Nadia Caraccio

Five‐year follow‐up of percutaneous ethanol injection for the treatment of hyperfunctioning thyroid nodules: a study of 117 patients

Percutaneous ethanol injection (PEI) has been suggested as an alternative to radioiodine and surgery for the treatment of autonomous thyroid nodules (ATN).

Neuromuscular symptoms and dysfunction in subclinical hypothyroid patients: beneficial effect of L‐T4 replacement therapy

The presence of neuromuscular symptoms was ascertained by questionnaire in 33 consecutive patients with subclinical hypothyroidism (sHT) as compared to 44 age‐ and sex‐matched controls. Blood was sampled for PTH, magnesium, phosphate, and total and ionized calcium determination. Patients reporting three or more symptoms were also studied by surface electromyography (sEMG). The study was repeated following a six‐month L‐T4 course.

Thyroid autoimmunity and dysfunction associated with type I interferon therapy

Abstract.Type I interferons are currently used for the treatment of chronic viral hepatitis, multiple sclerosis and several hematological and solid tumors. Side effects are not uncommon, and include multiple alterations in thyroid function, some of which are unrelated to autoimmunity. Review of the literature revealed an overall mean prevalence of incident thyroid dysfunction of 6.2%, hypothyroidism occurring more frequently (3.9%) than hyperthyroidism (2.3%). Destructive thyroiditis characterized by early transient thyrotoxicosis followed by hypothyroidism has also been described. Thyroid dysfunction was mainly subclinical, and spontaneous resolution occurred in almost 60% of patients with or without withdrawal of interferon. Risk factors for developing thyroid abnormalities were female sex and the presence of pre-existing autoimmune thyroiditis. Whether prolonged interferon therapy will increase the likelihood of experiencing thyroid dysfunction, as well as the relationship between incident thyroid autoimmunity and the efficacy of interferon therapy, are still open questions. Although the most-likely explanation for thyroid disease occurring with type I interferon therapy remains an autoimmune reaction or immune system dysregulation, a direct inhibitory effect on thyrocytes may be presumed in patients who developed hypothyroidism without autoimmunity. However, the mechanisms of thyroid damage induced by type I interferons have not yet been clarified in detail. We recommend routine evaluation of serum thyroid-stimulating hormone during interferon therapy. A systematic thyroid assessment is useful only for those patients with pre-existing thyroiditis or incident dysfunction. Although discontinuation of interferon therapy is seldom required, it may be necessary in patients who develop Graves’ disease and overt hyperthyroidism.

Percutaneous ethanol injection treatment of autonomous thyroid adenoma: hormonal and clinical evaluation

OBJECTIVE We have evaluated the efficacy of percutaneous ethanol Injection as an alternative to surgery and iodlne‐131 treatment in solitary autonomous thyroid adenoma.

Age and gender substantially influence the relationship between thyroid status and the lipoprotein profile: results from a large cross-sectional study.

BACKGROUND Conflicting data are reported on the association between mild thyroid failure and lipid profile, primarily regarding serum triglyceride values and patients with slightly elevated thyrotropin (TSH, <10 mIU/L). In this study, we assessed the possible influence of gender and age on this relationship. METHODS The study included 2308 consecutive patients who were seen for suspected or diagnosed thyroid disease (1874 women, 434 men, mean age 47.5±14.1 and 46.9±14.0 years, respectively) and on whom studies of thyroid status and lipoprotein profile were conducted after an overnight fast. Patients with uncontrolled diabetes mellitus and those taking lipid-lowering drugs were excluded. RESULTS There were 628 patients receiving L-thyroxine who had a diagnosis of hypothyroidism: 200 were hyperthyroid, and 120 were still hypothyroid. Overall, 648 patients were hypothyroid, and 290 were hyperthyroid. No gender difference in the frequency of TSH values in the ranges studied (i.e., TSH frequency distribution) was observed. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDLc) values (p<0.0003 and p<0.003, respectively) as well as the LDL/high-density lipoprotein cholesterol (HDLc) ratio (p<0.03) were elevated not only in unselected women with TSH values in the 4th TSH group (>10 mIU/L) but also in those of the 3rd group (3.6-10.0 mIU/L) who were older than 50 years (TC and LDLc p=0.01, LDL/HDLc ratio p=0.02 vs. euthyroid women). Among unselected men, only those of the 4th TSH group had elevated triglyceride (p<0.0001) but not cholesterol values. However, men of the 3rd and 4th TSH group who were older than 65 years had significantly higher TC, LDLc, and LDL/HDLc values as well (p=0.03, p=0.02 and p=0.01, respectively vs. euthyroid men). In the final model of stepwise regression for predicting each lipid parameter variation on the basis of age, TSH, free thyroxine (FT4), and body mass index (BMI) analysis, age had the highest standardized coefficient (0.36 and 0.37, respectively), followed by TSH (0.20 and 0.11, respectively) and FT4 (-0.11 and -0.09, respectively) when looking at TC and LDLc; whereas BMI had the highest standardized coefficient (0.28), followed by age (0.15) and TSH (0.11) when looking at triglyceride variation. CONCLUSIONS This study confirms a gender differentiation in the relationship between hypothyroidism and the lipid profile, which is substantially influenced by age, especially in patients with mild thyroid impairment (TSH<10 mIU/L).

1513A>C polymorphism in the P2X7 receptor gene in patients with papillary thyroid cancer: correlation with histological variants and clinical parameters

INTRODUCTION The modulation of the purinergic receptor P2X7 may be implicated in human carcinogenesis. The 1513A>C and 489C>T polymorphisms of P2X7R gene induce loss of function and gain of function, respectively. AIM The aim of the study was to assess the frequency of both 1513A>C and 489C>T polymorphisms in patients with papillary thyroid carcinoma (PTC) and to evaluate the possible association with clinical and histological features. PATIENTS AND METHODS P2X7R analysis was performed in lymphocytes from 121 PTC patients (100 women, 21 men; aged 43.4 +/- 13.6 yr), 100 matched healthy subjects, and 80 patients with nodular goiter. RESULTS The minor allele frequency for 1513A>C polymorphism in PTC patients with the classical variant was similar to controls (0.21 and 0.20, respectively), whereas it resulted in a significant increase in patients with the follicular variant (0.36; P = 0.01 vs. classical variant, and P = 0.005 vs. controls). In detail, 13.6% of patients with PTC follicular variant were homozygous for the 1513C allele, compared to 2.6% of patients with the classical variant and 2% of controls. Moreover, a positive relationship between 1513A>C polymorphism and either cancer diameter (Rho = 0.22; P = 0.02) or TNM stage (Rho = 0.38; P < 0.001) was found. No significant difference in the genotype frequency of 489C>T polymorphism between PTC patients and healthy controls was observed (0.42 and 0.47, respectively). CONCLUSIONS Our data show, for the first time, a strong association between 1513A>C polymorphism of P2X7R gene and the follicular variant of PTC. Further studies are needed to confirm the possible role of this polymorphism as a novel clinical marker of PTC follicular variant and its usefulness in selecting patients with different clinical outcome.

Does Treating Subclinical Hypothyroidism Improve Markers of Cardiovascular Risk

Subclinical hypothyroidism is defined as an elevated serum thyroid-stimulating hormone (TSH) level in the face of normal free thyroid hormone values. The overall prevalence of subclinical hypothyroidism is 4–10% in the general population and up to 20% in women aged >60 years. The potential benefits and risks of therapy for subclinical hypothyroidism have been debated for 2 decades, and a consensus is still lacking. Besides avoiding the progression to overt hypothyroidism, the decision to treat patients with subclinical hypothyroidism relies mainly on the risk of metabolic and cardiovascular alterations. Subclinical hypothyroidism causes changes in cardiovascular function similar to, but less marked than, those occurring in patients with overt hypothyroidism. Diastolic dysfunction both at rest and upon effort is the most consistent cardiac abnormality in patients with subclinical hypothyroidism, and also in those with slightly elevated TSH levels (>6 mIU/L). Moreover, mild thyroid failure may increase diastolic blood pressure as a result of increased systemic vascular resistance. Restoration of euthyroidism by levothyroxine replacement is generally able to improve all these abnormalities. Early clinical and autopsy studies had suggested an association between subclinical hypothyroidism and coronary heart disease, which has been subsequently confirmed by some, but not all, large cross-sectional and prospective studies. Altered coagulation parameters, elevated lipoprotein (a) levels, and low-grade chronic inflammation are regarded to coalesce with the hypercholesterolemia of untreated patients with subclinical hypothyroidism to enhance the ischemic cardiovascular risk. Although a consensus is still lacking, the strongest evidence for a beneficial effect of levothyroxine replacement on markers of cardiovascular risk is the substantial demonstration that restoration of euthyroidism can lower both total and low-density lipoprotein-cholesterol levels in most patients with subclinical hypothyroidism. However, the actual effectiveness of thyroid hormone substitution in reducing the risk of cardiovascular events remains to be elucidated. In conclusion, the multiplicity and the possible reversibility of subclinical hypothyroidism-associated cardiovascular abnormalities suggest that the decision to treat a patient should depend on the presence of risk factors, rather than on a TSH threshold. On the other hand, levothyroxine replacement therapy can always be discontinued if there is no apparent benefit. Levothyroxine replacement therapy is usually safe providing that excessive administration is avoided by monitoring serum TSH levels. However, the possibility that restoring euthyroidism may be harmful in the oldest of the elderly population of hypothyroid patients has been recently raised, and should be taken into account in making the decision to treat patients with subclinical hypothyroidism who are aged >85 years.

Age-Related Modifications in the Regulation of the Hypothalamic-Pituitary-Thyroid Axis

We studied the hypothalamic-pituitary-thyroid function in two groups of healthy elderly subjects: group A (n = 23, age range 65-80 years), and group B (n = 11, age range 81-92 years), and in 32 controls, aged 20-60. A TRH test for TSH and prolactin was performed in all subjects, while the TSH circadian modulation was evaluated in elderly subjects only. Group B showed significantly lower fT3 and TSH, and higher fT4 levels with respect to controls (fT3: 4.4 +/- 0.2 vs. 5.2 +/- 0.2 pmol/l, p < 0.05; fT4: 13.1 +/- 0.9 vs. 11.4 +/- 0.4 pmol/l, p < 0.05; TSH: 1.07 +/- 0.21 vs. 1.46 +/- 0.13 mIU/l, p < 0.05). Morning TSH showed an inverse correlation with age (r = -0.42; p < 0.02) among the 34 elderly subjects, but not among controls. Evidence for TSH circadian modulation was found only in group A (nighttime TSH: 1.60 +/- 0.17, vs. daytime: 1.25 +/- 0.13 mIU/l, p < 0.001). The TRH-stimulated TSH peak was reduced among all elderly subjects with respect to controls (A: 6.26 +/- 0.64 mIU/l, p = 0.01; B: 5.02 +/- 0.58 mIU/l, p < 0.01). The maximal PRL response was also blunted (A: 25.7 +/- 2.6 micrograms/l, B: 27.7 +/- 5.2 micrograms/l, p < 0.0005). In conclusion, a resetting of the pituitary threshold of the TSH feedback suppression, along with complex alterations in peripheral thyroid hormone levels, may progressively develop in older people, becoming apparent only with extreme senescence. Moreover, the TSH nocturnal surge may be lost with increasing age, thus providing evidence also for hypothalamic dysfunction.

Prevalence of cancer in follicular thyroid nodules: is there still a role for intraoperative frozen section analysis?

The optimal surgical management of follicular thyroid nodules and the effectiveness of frozen section (FS) analysis in planning the operation are still controversial. In this study, we reviewed the prevalence of cancer in 309 consecutive patients (230 females, 79 males, aged 42 +/- 13 years) with follicular nodules at fine-needle aspiration cytology (FNAC) and the efficacy of FS evaluation in selecting cancers. On the whole, the prevalence of cancer was 20.1%; the occurrence of follicular variants of papillary cancer (14.9%) was threefold higher than follicular cancers (5.2%). The presence of atypical features at FNAC selected nodules with a significantly higher prevalence of cancer (46.7%, p = 0.01). FS analysis was performed in 142 patients and recognized only 8 of 27 (30%) cancers, one fourth of them with atypia at FNAC. In conclusion, this study confirms a 20% overall prevalence of malignancy in patients with follicular thyroid nodules. The association of cell atypia with a follicular pattern may define a subgroup of nodules more likely to be malignant. FS was seldom effective in recognizing cancer confirming the doubt on its cost effectiveness in planning the surgical approach. Protocols aimed at a better cytologic identification of follicular variants of papillary cancer should be considered.

Human Mitochondrial Transcription Factor A Reduction and Mitochondrial Dysfunction in Hashimoto’s Hypothyroid Myopathy

BackgroundMitochondrial changes have been described in muscle tissue in acquired hypothyroidism. Among the molecular mechanisms by which thyroid hormones regulate expression of nuclear genes encoding for regulatory proteins of mitochondrial respiratory function, the mitochondrial transcription factor A (h-mtTFA) has been proposed to be a target of thyroid hormone action. The aim of this study has been to relate h-mtTFA levels in the skeletal muscle of patients affected by Hashimoto’s hypothyroidism and myopathy (HHM) to muscle disease and thyroid status.Patients and MethodsEleven HHM patients underwent complete thyroid status and neurologic assessment, along with determination of exercise lactate anaerobic threshold (LT) and muscle biopsy in which h-mtTFA levels were measured and mtDNA was analyzed.ResultsDecreased exercise lactate threshold, presence of cytochrome c oxidase negative fibers, reduction of cytochrome c oxidase activity, and mitochondrial DNA copy number at muscle biopsy were indicative of mitochondrial involvement in these patients. Furthermore, muscle h-mtTFA levels were reduced to a variable extent in comparison with a group of euthyroid controls. The h-mtTFA levels were inversely correlated with TSH and LT lactate, and positively correlated with FT4.ConclusionsThese results indicate that low levels of the h-mtTFA occur in skeletal muscle of HHM and suggest that abnormal h-mtTFA turnover may be implicated in the pathogenesis of mitochondrial alterations in this disease.