Pleural effusion

Japanese: 胸水

Definition/Concept Pleural fluid is a fluid present in the pleural cavity, present at approximately 0.26 mL/kg (10-20 mL). The pleura is a serous membrane that covers the surface of the lungs and the inner surface of the chest wall; the former is called the visceral pleura and the latter the parietal pleura. The two pleural membranes are continuous and everted at the hilum to form the pleural cavity (thoracic cavity). The presence of pleural fluid acts as a lubricant that supports the smooth sliding of the lungs and chest wall during breathing. The pleural surface is covered by a single layer of mesothelial cells. Mesothelial cells are flat cells 1-4 μm thick that have microvilli and perform a variety of functions, including differentiation into macrophages, production of extracellular matrix and cytokines, induction of fibroblasts, and regulation of the coagulation-fibrinolysis system.
Pathophysiology of pleural fluid production and absorption
1) Pleural effusion under physiological conditions:
Under physiological conditions, pleural fluid is produced in the capillaries of the parietal pleura and absorbed by the lymphatic system of the parietal pleura. As shown by Starling's law, the production of pleural fluid is determined by the balance between the hydrostatic pressure difference and the colloid osmotic pressure difference between the capillaries and the pleural cavity (Figure 2-27-1).
Q _f = movement of water into the pleural cavity, L _p = filtration coefficient/hydraulic conductivity of the membrane, A = surface area of the membrane, _P _cap = hydrostatic pressure of the capillaries, P _p _l = hydrostatic pressure of the pleura, σ _d = force restricting the passage of macromolecules through the membrane, π _cap = oncotic pressure of _the capillaries, π _p _l = oncotic pressure of the pleura.
Pleural fluid under physiological conditions has a similar basic composition to serum, except for its low protein concentration. Therefore, the oncotic pressure of pleural fluid is lower than that in the capillaries, and intrathoracic pressure is negative (there is a difference of about 7 cm _H2O between the apex and base of the lung due to gravity and lung strain), so water moves into the pleural cavity through the parietal pleura. On the other hand, the hydrostatic pressure of the capillaries of the visceral pleura is about 6 cm _H2O less than that of the parietal pleura. This is because the capillaries of the visceral pleura drain into the pulmonary veins. This is the only element that differs between the visceral and parietal sides, and because of this difference, the pressure difference through the visceral pleura is zero, so it is thought that there is no net water movement through the visceral pleura. It is also thought that _Lp (filtration coefficient of the membrane/hydraulic conductivity) of the visceral pleura is actually smaller than _Lp of the parietal pleura. This is because the visceral pleura is thicker than the parietal pleura, and blood flow is distributed further away from the visceral pleura than from the parietal pleura. Water movement through the pleura varies from place to place and is also affected by breathing. For example, the parietal pleura adjacent to the ribs produces more water than the parietal pleura between the ribs, and produces more water as the respiratory rate increases.
Pleural fluid is absorbed through lymphatic stoma (small holes with a diameter of 2-10 μm that open into the pleural cavity) in the parietal pleura. There are no lymphatic stoma in the visceral pleura. Proteins, water, and cells in the pleural fluid are cleared from here via lymphatic vessels.
2) Conditions that cause pleural effusion:
The drainage capacity of the lymphatic system in the parietal pleura varies greatly from person to person, ranging from 20 to 500 mL/hour, and is generally thought to have a clearance capacity approximately 20 times the rate of pleural fluid production. Meanwhile, the pulmonary interstitium is estimated to have a lymphatic flow of 20 mL/hour. If the balance between pleural fluid production and absorption is disrupted for some reason, pleural fluid will accumulate (Table 2-27-1). Increased hydrostatic pressure, decreased colloidal osmotic pressure (decreased serum protein or increased protein concentration in pleural fluid), and increased capillary permeability lead to increased production, while increased systemic venous pressure and lymphatic obstruction lead to decreased absorption.
In many pathological conditions, pleural effusion is thought to originate from the pulmonary interstitium. In both cases of increased permeability pulmonary edema and increased pulmonary vascular pressure pulmonary edema, edema occurs in the interstitium and then fluid flows into the pleural cavity. In other words, it is thought that pleural effusion occurs when the amount of water in the pulmonary extravascular interstitium rises above a certain threshold. Recently, it has been thought that hypoproteinemia alone is not a cause of pleural effusion.
diagnosis
1) Existence diagnosis:
Pleural effusion is visualized on a chest X-ray as an area of reduced radiolucency. Because pleural fluid is fluid, it moves to lower areas within the thoracic cavity under the influence of gravity. On an upright chest X-ray, blunting of the costophrenic angle (frontal view), blunting of the costovertebral angle (lateral view), and movement of the image of pleural effusion in the decubitas view are useful for diagnosis (Figure 2-27-2). Ultrasound examination is useful for diagnosing small amounts of pleural effusion. It is difficult to diagnose based on physical findings unless a certain amount of pleural effusion has accumulated, but on percussion the area of pleural effusion will have a dull sound and a tympany above it. On auscultation, reduced breath sounds and fricatives will be present in the area of pleural effusion.
2) Differentiation between transudative and exudative pleural effusion:
Pleural fluid is collected by thoracentesis, and the cause is diagnosed based on its characteristics and biochemical test results. If the amount of pleural fluid is small, it can be collected under ultrasound guidance. First, protein and LDH in the pleural fluid and serum are measured to determine whether it is a transudative or exudative pleural effusion (Figure 2-27-3). The light diagnostic criteria are: 1) pleural fluid/serum protein ratio > 0.5, 2) pleural fluid/serum LDH ratio > 0.6, and 3) pleural fluid LDH > 2/3 of the upper serum limit. If none of these criteria are met, the patient is diagnosed with transdative pleural effusion. If any one of these criteria is met, the patient may have exudative pleural effusion. Transudative pleural effusion is not caused by inflammation, and the most common causes are heart failure and hypoproteinemia (liver cirrhosis and nephrotic syndrome). It is usually bilateral, but unilateral pleural effusion is more common on the right side. On the other hand, exudative pleural effusion is caused by inflammation and has a variety of causative diseases (Table 2-27-2).
3) Differentiation of causes of exudative pleural effusion:
a) Appearance of pleural fluid: By evaluating the appearance, it is possible to diagnose empyema, hemothorax, chylothorax, etc.
i) Empyema: In cases of pleurisy caused by bacterial infection, the pleural fluid appears purulent to the naked eye. Empyema caused by anaerobic bacteria has a putrid odor. ii) Hemothorax: In cases of pleurisy caused by malignant tumors, pulmonary infarction, or other inflammation, bloody pleural fluid is observed. Hemothorax is defined as a condition in which the hematocrit value in the pleural fluid is 50% or more of that in peripheral blood. It is most commonly caused by trauma, but can also occur when blood vessels in the parietal pleural adhesions are ruptured during spontaneous pneumothorax. iii) Chylothorax: Chyle refers to milk-like lymphatic fluid, which is rich in fat components (chylomicrons) absorbed from the intestine and returns to the thoracic duct. Chylothorax is a condition in which chylic fluid accumulates in the thoracic cavity for some reason. It is often caused by thoracic duct damage following surgery for esophageal or lung cancer. The most common underlying disease is malignant lymphoma. In addition, lymphangioleiomyomatosis is caused by lymphatic dysfunction and blockage due to the proliferation of LAM cells.
b) Cell count and differential: A predominance of neutrophils suggests acute inflammation or bacterial infection. Tuberculous pleurisy is characterized by pleural effusions that are predominantly lymphocytes, but in the acute phase, neutrophils predominate. A predominance of lymphocytes generally suggests chronic inflammation, such as malignant pleurisy or pleurisy associated with collagen disease. An increase in eosinophils may indicate Churg-Strauss syndrome, drug-induced pleurisy, or parasitic diseases. An increase in eosinophils can also be seen with frequent thoracentesis or the introduction of air into the pleural cavity.
c) Glucose: Pleural fluid glucose should be routinely measured; a glucose level <60 mg/dL is indicative of one of four likely conditions: parapneumonic pleural effusion, malignant pleurisy, tuberculous pleurisy, or rheumatoid arthritis.
d) Cytology: This is essential for diagnosing malignant pleurisy. If the number of tumor cells in the pleural fluid is small, the accuracy rate decreases. The accuracy rate improves if cellular components from a large amount of pleural fluid are centrifuged to create a cell block. The accuracy rate is often low for lymphoma.
e) Bacteriological tests: If an infectious disease is suspected, Gram staining of smears and culture (aerobic, anaerobic) are performed. If tuberculous pleurisy is suspected, acid-fast bacillus tests (smear, culture, genetic testing) are performed, although the positive rate is not high.
f) Biochemical tests:
i) ADA (adenosine deaminase): useful in diagnosing tuberculous pleurisy. If ADA is >45-60 U/L, there is a high possibility of tuberculous pleurisy. ii) Amylase: P-type amylase increases in pleural effusions associated with pancreatitis, while S-type amylase increases in pleural effusions associated with esophageal rupture due to contamination with saliva. Amylase-producing tumors are sometimes encountered in malignant tumors, but S-type amylase is often the cause. iii) Tumor markers: Tumor markers in pleural effusion increase in carcinomatous pleurisy. Values six times higher than those in serum are considered to have high diagnostic significance. iv) Hyaluronic acid: If it is >100 μg/mL, it may be malignant mesothelioma. However, it does not increase in cases other than epithelial types. v) Neopterin: In cases of uremic pleural effusion, it shows high values of >200 nmol/L.
4) Pleural biopsy:
Pleural biopsy may be useful for confirming the diagnosis of tuberculous pleurisy or malignant mesothelioma. However, because it is a blind biopsy, the diagnostic rate is lower than that of thoracoscopic biopsy, which allows the lesion to be visually identified and biopsied. Recently, it has become less common.
5) Thoracoscopic biopsy:
This is a test method with a high diagnostic rate because the lesions can be visually identified and biopsied. Although it is highly invasive, it is becoming more common because it can be performed under local anesthesia. [Kuniaki Seyama]

Table 2-27-1
Causative diseases based on the mechanism of pleural effusion

Table 2-27-1

Table 2-27-2
Differential diagnosis of pleural effusion ">

Table 2-27-2

Figure 2-27-1
Physiological mechanism of pleural fluid production ">

Figure 2-27-1

Figure 2-27-3
Differentiation procedure between transudative and exudative pleural effusions ">

Figure 2-27-3

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

Japanese:

定義・概念
　胸水は，胸腔に存在する液体で，0.26 mL/kg程度（10～20 mL）存在している．胸膜は肺表面と胸壁の内面を覆う漿膜で，前者を臓側胸膜，後者を壁側胸膜とよぶ．2枚の胸膜は連続しており肺門部で翻転して胸膜腔（胸腔）をつくる．胸水の存在は呼吸に伴う肺と胸壁の滑らかな滑走を支える潤滑油の役割を果たしている．胸膜表面は一層の中皮細胞で覆われる．中皮細胞は微絨毛を有する厚さ1～4 μmの扁平な細胞で，マクロファージへの分化，細胞外マトリックスやサイトカインの産生，線維芽細胞の誘導，凝固線溶系の調節，などの多彩な機能を発揮する．
胸水の産生と吸収の病態生理
1）生理的状態における胸水：
生理的状態では，胸水は壁側胸膜の毛細血管から産生され，壁側胸膜のリンパ系から吸収される．胸水の産生は，Starlingの法則に示されるように，毛細血管と胸腔との静水圧較差と膠質浸透圧較差のバランスにより規定されている（図2-27-1）．
Q_f ＝胸腔への水の動き，L_p＝膜の濾過係数・水硬伝導率，A＝膜の表面積，P_ca_p＝毛細血管の静水圧，P_p_l＝胸膜の静水圧，σ_d＝膜の巨大分子通過を制限する力，π_ca_p＝毛細血管の膠質浸透圧，π_p_l＝胸膜の膠質浸透圧．
　生理的状態での胸水は，蛋白濃度が低いことを除けば基本的組成は血清と類似している．したがって胸腔液の膠質浸透圧は毛細血管内のそれより低く，また，胸腔内圧は陰圧であるため（重力や肺のひずみの影響で肺尖部と肺底部で約7 cm H₂Oの差がある），壁側胸膜を介した胸腔への水分の動きが生じる．一方，臓側胸膜の毛細血管の静水圧は，壁側胸膜のそれよりも約6 cm H₂O少ない．これは，臓側胸膜の毛細血管は肺静脈へ注ぐためである．これのみが，臓側と壁側で違う要素であり，この違いのため臓側胸膜を介した圧差は0となるため臓側胸膜を介した正味の水の動きはないと考えられる．また，臓側胸膜のL_p（膜の濾過係数・水硬伝導率）は壁側胸膜のL_pより実際には小さいと考えられる．というのは，臓側胸膜は壁側胸膜より厚いため，血流は壁側胸膜側に比べてより離れて分布しているためである．胸膜を介した水の動きは，場所によっても違うし，呼吸の影響も受ける．たとえば，肋骨に面した壁側胸膜は肋間の壁側胸膜より水をより多く産生し，呼吸数が増えるとより多く産生される．
　胸水は壁側胸膜のリンパ管小孔（lymphatic stoma，胸腔に開口している直径2～10 μmの小孔）から吸収される．臓側胸膜にはリンパ小孔はない．ここから胸水中の蛋白，水，細胞がリンパ管を介してクリアランスされる．
2）胸水の貯留する病態：
壁側胸膜のリンパ管系の排液能力には大きな個人差があり，20～500 mL/時とされ，一般に胸水産生スピードの約20倍のクリアランス能力があると考えられている．一方，肺間質には，20 mL/時のリンパ流があると推定される．何らかの要因により胸水の産生と吸収のバランスが崩れると，胸水が貯留する（表2-27-1）．静水圧上昇，膠質浸透圧低下（血清蛋白の低下あるいは胸水中蛋白質濃度増加），毛細血管透過性亢進，は産生増加をもたらし，全身の静脈圧の上昇やリンパ管の閉塞は吸収低下をもたらす．
　胸水の産生オリジンは，多くの病態では肺の間質由来と考えられている．透過性亢進型肺水腫でも肺血管圧上昇型の肺水腫でも，間質に水腫が生じてから胸腔に水が流出してくる．すなわち，肺血管外間質の水分量が一定の閾値をこえて上昇した場合に，胸水が生じると考えられている．最近は，低蛋白血症のみでは胸水産生の原因にはならないと考えられている．
診断
1）存在診断：
胸部X線写真により胸水はX線透過性の低下した領域として描出される．胸水は流動性があるため，重力の影響を受けて胸腔内で低い部位に移動する．立位胸部単純写真では肋骨横隔膜角の鈍化（正面像），肋骨脊柱角の鈍化（側面像），側臥位像（decubitas view）による胸水貯留像の移動，などが診断に有用である（図2-27-2）．少量の胸水を診断するには，超音波検査が有用である．一定量の貯留がないと身体所見で診断することは難しいが，打診では胸水貯留部位は濁音，その上部は鼓音となる．聴診では，胸水貯留部では呼吸音が減弱し，声音振盪も減弱する．
2）漏出性胸水と滲出性胸水の鑑別：
胸腔穿刺により胸水を採取し，その性状，生化学的検査所見により原因診断を行う．胸水が少量の場合には，超音波ガイド下に穿刺・採取することができる．　まず，胸水と血清中の蛋白質とLDHを測定し，漏出性胸水か滲出性胸水か，を決定する（図2-27-3）．①胸水/血清　蛋白比＞0.5，②胸水/血清　LDH比＞0.6，③胸水LDH＞血清上限値の2/3は，Light診断基準とよばれ，どれも満たない場合には漏出性胸水（transdative pleural effusion）と診断する．どれか1つでも満たしていれば滲出性胸水（exudative pleural effusion）である可能性がある．漏出性胸水は炎症によらない胸水で，心不全，低蛋白血症（肝硬変やネフローゼ症候群）が最も一般的な原因である．通常，両側性が多いが，一側性胸水では右側が多い．一方，滲出性胸水は炎症による胸水で，多種類の原因疾患がある（表2-27-2）．
3）滲出性胸水の原因の鑑別：
　a）胸水の外観：外観を評価することにより，膿胸，血胸，乳び胸などの診断が可能である．
　ⅰ）膿胸：細菌感染による胸膜炎の際には肉眼的に膿性の胸水となる．嫌気性菌による膿胸では腐敗臭がする．　ⅱ）血胸：悪性腫瘍，肺梗塞，その他の炎症による胸膜炎で血液の混入した血性胸水を認めるが，胸水中のヘマトクリット値が末梢血液の50％以上である場合を血胸という．外傷による場合が最も多いが，自然気胸に際して壁側胸膜癒着部の血管断裂に伴い生じることもある．　ⅲ）乳び胸：乳びはミルク様のリンパ液を指し，腸管から吸収された脂肪成分（カイロミクロン）を豊富に含み胸管へ還流する．何らかの原因により胸腔に乳び液が貯留した状態を乳び胸とよぶ．食道癌や肺癌の手術操作に伴う胸管損傷により起こることが多い．基礎疾患としては，悪性リンパ腫が多い．そのほかに，リンパ脈管筋腫症ではLAM細胞の増殖に伴うリンパ管機能障害・閉塞などにより生じる．
　b）細胞数や分画：好中球優位の場合には急性炎症，あるいは細菌感染を示唆する．結核性胸膜炎はリンパ球優位な胸水であることが特徴であるが，急性期には好中球優位である．リンパ球優位な胸水は一般に慢性炎症を示唆し，癌性胸膜炎，膠原病に伴う胸膜炎などがある．好酸球が増加している場合には，Churg-Strauss症候群，薬剤性胸膜炎，寄生虫疾患などがある．頻回の胸腔穿刺や胸腔内への空気の混入でも好酸球増加を認める．
　c）グルコース：胸水中のグルコースはルーチンに測定するべきで，＜60 mg/dLの場合には，肺炎随伴性胸水，癌性胸膜炎，結核性胸膜炎，関節リウマチ，の4疾患のうちのどれかである可能性が高い．
　d）細胞診：癌性胸膜炎の診断には必須である．胸水中の腫瘍細胞数が少ないと正診率が減少する．多量の胸水から細胞成分を遠心分離しセルブロックを作成すると正診率が向上する．リンパ腫では正診率が低いことが多い．
　e）細菌学的検査：感染性疾患を疑う場合には，塗抹Gram染色，培養（好気性，嫌気性）を行う．結核性胸膜炎を疑う場合には，陽性率は高くないが抗酸菌検査（塗抹，培養，遺伝子検査）を行う．
　f）生化学的検査：
　ⅰ）ADA（アデノシンデアミナーゼ）：結核性胸膜炎の診断に有用である．ADA＞45～60 U/Lであれば結核性胸膜炎の可能性が高い．　ⅱ）アミラーゼ：膵炎に伴う胸水ではP型アミラーゼの上昇，食道破裂でみられる胸水では唾液の混入によりS型アミラーゼが上昇する．悪性腫瘍でもときにアミラーゼ産生腫瘍を経験するが，S型アミラーゼであることが多い．　ⅲ）腫瘍マーカー：癌性胸膜炎では胸水中の腫瘍マーカーが増加する．血清中より6倍以上高値であると診断的意義が高いとされる．　ⅳ）ヒアルロン酸：＞100 μg/mLあると悪性中皮腫の可能性がある．しかし，上皮型以外では上昇しない．　ⅴ）ネオプテリン：尿毒症性胸水の場合＞200 nmol/Lと高値を示す．
4）胸膜生検：
結核性胸膜炎や悪性中皮腫の診断確定に胸膜生検が有用な場合がある．しかし，ブラインドで生検するため，病変を視認して生検可能な胸腔鏡下生検に比べ診断率は高くない．最近は，あまり実施されなくなっている．
5）胸腔鏡下生検：
病変を視認して生検可能であるため診断率の高い検査法である．侵襲度が大きいが，局所麻酔下でも施行可能であるため普及してきている．［瀬山邦明］

表2-27-1
胸水の貯留機転からみた原因疾患">

表2-27-1

表2-27-2
胸水の鑑別診断">

表2-27-2

図2-27-1
胸水産生の生理的メカニズム">

図2-27-1

図2-27-3
漏出性，滲出性胸水の鑑別手順">

図2-27-3

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