Portopulmonary hypertension

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Portopulmonary hypertension (PPH) is defined by the coexistence of portal and pulmonary hypertension. PPH is a serious complication of liver disease, present in 0.25 to 4% of all patients suffering from cirrhosis. Once an absolute contraindication to liver transplantation, it is no longer, thanks to rapid advances in the treatment of this condition.^[1] Today, PPH is comorbid in 4-6% of those referred for a liver transplant.^[2][3]

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PPH pathology arises both from the humoral consequences of cirrhosis and the mechanical obstruction of the portal vein.^[1] A central paradigm holds responsible an excess local pulmonary production of vasoconstrictors that occurs while vasodilatation predominates systemically^[2]. Key here are imbalances between vasodilatory and vasoconstricting molecules; endogenous prostacyclin and thromboxane (from Kuppfer Cells) ^[3][4] or nitrous oxide (NO) and endothelin-1 (ET-1).^[5] ET-1 is the most potent vasoconstrictor under investigation^[6] and it has been found to be increased in both cirrhosis^[7] and pulmonary hypertension. ^[8] Endothelin-1 has two receptors in the pulmonary arterial tree, ET-A which mediates vasoconstriction and ET-B which mediates vasodilation. Rat models have shown decreased ET-B receptor expression in pulmonary arteries of cirrhotic and portal hypertensive animals, leading to a predominant vasoconstricting response to endothelin-1. ^[9]

In portal hypertension, blood will shunt from portal to systemic circulation, bypassing the liver. This leaves unmetabolized potentially toxic or vasoconstricting substances to reach and attack the pulmonary circulation. Serotonin, normally metabolized by the liver, is returned to the lung instead where it mediates a smooth muscle hyperplasia and hypertrophy. ^[10]. Moreover, a key pathogenic factor in the decline in status of PPH patients related to this shunting is the cirrhotic cardiomyopathy with myocardial thickening and diastolic dysfunction.

Finally, the pulmonary pathology of PPH is very similar to that of primary pulmonary hypertension.^[11] The muscular pulmonary arteries fibrose and hypertrophy while the smaller arteries lose smooth muscle cells and their elastic intima. One study found at autopsy significant thickening of pulmonary arteries in cirrhotic patients.^[12] This thickening and remodeling forms a positive feedback loop that serves to increase PAP and induce right heart hypertrophy and dysfunction.

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PPH presents roughly equally in male and female cirrhotics; 71% female in an American series and 57% male in a larger French series.^[1][2] Typically, patients present in their fifth decade, aged 49 +/- 11 years on average.^[1][3]

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Following diagnosis, mean survival of patients with PPH is 15 months.^[1] The survival of those with cirrhosis is sharply curtailed by PPH but can be significantly extended by both medical therapy and liver transplantation, provided the patient remains eligible.

Eligibility for transplantation is generally related to mean pulmonary artery pressures (PAP). Given the fear that those PPH patients with high PAP will suffer right heart failure following the stress of post-transplant reperfusion or in the immediate perioperative period, patients are typically risk-stratified based on mean PAP. Indeed, the operation-related mortality rate is greater than 50% when pre-operative mean PAP values lie between 35 and 50 mm Hg; if mean PAP exceeds 40-45, transplantation is associated with a perioperative mortality of 70-80% (in those cases without preoperative medical therapy).^[2][3] Patients, then, are considered to have a high risk of perioperative death once their mean PAP exceeds 35 mm_Hg.^[4] The focus on mean PAP values as a chief prognostic index has achieved a consensus according to a recent multicenter study: 45% of patients with PPH were denied OLT candidacy based on the degree of their pulmonary hypertension, while no patient with mPAP < 35 mm_Hg was denied (Between those accepted and those denied, there was no significant difference in cardiac output or right atrial pressure).^[5]

Survival is best inferred from published institutional experiences. At one institution, without treatment, 1-year survival was 46% and 5-year survival was 14%. With medical therapy, 1-year survival was 88% and 5-year survival was 55%. Survival at 5 years with medical therapy followed by liver transplantation was 67%.^[6] At another institution, of the 67 patients with PPH from 1652 total cirrhotics evaluated for transplant, half (34) were placed on the waiting list. Of these, 16 (48%) were transplanted at a time when 25% of all patients who underwent full evaluation received new livers, meaning the diagnosis of PPH made a patient twice as likely to be transplanted, once on the waiting list. Of those listed for transplant with PPH, 11 (33%) were eventually removed because of PPH, and 5 (15%) died on the waitlist. Of the 16 transplanted patients with PPH, 11 (69%) survived for more than a year after transplant, at a time when overall one-year survival in that center was 86.4%. The three year post-transplant survival for patients with PPH was 62.5% when it was 81.02% overall at this institution.^[7]

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