Article Information

Kenneth J. Fearn, MD¹, Maximilian G. Mayr, BS², Carissa Walter, MPH³, Suzanne L. Hunt, MS, MA⁴, Jianghua He, PhD⁴, Yu Wang, MS, MA⁴, Jacqueline Hill, PhD, MPH⁵, Charles B. Davis, MD⁶, Travis Everett, MD⁷, Trevor Everett, MD⁸, Steve Lemons, MD³, Aaron Rohr, MD, MS³, Adam Alli, MD³

¹Radiology and Nuclear Medicine 2200 SW 10th Ave, Topeka, KS 66604 USA

²Kansas City University 2901 St Johns Blvd, Joplin, MO 64804 USA

³Department of Radiology University of Kansas Medical Center 3901 Rainbow Boulevard Kansas City, KS 66160 USA

⁴University of Kansas Medical Center Biostatistics & Data Science Department University of Kansas Medical Center 3901 Rainbow Boulevard Kansas City, KS 66160 USA

⁵Office of Faculty Affairs & Development Children’s Mercy Kansas City 2401 Gillham Road, Kansas City, MO 64108

⁶Department of Radiology University of Washington 1959 NE Pacific Street Seattle, WA 98195

⁷University of New Mexico School of Medicine MSC08 4720, 1 University of New Mexico Albuquerque, NM 87131

⁸Department of Radiology University of Wisconsin 600 Highland Ave Madison, WI 53792.

^*Corresponding author: Maximilian G. Mayr, Kansas City University 2901 St Johns Blvd, Joplin, MO 64804 USA.

Received: 09 January 2024; Accepted: 19 January 2024; Published: 13 February 2024

Citation: Kenneth J. Fearn, MD, Maximilian G. Mayr, BS, Carissa Walter, MPH, Suzanne L. Hunt, MS, MA, Jianghua He, PhD, Yu Wang, MS, MA, Jacqueline Hill, PhD, MPH, Charles B. Davis, MD, Travis Everett, MD, Trevor Everett, MD, Steve Lemons, MD, Aaron Rohr, MD, MS, Adam Alli, MD. Outcomes in Cirrhotic Patients Receiving Transjugular Intrahepatic Portosystemic Shunt (TIPS) Versus Repeat Paracentesis for Recurrent Ascites. Archives of Internal Medicine Research. 7 (2024): 21-26.

Abstract

Keywords

Cirrhotic; Transjugular Intrahepatic Portosystemic Shunt (TIPS); Paracentesis

Article Details

Introduction

Background

According to the 2017 Centers for Disease Control (CDC) national vital statistics, cirrhosis is the 10th leading cause of death in the United States with greater than 40,000 deaths per year [1]. Mortality due to chronic liver disease continues to be on the rise, especially in those patients with alcoholic cirrhosis [2,3]. In the United States, there was a 65% increase in cirrhosis deaths from 1999 to 2016 from approximately 20,000 to 34,000 [3]. Approximately .3 % (.27) of the population are affected by cirrhosis, with a greater incidence in non-Hispanic African Americans, Mexican Americans, and Native Americans seeing the highest rates [3,4]. Many patients may remain undiagnosed meaning the prevalence may be even higher in certain populations and communities [4,5,6].

Cirrhosis places a serious economic burden on patients [7,8]. The main financial burden of cirrhosis specifically was $7.37 billion based off the National Inpatient Sample (NIS) database [9]. Major etiologies include hepatitis B and C infections, alcohol abuse, and nonalcoholic steatohepatitis (NASH) [8]. The presence of cirrhosis and its comorbidities has further driven the increase in financial hardships [10]. Because of advances in pharmacotherapy and surgical intervention, the cost continues to rise [8]. The main drivers for increased cost are due to three procedural complications: mechanical ventilation, non-red blood cell transfusions, and hemodialysis [9]. Other complications associated with cirrhosis include acute kidney injury (AKI), infection, non-pulmonary hypertension, gastrointestinal (GI) bleed, ascites, hepatorenal syndrome, variceal bleeding, hepatocellular carcinoma, hepatic encephalopathy, hyponatremia, malnutrition, and spontaneous bacterial peritonitis [9]. Complications frequently include portal hypertension, which in turn may result in ascites, varices, and hepatic hydrothorax [9,11,12,13]. As longevity is increased with improving therapy, unfortunately so does the economic and financial burden [9,14].

Ascites associated with cirrhosis is the abnormal accumulation of transudative fluid in the peritoneal cavity due to portal hypertension. It is one of the main complications of cirrhosis which causes increased portal hypertension resulting in decreased hepatic perfusion [11,13]. Ascites is a poor prognostic indicator with a 15% mortality rate 1-year after first presentation and 44% mortality rate at 5-years after first presentation [15]. Ascites is considered refractory upon recurrence after paracentesis or when no longer tolerant or responsive to sodium restriction or diuretic therapy [11,16]. Treatment usually consists of routine paracentesis, pharmacotherapy, diet modulations, or TIPS [13,16].

TIPS is an image-guided endovascular procedure which bypasses blood flow from the portal venous system to the hepatic venous system, thus creating a new passage for venous blood flow. This interventional therapy is used to decrease portal venous and mesenteric venous pressure. These increased pressures may consequentially lead to bleeding varices, ascites, and other gastroenterological complications [17]. TIPS is used for control of ascites symptoms and has been shown to resolve ascites in 60-70% of patients, effectively reducing the need for serial paracentesis [11,17,18,19]. TIPS offers superior control compared to large volume paracentesis (LVP) in the management of refractory ascites and may also improve survival [20,21,22]. Mean hospital stays were also decreased in those with TIPS with an average of 17 days compared to those with LVP at 35 days [21].

The purpose of our study was to investigate whether TIPS placement reduced the time between paracenteses, reduced the number of hospitalizations due to hepatic encephalopathy (HE), spontaneous bacterial peritonitis, and gastroesophageal variceal bleeding in patients with refractory ascites due to end-stage liver disease.

Materials and Methods

Institutional review board approval was obtained, and patient medical records were reviewed in compliance with Health Care Portability and Accountability Act guidelines. Patients were included in this single institution study if they met the following inclusion criteria: were 18 years of age or older; had an image-based diagnosis of cirrhosis; were diagnosed with refractory ascites from May 2008 through December 2016. For the purpose of our study, refractory ascites was defined as having three therapeutic paracenteses within 365 days and/or received a TIPS. Patients were excluded from the study if they met any of the following criteria: were under 18 years of age; had a Model for End-Stage Liver Disease (MELD) score > 18 prior to TIPS placement; had a TIPS placed for reason other than refractory ascites; or received a liver transplant. In total, 344 patients were included in the study with 92 (26.8%) of them receiving a TIPS.

Relevant demographic, clinical (cirrhosis etiology and admission diagnoses when hospitalized), laboratory, procedural, and follow-up information (complications, including post-procedural encephalopathy, spontaneous bacterial peritonitis (SBP), and hemorrhage) were obtained from patient medical records and imaging exams. All data were stored in REDCap data capture tools [23].

A gap time analysis was utilized to determine if there was a difference in mean days between paracenteses in those patients who did not receive TIPS versus those receiving TIPS. The shared frailty model of time (days) between paracenteses contains a dichotomous covariate for MELD (<18, >=18), TIPS placement as a time-varying covariate, an interaction term between TIPS and dichotomous MELD and a random effect for each subject that controls for the correlation among a subject’s repeated measures. A significance level of 0.05 was used throughout the analysis of the primary aim. The analysis was completed with PROC PHREG in SAS software 9.4. Subjects were observed until transplant, death, or lost to follow-up. For most subjects, follow-up did not end with a paracentesis thus they were censored at the end. The null hypothesis was specified as H0: The risk of having a paracentesis is the same pre- and post-TIPS. Chi-squared tests were used to examine the association between TIPS and hospitalizations for hepatic encephalopathy, gastroesophageal variceal bleeding, spontaneous bacterial peritonitis.

Results

In total, 344 patients with refractory ascites were included. Median age at time of refractory ascites was 57 years and most patients were male (62%) and white (85%) (Table 1). The main etiologies of cirrhosis were alcohol induced (45%) and hepatitis C-induced (37%) (Table 2). Of these 344 patients that were included in the study, 92 (26.8%) received TIPS procedure. Median time of follow up after ascites became refractory was 466 days for patients who received a TIPS and 140 days for those not receiving a TIPS (Table 3).

Table 1: Demographic Characteristics

Table 2: Cirrhosis etiology

Table 3: Follow-Up Time (days)

The interaction of TIPS and dichotomous MELD (<=18, >18) does not have a statistically significant effect in the frailty model (Chi-square=1.39, p-value=0.24). In other words, the interaction term does not have a statistically significant association with time between paracenteses and therefore can be removed from the model.

After excluding the interaction term but keeping a random effect for each subject and dichotomous MELD (<=18, >18) as a covariate, the data demonstrate TIPS and the time between paracenteses are associated (Chi-sqr=77.9 p<0.01). A 59% reduction in the risk of a paracentesis post-TIPS was observed in our sample (estimated Hazard Ratio=0.41 estimated 95% CI (0.33, 0.50). The covariate, dichotomous MELD, is not statistically significantly associated with the time between paracenteses (Chi-sqr=0.23, p=0.63). Typically, MELD would be removed from the model and a simplified model would be constructed. However, given the role of MELD scores in deciding whether to place TIPS, we felt it was important to account for MELD in the analysis.

A third model of time between paracentesis was constructed that stratified by MELD and included TIPS placement as a time-varying covariate and a random effect for each subject. The observed data demonstrates TIPS and the time between paracenteses are associated (Chi-sqr=80.1 p<0.01). A 60% reduction in the risk of a paracentesis post-TIPS was observed in our sample (estimated Hazard Ratio=0.40 estimated 95% CI (0.33, 0.49).

The gap analysis showed patients averaged 26.2 days between paracentesis before TIPS. Those who went on to have TIPS averaged 51.5 days between paracentesis post-TIPS (Table 4). There was no difference in hospitalizations relating to bacterial peritonitis (p=0.13 X2=2.25 df=1), variceal bleeding (p=0.23 X2=1.46 df=1), and hepatic encephalopathy (p=0.46 X2=0.53 df=1) between patients who received a TIPS and those who did not (See Table 5).

Table 4: Time Between Paracenteses

*Chi-squared test, df=1

Table 5: Hospitalization Information

Discussion

This study found a 60% reduction in the risk of a paracentesis after patients received TIPS and is consistent with other findings in the literature. There was no statistically significant difference between TIPS and non-TIPS patients regarding hospital admissions from hepatic encephalopathy, variceal bleeding, and spontaneous bacterial peritonitis (See Table 5). This suggests that TIPS placement should be considered earlier in the cirrhosis disease process to improve symptomatic control and decrease the need and associated costs of frequent paracenteses.

Further studies should focus on deciphering whether there is a correlation between earlier TIPS intervention in refractory ascites, hepatic encephalopathy, variceal bleeding, and spontaneous bacterial peritonitis. Some physicians are weary of TIPS intervention due to a suspected increase in hepatic encephalopathy from unfiltered portal venous blood containing impurities and unprocessed metabolites and toxins such as ammonia, although risk is difficult to stratify amongst patients [24]. The question needing to be answered is whether this potential risk is outweighed by the other systemic benefits of TIPS while end-stage liver failure patients await transplantation.

Limitations to this study were due to variation in follow up times between those patients receiving TIPS and those who did not. Mean follow up time for those receiving TIPS was 466 days and 140 days for those not receiving TIPS. Longer follow up time for non-TIPS patients would provide more accurate comparison of outcomes and complications. An increase in follow-up or more symmetrical timing could lead to a more accurate representation and comparison of outcomes.

Conclusion

In conclusion, our study found that TIPS placement was associated with an increase in mean time between paracenteses. There was no statistically significant reduction in bacterial peritonitis, variceal bleeding, or hepatic encephalopathy. These findings suggest that TIPS placement should be considered earlier on in cirrhotic disease to improve symptomatic control of portal hypertension. In result, this would decrease the need for frequent paracentesis. Associated benefits including but not limited to hospital fees and risks of frequent paracenteses can also be reduced.

Acknowledgements

The abstract for this manuscript was presented by Kenneth Fearn MD at the 2018 annual meeting of the Radiological Society of North America (RSNA).

Declaration of interest

Contributing authors have no conflicts of interests to declare.

Author Contributions

1. Guarantor of integrity of the entire study: Alli, Lemons
2. Study concepts and design: Lemons, Fearn, Alli, Hill
3. Data collection: Everett, Everett, Davis
4. Literature research: Fearn, Lemons
5. Statistical analysis: Wang, Hunt, He
6. Manuscript preparation: Mayr
7. Manuscript editing: Walter, Mayr, Rohr, Fearn, Wang, Hunt, He

Ethical Standards

1. This study was funded by CTSA Award # UL1TR002366 for the data analysis and interpretation of data.
2. The authors declare that they have no conflict of interest.
3. For this type of study formal consent is not required. This article does not contain any studies with animals performed by any of the authors. IRB approval was obtained internally through the University of Kansas Medical Center’s IRB.
4. For this type of study informed consent is not required.
5. For this type of study consent for publication is not required.

References

1. Heron M. Deaths: Leading Causes for 2017. Natl Vital Stat Rep 68 (2019): 1-77.
2. QuickStats: Death Rates* for Chronic Liver Disease and Cirrhosis,(dagger) by Sex and Age Group - National Vital Statistics System, United States, 2000 and 2015. MMWR Morb Mortal Wkly Rep 66 (2017): 1031.
3. Tapper EB, Parikh ND. Mortality due to cirrhosis and liver cancer in the United States, 1999-2016: observational study. Bmj. 2018; 362 (2018): k2817.
4. Scaglione S, Kliethermes S, Cao G, et al. The Epidemiology of Cirrhosis in the United States: A Population-based Study. J Clin Gastroenterol 49 (2015): 690-696.
5. Guss D, Sherigar J, Mohanty SR. Missed Diagnosis of Liver Cirrhosis Leads to Disparities in Care for Older Patients. Gastroenterology Res 11 (2018): 333-339.
6. Martini A, Ceranto E, Gatta A, et al. Occult liver disease burden: Analysis from a large general practitioners' database. United European Gastroenterol J 5 (2017): 982-986.
7. Younossi ZM, Blissett D, Blissett R, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 64 (2016): 1577-1586.
8. Smith A, Baumgartner K, Bositis C. Cirrhosis: Diagnosis and Management. Am Fam Physician 100 (2019): 759-770.
9. Desai AP, Mohan P, Nokes B, et al. Increasing Economic Burden in Hospitalized Patients With Cirrhosis: Analysis of a National Database. Clin Transl Gastroenterol 10 (2019): e00062.
10. Hirode G, Saab S, Wong RJ. Trends in the Burden of Chronic Liver Disease Among Hospitalized US Adults. JAMA Netw Open 3 (2020): e201997. PubMed PMID: 32239220; PMCID: PMC7118516 fees from and serving as a member of the advisory board and speaker’s bureau of Gilead Sciences and receiving grants from AbbVie outside the submitted work. No other disclosures were reported.
11. Siqueira F, Kelly T, Saab S. Refractory Ascites: Pathogenesis, Clinical Impact, and Management: Gastroenterol Hepatol (N Y) 5 (2009): 647-656.
12. Garbuzenko DV, Arefyev NO. Hepatic hydrothorax: An update and review of the literature. World J Hepatol 9 (2017): 1197-204.
13. Nusrat S, Khan MS, Fazili J, et al. Cirrhosis and its complications: evidence based treatment. World J Gastroenterol 20 (2014): 5442-5460.
14. Neff GW, Duncan CW, Schiff ER. The current economic burden of cirrhosis. Gastroenterol Hepatol (N Y) 7 (2011): 661-671.
15. Chiejina M, Kudaravalli P, Samant H. et al. Treasure Island (FL): StatPearls Publishing Copyright © 2021, StatPearls Publishing LLC; (2021).
16. Fortune B, Cardenas A. Ascites, refractory ascites and hyponatremia in cirrhosis. Gastroenterol Rep (Oxf) 5 (2017): 104-112.
17. Strunk H, Marinova M. Transjugular Intrahepatic Portosystemic Shunt (TIPS): Pathophysiologic Basics, Actual Indications and Results with Review of the Literature. Rofo 190 (2018): 701-711.
18. Bercu ZL, Fischman AM. Outcomes of transjugular intrahepatic portosystemic shunts for ascites. Semin Intervent Radiol 31 (2014): 248-251.
19. Saad WE. The history and future of transjugular intrahepatic portosystemic shunt: food for thought. Semin Intervent Radiol 31 (2014): 258-261.
20. Hung ML, Lee EW. Role of Transjugular Intrahepatic Portosystemic Shunt in the Management of Portal Hypertension: Review and Update of the Literature. Clin Liver Dis 23 (2019): 737-754.
21. Bureau C, Thabut D, Oberti F, et al. Transjugular Intrahepatic Portosystemic Shunts With Covered Stents Increase Transplant-Free Survival of Patients With Cirrhosis and Recurrent Ascites. Gastroenterology 152 (2017): 157-163.
22. Narahara Y, Kanazawa H, Fukuda T, et al. Transjugular intrahepatic portosystemic shunt versus paracentesis plus albumin in patients with refractory ascites who have good hepatic and renal function: a prospective randomized trial. J Gastroenterol 46 (2011): 78-85.
23. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 42 (2009): 377-381.
24. Senzolo M, Zarantonello L, Formentin C, et al. Predictive value of induced hyperammonaemia and neuropsychiatric profiling in relation to the occurrence of post-TIPS hepatic encephalopathy. Metab Brain Dis 34 (2019): 1803-1812.