and /or pharmacological interference.Results: To reach the target serum TSH, the dose of thyroxine had to be increased in twelve out of thirteen (92%) hypothyroid patients with ulcerative colitis. The median thyroxine dose required by UC patients was 1.54 μg/kg weight/day, that is 26% higher than the control patients, to reach a similar TSH (1.23 μg/kg weight/day; p = 0.0002). Since half of our study group consisted of patients aged over 60 years old, we analyzed the effect of age on the subdivision in two classes. Six out of seven (86%) adult patients (<60 years) required more T4 than those in the respective control group (1.61 vs. 1.27 μg/kg weight/day; +27%; p < 0.0001). An increased dose (+17%; p = 0.0026) but to a lesser extent, was also observed in all patients over 60 years, as compared to the control group.Conclusions: In almost all hypothyroid patients with UC, the therapeutic dose of thyroxine is increased. Therefore, ulcerative colitis, even during clinical remission, should be included among the gastrointestinal causes of an increased need for oral thyroxine.

SAT-553 Gut Microbiota Involved in Thyroxine Metabolism and Development of Subclinical Hypothyroidism

The diversity, structure, and stability of the gut microbiota can influence hosts’ nutrition, energy, metabolism, and immunity through intestinal nutrient-sensing mechanisms, the gut-brain axis, or changes in intestinal permeability. It was reported that gut microbiota can influence hosts’ selenium concentration and 3,5,3’-triiodothyronine (T3) conversion, therefore participating in thyroid hormone metabolism. The detailed relationship of microbiota and thyroid disorder is not clear yet. In our study, an open-level randomized clinical trail (RCT) was performed in 100 people with subclinical hypothyroidism (SCH) in July 2017. Patients were randomly divided into L-thyroxine treated group (dosage was depended on thyroid function test) or untreated group. Fecal sample were collected and microbiome were analyzed by 16S rDNA high-throughput sequencing. The discrepancy of the microbiome community structure were obvious between not only the two groups, but also individuals with different drug dose within L-thyroxine group, as calculated by principle components analysis (PCA), principle coordinate analysis (PCoA) and non-metric multi-dimensional scaling (NMDS). Moreover, the microbial profile of certain patients, who were diagnosed to need to adjust their drug dose after nine months (March, 2018), showed same tendencies in PCA and NMDS analysis, which means microbiota may have correlation with the development of SCH. The abundance of some species (eg., Bacteroides, Lactobacillus, Streptococcus) showed a positive correlation with the drug dose. Those species were reported with sulfatase or glucuronidase activities, which could participate in the hydrolysis process of thyroid hormone and secondary bile acid. These results indicated that microbiota attributed in thyroxine absorption process in gut, and cholesterol or bile acid level might have correlation with thyroid dysfunction. However, in our test, we did not observe the obvious correlation between drug dose and serum cholesterol level. Taken together, these results indicated that gut microbiota may act as an important factor in influencing the occurrence, development and prognosis of thyroid dysfunction, and may partially responsible for the high risk of SCH in patients with hypercholesterolemia. The casual relationship between gut microbiota and thyroid dysfunction need to be further discussing.

The value of thyroxine absorption test followed by weekly thyroxine administration in determining the cause of persistent hypothyroidism despite high doseL-thyroxine treatment: a case report

The value of thyroxine absorption test followed by weekly thyroxine administration in determining the cause of persistent hypothyroidism despite high dose<scp>L</scp>-thyroxine treatment: a case report

A thyroxine absorption test followed by weekly thyroxine administration: a method to assess non-adherence to treatment

For patients who remain hypothyroid despite the administration of what would seem adequate doses of levothyroxine (L-T4), the underlying cause can be difficult to determine. The possibility of a biological cause should first be explored; however, in the majority of cases, poor adherence to medication is likely to be the main cause of treatment failure. When non-adherence is suspected but not volunteered, options to confirm the suspicion are limited. In this study, we identified patients for whom known drugs and pathological causes of L-T4 malabsorption were excluded, and despite often high doses of L-T4, the patients remained hypothyroid. Using a weight-determined oral L-T4 bolus administration, absorption was initially assessed in 23 patients. In nearly all patients, this was shown to be maximal at 120 min post-ingestion. This was then followed by the continued administration of a weekly T4 bolus for a 4-week period after which TSH and free T4 (fT4) levels were recorded. All patients showed a rise in fT4 at 120 min following the administration of the L-T4 bolus, with a mean increase of 54±3% from baseline. Following the treatment period, using an equivalent weekly L-T4 dose, which was significantly less than that of the daily dose taken by the patients before the test, TSH reduced from baseline in ~75% of cases. Using this combination of tests allows significant malabsorptive problems to be identified first and then potential non-adherence to be demonstrated. A management plan can then be implemented to increase adherence, aiming to improve treatment outcomes.

Thyroxine treatment: absorption, malabsorption, and novel therapeutic approaches

Although levothyroxine sodium is highly prescribed worldwide, the exact daily dosage, mode of assumption, and refractoriness to treatment are as yet matter of debate. Growing evidence highlighted that undertreatment with T4 has detrimental effects on several tissues and functions. This is even more proper during pregnancy, when an inadequate treatment may increase the likelihood of obstetric complications and may affect the neuropsychological performance during childhood [1]. In adult patients, subclinical hypothyroidism has been reported to be involved in impaired lipid metabolism and atherosclerosis as well as in cardiovascular disorders [2]. The need for an individually tailored dose potently emerges from these findings. Thyroxine treatment should no longer be prescribed according to the commercially available dose size, but rather related to the patient’s weight and age [3]. Two major issues are indeed crucial to obtain an optimal daily dose for a specific patient: an unbiased serum TSH value and an efficient absorption process of thyroxine. The assumption that serum TSH would be a reliable marker of pharmacologic euthyroidism in all tissues has been challenged since its value may be affected by a number of drugs, cosmetics, and pathophysiological conditions [4, 5]. Even the upper limit of normal serum TSH ( or [ 2.5 mU/l) has been questioned [5]. However, it still remains the best available marker, since the direct measurement of thyroxine absorption is not an easy task. Assuming an unbiased serum TSH value in each patient, the absorption process of T4 becomes key for a successful treatment. The daily dose required to obtain the desired TSH value/therapeutic effect is, in fact, not simply a mirror of the ingested dose of thyroxine. One of the major determinants on pharmacological thyroid homeostasis is, thus the incomplete absorption of oral thyroxine (60–80 % of the administered dose) which takes place at the intestinal level. Indeed, the absorbed dose of T4 may be considered the resultant of: (a) patient compliance; (b) some physiological (pregnancy, weight) and/or paraphysiological (behavioral, nutritional) or pharmacological conditions of increased or decreased T4 need; and (c) the presence of diseases which cause malabsorption of T4 (see [6] for review). Repeated failure to reach therapeutic target in response to an ‘‘adjusted’’ dose is a fairly common and frustrating experience. Larger doses of thyroxine are required to attain the desired serum TSH concentrations, leading to expensive and often inappropriate hormonal monitoring. Once attributed to pseudomalabsorption, the increased need for thyroxine may be also explained by an impaired absorption of levothyroxine. Recently, the modality of drug ingestion gained attention. There is now evidence that at least 1 h delay between T4 tablet ingestion and breakfast warrant the best therapeutic achievement [7]. According to Benvenga et al. [8], even the common use of coffee close to the T4 tablet ingestion results in an altered T4 absorption. According to these authors, coffee physically interacts with T4 tablets and retains thyroxine within the intestinal lumen thus making it less available for absorption [8]. This mechanism closely resembles the one suggested for the reduced absorption of thyroxine in patients with celiac sprue [9]. In these patients, the amount of active hormone available for the absorption may be M. Centanni Chief of Endocrinology Unit, Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy

Levothyroxine Pseudomalabsorption and Thyroxine Absorption Testing with Use of High-Dose Levothyroxine: Case Report and Discussion

To report the case of a 55-year-old woman who had been prescribed a daily dose of 1,000 μg of levothyroxine for the treatment of hypothyroidism but still had severe biochemical hypothyroidism and to discuss the use of thyroxine absorption testing to diagnose pseudomalabsorption. The patient was admitted to the hospital for supervised thyroxine absorption testing. Baseline thyroid function tests were performed. An oral dose of 1,000 μg of levothyroxine was administered while the patient had an empty stomach, and thyroid function tests were repeated at 2, 4, and 6 hours after administration. She was also given all her prescribed antihypertensive medications, and the blood pressure (which had been persistently high) was measured every 2 hours. After administration of 1,000 μg of levothyroxine, a rapid improvement in the results of her thyroid function tests was noted. Similarly, a rapid decrease in her blood pressure was observed after supervised administration of her antihypertensive medications. A diagnosis of nonadherence to treatment (pseudomalabsorption of levothyroxine) was made. After reduction of her levothyroxine dosage to 100 μg daily, results of thyroid function tests showed improvement. The doses of her antihypertensive medications were likewise altered. We suggest that patients who are receiving doses of levothyroxine of more than 2 μg/kg of body weight, with persistently increased thyroid-stimulating hormone levels, should undergo testing for malabsorption and pseudomalabsorption of levothyroxine. Thyroxine absorption testing with use of high-dose levothyroxine is useful in diagnosing pseudomalabsorption but needs formal evaluation and validation.

The difficult patient: drug interaction and the influence of concomitant diseases on the treatment of hypothyroidism

Although most hypothyroid patients do well with one single tablet of thyroxine daily, approximately 10% are dissatisfied and another important group of patients is difficult to control. We reviewed the most common causes for frequent-dose adjustment or high-dose requirement, including poor compliance with therapy and inadequate medication. Since these two causes have been ruled out, drug interaction and other concomitant diseases need to be investigated. Requirements of thyroxine increase in all conditions characterized by impaired gastric acid secretion. Proton-pump inhibitors, antacids and a long list of drugs may decrease thyroxine absorption. In addition, a series of diseases including celiac disease and chronic inflammatory intestinal diseases, as well as nutritional habits may be important in patient control. Finally, we mention the effects of a growing list of drugs and thyroid disruptors that may also affect thyroid hormone metabolism at many levels.

Conditions and drugs interfering with thyroxine absorption

Food, dietary fibre and espresso coffee interfere with the absorption of levothyroxine. Malabsorptive disorders reported to affect the absorption of levothyroxine include coeliac disease, inflammatory bowel disease, lactose intolerance as well as Helicobacter pylori (H. pylori) infection and atrophic gastritis. Many commonly used drugs, such as bile acid sequestrants, ferrous sulphate, sucralfate, calcium carbonate, aluminium-containing antacids, phosphate binders, raloxifene and proton-pump inhibitors, have also been shown to interfere with the absorption of levothyroxine.