Retrospective Study Open Access
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Apr 27, 2023; 15(4): 564-576
Published online Apr 27, 2023. doi: 10.4254/wjh.v15.i4.564
Peptic ulcer disease in non-alcoholic fatty liver disease hospitalizations: A new challenge on the horizon in the United States
Dushyant Singh Dahiya, Department of Internal Medicine, Central Michigan University College of Medicine, Saginaw, MI 48601, United States
Vinay Jahagirdar, Department of Internal Medicine, University of Missouri-Kansas City, Kansas City, MO 64110, United States
Hassam Ali, Department of Internal Medicine, East Carolina University, Greenville, NC 27858, United States
Manesh Kumar Gangwani, Department of Internal Medicine, The University of Toledo, Toledo, OH 43606, United States
Muhammad Aziz, Department of Gastroenterology, The University of Toledo, Toledo, OH 43606, United States
Saurabh Chandan, Division of Gastroenterology and Hepatology, CHI Creighton University Medical Center, Omaha, NE 68131, United States
Amandeep Singh, Madhusudhan R Sanaka, Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH 44195, United States
Abhilash Perisetti, Division of Gastroenterology and Hepatology, Kansas City Veterans Affairs Medical Center, Kansas City, MO 64128, United States
Aakriti Soni, Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA 01608, United States
Sumant Inamdar, Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
Mohammad Al-Haddad, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
ORCID number: Dushyant Singh Dahiya (0000-0002-8544-9039); Vinay Jahagirdar (0000-0001-6685-1033); Hassam Ali (0000-0001-5546-9197); Manesh Kumar Gangwani (0000-0002-3931-6163); Saurabh Chandan (0000-0002-2661-6693); Amandeep Singh (0000-0001-8581-1408); Abhilash Perisetti (0000-0003-4074-6395); Aakriti Soni (0000-0001-9732-2898); Sumant Inamdar (0000-0002-1002-2823); Madhusudhan R Sanaka (0000-0003-2506-8602); Mohammad Al-Haddad (0000-0003-1641-9976).
Author contributions: Dahiya DS, Ali H, Inamdar S, Sanaka MR, and Al-Haddad M were responsible for the conception and design; Dahiya DS, Inamdar S, Sanaka MR, and Al-Haddad M provided administrative support; Dahiya DS and Ali H were responsible for provision, collection, and assembly of data; all authors were responsible for review of literature, drafting the manuscript, and revision of key components of the manuscript; and all authors have read and approve the final version of the manuscript.
Institutional review board statement: The National Inpatient Sample database contains numerous safeguards to protect patient privacy. It also lacks patient- and hospital-specific identifiers. Therefore, our study was exempt from Institutional Review Board (IRB) evaluation as per guidelines put forth by our institutional IRB for analysis of HCUP databases.
Informed consent statement: The data for this study was collected from the National Inpatient Sample (NIS) database. As the NIS database lacks patient-specific and hospital-specific identifiers, this study did not require informed consent.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The National Inpatient Sample is a publicly available database that can be accessed at https://www.hcup-us.ahrq.gov. Due to the availability of a large sample size within the NIS database, it is an ideal choice for the estimation of national trends and clinical outcomes.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dushyant Singh Dahiya, MD, Doctor, Department of Internal Medicine, Central Michigan University College of Medicine, 1015 S Washington Ave, Third Floor, Saginaw, MI 48601, United States. dush.dahiya@gmail.com
Received: January 7, 2023
Peer-review started: January 7, 2023
First decision: February 21, 2023
Revised: February 24, 2023
Accepted: March 27, 2023
Article in press: March 27, 2023
Published online: April 27, 2023

Abstract
BACKGROUND

Peptic ulcer disease (PUD) is frequently seen in patients with liver cirrhosis. However, current literature lacks data on PUD in non-alcoholic fatty liver disease (NAFLD) hospitalizations.

AIM

To identify trends and clinical outcomes of PUD in NAFLD hospitalizations in the United States.

METHODS

The National Inpatient Sample was utilized to identify all adult (≥ 18 years old) NAFLD hospitalizations with PUD in the United States from 2009-2019. Hospitalization trends and outcomes were highlighted. Furthermore, a control group of adult PUD hospitalizations without NAFLD was also identified for a comparative analysis to assess the influence of NAFLD on PUD.

RESULTS

The total number of NAFLD hospitalizations with PUD increased from 3745 in 2009 to 3805 in 2019. We noted an increase in the mean age for the study population from 56 years in 2009 to 63 years in 2019 (P < 0.001). Racial differences were also prevalent as NAFLD hospitalizations with PUD increased for Whites and Hispanics, while a decline was observed for Blacks and Asians. The all-cause inpatient mortality for NAFLD hospitalizations with PUD increased from 2% in 2009 to 5% in 2019 (P < 0.001). However, rates of Helicobacter pylori (H. pylori) infection and upper endoscopy decreased from 5% in 2009 to 1% in 2019 (P < 0.001) and from 60% in 2009 to 19% in 2019 (P < 0.001), respectively. Interestingly, despite a significantly higher comorbidity burden, we observed lower inpatient mortality (2% vs 3%, P = 0.0004), mean length of stay (LOS) (11.6 vs 12.1 d, P < 0.001), and mean total healthcare cost (THC) ($178598 vs $184727, P < 0.001) for NAFLD hospitalizations with PUD compared to non-NAFLD PUD hospitalizations. Perforation of the gastrointestinal tract, coagulopathy, alcohol abuse, malnutrition, and fluid and electrolyte disorders were identified to be independent predictors of inpatient mortality for NAFLD hospitalizations with PUD.

CONCLUSION

Inpatient mortality for NAFLD hospitalizations with PUD increased for the study period. However, there was a significant decline in the rates of H. pylori infection and upper endoscopy for NAFLD hospitalizations with PUD. After a comparative analysis, NAFLD hospitalizations with PUD had lower inpatient mortality, mean LOS, and mean THC compared to the non-NAFLD cohort.

Key Words: Non-alcoholic fatty liver disease, Peptic ulcer disease, Trends, Outcomes, Mortality

Core Tip: Due to dietary and lifestyle changes, the prevalence of non-alcoholic fatty liver disease (NAFLD) is on the rise worldwide. Peptic ulcer disease (PUD) is commonly seen in patients with liver cirrhosis. However, data on PUD in NAFLD hospitalizations is currently lacking. In this study, we noted an increase in inpatient mortality for NAFLD hospitalizations with PUD in the United States. The rates of Helicobacter pylori infection and upper endoscopy for NAFLD hospitalizations with PUD were on the decline. Despite a higher comorbidity burden, inpatient mortality, mean length of stay, and mean total healthcare cost were lower for NAFLD hospitalizations with PUD compared to the non-NAFLD cohort.



INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide range of conditions primarily characterized by the presence of hepatic steatosis which is identified on radiological imaging or histology after other secondary causes of fat deposition have been excluded[1]. Based on histological findings, it is further subdivided into NAFL, which is hepatic steatosis without hepatocellular injury, and non-alcoholic steatohepatitis (NASH) characterized by hepatic steatosis and inflammation with hepatocyte injury. NAFLD usually progresses linearly from steatosis and hepatitis to fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Risk factors commonly implicated in the development of NAFLD include obesity, diabetes mellitus, hypertriglyceridemia, and metabolic syndrome[2]. The global prevalence of NAFLD is estimated to be 25% and is expected to rise further due to the rising incidence and prevalence of obesity worldwide[3]. In the United States, approximately 80 million people have NAFLD, with NASH being the second leading cause of liver transplant[4].

Peptic ulcer disease (PUD) involves acid-induced mucosal disruption in the upper gastrointestinal (GI) tract, usually in the stomach or proximal duodenum. Helicobacter pylori (H. pylori) infection and the excessive use of non-steroidal anti-inflammatory drugs are the leading causes of PUD[5]. Additionally, increasing age, smoking, alcohol use, and obesity have a strong association with PUD[6]. Although the prevalence of self-reported physician-diagnosed ulcer disease in the United States was as high as 10% at the end of the 20th century, there has been a decrease in prevalence and hospitalizations for PUD in the last few decades, primarily due to advancements in H. pylori eradication and increasing utilization of proton pump inhibitors for acid suppression[7,8].

The association between alcoholic liver disease and PUD has been well established with studies reporting a higher prevalence of PUD in patients with alcoholic liver cirrhosis[9]. Additionally, a study by Nojkov and Cappell noted that PUD was the most common cause of non-variceal hemorrhage in cirrhotics and carried a higher rate of re-bleeding, delayed ulcer healing, and recurrence when compared to the general population[10]. However, there continue to be significant knowledge gaps on PUD in NAFLD hospitalizations. Hence, we addressed the knowledge gaps in current literature as we identified hospitalization trends, outcomes, and predictors of mortality for NAFLD hospitalizations with PUD. Furthermore, we also performed a comparative analysis between NAFLD hospitalizations with PUD and non-NAFLD PUD hospitalizations to determine the influence of NALFD on PUD.

MATERIALS AND METHODS
Design and data source

The study cohort was derived from the National Inpatient Sample (NIS) database which is one of the largest, publicly available, multi-ethnic databases in the United States. The NIS, part of the Healthcare Cost and Utilization Project group of databases, consists of data on inpatient admissions submitted by hospitals across the United States to state-wide data organizations, covering 97% of the United States population[11]. It approximates a 20-percent stratified sample, and the dataset is weighted to obtain national estimates[12]. For the 2009-2019 study period, the NIS database was coded using the International Classification of Diseases (ICD)-9/10 coding systems.

Study population

We utilized the NIS to obtain all adult (≥ 18 years) NAFLD hospitalizations with PUD in the United States from 2009-2019. Furthermore, a control group of all adult PUD hospitalizations without NAFLD were identified for comparative analysis.

Statistical analysis and outcome measures

Statistical analysis was conducted using SAS 9.4 (SAS Institute Inc, Cary, NC) while accounting for the weights in the stratified survey design. The weights were considered during statistical estimation by incorporating variables for strata, clusters, and weight to discharges in the NIS. Descriptive statistics were provided, including mean (standard deviation) for continuous variables and count (percentage) for categorical variables. To test for the trend for proportions of binary variables in years, the Cochran-Armitage trend test was implemented. The trend for the averages of continuous variables in years was examined using linear regression. The Rao-Scott design-adjusted chi-square test, which takes the stratified survey design into account, examined the association between two categorical variables. All analytical results were statistically significant when the P-values ≤ 0.05.

Ethical considerations

The NIS database lacks any patient and hospital-specific identifiers. Hence, this study was exempt from Institutional Review Board (IRB) review as per guidelines put forth by our institutional IRB for research on database studies.

RESULTS
Hospitalization characteristics for NAFLD hospitalizations with PUD

Overall, there was no decline in the total number of NAFLD hospitalizations with PUD (3745 in 2009 to 3805 in 2019, with a peak of 6885 in 2014) (Table 1). The mean age increased from 56.0 years in 2009 to 63.0 years in 2019 (P < 0.001), with a significant increase noted for the 65-79 age group (26% in 2009 to 46% in 2019). A majority of NAFLD hospitalizations with PUD were for females and Whites. Racial differences were also noted as there was a declining trend of NAFLD hospitalizations with PUD for Blacks from 10% in 2009 to 5% in 2019 (P = 0.01) and Asians from 3% in 2009 to 2% in 2019 (P = 0.01), while Whites and Hispanics had a rising trend (Table 1 and Figure 1). Furthermore, rates of H. pylori infection and upper endoscopy decreased from 2009 to 2019 (Table 1). Most NAFLD hospitalizations with PUD were at large hospitals, and admissions in urban teaching hospitals increased from 40% in 2009 to 80% in 2019 (P < 0.001). Overall, Medicare was the largest insurer for NAFLD hospitalizations with PUD.

Figure 1
Figure 1  Racial trends for non-alcoholic fatty liver disease hospitalizations hospitalizations with peptic ulcer disease in the United States from 2009-2019.
Table 1 Hospitalization trends for non-alcoholic fatty liver disease hospitalizations with peptic ulcer disease in the United States from 2009-2019.
Variable
Years
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
Total hospitalizations3745456352305655575968855745288030703430
Mean age (yr)56.01 ± 0.857.07 ± 0.7556.68 ± 0.8157.1 ± 0.1457.1 ± 0.4157.4 ± 0.5957.5 ± 0.9762.4 ± 0.4162.8 ± 0.863.7 ± 0.74
Age groups, yr (%)
18-349888788342
35-4925242525232221121115
50-6439424139424239444036
65-7926252627282832424447
≥ 80< 1111< 1< 1< 1111
Gender (%)
Male45424343444445364040
Female55485758565655646050
Race (%)0.01
White72737071727170747676
Black10891091110655
Hispanic11131413121113141515
Asian3333233222
Native American1< 111111211
Other3333343324
CCI (%)
CCI = 00000000000
CCI = 134323432323131666
CCI = 22724232222222513810
CCI ≥ 339444347464744868686
Hospital region (%)
Northeast13121416151414131316
Midwest24242222222121282929
South39414321424344383735
West24232121212121202119
Hospital bed-size (%)
Small8111113111616151616
Medium25252229263229242528
Large67646759635255615956
Hospital location and teaching status (%)
Rural81011101077655
Urban non-teaching47504541372627212014
Urban teaching46404449536766737581
Primary payer
Medicare41424144434444536060
Medicaid13151415151616141111
Private36353533343333302526
Other108108877233
Median household income (%)
1st (0-25th)26273028312831312729
2nd (26th-50th)25242524262924273232
3rd (51st-75th)30242426242326242521
4th (76th-100th)19242122192019171518
Upper endoscopy (%)60596258595962202218
Outcomes for NAFLD hospitalizations with PUD

We noted a rising trend of all-cause inpatient mortality for NAFLD hospitalizations with PUD from 2% in 2009 to 5% in 2019 (P < 0.001) (Table 2). However, inpatient mortality for Whites declined from 81% in 2009 to 64% in 2019 (P = 0.04) within the race analysis. We did not find a statistically significant trend for mean length of stay (LOS) and mean total healthcare cost (THC). Furthermore, the rates of GI tract perforation decreased [33% (2009) to 8% (2019), P = 0.02] but the proportion of patients with GI bleeding increased [0% (2009) to 11% (2019), P = 0.04].

Table 2 Trends of outcomes for non-alcoholic fatty liver disease hospitalizations with peptic ulcer disease in the United States from 2009-2019.
Outcome
Years
Pvalue
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
Inpatient mortality (%)21222214455< 0.001
Gender-specific inpatient mortality (%)0.2
Male2521285753384037523231
Female7579724347626063484848
Race-specific inpatient mortality (%)0.4
White8153894879737371816164
Black7001404044611
Hispanic12471119161971781914
Asian000105004036
Native American00050070436
Others000504134460
Age-group specific inpatient mortality (%)0.1
18-3470000300000
35-491326161301714922146
50-645136333129343641523148
65-792824365671415050264845
≥ 800131400300030
Length of stay (d)17.1 ± 0.5911.8 ± 0.7616.3 ± 0.589.2 ± 0.859.0 ± 0.018.2 ± 0.6810.1 ± 0.339.6 ± 0.4917.3 ± 0.339.2 ± 0.9011.2 ± 0.220.06
Total hospital charge ($)182296 ± 760104265 ± 620215085 ± 130172837 ± 170157079 ± 890105031 ± 760136876 ± 800134573 ± 730373045 ± 450143284 ± 940174044 ± 5500.8
Complications (%)
Bleeding02100510717710110.4
Perforation33123529163131711380.02
Comparative analysis of NAFLD and non-NAFLD hospitalizations with PUD

NAFLD hospitalizations with PUD were younger (58.6 vs 65.3 years, P < 0.001), and had more Whites and Hispanics compared to the non-NAFLD subgroup (Table 3). A Charlson Comorbidity Index (CCI) ≥ 3 was noted in a higher proportion of NAFLD hospitalizations with PUD (55%) compared to non-NAFLD PUD hospitalizations (49%) (P < 0.001). Although NAFLD hospitalizations with PUD had a higher proportion of patients that underwent upper endoscopy (49% vs 41%, P < 0.001), the rates of H. pylori infection was not statistically different between the cohorts (Table 3).

Table 3 Comparative analysis of hospitalization characteristics for non-alcoholic fatty liver disease hospitalizations with peptic ulcer disease and non-NALFD hospitalizations with peptic ulcer disease in the United States from 2009-2019.

NAFLD hospitalizations with PUD
Non-NAFLD hospitalizations with PUD
P value
Total hospitalizations50769 (1%)4624628 (99%)
Mean age (yr)58.6 ± 0.2765.3 ± 0. 80< 0.001
Age group, yr (%)< 0.001
18-3466
35-492115
50-644033
65-793240
≥ 8016
Gender (%)< 0.001
Male4249
Female4851
Race (%)< 0.001
White7270
Black914
Hispanic139
Asian33
Native American11
Other33
CCI (%)< 0.001
CCI = 000
CCI = 12530
CCI = 22022
CCI ≥ 35549
Upper endoscopy (%)4941< 0.001
H. pylori (%)330.5
Hospital region (%)< 0.001
Northeast1418
Midwest2423
South4139
West2120
Hospital bed size (%)< 0.001
Small1416
Medium2728
Large5956
Hospital location and teaching status (%)< 0.001
Rural810
Urban nonteaching3234
Urban teaching6056
Expected primary payer (%)< 0.001
Medicare4761
Medicaid1412
Private3221
Other75
Median household income (quartile) (%)< 0.001
1st (0-25th)2931
2nd (26th-50th)2726
3rd (51st-75th)2524
4th (76th-100th)2019

Despite a higher CCI score, the all-cause inpatient mortality was lower (2% vs 3%, P = 0.0004), for NAFLD-PUD hospitalizations compared to the non-NAFLD-PUD hospitalizations (Table 4). Furthermore, the mean LOS was shorter (11.6 vs 12.1 d, P < 0.001), the and mean THC was lower ($178598 and $184727, P < 0.001) for NAFLD-PUD hospitalizations compared to non-NAFLD-PUD hospitalizations (Table 4). There was no statistical difference in the proportion of patients with complications such as GI bleeding and perforation between the 2 groups.

Table 4 Comparative analysis of outcomes for non-alcoholic fatty liver disease hospitalizations with peptic ulcer disease and non-NAFLD hospitalizations with peptic ulcer disease in the United States from 2009-2019.
Outcomes
NAFLD hospitalizations with PUD
Non-NAFLD hospitalizations with PUD
value
Inpatient mortality (%)230.0004
Gender-specific inpatient mortality (%)< 0.001
Male3854
Female6246
Race-specific inpatient mortality (%)< 0.001
White7072
Black612
Hispanic169
Asian34
Native American31
Others33
Age-group specific inpatient mortality (%)< 0.001
18-3412
35-49137
50-643930
65-794449
≥ 80212
Length of stay (d)11.612.1< 0.001
Total healthcare cost ($)178598184727< 0.001
Complications (%)
Bleeding860.2
Perforations14180.1
Predictors of mortality for NAFLD hospitalizations with PUD

Significant predictors of all-cause inpatient mortality for NAFLD hospitalizations with PUD included GI tract perforation (aHR = 2.71, 95%CI: 1.37-5.35, P = 0.004), coagulopathy (aHR = 2.24, 95%CI: 0.74-0.84, P < 0.001), fluid and electrolyte disorders (aHR = 1.92, 95%CI: 1.82-2.01, P < 0.001), alcohol abuse (aHR = 1.51, 95%CI: 1.42-1.61, P < 0.001), and protein-calorie malnutrition (aHR = 1.16, 95%CI: 1.11-1.22, P < 0.001) (Table 5).

Table 5 Predictors of all-cause inpatient mortality for non-alcoholic fatty liver disease hospitalizations with peptic ulcer disease in the United States from 2009-2019.
Variable
Adjusted hazard ratio
95% confidence interval
value
Coagulopathy2.242.14-2.34< 0.001
Obesity0.790.74-0.84< 0.001
Protein calorie malnutrition1.161.11-1.22< 0.001
Fluid and electrolyte disorder1.921.82-2.01< 0.001
Alcohol abuse1.511.42-1.61< 0.001
Perforation2.711.37-5.350.004
DISCUSSION

PUD is believed to be the most common cause of non-variceal GI bleeding in liver cirrhosis patients. However, data on PUD in NAFLD hospitalizations is lacking. Ours is the only study in current literature that evaluates the trends of hospitalization characteristics and outcomes for NAFLD hospitalizations with PUD and further compares NAFLD hospitalizations with PUD to non-NAFLD PUD hospitalizations using the NIS database. In this study, we did not find a decline in the total number of NAFLD hospitalizations with PUD. The all-cause inpatient mortality increased from 2% in 2009 to 5% in 2019 in the United States. However, the rates of upper endoscopy and H. pylori infection declined for NAFLD hospitalizations with PUD. Furthermore, NAFLD hospitalizations with PUD had lower mortality, LOS, and THC compared to the non-NAFLD group, despite a higher comorbidity burden. An understanding of the trends, outcomes, and influence of NAFLD on PUD is crucial as it may help gastroenterologists identify individuals at the greatest risk of adverse outcomes and complications, thereby preventing morbidity and mortality.

Recent studies have demonstrated a dramatic increase in the prevalence and hospitalization rates for patients with NAFLD, which could have led to the slightly increased number of hospitalizations noted in our study[13,14]. This is despite the fact that there has been an overall decline in hospitalization rates for PUD in the United States[15]. Furthermore, racial differences have also been noted in NAFLD hospitalizations for ethnic minorities. Per current literature, the highest and lowest rates of NAFLD hospitalizations are for Hispanics and African Americans, respectively[13,16]. This has been attributed to dietary habits, lifestyle, and genetics as Hispanics have an allele of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) that favors hepatic fat storage, while African Americans possess a different allele of the same gene associated with lower hepatic fat content[17,18]. Our study echoed similar findings as we noted a rising trend of NAFLD hospitalizations with PUD for Hispanics from 11% in 2009 to 15% in 2019 (P = 0.01) and a declining trend for Blacks from 10% in 2009 to 5% in 2019 (P = 0.01). These racial differences are important as we advocate for the need for aggressive public health measures for Hispanic populations to increase awareness about the burden of PUD in those who have NAFLD. Moreover, hospitalists and gastroenterologists who take care of NAFLD hospitalizations should have a high degree of suspicion of PUD in these patients.

In the United States, there has been a significant increase in inpatient mortality for NAFLD-cirrhosis by 32% between 2005-2015, despite a decrease in the inpatient mortality rates for patients with all other causes of liver cirrhosis[19]. However, there has been a significant decline in inpatient PUD mortality due to the increasing use of therapeutic endoscopic procedures for bleeding ulcers[20]. In our study, there was a rising trend of all-cause inpatient mortality for NAFLD hospitalizations with PUD (Table 2). From a race perspective, we noted an increasing trend of all-cause inpatient mortality for Blacks and Hispanics, while a decline was observed for Whites. The exact reasons for these findings are unknown, but they may, in part, be attributed to a higher comorbidity burden and the increasing mean age for NAFLD hospitalizations with PUD, particularly for ethnic minorities i.e., Blacks and Hispanics (Table 1), leading to greater severity of disease and adverse outcomes. Interestingly, we noted lower all-cause inpatient mortality, mean LOS, and mean THC for NAFLD hospitalizations with PUD compared to non-NAFLD PUD hospitalizations, despite a higher comorbidity burden. But there was no statistical difference in the proportion of patients with complications such as GI bleeding and perforation between the two groups. The exact reason for this protective effect of NAFLD is unclear and needs further investigation by multi-center prospective studies.

There has been a rapid decline in H. pylori infection rates in the western world secondary to higher standards of living and improved hygiene[21]. An analysis of outpatient endoscopy centers in the United States noted a significant fall in H. pylori infections from 11% in 2009 to 9% in 2018[22]. However, a recent cross-sectional study identified a positive relationship between H. pylori infection and NAFLD in females after adjusting for metabolic variables, gastrin factors, and liver enzymes[23]. This implies that rates of H. pylori infection may rise with an increasing prevalence of NAFLD. Our study contradicts these findings as we observed a declining trend of H. pylori infection in NAFLD hospitalizations with PUD (Table 1). Furthermore, we also noted a decline in the trends of utilization of upper endoscopy from 60% in 2009 to 19% in 2019. This may be due to increased adherence to guideline-directed management which advocates for non-endoscopic testing for uninvestigated dyspepsia without alarm features in individuals < 60 years of age[24]. However, due to an increasing trend of all-cause inpatient mortality in this subset population, it may be justified to perform upper endoscopy at an early stage to prevent adverse clinical outcomes. Interestingly, NAFLD hospitalizations with PUD had a higher proportion of patients that underwent upper endoscopy compared to non-NAFLD PUD hospitalizations. The exact reason for this is currently unknown and needs further investigation.

Our study has numerous strengths and some limitations. A key strength of this study is the study population, which is derived from one of the largest, publicly available, all-payer, multi-ethnic databases in the United States. An analysis over the 11-year study period allowed us to obtain meaningful information on the trends of hospitalization characteristics and outcomes for NAFLD hospitalizations with PUD, adding to scarce literature. Moreover, through our unique and multifaceted comparative analysis, we were able to determine the influence of NAFLD on PUD. Furthermore, as the NIS database covers 97% of the United States population, the results of our study are applicable to almost all NAFLD hospitalizations with PUD, offering a national perspective. However, we do acknowledge the limitations associated with our study. This was a retrospective study design which is subject to all biases associated with retrospective studies. The NIS database does not contain information on the severity, time from hospitalization to discharge, hospital course, and other treatment aspects of the disease. Lastly, the NIS is an administrative database maintained through data collection organizations that use the ICD coding system to store inpatient data. Hence, the possibility of human coding errors cannot be excluded. However, despite these limitations, we believe that the large sample size and a comprehensive analysis technique help us better understand the trends, characteristics, and outcomes of NAFLD hospitalizations with PUD, and promote future research on the topic.

CONCLUSION

NAFLD is a public health concern and places a significant burden on the United States healthcare system. There is a significant knowledge gap on PUD in patients with NAFLD who are admitted to the hospital. We noted an increase the all-cause inpatient mortality for NAFLD hospitalizations with PUD in the United States between 2009-2019. There was a rising trend of NAFLD hospitalizations with PUD for Hispanics, reflecting the need for urgent public health measures to increase awareness in this subset population. Compared to non-NAFLD PUD hospitalizations, NAFLD hospitalizations with PUD had lower inpatient mortality, mean LOS, and mean THC despite a higher comorbidity burden. However, there was no statistical difference in GI bleeding and perforation between the two groups. Perforation of the GI tract, coagulopathy, alcohol abuse, malnutrition, and fluid and electrolyte disorders were identified to be independent predictors of all-cause inpatient mortality for NAFLD hospitalizations with PUD. Additional multi-center prospective studies are needed to further confirm these findings.

ARTICLE HIGHLIGHTS
Research background

The association between peptic ulcer disease (PUD) and liver cirrhosis has been thoroughly investigated. However, there are knowledge gaps on PUD in non-alcoholic fatty liver disease (NAFLD) hospitalizations. As the prevalence of NAFLD continues to rise across the globe and in the United States, it is vital to identify individuals with NAFLD at high risk of adverse clinical outcomes from PUD.

Research motivation

In current literature, there is a knowledge gap on PUD in NAFLD hospitalizations. Hence, this study was designed to help fill the knowledge gaps that currently exist in this subset population.

Research objectives

Our main objective was to identify national trends in hospitalization characteristics, clinical outcomes, and complications for NAFLD hospitalizations with PUD. We also performed a comparative analysis between NAFLD and non-NAFLD hospitalizations with PUD to assess the influence of NAFLD on PUD.

Research methods

The National Inpatient Sample was used from 2009-2019 to identify all adult (≥ 18 years) NAFLD hospitalizations with PUD in the United States. Furthermore, a control group of all adult PUD hospitalizations without NAFLD were identified for comparative analysis. Statistical analysis was conducted using SAS 9.4. To test for the trend for proportions of binary variables, the Cochran-Armitage trend test was implemented. The trend for the averages of continuous variables in years was examined using linear regression. The Rao-Scott design-adjusted chi-square test examined the association between two categorical variables.

Research results

NAFLD-PUD hospitalizations increased from 3745 (2009) to 3805 (2019). Racial differences were noted as NAFLD hospitalizations with PUD increased for Whites and Hispanics, while a decline was observed for Blacks and Asians. There was an increase in all-cause inpatient mortality for NAFLD hospitalizations with PUD from 2% in 2009 to 5% in 2019 (P < 0.001). However, the rates of Helicobacter pylori (H. pylori) infection and upper endoscopy decreased during the study period. Despite a high comorbidity burden, we observed lower inpatient mortality, mean length of hospital stay, and mean total healthcare cost (THC) for NAFLD-PUD hospitalizations vs the non-NAFLD-PUD cohort. Perforation of the gastrointestinal tract, coagulopathy, alcohol abuse, malnutrition, and fluid and electrolyte disorders were identified as independent predictors of inpatient mortality for NAFLD hospitalizations with PUD.

Research conclusions

Between 2009-2019, inpatient mortality for NAFLD hospitalizations with PUD increased. However, there was a significant decline in H. pylori infections and esophagogastroduodenoscopy for NAFLD-PUD hospitalizations. After a comparative analysis, NAFLD-PUD hospitalizations had lower rates of mortality, mean length of hospital stay, and mean THC vs the non-NAFLD-PUD cohort despite a higher comorbidity burden.

Research perspectives

This is one of the few national studies which investigates trends, clinical outcomes, and complications of NAFLD hospitalizations with PUD, using one of the largest, multi-ethnic databases in the United States. Future research should be directed toward identifying the underlying cause of racial disparities for this subset population.

Footnotes

Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Corresponding Author’s Membership in Professional Societies: American College of Gastroenterology; American Society for Gastrointestinal Endoscopy; American Gastroenterological Association.

Specialty type: Gastroenterology and hepatology

Country/Territory of origin: United States

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): B, B

Grade C (Good): C

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Shiryajev YN, Russia; Sitkin S, Russia; Thapar P, India S-Editor: Wang JJ L-Editor: A P-Editor: Cai YX

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