High prevalence of functional dyspepsia in nonalcoholic fatty liver disease: a cross-sectional study

Abstract BACKGROUND: Gastrointestinal (GI) symptoms are frequent complaints from individuals with nonalcoholic fatty liver disease (NAFLD). Dyspepsia is a universal clinical symptom and is among the most common GI complaints observed in the general population, but its prevalence in the population with NAFLD has not been previously investigated. OBJECTIVE: To compare the prevalence of functional dyspepsia (FD) between patients with NAFLD and controls without liver disease. DESIGN AND SETTING: Cross-sectional study at the Outpatient Liver Clinic, University Hospital, Belo Horizonte, Brazil. METHODS: We included 96 NAFLD patients and 105 controls without liver disease. All participants were assessed for GI symptoms in accordance with the Rome III criteria. Evaluation methods included a questionnaire for FD (validated in Brazil), laboratory tests and upper GI endoscopy. RESULTS: Mean age and sex were similar between the groups. The NAFLD group presented higher frequency of proton-pump inhibitor usage (31.3% vs 4.8%; P < 0.001) and prevalence of FD (25.0% versus 12.4%; P = 0.021). The symptom frequencies were as follows: postprandial distress, 22.9% versus 11.4% (P = 0.030); postprandial fullness, 18.8% versus 10.5% (P = 0.095); early satiation, 8.3% versus 5.7% (P = 0.466); and epigastric pain or burning, 18.8% versus 5.7% (P = 0.004), in NAFLD patients and controls, respectively. Multivariate analysis demonstrated that female sex (odds ratio, OR 6.97; 95% confidence interval, CI: 1.51-32.12; P = 0.013) and NAFLD diagnosis (OR 2.45; 95% CI: 1.14-5.27; P = 0.021) were independently associated with FD occurrence. CONCLUSION: FD occurs more frequently in individuals with NAFLD than in controls without hepatic disease.


INTRODUCTION
Nonalcoholic fatty liver disease (NAFLD) is currently considered to be a public health problem in many countries, affecting both adults and children. This condition is characterized by hepatic steatosis, which is detected through ultrasound (US) or histological examination of the liver in individuals without a history of excessive alcohol consumption and with no other causes of liver disease. 1 NAFLD can progress to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocarcinoma. Obesity, insulin resistance, type 2 diabetes mellitus (DM) and other components of metabolic syndrome are common related comorbidities. 1 The global incidence of NAFLD is unknown since it depends on the population studied and on the methods used to diagnose this condition (e.g. liver biopsy, magnetic resonance spectroscopy or US). Despite these limitations, the prevalences of NAFLD and NASH in the general population in Western countries have been estimated to reach 20%-30% and 1%-3%, respectively. 1,2 NAFLD is considered to be a silent disease with asymptomatic evolution until its advanced stages. Studies have demonstrated a lack of specific symptoms in 45%-100% of patients. [3][4][5] The diagnosis is made unintentionally in asymptomatic patients through detecting elevated serum aminotransferase levels or steatosis on US performed as a routine test or during investigation of other comorbidities related to NAFLD. However, more recently, it has been suggested that NAFLD patients may present with multiple symptoms related to the gastrointestinal (GI) tract. For example, a high proportion of the patients with NAFLD that was incidentally detected through US examination initially sought medical attention due to the presence of functional GI symptoms. 6 Moreover, patients with functional dyspepsia (FD) who underwent US have also been described as having high prevalence of fatty liver. 7 Nevertheless, published data regarding the prevalence of GI symptoms specifically in the NAFLD population are scarce.
Dyspepsia is one of the most frequent GI symptoms observed in the general population. It is defined as a digestive disorder characterized by a set of symptoms related to the upper GI tract, such as pain, burning or discomfort in the upper abdomen, which may be associated with early satiety, postprandial nausea, vomiting, bloating or a feeling of abdominal distention. 8 The Rome III consensus defines FD as the presence of one or more of the following: epigastric pain or epigastric burning, bothersome postprandial fullness and early satiety with no evidence of a structural disease (including upper endoscopy evaluation) that would explain the symptoms. 9 Patients with these symptoms but without any structural disease upon diagnostic evaluation probably have FD, even though according to the Rome III guidelines, these criteria should be met during the last three months with symptom onset at least six months before the diagnosis.

OBJECTIVE
Considering the current increasing burden of NAFLD and the lack of knowledge regarding the characterization of GI symptoms in this population, we conducted this study to test the hypothesis that individuals with NAFLD have higher prevalence of FD than do subjects without fatty liver disease.

Study population and data collection
This cross-sectional study included 201 subjects who were prospectively selected between August 2015 and December 2016.

Rating of functional dyspepsia between the groups
The presence of GI symptoms was assessed by administering a questionnaire adapted from the criteria proposed in the Rome III 15 consensus, which has been validated for use in the Portuguese language. 16 The interpretation was also based on the Rome III definitions for functional disorders.  because they refused to undergo the procedure). Although FD and epigastric burning or pain occurred more frequently in the NAFLD patients, the frequencies of Helicobacter pylori infection, gastritis and pangastritis were similar in the two groups.

Characteristics of the patients
Out of the 27 NAFLD patients who underwent upper endoscopy, eight were diagnosed with Helicobacter pylori (29.6%) and were treated with conventional therapy. After six months of treatment, three of these patients achieved resolution of the dyspeptic symptoms, while the other five had persistent symptoms, despite undergoing a respiratory Helicobacter pylori test that confirmed that the treatment had been adequate. Patients with resolution after Helicobacter pylori eradication were not considered to have had FD. For better characterization of the patients with FD, we compared the individuals with and without FD inside each of the groups (i.e.
NAFLD and controls) according to age, sex and features of metabolic syndrome ( Table 3). Although the overall NAFLD group presented higher frequency of obese patients (

DISCUSSION
In this study, we found high prevalence of FD, according to the Rome III criteria, in the NAFLD group in comparison with its prevalence in the control group without hepatic disease. The frequency of FD was 25.0% in the NAFLD group and only 12.4% in the control group. The prevalence of FD in the control group was similar to what had previously been described in the general population, which ranged from 5.3% to 20.4%. 17 Although postprandial distress syndrome was more frequent among the patients with FD in the NAFLD group, the frequencies of early satiation and postprandial fullness were similar between the NAFLD and control individuals. The reasons for these findings are unknown and should be addressed in future studies.
Corroborating our findings, a recent study that included 195 patients with FD showed high prevalence of associated NAFLD (67%), diagnosed through US. 7 Our results also showed that a higher percentage of individuals with NAFLD used proton-pump inhibitors and had epigastric burning or pain complaints, than among the controls. To our knowledge, this was the first study evaluating FD according to the Rome III criteria among NAFLD patients. Two previous studies showed higher prevalence of GERD among NAFLD patients, 18,19 but no study had evaluated functional GI symptoms. We did not investigate functional heartburn because although all the patients with this complaint underwent endoscopy, they were not subjected to further investigations in order to make differential diagnoses regarding this condition. Thus, all the subjects with normal endoscopy results and complaints of heartburn were considered to have GERD. Interestingly, a recent meta-analysis showed high frequency of dyspepsia among subjects with GERD symptoms, which may suggest that that these conditions can overlap. 20 A heterogeneous group of pathophysiological mechanisms has been implicated in the pathogenesis of FD, including delayed gastric emptying, antral hypomotility, impaired intestinal motility, decreased gastric accommodation, increased visceral sensitivity, abnormal sensitivity to carbohydrates, poor fatty acid duodenal digestion, infiltration of the digestive tract by immune cells and psychological factors. Despite years of intense research, many controversies about the role of these factors and their causal relationship with FD symptoms remain to be elucidated. 20 Although the pathogenesis of NAFLD has not been fully elucidated, it is well known that this condition is strongly associated with insulin resistance, obesity and dyslipidemia. 1 Additionally, previous studies demonstrated that FD is associated with central obesity and DM. DM patients frequently report GI symptoms such as postprandial fullness, heartburn, bloating, abdominal pain, early satiety, vomiting and nausea. These symptoms were previously attributed to diabetic gastropathy as an expression of autonomic neuropathy; however, more recent data have suggested that those symptoms are probably due to multifactorial mechanisms. 21,22 Indeed, controversies regarding the association of DM with GI symptoms still exist. Some studies 23,24 did not show any differences in the prevalence of GI symptoms between individuals with and without DM, except for lower prevalence of heartburn in individuals with type 1 DM. In contrast, in other investigations, 25,26 subjects with DM reported significantly more GI symptoms than did control individuals without DM. However, those authors did not use the Rome III criteria for diagnosing FD. We did not find any association between FD and DM within the NAFLD group, or among the controls ( Table 3).
Female sex has also been associated with FD in diabetic and control populations. 26 It has been suggested that obesity may cause dyspeptic symptoms by means of different mechanisms, such as alterations in the function of GI neuropeptides; 27 excess visceral adiposity, which may increase intra-abdominal pressure; and secretion of adipokines and proinflammatory cytokines by visceral adipose tissue. 28 However, the epidemiological data linking obesity to functional GI disorders are inconsistent. 29 Although it is well established that obesity is associated with GERD, it remains unclear whether obesity is a risk factor for common functional GI disorders. 30 Recent studies have demonstrated an association between high BMI and increased risk of FD among females. 31,32 In the current study, we found an association between female sex and FD, thus corroborating the results from previous studies. Interestingly, one study identified a positive correlation between visceral adiposity and FD. Regarding GI symptoms, only epigastric pain was found to be associated with visceral adiposity. 33 Those results were different from ours, as our NAFLD patients and controls with FD did not present higher frequency of central obesity, considering each group individually ( Table 3).
Our study had limitations that should be noted. This strength is relevant in comparison with other observational studies in which the questionnaires were administered online or by telephone, or were handed to patients to be returned later. 31,34 Furthermore, we used the Rome III criteria instead of Rome IV because our team already had experience with its administration; and because Rome IV only presents minor changes in relation to Rome III. These changes were an attempt to increase the specificity of appropriate patient inclusion in clinical trials, whereas in clinical practice this precision may not be required. 35 Lastly, the controls did not undergo abdominal ultrasonography for diagnosing NAFLD. Thus, the study results may constitute an underestimation, considering that after excluding possible controls with undiagnosed NAFLD, the association between FD and the group with diagnosed fatty liver could even have been stronger than we found. Further studies are needed to confirm this.

CONCLUSION
In conclusion, the present study provides new evidence regarding the association between FD and NAFLD. The prevalence of FD was higher among individuals with NAFLD. Further studies are required in order to validate these observations and to establish optimal strategies for managing dyspeptic symptoms in these individuals.