Thyroid autoimmunity and hypothyroidism are associated with deep molecular response in patients with chronic myeloid leukemia on tyrosine kinase inhibitors.

PURPOSE: Thyroid alterations including de novo appearance of thyroid autoimmunity are adverse effects of tyrosine kinase inhibitors, used in solid and hematologic cancer therapy, but the relationship between thyroid alterations during this treatment and the outcome of chronic myeloid leukemia remains unclear. Aim of this study was to investigate whether the presence of thyroid alterations may affect the clinical outcome of chronic myeloid leukemia on tyrosine kinase inhibitors. METHODS: We evaluated thyroid function and autoimmunity in 69 chronic myeloid leukemia patients on long-term therapy looking at the association between thyroid abnormalities and disease molecular response. RESULTS: Overall, 24 of 69 (34.8%) had one or more thyroid abnormalities during therapy. A high percentage of patients (21/69, 30.4%) showed thyroid autoimmunity (positive thyroid autoantibodies with ultrasound hypoechogenicity), while clinical and subclinical hypothyroidism and subclinical hyperthyroidism were, respectively, found in 4 of 69 (5.8%) and 3 of 69 (4.3%) of cases. Second-generation tyrosine kinase inhibitors resulted significantly associated (14/32, 43.7%) with Hashimoto's thyroiditis, compared to first generation (7/37, 18.9%; p = 0.03). Interestingly, we also found a significant association between euthyroid (14/26, 53.8%) and hypothyroid Hashimoto's thyroiditis (4/26, 15.4%) in patients with deep molecular response, as compared to euthyroid (3/43, 7%; p = 0.0001) and hypothyroid (0/43, 0%; p = 0.02) Hashimoto's thyroiditis patients with major molecular response. CONCLUSIONS: Our study confirms and extends our knowledge on the tyrosine kinase inhibitors effects on thyroid, showing that thyroid autoimmunity is frequently observed in chronic myeloid leukemia patients on long-term therapy and is associated with a better oncological response.

Fifteen-year follow-up of thyroid function in lithium patients.

OBJECTIVE: To study prospectively the course of clinically relevant thyroid dysfunction in a cohort of patients on long-term lithium treatment. METHOD: Patients (no.=150) who had undergone a cross-sectional evaluation of their thyroid function in 1989, when they were at different stages of lithium treatment, were followed up for thyroid circulating thyroid antibodies, hypothyroidism, hyperthyroidism, and thyroidectomy, during a further period of lithium exposure of up to 15 yr. RESULTS: Annual rates of newly developed circulating thyroid antibodies and hypothyroidism were 1.7 and 1.5%, respectively. Subjects with thyroid antibodies had a higher chance of requiring substitution treatment with levothyroxine for hypothyroidism compared with subjects with no evidence of thyroid antibodies (6.4% annual rate compared to 0.8%; relative risk: 8.4; 95% confidence interval: 2.9-24.0). One case of hyperthyroidism was observed over 976 patient-yr. Three patients underwent thyroidectomy during followup (two for multinodular goiter and one for multicentric papillary carcinoma). CONCLUSIONS: Lithium may be associated with hypothyroidism in particular in the presence of circulating thyroid antibodies. Incidence of thyroid antibodies is comparable with that reported for the general population. Hyperthyroidism and thyroid cancer are rare.

High serum circulating telopeptide type I in multinodular goiter.

Recently, concentrations of serum carboxy-terminal-1-telopeptide (ICTP), a marker of bone collagen resorption, were found to be more sensitive than sex hormone-binding globulin (SHBG) in identifying peripheral overexposure to thyroid hormones in exogenous subclinical hyperthyroidism. The aim of the present study was to assess serum ICTP and SHBG in multinodular goiter with (pretoxic goiter) or without biochemical evidence of endogenous subclinical hyperthyroidism. Forty-five women affected by multinodular goiter were enrolled in this study. They were subdivided into two groups: group 1, consisting of 27 patients affected by pretoxic goiter; group 2, consisting of 18 patients affected by non toxic goiter; group 3, consisting of thirty-six euthyroid women matched with the other groups for age and lifestyle. In group 1, serum ICTP (mean +/- SD: 5.8 +/- 2.9 microg/l) concentrations were significantly higher when compared either to group 2 (3.6 +/- 1.2 microg/l; p < 0.02) or controls (2.7 +/- 0.7 microg/l; p < 0.0001); serum ICTP concentrations were also slightly but significantly higher in patients of group 2 compared to controls (p < 0.003). In contrast, mean serum SHBG concentrations did not show any difference among the three groups. No significant correlation was found between serum TSH and ICTP concentrations, while a weak positive correlation (p < 0.05) was only found between serum FT 3 and ICTP concentrations when data from the two patient groups were analyzed together. Moreover, when we subdivided patients into pre- and postmenopausal patients, we observed that SHBG but not ICTP serum concentrations were influenced by estrogenic status. In summary, the measurement of serum ICTP seems to be more suitable than SHBG for identifying those with a higher degree of peripheral thyroid hormone exposure in women affected by endogenous subclinical hyperthyroidism.

Independent expression of serological markers of thyroid autoimmunity and hepatitis virus C infection in the general population: results of a community-based study in north-western Sardinia.

To assess the relationship between serological markers of thyroid autoimmunity and chronic hepatitis C, we surveyed the general population of two villages in the region of Sardinia, Italy, where infection with hepatitis viruses is endemic and the prevalence of autoimmune diseases is elevated. A total of 1310 subjects aged 6-88 years (65% of the total resident population) participated in the survey, and 1233 (94%; 444 males and 789 females) agreed to provide a blood sample. Autoantibodies to thyroid peroxidase (anti-TPO) were measured by radioimmunoassay; antibodies to HCV (anti-HCV) by a third generation enzyme immunoassay and borderline positive results confirmed by recombinant immunoblot assay. For both anti-HCV and anti-TPO the age- and gender-standardized prevalence rates (SPR) were calculated and the significance of the association between the two antibodies tested by Yates corrected chi2 test. The overall SPR for anti-HCV was 50.7x10(-3) (86/1,233), similar between men [49.1x10(-3) (22/444)] and women [52.3x10(-3) (64/789)]. The overall SPR for anti-TPO was 136.9x10(-3) (204/1,233), and that among women [201x10(-3) (174/789)] was almost 3-fold that among men [71.6x10(-3) (30/444)]. A concurrent anti-HCV and anti-TPO positivity was found in a small minority of subjects [8/1,233 (0.65%)], all women aged 57-81 years. The SPR for the two concurrent events was 3.3x10(-3), which was not significantly different (Yates corrected chi2 test = 0.65) from that expected under the assumption of unrelated events. To explore whether HCV infection is a risk factor for anti-TPO positivity, we designed a case-control study with anti-TPO positive subjects as the cases, and anti-TPO negative subjects as the controls. The age- and gender-adjusted odd ratio (OR) was 0.4 (95% CI 0.2,0.7), indicating a negative association. In conclusion, no evidence for epidemiological association of circulating thyroid autoantibodies and antibodies to HCV was found. Our findings do not therefore support a pathogenetic link between HCV infection and thyroid autoimmunity.

Thyroid and celiac disease: clinical, serological, and echographic study.

OBJECTIVE: We sought to reevaluate the prevalence of thyroid dysfunction and thyroid autoimmunity in 47 patients with celiac disease; 91 healthy subjects were studied as controls. Both patients and controls were from Sardinia, Italy. METHODS: Diagnosis of celiac disease was made on the basis of clinical history, presence of positive antigliadin IgA (AGA-A) and IgG (AGA-G) antibodies, antireticulin antibodies (ARA), antiendomysium antibodies (EMA), and was confirmed by jejunal biopsy. HLA class II typing for DQB1 and DQA1 alleles was performed in 36/47 celiac patients. Thyroid was evaluated by palpation and echography; serum free thyroid hormones (FT4, FT3), thyrotropic hormone (TSH), and antithyroid peroxidase autoantibodies (anti-TPO) were assayed by radioimmunoassays. RESULTS: The prevalence of anti-TPO was higher in celiac patients (29.7%) than in healthy controls (9.6%) (p < 0.001) and thyroid echography frequently displayed (42.5%) a hypoechogenic pattern. Five anti-TPO-positive celiac patients were hypothyroid (two overt, three subclinical). A higher but not significantly different prevalence of anti-TPO (3/7 = 42.8%) was found in celiac patients displaying the DQB1*0502 genotype, when compared with the remaining patients (8/29 = 27.6%). CONCLUSIONS: An elevated prevalence of clinical and subclinical autoimmune thyroid autoimmunity was found in Sardinian celiac patients, especially in those displaying the DQB1*0502 genotype; this finding could be related to a particular genetic background of the Sardinian population.

Circulating telopeptide type I is a peripheral marker of thyroid hormone action in hyperthyroidism and during levothyroxine suppressive therapy.

The aim of the present investigation was to evaluate the clinical performance of serum carboxy-terminal-1-telopeptide (ICTP), a new marker of bone resorption, in identifying peripheral overexposure to thyroid hormones, as compared with serum osteocalcin (OC) and serum sex hormone binding globulin (SHBG). Serum ICTP, SHBG, and OC were assayed by specific radioassays in three study groups. Group 1: 50 perimenopausal women on long-term levothyroxine (LT4) suppressive treatment; group 2: 29 women with untreated hyperthyroidism; group 3: 36 normal euthyroid women matched with group 1 patients for age, alcohol, smoking habits, and lifestyle. Serum concentrations of SHBG, ICTP, and OC were markedly increased in hyperthyroid patients, whereas only serum ICTP was slightly but significantly increased in LT4 treated patients. Serum ICTP had higher diagnostic value for hyperthyroidism when compared with SHBG and to OC (sensitivity: 100%, 71%, 55%; accuracy: 97%, 88%, and 76%, respectively). In group 1, increased serum ICTP was observed in 30 of 50 patients, whereas increased SHBG and OC were found only in 11 of 50 (p < .001). Serum free thyroid hormone concentrations correlated with circulating ICTP and SHBG, and the correlation with serum OC was of lower significance. In conclusion, serum ICTP is a sensitive and reliable marker of peripheral thyroid hormone activity at the bone level; its clinical performance is higher than OC and even better than SHBG. Thus, serum ICTP is better than other peripheral markers in monitoring LT4 suppressive therapy in patients at increased risk for osteoporosis such as perimenopausal women.

Value of thyroid echography in the long-term follow-up of lithium-treated patients.

Psychiatric patients on long-term lithium (Li) therapy frequently develop goiter and/or hypothyroidism. It has also been suggested that Li may trigger/exacerbate thyroid autoimmunity. Previous studies provided evidence that underlying thyroid diseases represent important predisposing factors for the development of Li-induced thyroid dysfunction. The aim of the present paper was to assess the value of thyroid ultrasound-a simple and reliable tool to detect subtle thyroid abnormalities-in the longitudinal evaluation of 23 Li-treated psychiatric patients without evidence of biochemical thyroid abnormalities before therapy. For this purpose, thyroid ultrasound was associated with a clinical and laboratory (serum thyroxine, serum triiodothyronine, serum TSH, antithyroglobulin (AbTg), antithyroid microsomal (AbM) and antithyroid peroxidase autoantibodies) evaluation prior to and at 6- to 12-month intervals during Li treatment. On the basis of thyroid ultrasound before Li, patients were subdivided into two groups: group A (n = 15, 7 males, 8 females) with a normal echography and group B (n = 8, 5 males, 3 females) with mild ultrasound abnormalities. In group A the development of a small diffuse goiter was confirmed by physical examination during Li therapy; 2 patients displayed a transient increase of serum TSH concentration and none developed detectable serum antithyroid autoantibodies. Beside the small volumetric increase, no other ultrasound abnormalities were observed during the entire follow-up. In all group B patients a mild diffuse goiter was clinically detected before and on Li administration and no significant volumetric changes were observed during follow-up. Two patients developed high titers of AbM and AbTg 12 and 18 months after the beginning of Li, respectively; in 1 a persistent increase of serum TSH concentration was also observed. Thyroid echography before Li displayed different degrees of scattered or diffuse hypoechogenicity and a further decrease in echogenicity was detected during Li therapy in 2 patients. In conclusion, we provided further evidence that long-term Li administration is not associated with de novo appearance of thyroid autoimmune phenomena in humans, but rather with an exacerbation of underlying thyroid autoimmunity. In addition to thyroid autoantibody and TSH measurements, thyroid echography appears to be a sensitive tool in the identification of patients at risk of developing autoimmune hypothyroidism during long-term Li therapy.

Six-year follow-up of thyroid function during lithium treatment.

A cohort of patients at various stages of lithium treatment was followed up for 6 years in order to evaluate the course of thyroid abnormalities. Ultrasonography confirmed that lithium can increase thyroid size, especially in cigarette smokers, and that it can affect the texture of the gland. However, the incidence of clinical hypothyroidism or specific thyroid autoimmunity does not exceed that found in the general population. Repeated determinations of thyrotrophin (TSH) concentrations can prevent clinically relevant consequences. Addition of carbamazepine to lithium can counteract lithium-induced subclinical hypothyroidism, possibly improving prophylactic efficacy in recurrent affective disorders.

Study of serum 3,5,3'-triiodothyronine sulfate concentration in patients with systemic non-thyroidal illness.

Sulfation is an important pathway of triiodothyronine (T3) metabolism. Increased serum T3 sulfate (T3S) values have been observed during fetal life and in pathological conditions such as hyperthyroidism and selenium deficiency. Similar variations have also been reported in a small number of patients with systemic non-thyroidal illness, but the underlying mechanisms have not been elucidated. In this study, serum T3S concentrations have been measured by a specific radioimmunoassay in 28 patients with end-stage neoplastic disease (ESND) and in 44 patients with chronic renal failure (CRF); 41 normal subjects served as controls. Both ESND and CRF patients had lower serum total T4 (TT4) and total T3 (TT3) than normal controls, while serum reverse T3 (rT3) was increased significantly in ESND (0.7 +/- 0.5 nmol/l; p < 0.001 vs. controls) but not in CRF (0.3 +/- 0.1 nmol/l). The TT3/rT3 ratio, an index of type I iodothyronine monodeiodinase (type I MD) activity, was reduced significantly in both groups of patients. Serum T4-binding globulin (TBG) was decreased in CRF but not in ESND patients. Serum T3S was significantly higher both in ESND (71 +/- 32 pmol/l) and CRF (100 +/- 24 pmol/l) than in controls (50 +/- 16 pmol/l, p < 0.001). Serum T3S values showed a positive correlation with rT3 values and a negative correlation with both TT3 and FT3 values in ESND, but not in CRF. In the latter group a positive correlation was observed between T3S and TBG values. The T3S/FT3 ratio was higher both in CRF (18 +/- 5) and in ESND (23 +/- 18) as compared to controls (10 +/- 4). Serum inorganic sulfate was increased and correlated positively with T3S values in CRF patients. In conclusion, the results of this study in a large series of patients confirm that patients with systemic non-thyroidal illness have increased serum T3S levels. The mechanisms responsible for these changes appear to be different in ESND and CRF patients. In ESND the increase in serum T3S levels is mainly related to reduced degradation of the hormone by type I MD, whereas in CRF it might be driven by the enhanced sulfate ion concentration, and could be partially dependent on the impaired renal excretion of T3S. Because T3S can be reconverted to T3, it is possible that increased T3S concentrations contribute to maintenance of the euthyroid state in systemic non-thyroidal disease.

Enhanced susceptibility to amiodarone-induced hypothyroidism in patients with thyroid autoimmune disease.

BACKGROUND: The iodine-rich antiarrhythmic drug, amiodarone, can induce both thyrotoxicosis and hypothyroidism, the former being more frequent in iodine-deficient areas, the latter in iodine-sufficient areas. In this study we evaluated prospectively thyroid function in amiodarone-treated patients with positive or negative baseline thyroid autoantibody test results who resided in a moderately iodine-deficient area of Italy. SUBJECTS: Two groups of patients received long-term amiodarone treatment: Group 1 included 13 patients with negative thyroid autoantibody test results. Group 2 consisted of seven patients with positive thyroid autoantibody test results and thyroid ultrasound patterns compatible with Hashimoto's thyroiditis. The control group (group 3) included 16 untreated euthyroid patients with Hashimoto's thyroiditis. All subjects resided in a mildly iodine-deficient area of Italy (Southern Sardinia) and had low urinary iodine values. Patients in groups 1 and 2 had markedly elevated urinary iodine excretion during treatment. The follow-up period ranged from 6 to 29 months in group 1, from 4 to 9 months in group 2, and from 12 to 55 months in group 3. RESULTS: Two (15%) of 13 patients in group 1 with nodular goiter developed thyrotoxicosis. No patient in this group developed circulating thyroid autoantibodies. Five (71%) of seven patients in group 2 became hypothyroid after 4 to 9 months of amiodarone treatment associated with a rise in serum thyroid autoantibody levels. No patient in group 3 became hypothyroid. CONCLUSIONS: (1) Amiodarone administration can cause both thyrotoxicosis and hypothyroidism. (2) Hypothyroidism is far more frequent in patients with preexisting thyroid autoimmune disease. (3) Amiodarone can modify the natural history of Hashimoto's thyroiditis. (4) Circulating thyroid autoantibodies do not appear in amiodarone-treated patients who have negative test results prior to therapy.

Relationship of the increased serum interleukin-6 concentration to changes of thyroid function in nonthyroidal illness.

Variations in the serum concentration of interleukin-6 (IL-6) have been reported concomitantly with thyroid dysfunction: increased serum IL-6 levels have been found in patients with thyroidal destructive processes, such as subacute thyroiditis, some forms of amiodarone-induced thyrotoxicosis, or after percutaneous ethanol injection into "hot" thyroid nodules, as a result of the cytokine release from the damaged thyrocyte. In addition, recent in vitro evidence suggests that IL-6 might account, at least in part, for changes of thyroid economy found in nonthyroidal illness (NTI). In this cross-sectional study we addressed this problem by measuring serum IL-6 levels in 71 patients with NTI, due to neoplasia (n = 25), chronic liver disease (n = 9), chronic renal failure (n = 28), or other chronic nonthyroidal disorders (n = 9). These patients had reduced mean serum total T3 (TT3) and free T3 (FT3) concentrations, normal total and free T4 levels, normal TSH values, and increased serum reverse T3 (rT3) concentration (with the exception of chronic renal failure patients, who had normal rT3 levels). Serum IL-6 concentration was increased above normal (i.e. > 100 fmol/L) in almost all NTI patients, especially in those with low T3 values (median value: 258 fmol/L, range 73-3210, vs 152 fmol/L, range < 12.5-460, in patients with normal TT3 values, p < 0.001). Serum IL-6 values in NTI patients were negatively correlated with serum FT3 values (r = 0.56, p < 0.001), and positively correlated with serum rT3 values (r = 0.78, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Circulating antibodies to DNA-related antigens in patients with autoimmune thyroid disorders.

A high prevalence of antibodies to double-stranded DNA (AbDNAds) has been recently reported in serum of patients with autoimmune thyroid disorders, but the specificity of this finding has been questioned. For this reason, the prevalence of several antibodies to DNA-related nuclear antigens (AbDRENA) has been evaluated in sera of patients with autoimmune and non-autoimmune thyroid disease. The study group included: 46 Graves' disease patients, 28 Hashimoto's thyroiditis patients, 25 patients with toxic nodular goitre and 11 with non-toxic nodular goitre. Twenty-eight Graves' patients were retested during methimazole (MMI) therapy, and 5 after radioiodine administration. Twenty-two patients with systemic lupus erythematosus and 28 normal subjects served as positive and negative controls, respectively. AbDRENA included: AbDNAds by RIA or immunofluorescence (IF); antibodies to single-stranded DNA (AbDNAss) and antibodies to histone (AbHist) by ELISA methods; antibodies to nuclear antigens (ANA) by immunofluorescence. RIA values were considered to be abnormal when 2 SD above the mean of normal controls. In our study 13% of Graves' patients were positive for AbDNAds by RIA: all of them had negative tests by IF; 11% were positive for AbDNAss, 2% for AbHist and 7% for ANA. A comparable prevalence of positive results for AbDNAds by RIA, with negative IF tests, was found in Hashimoto's thyroiditis patients. No significant changes of antibody levels were observed in Graves' patients during MMI treatment or after radioiodine administration. A positivity for AbDNAds or AbDNAss was found in 8% of patients with toxic nodular goitre, but in none of those with non-toxic goitre.(ABSTRACT TRUNCATED AT 250 WORDS)

The nocturnal serum thyrotropin surge is abolished in patients with adrenocorticotropin (ACTH)-dependent or ACTH-independent Cushing's syndrome.

TSH secretion was evaluated in 10 patients with ACTH-dependent (pituitary microadenoma, n = 5) or ACTH-independent [adrenal adenoma (n = 4) or carcinoma (n = 1)] Cushing's syndrome, and in 12 normal controls matched for age and sex. Serum TSH concentration was assayed at night, from 2200-0200 h, and in the morning, both basally and 30 min after iv injection of 200 micrograms synthetic TRH. Patients with hypercortisolism showed significantly reduced serum total T4 and T3 and free T3 concentrations and increased serum reverse T3 levels. Their mean baseline serum TSH concentration in the morning, albeit slightly lower, did not significantly differ from those of controls. The mean peak TSH value after TRH was significantly reduced, and a blunted TSH response to TRH was found in 4 out of 10 patients. At variance with normal controls, who showed nighttime TSH values 63-228% higher than morning values, 9 out of 10 patients had nighttime levels not different from or even lower than those in the morning; the remaining patient had nighttime TSH values marginally (33%) higher than in the morning. An inverse relationship (r = 0.80, P less than 0.001) was found between serum cortisol and TSH values both at night and in the morning. No differences were found either in the pattern of TSH secretion or in the TSH response to TRH between patients with ACTH-dependent and those with ACTH-independent Cushing's syndrome. These results show a substantial impairment of TSH secretion, and in particular the loss of the nocturnal surge of the hormone, in patients with Cushing's syndrome. Although the origin of the nocturnal TSH rise is probably multifactorial, cortisol, at least when secreted in excess, appears to play an important role in its regulation.

More on smoking habits and Graves' ophthalmopathy.

Since a relationship between cigarette smoking and the occurrence of Graves' ophthalmopathy has been recently postulated, we reviewed the smoking habits of 1730 women, including subjects without thyroid disease, with nontoxic goiter (NTG), toxic nodular goiter or toxic adenoma (TNG), Hashimoto's thyroiditis (HT), Graves' disease without ophthalmopathy (GD) or with ophthalmopathy (GO). The prevalence of smokers in NTG, TNG and HT was about 30%, not different from that of controls. Smokers were 47.9% in GD and 64.2% in GO groups. The latter figures were highly different from those of the other groups and also from each other. The percentage of heavy smokers was higher in patients with more severe ophthalmopathy. No clear explanation for this phenomenon can be offered. The absence of a high prevalence of smokers among patients with non-toxic goiter, nonautoimmune hyperthyroidism and Hashimoto's thyroiditis, limits the impact that smoking might have had in the pathogenesis of goiter, hyperthyroidism and autoimmune phenomena of GD and GO.