Hepatopulmonary syndrome

　　1. Etiology

　　The causes of liver diseases that induce hypoxemia: various acute and chronic liver diseases can be accompanied by pulmonary vascular abnormalities and arterial hypoxemia, the most important being liver cirrhosis in patients with chronic liver disease, especially cryptogenic cirrhosis, alcoholic cirrhosis, hepatitis cirrhosis, and primary biliary cirrhosis. It can also be seen in chronic hepatitis, acute severe hepatitis, bile stasis, alpha-antitrypsin deficiency, Wilson's disease, tyrosinemia, and non-cirrhotic portal hypertension such as idiopathic portal hypertension and schistosomal cirrhosis. Extrahepatic portal vein obstruction can also be complicated by arterial hypoxemia. Observations of these patients suggest that portal hypertension may be the main pathogenic factor for hepatopulmonary syndrome. In 2000, Binay et al. found that progressive liver failure with hyperdynamic circulation is most likely to develop hepatopulmonary syndrome and did not find it to be correlated with the severity of liver cirrhosis.

　　2. Pathogenesis

　　1. Pathophysiology

　　The essence of hepatopulmonary syndrome is hypoxemia caused by pulmonary vascular dilation and abnormal arterial oxygenation during liver disease. Arterial hypoxemia is due to insufficient oxygenation of red blood cells in the blood as it flows through the lungs or to some blood that does not pass through the alveoli for oxygenation. Since primary心肺diseases have been excluded in HPS, the abnormal pathways through which red blood cells may pass include: through pleural and hilum bronchial vessels without reaching the alveoli; blood flow in the mediastinum directly enters the pulmonary veins due to the high-pressure portal venous system, thus bypassing the pulmonary circulation; and directly into the pulmonary veins through dilated alveolar capillaries or pulmonary arteriovenous fistulas. The expansion of alveolar capillaries may be more important in the formation of hypoxemia. Existing research data indicate that the occurrence of hepatopulmonary syndrome is at least related to systemic hyperdynamic state, portal hypertension, hepatic encephalopathy, hepatorenal syndrome, and pulmonary hypertension. Therefore, its cause is also systemic metabolic and hemodynamic disorders, which also participate in the formation of systemic metabolic and hemodynamic disorders, and has important pathophysiological significance.

　　(1)The basic pathological change of liver-lung syndrome is pulmonary vessel dilation, manifested as:

　　①Large-scale precapillary dilation.

　　②Formation and opening of arteriovenous fistulae at the base of the lung.

　　③Formation of pleural 'spider angiomas', mainly due to precapillary dilation.

　　In post-mortem examination, it has been found that the basic pathological changes in the lungs of patients with chronic liver diseases such as liver cirrhosis are widespread pulmonary vessel dilation and arteriovenous fistulae. Some people have found the above pathological changes and pulmonary base pleural vessel dilation or the formation of subpleural spider angiomas through vascular remodeling. Professor Gu Changhai of China summarized these pathological changes in 1997 as: uneven distribution of dilated pulmonary acinar arteries; the whole lower lobe can be seen with thin-walled vessels with a diameter of 60-80?m; the pulmonary vascular bed at the level of the precapillary capillaries in front of the adjacent alveolar gas front is widely dilated; pulmonary artery branches and pulmonary capillaries are significantly dilated, with a diameter up to 160?m. Electron microscopy shows that the walls of pulmonary capillaries and pulmonary small arteries are thickened, and the basal layer of small veins is also thickened.

　　(2)Factors affecting pulmonary vessel dilation: The mechanism of pulmonary vessel dilation has not been fully elucidated, and the possible influencing factors include:

　　①Increased activity of vasodilator substances: Various acute and chronic liver diseases, liver cell dysfunction, and metabolic disorders, especially the reduction in inactivation of vasoactive substances, can enter the systemic circulation directly through abnormal collateral vessels, causing systemic hemodynamic disorder, increased content of vasodilator substances in the blood circulation, similar to visceral congestion in patients with portal hypertension, acting on pulmonary vessels to cause pulmonary vessel dilation and congestion. The substances that cause vasodilation include: glucagon, prostaglandins, vasoactive intestinal peptide, nitric oxide, angiotensinase, bradykinin, and their endotoxins, etc.

　　②Reduction in vasoconstrictor substances or decreased sensitivity of pulmonary vascular bed to endogenous vasoconstrictor substances: such as norepinephrine, endothelin, atrial natriuretic peptide, antidiuretic hormone, serotonin, tyrosine, etc. The content of these substances is not absolutely reduced, and it is possible that their sensitivity of action is reduced. This leads to the opening of non-functional precapillary anastomoses that were originally closed, and the obstruction of normal hypoxic pulmonary vasoconstriction function, which is only 75% of normal.

　　③Nervous factors: The sympathetic nervous tension in patients with liver cirrhosis is hyperactive, but after the formation of portal hypertension, the function of sympathetic nervous system is damaged, which may play an important role, and portal hypertension animals often show abnormal pressor responses, the sensitivity of vessels to norepinephrine is reduced, leading to increased cardiac output, expansion of pulmonary vessel volume, and pulmonary high hemodynamic state, which is also a manifestation of systemic high hemodynamic state.

　　④The response of pulmonary vessels to hypoxia is reduced: In recent years, inert gas diffusion tests have found that patients with liver cirrhosis with more than two spider angiomas not only show liver function damage, but also the resistance of systemic and pulmonary vessels is reduced, and the responsiveness of vessels to hypoxia is also reduced, leading to pulmonary vessel dilation. However, some people have applied pulmonary angiography and found the dilatation of terminal artery vessels, but the response to oxygen supply is almost normal, which does not support this view.

　　⑤ Abnormal pulmonary vascular generation or development may also be one of the factors causing hepatopulmonary syndrome.

　　So far, the mechanism of pulmonary vascular dilation caused by hepatopulmonary syndrome is not clear. However, due to the long-term action of pulmonary vasoactive substances, it can cause a significant increase in intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP), leading to dysregulation of pulmonary vasoconstriction and vasodilation, pulmonary artery dilation, which may be an important cause of the disease and may also be a manifestation of systemic hyperdynamic circulation in the lungs. Due to the significant dilation of pulmonary capillaries and pre-capillaries, the part of blood in contact with the alveoli around the capillaries can still perform gas exchange, while the blood in the central part, due to the increased diffusion distance from the alveoli, cannot perform gas exchange sufficiently, leading to insufficient arterial oxygenation and a series of hypoxemia manifestations.

　　2, Pathogenesis

　　To date, the pathogenesis of this disease has not been elucidated. In view of the above pathophysiological changes and current research, it is believed that the onset of this disease may be the result of the combined action of factors such as ventilation insufficiency, diffusion障碍, ventilation/perfusion ratio disorder, and decreased oxygen-hemoglobin affinity.

　　(1) Ventilation insufficiency: Under normal circumstances, various causes can lead to ventilation insufficiency, resulting in insufficient oxygen in the alveoli and reduced oxygen exchange in the blood, which can cause hypoxemia, such as chronic bronchitis, tracheal foreign bodies, atelectasis, and respiratory muscle paralysis. However, there is still controversy about whether there is ventilation insufficiency in chronic liver disease and liver cirrhosis patients.

　　In 1982, Fujiwara studied the pulmonary function of 22 patients with decompensated liver cirrhosis and found that the patients' vital capacity (VC), functional residual capacity (FRC), and respiratory reserve volume (EVR) were significantly reduced, while the R/T ratio was slightly elevated, and there was no change in the 1-second forced expiratory volume (FEV1). It was believed that the pulmonary interstitial edema caused by liver cirrhosis led to mechanical compression of the lung tissue, and insufficient ventilation was the main reason for the impairment of pulmonary function. Later, Edison et al. also studied the pulmonary function of 21 patients with decompensated liver cirrhosis and found that their vital capacity, maximum ventilation volume (MVV), functional residual capacity, total lung capacity, and R/T ratio were all significantly reduced, and it was believed that liver cirrhosis patients had significant obstructive and restrictive ventilation insufficiency. This was due to the increase in intra-abdominal pressure, elevation of the diaphragm, reduction in thoracic cavity volume and pressure, and other compressions on the lung tissue and atelectasis. The decrease in the 1-second forced expiratory volume was due to the compression of the small bronchi by pulmonary interstitial edema and vascular expansion, leading to early closure of expiration. Theoretically, these factors can all lead to ventilation insufficiency and are one of the factors causing this disease. This was also confirmed by the fact that the arterial oxygen partial pressure increased and the CO2 partial pressure decreased after the pleural effusion of patients with liver cirrhosis accompanied by pleural effusion was drained, and the atelectasis part of the lung was restored. Of course, liver cirrhosis accompanied by pleural effusion, secondary lung infection, pulmonary edema, and circulatory system diseases can all cause significant ventilation insufficiency in the lung tissue, leading to hypoxemia.

　　On the contrary, some people believe that hypoxemia is not caused by insufficient ventilation. This is because when liver cirrhosis patients show a decrease in arterial blood oxygen partial pressure, it is not accompanied by hypercapnia. This may also be due to the fact that during hypoxemia, excessive ventilation by the patients can partially compensate, causing the arterial carbon dioxide partial pressure not to increase, but to decrease, even leading to respiratory alkalosis. Moreover, some liver cirrhosis patients without decompensated liver function can also have arterial hypoxemia. Even some people have found that lung function tests in the compensated phase of liver cirrhosis patients are all normal. Therefore, most scholars currently believe that insufficient ventilation is not the main cause of hypoxemia in liver cirrhosis patients.

　　(2) Diffusion Obstruction: The application of inert gas exclusion technology in patients with hepatopulmonary syndrome has indeed proven that there is a barrier to oxygen diffusion. This is determined by the basic pathological change of hepatopulmonary syndrome - pulmonary vascular dilation. Pulmonary angiography also shows fine spider-like to obvious sponge-like diffuse vascular dilation in the lungs. Due to the significant dilation of pulmonary capillaries and pre-capillaries, the diffusion distance between blood flow in the central part of the vessels and alveoli increases, hindering the entry of alveolar gas into pulmonary capillaries and affecting gas exchange. Studies have found that hypoxemia in liver cirrhosis patients often occurs or worsens during exercise, suggesting that there may be a diffusion barrier or limitation of oxygen in the lungs. Agusti et al. studied the pulmonary hemodynamics and gas exchange in liver cirrhosis patients during exercise and found that the PaO2 of the patients decreased significantly during exercise, while the PaCO2 only decreased slightly, suggesting that these changes in blood gas can be completely explained by extrapulmonary factors. In fact, liver cirrhosis patients do have factors that affect oxygen diffusion, but they are not enough to explain the obvious hypoxemia. Although patients with hepatopulmonary syndrome have peripheral vascular dilation, their arterial blood oxygen partial pressure can decrease when inhaling normal air, but it can significantly increase when inhaling pure oxygen. This further proves that although diffusion obstruction does exist and plays a certain role in the formation of the disease, it is not a major role.

　　(3) Ventilation/perfusion mismatch: Gas exchange is the main biological function of the lung tissue. This gas exchange must be completed under an appropriate ventilation/perfusion ratio. Under normal conditions (in the resting state of a normal adult), the physiologically most appropriate ventilation/perfusion ratio is 0.8. Any change in the ratio caused by any reason can affect gas exchange and lead to hypoxemia. The main cause of ventilation/perfusion mismatch in patients with liver-lung syndrome is pulmonary vascular dilation and arteriovenous分流.

　　①Pulmonary vascular dilation: Pulmonary vascular dilation has been confirmed by pathology and angiography. Due to pulmonary vascular dilation, it not only causes diffusion barrier but also, because oxygen molecules in the air cannot diffuse to the central part of the dilated vessels for gas exchange, it leads to a decrease in ventilation/perfusion ratio and a decrease in pulmonary artery oxygen partial pressure. This decrease in ventilation/perfusion ratio, combined with an increase in reactive cardiac output, shortens the time of blood flow through the capillary network, resulting in insufficient oxygenation. Hyperpnea can partially increase the patient's PaO2. If the alveolar oxygen partial pressure is increased at this time, oxygen molecules can partially reach the central part of the dilated vessels, causing an increase in arterial oxygen partial pressure. Therefore, some people call this phenomenon diffusion-perfusion disorder or functional intrapulmonary arteriovenous分流. It is not true intrapulmonary分流. Krowka observed a group of patients with liver-lung syndrome, 88% of whom showed hypoxemia in an upright position. It is believed that this is due to the effect of gravity, where this vascular dilation causes an increase in blood flow mainly in the middle and lower lung areas, and hypoxemia is more pronounced in an upright position.

　　②Arteriovenous分流: In liver cirrhosis, pulmonary arteriovenous fistula and pleural spider angiomata may occur, both of which can cause pulmonary artery blood flow to bypass gas exchange and directly shunt into the pulmonary veins, resulting in significant hypoxemia in patients, which cannot be corrected by oxygen inhalation and is considered true intrapulmonary shunting. This has been confirmed by examinations such as pulmonary tissue pathology, angiography, and two-dimensional contrast echocardiography. It is currently believed that pulmonary vascular casting is the most direct evidence for the determination of arteriovenous分流. The pulmonary arteriovenous fistula was first discovered by Rydell and Hottbauer, who injected vinyl acetate into the right pulmonary vessels of a 11-year-old patient with liver-lung syndrome who died, and found a large number of arteriovenous communications. Subsequently, many foreign scholars have reported related cases. This is because these arteriovenous communications, like portosystemic collateral circulation, are naturally present but normally in a closed state. However, under pathological conditions, they are re-opened due to the influence of numerous factors such as nerves and humoral substances. This intrapulmonary arteriovenous分流 is the main cause of通气/血流比例失常 leading to insufficient gas exchange. While pleural spider angiomata, due to less shunting, can also cause arteriovenous分流, they are generally not sufficient to cause significant hypoxemia. In addition, many studies in recent years have also found that some patients with liver cirrhosis have a small amount of portal-pulmonary venous分流, where blood flow also enters the systemic circulation without passing through alveolar gas exchange, which can also cause通气/血流比例失常 and insufficient gas exchange. Since this分流 is generally small and not enough to produce severe hypoxemia, it is not an important factor.

　　③ Airway closure: In 1971, Ruff et al. proved that the closed volume (CV) and total closed volume (CC) of liver cirrhosis patients were significantly increased, and more gas was trapped in the lower lung fields, resulting in extremely low ventilation/perfusion ratio in this area. It is considered that this is due to airway closure and reduced ventilation. In 1984, Furukawa et al. measured the pulmonary function of 105 liver cirrhosis patients and did not find any abnormalities, but most patients had flow-volume abnormalities, and the closed volume was significantly increased, indicating that the airway was prematurely closed, the ventilation/perfusion ratio decreased, which may also be an important cause of hypoxemia.

　　④ Decreased oxygen and hemoglobin affinity: A group of reports found that 15 cases of liver cirrhosis (most of them were alcoholic cirrhosis) had mild systemic or pulmonary vascular dilation, normal PaO2, mild hypocapnia, slightly shifted right hemoglobin dissociation curve, normal carbon monoxide diffusion, and mild ventilation/perfusion ratio imbalance. This indicates that the patient's oxygen dissociation curve shifts to the right due to a decrease in the affinity of hemoglobin and oxygen, which may be caused by an increase in the concentration of 2,3-diphosphoglycerate in red blood cells, but it is not an important factor in the occurrence of hypoxemia.

　　In summary, there are many factors that can cause hypoxemia, but it is difficult for any single factor to fully explain the pathogenesis of this disease. Due to the basic pathological changes of pulmonary vascular dilation and the opening of arteriovenous communications, combined with recent research results, it is suggested that the diffusion obstacle of oxygen in alveoli and pulmonary capillaries and the imbalance of ventilation/perfusion ratio may coexist, which is the main cause of hypoxemia in this disease. Other factors may worsen the anemia, which are secondary factors. Therefore, it is considered that it may be the result of the combined action of the above factors.

　　In addition to its clinical manifestations, hepatopulmonary syndrome can also cause other diseases. Patients may have: liver palm, enlargement of the liver and spleen, spider nevus, ascites; due to hypoxemia, patients may experience palpitations, chest tightness, and shortness of breath when changing from supine to standing.

　　The clinical manifestations of primary liver disease

　　Hepatopulmonary syndrome can occur in various liver diseases, but it is most common in chronic liver diseases, especially in liver cirrhosis caused by various reasons such as cryptogenic cirrhosis, alcoholic cirrhosis, hepatitis cirrhosis, post-necrotic cirrhosis, and biliary cirrhosis, etc. Most patients (about 80%) seek medical attention due to the clinical manifestations of various liver diseases, while at this time there are still no respiratory symptoms. The clinical manifestations of various liver diseases vary greatly due to the etiology, course, degree of liver cell function damage, and complications. The most common clinical manifestations include liver palm, spider nevus, jaundice, enlargement of the liver and spleen, ascites, gastrointestinal bleeding, and abnormal liver function, but there is no obvious correlation with hepatopulmonary syndrome. Some patients with relatively stable liver disease in clinical practice may also have progressive deterioration of pulmonary function. Data shows that in patients with chronic liver disease and liver cirrhosis, the presence of a spider nevus may indicate abnormal changes in the pulmonary vascular bed. Some people even believe that individuals with the sign of a spider nevus have obvious systemic and pulmonary vascular dilation, severe gas exchange disorder, indicating that they may be the epidermal marker of pulmonary vascular dilation.

　　Second, clinical manifestations of pulmonary dysfunction

　　Since patients with this disease do not have primary cardiovascular and pulmonary diseases, the majority (80% to 90%) of patients gradually develop respiratory system manifestations on the basis of various liver diseases, such as cyanosis, dyspnea, clubbing (of fingers or toes), orthostatic hypoxemia, supine breathing (platypnea), etc. Among them, progressive dyspnea is the most common pulmonary symptom of liver-lung syndrome. Binay et al. believe that cyanosis is the only reliable clinical sign, and supine breathing, orthostatic hypoxemia are the most characteristic manifestations of this syndrome. Pulmonary examination generally does not show obvious positive signs. A small number of patients (about 16% to 20%) may present with exercise-induced dyspnea as the main complaint without clinical manifestations of various liver diseases, and clinical attention should be paid to prevent misdiagnosis. Chinese Gao Zhi et al. have reported two cases of liver-lung syndrome patients who presented with cyanosis, palpitations, and shortness of breath after exercise. They found that they were accompanied by clinical manifestations of liver cirrhosis (such as palmar erythema, spider nevi, hepatosplenomegaly, ascites), which is conducive to the diagnosis of this disease. If liver disease patients are complicated with other pulmonary diseases (such as chronic bronchitis, emphysema, pneumonia, pleural effusion, etc.), they may coexist with liver-lung syndrome, which can cause obvious respiratory symptoms, and attention should be paid to differentiation. According to some research data, it takes an average of 2 to 7 years for patients with liver-lung syndrome to go from the initial onset of dyspnea to a clear diagnosis. Also, about 18% of patients may have dyspnea when the diagnosis of liver disease is clear.

　　1. Orthostatic hypoxemia (orthodeoxidation):When patients change from supine position to standing position, PaO2 decreases by more than 10%.

　　2. Supine breathing (platypnea):When patients change from supine position to standing position, they experience symptoms such as palpitations, chest tightness, and shortness of breath. When the patients return to the supine position, the above symptoms improve. According to Krowka's report, about 80% to 90% of liver-lung syndrome patients show the above two manifestations, which are mainly due to the expansion of pulmonary vessels in liver-lung syndrome patients being mainly distributed in the middle and lower lung fields. When patients change from supine to standing position, under the action of gravity, the blood flow in the middle and lower lungs increases, exacerbating hypoxemia caused by low oxygen levels. Although the above two manifestations are not unique to liver-lung syndrome, they indicate that the patient's pulmonary vascular system has significant abnormalities. If various liver disease patients show the above two manifestations, further examination should be conducted to confirm.

　　Various acute and chronic liver diseases can be accompanied by pulmonary vascular abnormalities and arterial hypoxemia, the most important being patients with liver cirrhosis caused by chronic liver disease, especially cryptogenic cirrhosis, alcoholic cirrhosis, hepatitis cirrhosis, and primary biliary cirrhosis. Therefore, the prevention of this disease should be targeted at the etiology, actively treat liver disease, reduce its damage to the blood vessels and affect blood supply, and thus avoid the occurrence of liver-lung syndrome.

　　One, Blood gas analysis

　　Hypoxemia is the basic pathophysiological change of liver-pulmonary syndrome, therefore, blood gas analysis is essential for the diagnosis of the disease. In patients with liver disease without primary cardiovascular disease, if there is significant hypoxemia, it suggests the diagnosis of the disease. The main manifestations are: arterial oxygen partial pressure (PaO2) <9.33kPa (70mmHg), blood oxygen saturation (SaO2) <94%, alveolar-arterial oxygen gradient increased (>4.53kPa or 34mmHg). Patients may develop respiratory alkalosis due to hypoxia: such as a decrease in arterial carbon dioxide partial pressure (PaCO2), an increase in pH value. Currently, it is considered that a decrease in PaO2 is a necessary condition, but some people believe that an increased alveolar-arterial oxygen gradient may be more sensitive.

　　Two, Pulmonary function measurement

　　It can measure vital capacity, maximum ventilation volume, functional residual capacity, total lung capacity, respiratory reserve volume, R/T, 1s forced expiratory volume, carbon monoxide diffusion capacity in the lungs, etc. In patients with liver-pulmonary syndrome without obvious chest or abdominal effusion, although the lung volume and expiratory volume can be basically normal, there is still a significant change in diffusion capacity, even after correction of hemoglobin, it is still significantly abnormal. Generally, in the late stage of liver disease, there is pulmonary dysfunction, which can be manifested as decreased pulmonary expiratory volume, increased respiratory resistance, and impaired gas diffusion function. When there is an increase in expiratory resistance in pulmonary function tests, corresponding examinations should be made; such as alpha-antitrypsin and phenotype, to distinguish the coexistence of liver cirrhosis and emphysema.

　　Three, X-ray examination

　　Generally, chest X-rays in patients may show no obvious abnormalities. Some patients may show enhanced interstitial shadows in the lower lung fields, mainly manifested as:

　　1, Increased interstitial texture of the lung, enhanced.

　　2, Diffuse small millet-like shadows mainly in the lower lung fields.

　　3, Pulmonary artery dilation.

　　Some people believe that the shadow of nodules or reticular nodules at the base of the lung is an indication of pulmonary vascular dilation, but such damage is difficult to find in post-mortem examination. The typical manifestation of X-ray examination presents as nodules or reticular nodules of medium size (1.3-1.6mm) at the base of the lung. The incidence rate is 5% to 13.8% in patients with chronic liver disease, and can be as high as 46% to 100% in patients with HPS. However, some people believe that this manifestation is not specific and can also exist in pulmonary fibrosis or granulomatous diseases. They can be distinguished by pulmonary function tests, angiography, or CT examination, etc.

　　Four, CT

　　It can show distal vascular dilation and a large number of abnormal terminal branches, and can exclude other causes of hypoxemia, such as emphysema or pulmonary fibrosis. However, the above changes are non-specific. Some people propose that using three-dimensional reconstruction spiral CT for pulmonary vascular imaging reconstruction may be a future hot spot. In distinguishing visible arterial-venous abnormalities, it has the same accuracy as selective pulmonary angiography.

　　Fifth, Two-dimensional echocardiography with contrast enhancement

　　The use of contrast-enhanced two-dimensional echocardiography is the preferred non-invasive examination method to confirm pulmonary vascular dilation. This method was first applied to detect pulmonary vascular dilation in patients with liver cirrhosis by Hind and Wong et al. The principle is that stirring normal saline and indocyanine green dye can produce microbubbles of 60-90μm, which are injected into the peripheral veins and deposited in the left atrium when passing through the dilated pulmonary vessels in the right heart. Under normal circumstances, these microbubbles are absorbed into the alveoli or dissolved in the blood during the first passage through the capillary bed (diameter 8-15μm) and cannot appear in the left atrium. This method relies on the time of appearance of microbubbles in the left atrium to distinguish intracardiac shunts and pulmonary shunts. Right-to-left intracardiac shunts can appear in the left atrium immediately after the microbubbles appear in the right atrium. If there is pre-capillary pulmonary dilation, the microbubbles will appear in the left atrium 4-6 heart cycles after leaving the right atrium. The method is to inject indocyanine green into the patient's vein, and when the microbubbles appear in the right atrium, a transient echo or cloud-like shadow can be produced on the two-dimensional echocardiography. After 3-6 heart cycles of the above ultrasound changes appear in the right atrium, the same changes also appear in the left atrium, indicating the presence of pulmonary vascular dilation. Negative results can basically exclude the diagnosis of hepatopulmonary syndrome. This method is more sensitive than arterial blood oxygen partial pressure and pulmonary scan and is currently the most suitable screening method. However, the disadvantage is that it cannot determine the specific location of the lesion vessels and cannot evaluate the degree of shunt. Recently, some people have applied transesophageal two-dimensional echocardiography to easily detect these tiny bubbles and can determine their distribution in the bronchus, thus used to locate whether the pulmonary vascular dilation occurs in the upper lung or lower lung.

　　Six, pulmonary angiography

　　It is a traumatic diagnostic technique, although it has certain risks, it is still considered the gold standard for determining pulmonary vascular changes and localization. It can not only distinguish hypoxemia caused by hepatopulmonary syndrome from that caused by pulmonary embolism, but also provide a basis for choosing surgical treatment methods for patients with hepatopulmonary syndrome. If the pulmonary vascular damage is relatively isolated, selective pulmonary artery embolism or pulmonary lobectomy can be considered. The pulmonary vascular lesions can have the following three manifestations: Type I spider-like diffuse dilation, common in the early stage of hepatopulmonary syndrome, which has a good response to pure oxygen inhalation during this period; Type II cavernous artery dilation, mainly located at the bottom of the lung, common in the middle stage of hepatopulmonary syndrome, which has a limited response to pure oxygen inhalation during this period; Type III direct pulmonary artery and vein communication, visible at the hilum level or located at the bottom of the lung, presenting as isolated earthworm-like or mass shadows, similar to arteriovenous malformations. During this period, clinical hypoxemia is severe, cyanosis is obvious, and there is no response to pure oxygen inhalation. China's Gao Zhi et al. believe that the sensitivity of pulmonary angiography is not as good as that of contrast-enhanced two-dimensional echocardiography and the following pulmonary scan examination. Some people also summarize the types of pulmonary angiography into the following two types: Type I diffuse pre-capillary dilation, displayed as spider-like or cavernous images by contrast (inhalation of 100% oxygen can increase PaO2), Type II intermittent local arteriovenous malformation or collateral formation, displayed as isolated earthworm-like or mass images by contrast (inhalation of 100% oxygen has almost no effect on PaO2). The disadvantage is that pulmonary angiography cannot display small peripheral arteriovenous malformations and may produce false-negative results.

　　Chapter 7: 99mTc-labeled Macroglobulin Lung Scanning (99mTc-MAA)

　　The principle of this method is the same as that of two-dimensional echocardiography with microbubble contrast enhancement. This method uses macroglobulin with particle diameter greater than 20μm, which cannot pass through the capillary network under normal circumstances. All pulmonary scanning substances are concentrated in the pulmonary vascular system, but when there is pulmonary vascular dilation and arteriovenous shunting, they can pass through and deposit in the liver, brain, and kidney tissues. Application of this method for radionuclide scanning can semi-quantitatively detect the degree of pulmonary vascular dilation and pulmonary shunting, and can track the changes in the condition. Abrams et al. believe that for patients with liver cirrhosis and HPS complicated with primary pulmonary disease, pulmonary perfusion scanning can assess the degree of impact of HPS on hypoxemia and help decide whether to perform liver transplantation as a treatment measure, because severe primary pulmonary disease-induced hypoxemia is a contraindication for liver transplantation, but a negative result cannot completely exclude HPS.

　　Chapter 8: Venous Catheterization for Pressure Measurement

　　Pulmonary venous pressure gradient (HVPG), mean pulmonary artery pressure (PAP), and pulmonary capillary wedge pressure (PCWP) can be measured through liver and pulmonary venous catheterization to understand whether there is pulmonary hypertension, etc. Binay et al. studied 3 patients with hepatopulmonary syndrome and showed that the pulmonary vascular resistance (PAR) and PCWP values were lower than those with negative bubble contrast echocardiography.

　　Chapter 9: Pathological Changes

　　It is the most reliable indicator for diagnosing HPS, with the basic pathological change being pulmonary vascular dilation, manifested as diffuse extensive precapillary dilation or discontinuous arteriovenous anastomoses. Acute liver failure and end-stage chronic liver disease patients have all been confirmed to have pulmonary vascular dilation. One type of structural change is the precapillary dilation adjacent to the normal pulmonary gas exchange unit, and the other is the larger arteriovenous shunts away from the pulmonary gas exchange unit. Angiography can show the abnormal vessels and their relationships and pathways, which is more convenient for discovering anatomically existing abnormal pathways (including changes in small vessels) than gross examination and microscopic examination under optical microscopy. Fritts et al. applied radioactive isotope Kr85 dissolved in water-soluble dye for intravenous injection, and the ratio of kr85 in arterial blood to dye can be used to estimate the shunting condition. Methyl丙烯酸酯 can be used for more detailed angiography studies.

　　Chapter 10: Other Examinations

　　Blood biochemical tests often show liver dysfunction, but the degree is not proportional to the progression of hepatopulmonary syndrome. Liver function tests, protein fractionation, virological markers, and other liver disease tests can be conducted. In addition, gastroscopy can be performed to detect the presence of portal hypertension.

　　16. Control calorie intake to facilitate the oxidation and consumption of fat in liver cells. Obese individuals should gradually lose weight to reduce body weight to the normal weight range.

　　15. Limit the intake of fat and carbohydrates, and avoid excessive sugar intake.

　　14. High-protein diet, as high protein can protect liver cells and promote the repair and regeneration of liver cells.

　　13. Ensure a supply of fresh vegetables, especially green leafy vegetables, to meet the body's need for vitamins.

　　12. Limit salt intake, with 6 grams per day being appropriate.

　　11. Adequate water intake to promote the metabolism of the body and the excretion of metabolic waste.

　　10. Foods rich in methionine, such as millet, sesame, and spinach, can promote the synthesis of phospholipids in the body and assist in the transformation of fat within liver cells.

　　7. Avoid spicy and刺激性 food.

　　1. Treatment

　　The basis for the occurrence of hepatopulmonary syndrome is the pre-existing liver disease. The frequency and severity of its occurrence are mostly related to the function of liver cells, but there are also cases of hepatopulmonary syndrome occurring in patients with chronic liver disease that is relatively stable and normal liver function. The pleural effusion, peritoneal effusion, pulmonary edema, and secondary infection that occur after the liver function becomes deranged can worsen the respiratory function damage in patients. Therefore, in the current situation where there is a lack of effective measures for the treatment of hepatopulmonary syndrome, the active and effective treatment of the primary liver disease is the basis for the treatment of this disease. Treatment of the primary disease includes correcting hypoalbuminemia, eliminating pleural and peritoneal effusions, improving liver function, and dealing with related complications, which can promote tissue oxygenation and increase arterial oxygen saturation. On this basis, the following treatment methods can be supplemented.

　　1. Oxygen inhalation and hyperbaric oxygen therapy:In 1988, Cotes et al. noticed that hypoxemia in patients with liver cirrhosis could be corrected by oxygen inhalation (100% O2). Subsequent observations by many people have proven that hypoxemia in patients with liver cirrhosis can be completely or partially corrected by oxygen inhalation. At the same time, oxygen therapy also helps in the differential diagnosis of intrapulmonary shunting: if PaO2 recovers after oxygen inhalation, it is intrapulmonary vascular dilation (IPVD); partial improvement may indicate the simultaneous existence of both anatomical and functional shunting in the lungs; and if ineffective, it may be an intrapulmonary arteriovenous fistula. It is currently believed that once the diagnosis is established, treatment should be given as soon as possible to correct hypoxemia. In the early stages of mild disease, even in patients with hypoxemia at the critical value (PaO2 of 8-9 kPa) accompanied by ascites, hemoglobin saturation may still be less than 85% during physical activity or even during sleep, indicating the need for oxygen therapy. Oxygen can be administered at a flow rate of 2-3L/min through a nasal cannula to improve hypoxemia. As the condition progresses, the oxygen flow rate needs to be gradually increased, and oxygen therapy via the trachea may be necessary. In the later stage, patients may use a ventilator for pressure oxygen therapy or hyperbaric oxygen therapy. For patients with severe disease, the effect of simple oxygen therapy is not significant.

　　2. Vasoactive drug therapy:The clinical treatment of hepatopulmonary syndrome with vasoactive drug therapy is the most studied in internal medicine, but due to the unclear pathogenesis and the difficulty in reversing primary liver disease, the clinical efficacy of drug treatment is still uncertain. Commonly used drugs include:

　　(1) Aminotriazine (allyl piperazine): Initially, Krowka et al. tried the drug in clinical trials in 1987, and it was believed that the drug could change the ventilation/perfusion ratio by increasing the pulmonary vascular tension, and only improved the symptoms of hypoxia and increased PaO2 > 1.33 kPa (10 mmHg) in one patient with liver-lung syndrome. The other four cases did not have a clear therapeutic effect. However, it is considered that the application of the drug can improve the ventilation/perfusion ratio in animal experiments and patients with chronic obstructive pulmonary disease.

　　(2) Somatostatin and its analogs: This class of drugs can block the vasodilatory effect of neuropeptides on pulmonary vessels and can also inhibit the production of glucagon. Salem et al. reported a case of using octreotide (Octreotide) to improve the PaO2 of patients with liver cirrhosis and severe hypoxemia rapidly, and successfully performed liver transplantation. However, the studies of Krowka and Schwarty et al. show that the therapeutic effect of this class of drugs on patients with liver-lung syndrome is not significant. Theoretically, the drug can block the vasodilatory effect of neuropeptides on pulmonary vessels, and there is also evidence that octreotide can block the symptoms of metastatic syndrome. The clinical efficacy still needs further research to be confirmed. Song et al. also found that long-acting aspirin therapy has a certain efficacy.

　　(3) Prostaglandin inhibitors: They can inhibit the synthesis of prostaglandin E2a in the lung, reduce the latter's effect on the expansion of the pulmonary vascular bed, and improve the oxygenation of arterial blood in pulmonary injury animals. Shijo et al. applied indomethacin to treat patients with liver-lung syndrome, which can increase PaO2 and decrease the alveolar-arterial oxygen pressure difference. Further clinical research is needed to confirm its application.

　　(4) Cyclophosphamide and glucocorticoids: Cadranel et al. reported a case of non-cirrhotic hepatocellular failure patient treated with cyclophosphamide and prednisone for 12 months, which successfully improved the patient's hypoxemia. It may be effective in the treatment of pulmonary lesions caused by immune dysfunction in chronic liver disease.

　　(5) Ephedrine atomization inhalation: Zhang Liming of China and others applied atomized inhalation of ephedrine hydrochloride to treat 12 cases of liver-lung syndrome, and the preliminary efficacy was significant. The mechanism is that ephedrine can excite the α-receptor of pulmonary vessels, causing bronchial mucosal and pulmonary capillary contraction, reducing bronchial mucosal edema, causing the dilated vessels in the lung to contract, reducing pulmonary shunting, and at the same time exciting the β2-receptor of the bronchus, dilating the bronchus, improving the ventilation/perfusion ratio, and alleviating hypoxia. It is worth further in-depth study.

　　(6) Other: There are reports that sympathomimetic drugs (isoproterenol), β-receptor blocking drugs (propranolol), and others can improve the symptoms of patients with liver-lung syndrome. Endothelin, estrogen inhibitors (Tamoxifen), and others are theoretically believed to reduce the skin spider nevi and pulmonary vascular dilatation in patients with cirrhosis, improve respiratory symptoms, but further research is still needed. Currently, nitric oxide (NO) is the subject of much research, with reports indicating that the use of NO synthase inhibitors can increase pulmonary vascular resistance. Alexander et al. applied NO to treat severe hypoxemia after liver transplantation and achieved good results. Durand et al. also reported that inhaling NO cured a child with HPS, whose mechanism and clinical efficacy are still waiting to be further confirmed by research.

　　3. Pulmonary artery embolism treatment:In 1987, Felt et al. first applied coil embolization to treat patients with hepatopulmonary syndrome, resulting in an increase in PaO2 and significant improvement in symptoms. Krowka et al. also treated patients with persistent hypoxemia after liver transplantation with pulmonary embolism, and the result was a significant increase in PaO2. It is generally believed that for patients with normal pulmonary angiography or cavernous vascular imaging with liver-kidney syndrome, pulmonary vasodilation can disappear after liver transplantation; for patients with diffuse pulmonary vascular dilation shown on pulmonary angiography, due to the extensive lesions and poor efficacy, the above two methods are not usually used for such embolization treatment, and only for isolated, severe pulmonary vascular dilation or arteriovenous fistula, local pulmonary vascular embolization therapy can be used to achieve better efficacy.

　　4. Liver transplantation:Reports on the use of liver transplantation for the treatment of hepatopulmonary syndrome are increasing year by year. Some believe that liver transplantation can cure hypoxemia and improve symptoms, while others believe that liver transplantation can worsen postoperative hypoxemia and increase mortality rate, which is actually caused by different indications for liver transplantation surgery. Currently, it is believed that liver transplantation may still be the fundamental measure for the treatment of hepatopulmonary syndrome. In the past, severe hypoxemia was considered an absolute contraindication for liver transplantation. Recent studies have shown that for patients with good alveolar gas diffusion function, good response to inhaled pure oxygen, and safe oxygenation during anesthesia, liver transplantation should be the first choice for treatment. Recent reports further confirm that hypoxemia after liver transplantation can be cured. Krowka et al. believe that progressive hypoxemia associated with HPS can be considered as an indication for liver transplantation based on literature review and case report analysis. Temporary hypoxemia after liver transplantation can be corrected by applying NO and adopting supine head-down and alternating lateral decubitus positions. For patients with severe hypoxemia and direct pulmonary artery-to-venous collateral circulation shown on pulmonary angiography, who are not responsive to inhaled pure oxygen, and whose hepatopulmonary syndrome is severe, the hypoxemic state is also difficult to improve after liver transplantation, the efficacy is limited, and it may even increase the risk during and after surgery, so liver transplantation treatment is not recommended.

　　5. Transjugular intrahepatic portosystemic shunt (TIPS):The basic pathological change of HPS is the abnormal dilation of pulmonary vessels. The dilation of pulmonary vessels is related to neural and humoral factors caused by increased portal vein pressure. Therefore, reducing portal vein pressure can improve intrapulmonary shunting, reduce the expansion of pulmonary vessels caused by neural and humoral factors, and its enhanced oxygenation effect has been confirmed. Selim et al. believe that TIPS is an effective method for the treatment of HPS, and its effect in improving symptoms, enhancing oxygenation, and reducing intrapulmonary shunting can last up to 4 months. Riegler et al. treated a patient with diffuse pulmonary vascular dilation unsuitable for vascular embolization with TIPS, and the result was that the patient's PaO2 significantly increased and hypoxemia was significantly improved. However, Coley et al. also reported a patient who showed no response after TIPs treatment, so its exact efficacy still needs to be studied.

　　6. Other treatments:Some people have used garlic to treat a patient with hepatopulmonary syndrome for 18 months, and the patient's oxygenation has been significantly improved, and the symptoms have been alleviated. There are also those who use plasma exchange therapy, which has a limited effect on the arterial oxygenation of patients with hepatorenal syndrome.

　　In summary, there is currently no effective treatment for hepatopulmonary syndrome. Since the basic cause of hepatopulmonary syndrome is the failure of liver cell function, the cause of death of patients is usually not lung function failure, and most of them die due to complications such as gastrointestinal bleeding, renal failure, hepatic encephalopathy, sepsis, etc. Therefore, we believe that the treatment of the primary liver disease is particularly important. Conservative treatment can be adopted if simple oxygen therapy or medication is effective in the early stage of hypoxemia. If liver transplantation is possible, it is the best option. Currently, it is widely believed that liver transplantation is a more certain and promising treatment option. If the patient's oxygenation effect is poor, and the diagnosis of pulmonary angiodysplasia or arteriovenous fistula in the lung is confirmed by pulmonary angiography, etc., pulmonary artery embolism treatment should be performed as soon as possible. For patients with significant portal hypertension, TIPS treatment can also be adopted.

　　II. Prognosis

　　Chronic liver disease and liver cirrhosis patients who have symptoms of respiratory system, such as hypoxia and dyspnea, and are diagnosed with hepatopulmonary syndrome often take many years even more than 10 years [average (4.8±2.5) years], a few patients may also develop acute disease in a short period of time, and there are also patients who present with dyspnea as the main complaint. However, chronic liver disease signs can still be traced. Once hepatopulmonary syndrome is established, there is significant hypoxemia, and the prognosis is poor, most of whom die within 2 to 3 years, and the cause of death is often complications of liver disease. If the patient's oxygenation is good, the hypoxemia can be spontaneously relieved or improved after liver transplantation or with the improvement of liver function, and the prognosis is good. If the patient's oxygenation function is severely deteriorated, the prognosis is extremely poor, and most of them die in a short period of time.

　　HPS often presents with a chronic course, although it is not a direct cause of death in patients with liver cirrhosis, it can significantly worsen the condition. Therefore, patients with liver cirrhosis, especially those with positive liver palms and spider nevi, and those with portal hypertension should be aware of the possibility of HPS, and timely detection and symptomatic treatment (such as low-flow oxygen therapy) can improve the prognosis of patients.