Chien－Hua Chen ^(1){ }^{1} ，Min－Ho Huang ^(1,**){ }^{1, *} ，Shi－Wei Huang ^(1){ }^{1} ，Chi－Chieh Yang ^(1){ }^{1} ， Der－Aur Chou ^(1){ }^{1} ，Yung－Hsiang Yeh ^(2){ }^{2} ，Lein－Ray Mo ^(3){ }^{3} Chien－Hua Chen ^(1){ }^{1} ，Min－Ho Huang ^(1,**){ }^{1, *} ，Shi－Wei Huang ^(1){ }^{1} ，Chi－Chieh Yang ^(1){ }^{1} ， Der－Aur Chou ^(1){ }^{1} ，Yung－Hsiang Yeh ^(2){ }^{2} ，Lein－Ray Mo ^(3){ }^{3}^(1){ }^{1} Digestive Disease Center，Changhua Show－Chwan Memorial Hospital，Changhua，Taiwan ^(1){ }^{1} Digestive Disease Center，Changhua Show－Chwan Memorial Hospital，Changhua，Taiwan^(2){ }^{2} Digestive Disease Center，Changbing Show－Chwan Memorial Hospital，Lukang，Taiwan ^(2){ }^{2} Digestive Disease Center，Changbing Show－Chwan Memorial Hospital，Lukang，Taiwan^(3){ }^{3} Digestive Disease Center，Tainan Municipal City Hospital，Tainan，Taiwan ^(3){ }^{3} Digestive Disease Center，Tainan Municipal City Hospital，Tainan，Taiwan
Abstract 抽象的
Intrahepatic stones represent the formation of pigment stones above the con－ fluence of the right and left hepatic ducts．The exact causes of intrahepatic stones are not yet fully understood，although microbial infection，ethnicity，parasites，or poor nutrition have been shown to be involved in its pathogenesis．Because of the high rate of treatment failure and recurrence，intrahepatic stones can lead to recur－ rent cholangitis，secondary biliary liver cirrhosis，and even cholangiocarcinoma． Successful management of intrahepatic stones relies on the multidisciplinary inte－ gration of medication，endoscopy，surgery，and radiology．While the incidence of intrahepatic stones in Taiwan has declined in recent decades，the condition has not been completely eliminated and is occasionally encountered among emigrants from Southeast Asia． 肝內結石是指在左右肝管匯合處上方形成的色素結石。肝內結石的具體病因尚不完全清楚，但已證明微生物感染、種族、寄生蟲或營養不良與其發病機制有關。由於治療失敗率和復發率高，肝內結石會導致復發性膽管炎、繼發性膽汁性肝硬化，甚至膽管癌。肝內結石的成功治療依賴於藥物、內視鏡、手術和放射學等多學科的整合。雖然近幾十年來台灣肝內結石的發生率有所下降，但這種疾病並未完全消除，在東南亞移民中偶爾也會遇到。
Intrahepatic stones，firstly described in 1930， are characterized by the formation of pigment stones above the confluence of the right and left hepatic ducts，and can be located intrahepatically or extrahe－ patically（Figure 1）（1）．However，the nomenclature for intrahepatic stones remains miscellaneous，such as hepatolithiasis，Oriental cholangiohepatitis，and recurrent pyogenic cholangitis，which complicates the direct comparison of studies on its epidemiology， pathogenesis，management，and long－term sequelae 肝內結石於1930年首次被描述，其特徵是在左右肝管匯合處上方形成色素結石，可位於肝內或肝外（圖1）（1）。然而，肝內結石的命名仍然很雜亂，例如肝內膽管結石、東方膽管肝炎和復發性化膿性膽管炎，這使得對其流行病學、發病機制、治療和長期後遺症的研究難以直接比較。
Figure 1．Brown pigment stones in the intrahepatic ducts． 圖 1．肝內膽管內的褐色色素結石。
(2-4). With a high rate of treatment failure and recurrence, complications include obstruction or stricture of the intrahepatic biliary tracts accompanied by recurrent attacks of cholangitis, liver cirrhosis with atrophy of the affected liver parenchyma, and even cholangiocarcinoma (5,6)(5,6). （2-4）治療失敗率及復發率較高，併發症包括肝內膽道阻塞或狹窄，伴隨膽管炎反覆發作、肝硬化、肝實質萎縮，甚至膽管癌 (5,6)(5,6) 。
EPIDEMIOLOGY
Intrahepatic stones are most prevalent in East and Southeast Asia, including Taiwan (7, 8). The reported prevalence varies from 30%-50%30 \%-50 \% in East Asia to 0.6%-1.3%0.6 \%-1.3 \% in Western countries (7,8,9)(7,8,9). There is no known up to date national survey of intrahepatic stones in Taiwan, but the reported prevalence of intrahepatic stones relative to cholelithiasis is about 20%20 \% (10). With the westernization of dietary habits, improved quality of healthcare, accessibility of environmental sanitation, and higher standards of personal hygiene, the prevalence of intrahepatic stones is expected to decrease progressively, although the incidence may increase slightly in the West due to people immigrating from endemic areas (11). 肝內結石在東亞和東南亞地區最常見，包括台灣（7, 8）。報告的盛行率從東亞的 30%-50%30 \%-50 \% 到西方國家的 0.6%-1.3%0.6 \%-1.3 \%(7,8,9)(7,8,9) 不等。目前尚無關於台灣地區肝內結石的最新全國性調查，但報告的肝內結石相對於膽結石的盛行率約為 20%20 \% (10)。隨著飲食習慣的西化、醫療保健品質的提高、環境衛生的便利性以及個人衛生標準的提高，預計肝內結石的盛行率將逐漸下降，儘管由於從流行地區遷入的人群，西方國家的發病率可能會略有上升 (11)。
Most patients with intrahepatic stones are typically diagnosed between the ages of 30 and 50, although many of them may have recurrent episodes of abdominal discomfort during their childhood (5,12)(5,12). After these episodes, patients may enter a symptomfree period, which is referred to as the “lucid interval.” This term is similar to the period between the preservation and deterioration of cognition in brain injury (13). 大多數肝內結石患者通常在30至50歲之間確診，儘管其中許多人可能在兒童時期反覆發作腹部不適 (5,12)(5,12) 。這些發作結束後，患者可能會進入一段無症狀期，稱為「清醒期」。此術語類似於腦損傷後認知功能維持與惡化之間的時期(13)。
Gallbladder stones are more prevalent in females, while intrahepatic stones have a similar prevalence between men and women, which may indirectly portend that sex hormones do not play an important role in the development of intrahepatic stones (14). 膽囊結石在女性中更為常見，而肝內結石在男性和女性中的盛行率相似，這可能間接預示性激素在肝內結石的發生和發展中並不發揮重要作用（14）。
TYPES OF STONE CONTENTS 石材種類
The majority of intrahepatic stones are classified as brown pigment stones, which are mainly composed 大多數肝內結石屬於褐色色素結石，主要成分為
of calcium bilirubinate (Figure 2). Cholesterol stones are also seen in some cases, particularly in secondary intrahepatic stones that result from gallbladder stones with or without common bile duct stones. The formation of stone crystals can occur due to various predisposing factors, including bile metabolism imbalance, bile stasis, abnormalities in biliary trees, and the presence of beta-glucuronidase-producing bacteria (15). 膽紅素鈣（圖2）。膽固醇結石也可見於某些病例，尤其是膽囊結石伴隨或不伴隨總膽管結石而導致的繼發性肝內結石。結石結晶的形成可能由多種誘發因素引起，包括膽汁代謝失衡、膽汁淤積、膽道系統異常以及存在產β-葡萄醣醛酸酶的細菌(15)。
CLASSIFICATION OF INTRAHEPATIC STONES 肝內結石的分類
In addition to the types of stone contents, the classification of intrahepatic stones can be made based on the anatomy of the intrahepatic biliary trees (Tsunoda classification) (16), the severity of symptoms (17), and proposed treatment methods (Dong’s classification) (18). 除了結石內容物的類型外，還可以根據肝內膽道系統的解剖結構（Tsunoda 分類）（16）、症狀的嚴重程度（17）和建議的治療方法（Dong 分類）（18）對肝內結石進行分類。
Tsunoda classification Tsunoda 分類
Type I: Without dilatation or stricture of the intrahepatic biliary trees. I 型：肝內膽管系統無擴張或狹窄。
Type II: With dilatation of the intrahepatic biliary trees, frequently accompanied by obstruction in the common bile duct. II 型：肝內膽管系統擴張，常伴隨總膽管阻塞。
Type III: dilatation and stricture of the unilateral intrahepatic biliary trees. 第三型：單側肝內膽道擴張、狹窄。
Type IV: dilatation and stricture of the bilateral intrahepatic biliary trees. 第四型：雙側肝內膽道擴張、狹窄。
Figure 2. Calcium bilirubinate stones in the intrahepatic ducts. 圖 2. 肝內膽管內的膽紅素鈣結石。
Grade of severity 嚴重程度
Grade I: Without symptoms. I 級：無症狀。
Grade II: Abdominal pain. Ⅱ級：腹痛。
Grade III: Transient jaundice or cholangitis. 三級：暫時性黃疸或膽管炎。
Grade IV: Persistent jaundice, biliary sepsis or cholangiocarcinoma. 四級：持續性黃疸、膽道膿毒症或膽管癌。
Dong's classification 董氏分類
Type I: Localized stone disease in uni-lobar or bi-lobar distribution. I 型：局限性結石疾病，單葉或雙葉分佈。
Type II: Diffuse stone distributions. Ⅱ型：彌散性結石分佈。
Type IIa: Neither intrahepatic biliary tree stricture nor liver atrophy. IIa 型：既無肝內膽道狹窄，也無肝萎縮。
Type IIb: Atrophy of one single segment or stricture of the intrahepatic biliary trees. IIb 型：肝內膽管系統單一節段萎縮或狹窄。
Type IIc: With biliary cirrhosis and portal hypertension. Ⅱ型：伴隨膽汁性肝硬化和門靜脈高壓。
Additional Type E 附加 E 型
Ea: Normal sphincter of Oddi. Ea：奧迪括約肌正常。
Eb: Loose sphincter of Oddi. Eb：奧迪氏括約肌鬆弛。
Ec: strictured sphincter of Oddi. Ec：奧迪括約肌狹窄。
PATHOGENESIS AND ETIOLOGIES 發病機轉和病因
The etiologies of intrahepatic stones are complex and multi-factorial, making it difficult to determine the exact pathogenesis. Although the supersaturation of the cholesterol in bile is similar in intrahepatic stones and gallbladder stones, the mechanisms of stone formation differ between intrahepatic stones and gallbladder stones (19). Intrahepatic stones have lower levels of phospholipid concentration in the bile and multidrug resistance 3 P-glycoprotein expression in the liver, but they are preserved in gallbladder stones. The potential etiologies of intrahepatic stones can be categorized into the following factors. 肝內結石的病因複雜，多因子參與，因此難以確定確切的發病機轉。雖然肝內結石和膽囊結石的膽汁膽固醇過飽和程度相似，但兩者的結石形成機制不同 (19)。肝內結石的膽汁中磷脂濃度較低，肝臟中存在耐多藥 3P 糖蛋白的表達，而膽囊結石則保留了這些蛋白。肝內結石的潛在原因可分為以下幾類。
ENVIRONMENTAL AND ETHNIC FACTORS 環境和種族因素
The incidence of intrahepatic stones varies with 肝內結石的發生率隨
different geographic distributions and decreases over time with follow-up. While there is a similar ethnic background in areas such as China ( 21%21 \% ), Taiwan (20%), Hong Kong (3%), and Singapore (2%), the relative prevalence of intrahepatic stones to all cholelithiasis cases varies, suggesting environmental or dietary habits as possible etiologies for intrahepatic stones (19). Westernization of dietary habits may impede the development of intrahepatic stones, as seen in Japan, where the incidence of intrahepatic stones decreased from 4.1%4.1 \% in 1970-1977 to 1.7%1.7 \% in 1993-1995 (20, 21). Ethnic and genetic factors may also play a role in the incidence of intrahepatic stones, as their incidence is lower in North America and Europe. 不同的地理分佈，且隨時間推移而下降。雖然中國大陸（ 21%21 \% ）、台灣（20%）、香港（3%）和新加坡（2%）等地區的種族背景相似，但肝內結石在所有膽結石病例中的相對盛行率各異，這表明環境或飲食習慣可能是肝內結石的病因 (19)。飲食習慣的西化可能會阻礙肝內結石的形成，例如日本，其肝內結石的發生率從 1970-1977 年的 4.1%4.1 \% 下降到 1993-1995 年的 1.7%1.7 \% (20, 21)。種族和遺傳因素也可能是肝內結石發生率的因素，因為北美和歐洲的肝內結石發生率較低。
The studies conducted in Taiwan and Japan support that poor nutrition or low hygiene standards may be related to the development of intrahepatic stones. Higher incidences can be found in the following scenarios: 1) living in rural areas or pockets of poverty, 2) poor hygiene water supply, or a history of using well water for people’s livelihood, 3) history of parasite infestation, and 4) low saturated protein and fat supply in the diet ( 19,20,22,2319,20,22,23 ). The low content of protein or fat in the diet can cause bile stasis due to low secretion of cholecystokinin, which stimulates gallbladder contractility, and impairs relaxation of the sphincter of Oddi (24). On the other hand, a lowcalorie diet can decrease biliary glucuronolactone, a major inhibitor of bacterial glucuronidase, which can increase unconjugated bilirubin and enhance the formation of intrahepatic stones (25). 台灣和日本的研究支持營養不良或衛生標準低可能與肝內結石的形成有關。以下情況發生率較高：1）居住在農村地區或貧困地區，2）衛生水源差或曾使用井水為生，3）有寄生蟲感染史，4）飲食中飽和蛋白質和脂肪供應低（ 19,20,22,2319,20,22,23 ）。飲食中蛋白質或脂肪含量低會導致膽囊收縮素分泌減少，進而引起膽汁淤積，膽囊收縮素會刺激膽囊收縮，並削弱奧狄氏括約肌的鬆弛（24）。另一方面，低熱量飲食會降低膽汁葡萄醣醛酸內酯，而膽汁葡萄醣醛酸內酯是細菌葡萄醣醛酸酶的主要抑制劑，會導致未結合膽紅素增加並促進肝內結石的形成（25）。
MICROBIAL INFECTION 微生物感染
Bacterial infection and parasite infestation are the two major types of microbes that have been associated with the development of intrahepatic stones. Evidence suggests there is a close relationship between bacteriobilia and the formation of pigment stones, as bacterial 16S rRNA has been found to coexist with intrahepatic brown pigment stones (26). The route for the bacterial infection into the biliary tree may 細菌感染和寄生蟲感染是與肝內膽管結石形成相關的兩種主要微生物。有證據表明，膽汁菌與膽色素結石的形成密切相關，因為細菌 16S rRNA 已被發現與肝內棕色色素結石共存(26)。細菌感染進入膽道系統的途徑可能
