A subclinical high tricuspid regurgitation pressure gradient independent of the mean pulmonary artery pressure is a risk factor for the survival after living donor liver transplantation

End-stage liver cirrhosis is often complicated with pulmonary capillary disorders. The most commonly found pulmonary vascular complication is hepatopulmonary syndrome (HPS), in which the pulmonary arteries dilate, resulting in arterial deoxygenation (an increased alveolar-arterial oxygen gradient [AaDO₂] with or without hypoxemia) [1]. Although not frequent, occasional reports of portopulmonary hypertension (POPH), in which the pulmonary arteries thicken, resulting in pulmonary hypertension (PH), have been described. The criteria for diagnosing POPH are PH (defined by a mean pulmonary artery pressure [mPAP] > 25 mmHg at rest via right heart catheterization) and high pulmonary vascular resistance without complicating left heart failure. These criteria indicate that POPH is a form of pulmonary hypertension not due to left ventricular heart failure in portal hypertensive patients. The prevalence of HPS in patients with cirrhosis ranges from 10 to 30%, while that of POPH ranges from 5 to 10% [2]. Both of these complications significantly worsen the prognosis and quality of life [3].

Given that HPS can be resolved after orthotopic liver transplantation (OLT) even when hypoxemia is severe (PaO₂ < 50 mmHg), the implications for OLT are understood to apply not only with deceased donor LT (DDLT) but also living donor related LT (LDLT). However, the post-OLT course of POPH-complicated patients is often unsatisfactory, and severe (mPAP > 45 to 50 mmHg) patients are considered absolutely contraindicated for OLT. The International Liver Transplant Society Practice Guidelines indicate that, unlike HPS, there are no data to support the concept that POPH (treated or untreated) should be an indication for OLT [4]. Several clinical studies have suggested that if mPAP is < 35 mmHg, then the perioperative mortality does not increase [5, 6]. Furthermore, the Practice Guidelines recommend that patients with mPAP < 35 mmHg be indicated for OLT, and PA-targeted therapy should be initiated in patients with mPAP ≥35 mmHg [4]. However, almost all of the patients in these articles had received DDLT, and no such analyses have been performed for LDLT patients. Given that left or right lobe LDLT grafts are smaller than DDLT grafts, PH-induced hepatic venous pressure might result in a strong congestive impact on the LDLT grafted liver.

The objective of the present study was to investigate the impact of cirrhosis-related cardio-pulmonary complications on the LDLT survival. Although patients with confirmed POPH and HPS are rare, those with mild pulmonary hypertension and mild HPS are more common. Given that right heart catheterization is not performed for all patients during the pre-operative investigation, the tricuspid regurgitation pressure gradient (TRPG) measured by transthoracic echocardiography (TTE) was adopted to estimate the PH-related congestive pressure in the transplanted liver. The peak systolic pressure gradient between the right ventricle (RV) and the right atrium (RA) can be estimated using the peak systolic TRPG [7]. The TRPG is calculated from the peak velocity of the tricuspid regurgitation (TR) measured by continuous-wave Doppler echocardiography using the modified Bernoulli equation [8].

The risk factors associated with the 3-month, 1-year, and 40-month survival were investigated.

In the present study, a high TRPG was a definite survival-defining factor after LDLT that might be able to be controlled before or during operation. Even in patients with a high mPAP-FIO₂0.6, the co-existence of subclinical HPS might reduce the TRPG, thus resulting in a good prognosis. The TRPG but not mPAP-FIO₂0.6 was a critical factor that may reflect the pressure directed to the grafted small living-donor liver. Given that this study was retrospective and the sample size was relatively small, larger prospective studies to confirm the present results are needed.

Reported factors associated with a worse survival after primary DDLT include a high MELD score, HCV positivity, aged recipient, aged donor [10], mechanical ventilation before OLT, and dialysis [11]. Although the present data did not include the hepatic venous pressure gradient (HVPG), which is an accurate reflection of the portal pressure gradient, we included the Child-Pugh score, MELD score and the history of variceal treatment to assess the severity of cirrhosis. As survival-related factors after LDLT, small-for-size graft syndrome is an additional important factor [12]. The present investigation indicated that a pre-LDLT subclinical high TRPG was an independent strong survival-determining factor after LDLT. Although not all patients with a subclinical high TRPG exhibited PH, congestive pressure to the grafted liver likely affected the small living donor graft function recovery post-LDLT.

In LDLT settings, graft blood flow in the initial few weeks after surgery has been reported to influence the overall outcome of small-for-size liver graft OLT. Poor venous outflow and resulting hepatic congestion have been shown to be strong factors for a poor graft function [13]. Several vascular surgical techniques to reduce hepatic venous congestion have been adopted to improve the living donor graft survival [14, 15]. These findings indicate that hepatic venous congestion and the resulting graft congestion are relatively frequent prognosis-defining factors in LDLT, although such congestion is not usually severely problematic in DDLT. The present results suggested that a high mPAP measured after general anesthesia did not affect the outcome post-LDLT; however, a subclinical high TRPG measured by TTE proved to be a strong predictor of a bad outcome. The most frequent causes of deaths in the subclinical high TRPG patients were infection and secondly vascular thrombus. Bacterial translocation from the intestine could be induced by pressure at the graft portal tract resulting in severe infection, and vascular thrombus could also be induced by pressure at the graft. These frequent causes of death in the subclinical high TRPG patients all involved, albeit indirectly, high pressure being applied to the grafts.

TRPG measured by TTE is usually positively correlated with mPAP measured by right heart catheterization [16]. However, several reports have published findings denying such a correlation [17, 18]. One analysis reported that over- and underestimation occurred equally frequently with TTE [19]. Another report stated that TTE underestimated PH more often than catheterization, especially in patients with RV enlargement or right heart failure [20]. However, a different report claimed that severe TR could induce altered right heart hemodynamics, resulting in the overestimation of PH [21]. These conflicting findings are partly because TRPG measures the indirect peripheral pulmonary arterial pressure to the right ventricle and right atrium, while mPAP measures the micro-vessel-level central pulmonary arterial pressure. Our present results indicated no significant correlation between mPAP-FIO₂0.6 and TRPG. Given that O₂ administration is an accepted supportive therapy for PH, the present mPAP-FIO₂0.6 may be lower than the mPAP measured by standard right heart catheterization used as a diagnostic marker for PH. Although the present mPAP-FIO₂0.6 is different from the mPAP measured by the standard method, all of our patients were in a similar medical condition, and therefore the investigation of the correlation in this population was deemed acceptable. The difference between standard mPAP and mPAP-FIO₂0.6 cannot be determined. The clinical impact of these values on the post-LDLT survival also differed, as a higher TRPG was significantly correlated with the outcome, while a higher mPAP-FIO₂0.6 was not. The patients included in our present study exhibited a relatively large left atrium with high AaDO₂ compared with the normal range observed in the Japanese population, indicating right-to-left shunt predominance with subclinical HPS. The co-existence of subclinical HPS was particularly predominant in Group 3, indicating that TRPG is not high even when mPAP is high. The pressure against the grafted liver is reflected by the TRPG, not by the mPAP, as the pressure may be reduced due to pulmonary arterial bypass with HPS. Given the small sample size, especially in Group 1 and 3, larger studies are needed to confirm this possibility.

HPS is more frequently found than POPH and has been acknowledged as a life-threatening complication; however, this condition can be resolved with OLT [22]. The pathophysiology of this condition is considered to be pulmonary vessel dilatation due to the easily identified vascular dilation-related hormonal changes in liver cirrhosis [1]. As we did not perform TTE with a bubble study, which is the standard sensitive imaging test for identifying intra-pulmonary vascular shunting, we diagnosed only one definite HPS patient by lung perfusion scintigraphy. However, the subclinical HPS patients who clinically exhibited HPS phenomena accounted for 33% of the included subjects. This subclinical HPS condition is frequently accompanied by end-stage liver disease. In our present analysis, the Group 3 patients with a relatively high mPAP and a low TRPG exhibited a higher frequency of subclinical HPS than the other groups. The definite POPH with definite HPS combination has been reported to be associated with a poor 1-year survival rate of 68%, while POPH alone is associated with a 91% survival rate excluding OLT recipients [23]. The post-OLT survival was worse in POPH patients with HPS (5 of 5 dead) than in patients with POPH alone (3 of 3 alive). However, our present results concerning the post-LDLT survival indicated the opposite effect. These patients may not be very sick, as they exhibited only “subclinical” high TRPG and HPS. They may therefore be in good enough health to benefit from HPS, although their mPAP-FIO₂0.6 values were high. Under these conditions, regurgitation pressure from the pulmonary artery might escape via an intra-pulmonary shunt.

The cardio-pulmonary clinical condition of Group 2, who had a high TRPG and low mPAP, was associated with the worst outcome of the examined groups. This condition is similar to left-to-right shunting or right heart failure although not clinically evident. In addition, the Group 2 patients exhibited a lower frequency of RA dilatation than those in Group 1, showing a high TR pressure without RA dilatation, which indicated a strong pressure directed to the grafted liver. RA dilatation may relieve the direct pressure to the graft.

TRPG as assessed by TTE may be more useful than mPAP by pre-operational right heart catheterization under FIO₂0.6 for predicting the post-OLT survival. A high TRPG, even below the limit of PH, may reflect pressure to the grafted liver that might be critical for relatively small-for-size LDLT. Given that this study was retrospective and the sample size was relatively small, larger prospective studies to confirm the present results are needed. When patients with a high TRPG undergo LDLT, the administration of therapies to reduce the TRPG should be considered.