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Abstract

Background: Chronic liver disease (CLD) progressively deteriorates liver function over time. Hyponatremia, serum sodium below 135 mmol/L, is common in decompensated cirrhosis patients and is associated with increased morbidity and mortality. Tolvaptan, a selective V2 receptor antagonist, induces water excretion without altering electrolyte levels but requires careful monitoring for renal safety and potential hepatotoxicity. Here, we evaluate outcomes of tolvaptan in outpatient CLD patients with hyponatremia. Methods: A retro-prospective observational study from September 2023 to June 2024, CLD outpatients aged 18 years or older with hyponatremia prescribed tolvaptan. Demographic and laboratory data before and after treatment were analyzed. Results: The study included 245 patients (11.4?males, 88.6% males) with a mean age of 58 ± 11 years. Alcohol, primary cause of CLD (51.4%), followed by NAFLD (17.1%). Diabetes mellitus was the most common comorbidity (88.6%). Child-Pugh classification: 66.5% class C, 22.9% class B, 10.6% class A. Median study duration was 7 days. Tolvaptan significantly increased serum sodium from 127 mmol/L to 130 mmol/L (p < 0.001) and improved liver function, electrolyte levels, hematological, and renal parameters (all p < 0.001). Conclusion: Tolvaptan significantly improved serum sodium levels, correcting hyponatremia, and positively affected liver function, electrolyte balance, and other health metrics in CLD patients. These findings underscore tolvaptan's efficacy in managing hyponatremia and enhancing overall health outpatient population.

Keywords

CLD, Cirrhosis, Hyponatremia, Tolvaptan, Liver function

Introduction

Chronic liver disease (CLD) is a progressive condition characterized by ongoing impairment of liver function lasting more than six months. Essential liver functions such as producing clotting factors and proteins, bile excretion, and detoxifying metabolic toxins are compromised in this condition[1]. CLD is one of the top causes of death and is strongly associated with lack of physical activity, excessive alcohol consumption, and obesity. Key contributors to this condition include viral infections, alcohol use, exposure to toxins, non-alcoholic fatty liver disease (NAFLD), autoimmune disorders, genetic factors, and metabolic disorders. Together these elements worsen liver damage [2,3]. CLD, involve continuous inflammation, destruction, and possible regeneration of liver tissues, ultimately leading to cirrhosis andfibrosis, notable disruption of liver structure, nodule formation, reconfiguration of blood vessels, new blood vessel growth (neoangiogenesis), and deposition of extracellular matrix[1].  Patients with decompensated liver cirrhosis and hyponatremia experience an increased mortality rate. Hyponatremia is a frequent and critical complication in these patients[10].CLD leads to more than two million deaths globally (4% of all deaths; one third women) .   Despite being the eleventh most common cause of death, liver mortality may be underestimated[4]. Cirrhosis patients possibly develop hyponatremia due to either hypovolemia (loss of extracellular fluid caused by diuretics) or hypervolemia (excess extracellular fluid volume due to the kidneys’ inability to excrete solute-free water in proportion to the amount ingested)[11]. Hyponatremia cirrhosis is characterized by serum sodium levels below 130 mEq/L[8]. Recent studies indicate that around half of patients suffering from cirrhosis and portal hypertension experience hyponatremia[16]. The severity of CLDcorrelates with the degree of hyponatremia[15]In people suffering from advanced liver cirrhosis, low levels of albumin and increased pressure in the portal vein contribute to low sodium levels predominantly due to dilution[17]. Tolvaptan, a vasopressin receptor antagonist, is currently becoming popular. This study aims to determine efficacy and safety of  tolvaptan and assess the changes in electrolytes, liver function, renal function and haematological profile in tolvaptan users among hyponatremic outpatients with  CLD.

Patients And Methods

Patient Population

CLD outpatients with hyponatremia prescribed Tolvaptan by the departments of GI Surgery or Gastroenterology. This retro-prospective observational study conducted over nine months, (September 2023 to June 2024) at a 1250-bedded tertiary care super-speciality referral teaching hospital in coastal South India (Amrita Institute of Medical Sciences & Research Centre,Kochi, Kerala) with  the approval of the institutional ethics committee. All authors had access to the study data and have reviewed and approved the final manuscript.

Inclusion Criteria

Patients with CLD and hyponatremia, registered in the outpatient department at the Amrita Institute of Medical Sciences & Research Centre, Kochi, Kerala, from September 2023 to June 2024, were included in this retro-prospective observational study. Inclusion criteria were patients aged 18 years or older, diagnosed with hyponatremia and CLD, and prescribed Tolvaptan for outpatient therapy by the departments of GI Surgery or Gastroenterology.

Exclusion Criteria

Chronic kidney disease (CKD) patients, hypovolemic hyponatremia, pregnant and lactating women and those who declined to participate were excluded.

Methodology

Patients are selected based on predefined inclusion and exclusion criteria. Data collected fromAmrita Healthcare Information System (AHIS) and direct review ofpatients' medical records, and information transcribed topredesigned data collection form. Laboratory parameters including serum electrolytes, liver function parameters, hematological parameters and renal function parameters were assessed prior to the initiation of outpatient management and after the treatment, to determine outcomes, collected data were entered into a custom-made Microsoft Excel sheet for statistical analysis.

Statistical Analysis

The data were examined using IBM SPSS Statistics version 25.  Median and standard deviation were computed for quantitative data, and percentages for qualitative variables. Chi square test was used to see if categorical variables were related.  P< 0.001 were deemed significant.

RESULTS

245 patients were enrolled (11.4% female and 88.6% male)  with mean age of 58 ± 11 years,  (age distribution: 30 to 88 years). CLD  most commonly attributed to alcohol (51.4%), followed by NAFLD (17.1%), NASH (11.4%), cryptogenic causes (10.3%), HBV (5.7%), and HCV (4.1%). Diabetes mellitus was the most prevalent co-morbidity, affecting 88.6% of patients, while systemic hypertension was present in 33.5%. Additionally, 53.1% had other co-morbidities including thyroid disorders, hernia, cancers, dyslipidemia, and rheumatoid arthritis. The majority in Child-Pugh class C (66.5%),  class B (22.9%) and class A (10.6%).Median study duration is 7 days. (Half of the cases had study periods shorter than 7 days). The study assessed the following effects of Tolvaptan  at a daily dose of 15 mg .

Changes in Serum Sodium Levels

Before treatment, the median sodium level in the study cohort was 127 mmol/L, with an interquartile range (IQR) spanning from 123.4 to 129.7 mmol/L. Tolvaptan increased the median sodium level to 130 mmol/L, with an IQR of 126.4 to 133.6 mmol/L,  demonstrating a statistically significant rise sodium levels (p< 0.001), reflecting better sodium balance by increasing aquaresis

Table 1 Change in serum sodium levels

Biomarkers

Time

Median

(Q1-Q3)

Statistical Significance

Na (mmol/L)

Before

127 (123.4-129.7)

p< 0.001

After

130 (126.4-133.6)

Changes in Liver Function Parameters

Liver function parameter results suggest that tolvaptan affects several biochemical parameters may be due to aquaresis, but it does not significantly alter liver enzyme levels, indicating its effectiveness in managing CLD without adversely impacting these enzymes.

Table 2 Changes in Liver Function Parameters

Biomarkers

Time

Median

(Q1-Q3)

Statistical Significance

T Bilirubin (mg/dL)

Before

3.4 (1.5-5.8)

p = 0.037

After

3.3 (1.6-6)

D Bilirubin (mg/dL)

Before

1.6 (0.8-3.4)

p = 0.049

After

1.7 (0.7-3.6)

SGOT (IU/L)

Before

47.8 (35.7-76.8)

p = 0.059

After

50.1 (35-81.3)

SGPT (IU/L)

Before

29.3 (19.9-49.8)

p = 0.771

After

30 (19.6-51.1)

ALP (IU/L)

Before

116 (83-115.8)

p < 0.001

After

125 (91-172)

T Protein (g/dL)

Before

6.1 (5.6-6.7)

p < 0.001

After

6.5 (5.9-7.1)

S Albumin (g/dL)

Before

2.9 (2.4-3.3)

p < 0.001

After

3.1 (2.7-3.6)

S Globulin (g/dL)

Before

3.3 (2.5-3.9)

p < 0.001

After

3.6 (3.0-4.2)

Changes in Serum Electrolyte Levels

Significant changes were observed in all measured parameters following treatment (Table 3). Potassium, magnesium, calcium, phosphorus and ammonia levels rose by end of day 7 which suggest that Tolvaptan effectively manages electrolyte imbalances and metabolic disturbances in CLD patients, underscoring its potential benefits for outpatient care.

Table 3 Changes in Serum Electrolyte Levels

Biomarkers

Time

Median

(Q1-Q3)

Statistical Significance

K (mmol/L)

Before

4.2 (3.9-4.6)

p < 0.001

After

4.5 (4-4.9)

Mg (mmol/L)

Before

1.9 (1.6-2.1)

p < 0.001

After

2 (1.8-2.5)

Ca (mg/dL)

Before

8.3 (7.8-8.9)

p < 0.001

After

8.9 (8.5-9.8)

P (mg/dL)

Before

3 (2.5-3.7)

p < 0.001

After

3.6 (2.9-4)

NH3 (µmol/L)

Before

60 (48.8-78.9)

p < 0.001

After

63 (50.8-78.8)

Changes in Haematological Parameters

Hematological parameters significantly improved. ( Table 4) Conversely, basophil, monocyte, and lymphocyte percentages, as well as mean corpuscular hemoglobin concentration, showed no significant changes. Basophil percentages remained at 0.5% (p = 0.219), monocyte percentages changed from 10.4% to 9.9% (p = 0.277), and lymphocyte percentages stayed at 15.7% (p = 0.461). MCHC levels remained nearly unchanged, from 34.3 g/dL to 34.1 g/dL (p = 0.853). Therefore, tolvaptan effectively improves several hematological parameters without adversely affecting others, indicating potential safety in CLD.

Table 4 Changes in Haematological Parameters

Variables

Time

Median

(Q1-Q3)

Statistical Significance

Hb (g/dL)

Before

9.1 (8.3-10.5)

p < 0.001

After

9.7 (8.6-11.2)

PCV (%)

Before

27 (24-31.4)

p < 0.001

After

29 (25.8-32.4)

Platelet (ku/ml)

Before

89 (55-144.5)

p < 0.001

After

97.7 (62-157.5)

WBC (K/uL)

Before

6.6 (4.8-9.5)

p < 0.001

After

7 (5.6-9.9)

Neutrophils (%)

Before

68.2 (60.6-77.9)

p = 0.008

After

69.4 (61-78)

Eosinophils (%)

Before

2.8 (1-4.8)

p = 0.016

After

2.4 (0.8-4.8)

Basophils (%)

Before

0.5 (0.2-0.8)

p = 0.219

After

0.5 (0.2-0.8)

Monocytes (%)

Before

10.4 (7.9-11)

p = 0.277

After

9.9 (7.6-12.9)

Lymphocytes (%)

Before

15.7 (10.1-22.4)

p = 0.461

After

15.4 (10-22.4)

RBC (M/uL)

Before

2.9 (2.4-3.3)

p < 0.001

After

3.1 (2.7-3.7)

RDW (%)

Before

16.1 (14.6-18.2)

p = 0.001

After

16.2 (15-18.5)

MCH (pg)

Before

32.7 (30-34.6)

p = 0.001

After

32.8 (30.2-35.2)

MCHC (g/dL)

Before

34.3 (33.2-35.3)

p = 0.853

After

34.1 (33-35.5)

MCV (fL)

Before

95.2 (88.5-100.6)

p = 0.027

After

95.8 (89.1-100)

Changes in Renal Function Parameters

Urea rose (median of 31.3 mg/dL (Q1-Q3: 20.2-48.8) to 34.8 mg/dL (Q1-Q3: 21.7-56), after tolvaptan treatment. Creatinine also increased from 0.9 mg/dL (Q1-Q3: 0.7-1.1) to 1 mg/dL (Q1-Q3: 0.8-1.5; p< 0.001.) possibly from excessive fluid loss due to tolvaptan underscoring the need for careful renal function monitoring during outpatient Tolvaptan treatment.

Table 5 Changes in Renal Function Parameters

Biomarkers

Time

Median

(Q1-Q3)

Statistical Significance

Urea

Before

31.3 (20.2-48.8)

p < 0.001

After

34.8 (21.7-56)

Creatinine

Before

0.9 (0.7-1.1)

p < 0.001

After

1 (0.8-1.5)

DISCUSSION

There is a significant correlation between serum sodium levels and the prognosis of patients with decompensated hepatic cirrhosis. Hyponatremia is among chronic liver disease (CLD) patients, with a substantial portion exhibiting dangerously low sodium levels. Lower sodium levels were associated with higher Model for End-Stage Liver Disease (MELD) and Child-Pugh (CPS) scores, both of which are critical indicators of liver disease severity and patient prognosis. The inverse relationship between serum sodium levels and the severity of liver disease underscores the importance of monitoring and managing electrolyte imbalances in CLD patients to potentially improve their survival rates and overall prognosis.[21] The study by Jong Hoon Kim et al.[32] highlights the significant correlation between serum sodium levels and the severity of complications in patients with liver cirrhosis. Analyzing data from 188 inpatients, the study found that dilutional hyponatremia, defined by serum sodium concentrations of ≤135 mmol/L, ≤130 mmol/L, and ≤125 mmol/L, was prevalent in 20.8%, 14.9%, and 12.2% of the patients, respectively. The findings indicate a strong association between lower serum sodium levels and greater liver function impairment, as assessed by Child-Pugh and MELD scores (p<0.0001). Notably, even mild hyponatremia (131-135 mmol/L) was linked to severe complications. Furthermore, serum sodium levels below 130 mmol/L were predictive of massive ascites (OR 2.685, p=0.007), grade III or higher hepatic encephalopathy (OR 5.891, p=0.011), spontaneous bacterial peritonitis (OR 2.562, p=0.020), and hepatic hydrothorax (OR 5.723, p=0.002). These results underscore the critical role of monitoring serum sodium levels in cirrhotic patients, as hyponatremia can be an indicator of severe complications and the need for more intensive management and intervention. In our study, majority of the study population with hyponatremia belonged to Child-Pugh class C.  The study by Kogiso et al.[24] on the effect of Tolvaptan on serum sodium levels in cirrhotic patients with ascites provides significant insights into the management of hyponatremia in this population. Similar to our study, on measuring difference in sodium levels after tolvaptan therapy, this study underscores the importance of addressing electrolyte imbalances to improve patient prognosis. In their single-center retrospective study of 95 Japanese cirrhotic patients, tolvaptan was shown to normalize serum sodium levels in a substantial proportion of patients within one week, with a notable improvement in survival rates for those achieving normal sodium levels. This finding aligns with our observation that meticulous management of hyponatremia in cirrhosis with tolvaptan can significantly influence patient outcomes. Both studies emphasize the critical need for targeted interventions in cirrhotic patients, highlighting the factor that hyponatremia must be rigorously managed to enhance survival rates. Additionally, the predictive value of pretreatment brain natriuretic peptide (BNP) levels for sodium normalization in the Kogiso study may provide a useful marker for tailoring individualized treatment strategies in cirrhosis management. Ji-Dong Jia et al.[10] provides valuable insights into the therapeutic potential of tolvaptan for managing hyponatremia in cirrhotic patients. This multi-center prospective cohort study, involving 49 cirrhotic patients treated with tolvaptan and 48 controls, demonstrates the efficacy of tolvaptan in normalizing serum sodium levels. On day 7, 61% of the tolvaptan group exhibited improved serum sodium levels compared to 35% in the control group (p = 0.011), underscoring tolvaptan’s role in correcting hyponatremia. The study also highlights the safety profile of tolvaptan, with no significant worsening of liver function and comparable adverse event rates between the tolvaptan and control groups. Importantly, patients who achieved normal serum sodium levels had a better 30-day survival rate, emphasizing the clinical significance of managing hyponatremia in cirrhosis. This aligns with our findings of improved outcomes with tolvaptan therapy, reinforcing the necessity of targeted interventions for electrolyte imbalances in cirrhotic patients to enhance survival rates.

REFERENCES

  1. Pradeep C, Sindhura G, et al. Prevalence of Hyponatremia in Chronic Liver Disease Patients and Its Correlation with the Severity of the Disease. Int J Sci Stud 2022;10(1):40-44.
  2. Sharma A, Nagalli S. Chronic liver disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554597/.
  3. Linden-Torres E, Zambrano-Galván G, Sahebkar A, et al. Coffee consumption has no effect on circulating markers of liver function but increases adiponectin concentrations: A systematic review and meta-analysis of randomized controlled trials. Int J Vitam Nutr Res. 2022;92(2-3):61-70.
  4. Devarbhavi H, Asrani SK, Arab JP, et al. Global burden of liver disease: 2023 update. J Hepatol. 2023 Aug;79(2):516-37.
  5. Mondal D, Das K, Chowdhury A. Epidemiology of Liver Diseases in India. Clin Liver Dis (Hoboken). 2022;19(3):114-7.
  6. Huang DQ, Terrault NA, Tacke F, et al. Global epidemiology of cirrhosis — aetiology, trends and predictions. Nat Rev Gastroenterol Hepatol. 2023;20:388-98.
  7. Smith A, Baumgartner K, Bositis C. Cirrhosis: Diagnosis and Management. Am Fam Physician. 2019;100(12):759-70.
  8. Alukal JJ, John S, Thuluvath PJ. Hyponatremia in Cirrhosis: An Update. Am J Gastroenterol. 2020;115(11):1775-85.
  9. Trikha A, Ray BR, Vohra V, et al. Pathophysiology of Chronic Liver Disease. In Peri-operative Anesthetic Management in Liver Transplantation. Singapore: Springer; 2023. doi: 10.1007/978-981-19-6045-1_4.
  10. Jia JD, Xie W, Ding HG, et al. Utility and Safety of Tolvaptan in Cirrhotic Patients with Hyponatremia: A Prospective Cohort Study. J Hepatol. 2021;75(2):335-43.
  11. John S, Thuluvath PJ. Hyponatremia in cirrhosis: pathophysiology and management. World J Gastroenterol. 2015;21(11):3197-205.
  12. Singh P, Arora S, Singh D, et al. Hyponatremia and Outcome: Is Severity More Important Than Etiology? Cureus. 2022;14(1):e14588.
  13. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia. N Engl J Med. 2006;355(22):2099-112.
  14. Cárdenas A, Ginès P, Marotta P, et al. Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis. J Hepatol. 2012;56(3):571-8.
  15. Bhandari A, Chaudhary A. Hyponatremia in Chronic Liver Disease among Patients Presenting to a Tertiary Care Hospital: A Descriptive Cross-sectional Study. J Nepal Health Res Counc. 2021;19(4):603-7.
  16. Gaglio P, Marfo K, Chiodo J III. Hyponatremia in Cirrhosis and End-Stage Liver Disease: Treatment with the Vasopressin V2-Receptor Antagonist Tolvaptan. Gastroenterol Hepatol (N Y). 2012;8(6):424-30.
  17. Jang C, Jung YK. Hyponatremia in Liver Cirrhosis. Clin Mol Hepatol. 2012;18(4):353-9.
  18. Praharaj DL, Anand AC. Clinical Implications, Evaluation, and Management of Hyponatremia in Cirrhosis. J Clin Exp Hepatol. 2021;11(6):731-41.
  19. Ginès P, Guevara M. Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management. Hepatology. 2008;48(3):1002-10.
  20. Dubois EA, Rissmann R, Cohen AF. Tolvaptan. Br J Clin Pharmacol. 2012;73(1):9-11.
  21. Bhardwaj B, Gupta S, Garg S. Hyponatremia in patients with chronic liver diseases. J Cardiovasc Dis Res. 2023;14(1):3055.
  22. Wang S, Zhang X, Han T, et al. Tolvaptan treatment improves survival of cirrhotic patients with ascites and hyponatremia. Liver Int. 2022;42(1):158-166.
  23. Khan MY, Rawala MS, Siddiqui M, et al. Tolvaptan-induced Liver Injury: Who is at Risk? A Case Report and Literature Review. Cureus. 2023;15(1).
  24. Kogiso T, Kobayashi M, Yamamoto K, et al. The Outcome of Cirrhotic Patients with Ascites Is Improved by the Normalization of the Serum Sodium Level by Tolvaptan. Hepatol Res. 2017;47(1):60-7.
  25. Adrogué HJ, Tucker BM, Madias NE. Diagnosis and Management of Hyponatremia: A Review. JAMA. 2022;328(3):280–91.
  26. Ishikawa T, Hasegawa H, Takeda K, et al. The role of vasopressin V2 receptor in drug-induced hyponatremia. Front Physiol. 2021;12:797032: 1-9.
  27. Adamczak M, Surma S, Wi?cek A. Hyponatremia in patients with arterial hypertension: pathophysiology and management. Arch Med Sci. 2023;19(6):1630-45.
  28. Guevara M, Baccaro ME, Torre A, et al. Hyponatremia is a risk factor of hepatic encephalopathy in patients with cirrhosis: a prospective study with time-dependent analysis. Am J Gastroenterol. 2009;104(6):1382-9.
  29. Hayashi M, Abe K, Fujita M, et al. Association between the Serum Sodium Levels and the Response to Tolvaptan in Liver Cirrhosis Patients with Ascites and Hyponatremia. Intern Med. 2018;57(17):2451-8.
  30. Dahl E, Gluud LL, Kimer N, et al. Meta-analysis: the safety and efficacy of vaptans (tolvaptan, satavaptan and lixivaptan) in cirrhosis with ascites or hyponatraemia. Aliment Pharmacol Ther. 2012;36(7):619-26.
  31. Lu J, Xu W, Gong L, et al. Efficacy and safety of tolvaptan versus placebo in the treatment of patients with autosomal dominant polycystic kidney disease: a meta-analysis. Int Urol Nephrol. 2023;55(3):631-40.
  32. Kim JH, Lee JS, Lee SH, et al. The association between the serum sodium level and the severity of complications in liver cirrhosis. Korean J Intern Med. 2009;24(2):106-12.

Reference

  1. Pradeep C, Sindhura G, et al. Prevalence of Hyponatremia in Chronic Liver Disease Patients and Its Correlation with the Severity of the Disease. Int J Sci Stud 2022;10(1):40-44.
  2. Sharma A, Nagalli S. Chronic liver disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554597/.
  3. Linden-Torres E, Zambrano-Galván G, Sahebkar A, et al. Coffee consumption has no effect on circulating markers of liver function but increases adiponectin concentrations: A systematic review and meta-analysis of randomized controlled trials. Int J Vitam Nutr Res. 2022;92(2-3):61-70.
  4. Devarbhavi H, Asrani SK, Arab JP, et al. Global burden of liver disease: 2023 update. J Hepatol. 2023 Aug;79(2):516-37.
  5. Mondal D, Das K, Chowdhury A. Epidemiology of Liver Diseases in India. Clin Liver Dis (Hoboken). 2022;19(3):114-7.
  6. Huang DQ, Terrault NA, Tacke F, et al. Global epidemiology of cirrhosis — aetiology, trends and predictions. Nat Rev Gastroenterol Hepatol. 2023;20:388-98.
  7. Smith A, Baumgartner K, Bositis C. Cirrhosis: Diagnosis and Management. Am Fam Physician. 2019;100(12):759-70.
  8. Alukal JJ, John S, Thuluvath PJ. Hyponatremia in Cirrhosis: An Update. Am J Gastroenterol. 2020;115(11):1775-85.
  9. Trikha A, Ray BR, Vohra V, et al. Pathophysiology of Chronic Liver Disease. In Peri-operative Anesthetic Management in Liver Transplantation. Singapore: Springer; 2023. doi: 10.1007/978-981-19-6045-1_4.
  10. Jia JD, Xie W, Ding HG, et al. Utility and Safety of Tolvaptan in Cirrhotic Patients with Hyponatremia: A Prospective Cohort Study. J Hepatol. 2021;75(2):335-43.
  11. John S, Thuluvath PJ. Hyponatremia in cirrhosis: pathophysiology and management. World J Gastroenterol. 2015;21(11):3197-205.
  12. Singh P, Arora S, Singh D, et al. Hyponatremia and Outcome: Is Severity More Important Than Etiology? Cureus. 2022;14(1):e14588.
  13. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia. N Engl J Med. 2006;355(22):2099-112.
  14. Cárdenas A, Ginès P, Marotta P, et al. Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis. J Hepatol. 2012;56(3):571-8.
  15. Bhandari A, Chaudhary A. Hyponatremia in Chronic Liver Disease among Patients Presenting to a Tertiary Care Hospital: A Descriptive Cross-sectional Study. J Nepal Health Res Counc. 2021;19(4):603-7.
  16. Gaglio P, Marfo K, Chiodo J III. Hyponatremia in Cirrhosis and End-Stage Liver Disease: Treatment with the Vasopressin V2-Receptor Antagonist Tolvaptan. Gastroenterol Hepatol (N Y). 2012;8(6):424-30.
  17. Jang C, Jung YK. Hyponatremia in Liver Cirrhosis. Clin Mol Hepatol. 2012;18(4):353-9.
  18. Praharaj DL, Anand AC. Clinical Implications, Evaluation, and Management of Hyponatremia in Cirrhosis. J Clin Exp Hepatol. 2021;11(6):731-41.
  19. Ginès P, Guevara M. Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management. Hepatology. 2008;48(3):1002-10.
  20. Dubois EA, Rissmann R, Cohen AF. Tolvaptan. Br J Clin Pharmacol. 2012;73(1):9-11.
  21. Bhardwaj B, Gupta S, Garg S. Hyponatremia in patients with chronic liver diseases. J Cardiovasc Dis Res. 2023;14(1):3055.
  22. Wang S, Zhang X, Han T, et al. Tolvaptan treatment improves survival of cirrhotic patients with ascites and hyponatremia. Liver Int. 2022;42(1):158-166.
  23. Khan MY, Rawala MS, Siddiqui M, et al. Tolvaptan-induced Liver Injury: Who is at Risk? A Case Report and Literature Review. Cureus. 2023;15(1).
  24. Kogiso T, Kobayashi M, Yamamoto K, et al. The Outcome of Cirrhotic Patients with Ascites Is Improved by the Normalization of the Serum Sodium Level by Tolvaptan. Hepatol Res. 2017;47(1):60-7.
  25. Adrogué HJ, Tucker BM, Madias NE. Diagnosis and Management of Hyponatremia: A Review. JAMA. 2022;328(3):280–91.
  26. Ishikawa T, Hasegawa H, Takeda K, et al. The role of vasopressin V2 receptor in drug-induced hyponatremia. Front Physiol. 2021;12:797032: 1-9.
  27. Adamczak M, Surma S, Wi?cek A. Hyponatremia in patients with arterial hypertension: pathophysiology and management. Arch Med Sci. 2023;19(6):1630-45.
  28. Guevara M, Baccaro ME, Torre A, et al. Hyponatremia is a risk factor of hepatic encephalopathy in patients with cirrhosis: a prospective study with time-dependent analysis. Am J Gastroenterol. 2009;104(6):1382-9.
  29. Hayashi M, Abe K, Fujita M, et al. Association between the Serum Sodium Levels and the Response to Tolvaptan in Liver Cirrhosis Patients with Ascites and Hyponatremia. Intern Med. 2018;57(17):2451-8.
  30. Dahl E, Gluud LL, Kimer N, et al. Meta-analysis: the safety and efficacy of vaptans (tolvaptan, satavaptan and lixivaptan) in cirrhosis with ascites or hyponatraemia. Aliment Pharmacol Ther. 2012;36(7):619-26.
  31. Lu J, Xu W, Gong L, et al. Efficacy and safety of tolvaptan versus placebo in the treatment of patients with autosomal dominant polycystic kidney disease: a meta-analysis. Int Urol Nephrol. 2023;55(3):631-40.
  32. Kim JH, Lee JS, Lee SH, et al. The association between the serum sodium level and the severity of complications in liver cirrhosis. Korean J Intern Med. 2009;24(2):106-12.

Photo
Anusree C. V.
Corresponding author

Amrita Institute of Medical Sciences, Kochi, India.

Photo
Roshni P. R.
Co-author

Amrita Institute of Medical Sciences, Kochi, India.

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Krishnanunni Nair
Co-author

Amrita Institute of Medical Sciences, Kochi, India.

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Renjitha Bhaskaran
Co-author

Amrita Institute of Medical Sciences, Kochi, India.

Anusree C. V.*, Roshni P. R., Krishnanunni Nair, Renjitha Bhaskaran, Determining the Outcome Measures for The Use of Tolvaptan in Outpatient Management of Hyponatremia Among Chronic Liver Disease Patients: A Tertiary Care Hospital Study in South India, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 6, 398-405. https://doi.org/10.5281/zenodo.15582322

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