Background

Pulmonary hypertension is not as common as its brother, arterial hypertension, the high blood pressure familiar to most of us. However, the diagnosis and treatment is in many ways, much more complicated. The classification and pathophysiology has undergone tremendous advances in recent years.

The current diagnostic classification proposed at the World Symposium on Primary Pulmonary Hypertension in 1998 is as follows:

CATEGORY	CHARACTERIZATION
Pulmonary hypertension associated with disorders of the respiratory system and/or hypoxemia	Parenchymal lung disease (chronic obstructive pulmonary disease, interstitial pulmonary fibrosis, and cystic fibrosis) Chronic alveolar hypoxemia (exposure to long-term low oxygen tension such as high altitudes)
Pulmonary venous hypertension	Mitral valve disease Chronic veno-occlusion disease Pulmonary veno-occlusion disease
Pulmonary hypertension due to chronic thrombotic and/or embolic disease	Thromboembolic obstruction of proximal pulmonary arteries Obstruction of distal pulmonary arteries
Pulmonary arterial hypertension	Primary arterial hypertension (sporadic, familial) Pulmonary arterial hypertension related to collagen vascular disease (scleroderma, lupus, rheumatoid arthritis), congenital systemic-to-pulmonary shunts (Eisenmenger syndrome), portoprimary hypertension, HIV infection, and drugs and toxins
Pulmonary hypertension due to disorders directly affecting the pulmonary vasculature	Inflammatory Pulmonary capillary hemangiomatosis

The evaluation of a patient with suspected pulmonary hypertension involves several diagnostic modalities. The evaluation will be guided by the suspected diagnosis of the associated condition. In general, a lung biopsy is usually not performed and may not be well tolerated by a patient with severe pulmonary hypertension.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
INCIDENCE	Rare 1-2/1,000,000
AGE RANGE-MEDIAN
SEX (M:F)	1:1.7-3.5 Female predominance
EPIDEMIOLOGIC ASSOCIATIONS	CHARACTERIZATION
Diet pills containing anorexigen aminorex fumarate (fenfluramine and phentermine)	N Engl J Med 1996;335:609-616 Overall incidence of hypertension was 1-3%
Pregnancy
Oral contraceptive	Chest 1976;69:143-147 Although it may exacerbate symptoms of PPH, it does not appear to increase the risk of developing the disease
Substance abuse	N Engl J Med 1996;335:609-616 Methamphetamines and cocaine

 

DISEASE ASSOCATIONS	CHARACTERIZATION
SICKLE CELL HEMOGLOBINOPATHY
Pulmonary hypertension in sickle cell hemoglobinopathy: A clinicopathologic study of 20 cases. Haque AK, Gokhale S, Rampy BA, Adegboyega P, Duarte A, Saldana MJ. Departments of Pathology and Internal Medicine, University of Texas Medical Branch, Galveston, TX, and University of Miami School of Medicine, Miami, FL.	Hum Pathol 2002 Oct;33(10):1037-43 Abstract quote Pulmonary hypertension is one of the major causes of morbidity and mortality of patients with sickle cell hemoglobinopathy (SCH). Although a clinically recognized complication of sickle cell disease (SCD), there are few published pathologic studies of pulmonary findings in these patients. The aim of this study was to define the pulmonary pathologic changes and to investigate correlation between the pathologic changes, the antemortem diagnosis of pulmonary hypertension, and the severity of SCH. Cases of SCH were identified from the autopsy database using Snomed codes. Clinical and echocardiograph data were collected for correlation with the pathologic data. A total of 20 adult patients (12 males and 8 females) were identified. Hemoglobin electrophoresis results were available for 16 patients, with hemoglobin S fraction percentages ranging from 23% to 97.8%. Eleven patients had SCD, 5 patients had sickle cell trait (SCT), and the remaining 4 patients without hemoglobin electrophoresis were included in the SCT group. The mean age of the SCT group was higher than that of the SCD group (P = 0.03). Histologically, all 20 patients demonstrated changes in pulmonary vasculature considered diagnostic of pulmonary hypertension grade I to grade IV, associated with plexiform lesions in 60% of patients. Medial hypertrophy and intimal hyperplasia/fibrosis, considered potentially reversible lesions, were seen in all patients. A weak association was found between SCD and plexiform lesions. Fibroelastic degeneration of small arteries, arterioles, and venules was identified in almost all (95%) cases. Clinically, tricuspid regurgitation was detected by echocardiogram in 10 of 20 (50%) patients; 6 of these 10 had significant regurgitation to allow estimation of systolic pressure. Sudden death occurred in 8 patients, with males having a significantly higher incidence. Cardiomegaly was present in 95% of patients, however, autosplenectomy and hepatic cirrhosis/hemochromatosis were observed almost exclusively in patients with SCD. Cirrhosis was found to have a strong positive association with SCD. This study demonstrates pulmonary hypertensive changes in all 20 autopsied patients who had SCH but died from various causes. We conclude that a high prevalence of pulmonary hypertension is associated with SCH with consequent high mortality. Therefore, patients with SCH would benefit from a regular periodic assessment for pulmonary hypertension regardless of age, sex, and severity of hemoglobinopathy.
VENO-OCCLUSIVE DISEASE
Pulmonary Veno-occlusive Disease and Pulmonary Capillary Hemangiomatosis: A Clinicopathologic Study of 35 Cases. Lantuejoul S, Sheppard MN, Corrin B, Burke MM, Nicholson AG. *Department of Histopathology, Royal Brompton and Harefield Hospitals, London, UK daggerDepartment of Pathology, CHU A Michallon, Grenoble, France.	Am J Surg Pathol. 2006 Jul;30(7):850-857. Abstract quote   Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are rare causes of pulmonary hypertension, regarded by some as distinct entities. However, their presentations are similar and both are associated with poor prognoses. We therefore reviewed 38 specimens [autopsies (n=15), surgical biopsies (n=15), explants (n=7), and pneumonectomy (1 case)] from 35 patients diagnosed as either PVOD (n=30; av. age 34 y, range 4 to 68 y; 19M:11F) or PCH (n=5, av. age 42 y, ranging from 9 months to 60 years; 3M:2F) to assess their interrelationship. PCH was identified in 24 (73%) cases diagnosed as PVOD, either as perivenular foci or diffuse involvement of the pulmonary parenchyma. Other features seen in PVOD were arterial medial hypertrophy and/or intimal fibrosis (88%), hemosiderosis (79%), venulitis (12%), infarction (9%), interstitial fibrosis (sometimes as localized scars) (48%), and a mild lymphocytic infiltrate (67%). In cases diagnosed as PCH, 4 showed venous and arterial changes of PVOD. Cases with PCH also all showed a mild interstitial lymphocytic infiltrate but there was no venulitis or infarction. Capillary proliferation was particularly well demonstrated by CD34 immunostaining and predominantly involved the alveoli, but was also seen within walls of bronchi and pulmonary vessels. Our data suggest that in the majority of cases PCH represents a secondary angioproliferative process caused by postcapillary obstruction rather than a separate disease. The cause of the venous obliteration was not identified but the occasional identification of phlebitis suggests this plays a role in venous damage in some cases.

 

PATHOGENESIS	CHARACTERIZATION
Genetic abnormalities in familial cases on chromosome 2q33	Am J Hum Genet 2000;67:737-744 Nat Genet 2000;26:81-84 Heterozygous germline mutations in the bone morphogenetic protein receptor II gene (BMPR2) encoding a transforming growth factor beta receptor There is an inciting event such as a collagen vascular disease, drugs, etc.
Sequence of events	Follows the histopathological changes: In situ thrombosis occurs from endothelial dysfunction Smooth muscle hypertrophy is secondary to chronic vasoconstriction Intimal and adventitial proliferation is dysfunctional response to vascular injury
Endothelial dysfunction	Secondary to: Decreased nitric oxide synthase Decreased prostacyclin production Increased thromboxane production Increased endothelin 1 production
Vascular smooth muscle dysfunction	Impaired voltage-gated potassium channel

 

LABORATORY/ RADIOLOGY	DIAGNOSIS OF ASSOCIATED CONDITIONS
Echocardiogram	Left ventricular dysfunction Left-sided valvular heart disease Congenital heart disease with systemic-to-pulmonary shunt
Chest radiograph Pulmonary function tests	Chronic obstructive pulmonary disease Cystic fibrosis Interstitial pulmonary fibrosis Thoracic cage abnormalities
Ventilation-perfusion scan Pulmonary angiogram Spiral computed tomogram	Chronic thromboembolic disease
Sleep study	Obstuctive sleep apnea
BLOOD TESTS
Liver function	Portopulmonary hypertension
Serologic (ANA, HIV)	Lupus, scleroderma, rheumatoid arthritis, HIV infection

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
General
VARIANTS
Familial	Autosomal dominant Majority of cases are sporadic but 6% are familial

 

HISTOLOGICAL TYPES	CHARACTERIZATION
General	There are three predominant histologic changes: In situ thrombosis Smooth muscle hypertrophy Intimal and adventitial proliferation
Plexiform lesion	A characteristic reduplication of intimal hyperplasia May be a dysfunctional response to vascular injury
VASCULAR
Morphology of the internal elastic lamina in arteries from pulmonary hypertensive patients: a confocal laser microscopy study. Aiello VD, Gutierrez PS, Chaves MJ, Lopes AA, Higuchi ML, Ramires JA. Laboratory of Pathology (VDA, PSG, MJFC, MLH) and Clinical Unity of Pediatric Cardiology (AABL, JAFR), Heart Institute (InCor) University of Sao Paulo Medical School, Sao Paulo, Brazil.	Mod Pathol 2003 May;16(5):411-6 Abstract quote The development and progression of pulmonary hypertension lesions involve continuous remodeling of the arterial wall, including the extracellular matrix components. The integrity of the internal elastic lamina may represent a barrier to cell migration and formation of intimal proliferative lesions. Some patients with congenital cardiac shunts develop precocious intimal occlusive lesions,whereas others evolve with isolated medial hypertrophy. We studied the 2-D and 3-D morphology of the internal elastic lamina of peripheral pulmonary arteries to search for any difference regarding the type of histological lesion. Fifteen lung biopsies collected for diagnostic purposes from patients with congenital shunts and 6 control lungs (mean ages, 15.8 and 14.7 mo) were studied using the confocal laser scanning microscope, under predetermined conditions of laser intensity, brightness and contrast. We measured the thickness of the internal elastic lamina and determined the number of gaps and projections of elastic tissue towards the medial and intimal layers. The mean internal elastic lamina thickness was significantly higher in arteries from cases with isolated medial hypertrophy when compared with controls and to those with proliferative lesions (P <.05). The number of gaps of the internal elastic lamina was higher in arteries >100 micro m in diameter from the group with intimal lesions when compared to the cases presenting with isolated hypertrophy, but did not differ from the controls. There was a positive linear correlation between the external arterial diameter and the thickness of the internal elastic lamina (r =.74, P <.001) in cases presenting isolated medial hypertrophy. The increased thickness and smaller number of gaps of the internal elastic lamina may act as a barrier that prevents smooth muscle cell migration in patients with pulmonary hypertension without intimal proliferative lesions. On the other hand, a greater number of gaps does not represent, by itself, unrestrained migration, because controls also showed fenestrated laminae.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS	About 75% of patients the pulmonary artery pressure will not respond to an acute vasodilator trial because the vascular changes have advanced to the proliferative irreversible phase-there should be a decrease in pulmonary artery pressure of greater than 10 mm Hg with no change or increase in cardic output
Survival	J Heart Lung Transplant 1997;16:691-712 5YRS after lung transplantation is 45-50%
Recurrence
TREATMENT	Anticoagulation with warfarin to an INR of 1.7-2.2 Smooth muscle hypertrophy and vasoconstriction treated with vasodilator therapy (usually calcium channel blockers) Continuous intravenous Epoprostenol as a vasodilator
	In patients who have advanced disease, a lung transplantation, either single or bilateral may be performed for patients who do not respond to medical therapy Heart lung transplantation may be used for patients with significant heart disease on the left side or complicated structural abnormalities with a congenital heart disease

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Last Updated July 10, 2006

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