Lipid Profiles as Markers for the Severity of Liver Diseases in Cirrhotic Patients

Liver cirrhosis is a diffuse process in which the anatomical structure and function of the liver are disturbed. Lipid metabolism occurs mainly in the hepatocytes. In liver cirrhosis, it is expected to detect abnormal lipid profile and abnormal neutrophil to lymphocyte ratio due to necroinflammation and hepatocyte dysfunction. This study aimed to estimate the lipid profile in patients with liver cirrhosis and to assess its relation to the severity of the liver disease based on Child-Pugh Turcotte score and Neutrophil to Lymphocyte Ratio (NLR).


INTRODUCTION
Liver cirrhosis is a diffuse liver disease including fibrosis and disturbance of normal liver architecture with the formation of cirrhotic nodules [1].
The global prevalence of cirrhosis from autopsy studies ranges from 4.5% to 9.5% of the general population [ 1 -32].
Multiple etiological factors contribute to the development of cirrhosis, as exemplified in epidemiological studies thatidentified regular (moderate) alcohol consumption, age above 50 years, and male gender as risk factors in chronic hepatitis C, or older age obesity, insulin resistance/type 2 diabetes, hypertension and hyperlipidemia (all features of the metabolic syndrome) in non-alcoholic steatohepatitis (NASH) [2,27].
The most common important causes of liver cirrhosis are chronic hepatitis B, chronic hepatitis C, and alcoholic and (NASH) [2 -4].
Several scoring systems have been developed to evaluate liver status as Child-Turcotte pugh score (CTP) and model for end-stage liver disease (MELD) [5,6].
Neutrophil to lymphocyte ratio (NLR) test has been developed as a simple test to expect the presence of infection and to predict the severity of multiple malignancies [7 -9]. NLR may be helpful in the prediction of liver disease severity because of the necroinflammatory changes occurring in different liver diseases and in liver cirrhosis [10 -12].
Lipid metabolism and lipoprotein biosynthesis occur mainly in the hepatocytes; abnormal lipid profiles can be detected in patients with severe liver dysfunction. There is a prominent decrease in plasma cholesterol and triglyceride (TG) levels in patients with severe hepatitis and hepatic failure [13].
The preceding studies have reported that cirrhotic patients have abnormal metabolism of lipids, especially reduction in cholesterol level and hypobetalipoproteinemia, and the lipid profile may be considered a valuable method in assessing liver disease [33].
The aim of this study was to estimate the lipid profile in patients with liver cirrhosis and to assess its relation to the severity of the disease based on Child-Pugh Turcotte Score (CTP) and NLR

METHODS
It was a cross-section study. It included 500 subjects in the Department of Tropical Medicine and Infectious diseases in Tanta University Hospital and Assiut University Hospital from January 2017 to December 2018. Institutional ethical committee approval was obtained before the start of the study, and informed consent was signed by every patient before enrolment in the study; and by abiding the rules and regulations as per Helsinki Declaration. This study has been approved by the institutional review board of the, (registration number, 32382\06\18).
All authors had access to the study data, and reviewed and approved the final manuscript.
Patients more than 18 years old with chronic liver disease, etiologies were included in the study.
Diagnosis of liver cirrhosis was based on history, ultrasound, fibroscan and upper gastro-intestinal endoscopy. Patients are known to have dyslipidemia before detection of chronic liver disease, taking lipid-lowering drugs or immunosuppressive drugs, history of taking glucose, recent parenteral nutrition, patients with body mass index (BMI) >30, or patients unwilling to participate in the study were excluded.
A detailed history was taken. A clinical examination was made. Laboratory and radiological evaluations have been made, including complete blood count, fasting lipid profile (including cholesterol, triglycerides (TG), low-density lipoprotein(LDL), high-density lipoprotein (HDL) and very low -density lipoprotein (VLDL).
Serum cholesterol and triglyceride levels were analysed by in vitro enzymatic colorimetric kit method. HDL estimation was done by the enzymatic kit method after precipitation of serum by phosphotungstate and magnesium chloride [ 27].
Liver function tests, and renal function tests, and ultrasonography on the abdomen and pelvis were conducted. Child-Pugh Turcotte score [14], NLR and platelet to lymphocyte ratio, and FIB 4 were calculated for all patients.
A total Child-Pugh score of 5 to 6 is considered Child-Pugh class A (well-compensated disease), 7 to 9 is class B (significant functional compromise), and 10 to 15 is class C (decompensated disease).
Statistical Analysis: The normality of the different variables was tested by the Shapiro Wilks test. Statistical package for social science (IBM SPSS Statistics for Windows, version 23, IBM corp., Armonk, N.Y USA). V 23 was used to analyze the data. Quantitative data were compared using ANOVA for normally distributed data and Kruskal Wallis test for non-normally distributed data with LSD or Tamhane as post hoc test. Pearson and Spearman correlation coefficients were used. A two-sided P value <0.05 was considered statistically significant.

RESULTS
A total of 500 patients were enrolled in this study; 12 patients were excluded (two patients were on the immunosuppressive drug, three patients had BMI >30, and seven patients took lipid-lowering drugs). Four hundred and eighty-eight patients were analyzed during the period of the study. There were 338 (69.3%) males and 150 ( A total Child-Pugh score of 5 to 6 is considered Child-Pugh class A (well-compensated disease), 7 to 9 is class B (significant functional compromise), and 10 to 15 is class C (decompensated disease).  Table 3). Cholesterol level was significantly higher in patients with CTP class A than in other classes (P <0.001 for each). Also, it was significantly higher in patients with class B than in class C (P<0.001). No significant difference in triglyceride level among the different classes (P =0.99). However, LDL cholesterol, VLDL cholesterol and HDL cholesterol were significantly higher in CTP class B than class C (P <0.001 for each); however, there was ( Table 4).
A significant negative correlation was found between each cholesterol level, LDL cholesterol, VLDL cholesterol and HDL cholesterol with CTP class (P <0.001 for each) ( Table 5 ). Also, there was a significant negative correlation between cholesterol level and each of NLR ratio and FIB4 (P <0.001 and 0.005 respectively) ( Table 6).

DISCUSSION
This study was conducted to reveal the relation between the severity of liver disease and the lipid profile. In our study, all of the lipid markers were considerably greater in Child-Pugh A, although they began to decline with the progression of liver cirrhosis. The total cholesterol level was significantly higher in patients with Child-score A than B and C. Cholesterol, LDL, and VLDL cholesterol were significantly higher in Child B than C. A significant negative correlation was found between cholesterol level and each of FIB4 and NLR ratios. This could be explained by a decrease in the synthetic function of the diseased liver [12].
These findings were in agreement with the previous studies; Muhammed and Jayaraj [15] stated that all parameters of lipid profile, including triglycerides, were significantly lower in cirrhotic patients and were inversely correlated with the severity of cirrhosis [15]. Tauseef et al. [ 29 ] also supported our results and concluded that the amount of decrements measured in the levels of serum total cholesterol, LDL, and HDL in patients with cirrhosis are related to the progress in cirrhosis [ 29].
However, a study in 2013 conducted by Mandel et al. compared the lipid profile in 150 cirrhotic patients with healthy control detected those lipid profile parameters, other than serum TG and HDL levels, were reduced with the severity of liver cirrhosis but without significant correlation between the severity of liver disease and lipid profile. This could be because the majority of patients had cirrhosis due to nonalcoholic fatty liver disease [16]. Also, Mohammad Reza Ghadir et al. revealed that serum lipid levels diminished linearly with the progression of liver damage except for serum triglyceride level [17]. Sen et al. concluded that HDL and TG were significantly elevated in the patients with grade III fatty liver [18].
Due to the major role of inflammation in the process of advanced cirrhosis [19 -21], and NLR is an indicator of inflammation (neutrophils present the inflammation and lymphocytes regulatory immune response) [22], NLR can act as a marker of severity of liver fibrosis. Our study was similar to the previous studies which detected a significant positive correlation between Child-score and N/L ratio as NLR was higher in Child C patients [23 -25].
Further studies are needed to confirm our results and to assess the predictive value of the lipid profile measurement in cirrhotic patients.

CONCLUSION
In conclusion, there was a significant negative correlation between the severity of liver cirrhosis and lipid profiles (except triglyceride), FIB4 and NLR ratio.

LIMITATION OF THE STUDY
It was a single-center study with a small number of patients. Further studies are needed.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE
This study has been approved by the Institutional Review Board of the Faculty of Medicine, Tanta University, Tanta, Egypt (registration number,32382\06\18).

HUMAN AND ANIMAL RIGHTS
No animals were used in this research. All human research procedures were followed in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2013.

CONSENT FOR PUBLICATION
Informed consent was signed by every patient before enrolment in the study.

AVAILABILITY OF DATA AND MATERIALS
Not applicable.

FUNDING
None.