Ascites

Japanese: 腹水

Definition/Concept: A small amount (20-50 mL) of serous fluid exists in the abdominal cavity to reduce friction between internal organs and facilitate smooth digestive tract movement, but ascites refers to fluid that accumulates in the abdominal cavity in excess of physiological limits. It is broadly divided into non-inflammatory transudate and tumorous or inflammatory exudate (or exudate).
Pathophysiology: Leakage occurs when there is no lesion in the peritoneum, and is caused by increased portal vein pressure or decreased plasma oncotic pressure, while exudate is a reaction caused by stimuli such as bacterial infection, inflammation, or infiltration of cancer cells in the peritoneal cavity.
1) Leaked fluid:
a) Hepatic ascites: The most common disease causing hepatic ascites is cirrhosis, and its mechanism of manifestation is multifactorial and complex. In cirrhotic livers, fibrosis and regenerative nodule formation compress the hepatic venous branches and intrahepatic portal vein branches, increasing intrasinusoidal hydrostatic pressure and portal vein pressure, which leads to increased hepatic lymphogenesis and increased permeability of the peripheral intraperitoneal portal vein branches. This, combined with a decrease in plasma colloid osmotic pressure due to hypoalbuminemia, is thought to result in the manifestation of ascites. Meanwhile, cardiac output and circulating blood volume increase in cirrhosis, but this is due to a decrease in peripheral vascular resistance and arteriovenous anastomoses in the skin, muscles, and various organs, and most of the blood is lost to the anastomoses, resulting in a decrease in effective circulating blood volume. A decrease in effective circulating blood volume and an increase in hepatic sinusoidal pressure stimulate various neurologic and humoral factors (the sympathetic nervous system, the renin-angiotensin-aldosterone system, endothelin, ADH, etc.), which in the kidneys causes a decrease in renal blood flow, abnormal intrarenal blood flow distribution, and increased reabsorption of sodium and water in the renal tubules. Factors involved in peripheral vasodilation include estrogen, vasoactive intestinal polypeptide (VIP), vasodilatory prostaglandins, substance P, and nitric oxide (NO). The significance of intestinal-derived endotoxin, a common stimulating factor for the sympathetic nervous system, endothelin, NO, etc., is also being reevaluated.
b) Renal ascites: In nephrotic syndrome, ascites can occur along with generalized edema due to a decrease in colloid oncotic pressure caused by hypoalbuminemia, and this occurs frequently in pediatric patients. In adults, ascites is caused not only by a decrease in colloid oncotic pressure, but also by increased hepatic sinusoidal pressure due to concomitant liver disease or congestive heart failure. The mechanism of ascites associated with end-stage renal failure is thought to be a combination of factors, including hepatic congestion due to chronic water load associated with dialysis therapy, increased peritoneal permeability, impaired peritoneal lymphatic perfusion, and hypoalbuminemia.
c) Cardiac ascites: In congestive heart failure, hepatic sinusoidal pressure increases, and portal vein pressure increases. Furthermore, effective circulating blood volume decreases due to a decrease in cardiac output, stimulating the sympathetic nervous system, renin-angiotensin-aldosterone system, and vasopressin, which increases reabsorption of sodium and water in the kidney.
d) Ascites due to hypothyroidism: Possible causes include protein leakage due to increased capillary permeability and impaired lymphatic drainage.
2) Exudate:
a) Malignant tumor ascites: The mechanisms underlying the accumulation of malignant tumor ascites include increased permeability of tumor blood vessels and impaired absorption of peritoneal lymphatic vessels. Tumor blood vessels proliferate markedly in the parietal peritoneum, and the degree of angiogenesis correlates with the amount of ascites. Furthermore, there is evidence that glycoproteins secreted by tumors are involved in increased vascular permeability, and that vascular endothelial growth factor (VEGF), vascular permeability factor (VPF), matrix metalloproteinases (MMPs), etc. are involved in tumor angiogenesis.
Direct tumor invasion into the diaphragmatic lymphatics impedes lymphatic perfusion, and obstruction of the thoracic duct results in chylous ascites.
b) Inflammatory ascites: In infectious peritonitis, inflammatory cells such as neutrophils are mobilized against the causative bacteria, and inflammatory mediators such as cytokines, prostaglandins, kinins, and histamines are produced in large quantities, while vascular permeability increases and exudate accumulates. Pancreatic ascites is caused by the rupture of pancreatic pseudocysts into the peritoneal cavity and leakage of pancreatic juice from the pancreatic duct, and when ascites amylase levels are high, this stimulates the outflow of albumin into the ascites.
Differential diagnosis
1) Proof of presence of ascites:
When ascites accumulates, patients complain of abdominal distension, and their abdominal circumference and weight increase. Physical examination findings include flank distension, dull areas in the flank, dullness conversion phenomenon, and evidence of wave motion, but it is difficult to confirm small amounts of ascites. Ultrasound examination can confirm echo-free space with as little as 100 mL of ascites, and CT examination can obtain a three-dimensional view of the accumulation of small amounts of ascites. When the patient is in the supine position, small amounts of ascites tend to accumulate in the right inferior hepatic fossa (Morrison's pouch) and perisplenic space in the upper abdomen, and in Douglas's pouch, and especially the right paracolic groove, in the lower abdomen.
2) Differentiation of ascites by puncture:
Figure 2-21-1 shows a flowchart for diagnosing the causative disease of ascites obtained by test paracentesis. It is possible to estimate the causative disease from the appearance of ascites alone; if it is purulent, it is likely to be purulent peritonitis or tuberculous peritonitis, and if it is bloody, it is often a malignant tumor. If it is chylous ascites, it is likely to be a malignant tumor or inflammation causing congestion or destruction of the lymphatic system. Among malignant tumors, gastric cancer, pancreatic cancer, and malignant lymphoma are common, and tuberculous chylous ascites is rarely seen these days. Bile ascites is seen in bile peritonitis, and pale gray-yellow jelly-like viscous ascites is characteristic of pseudomyxoma peritonei. Ascites has been defined as a transudate if its protein concentration is 2.5 g/dL or less, and an exudate if it is 4.0 g/dL or more, but there are cases where it is difficult to determine the correct diagnosis, and a useful differential diagnosis method is that if the albumin concentration difference between serum and ascites is 1.1 g/dL or more, it is a transudate, and if it is less than that, it is an exudate. This serum ascites albumin gradient reflects the hepatic sinusoidal pressure and hepatic venous pressure gradient, so if the serum ascites albumin gradient is 1.1 g/dL or higher, it is considered to be portal hypertension, and if it is less than that, it is considered to be non-portal hypertension.
3) Portal hypertension ascites:
Portal hypertensive ascites is further divided into cases where ascites protein is less than 2.5 g/dL and cases where it is 2.5 g/dL or more. Cases where it is less than 2.5 g/dL indicate that protein permeability through the sinusoids is hindered due to capillary formation of the sinusoids caused by fibrosis, and may be due to liver cirrhosis or late-stage Budd-Chiari syndrome. Cases where it is 2.5 g/dL or more indicate that the structure of the sinusoids is almost normal, and may be due to cardiac ascites, hepatic vein/sinusoidal obstruction, early Budd-Chiari syndrome, end-stage renal failure, or ascites associated with hypothyroidism. Particular attention should be paid to the complication of spontaneous bacterial peritonitis (SBP) in ascites caused by liver cirrhosis. Symptoms such as fever, abdominal pain, abdominal tenderness, and Blumberg's sign, which suggest this disease, are rare, so ascites neutrophil count and bacterial culture are essential. For bacterial culture, the method of directly placing ascites in a culture bottle at the bedside has high sensitivity. Since it takes one or two days to prove the presence of bacteria in the ascites, if there is no surgical intraperitoneal infection and the ascites neutrophil count is 250/μL or higher, early treatment is initiated for SBP.
4) Non-portal hypertension ascites:
It is important to differentiate between malignant tumor-related ascites and inflammatory ascites. Ascites bacterial culture test, cytology, and serum and ascites tumor marker measurements are performed, and if necessary, ultrasound, CT, MRI, and other imaging tests, as well as gastrointestinal X-rays and endoscopy are performed. The most common cause of carcinomatous peritonitis is peritoneal dissemination of carcinomas of intraperitoneal organs such as the stomach, pancreas, liver, colon, ovaries, and uterus, but ascites can also be caused by blood tumors such as adult T-cell leukemia. As the positivity rate for Mycobacterium tuberculosis in ascites smears and cultures is low, as is the positivity rate for PCR, tuberculous peritonitis must be diagnosed comprehensively, including imaging tests. Laparoscopy is sometimes useful, and yellowish-white nodules the size of a millet or red bean are seen diffusely on the peritoneum. These nodules are sampled and the presence of granulomas accompanied by caseous necrosis is confirmed by microscopic examination, nucleic acid amplification test, or culture. Increases in ascites amylase activity are seen in acute pancreatitis, chronic pancreatic disorders (pseudocysts, pancreatic duct rupture, pancreatic duct stenosis), and also in peritonitis due to peritoneal metastasis of malignant tumors and gastrointestinal or biliary necrosis. However, in cases where ascites amylase activity and protein content are significantly high, pancreatic ascites should be suspected first, and imaging diagnostics should be used to make a definitive diagnosis. Cytology is essential to distinguish between tumor-related ascites and cirrhosis-related ascites, and tumor-related ascites is suggested by the following: ascites LDH/serum LDH ratio > 1.0, ascites CEA > 10 ng/mL, fibronectin > 75 μg/mL, cholesterol > 48 mg/dL, and triglycerides > 75 mg/dL. In nephrotic syndrome, serum albumin is low due to protein leakage into the urine, and although ascites is a leaked fluid, the serum ascites albumin difference is less than 1.1 g/dL.
5) Bloody ascites:
Bloody ascites is significant when the number of red blood cells in the ascites is ¹⁰⁴ /mL or more, and is seen in particular with cancerous peritonitis caused by liver cancer, ovarian, uterine, stomach, intestinal and pancreatic cancer, as well as with tuberculous peritonitis and acute pancreatitis. Approximately one-third of the underlying diseases causing bloody ascites are liver cancer, and in addition to liver cancer rupture, causes include hepatomegaly, complete obstruction of the portal vein trunk due to tumor embolism, and direct infiltration of the diaphragm by liver cancer. If bloody ascites is observed along with sudden shock, liver cancer, ectopic pregnancy and ruptured aneurysm should be considered. [Fukui Hiroshi]

Figure 2-21-1
Differential diagnosis of ascites

Figure 2-21-1

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

定義・概念
　腹腔内には内臓相互の摩擦を少なくし，消化管の運動を円滑にするために少量（20〜50 mL）の漿液が存在しているが，腹水とは生理的限界をこえて腹腔内に貯留した液体のことをいう．非炎症性の漏出液（transudate）と腫瘍性ないし炎症性の滲出液（または浸出液，exudate）に大別される．
病態生理
　漏出液は腹膜に病変がなく，門脈圧の亢進，血漿膠質浸透圧の低下などが根底にあるもので，滲出液は腹腔内の細菌感染，炎症や癌細胞の浸潤が刺激となって起こる反応である．
1）漏出液：
　a）肝性腹水：肝性腹水の代表疾患は肝硬変で，その発現機序は多因子的で複雑である．硬変肝では線維増生，再生結節形成のために肝静脈枝，肝内門脈枝が圧迫され，類洞内静水圧，門脈圧が上昇するが，これらは肝リンパ生成の亢進と腹腔内門脈末梢枝の透過性亢進を導く．これに，低アルブミン血症による血漿膠質浸透圧の低下が加わり，腹水が発現すると考えられている．一方，肝硬変では心拍出量，循環血液量は増加しているが，これは末梢血管抵抗の低下および皮膚，筋肉，諸臓器における動静脈吻合のためであって，血液の多くは吻合部に奪われ有効循環血液量はむしろ減少している．有効循環血液量の減少と肝類洞圧の上昇は種々の神経性・体液性因子（交感神経系，レニン-アンジオテンシン-アルドステロン系，エンドセリン，ADHなど）を刺激し，腎では腎血流量の低下，腎内血流分布異常とともに尿細管でのNa・水再吸収亢進が起こる．末梢血管拡張にかかわる因子としてはエストロゲン，血管作動性腸ポリペプチド（VIP），血管拡張性プロスタグランジン，サブスタンスP，一酸化窒素（NO）などがある．また，交感神経系，エンドセリン，NOなどに共通する刺激因子として腸管由来のエンドトキシンの意義が見直されてきている．
　b）腎性腹水：ネフローゼ症候群では低アルブミン血症による膠質浸透圧の低下に伴い，全身性浮腫とともに腹水をきたすことがあり，小児患者にその頻度が高い．成人では膠質浸透圧の低下だけではなく，合併する肝疾患やうっ血性心不全による肝類洞圧の上昇が腹水発生の要因となる．末期腎不全に伴う腹水の発現機序としては透析療法に伴う慢性水負荷に伴う肝うっ血，腹膜透過性亢進，腹膜リンパ管灌流障害，低アルブミン血症などの複合要因が考えられる．
　ｃ）心臓性腹水：うっ血性心不全では肝類洞圧が上昇し，門脈圧が亢進する．さらに，心拍出量の低下のために有効循環血液量が減少し，交感神経系，レニン-アンジオテンシン-アルドステロン系，バソプレシンが刺激されて，腎でのNa・水の再吸収が亢進する．
　d）甲状腺機能低下症による腹水：毛細血管の透過性亢進による蛋白漏出，リンパ導出障害などが考えられている．
2）滲出液：
　a）悪性腫瘍性腹水：悪性腫瘍性腹水の貯留機序としては，腫瘍血管の透過性亢進と腹膜リンパ管の吸収障害が重要である．壁側腹膜には腫瘍血管が著明に増生し，血管新生の程度は腹水量に相関する．また，腫瘍が分泌する糖蛋白が血管の透過性亢進にかかわり，血管内皮細胞増殖因子（VEGF），血管透過性因子（VPF），マトリックスメタロプロテイナーゼ（MMP）などが腫瘍血管新生にかかわるとの成績がある．
　横隔膜リンパ管への腫瘍の直接浸潤はリンパ灌流を妨げ，胸管が閉塞したときは乳び腹水となる．
　b）炎症性腹水：感染性腹膜炎では起因菌に対して好中球などの炎症細胞が動員され，サイトカイン，プロスタグランジン，キニン，ヒスタミンなどの炎症性メディエーターが大量に産生されるとともに，血管透過性が亢進して滲出液が貯留する．膵性腹水は膵仮性囊胞の腹腔内破裂，膵管からの膵液漏などが原因となり，腹水アミラーゼが高値となるとこれが刺激となりアルブミンの腹水中への流出を招く．
鑑別診断
1）腹水の存在証明：
腹水貯留時には患者は腹部膨満感を訴え，腹囲，体重が増加する．身体所見としては側腹部の膨隆，側腹部の濁音界，濁音変換現象，波動の証明などがあるが，少量腹水の確認は困難である．超音波検査ではわずか100 mL の腹水でもecho-free spaceとして確認でき，CT検査では少量腹水の貯留状態を立体的に把握できる．仰臥位をとった場合に微量腹水は，上腹部では右肝下部窩（Morrison’s pouch）や脾周囲腔に，下腹部ではDouglas窩，特に右傍結腸溝に貯留しやすい．
2）穿刺腹水の鑑別：
試験穿刺により得た腹水の原因疾患診断のフローチャートを図2-21-1に示す．腹水の外観からでも原因疾患の推定は可能であり，膿性であれば化膿性腹膜炎や結核性腹膜炎が考えられ，血性であれば悪性腫瘍であることが多い．乳び腹水であれば，リンパ管系のうっ滞や破壊をきたす悪性腫瘍や炎症が考えられる．悪性腫瘍のなかでは胃癌，膵癌，悪性リンパ腫などの頻度が高く，結核性の乳び腹水は最近ではほとんどみられない．胆汁性腹水は胆汁性腹膜炎でみられ，淡灰黄色ゼリー状の粘性腹水は腹膜偽粘液腫に特徴的である．　腹水は，その蛋白濃度によって2.5 g/dL以下ならば漏出液，4.0 g/dL以上ならば滲出液と定義されてきたが，判断に迷う例もあり，血清と腹水のアルブミン濃度差が1.1 g/dL以上であれば漏出液，それ未満であれば滲出液という鑑別法が有用である．この血清腹水アルブミン較差は肝類洞圧，肝静脈圧較差を反映するため，血清腹水アルブミン較差が1.1 g/dL以上なら門脈圧亢進症性，それ未満であれば非門脈圧亢進症性と考える．
3）門脈圧亢進症性腹水：
門脈圧亢進症性腹水はさらに腹水蛋白が2.5 g/dL未満の例と2.5 g/dL以上の例に大別される．2.5 g/dL未満の例は線維増生による肝類洞の毛細血管化のために類洞の蛋白透過が妨げられた状態で，肝硬変や晩期のBudd-Chiari症候群などが考えられる．2.5 g/dL以上の例は肝類洞の構造がほぼ正常であることを意味し，心性腹水，肝静脈・類洞閉塞症，早期のBudd-Chiari症候群，末期腎不全，甲状腺機能低下症に伴う腹水などが考えられる．　肝硬変腹水で特に注意しなければならないのは特発性細菌性腹膜炎（spontaneous bacterial peritonitis： SBP）の合併である．本症を示唆する発熱，腹痛，腹部圧痛，Blumberg徴候などの頻度は低く，腹水好中球数算定と細菌培養は必須である．細菌培養ではベッドサイドで腹水をカルチャーボトルに直接入れる方法の感度が高い．腹水中の細菌の証明には一両日を要するため，外科的腹腔内感染がなく，腹水好中球数250/μL以上であればSBPとして早期治療に踏み切る．
4）非門脈圧亢進症性腹水：
悪性腫瘍性腹水と炎症性腹水の鑑別が重要である．腹水細菌培養検査，細胞診，血清・腹水腫瘍マーカーの測定を行い，必要に応じて超音波検査，CT，MRIなどの画像検査，消化管X線・内視鏡検査を加える．癌性腹膜炎の原因としては胃，膵，肝，大腸，卵巣，子宮などの腹腔内臓器の癌腫の腹膜播種の頻度が高いが，成人T細胞白血病のような血液腫瘍でも腹水をきたすことがある．腹水の塗抹・培養での結核菌陽性率は低く，PCR法での陽性率も低いことから，結核性腹膜炎については画像検査も合わせて総合的に判断する．腹腔鏡検査がときに有用であり，腹膜上に粟粒大ないし小豆大の黄白色結節をびまん性にみる．この小結節を採取し乾酪壊死を伴う肉芽腫や，鏡検あるいは核酸増幅試験や培養により結核菌の存在を証明する．　腹水アミラーゼ活性の上昇は，急性膵炎，慢性膵障害（偽囊胞，膵管破綻，膵管狭窄）などのほか，悪性腫瘍の腹膜転移や消化管，胆道壊死による腹膜炎でも認められるが，腹水アミラーゼ活性と蛋白量が著しく高い例では膵性腹水をまず疑い，画像診断を駆使して確定診断に努める．　腫瘍性腹水と肝硬変腹水を鑑別するうえで細胞診は欠かせないが，腹水中LDH/血清LDH比＞1.0，腹水中CEA＞10 ng/mL，フイブロネクチン＞75 μg/mL，コレステロール＞48 mg/dL，中性脂肪＞75 mg/dLは腫瘍性腹水を示唆する．　ネフローゼ症候群では尿中への蛋白漏出のために血清アルブミンが低値となり，腹水は漏出液であるが血清腹水アルブミン較差が1.1 g/dL未満となる．
5）血性腹水：
血性腹水は，腹水中赤血球数が10⁴個/mL以上のときに意味があり，特に肝癌，卵巣･子宮･胃･腸および膵癌などによる癌性腹膜炎のほか，結核性腹膜炎および急性膵炎時にもみられる．血性腹水の原疾患の約1/3は肝癌であり，肝癌破裂に加えて，肝腫大，腫瘍塞栓による門脈本幹の完全閉塞および肝癌の横隔膜への直接浸潤が原因となる．なお，突然のショックとともに血性腹水が認められた場合，肝癌，子宮外妊娠および動脈瘤の破裂を考える．［福井　博］

図2-21-1
腹水の鑑別診断">

図2-21-1

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