The hepatopulmonary syndrome.
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Hepatopulmonary Syndrome↗
Biomedical subjects
Michael B Fallon
Publications and source records attributed to Michael B Fallon.
Hepatopulmonary syndrome: more than just a matter of tone?
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Endothelium, Vascular↗
Effect of transjugular intrahepatic portosystemic shunt on pulmonary gas exchange in patients with portal hypertension and hepatopulmonary syndrome.
AIM: To assess the impact of transjugular intrahepatic portosystemic shunt (TIPS) on pulmonary gas exchange and to evaluate the use of TIPS for the treatment of hepatopulmonary syndrome ( HPS ). METHODS: Seven patients, three of them with advanced HPS, in whom detailed pulmonary function tests were performed before and after TIPS placement at the University of Alabama Hospital and at the Hospital Clinic, Barcelona, were considered. RESULTS: TIPS patency was confirmed by hemodynamic evaluation. No changes in arterial blood gases were observed in the overall subset of patients. Transient arterial oxygenation improvement was observed in only one HPS patient, early after TIPS, but this was not sustained 4 mo later. CONCLUSION: TIPS neither improved nor worsened pulmonary gas exchange in patients with portal hypertension. This data does not support the use of TIPS as a specific treatment for HPS. However, it does reinforce the view that TIPS can be safely performed for the treatment of other complications of portal hypertension in patients with HPS.
Adult↗
Hepatopulmonary syndrome.
The hepatopulmonary syndrome (HPS) is an important and often under-recognized vascular complication of cirrhosis and portal hypertension characterized by pulmonary vascular dilatation, which results in hypoxemia. This syndrome is identified in as many as 20% of patients who are evaluated for orthotopic liver transplantation (OLT), and it has recently been found to increase mortality in affected patients, particularly when hypoxemia is severe. Currently, OLT is the only therapy established to reverse intrapulmonary vasodilatation, although postoperative mortality is increased in patients with severe hypoxemia. No randomized controlled trials of pharmacologic therapies have been undertaken, but supplemental oxygen improves oxygenation. Data derived from case reports, small studies, and experimental models suggest that pharmacologic therapies may be effective. In cirrhotic patients with HPS, particularly those with moderate hypoxemia (PaO2 < 60 mmHg), OLT should be considered prior to the development of severe deoxygenation. Supplemental oxygen should be given to patients with a PaO2 < 60 mmHg or those with exercise oxygen desaturation. For those patients with mild hypoxemia or those who are not OLT candidates, a trial of pharmacologic treatment may be considered.
Journal Article↗
Hepatopulmonary syndrome.
The hepatopulmonary syndrome is an increasingly important vascular complication of cirrhosis where microvascular dilatation impairs arterial oxygenation in the setting of liver disease. This syndrome is identified in as many as 20% of patients evaluated for liver transplantation and results in increased mortality. No clearly effective medical therapies are available, and liver transplantation is the only established treatment. Pathophysiologic insights obtained from experimental models may lead to the development of novel and effective medical treatments.
Diagnosis, Differential↗
Cholangiocyte endothelin 1 and transforming growth factor beta1 production in rat experimental hepatopulmonary syndrome.
BACKGROUND & AIMS: Hepatic production and release of endothelin 1 plays a central role in experimental hepatopulmonary syndrome after common bile duct ligation by stimulating pulmonary endothelial nitric oxide production. In thioacetamide-induced nonbiliary cirrhosis, hepatic endothelin 1 production and release do not occur, and hepatopulmonary syndrome does not develop. However, the source and regulation of hepatic endothelin 1 after common bile duct ligation are not fully characterized. We evaluated the sources of hepatic endothelin 1 production after common bile duct ligation in relation to thioacetamide cirrhosis and assessed whether transforming growth factor beta1 regulates endothelin 1 production. METHODS: Hepatopulmonary syndrome and hepatic and plasma endothelin 1 levels were evaluated after common bile duct ligation or thioacetamide administration. Cellular sources of endothelin 1 were assessed by immunohistochemistry and laser capture microdissection of cholangiocytes. Transforming growth factor beta1 expression and signaling were assessed by using immunohistochemistry and Western blotting and by evaluating normal rat cholangiocytes. RESULTS: Hepatic and plasma endothelin 1 levels increased and hepatopulmonary syndrome developed only after common bile duct ligation. Hepatic endothelin 1 and transforming growth factor beta1 levels increased over a similar time frame, and cholangiocytes were a major source of each peptide. Transforming growth factor beta1 signaling in cholangiocytes in vivo was evident by increased phosphorylation and nuclear localization of Smad2, and hepatic endothelin 1 levels correlated directly with liver transforming growth factor beta1 and phosphorylated Smad2 levels. Transforming growth factor beta1 also stimulated endothelin 1 promoter activity, expression, and production in normal rat cholangiocytes. CONCLUSIONS: Cholangiocytes are a major source of hepatic endothelin 1 production during the development of hepatopulmonary syndrome after common bile duct ligation, but not in thioacetamide-induced cirrhosis. Transforming growth factor beta1 stimulates cholangiocyte endothelin 1 expression and production. Cholangiocyte-derived endothelin 1 may be an important endocrine mediator of experimental hepatopulmonary syndrome.
Animals↗
Carboxyhemoglobin levels in cirrhotic patients with and without hepatopulmonary syndrome.
BACKGROUND AND AIMS: Heme oxygenase (HO) catalyzes hemoglobin into bilirubin, iron, and carbon monoxide (CO), a known vasodilator. HO expression and CO production as measured by blood carboxyhemoglobin (COHb) levels increase in experimental hepatopulmonary syndrome (HPS) and contribute to vasodilatation. Whether CO contributes to HPS in humans is unknown. Our aim was to assess if arterial COHb levels are increased in cirrhotic patients with HPS relative to those without HPS. METHODS: We collected data prospectively in stable nonsmoking outpatients with cirrhosis. Demographic and clinical data and room-air arterial blood gases were collected and analyzed. HPS was diagnosed using established criteria. RESULTS: A total of 159 patients were studied. HPS was present in 27 (17%) patients. Mean age was 52 +/- 9 years, 54% were men, and hepatitis C and/or alcohol were the most common causes (53%). Fourteen percent were Child-Pugh class A, 53% were Child-Pugh class B, and 33% were Child-Pugh class C. Demographic and clinical features were similar between HPS and non-HPS patients except for the Child-Pugh score, which was lower in patients with HPS. Arterial Pa o 2 levels were lower and the alveolar-arterial oxygen gradient was higher in patients with HPS ( P < .001). COHb levels were increased in HPS relative to non-HPS ( P < .001) and correlated with Pa o 2 ( P < .001) and Aa po 2 ( P < .001) levels. CONCLUSIONS: COHb levels are increased in cirrhotic patients with HPS and correlate with gas exchange abnormalities. These results are consistent with findings in experimental HPS and suggest that CO may contribute to human HPS.
Bilirubin↗
Endothelin-B receptor overexpression prevents hypoxic pulmonary hypertension in cirrhotic rats.
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Animals↗
Mechanisms of pulmonary vascular complications of liver disease: hepatopulmonary syndrome.
Pulmonary vascular abnormalities occurring in the setting of liver disease have been increasingly recognized as important clinical entities that influence survival and liver transplant candidacy in affected patients. The most common such abnormality, the hepatopulmonary syndrome, is found in 15% to 20% of patients with cirrhosis. These disorders have no effective medical therapies. Experimental models of hepatopulmonary syndrome have identified a sequence of hepatic and pulmonary endothelial alterations that lead to nitric oxide and carbon monoxide-mediated intrapulmonary vasodilatation. A key role for shear stress-mediated pulmonary endothelial endothelin B receptor overexpression and cholangiocyte ET-1 production and release has emerged as a mechanism for local nitric oxide production in the lung. How these alterations are influenced by bacterial translocation and the systemic hyperdynamic circulatory state and whether similar changes occur in human disease are areas of ongoing investigation.
Animals↗
Hypoxic pulmonary hypertension is prevented in rats with common bile duct ligation.
Biliary cirrhosis in the rat triggers intrapulmonary vasodilatation and gas-exchange abnormalities that characterize the hepatopulmonary syndrome. This vasodilatation correlates with increased levels of pulmonary microcirculatory endothelial NO synthase (eNOS) and hepatic and plasma endothelin-1 (ET-1). Importantly, during cirrhosis, the pulmonary vascular responses to acute hypoxia are blunted. The purpose of this work was to examine the pulmonary vascular responses and adaptations to the combination of liver cirrhosis and chronic hypoxia (CH). In addition to hemodynamic measurements, we investigated whether pulmonary expression changes of eNOS, ET-1 and its receptors (endothelin A and B), or heme oxygenase 1 in experimental cirrhosis affect the development of hypoxic pulmonary hypertension. We induced cirrhosis in male Sprague-Dawley rats using common bile duct ligation (CBDL) and exposed them to CH (inspired PO2 approximately 76 Torr) or maintained them in Denver (Den, inspired PO2 approximately 122 Torr) for 3 wk. Our data show 1) CBDL-CH rats had a persistent blunted hypoxic pulmonary vasoconstriction similar to CBDL-Den; 2) the development of hypoxic pulmonary hypertension was completely prevented in the CBDL-CH rats, as indicated by normal pulmonary arterial pressure and lack of right ventricular hypertrophy and pulmonary arteriole remodeling; and 3) selective increases in expression of ET-1, pulmonary endothelin B receptor, eNOS, and heme oxygenase 1 are potential mechanisms of protection against hypoxic pulmonary hypertension in the CBDL-CH rats. These data demonstrate that unique and undefined hepatic-pulmonary interactions occur during liver cirrhosis and chronic hypoxia. Understanding these interactions may provide important information for the prevention and treatment of pulmonary hypertension.
Animals↗
The role of endothelin-1 and the endothelin B receptor in the pathogenesis of hepatopulmonary syndrome in the rat.
Endothelin-1 (ET-1) stimulation of endothelial nitric oxide synthase (eNOS) via pulmonary endothelial endothelin B (ET(B)) receptors and pulmonary intravascular macrophage accumulation with expression of inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) are implicated in experimental hepatopulmonary syndrome (HPS) after common bile duct ligation (CBDL). Our aim was to evaluate the role of ET-1 in the development of experimental HPS. The time course of molecular and physiological changes of HPS and the effects of selective endothelin receptor antagonists in vivo were assessed after CBDL. Effects of ET-1 on intralobar pulmonary vascular segment reactivity and on eNOS expression and activity in rat pulmonary microvascular endothelial cells (RPMVECs) were also evaluated. Hepatic and plasma ET-1 levels increased 1 week after CBDL in association with a subsequent increase in pulmonary microvascular eNOS and ET(B) receptor levels and the onset of HPS. Selective ET(B) receptor inhibition in vivo significantly decreased pulmonary eNOS and ET(B) receptor levels and ameliorated HPS. CBDL pulmonary artery segments had markedly increased ET(B) receptor mediated, nitric oxide dependent vasodilatory responses to ET-1 compared with controls and ET-1 triggered an ET(B) receptor dependent stimulation of eNOS in RPMVECs. Pulmonary intravascular macrophages also accumulated after CBDL and expressed HO-1 and iNOS at 3 weeks. Selective ET(B) receptor blockade also decreased macrophage accumulation and iNOS production. In conclusion, ET-1 plays a central role in modulating pulmonary micovascular tone in experimental HPS.
Animals↗
Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant database.
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PortoPH) are pulmonary vascular consequences of advanced liver disease associated with significant mortality after orthotopic liver transplantation (OLT). Data from 10 liver transplant centers were collected from 1996 to 2001 that characterized the outcome of patients with either HPS (n = 40) or PortoPH (n = 66) referred for OLT. Key variables (PaO2 for HPS, mean pulmonary artery pressure [MPAP], pulmonary vascular resistance [PVR], and cardiac output [CO] for PortoPH) were analyzed with respect to 3 definitive outcomes (those denied OLT, transplant hospitalization survivors, and transplant hospitalization nonsurvivors). OLT was denied in 8 of 40 patients (20%) with HPS and 30 of 66 patients (45%) with PortoPH. Patients with HPS who were denied OLT had significantly worse PaO2 compared with patients who underwent transplantation (47 vs. 52 mm Hg, P <.005). Transplant hospitalization survival was associated with higher pre-OLT PaO2 (55 vs. 37 mm Hg; P <.005). MPAP was significantly higher (53 vs. 45 mm Hg; P <.015) and PVR was significantly worse (614 vs. 335 dynes. s. cm(-5); P <.05) in patients with PortoPH who were denied OLT compared with patients who underwent transplantation. Transplant hospitalization mortality was 16% (5/32) in patients with HPS and 36% (13/36) in patients with PortoPH. All of the deaths in patients with PortoPH occurred within 18 days of OLT; 5 of the 13 deaths in patients with PortoPH occurred intraoperatively. We concluded that patients with HPS (based on a combination of low PaO2 and nonpulmonary factors) and patients with PortoPH (based on pulmonary hemodynamics) were frequently denied OLT because of pre-OLT test results and comorbidities. For patients who subsequently underwent OLT, transplant hospitalization mortality remained significant for both those with HPS (16%) and PortoPH (36%).
Adult↗
Hepatitis A.
Hepatitis A infection is typically transmitted by the fecal-oral route. Symptomatic infection is highly dependent on the age of the patient and usually follows a self-limited course. Once diagnosed, clinical and biochemical follow-up in the outpatient setting is generally appropriate. Treatment aims are to achieve symptomatic relief and to maintain adequate hydration and caloric intake. In patients with more severe disease, hospitalization may be needed to accomplish aggressive symptomatic therapy and close monitoring of liver function tests and mental status. Prompt evaluation for liver transplantation is appropriate in the rare case where fulminant liver failure develops. Given the absence of specific therapy for hepatitis A virus infection, the most important health care intervention is prevention of infection and/or transmission, which can be accomplished with the safe and effective use of immune globulin and commercially available vaccines.
Journal Article↗
Hepatopulmonary syndrome.
The hepatopulmonary syndrom occurs when pulmonary microvacular dilatation causes hypoxemia in cirrhosis. It is found in between 15-20% of patients with chronic liver diseases and should be considered in the differential diagnosis of dyspnea or abnormal arterial oxygenation in this group. The presence of HPS appears to significantly increase mortality in affected patients with cirrhosis. The mediators of intrapulmonary vasodilatation and HPS are not fully characterized although pulmonary nitric oxide overproduction appears to be a key event in human and experimental models. Contrast echocardiography is the best screening test for pulmonary vasodilatation. Currently there are no effective medical therapies for HPS, although liver transplantation results in reversal of HPS in most cases. However, mortality is higher in patients with HPS undergoing transplantation relative to those without HPS.
Hepatopulmonary Syndrome↗
ET-1 and TNF-alpha in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats.
Common bile duct ligation (CBDL) triggers a molecular cascade resulting in the hepatopulmonary syndrome (HPS). Both increased hepatic endothelin-1 (ET-1) production and pulmonary vascular ET(B) receptor expression with stimulation of endothelial nitric oxide synthase and TNF-alpha mediated inducible nitric oxide synthase and heme oxygenase-1 expression in pulmonary intravascular macrophages occur. Whether biliary cirrhosis is unique in triggering ET-1 and TNF-alpha alterations and HPS is unknown. We evaluated for HPS in rat prehepatic portal hypertension [partial portal vein ligation (PVL)], biliary (CBDL) and nonbiliary [thioacetamide treatment (TAA)] cirrhosis, and assessed ET-1 infusion in normal and PVL animals. Control, PVL, CBDL, TAA-treated, and ET-1-infused PVL animals had ET-1 and TNF-alpha levels measured and underwent molecular and physiological evaluation for HPS. HPS developed only in biliary cirrhosis in association with increased plasma ET-1 and TNF-alpha levels and the development of established molecular changes in the pulmonary microvasculature. In contrast, PVL did not increase ET-1 or TNF-alpha levels and TAA treatment increased TNF-alpha levels alone, and neither resulted in the full development of molecular or physiological changes of HPS despite portal pressure increases similar to those after CBDL. Exogenous ET-1 increased TNF-alpha levels and triggered HPS after PVL. Combination of ET-1 and TNF-alpha overproduction is unique to biliary cirrhosis and associated with experimental HPS. ET-1 infusion increases TNF-alpha levels and triggers HPS in prehepatic portal hypertension. ET-1 and TNF-alpha interact to trigger pulmonary microvascular changes in experimental HPS.
Animals↗
Analysis of pulmonary heme oxygenase-1 and nitric oxide synthase alterations in experimental hepatopulmonary syndrome.
BACKGROUND & AIMS: Cirrhosis and portal hypertension due to chronic common bile duct ligation reproduce the features of human hepatopulmonary syndrome, whereas portal hypertension alone due to partial portal vein ligation does not. Nitric oxide contributes to experimental hepatopulmonary syndrome, but the nitric oxide synthase forms involved remain controversial. Recently, increased pulmonary heme oxygenase-1 expression and carbon monoxide production have also been found after common bile duct ligation. Our aim was to explore the role of the heme oxygenase-1/carbon monoxide pathway in the pathogenesis of experimental hepatopulmonary syndrome. METHODS: Pulmonary heme oxygenase-1 expression and distribution were assessed in sham; 3-week partial portal vein ligation; and 1-, 2-, 3-, 4-, and 5-week common bile duct ligation animals by Northern, Western and immunohistochemical analysis relative to endothelial and inducible nitric oxide synthase levels and to hepatopulmonary syndrome development. In vivo heme oxygenase enzyme inhibition with tin protoporphyrin IX in common bile duct ligation animals was used to define effects on intrapulmonary vasodilatation and arterial blood gases. RESULTS: Heme oxygenase-1 expression in pulmonary intravascular monocytes/macrophages and arterial carboxyhemoglobin levels increased progressively from 3 to 5 weeks after common bile duct ligation relative to controls (5-week protein levels were 15.94 +/- 1.75-fold those of sham animals; P < 0.001). Inducible nitric oxide synthase increased transiently in pulmonary intravascular monocytes/macrophages in 3-week common bile duct ligation animals, whereas pulmonary microvascular endothelial nitric oxide synthase increases began at 2 weeks and correlated with the onset of hepatopulmonary syndrome. Tin protoporphyrin treatment normalized carboxyhemoglobin and improved arterial blood gases and intrapulmonary vasodilatation, reflecting partial reversal of hepatopulmonary syndrome. CONCLUSIONS: The heme oxygenase-1/carbon monoxide system is an important contributor to the progression of experimental hepatopulmonary syndrome in addition to alterations in the endothelial nitric oxide synthase/nitric oxide pathway.
Animals↗
Increased pulmonary vascular endothelin B receptor expression and responsiveness to endothelin-1 in cirrhotic and portal hypertensive rats: a potential mechanism in experimental hepatopulmonary syndrome.
BACKGROUND/AIMS: In experimental hepatopulmonary syndrome (HPS), hepatic endothelin-1 (ET-1) release during common bile duct ligation (CBDL) and ET-1 infusion in pre-hepatic portal hypertension after portal vein ligation (PVL) initiate vasodilatation through an endothelin B receptor mediated increase in pulmonary endothelial nitric oxide synthase (eNOS). We evaluated if pulmonary ET receptor expression changes in experimental cirrhosis and portal hypertension and confers susceptibility to HPS. METHODS: In normal, PVL and CBDL animals, lung ET receptor expression and localization were assessed and ET receptor levels and functional analysis of ET-1 effects on eNOS levels were evaluated in intralobar pulmonary artery (PA) and aortic (AO) segments. Normal rats underwent evaluation for HPS after ET-1 infusion. RESULTS: There was a selective increase in ET(B) receptor expression in the pulmonary vasculature from PVL and CBDL animals. ET-1 stimulated NO production and an ET(B) receptor mediated increase in eNOS levels in PA segments from PVL and CBDL animals, but not normal animals. ET-1 did not alter lung eNOS levels or cause HPS in normal rats. CONCLUSIONS: ET(B) receptor expression and ET-1 mediated eNOS and NO production are enhanced in the lung vasculature in cirrhotic and portal hypertensive animals and correlate with in vivo susceptibility to ET-1 mediated HPS.
Animals↗
Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation.
The hepatopulmonary syndrome (HPS) occurs in a subgroup of patients with cirrhosis and results from intrapulmonary vasodilatation, which may cause significant hypoxemia. Liver transplantation has emerged as a therapeutic option for patients with HPS based on retrospective case series and reports. However, morbidity and mortality appear to be increased after transplantation for HPS, and no prospective studies evaluating clinical features that may predict poor surgical outcome are available. Therefore, we prospectively evaluated the utility of the degree of hypoxemia, the arterial oxygen response to 100% oxygen administration, and the macroaggregated albumin (MAA) scan quantification of intrapulmonary shunting as predictors for outcome after liver transplantation. Our cohort consisted of 24 patients with cirrhosis and HPS who underwent liver transplantation over a 5-year period at 2 transplant centers who were followed at least 1 year after transplantation. All patients underwent preoperative evaluation for HPS with standardized methods. Seven patients (29%) died postoperatively, 5 of cardiorespiratory complications. All deaths occurred within 10 weeks after transplantation. A preoperative arterial oxygen tension (PaO(2)) of </= 50 mm Hg alone or in combination with a MAA shunt fraction >/= 20% were the strongest predictors of postoperative mortality. In conclusion, we found that mortality is increased after liver transplantation for HPS, particularly in patients with more severe hypoxemia and significant intrapulmonary shunting. Preoperative testing for the severity of HPS can be used to stratify patients according to the risk for postoperative mortality.
Adult↗