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。

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。

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。

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。

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\mathrm{\%}$$21\mathrm{\%}$21%21 \% ), Taiwan (20%), Hong Kong (3%), and Singapore (2%), the relative prevalence of intrahepatic stones to all cholelithiasis cases varies, suggesting environmental or dietary habits as possible etiologies for intrahepatic stones (19). Westernization of dietary habits may impede the development of intrahepatic stones, as seen in Japan, where the incidence of intrahepatic stones decreased from $4.1\mathrm{\%}$$4.1\mathrm{\%}$4.1%4.1 \% in 1970-1977 to $1.7\mathrm{\%}$$1.7\mathrm{\%}$1.7%1.7 \% in 1993-1995 (20, 21). Ethnic and genetic factors may also play a role in the incidence of intrahepatic stones, as their incidence is lower in North America and Europe.
不同的地理分佈，且隨時間推移而下降。雖然中國大陸（ $21\mathrm{\%}$$21\mathrm{\%}$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\mathrm{\%}$$4.1\mathrm{\%}$4.1%4.1 \% 下降到 1993-1995 年的 $1.7\mathrm{\%}$$1.7\mathrm{\%}$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 ( $19,20,22,23$$19,20,22,23$19,20,22,2319,20,22,23 ). The low content of protein or fat in the diet can cause bile stasis due to low secretion of cholecystokinin, which stimulates gallbladder contractility, and impairs relaxation of the sphincter of Oddi (24). On the other hand, a lowcalorie diet can decrease biliary glucuronolactone, a major inhibitor of bacterial glucuronidase, which can increase unconjugated bilirubin and enhance the formation of intrahepatic stones (25).
台灣和日本的研究支持營養不良或衛生標準低可能與肝內結石的形成有關。以下情況發生率較高：1）居住在農村地區或貧困地區，2）衛生水源差或曾使用井水為生，3）有寄生蟲感染史，4）飲食中飽和蛋白質和脂肪供應低（ $19,20,22,23$$19,20,22,23$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）。

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
include ascending infection through the sphincter of Oddi, hematogenous spreading of the bacteremia through the portal vein, or intestinal translocation of the gut microbiota (27).
包括經由奧狄氏括約肌的上行感染、經由門靜脈的血源性菌血症播散或腸道菌叢的腸道移位（27）。

Most bacteria found in the blood or bile culture for cholangitis are Gram-negative bacteria ( $88\mathrm{\%}$$88\mathrm{\%}$88%88 \% ), with $1/4$$1/4$1//41 / 4 of blood culture yielding polymicrobial infection in biliary bacteremia. Escherichia coli and Klebsiella pneumoniae are the most common pathogens. However, multi-drug resistance is relatively common in Aeromonas hydrophilia, Pseudomonas aeruginosa, and Citrobacter spp. Furthermore, Gram-negative, polymicrobial, or anaerobic infections are not associated with the prognosis of cholangitis (28).
膽管炎患者血液或膽汁培養中發現的大多數細菌為革蘭氏陰性菌（ $88\mathrm{\%}$$88\mathrm{\%}$88%88 \% ），其中 $1/4$$1/4$1//41 / 4 的血液培養結果提示膽道菌血症存在多種微生物感染。大腸桿菌和肺炎克雷伯菌是最常見的病原體。然而，嗜水氣單胞菌、綠膿桿菌和檸檬酸桿菌屬的多重抗藥性相對較常見。此外，革蘭氏陰性菌、多種微生物感染或厭氧菌感染與膽管炎的預後無關(28)。

The bacterial beta-glucuronidase can increase the unconjugated bilirubin in the bile, leading to the formation of brown pigment stones by combining with ionized calcium. Intrahepatic duct stones have lower amounts of total bile acids, unconjugated bile acid fraction, secondary bile acid, and ketonic bile acid to total bile acids than the extrahepatic duct stones, implying nonbacterial tissue-associated betaglucuronidase may play a role in the pathogenesis of intrahepatic stones (29).
細菌性β-葡萄醣醛酸酶可增加膽汁中的非結合膽紅素，並與離子鈣結合形成褐色色素結石。肝內膽管結石的總膽汁酸、非結合膽汁酸組分、次級膽汁酸和酮性膽汁酸佔總膽汁酸的比例低於肝外膽管結石，提示非細菌性組織相關β-葡萄醣醛酸酶可能在肝內膽管結石的發病機制中發揮作用(29)。

In areas with a high incidence of parasitic infestation, there is a higher prevalence of intrahepatic stones, but this does not fully explain the occurrence of intrahepatic stones in areas with a lower incidence of parasitic infestation, such as Japan and Taiwan, suggesting that other factors may also be involved $(30,31)$$(30,31)$(30,31)(30,31). The worms or eggs of the parasites may act as the nidus of the stones or cause inflammation and strictures in the biliary tree (12). The major liver flukes reportedly associated with intrahepatic stones consist of Clonorchis sinensis, Opisthorchis species, and Fascio hepatica. Ascaris lumbricoides, one of the most common helminthic infestations worldwide, has also been implicated in the development of intrahepatic stones, as evidenced by the presence of worms in the intrahepatic biliary tree or a positive reaction in enzyme-linked immunosorbent assay (ELISA) tests (12).
在寄生蟲感染高發生地區，肝內結石的盛行率較高，但這並不能完全解釋寄生蟲感染低發生地區（如日本和台灣）也發生肝內結石的原因，這表明可能還有其他因素參與其中 $(30,31)$$(30,31)$(30,31)(30,31) 。寄生蟲的蠕蟲或蟲卵可能成為結石的病灶，或導致膽道系統發炎和狹窄 (12)。據報道，與肝內結石相關的主要肝吸蟲包括華支睾吸蟲、後睾吸蟲和肝片吸蟲。蛔蟲是世界上最常見的蠕蟲感染之一，也與肝內結石的形成有關，肝內膽道系統中存在蠕蟲或酶聯免疫吸附試驗 (ELISA) 檢測呈陽性即可證明這一點 (12)。

It is quite common to find the co-existence of intrahepatic stones with biliary stricture or dilatation. The patients with stones within the gallbladder or common bile duct may finally develop intrahepatic stones secondary to bile stasis after changes in the biliary anatomy, inflammation can also induce biliary stricture or dilatation, which can lead to the development of intrahepatic stones. The distribution of intrahepatic stones is predominantly in the left hepatic duct, and this may be explained by the more angulated biliary tree with bile stasis.
肝內結石與膽道狹窄或擴張並存的情況相當常見。膽囊或總膽管有結石的患者，膽道解剖結構改變後，最終可能因膽汁淤積而形成肝內結石。發炎也會誘發膽道狹窄或擴張，進而導致肝內結石的形成。肝內結石主要分佈在左肝管，可能是由於膽道系統角度較大且膽汁淤積所致。

Chronic proliferative cholangitis, characterized by intramural and extramural glands proliferation in the biliary tree with epithelia hyperplasia lining, often precedes ductal stricture (32). Mucus produced in the inflammatory biliary trees can serve as a nidus to trap calcium salts and/or lipids for stone formation (33, 34). Furthermore, mucin can lower pH in the bile to decrease the solubility of bilirubin or calcium bilirubinate. Increased levels of phospholipase A2 and cyclooxygenase-2, two key enzymes involved in the inflammatory cascade, have been detected in the bile and biliary trees of patients with intrahepatic stones (35). Recurrent inflammation of the biliary tress can increase proliferation of the biliary epithelia, followed by production of mutagen after compromised DNA repair, increasing the risk of developing cholangiocarcinoma (36).
慢性增生性膽管炎的特徵是膽管壁內外腺體增生，並伴隨膽管上皮增生，常先於膽管狹窄發生（32）。發炎性膽管產生的黏液可作為病灶，捕獲鈣鹽和/或脂質，進而促進結石形成（33, 34）。此外，黏蛋白可降低膽汁 pH 值，進而降低膽紅素或膽紅素酸鈣的溶解度。在肝內結石患者的膽汁和膽管中，檢測到了參與發炎級聯反應的兩種關鍵酵素—磷脂酶 A2 和環氧合酶-2—的水平升高（35）。膽管反覆發炎可促進膽管上皮增生，繼而 DNA 修復受損並產生誘變劑，進而增加膽管癌的風險（36）。

In addition to brown pigment stones, approximately $20\mathrm{\%}$$20\mathrm{\%}$20%20 \% of intrahepatic stones have been found to have higher levels of cholesterol and lower bilirubin, similar to gallbladder stones. The development of intrahepatic stones is enhanced by the up-regulation of hepatic cholesterol synthesis by 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and downregulation of bile acid synthesis by cholesterol 7-alpha
除了褐色色素結石外，大約 $20\mathrm{\%}$$20\mathrm{\%}$20%20 \% 的肝內結石被發現膽固醇水平較高，膽紅素水平較低，與膽囊結石類似。 3-羥基-3-甲基戊二醯輔酶 A (HMG CoA) 還原酶上調肝臟膽固醇合成，以及膽固醇 7-α下調膽汁酸合成，會促進肝內結石的形成。
hydroxylase, leading to supersaturation of cholesterol in the bile (37). Patients with intrahepatic stones also have defects in the biliary secretion of phosphatidylcholine due to phosphatidylcholine transfer protein, and low hepatic levels of multidrug resistance 3 P-glycoprotein, a protein that limits biliary secretion of phospholipid (38). In brief, phosphatidylcholine and bile acids protect the biliary epithelia from damage by un-conjugated bile acids.
羥化酶，導致膽汁中膽固醇過飽和（37）。肝內膽結石患者由於磷脂醯膽鹼轉運蛋白的存在，膽汁磷脂醯膽鹼分泌有缺陷，且肝臟中多重抗藥性 3P-糖蛋白（一種限制膽汁磷脂分泌的蛋白質）含量較低（38）。簡而言之，磷脂醯膽鹼和膽汁酸保護膽道上皮免受非結合膽汁酸的損傷。

Cholangitis is typically characterized by Charcot’s triad of fever, jaundice, and right upper quadrant pain. In severe cases, the Reynolds’ pentad with Charcot’s triad adding alteration of conscious status and shock may be observed. Certain factors, including acute renal failure, septic shock, direct hyperbilirubinemia, and comorbidities based on Charlson Comorbidity Index, have been identified as predictors of 30-day mortality for cholangitis $(28,39)$$(28,39)$(28,39)(28,39). However, once drainage of biliary obstruction can be achieved, the mortality of biliary sepsis within 30 days is relatively low compared to bacteremia from other causes.
膽管炎的典型特徵是夏科氏三聯徵，即發燒、黃疸和右上腹疼痛。在嚴重病例中，可能會出現雷諾茲五聯徵，夏科氏三聯徵加上意識狀態改變和休克。某些因素，包括急性腎衰竭、感染性休克、直接高膽紅素血症以及基於查爾森合併症指數的合併症，已被確定為膽管炎 30 天死亡率的預測因素 $(28,39)$$(28,39)$(28,39)(28,39) 。然而，一旦膽道阻塞得以引流，膽道膿毒症 30 天內的死亡率與其他原因引起的菌血症相比相對較低。

While it is uncommon for all three symptoms of fever, jaundice, and right upper quadrant pain to present simultaneously, abdominal pain is the most frequent symptom, followed by fever and jaundice $(5,40)$$(5,40)$(5,40)(5,40). Historically speaking, the diagnosis of intrahepatic stones has been established in less than $30\mathrm{\%}$$30\mathrm{\%}$30%30 \% of patients during the first attack of cholangitis, particularly in the early decades of the twentieth century (1930s). Many patients with intrahepatic stones are initially diagnosed with peptic ulcer disease, indigestion, parasite infestation, or even no definite diagnosis. After recurrent episodes of cholangitis in childhood, some patients may experience a symptom-free “lucid interval” (13).
雖然發燒、黃疸和右上腹痛這三種症狀同時出現的情況並不常見，但腹痛是最常見的症狀，其次是發燒和黃疸 $(5,40)$$(5,40)$(5,40)(5,40) 。從歷史上看，在膽管炎首次發作期間確診肝內結石的患者不到 $30\mathrm{\%}$$30\mathrm{\%}$30%30 \% ，尤其是在1920世紀初（1930年代）。許多肝內結石患者最初被診斷為消化性潰瘍、消化不良、寄生蟲感染，甚至沒有明確的診斷。在兒童時期反覆發作膽管炎後，有些患者可能會經歷一段無症狀的「清醒期」(13)。

Without early diagnosis and treatment of intrahepatic stones, liver damage from recurrent cholangitis may progress to liver abscess, biliary cirrhosis, or cholangiocarcinoma. Rupture of the abscess into the
如果無法早期診斷和治療肝內結石，復發性膽管炎造成的肝損傷可能會發展為肝膿瘍、膽汁性肝硬化或膽管癌。膿腫破裂進入
peritoneum or fistula formation with the gastrointestinal tract, abdominal wall, pericardium, and pleural cavity may develop (41). Portal vein thrombosis, abscess of the lung or brain, or hemobilia have also been reported.
可能形成腹膜瘻管或與胃腸道、腹壁、心包膜和胸膜腔形成瘻管（41）。也有通報出現門靜脈血栓形成、肺膿瘍或腦膿瘍或膽道出血。

Although obtaining stones within the intrahepatic ducts is the gold standard for diagnosing intrahepatic stones, it is not always feasible in clinical settings. Therefore, image modalities are often used to document the presence of stones within the intrahepatic ducts. Liver biopsy is not routinely necessary for the diagnosis of intrahepatic stones, but it may be performed if a mass lesion is suspected or when the etiology of cholangiohepatitis is unknown. The most commonly used imaging modalities for diagnosing intrahepatic stones are hepatobiliary ultrasound, computed tomography (CT), magnetic resonance image (MRI), and cholangiography.
雖然肝內膽管取石是診斷肝內結石的黃金標準，但在臨床實務中並非總是可行。因此，影像學檢查常用於記錄肝內膽管內是否有結石。肝臟切片檢查並非肝內結石的常規診斷必要手段，但如果懷疑有腫塊或膽管肝炎病因不明，則可進行肝臟切片檢查。診斷肝內結石最常用的影像學檢查包括肝膽超音波、電腦斷層掃描 (CT)、磁振造影 (MRI) 和膽管造影。

US and X-ray are the most commonly used diagnostic tools for patients with abdominal discomfort. However, in contrast to calculi in the urinary system, X-ray is not sensitive in detecting cholelithiasis due to its low calcium content. In more than $90\mathrm{\%}$$90\mathrm{\%}$90%90 \% of patients with intrahepatic stones, strong echoes with acoustic shadows in dilated intrahepatic biliary ducts (known as the double channel sign in gray-scale ultrasound) can be seen (Figure 3). Additionally, US can detect associated liver abscess and cholangiocarcinoma. US can also to be used to guide biliary tree puncture through the percutaneous route for treatment.
超音波和 X 光是腹部不適患者最常使用的診斷工具。然而，與泌尿系統結石不同，由於膽結石含鈣量低，X 光對膽結石的檢測敏感度較低。超過 $90\mathrm{\%}$$90\mathrm{\%}$90%90 \% 的肝內膽結石患者，在擴張的肝內膽管中可見強迴聲和聲影（灰階超音波中稱為雙通道徵）（圖 3）。此外，超音波還可以檢測相關的肝膿瘍和膽管癌。超音波也可用於引導經皮膽道穿刺治療。

CT can provide a comprehensive view of the entire hepatobiliary system, allowing for a more precise assessment of the extent of involvement by intrahepatic stones (Figure 4), as well as detecting liver segment atrophy, abscesses or tumors. CT can also reveal dilated
CT 檢查可以全面顯示整個肝膽系統，從而更精確地評估肝內結石的受累程度（圖 4），並發現肝段萎縮、膿腫或腫瘤。 CT 檢查還可以顯示擴張的