PULMONARY HYPERTENSION IN CHRONIC LIVER DISEASE
Section snippets
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
References (137)
- et al.
Pulmonary artery hypertension complicating anesthesia for liver transplantation
Anesthesiology
(1992) - et al.
Laennec's cirrhosis and primary pulmonary hypertension
Am Heart J
(1980) - et al.
Coexistent pulmonary and portal hypertension: Morphologic and clinical features
J Am Coll Cardiol
(1987) - et al.
Primary pulmonary hypertension: Length of survival in patients referred for heart-lung transplantation
Chest
(1987) Systemic hemodynamics and cardiac function in patients undergoing orthotopic liver transplantation
Chest
(1990)- et al.
Echocardiographic features of primary pulmonary hypertension
Am J Cardiol
(1974) - et al.
Pulmonary hypertension complicating portal hypertension: Prevelance and relation to splanchnic hemodynamics
Gastroenterology
(1991) - et al.
Preservation of the inferior vena cava in orthotopic liver transplantation with selective use of veno-venous bypass: The piggy back operation
Transplant Proc
(1992) - et al.
Pulmonary aspects of chronic liver disease and liver transplantation
Mayo Clin Proc
(1985) Pulmonary arterial hypertension in portal hypertension
Clin Gastroenterol
(1985)
Comparison of Doppler-determined elevated pulmonary arterial pressure with pressure measured at cardiac catheterization
Am J Cardiol
Portal hypertension, congestive splenomegaly and portacaval shunt
Gastroenterology
Inhibition by nitric oxide and nitric oxide-producing vasodilators of DNA synthesis in vascular smooth muscle cells
Eur J Pharmacol
Histopathology of primary pulmonary hypertension
Chest
Nodular transformation of the liver associated with portal and pulmonary artery hypertension
Gastroenterology
Hemodynamic and metabolic changes in hepatic transplantation
Mayo Clin Proc
Pulmonary hypertension: A cellular basis for understanding the pathophysiology and treatment
J Am Coll Cardiol
Characteristics of surviving and nonsurviving patients with primary pulmonary hypertension
Am J Med
Postperfusion syndrome: Cardiovascular collapse following hepatic reperfusion during liver transplantation.
Transplant Proc
Pharmacotherapy of chronic pulmonary arterial hypertension value and limitations: Part I: Primary pulmonary hypertension
Angiology
Hypothyroidism and primary pulmonary hypertension: An autoimmune pathogenetic link?
Ann Intern Med
Characterization of thromboxane and prostacyclin effects on pulmonary vascular resistance
J Appl Physiol
Evidence for the association of unexplained pulmonary hypertension in children with major histocompatibility complex
Circulation
Role of humoral factors in the intestinal hyperemia associated with portal hypertension
Gastrointest Liver Physiol
Role of glucagon in splanchnic hyperemia of chronic portal hypertension
Am J Physiol
Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound
J Am Coll Cardiol
Effect of serotonin on portal venous flow
Gut
Pulmonary hypertension complicating portal hypertension: A case report with suggestions for a different therapeutic approach
Eur Heart J
Primary pulmonary hypertension: Case series from France.
Chest
New therapies for primary pulmonary hypertension.
Chest
Acute right sided heart failure: Patho-physiology, recognition and pharmacological management
Pulmonary hypertension complicating portal hypertension: Findings on chest radiographs
Am J Radiol
Persistence of portosystemic collaterals and splenomegaly on CT after orthotopic liver transplantation
Am J Radiol
An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension
N Engl J Med
Primary pulmonary hypertension: An unusual case associated with extrahepatic portal hypertension
Hepatology
Survival in patients with primary pulmonary hypertension: Results from a national prospective registry
Ann Intern Med
Primary pulmonary hypertension: The American experience.
Chest
Failure of hypoxic pulmonary vasoconstriction in patients with liver cirrhosis
J Clin Invest
Pulmonary hypertension in a patient undergoing liver transplantation
Transplant Proc
Right ventricular function after orthotopic liver transplantation
Anesth Analg
Pulmonary hypertension and liver transplantation [letter]
Anesthesiology
Impaired endothelial-dependent pulmonary artery relaxation in chronic obstructive lung disease
N Engl J Med
Pulmonary hypertension and fenfluramine
Br Med J
Clinical primary pulmonary hypertension: Three pathological types
Circulation
Right heart dysfunction, pulmonary embolism and paradoxical embolization during liver transplantation: A transesophageal two-dimensional echocardiographic study
Anesth Analg
Vascular remodelling in the lung
Eur Respir J
Dietary pulmonary hypertension
Circ Res
Primary pulmonary hypertension: Natural history and the importance of thrombosis
Circulation
Reperfusion during orthotopic liver transplantation: Analysis of right ventricular dynamics
Transplant Proc
An epidemic of pulmonary hypertension after toxic rapeseed ingestion in Spain
J Am Coll Cardiol
Cited by (142)
LTSI Consensus Guidelines: Preoperative Pulmonary Evaluation in Adult Liver Transplant Recipients
2023, Journal of Clinical and Experimental HepatologyLiver diseases and pulmonary vascular disorders
2018, Revue de Medecine InternePulmonary hypertension in liver diseases
2014, Presse MedicaleAbernethy malformation type II with nephrotic syndrome and other multisystemic presentation: An illustrative case for understanding pathogenesis of extrahepatic complication of congenital portosystemic shunt
2013, Human PathologyCitation Excerpt :As previously reported, the multiple liver nodules appear to be related to irregular blood flow and diversion of hepatotrophic substances (ie, insulin and glucagon) in the splanchnic venous blood away from the liver, resulting in alterations of development, function, and regenerative capacity of the liver, subsequently leading to increased frequency of hepatic neoplasms (ie, FNH, hepatic artery, and HCC) [6,7]. Mandell and Groves [13] postulated in 1996 that vasoactive substances that bypassed the liver through these shunts led to pulmonary arterial spasm and thrombosis, accounting for pulmonary hypertension that is now accepted as one of the many manifestations of this malformation. What has so far not been well documented in our understanding of this disease is the link with immune complex–mediated glomerular injury that we found in this patient.
Preemptive Venoarterial Extracorporeal Membrane Oxygenation for Liver Transplantation—Judicious Candidate Selection
2023, Journal of Clinical Medicine
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