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Title: Histopathological evaluation of liver following experimental hyperthyroidism in chicks

Author: Emadi Ladan 1* (DVM, PhD), Kheirandish Reza 2(DVM, PhD), Amiri Narjes 3(DVM)

 

ID: 29637-2011



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4.REPORT: This is a simple minor report of serum values and basic liver histology in chicks given levothyroxine. The data may have value for veterinary nutritionists and broiler industry only as long as the data has not been generated elsewhere as asserted in text by authors. The paper is very poor and most of the information in the introduction and discussion is superfluous, repetitive and irrelevant.  The English is also poor and this paper requires a major re-writing effort to be considered. ABSTRACT please see suggestion. Introduction delete most and retain purpose of experiment (to describe new data only) see suggestions. MATERIALS AND METHODS: This is also poorly described however the actual methods etc are sound. The treated v controls numbers were adequate, treatment and protocols are sound and laboratory assay descriptions are acceptable etc..see suggestions.. A ethics statement will be required for this work to be considered further. The DISCUSSION needs to be completely changed. See suggestions. In the discussion, authors should simply describe current significant findings and support with references. Most of the references are superfluous authors are obliged to delete/correct. See suggestions belo Reassess after major changes X There is no way this paper will be reconsidered without suggested changes thank you

ABSTRACT Poorly described written see suggested

In the present study, the influence of experimental hyperthyroidism on serum level of liver enzymes, triglyceride, cholesterol and histopathological abnormalities of liver, in broilers was evaluated. A total of 36 one-day-old male cockerels were randomly divided in 3 groups; included: control, treatment L1 and L2 which hyperthyroidism was induced via daily oral consumption of levothyroxine sodium in drinking water (250, 500 μg/Kg BW) started at the age of 14 days, for 25 days period. At the end of experiment, blood samples were taken and thyroid hormones (T3, T4), triglyceride, cholesterol, alanine amino transferase and aspartate amino transferase were measured in serum. Then the chicks were slaughtered and liver samples were taken for histopathological staining. The result of present study demonstrated that increase in dosage of levothyroxine sodium causes significant decrease in the serum levels of triglyceride, cholesterol and significant increase in serum enzyme activity of ALT and AST, so this effect was dose dependent. In histopathological study, basophilic cytoplasm and euchromatin nuclei were observed in the hepatic cells. Irregular arrangement of hepatocytes and hepatic centrilobular necrosis was especially obvious in treatment group L2.  Lymphopoiesis in hepatic parenchyma and vascular smooth muscle hypertrophy were observed in the both treatment groups. According to the results of present study, induction of hyperthyroidism causes the hepatic functional and histological abnormalities and also decreases in cholesterol and triglyceride serum levels in chicks.

Suggest: The effect of oral levothyroxine on serum biochemistry and liver histology was evaluated in Ross broiler chicks. Two groups of 12 chicks each were given daily oral levothyroxine sodium 250 (12) or 500 μg/Kg at 14 days age for 25 days to induce hyperthyroidism. Compared with non-treated control (12) values, increased levothyroxine correlated with decreased triglyceride and cholesterol but increased ALT and AST. Basophilic cytoplasm and euchromatin nuclei were observed in hepatocytes of treated chicks, but irregular arrangement of hepatocytes and hepatic centrilobular necrosis was more evident in chicks given 500 ug/kg levothyroxine.  Lymphopoiesis in hepatic parenchyma and vascular smooth muscle hypertrophy were observed in treated birds. The findings suggest that 250 ug/kg or more levothyroxin may induce hepatotoxicity in chicks.

Key Words: Hyperthyroidism, Hepatic function, Chicks

Introduction

The thyroid gland is an endocrine organ found in all vertebrates. Its hormones triiodothyronine (T3) and thyroxin (T4) are involved in wide range of metabolic activities influencing the growth and development of organisms. The thyroid hormones are primarily involved in energy production by increasing the metabolic rate (Stojevic et al 2000). Most of the actions of thyroid hormones seem to be dependent on the binding to a nuclear thyroid hormone receptor. Thyroid hormone receptors preferentially bind triiodothyronine (T3). Consequently the peripheral metabolism of T4 by activating and inactivating pathways is very important in the regulation of the availability of receptor-active T3 and hence of thyroid activity. The most important metabolic pathway for thyroid hormones is deiodination. The enzymes catalyzing thyroid hormones deiodination consist of three types: type I (D1), type II (D2) and type III (D3) (Darras et al 2000). They are responsible for the activation of T4 to T3, inactivation of T4 to rT3 and the conversion of rT3 and T3 to T2. The type 1 deiodinase is mainly found in liver and kidney and accounts for approximately 30-40% of extrathyroidal production of T3. The type 2 deiodinase is found in the pituitary, the CNS, and skeletal muscle and contributes 60-70% of extrathyroidal production of T3. Although both the D1 and D2 system can also inactivate T4 and T3, the major inactivator is the type 3 deiodinase system. It is found in the liver, skin and CNS, where it catalyses the conversion of T4 to rT3 and T3 to T2 (Malik and Hodgson 2002). In addition to the central role in deiodination to activate and deactivate thyroid hormones, the liver performs specific functions relating to thyroid hormone transport and metabolism (Malik and Hodgson 2002). Characteristic for the chicken is the presence of very high levels of T3 inactivating D3 enzyme in the liver (Darras et al 2000). Therefore the liver has an important role in chicken thyroid hormone metabolism. Besides the level of thyroid hormones are also important to normal hepatic function (Huang 1995). It has been recognized that AST and ALT are released to blood in liver damage (Pratt and Kaplan 2000, Zantop 1997). Although, AST has a wide distribution in the avian body ́s tissues, it is possibly the single most useful enzyme for indicating liver disease (Coles 1997).

 Thyroid diseases are frequently associated with liver injuries or biochemical test abnormalities (Huang 1995). For example thyroid disease maybe associated with elevation of alanine aminotransferase (ALT) in hyperthyroidism and aspartate aminotransferase (AST) in hypothyroidism (Huang 1995). 

The liver is the major site for cholesterol and triglyceride metabolism, and the thyroid hormones play an integral part in hepatic lipid homeostasis. Thyroid hormones increase the expression of LDL receptors on the hepatocytes, and increase the activity of lipid-lowering liver enzymes, resulting in a reduction in low density lipoprotein levels. Thyroid hormones also increase the expression of apolipoprotein A1, a major component of high density lipoprotein (Malik and Hodgson 2002). It has been suggested that triiodothyronine depressed growth, but not food intake and decreased lipogenesis in chickens (Rosebrough 1992).

To the author's knowledge there is currently no data in the literature about the effect of hyperthyroidism on serum level of triglyceride, cholesterol, ALT, AST and hepatic function abnormalities in broiler chickens. In this study, we attempted to evaluate some serum biochemical parameters and histopathologic abnormalities of liver following the induction of experimental hyperthyroidism in broiler chickens.

Suggest” INTRODUCTION

To the author's knowledge there is currently no data in the literature about the effect of hyperthyroidism on serum level of triglyceride, cholesterol, ALT, AST and hepatic function  in broiler chicks. Chick serum biochemistry and hepatic histology in hyperthyroid induced chicks is described.

Material and Method: Needs major corrections see text

The one day old Ross chicks were obtained from Mahan Company (Kerman –Iran).  At first 36 chicks were selected to body weight, by discarding those of extreme weights, from a population of approximately 50 birds. Then the chicks randomly divided in 3 groups, 12 chicks in each; included: control, treatment L1 and L2. In treatment groups L1 and L2, hyperthyroidism was induced via daily oral consumption of levothyroxine sodium (Euthyrox 100μg – Merk KGaA, Darmstadt, Germany), doses of 250, 500 μg/Kg BW respectively, in drinking water, started at the age of 14 days, for 25 days period (Luger 2002, Fowles 1997). At the end of experiment, blood samples were taken from the brachial vein of all chickens. To ensure the development of hyperthyroid condition the level of thyroid hormones (T3, T4) in the serum was detected by electrochemiluminescence immunoassay method using T3 and T4 Roche kits on Elecsys 2010 analyzer (Hitachi, Germany). Triglyceride was determined by GPO-PAP method in serum. Cholesterol was determined enzymatically by CHOD-PAP method in serum. ALT and AST were measured by Optimized Colorimetric test combination, according to Reitman and Frankel in serum. Finally the chickens were slaughtered and liver tissue samples were taken from the groups of control, treatment L1 and L2. The liver tissue was fixed in %10 formalin and embedded in paraffin following routine procedures. Tissue sections of 5 µm thickness were prepared and stained with Hematoxylin and Eosin.

The mean biochemical parameters levels in serum were compared using one-way ANOVA between the groups. A p value less than 0.05 were considered significant.

Data of histopathological study of liver were compared in descriptive way between the groups.

MATERIALS AND METHODS

Suggestions: One day old Ross chicks (36) were randomly divided into 3 groups of 12 controls, 12 low and 12 higher dose levothyroxine. Hyperthyroidism was induced via daily oral consumption of levothyroxine sodium (Euthyrox 100μg – Merk KGaA, Darmstadt, Germany), doses of 250, 500 μg/Kg BW in drinking water, at 14 days old for 25 days (Luger 2002, Fowles 1997). At the end of experiment, blood samples were taken from the brachial vein of all chickens.

To confirm hyperthyroidism, serum T3 and T4 was detected by electrochemo illuminescence inmmunoassay (Roche) on a Elecsys 2010 analyzer (Hitachi, Germany). Triglyceride was determined by GPO-PAP method in serum. Cholesterol was determined enzymatically by CHOD-PAP method in serum. ALT and AST were measured by Optimized Colorimetric test combination, according to Reitman and Frankel in serum. Chickens were slaughtered and liver tissue samples were taken from the groups of control, treatment L1 and L2. The liver tissue was fixed in %10 formalin and embedded in paraffin following routine procedures. Tissue sections of 5 µm thickness were prepared and stained with Hematoxylin and Eosin. The mean biochemical parameters levels in serum were compared using one-way ANOVA between the groups. P < 0.05 was considered significant.

Results are presented in Table you do not need to repeat them in text, delete text

Biochemical parameters and their comparisons among the all groups are presented in Table 1.

Laboratory investigation on biochemical parameters revealed that serum mean concentration of T3 (ng/dl) in treatment groups L1 (84.04 ± 11.31) and L2 (84.03 ± 13.97) significantly decreased compared to control group (171.32± 15.17) (P<0.05). Whereas significant elevation in serum mean concentration of T4 (ng/dl) was observed in treatment groups L1 (3182.5 ± 443.17) and L2 (4192.5 ± 817.53) compared to the control group (740.75±38.63) (P<0.05).

There were no significant differences in serum mean concentration of T3 and T4 between treatment groups L1 and L2 (P>0.05).

The serum level of ALT (IU/L) in treatment group L2 (43.26± 5.04) significantly increased compared to the control group (21.38±1.84) (P<0.05).A significant difference between treatment groups L1 (29±1.81) and L2 was observed (P<0.05). There was no difference in serum level of ALT (IU/L) between groups of treatment L1 and control (P>0.05).

Serum mean concentration of AST (IU/L) significantly increased in treatment groups L1 (345 ± 17.76) and L2 (348.75± 14.77) compared to the control group (265.75± 8.59) (P<0.05). There was no difference in serum level of AST (IU/L) between groups of treatment L1 and L2 significantly (P>0.05).

Serum mean concentration of triglyceride (mg/dl) significantly decreased in treatment groups L1 (73.11±3.63) and L2 (57.21 ± 3.23) compared with control group (100.41±4.83) (P<0.05). There were significant differences in serum mean concentration of triglyceride (mg/dl) between treatment groups L1 and L2 (P<0.05).

The serum level of cholesterol (%mg) significantly decreased in treatment groups L1 (116.06±6.31) and L2 (111.21±5.04) compared with control group (198.72±9.32) (P<0.05). There were no significant differences in serum levels of cholesterol (%mg) between treatment groups L1 and L2 (P>0.05).

Histopathlogical evaluation of liver samples in both treatment groups showed the basophilic cytoplasm and euchromatin nuclei in the hepatocytes. The microscopic study also showed irregular arrangement of hepatocytes and a few mitotic figures in these groups (see Fig. 1). Hepatic centrilobular necrosis was more obvious in treatment group L2 than L1. Lymphocytes aggregation in hepatic parenchyma and vascular smooth muscle hypertrophy were mainly observed in treatment group L2 (see Fig. 2, 3).

Histopathlogical study of hepatic samples in control group demonstrated that all samples were normal.

 

 

Table 1. Comparison of serum levels of biochemical parameters in all groups1

Parameters                                                            Groups                                             .

                                 C                                  L1                                         L2      

T3 (ng/dl)                 171.32 ±15.17ab                  84.04±11.31a                          84.03±13.97b

T4 (ng/dl)                 740.75±38.63ab                   3182.5±443.17a                               4192.5±817.53b

ALT (IU/L)                 21.38±1.84a                29±1.81b                              43.26±5.04ab

AST (IU/L)                 265.75±8.59ab                     345±17.76a                             348.75±14.77b

TG (mg/dl)               100.41±4.83ab                     73.11±3.63ac                          57.21±3.23bc

CHL (%mg)               198.72±9.32ab                     116.06±6.31a                          111.21±5.04b 

1Data are expressed as means ± SE; statistical significance with respect to each group has been shown by a, b & c.

Group C: Control animals

Group L1: Chicks which received 250 μg/Kg of levothyroxine sodium

Group L2: Chicks which received 500 μg/Kg of levothyroxine sodium

Figure 1: Liver. Treatment groups. Irregular arrangement of hepatocytes, Presence of a mitotic figure (arrow). H&E. Bar = 25 µm

Figure 2: Liver. Treatment groups. Lymphocytes aggregation in parenchyma. H&E. Bar = 25 µm

Figure 3: Liver. Treatment groups. Hypertrophy of vascular smooth muscle. H&E. Bar = 100 µm

Figure 4: Liver. Treatment groups. Centrilobular necrosis. H&E. Bar = 25 µm

Discussion rewrite entirely

The present results show that serum levels of ALT and AST are increased after induction of hyperthyroidism with 250 and 500 µg/kg Levothyroxin sodium.  An increase in the AST and ALT was reported in 27% and 37% of patients with thyrotoxicosis respectively (Malik and Hodgson 2002).  In other studies elevation in serum AST and ALT, concomitantly with liver necrosis was observed when joint administration of T3 and lindane was used in rat. It is concluded that hyperthyroidism increases the susceptibility of the liver to the toxic effect of lindane (Videla et al 1995). In agreement with present result, studies on the influence of long lasting hyperthyroidism on enzyme activity in the blood plasma of adult leghorn hens showed that activity of ALT and AST increased (Majewska et al 1983). It is also reported that induction of hyperthyroidism in rat by 5 week administration of l- thyroxine sodium salt in drinking water elevates AST and ALT activities (Messarah et al 2009).

In present study induction of experimental hyperthyroidism in chicken significantly decreased the serum levels of triglyceride and cholesterol. Adiponectin, an adipocyte derived hormone, has been shown to decrease body weight by increasing thermogenesis and lipid oxidation. Thyroid hormones have similar effect. It was investigated that serum adiponectin level of experimental hyperthyroidism rats was 3.2 fold higher than that of euthyroid ones and had a positive correlation with serum thyroxine (Aragao et al 2007). High serum liver enzyme activities and lower serum cholesterol in cat with hyperthyroidism was observed (Berent et al 2007).  In addition hypo- and hyperthyroid conditions had opposing effects on plasma cholesterol levels in mallards (Fowles et al 1997). A significant correlation was observed between the cholesterol, triglyceride and the thyroid hormone levels in hyperthyroid patients (Boda et al 1997).

 The mechanism of liver injury in hyperthyroidism is not well understood, but it has been suggested that the damage to hepatocytes is caused by relative cetrilobular hypoxia due to increased hepatocyte demand for oxygen without a concominant increase hepatic blood flow (Ichikawa 2009). In mild cases, liver histology shows non-specific changes, which on light microscopy consist of polymorphic neutrophils, eosinophils and lymphocytes associated with nuclear changes and kupffer cell hyperplasia (Malik and Hodgson 2002). A small proportion of patients have a progressive liver injury, which histological consist of centrizonal necrosis and perivenular fibrosis, affecting the areas in which hypoxia may be most prevalent (Malik and Hodgson 2002). In present study also hepatic centrilobular necrosis was especially obvious with 500 µg/kg. In histopathological study of treatment groups, existence of basophilic cytoplasm and euchromatin nuclei in the hepatic cells and hepatocytes with irregular arrangement, even mitosis occurrence indicate the increased cell activity. The association between thyroid diseases and hepatocellular carcinoma has not been well established. Although it was investigated a significant elevation risk association between hypothyroidism and hepatocellular carcinoma that was independent of established hepatocellular carcinoma risk factors (Hassan et al 2009). Also multicentric hepatocellular carcinoma associated with clinical hyperthyroidism was observed (Helzberg et al 1985). In our study Lymphocytes aggregation in hepatic parenchyma were observed in the treatment groups. Recently a study showed that triiodothyronine and thyroxin concentrations were positively associated with markers of inflammation, natural killer-like T cells, activated monocytes derived interleukin-6 (IL-6), higher expression of IL-2 receptor on CD3+ T-lymphocytes, and percentage expression of memory T-lymphocytes, memory T-helper lymphocytes and memory T-cytotoxic lymphocytes within normal physiological ranges (Hodkinson et al 2009). This is supported by previous findings that thyroid hormone was involved in primary and secondary lymphopoiesis, and blastogenic responses to T and B cell mitogens were also enhanced following thyroxin administration (Fabris et al 1995). Other studies showed that thyroxin substitutive treatment restored the euthyroid status and reversed the impairment of T-cell activation induced by chronic stress in mice (Frick et al 2009). These results indicated that thyroxin could enhance the immune response.

The microscopic evaluation of liver in the present study also showed hepatic vascular smooth muscle hypertrophy in treatment groups was especially obvious with 500 µg/kg. The cardiocirculatory changes in hyperthyroidism seem to be an accommodation to the increased metabolic demands and lead to an increased perfusion of the peripheral tissues (Gallowttsch 2005). Due to the influence of elevated thyroid hormone levels, cardiac contractility and cardiac output are enhanced. Thyroid hormone mediated effects on the systemic vasculature include relaxation of vascular smooth muscle resulting in decreased arterial resistance (Danzi et al 2004). Hyperthyroidism provokes peripheral vasodilation with the consequence of a decrease in renal perfusion pressure and the activation of rennin-angiotensin system. Besides increased sodium reabsorption and blood volume, angiotensin II stimulates vascular smooth muscle cell growth and matrix synthesis (Volzke et al 2004). It has also been shown that treatment with T3 causes hypertrophy of coronary arteries (Sernia et al 1993). Vascular hypertrophy is associated with increased vascular stiffness. Such increased vascular stiffness of the carotid arteries has recently been reported in patients with graves΄ disease (Czarkowska et al 2002). Increased thickness of arterial vessel walls in hyperthyroidism may reflect an adaptive response of the vessel wall to changes in shear stress and tensile stress. Such circumstance may also be caused by hyperthyroidism via an increased heart rate and an increased pulse pressure (Czarkowski et al 2002, Glagov et al 1992).

According to the histopathological findings of current study and regarding to some biochemical alteration in serum, it could be concluded that hyperthyroidism makes hepatotoxicity in chicks.

Suggest: DISCUSSION

Oral levothyroxin increased serum ALT and AST confirming findings in humans and rats (Malik and Hodgson 2002),  (Videla et al 1995), (Majewska et al 1983) and (Messarah et al 2009). Induction of hyperthyroidism in chicks appeared to decreased serum triglyceride and cholesterol. Hepatic centrilobular necrosis, basophilic cytoplasms and euchromatin nuclei in hepatic cells and hepatocytes with mitosis suggested increased cell activity. Hepatic vascular smooth muscle hypertrophy and lymphocyte aggregation in hepatic parenchyma in birds given 500 µg/kg levothyroxin were similar to findings of Fabris et al 1995. The findings suggest that levothyroxin may induce hepatotoxicity in chicks.

 

References delete most please check against text

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Emadi Ladan 1* (DVM, PhD), Kheirandish Reza 2(DVM, PhD), Amiri Narjes (DVM)