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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 1  |  Page : 69-75

Role of serotonin in development of esophageal and gastric fundal varices


1 Department of Tropical Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Tropical Medicine at Ministry of Health, Menouf Fever Hospital, Menoufia, Egypt

Date of Submission16-Sep-2018
Date of Decision14-Nov-2018
Date of Acceptance17-Nov-2018
Date of Web Publication25-Mar-2020

Correspondence Address:
Sabrin Mohammed Samy Asila
Sirses Alyanah, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_274_18

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  Abstract 

Objective
The aim was to determine the role of plasma free serotonin concentrations on the development of esophageal and gastric fundal varices.
Background
Esophageal and gastric varices are a serious consequence of portal hypertension in patients with the chronic liver disease. Several studies have evaluated possible noninvasive predictors for the presence of varices including plasma serotonin level.
Materials and methods
This study was conducted on 100 patients: 60 hepatic patients with esophageal and/or gastric varices, 20 hepatic patients without varices, and 20 nonhepatic patients who were admitted to Tropical Medicine Department in Menoufia University Hospitals. Patients and control were subjected to laboratory investigations, abdominal ultrasound, upper endoscopy, and quantitative measurement of plasma free serotonin using enzyme-linked immunosorbent assay technique.
Results
The plasma free serotonin levels were much higher in patients with liver cirrhosis with varices than in nonhepatic patients (mean: 92.240 ± 18.534 vs. 20.015 ± 3.042 ng/ml; P < 0.0001). Moreover, plasma serotonin level was much higher in patients with varices than patients without varices (mean: 92.240 ± 18.534 vs. 42.220 ± 9.891 ng/ml; P < 0.0001). The best cutoff value of free serotonin in the prediction of esophageal and gastric varices was greater than or equal to 25.3 ng/ml, with sensitivity of 98.75%, specificity of 100%, positive predictive value of 100.0%, and negative predictive value of 95.2%.
Conclusion
Free serotonin is significant in the development of esophageal and fundal varices, indicating the clinical value of serotonergic receptor blockers in these patients.

Keywords: esophageal varices, fundal varices, serotonin


How to cite this article:
El-Din Nouh MA, Mostafa Seleem HE, Elhefnawy SM, Samy Asila SM. Role of serotonin in development of esophageal and gastric fundal varices. Menoufia Med J 2020;33:69-75

How to cite this URL:
El-Din Nouh MA, Mostafa Seleem HE, Elhefnawy SM, Samy Asila SM. Role of serotonin in development of esophageal and gastric fundal varices. Menoufia Med J [serial online] 2020 [cited 2020 Jun 6];33:69-75. Available from: http://www.mmj.eg.net/text.asp?2020/33/1/69/281289




  Introduction Top


Varices are a sure manifestation of portal hypertension, with the commonest cause in our setting being cirrhosis. Upper digestive hemorrhage from esophageal variceal rupture is the most severe complication, with high mortality and reduced survival by 50% after 1 year[1]. In patients with compensated cirrhosis who have no varices on screening endoscopy, the esophagogastroduodenoscopy should be repeated in 2–3 years. In those who have small varices, the esophagogastroduodenoscopy should be repeated in 1–2 years[2]. Noninvasive identification of esophageal varices is usually based on regular laboratory parameters and clinical signs relevant to liver fibrosis and function, which is reproducible, costeffective, simple, and quick with no additional burden to patients[3]. Synthesis of serotonin (5-HT) by intestinal enterochromaffin cells begins with the conversion of dietary tryptophan to 5-hydroxy-l-tryptophan, which is catalyzed by tryptophan hydroxylase[4]. Serotonin is actively taken up by cells expressing the Na+/Cl dependent serotonin transporter (SERT) where it is stored in intracellular vesicles and released in response to various stimuli. Once bound to target receptors or taken up by the SERT, internalized serotonin can be metabolized by monoamine oxidase leading to the generation of 5-hydroxyindole acetaldehyde. Concentrations of 5-hydroxyindole acetaldehyde can be readily measured in the urine and are often used to detect changes in whole-body serotonin levels[5]. Serotonin is known to stimulate the contraction of the human hepatic artery, and in patients with liver cirrhosis, this contractility is moderately enhanced[6]. The hepatic stellate cell (HSC) has a significant position in the sinusoid for regulation of portal flow. During liver damage, HSCs are 'activated' which leads to HSC transformation into myofibroblast-like cells with a resulting increased collagen production[7]. Serotonin, at the level of hepatic sinusoids, causes endothelial fenestrae contractions of liver sinusoids through 5-HT1 receptors mediated by a Ca2+-dependent process. Owing to different proinflammatory mediators releasing from the damaged liver, it comes to platelet adherence to sinusoidal endothelium, translocation into Disse space and serotonin release. Thereafter, serotonin binds to receptors (5-HT2A, 5-HT1B, 5-HT1F, and 5-HT7) which are expressed on HSC and hepatocytes, which additionally interferes with HSC proliferation[8]. The aim of this study was to determine the significance of free plasma serotonin level in the development of esophageal and gastric varices.


  Materials and Methods Top


The present study was conducted at Menoufia University Hospital, including 100 patients. The studied patients were recruited from the Tropical Medicine Department during the period from December 2016 to September 2017. The age of all patients ranges from 28 to 71 years old, and the study included 67 males and 33 females. Patients were classified into three groups. Group I included 60 patients with chronic liver disease and with esophageal and/or gastric varices and this group was subdivided into three subgroups: group Ia includes 20 patients with esophageal varices, group Ib includes 20 patients with gastric varices, and group Ic includes 20 patients with esophageal and gastric varices. Group II includes 20 patients with the chronic liver disease without esophageal or gastric varices. Group III (control group) includes 20 nonhepatic patients subjected to upper endoscopy for any other causes. Exclusion criteria include patients with schizophrenia, obsessive-compulsive disorder, hypertension, Huntington's disease, Duchenne's muscular dystrophy, carcinoid syndrome, portal vein or splenic vein thrombosis, hepatocellular carcinoma, patients treated for bleeding esophageal varices either surgically or endoscopically (injection sclerotherapy or band ligation), and patients who received drugs for primary prophylaxis of variceal bleeding (e.g., β-blockers).

The study was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent, and the Ethics Committee of Faculty of Medicine, Menoufia University, approved the study protocol.

All patients were subjected to written consent before study enrollment; full detailed history taking with stress on past history of contact to water canal; tartar emetic injections; blood transfusion or previous surgical operations; abdominal ultrasonography done using Siemens Sonolone Sienna sonography for all patients to detect the presence of liver cirrhosis, splenomegaly, and ascites and to exclude hepatic focal lesion; Doppler study for portal vein for detection of dilated portal vein (>13 mm); and the upper endoscopy, performed using Pentax Videoscope G 3400 (Pentax medical, Tokyo, Japan), flexible endoscope, to measure the esophageal varices size, which was classified into four grades.

Then 10 ml of venous blood was withdrawn from every subject, and then 6 ml was transferred into a plain tube and centrifuged for 10 min at 4000 rpm. The serum obtained was kept frozen at −20°C till analysis of liver and kidney function tests. The remaining 4 ml was transferred into two EDTA tubes: one for complete blood count (CBC) and the other one was centrifuged for 10 min at 4000 rpm to get platelet-poor plasma for determination of serotonin levels. Quantitative measurement of plasma serotonin by enzyme-linked immunosorbent assay technique [supplied by Shanghai Sun Red bio (SRB) Technology Co. Ltd, Shanghai City, China].

The kit uses a double-antibody sandwich enzyme-linked immunosorbent assay. The chroma of color and the concentration of the human substance serotonin of sample were positively correlated. According to standard concentration and the corresponding optical density (OD) values calculate out the standard curve linear regression equation, and then apply the OD values of the sample on the regression equation to calculate the corresponding serotonin level.

Statistical analysis

All data were collected, tabulated, and statistically analyzed using SPSS 19.0 for Windows (SPSS Inc., Chicago, Illinois, USA) and Med Calc 13 for windows (Med Calc Software bvba, Ostend, Belgium), and for all the analysis, a P value less than 0.05 was considered statistically significant, and highly significant if P value is less than 0.001.

Analysis of variance is a collection of statistical models, and their associated estimation procedures (such as the 'variation' among and between groups) were used to analyze the differences among group means in a sample.


  Results Top


There was no significant difference between studied groups regarding age and sex distribution. There is a statistically significant difference in the comparison between groups regarding clinical signs of examination (liver, spleen, jaundice, spider nevaei, palmar erythema, ascites, and lower limb edema) [Table 1]. All clinical findings were more in the group of chronic liver disease with varices, and this indicates the severity of liver cirrhosis with hepatic decompensation. Regarding ultrasound findings, ascites was positive in all patients with varices (group I) by different grades; 25 (41.67%) patients had mild ascites, 21 (35.00%) patients had moderate ascites, and 14 (23.33%) patients had severe ascites, with highly significant difference among the three groups (P < 0.001). No ascites was observed by ultrasound in groups II and III. Splenomegaly was detected in all patients (100%) of chronic liver disease with varices (group I) as compared with four (20%) patients of chronic liver disease without varices (group II) [Table 2]. In the present study, spleen diameter by ultrasound was 18.077 ± 2.855, 12.310 ± 1.332, and 11.845 ± 0.946 and portal vein diameter was 15.327 ± 1.988, 10.235 ± 1.139, and 9.615 ± 0.629 in group I, group II, and group III, respectively, with a highly significant increase in group I than groups II and III (P < 0.001 for all). The laboratory parameters of patients and control showed that there was a statistically significant difference regarding the values of aspartate transaminase (AST), alanine transaminase (ALT), albumin, bilirubin, international normalized ratio (INR), and creatinine levels [Table 3]. The presence of a significant difference in such values indicated that these parameters more affected by the severity of the underlying liver disease. According to CBC findings, we found that there was a significant difference in comparison between groups and in the comparison between subgroups regarding hemoglobin level, with P less than 0.001 and P of 0.030, respectively. According to platelet count, there was a highly significant difference between groups but not in between subgroups. The mean and standard deviation was 94.683 ± 26.929, 196.250 ± 36.457, and 203.950 ± 32.484, in group I, group II, and group III, respectively (P < 0.001). No significance was found between groups or subgroups regarding white blood cells [Table 3]. In the present study, in group I, 8.33% of cases were Child A, 26.67% Child B, and 65% were Child C, and in group II, 100% of cases were Child A. A highly significant difference in Child's classification was found between either group I and II or between the three subgroups of group I (P < 0.001 for both). Esophageal varices were seen in 20 (100.00%) patients in group Ia. Isolated gastric varices and portal hypertensive gastropathy were seen in 15 (75.00%) patients in group Ib, whereas isolated gastric varices were seen only in five (25.00%) patients in the same subgroup. Esophageal varices and gastric varices were reported in 20 (100.00%) patients in group Ic. No varices were detected in all patients of group II (20 patients) (100.00%). In group III, there are wide variations of endoscopic findings: one (5.00%) patient had duodenal ulcer, three (15.00%) patients had pangastritis, eight (40.00%) patients had gastroesophageal reflux disease, one patient had monilial esophagitis, two patients were normal, one patient had gastric mass, two patients had duodenitis, and two patients had a hiatus hernia.
Table 1: Comparison between groups according to clinical examination

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Table 2: Comparison between groups according to liver and ascites seen by ultrasound

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Table 3: Comparison between groups according to laboratory finding

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The plasma free serotonin levels were much higher in patients with liver cirrhosis with varices than in nonhepatic patients (92.240 ± 18.534 vs. 20.015 ± 3.042 ng/ml, P < 0.0001) [Table 4]. There was a highly significant correlation between plasma free serotonin level and occurrence of varices (F = 222.018, P < 0.001). Serotonin level was 113.440 ± 6.888 in gastric and esophageal varices patients, 91.480 ± 6.477 in isolated gastric varices with portal hypertensive gastropathy patients, 91.687 ± 5.246 in patients with isolated gastric varices, 71.645 ± 8.374 in patients with esophageal varices only, and 42.220 ± 9.891 in hepatic patients without esophageal or gastric varices No significant relation between plasma free serotonin level and grade of varices in the present study was found (P = 0.394), but there was a significant correlation between plasma serotonin and Child's classification [Table 5].
Table 4: Comparison between groups according to serotonin level

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Table 5: Relation between serotonin level and child's classification

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The best cutoff value of plasma free serotonin in the diagnosis of esophageal and gastric varices was greater than 25.3 ng/ml, with sensitivity of 98.75%, specificity of 100%, positive predictive value (PPV) of 100.0% and negative predictive value (NPV) of 95.2%.


  Discussion Top


Liver cirrhosis is a common disease in Egypt[9]. Egypt has the highest prevalence of HCV in the world, estimated nationally at 14.7%[10]. Noninvasive predictors of esophageal varices represent a special importance in developing countries like Egypt, where it is not easy to perform screening endoscopies in a huge number of patients with cirrhosis[11].

The noninvasive predictive variables include platelet count, splenomegaly, spleen diameter, Child-Pugh, size of the right liver lobe, albumin level, and portal vein diameter. These means are costeffective, simple, and quick with no additional burden to patients[3]. In this study, the mean value of age was 48.633, 45.750, and 44.850 in group I, group II and group III, respectively, with no statistically significant difference between the three studied groups regarding age distribution (P = 0.250). The male/female ratio was 42/18, 14/6, and 11/9 in group I, group II, and group III, respectively, with no statistically significant difference between the three studied groups regarding sex distribution (P = 0.443), but sex distribution showed a male preponderance in the study population. In general, men are twofold more likely to die of chronic liver disease and cirrhosis than women are, according to an analysis by the National Center for Health Statistics that was reported in 2005[12]. This was against the study by Mohamed Elkhedr et al.[13] conducted on 100 patients, which revealed that 78 patients were males (78.00%) and 22 were females (22.00%). Among the twenty-five healthy volunteers, eight (32%) were females and 17 (68%) were males. The mean age for patients was 53.06 ± 7.55 years whereas the mean age for the control group was 41.15 ± 8.18 years[13]. In our study, we found that there was a significant statistical difference among studied groups regarding signs suggestive of hepatic decompensation such as jaundice, ascites, and lower limb edema [Table 1]. Patients with chronic live disease (CLD) in group I with gastroesophageal and/or fundal varices had higher incidence of these signs in comparison with patients of CLD without varices in group II. This is in agreement with the study by Shaker et al.[14], which found that ascites, LL edema, jaundice, and encephalopathy were present in 35.8, 49, 26.3, and 7.5% of the patients, respectively. Furthermore, regarding palpable liver, we found that there was a statistically significant difference between patients with cirrhosis (group I) in comparison with patients without cirrhosis (group II) and patients of control (group III) (P < 0.001) [Table 1]. This was in agreement with the study performed by McCormick and Nolan[15]. The laboratory parameters of patients and control in this study showed that there was a statistically significant difference about values of total bilirubin level in group I, group II, and group III (2.262 ± 1.066, 1.010 ± 0.210, and 0.925 ± 0.121, respectively; P < 0.001) [Table 3]. This is in agreement with Min et al.[16] who studied a clinical predictor of varices and portal hypertensive gastropathy in patients with the chronic liver disease, including 232 patients, and 102 patients of them had varices and Portal hypertenisive gastropathy (PHG), whereas 130 patients had no varices or PHG. They found that patients with varices had a significantly elevated total bilirubin level compared with patients without varices[16]. This is owing to decreased hepatocyte excretory function in patients with cirrhosis[17]. According to INR level in this study, it shows a high significance in the comparison between groups; the highest values were reported in the group of varices (group I) (1.896 ± 0.552 with a P < 0.001) [Table 3]. The study by Sebastiani et al.[18] reported the same results that there was a significant difference between groups regarding PT and INR. This is because the liver plays a central role in the maintenance of hemostasis. It serves as the site of synthesis of all clotting factors and their inhibitors. Thus, liver damage from chronic liver disease can develop multiple coagulation abnormalities that disturb the balance between clotting and fibrinolysis[19]. The mean values of serum ALT and AST in this study showed statistically significant difference between group I and group II, with a P value of less than 0.001, as shown in [Table 3]. This is owing to leakage from damaged hepatocytes in patients with liver cirrhosis[17]. This agreed with the study performed by Hasan et al.[20]. However, there was disagreement with Giannini et al.[21], who studied platelet count/spleen diameter ratio for the noninvasive diagnosis of esophageal varices. This was a multicenter, prospective, validation study that included 218 patients, where 118 patients of them had EV, whereas 100 patients had no varices. They found that liver enzymes (ALT and AST) were statistically nonsignificant in differentiation between patients with varices and patients without varices[21]. Regarding serum albumin, it was significantly lower in group I than groups II and III. The mean values were 2.400 ± 0.760, 3.870 ± 0.359, and 3.915 ± 0.310, respectively, with P value less than 0.001 [Table 3]. This agreed with the study performed by Augustin et al.[22]. Patients with advanced cirrhosis almost always have hypoalbuminemia caused by both decreased synthesis by the hepatocytes and water and sodium retention that dilutes the content of albumin in the extracellular space[23]. In this study, regarding serum creatinine, a significant statistical difference was observed in comparison between patients with varices (group I), patients without varices, and controls, with P value of 0.001 [Table 3]. The spectrum of causes for AKI in cirrhosis includes (a) prerenal AKI (i.e., hypovolemia owing to gastrointestinal bleeding, aggressive diuretic treatment, lactulose-induced diarrhea, or infections), (b) the hepatorenal syndrome-type AKI, which is defined as a potentially reversible deterioration of renal function unresponsive to volume resuscitation, caused by renal vasoconstriction in the absence of alternative identifiable causes[24], (c) intrinsic causes such as acute tubular necrosis and, although very rare, and (d) postrenal causes[25]. This was against Tafarel et al.[26], who studied prediction of esophageal varices in hepatic cirrhosis by noninvasive markers, including 300 patients, with most having chronic C hepatitis. Overall, 171 patients had EV, whereas 129 patients had no varices. They found different results in their study, with no significance between groups according to serum creatinine level[26]. In the current study, we found that there was a significance difference in comparison between groups and in the comparison between subgroups regarding hemoglobin level. The lowest mean and standard deviation was reported in group I and subgroup IC (9.642 ± 1.529 and 8.935 ± 1.321, respectively; P < 0.001 and 0.030, respectively) [Table 3]. Anemia of diverse etiology is a common complication of chronic liver diseases. The causes of anemia include acute or chronic gastrointestinal hemorrhage and hypersplenism secondary to portal hypertension[27]. This was against the study of Lee et al.[28], who studied that CBC reflects the degree of esophageal varices and liver fibrosis in patients with virus-related chronic liver disease. Their study was on 69 patients with esophageal varices and 136 patients without varices. Their results showed no significance between groups regarding hemoglobin level[28]. These differences may be owing to different populations studied regarding Child-Pugh class, where most patients in this study were Child B (26.67%) and Child C (73.33) in group I. According to platelet count in this study, there was a highly significant difference between groups but not in between subgroups. The mean and standard deviation was 94.683 ± 26.929, 196.250 ± 36.457, and 203.950 ± 32.484, in the three groups, respectively (P < 0.001) [Table 3]. In liver cirrhosis, many factors participate in thrombocytopenia such as splenic sequestration of platelets, suppression of platelet production in bone marrow, and decreased activity of the hematopoietic growth factor thrombopoietin[29]. This is in agreement with Mohamed Elkhedr et al.[13], who studied 100 patients, diagnosed as having HCV-related cirrhosis, who were classified as 50 patients having esophageal and/or gastric varices (group A), 50 patients without varices (group B), and 25 healthy volunteers included as controls. They found a lower platelet count in the group with varices[13]. In the present study, ultrasound findings showed that spleen diameter was 18.077, 12.310, and 11.845 and portal vein diameter 15.327, 10.235, and 9.615 in group I, group II, and group III, respectively, with a highly significant increase in group I than groups II and III (P < 0.001 for all). Rudić et al.[30] show disagreement with our study when they reported that, on 33 patients with liver cirrhosis and 24 healthy control, the average longitudinal splenic diameter was 17.5 ± 3.57 cm, which was significantly different in relation to the controls, in whom an average longitudinal diameter was 10.21 ± 1.65 cm (t-test, P < 0.05). We reported there was a highly significant difference among groups in plasma free serotonin level (P < 0.001). Its level in group I was 92.240, in group II was 42.220, and group III was 20.015 [Table 3]. Moreover, there was a highly significance difference between subgroups according to plasma free serotonin level (P < 0.001 for all). This was in agreement with Mohamed Elkhedr et al.[13], who noticed that the levels of free serotonin were higher in patients with liver cirrhosis than in healthy subjects (P < 0.001). In addition, it was in agreement with a study performed by Rudić et al.[30], who found that the levels of free serotonin were also higher in patients with liver cirrhosis than in healthy controls. In the present study, there was no significant relation between plasma free serotonin level and grade of varices (P = 0.394), but there was a significant relation either between plasma free serotonin level and Child's classification [Table 5] or between plasma free serotonin and occurrence of varices (P < 0.001 for both). The study by Rizk was conducted on 60 patients with liver cirrhosis and 20 healthy controls in Internal Medicine Department, Zagazig University. It confirmed our reports of increased serum serotonin in patients with liver cirrhosis, and also reported that there was no significant difference between serotonin concentrations in relation to the size of esophageal varices. However, the mean plasma free serotonin level was higher in patients with esophageal varices than in patients without varices. Furthermore, the correlation of plasma serotonin concentration and fundal varices was highly significant[31]. Rudić et al.[30] agreed with the results of the present study that plasma serotonin levels were higher in patients with liver cirrhosis than in healthy subjects, and there was a significant correlation between the free plasma serotonin level and Child's score. On the contrary, in the study by Mohamed Elkhedr et al.[13], there was no significant difference between different grades of Child's classification regarding serotonin plasma levels in patients with varices (P = 0.892). In the present study, receiver operating characteristic curve between cases and control shows at cutoff level greater than 25.3 ng/ml, sensitivity of 98.75%, specificity of 100.0%, NPV of 95.2%, and PPV of 100%. When Mohamed Elkhedr et al.[13] studied the diagnostic validity of plasma serotonin levels, receiver operating characteristic curve was used to define the best cutoff value of the serotonin plasma level, which was greater than 30 ng/ml, with sensitivity of 95%, specificity of 100%, PPV of 100%, NPV of 90.9%, with diagnostic accuracy of 98.7%.{Table 5}


  Conclusion Top


Our conclusion is that free serotonin is significant in the pathogenesis of portal hypertension especially in the development of esophageal and gastric fundal varices, which may have clinical value in use of serotonin receptor blockers in these patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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Introduction
Materials and Me...
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