The Search for Causes of Idiopathic Pulmonary Arterial Hypertension

By Akshay Bhatnagar, MD, Raed Dweik, MD, and Neal F. Chaisson, MD

Pulmonary hypertension is considered the final common pathway of many varied diseases and syndromes, and therefore one cannot say it is idiopathic without making a robust effort to identify features of alternative causes and rule out other contributing factors.

Although the exact etiology of idiopathic pulmonary arterial hypertension (PAH) is unclear, well-characterized imbalances in vascular homeostasis have been identified. These include processes that promote vasoconstriction, cell proliferation, and thrombosis (thromboxane A2, endothelin-1, and serotonin) and those that suppress prostacyclin, nitric oxide, and vasoactive intestinal peptide-mediated vasodilation. Furthermore, an abnormal angiogenic response to hypoxia and vascular endothelial growth factor has been observed.

Before considering a diagnosis of idiopathic PAH, a careful history is essential. Other causative agents include appetite-suppressing medications, such as fenfluramine derivatives or stimulants such as amphetamines. Human immunodeficiency virus (HIV) or hepatitis, a history of splenectomy and prior thyroid or liver disease are also common causes of PAH. Joint pain, myalgias, Raynaud features or a rash characteristic of connective tissue disease can be identified on history and physical examination. Worldwide, chronic exposure to high-altitude climates and exposure to schistosomiasis are significant causes of PAH, but are rarely seen in developed nations. Confirmatory serum tests for HIV, antinuclear antibody, scleroderma antibody and thyroid function are essential.

Genetic factors

If patients report having relatives with possible or probable PAH, genetic counseling is recommended, particularly for rare but causative gene mutations.

BMPR2, the gene that codes for the bone morphogenetic protein receptor type 2, can carry mutations with variable penetrance over the patient’s lifetime depending on other genetic polymorphisms, concurrent inflammation and the patient’s sex.

The population carrier estimates of BMPR2 mutations are only 0.001 to 0.01 percent, but mutations in this gene are identified in approximately 25 percent of nonfamilial PAH patients and in over 75 percent of those with a familial inheritance pattern. The BMPR2 protein is a part of the transforming growth factor beta family and is partially responsible for control of vascular cell proliferation. Mutations in this gene lead to PAH at a younger age than in those with mutation-negative idiopathic PAH and to a more severe clinical phenotype in terms of pulmonary vascular resistance and cardiac function.

Other mutations. Although BMPR2 is the most commonly identified gene mutation in patients with PAH, other gene mutations within this family have also been recognized. These include mutations in the genes for activin receptor-like kinase 1 and endoglin, which, although better known for their association with hereditary hemorrhagic telangiectasia, can lead directly to PAH.

More recently, a novel autosomal recessive gene mutation in eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) has been identified in patients with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, which are specific subclasses of WHO group 1 PAH. The mechanistic parallels between EIF2AK4and these diseases are not clear, but the prevalence of disease in those with a familial inheritance pattern and an EIF2AK4 mutation is nearly 100 percent. Thus, identification of this mutation has been accepted as a way to confirm pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis in patients suspected of PAH with features of these diseases.

Dr. Bhatnagar is staff in the Department of Regional Anesthesiology. Dr. Dweik is Chair, Respiratory Institute. Dr. Chaisson is staff in the Departments of Pulmonary and Critical Care Medicine, Respiratory Institute.

This abridged article originally appeared in Cleveland Clinic Journal of Medicine.