European Journal of Cardiovascular Medicine

Cirrhosis is a chronic liver injury with diffuse hepatic fibrosis that replaces normal liver structures with regenerative liver nodules ^[1,2]. The main causes of chronic liver disease (CLD) are alcohol consumption, nonalcoholic fatty liver disease (NAFLD), hepatitis viruses, and autoimmune diseases. As a result of chronic liver injury, the extracellular fibrotic tissue that accumulates in the liver prevents normal oxygenation and blood exchange in the liver parenchyma.^[3] Over time, this process results into marked structural changes that include hepatocyte extinction, micro and macrovascular remodeling, neo angiogenesis and development of portosystemic shunts collectively termed as ‘cirrhosis’ ^[4]. The course of cirrhosis is progressive with asymptomatic stages, such as compensated cirrhosis, leading to decompensated stages with a range of complications that include ascites, gastro-esophageal variceal (GEV) bleeding, and hepatic encephalopathy (HE). Cirrhosis may further advance to liver failure leading to death ^[5]. Portal hypertension is the major culprit in the transition from the compensated to the ‘decompensated’ stage of cirrhosis ^[6]. The increased intrahepatic resistance to the passage of blood flow due to cirrhosis and increased splanchnic blood flow plays an important role in the development of portal hypertension.   Cirrhosis is now seen as a dynamic disease able to progress and regress between the compensated and decompensated stages ^[3]. Acute decompensation (AD) refers to the development of one or more cirrhotic complications, and acute-on-chronic liver failure (ACLF) is defined as an acute liver function deterioration leading to extra-hepatic organ failure (OF) and short-term mortality ^[7,8].

 According to recent epidemiological studies, 5.2 million cases of chronic liver disease and cirrhosis occurred in 2017, representing a rise in the incidence of the condition in both men and women compared to 1990. In 2019, 1.48 million fatalities were attributed to cirrhosis, an 8.1% rise from 2017 ^[9]. Based on the most recent WHO data released in 2017, India accounted for one-fifth (18.3%) of all cirrhosis deaths worldwide, with 259,749 deaths from liver disease, or 2.95% of all deaths ^[10].Owing to the dynamic nature of the course of cirrhosis, it is critical to identify patients who are at risk of complications or who are at high risk of developing ACLF (acute on chronic liver failure) to prevent and reduce mortality and morbidity. 

Novel biomarkers and non-invasive measuring techniques that are simple, readily available, reproducible, low cost are needed at present for the detection of patients at risk for acute decompensation. One such tool is Neutrophil to Lymphocyte ratio (NLR) which has emerged as marker for systemic inflammatory response NLR combines the two aspects of the immune system. The innate immune response, primarily driven by neutrophils, and adaptive immunity, primarily facilitated by lymphocytes. It is computed as a ratio between the neutrophil and lymphocyte counts measured in peripheral blood. NLR in adults has a typical range of 1-2; values more than 2.72 and lower than 0.7 are abnormal. NLR was first studied in malignancy and acute coronary syndrome, where higher NLR has consistently been associated with worse outcomes and increased mortality ^[11,12].

In cirrhosis, NLR is a recognized predictor of survival in patients with hepatocarcinoma ^[13] or hepatitis B virus (HBV) infection, as well as in patients awaiting transplantation ^[14,15]. Almost all medical specialties now employ NLR extensively as a dependable and accessible indicator of immune response to a range of viral and non-infectious stimuli. Hence this study was done to find the NLR as marker to predict complications and as a prognostic significance in stable cirrhosis patients.

Objectives

• To determine the blood neutrophil to lymphocyte ratio in compensated liver cirrhosis patients and establish its relation with development of complications.
• To evaluate blood neutrophil to lymphocyte ratio as a prognostic marker in patients with compensated liver cirrhosis

The study population was done on 100. It is an observational study done at King George Hospital, Visakhapatnam over a period of one year from December 2022 to November 2023.

Inclusion Criteria

1. Age >18 yrs
2. Male and Female patients diagnosed with compensated Liver cirrhosis based on clinical history, laboratory parameters and ultrasound abdomen.
3. Patients with given informed consent.

Exclusion Criteria

1. Patients with immunodeficiency diseases like HIV, using corticosteroids and cytotoxic drugs.
2. Patients with hepatocellular cancer.
3. Patients with initial presentation to OPD as decompensated liver cirrhosis (Ascites, jaundice, variceal bleed, hepatic Encephalopathy).
4. Patients with ongoing Infection.
5. Pregnancy and lactation.

Methodology

After getting approval from Institutional Ethics Committee, this study was done in 100 patients diagnosed with compensated liver cirrhosis attending the General medicine and Gastroenterology department. Blood samples were taken from every patient, their neutrophil to lymphocyte ratio was computed, patients were followed for one year. The NLR ratio was computed by dividing the absolute neutrophil count by the absolute lymphocyte count. The Neutrophil to Lymphocyte ratio was calculated by using DYNACOUNT 3D 3 Part Hematology Analyzer and from manual peripheral smear counts. All these patients were followed for one year during their OP visits, inpatient admissions and through the phone calls. The in-patients were evaluated for the development of complications based on clinical and laboratory investigations such as complete blood count, liver function tests, serum electrolytes, renal function tests, ascitic fluid analysis and ultrasound abdomen. Patients who developed complications were identified and correlated with already calculated Neutrophil to Lymphocyte ratio and the results were analyzed

The study population included 100 patients who met all inclusion and exclusion requirements. Age and sex distribution are among the many distinctive features of the research population that were analyzed.

Table: 1 Shows in 100 patients, >40 years was the predominant age group in study population.

Table:1 Age group of study population

Table :2 Displays study population with increased M>F ratio. But women population was in relatively smaller portion. In women, the primary cause of cirrhosis was drunkenness.

Table:2 Male to female ratio

Table :3 NRL is the ratio of absolute neutrophil count to the absolute lymphocyte count. NLR has a cut-off value of 2.72. Table 3 shows 39 percent of patients were found to have raised NLR values and 61% found to have normal levels (<2.72).

Table :3 NLR LEVELS

Table: 4 Shows increased number of patients under the NLR range 2 to 4. It also shows 5 patients with >10 in whom complications also developed.

TABLE: 4 NLR DISTRIBUTION

Table :5 In 100 patients, Complications were seen in 42 patients. More prevalence of complications was seen in patients with elevated NLR group. P value = 0.00 which is statistically highly significant. Increased NLR is highly significant with the development of complications.

Table:5 NLR AND COMPLICATIONS

Figure:1 Shows patients with elevated NLR ratio were 39, out of which 32 developed complications and only 10 patients with normal NLR developed complications. We compared both the sample groups statistically

Table :6 Shows patients with 58% showing no complications. The remaining 42% of population 26% had single complication, remaining had combination. In which ascites with 15% was the most common single complication, followed by UGI bleeding. Only 1% of population had jaundice. The prevalence of complications among the study subjects was variable against other problems.

Table:7 Shows the higher prevalence of alcohol intake in the male population when compared to female patients

Table :7 SEX DISTRIBUTION IN ALCOHOLICS

Table:8 Shows 32 patients with raised NLR values among 80 alcoholic patients and 7 patients with elevated NLR in 20 nonalcoholic patients. The research cohort consisted of individuals who were known to have cirrhosis for a variety of reasons. P value being 0.682, which indicates statistical insignificance Therefore, in this study group of patients, alcoholism is not substantially associated with the elevated NLR ratio.

Table: 8 ALCOHOLISM AND NLR

In the present study,15% of the study are under the 40-year age group. The age range of 40 to 60 makes up a significant portion of the study population, suggesting a higher prevalence of cirrhosis in middle-aged individuals, who are generally the most productive in all facets of life. A small subset of patients was limited to those over 60. The mean age was 51.56 ± 12.58 years. 81% of the study population were males and the remaining were females. Similar findings were observed in Seyed Jalal Hashemi et.al ^[16], a retrospective cohort study, where 197 out of 256 participants are males (76.95%) and 59(23.15%) are females.in the study done by Vineeth et al ^[17],90 percent of 120 patients were men,10% were females.

The Cut off value of the NLR ratio is 2.72^[21], which is consistent with many other NLR ratio studies. In the present study, 61 patients out of 100 had normal NLR ratios (< 2.72), while 39 had increased NLR ratios (> 2.72). The lowest NLR value was 0.92, and the highest value was 14.88. Of the 39 patients with a high NLR, 32 patients experienced complications such as ascites, hepatic encephalopathy or upper gastrointestinal hemorrhage, either alone or in combination. 10 patients out of the 61 research participants with normal NLRs experienced complications, whereas the remaining 51patients did not. After comparing the two sample groups, the P value was determined.

The P value in the computation is 0.000, indicating a very significant result. This indicates that elevated NLR is associated with higher incidence of complications in individuals with cirrhosis. This study is consistent with other studies like Biyak et al ^[21] study, a retrospective observational cohort study, where NLR of at least 2.72 found to predictor of mortality independent of CTP and MELD scores in patients with liver cirrhosis. Moreau et al ^[18] demonstrated that the prognostic significance of NLR in patients with severe liver cirrhosis that was not dependent on the MELD score 57 which highlights the importance of inflammation in these patients' poor prognosis and is not taken into account by traditional prognostic metrics like the MELD score. Maccali et al^[19] study, prospective study found a direct correlation between the NLR and the MELD score as well as other disease severity markers in acute decompensated cirrhotic patients, emphasizing the significance of this measure as a predictor of unfavorable outcomes and mortality. Individuals with bacterial infections had greater NLRs than those without bacterial illnesses in this study.The NLR was also mentioned by Chiriac et al study ^[20], as an affordable way to forecast illness outcomes and complications in patients with severe liver cirrhosis receiving intensive care unit (ICU) treatment. In the study, the average NLR was11.7; those with higher NLR values had increased rates of coagulopathy, ascites, and other adverse outcomes, as well as higher bilirubin levels, Child-Pugh scores, and in- hospital mortality. Furthermore, there was a strong and direct correlation between the MELD score and the NLR.

The most common complications encountered in this study is ascites (15%) followed by upper gastrointestinal bleeding (8%). 16 % of total study population presented with more than 2 complications. These findings are consistent with Vineeth et al study where the majority of patients had complications with high NLR. Given the high prevalence of alcoholism among the study participants, research was conducted to determine whether alcohol consumption may be a contributing factor.  Among study population, 80% were not alcoholics and 20% were not. There is a clear correlation between the higher frequency of alcoholism in men than in women and the study's preponderance of male patients. 32 patients found to have raised NLR values among 80 alcoholic patients and 7 patients with elevated NLR in 20 nonalcoholic patients and the computed P value was 0.682, indicating statistical insignificance as it is greater than 0.05. Therefore, in this study, alcoholism is not substantially associated with the elevated NLR levels.

The present study suggests higher prevalence of cirrhosis in middle aged individuals with male preponderance. The study highlights the strong association of elevated NLR with higher incidence of complications in compensated liver cirrhosis patients making it as a potential marker for prognostication of cirrhosis. This study emphasizes in educating patients for frequent OP visits, timely and effective intervention strategies, and modification of treatment plan in compensated cirrhotic patients with elevated NLR levels to prevent complications and further to reduce morbidity and mortality. Elevated NLR in alcoholism found no statistical significance in the study.

CONFLICTS OF INTEREST – Nil

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