Objectives: Extrahepatic portal vein obstruction is the most common cause of portal hypertension in children. This study aimed to evaluate the causes, clinical, laboratory and endoscopic findings, treatment approaches, long-term results, and prognosis of extrahepatic portal vein obstruction in children.
Materials and Methods: We retrospectively evaluated 82 patients who were followed up with the diagnosis of extrahepatic portal vein obstruction at Gazi University Pediatric Gastroenterology clinic between January 1, 2011, and October 31, 2021.
Results: Among our patients, 58.5% were male, median age at presentation was 36 months (range, 1 month to 6 years), and the follow-up period was 2 years (range, 1-14 years). The most common reasons for admission were gastrointestinal bleeding and splenomegaly. All patients diagnosed with incidentally detected obstruction were children under 5 years of age. The most frequently detected risk factors were history of umbilical vein catheterization (50%) and presence of procoagulant status (31%). Esophageal varices (94.8%), variceal bleeding (73.2%), hypersplenism (64.6%), and growth failure (13.4%) were the most common complications. Weight and/or height z-scores were lower in children with esophageal varices, variceal bleeding, and hypersplenism. Endoscopic treatments were more frequently applied to those with splenomegaly, thrombocytopenia, red color sign, and esophageal variceal bleeding. Rates of splenomegaly, hypersplenism, esophageal variceal bleeding, advanced varicose veins, and portal biliopathy were higher in patients who underwent portosystemic shunt surgery than in patients who did not undergo it.
Conclusions: Morbidity and mortality rates of variceal bleeding in extrahepatic portal vein obstruction were lower than bleeding seen in cirrhotic prehepatic portal hypertension. In our study, no patients died from extrahepatic portal vein obstruction-related complications. One patient died from tuberculous meningitis.

Key words : Child, Esophageal varices, Extrahepatic portal vein obstruction, Portal vein thrombosis, Umbilical vein catheterization

Introduction

Extrahepatic portal vein obstruction (EHPVO) is the most common cause of prehepatic portal hypertension (PHT) in children.1 Thrombosis in the portal vein (PV) is the most important mechanism causing EHPVO.² Although its etiology is not fully known, EHPVO is seen in the presence of 1 or more risk factors that cause thrombosis. The most common cause of EHPVO in children is umbilical vein catheterization (UVC).³ Extrahepatic portal vein obstruction is usually diagnosed with clinical, laboratory, radiological, and endoscopic findings.³ Doppler ultrasonography is the imaging method that should be preferred first.⁴

In this study, we aimed to define the risk factors, clinical findings, treatment approaches, and complications in patients diagnosed and followed up with EHPVO in our department and to evaluate the relationship between clinical and laboratory findings, treatment, and prognosis.

Materials and Methods

This study was conducted at Gazi University, Department of Pediatric Gastroenterology. We retrospectively evaluated medical records of patients under the age of 18 years who were diagnosed with EHPVO clinically, radiologically, and/or endoscopically between January 1, 2011, and October 31, 2021. Patients with PV thrombosis secondary to cirrhosis, presence of tumor, and liver transplant, patients with isolated superior or inferior mesenteric vein thrombosis, and patients over 18 years of age were excluded. Demographic data, risk factors for EHPVO (UVC history, hereditary prothrombotic risk factors, intra-abdominal infection history, pancreatitis, perinatal infection history, previous surgeries such as splenectomy, cholecystectomy, pancreatic surgery), physical examination findings (anthropometric measurements, hepatomegaly, splenomegaly, jaundice), laboratory findings (liver enzymes, bilirubin, albumin, prothrombin time, activated partial thromboplastin time, international normalized ratio values, complete blood count, hemoglobin, leukocyte, and platelet values), imaging findings, treatments applied for PHT, and complications of PHT were obtained from hospital electronic data and file records.

Nutrition status of patients was evaluated by calculating weight and height z scores for age using reference values of Turkish children.⁵ We evaluated the presence of anemia, leukopenia, and thrombocytopenia and the severity of splenomegaly on ultrasonography by using reference values according to age and sex.⁶ We evaluated the relationship between risk factors and complications that cause EHPVO, clinical and laboratory findings and treatment methods, and their effects on morbidity and mortality.

The study received approval from Gazi University Ethics Commission (06.12.2021/2021-225).

Statistical analyses

We presented normally distributed continuous variables as mean ±SD and nonnormally distributed continuous variables as median (minimum-maximum). Normal distribution of numerical variables was examined with the Shapiro-Wilk test. Relationships between categorical variables were evaluated using Pearson chi-square analysis or the Fisher exact probability test in all cases where the expected value was less than 5. We compared numerical variables between 2 groups by using the Mann-Whitney U test if they were not normally distributed and by using the t test if normally distributed.

We used IBM SPSS statistics version 25.0 for statistical analyses. All hypothesis tests were applied 2-way at P < .05.

Results

Of the 82 patients diagnosed with EHPVO, 48 were boys (58.5%) and 34 were girls (41.5%). The median age at diagnosis of patients was 3 years (range, 1 month to 6 years), and the median follow-up period was 2 years (range, 1-14 years). Of our patients, 74.3% were diagnosed with EHPVO before the age of 5 years. Age at diagnosis was 3 years (range, 1-180 mo) in girls and 3 years (range, 2-132 mo) in boys. No significant difference was shown between boys and girls with regard to age at diagnosis(P = .393).

The most common reasons for hospital admission were gastrointestinal (GI) bleeding (n = 51; 62.2%) and splenomegaly (n = 23; 28%) (Table 1). All patients diagnosed with incidentally detected obstruction in PV on ultrasonography were children under 5 years of age(P = .027); 51.2% (n = 42) had a history of low birth weight (<2500 g), and 43.9% (n = 36) had a history of preterm birth (<37 weeks). History of admission to the neonatal intensive care unit was shown in 67.1% (n = 55). Median length of stay in the neonatal intensive care unit was 13 days (range, 0-120 days).

The most common risk factor for EHPVO in patients was UVC (Table 2). No risk factors were detected in 27 patients. Consanguinity between parents was shown in 24.4% (n = 20) of patients diagnosed with EHPVO.

Although 17% of patients had a height-for-age z score below -2, 12.1% had a weight-for-age z score below -2; growth retardation was detected in 13.4% of the patients. On physical examination, 23.1% (n = 19) had hepatomegaly, 91.4% (n = 75) had splenomegaly, and 7.3% (n = 6) had jaundice.

Protein C deficiency (n = 9; 19.6%) was the most frequently detected procoagulant state in patients whose anticoagulant levels such as protein C and S, antithrombin III, activated protein C resistance, and homocysteine were evaluated. Genetic test results of procoagulant disorders are given in Table 3.

Esophageal varices were observed in 94.8% of patients and variceal bleeding was observed in 73.2%. Grade 3 esophageal varices were observed in 50.7% of 73 patients with esophageal varices. A red color sign on the varices was observed in 29.9% of the cases. Portal hypertensive gastropathy was detected in 54.5% of the patients. It was observed that 68.3% of patients with varicose veins experienced GI bleeding at least once during clinical follow-up. One patient had GI bleeding twice, and 3 patients had GI bleeding 3 times.

The weight z score in patients with esophageal varices and portal biliopathy, which are complications of EHPVO, was significantly lower than in patients without these presentations (P = .004 and P = .04). Height and weight z scores in patients with esophageal variceal bleeding were significantly lower than those without bleeding (P = .018 and P = .009). Admission height z score was significantly lower in patients who received endoscopic treatment compared with patients who did not receive endoscopic treatment (P = .001).

The medical and surgical treatments applied to our patients are shown in Table 4. The neonatal intensive care unit admission rate and intensive care unit stay duration in patients who did not receive endoscopic treatment were significantly higher than those who received endoscopic treatment (P = .010 and P = .043).

Endoscopic treatment was given to patients with larger spleen size on physical examination (P = .012). Endoscopic treatment was also given at a higher rate to patients with thrombocytopenia detected in the complete blood count (P = .022), low hemoglobin (P = .007), and increased need for transfusion (P = .017). Portosystemic shunt surgery was performed more frequently in patients with esophageal varices, variceal bleeding, hypersplenism, and portal biliopathy than in those without. The difference between the 2 groups was significant for hypersplenism  (P = .010).

Discussion

Extrahepatic portal vein obstruction is a vascular disorder of the liver defined by obstruction and cavernous transformation of the PV.³ This condition, characterized by noncirrhotic PHT, is one of the most important causes of acute severe upper GI bleeding in children.⁷

In developed countries, EHPVO in children is responsible for approximately 5% to 10% of PHT cases; however, in developing countries, EHPVO is responsible for 50% to 75% of PHT cases.⁸ In our study, 82 cases were diagnosed with EHPVO over a 10-year period; 58.2% of the cases were boys, consistent with the literature.^9,10

Among our patients, ~60% with median age of diagnosis of 3 years were diagnosed with GI bleeding and ~30% were diagnosed with splenomegaly detected incidentally. Incidentally detected PV obstruction, thrombocytopenia, abdominal pain, and abdominal distension, respectively, are other reasons for admission of patients with EHPVO. Gürakan and colleagues stated that the average age of diagnosis of their patients was 5.5 ±3.8 years, with two-thirds diagnosed with GI bleeding and 30% with splenomegaly.⁹ Another study reported that ~70% of children were diagnosed with thrombocytopenia, 49% with upper GI bleeding, and 35% with splenomegaly.¹⁰ Similar to Gürakan and colleagues, two-thirds of our patients were diagnosed with esophageal variceal bleeding. The fact that most of our patients had bleeding may be related to the fact that our hospital is a reference center for endoscopic interventions and portosystemic shunt surgery.

In our study, admission with PV obstruction detected incidentally on Doppler ultrasonography was significantly higher in asymptomatic children under 5 years of age, as expected. Umbilical vein catheterization is a known risk factor for EHPVO, especially in patients admitted to the neonatal intensive care unit. Routine PV thrombosis examination with Doppler ultrasonography in patients undergoing UVC may increase the diagnosis rate in asymptomatic patients. However, in our study, no differences were found in the rates of incidentally detected PV obstruction between patients who underwent UVC and those who did not. Perhaps as age of patients increases, the severity of PHT may increase, the presentation of the disease may change, and presentations with GI bleeding, splenomegaly, and thrombocytopenia may increase. In our study, although the rates of diagnosis with GI bleeding and splenomegaly were higher in children older than 5 years of age, the difference was not significant.

The mechanism of PV thrombosis secondary to tumors or cirrhosis is different and rare in childhood.¹¹ Portal vein thrombosis is the most important mechanism causing EHPVO.² Rare congenital anomalies of the PV can also cause obstruction.

Thrombosis may be caused by direct damage or trauma to the vessel such as UVC and previous surgeries, local inflammatory processes such as neonatal umbilical sepsis, dehydration, pancreatitis, multiple exchange transfusions, and systemic causes such as hypercoagulability.^12,13 In all our cases, EHPVO was thought to be secondary to thrombosis. If time to presentation of patients is taken into consideration, it seems impossible to exclude rare anomalies of PV.

In most studies, high rates of UVC were reported in cases with EHPVO.^10,14 However, studies in the literature that find the risk factor for UVC to be lower are also noteworthy.¹⁵ In one of these studies, the causes of EHPVO were as follows: 53% idiopathic, 22% intra-abdominal sepsis, and 6% UVC.¹⁶ In another study, EHPVO risk factors were found to be idiopathic in 50%, intra-abdominal sepsis in 31%, umbilical sepsis in 11%, and UVC in 8%.¹⁷ In our cases, we evaluated risk factors on surgical history such as intra-abdominal infection, perinatal infection, neonatal omphalitis, pancreatitis, UVC, hypercoagulability, splenectomy, cholecystectomy, and pancreatic surgery. We found that no risk factor was detected in 32.9% of our cases. The most common risk factor in our patient group was UVC history (50%). Other risk factors were procoagulant mutations (30.5%) and intra-abdominal infection (9.7%). Frequency of UVC application in neonatal units has been reported to be between 5% and 32%.18 In another study, among patients who underwent UVC, ultrasonography detected PV thrombosis development in only 3% of patients.¹⁹ This suggests that factors other than UVC are necessary for the development of PV thrombosis. Low birth weight (<1500 g), catheterization time exceeding 6 days, transfusions, and location of the catheter have been reported as factors that increase the risk of thrombosis due to UVC; minimized catheterization time and placement of the catheter under ultrasonographic guidance can be used to prevent thrombus formation.²⁰

Prematurity and low birth weight are among the risk factors of EHPVO. In an evaluation 63 patients, 44% were premature and 38% had low birth weight,¹⁰ compared with our study patients with 43.9% having premature birth and 51.2% having low birth weight. Rather than a direct effect, premature birth can indirectly cause PV thrombosis development through long intensive care unit stay, use of the umbilical vein as an intravenous route, increased risk of sepsis, and intra-abdominal infection and inflammation such as necrotizing enterocolitis. When we compared patients who had versus did not have UVC, significantly more patients with preterm birth, neonatal intensive care unit admission, and longer length of stay underwent UVC.

The relationship between venous thrombosis and thrombophilia is well known. Different results have been reported in studies evaluating the effectiveness of thrombophilia in the etiology of EHPVO.^21,22 Although primary thrombophilic conditions and myeloproliferative diseases, especially factor V Leiden mutation, have been shown as risk factors in more than half of the patients with PVT in adults, this rate is much lower in pediatric patients.^23,24

Rates of prothrombotic status have varied in previous studies.^21,25,26 In our study, no mutations were shown in 29 of 60 patients whose mutations were examined; MTHFR C677T mutation was detected in 18 patients, MTHFR A1298C mutation in 8 patients, factor 5 Leiden mutation in 4 patients, and JAK2 mutation was detected in 1 patient. Protein C levels were low in 19.6% of the patients whose anticoagulant levels were checked, and protein S levels were low in 14.9%. Antithrombin III levels were low in only 2 cases. Homocysteine was found to be high in 3 patients. The low protein C, protein S, and antithrombin III levels may be associated with partially affected synthetic functions in EHPVO, vitamin K deficiency, and acute thrombosis rather than primary deficiency, and the decision of primary deficiency should be made with repeated tests. It is also thought that the MTHFR mutation, which is also common in healthy individuals, does not increase the risk of venous thromboembolism.¹⁴

Hypersplenism and cytopenias secondary to bleeding may be detected in the complete blood count. Hypersplenism is defined as hemoglobin level <10 g/dL, total leukocyte count <4000/mm³, and/or platelet count <100 000/mm3. Hypersplenism was observed in 65% of our patients. Highly variable rates of hypersplenism (13% to 98%) have been reported in the literature.^9,25,27

The most common cytopenia secondary to hypersplenism in EHPVO is thrombocytopenia. Leukope-nia and anemia are less common than thrombocytopenia.⁴ Although cytopenia is generally seen secondary to sequestration in the spleen, losses secondary to use and bleeding are also one of the important causes of cytopenia.¹⁴ In our study, thrombocytopenia was observed in 66.3% of the cases, anemia in 55%, and leukopenia in 42.5%.

The gold standard diagnostic method for diagnosing EHPVO is Doppler ultrasonography. Cavernomatous transformation of the PV (portal cavernoma) can be seen on ultrasonography.²⁸ In our study, PV could not be visualized in all patients with Doppler ultrasonography. Cavernomatous transformation in the PV was detected in 69.5% of the patients.

Esophageal varices and bleeding due to esophageal varices are important complications of PHT related to EHPVO. Although GI bleeding in PHT secondary to EHPVO is mostly caused by esophageal varices, it can also be caused by portal hypertensive gastropathy, gastric, duodenal, and rectal varices.1 In our study, varicose veins at different grades were detected in 73 patients. Approximately 30% had a positive “red color sign.” Portal hypertensive gastropathy accompanied endoscopic findings in approximately half of the patients. In EHPVO, GI bleeding can occur once or repeatedly in two-thirds of the cases during the disease¹⁰; we observed that 68.3% of our patients experienced GI bleeding once during clinical follow-up. Rates of recurrent varicose bleeding were low; use of endoscopic treatments by experienced providers in our center and the fact that we are the reference center for portosystemic shunt surgery, a curative method in the treatment of PHT secondary to EHPVO, could be reasons for the low incidence of recurrent variceal bleeding. The possibility of bleeding in esophageal varices is more common in advanced grades and in those with a bleeding focus on the varices.^29,30 Incidence of grade 3 esophageal varices, red color sign symptom, and portal hypertensive gastropathy were not significantly higher in patients with GI bleeding than in patients without GI bleeding in our study.

Although the use of beta-blockers is not recommended in the guidelines because of lack of sufficient evidence for the primary prophylaxis of esophageal varices in children,³¹ they are widely used (95%) in primary prophylaxis by many centers.¹⁰ Beta-blockers were used for prophylaxis in 86.6% of our cases.

Endoscopic band ligation is recommended for secondary prophylaxis of esophageal varices in children.^30,32 In our study, endoscopic treatment methods were used for two-thirds of patients with GI bleeding. Endoscopic band ligation was the preferred endoscopic method in half of the patients with bleeding and performed more frequently in patients with varicose veins with high risk of bleeding from esophageal varices and those with rejection red color sign symptom compared with those without this symptom.

Surgical shunt treatments are recommended in noncirrhotic PHT in cases where variceal bleeding cannot be eradicated by endoscopic treatment, symptomatic hypersplenism, symptomatic, and medically resistant hepatic encephalopathy, hepatopulmonary syndrome, portopulmonary hypertension, portal biliopathy, and growth retardation.³ Although meso-Rex shunt is recommended as the first choice in surgical treatments, splenorenal shunts should be preferred if meso-Rex shunts are not anatomically suitable or if the center does not have sufficient experience.²³ Portosystemic shunt surgery can both prevent and correct growth retardation, portal biliopathy, and hypersplenism by providing bleeding control. Shunt surgery was performed in 63.4% of our patients (46.3% with proximal splenorenal shunt, 15.9% with distal splenorenal shunt, 1.1% with meso-Rex shunt). Portosystemic shunt surgery has been performed more frequently in patients with GI bleeding, advanced esophageal varices, splenomegaly, hypersplenism, portal biliopathy, and patients who underwent endoscopic band ligation.

Growth failure is an important complication of EHPVO, with investigations showing a higher rate (29% to 50%) than in the normal population,¹⁰ but another showing no difference from the control group.²⁸ Growth failure is multifactorial. The most likely causes are chronic reduction of portal blood supply to the liver due to PV obstruction and malabsorption due to portal hypertensive gastropathy, enteropathy, and biliopathy. Early satiety and anemia caused by massive splenomegaly are other causes of growth retardation.²³ In our study, 13.4% of patients had growth retardation. Low frequency in the literature may be because of portosystemic shunt surgery being performed in the early period in most patients.

Portal biliopathy is a rare but important complication of EHPVO and is more common than other causes of PHT. Changes in the bile ducts due to PHT may be irreversible over time. A previous study reported a rate of 6% of children,³³ with portal biliopathy observed in 6.1% of our patients. Lower weight z score in our patients with portal biliopathy may be related to the severity of malabsorption and PHT secondary to cholestasis in these patients.

The morbidity and mortality rates of variceal bleeding in EHPVO were lower than bleeding seen in cirrhotic PHT. Mortality decreased to below 5% with endoscopic and surgical treatments.³⁴ None of our patients died due to EHPVO-related complications. One patient died due to tuberculous meningitis.

References:

1. Di Giorgio A, D’Antiga L. Portal hypertension in children. In: Guandalini S, Dhawan A, Branski D, eds. Textbook of Pediatric Gastroenterology, Hepatology and Nutrition, A Comprehensive Guide to Practice. Springer; 2016:791-817.
   CrossRef - PubMed
2. Mitra SK, Kumar V, Datta DV, et al. Extrahepatic portal hypertension: a review of 70 cases. J Pediatr Surg. 1978;13(1):51-57. doi:10.1016/s0022-3468(78)80212-7
   CrossRef - PubMed
3. Sar? S. Çocuklarda non-sirotik PHTa yakla??m. In: Dalg?ç B, ed. Çocuklarda karaci?er hastal?klar?n?n tan? ve tedavisi 1. Bask? Ankara Türkiye Klinikleri; 2021:72-86.
   CrossRef - PubMed
4. Khanna R, Sarin SK. Idiopathic portal hypertension and extrahepatic portal venous obstruction. Hepatol Int. 2018;12(Suppl 1):148-167. doi:10.1007/s12072-018-9844-3
   CrossRef - PubMed
5. Neyzi O, Günöz H, Furman A, Bundak R, Gökçay G, Darendeliler F. Türk çocuklar?nda vücut a??rl???, boy uzunlu?u, ba? çevresi ve vücut kitle indeksi referans de?erleri. Çocuk Sa?l??? ve Hastal?klar? Dergisi. 2008;51(1):1-14.
   CrossRef - PubMed
   
6. Behrman R, Kliegman R, Jenson H. Portal hypertension and varices. Nelson Pediatr. 2008:1346-1349.
   CrossRef - PubMed
7. Bozic MA, Puri K, Molleston JP. Screening and prophylaxis for varices in children with liver disease. Curr Gastroenterol Rep. 2015;17(7):27. doi:10.1007/s11894-015-0450-4
   CrossRef - PubMed
8. Cichoz-Lach H, Celinski K, Slomka M, Kasztelan-Szczerbinska B. Pathophysiology of portal hypertension. J Physiol Pharmacol. 2008;59 Suppl 2:231-238.
   CrossRef - PubMed
9. Gurakan F, Kocak N, Yuce A, Ozen H. Extrahepatic portal venous obstruction in childhood: etiology, clinical and laboratory findings and prognosis of 34 patients. Acta Paediatr Jpn. 1997;39(5):595-600. doi:10.1111/j.1442-200x.1997.tb03647.x
   CrossRef - PubMed
10. Grama A, Pirvan A, Sirbe C, et al. Extrahepatic portal vein thrombosis, an important cause of portal hypertension in children. J Clin Med. 2021;10(12) :2703. doi:10.3390/jcm10122703
    CrossRef - PubMed
    
11. Sarin SK, Sollano JD, Chawla YK, et al. Consensus on extra-hepatic portal vein obstruction. Liver Int. 2006;26(5):512-519. doi:10.1111/j.1478-3231.2006.01269.x
    CrossRef - PubMed
12. Sarin SK, Bansal A, Sasan S, Nigam A. Portal-vein obstruction in children leads to growth retardation. Hepatology. 1992;15(2):229-233. doi:10.1002/hep.1840150210
    CrossRef - PubMed
13. Alvarez F, Bernard O, Brunelle F, Hadchouel P, Odievre M, Alagille D. Portal obstruction in children. I. Clinical investigation and hemorrhage risk. J Pediatr. 1983;103(5):696-702. doi:10.1016/s0022-3476(83)80460-0
    CrossRef - PubMed
14. Karakurt N, Demirba? F, Çaltepe G, Albayrak C, Kalayc? AG. Hematological aspects of extrahepatic portal vein obstruction in childhood. Türk Hijyen ve Deneysel Biyoloji Dergisi. 2019;76(4):415-422.
    CrossRef - PubMed
15. Sarin SK, Agarwal SR. Extrahepatic portal vein obstruction. Semin Liver Dis. 2002;22(1):43-58. doi:10.1055/s-2002-23206
    CrossRef - PubMed
    
16. Househam KC, Bowie MD. Extrahepatic portal venous obstruction. A retrospective analysis. S Afr Med J. 1983;64(7):234-236.
    CrossRef - PubMed
17. Cardin F, Graffeo M, McCormick PA, McIntyre N, Burroughs A. Adult “idiopathic” extrahepatic venous thrombosis. Importance of putative “latent” myeloproliferative disorders and comparison with cases with known etiology. Dig Dis Sci. 1992;37(3):335-339. doi:10.1007/BF01307724
    CrossRef - PubMed
18. Devlieger H, Snoeys R, Wyndaele L, et al. Liver necrosis in the new-born infant: analysis of some precipitating factors in neonatal care. Eur J Pediatr. 1982;138(2):113-119. doi:10.1007/BF00441136
    CrossRef - PubMed
19. Gharehbaghi MM, Nemati M, Hosseinpour SS, Taei R, Ghargharechi R. Umbilical vascular catheter associated portal vein thrombosis detected by ultrasound. Indian J Pediatr. 2011;78(2):161-164. doi:10.1007/s12098-010-0223-x
    CrossRef - PubMed
20. Kim JH, Lee YS, Kim SH, Lee SK, Lim MK, Kim HS. Does umbilical vein catheterization lead to portal venous thrombosis? Prospective US evaluation in 100 neonates. Radiology. 2001;219(3):645-650. doi:10.1148/radiology.219.3.r01jn17645
    CrossRef - PubMed
    
21. Abd El-Hamid N, Taylor RM, Marinello D, et al. Aetiology and management of extrahepatic portal vein obstruction in children: King’s College Hospital experience. J Pediatr Gastroenterol Nutr. 2008;47(5):630-634. doi:10.1097/MPG.0b013e31817b6eea
    CrossRef - PubMed
22. Wani ZA, Bhat RA, Bhadoria AS, Maiwall R. Extrahepatic portal vein obstruction and portal vein thrombosis in special situations: need for a new classification. Saudi J Gastroenterol. 2015;21(3):129-138. doi:10.4103/1319-3767.157550
    CrossRef - PubMed
23. Flores-Calderon J, Moran-Villota S, Rouassant SH, et al. Guidelines for the diagnosis and treatment of extrahepatic portal vein obstruction (EHPVO) in children. Ann Hepatol. 2013;12 Suppl 1:S3-S24. doi:10.1016/S1665-2681(19)31403-6
    CrossRef - PubMed
24. Janssen HL, Meinardi JR, Vleggaar FP, et al. Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study. Blood. 2000;96(7):2364-2368.
    CrossRef - PubMed
    
25. Weiss B, Shteyer E, Vivante A, et al. Etiology and long-term outcome of extrahepatic portal vein obstruction in children. World J Gastroenterol. 2010;16(39):4968-4972. doi:10.3748/wjg.v16.i39.4968
    CrossRef - PubMed
26. Egesel T, Buyukasik Y, Dundar SV, Gurgey A, Kirazli S, Bayraktar Y. The role of natural anticoagulant deficiencies and factor V Leiden in the development of idiopathic portal vein thrombosis. J Clin Gastroenterol. 2000;30(1):66-71. doi:10.1097/00004836-200001000-00013
    CrossRef - PubMed
27. Kilambi R, Singh AN, Madhusudhan KS, et al. Portal hypertension and hypersplenism in extrahepatic portal venous obstruction: are they related? Indian J Gastroenterol. 2018;37(3):202-208. doi:10.1007/s12664-018-0864-7
    CrossRef - PubMed
28. Bellomo-Brandao MA, Morcillo AM, Hessel G, Cardoso SR, Servidoni Mde F, da-Costa-Pinto EA. Growth assessment in children with extra-hepatic portal vein obstruction and portal hypertension. Arq Gastroenterol. 2003;40(4):247-250. doi:10.1590/s0004-28032003000400009
    CrossRef - PubMed
    
29. Bass LM, Alonso EM. Portal hypertension. In: Wyliie R, Hyams JS, Kay M. Pediatric Gastrointestinal and Liver Disease. 5th ed. Elsevier; 2015:928-943.
    CrossRef - PubMed
    
30. de Franchis R, Baveno VIF. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop. Stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63(3):743-752. doi:10.1016/j.jhep.2015.05.022
    CrossRef - PubMed
31. Groszmann RJ, Garcia-Tsao G, Bosch J, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005;353(21):2254-2261. doi:10.1056/NEJMoa044456
    CrossRef - PubMed
32. Duche M, Ducot B, Ackermann O, Guerin F, Jacquemin E, Bernard O. Portal hypertension in children: high-risk varices, primary prophylaxis and consequences of bleeding. J Hepatol. 2017;66(2):320-327. doi:10.1016/j.jhep.2016.09.006
    CrossRef - PubMed
33. Gauthier-Villars M, Franchi S, Gauthier F, Fabre M, Pariente D, Bernard O. Cholestasis in children with portal vein obstruction. J Pediatr. 2005;146(4):568-573.
    CrossRef - PubMed
    
34. Sarma MS, Seetharaman J. Pediatric non-cirrhotic portal hypertension: endoscopic outcome and perspectives from developing nations. World J Hepatol. 2021;13(10):1269-1288. doi:10.4254/wjh.v13.i10.1269
    CrossRef - PubMed