作者：鲁开智,俞卫锋
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Hepatopulmonary Syndrome 肝肺综合征(英文)试读：
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Book Title: H epatopulmonary Syndrome
肝肺综合征（英文版）
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This book is for educational and reference purposes only. In view of the possibility of human error or changes in medical science, the author, editor, publisher and any other party involved in the publication of this work do not guarantee that the information contained herein is in any respect accurate or complete. The medicinal therapies and treatment techniques presented in this book are provided for the purpose of reference only.If readers wish to attempt any of the techniques or utilize any of the medicinal therapies contained in this book, the publisher assumes no responsibility for any such actions. It is the responsibility of the readers to understand and adhere to local laws and regulations concerning the practice of these techniques and methods.The authors, editors and publishers disclaim all responsibility for any liability, loss, injury, or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents of this book.
First published: 2016
ISBN: 978-7-117-23332-3/R·23333
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肝肺综合征=Hepatopulmonary Syndrome：英文/鲁开智，俞卫锋主编. —北京：人民卫生出版社，2016
ISBN 978-7-117-23332-3
Ⅰ. ①肝… Ⅱ. ①鲁… ②俞… Ⅲ. ①肝疾病-诊疗-英文②肺疾病-诊疗-英文 Ⅳ. ①R575 ②R563
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主 编：鲁开智 俞卫锋
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制作时间：2017年07月
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标准书号：ISBN 978-7-117-23343-9
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责任编辑：孙雪冰打击盗版举报电话：010-59787491 E-mail：WQ @ pmph.com注：本电子书不包含增值服务内容，如需阅览，可购买正版纸质图书。Contributors
Kaizhi Lu, PhD
Professor
Department of Anesthesia, Southwest Hospital, Third Military Medical University
Weifeng Yu, PhD
Professor
Department of Anesthesia, Eastern Hepatobiliary Surgical Hospital, Second
Military Medical University
Bin Yi, PhD
Professor
Department of Anesthesia, Southwest Hospital, Third Military Medical University
Jianteng Gu, PhD
Professor
Department of Anesthesia, Southwest Hospital, Third Military Medical University
Jing Zeng, PhD Candidate
Department of Anesthesia, Southwest Hospital, Third Military Medical University
Xiaobo Wang, PhD
Professor
Université P. Sabatier Toulouse Ⅲ and CNRS, LBCMCP
Toulouse Cedex 9, France
Karine Belguise, PhD
Professor
Université P. Sabatier Toulouse Ⅲ and CNRS, LBCMCP
Toulouse Cedex 9, France
Bing Chen, PhD Candidate
Department of Anesthesia, Southwest Hospital, Third Military Medical University
Lin Chen, PhD Candidate
Department of Anesthesia, Southwest Hospital, Third Military Medical University
Duo Xu, Master Candidate
Department of Anesthesia, Southwest Hospital, Third Military Medical University
Chang Liu, Master Candidate
Department of Anesthesia, Southwest Hospital, Third Military Medical University
Chengcheng Shen, Master Candidate
Department of Anesthesia, Southwest Hospital, Third Military Medical University
Jing Gao, Master Candidate
Department of Anesthesia, Southwest Hospital, Third Military Medical University
Yang Chen, MSc
Department of Anesthesia, Southwest Hospital, Third Military Medical University
Yong Yang, MSc
Department of Anesthesia, Southwest Hospital, Third Military Medical University
Jiaolin Ning, PhD
Associate professor
Department of Anesthesia, Southwest Hospital, Third Military Medical University
Yihui Yang, PhD candidate
Department of Anesthesia, Southwest Hospital, Third Military Medical University
Congwen, Yang PhD
Department of Anesthesia, Southwest Hospital, Third Military Medical UniversityAcknowledgments
The book is supported by grants nos. 81300039, 81170053, 81170414 and 81270510 from the National Science Foundation of China (NSFC).
Kaizhi Lu is thanked for his important contributions to the improvement of the hepatopulmonary syndrome (HPS) animal model and the establishment of the in vitro model; Bin Yi, for investigating the mechanisms underlying pulmonary vascular remodeling in HPS; Jing Zeng, for establishment of in vitro model of HPS and the identifcation of effective targets in the development of HPS; Bin Chen, for his work indicating that the development of experimental HPS underwent a process of initial pulmonary microvascular injury and later proliferation. Xiaobao Wang and Karine Belguise from Sabatier Toulouse Ⅲand CNRS, France, are thanked for their kindly constructive discussion of controversial issues and hypotheses in the fled of HPS.Chapter 1 History and Epidemiology of Hepatopulmonary SyndromeIntroduction
Hepatopulmonary syndrome (HPS) is defined as a triad of liver disease and/or portal hypertension, intrapulmonary vascular dilatations (IPVD) and increased alveolar-arterial oxygen gradient that causes a severe hypoxemia. Obviously, the pathological hallmark of HPS is IPVD.IPVD, an event that causes elevated arteriovenous shunts and ventilation-perfusion mismatch,increase pulmonary blood flow and cardiac output. In addition, compared to normal settings,oxygen molecules must traverse longer distance to bind to hemoglobin in erythrocytes in condition of enlarged alveolar capillary diameter, which leads to incomplete oxygen equilibration within erythrocytes exiting the pulmonary capillaries. Some studies also suggest that pulmonary angiogenesis participates in the pathogenesis of HPS. What's more, HPS occasionally accompanies with portopulmonary hypertension (PoPH), which further aggravates hypoxemia.HPS markedly decrease the life quality and increases the mortality of patients. Although HPS has been researched for nearly 30 years, until now, no clearly effective medical therapy for HPS is available except liver transplantation (LT).History of HPS1
The first report about HPS dates back to 1884 when Fluckiger described a 37-year-old woman with no cardio-respiratory dysfunction, but cyanosis and digital clubbing occurred after several years cirrhosis caused by syphilis, suggesting hypoxemia occurs in hepatic 23cirrhosis.In 1895, 1901 and 1937, Gilbert, Hijmans van den Bergh 4and Evans respectively further confirmed that cyanosis and finger clubbing did occur in hepatic cirrhosis. However, the first literature 5reported hypoxemia in cirrhosis patients was in 1935 by Snell who described three patients had liver disease with hemoglobin 4,6-20desaturation. In the fowing 30 years a large number of studies found the association of hepatic cirrhosis with arterial oxygen desaturation.However, the term “hepatopulmonary syndrome” was put 21forward until 1977 by Kennedy and Knudson. They, using an illustrative case, described a syndrome, which is characterized by alcoholic cirrhosis, hypoxemia and hyperdynamic circulation but is normal in the indices of pulmonary air flow, volume, and distribution of ventilation. Moreover, exercise, orthodeoxia and hypocapnia would aggravate the hypoxemia. The features of this syndrome analogous to the hepatorenal syndrome, which is defned as renal vasoconstriction, reduced renal plasma fow and the rate of glomerular fltration, cortical oligemia, and progressive renal failure occurring in histologically normal kidneys. Sometimes, such kind of kidneys can be served as donor organs with normal function and the azotemia can be improved 22after improvement in hepatic function.These results indicating some extrinsic factors stemming from hepatic failure are responsible for renal dysfunction, rather than intrinsic renal pathologic changes. These extrinsic factors may affect pulmonary circulation in HPS, which is hinted by the report of hepatic function improvement reduced intrapulmonary shunting. The word “hepatopulmonary syndrome”, which describes the relationship between hypoxemia and pulmonary vascular abnormalities caused by hepatic dysfunction, was offcially named in the eighth edition (1989) of Disorders of the Liver and Biliary 23System by Dame Sheila Sherlock.
Why HPS caused so much attention among clinical physicians. Initially, severe hypoxemia(PaO＜50 mmHg) on room air in patients 2with HPS was considered to be an “absolute”contraindication to liver 24transplantation in 1984. However, nowadays such hypoxemia is now considered to be a “relative” contraindication to transplantation with the 25,26success in liver transplantation success . So how to recognize HPS? Are there any medical strategies to improve HPS? Is hypoxemia associated with HPS a contraindication to liver transplantation?Does hypoxemia resolve following successful transplantation? These 27questions drove physicians to research HPS. In 1999, Mokhashi summarized there are several compelling reasons why internists need to be aware of the HPS. First, the relatively high prevalence of the syndrome: 47%of patients investigated with end stage liver disease and 38% with less severe liver disease, were shown to have intrapulmonary shunting. Second, commonly encountered liver diseases, such as alcoholic cirrhosis and chronic active hepatitis, can present with HPS. Third, clinical features of HPS (dyspnoea and clubbing) are non-specifc. Although the majority presents with hepatic manifestations, up to 18% of patients with HPS have presented with predominantly pulmonary symptoms. Fourth, the oxygenation can be aggressively declined despite the hepatic function is table and according to a report 41% mortality occurred in a mean of 2.5 years after the onset of dyspnea, so failure to recognize HPS is serious. Fifth, clinical diagnosis of HPS at early stage facilitates the treatment decision with either selective embolization of the dilated pulmonary vasculature or liver transplantation. Last, diagnosis of HPS is easy and 28requires no fancy equipment. In addition, Molleston et al in 1999 reported brain abscess developed one year after HPS was diagnosed in a teenager with well-compensated cirrhosis induced by biliary atresia.They proposed brain abscess maybe resulted from intrapulmonary shunting of contaminated venous blood. Moreover, 29Alonso et al found the coexistence of HPS worsened the prognosis in liver cirrhosis.
The pathophysiological alteration of HPS underwent a long-term 6research. At first, Keys and Snell in 1938 suggested that HPS is associated with abnormal oxygen tension-saturation relations in 11,12cirrhotic patients, but Rodman and Heinemann's results did not consistent with this hypothesis. Afterwards, Caldwell, Fritts and 20Cournand focused on abnormal oxygen tensionsaturation relations again but concluded that the contribution of these toward hypoxemia was probably small. Then, the possibility of anastomoses between the 8-19pulmonary arteries and veins has been stressed. Although 30Mellemgaard and his colleagues in 1963 found intrapulmonary shunting of blood in portal hypertension patients using radioactive 31tritium, Fritts et al in 1960 using krypton gas did not demonstrate this. Functioning portapulmonary anastomoses have been 30,32,33demonstrated , but in theory, such shunts to produce marked arterial oxygen desaturation is impossible thanks to the two reasons, one is the high oxygen content of portal venous blood and another is that it is probably small for the blood fow through these pathways in 34life. These results suggest that there are some other pulmonary alterations, which contribute to hypoxemia induced by liver diseases.
To explore any further anatomic basis for the hypoxemia, 35Berthelot and his co-workers in 1966 studied the lung vasculature alterations in cirrhosis patients. In all 13 cases of cirrhosis patients without clinical evidence of lung diseases, they found the microvessels in the fine peripheral branches of the respiratory part of the lungs in all cases were markedly dilatated, and in 6 cases there were apparent “spider nevi” on the pleura. This dilatation mainly located at the precapillary levels and affected arterial branches which were below 500 μm in diameters. In fact, Rydell and Hoffbauer in 1956 had described the dilated pulmonary vessels in a 17-year-old boy who presented with dyspnea after 3 years cirrhosis. This study also found only 1 patient had precapillary arteriovenous anastomoses, which further demonstrated intrapulmonary shunting of blood was not the main cause of arterial oxygen unsaturation. Since then, a large number of literatures demonstrated IPVD was the pathophysiological alteration of HPS by using different kinds of tools, such as contrast enhanced echocardiography, perfusion lung scanning, pulmonary angiography and high-resolution computerized tomography (HRCT) scanning, as well as autopsy results. However, the pathogenesis of this vasodilatation was undefned. The majority of patients with HPS had portal hypertension, but it was unlikely to be a simply mechanical result since the pulmonary veins were not dilated and connective-tissue septums had no edema. Thus, a humoral mechanism was possible. Nowadays, many studies have demonstrated abnormal vasodilators play a key role in IPVD.
Several lines of proofs suggest that angiogenesis plays an important role in the pathophysiology of HPS in addition to IPVD. In 1966, autopsy studies to 13 case of cirrhosis patients by Berthelot and 35his colleagues not only found a marked pulmonary arterial dilatation but also an increased pulmonary capillary density, but at that time the increased vascular density did not show any correlation with 36hypoxemia. In 1997, Schraufnagel et al found alveolar capillary density was increased in experimental HPS, suggesting angiogenesis 37-40may participate in the development of HPS. Recent studies further confirmed angiogenesis and elevated angiogenic factors in experimental and human HPS. However, the roles of angiogenesis in HPS need further demonstration.
PoPH is also an important alteration companied with HPS. In 411999, Mal et al frst reported a patient with liver cirrhosis who successively developed HPS and PoPH. Initially, the patient presented with severe dyspnea and hypoxemia at rest. HPS was confirmed by right-to-left shunting using perfusion lung scanning and a hyperdynamic state with low pulmonary vascular resistance using hemodynamic study. More than 2 years later, severe pulmonary hypertension was demonstrated by right-sided heart catheterization, which suggested PoPH might occur following HPS in cirrhosis patients. At the same year, a case illustrated the occurrence of HPS and PoPH 42in the same patient. Then, a series of studies reported HPS and PoPH occurred in the patients with cirrhosis or portal hypertension. However, the morbidity of PoPH (1%) is lower than that of HPS(4%～10%). Taken together, these results suggest that hypoxemia in HPS may be the incentive to PoPH in patients with cirrhosis or portal hypertension.
A well representative and easily available animal model that can mimic human disease is very important for exploring pathogenic alterations and mechanisms of the disease. Common bile duct ligation 43(CBDL) rat is the only, until now, accepted animal model of HPS. According to the literature, it was frstly proposed in 1992 by Shih-wen Chang and Narumi Ohara. They found that 5 to 6 wk CBDL rats exhibited impaired gas exchange associated with a reversible depression of hypoxic pulmonary vasoconstriction, which was closely 44parallel with human HPS. Then in 1997,Michael B. Fallon et al reported that CBDL rats could be served as a HPS model. They found that IPVD was occurred in 2 and 5 wk CBDL rats by using microspheres compared with 3 wk partial portal vein ligation (PVL) 45rats. Hence, CBDL rat has been recognized as a HPS model to study the mechanisms of human HPS. Due to the high mortality of this 46model, Lu et al improved this model by ligating the bile duct at the junction of the hepatic ducts which signifcantly decreased rats mortality 47induced by CBDL. In 2007, Zhang et al described multiple pathogenic factors including high fat diet, alcohol, cholesterol and CCl 4induced cirrhosis can be a non-invasively induced HPS model. In 482014, Zhang et al reported intra-abdominal hypertension (IAP) induced by subcutaneous injection of carbon tetrachloride led to the decrease of arterial partial pressure,the increase of difference of alveolar arterial oxygen pressure, the accumulation of macrophages in the alveolar spaces and alveolar walls widened in mice, suggesting this as a potentially novel mouse model of HPS. However, the latest two models still need to be confrmed.Present situation of HPSEpidemiology
The reported prevalence of HPS varies depending on the population studied and the criteria used to define arterial deoxygenation and IPVD. The severity of the syndrome is not directly correlated with the severity or cause of the underlying liver disease, it 49can be seen also in patients with relatively mild liver diseases. The morbidity of HPS between men and women has no difference, and 50HPS can also occur in children but no statistical data. According to different literatures, the frequency of HPS ranges between 5% and 51-5447%, most of these data are from western countries. A recent study from India shown the morbidity of HPS in patients with cirrhosis 55was 6.7%. The reported HPS morbidity in children with polysplenia syndrome, biliary atresia, Budd-Chiari syndrome and chronic liver diseases, is 0.5, 20, 28 and 8-13%, respectively,and 17-19% in the 56-6162recipients of LT. Whitworth et al recently reported that advanced 63liver disease increases the frequency of HPS in children. Anand et al reported HPS is present in 17.5% patients with cirrhosis, 13.3% with non-cirrhotic portal fbrosis and 10% with extrahepatic portal vein 63obstruction. According to a retrospective study, HPS occurred more frequently in cirrhosis (40%) than extrahepatic portal venous obstruction (13%) when the age is between 1 to 18 years of age (total 54135 children). Schenk et al have reported that 27 (24%) patients had HPS among 111 patients with cirrhosis. The median survival among patients with HPS was significantly shorter (10.6 months) than patients without HPS (40.8 months). If adjusting the severity of underlying liver diseases and excluding patients who underwent liver transplantation during follow-up, the mortality in those with HPS is higher than those without HPS. In the aspect of clinical manifestations, the incidence of dyspnea, platypnea, clubbing and spider nevi is associated with patients with HPS.Table 1. Demographic and clinical data of patients with HPSContinued(NC, non-cirrhosis; LTC, liver transplant candidates; PH, portal hypertension; NCPF, non-cirrhotic portal fbrosis; EHPVO,extra-hepatic portal vein obstruction; AC, alcoholic cirrhosis; VC, viral cirrhosis; SMPF, schistosoma mansoni periportal fbrosis; CLD, chronic liver disease; HP, hypoxic hepatitis.)Etiology
Although HPS typically occurs in the setting of cirrhosis or portal hypertension, it may also develop in patients with acute and chronic hepatitis in which the portal hypertension is not established, and in the presence of vascular abnormalities in which the hepatic venous outfow to the lung is limited, such as Abernathy malformation, cavopulmonary shunts, Budd-Chiari syndrome. There are no significant risk factors for the development of HPS, and this maybe because patients detected with HPS is not enough. However, greatly higher morbidity of HPS in cirrhotic patients indicates hepatic dysfunction and portal hypertension probably involved in this abnormality. HPS particularly occurs in cirrhotic portal hypertensive patients with severe hepatic dysfunction. For example, chronic viral hepatitis, biliary atresia, primary biliary cirrhosis,alcoholic liver cirrhosis, alpha 1 antitrypsin deficiency, cryptogenic liver cirrhosis, wilson's disease, tyrosinemia. HPS also 64reported occurred in patients with cystic fbrosis, schistosomal liver 656667disease, Gaucher disease, autoimmune liver cirrhosis. It has also been detected in acute hepatic conditions, such as ischemic hepatitis and viral hepatitis, and in non-cirrhotic portal hypertension, 68-70such as inferior vena cava obstruction. Regev et al and Fuhrmann et al demonstrated that HPS could be transient in the cases of acute 71,72hepatitis .Diagnosis
The discovery of HPS requires a high degree of clinical suspicion
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