Abstract
BACKGROUND:
Patients with chronic hepatitis C virus (HCV) usually have different abdominal complaints without any organic lesions. The functional cause of these complaints is claimed in most patients. This study aimed to evaluate functional gastrointestinal disorders (FGIDs) in patients with chronic hepatitis C using Rome IV diagnostic criteria.
METHODS:
This study included 1506 participants (1006 patients with chronic HCV, and 500 controls). All individuals were subjected to taking thorough medical history, basic investigations (complete blood counts, liver and renal functions tests), international normalized ratio (INR), alpha-fetoprotein, HCV RNA PCR (polymerase chain reaction), abdominal ultrasonography, and upper gastrointestinal tract (GIT) endoscopy for patients only), and Rome IV diagnostic questionnaire.
RESULTS:
Patients with HCV had symptoms of FGIDs including functional dyspepsia (FD) (P=0.009), early satiety (P=0.002), postprandial distress (P=0.02), epigastric pain (P=0.03), Inflammatory bowel syndrome (IBS) (P<0.001), IBS predominant constipation (P<0.001), IBS predominant diarrhea (P<0.001), and IBS mixed (P<0.001). There were multiple factors for the prediction of FD in patients with HCV, including high body mass index (BMI), education level, positive polymerase chain reaction (PCR), and fibrosis stage. Also, there were multiple factors for the prediction of IBS in patients with HCV, including male gender, high BMI, urban residence, education level, positive PCR, and fibrosis stage.
CONCLUSIONS:
FD is a prevalent finding in obese patients with HCV and with higher fibrosis scores. IBS is also prevalent in male patients with HCV.
Keywords: Rome IV diagnostic criteria, Hepatitis C virus, Functional gastrointestinal disorders, Functional dyspepsia, Irritable bowel syndromes
INTRODUCTION
Hepatitis C virus (HCV) is considered as the main cause of chronic liver disease with nearly 71 million chronically infected patients worldwide in 2017.1,2The liver is the main site for replication of the virus, but it can be replicated at other extrahepatic sites.3,4 Dyspepsia is a very common phenomenon in patients with chronic HCV.5
Patients with chronic HCV usually have different upper and lower abdominal complaints. Dyspepsia is very common in patients with chronic HCV with different clinical presentations such as epigastric pain and heart burn.6 Abdominal pain is usually seen in clinical practice in patients with chronic HCV without any organic lesions. The functional cause of these abdominal complaints is claimed in most of patients.2,7 Various abnormalities in gastrointestinal function and structure have been studied in patients with chronic liver diseases, such as altered gastrointestinal motility, intestinal permeability, and absorption.8,9
Functional gastrointestinal disorders (FGIDs) are classified and diagnosed using the Rome criteria. The criteria may change in time as new scientific data emerge.10,11 The Rome IV diagnostic criteria were released in May 2016. Now, FGIDs are called disorders of gut-brain interaction.12The aim of this study was to evaluateFGID in patients with chronic hepatitis C usingRome IV diagnostic criteria.
MATERIALS AND METHODS
This cross-sectional, observational study involved 1090 patients with chronic HCV, in addition to 500 healthy controls matched for age, gender, and educational level. The patients with chronic HCV were selected randomly from the outpatient clinic of the Tropical Medicine Department, Minia University Hospital. The controls were selected randomly from the relatives of the patients and outpatient clinic. Written informed consent was obtained from all subjects (for both participation and publication of the work).
All individuals (patients and controls) were subjected to:
History taking including personal history (name, gender, age, occupation, educational level, residencial status, and body mass index [BMI] symptomatology), medical history stressing on history of diabetes mellitus (DM), lipid disorders, and drug history.
Basic investigations including complete blood count (CBC), liver and renal function tests, international normalized ratio (INR), random blood glucose, alpha-fetoprotein, HCV RNA PCR, and abdominal ultrasonography for patients only.
Upper gastrointestinal tract (GIT) endoscopy for patients only.
Rome IV diagnostic questionnaire that was downloaded from the Rome Foundation website (http://www.romecriteria.org/questionnaires/): The purpose of that questionnaire is to know more about the health problems that people sometimes have with their intestines and stomach. The questionnaire will take about 15-20 minutes to be completed.
Of the 1090 patients with chronic HCV who were included in the study; 1077 patients fulfilled the criteria for FGID and underwent upper GIT endoscopy (13 patients refused to do upper endoscopy). About 1006 patients had no abnormality in the upper endoscopy and were diagnosed as having FGID, 17 patients had gastroesophageal reflux disease, 22 patients had gastroesophagitis, peptic ulcer was recorded in 4 patients, and 28 patients had esophageal varcies.
The collected data were inserted, tabulated, and statistically evaluated using SPSS software version 24. Quantitative data were expressed as mean ± standard deviation (SD), while qualitative data were expressed as proportions. Comparisons between groups for normally distributed quantitative data were performed by using Mann-Whitney test. Qualitative data were analyzed by chi-square (χ2) test. Statistical significance was defined as P values less than 0.05.
RESULTS
Sociodemographic data for the two groups are shown in Table 1. There was no statistically significant difference between the two groups in regard to the demographic data. The prevalence of the functional gastrointestinal symptoms between the studied groups is shown in Table 2. There was a statistically significant difference between the two groups in regard to the prevalence of the symptoms of FGIDs in patients with chronic HCV including functional dyspepsia (FD) (P = 0.009), early satiety (P = 0.002), postprandial distress (P = 0.02), epigastric pain (P = 0.03), inflammatory bowel syndrome (IBS, P < 0.001), IBS constipation (P < 0.001), IBS diarrhea (P < 0.001), and IBS mixed (P < 0.001). Simple and multiple logistic regression for prediction of risk factors for FD in HCV positive patients are shown in Tables 3 and 4. There were multiple risk factors for the prediction of FD in patients with chronic HCV, including high BMI, higher level of education, positive PCR, and FIB4 (fibrosis score 4)(≥ 3.45) with statistically significant P values (0.001, 0.026, 0.001, and 0.001, respectively). Simple and multiple logistic regression for the prediction of risk factors for IBS in patients with chronic HCV are shown in Tables 5 and 6. There were multiple risk factors for the prediction of IBS in patients with chronic HCV such as male gender, high BMI, urban residence, higher level of education, positive PCR, and FIB4 (≥ 3.45) with statistically significant P values (0.002, 0.005, 0.001, 0.001, 0.001, and 0.032, respectively). The prevalence of IBS subtypes between the two groups is shown in Table 2. In patients with chronic HCV and IBS, IBS constipation was the most predominant type (33%) followed by IBS mixed (23.9%), and IBS diarrhea (14.3%).
Table 1: Sociodemographic data of the studied groups .
| Control | Cases | P value | ||
| N=500 | N=1006 | |||
| Age | Range Mean ± SD |
(27-75) 38.4 ± 9 |
(19-78) 38.4 ± 12 |
0.911 |
| BMI | Range Mean ± SD |
(22-39) 26.3 ± 2.4 |
(20-39) 26.5± ± 2.6 |
0.357 |
| Sex | Male Female |
370(74%) 130(26%) |
741(73.7%) 265(26.3%) |
0.887 |
| Residence | Urban Rural |
256(51.2%) 244(48.8%) |
512(50.9%) 494(49.1%) |
0.911 |
| Education | No Yes |
296(59.2%) 204(40.8%) |
576(57.3%) 430(42.7%) |
0.472 |
Independent samples T test for parametric quantitative data between the two groups.Chi square test for qualitative data between the two groups.
*: Significant level at P value < 0.05
Table 2: Prevalence of the functional gastrointestinal symptoms between the studied groups .
| Control | Cases | P value | ||
| n = 500 | n = 1006 | |||
| Functional dyspepsia syndrome | No | 284 (56.8%) | 500 (49.7%) | 0.009* |
| Yes | 216 (43.2%) | 506 (51.3%) | ||
| Early satiety | No | 268 (53.6%) | 452 (44.9%) | 0.002* |
| Yes | 232 (46.4%) | 554 (55.1%) | ||
| Post-prandial distress | No | 282 (56.4%) | 504 (50.1%) | 0.021* |
| Yes | 218 (43.6%) | 502 (49.9%) | ||
| Epigastric pain | No | 296 (59.2%) | 536 (53.3%) | 0.030* |
| Yes | 204 (40.8%) | 470 (46.7%) | ||
| IBS | No | 198 (39.6%) | 290 (28.8%) | < 0.001* |
| Yes | 302 (60.4%) | 716 (71.2%) | ||
| IBS (sub types) | No | 198 (39.6%) | 290 (28.8%) | < 0.001* |
| Constipation | 156 (31.2%) | 332 (33%) | ||
| Diarrhea | 77 (15.4%) | 144 (14.3%) | ||
| Mixed | 69 (13.8%) | 240 (23.9%) | ||
Chi-square test for qualitative data between the two groups
* Significant level at P value < 0.05
Table 3: Simple logistic regression for the prediction of risk factors for functional dyspepsia in patients with chronic HCV .
| Variables | Functional dyspepsia | P value | ||
| No | Yes | |||
| n = 500 | n = 506 | |||
| Hemoglobin level | Range | (9-16) | (9-16) | 0.534 |
| Mean ± SD | 12.5 ± 1.2 | 12.6 ± 1.3 | ||
| Platelets | Range | (3.2-3300) | (13-3870) | 0.919 |
| Mean ± SD | 331 ± 530.3 | 351.7 ± 562.7 | ||
| Median | 208 | 206 | ||
| Alanine transaminase | Range | (12-171) | (10-170) | 0.779 |
| Mean ± SD | 31.6 ± 22 | 32.8 ± 22.3 | ||
| Median | 23 | 25 | ||
| Bilirubin | Range | (0.5-2) | (0.2-2) | 0.163 |
| Mean ± SD | 1 ± 0.1 | 1 ± 0.1 | ||
| Albumin | Range | (3-5) | (3-5) | 0.874 |
| Mean ± SD | 4.4 ± 0.5 | 4.4 ± 0.5 | ||
| International randomized ratio | Range | (1-1.40) | (1-1.40) | 0.136 |
| Mean ± SD | 1.06 ± 0.09 | 1.05 ± 0.12 | ||
| Creatinine | Range | (0.2-1.5) | (0.1-1.5) | 0.242 |
| Mean ± SD | 1 ± 0.1 | 1 ± 0.1 | ||
| Alfa fetoprotein | Range | (1-100) | (1-111) | 0.649 |
| Mean ± SD | 7.7 ± 8.8 | 7.1 ± 8.6 | ||
| Median | 5 | 5 | ||
| Polymerase chain reaction | Range | (0.3-4.2) | (0-5) | < 0.001* |
| Mean ± SD | 2 ± 0.7 | 2.7 ± 0.8 | ||
| FIB 4 | Range | (0.3-5) | (0.4-5) | 0.002* |
| Mean ± SD | 1.6 ± 1 | 1.9 ± 1.2 | ||
| Median | 1 | 1.2 | ||
| FIB 4 | F1-F2 | 462(92.4%) | 428(84.6%) | < 0.001* |
| F3-F4 | 38(7.6%) | 78(15.4%) | ||
| OR | 95% CI | P value | ||
| High BMI | 1.13 | 1.07-1.19 | < 0.001* | |
| Education | 0.006* | |||
| No | Ref. | |||
| Yes | 1.43 | 1.11-1.83 | ||
| Positive polymerase chain reaction | 3.69 | 2.98-4.57 | < 0.001* | |
| FIB 4 | < 0.001* | |||
| < 3.45 | Reference | |||
| ≥ 3.45 | 2.22 | 1.47-3.34 | ||
OR: odds ratio, CI: confidence interval.
* Significant level at P value < 0.05
Table 4: Multiple logistic regression for prediction of risk factors for functional dyspepsia in chronic HCV patients .
| Variables | AOR | 95% CI | P value |
| High BMI | 1.09 | 1.04-1.15 | 0.001* |
| Education | 0.026* | ||
| No | Ref. | ||
| Yes | 1.38 | 1.04-1.8 | |
| Positive Polymerase chain reaction | 3.54 | 2.86-4.38 | < 0.001* |
| FIB 4 | 0.001* | ||
| < 3.45 | Reference | ||
| ≥ 3.45 | 2.19 | 1.39-3.43 |
AOR: adjusted odds ratio, CI: confidence interval
* Significant level at P value < 0.05
Table 5: Simple logistic regression for the prediction of risk factors for IBS in patients with chronic HCV .
| Variables | IBS | P value | ||
| No | Yes | |||
| N = 290 | N = 716 | |||
| Hemoglobin level | Range | (9-16) | (9-16) | 0.086 |
| Mean ± SD | 12.7 ± 1.4 | 12.5 ± 1.2 | ||
| Platelets | Range | (100-3200) | (3.2-3870) | 0.064 |
| Mean ± SD | 348.7 ± 505.3 | 338.4 ± 562.8 | ||
| Median | 210 | 204.5 | ||
| Alanine transaminase | Range | (12-121) | (10-171) | 0.001* |
| Mean ± SD | 32.6 ± 17.5 | 32 ± 23.8 | ||
| Median | 28 | 23 | ||
| Bilirubin | Range | (0.9-2) | (0.2-2) | 0.642 |
| Mean ± SD | 1 ± 0.1 | 1 ± 0.1 | ||
| Albumin | Range | (3-5) | (3-5) | 0.087 |
| Mean ± SD | 4.4 ± 0.5 | 4.4 ± 0.5 | ||
| International randomized ratio | Range | (1-1.4) | (1-1.4) | 0.115 |
| Mean ± SD | 1.05 ± 0.09 | 1.04 ± 0.11 | ||
| Creatinine | Range | (0.7-1.4) | (0.1-1.5) | 0.158 |
| Mean ± SD | 1 ± 0.1 | 1 ± 0.1 | ||
| Polymerase chain reaction | Range | (0-3.3) | (0.6-5) | < 0.001* |
| Mean ± SD | 1.7 ± 0.7 | 2.6 ± 0.7 | ||
| FIB 4 | Range | (0.3-4) | (0.3-5) | 0.169 |
| Mean ± SD | 1.6 ± 1 | 1.7 ± 1.1 | ||
| Median | 1 | 1.1 | ||
| FIB 4 | < 3.45 | 268 (92.4%) | 622 (86.9%) | 0.013* |
| ≥ 3.45 | 22 (7.6%) | 94 (13.1%) | ||
| OR | 95% CI | P value | ||
| Gender | ||||
| Female | Ref. | |||
| Male | 1.53 | 1.13-2.06 | 0.006* | |
| High BMI | 1.15 | 1.08-1.22 | < 0.001* | |
| Residence | ||||
| Rural | Ref. | |||
| Urban | 1.93 | 1.46-2.55 | < 0.001* | |
| Education | ||||
| No | Ref. | |||
| Yes | 2.89 | 2.13-3.9 | < 0.001* | |
| Chronic disease | ||||
| No | Ref. | |||
| DM | 0.87 | 0.56-1.36 | 0.543 | |
| HTN | 0.16 | 0.05-0.5 | 0.002* | |
| Positive PCR | 5.94 | 4.57-7.72 | < 0.001* | |
| FIB 4 | ||||
| < 3.45 | Reference | |||
| ≥ 3.45 | 1.84 | 1.13-2.99 | 0.014* | |
OR: odds ratio, CI: Confidence Interval
* Significant level at P value < 0.05
Table 6: Multiple logistic regression for the prediction of risk factors for IBS in patients with chronic HCV .
| Variables | AOR | 95% CI | P value |
| Gender | 0.002* | ||
| Female | Ref. | ||
| Male | 1.82 | 1.23-2.68 | |
| High BMI | 1.11 | 1.03-1.19 | 0.005* |
| Residence | < 0.001* | ||
| Rural | Ref. | ||
| Urban | 2.09 | 1.48-2.95 | |
| Education | < 0.001* | ||
| No | Ref. | ||
| Yes | 4.29 | 2.92-6.29 | |
| Positive polymerase chain reaction | 6.37 | 4.83-8.41 | < 0.001* |
| FIB 4 | 0.033* | ||
| < 3.45 | Reference | ||
| ≥ 3.45 | 1.92 | 1.06-3.5 |
OR: odds ratio, CI: Confidence Interval
* Significant level at P value < 0.05
DISCUSSION
Patients with chronic hepatitis C usually have different abdominal complaints. Dyspepsia is very frequent in HCV patients with different presentations such as epigastric pain and heart burn.6Abdominal pain is seen frequently in clinical practice in patients with chronic HCV without any organic cause. The current study was designed to evaluateFGIDs in patients with chronic hepatitis C. In the present study, we evaluated the presence of FD in patients with chronic HCV. Our data showed that there was a significant difference in FD between the patients with chronic HCV, and the controls. The percentage of FD according to Rome IV criteria was significantly higher in patients with chronic HCV than normal controls (51.3% vs. 43.2%, respectively). Regarding FD subtypes, postprandial distress syndrome (PDS) was more predominant than epigastric pain syndrome (EPS). In addition, there were multiple risk factors for the prediction of FD in patients with chronic HCV, including high BMI, higher level of education, positive PCR, and FIB4(≥ 3.45). FD is more prevalent in obese patients with chronic HCV who had high education levels and higher fibrosis scores. Our results are in accordance with the report by Grassi and colleagues13 who reported the presence of FD in about 28.8 % of the patients with chronic liver diseases. About 71.2 % had an organic cause of dyspepsia, such as gastroesophageal reflux disease, gallbladder stones, and ulcers. The most important factors that predict the presence of FD were fibrosis scores and BMI, while age, gender, smoking, and residential status were not significantly associated. Also, our results were in agreement with Aro and colleagues14 who found that PDS in Sweden was more prevalent than EPS, and obesity was predictive for FD. Mohamed et al15reported the same result. They found that the percentage of patients with FD according to Rome III criteria were significantly higher in patients with chronic HCV than controls (65.9%, and 28.7%, respectively). Regarding FD subtypes, the PDS subtype was more predominant than the EPS in both groups. The study included 251 patients infected with HCV. 187 patients showed the criteria of FD and underwent upper GIT endoscopy. About 166 patients had normal endoscopic findings and were diagnosed as having FD. Similar results were obtained from the study of Ahmed et al16 which included 266 patients with chronic HCV and 170 normal healthy controls. Upper GIT endoscopy was performed for all patients to exclude any organic causes. The prevalence of FD was significantly higher in patients with chronic HCV than the controls (67.8% vs. 32.4%, respectively). PDS subtype was more prevalent than EPS subtype. Also, elevated ALT levels and high fibrosis scores were significantly higher in patients with FD than in patients without FD, and the most predictors of FD were fibrosis score and BMI. These findings indicate that patients with chronic HCV may have meal-related disorders, which may be needed further investigations of gastric neuromuscular function and gastric emptying studies.17 These symptoms may be explained by the increase in the portal blood flow and volume changes of the liver after the meal, which may result in the stretch of the capsule, more congestion,18 and subsequently lead to vagal stimulation, which may result in symptoms of postprandial fullness, nausea, and pain.19 In our study, we assessed the presence of IBS symptoms in patients with chronic HCV. Our data showed that the prevalence of IBS was significantly higher in patients with chronic HCV (71.1%) than the controls. Regarding IBS subtypes, IBS with constipation was the most predominant type, in addition, there were multiple risk factors for the prediction of IBS in patients with chronic HCV in the form of the male gender, high BMI, urban residence, higher level of education, positive PCR, and FIB4 (≥ 3.45). Similar results were reported by Fouad and colleagues20 who included 258 patients with chronic HCV, 36 patients with chronic HBV, and 160 healthy control in their study. All individuals were administered a questionnaire of IBS according to Rome III criteria. They noted that the prevalence of IBS was significantly higher in patients with chronic HCV (66%) than patients with chronic hepatitis B and normal controls. While there was no significant difference between the patients with chronic hepatitis B and normal controls, IBS with constipation was the most predominant type (51%) followed by mixed IBS (43%), in addition, the prevalence of IBS was significantly higher in female patients than male patients (91%) and in HCV patients with a high fibrosis score. These finding indicate that the association between HCV and IBS whether is due to infectious changes, psychological factors, or motor dysfunctions remains to be further studied.21
Thus, in summary, FGIDs, including FD and IBS, are a prevalent finding in patients with chronic HCV, and their pattern of presentations are similar to that of the general population. IBS with constipation and mixed IBS are the predominant types. Obese patients with chronic HCV with higher fibrosis scores and a high level of education are more likely to have FD.
Please cite this paper as: Hassnine A, Saad Z. Rome IV diagnostic criteria for functional gastrointestinal disorders in patients with chronic hepatitis C virus. Middle East J Dig Dis 2022;14(2):214-221. doi: 10.34172/mejdd.2022.275.
Footnotes
ETHICAL APPROVAL
Local Ethics Committee for human subject research reviewed and approved the study protocol and consent forms (Approval No 23-2019).
CONFLICT OF INTEREST
The authors declare no conflict of interest related to this work.
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