Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report

There is a frequently encountered subset of hypothyroid patients who are refractory to standard thyroid hormone replacement treatment and require unexpectedly high doses of levothyroxine. In addition to clinical situations where hypothyroid patients are non-compliant, or where there is the possibility of excipient-induced disease exacerbation (gluten/celiac disease), therapeutic failure may be due to impaired absorption of the administered drug. The common approach to managing patients with unusual thyroxine needs is to escalate the dose of levothyroxine until targeted TSH levels are achieved. This approach can increase the risk for prolonged exposure to supratherapeutic doses of levothyroxine, which increase the chances of adverse outcomes. Repeated adjustments of levothyroxine can also escalate the costs of treatment, as frequent office visits and laboratory tests are required to determine and maintain the desired dose. Clinicians should take a systematic approach to managing patients whom they suspect of having treatment-refractory hypothyroidism. This may include searching for, and adjusting, occult medical conditions and/or other factors that may affect the absorption of levothyroxine, before up-titrating the dose of traditional levothyroxine therapy. Depending on the underlying pathology, another approach that may be considered is to try alternative formulations of levothyroxine that are less susceptible to intolerance issues related to excipients, or, in some cases, to malabsorption. The early discovery of these factors via a thoughtful patient work-up may avoid unnecessary thyroid medication adjustments and their consequences for both patients and clinicians

Editorial: The Association of Other Autoimmune Diseases in Patients With Thyroid Autoimmunity

Autoimmune thyroid diseases (AITD) are T cell-mediated organ-specific autoimmune disorders resulting from an immune dysregulation leading to a thyroid immune attack (Antonelli and Benvenga). Graves’ disease and Hashimoto’s thyroiditis are the two main clinical presentations of AITD, and their clinical hallmarks are thyrotoxicosis and hypothyroidism, respectively. In many cases, AITD may be associated in the same patient with other organ-specific autoimmune attacks (such as in the case of type II autoimmune polyglandular syndrome, or type I diabetes, etc). Furthermore, AITD and thyroid function abnormalities have been frequently described in patients with systemic rheumatologic autoimmune diseases. Conversely, patients affected with the above mentioned autoimmune disorders are more frequently affected by AITD.In this Research Topic, constituted by nineteen papers, we review and discuss new evidence about the association of other autoimmune diseases in patients with AITD. Among other organ-specific autoimmune disorders, the associations of AITD with chronic autoimmune gastritis (Cellini et al.), vitiligo (Baldini E et al.), lichen (Guarneri et al.), psoriasis (Ruffilli et al.), myasthenia gravis (Lopomo and Berrih-Aknin) and glomerulopathies (Santoro et al.) have been treated. Also the associations of AITD, in systemic autoimmune diseases have been treated (as Sjögren’s syndrome, Baldini C et al.; systemic sclerosis, Fallahi et al.; systemic lupus erythematosus, Ferrari et al.; Antiphospholipid syndrome, Versini; sarcoidosis, Fazzi et al.; the autoimmune/inflammatory syndrome induced by adjuvants, Watad et al.; rheumatoid arthritis, Bliddal et al.; Hepatitis C Virus and mixed cryoglobulinemia, Ferri et al.; and, psoriathic arthritis, Ruffilli et al.). Furthermore peculiar aspects associated with post partum thyroiditis have been reviewed too (Di Bari et al., Le Donne et al.).The exact pathogenetic mechanisms underlying the above reported associations are not completely known. It has been hypothesized that the influence of genetic (Coppedè), and environmental factors (Antonelli and Benvenga), could lead to the onset of autoimmune phenomena in different organs in the same subject, characterized by predominance of a Th1 immune pattern at the beginning, and in the active phase of these disorders.In conclusion, an association of other autoimmune diseases in patients with thyroid autoimmunity has been shown, and this Research Topic provides an extensive update of the literature, and suggests interesting points for new investigations

Thyroid disorders induced by checkpoint inhibitors

Immune checkpoint inhibitors are drugs that inhibit the "checkpoint molecules". Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). The increased immune response induced by these agents leads to immune-related adverse events (irAEs), that can vary from mild to fatal, according to the organ system and severity. Immune-related endocrine toxicities are thyroid dysfunctions, hypophysitis, adrenal insufficiency, and type 1 diabetes mellitus, and are usually irreversible in 50%. In particular, hypophysitis is the most frequent anti-CTLA-4-antibodies-related irAE, while thyroid abnormalities (as hypothyroidism, thyrotoxicosis, painless thyroiditis, or even "thyroid storm") are more frequently associated with anti-PD-1-antibodies. The combination of anti-CTLA-4-antibodies, with anti-PD-1-antibodies, is associated with about 30% of irAEs. Clinical signs and symptoms vary according to the influenced target organ. Endocrinopathies can often be managed by the treating oncologist. However in more severe cases (i.e. in the presence of insulin-dependent diabetes, adrenal insufficiency, or disorders of gonadal hormones, or severe hyperthyroidism, or hypothyroidism, or long-lasting management of hypophysitis) an endocrinological evaluation, and a prompt therapy, are needed

The tyrosine kinase receptor c-met, its cognate ligand HGF and the tyrosine kinase receptor trasducers STAT3, PI3K and RHO in thyroid nodules associated with Hashimoto's thyroiditis: an immunohisto-chemical characterization

Hepatocyte growth factor (HGF) exerts proliferative activities in thyrocytes upon binding to its tyrosine kinase receptor c-met and is also expressed in benign thyroid nodules as well as in Hashimoto's thyroiditis (HT)

The Stability of TSH, and Thyroid Hormones, in Patients Treated With Tablet, or Liquid Levo-Thyroxine

Approximately, 5% of the population is affected by hypothyroidism, mainly women and persons aged more than 60 years. After the diagnosis of hypothyroidism the usual therapy is tablet levothyroxine (L-T4), with a monitoring of the thyroid-stimulating hormone (TSH) level in primary hypothyroidism every 6-8 weeks and L-T4 is adjusted as necessary to reach an euthyroid state. Once TSH is stabilized in the normal range, it is recommended to conduct annual testing in the treated subjects to warrant suitable replacement. More recently advances regarding L-T4 treatment are the introduction of new oral formulations: the liquid solution, and soft gel capsule. The soft gel capsule permits a quick dissolution in the acid gastric pH. The liquid preparation does not require an acid gastric environment. Many pharmacokinetic studies demonstrated a more rapid absorption for the liquid L-T4, or capsule, than with tablet. Many studies have shown that the liquid, or capsule, formulations can overcome the interaction with foods, drugs or malabsorptive conditions, that are able to impair the tablet L-T4 absorption. Lately studies have suggested that liquid L-T4 can permit to maintain more efficiently normal TSH levels in hypothyroid patients in the long-term follow-up, than tablet L-T4, both in patients with malabsorptive states, and in those without malabsorption. Further large, prospective, longitudinal studies are needed to evaluate the stability of TSH, in hypothyroid patients treated with different L-T4 formulations

Thyroid dysfunctions induced by tyrosine kinase inhibitors

INTRODUCTION: Recently, tyrosine kinase inhibitors (TKIs) have emerged as a new class of anticancer therapy. Although generally considered less toxic than cytotoxic chemotherapy, TKIs do cause significant side effects including fatigue and hypertension. In addition, thyroid dysfunction is a well-known adverse effect of TKI. AREAS COVERED: This review provides a comprehensive assessment of TKI-induced thyroid dysfunctions by sunitinib, sorafenib, pazopanib, imatinib, dasatinib, nilotinib, vandetanib, axitinib, motesanib and tivozanib. Furthermore, the potential mechanisms that result in this toxicity, the clinical impact of thyroid dysfunction in these patients and the controversies regarding treatment with thyroid hormone (TH) therapy are evaluated. EXPERT OPINION: Detection of TKI-induced thyroid dysfunction requires routine monitoring of thyroid function and may necessitate treatment. Potential benefits in developing thyroid dysfunction and potential harm in treating it necessitate controlled studies. Finally, if treatment is pursued, appropriate dosing and timing of TH replacement will require prospective clinical evaluation

Nutraceuticals in thyroidology: A review of in vitro, and in vivo animal studies

Nutraceuticals are defined as a food, or parts of a food, that provide medical or health benefits, including the prevention of different pathological conditions, and thyroid diseases, or the treatment of them. Nutraceuticals have a place in complementary medicines, being positioned in an area among food, food supplements, and pharmaceuticals. The market of certain nutraceuticals such as thyroid supplements has been growing in the last years. In addition, iodine is a fundamental micronutrient for thyroid function, but also other dietary components can have a key role in clinical thyroidology. Here, we have summarized the in vitro, and in vivo animal studies present in literature, focusing on the commonest nutraceuticals generally encountered in the clinical practice (such as carnitine, flavonoids, melatonin, omega-3, resveratrol, selenium, vitamins, zinc, and inositol), highlighting conflicting results. These experimental studies are expected to improve clinicians’ knowledge about the main supplements being used, in order to clarify the potential risks or side effects and support patients in their use

CXCL8 and CXCL11 chemokine secretion in dermal fibroblasts is differentially modulated by vanadium pentoxide

An increase in skin rashes or atopic dermatitis has been observed in individuals working with vanadium. However, to the best of our knowledge no in vivo or in vitro studies have evaluated the effect of exposure to vanadium in dermal fibroblasts. Cells viability and proliferation were assessed by WST-1 assay, cells were treated with increasing concentrations of V2O5(1, 10 and 100 nM). CXCL8 and CXCL11 concentrations were measured in the supernatants using an ELISA assay. V2O5was not observed as having a significant effect on dermal fibroblast's viability and proliferation. However, it was revealed that V2O5was able to induce the secretion of CXCL8 and CXCL11 chemokines into dermal fibroblasts. V2O5synergistically increased the effect of interferon (IFN)? on CXCL11 secretion. In addition, V2O5synergistically increased the effect of the tumor necrosis factor a on CXCL8 secretion and abolished the inhibitory effect of IFN?. V2O5induction of CXCL8 and CXCL11 chemokines may lead to the appearance and perpetuation of an inflammatory reaction into the dermal tissue. Further studies are required to evaluate dermal integrity and manifestations in subjects occupationally exposed, or living in polluted areas

The Daily Consumption of Cola Can Determine Hypocalcemia: A Case Report of Postsurgical Hypoparathyroidism-Related Hypocalcemia Refractory to Supplemental Therapy with High Doses of Oral Calcium

The consumption of soft drinks is a crucial factor in determining persistent hypocalcemia. The aim of the study is to evaluate the biochemical mechanisms inducing hypocalcemia in a female patient with usual high consumption of cola drink and persistent hypocalcemia, who failed to respond to high doses of calcium and calcitriol supplementation. At baseline and after pentagastrin injection, gastric secretion (Gs) and duodenal secretion (Ds) samples were collected and calcium and total phosphorus (Ptot) concentrations were evaluated. At the same time, blood calcium, Ptot, sodium, potassium, chloride, magnesium concentrations, and vitamin D were sampled. After intake of cola (1 L) over 180 min, Gs and Ds and blood were collected and characterized in order to analyze the amount of calcium and Ptot or sodium, potassium, magnesium, and chloride ions, respectively. A strong pH decrease was observed after cola intake with an increase in phosphorus concentration. Consequently, a decrease in calcium concentration in Gs and Ds was observed. A decrease in calcium concentration was also observed in blood. In conclusion, we confirm that in patients with postsurgical hypoparathyroidism, the intake of large amounts of cola containing high amounts of phosphoric acid reduces calcium absorption efficiency despite the high doses of calcium therapy

Difficult abdominal access in laparoscopic cholecystectomy in elderly patients: our experience and literature review.

AbstractLaparoscopic cholecystectomy (LC) is currently the gold standard treatment for symptomatic cholelithiasis. LC is actually condidered a medium complexity surgical operation. LC could be technically hard, especially if patient underwent previous surgical operation. These difficulties increase in outcome of previous operation in right upper quadrant (RUQ): in this case laparoscopic access is defined as an “hard access”. We present two cases in which an unconventional access was performed: laparoscopic cholecistectomy is a safe and feasible procedure, although a careful assessment preoperative is indispensable. In particular, caution is required in both the triangulation of the trocar, which in pneumoperitoneum induction