Portopulmonary hypertension

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. Today, PPH is comorbid in 4-6% of those referred for a liver transplant. 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. Today, PPH is comorbid in 4-6% of those referred for a liver transplant. PPH presents roughly equally in male and female cirrhotics; 71% female in an American series and 57% male in a larger French series. Typically, patients present in their fifth decade, aged 49 +/- 11 years on average. In general, PPH is diagnosed 4–7 years after the patient is diagnosed with portal hypertension and in roughly 65% of cases, the diagnosis is actually made at the time of invasive hemodynamic monitoring following anesthesia induction prior to liver transplantation. Once patients are symptomatic, they present with right heart dysfunction secondary to pulmonary hypertension and its consequent dyspnea, fatigue, chest pain and syncope. Patients tend to have a poor cardiac status, with 60% having stage III-IV NYHA heart failure. PPH is actually independent of the severity of cirrhosis but may be more common in specific types of cirrhosis, in one series more so in Autoimmune Hepatitis and less in Hepatitis C cirrhosis, while in another it was equally distributed throughout the diagnoses. PPH pathology arises both from the humoral consequences of cirrhosis and the mechanical obstruction of the portal vein. A central paradigm holds responsible an excess local pulmonary production of vasoconstrictors that occurs while vasodilatation predominates systemically. Key here are imbalances between vasodilatory and vasoconstricting molecules; endogenous prostacyclin and thromboxane (from Kupffer Cells) or nitrous oxide (NO) and endothelin-1 (ET-1). ET-1 is the most potent vasoconstrictor under investigation and it has been found to be increased in both cirrhosis and pulmonary hypertension. 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. 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. 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. The muscular pulmonary arteries become fibrotic 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. This thickening and remodeling forms a positive feedback loop that serves to increase PAP and induce right heart hypertrophy and dysfunction. The diagnosis of portopulmonary hypertension is based on hemodynamic criteria: