Melatonin effects on pulmonary tissue in the experimental model of Hepatopulmonary Syndrome / Efeitos da melatonina sobre o tecido pulmonar no modelo experimental de Síndrome Hepatopulmonar

ABSTRACT Objective: To evaluate the pulmonary alterations of animals with Hepatopulmonary Syndrome (HPS) submitted to Biliary Duct Ligature (BDL), as well as the antioxidant effect of Melatonin (MEL). Methods: Sixteen male Wistar rats, divided into four Sham groups: BDL group, Sham + MEL group and BDL + MEL. The pulmonary and hepatic histology, lipoperoxidation and antioxidant activity of lung tissue, alveolar-arterial O2 difference and lung / body weight ratio (%) were evaluated. Results: When comparing the groups, could be observed an increase of vasodilation and pulmonary fibrosis in the BDL group and the reduction of this in relation to the BDL + MEL group. It was also observed significant changes in the activity of catalase, ApCO2, ApO2 in the LBD group when compared to the other groups. Conclusion: The use of MEL has been shown to be effective in reducing vasodilation, fibrosis levels and oxidative stress as well as gas exchange in an experimental HPS model.

RESUMO Objetivo: Avaliar as alterações pulmonares de animais com Síndrome Hepatopulmonar (SHP), submetidos à ligadura de ducto biliar (LDB), bem como o efeito antioxidante da Melatonina (MEL). Métodos: Dezesseis ratos machos da espécie Wistar, divididos em quatro grupos: Sham, Grupo LDB, Grupo Sham + MEL e LDB + MEL. Foram avaliadas a histologia pulmonar e hepática, a lipoperoxidação e atividade antioxidante do tecido pulmonar, diferença álveolo-arterial de O2 e relação peso pulmonar/peso corporal (%). Resultados: Quando comparados os grupos, observamos um aumento da vasodilatação e fibrose pulmonar no grupo LDB e a redução deste em relação ao grupo LDB+MEL. Observamos ainda alterações significativas na atividade da catalase, PaCO2, PaO2 no grupo LBD quando comparado aos demais grupos. Conclusões: A utilização da MEL demonstrou-se eficaz na redução da vasodilatação, níveis de fibrose e estresse oxidativo assim como na troca gasosa em modelo experimental de SHP.

Ocorrência de síndrome hepatopulmonar em pacientes cirróticos candidatos a transplante de fígado / Occurrence of hepatopulmonary syndrome in patients with cirrhosis who are candidates for liver transplantation

OBJETIVO: Verificar a ocorrência da síndrome hepatopulmonar (SHP) em pacientes cirróticos candidatos a transplante de fígado; comparar as características demográficas, clínicas, laboratoriais e espirométricas, resultados de ecocardiografia, análise de gases arteriais e da gravidade da doença hepática nos pacientes com e sem SHP; e descrever a ocorrência de SHP no subgrupo de pacientes com cirrose associada à esquistossomose mansônica (doença hepática mista). MÉTODOS: Entre janeiro e novembro de 2007, foram avaliados 44 pacientes inscritos no Ambulatório de Transplante Hepático do Hospital das Clínicas da Universidade Federal de Pernambuco, em Recife (PE). Os critérios diagnósticos para SHP foram a presença de dilatações vasculares intrapulmonares, identificadas por ecocardiografia transtorácica, assim como diferença alveoloarterial de oxigênio > 15 mmHg ou PaO2 < 80 mmHg. RESULTADOS: A idade média foi 52 anos, e 31 pacientes (70 por cento) eram do sexo masculino. A causa mais frequente de cirrose foi uso de etanol. A esquistossomose esteve presente em 28 pacientes (64 por cento). Dos 44 pacientes, 20 (45,5 por cento) foram diagnosticados com SHP. Não foram observadas diferenças significativas em relação às características estudadas. No subgrupo de pacientes com cirrose associada à esquistossomose, 10/28 (35,7 por cento) receberam o diagnóstico de SHP. CONCLUSÕES: A SHP apresentou elevada prevalência nesta população estudada, não sendo observadas associações entre a sua ocorrência e as variáveis analisadas.

OBJECTIVE: To determine the occurrence of hepatopulmonary syndrome (HPS) in patients with cirrhosis who are candidates for liver transplantation; to compare demographic, clinical, laboratory, and spirometric characteristics, as well as echocardiography results, arterial blood gas analysis, and severity of liver disease between the groups of patients with and without HPS; and to describe the occurrence of HPS in the subgroup of patients with cirrhosis and schistosomiasis mansoni (mixed liver disease). METHODS: Between January and November of 2007, we evaluated 44 patients under treatment at the Liver Transplant Outpatient Clinic of the Federal University of Pernambuco Hospital das Clínicas, in the city of Recife, Brazil. The diagnostic criteria for HPS were intrapulmonary vascular dilatation, identified by transthoracic echocardiography, and an alveolar-arterial oxygen tension difference > 15 mmHg or a PaO2 < 80 mmHg. RESULTS: The mean age of the patients was 52 years, and 31 patients (70 percent) were male. The most common cause of cirrhosis was alcohol use. Schistosomiasis was present in 28 patients (64 percent). Of the 44 patients, 20 (45.5 percent) were diagnosed with HPS. No significant differences were found between those patients and the patients without HPS in terms of any of the characteristics studied. Of the 28 patients with cirrhosis and schistosomiasis, 10 (35.7 percent) were diagnosed with HPS. CONCLUSIONS: In the population studied, HPS was highly prevalent and did not correlate with any of the variables analyzed.

Síndrome hepatopulmonar e hipertensión portopulmonar: dos entidades a diferenciar / Hepatopulmonary syndrome and portopulmonary hypertension: two distinct entities

The clinical course of patients with portal hypertension or liver disease may be complicated by two low prevalence entities with high morbimortality: the hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHT). Each one is a consequence ofan impaired hepatic clearance of several vascular mediators, triggering vasodilation of the pulmonary vascular territory in HPS and vasoconstriction with vessel remodelation in PPHT. Both disorders have some similar clinical findings, but useful findings for differential diagnosis are the presence of platypnoea and orthodeoxia in HPS, and echocardiographic extracardiac and intrapulmonary shunt in HPS or pulmonary hypertension in PPHT. Currently, liver transplantation is the only effective treatment for both entities provided that indication and timing must be accurately evaluated. We present a review and three cases of both entities.

El curso clínico de los pacientes con cirrosis y/o hipertensión portal puede verse complicado por dos entidades de baja prevalencia pero de elevada morbimortalidad, que corresponden al síndrome hepatopulmonar (SHP) y la hipertensión portopulmonar (HPP). Ambas se presentan a consecuencia de un déficit en la depuración hepática de diversos mediadores vasculares, provocando en el territorio pulmonar una vasodilatación en el SHP y una vasoconstricción con remodelación vascular en la HPP. Si bien estas entidades comparten algunos aspectos clínicos, resulta útil en su diferenciación la presencia de platipnea y ortodeoxia y el hallazgo ecocardiográfico de un shunt extracardíaco e intrapulmonar en el SHP, o de hipertensión pulmonar en HPP. Hasta el momento la única terapia efectiva para ambas entidades es el trasplante hepático, cuya indicación exige una evaluación rigurosa y oportuna. Se presenta una revisión y tres casos clínicos de ambas entidades.

Modelos experimentais para avaliação das alterações pulmonares na síndrome hepatopulmonar / Experimental models for assessment of pulmonary alterations in hepatopulmonary syndrome

OBJETIVO: O objetivo deste trabalho foi avaliar o melhor modelo experimental para observar alterações pulmonares que caracterizam a síndrome hepatopulmonar (SHP). MÉTODOS: Ratos machos Wistar, com peso médio de 250 g foram usados em quatro modelos experimentais: tetracloreto de carbono inalatório; tetracloreto de carbono intraperitoneal; ligadura parcial de veia porta; e ligadura de ducto biliar (LDB). Em todos os grupos os animais foram divididos em controle e experimental. Foram avaliadas as seguintes variáveis: transaminases; gasometria; lipoperoxidação por substâncias que reagem ao ácido tiobarbitúrico (TBARS) e por quimiluminescência; e atividade antioxidante da enzima superóxido dismutase (SOD). Foi feito também o exame anatomopatológico do pulmão. RESULTADOS: Observou-se diferenças significativas entre os grupos LDB controle e experimental: aspartato amino transferase (105,3 ± 43 vs. 500,5 ± 90,3 UI/L); alanino aminotransferase (78,75 ± 37,7 vs. 162,75 ± 35,4 UI/L); fosfatase alcalina (160 ± 20,45 vs. 373,25 ± 45,44 UI/L); pressão parcial de oxigênio (85,25 ± 8,1 vs. 49,9 ± 22,5 mmHg); e saturação de hemoglobina (95 ± 0,7 vs. 73,3 ± 12,07 por cento). A lipoperoxidação e a atividade antioxidante também demonstrou diferenças entre os dois grupos LDB (controle vs. experimental): TBARS (0,87 ± 0,3 vs. 2,01 ± 0,9 nmol/mg proteína); quimiluminescência (16008,41 ± 1171,45 vs. 20250,36 ± 827,82 cps/mg proteína); e SOD (6,66 ± 1,34 vs. 16,06 ± 2,67 UI/mg proteína). No exame anatomopatológico observou-se vasodilatação pulmonar no modelo de LDB. CONCLUSÕES: Os dados sugerem que o modelo de LDB pode ser usado para outros estudos envolvendo alterações hepáticas e suas relações com o estresse oxidativo e a SHP.

OBJECTIVE: The aim of this study was to identify the best experimental model in which to observe the pulmonary alterations characterizing hepatopulmonary syndrome (HPS). METHODS: Male Wistar rats, with mean weight of 250 g, were used in four experimental models: inhaled carbon tetrachloride; intraperitoneal carbon tetrachloride; partial portal vein ligation; and bile duct ligation (BDL). The animals in all groups were divided into control and experimental subgroups. The following variables were measured: transaminase levels; blood gases; lipoperoxidation, using thiobarbituric acid reactive substances (TBARS) and chemiluminescence; and levels of superoxide dismutase (SOD) anti-oxidant activity. Anatomopathological examination of the lung was also performed. RESULTS: There were statistically significant differences between the BDL control and BDL experimental groups: aspartate aminotransferase (105.3 ± 43 vs. 500.5 ± 90.3 IU/L); alanine aminotransferase (78.75 ± 37.7 vs. 162.75 ± 35.4 IU/L); alkaline phosphatase (160 ± 20.45 vs. 373.25 ± 45.44 IU/L); arterial oxygen tension (85.25 ± 8.1 vs. 49.9 ± 22.5 mmHg); and oxygen saturation (95 ± 0.7 vs. 73.3 ± 12.07 percent). Lipoperoxidation and antioxidant activity also differed significantly between the two BDL groups (control vs. experimental): TBARS (0.87 ± 0.3 vs. 2.01 ± 0.9 nmol/mg protein); chemiluminescence (16008.41 ± 1171.45 vs. 20250.36 ± 827.82 cps/mg protein); and SOD (6.66 ± 1.34 vs. 16.06 ± 2.67 IU/mg protein). The anatomopathological examination confirmed pulmonary vasodilatation in the BDL model. In the other models, there were no alterations that were characteristic of HPS. CONCLUSIONS: The data obtained suggest that the BDL model can be used in future studies involving hepatic alterations related to oxidative stress and HPS.

Complicaciones pulmonares de la cirrosis hepática: hipertensión portopulmonar y síndrome hepatopulmonar: la paradoja de la vasoconstricción y vasodilatación pulmonar / Pulmonary complications of hepatic cirrhosis: portopulmonary hypertension and hepatopulmonary syndrome: the paradox of pulmonary vasoconstriction and vasodilation

Las complicaciones pulmonares de las enfermedades crónicas del hígado han sido descritas desde hace más de un siglo. Aunque originadas por una lesión común y vías fisiopatológicas similares, sus manifestaciones clínicas y el diagnóstico son divergentes. Su impacto clínico es importante ya que afectan de forma deletérea el pronóstico de los pacientes. Hasta el momento no existe un tratamiento efectivo para el manejo de estas enfermedades y el trasplante hepático debe ser evaluado de forma muy cuidadosa. En esta revisión se analizan los aspectos más importantes de la hipertensión portopulmonar y del síndrome hepatopulmonar, entidades que bajo el entorno de la hipertensión portal se caracterizan respectivamente por procesos de vasoconstricción y vasodilatación pulmonar.

Cardiopulmonar complications in chronic liver diseases were described 100 years ago. Altough both hepatopulmonary sindrome and portopulmonary hypertension originates from liver damage, clinical findings and diagnosis are very different. These complications are important due to the highly deleterous impact on disease evolution and prognosis. Currently, there is not an ideal treatment for these diseases and liver transplantation should be adequately evaluated. In this review we analyze the most important issues on hepatopulmonary sindrome and portopulmonary hypertension. These complications,under the cornerstone of portal hypertension are characterized by pulmonary constriction and dilatation, respectively.

Sindrome hepatopulmonar / Hepatopulmonary syndrome

El síndrome hepatopulmonar constituye una causa conocida de insuficiencia respiratoria en cirrosis hepática. Se define en base a la tríada de enfermedad hepática generalmente con hipertensión portal, hipoxemia arterial y vasodilatación pulmonar capilar y precapilar, que condicionan shunts de derecha a izquierda, alteraciones en la ventilación-perfusión y en la difusión. Su incidencia oscila entre el 15 y 47 por ciento, y aunque se puede presentar en pacientes con hepatopatía aguda, es una complicación característica de pacientes con cirrosis. Clinicamente existe disnea de esfuerzo, platipnea y ortodeoxia, además de cianosis, acropaquia y nevi aracniformes. Su diagnóstico se basa en el estudio de la función pulmonar y el ecocardiograma con contraste de burbujas. La gammagrafía pulmonar de perfusión con albúmina macroagregada marcada con tecnesio-99m permite la estimación de la fracción del shunt. El trasplante hepático es el único tratamiento demostradamente eficaz, excepto en aquellos pacientes con un trastorno ventilatorio más grave, por su mayor morbi-mortalidad.

The Hepatopulmonary syndrome is a know cause of respiratory failure in cirrhosis. It is a clinical triad characterized by liver disease generally with portal hypertension, arterial hypoxaemia and precapillary-capillary intrapulmonary vascular dilatation leading to right and left shunts, ventilation/perfusion defects and diffusion impairment. Its incidence is about 15 to 47 percent in patients with acute liver disease but characteristly in chronic liver disease. Shortness of breath, orthodeoxia and platypnoea, togheter with cyanosis, digital clubbing and spider naevi are common. Its diagnosis on the basis of the pulmonary gas exchange abnormality and contrast-enhanced echocardiography. The perfusion lung scanning using technetium-labelled macro-aggregatesalbumin estimate the shunt fraction. The orthotopic liver transplantation is the only efficacy treatment in patients without several gas exchange abnormality.

Clinical and diagnostic characteristics of hepatopulmonary syndrome among iranian patients with cirrhosis

Hepatopulmonary syndrome [HPS] is one of the pulmonary complications of cirrhosis, which is manifested by reduction in arterial blood oxygen. The present study was conducted to evaluate the frequency, clinical and para clinical features of HPS, and to determine their predictive values in diagnosis in a group of Iranian patients. This case series study was performed on 54 cirrhotic patients referred consecutively to the gastroenterology department of Taleghani Hospital between 2003 and 2004. Patients underwent pulmonary echo-contrast to detect intra-pulmonary and intra-cardiac shunts. Arterial blood oxygen, 0[2] gradient [A-a] and orthodoxy were measured in these patients by ABG. All patients underwent endoscopy for possible esophageal varices. Patients who met the following three diagnostic criteria including hepatic cirrhosis, arterial blood deoxygenation [P0[2]<80mmHg] and rapulmonary arterial dilation were classified as clinical HPS while those manifested solely with intrapulmonary arterial dilation were defined as subclinical HPS. Of 54 patients, 10 [18.5%] fulfilled clinical and 7 [13%] subclinical HPS criteria. Patients aged 71-80 years were more commonly affected. Hepatitis B was the most common etiologic factor. Dyspnea [100%] and cyanosis [90%] were the most prevalent clinical features. Dyspnea and clubbing were the most sensitive and specific clinical features, respectively. Pao[2]<70mmHg and arterial-alveolar gradient had the highest sensitivity for HPS diagnosis. Clubbing with the highest positive predictive value [75%] and dyspnea whit the highest negative predictive value [100%] were the best clinical features to diagnose HPS. PaO[2]<70mmHg and P[A-a]0[2]>30 and their sum, have the highest positive and negative predictive values in HPS diagnosis