Total thyroidectomy, without prophylactic central lymph node dissection, in the treatment of differentiated thyroid cancer. Clinical retrospective study on 221 cases.

Total thyroidectomy (TT) is the standard of care for differentiated thyroid cancer (DTC), but still there is no consensus about the role of routine use of prophylactic central lymph node dissection. The aim of this study was to analyze our results of TT without prophylactic central lymphadenectomy in the treatment of DTC. Clinical records, between January 1998 and December 2005, of 221 patients undergoing TT, without prophylactic central lymph node dissection, were retrospectively evaluated. Two hundred and eleven patients (95.47 %) also underwent radioiodine (RAI) ablation followed by thyroid stimulating hormone (TSH) suppression therapy. In patients with loco-regional lymph nodal recurrence, lateral and central lymph node dissection was performed. The incidence of permanent hypoparathyroidism (iPTH <10 pg/ml) and permanent vocal fold paralysis were, respectively, 0.91 and 0.91 %. After a 9.6 ± 3.5 years mean follow-up, the rate of loco-regional recurrence, with positive cervical lymph nodes, was 3.16 % (7/221 patients). In these cases a lateral and central lymphadenectomy was carried out without significant complications. Our results showed that TT without prophylactic central lymph node dissection, followed by RAI ablation, was associated with low morbidity and low loco-regional recurrence rate, even if the lack of a control group treated with TT plus prophylactic central lymphadenectomy suggests caution against generalization of our assumption. Such last combined procedure could be indicated in high-risk patients, in whom loco-regional recurrence is more frequent. However, given the trend in the literature toward prophylactic lymphadenectomy and the avoidance of RAI treatment, prospective randomized trials should be conducted to better clarify this issue.

Decreased serum vascular endothelial growth factor-D levels in metastatic patients with differentiated thyroid carcinoma.

OBJECTIVE: Vascular endothelial growth factor-D (VEGF-D) has been identified as one of the lymphangiogenic growth factors involved in metastatic diffusion. The aim of this study is to evaluate the serum VEGF-D levels in patients with differentiated thyroid cancer at different conditions of disease. DESIGN AND PATIENTS: We studied prospectively the VEGF-D plasma levels in 96 subjects affected by differentiated thyroid cancer. The patients were divided into three groups according to the clinical and biochemical findings: patients with no evidence of disease (Cured), patients with pathological (>1 ng/ml) stimulated thyroglobulin (Tg) (Path-Tg/rhTSH) levels only after rhTSH and patients with elevated basal Tg levels (Path-Tg/LT4). RESULTS: The serum VEGF-D concentrations in patients of group Cured were not different from the controls, while group Path-Tg/rhTSH showed baseline serum VEGF-D levels significantly lower than group Cured and controls (P < 0·001 and P < 0·01, respectively). Moreover, the patients of group Path-Tg/LT4 showed median serum cytokine concentrations at baseline not significantly different from the patients of group Path-Tg/rhTSH. The rhTSH stimulation did not modify the difference in serum VEGF-D levels in patients of group Cured and group Path-Tg/rhTSH. CONCLUSIONS: Our data demonstrate that the VEGF-D serum levels are reduced in patients with metastases of differentiated thyroid cancer, regardless of the degree of metastatic spread. It is possible that some other molecule produced by the tumoral tissue could affect the VEGF-D physiologically produced of from different tissues, thus conducting to a decrease in the VEGF-D found in blood of patients with evidence of metastatic differentiated thyroid cancer.

Cytologic, flow cytometry, and molecular assessment of lymphoid infiltrate in fine-needle cytology samples of Hashimoto thyroiditis.

BACKGROUND: The thyroidal lymphoid infiltrate (TLI) in Hashimoto thyroiditis (HT) represents the substrate from which thyroid lymphoma may arise. The objective of the current study was to classify the TLI in HT by comparing the cytologic features with flow cytometry (FC) data and evaluating the kappa/lambda light chain ratio and its molecular assessment. METHODS: Fine-needle aspiration cytology (FNAC) was performed in 34 patients with HT with nodular or diffuse palpable enlargement of the gland. Two or 3 passes were performed to prepare traditional smears, FC, and immunophenotyping, and RNAlater suspensions for molecular assessment. FC was performed using the following antibodies: CD3, CD5, CD4, CD8, CD10, CD19, and kappa and lambda light chains. In 4 cases, high molecular weight DNA was extracted and used for polymerase chain reaction (PCR) to amplify the variable diversity joining region of the heavy chain immunoglobulin (Ig) genes (IgH). Statistical analysis was performed to evaluate possible associations between clinical ultrasound presentation, cytologic pattern, and TLI phenotype. Light chain expression was evaluated as the percentage of the expressing cells (20%) and as the kappa/lambda ratio. RESULTS: Smears were classified as "lymphocytic," "lymph node-like," or "mixed." FC demonstrated T cells (CD3 positive [+], CD5+) in all cases, and T cells and B cell (CD19+, CD10+/-) lymphocytes in 22 cases. Light chains were expressed in 30 cases (in <20% of the gated cells in 13 cases and in >20% of the gated cells in 17 cases). Five cases demonstrated small kappa/lambda ratio imbalances and PCR analysis demonstrated diffuse bands in the gel and Gaussian curves at the heteroduplex. Statistical analysis indicated significant associations between the "lymphocytic" pattern and T-cell phenotype and between the "lymph node-like" pattern and B-cell phenotype. A significant association also was observed between light chain restriction and low light chain expression (P < .005). CONCLUSIONS: The cytologic pattern of TLI in HT is quite representative of the clinical presentation and phenotypic cell type. Small light chain imbalances are not sustained by heavy chain Ig gene (IgH) rearrangements. FNA coupled with FC may contribute to making the distinction between florid TLI and non-Hodgkin lymphoma.

Imbalance of the osteoprotegerin/RANKL ratio in bone marrow microenvironment after allogeneic hemopoietic stem cell transplantation.

BACKGROUND: Bone loss is a common complication after allogeneic stem cell transplantation. Osteoprotegerin (OPG) plays a critical role in bone remodeling by neutralizing the effect of receptor activator of nuclear factor-kappaB ligand (RANKL) on differentiation and activation of osteoclasts. We investigated OPG and RANKL in serum and marrow plasma in transplanted patients. MATERIALS AND METHODS: In 36 patients and 36 controls, the relationships among bone mineral density, circulating OPG, RANKL, interferon-gamma, and interleukin-6 levels were investigated; in addition, OPG and RANKL were measured in marrow plasma and in conditioned medium of long-term cultures of marrow mesenchymal-derived osteogenic cells. RESULTS: Lumbar and femoral bone mineral density were lower in patients than in controls (P<0.01). Serum OPG (sOPG) and interferon-gamma were significantly higher in patients than in controls (P<0.05). Patients' interferon-gamma correlated with sOPG levels (r=0.4; P=0.03). Interleukin-6 did not differ between patients and controls. By contrast, OPG levels were lower in patients than in controls in marrow plasma (P<0.001) and in conditioned media after one (P=0.035) and three months (P=0.003) of culture of marrow mesenchymal-derived osteogenic cells. RANKL was similar in patients and controls. The OPG/RANKL ratio "in situ" was significantly lower in patients than in controls (P<0.05). There was no correlation between sOPG and marrow OPG, RANKL levels, densitometric values, and chronic graft-versus-host disease. CONCLUSION: Our findings suggest that after allogeneic stem cell transplantation: 1) sOPG bear no relationship with OPG in the bone marrow; 2) increased sOPG can be the result of its enhanced production in extra bone tissues triggered by inflammatory cytokines; 3) low bone marrow OPG levels may be partly related to the persistent quantitative and qualitative deficit of osteoblastic precursors; and 4) reduced OPG/RANKL ratio in bone microenvironment may increase bone remodeling by promoting bone resorption.

HMG-CoA reductase inhibitors inhibit rat propylthiouracil-induced goiter by modulating the ras-MAPK pathway.

The aim of this study was to evaluate in vivo the antiproliferative effect of an inhibitor of isoprenoids metabolism, lovastatin, in an experimental model of propylthiouracil-induced goiter. In thyroid cells, thyrotropin (TSH)-induced proliferation requires active isoprenoid synthesis, and the HMG-CoA reductase inhibitors have antiproliferative effects in vitro. Propylthiouracil treatment (PTU) of rats led to thyroid hypertrophy and hyperplasia by TSH-induced activation of the mitogen-activated protein kinase (MAPK) pathway. Immunohistochemistry showed an increased number of proliferating cell nuclear antigen (PCNA)-positive cells in the thyroid gland of PTU-treated rats. Moreover, the phosphorylation of ERK1 and ERK2 was increased in the extract from goiter tissue as compared with the thyroid tissue of untreated rats. To determine whether the inhibition of selected pro-survival pathways (i.e., p21ras-MAPK) was sufficient to affect goitrogenesis, thyroids from 12 PTU-treated rats were injected in vivo with an adenovirus transducing a dominant-negative ras gene (Rad-L61.S186) and another set of 12 rats were injected with a pharmacological inhibitor of MAPK (PD98059). Both Rad-L61.S186 and PD98059 were able to inhibit the PTU-induced goiter. It is interesting to note that lovastatin, when administered in drinking water, significantly prevented the thyroid gland enlargement. Therefore, lovastatin-treated thyroid glands were significantly smaller than those treated with PTU alone. In addition, the lovastatin-treated glands also showed a decreased expression of phosphorylated ERK1/2 and a number of PCNA-positive cells. Our data suggest that lovastatin is an efficient inhibitor of goitrogenesis and provide a rationale for innovative therapeutic strategies employing statins in the treatment of nodular goiter in humans.

Increased serum osteoprotegerin values in long-lived subjects: different effects of inflammation and bone metabolism.

AIM: To evaluate serum osteoprotegerin (OPG) concentrations in relation to age-dependent changes in serum markers of bone metabolism and systemic inflammation. METHODS: Two-hundred and eighty-three healthy subjects were evaluated for plasma estimated creatinine clearance (Cr-clearance), C-reactive protein (CRP), bone alkaline phosphatase, C-telopeptides of type-1 collagen (CrossLaps), nuclear factor-kappaB ligand (RANKL) and OPG concentrations. RESULTS: In adult subjects (82 cases aged between 27 and 64 years) serum OPG concentrations were significantly and independently correlated with RANKL and Cr-clearance (R(2): 0.29), but not with CRP and biochemical markers of bone metabolism. In old subjects who were between 65 and 84 years of age (52 cases) serum OPG concentrations were significantly higher as compared with the adult subjects and correlated independently and significantly with serum RANKL, Cr-clearance and CrossLaps values (R(2): 0.63). The highest OPG values were found in the long-lived subjects (149 cases with ages between 85 and 110 years) who also showed increased serum CrossLaps and CRP concentrations as compared with the younger subjects. However, in the long-lived subjects serum OPG concentrations were significantly and independently correlated with Cr-clearance and CRP (R(2): 0.45) but not with CrossLaps values. CONCLUSIONS: These data would suggest that different factors might be responsible for the age-dependent enhancement of OPG production. Bone metabolism would seem to be the most important factor influencing serum OPG concentrations in old subjects under 85 years of age, whereas in long-lived subjects the circulating values of this cytokine seem to be mainly correlated with serum CRP which could be a marker of inflammation and cardiovascular risk.

Recombinant human TSH modulates in vivo C-telopeptides of type-1 collagen and bone alkaline phosphatase, but not osteoprotegerin production in postmenopausal women monitored for differentiated thyroid carcinoma.

UNLABELLED: In women monitored for thyroid carcinoma, short-term stimulation with rhTSH induced an acute decrease in serum C-telopeptides of type-1 collagen and an increase in serum BALP levels without any effect on OPG production. The inhibitory effect of TSH on bone resorption occurred only in postmenopausal women who showed low BMD and a high bone turnover rate as an effect of L-thyroxine suppressive therapy. INTRODUCTION: It has been recently shown that thyrotropin (TSH) has an inhibitory activity on skeletal remodeling in in vitro conditions. Here, we have aimed at evaluating whether TSH has similar effects in vivo. For this purpose, we have evaluated the sequential profile of serum bone metabolism markers during acute stimulation with recombinant human TSH (rhTSH) in thyroidectomized women monitored for thyroid carcinoma. MATERIALS AND METHODS: The study group included 66 thyroidectomized patients, of whom 38 were premenopausal and 28 postmenopausal, who underwent routine rhTSH-assisted whole body radioactive iodine scanning for differentiated thyroid carcinoma. The patients were sequentially evaluated for TSH, free triiodothyronine (FT3), free thyroxine (FT4), bone alkaline phosphatase (BALP), C-telopeptides of type-1 collagen (CrossLaps), and osteoprotegerin (OPG) levels during rhTSH stimulation. The samples were drawn just before and 2 and 7 days after the first administration of rhTSH. BMD was evaluated by ultrasonography at baseline. Seventy-one healthy women (41 premenopausal and 30 postmenopausal) acted as a control group. RESULTS AND CONCLUSIONS: At study entry, all patients had subclinical thyrotoxicosis as effect of L-thyroxine (L-T4) treatment. The patients had higher serum CrossLaps and OPG levels and lower BMD than healthy subjects. Postmenopausal patients showed comparable serum FT4 and FT3 concentrations with those found in premenopausal patients. However, postmenopausal patients showed higher serum CrossLaps (p < 0.001), OPG (p = 0.03), and BALP (p < 0.001) levels and lower BMD (p < 0.001) than those measured in premenopausal patients. Two days after the first administration of rhTSH, all patients had serum TSH values >100 mUI/liter. At this time, serum CrossLaps levels decreased significantly (p < 0.001) and BALP values increased (p = 0.001) with respect to the baseline values in postmenopausal but not in premenopausal patients. rhTSH did not induce any significant change in serum OPG values either in premenopausal or in postmenopausal patients. One week after the first rhTSH administration, serum CrossLaps values decreased again to values comparable with those measured at baseline, whereas serum BALP values remained high. This study shows that subclinical thyrotoxicosis is accompanied by high bone turnover rate with an increase in serum OPG levels compared with euthyroid healthy subjects. Acute increase in serum TSH levels is accompanied by a reversible inhibition of bone resorption. This effect is characterized by a decrease in serum CrossLaps and an increase in BALP levels without any evident effect on OPG production. The activity of TSH occurs specifically in postmenopausal women in whom the negative effects of L-T4 suppressive therapy on bone mass and metabolism are more marked compared with premenopausal women.

Effects of increased thyroxine dosage pre-conception on thyroid function during early pregnancy.

OBJECTIVE: To compare the effects of pregnancy on the serum free thyroxine (FT4) levels in two cohorts of primary hypothyroid women treated with different levothyroxine (L-T4) doses before gestation. DESIGN AND METHOD: Twenty-five women with compensated hypothyroidism of different aetiology (thyroidectomized and Hashimoto's thyroiditis) were enrolled in this prospective study. The women were receiving substitutive doses of L-T4 and were anticipating pregnancy. They were assigned to two groups: 14 patients (group I) were switched to partially suppressive treatment while 11 patients (group II) continued the same therapeutic regimen. RESULTS: Pre-conceptional thyroid function evaluation demonstrated significantly higher FT4 and lower TSH in group I (P<0.001, for both hormones) and comparable free 3,5,3'-triiodothyronine (FT3) levels. The first post-conception thyroid function evaluation occurred at a median time of 6 (5-8) and 7 (5-9) weeks of gestation, for groups I and II respectively (P<0.05); all women in group I showed adequate serum FT4 levels while three patients in group II showed low-normal FT4 levels and one case was below normal levels. Statistical analysis demonstrated significantly higher frequencies (0% vs 36.4%; P<0.05) of low-normal FT4 levels in patients receiving substitutive doses of L-T4. None of the Hashimoto's-affected patients showed low or low-normal serum FT4 levels regardless of their therapeutic regimen. CONCLUSION: Our results suggest that in hypothyroid women anticipating pregnancy (with serum TSH in the lower quartile of normal range), the pre-conception adjustment of L-T4 doses may result in adequate maternal thyroid function up to the first post-conception evaluation. The procedure seems safe and inexpensive; it may be a worthwhile treatment, at least in thyroidectomized women, in view of the well-known potential effects of even marginal maternal thyroid hypofunction on the subsequent IQ of the progeny.

High serum leptin in patients with chronic graft-versus-host disease after hematopoietic stem cell transplantation.

BACKGROUND: Increased serum leptin has been described after various organ transplants, with a mechanism that is still unclear. METHODS: We measured serum leptin in 60 patients before and after allogeneic (allo) or autologous (auto) stem cell transplant (SCT) and in 60 healthy controls, matched for age and body mass index (BMI). RESULTS: Serum leptin was higher in patients after SCT than before and in controls. Leptin production was higher after allo- than after auto-SCT; the presence of chronic graft-versus-host disease (cGVHD) was associated with the highest values. The physiological correlation with BMI was lost in the allogeneic setting, indicating a strong influence of factors other than the nutritional status on circulating leptin. No relationship was found between serum leptin levels and time from transplant, age, cortisol, C-reactive protein, and T-lymphocyte CD4-to-CD8 ratio. Among the cytokines secreted by type-1/type-2 T-helper lymphocytes, only serum interferon-gamma significantly correlated with serum leptin levels. Anti-leptin blocking antibodies partially inhibited T-cell activation in mixed lymphocyte reaction, suggesting a link between leptin and T-lymphocyte activation in the allo-SCT setting. CONCLUSION: Taken together, these findings suggest that increased serum leptin concentrations may contribute to T-cell activation during development of cGVHD.

Recombinant human thyrotropin reduces serum vascular endothelial growth factor levels in patients monitored for thyroid carcinoma even in the absence of thyroid tissue.

In this study, we have investigated in vivo the time-dependent effects of TSH on vascular endothelial growth factor (VEGF) production in patients monitored for thyroid carcinoma. Serum VEGF, thyroglobulin (Tg), and TSH levels were assayed at baseline and 6, 24, 30, 48, 72, and 96 h and 1 wk after administration of recombinant human TSH (rhTSH) in 45 thyroidectomized patients affected by differentiated thyroid carcinoma. At baseline, the patients with metastasis (18 cases) showed serum Tg and VEGF values significantly higher than those seen in the cured patients (27 cases). During rhTSH stimulation, the mean VEGF levels decreased significantly in both patient groups. In 60% of patients with metastasis, VEGF nadir occurred at the same time as serum TSH reached the highest values, whereas in 85.7% of the cured patients VEGF decreased after the TSH peak (P = 0.003). In conclusion, we demonstrate for the first time that short-term administration of rhTSH in patients monitored for differentiated thyroid carcinoma induces a significant reduction in serum VEGF values even in the absence of thyroid tissue. This result would suggest that TSH may be able in vivo to regulate VEGF production from tissues other than the thyroid gland.

Grey-scale analysis allows a quantitative evaluation of thyroid echogenicity in the patients with Hashimoto's thyroiditis.

OBJECTIVE: In the present study we have performed a grey-scale quantitative analysis of thyroid echogenicity in the patients affected by Hashimoto's thyroiditis (HT), obtaining a numerical estimate of the degree of hypoechogenicity associated with the appearance of thyroid dysfunction. MATERIALS AND METHODS: The study group included 89 patients with serum positivity for thyroglobulin (TgAb) and/or peroxidase (TPOAb) antibodies. Ultrasound (US) evaluation of thyroid gland and biochemical assay of serum thyrotropin (TSH), free-thyroxine (FT4) and free-triiodiothyronyne (FT3) were performed in all patients, and in 40 healthy subjects enrolled as control group. Thyroid echogenicity was compared with that of the surrounding neck muscles, using the grey-scale histogram analysis. The echogenicity was expressed in grey-scales (GWE). RESULTS: In HT patients, the mean of thyroid echogenicity was lower when compared to the normal thyroid (61.9 +/- 8.3 GWE vs. 71.9 +/- 3.1 GWE; P = 0.01). In all HT patients the lowest limit of thyroid echo distribution was in the echogenicity range of the surrounding muscle, the overlapping ranging between 3.4% and 95.0% (mean +/- SD 48.4 +/- 20.9%). The extension of like-muscle hypoechogenicity into the thyroid gland was significantly correlated with serum TSH values (r = 0.37; P < 0.001), serum FT4 values (r = -0.60; P < 0.001), and serum TPOAb values (r = 0.31; P = 0.004). Nobody was hypothyroid when the hypoechogenicity was less than 38.0%, whereas hypothyroidism occurred in all cases with hypoechogenicity of more than 68.9%. The receiving operating characteristic curve demonstrated that 48.3% was the best cut-off for identifying hypothyroid patients with sensitivity, specificity and diagnostic accuracy of 88.9%, 86.3% and 87.6%, respectively. CONCLUSIONS: In conclusion, the grey-scale quantitative analysis has provided a measure of thyroid hypoechogenicity associated with the appearance of hypothyroidism during the course of HT. The results of the present study would encourage the application of the computerized grey-scale analysis as complementary tool to US evaluation in the patients affected by HT.

Serum and follicular fluid cytokines in polycystic ovary syndrome during stimulated cycles.

OBJECTIVE: To investigate the serum and intrafollicular tumor necrosis factor-alpha and interleukin-6 concentrations in infertile women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF). METHODS: Thirty-one patients with PCOS undergoing IVF were studied. Thirty-nine normally ovulating women matched for age and body mass index and undergoing IVF for male infertility were the control group. Serum tumor necrosis factor-alpha, interleukin-6, and estradiol levels were assayed before recombinant follicle-stimulating hormone stimulation under gonadotropin-releasing hormone analogue suppression and 34-36 hours after human chorionic gonadotropin (hCG) administration at the time of the oocyte retrieval. Cytokine and estradiol concentrations were also evaluated in the follicular fluids obtained at the time of oocyte retrieval. RESULTS: The patients with PCOS had higher serum and follicular fluid tumor necrosis factor-alpha and interleukin-6 concentrations (P <.001) and lower follicular fluid estradiol levels (P <.05) than control women. In both groups, the serum tumor necrosis factor-alpha, interleukin-6, and estradiol values increased significantly after hCG stimulation. In both groups, the follicular fluid cytokine concentrations were higher than those found in the serum. In the PCOS women the follicular fluid tumor necrosis factor-alpha values were significantly and inversely correlated to the follicular fluid estradiol values (rho = -0.79; P <.001); this correlation was not found in the control subjects. CONCLUSION: In infertile women with PCOS, 1). serum and follicular fluid interleukin-6 and tumor necrosis factor-alpha values were higher than those found in control women, 2). the cytokine concentrations were higher in the follicular fluid than in the serum, and 3). the intrafollicular tumor necrosis factor-alpha concentrations were significantly and inversely correlated to the estradiol levels. These results suggest an involvement of the immune system in PCOS.

Type-1 response in peripheral CD4+ and CD8+ T cells from patients with Hashimoto's thyroiditis.

OBJECTIVE: In this study we performed single-cell analysis of the intracellular cytokine expression in peripheral CD4+ and CD8+ lymphocytes from patients with Hashimoto's thyroiditis (HT) to investigate the type-1 response separately for the two lymphocyte sub-populations. DESIGN AND METHODS: Twenty-nine patients affected by HT and 20 healthy subjects, matched for sex and age, were enrolled. After the analysis of the lymphocyte sub-populations, the intracellular content of interferon-gamma (IFN-gamma) in phorbolmyristate acetate (PMA)-stimulated CD4+ and CD8+ lymphocytes was assayed. Moreover, the CD4+ lymphocytes were also evaluated for the intracellular expression of IL-4. RESULTS: No significant differences in CD3+, CD4+ and CD8+ lymphocytes were found between HT patients and control subjects. However, the HT patients showed higher numbers of CD4+ IFN-gamma+, CD4+ IL-4+ and CD8+ IFN-gamma+ (t-test, P< or =0.001) cells than the control subjects. Analysing the intracellular expression of IFN-gamma and IL-4 in relation to thyroid function, we found that the euthyroid patients (18 cases) showed more expression of IL-4 in CD4+ lymphocytes than the control subjects, without any significant modification of IFN-gamma expression in CD4+ and CD8+ lymphocytes. However, the hypothyroid patients (11 cases) showed an increase of IFN-gamma expression in both CD4+ and CD8+ lymphocytes with respect to the control subjects and the euthyroid patients. Moreover, the expression of IL-4 in CD4+ cells from hypothyroid patients was significantly lower than that seen in the euthyroid cases and comparable to that found in the control subjects. CONCLUSIONS: Our study has demonstrated that the peripheral CD4+ and CD8+ T lymphocytes from the HT patients show a type-1 activation strictly correlated to the occurrence of hypothyroidism. Further studies will be needed to clarify the exact role of peripheral lymphocytes in HT and whether they could provide a reliable marker of thyroid immune involvement.

Increased serum reverse triiodothyronine levels at diagnosis of hepatocellular carcinoma in patients with compensated HCV-related liver cirrhosis.

OBJECTIVE: The aim of this study was to investigate changes in thyroid hormone metabolism in relation to the development of hepatocellular carcinoma (HCC) in patients with HCV-related liver cirrhosis. MATERIALS AND METHODS: The study group (Group A) comprised 31 patients (25 M, 6 F; median age 62.1 years, range 54.0-81.5 years) affected by HCV-related liver cirrhosis with superimposed HCC. Acute and chronic systemic disease, other than cirrhosis, inducing 'euthyroid sick syndrome' was excluded in all patients. Serum TSH, FT4, FT3, rT3, and thyroxine-binding globulin (TBG) levels were retrospectively evaluated in frozen aliquots drawn at the time of tumour diagnosis and every 6 months for 3-7 years before HCC diagnosis. The control group (Group B) comprised 29 patients affected by HCV-related liver cirrhosis without HCC, matched for sex, age and grade of liver dysfunction. RESULTS: At the time of HCC diagnosis, all patients in Group A were euthyroid with serum TSH, FT4, FT3 and TBG values not significantly different from those of cirrhotic patients of Group B. However, at diagnosis Group A patients had serum rT3 values that were significantly higher than those in Group B (35.0 ng/dl, range 12.0-162.0 vs. 19.0 ng/dl, range 10.0-51.0; Group A vs. Group B; P < 0.001). Serum rT3 values above the normal range were found in 12 patients in Group A (38.7%) but in only one of the patients from Group B (3.4%) (chi2 10.2; P = 0.001). The serum rT3 levels were not significantly correlated to the Child grade of liver cirrhosis (rho 0.1; P = 0.5). The intrasubject analysis demonstrated that a significant increase in serum rT3 levels occurred at the time of HCC diagnosis but serum FT4, FT3 and TSH values did not change significantly. A receiver operating curve (ROC) demonstrated that a 6-monthly increase in serum rT3 levels of at least +22.5% identified patients with HCC with a diagnostic accuracy of 81.7%. CONCLUSIONS: Our study has demonstrated that development of hepatocellular carcinoma is accompanied by a significant increase in serum rT3 levels in patients with low-grade HCV-related liver cirrhosis who had no other illness causing the 'euthyroid sick syndrome'.

Serum insulin-like growth factor I evaluation as a useful tool for predicting the risk of developing hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: a prospective study.

BACKGROUND: Although experimental studies have demonstrated an important role of insulin-like growth factor I (IGF-I) in hepatocarcinogenesis, the clinical data about IGF-I in patients with hepatocellular carcinoma (HCC) are scarce and controversial. To the authors' knowledge, this is the first prospective study investigating the longitudinal correlation between modifications in serum IGF-I levels and the development of HCC in a cohort of patients with hepatitis C virus (HCV)-related cirrhosis. METHODS: One hundred fourteen consecutive patients with HCV-related Child Grade A cirrhosis were followed prospectively at the Second University of Naples for 56.4 +/- 12.0 months with ultrasound examinations of the liver and serum alpha-fetoprotein determination every 6 months. At each clinical evaluation, the severity of disease was graded according to the established Child-Pugh scoring system. Serum IGF-I levels were measured prospectively at the study entry and at least every 12 months throughout follow-up. RESULTS: Twenty patients (19.2%) developed HCC during follow-up. Eleven of these patients had persistent Child Grade A cirrhosis for the whole study, whereas the other 9 patients developed HCC after their cirrhosis progressed from Child Grade A to Grade B. In patients who remained free of HCC for the whole study, serum IGF-I concentrations did not modify significantly during follow-up. Conversely, in patients who developed HCC, IGF-I levels decreased significantly during follow-up (from 72.6 +/- 29.9 microg/L to 33.8 +/- 14.5 microg/L; P = 0.001). In these patients, the significant decrease occurred both in patients with persistent Child Grade A cirrhosis and in patients with cirrhosis that progressed from Child Grade A to Grade B. The reduction in IGF-I level preceded the diagnosis of HCC by 9.3 +/- 3.1 months. CONCLUSIONS: This prospective study demonstrates that, in patients with HCV-related cirrhosis, 1) the development of HCC is accompanied by a significant reduction of serum IGF-I levels independent of the grade of impairment of liver function; and 2) modification of the IGF-I level precedes the morphologic appearance of HCC, permitting a precocious diagnosis of the tumor.

Iodized salt improves the effectiveness of L-thyroxine therapy after surgery for nontoxic goitre: a prospective and randomized study.

OBJECTIVE: To investigate whether the addition of iodized salt to daily diet in thyroidectomized patients for nontoxic goitre could influence the effectiveness of nonsuppressive L-thyroxine (L-T4) therapy on thyroid remnant size, during 12 months' follow-up after thyroid surgery. DESIGN AND PATIENTS: A consecutive series of selected 139 patients (26 males, 113 females; median age 45 years, range 30-69 years) living in a moderate iodine-deficient area, and undergoing thyroid surgery for nontoxic multinodular goitre, was enrolled. Patients were assigned randomly to two different therapeutic regimens: 70 patients received L-T4 therapy alone (Gr. L-T4), while the remaining 69 patients took iodized salt on a daily basis in addition to L-T4 treatment (Gr. L-T4 + I). In both groups, the initial L-T4 dose was 1.5 microg/kg/day, which, in our experience, has been shown to be intermediate between suppressive and replacement doses. To avoid the risks of mild thyrotoxicosis and to limit the excessive TSH stimulation of the thyroid remnant, the L-T4 dose was adjusted in those patients with serum TSH levels outside the lowest two-thirds of the normal range (0.3-2.5 mU/l). An ultrasound evaluation of thyroid remnant size was performed after thyroid surgery and 12 months later. RESULTS: After surgery, the median thyroid remnant volume was 3.5 ml (range 0.4-13.9 ml) in Gr. L-T4 and 4.6 ml (range 0.5-12.7 ml) in Gr. L-T4 + I (P = 0.06). After 1 year of follow-up, the patients treated with L-T4 + I obtained a remnant volume reduction (-39.7%, range -87.0% to +91.2%) significantly (P = 0.006) greater than that observed in patients assuming L-T4 alone (-10.2%, range -89.4% to +85.0%). However, the percentage of patients showing an increase in remnant size in the months following surgery was higher in Gr. L-T4 than in Gr. L-T4 + I (22/60 vs. 9/66; P = 0.01). In Gr. L-T4 patients the thyroid remnant volume variation throughout 12 months of treatment was correlated significantly with the size of the thyroid remnant found at the first ultrasound evaluation (R(2) = 0.3; P < 0.001). No such correlation was found in Gr. L-T4 + I patients, for whom the therapy maintains a similar effectiveness in patients with either a large or a small postsurgery thyroid remnant. In patients treated with L-T4 alone, the remnant volume variation was correlated significantly with the median serum TSH values attained in the course of treatment (R2 = 0.4; P < 0.001). The highest reduction in remnant volume was observed only by lowering the serum TSH concentrations. In patients treated with L-T4 plus iodine, instead, the thyroid remnant volume reduction occurred independently of the plasma TSH levels attained in the course of treatment. CONCLUSIONS: Our short-term prospective and randomized study leads us to conclude that, in patients living in a moderate iodine-deficient area and undergoing thyroid surgery for nontoxic goitre: (1) the iodine prophylaxis improves the effects of postsurgery nonsuppressive L-T4 therapy on thyroid remnant size. (2) In patients treated with L-T4 alone the therapeutic effectiveness decreases in the presence of a large postsurgery thyroid remnant. With the addition of iodine, the L-T4 maintains a similar efficacy in patients with either a large or a small remnant. (3) During treatment with L-T4 alone the highest therapeutic effectiveness is attained by lowering the plasma TSH concentration. With the addition of iodized salt to the daily diet the effects of L-T4 on remnant size are relevant independently of the TSH levels.

Long-term effects of lanreotide SR and octreotide LAR on tumour shrinkage and GH hypersecretion in patients with previously untreated acromegaly.

BACKGROUND AND OBJECTIVE: The therapeutic efficacy of lanreotide SR and octreotide LAR has been studied widely in patients treated previously with neurosurgery and/or radiotherapy. These therapies limit the evaluation of the long-term effects of somatostatin analogues on tumour shrinkage. Neurosurgical and radiotherapy treatments cause irreversible anatomical changes in pituitary morphology, which can make accurate evaluation of tumour shrinkage difficult. The aim of this study was to investigate the therapeutic efficacy of lanreotide SR and octreotide LAR in previously untreated patients with acromegaly. We aimed to investigate the long-term effects of these drugs on tumour shrinkage and growth hormone (GH) hypersecretion without the confounding influences of previous therapy. PATIENTS AND METHODS: Twenty-three newly diagnosed patients with acromegaly (14 women, nine men) with active disease began the study; of these, three were lost for follow-up, leaving a total of 20 patients to complete the study. Patients were assigned randomly to lanreotide SR (12 patients) and octreotide LAR (eight patients), and the randomization stratified patients to assure a balance between the groups with respect to baseline tumour dimension, age and sex. Tumour volume was evaluated by magnetic resonance imaging of the sella, and calculated with the rotating ellipsoid formula. A morphological and biochemical evaluation was performed at baseline, 12 and 24 months after beginning lanreotide SR and octreotide LAR treatment. A reduction of tumour volume of at least 10% was considered significant. RESULTS: Biochemical control increased progressively throughout the study in patients with microadenomas more than in patients with macroadenomas (70% vs. 10%; P < 0.05) and without a difference between lanreotide SR and octreotide LAR (41.0% vs. 37.5%; P not significant). After 12 months of treatment, mean tumour shrinkage was 28.3 +/- 18.0%. A greater reduction was observed in macro- vs. microadenomas (40.5 +/- 17.0% vs. 16.1 +/- 8.0%, respectively; P < 0.05). No statistical difference in the tumour shrinking effects of lanreotide SR vs. octreotide LAR was observed (26.5 +/- 17.3% vs. 31.1 +/- 16.1%, respectively). At the 24th month of therapy, no further overall shrinkage was observed, compared to the 12-month evaluation (31.9 +/- 17.2% vs. 28.3 +/- 18.0%) at which there was no difference between lanreotide SR and octreotide LAR (30.0 +/- 17.2% vs. 34.8 +/- 16.5%, respectively). CONCLUSIONS: This study showed that the new long-acting somatostatin analogues, lanreotide SR and octreotide LAR, cause significant shrinkage of pituitary GH-secreting adenomas in previously untreated patients with acromegaly. This effect was more marked in macroadenomas than microadenomas, and did not correlate with control of GH hypersecretion.