The Relation between Thyroid Dysfunction and Metabolic Dysfunction-Associated Fatty Liver Disease in Egyptian Patients

Background and study aim


INTRODUCTION
One of the most common causes of chronic liver diseases worldwide is Metabolic dysfunction-associated fatty liver disease (MAFLD), it affects about 30% of the adults [1,2].MAFLD means fatty infiltration of the liver (FLD) associated with metabolic dysfunctions.Some studies reported that the complications of MAFLD made it one of the most common causes of liver transplantation [3].
Dysfunctions of thyroid gland have been implicated as one of the most important risk factors of MAFLD due to its important role on hepatic synthesis of fatty acid and cholesterol [5,6].
Maintaining liver metabolism needs thyroid function to be normal ; while thyroid disorders may lead to liver disease progression [7].
All thyroid hormones give an image for the decrease of thyroid function, while high TSH level more than the normal range usually means hypoactivity of the thyroid gland , as in subclinical hypothyroidism (

PATIENTS AND METHODS
This cross-sectional study carried out on 100 patients who attended to Tanta tropical medicine outpatient clinic, faculty of medicine.From October 2021 until October 2022.
While we excluded patients who aged < 18 years , taking medication that may affect thyroid functions or lipid levels , had alcoholic liver disease taking more than 40g of alcohol (or four units) per day , had viral hepatitis ,Pregnant women and who unwilling to participate in our study.
All the patients were subjected to; Personal history (name, age, sex, occupation, residence and marital state),Anthropometric measures: weight, length, BMI, waist circumference and complaint.
In addition to FreeT3, Free T4, TSH.,Lipid profile (triglycerides, HDL, LDH, cholesterol level) , Fasting Blood glucose level and or HBA1C, PCR for HCV for exclusion of viral hepatitis , liver enzymes , ultrasound on abdomen and pelvis for evaluation of liver condition and Fibroscan were done for all patients.
Fibroscan was used to assess the stages of fibrosis and steatosis using Dimensional ultrasound TE (transient elastography).Dimensional ultrasound TE (transient elastography) was used for staging liver fibrosis and steatosis by measuring the velocity of a lowfrequency (50 Hz) elastic shear wave propagating through the liver.This velocity has direct relation to the stiffness of the tissue, called the elastic modules (expressed as E=3qv2, where v is the shear velocity and q is the density of tissue, assumed to be constant).When the tissue is stiffer, the shear wave is propagating faster.
The results are expressed in Kilopascals (KPa) and range from 1.5 to 75 KPa with 5 KPa as normal value higher in men and in patients with low or high body mass index (BMI) (U-shaped distribution).
The liver stiffness is measured by the fibrosis score which is an indication of scarring.A fibrosis score F0 to F1 ( 2 to 7 kPa) means there is little or no scarring on the liver, while F2 (7.5 to 10 kPa) means moderate scarring that has spread outside the liver, while F3 (10 to 14 kPa) indicates severe scarring which has spread and disrupts normal blood flow, finally F4 ( 14 kPa or higher) means late-stage scarring or cirrhosis, where the scarring is permanent and the damage is irreversible.

Statistical analysis:
The organization, tabulation, presentation, and analysis of data were performed by using SPSS IBM Chicago, version 23.Qualitative data was divided into categories and presented as frequency number and percentage, with the chi square test used to determine the relationship between groups.Quantitative data was presented as mean ± SD and the relationship between groups was done by using independent student t test.The level of significance adopted was p < 0.05.

RESULTS
Study population consisted of 100 subjects including 45 men and 55 women.There were 50 patients with diabetes mellitus and 64 patients were hypertension, as demonstrated in table (1).
There were 67% cases Euthyroidism , 29% cases Subclinical hypothyroidism and 4% cases Overt hypothyroidism.as demonstrated in table (2).Subclinical hypothyroidism, defined as elevated TSH with free T4 concentrations at the lower end of the euthyroid range.In overt primary hypothyroidism, TSH levels are high and T4 and T3 levels are low.
There was a significant difference in waist circumference, HDL and triglyceride among different thyroid dysfunction groups.There was a difference in LDL and FBS, but not statistically significant ,as demonstrated in table (5) .
There was a significant positive correlation between TSH (waist circumference and TG), but there was a significant negative correlation between TSH and HDL.There was a significant negative correlation between T3 (waist circumference, TG and HDL), There was a significant negative correlation between T4 (waist circumference, TG and HDL) and regarding steatosis grade there was a significant positive correlation between the grade of steatosis and the level of TSH , as demonstrated in table (6).But there was no significant difference between the grade of steatosis and T3, T4 levels.

DISCUSSION
In 2020 the MAFLD is prepared to replace NAFLD definition .So, many studies had been made to find the associations between thyroid dysfunction and NAFLD, reported that NAFLD patients are always characterized by low T4, FT4 levels and high TSH levels [13].
The prevalence of thyroid dysfunction and hypothyroidism in metabolic syndrome patients is higher than the prevalence in the normal population, which is 5.9% for thyroid dysfunction and 4.6% for hypothyroidism (0.3% overt and 4.3% subclinical hypothyroidism) Metabolism has a sex dimorphism, which results in different disease risks for men and women, there are several studies including the general population reported that females had thyroid dysfunction more than males [18] this is in agreement with our result as the percentage of females with subclinical hypothyroidism were (40%) but males with subclinical hypothyroidism were (15.6%).
Thyroid hormones are recognized as catabolic hormones and they regulate various processes of metabolism, including the synthesis, mobilization, and breakdown of lipids.Hypothyroidism had been reported to be associated with an increased risk for dyslipidemia and atherosclerotic cardiovascular disease, in our study there was a significant negative correlation between T4 and TG and this was in agreement with Jang J, et al. that found a negative association between triglycerides and FT4 [19] .
waist circumference was significantly different between patients with and without thyroid dysfunction this was in agreement with Khatiwada S, et al [20].
The positive association of TSH with TC and LDL-c may be due to autoimmune activation involving lipoprotein(a).In our study HDL cholesterol had a significant negative association with TSH level and this was reported also by Khatiwada S, et al and Rajendra Kc ,et al [20,21].
The study done in India founded that subclinical hypothyroidism had a significant association between the levels of TSH and cholesterol level ,triglycerides, LDL, and HDL across the metabolic syndrome group [22].
In our study there was a significant positive correlation between TSH and waist circumference, a significant positive correlation between TSH and TG, and significant negative correlation between TSH and HDL.However, a study done in Turkey showed that TSH was not correlated with any metabolic syndrome parameters [23].But the study done by Fan et al , reported that patients suffered from thyroid hypofunction were more likely to be old age , females , and total cholesterol, , low-density lipoprotein (LDL), triglycerides were high in them [16].
Higher TSH levels can induce steatosis via TSH receptor (TSHR) signaling.TSH not only contributes to the negative feedback regulation of T4 secretion via TSHR in the thyroid gland but may also increase hepatic gluconeogenesis , decrease hepatic bile acid synthesis, and cause hypercholesterolemia by decreasing 3-hydroxy-3-methylglutaryl-CoAreductase phosphorylation, In this study we reported that the grades of steatosis in MAFLD patients were positively correlated with the level of TSH and this was the same results found by Chung et al and Xu et al,who reported that grades of fatty liver increased more in patients who had high TSH and this relationship was statistically significant (p = 0.001) ,this was reported by other studies that identified a positive association between NAFLD and TSH On the other hand Ittermann et al, detected no consistent association between serum TSH concentrations and hepatic steatosis [28].
While other study showed highly significant relationship between serum TSH levels and increasing the grades of fatty liver [29].
This study had some limitations: firstly, fatty liver disease was diagnosed by ultrasound and fibroscan, secondly, the sample size in our study is relatively small and finally, the study population was from one hospital and cannot represent the general population.Therefore, findings need to be validated using more sophisticated techniques as liver biopsies and a more representative population.

CONCLUSION
In conclusion, keeping in mind that thyroid dysfunction particularly subclinical hypothyroidism is one of the most common endocrine abnormalities that may occur in MAFLD especially in females .hence,thyroid function tests may be included as a routine investigation in all MAFLD patients especially females.

[ 24 ,
25].The studies done byCarulli et  al. and Pagadala et al, suggested that the serum TSH concentration is correlated with the severity of the hepatic steatosis [26,27] .