European Journal of Cardiovascular Medicine

When liver processes, such as protein synthesis, detoxification of toxic metabolic byproducts, and bile excretion, continue to decline over a period of six months or more, we say that the patient has chronic liver disease (CLD). In chronic liver disease (CLD), the liver parenchyma undergoes a never-ending cycle of inflammation, damage, and regeneration that eventually results in fibrosis and cirrhosis. Chronic liver disease can have many different causes, including exposure to harmful substances, heavy alcohol consumption, infections, autoimmune diseases, genetic abnormalities, and metabolic disorders. Chronic liver disease progresses to cirrhosis, which disrupts liver architecture, forms extensive nodules, reorganises blood vessels, creates new blood vessels (neo-angiogenesis), and deposits an extracellular matrix. In fibrosis, stellate cells and fibroblasts are recruited, leading to fibrosis; in cirrhosis, hepatic stem cells are responsible for parenchymal regeneration. It is a chronic illness that lasts longer than six months and includes cirrhosis and chronic hepatitis, among other liver diseases. The liver, a vital organ responsible for multiple metabolic, synthetic, and detoxifying functions, undergoes gradual deterioration in chronic liver disease, which severely impacts overall health.1

The clinical presentation of chronic liver disease varies based on its etiology and stage. In the early stages, patients may be asymptomatic or experience nonspecific symptoms like fatigue, weakness, anorexia, and weight loss. As the disease progresses, signs of liver dysfunction become more apparent, including jaundice, pruritus, ascites, splenomegaly, and coagulopathy.2 When cirrhosis progresses to a stage where the liver can no longer compensate for the damage, decompensated cirrhosis occurs. At this stage, the liver's ability to manage its functions deteriorates significantly, and symptoms like jaundice, ascites, variceal bleeding, or hepatic encephalopathy become evident, marking a severe progression of the disease with an increased risk of life-threatening complications.3 The high levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the blood are a result of the inflammation and hepatocyte death that occurs in chronic liver disease. Cholestatic diseases, such as PBC, also seem to increase other LFT markers, ALP and GGT. Cirrhosis can still be present with normal levels of AST and ALT, which are typically two to three times the normal limit.4 Increases in PT/INR and APTT are caused by decreased synthesis of clotting factors.

Decompensated cirrhosis manifests with life-threatening complications such as ascites, portal hypertension, upper gastrointestinal bleeding, hepatorenal syndrome, coagulopathy, spontaneous bacterial peritonitis, and hepatic encephalopathy. These complications arise due to the progressive impairment of hepatic function, leading to disturbances in metabolic, hemodynamic, and immunologic homeostasis. Portal hypertension, a key feature of cirrhosis, results from increased resistance to blood flow through the liver and contributes to the development of varices, ascites, and splenomegaly.5 Spontaneous bacterial peritonitis (SBP), a potentially fatal illness that arises without a clear intra-abdominal cause, frequently makes it worse.6

Hepatic encephalopathy, another critical complication, arises due to the accumulation of neurotoxic substances, primarily ammonia, in the bloodstream as a result of impaired hepatic detoxification. Coagulopathy in cirrhosis results from the liver’s inability to synthesize essential clotting factors, increasing the risk of both bleeding and thrombotic events. Hepatorenal syndrome (HRS), a severe form of renal dysfunction in cirrhosis, occurs due to profound renal vasoconstriction secondary to splanchnic arterial vasodilation. It is associated with high mortality if left untreated.7

The study aimed at assessing serum sodium levels as a prognostic factor in “decompensated liver disease” (DCLD).

The study was conducted in the General Medicine Department of SGT Hospital, utilizing the inpatient (IPD) settings over a period of 18 months. Patients presenting with clinical symptoms of decompensated cirrhosis, such as ascites, hepatic encephalopathy, and gastrointestinal bleeding, were screened and enrolled in the study. A total of 60 patients diagnosed with decompensated liver disease were included in the study. Inclusion criteria- Decompensated chronic liver disease patients between age 18 to 55 years diagnosed by •Clinical history and examination. •Biochemical investigations (Serum Bilirubin, Serum Albumin, Prothrombin time, AST, ALT, Serum Sodium, Serum Creatinine and other investigations as indicated) •Imaging studies like USG Abdomen (to look for liver size, echotexture, surface nodularity, collaterals, ascites and portal vein diameter) Exclusion criteria- •Patients with comorbidities like CCF, CKD. •Pregnant female •Age >55yrs Study Tools Informed consent was obtained from each subject after explaining the aim of the study in their native language to ensure complete understanding. Child-Pugh Score The Child-Pugh Score was used to classify the severity of chronic liver disease based on five clinical parameters: •Total bilirubin •Serum albumin •Prothrombin time (INR) •Ascites severity •Hepatic encephalopathy Based on the score, patients were classified as: •Class A (5-6 points) – Least severe disease; 1- to 5-year survival rate of 95%. •Class B (7-9 points) – Moderately severe disease; 1- to 5-year survival rate of 75%. •Class C (10-15 points) – Most severe disease; 1- to 5-year survival rate of 50%. MELD Score The Model for End-Stage Liver Disease (MELD) Score was used to prioritize patients for liver transplantation and assess disease severity. Data Analysis •Data were analyzed using SPSS version 23.0. •Descriptive statistics (mean, standard deviation, percentages) were used to summarize the study population. •Chi-square test and Fisher’s exact test were performed to evaluate the association between serum sodium levels and disease complications. •Logistic regression analysis was used to determine whether hyponatremia was an independent predictor of disease severity and mortality. •A p-value <0.05 was considered statistically significant. Ethical Considerations •The study was approved by the Institutional Ethics Committee of SGT Hospital. •Informed consent was obtained from all participants before enrolment.’ •All patient data were kept confidential and used solely for research purposes. •Patients requiring specialized treatment or liver transplantation were referred accordingly.

Table 1: Age and gender distribution

The mean age of participants was 46.3 ± 6.8 years, with an age range spanning from 18 to 55 years, reflecting the inclusion criteria. A significant proportion of patients, approximately 55%, were aged 41 to 55 years, while 40% were within the 30 to 40 years category. The younger cohort (18–29 years) comprised only 5% of the study population. Gender distribution revealed a marked male predominance, with 78.3% (47/60) of the patients being male, while 21.7% (13/60) were female.

Table 2: Socioeconomic status and risk factors

A significant proportion (20%) belonged to the lower class group, while 45% were from the lower middle class group. Only 15% of the patients belonged to the middle class category, with 3% in upper middle and 1.6% in upper class category. In this study, alcohol consumption emerged as the most prominent risk factor, with 70% (42/60) of patients having a documented history of chronic alcohol use. Smoking was another significant factor, with 50% (30/60) of the participants identified as active smokers.

Table 3: Distribution of Serum Sodium Levels among Patients

Serum sodium levels were assessed across the cohort, revealing a mean sodium level of 131.8 ± 5.7 mEq/L. The classification of patients based on sodium levels demonstrated a significant prevalence of hyponatremia, affecting 66.7% (40 out of 60) of patients with sodium levels below 135 mEq/L. Among them, 22 patients (36.7%) had mild hyponatremia (130-134 mEq/L), 12 patients (20.0%) had moderate hyponatremia (125-129 mEq/L), and 6 patients (10.0%) had severe hyponatremia (<125 mEq/L). In contrast, normonatremia (135-145 mEq/L) was observed in 20 patients (33.3%).

Table 4: Relationship Between Serum Sodium and Child-Pugh Score

Patients classified as Child-Pugh Class A (least severe disease) had a mean serum sodium of 137.2 ± 3.1 mEq/L, whereas those in Child-Pugh Class B (moderate disease severity) had a mean sodium level of 132.1 ± 4.2 mEq/L. Patients with Child-Pugh Class C (most severe disease) exhibited significantly lower sodium levels, with a mean of 126.8 ± 5.5 mEq/L (p < 0.001).

Table 5: Relationship Between Serum Sodium and MELD Score

Patients with higher MELD scores exhibited significantly lower serum sodium levels. The Pearson correlation coefficient (r = -0.72, p < 0.001) suggested a strong inverse correlation between serum sodium and disease severity.

Table 6: Statistical Correlation Between Serum Sodium and Disease Severity

The correlation coefficient between serum sodium and Child-Pugh score was found to be r = -0.78, p < 0.001, indicating a statistically significant association. Similarly, the correlation between serum sodium and MELD score was r = -0.72, p < 0.001, reinforcing the trend that lower sodium levels are associated with more severe liver dysfunction. These findings suggest that patients with lower sodium levels are more likely to have a higher Child-Pugh and MELD score, thereby signifying more advanced liver disease and a poorer prognosis. A linear regression model was applied to determine the predictive ability of serum sodium in relation to liver disease severity. The results confirmed that for every 1 mEq/L decrease in serum sodium, the Child-Pugh score increased by approximately 0.85 points (p < 0.001), while the MELD score increased by 1.1 points (p = 0.002). The 95% confidence interval (CI) for the Child-Pugh correlation was 0.89 – 0.96, while that for the MELD score was 0.82 – 0.91, confirming the robustness of these correlations.

Table 7: Association Between Hyponatremia and Hepatic Encephalopathy, Ascites Severity, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome

Patients without HE had a mean serum sodium of 135.2 ± 3.4 mEq/L, while those with mild HE (Grade 1-2) had a sodium level of 129.7 ± 4.5 mEq/L. More importantly, patients with severe HE (Grade 3-4) exhibited significantly lower sodium levels, with a mean of 124.6 ± 5.2 mEq/L. The observed difference was found to be statistically significant (p = 0.004), suggesting that hyponatremia may contribute to the worsening of neurological symptoms in DCLD patients. Among the 28 patients with severe ascites (46.7%), the mean serum sodium level was 126.7 ± 5.1 mEq/L, whereas patients with mild to moderate ascites (18 patients, 30%) had a mean sodium level of 132.4 ± 3.8 mEq/L. Patients without ascites had significantly higher sodium levels (136.4 ± 2.9 mEq/L, p < 0.001). Spontaneous bacterial peritonitis (SBP) is a life-threatening complication of decompensated liver disease, typically arising in patients with severe ascites. In this study, 12 patients (20%) developed SBP, and their mean serum sodium level was 125.3 ± 5.7 mEq/L. This was significantly lower than the sodium levels observed in patients without SBP (p = 0.001), indicating a potential role of hyponatremia in increasing susceptibility to SBP. In this study, 5 out of 60 patients (8.3%) developed HRS, and their mean serum sodium level was 122.5 ± 4.3 mEq/L, which was significantly lower than the sodium levels observed in non-HRS patients (p < 0.001).

The present study aimed to investigate the role of serum sodium as a prognostic factor in DCLD and its association with disease severity, complications, and mortality. The results indicate a strong inverse correlation between serum sodium levels and the severity of liver disease, as assessed by the Child-Pugh and MELD scores.

One of the most significant findings of this study was the strong negative correlation between serum sodium levels and disease severity, as measured by both the Child-Pugh and MELD scores. The statistical analysis demonstrated that patients with higher Child-Pugh and MELD scores exhibited significantly lower serum sodium levels, with a p-value of <0.001, indicating a highly significant association. These findings are consistent with previous studies that have highlighted the role of hyponatremia as a marker of advanced liver dysfunction.8,9 The present study found that patients classified as Child-Pugh Class C exhibited significantly lower serum sodium levels compared to those in Class A and B, reinforcing the association between sodium levels and worsening liver function. This observation aligns with the findings of Arroyo et al10 (2017), who reported that hyponatremia is more prevalent in patients with advanced cirrhosis and is associated with worse survival outcomes.

Patients with a MELD score ≥30 had markedly lower sodium levels compared to those with a MELD score <10, with an observed p-value of <0.001, indicating statistical significance. This finding is in agreement with previous research by Biggins et al11 (2020), who demonstrated that incorporating serum sodium into the MELD score (MELD-Na) significantly improved its predictive accuracy for mortality in cirrhotic patients. Given the strong correlation between sodium levels and liver disease severity, these findings support the integration of serum sodium into existing prognostic models to enhance risk stratification and clinical decision-making. Hepatic encephalopathy (HE) is a severe neurological complication of decompensated cirrhosis, characterized by altered mental status, cognitive dysfunction, and in severe cases, coma. In this study, patients with HE had significantly lower serum sodium levels compared to those without HE (p = 0.004), with the lowest sodium levels observed in patients with severe HE (Grade 3-4). The findings support previous research indicating that hyponatremia exacerbates neuropsychiatric dysfunction in cirrhosis by contributing to astrocyte swelling and increased brain edema (Montoliu et al., 2019).12

Hyponatremia plays a key role in cerebral edema and astrocyte dysfunction, as dilutional hyponatremia leads to hypo-osmolality, which disrupts the blood-brain barrier and increases ammonia-induced neurotoxicity (Cordoba, 2020).13 Several studies have reported that hyponatremia is independently associated with the severity of HE and an increased risk of hospitalization in cirrhotic patients (Mendez-Guerrero et al., 2018; Rahimi et al., 2021).14,15 Given these findings, monitoring and correcting sodium imbalances in HE patients is crucial to improving neurological outcomes. The findings of this study also demonstrated a significant association between hyponatremia and ascites severity, with patients exhibiting severe ascites having a mean serum sodium level of 126.7 ± 5.1 mEq/L, compared to 132.4 ± 3.8 mEq/L in those with mild ascites (p < 0.001). The mechanism underlying this association involves sodium and water retention due to splanchnic vasodilation, reduced effective circulating volume, and inappropriate ADH secretion, leading to worsening ascites and dilutional hyponatremia (Runyon, 2019).16

Additionally, hyponatremia was significantly associated with the development of SBP, a life-threatening complication in cirrhotic patients with ascites. The study found that SBP patients had significantly lower sodium levels (mean = 125.3 ± 5.7 mEq/L, p = 0.001) compared to those without SBP, reinforcing the link between sodium derangement and increased risk of infection. Previous studies have shown that hyponatremia impairs immune function, disrupts peritoneal fluid homeostasis, and contributes to bacterial translocation, increasing the risk of peritonitis in cirrhotic patients (Tandon & Garcia-Tsao, 2020).17 HRS is one of the most severe complications of decompensated liver disease, marked by progressive renal failure due to impaired renal perfusion and vasoconstriction. This study observed that patients with HRS had significantly lower sodium levels (mean = 122.5 ± 4.3 mEq/L, p < 0.001), confirming the association between worsening sodium imbalance and renal dysfunction. The findings align with previous research by Angeli et al18 (2018), which reported that hyponatremia is a key predictor of acute kidney injury and HRS development in cirrhotic patients. The results of this study align with previous research highlighting the prognostic significance of hyponatremia in cirrhotic patients. Studies by Kim et al8 (2019) and Wong et al9 (2020) similarly reported that lower serum sodium levels were associated with increased mortality and worsened disease severity, reinforcing the findings of the present study. Furthermore, the integration of MELD-Na scoring into liver transplantation models has been widely recommended based on evidence demonstrating its superior predictive accuracy over the standard MELD score, which further supports the clinical relevance of the current findings (Biggins et al., 2020).11

One of the strengths of this study is its comprehensive evaluation of multiple clinical parameters, including disease severity, complications, and mortality, allowing for a thorough assessment of the prognostic utility of serum sodium in decompensated liver disease. Additionally, the study included a diverse cohort of patients, minimizing selection bias and ensuring generalizability of the findings. 

In conclusion, this study provides compelling evidence that serum sodium is an independent and reliable predictor of disease severity, complications, and mortality in decompensated liver disease. The strong associations observed between hyponatremia and adverse outcomes reinforce the need for early detection, continuous monitoring, and targeted therapeutic interventions. The integration of serum sodium assessment into routine liver disease management and transplantation evaluation has the potential to enhance risk stratification, guide therapeutic decision-making, and ultimately improve patient outcomes. Future research should focus on developing standardized guidelines for the correction of hyponatremia and investigating novel treatment strategies to optimize sodium balance in cirrhotic patients.

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