Extra hepatic portal vein obstruction

Non cirrhotic portal hypertension, Extra hepatic portal vein obstruction

1. Noncirrhotic portal hypertension Extrahepatic portal vein obstruction Pratap Sagar Tiwari Total slides: 57

2. Introduction Portal hypertension is a clinical manifestation which is defined as the presence of a Hepatic venous pressure gradient > 5 mmHg ( 1 ). The MC cause of PHTN is LC . There are, however, a variety of disorders which develop PHTN without LC and falls under the category of Non-Cirrhotic portal hypertension. The diseases leading to NCPH are primarily vascular in nature and classified anatomically on the basis of site of resistance to BF , as prehepatic, hepatic, and post-hepatic – hepatic causes are further subdivided into pre-sinusoidal, sinusoidal and post-sinusoidal [2,3]. Sanyal AJ, Bosch J, Blei A, Arroyo V. Portal hypertension and its complications. Gastroenterology 2008;134:1715–1728. Sarin SK, Kumar A. Noncirrhotic portal hypertension. Clin Liver Dis 2006;10:627–651. Schouten JNL, Garcia-Pagan JC, Valla DC, Janssen HLA. Idiopathic noncirrhotic portal hypertension. Hepatology 2011;54:1071–1081. Sarin SK, Agarwal SR. Extrahepatic portal vein obstruction. Semin Liver Dis 2002;22:43–58. Garcia-Pagan JC, Hernandez-Guerra M, Bosch J. Extrahepatic portal vein thrombosis. Semin Liver Dis 2008;28:282–292. Most of the times, PHT is a late manifestation of the primary disease. However, NCPF and EHPVO are two disorders, which present only with features of PHT without any evidence of significant parenchymal dysfunction [2–5].

3. Causes of NCPH Sarin SK. Idiopathic portal hypertension and extrahepatic portal venous obstruction. Hepatology International 2018, Volume 12, Supplement 1, pp 148–167 3

4. Definition: EHPVO As per the APASL:2006 consensus, EHPVO is defined as ‘‘ a vascular disorder of liver, characterized by obstruction of the extra-hepatic PV with or without involvement of intra-hepatic PV radicles or splenic or SMV ’’ [1]. Baveno VI consensus incorporates recent thrombus in the PV in the definition along with the presence of cavernoma , however, excludes LC and other liver diseases like NCPF, as well as HCC, and emphasizes that EHPVO in these settings as different entity [2]. Acute PVT does not necessarily lead to cavernoma formation and hence is excluded. Similarly, isolated occlusion of the SV/SMV has an altogether different etiological & clinical presentation, and is, therefore, removed from the defining criteria of EHPVO. Sarin SK, Sollano JD, Chawla YK, Amarapurkar D, Hamid S, Hashizume M, et al. Members of the APASL working party on portal hypertension. Consensus on extra-hepatic portal vein obstruction. Liver Int 2006;26:512–519. De Franchis R, Baveno VI Faculty. Expanding consensus in portal hypertension report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743–752 EHPVO is a distinct disease entity and should neither be considered an event in the natural history nor an association of primary liver disease. 4

5. It is a major cause of PHTN (54%) and UGIB in children (68–84%) from the developing world [1,2]. In the West, non-cirrhotic non-tumoral PVT is the second most frequent cause of PHTN in adults after cirrhosis [4], while in children, it constitutes a small proportion (11–12%) [2]. Poddar U, Thapa BR, Rao KL, Singh K. Etiological spectrum of esphageal varices due to portal hypertension in Indian children: is it different from the West? J Gastroenterol Hepatol 2008;23:1354–1357 Fagundes ED, Ferreira AR, Roquete ML, Penna FJ, Goulart EM, Figueiredo Filho PP, Bittencourt PF, Carvalho SD, Albuquerque W. Clinical and laboratory predictors of esophageal varices in children and adolescents with portal hypertension syndrome. J Pediatr Gastroenterol Nutr 2008;46(2):178–183 Duche ´ M, Ducot B, Ackermann O, Gue´rin F, Jacquemin E, Bernard O. Portalhypertension in children: high-risk varices, primary prophylaxis and consequencesof bleeding. J Hepatol 2017;66(2):320–327 Garcia-Pagan JC, Hernandez-Guerra M, Bosch J. Extrahepatic portal vein thrombosis. Semin Liver Dis 2008;28(3):282–292 5 From the largest French series on pediatric PHTN, EHPVO constitutes 12% of overall causes , and second commonest single etiology after biliary atresia [3].

6. Etiological factors differ among pediatric and adult populations and despite extensive history and laboratory work-up, idiopathic cases constitute around 13–28% of adults and 26–62% of children with EHPVO. Congenital anomalies have been reported in 30% of children with EHPVO —more often in those without history of omphalitis—the commonest ones were cardiovascular and urinary tract abnormalities, others had Turner’s syndrome, cleft lip and palate, coloboma, external ear, and limb deformities [1,2]. 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;47:630–634 Odie`vre M, Pige ´ G, Alagille D. Congenital abnormalities associated with extrahepatic portal hypertension. Arch Dis Child 1977;52(5):383–385 6

7. Frequency of causes a/with EHPVO in children. Calderón JF, et al. Guidelines for the diagnosis and treatment of extrahepatic portal vein obstruction (EHPVO) in children. Annals of hepatology 2013; 12 (Suppl.1): s3-s24 7

8. Schouten et al Sarin and Kumar Sato and Kitao et al 8

9. Pathogenetic theories The Unifying hypothesis proposed by Sarin and Kumar gives a common explanation of the pathogenesis of NCPF/IPH and EHPVO [1]. A major thrombotic event occuring at a young age involves main PV and results in EHPVO , whereas repeated microthrombotic events later in life involve small or medium branches of PV leading to NCPF. As per dual theory proposed by Schouten et al , both increased splenic blood flow and intrahepatic obstruction (obliterative venopathy ) have a role. High levels of inducible ( iNOS ) as well as endothelial nitric oxide synthase ( eNOS ) in splenic endothelial cells lead to dilatation of splenic sinuses and increased splenic venous inflow [2]. Sarin SK, Kumar A. Noncirrhotic portal hypertension. Clin Liver Dis 2006;10:627–651. Schouten JNL, Garcia-Pagan JC, Valla DC, Janssen HLA. Idiopathic noncirrhotic portal hypertension. Hepatology 2011;54:1071–1081. 9

10. Pathogenetic theories Endothelial-mesenchymal transition ( EndMT ) theory by Sato and Kitao et al . says that vascular endothelial cells of portal venules acquire myofibroblastic features as evidenced by reduced expression of vascular endothelial cell marker CD34, and increased expression of mesenchymal cell markers S100A4, a-SMA, COL1A1, and pSmad2 . Transforming growth factor-b1 (TGF-b1) acts as a potent inducer of EndMT . Following transformation, these cells synthesize type I collagen, which causes obliterative portal venopathy and presinusoidal PHT [1]. Sato Y, Nakanuma Y. Role of endothelial-mesenchymal transition in idiopathic portal hypertension. Histol Histopathol 2013;28:145–154. 10

11. Pathogenesis In most of the pts, the acute inciting event leading to EHPVO often goes unrecognized and thrombus gradually becomes organized . Multiple tortuous hepatopetal collaterals, which develop around and inside the thrombus within the PV, known as cavernoma , appear within a span of 6–20 days following PV flow interruption. These collaterals tend to overcome the prehepatic obstruction and terminate in middle-sized intrahepatic PV branches , but remain insufficient to decompress high pressure in the splanchnic bed and to compensate the reduction of total hepatic blood flow. Hence, hepatofugal vessels do develop at the sites of portosystemic communications and transform into varices, hemorrhoids, collaterals, or spontaneous shunts [1]. 11

12. Clinical features EHPVO has a bimodal age of presentation —those secondary to UVC, omphalitis, or perinatal events usually manifest early (3 years), while those following intraabdominal infections or idiopathic ones manifest late (8 years) or sometimes into early adulthood [1]. Variceal bleed (49–85%) and splenomegaly (63–88%) are the commonest presentations in children. Mean ages of first bleeding episode are around 3.8–5.2 years [2-10]. Khanna R, Sarin SK. Non-cirrhotic portal hypertension. J Hepatol 2014;60:421–441 Poddar U, Thapa BR, Rao KL, Singh K. Etiological spectrum of esphageal varices due to portal hypertension in Indian children: is it different from the West? J Gastroenterol Hepatol 2008;23:1354–1357 El- Karaksy H, El- Koofy N, El- Hawary M, et al. Prevalence of factor V Leiden mutation and other hereditary thrombophilic factors in Egyptian children with portal vein thrombosis: results of a single-center case–control study. Ann Hematol 2004;83:712–715 El- Karaksy HM, El- Koofy N, Mohsen N, Helmy H, Nabil N, El- Shabrawi M. Extrahepatic portal vein obstruction in Egyptian children. J Pediatr Gastroenterol Nutr 2015;60(1):105–109 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;47:630–634 Pietrobattista A, Luciani M, Abraldes JG, Candusso M, Pancotti S, Soldati M, Monti L, Torre G, Nobili V. Extrahepatic portal vein thrombosis in children and adolescents: Influence of genetic thrombophilic disorders. World J Gastroenterol 2010;16(48):6123–6127 Weiss B, Shteyer E, Vivante A, et al. Etiology and long-term outcome of extrahepatic portal vein obstruction in children. World J Gastroenterol 2010;16:4968–4972 Ferri PM, Rodrigues Ferreira A, Fagundes ED, Xavier SG, Dias Ribeiro D, et al. Evaluation of the presence of hereditary and acquired thrombophilias in brazilian children and adolescents with diagnoses of portal vein thrombosis. J Pediatr Gastroenterol Nutr 2012;55(5):599–604 Shneider BL, de Ville de Goyet J, Leung DH, Srivastava A, Ling SC, Duche ´ M, et al. Primary prophylaxis of variceal bleeding in children and the role of Meso-Rex bypass: summary of the Baveno VI pediatric satellite symposium. Hepatology 2016;63(4):1368–1380 Alberti D, Colusso M, Cheli M, Ravelli P, Indriolo A, Signorelli S, Fagiuoli S, D’Antiga L. Results of a stepwise approach to extrahepatic portal vein obstruction in children. J Pediatr Gastroenterol Nutr 2013;57(5):619–626 12

13. VH episodes are often recurrent, related to febrile illnesses, use of NSAID, and ↑ in frequency and severity with age till adolescence. In contrast to cirrhosis, these bleeding episodes are well tolerated in view of preserved liver synthetic functions . Noronha Ferreira C, Seijo S, Plessier A, Silva-Junior G, Turon F, Rautou PE, et al. Natural history and management of esophagogastric varices in chronic noncirrhotic, nontumoral portal vein thrombosis. Hepatology 2016;63(5):1640–1650 13 From a series of 178 adults followed up with splanchnic venous thrombosis, variceal bleeding was seen in 32%; 15% at presentation and 17% at a median follow-up of 4 years . The source of bleeding was EV in 84%, GV in 7%, PHG in 7%, and ectopic varices in 2% [1].

14. Moderate splenomegaly is characteristically present which ↑ with the age of the child, but without any correlation with frequency and severity of bleeds [1]. Ascites is present in 4% of children and in up to 21% of adults and is often transient, related to the bleeding episode, growth failure, and hypoalbuminemia [2,3]. Persistent ascites is usually seen late in the course of disease as part of prolonged duration of PHTN with subsequent progressive deterioration of liver functions [3]. Khanna R, Sarin SK. Non-cirrhotic portal hypertension. J Hepatol 2014;60:421–441 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;47:630–634 Rangari M, Gupta R, Jain M, Malhotra V, Sarin SK. Hepatic dysfunction in patients with extrahepatic portal venous obstruction. Liver Int 2003;23(6):434–439 14

15. In study by Sarin  et al .  in 499 (1983-2005) EHPVO pts. The clinical and demographic profile is as shown below.[1] Kumar A, Sharma BC, Sarin SK. Profile of gastrointestinal hemorrhage in 499 patients of extra-hepatic portal vein obstruction (EHPVO) [abstract] Indian J Gastroenterol. 2005;24(Suppl 1):A69. 15

16. Laboratory evaluation Hypersplenism is commonly seen, in up to 85%, but is mostly asymptomatic. Liver functions are well preserved in most individuals; a proportion (4–9%) may have abnormal transaminases . Elevations of alkaline phosphatase and GGT are seen with development of portal biliopathy , while hypoalbuminemia may be seen during bleed episodes particularly in the setting of growth failure [1, 2]. Khanna R, Sarin SK. Non-cirrhotic portal hypertension. J Hepatol 2014;60:421–441 Garcia-Pagan JC, Hernandez-Guerra M, Bosch J. Extrahepatic portal vein thrombosis. Semin Liver Dis 2008;28(3):282–292 16

17. Hemodynamics Intra-splenic (ISP) and intra-variceal pressures (IVP) are significantly elevated in both NCPF/IPH as well as EHPVO as compared to WHVP and intrahepatic pressures (IHP), suggesting a presinusoidal level of block. Hepatic blood flow is normal or decreased , depending on collateral flow and hepatic arterial buffer response. Hyperdynamic circulatory state in EHPVO subjects has been shown to be comparable to cirrhotics , which is possibly related to elevated nitric oxide levels [1,2]. Khanna R, Sarin SK. Non-cirrhotic portal hypertension. J Hepatol 2014;60:421–441 Jha SK, Kumar A, Sharma BC, Sarin SK. Systemic and pulmonary hemodynamics in patients with extrahepatic portal vein obstruction is similar to compensated cirrhotic patients. Hepatol Int 2009;3:384–391 17

18. Endoscopic findings Esophageal, gastric, and anorectal varices are common ( 90 Vs 70 , 44 Vs 22 , and 89 Vs 56 %), while PHG is less frequent ( 5 Vs 11 %) in adults with EHPVO in contrast to their cirrhotic counterparts [1-5]. EV are more often large. IGV1 are present in up to 6% of EHPVO pts. Comparable data in pediatric population also reveal that EHPVO children have greater proportion of high risk varices than the cirrhotic etiologies (70 vs 32%)—EV are seen in 85–94% and two-thirds have large varices with RCS [6]. PHG usually develops after variceal eradication , and is often transient, non-progressive, and asymptomatic [3,7,8]. Khanna R, Sarin SK. Non-cirrhotic portal hypertension. J Hepatol 2014;60:421–441 Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK. Prevalence, classification and natural history of gastric varices: a long-term follow up study in 568 portal hypertension patients. Hepatology 1992;16:1343–1349 Sarin SK, Shahi HM, Jain M, et al. The natural history of portal hypertensive gastropathy: influence of variceal eradication. Am J Gastroenterol 2000;95:2888–2893 Chawla Y, Dilawari JB. Anorectal varices—their frequency in cirrhotic and non-cirrhotic portal hypertension. Gut 1991;32:309–311 Noronha Ferreira C, Seijo S, Plessier A, Silva-Junior G, Turon F, Rautou PE, et al. Natural history and management of esophagogastric varices in chronic noncirrhotic, nontumoral portal vein thrombosis. Hepatology 2016;63(5):1640–1650 Duche ´ M, Ducot B, Ackermann O, Gue´rin F, Jacquemin E, Bernard O. Portalhypertension in children: high-risk varices, primary prophylaxis and consequencesof bleeding. J Hepatol 2017;66(2):320–327 Zargar SA, Yattoo GN, Javid G, Khan BA, Shah AH, Shah NA, et al. Fifteen-year follow up of endoscopic injection sclerotherapy in children with extrahepatic portal venous obstruction. J Gastroenterol Hepatol 2004;19:139–145 Itha S, Yachha SK. Endoscopic outcome beyond esophageal variceal eradication in children with extrahepatic portal venous obstruction. J Pediatr Gastroenterol Nutr 2006;42(2):196–200 18

19. Radiological features Doppler USG of splenoportal axis reveals cavernoma and is the diagnostic investigation of choice with a SN and SP of >95% [1, 2]. Splenoportography or arterial portography , used in old days, has now become obsolete and has been replaced by non-invasive methods— CT and magnetic resonance (MR) portovenography . The later two techniques also provide an anatomical road-map prior to shunt surgery [3]. Splenic stiffness on TE is high in pts with EHPVO and a value above 42.8 kPa is shown to predict variceal bleed with a SN and SP of 88 and 94%, respectively [4]. Khanna R, Sarin SK. Non-cirrhotic portal hypertension. J Hepatol 2014;60:421–441 Garcia-Pagan JC, Hernandez-Guerra M, Bosch J. Extrahepatic portal vein thrombosis. Semin Liver Dis 2008;28(3):282–292 Shneider BL, de Ville de Goyet J, Leung DH, Srivastava A, Ling SC, Duche ´ M, et al. Primary prophylaxis of variceal bleeding in children and the role of Meso-Rex bypass: summary of the Baveno VI pediatric satellite symposium. Hepatology 2016;63(4):1368–1380 Sharma P, Mishra SR, Kumar M, Sharma BC, Sarin SK. Liver and spleen stiffness in patients with extrahepatic portal vein obstruction. Radiology 2012;263(3):893–899 19

20. Liver biopsy Liver biopsy is not required in children with EHPVO unless and until there is a strong clinical suspicion of underlying liver disease . In adults with EHPVO, there may be occasions where liver biopsy is required to rule out cirrhosis [1]. De Franchis R, Baveno VI Faculty. Expanding consensus in portal hypertension report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743–752 20

21. Diagnosis Diagnosis of EHPVO is based on Baveno VI consensus , i.e., demonstration of portal cavernoma on USG Doppler in the absence of features of cirrhosis or CLD . Liver biopsy and HVPG are recommended only if the liver is dysmorphic on imaging or with abnormal liver function tests [1]. De Franchis R, Baveno VI Faculty. Expanding consensus in portal hypertension report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743–752 21

22. Natural history From a large series of 178 adults, the 1-, 3-, and 5-year survival is 99, 98, and 96%. Following eradication of EV with EST or EVL, GOV1 also decrease , while GOV2, IGV1 and PHG increase [1,2,3]. Mortality related to variceal bleed and intestinal infarction is <5% [4]. Although the long-term (≥ 10-year) survival of EHPVO is around 90%, significant morbidity affects the QOL of these children and young adults. In the pediatric age-group, growth failure, and splenomegaly , and in the older age-group, portal biliopathy, minimal HE, parenchymal extinction, and complications related to myeloproliferative state itself outnumber the bleeding risk [5]. Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK. Prevalence, classification and natural history of gastric varices: a long-term follow up study in 568 portal hypertension patients. Hepatology 1992;16:1343–1349 Sarin SK, Shahi HM, Jain M, et al. The natural history of portal hypertensive gastropathy: influence of variceal eradication. Am J Gastroenterol 2000;95:2888–2893 Zargar SA, Yattoo GN, Javid G, Khan BA, Shah AH, Shah NA, et al. Fifteen-year follow up of endoscopic injection sclerotherapy in children with extrahepatic portal venous obstruction. J Gastroenterol Hepatol 2004;19:139–145 Noronha Ferreira C, Seijo S, Plessier A, Silva-Junior G, Turon F, Rautou PE, et al. Natural history and management of esophagogastric varices in chronic noncirrhotic, nontumoral portal vein thrombosis. Hepatology 2016;63(5):1640–1650 Khanna R, Sarin SK. Non-cirrhotic portal hypertension. J Hepatol 2014;60:421–441 22

23. Natural history of bleeding after EV eradication in pts with EHPVO; a 20-year follow-up Background Long-term follow-up studies of pts with EHPVO after eradication of EV using EST are limited. Methods Between 1985 and 1994, 223 pts with bleeding EV due to EHPVO underwent variceal eradication using EST. Regular annual clinical and endoscopic follow-up data were available for 198 of these pts for a mean period of 19.8 (range: 14–23) yrs. These data were analyzed retrospectively. Results Of the 198 pts, 34 (17.2%) had rebleeding after variceal eradication. The mean duration from variceal eradication to recurrence of bleeding was 5.4 years. The causes of rebleeding were: recurrent EV in 21 pts, FV in eight, PHG in three, and ectopic varices in two pts. EV reappeared in 39 (19.7%) pts. Fundal varices appeared in 19 (9.5%) pts during follow-up. Conclusions EST is an effective RX modality for bleeding EV due to EHPVO . During a follow- up of nearly 20 yrs after variceal eradication, only about one-sixth of the pts had recurrence of GIB . Bleeding was unusual after 10 yrs had passed since initial variceal eradication. Thomas V, Jose T, Kumar S. Natural history of bleeding after esophageal variceal eradication in patients with extrahepatic portal venous obstruction; a 20-year follow-up. Indian J Gastroenterol 2009(November–December):28(6):206–211 23

24. Results of long term follow-up studies of children with EHPVO after variceal eradication with EST Zargar SA, Yattoo GN, Javid G, et al. Fifteen-year follow up of endoscopic injection sclerotherapy in children with extrahepatic portal venous obstruction. J Gastroenterol Hepatol 2004;19:139–45. Yachha SK, Sharma BC, Kumar M, Khanduri A. Endoscopic sclerotherapy for esophageal varices in children with extrahepatic portal venous obstruction: a follow-up study. J Pediatr Gastroenterol Nutr 1997;24:49–52. Howard ER, Stringer MD, Mowat AP. Assessment of injection sclerotherapy in the management of 152 children with oesophageal varices. Br J Surg 1988;75:404–8. Hill ID, Bowie MD. Endoscopic sclerotherapy for control of bleeding varices in children. Am J Gastroenterol 1991;86:472–6. Dilawari JB, Chawla YK, Ramesh GN, Mitra SK, Walia BN. Endoscopic sclerotherapy in children. J Gastroenterol Hepatol 1989;4:155–60. 24

25. Growth retardation Almost one-third to half of these children have wasting and stunting [1,2]. The severity of growth failure is related to duration of PHT and is independent of appropriate energy intake [1]. Growth failure in EHPVO is multifactorial and is related to (1) deprivation of portal blood flow leading to reduction of hepatotropic factors; (2) malabsorption secondary to portal hypertensive enteropathy, the fact which is supported by studies where improvement in growth indices is shown after portosystemic shunt surgery; (3) early satiety due to massive splenomegaly; (4) growth hormone (GH) resistance evidenced by high levels of GH and low levels of insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3); (5) anemia and hypersplenism [1-3]. Sarin SK, Bansal A, Sasan S, Nigam A. Portal-vein obstruction in children leads to growth retardation. Hepatology 1992;15:229–233 Mehrotra RN, Bhatia V, Dabadghao P, Yachha SK. Extrahepatic portal vein obstruction in children: anthropometry, growth hormone and insulin-like growth factor I. J Pediatri Gastroenterol Nutr 1997;25:520–523 Khanna R, Sarin SK. Non-cirrhotic portal hypertension. J Hepatol 2014;60:421–441 25

26. Impaired quality of life (QoL) Children with EHPVO have poor health-related QoL with lower median scores in physical, social, emotional, and school functioning health domains in contrast to healthy children, and these are primarily affected by spleen size and growth failure, but are unrelated to variceal eradication. An improving QoL has been demonstrated following shunt surgery [87]. Krishna YR, Yachha SK, Srivastava A, Negi D, Lal R, Poddar U. Quality of life in children managed for extrahepatic portal venous obstruction. J Pediatr Gastroenterol Nutr 2010;50(5):531–536 26

27. Minimal hepatic encephalopathy (MHE) MHE is well described in the setting of EHPVO with or without shunt surgery [1-3]. Following shunt surgery, toxic substances directly enter from portal blood into systemic circulation, and hence, MHE is more prevalent with non-selective in comparison to selective shunts . However, MHE is also seen in 32–35% cases in the absence of shunt on the basis of abnormalities in critical flicker frequency, psychometric tests, and P300 auditory event-related potential [2]. This may be related to chronic deprivation of hepatic BF leading to parenchymal extinction and is evidenced by ↑ brain glutamine and glutamine/creatine ratio on MR spectroscopy, ↑ blood ammonia, and proinflammatory cytokines (TNF-a and IL-6)[3]. Sharma P, Sharma BC, Puri V, Sarin SK. Minimal hepatic encephalopathy in patients with extrahepatic portal vein obstruction. Am J Gastroenterol 2008;103(6):1406–1412 Yadav SK, Srivastava A, Srivastava A, Thomas MA, Agarwal J, Pandey CM, et al. Encephalopathy assessment in children with extra-hepatic portal vein obstruction with MR, psychometry and critical flicker frequency. J Hepatol 2010;52:348–354 Srivastava A, Yadav SK, Yachha SK, Thomas MA, Saraswat VA, Gupta RK. Pro-inflammatory cytokines are raised in extrahepatic portal venous obstruction with minimal hepatic encephalopathy. J Gastroenterol Hepatol 2011;26(6):979–986 27

28. Parenchymal extinction and liver dysfunction Progressive deterioration of liver functions, ascites, and encephalopathy may develop with increasing age and prolonged duration of disease, and is a/with more severe portal biliopathy changes [80]. 28

29. Portal cavernous cholangiopathy Anatomy Definition Classification Management 29

30. Vascular anatomy of bile ducts General pattern of arterial supply and venous drainage of the bile ducts is quite similar. Two venous plexuses drain the biliary tract. The fine reticular epicholedochal venous plexus of Saint on the wall of the bile duct drains into the paracholedochal venous plexus of Petren (also called marginal veins or parabiliary venous system) which in turn is connected to the posterior superior pancreaticoduodenal vein, gastrocolic trunk, right gastric vein, SMV inferiorly and intrahepatic PV branches superiorly. Sharma MM. Portal cavernoma cholangiopathy: an endoscopic ultrasound based imaging approach. Journal of clinical and experimental hepatology 2014 30

31. Vascular anatomy of bile ducts Fine branches from the posterior superior pancreaticoduodenal, retroportal , gastroduodenal, hepatic and cystic arteries form two plexuses to supply the bile ducts . The paracholedochal plexus , as right and left marginal arteries, runs along the margins of the bile duct and the reticular epicholedochal plexus lies on the surface. Sharma MM. Portal cavernoma cholangiopathy: an endoscopic ultrasound based imaging approach. Journal of clinical and experimental hepatology 2014 31

32. In conditions of porto -mesenteric venous obstruction, these plexuses enlarge to form a portal cavernoma surrounding the bile duct and bring about morphological changes observed in PCC. Biliary changes seen in PCC may be due to compression by large collaterals or may be ischemic, due to PVT and/or prolonged biliary compression . Compression of paracholedochal venous plexus leads to varicoid type of PB involving entire biliary system giving a wavy or undulating contour, and may show favourable response following shunt surgery. Contrastingly, chronic inflammation and ischemia lead to scarring of bile duct wall causing fibrotic type of PB producing single or multiple segmental strictures with upstream dilatation, the changes which are possibly non-reversible [1]. Shin SM, Kim S, Lee JW, Kim CW, Lee TH, Lee SH, Kim GH. Biliary abnormalities associated with portal biliopathy: evaluation on MR cholangiography. AJR Am J Roentgenol 2007;188(4):W341–W3417 32

33. Relationship between jaundice and EHPVO The relationship between jaundice and EHPVO was first reported by Gibson et al in 1965.[1] After that several reports of jaundice or varices along the bile duct in pts of EHPVO are available in the literature.[2–4] The first description of the cholangiographic changes in EHPVO was by Williams et al in 1982 who demonstrated varices along the bile duct.[5] The first prospective case series describing biliary abnormalities on ERC in pts of EHPVO was published by Dilawari and Chawla in 1992.[6] All 20 pts were found to have biliary abnormalities similar to that seen in sclerosing cholangitis, mainly involving the left hepatic duct and mid CBD. Gibson JB, Johnston GW, Fulton TT, et al. Extrahepatic portal venous obstruction. Br J Surg. 1965;52:129–139. Dan SJ, Train JS, Cohen BA, Mitty MA. Common bile duct varices cholangiographic demonstration of a hazardous portosystemic communication. Am J Gastroenterol. 1983;78:42–43. Spira R, Widrich WC, Keush KD, Jackson BT, Katzman HE, Coello AA. Bile duct varices. Arch Surg. 1985;120:1194–1196. Kim S, Chew FS. Choledochal varices. AJR. 1988;150:578–580. Williams SM, Burnett DA, Mazer MU. Radiographic demonstration of common bile duct varices. Gastrointest Radiol . 1982; 7:69–70. Dilawari JB, Chawla YK. Pseudosclerosing cholangitis in extrahepatic portal venous obstruction. Gut. 1992;33:272–276. 33

34. Biliary changes in EHPVO Subsequently biliary changes were also demonstrated in other causes of PHTN like NCPF and LC , albeit with less frequency.[1-3] Biliary changes are seen on cholangiography in 81–100% of pts with EHPVO [4-12] compared with 0–33% in LC [1,8,13] and 9–40% in NCPF .[1,13] This is probably due to the longer duration of PHTN in cases of EHPVO in many of whom the obstruction to the PV occurs in infancy or childhood compared to LC. This is supported by also a significantly higher frequency of anorectal varices, LEV and variceal bleeding in pts with EHPVO compared with those having LC.[14,15] However, despite the high frequency of cholangiographic changes these same studies found that only a minority of these pts are symptomatic. References are at the end of the slides 34

35. Frequency of Biliary Changes in Pts with EHPVO 1 3 11 9 7 5 4 6 8 10 References are at the end of the slides 35

36. Portal biliopathy Sarin et al have defined portal biliopathy broadly as biliary ductal and gallbladder wall abnormalities seen in pts with PHTN which though simple, is vague and would include biliary changes due to any other disease in a pt who happens to have PHTN also.[1] Dhiman et al have proposed a more descriptive definition as abnormalities of the entire biliary tract including intrahepatic and extrahepatic bile ducts, cystic duct and gallbladder in pts with PHTN.[ 2] This definition also does not specify what changes are to be included and in which portions of the biliary tree the changes are mandatory. The need was felt to have a definition which would be specific to this condition so as to have reproducibility between studies from different authors on this subject. Sarin SK, Bhatia V, Makwana U. Portal biliopathy in extrahepatic portal venous obstruction [abstract]. Indian J Gastroenterol. 1992;11(suppl 1):A82. J Gastroenterol Hepatol2006;21:A504. Dhiman RK, Behera A, Chawla YK, Dilawari JB, Suri S. Portal hypertensive biliopathy. Gut. 2007;56:1001–1008. 36

37. PCC: Definition IASL defined PCC as abnormalities in the extrahepatic biliary system including the cystic duct and gallbladder with or without abnormalities in the 1st and 2nd generation biliary ducts in a patient with portal cavernoma . For the DX to be established all of the following 3 criteria would have to be fulfilled: 1. The presence of a portal cavernoma, 2. Cholangiographic changes on ERC or MRC consistent with typical changes described for this entity. 3. Absence of other causes of these biliary changes like bile duct injury, PSC, CCA etc. Yogesh Chawla, Swastik Agrawal. Portal Cavernoma Cholangiopathy – History, Definition and Nomenclature. J CLIN EXP HEPATOL 2014;4:S15–S17 37

38. In EHPVO, it has been shown that those symptoms due to PCC usually start a decade later than variceal bleed and are common when PVT extends into mesenteric veins or when the bile duct is more acutely angulated [2-4]. ERCP is the diagnostic gold standard; but is now being replaced by non-invasive MRCP which when combined with portovenography helps in detection of choledochal and epicholedochal varices [5]. EUS is also useful for detection of perforators and intracholedochal varices [6]. Natural history of biliopathy is poorly defined, but a slow progression is well known with development of symptoms over a decade. Overall 4–10% pts develop complications like choledocholithiasis, cholangitis, and secondary biliary cirrhosis [1,2]. {5-50 % [7]} Chandra R, Kapoor D, Tharakan A, Chaudhary A, Sarin SK. Portal biliopathy. J Gastroenterol Hepatol 2001;16:1086–1092 Khuroo MS, Yattoo GN, Zargar SA, Javid G, Dar MY, Khan BA, et al. Biliary abnormalities associated with extrahepatic portal venous obstruction. Hepatology 1993;17:807–813 Shin SM, Kim S, Lee JW, Kim CW, Lee TH, Lee SH, Kim GH. Biliary abnormalities associated with portal biliopathy: evaluation on MR cholangiography. AJR Am J Roentgenol 2007;188(4):W341–W3417 Chattopadhyay S, Govindasamy M, Singla P, Varma V, Mehta N, Kumaran V, Nundy S. Portal biliopathy in patients with noncirrhotic portal hypertension: does the type of surgery affect outcome? HPB (Oxford) 2012;14(7):441–447 Jabeen S, Robbani I, Choh NA, Ashraf O, Shaheen F, Gojwari T, et al. Spectrum of biliary abnormalities in portal cavernoma cholangiopathy (PCC) secondary toidiopathic extrahepatic portal vein obstruction (EHPVO)—a prospective magnetic resonance cholangiopancreaticography (MRCP) based study. Br J Radiol 2016;89(1068):20160636 Rai GP, Nijhawan S, Madhu MP, Sharma SS, Pokharna R. Comparative evaluation of magnetic resonance cholangiopancreatography/magnetic resonance splenoportovenography and endoscopic ultrasound in the diagnosis of portal cavernoma cholangiopathy. Indian J Gastroenterol 2015;34(6):442–447 Duseja A. Portal cavernoma cholangiopathy (PCC)—clinical characteristics. J Clin Exp Hepatol. 2014;4:S34–S36. 38

39. INASL 2014 STATEMENT ERC has no diagnostic role because it is invasive and is a/with risk of complications. ERC is reserved for therapeutic procedures. USG with Color Doppler should be the initial imaging modality for suspected cases of PCC MRC with MR portovenography is a noninvasive and comprehensive imaging technique, and is the modality of choice for mapping of the biliary and vascular abnormalities in patients with PCC MRC is as accurate as ERC in delineating biliary changes . MRC with MR portovenography demonstrates relationship of biliary changes with collaterals and the presence of shuntable vein. It also helps to distinguish between bile duct varices and CBD stones. EUS is useful when other imaging modalities are unrevealing or inconclusive in delineating the cause of biliary obstruction. 39

40. Stages in the Natural History of PCC 40

41. MANAGEMENT Control and prophylaxis of variceal bleed Role of surgery Role of interventional radiology techniques Management of portal biliopathy Role of anti-coagulation Surveillance 41

42. Algorithmic approach for the DX of EHPVO and MX of esophageal and gastric varices. 42

43. 43

44. Surgical considerations in EHPVO. 44

45. Types of Shunts & its variants Rex Shunt Spleno-renal shunts Meso-caval Porta-caval Selective (decompressing GEV but maintaining the SMV flow to the liver, as in DSRS . Non-selective (decompressing all PHTN) 45

46. Algorithm for management of PCC in EHPVO 46

47. Algorithm for management of PCC in EHPVO *EUS with Doppler for evaluation of biliary obstruction when other imaging modalities are unrevealing; endoscopic treatment includes endoscopic sphincterotomy, stone extraction with or without the help of mechanical lithotripsy, plastic biliary stent placement, etc ; endoscopic treatment includes endoscopic sphincterotomy and stricture dilatation, followed by stone extraction with or without the help of mechanical lithotripsy. P1, phase 1; P2, phase 2 and P3, phase 3. (Modified from Dhiman RK, et al. Gut 2007;56:1001–8). 47

48. The Three Phase approach Treatment of symptomatic PCC can be approached in a phased manner, first with biliary clearance ; second , with portal decompression ; and third , with Surgery for persistent biliary obstruction . The third phase involves MX of cases who continue to have biliary obstruction and remain symptomatic despite shunt procedure either due to blockage of shunt or due to persistent obstruction despite patent shunt. Second-stage biliary drainage surgery like hepaticojejunostomy or choledochoduodenostomy surgery on the bile ducts is performed in most of these cases with good resolution of symptoms as well as LFT. In symptomatic PCC, the second phase involves portal decompression surgery by PSRS or TIPS. In pts with biliary obstruction with or without calculi, the first phase involves sphincterotomy and biliary drainage , with CBD stone removal if present. 48

49. Algorithm for management of PCC in EHPVO Symptomatic biliopathy is one of the few indications where portosystemic shunting is considered even in the absence of variceal bleeding [1-4]. Secondary biliary cirrhosis is the only accepted indication for LT in pts with complicated PCC. (INASL) Chaudhary A, Dhar P, Sarin SK, Sachdev A, Agarwal AK, Vij JC, et al. Bile duct obstruction due to portal biliopathy in extrahepatic portal hypertension: surgical management. Br J Surg 1998;85:326–329. Oo YH, Olliff S, Haydon G, Thorburn D. Symptomatic portal biliopathy: a single centre experience from the UK. Eur J Gastroenterol Hepatol 2009;21:206–213. Chattopadhyay S, Govindasamy M, Singla P, Varma V, Mehta N, Kumaran V, et al. Portal biliopathy in patients with non-cirrhotic portal hypertension: does the type of surgery affect outcome? HPB (Oxford)2012;14:441–447. Agarwal AK, Sharma S, Singh S, Agarwal S, Girish SP. Portal biliopathy: a study of 39 surgically treated patients. HPB 2011;13:33–39. 49 Asymptomatic portal biliopathy needs regular follow-up with LFTs and does not require any RX Symptomatic biliopathy is a definite indication for intervention – endoscopic or surgical.

50. Classification of cholangiographic abnormalities in PCC ( Chandra et al) On the basis of location and extent of abnormalities, changes are classified as Type I: Involvement of only extrahepatic bile duct (a); Type II: Involvement of only intrahepatic bile duct (b); Type III a: Involvement of extrahepatic and unilateral (right or left) intrahepatic bile duct (c and d) Type III b: Involvement of extrahepatic and bilateral intrahepatic ducts (e) [1]. Chandra R, Kapoor D, Tharakan A, Chaudhary A, Sarin SK. Portal biliopathy. J Gastroenterol Hepatol 2001;16:1086–1092. Llop E, de Juan C, Seijo S, et al. Portal cholangiopathy: radiological classification and natural history. Gut. 2011;60:853–860. Llop et al[2] classification grade I: irregularities or angulations of the biliary tree. grade II: indentations or strictures without upstreambiliary dilation. grade III: strictures with upstream biliary dilation. Dilatation is defined as ductal diameter of >7 mm for extra-hepatic duct and/or >4 mm for intra-hepatic ducts. 50

51. Other interventional radiology techniques Partial splenic artery embolization (PSE) is sometimes offered as a relative safe alternative to splenectomy for hypersplenism . [1]. Percutaneous transhepatic/trans-splenic variceal embolization using sclerosants, glue, or coils is sometimes done in pts with life-threatening variceal hemorrhage especially when the bleeding is from IGV. Finally, shunt reduction or closure can be done using coils or BRTO [2]. Ozturk O, Eldem G, Peynircioglu B, Kav T, Go¨rmez A, Cil BE, et al. Outcomes of partial splenic embolization in patients with massive splenomegaly due to idiopathic portal hypertension. World J Gastroenterol 2016;22(43):9623–9630 Pargewar SS, Desai SN, Rajesh S, Singh VP, Arora A, Mukund A. Imaging and radiological interventions in extra-hepatic portal vein obstruction. World J Radiol 2016;8(6):556–570 51

52. Role of anti-coagulation There is no consensus on the role or indication of anticoagulation therapy. However, in a known prothrombotic state, this should be considered to prevent recurrent thrombosis. 52

53. TIPS in EHPVO For pts who have a favourable anatomy including patency of intrahepatic LPV in the Rex recessus , patency of SMV, the first choice of treatment without doubt is the meso-Rex bypass , as this operation results in a physiologic restoration of normal BF to the liver.[1-3] This operation, however, has not been widely used owing to its complexity and high technique demanding . In addition, meso-Rex bypass may be unfeasible in some pts owing to anatomic issues or lack of useable vessels . [3,4] Surgical portosystemic shunts have historically been the primary option for reducing PP with recurrent VH or in whom endoscopic and medical RX have failed.[3] Shneider BL, Bosch J, de Franchis R, et al. Portal hypertension in children: expert pediatric opinion on the report of the Baveno v Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension. Pediatr Transplant 2012;16:426–37. Lautz TB, Keys LA, Melvin JC, et al. Advantages of the meso-Rex bypass compared with portosystemic shunts in the management of extrahepatic portal vein obstruction in children. J Am Coll Surg 2013;216:83–9. Giouleme O, Theocharidou E. Management of portal hypertension in children with portal vein thrombosis. J Pediatr Gastroenterol Nutr 2013;57:419–25. Superina R, Shneider B, Emre S, et al. Surgical guidelines for the management of extra-hepatic portal vein obstruction. Pediatr Transplant 2006;10:908–13. 53

54. TIPS in EHPVO Studies have demonstrated that TIPS was equally effective compared with surgical portosystemic shunts— both ↓ the incidence of variceal rebleeding and improving growth impairment.[1] The advantage that TIPS offer over surgical portosystemic shunts is its mini-invasiveness, but short-term patency of TIPS is a large concern. Because of the use of ePTFE -covered stentgrafts , a significant improvement in patency rates and a ↓ in reintervention rate have, however, been reported.[2-4] Therefore, TIPS procedure, if feasible, could represent a less-invasive alternative to traditional surgical portosystemic shunting or a valuable RX option if surgery and endoscopic treatment failed and an anatomy unsuitable for meso-Rex bypass. Kato T, Romero R, Koutouby R, et al. Portosystemic shunting in children during the era of endoscopic therapy: improved postoperative growth parameters. J Pediatr Gastroenterol Nutr 2000;30:419–25. Di Giorgio A, Agazzi R, Alberti D, et al. Feasibility and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) in children. J Pediatr Gastroenterol Nutr 2012;54:594–600. Zurera LJ, Espejo JJ, Lombardo S, et al. Safety and efficacy of expanded polytetrafluoroethylene-covered transjugular intrahepatic portosystemic shunts in children with acute or recurring upper gastrointestinal bleeding. Pediatr Radiol 2015;45:422–9. Yang Z, Han G, Wu Q, et al. Patency and clinical outcomes of transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stents versus bare stents: a meta-analysis. J Gastroenterol Hepatol 2010;25:1718–25. 54

55. Prognosis Pts with symptomatic PCC who achieve adequate stone clearance and biliary drainage endoscopically have been reported to have an excellent outcome in follow-up studies.[1-4] The reported follow-up of surgically managed pts with PCC is relatively longer, ranging from 14 months to 12 years. However, pts without shuntable veins and advanced biliary changes of PCC cannot undergo shunt surgery. These pts may develop recurrent cholangitis[1,2,5] and, eventually, liver dysfunction either due to secondary biliary cirrhosis or due to chronically diminished portal inflow.[6,7] Attrition of hepatocellular function in these pts may reach the stage that they are candidates for LT.[5,8-10] References are at the end of the slides 55

56. Surveillance Regular 6 monthly follow-up of all pts with EHPVO is mandatory to look for spleen size, growth, quality of life, school performance, development of jaundice, decompensation, PB, and HPS, and to assess their laboratory values and imaging for PVT and PB [1]. Khanna R, Sarin SK. Non-cirrhotic portal hypertension. J Hepatol 2014;60:421–441 56

57. Summary EHPVO is a childhood disorder causing PHT, where the etiology is either perinatal or early childhood vascular insult. The diagnosis is relatively easy if a high index of suspicion is kept. The management is mostly endoscopic with a good long-term outcome. Minimal hepatic encephalopathy and parenchymal extinction are poorly understood scenarios and need further research. 57 End of Slides Thankyou

58. Differentiating Features of Ncpf , Ehpvo,Cirrhosis AK Gupta, Jacob George, Prithvi Giri , R Gupta. Non-Cirrhotic Portal Fibrosis. Medicine Update 2010  Vol. 20

59. Frequency of Biliary Changes in Pts with EHPVO Dilawari JB, Chawla YK. Pseudosclerosing cholangitis in extrahepatic portal venous obstruction. Gut. 1992;33:272–276. Sarin SK, Bhatia V, Makwana U. Poratal biliopathy in extrahepatic portal venous obstruction [abstract]. Indian J Gastroenterol. 1992;11(suppl 1):A82. Khuroo MS, Yatoo GN, Zargar SA, et al. Biliary abnormalities associated with extrahepatic portal venous obstruction. Hepatology. 1993;17:807–813. Bayraktar Y, Balkanci F, Kayhan B, et al. Bile duct varices or ‘‘pseudo-cholangiocarcinoma sign’’ in portal hypertension due to cavernous transformation of the portal vein. Am J Gastroenterol. 1992;87:1801–1806. Malkan GH, Bhatia SJ, Bashir K, et al. Cholangiopathy associated with portal hypertension: diagnostic evaluation and clinical implications. Gastrointest Endosc . 1999;49:344–348. Nagi B, Kochhar R, Bhasin D, et al. Cholangiopathy in extrahepatic portal venous obstruction. Radiological appearances. Acta Radiol . 2000;41:612–615. Condat B, Vilgrain V, Asselah T, et al. Portal cavernoma associated cholangiopathy: a clinical and MR cholangiography coupled with MR portography imaging study. Hepatology. 2003;37:1302–1308. Sezgin O, Oguz D, Attintas E, et al. Endoscopic management of biliary obstruction caused by cavernous transformation of the portal vein. Gastrointest Endosc . 2003;68:602–608. Dhiman RK, Chawla Y, Duseja A, et al. Portal hypertensive biliopathy (PHB) in patients with extrahepatic portal venous obstruction (EHPVO) [abstract]. J Gastroenterol Hepatol. 2006;21:A504. Chevallier P, Denys A, Novellas S, Schmidt S, Schnyder P, Bruneton JN. Magnetic resonance cholangiography features of biliary abnormalities due to cavernous transformation of the portal vein. Clin Imaging. 2006;30:190–194. Llop E, de Juan C, Seijo S, et al. Portal cholangiopathy: radiological classification and natural history. Gut. 2011;60:853–860. 59

60. Prognosis Dhiman RK, Behera A, Chawla YK, Dilawari JB, Suri S. Portal hypertensive biliopathy. Gut. 2007;56:1001–1008. Sezgin O, Oguz D, Attintas E, et al. Endoscopic management of biliary obstruction caused by cavernous transformation of the portal vein. Gastrointest Endosc . 2003;68:602–608. Bhatia V, Jain AK, Sarin SK. Choledocholithiasis associated with portal biliopathy in patients with extrahepatic portal vein obstruction. Management with endoscopic sphincterotomy. Gastrointest Endosc . 1995;42:178–181. Dumortier J, Vaillant E, Boillot O, et al. Diagnosis and treatment of biliary obstruction caused by portal cavernoma. Endoscopy. 2003;35:446–450. Oo YH, Olliff S, Haydon G, Thorburn D. Symptomatic portal biliopathy: a single centre experience from the UK. Eur J Gastroenterol Hepatol. 2009;21:206–213. Webb LJ, Sherlock S. The aetiology , presentation and natural history of extra-hepatic portal venous obstruction. Q J Med. 1979;48:627–639. Rangari M, Gupta R, Jain M, et al. Hepatic dysfunction in patients with extrahepatic portal vein obstruction. Liver Int. 2003;23:434–437. Filipponi F, Urbani L, Catalano G, et al. Portal biliopathy treated by liver transplantation. Transplantation. 2004;77:326–327. Hajdu CH, Murakami T, Diflo T, et al. Intrahepatic portal cavernoma as an indication for liver transplantation. Liver Transpl . 2007;13:1312–1316. Gupta S, Singhal A, Goyal N, Vij V, Wadhawan M. Portal biliopathy treated with living donor liver transplant: index case. Exp Clin Transpl . 2011;9:145–149. 60

61. Biliary changes in EHPVO Malkan GH, Bhatia SJ, Bashir K, et al. Cholangiopathy associated with portal hypertension: diagnostic evaluation and clinical implications. Gastrointest Endosc . 1999;49:344–348. DhimanRK,Chawla Y, Vasishta RK, et al.Non -cirrhotic portal fibrosis (idiopathic portal hypertension): experience with 151 patients and a review of the literature. J Gastroenterol Hepatol. 2002;17:6–16. Gibson JB, Johnston GW, Fulton TT, et al. Extrahepatic portal venous obstruction. Br J Surg. 1965;52:129–139. Dilawari JB, Chawla YK. Pseudosclerosing cholangitis in extrahepatic portal venous obstruction. Gut. 1992;33:272–276. Sarin SK, Bhatia V, Makwana U. Portal biliopathy in extrahepatic portal venous obstruction [abstract]. Indian J Gastroenterol. 1992;11(suppl 1):A82. J Gastroenterol Hepatol2006;21:A504. Khuroo MS, Yatoo GN, Zargar SA, et al. Biliary abnormalities associated with extrahepatic portal venous obstruction. Hepatology. 1993;17:807–813. Bayraktar Y, Balkanci F, Kayhan B, et al. Bile duct varices or ‘‘pseudo-cholangiocarcinoma sign’’ in portal hypertension due to cavernous transformation of the portal vein. Am J Gastroenterol. 1992;87:1801–1806. Bayraktar Y, Balkanci F, Ozenc A, et al. The ‘‘pseudo-cholangiocarcinoma sign’’ in patients with cavernous transformation of the portal vein and its effect on the serum alkaline phosphatase and bilirubin levels. Am J Gastroenterol. 1995;90:2015–2019. Nagi B, Kochhar R, Bhasin D, et al. Cholangiopathy in extrahepatic portal venous obstruction. Radiological appearances. Acta Radiol . 2000;41:612–615. Condat B, Vilgrain V, Asselah T, et al. Portal cavernoma associated cholangiopathy: a clinical and MR cholangiography coupled with MR portography imaging study. Hepatology. 2003;37:1302–1308. Sezgin O, Oguz D, Attintas E, et al. Endoscopic management of biliary obstruction caused by cavernous transformation of the portal vein. Gastrointest Endosc . 2003;68:602–608. Dhiman RK, Chawla Y, Duseja A, et al. Portal hypertensive biliopathy (PHB) in patients with extrahepatic portal venous obstruction (EHPVO) [abstract]. J Gastroenterol Hepatol. 2006;21:A504 Chandra R, Kapoor D, Tharakan A, et al. Portal biliopathy. J Gastroenterol Hepatol. 2001;16:1086–1092. Chawla Y, Dilawari JB. Anorectal varices: their frequency in cirrhotic and noncirrhotic portal hypertension. Gut. 1991;32:309–311. Chawla Y, Dilawari JB, Katariya S. Gallbladder varices in portal vein thrombosis. AJR Am J Roentgenol . 1994;162:643–645. 61