الفهرس 
Chapter I: Introduction and Review of LiteraturesOnly 14 pages are availabe for public view
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Abstract
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Summary
In mammals, TH is necessary for growth and development of the kidney and for the maintenance of water and electrolyte homeostasis. TH has multiple effects on liver function including stimulation of enzymes regulating lipogenesis and lipolysis as well as oxidative processes. Moreover, hyperthyroidism has been reported to induce mild hyperhomocysteinemia and endothelial dysfunction. So, the impact of hyperhomocysteinemia explains increase oxidative stress and alternation in some parameters of liver and kidney as creatinine and cholesterol. On the other hand, folic acid has been reported to have an antioxidant power against free radicals, and an alleviating role in hyperhomocysteinemia and the associated endothelial dysfunction. Also, progressive folate deficiency was suggested to develop with hyperthyroidism.
The present study aimed to declare the effect of low thyroid hormone status on the liver and the kidney functions and oxidative stress parameters which affect respectively on liver and kidney functions. It also aimed to elucidate the role of folic acid supplementation in reducing these changes and building up the antioxidant status as a concurrent treatment with hyperthyroidism and as a post-treatment after restoration of the euthyroid state.
The experiment was performed on (50) male albino rats dividing in five groups of 6-7 week’s age. All the experiments were done in compliance with the guiding principles in the care and use of laboratory animals. The rats were equally divided into five groups:
Group 1: Rats of this group never received any treatment and consider as negative control.
Group 2: Animals received folic acid (El Nasr Pharmaceutical Chemicals Co.) at a dose level of (8 mg/kg of body weight/ day) for three weeks from 3rd week to 6th week (Tousson et al., 2012).
Group 3: Rats of this group were received L-thyroxin sodium (100 μg/kg / body weight) (Sahoo et al., 2008) for three weeks to induce hyperthyroidism.
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Group 4: Rats of this group were received L-thyroxin sodium (100 μg/kg / body weight/day) for three weeks, followed by folic acid 8 mg/ kg/body weight/day for another three weeks.
Group 5: Rats of this group were received L-thyroxin sodium n (100 μg/kg / body weight/day) for three weeks and left without treatment for another three weeks.
Blood samples were individually collected from each rat and the serum samples subjected to the estimation of thyroid function tests, kidney function tests and liver function tests. Different homogenates of the liver and kidney tissues were prepared and used for estimation of malondialdehyde (MDA) concentration, reduced glutathione (GSH), and nitric oxide (NO) in these tissues.
Kidney and liver of rats from different studied groups were also prepared for histological and immunohistochemical investigations.
Serum triiodothyronine (T3) and serum thyroxin (T4) levels showed a significant increase respectively in L-thyroxin treated rats and a significant decrease in treated rats with L-thyroxin and folic acid groups as compared to controls. Thyroid stimulating hormone (TSH) levels showed a significant decrease in L-thyroxin treated rats and increase respectively in rats treated with L-thyroxin and folic acid. Meanwhile, there was a significant change in T3 and TSH levels after restoration of euthyroid in post treated group as compared to L-thyroxin group.
Histological studies for L-thyroxin treated rats indicate that there are different histopathological lesions such as congestion of renal vessels and leucocytic infiltrations, swelling and cytoplasmic vaculation of the epithelial lining of the tubules were observed, the glomeruli were fragmented and atrophied, also there are some changes in liver tissue represent in impaired structural organization of the hepatic lobules. In addition central and portal veins were congested and enlarged with blood and surrounded by leucocytic infiltration. Most of hepatocytes displayed cytoplasmic vaculation and the nuclei are pyknotic, fatty infiltrations were observed in different parts of the liver section. Also these studies indicate the role of folic acid
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and restoration of euthyroid state at tissue level. Additionally, folic acid was found to alleviate liver and kidney functions degeneration observed in the hyperthyroid group. However, better results were found in case of using folic acid as an adjuvant therapy after restoring the euthyroid state (post treated group). If confirmed in human beings, these results could propose that folic acid can be used as an adjuvant therapy with thyroxin replacement therapy in hyperthyroidism disorders.
In the present study serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) revealed a significant increase in L-thyroxin treated rats when compared with control group. These results are in agreement with a number of studies which provided evidence that hyperthyroidism causes an adverse effect on the liver. AST elevation may be attributed to myopathies which are usually associated with hyperthyroidism, in addition disturbance in liver function.
Treating rats with L-thyroxin leading to a significant decrease in serum creatinine and urea in L-thyroxin group as compared to control group. Thyroidal status influences kidney function both during embryonic development and in the mature functioning of the kidney, directly by affecting glomerular function, the tubular secretory and absorptive capacities, electrolyte pumps and kidney structure and indirectly by affecting the cardiovascular system through its influence on renal blood flow which decrease in hypothyroidism. Decrease in serum creatinine is reversible in hyperthyroid state after restore thyroid hormone normal level in post treated group.
Serum cholesterol, triglycerides, HDL and LDL in L-thyroxin group showed a significant decrease as compared to control group. It has been well established that thyroid hormone affects cholesterol concentration, hepatic metabolism and cholesterol synthesis. Total cholesterol, HDL, LDL, VLDL and triglycerides levels were found to be decreased in hyperthyroidism and this may be due to the rapid clearing of chylomicron remnants from blood stimulating cholesteryl ester transfer which in turn stimulate lipoprotein lipase. The main cause of the differences in total
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cholesterol concentrations is the alterations of LDL-C levels due to the increase in LDL receptor mRNA gene expression, which leads to an increase in activity and number of LDL receptors and enhance LDL receptor-mediated catabolism of LDL particles. This reflects role of folic acid and restoration of euthyroid state.
The present study indicates that hyperthyroidism increases lipid peroxidation; there is a significant increase in MDA and NO in L-thyroxin group as compared to control group. The increase of some antioxidant enzymes activities such as malondialdehyde and nitric oxide may be an indication of the failure of compensating the induced oxidative stress. Antioxidant power of folic acid and restoration of euthyroid state decrease MDA. While there is a significant decrease in GSH in L-thyroxin group as compared to control group. This contradicting finding may be attributed to duration of drug administration. Increased oxidative stress is a well-known phenomenon in the hyperthyroid state. Hyperthyroidism is believed to accelerate free radical generation that leads to oxidative damage of lipids. This reduction in glutathione levels in hyperthyroid rats as compared to the control rats not only confirms the main role of the thyroid hormones in regulating the oxidative stress in target cells, but also is in agreement with previous data.