乳糜性腹水文獻複習之一

胸腹部手術後乳糜性腹水是一種少見的併發症，微信群裡討論時多數憑藉自己的想像與推理做出決定和建議。我們受朋友委託檢索了幾篇相關文章，編譯後和大家分享因為篇幅較長，分次發布。如果需要更多資訊，請關注微信公眾號留言索取或查看相關連結。本文得到暨南大學附屬第一醫院胃腸減重代謝外科董志勇博士校對，在此表示感謝！

Review article: the diagnostic approach andcurrent management of chylous ascites

B. Lizaola 1 | A. Bonder 2 | H. D. Trivedi 2 | E.B. Tapper 3 | A. Cardenas

文獻回顧：乳糜性腹水的診斷方法與現代治療

翻譯：清遠市第二人民醫院普外科 劉為民

審校：暨南大學附屬第一醫院胃腸減重代謝外科 董志勇博士

Summary

Background: Chylous ascites is rare, accounting for less than 1% of cases. An appropriate and stepwise approach to its diagnosis and management is of key importance.

Aim: To review the current diagnostic approach and management of chylous ascites.

Methods: A literature search was conducted using PubMed using the key words 『chylous』, 『ascites』, 『cirrhosis』,『pathophysiology』, 『nutritional therapy』, 『paracentesis」, 「transjugular intrahepatic portosystemic shunt」 and 「TIPSS』. Only articles in English were included.

摘要

背景：乳糜性腹水是一種少見疾病，其發病率不足1%。運用一種適當和逐步進行的方法對乳糜性腹水的診斷和治療至關重要。

目的：複習乳糜性腹水當前診斷和治療的文獻。

方法：在pubmed上檢索相關文獻，關鍵詞包括：乳糜性腹水、肝硬化、病理生理學、營養治療、穿刺術、經頸靜脈肝內門腔分流術和TIPSS。檢索文獻僅限於英語文獻。

Results: Chylous ascites is caused by the traumatic or obstructive disruption of the lymphatic system that leads to extravasation of thoracic or intestinal lymph into the abdominal space and the accumulation of a milky fluid rich in triglycerides. The most common causes are malignancy, cirrhosis and trauma after abdominal surgery. This condition can lead to chyle depletion, which results in nutritional, immunologic and metabolic deficiencies. An ascitic triglyceride concentration above 200 mg/dL is consistent with chylous ascites. Treatment is based on management of the underlying cause and nutritional support.

結果：乳糜性腹水可以因淋巴系統創傷和梗阻導致的淋巴系統的破裂引起，進一步導致胸或腸淋巴外滲到腹腔，集聚成富含甘油三酯的乳糜樣液體。最常見的原因為惡性腫瘤、肝硬化和腹部手術創傷。這種疾病可以導致乳糜耗竭，出現營養、免疫和代謝缺陷。腹水中甘油三酯的濃度超過200 mg/dL可以診斷為乳糜性腹水。治療的基礎為針對發病原因治療和營養支持。

Conclusions: Chylous ascites is mostly due to malignancy and cirrhosis in adults, and congenital lymphatic disorders in children. Treatment with nutritional optimization and management of the underlying etiology are the cornerstones of therapy. When conservative measures fail, other interventions such as octreotide/somatostatin analogues, surgical ligation, embolization and transjugular intrahepatic portosystemic shunt in patients with cirrhosis can be considered.

結論：乳糜性腹水最常見的原因在成人為惡性腫瘤和肝硬化；兒童中為先天性淋巴系統疾病。優化營養和針對潛在病因的治療為治療的基礎。當保守治療失敗時，可以考慮其他幹預方法。包括：奧曲肽或善德定類似物、手術結紮、栓塞、肝硬化病人行經頸靜脈肝內門腔分流。

1 | INTRODUCTION

Chylous ascites is defined as a milky appearing,triglyceride-rich peritoneal fluid, characterised by the presence of thoracicor intestinal lymph in the abdominal cavity1. Abdominal malignancy, cirrhosis,lymphatic disruption after abdominal surgery, and infections represent the leading causes in adults2. In children, congenital lymphatic abnormalities and trauma are considered the most common etiologies3.

1 引言

乳糜性腹水定義為奶樣、富含甘油三酯的腹腔積液，具有胸腔和腹腔中腸道淋巴液的特徵1。腹部惡性腫瘤、肝硬化、腹部手術後淋巴管破裂和感染為成人發病的主要原因2。兒童中先天性淋巴系統異常和創傷被認為是最主要的發病原因3。

Its incidence is not well established, however,previous data from Press et al published in 1984 indicates that it accounts for 1 per 20 000 hospital admissions overall, since then no further epidemiological studies have been performed, thus the current incidence is not well known4. Chylous ascites is rich in nutrients and immunoglobulins, which become no longer biologically available after accumulating in the peritoneum. This can lead to dehydration, malnutrition, electrolyte imbalance and immunosuppression5.Therefore, prompt diagnosis and treatment is warranted. Herein, we review best practices for diagnosis and conservative treatment as well as emerging therapeutic options for refractory cases of chylous ascites.

儘管其發病率尚未確定，然而，1984年Press等人發表的出版物中提供的資料顯示住院病人整體發現率為兩萬分之一，此後未再發現進一步的流行病學研究，因此，當前的發生率了解不多4。乳糜性腹水富含營養成分和免疫球蛋白，因此，積聚在腹膜腔中的乳糜性腹水不再是生物學上可利用的營養成分。乳糜性腹水會引起脫水、營養不良、電解質失平衡和免疫抑制狀態5。因此要求及時診斷與治療。在此我們針對難治性乳糜性腹水病例，回顧了診斷、保守治療和最新的治療選擇的最佳臨床實踐文獻。

2 | METHODS

A literature search was conducted using PubMedusing the key words 『chylous』, 『ascites』, 『cirrhosis』, 『pathophysiology』,『nutritional therapy』, 『paracentesis」 and 「TIPSS』. Only articles in English were included.

2 方法

在PubMed資料庫中應用下列關鍵詞進行了文獻檢索：乳糜、腹水、肝硬化、病理生理學、營養治療、腹腔穿刺術和TIPSS，檢索文獻僅包括英語文獻。

2.1 | Pathophysiology

The underlying cause of chylous ascites is the disruption of lymphatic flow. An interconnected network moves lymph—a complex mixture of proteins, lipids/chylomicra, and immune cells—from the body to the thoracic duct where it empties into the venous circulation at the union of the left internal jugular vein and the subclavian vein. Lymph is propelled through its circuit by the active, intrinsic contraction/relaxation of lymphatic vessels and passive, external compressive forces (skeletal muscles, central venous pressure variations, respiratory movement and pulsations of adjacent arteries) 6.

2.1 病理生理學

乳糜性腹水的潛在病因為淋巴管破裂。相互交通的網絡系統將淋巴液從軀體轉運到胸導管，經胸導管在鎖骨下靜脈和頸內靜脈交匯處進入靜脈循環系統，淋巴液的成分包括多種蛋白質的混合物、脂類、乳糜顆粒和免疫細胞。淋巴流動的動力包括淋巴循環的推動力、淋巴管固有的收縮與舒張力、主動外部壓迫力量（骨骼肌、中心靜脈壓力變化、呼吸運動鄰近動脈波動）6。

Approximately half of the lymph originates in the intestine. After hydrolysis and emulsification, fatty acids and monoglycerides are converted into triglycerides, which are subsequently absorbed into the lymphatic system as chylomicrons. Hence, the milky appearance of the lymph is attributed to its high triglyceride and free fatty acid content.

大約一半的淋巴液來源於腸道。水解乳化後，脂肪酸和甘油一酯轉化成甘油三酯，後者接下來以乳糜顆粒的形式吸收進入淋巴系統。淋巴液呈現乳糜樣原因為富含甘油三酯和游離脂肪酸成分。

Browse et al 7 proposed three pathophysiologic mechanisms by which chylous ascites occurs (Table 1): acquired lymphatic disruption,fibrosis of the lymphatic system and congenital causes. Acquired lymphatic disruption from surgery or trauma, leads to dilation of the retroperitoneal lymphatics with subsequent drainage of lymph into the abdomen through a lymphoperitoneal fistula. This dilation of lymphatic vessels also occurs as a result of the increased lymph production and elevated hepatic venous pressure seen in patients with cirrhosis and constrictive pericarditis. Cardiac conditions such as right heart failure and dilated cardiomyopathy lead to an increased lymphatic pressure from disrupted lymphatic drainage, thereby causing lymphstasis, lymphatic dilation and chylous ascites.

Browse 7等人提出發生乳糜性腹水的三個病理生理機制(Table 1)：獲得性淋巴管破裂、淋巴系統纖維化和先天因素。手術或創傷引起的獲得性淋巴管破裂導致腹膜後淋巴管擴張伴隨淋巴液通過淋巴腹膜瘻進入腹腔。淋巴管擴張也可以給發生在淋巴液產生過多和肝硬化病人和縮窄性心包炎導致的肝內門靜脈高壓症。心臟疾病（比如充血性心力衰竭、擴張性心肌病）可以引起淋巴破裂淋巴管壓力增加，進一步導致淋巴瘀滯、淋巴管擴張和乳糜性腹水。

The caval and hepatic venous hypertension precipitates an increment in the production of hepatic lymph. 8 The second proposed mechanism is lymph node fibrosis, most commonly due to malignancy causing lymph flow obstruction from the gut into the cysterna chyli, resulting in leakage from the dilated subserosal lymphatics into the peritoneum. The chronic effects of a persistently elevated lymphatic pressure may lead to collagen deposition at the basement membrane of the lymphatics, impairing the intestinal mucosal absorptive capacity. This process can cause protein-losing enteropathy with malabsorption,chronic steatorrhea and malnutrition. Last, congenital causes like congenital lymphangiectasia lead to exudation and leakage of lymph through a fistula intothe peritoneal cavity due to the absence of lymphatic valves.

腔靜脈和肝靜脈壓力增高使淋巴液生成增加8。第二個提出的機制是淋巴結纖維化，大多數通常因為惡性腫瘤引起的淋巴從腸道向中央乳糜池流動受阻，使擴張的漿膜下淋巴漏向腹腔。慢性持續性淋巴管壓力增加導致淋巴管膠原沉積，損害腸黏膜吸收能力。這一過程可以引起蛋白質丟失腸道疾病伴隨吸收不良、慢性脂肪瀉和營養不良。最後，像先天性淋巴管擴張等先天性病因可以導致淋巴滲出和淋巴瘻，由於淋巴管不存在瓣膜，淋巴液可以通過瘻進入腹腔中。

2.2 | Etiologies

Multiple etiologies have been described as causes of chylous ascites. Traditionally, the most common causes in western countries are abdominal malignancy and cirrhosis, accounting for two-thirds of atraumatic chylous ascites cases. 4 In developing and eastern countries, infections, such as tuberculosis and filariasis, are responsible for the majority of cases.However, Steinemann et al 3 performed a systematic review of 190 patients with chylous ascites where a total of 41 different etiologies were identified. The most common cause was lymphatic anomalies (32%), a condition more prevalent in the paediatric population. Malignant diseases were the second most frequent etiology(7%). Cirrhosis and mycobacterial infections were identified in 11% and 10% of the cases respectively.

2.2 病因學

大多數乳糜性腹水的病因都過文獻描述。傳統上來說，西方國家大多數病因為腹部惡性腫瘤和肝硬化，約佔非創傷性乳糜性腹水病例的三分之二4。在發展中國家和東方國家中，像結核和絲蟲病等感染是主要發病原因。然而，Steinemann等人的做的包括190例乳糜性腹水病人的系統回顧顯示，一共存在41種致病原因。最常見的病因為淋巴管異常(32%),一種兒童中常見疾病。惡性疾病為第二常見病因(7%)。肝硬化和分枝桿菌感染分別佔11% 和 10%。

2.2.1 | Malignancy

Malignancy causes chylous ascites through the invasion and disruption of the normal lymph flow. 7 The most commonma lignancies reported to cause chylous ascites are lymphomas, neuroendocrine tumors,sarcomas (Kaposi sarcoma) and leukemias (chronic lymphatic leukemias) in order of prevalence. 3 Among the group of the above mentioned malignancies, lymphoma accounts for at least one-third of the cases 3 Solid malignancies can also cause chylous ascites. 9,10

2.2.1惡性腫瘤

惡性腫瘤通過侵犯和幹擾正常淋巴液流動引起乳糜性腹水7。據報導最常見引起乳糜性腹水的惡性腫瘤按發病率順序依次為淋巴瘤、神經內分泌性腫瘤、肉瘤（Kaposi 氏肉瘤）和白血病（慢性淋巴細胞性白血病）3。在上面所提及的惡性腫瘤中，淋巴瘤至少佔所有疾病的三分之一3，實體惡性腫瘤也可以引起乳糜性腹水9,10。

2.2.2 | Cirrhosis

Only 0.5%–1% of all cases of cirrhosis-relatedascites are chylous in nature. 8,11 Runyon et al 12 analyzed a total of 901 ascites samples where eleven were chylous ascites; 10 of them were found to be secondary to cirrhosis and one due to malignancy. The underlying etiology is unclear but may be related to excessive hepatic and gastrointestinal lymph flow (up to 20L/day) secondary to portal hypertension, leading to spontaneous rupture of the serosal lymphatic channels. Although data is limited, transjugular intrahepaticportosystemic shunt has proven effective for cases of refractory chylous ascites.13,14 The decompression of the portal vein has shown to relieve lymphatic hypertension. 15

2.2.2 肝硬化

本質上，肝硬化相關腹水病例中僅有0.5%–1%為乳糜性8,11。Runyon等人12分析了901例腹水標本，其中11例為乳糜性腹水，此11例病人中10例繼發於肝硬化，1例為惡性腫瘤。乳糜性腹水潛在的發病原因尚不清楚，但是可能與繼發於門靜脈高壓引起的過多的淋巴流量(多於20 L/day)相關，因為門靜脈高壓可以導致漿膜淋巴管自發性破裂。儘管參考資料有限，已經證實TIPSS對難治性乳糜性腹水有效13,14。門靜脈減壓已被證明可以緩解淋巴高壓症15。

2.2.3 | Infection

Mycobacterium tuberculosis and filariasis represent the most common causes of chylous ascites in third world countries. 3 Granulomatous lymphadenitis is thought to be the central cause of lymphatic obstruction and development of chylous ascites in M. tuberculosis infection. It is important to also consider the diagnosis of tuberculosis in patients with alcohol abuse and malnutrition due to their relative immunocompromised state.Among patients with HIV, chylous ascites can occur in association with M.tuberculosis, Mycobacterium avium Complex and Kaposi sarcoma as a complication of immune reconstitution inflammatory syndrome. 16,17 Filariasis, an infection causedby the parasite Wuchereria bancrofti in third world countries, causes a severe inflammatory reaction in the lymphatics that results in lymphedema and chylous ascites.

2.2.3感染

分枝結核桿菌和絲蟲病代表了第三世界國家最常見的乳糜性腹水的原因3。肉芽腫性淋巴結炎被認為是在分枝結核桿菌感染患者淋巴管梗阻和乳糜性腹水主要原因。在酗酒和營養不良病人中，由於相對處於免疫抑制狀態，此時考慮到結核診斷也十分重要。在HIV病人中，由於免疫重建炎症症候群，乳糜性腹水可以和分枝桿菌、鳥型分支桿菌感染和Kaposi肉瘤同時發生16,17。第三世界國家中由 班氏吳策線蟲的寄生蟲感染，絲蟲病在淋巴系統中引起一種嚴重的炎症反應，可以導致淋巴水腫和乳糜性腹水。

2.2.4 | Congenital

The congenital causes of chylous ascites are more commonly seen in the paediatric population. Steinemann et al found lymphangiectasia as the most common cause of congenital anomaly in children(84%). 3 Lymphangiectasia or Waldmann’s disease is characterised by the presence of dilated lymph vessels due to the lack of valves in the submucosa of the small bowel resulting in leakage of lymph. Waldmann first described this disorder in 1961 as a cause of protein-losing enteropathy, lymphopenia,hypoalbuminemia and hypogammaglobulinemia. 18 Lymphatic anomalies account for only 8% of atraumatic cases of chylous ascites. 3 Other lymphatic anomalies exist, but constitute a smaller percentage of cases of congenital chylous ascites. For example, yellow-nail syndrome causes chylous ascites due to hypoplastic lymphatics and consists of the triad of lymphedema, pleural effusion and/or chylous ascites and yellow discoloration with nail dystrophy.19 The Klippel–Trenaunay syndrome is an inherited autosomal dominant disorder that is characterised by capillary and lymphatic hypoplastic malformations that causes chylous ascites and is associated with soft tissue and bony hypertrophy.20-22 Lymphangiomas arise from sequestration of lymphatic tissue, which fail to communicate with the lymphatic system, and can reside in the neck, intestine,pancreas or mesentery. 23,24

2.2.4先天性因素

乳糜性腹水的先天性因素在兒童中非常常見。Steinemann等人發現淋巴管擴張為兒童中先天性異常最常見的原因(84%)3。淋巴管擴張症和沃爾德曼病的特徵是繼發於小腸黏膜下淋巴管缺乏瓣膜導致的擴張，繼而引起淋巴瘻。Waldmann於1961年首次描述了作為腸道蛋白質丟失腸病、淋巴細胞減少症、低白蛋白血症和低伽馬球蛋白血症的原因的這種疾病18。淋巴管異常佔所有非創傷性乳糜性腹水發病原因的8%3。其他的淋巴管異常也同樣存在，但是僅構成先天性乳糜性腹水病因的一小部分。例如，黃甲症候群由於淋巴管發育不全引起乳糜性腹水，由淋巴水腫、胸腔積液和或乳糜性腹水三聯徵組成，以及指甲營養不良變黃19。Klippel–Trenaunay症候群是一種常染色體顯性遺傳病，其特徵為毛細血管和淋巴管發育不良進而引起乳糜性腹水，常與軟組織和骨性過度增生相關20-22。淋巴管瘤產生於淋巴組織形成分割，致使淋巴系統不能相互交通，病變可以發生在頸部、小腸、胰腺或腸繫膜中23,24。

2.2.5 | Inflammatory

Chylous ascites may occur due to radiotherapy,retroperitoneal fibrosis (Ormond’s disease), and autoimmune diseases like sarcoidosis, Behcet’s disease, Henoch–Schonlein purpura and systemic lupus erythematous.25,26 Radiation has the same pathophysiological mechanism as retroperitoneal fibrosis; both cause fibrosis and obstruction of the lymphatics in the small bowel and mesentery with the development of chylous ascites. 27-29 Sarcoidosis can produce chylous ascites by producing intrathoracic nodal fibrosis and lymphatic obstruction. Chylous ascites from systemic lupus erythematous is more often seen in the elderly who have an insidious onset of disease, which is less commonly associated with the classic rheumatologic manifestations. 30,31 It is proposed that the inflammation of the lymphatic vessels causes an increase in the endoluminal pressure disrupting permeability of the lymphatic walls and leading to extravasation of chyle. 32-34

2.2.5炎症

乳糜性腹水可以繼發於放射治療、腹膜後纖維化(Ormond’s disease)、自身免疫性疾病如肉瘤樣病變、Behcet’s病、Henoch–Schonlein紫癜和系統性紅斑狼瘡25,26。放射線與腹膜後纖維化具有同樣的病理生理學機制；兩者均可以引起纖維化和小腸和腸繫膜中淋巴管梗阻，形成乳糜性腹水27-29。肉瘤樣變可以通過胸腔內淋巴結纖維化和淋巴管梗阻形成乳糜性腹水。系統性紅斑狼瘡引起的乳糜性腹水在老年人中比較常見，這些老年人處於潛伏的疾病發病階段。這些疾病與典型的風溼病症狀存在較少相關性30,31。有人建議淋巴管炎症引起腔內壓力增高，破壞了淋巴管的通透性，導致淋巴液外滲32-34。

2.2.6 | Traumatic and post-operative

Any abdominal trauma that disrupts the lymphatic vessels can cause chylous ascites. 35 In children, battered child syndrome should be excluded in the presence of chylous ascites, as it accounts for 10% of cases in the paediatric population. 36,37 Chylous ascites can occur early(around 1 week) after abdominal surgery due to disruption of the lymphatic vessels or late (weeks to months) due to adhesions or extrinsic compression of lymphatic vessels. Chylous ascites has been reported after many surgical procedures, including thoracic or abdominal aneurysm repair, retroperitoneal lymphadenectomy catheter placement for peritoneal dialysis, inferior vena cava resection, vagotomy, Nissen fundoplication, gastric bypass, pancreaticoduodenectomy and gynecological surgery.

2.2.6創傷和手術後

任何破壞淋巴管的腹部創傷均可以引起乳糜性腹水35。在兒童中，受虐兒童症候群應該排除在乳糜性腹水之外，因為這種原因僅佔兒童人群病例的10% 36,37。乳糜性腹水可以發生在腹壁手術後早期（約一周左右）其原因為淋巴管破裂；也可以發生在晚期，原因為黏連和淋巴管的外部壓迫。據報導很多手術後可以發生乳糜性腹水，包括：胸部或腹部血管瘤修補手術、腹膜後淋巴結切除、腹膜透析置管術、下腔靜脈切除術、迷走神經切除術、胃底摺疊術和婦科手術。

Liver and kidney transplants have also been associated with post-operative chylous ascites. 38-40 Yilmaz et al 41 reported a post-operative incidence of chylous ascites of 4.6% in a total of 516 liver transplant cases over a 9-year period. Low albumin, the presence of ascites before transplantation, and the use of LigaSure vessel sealing system instead of conventional suture were recognised as risk factors for developing chylous ascites.

肝臟和腎臟移植術也與術後乳糜性腹水相關38-40。Yilmaz等人報導了9年間516例肝移植病人手術後乳糜性腹水發生率為4.6%。移植手術前低蛋白血症和存在腹水，應用LigaSure血管封閉系統而不是常規結紮被認為是形成乳糜性腹水的危險因素。

2.2.7 | Other causes

Other less common causes include cardiac conditions, nephrotic syndrome, pancreatitis, coeliac sprue, Whipple’s disease and retractile mesenteritis. Cardiac disease with increased right-venous pressures can lead to increased hepatic lymph production; causing impaired drainage,chyle stasis, lymphatic dilation and ultimately chylous ascites. 48-50 These include right heart failure, dilated cardiomyopathy and constrictive pericarditis. Chen et al, reported a case of chylous ascites secondary to cardiac amyloidosis, where the contributing factor was thought to be increased left subclavian venous pressure. Both acute necrotizing pancreatitis and chronic pancreatitis are associated with chylous ascites; the underlying mechanism remains unknown but is thought to be due to direct compression of lymphatic channels.52,53

2.2.7其他病因

其他不常見的發病原因包括心臟疾病、腎病症候群、胰腺炎、coeliac sprue（見備註）、Whipple’s病和 縮窄性腸繫膜炎42-47。右心壓力增高等心臟疾病可以導致肝臟淋巴產生增多；引起引流受阻乳糜瘀滯、淋巴管擴張，最終形成乳糜性腹水48-50。這類心臟疾病包括：右心衰竭、擴張性心肌病、限制性心包炎。Chen等人51報導了一例繼發於心臟澱粉樣變性引起的乳糜性腹水，其促發因素被認為是左鎖骨下靜脈壓力增加。急性壞死性胰腺炎和慢性胰腺炎均與乳糜性腹水相關；其潛在機制尚未得知，有人認為是淋巴管直接受壓所致52,53。

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劉為民

清遠市第二人民醫院普外科 副主任醫師

外科學博士

美國疝學會中國會員

廣東省中西醫結合微創外科分會常委

廣東省肝病學會人工肝分會常委

廣東省肝病學會微創分會會員

廣東省微創工作委員會委員

廣東省肝病學會微創分會會員

廣東省外科學會胰腺外科分會委員

廣東省外科學會腹壁疝外科分會委員

發表論文19篇 其中SCI三篇。

董志勇

廣州暨南大學附屬第一醫院，胃腸疝外科副主任醫師，暨南大學副教授

醫學博士，

美國西北大學研究學者

國際循證醫學Cochrane Collaboration 成員

海峽兩岸醫藥衛生交流協會

消化道外科專委會委員

《中國普通外科雜誌》青年編委。

師從國內微創外科名醫王存川教授。主要從事胃腸腹壁疝以及減重代謝外科臨床研究。博士期間在王存川教授指導下與美國西北大學和澳大利亞外科學者合作發表SCI論文8篇。

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