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.
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.
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.
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).
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.
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.
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.
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.
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).
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.
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.
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.
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.
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).
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.
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.
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).
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.
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.
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.
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).
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).
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/).
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.
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