Peptide receptor radionuclide therapy in patients with medullary thyroid carcinoma: predictors and pitfalls.

BACKGROUND: For progressive metastatic medullary thyroid carcinoma (MTC), the available treatment options with tyrosine kinase inhibitors result in grade 3-4 adverse events in a large number of patients. Peptide Receptor Radionuclide Therapy (PRRT), which has also been suggested to be a useful treatment for MTC, is usually well tolerated, but evidence on its effectivity is very limited. METHODS: Retrospective evaluation of treatment effects of PRRT in a highly selected group of MTC patients, with progressive disease or refractory symptoms. In addition, a retrospective evaluation of uptake on historical 111In-DTPA-octreotide scans was performed in patients with detectable tumor size > 1 cm. RESULTS: Over the last 17 years, 10 MTC patients were treated with PRRT. Four out of 10 patients showed stable disease at first follow-up (8 months after start of therapy) whereas the other 6 were progressive. Patients with stable disease were characterized by a combination of both a high uptake on 111In-DTPA-octreotide scan (uptake grade ≥ 3) and a positive somatostatin receptor type 2a (SSTR2a) expression of the tumor by immunohistochemistry. Retrospective evaluation of historical 111In-DTPA-octreotide scans of 35 non-treated MTC patients revealed low uptake (uptake grade 1) in the vast majority of patients 31/35 (89%) with intermediate uptake (uptake grade 2) in the remaining 4/35 (11%). CONCLUSIONS: PRRT using 177Lu-octreotate could be considered as a treatment in those patients with high uptake on 111In-DTPA-octreotide scan (uptake grade 3) and positive SSTR2a expression in tumor histology. Since this high uptake was present in a very limited number of patients, this treatment is only suitable in a selected group of MTC patients.

[An unexpected cause of nausea]. / Een onverwachte oorzaak van misselijkheid.

An 88-year old woman had a sudden onset of nausea and vomiting. She had an end colostomy following a curative resection of rectal cancer six years earlier. As we suspected a high gastrointestinal obstruction, an abdominal CT scan was made. This showed a paracolostomic herniation, including herniation of the stomach.

Effects of Thyrotropin on Peripheral Thyroid Hormone Metabolism and Serum Lipids.

BACKGROUND: Subclinical hypothyroidism is associated with dyslipidemia and atherosclerosis. Whether these effects are in part mediated via direct effects of thyrotropin (TSH) on peripheral thyroid hormone (TH) metabolism and/or concentrations of serum lipids is not clear. OBJECTIVE: This study examined whether TSH has direct effects on peripheral TH metabolism and serum lipids. METHODS: Eighty-two patients with differentiated thyroid cancer were retrospectively analyzed. All patients had undergone total thyroidectomy and 131I remnant ablation. During follow-up, two successive injections of recombinant human TSH (rhTSH) were administered to patients on a stable dose of levothyroxine. In all patients, TSH, thyroxine (T4), free T4 (fT4), triiodothyronine (T3), reverse T3 (rT3), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, lipoprotein(a), and triglyceride levels were measured immediately before the first and approximately 72 hours after the second injection of rhTSH. RESULTS: After rhTSH stimulation, T3 values decreased (from 1.91 to 1.81 nmol/L; p < 0.001). T4, fT4, and rT3 did not change. After rhTSH, median apolipoprotein B increased from 0.90 to 0.92 g/L (p = 0.03), lipoprotein(a) from 0.21 to 0.24 g/L (p < 0.001), and triglycerides from 1.98 to 2.50 mmol/L (p < 0.001). Serum high-density lipoprotein cholesterol decreased from 0.98 to 0.81 mmol/L (p < 0.001). Multiple regression analysis showed that the changes in lipids were most closely associated with the decrease in T3 levels. CONCLUSIONS: TSH has direct effects on peripheral TH metabolism by decreasing T3 levels in levothyroxine-treated thyroidectomized patients. This decrease in T3 levels is accompanied by unfavorable changes in serum lipids.

Serum microRNA profiles in athyroid patients on and off levothyroxine therapy.

BACKGROUND: Levothyroxine replacement treatment in hypothyroidism is unable to restore physiological thyroxine and triiodothyronine concentrations in serum and tissues completely. Normal serum thyroid stimulating hormone (TSH) concentrations reflect only pituitary euthyroidism and, therefore, novel biomarkers representing tissue-specific thyroid state are needed. MicroRNAs (miRNAs), small non-coding regulatory RNAs, exhibit tissue-specific expression patterns and can be detectable in serum. Previous studies have demonstrated differential expression of (precursors of) miRNAs in tissues under the influence of thyroid hormone. OBJECTIVE: To study if serum miRNA profiles are changed in different thyroid states. DESIGN AND METHODS: We studied 13 athyroid patients (6 males) during TSH suppressive therapy and after 4 weeks of thyroid hormone withdrawal. A magnetic bead capture system was used to isolate 384 defined miRNAs from serum. Subsequently, the TaqMan Array Card 3.0 platform was used for profiling after individual target amplification. RESULTS: Mean age of the subjects was 44.0 years (range 20-61 years). Median TSH levels were 88.9 mU/l during levothyroxine withdrawal and 0.006 mU/l during LT4 treatment with a median dosage of 2.1 µg/kg. After normalization to allow inter-sample analysis, a paired analysis did not demonstrate a significant difference in expression of any of the 384 miRNAs analyzed on and off LT4 treatment. CONCLUSION: Although we previously showed an up-regulation of pri-miRNAs 133b and 206 in hypothyroid state in skeletal muscle, the present study does not supply evidence that thyroid state also affects serum miRNAs in humans.

Effects of Thyroid Hormone on Urinary Concentrating Ability.

BACKGROUND: Hypothyroidism has been associated with impaired urinary concentrating ability. However, previous reports on thyroid hormone and urinary concentrating ability in humans only studied a limited number of patients with autoimmune thyroid disease or used healthy controls instead of paired analysis within the same patients. OBJECTIVE: To study the urinary concentrating ability in athyreotic patients with differentiated thyroid cancer on and off levothyroxine treatment as they are exposed to different thyroid states as part of their treatment in the absence of an autoimmune disease. DESIGN AND METHODS: We studied 9 patients (mean age of 42.7 years) during severe hypothyroid state (withdrawal of levothyroxine before radioactive iodine therapy) and TSH-suppressed state (on levothyroxine therapy). At these two points, serum and urine samples were collected after 14 h of overnight fasting without any food or drink. RESULTS: Serum and urine osmolality were not significantly different between on and off levothyroxine treatment. Serum creatinine levels were significantly higher in patients off versus on levothyroxine treatment (87.0 vs. 71.0 µmol/L, respectively; p = 0.044) and, correspondingly, the estimated glomerular filtration rate was significantly lower (89.6 vs. 93.1 mL/min, respectively; p = 0.038). CONCLUSION: Short-term, severe hypothyroidism has no effect on urinary concentrating ability. Our study confirms the well-known effects of thyroid hormone on serum creatinine concentrations.

Sorafenib-Induced Changes in Thyroid Hormone Levels in Patients Treated for Hepatocellular Carcinoma.

Context: The pathogenesis of tyrosine kinase inhibitor-induced thyroid hormone (TH) alterations are still a matter of debate. Objective: The objective of this study was to determine the effects of sorafenib on TH levels in patients with hepatocellular carcinoma (HCC) and to evaluate possible mechanisms. Design: We performed a prospective cohort study between 2009 and 2016. Setting: This study was conducted at a tertiary referral center. Patients: This study included 57 consecutive patients with HCC who were treated with sorafenib. Main Outcome Measure: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels were measured every 6 weeks, and extensive thyroid function tests (TFTs) were measured before treatment (t0), after 6 weeks (t6), and at the end of therapy. The effect of sorafenib on TH transport by monocarboxylate transporter (MCT)8 or MCT10 was tested in transfected COS1 cells. Results: Four patients (7%) developed thyroiditis. Among the other patients, 30% had elevation of TSH or FT4 above the normal range. Overall, between t0 and t6, mean TSH increased from 1.28 to 1.57 mU/L (P < 0.001) and mean FT4 from 18.4 to 21.2 pmol/L (P < 0.001). Simultaneously, the serum triiodothyronine (T3)/reverse triiodothyronine ratio and the (T3/thyroxine) ×100 ratio decreased. Sorafenib decreased cellular T3 uptake by MCT8 and to a lesser extent by MCT10. Conclusions: These in vivo data suggest that sorafenib affects TFTs on multiple levels. Our in vitro experiments suggest a possible role of sorafenib-induced inhibition of T3 transport into the cell by MCT8 and MCT10.

Selenium Status Is Positively Associated with Bone Mineral Density in Healthy Aging European Men.

OBJECTIVE: It is still a matter of debate if subtle changes in selenium (Se) status affect thyroid function tests (TFTs) and bone mineral density (BMD). This is particularly relevant for the elderly, whose nutritional status is more vulnerable. DESIGN AND METHODS: We investigated Se status in a cohort of 387 healthy elderly men (median age 77 yrs; inter quartile range 75-80 yrs) in relation to TFTs and BMD. Se status was determined by measuring both plasma selenoprotein P (SePP) and Se. RESULTS: The overall Se status in our population was low normal with only 0.5% (2/387) of subjects meeting the criteria for Se deficiency. SePP and Se levels were not associated with thyroid stimulating hormone (TSH), free thyroxine (FT4), thyroxine (T4), triiodothyronine (T3) or reverse triiodothyronine (rT3) levels. The T3/T4 and T3/rT3 ratios, reflecting peripheral metabolism of thyroid hormone, were not associated with Se status either. SePP and Se were positively associated with total BMD and femoral trochanter BMD. Se, but not SePP, was positively associated with femoral neck and ward's BMD. Multivariate linear analyses showed that these associations remain statistically significant in a model including TSH, FT4, body mass index, physical performance score, age, smoking, diabetes mellitus and number of medication use. CONCLUSION: Our study demonstrates that Se status, within the normal European marginally supplied range, is positively associated with BMD in healthy aging men, independent of thyroid function. Thyroid function tests appear unaffected by Se status in this population.

Novel risk factors for hospital-acquired hyponatraemia: a matched case-control study.

BACKGROUND: Hospital-acquired hyponatraemia is a common and potentially serious condition. Risk factors for hospital-acquired hyponatraemia have not been studied in a controlled fashion. Methods From 1501 patients in whom serum sodium (S(Na)) was determined, 50 cases with hospital-acquired hyponatraemia (in-hospital decrease in S(Na)>or= 7 mmol/l to < 136 mmol/l) were identified. They were matched by age, gender and department to 69 normonatraemic controls. RESULTS: In the 50 cases, S(Na) fell from 141 +/- 2 to 130 +/- 4 mmol/l, while controls remained normonatraemic. During the development of hyponatraemia, C-reactive protein (CRP) increased in cases (median from 23 to 146 mg/l), whereas it decreased in controls (median from 31 to 24 mg/l, P = 0.008). Additional factors associated with hospital-acquired hyponatraemia included diabetes mellitus (16/50 vs. 10/69, P = 0.009) and the use of insulin (12/50 vs. 4/69, P = 0.007), antibiotics (41/50 vs. 38/69, P = 0.006) and opioids (32/50 vs. 27/69, P = 0.005). Multivariate conditional logistic regression showed that the use of insulin [odds ratio (OR) 10.5, 95% confidence interval (CI) 1.5-72.4], antibiotics (OR 4.5, 95% CI 1.4-14.6) and opioids (OR 2.9, 95% CI 1.1-7.8) was also independently associated with hospital-acquired hyponatraemia. Mortality (6/50 vs. 1/69, P = 0.04) and intensive care admission (15/50 vs. 7/69, P = 0.008) were higher in cases. CONCLUSIONS: An increase in CRP and the use of insulin, antibiotics and opioids are novel risk factors for hospital-acquired hyponatraemia. These factors represent interesting new clues regarding the pathophysiology of hospital-acquired hyponatraemia, suggesting that the acute-phase response, pain and/or direct drug effects could be involved in the release of antidiuretic hormone.