Brief Article Open Access
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Dec 7, 2013; 19(45): 8301-8311
Published online Dec 7, 2013. doi: 10.3748/wjg.v19.i45.8301
Nonalcoholic fatty liver disease is associated with benign gastrointestinal disorders
Srinevas K Reddy, Min Zhan, H Richard Alexander, Samer S El-Kamary
Srinevas K Reddy, H Richard Alexander, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States
Min Zhan, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, United States
Samer S El-Kamary, Departments of Pediatrics, Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, United States
Author contributions: Reddy SK, Zhan M and EL-Kamary SS designed the project; Reddy SK extracted and analyzed the data, and wrote the manuscript; Zhan M provided biostatistical expertise; Alexander HR critically revised the manuscript; El-Kamary SS analyzed the data, and critically revised the manuscript.
Supported by NIH 2K12HD043489-11
Correspondence to: Dr. Srinevas K Reddy, Assistant Professor, Department of Surgery, University of Maryland School of Medicine, 22 South Greene Street-Rm S4B18, Baltimore, MD 21201, United States. sreddy@smail.umaryland.edu
Telephone: +1-919- 4233291 Fax: +1-410-3285919
Received: May 22, 2013
Revised: July 11, 2013
Accepted: July 18, 2013
Published online: December 7, 2013

Abstract

AIM: To explore associations between nonalcoholic fatty liver disease (NAFLD) and benign gastrointestinal and pancreato-biliary disorders.

METHODS: Patient demographics, diagnoses, and hospital outcomes from the 2010 Nationwide Inpatient Sample were analyzed. Chronic liver diseases were identified using International Classification of Diseases, the 9th Revision, Clinical Modification codes. Patients with NAFLD were compared to those with other chronic liver diseases for the endpoints of total hospital charges, disease severity, and hospital mortality. Multivariable stepwise logistic regression analyses to assess for the independent association of demographic, comorbidity, and diagnosis variables with the event of NAFLD (vs other chronic liver diseases) were also performed.

RESULTS: Of 7800441 discharge records, 32347 (0.4%) and 271049 (3.5%) included diagnoses of NAFLD and other chronic liver diseases, respectively. NAFLD patients were younger (average 52.3 years vs 55.3 years), more often female (58.8% vs 41.6%), less often black (9.6% vs 18.6%), and were from higher income areas (23.7% vs 17.7%) compared to counterparts with other chronic liver diseases (all P < 0.0001). Diabetes mellitus (43.4% vs 28.9%), hypertension (56.9% vs 47.6%), morbid obesity (36.9% vs 8.0%), dyslipidemia (37.9% vs 15.6%), and the metabolic syndrome (28.75% vs 8.8%) were all more common among NAFLD patients (all P < 0.0001). The average total hospital charge ($39607 vs $51665), disease severity scores, and intra-hospital mortality (0.9% vs 6.0%) were lower among NALFD patients compared to those with other chronic liver diseases (all P < 0.0001).Compared with other chronic liver diseases, NAFLD was significantly associated with diverticular disorders [OR = 4.26 (3.89-4.67)], inflammatory bowel diseases [OR = 3.64 (3.10-4.28)], gallstone related diseases [OR = 3.59 (3.40-3.79)], and benign pancreatitis [OR = 2.95 (2.79-3.12)] on multivariable logistic regression (all P < 0.0001) when the latter disorders were the principal diagnoses on hospital discharge. Similar relationships were observed when the latter disorders were associated diagnoses on hospital discharge.

CONCLUSION: NAFLD is associated with diverticular, inflammatory bowel, gallstone, and benign pancreatitis disorders. Compared with other liver diseases, patients with NAFLD have lower hospital charges and mortality.

Key Words: Nationwide inpatient sample, Nonalcoholic fatty liver disease, Chronic liver disease, Diverticular disease, Pancreatitis, Gallstones, Inflammatory bowel disease

Core tip: This study analyzed the 2010 Nationwide Inpatient Sample to compare outcomes and associations between patients with nonalcoholic fatty liver disease (NAFLD) and other chronic liver diseases. Compared with other liver diseases, NAFLD is associated with diverticular, inflammatory bowel, gallstone, and benign pancreatitis disorders when these latter disorders are considered as either the principal or associated diagnoses on discharge. These associations suggest shared mechanisms of pathology between NAFLD and these benign gastrointestinal disorders. Furthermore, patients with NAFLD have lower hospital mortality and consume fewer healthcare resources compared to patients with other chronic liver diseases.



INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States[1].Outpatient primary care and specialist cohort series report prevalence proportions of 25%-46%[2-4]. Yet the proportion of hospitalized patients diagnosed with NAFLD is unknown. The prevalence of NAFLD in hospitalized patients maybe similar to outpatient cohorts given the associations between NAFLD and disorders common among hospitalized patients--including diabetes, cardiovascular disease, venous thromboembolism, colorectal cancer, and inflammatory bowel disease[5-13]. Conversely, NAFLD may comprise a small percentage of chronic liver disease among hospitalized patients because hepatic complications (such as ascites, variceal bleeding, and hepatocellular carcinoma) are less common with NAFLD compared to hepatitis B, hepatitis C, and alcohol associated liver diseases[10,14-19]. Finally, it is unclear if NAFLD is widely recognized by health care providers. This knowledge gap is important given recent small, single institutional studies suggesting relationships between NAFLD and benign digestive and pancreato-biliary disorders including diverticular disease, gallstone disorders, and inflammatory bowel disease[20-23]. Recognition of associations between NAFLD and these conditions may reveal insights into the pathologic mechanisms of all disorders.

The objectives of this study were to estimate the prevalence of the diagnosis of NAFLD among hospitalized patients in the United States and to explore associations between NAFLD and benign gastrointestinal and pancreato-biliary disorders.

MATERIALS AND METHODS
Database

Data were abstracted from the 2010 Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality (AHRQ). The 2010 NIS contains discharge information from 1051 non-Federal, short-term, general, and specialty hospitals located in 45 states; approximating a 20% stratified sample of United States community hospitals[24]. This study was deemed exempt by the Institutional Review Board at the University of Maryland School of Medicine.

Sample identification

This study comprised patients with a diagnosis of chronic liver disease and compared patients with NAFLD vs any other chronic liver disease. All 25 diagnoses listed in each record were searched in creating each subsample in this study. The International Classification of Diseases, the 9th Revision, Clinical Modification (ICD-9-CM) diagnosis code of 571.8 (“other chronic nonalcoholic liver disease”) was used to identify the NAFLD subsample. The “other chronic liver disease” subsample was identified using diagnosis codes describing other recognized etiologies of chronic liver disease, chronic liver disease of unknown etiology, and viral infections and errors in mineral metabolism which may lead to chronic liver disease (Table 1). Patient discharge records with diagnoses representing other liver diseases were eliminated from the NAFLD subsample. To eliminate records with possible alcoholic liver disease from the NAFLD subsample, records which included diagnoses pertaining to ethanol abuse, dependence, and/or overdose (Table 1) were removed from the NAFLD subsample. Similarly, records with an ICD-9-CM diagnosis code of 571.8 were eliminated from the “other chronic liver disease”subsample. Nationwide prevalence estimates were calculated using both unweighted and discharge weights, which account for the number of calendar quarters for which each hospital contributed discharges to the NIS[24,25].

Table 1 International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes used to identify disease.
ICD-9-CM diagnosisDiagnosis
The “other liver disease” cohort571Chronic liver disease and cirrhosis
571Alcoholic fatty liver
571.1Acute alcoholic hepatitis
571.2Alcoholic cirrhosis of liver
571.3Alcoholic liver damage, unspecified
571.4Chronic hepatitis
571.4Chronic hepatitis unspecified
571.41Chronic persistent hepatitis
571.42Autoimmune hepatitis
571.49Other chronic hepatitis
571.5Cirrhosis of liver without mention of alcohol
571.6Biliary cirrhosis
571.9Other unspecified chronic liver disease without mention of alcohol
573Other disorders of liver
573.1Hepatitis in viral diseases classified elsewhere
573.2Hepatitis in other infectious diseases classified elsewhere
573.3Hepatitis, unspecified
573.8Other specified disorders of liver
573.9Unspecified disorder of liver
70Viral hepatitis
70Viral hepatitis A with hepatic coma
70.1Viral hepatitis A without mention of hepatic coma
70.2Viral hepatitis B with hepatic coma
70.2Viral hepatitis B with hepatic coma, acute or unspecified without hepatitis delta
70.21Viral hepatitis B with hepatic coma, acute or unspecified with hepatitis delta
70.22Chronic viral hepatitis B with hepatic coma without hepatitis delta
70.23Chronic viral hepatitis B with hepatic coma with hepatitis delta
70.3Viral hepatitis b without mention of hepatic coma
70.3Viral hepatitis B without mention of hepatic coma, acute or unspecified, without mention of hepatitis delta
70.31Viral hepatitis B without mention of hepatic coma, acute or unspecified, with hepatitis delta
70.32Chronic viral hepatitis B without mention of hepatic coma without mention of hepatitis delta
70.33Chronic viral hepatitis B without mention of hepatic coma with hepatitis delta
70.4Other specified viral hepatitis with hepatic coma
70.41Acute hepatitis C with hepatic coma
70.42Hepatitis delta without mention of active hepatitis B disease with hepatic coma
70.43Hepatitis E with hepatic coma
70.44Chronic hepatitis C with hepatic coma
70.49Other specified viral hepatitis with hepatic coma
70.5Other specified viral hepatitis without mention of hepatic coma
70.51Acute hepatitis C without mention of hepatic coma
70.52Hepatitis delta without mention of active hepatitis B disease or hepatic coma
70.53Hepatitis E without mention of hepatic coma
70.54Chronic hepatitis C without mention of hepatic coma
70.59Other specified viral hepatitis without mention of hepatic coma
70.6Unspecified viral hepatitis with hepatic coma
70.7Unspecified viral hepatitis c
70.7Unspecified viral hepatitis C without hepatic coma
70.71Unspecified viral hepatitis C with hepatic coma
70.9Unspecified viral hepatitis without mention of hepatic coma
V02.6Carrier or suspected carrier of viral hepatitis
V02.60Viral hepatitis carrier, unspecified
V02.61Hepatitis B carrier
V02.62Hepatitis C carrier
V02.69Other viral hepatitis carrier
275Disorders of iron metabolism
275.01Hereditary hemochromatosis
275.02Hemochromatosis due to repeated red blood cell transfusions
275.03Other hemochromatosis
275.09Other disorders of iron metabolism
275.1Disorders of copper metabolism
Alcohol abuse, dependence, and/or overdose291Alcohol-induced mental disorders
291Alcohol withdrawal delirium
291.1Alcohol-induced persisting amnestic disorder
291.2Alcohol-induced persisting dementia
291.3Alcohol-induced psychotic disorder with hallucinations
291.4Idiosyncratic alcohol intoxication
291.5Alcohol-induced psychotic disorder with delusions
291.8Other specified alcohol-induced mental disorders
291.81Alcohol withdrawal
291.82Alcohol-induced sleep disorder
291.89Other alcoholic psychosis
291.9Unspecified alcohol-induced mental disorders
303Alcohol dependence syndrome
303Acute alcoholic intoxication
303Acute alcoholic intoxication in alcoholism unspecified drinking behavior
303.01Acute alcoholic intoxication in alcoholism continuous drinking behavior
303.02Acute alcoholic intoxication in alcoholism episodic drinking behavior
303.03Acute alcoholic intoxication in alcoholism in remission
303.9Other and unspecified alcohol dependence
303.9Other and unspecified alcohol dependence unspecified drinking behavior
303.91Other and unspecified alcohol dependence continuous drinking behavior
303.92Other and unspecified alcohol dependence episodic drinking behavior
303.93Other and unspecified alcohol dependence in remission
Demographics and diagnoses

The location of patient’s residence included central counties of greater than one million population, fringe counties of metropolitan areas of greater than one million population, counties in metropolitan areas of 250000-999999 population, counties in metropolitan areas of 50000-249999 population, and micropolitan counties in areas of less than 50000 population. The reported median income is the median income for the population in the zip code from which the patient pertaining to that particular discharge record resides[25].

All diagnoses were searched to determine the presence of obesity (ICD-9-CM codes 278, 278.0, 278.00, 278.01, 278.02, or 278.03) and dyslipidemia (ICD-9-CM codes 272, 272.0, 272.1, 272.2, 272.3, 272.4, 272.5, 272.8, or 272.9). The presence of associated diagnoses (principal or secondary) were determined using the clinical classification software provided by the AHRQ[26] (Table 2). Criteria for the metabolic syndrome include the presence of any three of obesity, diabetes mellitus, hypertension, and dyslipidemia[27,28]. Principal discharge diagnoses were also identified by the Disease Staging© (Thomson Reuters) classification system[29] (Table 3). The all patient refined diagnosis related group (APR-DRG© 3M) assesses severity of illness and mortality risk of the DRG pertaining to each patient discharge record[30].

Table 2 Clinical classification software categories used to identify comorbidities and associated diagnoses.
CCS CategoryDiagnosis
98 and 99Hypertension
49 and 50Diabetes mellitus
138Esophageal disorders (excluding ICD-9-CM diagnoses f.or varices)
139Gastroduodenal ulcer
140Gastritis and/or duodenitis
141Other disorders of stomach and duodenum
142Appendicitis
143Abdmoninal and groin hernia
144Inflammatory bowel diseases
145Intestinal obstruction
146Diverticular disease
147Anal and rectal conditions
148Peritonitis and intestinal abscess
149Benign biliary tract disease
152Benign pancreatic disorders excluding diabetes mellitus
153Gastrointestinal hemorrhage
154Noninfectious gastroenteritis
Table 3 Disease Staging© (Thomson Reuters) classification system used to identify principal discharge diagnoses.
Discharge categoryDescription
GIS03, GIS04, GIS18Benign anal-rectal disorders
GIS05Appendicitis
GIS09 or GIS37Inflammatory bowel disease
GIS10Diverticular disease
GIS17 or GIS84Gastroduodenitis
GIS19Hernia
GIS20Esophagitis
GIS25-30, HEP11, GIS82-83Upper gastrointestinal cancers
GIS31Gastroduodenal ulcer
HEP01 or HEP 84Gallstone related disorders
HEP12 or HEP85Non-malignant pancreatitis
HEP81 or HEP82Hepatobiliary malignancies
Statistical analysis

Discrete and continuous variables were compared using χ2 and Student’s t tests with two-sided P values. Multivariable stepwise logistic regression analyses to assess for the independent association of each variable with the event of NAFLD were performed. The P value for variable entry and stay was 0.05. OR point estimates with 95% Wald confidence limits are reported. Results for those variables that did not stay in each model were not reported. Two multivariable analyses were performed-one using associated diagnoses and another using principal diagnoses. SAS© Version 9.2 (SAS Institute, Inc., Cary, NC, United States) was used to perform all analyses.

RESULTS
Patient demographics and comorbidities

Of the 7800441 discharge records in the 2010 NIS, 314109 (4.0%) included a diagnosis describing any chronic liver disease (Figure 1). After excluding patients with diagnoses describing ethanol abuse, dependence, and/or overdose and those with other chronic liver diseases in addition to NAFLD, 32347 (0.4%) records contained the NAFLD diagnosis. Similarly, 271049 (3.5%) records included diagnosis codes describing other chronic liver diseasesand did not include NAFLD. When using discharge weighted analyses, 3.9% of all discharge records included a principal or secondary diagnosis describing any chronic liver disease. 0.4% and 3.4% records included diagnoses describing NAFLD and other chronic liver diseases excluding NAFLD, respectively.

Figure 1
Figure 1 Identification of nonalcoholic fatty liver disease and “other chronic liver diseases” subsamples from the Nationwide Inpatient Sample. NAFLD: Nonalcoholic fatty liver disease.

NAFLD patients were younger, more often female, and less often black compared to counterparts with other chronic liver diseases (Table 4). Diabetes mellitus, hypertension, obesity, and dyslipidemia were all more common among NAFLD patients. Nearly 29% of the patients in the NAFLD subsample had the metabolic syndrome. NAFLD patients were from higher income areas and more often had private health insurance. The average total hospital charge and length of hospital stay were significantly shorter than among patients with other chronic liver diseases. Rates of NAFLD intra-hospital mortality and advanced APRDRG mortality and disease severity scores were all significantly lower than among patients with other chronic liver diseases.

Table 4 Demographics and hospital outcomes of discharge records stratified by background liver disease n (%).
NAFLD (n = 32347)Other liver diseases (n = 271049)P valueMissing
Average age (yr)52.3 ± 16.555.3 ± 15.4< 0.00010
Female gender19027 (58.8)112788 (41.6)< 0.000178 (0.0003)
Non-elective admission25291 (78.4)231024 (85.4)< 0.0001521 (0.2)
Ethnicity< 0.000129349 (9.7)
White20536 (70.7)152778 (62.4)
Black2798 (9.6)45634 (18.6)
Hispanic4135 (14.2)32124 (13.1)
Asian/Pacific Islander592 (2.0)5720 (2.3)
Native American191 (0.7)2075 (0.9)
Other797 (2.7)6667 (2.7)
Diabetes mellitus14027 (43.4)78011 (28.9)< 0.0001
Hypertension18413 (56.9)129031 (47.6)< 0.0001
Obesity11920 (36.9)21677 (8.0)< 0.0001
Dyslipidemia12262 (37.9)42299 (15.6)< 0.0001
Metabolic syndrome9286 (28.7)23888 (8.8)< 0.0001
Location< 0.000113512 (4.4)
Central Metropolitan9115 (28.8)91426 (35.4)
Fringe Metropolitan8540 (27.0)58794 (22.8)
Metro below one million6003 (19.0)48308 (18.7)
50000-250000 population2563 (8.1)19519 (7.6)
Micropolitan3482 (11.0)24641 (9.5)
Other1948 (6.2)15545 (6.0)
Median zip code income ($)< 0.000113104 (4.3)
< 390008003 (25.3)89265 (34.5)
39000-479998140 (25.7)65082 (25.2)
48000-629998006 (25.3)58595 (22.7)
≥ 630007488 (23.7)45713 (17.7)
Primary payer< 0.0001870 (0.3)
Medicare10429 (32.3)104892 (38.8)
Medicaid4461 (13.8)65829 (24.4)
Private13602 (42.1)59410 (22.0)
Self-pay2454 (7.6)24729 (9.2)
No charge244 (0.8)2917 (1.1)
Other1107 (3.4)12452 (4.6)
Major operative procedure9804 (30.3)47187 (17.4)< 0.00010
Average total hospital charges ($)39607.3 ± 5251251665 ± 90685< 0.00010
Average length of hospital stay (d)4.7 ± 6.06.6 ± 9.7< 0.00010
Discharge disposition< 0.0001420 (0.001)
Routine25703 (79.5)167545 (61.9)
Acute care660 (2.0)9190 (3.4)
Another health facility2273 (7.0)39311 (14.5)
Home Health3114 (9.6)30276 (11.2)
AMA269 (0.8)7691 (2.8)
Other10 (0.03)479 (0.2)
Died in hospital301 (0.9)16154 (6.0)< 0.0001571 (0.2)
Aprdrg mortality risk< 0.0001347 (0.1)
Minor14347 (44.4)82849 (30.4)
Moderate11678 (36.1)84343 (31.1)
Major4921 (15.2)63614 (23.5)
Extreme1377 (4.3)40280 (14.9)
Aprdrg severity< 0.0001347 (0.1)
Minor functional loss814 (2.5)12242 (4.5)
Moderate functional loss18105 (56.0)88446 (32.6)
Major functional loss11156 (35.0)116365 (43.0)
Extreme functional loss2248 (7.0)53673 (19.8)
Associated Diagnoses
Abdominal Hernia3459 (10.7)12755 (4.7)< 0.0001
Appendiceal disorders254 (0.8)728 (0.3)< 0.0001
Benign anus-rectum disorders174 (0.5)1401 (0.5)0.62
Benign biliary disorders5421 (16.8)19306 (7.1)< 0.0001
Benign pancreatic disorders3379 (10.5)15898 (5.9)< 0.0001
Diverticular disease2845 (8.8)8697 (3.2)< 0.0001
Esophageal disorders (non-variceal)9114 (28.2)41835 (15.4)< 0.0001
Gastritis/duodenitis2163 (6.7)11220 (4.1)< 0.0001
Gastroduodenal ulcer1011 (3.1)7477 (2.8)0.002
Gastrointestinal hemorrhage1119 (3.5)23651 (8.7)< 0.0001
Gastrointestinal malignancies688 (2.1)6871 (2.5)< 0.0001
Hepatobiliary malignancies84 (0.3)7903 (2.9)< 0.0001
Inflammatory bowel disease555 (1.7)2659 (1.0)< 0.0001
Intestinal infection886 (2.7)5904 (2.2)< 0.0001
Intestinal obstruction1346 (4.2)7898 (2.9)< 0.0001
Peritonitis-abscess326 (1.0)5772 (2.1)< 0.0001
Principal discharge diagnoses
Appendicitis217 (0.7)554 (0.2)< 0.0001
Benign anus-rectal disorders163 (0.5)1694 (0.6)0.008
Benign pancreatitis2224 (6.9)7074 (2.6)< 0.0001
Diverticular disease898 (2.8)1805 (0.7)< 0.0001
Esophagitis306 (1.0)1762 (0.7)< 0.0001
Gallstone disorders2622 (8.1)5978 (2.2)< 0.0001
Gastroduodenal ulcer232 (0.7)2572 (1.0)< 0.0001
Gastroduodenitis713 (2.2)3481 (1.3)< 0.0001
Gastrointestinal malignancies338 (1.0)3017 (1.1)0.27
Hepatobiliary malignancies68 (0.2)2837 (1.1)< 0.0001
Hernia204 (0.6)1497 (0.6)0.07
Inflammatory bowel disease242 (0.8)696 (0.3)< 0.0001
Intestinal Infection235 (0.7)1999 (0.7)0.83
Associated gastrointestinal and pancreato-biliary disorders

As a principal or secondary (e.g., associated) diagnoses, abdominal hernia, appendiceal disorders, benign biliary and pancreatic disorders, diverticular disease, non-variceal esophageal disorders, gastritis/duodenitits, gastroduodenal ulcer, inflammatory bowel disease, and intestinal infection were all significantly more common among NAFLD patients (Table 5). Conversely, gastrointestinal and hepatobiliary malignancies, gastrointestinal hemorrhage, and peritonitis/intra-abdominal abscess were all more common among patients with other chronic liver diseases. NAFLD patients were more likely to have a principal diagnosis on discharge of appendicitis, benign pancreatitis, diverticular disease, esophagitis, gallstone disorders, gastroduodenitis, and inflammatory bowel disease. In contrast, benign ano-rectal disorders, gastroduodenal ulcers, and hepatobiliary cancers were more common among patients with other chronic liver diseases.

Table 5 Multivariable logistic regression for factors associated with nonalcoholic fatty liver disease compared to other liver diseases using associated diagnoses.
VariableP valueOR (95%CI)
Age (reference ≤ 70 yr)< 0.00010.79 (0.76-0.83)
Gender (reference female)< 0.00010.58 (0.57-0.60)
Diabetes< 0.00011.41 (1.37-1.45)
Hypertension0.050.97 (0.94-1.0)
Obesity< 0.00014.47 (4.34-4.61)
Dyslipidemia< 0.00012.35 (2.28-2.42)
Location (reference central metropolitan)< 0.0001
50000-250000 population1.2 (1.1-1.3)
Fringe metropolitan1.1 (1.1-1.2)
Metro 250000 - one million population1.2 (1.1-1.2)
Micropolitan1.4 (1.4-1.5)
Other1.4 (1.3-1.4)
Income (reference ≥ $63000)< 0.0001
$39000-$479990.80 (0.77-0.83)
$48000-$629990.86 (0.82-0.89)
< $390000.64 (0.62-0.67)
Payer (reference private insurance)< 0.0001
Medicaid0.42 (0.41-0.43)
Medicare0.46 (0.44-0.47)
No charge0.61 (0.53-0.70)
Other0.55 (0.51-0.59)
Self-pay0.65 (0.62-0.68)
Associated diagnoses
Abdominal hernia< 0.00011.70 (1.63-1.79)
Appendiceal disorders< 0.00012.58 (2.19-3.04)
Benign biliary disorders< 0.00012.11 (2.03-2.19)
Benign pancreatic disorders< 0.00011.57 (1.50-1.64)
Diverticular disease< 0.00012.22 (2.11-2.34)
Esophageal disorders (non-variceal)< 0.00011.52 (1.48-1.57)
Gastroduodenal ulcer< 0.00011.41(1.33-1.49)
Gastrointestinal hemorrhage< 0.00010.41 (0.38-0.44)
Gastrointestinal malignancies< 0.00010.83 (0.76-0.91)
Hepatobiliary malignancies< 0.00010.12 (0.10-0.15)
Inflammatory bowel disease< 0.00011.68 (1.52-1.86)
Intestinal infection< 0.00011.29 (1.19-1.40)
Intestinal obstruction< 0.00011.30 (1.22-1.39)
Peritonitis-abscess< 0.00010.47 (0.42-0.53)

All variables with statistically significant differences (P < 0.05) on univariable analysis (Table 4) were included in multivariable logistic regression models. When considering each gastrointestinal, hepatic, or pancreato-biliary diagnosis as an associated diagnosis, the patterns of association observed on univariable comparisons were maintained on multivariable logistic regression (Table 5). When considering each disorder as the principal diagnosis, appendicitis, benign pancreatitis, diverticular disease, esophagitis, gallstone disorders, Gastroduodenitis, and hernia were all associated with NAFLD on multivariable logistic regression (Table 6). Hepatobiliary cancers were independently associated with other liver diseases. In both analyses, female gender, younger patient age, diabetes mellitus, obesity, dyslipidemia, higher income, and private health insurance were independently associated with NAFLD.

Table 6 Multivariable logistic regression for factors associated with nonalcoholic fatty liver disease compared to other liver diseases using principal diagnoses.
VariableP valueOR (95%CI)
Age (reference ≤ 70 yr)< 0.00010.84 (0.81-0.88)
Gender (reference female)< 0.00010.55 (0.53-0.56)
Diabetes< 0.00011.38 (1.35-1.42)
Obesity< 0.00014.75 (4.61-4.89)
Dyslipidemia< 0.00012.51 (2.44-2.58)
Location (reference central metropolitan)< 0.0001
50000-250000 population1.21 (1.14-1.27)
Fringe metropolitan1.12 (1.09-1.17)
Metro 250000 - one million population1.15 (1.11-1.20)
Micropolitan1.44 (1.37-1.51)
Other1.37 (1.29-1.45)
Income (reference > $63000)< 0.0001
$39000-$479990.80 (0.77-0.83)
$48000-$630000.86 (0.83-0.89)
< $390000.64 (0.62-0.67)
Payer (reference private insurance)< 0.0001
Medicaid0.42 (0.40-0.43)
Medicare0.47 (0.46-0.49)
No charge0.60 (0.52-0.69)
Other0.54 (0.50-0.58)
Self-pay0.62(0.59-0.65)
Principal discharge diagnosis
Appendicitis< 0.00013.53 (2.96-4.22)
Benign pancreatitis< 0.00012.95 (2.79-3.12)
Diverticular disease< 0.00014.26 (3.89-4.67)
Esophagitis< 0.00011.69 (1.48-1.93)
Gallstone disorders< 0.00013.59 (3.40-3.79)
Gastroduodenitis< 0.00012.09 (1.91-2.29)
Hepatobiliary malignancies< 0.00010.29 (0.22-0.37)
Hernia0.011.23 (1.04-1.45)
Inflammatory bowel disease< 0.00013.64 (3.10-4.28)
Subgroup analysis for selected disorders

We performed subgroup analyses of records with a principal discharge diagnosis of diverticular disease, gallstone related disordersor benign pancreatitis. We chose these disorders because of their high prevalence in our sample. When stratified by type of background liver disease, similar differences in ethnicity, gender, comorbidities, health insurance payer, age, hospital charges, and income existed for each subgroupas in the overall sample (Table 7). As in the overall sample, total hospital charges, length of hospital stay, discharge disposition, rates of hospital death and APRDRG mortality and disease severity scores were all greater among patients with other chronic liver diseases in each subgroup.

Table 7 Demographics and hospital outcomes of discharge records of patients with a principal discharge diagnosis of diverticular disease, gallstone disease or benign pancreatitis stratified by background liver disease n (%).
Diverticular disease (n = 2703)
Gallstone disease (n = 8600)
Benign pancreatitis (n = 9298)
NAFLD (n = 898)OLD (n = 1805)P valueNAFLD (n = 2622)OLD (n = 5978)P valueNAFLD (n = 2224)OLD (n = 7074)P value
Average age (yr)55.1 ± 13.562.7 ± 14.2< 0.000150.5 ± 16.757.7 ± 17.4< 0.000147.8 ± 15.551.9 ± 14.0< 0.0001
Female Gender501 (55.8)897 (49.7)< 0.0031606 (61.3)3056 (51.2)< 0.00011058 (47.6)2796 (39.5)< 0.0001
Non-elective admission791 (88.3)1612 (89.5)0.362305 (88.4)5137 (86.0)< 0.00012110 (95.1)6680 (94.5)< 0.0001
Ethnicity< 0.0001< 0.0001< 0.0001
White610 (74.5)1174 (72.1)1575 (65.3)3532 (65.5)1376 (67.8)3910 (60.8)
Black48 (5.9)236 (14.5)166 (6.9)633 (11.7)196 (9.7)1355 (21.1)
Hispanic128 (15.7)159 (9.8)519 (21.5%)882 (16.4)339 (16.7)854 (13.3)
Other33 (4.0)60 (3.7)152 (6.3)344 (6.4)119 (5.9)313 (4.9)
Diabetes mellitus276 (30.7)440 (24.4)0.0004816 (31.1)1603 (26.8)< 0.0001984 (44.2)1974 (27.9)< 0.0001
Hypertension490 (54.6)1021 (56.6)0.321285 (49.0)2892 (48.4)< 0.00011222 (55.0)3524 (49.8)< 0.0001
Obesity252 (28.1)200 (11.1)< 0.00011010 (38.5)770 (12.9)< 0.0001680 (30.6)561 (7.9)< 0.0001
Dyslipidemia319 (35.5)451 (25.0)< 0.0001818 (31.2)1233 (20.6)< 0.00011093 (49.2)1359 (19.2)< 0.0001
Metabolic syndrome178 (19.8)195 (10.8)< 0.0001567 (21.6)638 (10.7)< 0.0001662 (29.8)721 (10.2)< 0.0001
Location0.02< 0.0001< 0.0001
Central Metro268 (30.6)537 (30.7)835 (32.5)1775 (30.7)603 (27.8)2184 (32.6)
Fringe Metro247 (28.2)436 (24.9)707 (27.5)1379 (23.9)600 (27.6)1554 (23.2)
Metro below one million185 (21.1)322 (18.4)505(19.7)1132 (19.6)406 (18.7)1373 (20.5)
50000-25000053 (6.1)147 (8.4)160 (6.2)427 (7.4)185 (8.5)536 (8.0)
Micropolitan81 (9.3)187 (10.7)237 (9.2)651 (11.3)238 (11.0)626 (9.3)
Other42 (4.8)119 (6.8)124 (4.8)411 (7.1)140 (6.5)437 (6.5)
Median zip code income ($)0.0008< 0.0001< 0.0001
< 39000202 (22.8)502 (28.5)632 (24.6)166 (28.9)556 (25.6)2334 (34.4)
39000-47999209 (23.5)437 (24.8)640 (24.9)1550 (26.9)534 (24.6)1734 (25.5)
48000-63000233 (26.2)445 (25.2)676 (26.3)1446 (25.1)564 (25.9)1527 (22.5)
> 63000244 (27.5)380 (21.5)618 (24.1)1107 (19.2)520 (23.9)1196 (17.6)
Primary payer< 0.0001< 0.0001< 0.0001
Medicare256 (28.5)866 (48.1)659 (25.2)2461 (41.2)523 (23.6)2028 (28.8)
Medicaid60 (6.7)181 (10.1)382 (14.6)1016 (17.0)320 (14.4)1682 (23.9)
Private469 (52.2)562 (31.2)1229 (46.9)1687 (28.3)971 (43.7)1742 (24.7)
Self-pay75 (8.4)119 (6.6)215 (8.2)531 (8.9)295 (13.3)1054 (15.0)
No charge6 (0.7)15 (0.8)27 (1.0)53 (0.9)24 (1.1)128 (1.8)
Other32 (3.6)58 (3.2)106 (4.1)219 (3.7)87 (3.9)418 (5.9)
Major operative procedure109 (12.1)333 (18.5)< 0.00012002 (76.4)3327 (55.7)< 0.0001294 (13.2)652 (9.2)< 0.0001
Average total hospital charges ($)26868.7 ± 26364.646666.9 ± 80222.8< 0.000140016.5 ± 32898.649682.8 ± 65425.9< 0.000132680.5 ± 42691.045115.5 ± 83193.4< 0.0001
Average length of hospital stay (d)4.2 ± 3.46.0 ± 8.3< 0.00014.0 ± 3.45.6 ± 6.1< 0.00014.9 ± 4.46.2 ± 8.4< 0.0001
Discharge Disposition< 0.0001< 0.0001< 0.0001
Routine821 (91.4)1355 (75.2)2403 (91.8)4492 (75.3)2013 (90.5)5396 (76.3)
Acute care2 (0.2)33 (1.8)32 (1.2)240 (4.0)45 (2.0)209 (3.0)
Another health facility25 (2.8)158 (8.8)66 (2.5)503 (8.4)47 (2.1)480 (6.8)
Home Health44 (4.9)184 (10.2)101 (3.9)487 (8.2)86 (3.9)361 (5.1)
AMA5 (0.6)17 (0.9)14 (0.5)81 (1.4)22 (1.0)325 (4.6)
Other03 (0.2) 07 (0.1)04 (0.1)
Died in hospital1 (0.1)53 (2.9)< 0.00013 (0.1)157 (2.6)< 0.000111 (0.5)296 (4.2)< 0.0001
APRDRG Mortality risk< 0.0001< 0.0001< 0.0001
Minor530 (59.0)783 (43.4)1457 (55.6)2123 (35.5)1177 (52.9)2658 (37.6)
Moderate278 (31.0)563 (31.2)936 (35.7)2095 (35.1)746 (33.5)2308 (32.6)
Major82 (9.1)291 (16.1)188 (7.2)1187 (19.9)238 (10.7)1318 (18.6)
Extreme8 (0.9)167 (9.3)37 (1.4)571 (9.6)61 (2.7)785 (11.1)
APRDRG Severity< 0.0001< 0.0001< 0.0001
Minor functional loss0163 (9.0)1 (0.04%)377 (6.3)1 (0.04)347 (4.9)
Moderate functional loss645 (71.8)747 (41.4)1828 (69.7)2371 (39.7)1318 (59.3)2721 (38.5)
Major functional loss231 (25.7)697 (38.6)715 (27.3)2393 (40.0)791 (35.6)2855 (40.4)
Extreme functional loss22197 (10.9)74835 (14.0)112 (5.0)1146 (16.2)
 -2.5  -2.8
DISCUSSION

The diagnosis of NAFLD among hospitalized patients is much less common compared to that noted in outpatient cohort studies[2-4]. Our findings that patients with NAFLD were more likely to be female, obese, and non-Black and more likely have diabetes mellitus, hypertension, dyslipidemia, and the metabolic syndrome compared to patients with other chronic liver diseases is in agreement with other studies[10,14-19]-suggesting that our methods to identify these patients were accurate. Similarly, patients with other liver diseases were more frequently from low-income regions and less likely to have private insurance as the primary health care payer; reflecting the higher prevalence of hepatitis C viral infections and alcohol abuse in low-income areas. The discrepancy in prevalence of NAFLD in outpatient series compared with hospitalized patients shows that NAFLD is under-recognized in hospital patients and that the impact of NAFLD on clinical outcomes and health care resource utilizationis unrecognized.

NAFLD is associated with several benign gastrointestinal and pancreato-biliary disorders. The exceptions were gastrointestinal hemorrhage and peritonitis, which are expected to occur in patients with decompensated liver disease and thus are less likely in NAFLD patients compared to those with other chronic liver diseases[10,14-19]. Several studies have established the role of bacterial translocation in nonalcoholic steatohepatitis and severe steatosis[20,21,31-33]. This could be a potential mechanism for which diverticular disorders in particular are more commonly associated with NAFLD compared to other chronic liver diseases[21].Our finding of the association between NAFLD and gallstone disease is in agreement that a recent Italian study which noted a high prevalence of gallstone disease among patients with NAFLD[22]. Other series have noted similar findings[23,34].

Patients with NAFLD have better hospital outcomes, less severe disease severity and mortality risk, and utilize fewer health care resources compared to patients with other chronic liver diseases (Table 4). These relationships occurred despite the fact that more NAFLD patients underwent major operations, and were maintained in subgroup analysis of diverticular disease, gallstone disease, and benign pancreatitis (Table 7). Given that hepatic related morbidity more often occurs with other chronic liver diseases (such as hepatitis C and alcoholic liver disease) compared to NAFLD[10,14-19], these findings suggest that the type and severity of background liver disease plays a vital role in determining overall patient outcomes and health care resource utilization.

There are several limitations to this study. It is unknown how background liver disease diagnoses were derived. Thus, the accuracy of NAFLD in this sample cannot be verified-especially when discharge abstracts used to construct this database were intended for reimbursement and not clinical research purposes. Similar problems regarding the accuracy of entered codes may exist when using ICD-9 diagnosis codes for elements of the metabolic syndrome, gastrointestinal disorders, and pancreato-biliary diseases. Distinctions between simple hepatic steatosis, steatohepatitis, and degrees of fibrosis cannot be made in the NIS. Because medications were not included in the NIS, we were not able to account for drug induced fatty liver disease. This limitation has minimal influence on our conclusions since less than 2% of steatohepatitis is drug induced[9]. We attempted to homogenize the NAFLD subsample by using only one ICD-9-DM identifier and eliminating any records listing any other major potential etiology of background liver disease. We focused on patients with any diagnosis of chronic liver disease and postulated that these patients are the most likely to have undergone evaluation for NAFLD. NAFLD may coexist with other chronic liver diseases in a minority of patients[35-37]. It is therefore possible that we may have included patients with undiagnosed NAFLD in the “other liver disease”sample. The NIS is a discharge level database where each entry represents a hospital admission and not an individual patient-thus multiple readmissions for a single patient may have biased our results.

In conclusion, NAFLD is widely under diagnosed among hospitalized patients in the United States. NAFLD is associated with diverticular, gallstone, and benign pancreatic disorders. The type of background liver disease is a key factor in hospital outcomes and healthcare resource utilization among hospitalized patients.

COMMENTS
Background

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the developed world. While prevalence proportions among outpatient series are well described, the proportion of hospitalized patients diagnosed with NAFLD is unknown. Moreover, associations of NAFLD to other gastrointestinal disorders are not well established.

Research frontiers

The important research hotspots related to this article include (1) the prevalence of NAFLD diagnosis among hospitalized patients; (2) outcomes among hospitalized patients with NAFLD; and (3) relationships between NAFLD and other gastrointestinal disorders.

Innovations and breakthroughs

Most prior reports examining the prevalence of NAFLD are based on outpatient or cohort registry studies-data regarding the prevalence of NAFLD among hospitalized patients are sparse. Few studies have examined hospital outcomes among patients with NAFLD-most focus on long-term survival related to hepatic or cardiovascular complications. Previous studies looking at associations between NAFLD and other gastrointestinal disorders are small, single institution based, and often biased by patient selection and particular care settings. To overcome these obstacles, the authors used a large database that provides an accurate estimate of the prevalence of NALFD diagnosis among hospitalized patients across the United States. Analyses of these data show that patients with NAFLD have a lower frequency of hospital mortality and consume fewer healthcare resources compared to those with other chronic liver diseases. Finally, authors’ study demonstrates that NAFLD is associated with diverticular, inflammatory bowel, gallstone, and benign pancreatitis disorders independent of demographics or other comorbidities.

Applications

The study results suggest that suggest that the type of background liver disease plays a vital role in determining overall patient outcomes and health care resource utilization among hospitalized patients. The results also suggest shared mechanisms of disease pathology between NAFLD and diverticular, inflammatory bowel, gallstone, and benign pancreatitis disorders.

Terminology

A principal diagnosis is the one diagnosis describing the main indication for admission and/or the condition which was the central focus of management during hospitalization. Associated diagnoses include the principal diagnosis, comorbid conditions, and disorders previously managed but not the focus of the particular hospitalization.

Peer review

The authors mentioned the prevalence of NAFLD and the associations between NAFLD and other common gastrointestinal and pancreato-biliary disorders among hospitalized patients. The authors also discussed the impact of NAFLD on healthcare resource utilization.

Footnotes

P- Reviewer: Celikbilek M S- Editor: Wen LL L- Editor:A E- Editor: Wang CH

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