Dig Dis Sci DOI 10.1007/s10620-014-3113-7
ORIGINAL ARTICLE
Nonalcoholic Fatty Liver Disease Increases Risk for Gastroesophageal Reflux Symptoms Roberto Catanzaro • Federica Calabrese • Sergio Occhipinti • Maria Grazia Anzalone • Angelo Italia • Michele Milazzo • Francesco Marotta
Received: 22 January 2014 / Accepted: 11 March 2014 Ó Springer Science+Business Media New York 2014
Abstract Background Nonalcoholic fatty liver disease (NAFLD) is now recognized as a leading cause of liver dysfunction. Gastroesophageal reflux disease (GERD) is a common disorder causing symptoms that often impair patients’ quality of life. In recent years, the prevalence of both these diseases has increased, partially overlapping the rise of metabolic disorders. Aims We investigated whether a relation does exist between NAFLD and GERD symptoms. Methods Cross-sectional study among 206 outpatients diagnosed with NAFLD and 183 controls. We collected clinical and laboratory data, assessed severity and R. Catanzaro (&) F. Calabrese S. Occhipinti M. G. Anzalone A. Italia M. Milazzo Section of Gastroenterology, Department of Medical and Pediatric Sciences, Institute of Internal Medicine ‘‘A. Francaviglia’’, University of Catania, ‘‘G. Rodolico’’ Hospital, Bldg. 4 - I Floor, Room 17, Via S. Sofia, 78, 95123 Catania, Italy e-mail: [email protected] F. Calabrese e-mail: [email protected] S. Occhipinti e-mail: [email protected] M. G. Anzalone e-mail: [email protected] A. Italia e-mail: [email protected] M. Milazzo e-mail: [email protected] F. Marotta ReGenera Research Group for Aging Intervention, Piazza Firenze, 12, 20154 Milan, Italy e-mail: [email protected]
frequency of GERD symptoms and the esophageal endoscopic pattern. Results The prevalence of GERD symptoms was higher in NAFLD patients than controls (61.2 vs. 27.9 %, p \ 0.001). We found a positive association between NAFLD and the experiencing of heartburn, regurgitation and belching. GERD symptoms were related to body mass index (BMI) and metabolic syndrome (MetS); a strong association persisted after adjustment for all the covariates (adjusted OR 3.49, 95 CI % 2.24–5.44, p \ 0.001). Conclusions Our data show that the prevalence of GERD typical symptoms is higher in patients with NAFLD. GERD was associated with higher BMI and MetS, but not with age and diabetes type 2. NAFLD remained strongly associated with GERD, independently of a coexisting MetS status. Consistent with these findings, MetS can be considered a shared background, but cannot completely explain this correlation. We suggest NAFLD as an independent risk factor for GERD symptoms. Keywords Nonalcoholic fatty liver Gastroesophageal reflux disease Obesity Metabolic syndrome
Introduction Nonalcoholic fatty liver disease (NAFLD) is defined as fatty accumulation exceeding 5 % of hepatocytes, without significant alcohol intake and any specific etiological liver disease [1]. It ranges from simple steatosis to steatohepatitis, progressive fibrosis and cirrhosis. Its prevalence is estimated at 25–30 %, and nowadays NAFLD is considered as the most common liver dysfunction worldwide and an important burden for public health. People with preexisting metabolic disorders such as obesity, type 2 diabetes,
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dyslipidemia and metabolic syndrome (MetS) are more likely to develop NAFLD [2–5]. Gastroesophageal reflux disease (GERD) is a chronic condition caused by gastric and duodenal content refluxing into the distal esophagus [6, 7]. GERD has a negative impact on the quality of life, related to symptom frequency and severity. Its prevalence has been rising rapidly to about 30 % in the general population, with an increasing overall incidence [8–10]. Looking through epidemiological and pathophysiological evidences, we wanted to investigate a potential relationship between the presence of NAFLD and the occurrence of GERD symptoms.
Methods Study Population We conducted a cross-sectional retrospective study among outpatients who came to the Gastroenterology Outpatient Clinic at Policlinico ‘‘G. Rodolico’’ in Catania—Italy, in the period between January 2012 and December 2013. We set the following inclusion criteria: (a) presence of fatty liver (FL) at abdominal ultrasonography, (b) absence of any liver disease other than NAFLD (i.e., viral, autoimmune, hemochromatosis, Wilson’s Disease, alpha 1-Antitrypsin deficiency, primary biliary cirrhosis, drug induced liver disease), (c) no alcohol consumption (less than 30 g alcohol/day for men and less than 20 g for women). A total of 206 outpatients met those criteria and constituted the NAFLD group. After exclusion of FL, 183 subjects were defined as the control group. In both the two groups, the diagnosis of FL was established or ruled out only based on the ultrasonographic evaluation. We found it neither necessary nor ethical to execute a liver biopsy. We conducted the study according to ethical guidelines, respecting patients’ privacy. The protocol was approved by the Institutional Review Board of Policlinico Universitario ‘‘G. Rodolico’’ in Catania, Italy. Medical History and Laboratory Data We recorded sex, age, weight and self-reported lifestyle (smoking, coffee and alcohol consumption) from all the patients. We collected some clinical and laboratory data in order to describe the metabolic profile of the subjects in the study: blood pressure, fasting plasma glucose, serum lipid profile (i.e., triglycerides, total cholesterol and high density lipoproteins-HDL), liver function tests, including aspartatetransaminase, alanine transaminase and c-glutamyl transpeptidase.
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Body mass index (BMI) was calculated as weight (kg)/ height (m2) and was used as index of body fat. Obesity was defined as a BMI C30 kg/m2, based on the World Health Organization (WHO) guidelines. MetS was diagnosed whenever a patient satisfied C3 criteria, according to the National Cholesterol Education Program Adult Treatment Panel III (ATPIII) criteria [11]. Assessment of GERD-Related Symptoms and Conditions We considered typical symptoms (heartburn, regurgitation, belching) and atypical symptoms, both esophageal (dysphagia, nausea and vomiting, sialorrhea, noncardiac chest pain) and extra-esophageal (chronic cough, hoarseness and dysphonia, epigastric pain). We assessed severity and frequency of reflux symptoms as patients referred during the visit. We included all patients experiencing one or more symptoms at least once per week. We classified a patient as having both heartburn and regurgitation, if he had previously received a diagnosis of GERD and was already in treatment with anti-reflux medications. Patients with clinical signs suggestive of complicated GERD (significant involuntary weight loss, persistent vomiting, bleeding, anemia) or extra-esophageal manifestations of reflux and those non-responding to appropriate medical therapy underwent an esophagogastroduodenoscopy, according to Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy guidelines [12]. We considered endoscopic assessment of lower esophageal sphincter (LES) incompetence, hiatal hernia, erosive esophagitis, gastritis and Helicobacter pylori infection. Statistical Analysis Categorical variables were presented as number (n) and percentage (%). Continuous variables were expressed as mean ± standard deviation (SD) when data were normally distributed, whereas median and interquartile range (IQR) were used for skewed samples. The assumption that data were normally distributed was tested using the Shapiro– Wilk test. The Pearson’s chi-square test with Yates’ continuity correction was used for comparisons of categorical variables. The Student’s t test or the Mann–Whitney U test was used for comparisons of continuous data, as appropriate. Logistic regression analysis was performed to assess the association between the presence of NAFLD and GERD symptoms, before and after adjustment for confounding factors. First, the Spearman’s rank correlation coefficient was used to examine the linearity among the
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variables. Results were presented as odds ratio (OR) and 95 % confidence interval (CI). The level of significance was set at p \ 0.05.
Results Characteristics of Participants Characteristics of participants are presented in Table 1. The NAFLD group included 206 outpatients, 85 males and 121 females, with a median age of 56 years (IQR 44–67). Controls were 183 subjects without FL, 71 males and 112 females, with a median age of 51 years (IQR 37–65). The two groups were similar in percentage of smokers and coffee drinkers. Patients in the NAFLD group presented significantly higher values of BMI, fasting blood glucose, total cholesterol and triglycerides and were more likely to have diabetes and MetS. HDL levels were significantly lower in the population with NAFLD. The endoscopic evaluation showed a higher prevalence of LES incompetence in the NAFLD group compared with controls (35.4 vs. 20.2 %, p \ 0.001). There were no significant differences about prevalence of erosive esophagitis (10.7 vs. 5.5 %, NS) and gastritis (23.3 vs. 26.2 %, NS). Patients with NAFLD were more likely to be in anti-reflux treatment (31.6 vs. 11.5 %, p \ 0.001). However, no differences were obtained concerning the use of PPIs (53.9 vs. 52.4 %, NS), antacids (24.6 vs. 19.0 %, NS) or PPIs plus antacids (21.5 vs. 28.6 %, NS) in the two groups (Table 1). GERD Symptoms Type and prevalence of GERD symptoms are displayed in Table 2. Patients with NAFLD were more likely to experience GERD symptoms than controls (61.2 vs. 27.9 %, p \ 0.001). In the NAFLD group, we found a higher prevalence of heartburn (48.5 vs. 18 %, p \ 0.001), regurgitation (38.3 vs. 16.9 %, p \ 0.001), both heartburn and regurgitation (34.5 vs. 15.3 %, p \ 0.001) and belching (38.3 vs. 17.5 %, p \ 0.001). Patients in the two groups were similar in some atypical symptoms: dysphagia (16.5 vs. 10.9 %, NS), sialorrhea (7.3 vs. 7.7 %, NS), chronic cough (11.7 vs. 8.7 %, NS), hoarseness and dysphonia (12.6 vs. 9.8 %, NS). In unadjusted analysis, NAFLD has been associated with GERD symptoms with a simple OR of 4.08 (95 % CI 2.66–6.25), with p \ 0.001. We found an OR of 4.29 (95 % CI 2.69–6.83) with p \ 0.001 for heartburn, an OR of 3.05 (95 % CI 1.89–4.92) with p \ 0.001 for regurgitation, an OR of 2.91 (95 % CI 1.77–4.77) with p \ 0.001
Table 1 Background characteristics of the study population Characteristics
NAFLD (n = 206)
Controls (n = 183)
p value
Sex: male/female
85 (41.3)/121 (58.7)
71 (38.8)/112 (61.2)
NS
Age (years)
56 (44–67)
51 (37–65)
\0.05
Current smoking Coffee drinking
30 (14.6) 163 (79.1)
29 (15.8) 144 (78.7)
NS NS
BMI (kg/m2)
28.07 (23.44–33)
22.03 (20.76–24.53)
\0.001
Obesity
82 (39.8)
15 (8.2)
\0.001
Hypertension
65 (31.6)
37 (20.2)
\0.05
Fasting glucose (mg/ dL)
93 (84–105)
89 (81–99)
\0.05
Diabetes
60 (29.1)
16 (8.7)
\0.001
Total cholesterol (mg/dL)
197 ± 49.72
175 (154–196)
\0.001
Hypercholesterolemia
91 (44.2)
40 (21.9)
\0.001
HDL
49 (42–57)
54 (48-66)
\0.001
l-HDL
73 (35.4)
32 (17.5)
\0.001
Triglycerides (mg/ dL)
122 (81–187)
83 (61–108)
\0.001
Hypertriglyceridemia
83 (40.3)
12 (6.6)
\0.001
Metabolic syndrome
52 (25.2)
8 (4.4)
\0.001
AST ALT
24 (18–35) 29 (18–48)
20 (17–25) 20 (15–28)
\0.001 \0.001
cGT
28 (17–52)
17 (12–25)
\0.001
Upper GI endoscopy
100 (53.4)
85 (46.4)
NS
LES incompetence
73 (35.4)
37 (20.2)
\0.001
Hiatal hernia
28 (13.6)
13 (7.1)
\0.05
GERD
49 (23.8)
22 (12)
\0.05
Erosive esophagitis
22 (10.7)
10 (5.5)
NS
Gastritis
48 (23.3)
48 (26.2)
NS
H. Pylori infection
25 (12.1)
22 (12)
NS
Anti-reflux treatment
65 (31.6)
21 (11.5)
\0.001
PPIs
35 (53.9)
11 (52.4)
NS
Antacids
16 (24.6)
4 (19.0)
NS
PPIs ? antacids
14 (21.5)
6 (28.6)
NS
Categorical values are number (n) and percentage (%). Continuous variables are median and interquartile range (IQR) or mean ± standard deviation (SD) NAFLD nonalcoholic fatty liver disease, BMI body mass index, HDL high density lipoproteins, l-HDL low level of high density lipoproteins, AST aspartate-transaminase, ALT alanine transaminase, cGT c-glutamyl transpeptidase, GI gastrointestinal, LES lower esophageal sphincter, GERD gastroesophageal reflux disease, H. Pylori Helicobacter pylori, PPIs proton-pump inhibitors
for both heartburn and regurgitation and an OR of 2.93 (95 % CI 1.83–4.71) with p \ 0.001 for belching (Table 3).
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Dig Dis Sci Table 2 Type and prevalence of reported gastroesophageal reflux symptoms in the study population
Table 4 Association between nonalcoholic fatty liver disease and the presence of one or more gastroesophageal reflux symptom(s)
Symptoms
NAFLD (n = 206)
CONTROLS (n = 183)
p value
OR (95 % CI)
For 1 or more symptom(s)
p value
Unadjusted OR
4.08 (2.66–6.25)
\0.001
Heartburn
100 (48.5)
33 (18)
\0.001
Adjusted OR for age and BMI
3.25 (2.03–5.21)
\0.001
Adjusted OR for MetS factors
3.49 (2.24–5.44)
\0.001
Regurgitation
79 (38.3)
31 (16.9)
\0.001
Heartburn and regurgitation
71 (34.5)
28 (15.3)
\0.001
Belching
79 (38.3)
32 (17.5)
\0.001
Dysphagia
34 (16.5)
20 (10.9)
NS
Nausea and vomiting
39 (18.9)
21 (11.5)
\0.05
Sialorrhea
15 (7.3)
14 (7.7)
NS
Noncardiac chest pain
21 (10.2)
5 (2.7)
\0.05
Epigastric pain
66 (32)
40 (21.9)
\0.05
Chronic cough Hoarseness and dysphonia
24 (11.7) 26 (12.6)
16 (8.7) 18 (9.8)
NS NS
A high BMI was found as a risk factor for experiencing reflux symptoms (26.7 vs. 23.0, p \ 0.05). Once NAFLD was introduced, the correlation with age was no longer significant (OR 1.01, 95 % CI 0.99–1.03, NS), but BMI remained weakly related (OR 1.05, 95 % CI 1.03–1.09, p \ 0.05).
126 (61.2)
51 (27.9)
\0.001
GERD Symptoms and Confounding Factors in NAFLD
1 or more symptom(s)
Values are number (n) and percentage (%) NAFLD nonalcoholic fatty liver disease
Table 3 Association between nonalcoholic fatty liver disease and the prevalence of various gastroesophageal reflux symptoms Symptoms
Unadjusted OR (95 % CI)
p value
Heartburn
4.29 (2.69–6.83)
\0.001
Regurgitation
3.05 (1.89–4.92)
\0.001
Heartburn and regurgitation
2.91 (1.77–4.77)
\0.001
Belching
2.93 (1.83–4.71)
\0.001
Dysphagia
1.61 (0.89–2.91)
NS
Nausea and vomiting
1.8 (1.02–3.19)
\0.05
Sialorrhea Noncardiac chest pain
0.95 (0.44–2.02) 4.04 (1.49–10.95)
NS \0.05
Epigastric pain
1.68 (1.07–2.66)
\0.05
Chronic cough
1.38 (0.7–2.68)
NS
Hoarseness and dysphonia
1.32 (0.7–2.5)
NS
1 or more symptom(s)
4.08 (2.66–6.25)
\0.001
Results of logistic regression analysis
Results of logistic regression analysis OR odd ratio, CI confidence interval, BMI body mass index, MetS metabolic syndrome
We identified factors reasonably involved in the pathogenesis of NAFLD within the study population: obesity, diabetes, hypertriglyceridemia, low level of HDL (l-HDL) and MetS were all included. Therefore, we searched for a possible association between those factors and the occurrence of GERD symptoms. The chi-square test pointed out a highly significant relationship between GERD symptoms and both obesity (61.9 vs. 40.1 %, p \ 0.001) and MetS (70 vs. 41 %, p \ 0.001) and a weakly relationship with l-HDL (55.2 vs. 41.9 %, p \ 0.05). Neither diabetes (46.1 vs. 45.4 %, NS) nor hypertriglyceridemia (52.6 vs. 43.2 %, NS) were related. In the NAFLD group, obesity (OR 1.82, 95 % CI 1.01–3.3, p \ 0.05) and MetS (OR 1.96, 95 % CI 1.05–3.7, p \ 0.05) remained significantly related to GERD symptoms. Finally, the presence of NAFLD was evidenced as a predictive factor for development of reflux symptoms, independently from age and BMI with an adjusted OR of 3.25 (95 % CI 2.03–5.21), with p \ 0.001 and independently from MetS factors, with an adjusted OR of 3.49 (95 % CI 2.24–5.44), with p \ 0.001 (Table 4).
OR odd ratio, CI confidence interval
Discussion GERD Symptoms by Sex, Age, and BMI We evaluated GERD symptoms within all the population, in relation to sex, age and BMI, by comparative analysis among subclasses. There were no statistically significant differences between males and females (respectively, 40.4 vs. 48.9 %, NS), whereas a higher prevalence of symptoms was observed in older subjects (58 vs. 51 years, p \ 0.05).
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In this study, we aimed to investigate the prevalence of GERD symptoms in patients diagnosed with NAFLD. Our results provided evidence that a higher prevalence of typical GERD symptoms (e.g., heartburn and regurgitation) is significantly associated with NAFLD (about 60 % in the NAFLD group vs about 30 % in the control group). Patients with NAFLD have shown up to a four-times higher risk of developing symptoms
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than controls, and this association persisted after adjustment for potential confounding factors, including BMI and other components of MetS. Even if it has been considered as a related risk factor for GERD, the presence of type 2 diabetes is not statistically significant in our study [13, 14]. On the other hand, no relevant differences were shown within atypical reflux symptoms. The finding of a low prevalence of erosive esophagitis suggested that simple steatosis is not directly related with a higher severity of disease. Findings of our study raise the question of whether NAFLD may be involved in the pathogenesis of reflux. In our subpopulation with NAFLD, the prevalence of GERD symptoms was influenced by BMI, but not sex and age. A coexisting MetS status seemed to be linked to a higher prevalence of symptoms, and among its related disorders, obesity and l-HDL were involved too. Therefore, our results are consistent with previous studies suggesting a link between GERD and both obesity and MetS, through changes in lifestyle and pandemic of obesity [15–20]. Several factors can be involved. Visceral obesity can be considered as a mechanical factor for the appearance of GERD symptoms. Increased intra-gastric pressure and trans-esophageal pressure gradient can induce anatomic alteration of the gastroesophageal junction, including shortening of LES length and development of hiatal hernia with consequently reflux [15, 20–22]. High-fat diet or excessive caloric intake, that are long-term responsible for an increase in weight and obesity, can determine frequency and severity of esophageal exposure to acid, reducing LES pressure and increasing the number of transient LES relaxations [21, 23–25]. It has been also demonstrated that the introduction of lipids within the duodenum can increase esophagus sensitivity to acid and that is recognized as a pathogenic factor for non-erosive reflux disease [26, 27]. Cytokines, such as IL-8 and platelet-activating factor (PAF), have been found to be overexpressed in the esophageal mucosa of GERD patients [28–33]. Thus, it has been hypothesized that a cytokine-mediated mechanism, in addition to a direct effect of gastric juice reflux, is responsible for both hypersensitivity to intra-luminal stimuli and mucosal damage [29, 34, 35]. As adipose tissue and resident macrophages are known to produce a variety of cytokines [36–41], inflammation in obesity can be supposed too in triggering esophageal injury. Moreover, even independently from obesity, higher serum levels of IL-6 and IL-8 have been shown in both animal models and patients with NAFLD [42–44]. Lastly, overweight has been directly associated with increased oxidative damage, and it has been reported that obese adults with MetS have higher plasma concentration of oxidative stress biomarkers [40, 45–47]. At the same time, reactive oxygen species (ROS) have been implicated in the pathogenesis of various gastrointestinal diseases,
including GERD [48]. Increase in sensitivity to H2O2 and lipid peroxidation were observed in GERD patients compared with controls [49, 50], suggesting a combination of acid exposure and subsequent ROS generation in worsening mucosal damage [51, 52]. Indeed, it is well known that ROS may contribute in hepatocellular injury and inflammation, and various sources of increased ROS production have been proven, even systemic, such as circulating free fatty acids, iron overload, dysfunctional mitochondria and intestinal bacterial overgrowth [46, 53–58]. One of the possible objections for the association we found could be that our observations are simply confounded by the shared background of obesity and MetS. Our study, however, identifies a strong association between NAFLD and GERD symptoms independently of MetS and its other features. Therefore, obesity and MetS have to be reasonably considered as playing their role but cannot completely explain the correlation between those diseases, and it has to be still investigated. Nevertheless, the results of this study have some limitations. We have reported our single-center experience and our population cannot be considered strictly representative of the general population, as our patients all came for gastroenterological problems. We based on anamnestic evaluation of symptoms and used only BMI to assess obesity; no highly accurate diagnostic tools have been used for steatosis (e.g., liver biopsy). In conclusion, our results demonstrate a significant correlation between NAFLD and the appearance of both heartburn and regurgitation, and it can be partially explained by coexisting MetS and some factors involved in its pathogenesis (high BMI and l-HDL). These findings are consistent with reported trends and are partially supported by some similar recent studies [59, 60]. Further studies are warranted to help understanding underlying mechanisms and maybe contribute to eventual developments of new prevention and treatment strategies. Conflict of interest
None.
References 1. Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, RoudotThoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58:593–608. 2. Tarantino G, Saldalamacchia G, Conca P, Arena A. Non-alcoholic fatty liver disease: further expression of the metabolic syndrome. J Gastroenterol Hepatol. 2007;22:293–303. 3. Kopec KL, Burns D. Nonalcoholic fatty liver disease: a review of the spectrum of disease, diagnosis, and therapy. Nutr Clin Pract. 2011;26:565–576. 4. Attar BM, Van Thiel DH. Current concepts and management approaches in nonalcoholic fatty liver disease. Sci World J. 2013;2013:481893.
123
Dig Dis Sci 5. Obika M, Noguchi H. Diagnosis and evaluation of nonalcoholic fatty liver disease. Exp Diabetes Res. 2012;2012:145754. 6. Lipan MJ, Reidenberg JS, Laitman JT. Anatomy of reflux: a growing health problem affecting structures of the head and neck. Anat Rec B New Anat. 2006;289:261–270. 7. Wu P, Zhao XH, Ai ZS, et al. Dietary intake and risk for reflux esophagitis: a case-control study. Gastroenterol Res Pract. 2013;2013:691026. 8. Ronkainen J, Agre´us L. Epidemiology of reflux symptoms and GORD. Best Pract Res Clin Gastroenterol. 2013;27:325–337. 9. El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2013. doi:10.1136/gutjnl-2012-304269. 10. Camilleri M, Dubois D, Coulie B, et al. Prevalence and socioeconomic impact of upper gastrointestinal disorders in the United States: results of the US Upper Gastrointestinal Study. Clin Gastroenterol Hepatol. 2005;3:543–552. 11. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143–3421. 12. Standards of Practice Committee, Lichtenstein DR, Cash BD, et al. Role of endoscopy in the management of GERD. Gastrointest Endosc. 2007;66(2):219–24. 13. Krishnan B, Babu S, Walker J, Walker AB, Pappachan JM. Gastrointestinal complications of diabetes mellitus. World J Diabetes. 2013;4:51–63. 14. Promberger R, Lenglinger J, Riedl O, et al. Gastro-oesophageal reflux disease in type 2 diabetics: symptom load and pathophysiologic aspects—a retro-pro study. BMC Gastroenterol. 2013;13:132. 15. Ayazi S, Hagen JA, Chan LS, et al. Obesity and gastroesophageal reflux: quantifying the association between body mass index, esophageal acid exposure, and lower esophageal sphincter status in a large series of patients with reflux symptoms. J Gastrointest Surg. 2009;13:1440–1447. 16. Hampel H, Abraham NS, El-Serag HB. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann Intern Med. 2005;143:199–211. 17. El-Serag HB, Graham DY, Satia JA, Rabeneck L. Obesity is an independent risk factor for GERD symptoms and erosive esophagitis. Am J Gastroenterol. 2005;100:1243–1250. 18. Ierardi E, Rosania R, Zotti M, et al. Metabolic syndrome and gastroesophageal reflux: a link towards a growing interest in developed countries. World J Gastrointest Pathophysiol. 2010;1:91–96. 19. Lee YC, Yen AM, Tai JJ, et al. The effect of metabolic risk factors on the natural course of gastro-oesophageal reflux disease. Gut. 2009;58:174–181. 20. Festi D, Scaioli E, Baldi F, et al. Body weight, lifestyle, dietary habits and gastroesophageal reflux disease. World J Gastroenterol. 2009;15:1690–1701. 21. Jung HS, Choi MG, Baeg MK, et al. Obesity is associated with increasing esophageal acid exposure in Korean patients with gastroesophageal reflux disease symptoms. J Neurogastroenterol Motil. 2013;19:338–343. 22. Hajar N, Castell DO, Ghomrawi H, Rackett R, Hila A. Impedance pH confirms the relationship between GERD and BMI. Dig Dis Sci. 2012;57:1875–1879. 23. Fox M, Barr C, Nolan S, Lomer M, Anggiansah A, Wong T. The effects of dietary fat and calorie density on esophageal acid exposure and reflux symptoms. Clin Gastroenterol Hepatol. 2007;5:439–444. 24. Wu JC, Mui LM, Cheung CM, Chan Y, Sung JJ. Obesity is associated with increased transient lower esophageal sphincter relaxation. Gastroenterology. 2007;132:883–889.
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25. Shapiro M, Green C, Bautista JM, et al. Assessment of dietary nutrients that influence perception of intra-oesophageal acid reflux events in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2007;25:93–101. 26. Lacy BE, Carter J, Weiss JE, et al. The effects of intraduodenal nutrient infusion on serum CCK, LES pressure, and gastroesophageal reflux. Neurogastroenterol Motil. 2011;23(7):631–e256. 27. Holloway RH, Lyrenas E, Ireland A, Dent J. Effect of intraduodenal fat on lower oesophageal sphincter function and gastrooesophageal reflux. Gut. 1997;40:449–453. 28. Altomare A, Ma J, Guarino MP, et al. Platelet-activating factor and distinct chemokines are elevated in mucosal biopsies of erosive compared with non-erosive reflux disease patients and controls. Neurogastroenterol Motil. 2012;24(10):943–e463. 29. Souza RF, Huo X, Mittal V, et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology. 2009;137:1776–1784. 30. Mo¨nkemu¨ller K, Wex T, Kuester D, et al. Interleukin-1beta and interleukin-8 expression correlate with the histomorphological changes in esophageal mucosa of patients with erosive and nonerosive reflux disease. Digestion. 2009;79:186–195. 31. Rieder F, Cheng L, Harnett KM, et al. Gastroesophageal reflux disease-associated esophagitis induces endogenous cytokine production leading to motor abnormalities. Gastroenterology. 2007;132:154–165. 32. Yoshida N, Uchiyama K, Kuroda M, et al. Interleukin-8 expression in the esophageal mucosa of patients with gastroesophageal reflux disease. Scand J Gastroenterol. 2004;39:816–822. 33. Isomoto H, Saenko VA, Kanazawa Y, et al. Enhanced expression of interleukin-8 and activation of nuclear factor kappa-B in endoscopy-negative gastroesophageal reflux disease. Am J Gastroenterol. 2004;99:589–597. 34. Ma J, Altomare A, de la Monte S, et al. HCl-induced inflammatory mediators in esophageal mucosa increase migration and production of H2O2 by peripheral blood leukocytes. Am J Physiol Gastrointest Liver Physiol. 2010;299:G791–G798. 35. Tutuian R, Castell DO. Review article: complete gastro-oesophageal reflux monitoring—combined pH and impedance. Aliment Pharmacol Ther. 2006;24:27–37. 36. McGown C, Birerdinc A, Younossi ZM. Adipose tissue as an endocrine organ. Clin Liver Dis. 2014;18:41–58. 37. Coelho M, Oliveira T, Fernandes R. Biochemistry of adipose tissue: an endocrine organ. Arch Med Sci. 2013;9:191–200. 38. Kwon H, Pessin JE. Adipokines mediate inflammation and insulin resistance. Front Endocrinol. 2013;4:71. 39. Haase J, Weyer U, Immig K, et al. Local proliferation of macrophages in adipose tissue during obesity-induced inflammation. Diabetologia. 2013. doi:10.1007/s00125-013-3139-y. 40. Blu¨her M. Adipose tissue dysfunction contributes to obesity related metabolic diseases. Best Pract Res Clin Endocrinol Metab. 2013;27:163–177. 41. Harwood HJ Jr. The adipocyte as an endocrine organ in the regulation of metabolic homeostasis. Neuropharmacology. 2012;63:57–75. 42. Braunersreuther V, Viviani GL, Mach F, Montecucco F. Role of cytokines and chemokines in non-alcoholic fatty liver disease. World J Gastroenterol. 2012;18:727–735. 43. Jarrar MH, Baranova A, Collantes R, et al. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2008;27:412–421. 44. Garcı´a-Galiano D, Sa´nchez-Garrido MA, Espejo I, et al. IL-6 and IGF-1 are independent prognostic factors of liver steatosis and non-alcoholic steatohepatitis in morbidly obese patients. Obes Surg. 2007;17:493–503. 45. Karbownik-Lewinska M, Szosland J, et al. Direct contribution of obesity to oxidative damage to macromolecules. Neuro Endocrinol Lett. 2012;33:453–461.
Dig Dis Sci 46. Palmieri VO, Grattagliano I, Portincasa P, Palasciano G. Systemic oxidative alterations are associated with visceral adiposity and liver steatosis in patients with metabolic syndrome. J Nutr. 2006;136:3022–3026. 47. Furukawa S, Fujita T, Shimabukuro M, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114:1752–1761. 48. Kim YJ, Kim EH, Hahm KB. Oxidative stress in inflammationbased gastrointestinal tract diseases: challenges and opportunities. J Gastroenterol Hepatol. 2012;27:1004–1010. 49. Erbil Y, Tu¨rkoglu U, Barbaros U, et al. Oxidative damage in an experimentally induced gastric and gastroduodenal reflux model. Surg Innov. 2005;12:219–225. 50. Wetscher GJ, Hinder RA, Bagchi D, et al. Reflux esophagitis in humans is mediated by oxygen-derived free radicals. Am J Surg. 1995;170(6):552–556; discussion 556–557. 51. Farhadi A, Fields J, Banan A, Keshavarzian A. Reactive oxygen species: are they involved in the pathogenesis of GERD, Barrett’s esophagus, and the latter’s progression toward esophageal cancer? Am J Gastroenterol. 2002;97:22–26. 52. Oh TY, Lee JS, Ahn BO, et al. Oxidative damages are critical in pathogenesis of reflux esophagitis: implication of antioxidants in its treatment. Free Radic Biol Med. 2001;30:905–915. 53. Basaranoglu M, Basaranoglu G, Sentu¨rk H. From fatty liver to fibrosis: a tale of ‘‘second hit’’. World J Gastroenterol. 2013;19: 1158–1165.
54. Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury: present concepts. J Gastroenterol Hepatol. 2011;26: 173–179. 55. Seki S, Kitada T, Sakaguchi H, et al. Clinicopathological significance of oxidative cellular damage in non-alcoholic fatty liver diseases. Hepatol Res. 2005;33:132–134. 56. Chalasani N, Deeg MA, Crabb DW. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2004;99: 1497–1502. 57. Van de Wier B, Balk JM, Haenen GR, et al. Elevated citrate levels in non-alcoholic fatty liver disease: the potential of citrate to promote radical production. FEBS Lett. 2013;587:2461–2466. 58. Duseja A, Chawla YK. Obesity and NAFLD: the role of bacteria and microbiota. Clin Liver Dis. 2014;18:59–71. 59. Miele L, Cammarota G, Vero V, et al. Non-alcoholic fatty liver disease is associated with high prevalence of gastro-oesophageal reflux symptoms. Dig Liver Dis. 2012;44:1032–1036. 60. Fujikawa Y, Tominaga K, Fujii H, et al. High prevalence of gastroesophageal reflux symptoms in Patients with non-alcoholic fatty liver disease associated with serum levels of triglyceride and cholesterol but not simple visceral obesity. Digestion. 2012;86: 228–237.
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ORIGINAL ARTICLE
Nonalcoholic Fatty Liver Disease Increases Risk for Gastroesophageal Reflux Symptoms Roberto Catanzaro • Federica Calabrese • Sergio Occhipinti • Maria Grazia Anzalone • Angelo Italia • Michele Milazzo • Francesco Marotta
Received: 22 January 2014 / Accepted: 11 March 2014 Ó Springer Science+Business Media New York 2014
Abstract Background Nonalcoholic fatty liver disease (NAFLD) is now recognized as a leading cause of liver dysfunction. Gastroesophageal reflux disease (GERD) is a common disorder causing symptoms that often impair patients’ quality of life. In recent years, the prevalence of both these diseases has increased, partially overlapping the rise of metabolic disorders. Aims We investigated whether a relation does exist between NAFLD and GERD symptoms. Methods Cross-sectional study among 206 outpatients diagnosed with NAFLD and 183 controls. We collected clinical and laboratory data, assessed severity and R. Catanzaro (&) F. Calabrese S. Occhipinti M. G. Anzalone A. Italia M. Milazzo Section of Gastroenterology, Department of Medical and Pediatric Sciences, Institute of Internal Medicine ‘‘A. Francaviglia’’, University of Catania, ‘‘G. Rodolico’’ Hospital, Bldg. 4 - I Floor, Room 17, Via S. Sofia, 78, 95123 Catania, Italy e-mail: [email protected] F. Calabrese e-mail: [email protected] S. Occhipinti e-mail: [email protected] M. G. Anzalone e-mail: [email protected] A. Italia e-mail: [email protected] M. Milazzo e-mail: [email protected] F. Marotta ReGenera Research Group for Aging Intervention, Piazza Firenze, 12, 20154 Milan, Italy e-mail: [email protected]
frequency of GERD symptoms and the esophageal endoscopic pattern. Results The prevalence of GERD symptoms was higher in NAFLD patients than controls (61.2 vs. 27.9 %, p \ 0.001). We found a positive association between NAFLD and the experiencing of heartburn, regurgitation and belching. GERD symptoms were related to body mass index (BMI) and metabolic syndrome (MetS); a strong association persisted after adjustment for all the covariates (adjusted OR 3.49, 95 CI % 2.24–5.44, p \ 0.001). Conclusions Our data show that the prevalence of GERD typical symptoms is higher in patients with NAFLD. GERD was associated with higher BMI and MetS, but not with age and diabetes type 2. NAFLD remained strongly associated with GERD, independently of a coexisting MetS status. Consistent with these findings, MetS can be considered a shared background, but cannot completely explain this correlation. We suggest NAFLD as an independent risk factor for GERD symptoms. Keywords Nonalcoholic fatty liver Gastroesophageal reflux disease Obesity Metabolic syndrome
Introduction Nonalcoholic fatty liver disease (NAFLD) is defined as fatty accumulation exceeding 5 % of hepatocytes, without significant alcohol intake and any specific etiological liver disease [1]. It ranges from simple steatosis to steatohepatitis, progressive fibrosis and cirrhosis. Its prevalence is estimated at 25–30 %, and nowadays NAFLD is considered as the most common liver dysfunction worldwide and an important burden for public health. People with preexisting metabolic disorders such as obesity, type 2 diabetes,
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dyslipidemia and metabolic syndrome (MetS) are more likely to develop NAFLD [2–5]. Gastroesophageal reflux disease (GERD) is a chronic condition caused by gastric and duodenal content refluxing into the distal esophagus [6, 7]. GERD has a negative impact on the quality of life, related to symptom frequency and severity. Its prevalence has been rising rapidly to about 30 % in the general population, with an increasing overall incidence [8–10]. Looking through epidemiological and pathophysiological evidences, we wanted to investigate a potential relationship between the presence of NAFLD and the occurrence of GERD symptoms.
Methods Study Population We conducted a cross-sectional retrospective study among outpatients who came to the Gastroenterology Outpatient Clinic at Policlinico ‘‘G. Rodolico’’ in Catania—Italy, in the period between January 2012 and December 2013. We set the following inclusion criteria: (a) presence of fatty liver (FL) at abdominal ultrasonography, (b) absence of any liver disease other than NAFLD (i.e., viral, autoimmune, hemochromatosis, Wilson’s Disease, alpha 1-Antitrypsin deficiency, primary biliary cirrhosis, drug induced liver disease), (c) no alcohol consumption (less than 30 g alcohol/day for men and less than 20 g for women). A total of 206 outpatients met those criteria and constituted the NAFLD group. After exclusion of FL, 183 subjects were defined as the control group. In both the two groups, the diagnosis of FL was established or ruled out only based on the ultrasonographic evaluation. We found it neither necessary nor ethical to execute a liver biopsy. We conducted the study according to ethical guidelines, respecting patients’ privacy. The protocol was approved by the Institutional Review Board of Policlinico Universitario ‘‘G. Rodolico’’ in Catania, Italy. Medical History and Laboratory Data We recorded sex, age, weight and self-reported lifestyle (smoking, coffee and alcohol consumption) from all the patients. We collected some clinical and laboratory data in order to describe the metabolic profile of the subjects in the study: blood pressure, fasting plasma glucose, serum lipid profile (i.e., triglycerides, total cholesterol and high density lipoproteins-HDL), liver function tests, including aspartatetransaminase, alanine transaminase and c-glutamyl transpeptidase.
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Body mass index (BMI) was calculated as weight (kg)/ height (m2) and was used as index of body fat. Obesity was defined as a BMI C30 kg/m2, based on the World Health Organization (WHO) guidelines. MetS was diagnosed whenever a patient satisfied C3 criteria, according to the National Cholesterol Education Program Adult Treatment Panel III (ATPIII) criteria [11]. Assessment of GERD-Related Symptoms and Conditions We considered typical symptoms (heartburn, regurgitation, belching) and atypical symptoms, both esophageal (dysphagia, nausea and vomiting, sialorrhea, noncardiac chest pain) and extra-esophageal (chronic cough, hoarseness and dysphonia, epigastric pain). We assessed severity and frequency of reflux symptoms as patients referred during the visit. We included all patients experiencing one or more symptoms at least once per week. We classified a patient as having both heartburn and regurgitation, if he had previously received a diagnosis of GERD and was already in treatment with anti-reflux medications. Patients with clinical signs suggestive of complicated GERD (significant involuntary weight loss, persistent vomiting, bleeding, anemia) or extra-esophageal manifestations of reflux and those non-responding to appropriate medical therapy underwent an esophagogastroduodenoscopy, according to Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy guidelines [12]. We considered endoscopic assessment of lower esophageal sphincter (LES) incompetence, hiatal hernia, erosive esophagitis, gastritis and Helicobacter pylori infection. Statistical Analysis Categorical variables were presented as number (n) and percentage (%). Continuous variables were expressed as mean ± standard deviation (SD) when data were normally distributed, whereas median and interquartile range (IQR) were used for skewed samples. The assumption that data were normally distributed was tested using the Shapiro– Wilk test. The Pearson’s chi-square test with Yates’ continuity correction was used for comparisons of categorical variables. The Student’s t test or the Mann–Whitney U test was used for comparisons of continuous data, as appropriate. Logistic regression analysis was performed to assess the association between the presence of NAFLD and GERD symptoms, before and after adjustment for confounding factors. First, the Spearman’s rank correlation coefficient was used to examine the linearity among the
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variables. Results were presented as odds ratio (OR) and 95 % confidence interval (CI). The level of significance was set at p \ 0.05.
Results Characteristics of Participants Characteristics of participants are presented in Table 1. The NAFLD group included 206 outpatients, 85 males and 121 females, with a median age of 56 years (IQR 44–67). Controls were 183 subjects without FL, 71 males and 112 females, with a median age of 51 years (IQR 37–65). The two groups were similar in percentage of smokers and coffee drinkers. Patients in the NAFLD group presented significantly higher values of BMI, fasting blood glucose, total cholesterol and triglycerides and were more likely to have diabetes and MetS. HDL levels were significantly lower in the population with NAFLD. The endoscopic evaluation showed a higher prevalence of LES incompetence in the NAFLD group compared with controls (35.4 vs. 20.2 %, p \ 0.001). There were no significant differences about prevalence of erosive esophagitis (10.7 vs. 5.5 %, NS) and gastritis (23.3 vs. 26.2 %, NS). Patients with NAFLD were more likely to be in anti-reflux treatment (31.6 vs. 11.5 %, p \ 0.001). However, no differences were obtained concerning the use of PPIs (53.9 vs. 52.4 %, NS), antacids (24.6 vs. 19.0 %, NS) or PPIs plus antacids (21.5 vs. 28.6 %, NS) in the two groups (Table 1). GERD Symptoms Type and prevalence of GERD symptoms are displayed in Table 2. Patients with NAFLD were more likely to experience GERD symptoms than controls (61.2 vs. 27.9 %, p \ 0.001). In the NAFLD group, we found a higher prevalence of heartburn (48.5 vs. 18 %, p \ 0.001), regurgitation (38.3 vs. 16.9 %, p \ 0.001), both heartburn and regurgitation (34.5 vs. 15.3 %, p \ 0.001) and belching (38.3 vs. 17.5 %, p \ 0.001). Patients in the two groups were similar in some atypical symptoms: dysphagia (16.5 vs. 10.9 %, NS), sialorrhea (7.3 vs. 7.7 %, NS), chronic cough (11.7 vs. 8.7 %, NS), hoarseness and dysphonia (12.6 vs. 9.8 %, NS). In unadjusted analysis, NAFLD has been associated with GERD symptoms with a simple OR of 4.08 (95 % CI 2.66–6.25), with p \ 0.001. We found an OR of 4.29 (95 % CI 2.69–6.83) with p \ 0.001 for heartburn, an OR of 3.05 (95 % CI 1.89–4.92) with p \ 0.001 for regurgitation, an OR of 2.91 (95 % CI 1.77–4.77) with p \ 0.001
Table 1 Background characteristics of the study population Characteristics
NAFLD (n = 206)
Controls (n = 183)
p value
Sex: male/female
85 (41.3)/121 (58.7)
71 (38.8)/112 (61.2)
NS
Age (years)
56 (44–67)
51 (37–65)
\0.05
Current smoking Coffee drinking
30 (14.6) 163 (79.1)
29 (15.8) 144 (78.7)
NS NS
BMI (kg/m2)
28.07 (23.44–33)
22.03 (20.76–24.53)
\0.001
Obesity
82 (39.8)
15 (8.2)
\0.001
Hypertension
65 (31.6)
37 (20.2)
\0.05
Fasting glucose (mg/ dL)
93 (84–105)
89 (81–99)
\0.05
Diabetes
60 (29.1)
16 (8.7)
\0.001
Total cholesterol (mg/dL)
197 ± 49.72
175 (154–196)
\0.001
Hypercholesterolemia
91 (44.2)
40 (21.9)
\0.001
HDL
49 (42–57)
54 (48-66)
\0.001
l-HDL
73 (35.4)
32 (17.5)
\0.001
Triglycerides (mg/ dL)
122 (81–187)
83 (61–108)
\0.001
Hypertriglyceridemia
83 (40.3)
12 (6.6)
\0.001
Metabolic syndrome
52 (25.2)
8 (4.4)
\0.001
AST ALT
24 (18–35) 29 (18–48)
20 (17–25) 20 (15–28)
\0.001 \0.001
cGT
28 (17–52)
17 (12–25)
\0.001
Upper GI endoscopy
100 (53.4)
85 (46.4)
NS
LES incompetence
73 (35.4)
37 (20.2)
\0.001
Hiatal hernia
28 (13.6)
13 (7.1)
\0.05
GERD
49 (23.8)
22 (12)
\0.05
Erosive esophagitis
22 (10.7)
10 (5.5)
NS
Gastritis
48 (23.3)
48 (26.2)
NS
H. Pylori infection
25 (12.1)
22 (12)
NS
Anti-reflux treatment
65 (31.6)
21 (11.5)
\0.001
PPIs
35 (53.9)
11 (52.4)
NS
Antacids
16 (24.6)
4 (19.0)
NS
PPIs ? antacids
14 (21.5)
6 (28.6)
NS
Categorical values are number (n) and percentage (%). Continuous variables are median and interquartile range (IQR) or mean ± standard deviation (SD) NAFLD nonalcoholic fatty liver disease, BMI body mass index, HDL high density lipoproteins, l-HDL low level of high density lipoproteins, AST aspartate-transaminase, ALT alanine transaminase, cGT c-glutamyl transpeptidase, GI gastrointestinal, LES lower esophageal sphincter, GERD gastroesophageal reflux disease, H. Pylori Helicobacter pylori, PPIs proton-pump inhibitors
for both heartburn and regurgitation and an OR of 2.93 (95 % CI 1.83–4.71) with p \ 0.001 for belching (Table 3).
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Dig Dis Sci Table 2 Type and prevalence of reported gastroesophageal reflux symptoms in the study population
Table 4 Association between nonalcoholic fatty liver disease and the presence of one or more gastroesophageal reflux symptom(s)
Symptoms
NAFLD (n = 206)
CONTROLS (n = 183)
p value
OR (95 % CI)
For 1 or more symptom(s)
p value
Unadjusted OR
4.08 (2.66–6.25)
\0.001
Heartburn
100 (48.5)
33 (18)
\0.001
Adjusted OR for age and BMI
3.25 (2.03–5.21)
\0.001
Adjusted OR for MetS factors
3.49 (2.24–5.44)
\0.001
Regurgitation
79 (38.3)
31 (16.9)
\0.001
Heartburn and regurgitation
71 (34.5)
28 (15.3)
\0.001
Belching
79 (38.3)
32 (17.5)
\0.001
Dysphagia
34 (16.5)
20 (10.9)
NS
Nausea and vomiting
39 (18.9)
21 (11.5)
\0.05
Sialorrhea
15 (7.3)
14 (7.7)
NS
Noncardiac chest pain
21 (10.2)
5 (2.7)
\0.05
Epigastric pain
66 (32)
40 (21.9)
\0.05
Chronic cough Hoarseness and dysphonia
24 (11.7) 26 (12.6)
16 (8.7) 18 (9.8)
NS NS
A high BMI was found as a risk factor for experiencing reflux symptoms (26.7 vs. 23.0, p \ 0.05). Once NAFLD was introduced, the correlation with age was no longer significant (OR 1.01, 95 % CI 0.99–1.03, NS), but BMI remained weakly related (OR 1.05, 95 % CI 1.03–1.09, p \ 0.05).
126 (61.2)
51 (27.9)
\0.001
GERD Symptoms and Confounding Factors in NAFLD
1 or more symptom(s)
Values are number (n) and percentage (%) NAFLD nonalcoholic fatty liver disease
Table 3 Association between nonalcoholic fatty liver disease and the prevalence of various gastroesophageal reflux symptoms Symptoms
Unadjusted OR (95 % CI)
p value
Heartburn
4.29 (2.69–6.83)
\0.001
Regurgitation
3.05 (1.89–4.92)
\0.001
Heartburn and regurgitation
2.91 (1.77–4.77)
\0.001
Belching
2.93 (1.83–4.71)
\0.001
Dysphagia
1.61 (0.89–2.91)
NS
Nausea and vomiting
1.8 (1.02–3.19)
\0.05
Sialorrhea Noncardiac chest pain
0.95 (0.44–2.02) 4.04 (1.49–10.95)
NS \0.05
Epigastric pain
1.68 (1.07–2.66)
\0.05
Chronic cough
1.38 (0.7–2.68)
NS
Hoarseness and dysphonia
1.32 (0.7–2.5)
NS
1 or more symptom(s)
4.08 (2.66–6.25)
\0.001
Results of logistic regression analysis
Results of logistic regression analysis OR odd ratio, CI confidence interval, BMI body mass index, MetS metabolic syndrome
We identified factors reasonably involved in the pathogenesis of NAFLD within the study population: obesity, diabetes, hypertriglyceridemia, low level of HDL (l-HDL) and MetS were all included. Therefore, we searched for a possible association between those factors and the occurrence of GERD symptoms. The chi-square test pointed out a highly significant relationship between GERD symptoms and both obesity (61.9 vs. 40.1 %, p \ 0.001) and MetS (70 vs. 41 %, p \ 0.001) and a weakly relationship with l-HDL (55.2 vs. 41.9 %, p \ 0.05). Neither diabetes (46.1 vs. 45.4 %, NS) nor hypertriglyceridemia (52.6 vs. 43.2 %, NS) were related. In the NAFLD group, obesity (OR 1.82, 95 % CI 1.01–3.3, p \ 0.05) and MetS (OR 1.96, 95 % CI 1.05–3.7, p \ 0.05) remained significantly related to GERD symptoms. Finally, the presence of NAFLD was evidenced as a predictive factor for development of reflux symptoms, independently from age and BMI with an adjusted OR of 3.25 (95 % CI 2.03–5.21), with p \ 0.001 and independently from MetS factors, with an adjusted OR of 3.49 (95 % CI 2.24–5.44), with p \ 0.001 (Table 4).
OR odd ratio, CI confidence interval
Discussion GERD Symptoms by Sex, Age, and BMI We evaluated GERD symptoms within all the population, in relation to sex, age and BMI, by comparative analysis among subclasses. There were no statistically significant differences between males and females (respectively, 40.4 vs. 48.9 %, NS), whereas a higher prevalence of symptoms was observed in older subjects (58 vs. 51 years, p \ 0.05).
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In this study, we aimed to investigate the prevalence of GERD symptoms in patients diagnosed with NAFLD. Our results provided evidence that a higher prevalence of typical GERD symptoms (e.g., heartburn and regurgitation) is significantly associated with NAFLD (about 60 % in the NAFLD group vs about 30 % in the control group). Patients with NAFLD have shown up to a four-times higher risk of developing symptoms
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than controls, and this association persisted after adjustment for potential confounding factors, including BMI and other components of MetS. Even if it has been considered as a related risk factor for GERD, the presence of type 2 diabetes is not statistically significant in our study [13, 14]. On the other hand, no relevant differences were shown within atypical reflux symptoms. The finding of a low prevalence of erosive esophagitis suggested that simple steatosis is not directly related with a higher severity of disease. Findings of our study raise the question of whether NAFLD may be involved in the pathogenesis of reflux. In our subpopulation with NAFLD, the prevalence of GERD symptoms was influenced by BMI, but not sex and age. A coexisting MetS status seemed to be linked to a higher prevalence of symptoms, and among its related disorders, obesity and l-HDL were involved too. Therefore, our results are consistent with previous studies suggesting a link between GERD and both obesity and MetS, through changes in lifestyle and pandemic of obesity [15–20]. Several factors can be involved. Visceral obesity can be considered as a mechanical factor for the appearance of GERD symptoms. Increased intra-gastric pressure and trans-esophageal pressure gradient can induce anatomic alteration of the gastroesophageal junction, including shortening of LES length and development of hiatal hernia with consequently reflux [15, 20–22]. High-fat diet or excessive caloric intake, that are long-term responsible for an increase in weight and obesity, can determine frequency and severity of esophageal exposure to acid, reducing LES pressure and increasing the number of transient LES relaxations [21, 23–25]. It has been also demonstrated that the introduction of lipids within the duodenum can increase esophagus sensitivity to acid and that is recognized as a pathogenic factor for non-erosive reflux disease [26, 27]. Cytokines, such as IL-8 and platelet-activating factor (PAF), have been found to be overexpressed in the esophageal mucosa of GERD patients [28–33]. Thus, it has been hypothesized that a cytokine-mediated mechanism, in addition to a direct effect of gastric juice reflux, is responsible for both hypersensitivity to intra-luminal stimuli and mucosal damage [29, 34, 35]. As adipose tissue and resident macrophages are known to produce a variety of cytokines [36–41], inflammation in obesity can be supposed too in triggering esophageal injury. Moreover, even independently from obesity, higher serum levels of IL-6 and IL-8 have been shown in both animal models and patients with NAFLD [42–44]. Lastly, overweight has been directly associated with increased oxidative damage, and it has been reported that obese adults with MetS have higher plasma concentration of oxidative stress biomarkers [40, 45–47]. At the same time, reactive oxygen species (ROS) have been implicated in the pathogenesis of various gastrointestinal diseases,
including GERD [48]. Increase in sensitivity to H2O2 and lipid peroxidation were observed in GERD patients compared with controls [49, 50], suggesting a combination of acid exposure and subsequent ROS generation in worsening mucosal damage [51, 52]. Indeed, it is well known that ROS may contribute in hepatocellular injury and inflammation, and various sources of increased ROS production have been proven, even systemic, such as circulating free fatty acids, iron overload, dysfunctional mitochondria and intestinal bacterial overgrowth [46, 53–58]. One of the possible objections for the association we found could be that our observations are simply confounded by the shared background of obesity and MetS. Our study, however, identifies a strong association between NAFLD and GERD symptoms independently of MetS and its other features. Therefore, obesity and MetS have to be reasonably considered as playing their role but cannot completely explain the correlation between those diseases, and it has to be still investigated. Nevertheless, the results of this study have some limitations. We have reported our single-center experience and our population cannot be considered strictly representative of the general population, as our patients all came for gastroenterological problems. We based on anamnestic evaluation of symptoms and used only BMI to assess obesity; no highly accurate diagnostic tools have been used for steatosis (e.g., liver biopsy). In conclusion, our results demonstrate a significant correlation between NAFLD and the appearance of both heartburn and regurgitation, and it can be partially explained by coexisting MetS and some factors involved in its pathogenesis (high BMI and l-HDL). These findings are consistent with reported trends and are partially supported by some similar recent studies [59, 60]. Further studies are warranted to help understanding underlying mechanisms and maybe contribute to eventual developments of new prevention and treatment strategies. Conflict of interest
None.
References 1. Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, RoudotThoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58:593–608. 2. Tarantino G, Saldalamacchia G, Conca P, Arena A. Non-alcoholic fatty liver disease: further expression of the metabolic syndrome. J Gastroenterol Hepatol. 2007;22:293–303. 3. Kopec KL, Burns D. Nonalcoholic fatty liver disease: a review of the spectrum of disease, diagnosis, and therapy. Nutr Clin Pract. 2011;26:565–576. 4. Attar BM, Van Thiel DH. Current concepts and management approaches in nonalcoholic fatty liver disease. Sci World J. 2013;2013:481893.
123
Dig Dis Sci 5. Obika M, Noguchi H. Diagnosis and evaluation of nonalcoholic fatty liver disease. Exp Diabetes Res. 2012;2012:145754. 6. Lipan MJ, Reidenberg JS, Laitman JT. Anatomy of reflux: a growing health problem affecting structures of the head and neck. Anat Rec B New Anat. 2006;289:261–270. 7. Wu P, Zhao XH, Ai ZS, et al. Dietary intake and risk for reflux esophagitis: a case-control study. Gastroenterol Res Pract. 2013;2013:691026. 8. Ronkainen J, Agre´us L. Epidemiology of reflux symptoms and GORD. Best Pract Res Clin Gastroenterol. 2013;27:325–337. 9. El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2013. doi:10.1136/gutjnl-2012-304269. 10. Camilleri M, Dubois D, Coulie B, et al. Prevalence and socioeconomic impact of upper gastrointestinal disorders in the United States: results of the US Upper Gastrointestinal Study. Clin Gastroenterol Hepatol. 2005;3:543–552. 11. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143–3421. 12. Standards of Practice Committee, Lichtenstein DR, Cash BD, et al. Role of endoscopy in the management of GERD. Gastrointest Endosc. 2007;66(2):219–24. 13. Krishnan B, Babu S, Walker J, Walker AB, Pappachan JM. Gastrointestinal complications of diabetes mellitus. World J Diabetes. 2013;4:51–63. 14. Promberger R, Lenglinger J, Riedl O, et al. Gastro-oesophageal reflux disease in type 2 diabetics: symptom load and pathophysiologic aspects—a retro-pro study. BMC Gastroenterol. 2013;13:132. 15. Ayazi S, Hagen JA, Chan LS, et al. Obesity and gastroesophageal reflux: quantifying the association between body mass index, esophageal acid exposure, and lower esophageal sphincter status in a large series of patients with reflux symptoms. J Gastrointest Surg. 2009;13:1440–1447. 16. Hampel H, Abraham NS, El-Serag HB. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann Intern Med. 2005;143:199–211. 17. El-Serag HB, Graham DY, Satia JA, Rabeneck L. Obesity is an independent risk factor for GERD symptoms and erosive esophagitis. Am J Gastroenterol. 2005;100:1243–1250. 18. Ierardi E, Rosania R, Zotti M, et al. Metabolic syndrome and gastroesophageal reflux: a link towards a growing interest in developed countries. World J Gastrointest Pathophysiol. 2010;1:91–96. 19. Lee YC, Yen AM, Tai JJ, et al. The effect of metabolic risk factors on the natural course of gastro-oesophageal reflux disease. Gut. 2009;58:174–181. 20. Festi D, Scaioli E, Baldi F, et al. Body weight, lifestyle, dietary habits and gastroesophageal reflux disease. World J Gastroenterol. 2009;15:1690–1701. 21. Jung HS, Choi MG, Baeg MK, et al. Obesity is associated with increasing esophageal acid exposure in Korean patients with gastroesophageal reflux disease symptoms. J Neurogastroenterol Motil. 2013;19:338–343. 22. Hajar N, Castell DO, Ghomrawi H, Rackett R, Hila A. Impedance pH confirms the relationship between GERD and BMI. Dig Dis Sci. 2012;57:1875–1879. 23. Fox M, Barr C, Nolan S, Lomer M, Anggiansah A, Wong T. The effects of dietary fat and calorie density on esophageal acid exposure and reflux symptoms. Clin Gastroenterol Hepatol. 2007;5:439–444. 24. Wu JC, Mui LM, Cheung CM, Chan Y, Sung JJ. Obesity is associated with increased transient lower esophageal sphincter relaxation. Gastroenterology. 2007;132:883–889.
123
25. Shapiro M, Green C, Bautista JM, et al. Assessment of dietary nutrients that influence perception of intra-oesophageal acid reflux events in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2007;25:93–101. 26. Lacy BE, Carter J, Weiss JE, et al. The effects of intraduodenal nutrient infusion on serum CCK, LES pressure, and gastroesophageal reflux. Neurogastroenterol Motil. 2011;23(7):631–e256. 27. Holloway RH, Lyrenas E, Ireland A, Dent J. Effect of intraduodenal fat on lower oesophageal sphincter function and gastrooesophageal reflux. Gut. 1997;40:449–453. 28. Altomare A, Ma J, Guarino MP, et al. Platelet-activating factor and distinct chemokines are elevated in mucosal biopsies of erosive compared with non-erosive reflux disease patients and controls. Neurogastroenterol Motil. 2012;24(10):943–e463. 29. Souza RF, Huo X, Mittal V, et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology. 2009;137:1776–1784. 30. Mo¨nkemu¨ller K, Wex T, Kuester D, et al. Interleukin-1beta and interleukin-8 expression correlate with the histomorphological changes in esophageal mucosa of patients with erosive and nonerosive reflux disease. Digestion. 2009;79:186–195. 31. Rieder F, Cheng L, Harnett KM, et al. Gastroesophageal reflux disease-associated esophagitis induces endogenous cytokine production leading to motor abnormalities. Gastroenterology. 2007;132:154–165. 32. Yoshida N, Uchiyama K, Kuroda M, et al. Interleukin-8 expression in the esophageal mucosa of patients with gastroesophageal reflux disease. Scand J Gastroenterol. 2004;39:816–822. 33. Isomoto H, Saenko VA, Kanazawa Y, et al. Enhanced expression of interleukin-8 and activation of nuclear factor kappa-B in endoscopy-negative gastroesophageal reflux disease. Am J Gastroenterol. 2004;99:589–597. 34. Ma J, Altomare A, de la Monte S, et al. HCl-induced inflammatory mediators in esophageal mucosa increase migration and production of H2O2 by peripheral blood leukocytes. Am J Physiol Gastrointest Liver Physiol. 2010;299:G791–G798. 35. Tutuian R, Castell DO. Review article: complete gastro-oesophageal reflux monitoring—combined pH and impedance. Aliment Pharmacol Ther. 2006;24:27–37. 36. McGown C, Birerdinc A, Younossi ZM. Adipose tissue as an endocrine organ. Clin Liver Dis. 2014;18:41–58. 37. Coelho M, Oliveira T, Fernandes R. Biochemistry of adipose tissue: an endocrine organ. Arch Med Sci. 2013;9:191–200. 38. Kwon H, Pessin JE. Adipokines mediate inflammation and insulin resistance. Front Endocrinol. 2013;4:71. 39. Haase J, Weyer U, Immig K, et al. Local proliferation of macrophages in adipose tissue during obesity-induced inflammation. Diabetologia. 2013. doi:10.1007/s00125-013-3139-y. 40. Blu¨her M. Adipose tissue dysfunction contributes to obesity related metabolic diseases. Best Pract Res Clin Endocrinol Metab. 2013;27:163–177. 41. Harwood HJ Jr. The adipocyte as an endocrine organ in the regulation of metabolic homeostasis. Neuropharmacology. 2012;63:57–75. 42. Braunersreuther V, Viviani GL, Mach F, Montecucco F. Role of cytokines and chemokines in non-alcoholic fatty liver disease. World J Gastroenterol. 2012;18:727–735. 43. Jarrar MH, Baranova A, Collantes R, et al. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2008;27:412–421. 44. Garcı´a-Galiano D, Sa´nchez-Garrido MA, Espejo I, et al. IL-6 and IGF-1 are independent prognostic factors of liver steatosis and non-alcoholic steatohepatitis in morbidly obese patients. Obes Surg. 2007;17:493–503. 45. Karbownik-Lewinska M, Szosland J, et al. Direct contribution of obesity to oxidative damage to macromolecules. Neuro Endocrinol Lett. 2012;33:453–461.
Dig Dis Sci 46. Palmieri VO, Grattagliano I, Portincasa P, Palasciano G. Systemic oxidative alterations are associated with visceral adiposity and liver steatosis in patients with metabolic syndrome. J Nutr. 2006;136:3022–3026. 47. Furukawa S, Fujita T, Shimabukuro M, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114:1752–1761. 48. Kim YJ, Kim EH, Hahm KB. Oxidative stress in inflammationbased gastrointestinal tract diseases: challenges and opportunities. J Gastroenterol Hepatol. 2012;27:1004–1010. 49. Erbil Y, Tu¨rkoglu U, Barbaros U, et al. Oxidative damage in an experimentally induced gastric and gastroduodenal reflux model. Surg Innov. 2005;12:219–225. 50. Wetscher GJ, Hinder RA, Bagchi D, et al. Reflux esophagitis in humans is mediated by oxygen-derived free radicals. Am J Surg. 1995;170(6):552–556; discussion 556–557. 51. Farhadi A, Fields J, Banan A, Keshavarzian A. Reactive oxygen species: are they involved in the pathogenesis of GERD, Barrett’s esophagus, and the latter’s progression toward esophageal cancer? Am J Gastroenterol. 2002;97:22–26. 52. Oh TY, Lee JS, Ahn BO, et al. Oxidative damages are critical in pathogenesis of reflux esophagitis: implication of antioxidants in its treatment. Free Radic Biol Med. 2001;30:905–915. 53. Basaranoglu M, Basaranoglu G, Sentu¨rk H. From fatty liver to fibrosis: a tale of ‘‘second hit’’. World J Gastroenterol. 2013;19: 1158–1165.
54. Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury: present concepts. J Gastroenterol Hepatol. 2011;26: 173–179. 55. Seki S, Kitada T, Sakaguchi H, et al. Clinicopathological significance of oxidative cellular damage in non-alcoholic fatty liver diseases. Hepatol Res. 2005;33:132–134. 56. Chalasani N, Deeg MA, Crabb DW. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2004;99: 1497–1502. 57. Van de Wier B, Balk JM, Haenen GR, et al. Elevated citrate levels in non-alcoholic fatty liver disease: the potential of citrate to promote radical production. FEBS Lett. 2013;587:2461–2466. 58. Duseja A, Chawla YK. Obesity and NAFLD: the role of bacteria and microbiota. Clin Liver Dis. 2014;18:59–71. 59. Miele L, Cammarota G, Vero V, et al. Non-alcoholic fatty liver disease is associated with high prevalence of gastro-oesophageal reflux symptoms. Dig Liver Dis. 2012;44:1032–1036. 60. Fujikawa Y, Tominaga K, Fujii H, et al. High prevalence of gastroesophageal reflux symptoms in Patients with non-alcoholic fatty liver disease associated with serum levels of triglyceride and cholesterol but not simple visceral obesity. Digestion. 2012;86: 228–237.
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