SERUM T3 LEVEL AND ITS RELATION TO CHRONIC HAPATITIS C VIRUS IN DIABETIC VERSUS NON DIABITIC PATIENTS

By

Mohammed M Hashim*, Tarek M Emran**and Fahmy A Abd El-Aziz**

* Microbiology Department, Faculty of Science, Ain Shams University, Cairo, Egypt.

** Clinical Pathology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt.

*** MicrobiologyDepartment, Faculty of Science, Ain Shams University, Cairo, Egypt.

**** International Medical Center Hospital, Shubra, Cairo, Egypt.

ABSTRACT

Background: Thyroid gland disorders represent one of the commonest endocrine manifestations of chronic hepatitis C (HCV).

Objective: This study was performed to evaluate thyroid hormones profile in patients with chronic hepatitis C and its relation to severity of liver damage in the presence or absence of diabetes mellitus.

Patients and methods: This study was performed on sixty patients with liver cirrhosis due to hepatitis C virus with or without diabetes mellitus. The patients were divided into three equal groups according to Child-Pough score as following: Group A, group B and group C. All patients were subjected to medical history, clinical examination and laboratory investigations including liver functions tests, renal function tests, complete blood picture (CBC), viral markers for hepatitis, hepatitis C virus antibody (HCV-Ab) and hepatitis B virus antigen (HBs-Ag), polymerase chain reaction (PCR), fasting blood sugar (FBS), postprandial blood sugar(PPBS) hemoglobin A1 C (HbA1c),  tetra-iodothyronin (T4), tri-iodothyronin( FT3), thyroid stimulating hormone (TSH) and abdominal ultrasound.

Results: Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood platelet and FT3 were significantly lower in group C than group B and group A, while serum levels of bilirubin andprothrombin time(PT) were significantly higher in group C than B and A. Serum levels of FT3 was positively correlated with serum albumin and negatively correlated with serum bilirubin and PT. There were no significant changes in the serum levels of FT3, FT4 and TSH between diabetic and non-diabetic patients. On the other hand, serum levels of ALT, AST, and albumin  significantly elevated in diabetic versus non-diabetic patients.

Conclusions: A highly significant reduction of serum FT3 in liver cirrhosis with normal serum FT4 and TSH levels was attributive to decreased deiodination of T4 to T3. Decreased serum FT3 level correlated with the severity of liver disease, and may be helpful in assessing the course and diagnosis of liver cirrhosis. Also, serum FT3 hormone level could be used as a marker for grading and assessment of the severity of hepatic dysfunctions.

Key words:  Thyroid disorders, FT3, Chronic HCV, Diabetes mellitus.

INTRODUCTION

      Hepatitis virus infection is an increas-ing problem and millions of hLiver has an important role in the metabolism of thyroid hormones as it is the most important organ in the peripheral conver-sion of tetra-iodothyronin (T4) to tri-iodothyronin (T3) by type 1deiodinase resulting to 5^,deiodination of T4. Also, it is involved in conjugation and circulation of thyroid hormones by synthesis of thyroid binding proteins (Mansour-Ghanaei et al., 2012 and Eshraghian et al., 2013).

    Evidences that HCV may induce metabolic and autoimmune disturbances leading to hypobetalipoproteinemia, steatosis, insulin resistance, impaired glucose tolerance, thyroid disease, and gonadal dysfunction have been found (García et al., 2015).

    Kayacetin et al. (2003) and Eshraghian & Taghavi (2014) showed that there are evidences of association between chronic liver diseases and changes in thyroid gland. Furthermore, they demonstrated that levels of thyroid hormones and their binding proteins are altered in patients with hepatic disorders especially cirrhosis. Merat et al. (2010) and Eshraghian &  Hamidian Jahromi  (2014) evaluated thyroid hormones profile in patients with hepatic cirrhosis due to chronic HCV infections and found that there was a relationship between thyroid hormones and severity of liver damage. On the other hand, thyroxine and tri-iodothyronine modulate hepatic function by regulating hepatocyte basal metabolic rate, besides all other body cells. Also, lower total serum T3 dedicates to a lower basal metabolic rate within hepatocyte leading to preservation of liver function and total body protein storage (Malik and Hodgson, 2002).

    Thyroid hormones play a key role in the regulation and activation of insulin receptor and glucose transporter proteins (Amati et al., 2009). Thyroid disorders have also been associated with defective insulin secretion, hyperinsulinemia, altered peripheral glucose disposal, and insulin resistance (Maratou et al., 2009). Insulin resistance is the central pathophysio-logical phenomenon of metabolic syndrome, and it has been shown that thyroid hormones and TSH are associated with several components of metabolic syndrome in euthyroid subjects (Kumar et al., 2009 and Dullaart et al., 2014).

     The present study was performed to evaluate thyroid hormones profile especially serum T3 hormone level in patients with chronic hepatitis C and its relation to severity of liver damage in the presence and absence of diabetes mellitus.

PATIENTS AND METHODS

     Sixty patients with liver cirrhosis due to hepatitis C virus, whether diabetic or non diabetic patients, were included in this study. The patients enrolled in this study were taken from inpatient and outpatient clinic of Internal Medicine Department of Al-Azhar university hospital at New Damietta in the period from April 2013 to march 2014. Diagnosis of diabetes mellitus was based on criteria of American Diabetes Association (ADA) standards of medical care in diabetes (ADA, 2010).

     The patients were divided into three equal groups according to Child-Pough score(Child and  Turcotte (1964) and Cholongitas et al. (2005). Group A with evidence of HCV infection and elevated liver enzymes, their  ages ranged  between 30 and 52 years, Group B  with evidence of HCV infection and cirrhosis; their  ages ranged  between 43 and 66 years, and Group C with  evidence of chronic HCV infection, and advanced cirrhosis their  ages ranged  between 48 and 66 years.

     Exclusion criteria: Patients suffering from previous or present thyroid dysfunctions, patients on medications that affect the study outcome (including carbamazepine, phenytoin, phenobarbi-tone, salicylates and non-steroidal anti-inflammatory drugs, inderal and steroids), patients under treatment by thyroid stimulating/inhibiting agents, subjects with history of alcohol consumption at last 6 months before the study, patients under treatment by antiviral drugs (ribavirine and interferon), and patients with autoimmune hepatitis and other autoimmune diseases.

     All patients were subjected to the following; careful history taking, thorough clinical examination and laboratory investigations including liver functions tests [liver enzymes (AST and ALT), total bilirubin, serum albumin, PT and INR], Renal function tests (blood urea and serum creatinine, serum uric acid), complete blood count, viral markers (HCV-Ab and HBs-Ag), polymerase chain reaction(PCR), fasting and two hours postprandial blood glucose, HbA1c, thyroid hormones estimation(TSH, FT3, FT4), and abdominal ultrasound was done for all groups.

    Blood samples were collected by vein-puncture and divided into two parts: The first part was treated immediately with EDTA-K3 for complete blood count and HbA1c, and in the second part  sera were separated from the rest of blood samples and were freshly analyzed for other tests required in this study.

Hematological and biochemical tests: Complete blood pictures including platelets counting were determined by Sysmex XS 500 automated hematology analyzer (Sysmex Corporation, Japan). Liver function tests were measured on an automated biochemistry analyzer (Roche/Hitachi 902). Quantitative HCV ribonucleic acid (RNA) by PCR was assayed by applied biosystems(Model 7500 system, Singapore), thyroid hormones (TSH, FT3 and FT4) were measured by chemiluminescence with Immulite(1000)with kit (Diagnostic Products Corporation; Los Angeles, CA, USA).

     Informed consent was taken from all subjects.

Statistical analysis: Statistical analysis of the results was performed using  ANOVA test for comparison among different items in the same group in quantitative data. Data were expressed as Mean ± SD using student's t-test for unpaired data.  A value of P ≤ 0.05 was considered significant.

RESULTS

     Serum levels of ALT, AST, blood platelets and FT3 were significantly lower in group C than group B and group A, while serum levels of serum bilirubin and PT were significantly higher in group C than B and A. On the other hand, no significant changes were found on other parameters among three patient groups (Table 1).

     Serum levels of FT3 were positively correlated with serum albumin ( p<0.038) and negatively correlated with serum levels of bilirubin (p<0.045) and PT (p<0.03). Accordingly, FT3 was inversely correlated to Chlid-Pough score (p < 0.0001), on the other hand, no correlations were found between FT4 and TSH and other laboratory investigations (Table 2).

     There were no significant changes in the serum levels of FT3, FT4 and TSH between diabetic and non-diabetic patients (Table 3). On the other hand, serum levels of ALT, AST, and albumin significantly elevated in diabetic versus non-diabetic patients with chronic liver diseases (Table 4).

Table (1): Statistical comparison between the studied groups as regard laboratory investigations

 P < 0.05 (*=significant), + = insignificant

Table (2): Correlation between TSH, FT3and FT4 versus different variables among all patients

Table (3): Statistical comparison between TSH, FT3, FT4 and diabetic patients in all patients.

Table (4): Statistical comparison between diabetic patients and liver function in all patients

DISCUSSION

     Liver plays an important role in the metabolism of thyroid hormones, as it is the most important organ in the peripheral conversion of tetraiodothyronin (T4) to triiodothyronin (T3) by type 1deiodinase resulting to 5 deiodination of T4. Moreover, it is involved in conjugation and circulation of thyroid hormones by synthesis of thyroid binding proteins (Mansour- Ghanaei et al., 2012 and Eshraghian & Taghavi, 2014).

     In the present study, the incidence of fatigability, bleeding tendency, pallor, jaundice, lower limbs edema, ascitis and encephalopathy significantly elevated in patients with group C than group B and in group B than group A. This was in consistent with findings by Fabrizi et al. (2003) in their study on 59 patients with chronic liver diseases.

     In our study, serum levels of ALT, AST, blood platelet and FT3 were signifi-cantly lower in group C than group B and group A, while serum levels of serum bilirubin and PT were significantly higher in group C than B and A. Htoo et al. (2012) reported that alanine amino trans-ferase  (ALT)  and  aspartate  amino trans-ferase  (AST)  indicate  the  concentration  of  hepatic  intracellular enzymes that have leaked into the circulation which are the markers for hepatocellular injury.

     In our study, serum FT3 levels (not FT4 and TSH) were significantly lower among patients of group C in comparison to other groups and correlated with serum albumin, bilirubin and PT in all studied patients. Kayacetin et al. (2003) and Eshraghian & Taghavi (2014) reported low serum FT3 levels in cirrhotic patients and its association with worsening liver function by Child Pugh classification with absence of correlation between serum FT4 and TSH levels. On the other hand, Malik and Hodgson (2002) and Eshraghian & Taghavi (2014) reported that hypothyroi-dism occur more in acute and chronic hepatitis and cirrhosis as a complication of chronic of liver diseases. This is in accordance with Tran et al. (2009) who reported that a significant correlation of low serum FT3 levels in relation to decreased serum albumen, while a negative correlation was found with serum bilirubin levels, and reported that liver and thyroid hormones are intricately correlated. So, thyroid hormone abnorma-lities are  seen  in  patients  of  liver  diseases,  although  they  are  clinically euthyroid.

     Green et al. (1997) showed that low serum FT3 levels corresponding to lower serum albumin levels who also documen-ted a significant correlation between the clinical severity and prognosis of the disease and serum thyroid hormone levels, and founded that serum FT3 levels in cirrhotic patients correlated with serum albumin values.

     One of side effects of liver dysfunc-tions on thyroid is the reduced serum T3 concentrations which are due to reduced activity of deiodinase enzyme that catalyzing the convertion of  T4 into T3 but the reverse T3 is not reduced because the activity of responsible enzyme is not altered. As whole in liver diseases, T3 is reduced firstly by lower activity of enzyme responsible for conversion of T4 into T3 (Mansour- Ghanaei et al., 2012).

     As regards HCV-RNA, there was a highly statistically significant difference between studied groups in viral load by PCR. On the other hand, there was no statistically significant correlation between thyroid hormones and viral load. Also, our study reported that there were no significant changes in the serum levels of FT3, FT4 and TSH between diabetic and non-diabetic patients.  On the other hand serum levels of ALT, AST, and albumin significantly elevated in diabetic versus non-diabetic patients with chronic liver diseases.

     Liu et al, (2012) examined the relation-ship between HCV infection and severity of liver diseases in relation to diabetes in a large community screening program, He reported that positive anti-HCV antibody and diabetes were found in (10.2%) of studied patients and (9.6%) subjects, respectively. The crude prevalence of diabetes was 10.5% in subjects with positive anti HCV and 9.4% in subjects with negative anti HCV and elevated liver enzymes were associated with diabetes 

CONCLUSION

     Highly significant reduction of serum FT3 in liver cirrhosis with normal serum FT4 and TSH levels. The finding of decreased FT3 in those patients may be due to decreased deiodination of T4 to T3. Decreased serum FT3 level correlated well with the severity of liver disease and may be helpful in assessing the course and diagnosis of liver cirrhosis. Also serum FT3 hormone level could be used as marker for grading and assessment of the severity of hepatic dysfunctions.

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