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Short Communication: Hepatology

Unusual Clinical Course for Untreated Malformative Biliary Atresia Infant: Is Portal Hypertension an Important Driver of Liver Fibrosis?

Di Dato, Fabiola; Ranucci, Giulia; de Ville de Goyet, Jean; Alberti, Daniele; Iorio, Raffaele

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Journal of Pediatric Gastroenterology and Nutrition: February 2021 - Volume 72 - Issue 2 - p 216-219
doi: 10.1097/MPG.0000000000002932
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What Is Known

  • Untreated biliary atresia, or unsuccessful bile flow restoration, are fatal.
  • They proceeds through rapid cirrhosis, severe portal hypertension, and liver failure.
  • Main cause of death of infants listed for liver transplantation before 1 year of age.

What Is New

  • Extremely rarely, portal vein thrombosis may be observed in polysplenia syndrome.
  • Absence of bile flow may not be necessarily associated to rapid cirrhosis and complicated portal hypertension; possibly it is not the single trigger of liver fibrosis.
  • We hypothesized that sinusoidal hypertension may be an independent trigger of sinusoidal fibrosis—acting as a vicious loop.

Untreated biliary atresia's (BA) natural evolution is towards cirrhosis and severe portal hypertension (PHT), steady deterioration of the clinical condition, eventual variceal bleeding and/or hepatic failure, and death within 3 years of life in most cases (1–8). We report a BA patient surviving with her native liver over the age of 3 years, in satisfactory condition in the absence of overt signs of PTH, ascites, or liver failure. Possible pathogenetic mechanisms are discussed.


Retrospective analysis of clinical course of 5 children who were managed at our centre in last 4 years for biliary atresia splenic malformation syndrome (BASM) (2,9,10). Collection, analysis, and publication of patient data had been prospectively accepted by each patient/family by a dedicated informed consent—a standard practice at each admission in our hospital. Studied patient (case 1) had no Kasai portoenterostomy (KPE) and much unusual clinical course.

Patient 1

At age 2 months, BASM (2,8,9) was diagnosed by imaging, and explorative laparotomy was carried on with liver biopsy and cholangiogram. Surgical exploration was performed by a surgeon with extensive experience in KPE (>200 personal KPE surgeries and 63.1% 5-year native liver survival); macroscopic and microscopic (biopsy) findings confirmed BA and BASM, with quasi absence of extrahepatic biliary structures that were reduced to a fibrotic gallbladder and minimal residue (fibrotic cone) at the portal plate. As the porta hepatis showed cavernomatous transformation of the portal vein (CPV), Kasai porto-enterostomy was not performed (surgical dissection of the liver hilum was considered hazardous in such conditions). Intrahepatic portal venous pressure was measured as 13 mmHg during surgery, and moderate liver fibrosis was found on biopsy. CPV was confirmed at imaging, as well as microspleen (reduced to a 1,5 cm node) (Fig. 1). Enteral feeding and supportive care was associated with improvement of the condition during first year of life, with Pediatric End-stage Liver disease (PELD) score decreasing to 4 at ages 12 months; more remarkably, this good condition remained stable, with no further active medical support, afterwards (Fig. 2).

Imaging in 5 infants with biliary atresia splenic malformation syndrome (patients numbered 1------5). The upper figures show, in each patient, the splenic tissue volume: from a microsplenia in patients 1and 2 (spleen span 2 cm), to splenomegalia in patients 3 to 5 (spleen span of 8, 9, and 9.8 cm, respectively). The lower figures show absent/thrombosed portal vein trunk and portal cavernoma in patient 1, and a normal calibre preduodenal portal vein in patients 2 to 4; portal vein was hypoplastic with inversed flow in patient 5.
Evolution of PELD score with time, while waiting for liver transplantation (∗), in 5 infants with biliary atresia splenic malformation syndrome. Patient 1, who had portal cavernomatous transformation and severe hyposplenia, showed remarkable evolution: she is alive and well over 36 months of age, with stable hepatic function and moderate uncomplicated portal hypertension.

Esophagogastroduodenoscopy at age 5, 20, and 38 months, showed small (F1) nonprogressing varices. Splenic node grew slowly (from the initial 1.5 cm to diameter 2.8 cm at 36 months), and hepatopetal flow has been preserved through the cavernoma (Fig. 1). Until the time of writing, the patient has remained in surprisingly good condition for 3 consecutive years, with sufficient height and weight gain, normal psychomotor development for age, and stable cholestasis and hepatic function (PELD score: 5 at age 36 months) (Fig. 2).

Patients 2 to 5

Patients 3 and 4 (P3 and P4) had been managed at our centre from diagnosis (as well was patient 1 [P1]), whereas patient 2 (P2) and patient 5 (P5) were admitted at 8 and 22 months of age, respectively, for complicated post-KPE course and the need for urgent transplantation. P2 to P5 were transplanted at 8, 11, 13, and 24 months of age, and weighing 4, 9.4, 9.4, and 9.6 kg, respectively.

Of these patients, all but P4 had unsuccessful KPE; all but 1 (P5) had preduodenal vein and intestinal malrotation. All had variant hepatic arteries, absent retrohepatic vena cava, and microsplenia (P2—splenic node measuring 2 cm) or multiple spleens with variable enlargement (8, 9, and 9.8 cm in patients 3,4, and 5, respectively) (Fig. 1). P2, P3, and P4 had a satisfactory hepatopetal portal flow at initial assessment, whereas in P5, the vein was very hypoplastic (3 mm) with hepatopetal flow at assessment switching to hepatofugal flow in the final pretransplant phase.

Endoscopy (P3 and P4) showed F1 varices. Symptomatic portal hypertension (ascites) was present in all, with some degree of liver failure (from moderate to severe), as follows:

  • 1. P2 had diaphragmatic splinting as a consequence of untreatable massive ascites, and mild cardiac decompensation related to complex cardiac malformation (with left isomerism) and cirrhosis. Because of these associated conditions, she had progressive respiratory failure and necessitated noninvasive respiratory assistance (positive pressure ventilation) for 1 month followed by mechanical ventilation and continuous ascite drainage in last 4 weeks before transplant. She was transplanted urgently from a living related donor.
  • 2. P3, who had moderate ascites and responded well to treatment, was transplanted early (ages 13 months) in good condition.
  • 3. P4 had early ascitic decompensation, rapidly progressing within 3 months to an uncontrollable condition and hepatic failure in last 4 weeks before transplantation. His PELD was >30 during last month and he was transplanted in emergency as a rescue procedure (Fig. 2).
  • 4. P5 was of age 22 months when she was admitted. She had massive ascites with hypo-albuminemia and coagulopathy (PELD 21 at admission). PELD improved rapidly as a consequence of medical support and correction of albumin level, as ascites became a major problem after skin ruptured at the level of a huge umbilical hernia, necessitating repeated albumin infusions and heavy diuretic management until transplant.

Evolution of PELD score is detailed in Figure 2. In P2 and P5, PELD score improved apparently after they started care at our centre, as a predictable effect of medically supporting coagulopathy and hypo-albuminemia (Fig. 1). In P3 and P4 who were followed from diagnosis, PELD deteriorated steadily (Fig. 2).

All 4 transplant procedures were performed using left liver lobe grafts (reduced to a monosegment 2 in P2). Longitudinal plasty of preduodenal portal vein was performed in P2, P3, and P4 (with direct anastomosis into Rex recessus) (11), and in P5, portal revascularization was with vascular homograft from the superior mesenteric vein. All other vascular anastomosis were end-to-end donor-recipient type. Transplantations were successful with all 4 patients alive and well at 1 to 26 months follow-up (15 months mean follow-up).


Natural history of untreated BA, or unsuccessful KPE, is characterized by persistent cholestasis and rapid worsening of condition (3,5,12,13), growth failure, recurrent complications of PHT, hepatic failure and death (1–8), with P2 and P4 being typical examples. Although untreated BA infants have been reported surviving until their third or fourth year of life, they all show steadily deteriorating condition until death—or transplantation—occurs (1–5,12,13).

The worsening of children's condition while they wait for a transplant is a well-known, possibly the more concerning, problem of infants and small children waiting on lists: it is found worldwide, progressing independently of care quality, and is associated with a risk of pretransplant deaths and with increased peritransplant morbidity (12,13).

In this short series, P4 was much similar to P1 (BASM, no KPE) and demonstrated a rapid progression of portal hypertension and liver failure, and needing rescue transplantation (Fig. 2). Ascites secondary to PHT was present in all cases but in P1, and was associated with liver dysfunction or failure in every case with ascites, as evidenced by PELD score. On the contrary, P1 not only has been surviving until the age of 3 years but oppositely to the other cases (and to usual BA patient who are candidates for transplantation), has been surprisingly stable with none of the above features and no worsening of liver function or portal hypertension over time. Moreover, she entered her fourth year of life without having had serious complications related to her disease, with satisfactory staturoponderal growth, and a preserved hepatic function (Fig. 2). This is, to our knowledge, a unique, yet unreported, case and course. Portal pressure was measured 13 mmHg at surgical exploration—which is a moderate pressure level, in line with usual pressure measurements in BA patients at the time of KPE (14,15); more interesting, that pressure level have shown association with prolonged native liver survival when KPE is successful (13,14). P1 clinical course suggests that neither PHT nor liver disease did worsen with time—which is surprising—as CPV is a pre-hepatic block that per itself that is associated with progressing PHT even in the absence of liver disease (16), and liver fibrosis progresses naturally to cirrhosis in BA patient with unsuccessful KPE. Over 3 years, oesophageal varices were stable (F1), no ascites and no chronic anaemia, or gastrointestinal bleeding were observed, and she maintained a good appetite and satisfactory intestinal absorption. At the same time interval (age 5-- 31 months), the splenic node grew from 1.65--2.66 cm, which is compatible with child's growth (from 5.23 to 11.1 kg). Interestingly, the hepatic function also did not deteriorate with time, which is possibly even more remarkable in a BA patient who had no KPE. Because of the uniqueness of the anatomical characteristics of this patient (combination of BASM with microsplenia and CPV, and absence of evolution towards severe PHT), we questioned the remarkable clinical course to be coincidental or related to the former anatomy.

The first interesting aspect is the absence of complications related to PHT, as portal pressure was moderate, with no worsening along time. Two factors may have contributed:

  • 1. Splenic mass was quasi absent at diagnosis and did not grow with time (at age 38 months and 11.1 kg of weight, the splenic node is 2.8 cm). A spleen is very sensitive to portal pressure that directly causes splenic enlargement; as the splenic mass increases, splenic blood flow augments, which in turn contributes directly to increasing venous pressure and PHT (16,17). Established PHT causes splanchnic vasodilatation that consolidates the former, and further worsens it in a vicious circle (16–19). In this patient, the quasi absent splenic mass avoided the former phenomenon and this contributed to keep splanchnic pressure moderately low (16–19).
  • 2. Although there has been no longitudinal study of hepatic fibrosis in this case, some facts suggest that fibrosis did not worsen much with time in this case: hepatic function remained stable, coagulopathy absent and albuminemia normal. The persistence of hepatopetal flow through the cavernoma over the 3 years supports that fibrosis did not progress much.

The second, more interesting aspect is the association of stable hepatic fibrosis (when other patients rapidly deteriorate) and CPV. CPV is a prehepatic resistance to the portal flow, and acting as a regulator of flow, thus also a regulator of pressure downstream. In these conditions, the pressure in intrahepatic portal venous system is lower than that of splanchnic venous system. Through the latter mechanisms, CPV may have played an important role in the favourable evolution of P1 compared with others. On the contrary, Budd-Chiari syndrome, veno-occlusive disease or arterioportal high-flow fistula are all conditions in which a liver parenchyma evolves very rapidly from normal (initially) into severe fibrosis and cirrhosis; they all are characterized by early sinusoidal hypertension, followed by sinusoidal fibrosis—and a subsequent worsening as vicious cycle ending in cirrhosis (16–19).

Other liver fibrotic diseases evolve, on the contrary, very slowly—as hepatic fibrosis, hepatic disease associated to cystic fibrosis, and hepatic schistosomiasis—that are associated to a predominantly precapillary fibrotic lesion (16). All these 3 diseases are characterized by long-lasting hepatic function preservation despite progression of PHT and related complications; in these diseases, the sinusoids are protected from excessive pressure by the presinusoidal blockage.

When comparing all the above-mentioned diseases and looking at the speed (rapid or slow) of worsening of hepatic fibrosis, and at distribution of portal pressure along the sinusoids, there is a clear relation between sinusoidal hypertension and progression of fibrosis; it suggests that portal sinusoidal hypertension may be per se an independent driver of fibrosis, acting in a vicious cycle. Liver sinusoids are very delicate specialized structures, rich in stellate cells. Stellate cell activation is a well-known and strong inductor of sinusoidal fibrosis (19–22) and are sensitive to barotraumatism; the latter can be caused by raised portal pressure, raised portal flow, or a combination of both (19,21).

BA patients may be an extreme representative of this pattern, as BA condition associate typically biliary inflammation (a strong driver of fibrosis) (22), and also portal hypertension and, more unique in PHT pathophysiology, a hyper-arterialization of sinusoids (23).

One can thus hypothesize that the favourable evolution in P1 relates to minimal progression of hepatic fibrosis secondary to lower than usual sinusoidal pressure, compared with other BA cases. Further studies are necessary to support this hypothesis, and possibly studying if acting more aggressively on PHT after unsuccessful KPE may slow hepatic deterioration and result in a need for early transplantation. Some common drugs, such as amiloride or propranolol, used in that age range though not labeled for it, have been suggested recently for prospective studies (20,24).


1. Serinet MO, Broué P, Jacquemin E, et al. Management of patients with biliary atresia in France: results of a decentralized policy 1986–2002. Hepatology 2006; 44:75–84.
2. Lakshminarayanan B, Davenport M. Biliary atresia: a comprehensive review. J Autoimm 2016; 73:1–9.
3. Sundaram SS, Mack CL, Feldman AG, et al. Biliary atresia: indications and timing of liver transplantation and optimization of pre-transplant care. Liver Transpl 2017; 23:96–109.
4. Ferreira AR, Queiroz TCN, Vidigal PVT, et al. Multivariate analysis of biliary flow-related factors and post-Kasai survival in biliary atresia patients. Arq Gastroenterol 2019; 56:71–78.
5. Shneider BL, Brown MB, Haber B, et al. Biliary Atresia Research Consortium. A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. J Pediatr 2006; 148:467–474.
6. Duché M, Ducot B, Ackermann O, et al. Portal hypertension in children: high-risk varices, primary prophylaxis and consequences of bleeding. J Hepatol 2017; 66:320–327.
7. D'Souza R, Grammatikopoulos T, Pradhan A, et al. Acute-on-chronic liver failure in children with biliary atresia awaiting liver transplantation. Pediatr Transplant 2019; 23:e13339.
8. Davenport M, Tizzard SA, Underhill J, et al. The biliary atresia splenic malformation syndrome: a 28-year single-center retrospective study. J Pediatr 2006; 149:393–400.
9. Davenport M, Savage M, Mowat AP, et al. Biliary atresia splenic malformation syndrome: an etiologic and prognostic subgroup. Surgery 1993; 113:662–668.
10. di Francesco F, Caruso S, Bonsignore P, et al. Preduodenal portal vein reconstruction at liver transplantation: the challenges and a solution. Liver Transpl 2019; 25:1841–1844.
11. Arnon R, Annunziato RA, D’Amelio G, et al. Liver transplantation for biliary atresia: is there a difference in outcome for infants? J Pediatr Gastroenterol Nutr 2016; 62:220–225.
12. van der Doef HPJ, van Rheenen PF, van Rosmalen M, et al. Wait-list mortality of young patients with biliary atresia: competing risk analysis of a eurotransplant registry-based cohort. Liver Transpl 2018; 24:810–819.
13. Shalaby A, Makin E, Davenport M. Portal venous pressure in biliary atresia. J Pediatr Surg 2012; 47:363–366.
14. Duché M, Fabre M, Kretzschmar B, et al. Prognostic value of portal pressure at the time of Kasai operation in patients with biliary atresia. J Pediatr Gastroenterol Nutr 2006; 43:640–645.
15. Khanna R, Sarin SK. Non-cirrhotic portal hypertension - diagnosis and management. J Hepatol 2014; 60:421–441.
16. Luca A, Miraglia R, Caruso S, et al. Effects of splenic artery occlusion on portal pressure in patients with cirrhosis and portal hypertension. Liver Transpl 2006; 12:1237–1243.
17. Møller S, Bendtsen F. The pathophysiology of arterial vasodilatation and hyperdynamic circulation in cirrhosis. Liver Int 2018; 38:570–580.
18. Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis - current status and future directions. J Hepatol 2014; 61:912–924.
19. Steib CJ, Bilzer M, Härtl JM, et al. Kupffer cell activation by hydrogen peroxide: a new mechanism of portal pressure increase. Shock 2010; 33:412–418.
20. Ding Q, Li Z, Liu B, et al. Propranolol prevents liver cirrhosis by inhibiting hepatic stellate cell activation mediated by the PDGFR/Akt pathway. Hum Pathol 2018; 76:37–46.
21. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 2017; 14:397–411.
22. Liu R, Li X, Zhu W, et al. Cholangiocyte-derived exosomal long noncoding RNA H19 promotes hepatic stellate cell activation and cholestatic liver fibrosis. Hepatology 2019; 70:1317–1335.
23. Allam A, El-Guindi M, Konsowa H, et al. Expression of vascular endothelial growth factor A in liver tissues of infants with biliary atresia. Clin Exp Hepatol 2019; 5:308–316.
24. Steib CJ, Hennenberg M, Beitinger F, et al. Amiloride reduces portal hypertension in rat liver cirrhosis. Gut 2010; 59:827–836.

biliary atresia and splenic malformation syndrome; Kasai porto-enterostomy; Pediatric End-stage Liver Disease (PELD) score; portal cavernoma

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