jaundice

Japanese: 黄疸

Concept Jaundice is a condition in which elevated bilirubin in the blood is deposited on the skin and mucous membranes, staining them yellow. Jaundice becomes visible when the total serum bilirubin level reaches approximately 2.5 mg/dL (overt jaundice). The skin color is lemon-colored in hemolytic jaundice and orange in hepatocellular jaundice, and turns green if cholestasis persists for a long period of time.
Pathophysiology [⇨9-1-3)]
Differential diagnosisHyperbilirubinemia occurs in diseases such as those listed in Table 2-3-1, but it is easier to understand the pathophysiology if you first classify it according to whether direct or indirect bilirubin is predominant. Most patients who visit the hospital with the main complaint of jaundice have jaundice with a predominance of direct bilirubin, and it should be kept in mind that there are many cases of hepatocellular jaundice and obstructive jaundice, especially acute viral hepatitis, drug-induced liver injury, and biliary obstruction due to malignant tumors.
1) Medical interview:
During the medical interview, it is important to check the color of the urine and stool. In common hepatocellular jaundice and obstructive jaundice, conjugated bilirubin refluxes into the bloodstream when there is severe impairment of intestinal excretion, resulting in dark-colored urine and light-colored stool.
Next, check for symptoms associated with acute hepatocellular damage, such as fatigue and loss of appetite. If these are not present, keep intrahepatic cholestasis and obstructive jaundice in mind and check for the presence or absence of medication (the former is often drug-induced) and abdominal pain, which are necessary for the differentiation of obstructive jaundice, and weight loss.
If symptoms of acute hepatocellular damage are present, keep in mind other types of hepatocellular damage, such as acute viral hepatitis, alcoholic hepatitis, and drug-induced liver injury, and ask questions necessary for differentiation, such as a history of recent overseas travel, whether or not the patient has had sexual intercourse with multiple people, ingestion of raw foods, alcohol or drug use, and a family history of liver disease. There are other necessary questions to ask, but these will be asked again once the direction of diagnosis has been determined.
2) Medical examination:
The serum bilirubin level can be estimated to some extent from the degree of yellowing of the skin. Examination should be performed for hepatic, biliary, and pancreatic diseases, including the presence or absence of hepatosplenomegaly, palpability of abdominal masses, and tenderness.
3) Blood test:
Total bilirubin, direct bilirubin, AST, ALT, LDH, ALP, and γ-GTP are important for differential diagnosis. Once the results of blood tests are known, it will be clear whether the increase in serum bilirubin is due to direct or indirect type, and if the increase is due to indirect type, the possible diseases are quite limited. If the increase is due to direct type, a differential diagnosis should be made considering hepatocellular jaundice if there is a predominant increase in transaminases, and intrahepatic cholestasis and obstructive jaundice if there is a predominant increase in biliary enzymes (ALP and γ-GTP). If all liver enzymes are normal, constitutional jaundice is suspected.
4) Diagnostic imaging:
It is useful for confirming the presence or absence of obstructive jaundice and for differential diagnosis. If immediately possible, abdominal ultrasound or abdominal contrast CT should be performed before and after blood sampling for blood tests. If no symptoms other than jaundice are observed, obstructive jaundice or intrahepatic cholestasis is likely, and imaging diagnosis is useful for differentiating between the two.
5) Differentiation points for each disease:
Below, the points to distinguish between each disease will be explained in the order shown in Table 2-3-1.
a) Indirect bilirubin-dominant jaundice: In cases where indirect bilirubin is predominant, if there is an increase in serum LDH, hemolytic jaundice is suspected, and confirmation is made of an increase in reticulocytes, strongly positive urinary urobilinogen, and a decrease in serum haptoglobin levels. If hemolysis is ruled out, constitutional jaundice may be considered.
Gilbert syndrome and Crigler-Najjar syndrome are both caused by genetic abnormalities in bilirubin UDP-glucuronosyltransferase (UGT1A1), and are diseases that could be called nonhemolytic hereditary indirect bilirubinemia. Clinically, the two are distinguished by total bilirubin levels of less than 6 mg/dL and more than 6 mg/dL. [⇨9-10]
b) Hepatocellular jaundice: Acute viral hepatitis is most common, followed by hepatocellular-damaging drug-induced liver injury. Various viral markers, IgG, and antinuclear antibodies are examined. If these results rule out acute viral hepatitis (including acute exacerbation of chronic hepatitis B), alcoholic hepatitis, and autoimmune hepatitis, the possibility of drug-induced liver injury increases, so a detailed drug history, including health foods, should be obtained.
Liver cirrhosis with jaundice is in the decompensated stage or is complicated by advanced hepatocellular carcinoma, and imaging diagnosis is easy. c) Intrahepatic cholestasis: Acute cases are often caused by drugs.
Recurrent intrahepatic cholestasis is a rare disease in Japan. Benign recurrent cholestasis can be diagnosed by checking the history of jaundice and the causative gene FIC1.
Genetic analysis is performed for the following. Pregnancy-related jaundice is diagnosed based on the exclusion of other diseases and the rapid improvement after delivery. d) Obstructive jaundice: Severe jaundice is often due to tumors (biliary tract cancer, pancreatic head cancer, and duodenal papilla cancer), and jaundice caused by gallstones or biliary tract infection is generally mild. In addition to ultrasound, contrast CT is performed. MRCP (magnetic resonance cholangiopancreatography) is also useful. If necessary, ERC (endoscopic retrograde cholangiopancreatography) is performed for treatment as well. e) Constitutional jaundice with a predominant direct bilirubin content: Dubin-Johnson syndrome and Rotor syndrome are both rare diseases. ICG tests are useful for differentiating between the two, with the former being almost normal, while the latter being highly delayed. For Dubin-Johnson syndrome, urinary coproporphyrin fractions are examined, and if there is interest, the causative gene MRP2 is analyzed. [Takikawa Hajime]

Table 2-3-1
Causes of hyperbilirubinemia ">

Table 2-3-1

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

Japanese:

概念
　血中で上昇したビリルビンが皮膚や粘膜に沈着して黄染した状態を黄疸という．血清総ビリルビン値が2.5 mg/dL程度となると黄疸が認められるようになる（顕性黄疸）．皮膚の色は溶血性黄疸ではレモン色調，肝細胞性黄疸ではオレンジ色調であり，胆汁うっ滞が長期に持続すると緑色調を呈する．
病態生理
　【⇨9-1-3）】
鑑別診断
　高ビリルビン血症は表2-3-1のような疾患で起こるが，まず直接型，間接型ビリルビンのどちらが優位かで分類すると，病態生理上，理解しやすい．黄疸を主訴に来院する患者のほとんどは直接型ビリルビン優位の黄疸であり，肝細胞性黄疸と閉塞性黄疸，なかでも急性ウイルス肝炎，薬物性肝障害，悪性腫瘍による胆道閉塞が多いことを考慮する．
1）問診：
問診上，尿と便の色の確認が重要である．頻度の高い肝細胞性黄疸および閉塞性黄疸では，抱合ビリルビンは腸管への排泄障害が高度になると血中に逆流して増加し，この結果，尿が濃染し便の色が薄くなる．
　ついで，倦怠感，食欲不振などの急性肝細胞障害に伴う症状の有無を確認する．これらを認めなければ，肝内胆汁うっ滞および閉塞性黄疸を念頭において，薬物の服用（前者では薬物性が多い）や閉塞性黄疸の鑑別に必要な腹痛の有無，体重減少を確認する．
　急性肝細胞障害の症状があれば，急性ウイルス肝炎，アルコール性肝炎，薬物性肝障害などの肝細胞障害型を念頭において，鑑別に必要な最近の海外渡航歴，不特定多数との性行為の有無，生ものの摂取，飲酒および薬物服用，肝疾患の家族歴などを聴取する．このほかにも必要な問診はあるが，診断の方向性のついた時点であらためて聴取する．
2）診察：
皮膚の黄染の程度から血清ビリルビン値はある程度，類推可能である．肝脾腫の有無，腹部腫瘤の触知，圧痛など，肝胆膵疾患に対する診察を行う．
3）血液検査：
総ビリルビン，直接ビリルビン，AST，ALT，LDH，ALP，γ-GTPが鑑別上，重要である．血液検査の結果が判明すれば，血清ビリルビン上昇が直接型，間接型どちらが優位かわかり，間接型優位であれば疾患はかなり限られる．直接型優位では，トランスアミナーゼ優位の上昇であれば肝細胞性黄疸を，胆道系酵素（ALPとγ-GTP）優位の上昇であれば肝内胆汁うっ滞と閉塞性黄疸を考え，鑑別診断を行う．肝酵素がすべて正常の場合は体質性黄疸を疑う．
4）画像診断：
閉塞性黄疸の有無の確認と鑑別診断に有用である．すぐ実施可能であれば，腹部超音波検査もしくは腹部造影CTを血液検査のための採血の前後に行うのがよい．黄疸以外の症状がみられない場合は閉塞性黄疸か肝内胆汁うっ滞の可能性が高く，画像診断は両者の鑑別に有用である．
5）各疾患の鑑別のポイント：
以下，各疾患の鑑別のポイントを表2-3-1の順序に従って説明する．
　a）間接ビリルビン優位の黄疸：間接型優位では，血清LDH上昇があれば溶血性黄疸を疑い，網状赤血球の増加，尿中ウロビリノーゲンの強陽性，血清ハプトグロビン値の低下を確認する．溶血が否定されれば体質性黄疸が考えられる．
　Gilbert症候群とCrigler-Najjar症候群は，ともにビリルビンUDP-グルクロン酸転位酵素（UGT1A1）の遺伝子異常で起こり，非溶血性遺伝性間接ビリルビン血症とでもよぶべき疾患である．臨床的には，総ビリルビン値6 mg/dL未満と以上で両者を区別する．【⇨9-10】
　b）肝細胞性黄疸：急性ウイルス肝炎の頻度が高く，肝細胞障害型の薬物性肝障害がこれにつぐ．各種ウイルスマーカー，IgG，抗核抗体を調べる．これらの結果から，急性ウイルス肝炎（Ｂ型慢性肝炎の急性増悪も含めて），アルコール性肝炎，自己免疫性肝炎が否定されると，薬物性肝障害の可能性が高くなるので，健康食品も含めた薬物服用歴を詳細に聴取する．
　黄疸のある肝硬変は非代償期や進行肝細胞癌合併例であり，画像診断が容易である．　c）肝内胆汁うっ滞：急性は薬物による場合が多い．
　反復性の肝内胆汁うっ滞はわが国ではまれな疾患である．良性反復性は黄疸の既往歴の確認と原因遺伝子FIC1
の遺伝子分析を行う．妊娠性のものは，他疾患の除外と出産後，速やかに軽快することから診断する．　d）閉塞性黄疸：高度の黄疸は腫瘍（胆道癌，膵頭部癌，十二指腸乳頭部癌）によることが多く，胆石や胆道感染症では，黄疸の程度は概して軽度である．超音波検査に加えて造影CTを行う．MRCP（magnetic resonance cholangiopancreatography）も有用である．必要があれば治療もかねてERC（endoscopic retrograde cholangiopancreatography）を行う．　e）直接ビリルビン優位の体質性黄疸：Dubin-Johnson症候群，Rotor症候群ともまれな疾患である．ICG試験が両者の鑑別に有用で，前者ではほぼ正常であるが，後者では高度に遅延する．Dubin-Johnson症候群については，尿中コプロポルフィリン分画を調べ，興味があれば原因遺伝子MRP2の分析を行う．［滝川　一］

表2-3-1
高ビリルビン血症の原因疾患">

表2-3-1

出典　内科学第10版内科学第10版について　情報

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