الفهرس 
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Abstract
The purpose of the study was to investigate the significance of genetic studies of the patatin like phospholipase domain-containing-3 (PNPLA3) gene and Sterol regulatory element-binding factor 2 in the diagnosis of MAFLD in insulin-resistant patients and their use as a factor in determining the severity of MAFLD, as well as the significance of serum levels of CK18, IL-6, and TNF-alpha as diagnostic biomarkers for NAFLD.
Patients and methods: The research was carried out on a group of patients diagnosed with MAFLD disease. These individuals were chosen at random from the patients who had attended the Internal Medicine and the Hepatology Clinics at Minia University hospital.
In the course of our research, we looked at a total of 80 people who had been diagnosed with MAFLD. These patients were separated into two groups: those who were overweight (45) and those who were not (35),additionally third control group of apparently health 20 persons.
All included patients and controls were subjected to:Full cinical history, examination and calculation of anthrobometric measurements(body mass index (BMI). ,waist circumference ,hip circumference and waist hip ratio). They indergo to basic investigation of complete liver function,renal function CBC,fasting lipid profil and thyroid function tests additionaly Fasting blood sugar. Fasting insulin for estimate HOMA-IR, Serum ferritin. Serum ceruloplasmin. Antinuclear antibody and HBs Ag ,HCV antibodies.The specific tests that included serum levels of CK-18,IL-6 and TNF alpha by ELISA,PCR for evulation rs738409 C>G variant in the patatin like phospholipase domain-containing-3 (PNPLA3) gene and rs133291 variation of the sterol regulatory element binding factor 2 (SREBF2) gene.The detection of fatty liver by abdominal ultrasound then the patients undergo to MRI of liver for assessment degree of steatosis and share wave elastography for determine grade of liver fibrosis.also we used clinical scores for detect liver steatosisand its degree by HIS and FLI and liver fibrosis by using Fib 4 and Fib 6 scores and NFS.
Results: The following information was gleaned from this study: The participants in the study are comparable with each other as regard to age and gender. Our MAFLD patients had a significantly higher frequency of high systolic blood pressure (SBP) and high diastolic blood pressure (DBP), as well as diabetes mellitus, as compared to the controls (P< 0.001). There was a statistically significant gap between the patients and the controls in terms of anthropometric measurements.At the same time, patients with MAFLD had significantly higher values of ALT, AST, alkine phosphatase, and GGT than controls, with a P value that is less than 0.001. Additionally, there was a substantial rise in TLC (P< 0.001) and platelets (P = 0.006) in our MAFLD patients as compared to the controls, which indicates a persistent chronic inflammatory condition. When individuals with MAFLD were compared to healthy controls, there was a statistically significant increase in TSH (P 0.001).At the same time, participants with MAFLD have significantly higher values of cholesterol, triglyceride, fasting blood glucose, and HOMA-IR (P< 0.001) than healthy individuals. In addition, ferritin levels were found to be considerably greater in MAFLD patients compared to those seen in controls (P< 0.001). The levels of the inflammatory markers TNF-α , IL6, and CK18 were significantly greater in MAFLD patients than they were in the control group.(P value < 0.001).
When compared to the other groups of people with MAFLD and the control group, the obese diabetic MAFLD showed a significantly greater level of the inflammatory markers TNF-α and IL6.
When compared to the control group, the MAFLD cases had significantly higher levels of TNF-α (p< 0.001).In MAFLD cases, the frequency of the mutant form of the PNPLA3 polymorphism gene was typically greater than in the control group. This was the case regardless of whether or not the patients had diabetes or obesity.
In contrast, the wild type of the SREBP-2 polymorphism gene was shown to be more commonly higher in MAFLD patients than in the control group (P value< 0.001), and this was the case independent of whether or not the patients had diabetes or obesity. (P value < 0.004).
There was a significantly positive relationship among HOMA-IR and TNF α level (r=0.253, P=0.024). This correlation was statistically significant. There were statistically significant positive correlation across grade of steatosis and TNF-α level (r=0.542, P=<0.001), IL-6 (r=0.525, P=<0.001),CK-18 level (r=0.449, P=<0.001) and PNPLA3 gene polymorphism (r=0.326, P=0.003), on the other hand there were statistically significant negative correlation across grade of steatosis and SREBP-2gene polymorphism(r=-0.269, P=0.016).
A statistically significant positive correlation was found among grade of fibrosis and TNF-α (r=0.296, P=0.008), IL-6 (r=0.254, P=0.023), and CK-18level (r=0.328, P=0.003).
On the other hand, there was a statistically significant negative correlation across grade of fibrosis and SREBP-2gene polymorphism (r= 0.239, P=0.033).
Our study resulted in functional discriminant score for diagnosis of steatosis as followed Discriminant score = -4.691 + (1.603 x TSH)
Our study resulted in functional discriminant score for diagnosis of steatosis as followed
Discriminant score = -1.667 + (0.092 x age) + (-1.255 x S. albumin) + (0.366 x HB) + (-0.005 x Platelets).
Conclusion
In conclusion, the findings of our research indicate that MAFLD is a syndrome that is characterized by a high level of proinflammatory cytokines (IL-6, TNF-α ),which indicates a chronic inflammatory condition.
The role of the PNPLA-3(GG) polymorphism mutant genotype and the SREBP-2 (GG) wild genotype in the onset and progression of MAFLD can be deduced from their respective genetic predispositions.
In addition, an increased CK-18 level is a predictor of severe liver fibrosis and more evidence that MAFLD is a progressive disease.
The TNF-α is a useful indicator of the severity of hepatic steatosis.
Subclinical or low-normal thyroid function is associated with MAFLD to a large degree.
Recommendations
• Our recommendations include
1- Increasing the sample size of the patients with MAFLD for precise evaluation of the levels of our markers and its role in early diagnosis of MAFLD.
2- Taking in consider the role of genes and epigenes in pathogenesis of MAFLD especially in lean individuals.
3- Evaluation of thyroid function in MAFLD patients that help us in management.
4- Evaluation of inflammatory markers in MAFLD patients that help us in follow up and management.
5- We recommend conduction of validation study to evaluate accuracy of clinical scores in diagnosis of hepatic steatosis and fibrosis.