Congenital absence of the portal vein, also known as Abernethy syndrome, is a rare disorder with 19 cases reported since its original description in 1793 (2
). Its association with pulmonary AVMs was described in three cases (5
) in the more recent era but none were associated with PAH until a recent report of three additional cases (8
). In the historical cases, additional features, such as a predominantly female disposition, polysplenia, biliary atresia, and interrupted IVC, suggest it may be associated with left isomerism heterotaxy syndrome. In fact, one has to wonder if other cases cited (9
) of dilated vessels and intrapulmonary shunting seen in patients with heterotaxy and polysplenia, may in fact have had absent portal veins that had gone unnoticed.
With broader identification and longer experience with the use of pulmonary arterial-specific vasodilators, medical management of PPHTN may now allow the safe performance of liver transplantation. Both patients in this report did not have serious adverse effects from pulmonary vasodilators. The headaches and erections were reversible and did not return when a smaller dose was used. Clearly, no strong conclusion can be made but neither patient seemed to have had a robust response to sildenafil or oxygen and nitric oxide in the cathlab. However, one may have responded to bosentan and the other to intravenous prostanoid. Interestingly, after transplantation, case 2 reacted for the first time to nitric oxide. In contrast, a case series of pediatric patients with PPHTN from Condino et al. (11
) reported 4/7 pediatric patients succumbing to PAH in the setting of advanced liver disease or portal vein thrombosis. However, these subjects were older, did not present with vascular disease until years later, and had significantly longer follow-up. Krowka et al. (12
) provided hemodynamic guidelines to risk stratify cirrhotic patients with PPHTN for liver transplantation, and Arguedas et al. (14
) and Krowka et al. (13
) also described acceptable transplant outcome data for HPS. Hence, early diagnosis in conjunction with close monitoring for cyanosis and PAH (low threshold for catheterization) without delay in medical intervention may be the reason for the short-term success of liver transplantation, particularly in alleviating PAH, as seen in case 2. To this end, the work up of left isomerism heterotaxy syndrome should include identification of the portal vein. Alternatively, in the differential diagnosis of unexplained cyanosis or pulmonary hypertension, absent portal vein should be considered.
It may seem unusual for the portal vein to be absent in left isomerism heterotaxy syndrome because the spleen, a “left”-sided structure, and its vein are present (unlike right isomerism). The splenic vein still joins other intestinal veins that would otherwise be labeled as the portal vein if it were not for the connection to the azygous vein. Hence, the portal vein is clearly not absent or aplastic. Instead, in the setting of left isomerism, the contralateral side’s “right”-sided structures are absent so that the portal vein cannot home in to the portahepaticus and further divide into venules that are part of the portal triad. Perhaps, a better description of this vascular malformation in heterotaxy syndrome would be “anomalous portal venous return,” conforming to the classification of other congenital vascular malformations such as “anomalous pulmonary venous return.”
In patients with portal-systemic venous shunts, the pulmonary manifestations are generally vascular dilatation or PAH in isolation. The rare presence of one entity followed by the other has also been described (15
). Their coexistence in liver disease, as described in case 1, is rare and described in only one other case series (8
). In this report of three children with Abernethy syndrome, PAH coexisted with vascular dilatation and hypoxemia although the degree of each was not quantified. Other than supplemental oxygen, pulmonary vasodilators were not administered, and it is unclear how symptomatic these children were. Interestingly, a hypoplastic portal vein was identified in each of the patients by direct angiography, and all underwent portovenous shunt occlusion percutaneously with short-term improvement of hypoxemia and pulmonary hypertension in two obviating the need for transplantation or pulmonary artery-specific vasodilators. It is difficult to compare the severity of these two groups of patients, but the fact that they were treated very differently illustrates some important facets of the syndrome. First, it is difficult to image the mesenteric venous anatomy but a portal venous connection to the liver was identified by meticulous imaging, allowing the occlusion of the alternative venous pathway (portovenous shunt). Similar cross-sectional body imaging and direct angiography in case 1 plus direct visualization at liver transplant in case 2 did not reveal a portal venous connection to the liver. Either because the portal venous structure was never present or it became too small to recognize over time as the children in our case series were older at the time of diagnosing Abernethy syndrome compared to Newman et al. Second, a clinical response is seen when the shunt is eliminated, and the portal venous flow reestablished either by shunt occlusion or by liver transplantation, indicating the disease process is reversible. In fact, because there was no adverse outcome of shunt occlusion in the setting of a patent portal vein, this intervention should be attempted first with liver transplantation as backup. In the cases of congenital absence of the portal vein and pulmonary hypertension, liver transplantation should be considered as a primary option early in the disease course, so as to prevent the scenario of severe pulmonary hypertension (mean PAP greater than 2/3rd mean systemic arterial pressure) at the time of transplant. There remains a role for pulmonary arterial vasodilators. Because pulmonary hypertension is likely to be progressive in this disease, minimization of reversible and irreversible pulmonary vascular remodeling with medical therapy is indicated. As shown in this case series, medical therapy allowed the second case to receive a liver transplant alone with steady improvements in PAH before and after sequential liver transplants.
It may also seem paradoxical or at least pathologically divergent to have exuberant vascular dilatation in the same organ as vasoconstrictive disease. However, coexistence of at least AVMs and PAH is observed in patients with hereditary hemorrhagic telangiectasia (17
). Although the exact mechanism is unclear, it may reside in the emerging role of the superfamily of TGF-β
receptors in disease. ALK
1 and endoglin mutations are thought to be the molecular genetic basis behind hereditary hemorrhagic telangiectasia. Mutations in another TGF-β
receptor superfamily member, BMPR
2, have been identified in familial PAH. The TGF-β
receptor gene itself is mutated in some patients with a syndrome of dilated vasculopathy that is now labeled as Loeys-Dietz (18
). Similarly, there is suggestion that the fibrillin mutation can also lead to abnormal signaling in the TGF-β
receptor in Marfan syndrome, in which the hallmark is a dilated vasculopathy of the ascending aorta (19
). Therefore, one may speculate whether it is the regulation of TGF-β
receptor stimulation/inhibition by mediators from the liver, dictated by whether the liver has the opportunity to perform first pass metabolism of portal venous blood that is important in the development of pulmonary vasculopathy, as opposed to an isolated imbalance of circulating vasodilators and vasoconstrictors. Although the description of the vascular malformation in patients with Abernethy or left isomerism syndrome includes AVMs and HPS predominantly involves capillaries, when the disease process is diffuse, it is likely that precapillary/capillary dilatation and AVMs coexist. In case 1, for example, although small vessel involvement was clearly identified and no gross AVMs were seen, it is difficult to differentiate tiny or miliary AVMs from precapillary and capillary malformations alone. As a result, the cases of small diffuse AVMs in some reports and capillary dilatations in others may possibly involve both in the same patients.
It is also of interest that patients with congenital heart disease whose sole pulmonary blood supply is from a surgically created SVC anastomosis to the pulmonary artery (Glenn or cavopulmonary shunt) also have a disposition to the formation of dilated pulmonary vessels and/or AVMs (20
). These “AVMs” tend to be very small and diffuse and not amenable to coil embolization. These patients have normal portal venous return to the liver. Addition of hepatic venous blood directly or unfiltered (not second pass such as after traversing another capillary bed) via a systemic arterial shunt to their pulmonary circulation will prevent these vascular malformations. Thus, it appears that portal blood that has undergone hepatic passage delivered to the lungs without traversing another tissue bed may be the circulatory prerequisite to mitigate the development of dilated vasculopathy and intravascular shunting or possibly even constrictive arteriopathy in the lungs.