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Biomedical subjects

Michael B Fallon

Publications and source records attributed to Michael B Fallon.

31 records · Page 2Linked to original sources
PubMed2004

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↗
PubMed2004

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↗
PubMed2003

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↗
PubMed2003

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↗
PubMed2003

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↗
PubMed2003

Screening for hepatocellular carcinoma in patients with hepatitis C cirrhosis: a cost-utility analysis.

OBJECTIVES: Screening for hepatocellular carcinoma (HCC) is advocated in cirrhotic patients to optimize early detection and treatment. However, the cost-effectiveness is not well defined. Our objective was to perform a cost-utility analysis from a third-party payer's perspective of no screening, alpha-fetoprotein (AFP) concentration measurement alone, abdominal ultrasound (US) and AFP, abdominal three-phase CT and AFP, and abdominal magnetic resonance imaging (MRI) and AFP. METHODS: A Markov model was constructed simulating the natural history of hepatitis C-related cirrhosis in a cohort of patients age 50 yr over a time horizon of their remaining life expectancy. Transition probabilities were obtained from published data and U.S. vital statistics. Costs represented Medicare reimbursement data. Costs and health effects were discounted at a 3% annual rate. RESULTS: Screening with ultrasonography and AFP concentration measurement was associated with an incremental cost-utility ratio of 26,689 US dollars per quality-adjusted life year, whereas screening with abdominal three-phase CT and AFP concentration measurement was associated with an incremental cost-utility ratio of 25,232 US dollars per quality-adjusted life year compared with no screening. Compared with three-phase CT and AFP, magnetic resonance and AFP imaging costs 118,000 US dollars per quality-adjusted life year. Sensitivity analysis demonstrated that the results are most sensitive to the annual incidence of HCC, proportion of tumors amenable to treatment, and to transplant candidacy, whereas the choice of screening strategy is most sensitive to the test characteristics and cost. CONCLUSIONS: Screening for HCC with CT is a cost-effective strategy in transplant-eligible patients with cirrhosis secondary to chronic hepatitis C viral (HCV) infection, comparable with other commonly accepted screening interventions such as mammography and colonoscopy.

Aged↗
PubMed2002

Implementation of vaccination in patients with cirrhosis.

Vaccination for hepatitis A, hepatitis B, pneumococcus, and influenza in patients with chronic liver disease is recommended. Our purpose was to determine the degree of adherence to these recommendations in cirrhotics presenting for liver transplantation evaluation. Our sample consisted of 105 patients presenting for evaluation for liver transplantation. Data were obtained by medical record review and patient interview. The age of the patients was 52 +/- 9 years (mean +/- SD) and the Child-Pugh score was 9 +/- 2. Twenty-nine patients had natural immunity for hepatitis A. Of the remaining 76, 20 (26.3%) received vaccine. Of the 89 patients without evidence of prior exposure to hepatitis B, 23 (25.8%) received vaccine. Pneumococcal and influenza vaccination was performed in 36 (34%) and 58 (55%) respectively. In conclusion, vaccination for viral hepatitis, pneumococcus, and influenza not being consistently performed. Public health efforts aimed at raising awareness about implementing vaccination in these patients are strongly encouraged.

Female↗
PubMed2002

Utility of pulse oximetry in the detection of arterial hypoxemia in liver transplant candidates.

Hepatopulmonary syndrome, arterial hypoxemia caused by intrapulmonary vasodilatation, occurs in approximately 10% of patients with cirrhosis. The severity of hypoxemia affects liver transplant candidacy and is associated with increased morbidity and mortality posttransplantation. Screening guidelines for detecting the presence of arterial hypoxemia do not exist. The aim of this study is to investigate the accuracy and utility of pulse oximetry in the detection of hypoxemia (PaO(2) < 70 mm Hg) in patients with cirrhosis. Two hundred prospective liver transplant candidates were compared with 94 controls. Arterial oxyhemoglobin saturation was obtained by pulse oximetry (SpO(2)) and compared with simultaneous arterial blood gas (ABG) oxyhemoglobin values (SaO(2); bias = the difference). PaO(2), carboxyhemoglobin, methemoglobin, and routine clinical and biochemical parameters were investigated to account for the bias. SpO(2) overestimated SaO(2) in 98% of patients with cirrhosis (mean bias, 3.37%; range, -1% to 10%). Forty-four percent of patients with cirrhosis and controls had a bias of 4% or greater. No clinical or biochemical parameters of cirrhosis accounted for the overestimation of pulse oximetry. Twenty-five subjects with cirrhosis were hypoxemic, and an SpO(2) of 97% or less showed a sensitivity of 96% and a positive likelihood ratio of 3.9 for detecting hypoxemia. An SpO(2) of 94% or less detected all subjects with an arterial PaO(2) less than 60 mm Hg. Pulse oximetry significantly overestimates arterial oxygenation, and the inaccuracy is not influenced by liver disease. Nevertheless, pulse oximetry can be a useful screening tool to detect arterial hypoxemia in patients with cirrhosis, but a higher threshold for obtaining an ABG must be used.

Adult↗
PubMed2002

The cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C viral infection in the United States.

OBJECTIVE: Hepatitis A vaccination is recommended for patients with chronic hepatitis C. Our aim was to analyze the cost-effectiveness of hepatitis A vaccination in these patients. The specific strategies evaluated were: no vaccination, targeted vaccination, and universal vaccination. METHODS: Clinical estimates were based on published data. Costs estimates were based on published data and institutional Medicare reimbursement rates. Health-related quality-of-life weights were derived from published data and expert estimates. The target population consisted of patients 45 yr of age with chronic hepatitis C followed every 6 months until death. We adopted a societal perspective. RESULTS: Compared with no vaccination, targeted vaccination was associated with an incremental cost-effectiveness ratio of $51,000 per quality-adjusted life-year. The incremental cost-effectiveness ratio of universal vaccination compared with targeted vaccination was $3,900,000 per quality-adjusted life-year. The results were particularly sensitive to the incidence of hepatitis A, probability of fulminant hepatic failure, and costs of hepatitis A antibody screening and vaccination. CONCLUSIONS: Targeted vaccination for hepatitis A in patients with chronic hepatitis C may be a cost-effective strategy to decrease the morbidity and mortality associated with hepatitis A superinfection. Universal vaccination is not a cost-effective alternative to targeted vaccination in this target population.

Aged↗
PubMed2002

Cost-effectiveness of screening, surveillance, and primary prophylaxis strategies for esophageal varices.

OBJECTIVE: Screening for varices is recommended in patients with cirrhosis to institute primary prophylaxis to prevent variceal bleeding. Our aim was to compare the cost-effectiveness of four strategies, including no screening/no prophylaxis, universal screening and primary prophylaxis with beta-blockers, universal screening and primary prophylaxis with variceal ligation, and universal institution of primary prophylaxis with beta-blockers without screening. METHODS: We constructed a Markov simulation model in two hypothetical cohorts of 50-yr-old patients with cirrhosis (one compensated and one decompensated), who were followed for 5 yr. Transition probabilities were derived from the medical literature, and costs reflected Medicare reimbursement rates at our institution. RESULTS: In patients with compensated cirrhosis, screening and primary prophylaxis with beta-blockers is associated with an incremental cost-effectiveness ratio of $3605 per year of life saved. The results were most sensitive to the prevalence of varices and risk of variceal bleeding. In patients with decompensated liver disease, primary prophylaxis without screening was associated with an incremental cost-effectiveness ratio of $1154 per year of life saved. The results were most sensitive to the cost of beta-blockers and endoscopy. CONCLUSIONS: Screening for varices is an affordable strategy in compensated liver disease, whereas universal primary prophylaxis with beta-blockers is cost-effective in decompensated patients.

Cost-Benefit Analysis↗
PubMedDate not supplied

Garlic and its active metabolite allicin produce endothelium- and nitric oxide-dependent relaxation in rat pulmonary arteries.

1. The aims of the present study were to investigate the effects of fresh garlic and one of its active metabolites, allicin, on rat isolated pulmonary arteries (RPA). 2. In endothelium-intact and phenylephrine-precontracted RPA, the addition of a water or a 5% ethanol extract of fresh garlic (1-500 microg/mL) resulted in a dose-dependent relaxation reaching a maximum (mean +/- SEM) of -91 +/- 3 and -93 +/- 2%, respectively, with an ED(50) of 113 +/- 12 and 106 +/- 10 microg/mL, respectively. The vasorelaxation was readily reversible upon washing and no tachyphylaxis was noted. 3. An extract of the external garlic storage leaf produced a significantly greater relaxation than the inner stem. Microfiltration of extracts with a 10,000 molecular sieve did not attenuate relaxation. Inactivation of alliinase and allicin formation, with either boiling of the garlic clove for 30 min or 100% ethanol treatment, completely abolished relaxation. In contrast, similar treatment of crushed garlic with formed allicin retained the relaxation response. 4. Pure allicin produced a similar relaxation as garlic extract, with an EC(50) of approximately 0.8 microg/mL. Disruption of endothelium or N(G)-nitro-L-arginine methyl ester pretreatment attenuated the relaxation, whereas indomethacin had no effect. 5. Prior garlic (500 microg/mL) treatment enhanced acetylcholine relaxation by shifting the response curve to the left, but had no effect on nitric oxide (NO) donor-induced responses. 6. These results demonstrate that garlic and the active metabolite allicin are capable of eliciting a NO-dependent relaxation in RPA and that this response is likely to be mediated via garlic activation of NO formation rather than its stabilization.

Animals↗