Prevalence of biopsy-proven non-alcoholic fatty liver disease in severely obese subjects without metabolic syndrome.

Obesity is a major risk factor for non-alcoholic fatty liver disease (NAFLD). NAFLD encompasses simple fatty liver (FL) and non-alcoholic steatohepatitis (NASH) in its spectrum. NASH can progress to liver cirrhosis and is associated with liver cancer. Not all obese subjects have insulin resistance (IR) or develop metabolic syndrome (MS). This study evaluates the prevalence of NAFLD in severely obese subjects without MS. We retrospectively reviewed 445 charts from our database of severely obese subjects with clinical suspicion of NAFLD and who were selected for laparoscopic Roux-en-Y gastric bypass surgery. One hundred five subjects who did not have MS, as defined by the International Diabetes Foundation, based on comprehensive pre-operative metabolic evaluation were included. Liver biopsy specimens were evaluated for NAFLD. 24% of morbidly obese (mean body mass index [BMI] 48 kg m(-2) ) adult subjects (mean age 38 years) who underwent bariatric surgery did not have MS. NAFLD was identified in 77 (73%) on liver biopsy, out of which 59 (56%) were labelled as FL and 18 (17%) had histological diagnosis of NASH. Age, gender, race and BMI were the same among all groups. Among NAFLD subjects, 22% did not have any additional metabolic component of MS, while 36% had low high-density lipoprotein, 27% had hypertension, 8% had high triglycerides and 6% had hyperglycaemia. IR calculated by HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) and diagnosis of hyperglycaemia was statistically higher in NASH group compared to those who did not have NASH. NAFLD is highly prevalent in morbidly obese individuals who undergo bariatric surgery despite the absence of MS. Diagnosis of hyperglycaemia in such subjects suggests the presence of IR and may have underlying NASH, which is a progressive form of NAFLD.

Hepatic venous pressure gradient measurements to assess response to primary prophylaxis in patients with cirrhosis: a decision analytical study.

BACKGROUND: The measurement of the hepatic venous pressure gradient may identify a suboptimal response to beta-blockers in patients with varices at risk for bleeding. However, the cost-effectiveness of routine hepatic venous pressure gradient measurements to guide primary prophylaxis has not been examined. METHODS: We used decision analysis to evaluate two hepatic venous pressure gradient measurement strategies relative to standard beta-blocker therapy in a hypothetical cohort of patients with high-risk varices: (i) hepatic venous pressure gradient measurement 4 weeks after the initiation of beta-blocker therapy; and (ii) hepatic venous pressure gradient measurement prior to and 4 weeks after the initiation of beta-blocker therapy. The total expected costs, variceal bleeding episodes and deaths were calculated over a 1-year time horizon. RESULTS: Beta-blocker therapy was associated with total costs of $1464, seven variceal bleeding episodes, one variceal bleeding episode-related death and 15 deaths. One hepatic venous pressure gradient measurement was associated with total costs of $5015, four variceal bleeding episodes, one variceal bleeding episode-related death and 15 deaths. Two hepatic venous pressure gradient measurements were associated with total costs of $8657, four episodes of variceal bleeding, one variceal bleeding episode-related death and 15 deaths. Compared with beta-blocker therapy alone, the incremental costs per variceal bleeding episode prevented and death averted were, respectively, $108 185 and $355 100 (one hepatic venous pressure gradient measurement) and $202 796 and $719 300 (two hepatic venous pressure gradient measurements). The results were sensitive to the time horizon of the analysis, the probability of bleeding whilst on beta-blockers and the cost of hepatic venous pressure gradient measurement. CONCLUSION: Hepatic venous pressure gradient measurement to guide primary prophylaxis is an expensive strategy for reducing variceal bleeding or death, especially in patients with limited life expectancy, such as those with advanced, decompensated cirrhosis.

Morphology and immunohistochemistry of spontaneous chronic corneal epithelial defects (SCCED) in dogs.

PURPOSE: To determine the morphologic features of the epithelium and extracellular matrix in spontaneous chronic corneal epithelial defects (SCCED) in dogs. METHODS: Forty-eight superficial keratectomy specimens were obtained after confirmation of the presence of a superficial corneal erosion for longer than 3 weeks with no discernible underlying cause. Histologic samples were examined by light microscopy, scanning electron microscopy, and transmission electron microscopy. Immunolocalization of laminin, collagen IV, fibronectin, and collagen VII was performed. RESULTS: Epithelial cells adjacent to the defect were poorly attached to the underlying extracellular matrix. A prominent superficial stromal hyaline acellular zone composed of collagen fibrils in the area of the erosion was present in most specimens. Samples exhibited a varying degree of fibroplasia, vascularization, and leukocytic infiltrate. Laminin, collagen IV, and collagen VII were usually either not present or were present only in discontinuous segments on the surface of the erosion. Fibronectin usually coated the surface of the erosion, either as a continuous sheet or in discontinuous segments. Transmission electron microscopy of 15 samples revealed that the basement membrane was either absent in the area of the erosion or was present only in discontinuous segments. Scanning electron microscopy of eight of nine samples confirmed the absence of continuous basement membrane. Epithelial and extracellular matrix components in the peripheral cornea appeared normal. CONCLUSIONS: Most canine patients with spontaneous chronic corneal epithelial defects do not have a normal basement membrane structure in the region of the epithelial defect and have other abnormalities in the subjacent extracellular matrix that may reflect a part of the underlying pathophysiology of chronic and recurrent erosions.

Spontaneous chronic corneal epithelial defects (SCCED) in dogs: clinical features, innervation, and effect of topical SP, with or without IGF-1.

PURPOSE: To delineate the clinical features and alterations in innervation and substance P (SP) content in spontaneous chronic corneal epithelial defects (SCCED) in dogs and to conduct a preliminary investigation evaluating the efficacy of topical SP, with or without insulin-like growth factor (IGF)-1, in the treatment of this disorder. METHODS: Complete ophthalmic examinations, including Cochet-Bonnet aesthesiometry, were performed in 45 canine patients that had spontaneous corneal epithelial defects of at least 3 weeks' duration and with no identifiable cause. Eighteen patients had superficial keratectomies performed, and the corneal nerves were labeled immunohistochemically with antibodies against protein gene product (PGP)-9.5, SP, vasoactive intestinal peptide (VIP), and tyrosine hydroxylase (TH). Relative fiber densities were assessed qualitatively and quantitatively. Corneal epithelial cell and tear SP contents were determined in affected and normal dogs by an enzyme immunoassay. A preliminary open-label treatment trial of topical SP, with and without IGF-1, was conducted in 21 dogs. RESULTS: The duration of the erosion before admittance into the study was a mean of 9.22 weeks (range, 3-52). The average patient was middle aged (mean, 9.25 +/- 1.85 years [SD]); no sex predisposition of the disease was identified. Boxers, golden retrievers, and keeshonds were overrepresented when compared with the normal hospital population. Corneal sensation was normal. Marked alterations in corneal innervation were identified in affected dogs with abnormal increased SP and calcitonin gene-related peptide (CGRP)-immunoreactive nerve plexuses identified surrounding the periphery of the epithelial defect. The SP content of epithelial cells surrounding the defect increased, whereas the tear SP content remained unchanged. Of the canine patients treated with SP, with or without IGF-1, 70% to 75% had complete healing of the defect. CONCLUSIONS: This idiopathic spontaneous corneal disease in dogs shares clinical features with chronic epithelial defects in humans. The presence of marked alterations in peptidergic innervation and positive response to topical therapy with SP suggest that SP plays a critical role in corneal wound-healing processes.

Biliary cyst fluid from common bile duct-ligated rats stimulates endothelial nitric oxide synthase in pulmonary artery endothelial cells: a potential role in hepatopulmonary syndrome.

The hepatopulmonary syndrome (HPS) results from pulmonary microvascular dilatation in cirrhosis and is associated with increased pulmonary endothelial nitric oxide synthase (eNOS) levels. In the common bile duct ligation (CBDL) model, endothelin-1 (ET-1) released from the liver contributes to the rise in pulmonary eNOS and intrapulmonary vasodilatation. Whether substances, including ET-1, are found in the biliary tree and selectively enter the circulation after CBDL to influence the pulmonary vasculature is unknown. We assessed if control bile and fluid obtained from the obstructed biliary tree in CBDL animals contains ET-1 and alters eNOS expression and activity in bovine pulmonary artery endothelial cells (BPAECs). Control bile and biliary cyst fluid contained concentrations of ET-1 25- to 42-fold normal plasma levels, and hepatic venous concentrations of ET-1 were selectively increased after CBDL. Biliary cyst fluid caused a dose-dependent induction of eNOS messenger RNA (mRNA) (1.9-fold control), protein (2.5-fold control), and enzyme activity (2.2-fold control) maximal at a 1:10 dilution. The increases were associated with enhanced nitric oxide (NO) production (3.1-fold control) and were inhibitable with an ET(B) receptor antagonist. Bile from sham and portal vein-ligated animals did not increase eNOS expression and at dilutions of 1:100 and 1:10 caused cell toxicity. These results show that bile and biliary cyst fluid contain high concentrations of ET-1 that are specifically increased in hepatic venous blood after CBDL. Biliary cyst fluid increases eNOS expression and activity in an ET(B) receptor-dependent manner in BPAECs. The findings suggest a novel mechanism for the susceptibility of CBDL animals to the HPS.

The use of screening and preventive therapies for gastroesophageal varices in patients referred for evaluation of orthotopic liver transplantation.

OBJECTIVE: Screening for varices has been recommended in patients with cirrhosis to prevent variceal hemorrhage (primary prophylaxis). In addition, therapy is recommended after the initial episode of variceal bleeding to prevent recurrence (secondary prophylaxis). However, the degree of adherence to these recommendations remains unclear. The purpose of our study was to determine whether these recommendations are being followed in patients presenting for evaluation of orthotopic liver transplantation. METHODS: One hundred twenty-five patients referred for liver transplantation were evaluated. Data regarding demographics, clinical information, relevant time intervals (diagnosis of cirrhosis to screening, screening to initial variceal bleeding, variceal bleeding to referral, diagnosis of cirrhosis to referral), screening strategies used, and implementation of primary or secondary prophylaxis was obtained. The differences among quantitative variables were analyzed with Student's t test. Qualitative variables were evaluated with the Mantel-Haenzel chi2 test or Fisher's exact test. Statistical significance was designated at p < 0.05. RESULTS: Our study found that 46% of patients presenting for evaluation of liver transplantation had screening endoscopy or radiological studies to detect the presence of varices. On the contrary, secondary prophylaxis was performed in all patients with a prior history of variceal hemorrhage. Screening for varices displayed no regional differences. CONCLUSIONS: In our cohort, screening for varices is not being consistently performed, thus delaying the timely implementation of primary prophylaxis. Therefore, the adherence to currently available practice guidelines and the education of physicians to implement screening in this patient population is an important goal.

Hepatopulmonary syndrome.

Hepatopulmonary syndrome is caused by intrapulmonary vasodilation that leads to abnormal arterial gas exchange in the setting of liver disease or portal hypertension. It is seen in up to 15% of cirrhotics and is an increasingly common indication for liver transplantation. Testing for the presence of oxygenation abnormalities and intrapulmonary vasodilation is needed to make the diagnosis. Excess production of nitric oxide in the lung contributes to pulmonary vasodilation and may be triggered by the release of mediators from the damaged liver. No medical therapies are established as effective, and liver transplantation is the only documented curative treatment.

Nanoscale topography of the basement membrane underlying the corneal epithelium of the rhesus macaque.

This paper quantitatively defines the nanoscale topography of the basement membrane underlying the anterior corneal epithelium of the macaque. Excised corneal buttons from macaques were placed in 2.5 mM ethylenediaminetetraacetate (EDTA) for 2.5 h, after which the epithelium was carefully removed to expose the underlying basement membrane. The integrity of the remaining basement membrane was verified using fluorescent microscopy in conjunction with antibody staining directed against laminin and collagen type IV as well as transmission electron microscopy. Characterization of the surface of the basement membrane was performed using transmission electron microscopy, high-resolution, low-voltage scanning electron microscopy, and atomic force microscopy. Quantitative data were obtained with all three imaging techniques and compared. The basement membrane has a complex topography consisting of tightly cross-linked fibers intermingled with pores. The mean elevation of features measured by transmission electron microscopy, scanning electron microscopy, and atomic force microscopy was 149 +/- 60 nm, 191 +/- 72 nm, and 147 +/- 73 nm, respectively. Mean fiber diameter as measured by SEM was 77 +/- 44 nm and pore diameter was 72 +/- 40 nm, with pores occupying approximately 15% of the total surface area. Similar feature types and dimensions were also found for Matrigel, a commercially available basement membrane-like complex, supporting that a minimum of artifact was introduced by corneal preparative procedures to remove the overlying epithelium. Topographic features amplified the surface area over which cell-substratum interactions occur by an estimated 400%. The three-dimensional structure of the basement membrane exhibits a rich complex topography of individual features, consisting of pores and fibers with dimensions ranging from 30 to 400 nm. These nanoscale substratum features may modulate fundamental cell behaviors such as adhesion, migration, proliferation, and differentiation.

Nanoscale topography of the corneal epithelial basement membrane and Descemet's membrane of the human.

PURPOSE: Quantitatively define and compare the nanoscale topography of the corneal epithelial basement membrane (anterior basement membrane) and Descemet's membrane (posterior basement membrane) of the human. METHODS: Human corneas not suitable for transplantation were obtained from the Wisconsin Eye Bank. The corneas were placed in 2.5 mM EDTA for 2.5 h or 30 min. for removal of the epithelium or endothelium, respectively. After removal of the overlying cells, specimens were fixed in 2% glutaraldehyde and either examined in this state by atomic force microscopy only or dehydrated through an ethanol series and prepared for transmission electron microscopy (TEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM). RESULTS: The subepithelial and subendothelial basement membrane surfaces have a similar appearance that consists of an interwoven meshwork of fibers and pores. Topographic feature sizes were found to be in the nanometer size range with the epithelial basement membrane features larger and less densely packed than Descemet's membrane features. The topographic features are fractile in nature and increase surface area for cell contact. CONCLUSION: With the use of the TEM, SEM, and AFM, a detailed description of the surface topography of corneal epithelial basement membrane and Descemet's membrane of the human cornea are provided. The significance of differences in corneal basement membrane topography may reflect differences in function of the overlying cells or may be related to differences in cell migration and turnover patterns between the epithelium and endothelium.

Hepatopulmonary syndrome and venous emboli causing intracerebral hemorrhages after liver transplantation: a case report.

Increasing experience has fostered the acceptance of liver transplantation as a treatment for patients with hepatopulmonary syndrome. Morbidity and mortality is most commonly attributed to progressive arterial hypoxemia postoperatively. A cerebral hemorrhage has been reported in one patient with hepatopulmonary syndrome after transplantation. However, a postmortem examination of the brain was not performed and the pathogenesis or type of cerebral hemorrhage was undefined. We report on a patient with severe hepatopulmonary syndrome who developed multiple intracranial hemorrhages after transplantation. The intracerebral hemorrhages were most consistent with an embolic etiology on postmortem examination. We postulate that venous embolization, caused by the manipulation of a Swan Ganz catheter in a thrombosed central vein, resulted in pulmonary emboli that passed through dilated intrapulmonary vessels into the cerebral microcirculation. Special attention to central venous catheters and avoidance of manipulation may be warranted in subjects with severe hepatopulmonary syndrome after liver transplantation.

Endothelin-1 stimulation of endothelial nitric oxide synthase in the pathogenesis of hepatopulmonary syndrome.

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 nitric oxide synthase (eNOS) and hepatic and plasma endothelin-1 (ET-1). Prehepatic portal hypertension induced by portal vein ligation (PVL) does not cause similar changes, suggesting that ET-1 in cirrhosis may modulate pulmonary eNOS and vascular tone. We assessed whether ET-1 altered eNOS expression and nitric oxide production in bovine pulmonary artery endothelial cells (BPAECs) and if a 2-wk low-level intravenous ET-1 infusion in PVL animals modulated pulmonary eNOS levels, microcirculatory tone, and gas exchange. ET-1 caused a 2.5-fold increase in eNOS protein in BPAECs, inhibitable with an endothelin B receptor antagonist, and an increase in eNOS mRNA and nitrite production. ET-1 infusion in PVL animals caused increased pulmonary eNOS levels, intrapulmonary vasodilatation, and gas exchange abnormalities without increasing pulmonary arterial pressure. ET-1 produced during hepatic injury may contribute to the hepatopulmonary syndrome by modulating eNOS and inducing pulmonary microcicrulatory vasodilatation.

Effects of synthetic micro- and nano-structured surfaces on cell behavior.

Topographical cues, independent of biochemistry, generated by the extracellular matrix may have significant effects upon cellular behavior. Studies have documented that substratum topography has direct effects on the ability of cells to orient themselves, migrate, and produce organized cytoskeletal arrangements. Basement membranes are composed of extracellular matrix proteins and found throughout the vertebrate body, serving as substrata for overlying cellular structures. The topography of basement membranes is a complex meshwork of pores, fibers, ridges, and other features of nanometer sized dimensions. Synthetic surfaces with topographical features have been shown to influence cell behavior. These facts lead to the hypothesis that the topography of the basement membrane plays an important role in regulating cellular behavior in a manner distinct from that of the chemistry of the basement membrane. This paper describes the topography of the basement membrane and reviews the fabrication of synthetic micro- and nano-structured surfaces and the effects of such textured surfaces on cell behavior.

Oral thymic extract for chronic hepatitis C in patients previously treated with interferon. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Hepatitis C is an important cause of chronic liver disease. It is claimed that Complete Thymic Formula, an over-the-counter herbal dietary supplement, is beneficial for patients with hepatitis C. OBJECTIVE: To evaluate the efficacy and safety of Complete Thymic Formula. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Tertiary referral center. PATIENTS: 38 patients with hepatitis C who did not respond to or were intolerant of interferon therapy. INTERVENTION: Complete Thymic Formula for 3 to 6 months or placebo for 3 months. MEASUREMENTS: Serial measurements of hepatitis C virus (HCV) RNA titers. RESULTS: No differences were noted at 3 months between the placebo group (n = 13) and the treatment group (n = 19) in mean HCV RNA titers (4.06 +/- 1.52 x 10(6) copies/mL compared with 3.48 +/- 1.92 x 10(6) copies/mL; P > 0.2). The 19 patients who completed 6 months of treatment with Complete Thymic Formula remained positive for HCV, and their mean HCV RNA titers were similar at 6 months and at baseline (2.78 +/- 1.96 x 10(6) copies/mL compared with 3.12 +/- 1.94 x 10(6) copies/mL; P > 0.2). CONCLUSIONS: Complete Thymic Formula did not benefit patients who had previously received interferon therapy. Patients should be advised about use of this over-the-counter compound.

Treatment of hepatopulmonary syndrome with Allium sativum L. (garlic): a pilot trial.

No medical therapy exists for subjects with hepatopulmonary syndrome (HPS). A patient with HPS was reported to have improvement in arterial oxygenation while self-administering garlic. Our goal was to determine whether a standardized garlic powder improves arterial oxygenation and dyspnea in subjects with HPS. A prospective, open label uncontrolled pilot study in 15 subjects with HPS were administered garlic powder capsules daily for a minimum of 6 months. Arterial blood gases were determined every 4-8 weeks, in the same position on room air, and a subjective dyspnea transition index was reported. Six of 15 subjects (40%, confidence interval: 0.15-65) had at least a 10 mmHg increase in the P(O2) or decrease in the alveolar-arterial gradient. The mean pre- and postarterial difference in these patients were: P(O2) (14+/-4 mmHg) and alveolar-arterial gradient (18+/-5 mmHg). All 6 subjects who responded to garlic had less dyspnea on exertion. Garlic improved arterial oxygenation in younger subjects (mean 40 versus 56 years old; p = 0.021) or those with lower macroaggregated albumin shunt fractions (mean 21 versus 44%, p = 0.058). Garlic may improve arterial oxygenation and symptoms in patients with hepatopulmonary syndrome and warrants further investigation.

Endothelin-1 in the rat bile duct ligation model of hepatopulmonary syndrome: correlation with pulmonary dysfunction.

BACKGROUND/AIMS: Models of hepatopulmonary syndrome require both hepatic injury and portal hypertension to develop pulmonary microvascular and gas exchange abnormalities. Recently, increased endothelin-1 levels associated with vasodilatation, have been observed in cirrhosis. We investigated endothelin-1 production in common bile duct ligated animals with hepatopulmonary syndrome in comparison to partial portal vein ligated animals that do not develop hepatopulmonary syndrome. METHODS: Organ and plasma endothelin-1 were measured in sham, bile duct ligated and portal vein ligated rats, and Northern analysis and immunohistochemistry were performed in liver. Plasma endothelin-1 levels were correlated with pulmonary endothelial nitric oxide synthase levels and alveolar-arterial oxygen gradients. RESULTS: Hepatic and plasma endothelin-1 increased only after bile duct ligation, and were accompanied by increased hepatic endothelin-1 mRNA and increased endothelin-1 protein in biliary epithelium. Plasma endothelin-1 levels correlated directly with both pulmonary endothelial nitric oxide synthase levels and alveolar-arterial gradients. CONCLUSIONS: Enhanced hepatic production and increased plasma levels of endothelin-1 occur after bile duct ligation, but not after portal vein ligation, and correlate with associated molecular and gas exchange alterations in the lung. Endothelin-1 may contribute to the pathogenesis of hepatopulmonary syndrome.

Garlic prevents hypoxic pulmonary hypertension in rats.

Hypoxic pulmonary vasoconstriction underlies the development of high-altitude pulmonary edema. Anecdotal observations suggest a beneficial effect of garlic in preventing high-altitude symptoms. To determine whether garlic influences pulmonary vasoconstriction, we assessed the effect of garlic on pulmonary pressures in rats subjected to alveolar hypoxia and on vasoconstriction in isolated pulmonary arterial rings. Garlic gavage (100 mg/kg body wt) for 5 days resulted in complete inhibition of acute hypoxic pulmonary vasoconstriction compared with the control group. No difference in mean arterial pressure or heart rate response to hypoxia was seen between the groups. Garlic solution resulted in a significant dose-dependent vasorelaxation in both endothelium-intact and mechanically endothelium-disrupted pulmonary arterial rings. The administration of NG-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor) inhibited the vasodilatory effect of garlic by 80%. These studies document that garlic blocks hypoxic pulmonary hypertension in vivo and demonstrate a combination of endothelium-dependent and -independent mechanisms for the effect in pulmonary arterial rings.

Use of macroaggregated albumin lung perfusion scan to diagnose hepatopulmonary syndrome: a new approach.

BACKGROUND & AIMS: We have reported that contrast echocardiography is a sensitive screening test for the hepatopulmonary syndrome (HPS). However, contrast echocardiography lacks specificity because many cirrhotic patients have positive study results with normal arterial blood gases and therefore do not fulfill criteria for HPS. The aim of this study was to assess the role of macroaggregated albumin lung perfusion scans (MAA scans) in the diagnosis of HPS. METHODS: MAA scans were performed in 25 patients with HPS, 25 cirrhotic patients without HPS, and 15 hypoxemic subjects with intrinsic lung disease alone. An MAA shunt fraction was calculated from brain and lung counts. RESULTS: MAA scan results were positive in 21 of 25 patients with HPS and negative in all controls. All 21 patients with positive MAA scans had PO2 values of <60 mm Hg. There was a strong inverse correlation between the degree of the MAA shunt fraction and arterial hypoxemia (r = -0.726). CONCLUSIONS: A positive MAA scan result in cirrhosis is specific for the presence of moderate to severe HPS. We speculate that MAA scans may be particularly useful in evaluating the contribution of HPS to the hypoxemia in cirrhotic patients with intrinsic lung disease.

The role of endothelial nitric oxide synthase in the pathogenesis of a rat model of hepatopulmonary syndrome.

BACKGROUND & AIMS: The hepatopulmonary syndrome occurs when intrapulmonary vasodilatation causes impaired arterial gas exchange in liver disease. The pathogenesis is poorly understood, although nitric oxide may be involved. Common bile duct ligation in the rat is a model of the hepatopulmonary syndrome, but no studies have evaluated NO in pulmonary vasodilatation in this model. The aim of this study was to determine whether NO contributes to intrapulmonary vasodilatation after bile duct ligation. METHODS: Endothelial and inducible NO synthase (NOS) levels and localization and NO activity in pulmonary artery rings were assessed after bile duct ligation. RESULTS: Pulmonary endothelial NOS levels increased and alveolar vascular staining was enhanced after bile duct ligation. No change in pulmonary inducible NOS levels or localization was detected. Increased endothelial NOS levels correlated with alterations in gas exchange and were accompanied by enhanced NO activity and a blunted response to phenylephrine, reversible by NOS inhibition, in pulmonary artery rings. Portal-vein-ligated animals, which do not develop intrapulmonary vasodilatation, had no changes in pulmonary NOS production or in NO activity in pulmonary artery rings. CONCLUSIONS: NO, derived from pulmonary vascular endothelial NOS, contributes to intrapulmonary vasodilation in animal hepatopulmonary syndrome.

The hepatopulmonary syndrome.

The hepatopulmonary syndrome occurs in subjects with chronic liver disease and/or portal hypertension who develop intrapulmonary vasodilation resulting in arterial deoxygenation. Clinical and basic science studies investigating the pathophysiology of HPS are presented. A diagnostic algorithm is provided using contrast echocardiography, the lung perfusion scan, and pulmonary angiography. Medical therapy and experience with liver transplantation are reviewed.