Progress in investigating the pathogenesis of hepatopulmonary syndrome

Zhao-Jie Zhang and Chang-Qing Yang

Shanghai, China

Progress in investigating the pathogenesis of hepatopulmonary syndrome

Zhao-Jie Zhang and Chang-Qing Yang

Shanghai, China

(Hepatobiliary Pancreat Dis Int 2010; 9: 355-360)

hepatopulmonary syndrome;cirrhosis;pathogenesis;angiogenesis;intestinal endotoxemia;nitric oxide;carbon monoxide

Introduction

Hepatopulmonary syndrome (HPS) is a triad of liver disease, pulmonary vascular ectasia,and severe hypoxemia associated with hepatic disease.[1]The prevalence of cirrhosis varies from 4%to 47%,[2,3]but it has also been reported in patients with portal hypertension not associated with cirrhosis and acute or chronic liver disease.[4,5]Currently, intrapulmonary vascular dilatation, especially in alveolar regions, is the de fi ning pathological hallmark of HPS and is thought to be responsible for hypoxemia, but the pathogenesis of HPS is complicated and remains unknown. Recent studies found that angiogenesis is an important modi fi able feature of experimental HPS. This review aims to provide updated information about the pathogenesis of HPS.

De fi nition of HPS

HPS is classically de fi ned by a widened alveolar-arterial oxygen difference (AaDO2) in room air (＞15 mmHg,or ＞20 mmHg in patients ＞64 years of age), with or without hypoxemia resulting from intrapulmonary vasodilatation in the presence of hepatic dysfunction or portal hypertension.[6]From a practical vantage point, identifying patients with PaO2＜70 mmHg is useful to recognize those with clinically signi fi cant HPS. The presence of clubbing has the highest positive predictive value (75%), and dyspnea has the highest negative predictive value (100%) for HPS.[1]Early studies emphasized that the exclusion of all other causes of cardiopulmonary dysfunction was required to establish the diagnosis of HPS. In addition, the AaDO2normally increases with age and varies signi fi cantly even in healthy adults. Therefore, using values above the 95%con fi dence interval for the age-corrected AaDO2is appropriate to avoid over-diagnosis of HPS.[6-9]

Pathogenesis of HPS

The pathogenesis of HPS remains unknown. The physiologic mechanisms commonly used to explain why hypoxemia occurs in patients who have HPS include:1) enhanced mismatching of alveolar ventilation with pulmonary vascular perfusion (VA/Q), 2) a diffusionperfusion defect, 3) the fl ow of deoxygenated blood through abnormally dilated vessels that join pulmonary arteries directly to pulmonary veins, bypassing the pulmonary-capillary alveolar surface, 4) oxyhemoglobin af fi nity disorders, and 5) accompanying mechanical effects such as ascites.[6,7,10]

These changes may result from expansion of the pulmonary blood vessels, which may be due to impaired liver function, imbalance between vasodilation and vasoconstriction,[8,11]intestinal bacterial translocation,[12]intestinal endotoxemia,[13]and activation of the lung monocyte-macrophage system.[7,10]A recent study has found that angiogenesis is also an important factor in the pathogenesis of experimental HPS.[14]

Nitric oxide (NO)

NO, also known as the endothelium-derived relaxing factor, is biosynthesized endogenously from arginine and oxygen by various nitric oxide synthase(NOS) enzymes and by reduction of inorganic nitrate.There are two subtypes, inducible NOS (iNOS) and endothelial NOS (eNOS); the latter is expressed under physiological conditions, but the former is not. iNOS is activated by interferon-gamma (IFN-γ) as a single signal or by tumor necrosis factor (TNF) along with a second signal. In patients with chronic liver disease, especially cirrhosis, due to intestinal bacterial translocation, a large number of bacteria enter the bloodstream to stimulate the production of endotoxin. While the liver detoxi fi cation function is weakened, these endotoxins and cytokines, especially TNF-α, can activate iNOS,leading to increased local or systemic NO levels.[6,13]

Many studies have con fi rmed the close relationships of NO, pulmonary vascular dilation and HPS with liver cirrhosis.[15-17]This is based on the observation that exhaled NO levels, a measure of pulmonary production, are increased in cirrhotic patients with HPS and normalize after orthotopic liver transplantation.This may be due to NO induced by the stimulation of endotoxin which, because of liver cirrhosis shunting and decreased reticuloendothelial cell function, cannot be effectively eliminated.[16]In addition, methylene blue, a NOS inhibitor, rapidly and transiently improves hypoxemia in patients with HPS.[17,18]In an experimental rat model of HPS, researchers found that the levels of NO and endothelin-1 (ET-1) in the plasma, liver and lung tissue homogenates are signi fi cantly elevated, suggesting that ET-1/NO systems play an important role in the pathogenesis of HPS.[11]

The increase of pulmonary eNOS synthesis is closely related to the increased level of plasma ET-1. Normally ET-1, a vasoconstrictor, facilitates vasodilation when it binds to endothelial B-type receptors, by increasing the synthesis of endothelial NO. The levels of pulmonary eNOS and NO are regulated through a receptordependent ET-1, which has two kinds of receptors,B-type (ETRB) and A-type (ETRA). The combination of ET-1 and ETRA or ETRB may also lead to vasoconstriction, but ET-1 can also combine with ETRB,which releases endothelium-derived NO and leads to vasoconstriction.[6]Over-production of ET-1 occurs in the liver of patients with HPS, and it can move into the blood circulation through tight junctions, resulting in a kind of endocrine vasodilator role, binding the ET receptor in the lung vascular endothelial cells, leading to an increase of eNOS expression and activity, and fi nally causing pulmonary vasodilation. Accordingly,administration of a selective ETRB antagonist to chronic common bile duct ligation in animals decreases pulmonary endothelial eNOS and ETRB levels and signi fi cantly improves HPS.[19-21]

Studies found that the expression of pulmonary vascular ETRB is increased selectively, thus leading to an increase of endogenous NO generation through ETRB mediated ET-1 and the pulmonary vasodilation in patients with cirrhosis.[22,23]Besides, experimental HPS in ETRB de fi cient rats showed that compared with controls, plasma ET-1 levels were not elevated in ETRB de fi cient rats, Akt and eNOS expression and activation were not increased, and no HPS developed.ETRB de fi ciency inhibits lung Akt/eNOS activation and prevents the onset of experimental HPS.[24]These results demonstrate that ET-1/ETRB signaling plays a key role in the initiation of experimental HPS.

Carbon monoxide (CO)

CO is another common messenger molecule which is produced in at least two ways. The main pathway is by heme metabolism. Heme, in the heme oxygenase (HO)catalyzed oxidation of CO and biliverdin, reduces the latter to bilirubin. The secondary pathway is a chemical mechanism of oxidation by a number of organic molecules, including salt, alkyl phenols and autooxidation, membrane lipid peroxidation, and oxidation of organic compounds.

There are three kinds of HO isozymes: HO-1, HO-2,and HO-3. HO-1 is induciblely expressed by some stimuli; HO-2 and HO-3 are structured in cells in a physiological state. The three kinds of isozymes have their own characteristics and play different roles in different tissues. HO-1 is mainly distributed in the spleen, liver,reticuloendothelial system, and bone marrow; HO-2 is mainly distributed in the brain, blood vessels, testes, and other parts; HO-3 is found in the spleen, liver, heart,kidney, brain, and testes and other parts.[21,25,26]

In cirrhotic patients with HPS, studies have found that HO-1 levels in pulmonary intravascular macrophages are elevated, with increased CO generation compared with those without HPS.[27,28]Common bile duct ligation in the rat is the only established model that reproduces the physiologic features of human HPS.[20,29]One study found that HO-1 levels in pulmonary vascular macrophages are elevated.[30]An experimental HPS study found that HO-1 in pulmonary vascular macrophages is highly and persistently expressed, while after administration of the HO-1 inhibitor, zinc protoporphyrin (ZnPP-Ⅸ), the arterial blood carboxyhemoglobin is normal, pulmonary vasodilation is released, and HPS symptoms are improved.[28]These studies support the idea that the HO-1/CO systems play important roles in the pathogenesis of HPS. Similar results have been supported by another study, but administration of HO-1 inhibitors slowly and partially improves contraction in the vascular response to hypoxia, and administration of the NOS inhibitor,L-nitro-L-arginine methylester (L-NAME), brings HO-1 expression and vascular hypoxic vasoconstriction back to normal.[31,32]This evidence suggests that NO causes hypoxic contraction insensitivity, and induces the production of HO-1, thereby enabling an increase in CO production,which synergistically contributes to the pathogenesis of HPS. The endogenous NOS/NO and HO/CO systems may relatively independently or synergistically contribute to the pathogenesis of HPS.[6,32]

Intestinal endotoxemia and monocyte/macrophage system (IETM)

Studies of liver cirrhosis and portal hypertension in humans and experimental animals found that intestinal bacterial translocation causes dysfunction of liver endotoxin clearance and portosystemic shunt, resulting in IETM.[12,13,18,33]Endotoxin induces and activates the monocyte/macrophage system in vivo, including liver Kupffer cells, splenic macrophages, pulmonary intravascular macrophages (PIMs), and blood mononuclear cells.[34-36]

Because of decreased liver detoxi fi cation, the lung cleans up the bacteria and toxins in compensation.Subsequently, blood mononuclear cells, accumulate in the pulmonary vascular endothelium, and then differentiate into PIMs. The function of PIM phagocytosis is enhanced to remove the bacteria and toxins from the blood. After phagocytizing the foreign bodies in blood, PIMs are activated and secrete a variety of active substances such as NO, CO, TNF-α, IL-1, IL-6, IL-8, and other in fl ammatory mediators. These substances play an important role in the occurrence and development of HPS. Studies also found that administration of nor fl oxacin inhibits intestinal bacteria, reduces endotoxin injury to the lung, and improves the symptoms of HPS.[37,38]After administration of pentoxifylline (PTX), a TNF-α inhibitor, to cirrhotic rats with HPS for 5 weeks, the blood concentrations of TNF-α decrease, PIM adhesion decreases, phagocytosis weakens, and iNOS expression in lung tissue decreases.These results support the notion that inhibiting TNF-α reduces the number and activity of PIMs, and improves and prevents HPS.[39-41]Similar results were reported in the model of common bile duct ligation by administering nor fl oxacin.[35]

Angiogenesis

Recent studies have found that angiogenesis is an important factor in the formation of experimental HPS.[14]Common bile duct ligation in the rat is an established experimental model for human HPS.[41]In this model, increased numbers of lung microvessel,increased lung monocyte accumulation, and activation of Akt and eNOS are all related to the angiogenesis signaling pathways.[20,41]PTX treatment reduces the numbers of microvessels, reduces lung monocyte accumulation, down-regulates pulmonary angiogenic factors, and improves the symptoms of HPS.[24,36,39,41]The studies also found that there are increased levels of vascular endothelial growth factor A (VEGF-A) levels in alveolar macrophages and blood vessel endothelial cells.In thioacetamide (TAA)-induced nonbiliary cirrhosis,angiogenesis is not found, and monocyte accumulation is signi fi cantly less than in the common bile duct ligation-induced HPS model. Activation of Akt, eNOS,VEGF-A are not found.[41]

In the liver and splanchnic vasculature, angiogenesis has recently been recognized to be mediated in part through VEGF-dependent pathways.[42-45]The VEGF family consists of six members, VEGF-A, VEGF-B,VEGF-C, VEGF-D, VEGF-E, and placental growth factor, among which VEGF-A is the best characterized.There are fi ve kinds of variants of VEGF-A and the precise physiological effect of each amino acid variant is different.[46]In many pathological situations, the expression of VEGF-A165, a subtype of VEGF-A, has been con fi rmed in experimental liver cirrhosis. Angiogenesis,the process of growth of new vessels and capillary networks, is tightly regulated by angiogenic factors.VEGF angiogenic signaling occurs through interaction with speci fi c VEGF receptors (VEGFR-1 and VEGFR-2).Subsequently, VEGFR-2 activation triggers downstream signaling in part through Akt and eNOS.[24,47]

Pulmonary intravascular monocyte accumulation is minimal and VEGF-A expression is not signi fi cantly increased in TAA-induced cirrhosis, while monocyte accumulation is evident and VEGF-A expression is signi fi cantly increased in the common bile duct ligation model, and is markedly reduced by PTX, which is known to inhibit mononuclear cell-endothelial adhesion.This is also consistent with a role for this cell type in angiogenesis in experimental HPS.[39]One postulated trigger for monocyte accumulation in the pulmonary microvasculature in HPS is bacterial translocation and increased production of circulating TNF-α.[13,38]One mechanism for the bene fi cial effect of PTX could be the inhibition of TNF-α signaling.[24,39]However, in other studies, circulating TNF-α levels have been found to be signi fi cantly elevated in TAA cirrhosis, yet monocyte accumulation is minimal and HPS does not develop.[48]Together, these results suggest that other mechanisms are involved in monocyte accumulation in experimental HPS and this needs further study.

Conclusion

A prospective study showed that the presence of HPS is a major independent risk factor for the survival of patients with cirrhosis. In this study, the median survival time in cirrhotic patients with HPS was 10.6 months compared with 40.8 months in cirrhotic patients without HPS. In a retrospective study, however, the mortality rate was 41% after a mean time of 2.5 years after diagnosis.[1-3,49]The pathogenesis of HPS is poorly understood, and has hampered the development of effective treatments.The only de fi nitive treatment is orthotopic liver transplantation. Unfortunately the mortality after liver transplantation is signi fi cantly increased in HPS patients as high as 33%.[50]Recent studies have found that pulmonary angiogenesis is a modi fi able feature that contributes to experimental HPS. So angiogenesis inhibition may be a potential therapeutic approach for the treatment of HPS.

Funding: This study was supported by grants from the Shanghai International Co-operation Program (09410705200) and the Shanghai Excellent Academic Leaders Program (08XD14045).

Ethical approval: Not needed.

Contributors: ZZJ wrote the main body of the article under the supervision of YCQ. Both authors contributed to the design and interpretation of the study and to further drafts. YCQ is the guarantor.

Competing interest: No bene fi ts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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BACKGROUND: The pathogenesis of hepatopulmonary syndrome is complicated and remains unknown. This review aims to provide an updated knowledge about the pathogenesis of the syndrome.

DATA SOURCES: Five medical databases, MEDLINE, Science-Direct, OVID, Springer Link, and Wiley InterScience were searched for articles on "hepatopulmonary syndrome","cirrhosis", "angiogenesis", "intestinal endotoxemia", "nitric oxide", "carbon monoxide", and other related subjects.

RESULTS: Currently, imbalance between vasodilation and vasoconstriction, intestinal bacterial translocation, intestinal endotoxemia, and activation of the lung monocyte/macrophage system may play important roles in the pathogenesis of hepatopulmonary syndrome. Recent studies found that angiogenesis is also an important factor in the pathogenesis of experimental hepatopulmonary syndrome.

CONCLUSION: Angiogenesis inhibition may be a potential approach for the treatment of hepatopulmonary syndrome in the future.

Author Af fi liations: Division of Gastroenterology and Institute of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China (Zhang ZJ and Yang CQ)

Chang-Qing Yang, MD, PhD, Division of Gastroenterology and Institute of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China (Tel: 86-21-66111604;Fax: 86-21-56050502; Email: cqyang@tongji.edu.cn)

© 2010, Hepatobiliary Pancreat Dis Int. All rights reserved.

October 12, 2009

Accepted after revision March 6, 2010