4 Pulmonary Arterial Hypertension
4. CONDITIONS ASSOCIATED WITH PULMONARY ARTERIAL HYPERTENSION
3.6. L-tryptophan
L-tryptophan was prescribed as a treatment for insomnia and neuras-thenia and was widely used as a self-medication for improving health in various ways. By 1989, an estimated 2% of Americans were using this agent; however, case reports began to appear of a life-threatening disease seemingly related to tryptophan use: the eosinophilia-myalgia syndrome (50). Approximately 1,500 individuals with the syndrome, characterized by eosinophilia, fasciitis, and, in some cases, sclerodermiform skin changes, Raynaud’s phenomenon, and, occasionally, severe pulmonary hypertension, were reported.
Interestingly, the pathology resembles the toxic oil syndrome in numerous respects (51,52). Despite a considerable literature on this disease, its cause remains unknown and controversial; both L-tryptophan itself and contaminants of the manufacturing process have been implicated (53).
4. CONDITIONS ASSOCIATED WITH PULMONARY
Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telang-iectasias) (54–56). At autopsy, up to 80% of individuals will have histopathological changes consistent with PAH; however, only 10–15% will develop clinically apparent disease. Histology consistent with PAH has also been observed in systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and rheumatoid arthritis (RA). In all of these disorders, there is a strong association between the presence of pulmonary hypertension and the presence of Raynaud‘s phenomenon, suggesting that there may be similarities in these vasculopathies (57).
4.2. Infection with the Human Immunodeficiency Virus (HIV)
An association between HIV infection and pulmonary hypertension was first reported in 1991; initial cases occurred primarily in those individuals who acquired HIV infection after receiving blood products for hemophilia (58,59). Since then, almost 150 cases have been reported and have encompassed all etiologies for acquiring HIV infection. Population studies of individuals infected with HIV suggest that the incidence of pulmonary hypertension is approximately 0.5%, or 6–12 times that of the general population. The occurrence of pulmonary hypertension is independent of the CD4 count but appears related to the duration of HIV infection. Many of these patients also have foreign-body emboli from the use of intravenous drugs and/or portal hypertension from a concomitant infection with hepatitis B or C;
moreover, both of these entities, intravenous drug use and portal hyper-tension, have been associated with pulmonary hypertension. Because HIV does not directly infect endothelial cells, the mechanism of pulmonary hypertension in HIV infection is unclear.
4.3. Portal Hypertension
Although uncommon, an association between portal hypertension and the development of pulmonary hypertension exists. In a large autopsy series, histological changes consistent with pulmonary hyper-tension occurred in 0.73% of individuals with cirrhosis, six times the prevalence in all autopsies (60). Hemodynamic studies have estimated the prevalence of pulmonary hypertension in these individuals at 2%
and 5% (61); however, the prevalence may be higher in patients referred for liver transplantation, ranging from 3.5% to 8.5% (62).
In studies using two-dimensional echocardiography of patients under-going evaluation for orthotopic liver transplantation, the incidence of
pulmonary hypertension was estimated at 12%; however, this incidence was not confirmed by right heart catheterization (63). With right heart catheterization, the incidence of pulmonary hypertension in these patients is approximately 6% (64). The diagnosis of pulmonary hyper-tension is usually made four to seven years after the diagnosis of portal hypertension (65) but, in some cases, may precede it. In addition, the risk of developing pulmonary hypertension increases with the duration of portal hypertension. The mechanism of this association is unclear, but cirrhosis without the presence of portal hypertension appears to be insufficient for the development of pulmonary hypertension.
4.4. Thrombocytosis
There is an also association among thrombocytosis, chronic myelodysplastic syndrome, and the development of pulmonary hyper-tension (66,67). Although there are several case reports and small series of the two entities occurring simultaneously, there is one large reported cohort of 26 patients with chronic myelodysplastic syndrome and unexplained pulmonary hypertension; of these patients, 14 of 26 had elevated platelet counts (median: ∼600 × 109) (67). In this group of patients, the incidence of pulmonary hypertension was 5 to 40 times greater than that in the general population, occurred at a much later age than IPAH, and portended a worse prognosis than in IPAH not associated with chronic myelodysplastic syndrome.
Possible explanations invoked for the association of the two diseases include the hypermetabolism associated with chronic myelodysplastic syndrome resulting in a chronic high-output state, the chronic dissem-inated intravascular coagulation associated with CMD leading to the deposition of microthrombi in the pulmonary circulation, and the increased incidence of portal hypertension in these patients.
In many cases, the degree of pulmonary hypertension correlated directly with the platelet count, patients’ symptoms mirrored changes in platelet counts, and, in two cases, direct obstruction of pulmonary arteries by circulating megakaryocytes was demonstrated, suggesting that platelets play a central role in the etiology of this process (68).
Thus, it is possible that platelet-derived products, such as serotonin or platelet-derived growth factor, are important in the development of pulmonary hypertension in these patients. Platelet-derived growth factor is a strong stimulus for smooth muscle proliferation, and in an animal model of pulmonary hypertension, control of the platelet count retards the development of pulmonary hypertension.
4.5. Asplenia
An increased incidence of asplenia has been reported in patients with pulmonary hypertension (69,70). In one study, the prevalence of postsplenectomy asplenia in patients with pulmonary hypertension was 11.5%; there were no cases of asplenia in the control group (patients without pulmonary hypertension) (69). Lung specimens from postsplenectomy patients with pulmonary hypertension demonstrate abundant thrombotic lesions, intimal fibrosis, and plexiform lesions.
It has been speculated that after splenectomy, abnormal erythro-cytes remain in the circulatory system longer and trigger platelet activation, leading to thrombi in the pulmonary vascular bed; however, splenectomy can also cause portal hypertension, a risk for the devel-opment of pulmonary hypertension (70). In addition, as the spleen buffers circulating platelet counts, asplenia is also associated with significant elevations in circulating platelets. Thus, although it appears that splenectomy is a risk factor for the development of pulmonary hypertension, the pathogenic mechanism(s) is not yet clear and likely complicated.
4.6. Hemoglobinopathies
Several studies have documented pulmonary hypertension and right ventricular dysfunction in patients with thalassemia, partic-ularly homozygous beta-thalassemia (71,72). Although one study found evidence of pulmonary hypertension in 75% of patients with beta-thalassemia, this study and others have relied on echocardiog-raphy, not right heart catheterization, for the diagnosis of pulmonary hypertension.
Likewise, in sickle cell anemia, using echocardiography as the diagnostic tool, the estimated incidence of pulmonary hypertension has been variable (8–30%) (73). In a recent catheterization study of 34 adult patients with sickle cell disease (74), 20 patients were diagnosed with pulmonary hypertension (average mean pulmonary artery pressure: 36 mm Hg); several of these patients had elevated pulmonary capillary wedge pressures consistent with a component of left ventricular diastolic dysfunction. Mean pulmonary artery pressure was inversely related to survival: Each increase of 10 mm Hg in mean pulmonary artery pressure was associated with a 1.7-fold increase in the rate of death. More recent data confirm that pulmonary hyper-tension increases the risk of death in patients with sickle cell disease (75). Historically, recurrent episodes of acute chest syndrome have been considered the most important risk factor for the development
of pulmonary hypertension (76); however, recent data suggest this may not be the case. Destruction of bioactive nitric oxide by free hemoglobin (77) and an increase in the production of reactive oxygen species (78,79) may be more important for the development of pulmonary hypertension in patients with a hemolytic anemia than in those without a hemolytic anemia. For example, in sickle cell anemia, the plasma levels of oxyhemoglobin are high because of intravas-cular hemolysis; this cell-free hemoglobin can impair responses to intrinsic and exogenously delivered nitric oxide. Likewise, in sickle cell anemia, there are increased circulating and intracellular levels of reactive oxygen species, which can inactivate nitric oxide.
4.7. Hereditary Spherocytosis
Hereditary spherocytosis has been associated with pulmonary hyper-tension in limited case reports (80). A recent review of the reported cases (81) suggests that this association may, in part, be explained by thrombocytosis and chronic thromboembolic disease accompanying the underlying hematological disorder.
4.8. Hereditary Hemorrhagic Telangiectasia
Pulmonary hypertension clinically and histologically indistin-guishable from IPAH has been observed in approximately 15% of individuals with hereditary hemorrhagic telangiectasia (HHT; also known as Osler-Weber-Rendu syndrome), an autosomal dominant vascular dysplasia (82,83). Mutations in two genes encoding the
TGF- receptors, endoglin and activin-receptor-like kinase 1 (ALK1), have been associated with HHT.
5. GENETIC ABNORMALITIES ASSOCIATED