PULMONARY HYPERTENSION IN CHRONIC LIVER DISEASE

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HISTORY AND DEFINITIONS

Pulmonary hypertension, defined as a resting mean pulmonary artery pressure in excess of 25 mm Hg, is a complex condition resulting from several causes. Physiologic abnormalities producing excessive pulmonary venous pressure, such as left ventricular failure or increased pulmonary flow found in congenital heart disease, with large left-to-right shunts can result in elevation of pulmonary arterial pressure. An increase in vascular resistance caused by pathologic changes initiated in pulmonary

Description and Classification of Pathology

Certain lesions characteristically are identified by microscopic examination of pulmonary vessels from patients with PPH.29, 87, 125, 131 This histologic picture has been termed plexogenic pulmonary arteriopathy and, in the absence of congenital heart disease, previously was considered synonymous with a diagnosis of PPH. Identical histologic findings have been made in patients with PHPAH and are used as a criterion for disease confirmation.28

Plexogenic pulmonary arteriopathy primarily is a

SUBCLASSIFICATION OF HISTOLOGIC LESIONS

Based on histologic description, three subtypes of pulmonary arteriopathy have been reported —isolated medial hypertrophy, plexogenic pulmonary arteriopathy, and thrombotic pulmonary arteriopathy.87, 131 These findings have been derived from studies on PPH, with similar observations reported in PHPAH.28 Although most patients have several types of pulmonary arterial abnormalities observed histologically at any one time, the predominant vascular lesion is used as a basis for subclassification.

DEMOGRAPHICS

The demographic characteristics of PHPAH reveal a distribution distinct from PPH. The mean age at which pulmonary hypertension is diagnosed in patients with portal hypertension is 47 years, with a range of 30 to 60 years of age.11 In contrast, the mean age at the time of diagnosis of PPH is 36 years of age, with 35% of patients under the age of 30 years.21, 43 There is a 3% to 6% incidence of familial PPH.61 To our knowledge, no familial cases of PHPAH have been reported.

No gender bias was

ETIOLOGY

The association between portal hypertension and the development of pulmonary hypertension now is well recognized. To identify possible causative factors that result in pulmonary vascular arteriopathy, physiologic changes that accompany portal hypertension have been examined. Portal hypertension is associated with the development of a hyperdynamic circulatory state in most patients.71 Low systemic vascular resistance and high cardiac output cause increased blood flow through the pulmonary

ENDOTHELIAL CELL

Endothelium is a complex metabolic network that elaborates vasoactive substances that regulate pulmonary vascular growth, coagulation, and vasomotor tone. Some endothelial cells respond to these chemical messages; others appear to function as signalers.37, 124 The vasodilators produced by the endothelium, such as prostacyclin and nitric oxide, function as messengers, inhibiting platelet-endothelial adhesion, expressing antimitogenic activity for smooth muscle cell, and decreasing vascular tone.4

DIAGNOSIS

Diagnosis of a pathologic process usually depends on the development of clinical symptoms that result from physiologic dysfunction. Patients with pulmonary hypertension often delay in seeking medical attention because symptoms initially are subtle. Clinicians also may delay in disease identification unless there is a heightened awareness of the disease association, diagnostic approach, and significant findings.

Analysis of information obtained from the Registry on PPH showed that the majority of

PHARMACOTHERAPY OF PULMONARY HYPERTENSION

The early identification of arteriolar vasoconstriction as a contributing factor in the development of pulmonary hypertension led clinicians to administer vasodilators in an attempt to arrest or reverse the disease process. Uncontrolled trials with a number of vasodilators in patients with pulmonary hypertension gave varying results. Subsequently, investigational protocols were formulated and large clinical trials initiated.52, 93, 97, 100

A positive response has been defined by one or more of

SURVIVAL AND CHARACTERISTICS

Following the diagnosis of pulmonary hypertension, the survival of patients with portal hypertension has ranged from 0 to 84 months, with a mean of 15 months.73, 104 At 6 months, only 50% of patients are alive.104 Half the deaths within 1 year of diagnosis were attributable to hepatic causes, whereas the others died of complications related to pulmonary hypertension.46 Patients with PPH have a wider range of survival, with a mean of 24 to 36 months; and over 50% of patients are alive at 2 years.

NATURAL HISTORY

The natural history of pulmonary artery hypertension in most individuals is marked by increasing and sustained elevation of pulmonary pressures.46, 107 Endothelial injury induces alterations in vasoactive control and growth of the pulmonary vasculature, resulting in a progressive disease complex.50

Although there is no direct correlation between disease duration and histologic changes, it is suggested that isolated pulmonary arteriolar muscular hypertrophy is an early and potentially reversible

PROGNOSTIC FACTORS

Progression of disease over time varies with the individual, but specific indicators have been identified that have prognostic value. In general, more severe symptoms, reflected by the New York Heart Association classes III and IV, are associated with higher pulmonary artery pressures, lower cardiac output, and a poorer prognosis.100, 108 In patients with pulmonary artery hypertension uncomplicated by portal hypertension, isolated dyspnea on exertion is associated with significant elevation of

LIVER TRANSPLANTATION

As liver transplantation has become an accepted mode of therapy for end-stage hepatic disease, an increasing number of patients with pulmonary hypertension are presenting for surgery. In view of the scarcity of donor organs, important issues must be addressed regarding surgical intervention in such patients. The preoperative and intraoperative risk of patients with PHPAH must be recognized when the option of transplantation is discussed. Factors predicting operative outcome will aid in these

CONCLUSIONS

An unquestionable association has been identified between the development of pulmonary and portal hypertension. Prevalence of pulmonary hypertension has been estimated at approximately 2% in patients with portal hypertension. Similarities in histology and natural history suggest common ground between PPH and PHPAH. Differences in demographics, survival, and response to vasodilators, however, suggest PHPAH is a distinct disease complex.

Identical histologic findings from several types of

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    Address reprint requests to M. Susan Mandell, MD, PhD, Department of Anesthesiology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Box B113, Denver, CO 80262

    *

    From the Departments of Anesthesiology (MSM) and Medicine (BMG), and Cardiac Catheterization Laboratories (BMG), University of Colorado Health Sciences Center, Denver, Colorado

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