Current Pediatric Research

Abstract

Portal hypertension is a clinical syndrome in which the portal venous pressure gradient between the portal vein and inferior vena cava exceeding 5 mmHg. Clinically significant portal hypertension is diagnosed when clinical manifestations of the disease appear or the portal pressure gradient exceeding 10 mmHg. For better management, it is important to determine the underlying cause. This study aimed to evaluate the aetiology, presentation and quality of life in pediatric portal hypertension patients. This cross-sectional study was done on ninety-one consecutive cases of portal hypertension enrolled from 2016 to 2019. Demographic data, etiology, clinical presentation, endoscopic interventions, and quality of life were all assessed. The mean age of participants was 5.55 ± 4.30 years with a male to female ratio of 1.5:1. Out of 91 children, 56.1% developed portal hypertension due to extrahepatic causes and 42.9% due to hepatic causes. In extrahepatic causes portal vein obstruction was the most common aetiology representing 39.6% Splenomegaly was the commonest presentation of PHT and esophageal varices were the commonest complication. QoL scores, total and individual domains, were lower in all our PHT children. Conclusion: Extra hepatic portal vein obstruction was the most common etiology of portal hypertension in studied cases. Poor QOL was reported in all patients irrespective of the etiology of portal hypertension.

Keywords

Portal hypertension, Egyptian children and adolescents, Extrahepatic disease, Quality of life.

Introduction

Portal Hypertension (PHT) is a clinical syndrome in which the portal venous pressure gradient between the Portal Vein (PV) and inferior vena cava exceeding 5 mmHg [1]. Portal hypertension is considered one of the major problems which count morbidity and mortality in children with liver disease. Portal hypertension results in the formation of portal-systemic collaterals that shunt a portion of the blood flow of the portal to the systemic circulation [2].

By passing the liver; it can arise from disorders with blood flow at any level within the portal system [3]. Usually, portal hypertension is associated with an increased cardiac index, hyperkinetic syndrome, characterized by hypervolemia, hypotension, and reduced systemic vascular resistance. Moreover, several studies have reported the pattern of portal hypertension to be different in children and adults; in adults its pattern is mostly intrahepatic, whereas the pattern is extra-hepatic in children [4].

Causes of portal hypertension can be classified according to their anatomical location: prehepatic (involving the splenic–portal–mesenteric venous axis), intrahepatic, and post-hepatic [5]. In clinical practice, a bleeding episode from esophageal varices is a major clinical event that is associated with significant adverse sequelae [6]. The major complications of portal hypertension are variceal hemorrhage, ascites, hypersplenism, hepatopulmonary syndrome, porto-pulmonary hypertension, hepatorenal syndrome, and hepatic encephalopathy which can affect the quality of life of the children. This work aimed to explore the etiology, presentation, complications, and management of pediatric patients with portal hypertension.

Methods

This cross-sectional study included 91 patients diagnosed with portal hypertension based on combined clinical and radiological evidence from 2016 to 2019. Children with a history of significant developmental delay, psychological issues, or taking other medications confounding responses to assessments were excluded from the study. Written informed consents were obtained from participating children and or their parents; also ethical approval was obtained from the research ethics committee at the faculty of medicine, Ain Shams university hospital (FWA000017585).

All patients were subjected to: Full history taking including demographic data, history stressing on admission in Neonatology Unit (NICU), duration of NICU stays, exchange transfusion, umbilical catheterization, and previous blood transfusion). Family history also was evaluated including a history of liver disease, sibling death from the same disease, and consanguinity. Clinical evaluation: including etiology of portal hypertension, symptoms, and signs of portal hypertension like hematemesis, abdominal distension, jaundice, symptoms of hepatic encephalopathy, and chronic liver disease. Laboratory investigations: were done to confirm and evaluate the etiology and complications of portal hypertension. Patients were subjected to routine laboratory investigations including complete blood count. Liver enzyme: Alanine Transaminase (ALT), Aspartate Aminotransferase (AST), albumin, bilirubin, Prothrombin Time (PT), and International Normalized Ratio (INR).

Upper GIT endoscopy was performed to detect and grade the presence of esophageal varices and Portal Hypertensive Gastropathy (PHG), varices were graded according to japanese research for portal hypertension classification system as follows: grade Gr-I: Small esophageal varices which flatten with insufflation or minimally protrude into the esophageal lumen, Gr-II: Moderated sized varices with minimal obscuring of the gastroesophageal junction, Gr-III: Large varices showing luminal prolapse substantially obscuring the gastroesophageal junction ,and Gr-IV: Very large esophageal varices that completely obscuring the gastroesophageal junction and do not flatten on insufflation [3].

Quality of life was evaluated after obtaining informed consent using PedsQL™-4.0 generic core scale, Arabic version: questionnaire (face to face interview with parents and patients using structured questionnaire and the information collected include the effect of the disease (PHT) on physical, social, psychological, and school performance of patients). It consists of four scales divided into 23 items assessing the level of psychosocial and physical functioning of children. There are 8 items of physical functioning.

Three subscales are categorized into psychosocial functioning: social, emotional, and school functioning, each consisting of 5 items. The instructions ask for the degree of a problem during the previous month for each item. The Likert response scale of five points is used (0: Never a problem, 4: Almost always a problem). Items are reversed and translated to a scale of 0-100 linearly, with higher scores indicating better HRQOL. Scale scores are computed as the sum of items divided by the number of items answered (accounting for missing data) [7]. Linguistic validation and psychometric properties are well documented [8].

Statistical Analysis

Using IBM SPSS software package version 25, the data was fed to the computer and analyzed. Numbers and percentages were used to define qualitative results. Parametric numerical data were given as mean ± Standard Deviation (SD), while frequency, and percentage (%) for non-numerical data. The tests used were a Chi-square test for categorical variables to be compared between different groups. Fisher’s Exact: Correction for chi-square when more than 20% of the cells are predicted to count less than 5. F-test (ANOVA): For normally quantitative variables, to compare between more than two groups. P<0.05 is considered statistically significant.

Results

Patients’ characteristics

Table 1 showed some of the patients’ characteristics. In the present study, 91 patients were diagnosed with portal hypertension. Their mean age was 5.55 ± 4.30 years. More than 70% of patients were males, and from a rural area, it was found that 44 (48.4%) patients out of 91 were admitted to NICU (72% of them were diagnosed with PV obstruction versus 11.4% were diagnosed as CHF), five patients 5.5% had a history of exchange transfusion, and nine 9.9% had a history of umbilical catheterization.

As for the family history of the studied patients, thirty-three patients had positive consanguinity, eight patients (5 were diagnosed with CHF, 3 were cryptogenic cirrhosis) had a positive family history of liver diseases, only two CHF patients had a positive family history of sibling death of the same disease. In this study, PV obstruction was the most common cause of PHT 39.6%. Other causes of PHT were CHF 23.1%, budd chiari syndrome 16.5%, liver cirrhosis 13.2%, biliary atresia 3.3%, autoimmune hepatitis 3.3%. Patients with PV obstruction presented at earlier age (4.01 ± 3.46) year, followed by cases with CHF (5.86 ± 3.71) years. Cases with Budd Chiari and cryptogenic cirrhosis presented at an older age (12.86 ± 4.95 and 9.22 ± 5.40) respectively (p<0.001).

Table 1. Patients characteristics.

Eighty-five patients underwent endoscopy, more than 85% of them had varices distributed as 38.8% showed grade I-II while 45.9% showed grade III varices, and 10.6% of cases had portal hypertensive gastropathy. As for therapeutic endoscopic modalities, 58 patients underwent therapeutic endoscopic procedures in the form of band ligation in 44 cases and combined sclerotherapy and band ligation in 14 cases. B blockers were prescribed in 89 patients to decrease splanchnic blood flow.

Clinical profile

As regard initial clinical presentation, most PV obstruction patients were presented by hemostasis and melena, while abdominal distension was commonly presented in cirrhosis, CHF and, budd chiari patients. As regards the clinical signs of PHT, splenomegaly was reported in all cases of different etiology. Varices were the major complication of PHT which occurred in 90.1% of cases, followed by pancytopenia with splenomegaly in 60.4%, ascites in 26.4%, and liver failure in 2.2% (Table 2).

Table 2. Clinical presentation and complications in different etiological of PHT patients: X2: Chi square test; FE: Fisher’s Exact test.

Laboratory profile

Among the studied cases, 91.2% suffered from anemia and 73.6% suffered from thrombocytopenia, their hemoglobin ranged from 6-12.6 g/dl, and their platelets number ranged from 54-375 (× 103 cells/µl). It was found that the level of AST was increased in cirrhotic patients in 100% of cases versus 19.4% of PV obstruction cases and 33.3% of CHF cases and 33.3% of BCS, which was statistically significant while, there was preservation of other liver functions in the majority of cases of PV obstruction (Table 3).

Table 3. Liver functions in different etiologies of PHT. X2, p: X2 and p values for Chi square test for comparing between the two groups. *: Statistically significant at p ≤ 0.05; AST (u/l): Normal (18-63); ALT (u/l): Normal (20-60); PT (sec.): Normal (11-14); Alb (g/dl): 3.1-4.8; Bil (mg/dl): Normal (0.2-1.3).

Regarding quality-of-life score

It was noted that there was a lowering in all health domains (Table 4). Moreover, QOL scores total and in individual domains, were significantly lower in children with hypersplenism in comparison to children without hypersplenism (Table 5).

Table 4. Individual pediatric quality of life in different etiologies of PHT groups.

Table 5. Pediatric quality of life inventory scores of children (n: 91) with and without hypersplenism. Values are expressed as median (range). QOL ¼ Quality Of Life.

Discussion

The present study summarizes our experience of PHT in children attending the hepatology clinic from 2016 to 2019. The study included 91 patients; their mean age was 5.55 ± 4.30 years. More than 70% of patients were males and from rural areas. Nearly matching with our results, El-Karaksy et al. reported the age of presentation ranged from 1 month to 12 years; 101 out of 169 were boys [9]. It was noted that Portal vein obstruction 39.6% is the commonest cause of portal hypertension at all. followed by CHF 23.1% and 16.5% had Budd Chiari, these results were in concordance to the results of Khanna et al. reported that although EHPVO is relatively uncommon in Western countries, it is a significant cause of pediatric portal hypertension in the developing world (54% of cases) and accounts for most pediatric upper gastrointestinal bleeding 68%-84% [6].

Also, this was in line with another study to evaluate the etiology of portal hypertension in children admitted in a tertiary care center of Bangladesh on 40 consecutive cases of portal hypertension enrolled from April 2014 to March 2015. This study was conducted by Mahmud et al. reported that 32 (80%) out of 40 children developed portal hypertension because of pre-hepatic causes and 8 (20%) because of hepatic causes. Of 32 children, portal vein obstruction was found in 20 (62.5%) cases in pre-hepatic causes of portal hypertension, splenic vein thrombosis was idiopathic in 4 (12.5%) and 8 (25%) [10]. On the other hand, Grimaldi et al. have reported that the main causes of portal hypertension in children are cirrhosis and congenital hepatic fibrosis [11].

Also, Bernard et al. have reported that cirrhosis was responsible for 51% of portal hypertension cases and extra-hepatic portal venous obstruction was found in 34% of cases [12]. The difference of the current study from other studies as to regard the etiology could be attributed to differences in the living conditions, low socioeconomic, standards of hygiene, and perinatal care which lead to umbilical sepsis, ethnicity, reporting bias as well as diagnostic criteria utilized. This explanation was in line with other studies conducted by Sarin et al. and Omanwar et al. which reported rarity of the PV obstruction in the west, a declining trend with improved standards of living and hygienic conditions support the role of infections, at an early age in the disease pathogenesis [13,14]. In the current study, the patients with the diagnosis of PV obstruction were presented at an earlier age than patients with other etiologies like CHF, Budd Chiari syndrome, or cryptogenic cirrhosis. These results are in agreement with Imanieh et al. reported that EHPVO can present as early as 6 weeks [15].

As observed in the present study, splenomegaly, abdominal distention, and bleeding were the main clinical presentation of patients suffering from PHT. As regarded the clinical signs of PHT, it was found that all cases of PHT had splenomegaly. These results are in agreement with El-Karaksy et al. reported that splenomegaly was present in 87% and hematemesis was a presenting symptom in 58% [9]. Sarin et al., Banerjee et al. and Mitra et al., reported that splenomegaly is present in all cases of PHT [16-18]. Contradictory to our results, other descriptive studies of 55 children and adolescents’ cases by Ferri et al. in the pediatric hepatology clinic of the clinical hospital showed that the clinical manifestation of splenomegaly was found in 36.4% of cases [19]. The differences between the results may be attributed to the most studies discussed are stressing on the PV obstruction only and the variation in the number of studied patients. The complications of PHT were developed in ninety percent of our cases. Varices were the major complication of PHT which occurred in 90.1% of the patients, followed by pancytopenia with splenomegaly in 60.4%. These results are in agreement with the majority of the other studies performed by Banerjee et al. [17] Mileti et al. reported that the most important complication of PHT is variceal bleeding [20]. Also, Duché et al. and Lykavieris et al. reported that up to 70% of children with biliary atresia or portal vein thrombosis have esophageal varices, while Bajaj et al. found that Hypersplenism leading to thrombocytopenia was detected in 61.8% of patients [21-23].

In the current study, the history of patients suffering from PHT revealed that: 48.4% of patients admitted to NICU, 72% of them were diagnosed with PV obstruction versus 20% were diagnosed as CHF. NICU admission may be a risk factor to acquire PV obstruction, although, in this study, there was a shortage of data about neonatal events except in 9 patients and, so comparison with other studies was difficult.

Lots of studies as Abd El-Hamid et al., Morag et al. and Weiss et al. reported that Neonatal events, including umbilical catheterization and sepsis, were possible causes of EHPVO in a small number of patients [24-26]. It was observed that liver functions were preserved in patients with PV obstruction while, in patients with cirrhosis there were elevated liver functions, prolongation of PT, and low albumin level. Matching with the current study Chawla et al. reported that in PV obstruction the liver function is normal or near-normal except if PV obstruction occurs in a patient with cirrhosis [27]. In patients with PV obstruction who have ascites, the liver function tests are reported to be slightly abnormal as showed by Rangari et al. in their study about Hepatic dysfunction in patients with extrahepatic portal venous obstruction [28]. Costaguta and Alvarez reported that patients with congenital hepatic fibrosis characteristically have a well-preserved liver function; they behave like those with portal vein obstruction regarding the risk and tolerance to bleeding [29].

In the present study, upper GIT endoscopy was done on 85 patients. More than 90.1% had varices (82 cases). Matching with our results, Ferri et al. in their study reported that 84.9% of the evaluated patients with the endoscopic procedure had esophageal varices [19]. Through this work, propranolol was used in 89 cases while endoscopic band ligation was done in 44 cases and both sclerotherapy and band ligation was done in 14 cases. In agreement with these findings, Gürakan et al. reported that propranolol for prophylaxis of variceal bleeding and sclerotherapy might be the preferred modalities in their study [30]. In contrast, Theocharidou et al. reported that treatment includes pharmacologic, endoscopic, and surgical modalities [31]. Because of their unproven effectiveness and severe adverse effects, β-Adrenergic blockers are not commonly used in children. In the treatment of acute variceal bleeding and varicose eradication, endoscopic approaches such as sclerotherapy and Endoscopic Variceal Ligation (EVL) are highly efficient. There was noted that QOL scores, total and individual domains, that is physical, psychological, emotional, social, and school functioning were significantly lower in all our PHT children, moreover, patients with hypersplenism had lower median total QOL scores in all individual domains than patients without hypersplenism. Hypersplenism is known to develop in the presence of splenomegaly. These results were in concordance to the results of Krishna et al. 32 reported that patients with hypersplenism had lower median total QOL scores in all individual domains than patients without hypersplenism [32].

Conclusion

From this observational study, we concluded that PHT affects the quality of life of Egyptian children. The most common cause of PHT in children and adolescents was PV obstruction. Splenomegaly was the commonest presentation of PHT, and esophageal varices were the commonest complication.

Limitation of the study

This study has some limitations. Firstly, the present study was a hospital-based cross-sectional study that included only participants from one centre. Therefore, it may not represent the actual scenario of the community epidemiological variables. Secondly, the source of some data as family history and NICU admission in this study was collected from the child’s parents which, can lead to a recall bias and limits the number of variables that the study can analyses reliably.

Abbreviations

PHT: Portal Hypertension; PV: Portal Vein; QOL: Quality of Life; HRQOL: Health Related Quality of Life; EHPVO: Extra Hepatic Portal Vein Obstruction; CHF: Congenital Hepatic Fibrosis; PHG: Portal Hypertensive Gastropathy; NICU: Neonatal Intensive Care Unit; EVL: Endoscopic Variceal Ligation; CBC: Complete Blood Count; ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase.

Competing Interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Authors’ Contributions

LE designed and directed the study. AA, RA, and MF conducted the study and analyzed the data. LE, AA, RA wrote the manuscript. All authors have read and approved the manuscript.

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