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Biomedical subjects

Michael B Fallon

Publications and source records attributed to Michael B Fallon.

At least 19 recordsLinked to original sources
PubMed2007

Cost-effectiveness of screening for hepatopulmonary syndrome in liver transplant candidates.

The hepatopulmonary syndrome (HPS) is present in 15-20% of patients with cirrhosis undergoing orthotopic liver transplantation (OLT) evaluation. Both preoperative and post-OLT mortality is increased in HPS patients particularly when hypoxemia is severe. Screening for HPS could enhance detection of OLT candidates with sufficient hypoxemia to merit higher priority for transplant and thereby decrease mortality. However, the cost-effectiveness of such an approach has not been assessed. Our objective was to perform a cost-effectiveness analysis from a third-party payer's perspective of screening for HPS in liver OLT candidates. The costs and outcomes of 3 different strategies were compared: (1) no screening, (2) screening patients with a validated dyspnea questionnaire, and (3) screening all patients with pulse oximetry. Arterial blood gas analyses and contrast echocardiography were performed in patients with dyspnea or a pulse oximetry (SpO(2)) < or =97% to define the presence of HPS. A Markov model was constructed simulating the natural history of cirrhosis in a cohort of patients 50 years old over a time horizon of their remaining life expectancy. Transition probabilities were obtained from published data available through Medline and U.S. vital statistics. Costs represented Medicare reimbursement data at our institution. Costs and health effects were discounted at a 3% annual rate. No screening was associated with a total cost of 291,898 dollars and a life expectancy of 11.131 years. Screening with pulse oximetry was associated with a cost of 299,719 dollars and a life expectancy of 12.27 years. Screening patients with the dyspnea-fatigue index was associated with a cost and life expectancy of 300,278 dollars and 12.28 years, respectively. The incremental cost-effectiveness ratio of screening with pulse oximetry (compared to no screening) was 6,867 dollars per life year gained, whereas that of the dyspnea-fatigue index (compared to pulse oximetry) was 55,900 dollars per life year gained. The cost-effectiveness of screening depended on the prevalence and severity of HPS, and the choice of screening strategy was dependent on the sensitivity of the screening modality. In conclusion, screening for HPS, especially with pulse oximetry, is a cost-effective strategy that improves survival in transplant candidates predominantly by targeting the transplant to the subgroup of patients most likely to benefit. The utility of screening depends on the prevalence and severity of HPS in the target population.

Cost-Benefit Analysis↗
PubMed2006

Pentoxifylline attenuation of experimental hepatopulmonary syndrome.

Hepatopulmonary syndrome (HPS) following rat common bile duct ligation results from pulmonary molecular changes that may be influenced by circulating TNF-alpha and increased vascular shear stress, through activation of NF-kappaB or Akt. Increased pulmonary microvascular endothelin B (ET(B)) receptor and endothelial nitric oxide synthase (eNOS) levels contribute to nitric oxide production and the development of experimental HPS. Pentoxifylline (PTX), a phosphodiesterase and nonspecific TNF-alpha inhibitor, ameliorates experimental HPS when begun before hepatic injury. However, how PTX influences the molecular events associated with initiation of experimental HPS after liver injury is established is unknown. We assessed the effects of PTX on the molecular and physiological features of HPS in vivo and on shear stress or TNF-alpha-mediated events in rat pulmonary microvascular endothelial cells in vitro. PTX significantly improved HPS without altering portal or systemic hemodynamics and downregulated pulmonary ET(B) receptor levels and eNOS expression and activation. These changes were associated with a reduction in circulating TNF levels and NF-kappaB activation and complete inhibition of Akt activation. In rat pulmonary microvascular endothelial cells, PTX inhibited shear stress-induced ET(B) receptor and eNOS expression and eNOS activation. These effects were also associated with inhibition of Akt activation and were reproduced by wortmanin. In contrast, TNF-alpha had no effects on endothelial ET(B) and eNOS alterations in vitro. PTX has direct effects in the pulmonary microvasculature, likely mediated through Akt inhibition, that ameliorate experimental HPS.

Animals↗
PubMed2006

Portopulmonary hypertension.

Portopulmonary hypertension is a common condition in patients who have portal hypertension. This article reviews the definition and clinical presentation of this disorder and outlines our current understanding of its pathophysiology. A diagnostic approach is provided , and novel medical therapies that are being investigated to treat this condition are discussed. Finally, the safety of liver transplantation in patients who have portopulmonary hypertension is reviewed.

Antihypertensive Agents↗
PubMed2005

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↗
PubMed2005

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↗
PubMed2005

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↗
PubMed2005

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↗
PubMed2005

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↗
PubMed2005

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↗
PubMed2004

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↗
PubMed2004

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↗
PubMed2004

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↗
PubMed2004

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↗