Prevalence of subclinical hypothyroidism in hypercholesterolemic adults and influence of serum TSH on the serum total cholesterol level / 대한내과학회지

BACKGROUND: Subclinical hypothyroidism is frequently discovered from hypercholesterolemic adults. It is defined as an asymptomatic state which characterized by normal free thyroxine (FT4) and elevated thyroid stimulating hormone (TSH) level. Hypercholesterolemia is a major risk factor for coronary heart disease, however hypercholesterolemia caused by hypothyroidism can be easily managed by thyroid hormone replacement. The screening of thyroid disease in hypercholesterolemia patient must be emphasized in order to find out correctable hypothyroidism. So we screened the prevalence of overt and subclinical hypothyroidism at different hypercholesterol levels in middle-aged men and women and also analyzed the correlation between TSH and total cholesterol level. METHODS: We measured serum TSH levels and FT4 by radioimmunoassay from 491 patients with hypercholesterolemia. The subjects were divided into two groups according to serum cholesterol level. Group I was serum cholesterol > or = 240 - or = 300 mg/dL. Subclinical hypothyroidism was defined as TSH levels higher than 4 mU/L, in the presence of normal FT4 concentration. RESULTS: The overall prevalence of subclinical and overt hypothyroidism was 3.4% and 2.5% in men and 4.7% and 3.5% in women of middle age. In men the prevalence of overt and subclinical hypothyroidism increased from 2.3% of group I to 16.1% in the group II (p<0.05). In women that increased from 5.2 % to 12.9 % (p<0.05). After age correction, an increase of 1 mU/L TSH in men was associated with an increase of 3.2 mg/dL total cholesterol (p<0.01). A similar trend was also found in women (2.1 mg/dL p=0.052). CONCLUSION: In this population, the prevalence of hypothyroidism is up to 16.1% in middle-aged men, 12.9% in middle-aged women with high total cholesterol and it may justify screening of thyroid disease in hypercholesterolemic patients especially in clinical practice.

Gene Expression of Somatostatin Receptor (Subtype 2 & 5), Gi2 alpha and Pit-1 in GH-secreting Pituitary Adenomas / 대한내분비학회지

BACKGROUND: Mutation of Gs protein subunit (gsp oncogene), detected in about 30~40% of growth hormone (GH)-secreting pituitary tumors, is associated with an increased long-acting somatostatin analog octreotide sensitivity. However, the mRNA expression of somatostatin receptor (sst) was not changed in the GH-secreting pituitary tumor, regardless of whether they were gsp oncogene positive or negative. This suggests that the expression of genes coding for Gi2 alpha , Pit-1 and the other factors involved in the regulation of secretory activity in somatotrophs is likely to be altered in gsp oncogene positive tumors. We observed the impact of the gsp oncogene on the expression of the genes coding for Gi2 alpha, Pit-1 and sst (2&5) in GH-secreting pituitary tumors. METHODS: The GH response to octreotide was examined in 13 acromegalic patients before transsphenoidal adenomectomy. Genomic DNA and RNA were extracted from fresh frozen tumor tissues. PCR was performed to amplify and sequence the region between codon 184 and 251 that includes exons 8 and 9 of the Gs gene. Sst2, sst5, Gi2 alpha and Pit-1 mRNA levels were measured by semi-quantitative RT-PCR. RESULTS: Sst2 and sst5 mRNA transcripts were detected in all tumors (7 gsp +, 6 gsp-). The amount of sst transcripts varied considerably varied between the tumors. There were no significant differences in sex, age, tumor size, grade or basal GH levels. Pit-1 and sst2 mRNA levels were not different. In contrast, Gi2 alpha mRNA levels were significantly higher in gsp (+) while sst5 mRNA levels were higher in gsp (-). CONCLUSION: These data suggests that gsp oncogene may increase Gi2 alpha levels but decrease sst5 mRNA levels. However, Pit-1 and sst2 mRNA expression may not be affected by gsp oncogene. The increased expression of the Gi2 alpha gene might be an inhibitory compensatory response to the action of gsp oncogene.

Gene Expression of the Somatostatin Receptors, Gi2 alpha and Pit-1 alpha in GH3 Cells Permanently Transfected with a Mutant Gs alpha Gene / 대한내분비학회지

BACKGROUND: Cyclic AMP stimulates the expression of the somatostatin (SRIF) receptor (sst1-5) and human growth hormone (GH)-secreting pituitary tumors with the gsp oncogene which increases intracellular cAMP levels, and shows a good inhibitory response of the GH to SRIF. Taken together, we hypothesized that the gsp oncogene may increase the SRIF receptor expression or and factors related to the postreceptor signal transduction of the SRIF, in order to enhance its responsiveness to SRIF. To test this hypothesis, we investigated if the gsp oncogene could increase the sst1, sst2, Gi2 alpha, and pit-1 alpha gene expression in GH3 cells. METHODS: GH3 cells were permanently transfected with the plasmid expressing Gs alpha gene, where the arginine of codon 201 was replaced with histidine. Intracellular cAMP levels and GH concentrations were measured by radioimmunoassays. Gene expressions of the sst1, sst2, Gi2 alpha, and pit-1 alpha were determined by RT-PCR. RESULTS: Intracellular cAMP levels and medium GH release were increased by 1.7 and 2.7-fold in GH3 cells expressing the gsp oncogene, respectively. In GH3 cells expressing the gsp oncogene, the sst1 mRNA levels were decreased, whereas those of the sst2, Gi2 alpha and pit-1 alpha mRNA were increased. A 4-h forskolin (10 M) stimulation remarkably increased the sst1 and sst2 mRNA levels in GH3 cells expressing wild and mutant Gs alpha . However, forskolin did not affect the Gi2 alpha and pit-1 alpha mRNA levels. In contrast, SRIF (1 M, 2 h) decreased the sst2 mRNA levels only in GH3 cells expressing the gsp oncogene. CONCLUSION: These results suggest that higher expressions of sst2, Gi2 alpha, and pit-1 alpha, induced by the gsp oncogene may be a mechanism by which gsp-positive pituitary tumors show a greater response to SRIF. The discrepancy between these and in vivo results should be explored further.

Expression of TRH Receptor Gene in GH-Secreting Piruitary Adenomas / 대한내분비학회지

Background: To test the hypothesis that Galphas gene mutation may suppress the expression of TRH-R gene, we investigated whether hTRH-R gene expression is lower in human GH-secreting pituitary adenomas with Galphas mutation than in tumors without the mutation. Method: TRH-induced paradoxical response of GH was observed in 8 acromegalic patients. The mutation of gene was identified by direct sequencing of the genomic DNA prepared from GH-secreting pituitary adenomas. The expression of hTRHT mRNA was quantitated by RT-PCR. Results: The transcript of hTRH-R gene was detected in 6 of 8(75%) tumors. Three of these(50%) showed the paradoxical GH response to TRH and the other three patients did not show the response. The relative expression of hTRH-R mRNA in the tumors from patients with the paradoxical response of GH to TRH did not differ from that in the tumors from patients without the paradoxical response. Direct PCR sequencing of Galphas disclosed a mutant allele and a normal allele only at codon 201 in 4 of 8 tumors. The paradoxical response to TRH was observed in 2 of 4 patients without the mutation, and 2 of 4 patients with the mutation. The hTRH-R gene expression of pituitary adenomas did not differ between the tumors without the mutation and those with mutation. Conclusion: This study suggests that the expression of TRH-R gene is not likely to be a main determinant for the paradoxical response of GH to TRH, and that Galphas mutation does not seem to suppress the gene expression of TRH-R in GH secreting adenoma.

Long-Term Follow up of Thyroid Functions in Patients with Successful Renal Transplantation (RT) / 대한내과학회지

BACKGROUND: Thyroid status in uremia is still inconclusive due to the complexicity of the system. No single pathogenetic event may explain the thyroid function abnormalities in end stage renal disease (ESRD). Defects at all levels of the hypothalamic-pituitary-thyroid axis have been identified. Regarding the thyroid dysfunction in ESRD it is well recognized that the TSH response to TRH is blunted and serum concentrations of thyroid hormones are decreased in patients with ESRD. Whether or not on maintenance hemodialysis. Restoration of renal function with renal transplantation resulted in normalization of all parameters of thyroid function with exception of blunted TSH response to TRH. We evaluated the long-term changes of the thyroid function in 10 patients to know whether the thyroid function and the hypothalamo-pituitary axis were improved with the recovery of the renal function under maintenance low-dosage steroid administration after renal transplantation. METHODS: These tests were performed during the morning in the fasting state in 10 ESRD patients before, 1 month and 6 years after renal transplantation (RT). Thyroid function tests. Serum T3, T4 were measured by RIA kit and serum TSH was measured by IRMA kit. TRH stimulation test. Serum blood samples were obtained 0, 30, 60, 90, 120 min after TRH (400microgram) administration. Statistical analysis. All grouped data were expressed as mean+/-SD. Student t-test was used to assess the statistical difference between any two means. RESULTS: 1) The mean basal level of serum T3 was reduced in ESRD patients (53.6+/-33.2ng/dL) and increased to the low normal level 1 month after RT (87.8+/-25.4ng/dL), improved to the normal level 6 years after RT (116.3+/-28.8ng/dL). 2) The mean basal level of T4 was within normal range before RT (5.9+/-1.1microgram/dL), after 1 month (6.2+/-1.2microgram/dL) and after 6 years (6.5+/-1.4microgram/dL) of RT. 3) The mean basal level of TSH was within normal range before RT (2.0+/-1.2microU/mL), after 1 month (1.1+/-0.7microU/mL), and after 6 years (0.7+/-0.5microU/mL) of RT. Rut the mean TSH level of 6 years of RT was significantly decreased within the normal range. 4) In ESRD the TSH response to TRH was blunted, had a diminished peak and delayed fall before RT. After 1 month of RT, the TSH response to TRH was persistently blunted, however showed more rapid fall of TSH. After 6 years of RT, the TSH response to TRH normalized, but the absolute level of TSH and the peak level of TSH to TRH were less than before and after 1 month of RT. CONCLUSIONS: The abnormalities of thyroid hormones in uremic patients were improved partially after 1 month of RT and almost completely after 6 years of RT. But the level of T3H and the peak level of TSH to TRH were low within normal range, these results may be a direct consequence of low-dosage and long-term glucorcorticoid administration.

Changes of Serum Lipoprotein (a) Concentrations According to the Severity of Diabetic Nephropathy / 대한내과학회지

BACKGROUND: Lipoprotein(a)[Lp(a)] is a subspecies of low-density lipoprotein and has been shown to be associated with pathogenesis of thrombosis-related disease. It is already known that patients with diabetic nephropathy are usually complicated by vascular complications such as coronary artery diseases and cerebrovascular accidents. According to the recent data, Lp(a) level tends to be increased as the proteinuria is increased and renal function are decreased. We evaluated the Lp(a) level to know whether its level is correlated to the severity of diabetic nephropathy. METHODS: We investigated Lp(a) levels in eighty-one patients with Type 2 (non-insulin-dependent) diabetic patients. They were divided into four groups according to the level of urinary albumin excretion and serum creatinine level: Group 1 (n=30): normal renal function + urine microalbumin or=1.5mg/dL. Blood samples were obtained during the morning in the fasting state and separated serum from the it and reserved at -70degrees C. Lp(a) concentration was checked by one-step sandwich ELISA test. All grouped data were expressed as mean+/-SD. ANOVA and unpaired t-test was used to assess the statistical difference between any two means. RESULTS: Lp(a) levels were 30.2+/-4.6mg/dL in Group 1, 42.7+/-8.2mg/dL in group 2, 73.4+/-19.7mg/dL in group 3, and 80.7+/-14.8mg/dL in group 4. The level of Lp(a) in group4, group 3, and group 2 was significantly higher than that of group 1 respectively (P=0.009, 0.001, 0.038). However, no significant correlation was observed between the level of Lp(a) and that of total cholesterol, triglyceride and total lipid in all groups. CONCLUSIONS: these results indicate that Lp(a) concentrations are increased in the patients with diabetic nephropathy with microalbuminuria or overt proteinuria. So, the presence of albuminuria may be the important determinant for the elevated Lp(a) level in diabetic nephropathy.