Liver transplantation for portopulmonary hypertension

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Abbreviations

LT

liver transplantation

MELD

model for end‐stage liver disease

mPAP

mean pulmonary arterial pressure

PAH

pulmonary arterial hypertension

PAOP

pulmonary arterial occlusion pressure

PoPH

portopulmonary hypertension

PVR

pulmonary vascular resistance.

Pulmonary arterial hypertension (PAH), arising in the setting of portal hypertension, with or without liver cirrhosis, is called portopulmonary hypertension (PoPH). The definition of PoPH is comprised of three essential elements:

1. Mean pulmonary arterial pressure (mPAP) greater than 25 mmHg.

2. Pulmonary vascular resistance (PVR) greater than 240 dynes/second/cm⁵.

3. Pulmonary arterial occlusion pressure (PAOP) less than or equal to 15 mmHg.1

The diagnosis of PoPH carries great significance because these individuals have markedly increased morbidity and mortality, even when treated with specific pulmonary vasodilator agents. Krowka et al. reviewed a large US registry database of individuals with PAH and showed that patients with PoPH had a 5‐year survival of 40% compared to 64% in those patients with idiopathic/familial PAH (Fig. 1).2 These worse outcomes were observed even in patients with moderate elevations in mPAP and PVR and higher cardiac outputs at study entry. Additionally, 51% of PoPH patients were hospitalized during the first 2 years of follow‐up. These results were observed despite the introduction of pulmonary vasodilators within 1 year of enrollment in the majority of PoPH patients. Individual hemodynamic markers for PoPH patients were not predictive of survival.

Figure 1.

Five‐year survival from diagnosis. ^aOnly patients enrolled within 5 years of diagnosis were included in the 5‐year survival from diagnosis curve. See Figure 1 legend for expansion of abbreviations.

Swanson et al. performed a retrospective analysis of all 74 PoPH patients seen at Mayo Clinic from 1994 through early 2007.3 Nineteen individuals who did not receive pulmonary hypertension therapy had a median survival of 15 months with 5‐year survival of 14%. Median survival was improved to 46 months, and 5‐year survival was improved to 45% in those 43 patients who received pulmonary vasodilators without a transplant (Fig. 2). Baseline hemodynamics and Model for End‐Stage Liver Disease (MELD) scores were not prognostic for survival in either group.

Figure 2.

Survival curves comparing patients who were not selected to receive medical therapy for pulmonary hypertension (natural history) with those who were in the absence of liver transplantation.

Given the poor prognosis, even with medical therapy, of cirrhotic patients with PoPH, liver transplantation (LT) has become an important therapeutic option; however, LT is fraught with perioperative surgical risk. In a landmark article, Krowka et al. reported that a preoperative or intraoperative mPAP greater than 50 mmHg was associated with 100% mortality, whereas mPAP between 35 to 50 mmHg with a PVR above 250 dynes/second/cm⁵ was associated with 50% mortality.4 Those patients with mPAP below 35 mmHg had 100% survival. Based on Krowka et al.'s data, the accepted guidelines for listing a patient with PoPH for transplantation are achieving mPAP below 35 mmHg (Table 1).

Table 1.

Current Mayo Clinic Intraoperative Guidelines Concerning Pulmonary Hemodynamics in Patients With Portopulmonary Hypertension

Mean Pulmonary Artery Pressure (MPAP)	Intraoperative Guideline	Reported Mortality (%)
<35 mm Hg	Proceed with OLT	0/14 (0)
35‐50 mm Hg	If PVRa <250 proceed with OLT	0/6 (0)
	If PVR >250 cancel OLT	7/14 (50)c
>50 mm Hg	Cancel OLTb	6/6 (100)

^aPVR in dynes·s·cm⁻⁵.

^bIf untreated, refer for additional pulmonary hypertension evaluation/therapeutic considerations and reevaluate for OLT.

^cOne patient died post‐transplantation hospitalization of right cardiac failure.

Despite this data, liver transplantation for patients with PoPH still is not a standard approach at most institutions due to the uncertainty of posttransplant survival and the unpredictable reversibility of the pulmonary hypertension. An early study by Krowka et al. reported 36% mortality for 36 patients undergoing transplantation, with all deaths occurring by postoperative day 18.5 There were no differences found in PAP, cardiac output, or PVR between survivors and nonsurvivors, whereas only one of 13 nonsurvivors was pretreated with a prostacyclin. Furthermore, 92% of nonsurvivors had a pretransplant mPAP greater than 35 mmHg, and 62% had a PVR greater than 250 dynes/second/cm⁵. The authors hypothesized that increased utilization of prostacyclins prior to LT could improve posttransplant survival.

Later investigations have now supported the use of prostacyclins prior to transplantation. Sussman et al. described eight individuals with PoPH who were treated with epoprostenol for an average of 6.5 months and who were listed for transplantation if mPAP fell below 35 mmHg.6 Seven patients met the criteria; of those, four underwent transplantation. At the time of publication, all four were alive, with two being off all pulmonary vasodilator agents and the other two able to deescalate to oral pulmonary vasodilators.

Ashfaq et al. reported on a larger cohort of 16 patients with moderate to severe PoPH, most of who were treated with epoprostenol.7 Among the 12 patients who had a drop in mPAP below 35 mmHg after an average of 7.4 months treatment, 11 underwent successful transplantation. Survival for the transplant patients at 1, 2, and 5 years was 90.9%, 80.8%, and 67.3%, respectively. Importantly, nine of the 11 transplanted patients were able to stop all pulmonary vasodilators a median of 9.2 months after transplantation. In contrast, median survival was only 8 months among those patients whose mPAP failed to respond to pulmonary vasodilator therapy. In light of the excellent results from medical treatment, combined with LT and the dire consequences of medical management alone, PoPH is one of the conditions for which MELD “exception” points are awarded in the United States (Table 2).

Table 2.

MELD Exception from Organ Procurement and Transplantation Network

Criteria for MELD Exception
1. Initial abnormal mPAP and PVR.
2. Documentation of pulmonary vasodilator treatment.
3. Posttreatment achievement of mPAP < 35 mmHg and PVR < 400 dynes/second/cm−5.
4. Transpulmonary gradient (mPAP–PAOP) ≥ 12 mmHg to correct for volume overload.
MELD Score of 22a If Above Met

^aMELD SCORE increases by 10% every 3 months if hemodynamic parameters by right heart catheterization are maintained.

Based on these prior studies, which showed that aggressive treatment of PoPH and subsequent transplantation can lead to the reversal of the disease, our LT center has adopted a similar approach. We have reported the outcomes in 11 patients with moderate to severe PoPH who were treated with sildenafil and/or treprostinil (a prostacyclin analog) followed by LT.8 Ten of 11 patients achieved a mPAP below 35 mmHg or a PVR less than 240 dynes/second/cm⁵ after an average treatment time of 11 months. Average MELD score at the time of transplantation was 17.9, with seven of 11 patients receiving MELD exception scores for their PoPH. The mean duration on the wait list until transplantation was 108.6 days. All patients were alive at an average follow‐up of 30 months, with seven of 11 (64%) patients able to discontinue all therapies for PoPH by a mean of 13.7 months.

These recent single center investigations have shown that LT can be successfully undertaken in patients with moderate to severe PoPH who have been pretreated with pulmonary vasodilators to obtain mPAP below 35 mmHg and/or a PVR below 240 dynes/second/cm⁵. For patients marginally meeting these hemodynamic parameters, inclusion of the right ventricular function can help determine candidacy for listing. These studies also indicate that even moderate to severe PoPH can be reversible with transplantation because most patients were able to either discontinue all pulmonary vasodilators or deescalate from prostacyclins to oral agents. Whether to proceed with transplantation in patients with mild PoPH, that is, mPAP less than 35 mmHg at diagnosis, is a more difficult decision. However, given that hemodynamic parameters do not predict survival, a case can be made to pursue listing. Given the small number of patients transplanted to date and presented in the above studies, future studies are required to confirm that LT is the best approach for patients with PoPH.

One challenge specific to the United States is that the existing regional model for distributing liver transplant organs from deceased donor (the so‐called Share 35 rule) tends to discriminate against PoPH patients because they rarely generate a sufficient score, even with MELD exception (see Table 2). Consideration should be given to raising the MELD exception score to facilitate earlier transplantation based on the poor outcomes and unreliability of prognostic predictors in this population.