Secondary Logo

Journal Logo

Invited Review

Congenital Portosystemic Shunts: Current Diagnosis and Management

McLin, Valérie A.; Franchi Abella, Stephanie†,‡; Debray, Dominique§; Guérin, Florent||; Beghetti, Maurice; Savale, Laurent#,∗∗,††; Wildhaber, Barbara E.‡‡; Gonzales, Emmanuel§§; on Behalf of the Members of the International Registry of Congenital Porto-Systemic Shunts

Author Information
Journal of Pediatric Gastroenterology and Nutrition: May 2019 - Volume 68 - Issue 5 - p 615-622
doi: 10.1097/MPG.0000000000002263
  • Free

Abstract

What Is Known

  • Congenital portosystemic shunts are vascular malformations leading to systemic complications.
  • Congenital portosystemic shunts can be diagnosed at any age.

What Is New

  • Occlusion test with portosystemic gradient measurement is essential before closure.
  • Interventional radiology is the preferred method of closure.

Congenital portosystemic shunts (CPSS) are rare congenital, abnormal venous communications between the portal venous system and the systemic circulation affecting an estimated 1:30,000 to 1:50,000 newborns (1,2). They are accepted to arise from incomplete vascular remodeling between the symmetric embryonic and asymmetric fetal hepatic and perihepatic circulations (Fig. 1). Historically, CPSS were described as either Abernethy malformation type I or II, and recently this definition has been refined with a view to characterize different phenotypic subtypes (3–6). It is now understood that CPSS come in different shapes and sizes and may be associated with other vascular or anatomical abnormalities (Fig. 2). The relative frequency of the different types has changed over time as they have become increasingly diagnosed antenatally. They are usually low-pressure systems, meaning they typically are not associated with portal hypertension. Currently, CPSS are often identified on prenatal ultrasound (US). Historically, however, this was not the case. Therefore, those that do not close spontaneously may go unnoticed for years and may only present with severe, and sometimes life-threatening complications later in life. To date, several questions remain unanswered: which patients are at risk of developing complications, in which patients will the shunt close spontaneously, and conversely, which patients have multiple shunts or will open new shunts in response to surgical or interventional treatment. In the present review, we suggest an approach to managing the patient with CPSS based on current knowledge.

FIGURE 1
FIGURE 1:
Development of the human hepatic vasculature. A, Embryonic development (4 weeks’ gestation). B, Vascular remodeling between weeks 4–6. C, Fetal circulation (from 6–8 weeks’ gestation). D, Neonatal circulation. C = cardinal veins (blue); DV = ductus venosus (orange); HP = hepatic primordium; PV = portal vein; SV = sinus venosus (blue); U = umbilical veins (orange); V = vitelline veins (green). Colors are used to illustrate the origin of each structure.
FIGURE 2
FIGURE 2:
Anatomical forms of congenital portosystemic shunt (CPSS). The portohepatic shunt and patent ductus venosus are considered intrahepatic shunts. The bottom 3 diagrams are considered extrahepatic shunts. Note the minimal or absent portal venous flow owing to the large portosystemic communication. ES = end-to-side; PS = portosystemic; SS = side-to-side.

MODE OF PRESENTATION IN HUMAN SUBJECTS AND ANIMAL MODELS

In human subjects, CPSS are identified in 1 of 4 ways: antenatal US, neonatal cholestasis, incidental finding, or the shunt is identified as part of a work-up for a systemic complication. In addition, shunts may be associated with renal, skeletal, and cardiac morphological anomalies (2,7,8). It is recommended that these be sought at the time of work up. As such, it is the assessment of this panel that patients with complex syndromes, especially complex cardiac malformations (ie, isomerisms), should benefit from an abdominal Doppler US to look for CPSS. Syndromes and chromosomal anomalies in which CPSS have been identified are summarized elsewhere (7). Animal models which may offer insight in the understanding of human disease are summarized in Table 1.

TABLE 1
TABLE 1:
Lessons from animal models

The basic pathophysiology underlying the clinical manifestations of CPSS is accepted to be portosystemic (PS) bypass. Simply put, the liver is deprived of certain molecular substrates and signals coming from the mesenteric territory, whereas the remainder of the body is exposed to these, something it is not equipped to handle.

Liver

Shunts may be identified by abdominal imaging performed for the work-up of abnormal liver enzymes, elevated plasma ammonia, a liver nodule, or fortuitously (2,20,21). Liver nodules are accepted to be the consequence of abnormal blood flow through the liver and typically are identified beyond the neonatal period. Nodules include focal nodular hyperplasia, hepatocellular adenoma, hepatoblastoma, hepatocellular carcinoma, and others (22–24).

Conversely, shunts can present in the neonatal period in a number of ways including neonatal cholestasis (20). It is unclear whether cholestasis is the cause or consequence of PS shunting. In other words, increased intrahepatic resistance due to cholestatic liver disease may lead to preferential flow through a shunt, such as the ductus venosus (DV), which may otherwise have closed (25). Alternatively, insufficient portal flow probably leads to cholestasis, although the underlying pathophysiology is unclear (26). Of note, in case of neonatal cholestasis, the DV has been described as malformed with a comparatively larger diameter than that of those, which have remained open to palliate portal hypertension (27).

Neurological

PS shunting can be associated with type B hepatic encephalopathy (HE), meaning HE due to liver bypass alone without cirrhosis (28). The following symptoms may be suggestive of PS shunting: school difficulties, epilepsy, absences, unexplained mental retardation/neurocognitive delay, attention deficit disorder, psychiatric disease, and seizures (2). Often, these signs and symptoms may be subtle, and therefore HE overlooked or underestimated.

Cardiopulmonary

Secondary cardiopulmonary complications can arise at any age and include high-output heart failure, hepatopulmonary syndrome (HPS), portopulmonary hypertension, and sudden death (29). Unexplained high-output heart failure should prompt cardiologists to request an abdominal imaging to search for CPSS. Likewise, the initial work up of pulmonary right-to-left shunting should include an abdominal US to seek for PS shunting (30). Finally, abdominal imaging is indispensable in the initial work up of any patient presenting with de novo pulmonary arterial hypertension, especially in subjects with no significant past medical history (31). These complex conditions need to be evaluated and managed in a specialized center for optimal patient care.

Hematological

Fluctuations in clotting factors and circulating anticoagulants have been documented in animals with CPSS (19,32). Although there is no such report in human subjects, there is 1 report of excessive vaginal bleeding (6). Expert opinion suggests that patients with CPSS present with coagulation abnormalities suggestive of low grade consumption: decreased factors V, VII-X, and prolonged prothrombin time, which may or may not be associated with thrombopenia. In a small study, normalization of coagulation factors was attributed to improved liver function, although this may be due to improved hemodynamics and decreased consumption as shown in other mammals (19,33). These clinical impressions remain to be validated in humans.

Endocrine

The liver is an endocrine organ involved in the synthesis and degradation of hormones. It follows that complete or partial liver bypass would be associated with endocrine abnormalities. Among these, 2 stand out: abnormal newborn screening for galactosemia and hyperinsulinemic hypoglycemia (34,35). Although less well characterized, gonadal dysregulation including hyperandrogenism has been described in girls (36,37). Low thyroxin levels secondary to insufficient thyroxin-binding protein have also been reported (37). Finally, growth may be affected in utero or later in childhood (38). In utero, fetuses present with growth retardation, whereas in childhood patients can present with overgrowth syndromes. Patients with CPSS have been described to exceed predicted familial height by centers following such patients something which has only been reported in patients following surgical PS shunts (39,40) The underlying mechanisms are not known but are probably related to the liver's endocrine role.

Renal

Membranoproliferative renal disease has been described in both humans and dogs with CPSS (41,42). A detailed analysis of renal function and size has not been performed in human subjects with CPSS to date. There are, however, compelling canine studies that suggest that shunt closure is associated with significant changes in both renal function and size (43,44). Transjugular portosystemic shunts (TIPS) in humans with cirrhosis are associated with changes in renal function, and membranoproliferative glomerulonephritis has been associated with TIPS (45). The proposed mechanism was defective immune complex clearance, something which is relevant to CPSS, given the central role of the liver in the clearance of immune complexes (46,47).

Immune/Infectious Disease

The liver is an integral part of the reticuloendothelial system and serves as a filter for the blood returning to the heart from the gastrointestinal tract. Logically, bypass of this vast network of sinusoids, enriched in resident macrophages (Kupffer cells), exposes the host to blood-borne infections. In addition, patients with both CPSS and intrapulmonary shunting are at risk of brain abscesses as they lack 2 filters: liver and lung (48,49). Furthermore, impaired clearance of immune globulin by the liver arguably exposes subjects to immune-mediated disease (see renal above), although this is another area ripe for research.

DIAGNOSTIC WORKUP OF A PATIENT WITH SUSPECTED CONGENITAL PORTOSYSTEMIC SHUNTS: LOOKING FOR SYSTEMIC COMPLICATIONS

A complete head-to-toe approach is recommended when assessing the patient with suspected CPSS. First, complications of PS shunting need to be sought. Second, looking for associated malformations may orient management or point to an underlying condition or syndrome (7). All systems described above in the section on clinical presentation should be assessed at the time of diagnosis and in the event of any new clinical event.

Liver

Abdominal US is the first-line examination to assess for the presence of a shunt. Angio-computed tomography or magnetic resonance imaging (MRI) are the next best method of choice to evaluate shunt anatomy and liver parenchyma (29). Direct visualization of the shunt by angiography is critical: retrograde for intrahepatic shunts, and anterograde with balloon closure for extrahepatic shunts. Portal angiography affords interventional radiologists the opportunity to look for hypoplastic and/or ectopic portal vessels feeding the liver and to measure pressure in the portal venous system following balloon occlusion of the abnormal PS vessel. This is a critical step in planning shunt closure (see below). Although critical in theory, on occasion, the size of the shunt may preclude complete intravascular shunt occlusion: if the shunt's diameter is greater than that of commercially available occlusion balloons and occlusion devices, it will not lend itself to endovascular occlusion and limit the reliability of pressure measurements. Interventional radiology (IR) is also an opportunity to biopsy the liver and any liver mass of unclear etiology.

Neurological

The workup of the patient with CPSS and neurological symptoms usually includes measurement of plasma ammonia, neurocognitive evaluation, and MRI of the central nervous system (CNS) to look for characteristic findings in the globus pallidus(50). A hyperintense T1 signal of the globus pallidus akin to what is described in chronic HE in adults and children should serve as a red flag to any radiologist who identifies such a finding incidentally on MRI (50,51). There are no data on the value of performing an abdominal US with Doppler on the vast number patients presenting with nonspecific neurological findings in the general population. A practical approach may be to assess the T1 signal in the globus pallidus in patients who undergo brain MRI for neurological indications, and only perform abdominal Doppler US in those patients who display an abnormal signal or who may have evidence of elevated plasma ammonia concentrations, although plasma ammonia is generally unreliable as a biomarker for pediatric HE.

Cardiopulmonary Manifestations

Together with CNS involvement, cardiopulmonary complications related to CPSS are among the most severe and potentially life threatening. Therefore, the diagnosis of CPSS warrants both careful initial assessment and regular follow-up. Initial work-up includes a thorough history looking for symptoms such as dyspnea on exertion, syncope, or hoarseness. Findings on physical examination compatible with cardiopulmonary involvement in the setting of chronic liver disease or PSS include clubbing, telangiectasias, palmar erythema, and hyperemic lips.

Hepatopulmonary Syndrome

In adults, pulse oximetry orients toward the diagnosis of HPS if <96% (52). Contrast-enhanced transthoracic cardiac echography (CE-TTE) and arterial blood gases are accepted as the gold standard for diagnosis of HPS in adults. In children, it has been suggested that arterialized capillary blood gases may be a better indicator (53). Likewise, in children, lung perfusion scanning using 99mTc macroaggregated albumin may be more sensitive than CE-TTE, something which needs further investigation (54).

Portopulmonary Hypertension

The initial test of choice is echocardiography. Evidence or suspicion of elevated right side pressures should warrant right heart catheterization to measure pulmonary pressures and calculate pulmonary vascular resistance (52,55).

High-output Heart Failure

Patients who display the cardinal signs of high-output cardiac failure of unclear etiology should undergo both TTE and abdominal US to look for a large venous malformation as the underlying etiology.

Hematological

A full blood count and coagulation profile may reveal some degree of consumption coagulopathy. Unlike in chronic liver disease, low platelets are unlikely to suggest portal hypertension, given that CPSS are not normally associated with an elevated PS pressure gradient.

Endocrine

Although endocrine complications are still rather uncharacterized, it is recommended to look for hyperinsulinemic hypoglycemia especially in the neonatal period, to measure growth factors, thyroid function, and sex hormones (37).

Renal

It is recommended that both the work-up and follow-up of patients with CPSS include complete assessment of both glomerular and tubular function using conventional methods.

Immune/Infectious Disease

Deep tissue infections, especially CNS abscesses, should be sought in patients with known CPSS and persistent or recurrent fevers or focal symptoms. The postulate here is that the risk of infection may be greater given the bypass of the reticuloendothelial function of the liver (49).

EVALUATION AND METHODS FOR SHUNT CLOSURE

The approach for closure is dependent on 2 factors: (1) anatomy and (2) PS pressure gradient measured during the occlusion test (29). IR is the method of choice for most CPSS. Rarely, CPSS will require surgery. To date the rule of thumb guiding the choice between IR versus surgical closure has been 2-fold: first, the size of the occlusion device cannot impinge on “normal” neighboring vessels, and second, the PS gradient cannot exceed 18 to 25 mmHg during the occlusion test (the range varies according to authors), in which case a 2-step procedure, typically surgical, is preferred. The advantage of a surgical approach is that it affords the surgeons the possibility of using intestinal venous stasis as a readout to modulate the degree of shunt closure (6,29,56).

Recent reports are, however, auspicious for increasingly inventive endovascular approaches, perhaps further restricting the need for surgery. In 1 report, the authors used a ductus arteriosus device to close an extrahepatic type II shunt (side-to-side) successfully in a neonate (57). Another center reports designing a tailor-made flow restrictor for occlusion of a shunt arising in a child with situs inversus and a congenital splenorenal shunt (58). Finally, the use of a double-barrel endovascular approach to overcome both issues of size and pressure gradient may further obviate the need for open attenuation (59).

Historically, liver transplantation has been used as a corrective measure, something which is increasingly falling out of favor owing to the interventional techniques highlighted above (60). The option of rescue liver transplantation for intrahepatic CPSS, however, remains if all else fails to mitigate the complications of CPSS or the complications after closure of CPSS. This possibility is important to bear in mind if patients require repetitive endovascular procedures exposing them to the risk of thrombosis extending beyond the vessel of interest, thereby potentially compromising the success of rescue transplantation. Finally, liver transplantation remains a life-saving procedure for patients presenting with liver malignancies related to their CPSS.

WHOM TO CLOSE AND WHEN

Given that it is unclear which patients will develop systemic complications from PS shunting, there is no hard and fast rule regarding who will benefit from closure. Figure 3 serves as a proposed algorithm for closure.

FIGURE 3
FIGURE 3:
Proposed clinical approach to the patient with suspected CPSS. CPSS = congenital portosystemic shunt.

Basic Principles

In a nutshell, there are 3 basic principles to keep in mind when approaching a patient with CPSS. First, except in extreme cases of Abernethy type I (end-to-side porto-caval shunts), intrahepatic hypoplasia of the portal system can be rescued (6,29). Second, complete closure of the PSS and rescue of normal portal flow is the goal, but symptoms may improve even if closure is incomplete, in other words if partial portal flow is achieved (6). Third, shunts upstream of the portal bifurcation tend to be associated with extrahepatic portal vein hypoplasia, which may be more difficult to rescue than intrahepatic venous hypoplasia; these patients may benefit from earlier closure than the 2-year limit (6) to preserve the portal vein and intrahepatic portal vasculature.

Timing of Shunt Closure

Shunts diagnosed on prenatal US should be followed postnatally at regular intervals. Many are portohepatic and close spontaneously in the postnatal period (61). If they do not, exploration is warranted. Importantly, seemingly benign shunts labeled as “intrahepatic” may in fact be persistent DV. Therefore, it is the opinion of the authors that CPSS persisting beyond the age of 2 years, should be closed preventively. The rationale for preventative closure, is, based on expert opinion, that spontaneous closure beyond this age is unlikely, and that complications potentially can be severe (6,8). With the advent of IR approaches, at the present time the risk-benefit ratio is often in favor of closure. Nonetheless, each patient should be evaluated on a case-by-case basis, as some shunts may be more amenable to IR closure than others, something to be weighed against the risk of complications related to the procedure itself (see below).

Congenital Portosystemic Shunts Needing Special Consideration

The following types of CPSS warrant special mention.

Shunts Upstream of the Portal Vein

Patients diagnosed prenatally with shunts that are situated upstream of the portal vein (ie, extrahepatic CPSS) should be considered for closure very early in life because of the risk of developing hypoplasia of the intrahepatic portal vasculature from nonuse secondary to preferential flow through the shunt after umbilical vein closure (6). Yet, risks and benefits of neonatal IR or surgical closure must be well considered.

Patent Ductus Venosus

Patients with patent DV on transabdominal US at birth warrant special attention, because it has been shown that if the DV does not close in the first 30 days postnatally, it is unlikely that it will close spontaneously (20). One of the reasons it may not close is because of increased intrahepatic resistance; these patients typically need a work-up for intrahepatic liver disease or hepatic arterioportal fistula (25). Therefore, unlike most other shunts, this is probably 1 scenario where it is of benefit to the asymptomatic patient to close the shunt before the age of 2 years to avoid systemic complication of PS bypassing and to establish a normal intrahepatic portal vasculature.

Shunts Not Amenable to Interventional Radiology or Surgical Closure

Examples include patients in whom the shunt is associated with a liver malignancy (62,63), or patients with shunts too numerous to close simultaneously or sequentially, although less frequent, patients with life-threatening extrahepatic complications may not withstand multiple IR procedures. These may benefit from primary liver transplantation to restore normal portal flow (60).

OUTCOMES AFTER SHUNT CLOSURE

Although much is still unknown about who will or will not develop complications of CPSS, it is safe to say that published reports concur: symptomatic CPSS should be closed. The positive consequences of closure include regression of liver nodules, resolution of hyperammonemia and improvement of neurocognitive symptoms, resolution of glomerulonephritis, reversal of HPS, and stabilization of pulmonary hypertension (6,8,55,64–67).

At this juncture, pulmonary hypertension remains the rate limiting step in the management and long-term outcome of patients with CPSS, because it will likely not improve following closure, and may even worsen if one looks to the liver transplant literature (68). Although no clear recommendations can currently be advised in the specific setting of CPSS, initiating combination pulmonary vasodilator therapy before shunt closure with regular follow-up after closure may ameliorate outcomes (55).

Conversely, complications and risks of CPSS closure can be challenging. There are 3 major types: thrombotic, occlusion device migration, and portal hypertension.

Thrombotic Complications

These include portal vein thrombosis (8,69), and the theoretical risk of pulmonary embolus, something of which there is no report in the literature and mitigated in most centers by prophylactic heparin use. Importantly, the thrombus can extend upstream from the shunt, potentially compromising the benefit of shunt closure in the long run. For example, if the thrombus extends to the portal vein or mesenteric vein, the patient is at risk of developing portal hypertension, potentially opening de novo shunts to palliate the portal hypertension, thereby recapitulating the original pathophysiology and symptoms leading to initial shunt closure. Prophylactic anticoagulation to prevent thrombosis after closure is recommended by some teams (8,21,69).

Portal Hypertension

In addition to the above, patients with cardiac malformations or pulmonary hypertension and right ventricular dysfunction warrant special mention owing to the risk of portal hypertension. Indeed, in this unique subset of patients, residual post-hepatic outflow obstruction may result in ongoing portal hypertension following closure. Whether in these patients or in other patients, closure of 1 shunt may be associated with spontaneous opening of another to palliate for secondary or ongoing portal hypertension. In case of ongoing portal hypertension owing to intrahepatic revascular modeling, raised portal pressure may be transient (22), whereas in patients with intrinsic cardiac disease it may not. But the risk of portal hypertension needs to be weighed against the benefit of some portal perfusion, increasingly accepted to be beneficial even if incomplete (22).

Device Migration

Among other clinically relevant complications, we witnessed the migration of the vascular plug leading to hemodynamic compromise of the patient (unpublished), something reported in the literature for transjugular intrahepatic portosystemic shunt (TIPS) placement (70).

Finally, there are the inherent risks of vascular access and anesthesia, especially in patients with pulmonary hypertension or complex heart disease. These are the reasons why we suggest evaluating patients on a case-by-case basis to assess the risk/benefit ratio of closure.

AREAS FOR RESEARCH

CPSS are rare malformations the incidence and prevalence of which are unknown. Beyond a more reliable estimate of prevalence, much remains to be understood to ultimately counsel patients on the risk of complications and the need for closure. Understanding the natural history is a first step in the management of these patients. In addition, the need for an unequivocal, consensual nomenclature is essential for the purposes of working collaboratively. Finally, understanding the pleiotropic consequences of PS shunting and the molecular and genetic underpinnings are 2 areas ripe for research and will contribute to a heightened understanding of liver physiology. Such are the aims of the International Registry of Congenital Porto-Systemic Shunts (http://www.espghan.org/about-espghan/committees/hepatology/working-groups/congenital-porto-systemic-shunts/).

Acknowledgments

The authors are grateful to the ESPGHAN Hepatology Committee for their support, to Dr Simona Korff for the development of the International Registry of Congenital Porto-Systemic Shunts, to Khaled Mostaguir for his expertise in designing and maintaining the database, and to Simon Tschopp for illustrations.

REFERENCES

1. Ono H, Mawatari H, Mizoguchi N, et al. Clinical features and outcome of eight infants with intrahepatic porto-venous shunts detected in neonatal screening for galactosaemia. Acta Paediatr 1998; 87:631–634.
2. Bernard O, Franchi-Abella S, Branchereau S, et al. Congenital portosystemic shunts in children: recognition, evaluation, and management. Semin Liver Dis 2012; 32:273–287.
3. Abernethy J. Account of two instances of uncommon formation in the viscera of the human body. Philos Trans R Soc 1793; 83:59–66.
4. Howard ER, Davenport M. Congenital extrahepatic portocaval shunts—the Abernethy malformation. J Pediatr Surg 1997; 32:494–497.
5. Morgan G, Superina R. Congenital absence of the portal vein: two cases and a proposed classification system for portasystemic vascular anomalies. J Pediatr Surg 1994; 29:1239–1241.
6. Lautz TB, Tantemsapya N, Rowell E, et al. Management and classification of type II congenital portosystemic shunts. J Pediatr Surg 2011; 46:308–314.
7. Sokollik C, Bandsma RH, Gana JC, et al. Congenital portosystemic shunt: characterization of a multisystem disease. J Pediatr Gastroenterol Nutr 2013; 56:675–681.
8. Franchi-Abella S, Branchereau S, Lambert V, et al. Complications of congenital portosystemic shunts in children: therapeutic options and outcomes. J Pediatr Gastroenterol Nutr 2010; 51:322–330.
9. Dasarathy S, Dodig M, Muc SM, et al. Skeletal muscle atrophy is associated with an increased expression of myostatin and impaired satellite cell function in the portacaval anastamosis rat. Am J Physiol Gastrointest Liver Physiol 2004; 287:G1124–G1130.
10. Kumar KV, Pawah AK, Manrai M. Occult endocrine dysfunction in patients with cirrhosis of liver. J Family Med Prim Care 2016; 5:576–580.
    11. Garcia C, Gine E, Aller MA, et al. Multiple organ inflammatory response to portosystemic shunt in the rat. Cytokine 2011; 56:680–687.
    12. Desjardins P, Todd KG, Hazell AS, et al. Increased “peripheral-type” benzodiazepine receptor sites and mRNA in thalamus of thiamine-deficient rats. Neurochem Int 1999; 35:363–369.
    13. Gandhi CR, Murase N, Subbotin VM, et al. Portacaval shunt causes apoptosis and liver atrophy in rats despite increases in endogenous levels of major hepatic growth factors. J Hepatol 2002; 37:340–348.
    14. Cudalbu C, McLin VA, Lei H, et al. The C57BL/6J mouse exhibits sporadic congenital portosystemic shunts. PLoS One 2013; 8:e69782.
    15. Soares AF, Lei H. Non-invasive diagnosis and metabolic consequences of congenital portosystemic shunts in C57BL/6 J mice. NMR Biomed 2018; 31:
      16. Lahvis GP, Lindell SL, Thomas RS, et al. Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice. Proc Natl Acad Sci U S A 2000; 97:10442–10447.
      17. Or M, Peremans K, Martle V, et al. Regional cerebral blood flow assessed by single photon emission computed tomography (SPECT) in dogs with congenital portosystemic shunt and hepatic encephalopathy. Vet J 2017; 220:40–42.
      18. Van den Bossche L, Van Steenbeek FG, Favier RP, et al. Distribution of extrahepatic congenital portosystemic shunt morphology in predisposed dog breeds. BMC Vet Res 2012; 8:112.
        19. Tzounos CE, Tivers MS, Adamantos SE, et al. Haematology and coagulation profiles in cats with congenital portosystemic shunts. J Feline Med Surg 2017; 19:1290–1296.
        20. Paganelli M, Lipsich JE, Sciveres M, et al. Predisposing factors for spontaneous closure of congenital portosystemic shunts. J Pediatr 2015; 167:931.e12–935.e12.
        21. Chocarro G, Amesty MV, Encinas JL, et al. Congenital portosystemic shunts: clinic heterogeneity requires an individual management of the patient. Eur J Pediatr Surg 2016; 26:74–80.
        22. Lautz TB, Shah SA, Superina RA. Hepatoblastoma in children with congenital portosystemic shunts. J Pediatr Gastroenterol Nutr 2016; 62:542–545.
        23. Chandler TM, Heran MK, Chang SD, et al. Multiple focal nodular hyperplasia lesions of the liver associated with congenital absence of the portal vein. Magn Reson Imaging 2011; 29:881–886.
        24. Yamagami T, Arai Y, Takeuchi Y, et al. Intrahepatic portosystemic venous shunt associated with a large abdominal tumour. Br J Radiol 1999; 72:815–817.
        25. Farrant P, Meire HB, Karani J. Ultrasound diagnosis of portocaval anastomosis in infants—a report of eight cases. Br J Radiol 1996; 69:389–393.
        26. Akerboom T, Schneider I, Vom Dahl S, et al. Cholestasis and changes of portal pressure caused by chlorpromazine in the perfused rat liver. Hepatology 1991; 13:216–221.
        27. Farrant JM, Traill Z, Conlon C, et al. Pigbel-like syndrome in a vegetarian in Oxford. Gut 1996; 39:336–337.
        28. Dharel N, Bajaj JS. Definition and nomenclature of hepatic encephalopathy. J Clin Exp Hepatol 2015; 5 (suppl 1):S37–S41.
        29. Franchi-Abella S, Gonzales E, Ackermann O, et al. Congenital portosystemic shunts: diagnosis and treatment. Abdom Radiol (NY) 2018; 43:2023–2036.
        30. Fu L, Wang Q, Wu J, et al. Congenital extrahepatic portosystemic shunt: an underdiagnosed but treatable cause of hepatopulmonary syndrome. Eur J Pediatr 2016; 175:195–201.
        31. Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J 2015; 46:903–975.
        32. Niles JD, Williams JM, Cripps PJ. Hemostatic profiles in 39 dogs with congenital portosystemic shunts. Vet Surg 2001; 30:97–104.
        33. Kummeling A, Teske E, Rothuizen J, et al. Coagulation profiles in dogs with congenital portosystemic shunts before and after surgical attenuation. J Vet Intern Med 2006; 20:1319–1326.
        34. Yoshii K, Noda M, Naiki Y, et al. Portosystemic shunt as a cause of congenital hyperinsulinemic hypoglycemia. Pediatr Int 2017; 59:512–514.
        35. Duprey J, Gouin B, Benazet MF, et al. Glucose intolerance and post-stimulatory hypoglycemia secondary to a probably congenital intrahepatic portacaval anastomosis [in French]. Ann Med Interne (Paris) 1985; 136:655–658.
        36. Satoh M, Yokoya S, Hachiya Y, et al. Two hyperandrogenic adolescent girls with congenital portosystemic shunt. Eur J Pediatr 2001; 160:307–311.
        37. Bas S, Guran T, Atay Z, et al. Premature pubarche, hyperinsulinemia and hypothyroxinemia: novel manifestations of congenital portosystemic shunts (Abernethy malformation) in children. Horm Res Paediatr 2015; 83:282–287.
        38. Delle Chiaie L, Neuberger P, Von Kalle T. Congenital intrahepatic portosystemic shunt: prenatal diagnosis and possible influence on fetal growth. Ultrasound Obstet Gynecol 2008; 32:233–235.
        39. Alvarez F, Bernard O, Brunelle F, et al. Portal obstruction in children. II. Results of surgical portosystemic shunts. J Pediatr 1983; 103:703–707.
        40. 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; 30:419–425.
        41. Tisdall PL, Rothwell TL, Hunt GB, et al. Glomerulopathy in dogs with congenital portosystemic shunts. Aust Vet J 1996; 73:52–54.
        42. Karashima S, Hattori S, Nakazato H, et al. Membranoproliferative glomerulonephritis in congenital portosystemic shunt without liver cirrhosis. Clin Nephrol 2000; 53:206–211.
        43. Deppe TA, Center SA, Simpson KW, et al. Glomerular filtration rate and renal volume in dogs with congenital portosystemic vascular anomalies before and after surgical ligation. J Vet Intern Med 1999; 13:465–471.
        44. Van Dongen AM, Heuving SM, Tryfonidou MA, et al. Increased bone morphogenetic protein 7 signalling in the kidneys of dogs affected with a congenital portosystemic shunt. Vet J 2015; 204:226–228.
        45. Hernandez-Jaras J, Espi-Reig J, Alis R, et al. Immune complex membranoproliferative glomerulonephritis associated with transjugular intrahepatic portosystemic shunts in alcoholic cirrhosis: two case reports. Med Princ Pract 2017; 26:286–288.
        46. Rojko JL, Evans MG, Price SA, et al. Formation, clearance, deposition, pathogenicity, and identification of biopharmaceutical-related immune complexes: review and case studies. Toxicol Pathol 2014; 42:725–764.
        47. Ganesan LP, Kim J, Wu Y, et al. FcgammaRIIb on liver sinusoidal endothelium clears small immune complexes. J Immunol 2012; 189:4981–4988.
        48. Alvarez AE, Ribeiro AF, Hessel G, et al. Abernethy malformation: one of the etiologies of hepatopulmonary syndrome. Pediatr Pulmonol 2002; 34:391–394.
        49. Ohnishi Y, Ueda M, Doi H, et al. Successful liver transplantation for congenital absence of the portal vein complicated by intrapulmonary shunt and brain abscess. J Pediatr Surg 2005; 40:e1–e3.
        50. Hanquinet S, Morice C, Courvoisier DS, et al. Globus pallidus MR signal abnormalities in children with chronic liver disease and/or porto-systemic shunting. Eur Radiol 2017; 27:4064–4071.
        51. Spahr L, Butterworth RF, Fontaine S, et al. Increased blood manganese in cirrhotic patients: relationship to pallidal magnetic resonance signal hyperintensity and neurological symptoms. Hepatology 1996; 24:1116–1120.
        52. Krowka MJ, Fallon MB, Kawut SM, et al. International liver transplant society practice guidelines: diagnosis and management of hepatopulmonary syndrome and portopulmonary hypertension. Transplantation 2016; 100:1440–1452.
        53. Hoerning A, Raub S, Neudorf U, et al. Pulse oximetry is insufficient for timely diagnosis of hepatopulmonary syndrome in children with liver cirrhosis. J Pediatr 2014; 164:546–52.e1–2.
        54. El-Shabrawi MH, Omran S, Wageeh S, et al. (99m)Technetium-macroaggregated albumin perfusion lung scan versus contrast enhanced echocardiography in the diagnosis of the hepatopulmonary syndrome in children with chronic liver disease. Eur J Gastroenterol Hepatol 2010; 22:1006–1012.
        55. Uike K, Nagata H, Hirata Y, et al. Effective shunt closure for pulmonary hypertension and liver dysfunction in congenital portosystemic venous shunt. Pediatr Pulmonol 2018; 53:505–511.
        56. Knirsch W, Benz DC, Buhr P, et al. Catheter interventional treatment of congenital portosystemic venous shunts in childhood. Catheter Cardiovasc Interv 2016; 87:1281–1292.
        57. Alharbi A, Abdulrahman S, AlOtaibi M, et al. Congenital extrahepatic portosystemic shunt embolization with the use of a duct occluder in a neonate with liver dysfunction and hyperammonemia. J Vasc Interv Radiol 2017; 28:1291–1293.
        58. Roggen M, Cools B, Maleux G, et al. A custom-made percutaneous flow-restrictor to manage a symptomatic congenital porto-systemic shunt in an infant. Catheter Cardiovasc Interv 2018; [Epub ahead of print].
        59. Bruckheimer E, Dagan T, Atar E, et al. Staged transcatheter treatment of portal hypoplasia and congenital portosystemic shunts in children. Cardiovasc Intervent Radiol 2013; 36:1580–1585.
        60. Elias N, Scirica CV, Hertl M. Liver transplantation for the Abernathy malformation. N Engl J Med 2008; 358:858.
        61. Francois B, Lachaux A, Gottrand F, et al. Prenatally diagnosed congenital portosystemic shunts. J Matern Fetal Neonatal Med 2018; 31:1364–1368.
        62. Correa C, Luengas JP, Howard SC, et al. Hepatoblastoma and abernethy malformation type I: case report. J Pediatr Hematol Oncol 2017; 39:e79–e81.
        63. Benedict M, Rodriguez-Davalos M, Emre S, et al. Congenital extrahepatic portosystemic shunt (Abernethy malformation type Ib) with associated hepatocellular carcinoma: case report and literature review. Pediatr Dev Pathol 2016; [Epub ahead of print].
        64. Osorio MJ, Bonow A, Bond GJ, et al. Abernethy malformation complicated by hepatopulmonary syndrome and a liver mass successfully treated by liver transplantation. Pediatr Transplant 2011; 15:E149–E151.
        65. Iida T, Ogura Y, Doi H, et al. Successful treatment of pulmonary hypertension secondary to congenital extrahepatic portocaval shunts (Abernethy type 2) by living donor liver transplantation after surgical shunt ligation. Transpl Int 2010; 23:105–109.
        66. Hori T, Yonekawa Y, Okamoto S, et al. Pediatric orthotopic living-donor liver transplantation cures pulmonary hypertension caused by Abernethy malformation type Ib. Pediatr Transplant 2011; 15:e47–e52.
        67. Emre S, Arnon R, Cohen E, et al. Resolution of hepatopulmonary syndrome after auxiliary partial orthotopic liver transplantation in Abernethy malformation. A case report. Liver Transpl 2007; 13:1662–1668.
        68. Sato H, Miura M, Yaoita N, et al. Pulmonary arterial hypertension associated with congenital portosystemic shunts treated with transcatheter embolization and pulmonary vasodilators. Intern Med 2016; 55:2429–2432.
        69. Blanc T, Guerin F, Franchi-Abella S, et al. Congenital portosystemic shunts in children: a new anatomical classification correlated with surgical strategy. Ann Surg 2014; 260:188–198.
        70. Ding PX, Han XW, Hua ZH, et al. Stent fracture and fragment migration to chordae tendineae of the tricuspid valve after transjugular intrahepatic portosystemic shunt procedure. J Vasc Interv Radiol 2017; 28:1293–1295.
        Keywords:

        congenital portosystemic shunts; hepatopulmonary syndrome; liver nodules; neurocognitive delay; occlusion test; portopulmonary hypertension

        Copyright © 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition