Advances in Anatomic Pathology:
Primary Hepatolithiasis, Recurrent Pyogenic Cholangitis, and Oriental Cholangiohepatitis—A Tale of 3 Countries
Tsui, Wilson M.S. FRCPath, MD*; Lam, Polly W.Y. FRCPA†; Lee, Wai-ki FRCPA‡; Chan, Yiu-kay FRCP§
*Department of Pathology, Caritas Medical Centre
†Department of Pathology, Queen Elizabeth Hospital
‡Department of Pathology, Tuen Mun Hospital
§Department of Medicine and Geriatrics, Caritas Medical Centre, Hong Kong, China
The authors declare no conflict of interest.
Reprints: Wilson M.S. Tsui, FRCPath, MD, Department of Pathology, Caritas Medical Centre, Wing Hong St., Shamshuipo, Kowloon, Hong Kong (e-mail: firstname.lastname@example.org).All figures can be viewed online in color at http://www.anatomicpathology.com.
Primary hepatolithiasis (HL), recurrent pyogenic cholangitis, and oriental cholangiohepatitis are terms commonly used in Japan, Hong Kong, and Korea respectively, and describing the different aspects of the same disease, with “HL” indicating the pathologic changes, “recurrent pyogenic cholangitis” emphasizing the clinical presentation and suppurative inflammation, and “oriental cholangiohepatitis” highlighting its ethnic preference and mysterious nature. HL is predominantly a disease of the far east and shows great regional differences in the incidence and the type of intrahepatic stones. Pathologically, it is characterized by pigmented calcium bilirubinate stones within dilated intrahepatic bile ducts featuring chronic inflammation, mural fibrosis, and proliferation of peribiliary glands, without extrahepatic biliary obstruction. Episodes of suppurative inflammation cumulate in sclerosing cholangitis in peripheral ducts and parenchymal fibrosis from scarring and collapse. Mass-forming inflammatory pseudotumor and neoplasms-like intraductal papillary neoplasms and cholangiocarcinoma are increasingly recognized complications. Bacterial infection and dietary factors are believed to be important in the formation of pigment stones within intrahepatic bile ducts, whereas parasitic infestation is likely coincidental. With improvement of environmental conditions and westernization of diet, the incidence of pigment stones has decreased. At the same time, cholesterol stones with milder clinical manifestations and pathologic changes are increasingly recognized, and for which stone dissolution therapy can be considered. Understanding the underlying pathology avoids confusion with other diseases more prevalent in the western world, and allows correct selection of the appropriate treatment.
BACKGROUND AND NOMENCLATURE
The term “recurrent pyogenic cholangitis” (RPC) is used to name a disease based on its clinical profile-recurrent attacks of suppurative cholangitis.1,2 This clinical entity was first described by Digby3 as a type of cholangiohepatitis in the Chinese; but it was Cook et al1 who first used the term RPC. Various other names such as “biliary obstruction syndrome of the Chinese,”4 “Hong Kong disease,”5 “oriental cholangiohepatitis,”6 and “oriental cholangitis”7 have been used in the western literature to describe this mysterious oriental syndrome. It is a distinct clinicopathologic syndrome of repeated attacks of suppurative cholangitis associated with hepatolithiasis (HL), the stones being formed in the intrahepatic bile ducts without functional or organic extrahepatic biliary obstruction,8,9 and is quite different from the western cholangitis that complicates cholecystitis and cholelithiasis.10,11 In older literature of RPC, bile duct stones were said to be present in approximately 75% to 80% of cases. In the remaining cases, the biliary tree was infected recurrently in the absence of stone. According to the current knowledge, these latter cases may be suffering from other bile duct abnormalities leading to recurrent cholangitis, as listed in the pathologic differential diagnoses in the text.
HL is defined as the presence of calculi (stone, mud, and/or sludge) within the intrahepatic bile ducts proximal to the common hepatic duct (confluence of the right and left hepatic ducts).12 The basic pathology of RPC is HL that is a term preferred for this disease in the Japanese literature.13–15 RPC is a primary form of HL16 which refers to stones formed de novo in the intrahepatic ducts, whereas secondary HL17 refers to a retrograde migration of stones from the extrahepatic ducts and gallbladder, and those liver conditions with secondary stone formation in intrahepatic bile ducts. Primary HL can be classified into at least 3 types—calcium bilirubinate stones, cholesterol stones, and mixed stones.18,19
Oriental cholangiohepatitis (OCH) is the term commonly used in the Korean literature.20 Apart from presence of intrahepatic stones, a strong association with parasitic infestation of the biliary tree is suggested.21
INCIDENCE AND EPIDEMIOLOGY
HL is predominantly a disease of the far east and has been a common clinical problem in China, Taiwan, Hong Kong, Korea, Japan, Indonesia, and the Philippines. The incidence had been reported to be between 4% and 52% in these countries, but only 0.6% to 1.3% in the west.22 RPC is occasionally encountered in the west, mainly in the Asian immigrants.7,23–25 However, the true incidence of RPC is difficult to assess, its prevalence is only indicated by the relative incidence among all patients with biliary calculi. Studies from Taiwan reported the highest incidence of 30% to 50% among patients with gallstones.26,27 Figures from Japan are 3% to 15%, Korea 17%, Malaysia 10%, Hong Kong 3%, and Singapore 1.7%.28
Alongside improvement in nutrition, public health, hygiene, standard of living, and westernized eating habit, there is a progressive decrease of RPC in East Asia. The average number of RPC patients managed in a teaching hospital in Hong Kong decreased from 30 per year in 1950 to 1952 to 22.8 per year between 1984 and 1989, despite population growth.1,29 A Taiwan nationwide survey showed that HL decreased from 21.3% to 18.7%, whereas that of gallbladder stone increased from 50.8% to 63% between the years 1981 and 1989.30 In Japan, a nationwide survey in the 1970s showed that, of the 38,606 patients with biliary calculi who had undergone operation, 1590 (4.1%) had HL.13,28 This was much lower than that in the prewar era, and the decrease was most marked in the urban areas. The only exception is Korea where the prevalence of HL remained high and unchanged (11% to 15%).31 These data may represent a genuine decrease in incidence of HL and/or a relative increase in other cholelithiasis. It had been reported that the peak age at presentation was from age 20 to 40 years.2 More recent data showed that the average age at presentation is in the 50s and 60s.29 Sex incidence has remained equal throughout the years.19,29 It is believed that this disease is associated with poor social economic class and the habit of eating high carbohydrate, low protein, and low fat diet.32
CLINICAL MANIFESTATION AND DIAGNOSIS
Patient with RPC often presents acutely with bouts of fever, right upper quadrant abdominal pain, and jaundice (Charcot triad). Pyogenic cholangitis with microabscess formation in the liver may culminate in gram-negative septicemia, pyemia, or endotoxic shock.6 In the later situation, patient develops hypotension and mental confusion (Reynold pentad) which is associated with guarded prognosis. Sometimes, the clinical course may be further complicated by renal failure and even multiorgan failure, particularly in elderly patients with multiple comorbidities.
Apart from acute cholangitis, HL may present with biliary colic, acute pancreatitis, obstructive jaundice, and less commonly, hepatomegaly and abnormal liver biochemistry.22,29 With early treatment, complications of bile duct perforation and bile peritonitis, secondary biliary cirrhosis with its associated complication such as variceal bleeding, thrombophlebitis, and occlusive thrombosis of the portal or hepatic veins, splenomegaly and even pulmonary thromboembolism had become a rarity nowadays.22,29
Diagnosis is established by a combination of laboratory and radiologic findings.20,33 Laboratory tests often shows leucocytosis, neutrophilia, abnormal liver biochemistry of an obstructive pattern with raised serum alkaline phosphatase activities and bilirubin, and sometimes elevated amylase.34 Imaging studies reveal intrahepatic and/or extrahepatic stones, dilatation of extrahepatic bile ducts, localized dilatation of the lobar or segmental ducts, focal strictures, and segmental hepatic atrophy (especially left lateral segment and right posterior segment).20,35–39 Bile cultures yield Escherichia coli or other enteric bacteria during acute attacks.
The clinical course of RPC, as implied by its name, is characterized by recurrent attacks of abdominal pain and cholangitis, requiring multiple interventional therapies to establish drainage of the biliary system (endoscopic intervention, interventional radiology, and operative intervention by laparoscopy or open surgery). The incidence of residual stones after surgery was reported to be 77% and the incidence of recurrent stones was 15%.22
Difference in Clinical Manifestation
In Japan, a significant percentage (up to 40% in 1 series) of patients with HL are asymptomatic, the disease being discovered on medical checkup.40 For those cases diagnosed incidentally or found during autopsy, the symptoms of previous attacks of cholangitis or biliary problems are mild.
Korean patients experience similar clinical problems as the Chinese. Often the associated parasitic infestation leads to more acute severe manifestations and frequent recurrent attacks, usually once or twice a year.20,21
The basic pathology is the presence of calculi in the intrahepatic biliary tree and accompanying inflammation, both chronic and acute, with ensuing changes.
The calculi in RPC are mainly calcium bilirubinate stones, which comprise 30% to 80% calcium bilirubinate and <30% cholesterol.34,41 The stones are multiple, small, and dark brown to black in color. They vary in appearance from clay-like muddy material to irregular concrete stones that are soft and friable. Histologic section shows multiple concentric pigmented layers with varying shades of brown color. They are composed of calcium salts of bilirubin, fatty acid (mostly palmitate), and cholesterol arranged in a glycoprotein matrix. A mucus surface coating is present. Under scanning electron microscopy, microcolonies of bacteria may be seen mixed with the crystals.
Intrahepatic cholesterol stones are made up of >70% of cholesterol. These stones are white to yellow in color. The cross-sectional appearance of these stones is similar to that of cholesterol stones found in the gallbladder. This type of stone is much less common and accounts for 11% in a Japanese study of 411 intrahepatic stones.18 Pure cholesterol stones are increasingly recognized in Japan and are associated with milder clinical symptoms, and less fibroinflammatory changes of bile ducts, proliferation of periductal glands, and mucin production.42–45 Cholesterol crystals and granulomas can be detected in the bile ducts.
Mixed stones are composed of varying chemical composition between those of calcium bilirubinate stone and cholesterol stone. These stones have a smooth 1-mm black surface outer shell surrounding a yellowish inner matrix and are hard in consistency, ovoid or faceted in shape. These stones consist of mainly bilirubin polymers and to a lesser degree, calcium palmitate.33 One-third of the stones belonged to this type in a Korean study.19 These mixed stones may be intermediate products in a transitional process from calcium bilirubinate to cholesterol stones, as there has been a general trend toward an increased cholesterol content in intrahepatic stones compared with those analyzed 30 to 40 years ago.18,46 This change is attributable to a change to a western-type diet and improvement of environmental hygiene.
Intrahepatic Bile Ducts
The large hilar or lobar bile ducts show saccular or fusiform dilatations and stenoses (relative stricture) that are irregularly distributed, and their walls show fibrous thickening. They contain the pigmented stones and mud (Fig. 1). The dilatation is mainly central with rapid tapering toward the periphery. The first and second divisions of the ducts are dilated, whereas the third and fourth divisions of the ducts are not. The strictures are relative only to the dilated areas and to the retained stones; their calibers are actually larger than the original normal ducts. Regarding the location, the left lateral segmental duct is preferentially affected first and more severely, followed by the posterior segmental duct of the right lobe. This may be related to the more acute angulation of these ducts and hence poorer drainage of bile.
Histologically, the stone-containing bile ducts and their neighboring bile ducts show fibrous thickening of the ductal wall and fibrosis in periductal tissue. There are chronic inflammatory infiltrate (sometimes with lymphoid follicles formation) and proliferation of the peribiliary glands (intramural and extramural) within ductal walls and in periductal tissue (Fig. 2). The term ‘chronic proliferative cholangitis’ is applied to these lesions.14,15 The glands produce much neutral and acid mucin, which is also part of the component of the stones. The segmental and septal bile ducts proximal to stone-containing large ducts often show periductal lamellar fibrosis and hyperplastic epithelium, sometimes atrophy with thickened basement membrane, and even fibrous obliteration.
Extrahepatic Bile Ducts
In 60% of the cases, stones are also present in common bile duct and common hepatic duct. They are usually dilated diffusely, and strictures are very unusual along the ducts. The histologic changes are similar to the stone-bearing intrahepatic ducts. In some cases, there is periampullary stricture due to repeated passage of stones and resultant fibrosis. Coexisting gallbladder stones (with more cholesterol component) are seen in 30%. The gallbladder wall shows nonspecific chronic inflammation; Rokitansky-Aschoff sinuses are generally not present except in those with gallstones.
The hepatic lobe or area(s) containing intrahepatic calculi are usually atrophic, and capsular adhesions are evident. Occasionally, the hepatic parenchyma is totally lost in the involved area(s). The left lobe is predominantly affected (Fig. 1).
The interlobular bile ducts proximal to stone containing large ducts show periductal lamellar fibrosis, and even fibrous obliteration and duct loss. In fact, changes of sclerosing cholangitis affect the interlobular bile ducts in all cases of primary HL, particularly prominent in chronic and advanced stage. As many as 85% of the medium-sized septal bile ducts exhibit periductal fibrosis, whereas duct loss (20%), ductal atrophy (10%), and fibroobliterative scars (7%) are observed in the small interlobular bile ducts (Fig. 3).47 Florid ductular proliferation of the type associated with ductopenia is only rarely observed. The portal tracts show variable fibrous expansion and only patchy chronic inflammatory infiltrate. There is no chronic cholestasis or progression to biliary cirrhosis as long as biliary obstruction can be relieved.
Liver parenchyma in segments harboring stones shows variable degree of atrophy, coarse scarring, and biliary fibrosis. Cirrhosis of the type resulting from biliary obstruction or chronic hepatitis is exceptional.
Small portal vein branches are reduced in number or showed fibrous obliteration, whereas medium-to-large sized ones frequently exhibit phlebosclerosis. In places, there are large areas of collapse fibrosis (Fig. 4), and the remaining hepatic arterial branches approximate together, reminiscent of a vascular malformation lesion.
During acutely infected episodes, there are acute portal inflammation, suppurative cholangitis, and multiple abscesses. The large ductal mucosa is ulcerated and acutely inflamed. Some small interlobular bile ducts are disrupted and destroyed, whereas others show pericholangitis and ensuing periductal fibrosis (Fig. 5). Ductular reaction, acute (canalicular and hepatocellular) cholestasis is present, and progression to chronic cholestasis with copper-associated protein accumulation is observed in some subacute cases. Thrombophlebitis of portal vein branches is common (Fig. 6). Enteric organisms, chiefly E. coli, can generally be cultured from the bile in 95% of the patients and from the portal blood in 40% during acute attacks.2
Some of the above mentioned chronic changes in the bile ducts and parenchyma are sequelae to acute suppuration. As these acute elements are only revealed in autopsy of patents dying of acute complications and specimens resected during acute phase, the way they give rise to the final pathologic pictures is underrecognized. In particular, the small duct sclerosing cholangitis is principally the result of acute inflammatory destruction, the vascular changes with large areas of parenchymal collapse fibrosis are due to inflammatory vascular obliteration and ischemia, and the irregular scars are the tombstones of abscesses. The different causes and patterns of fibrosis are summarized in Table 1. In contrast, the peribiliary glandular proliferation in large ducts may be related to chronic stone irritation.
Suppurative cholangitis, liver abscess, empyema gallbladder, acute pancreatitis, thrombophlebitis of hepatic or portal veins, and septicemia are acute complications of the disease to which patients may succumb during the acute attacks.
Mass-forming inflammatory lesions apart from abscess are occasionally recognized. Inflammatory pseudotumor of xanthogranuloma type, single or multiple, and 2 to 7 cm in sizes has been described in 1 series.48 Their cut surfaces show a variegated appearance with tan, chalky yellow necrotic, or focally hemorrhagic areas. Histologically, the central area comprises chronic inflammatory infiltrate with foamy histiocytes, plasma cells, and lymphocytes, whereas the periphery and internal septa feature fibroblastic proliferation.
Cholangiocarcinoma has become an important late complication of HL. In Taiwan, the incidence of associated carcinoma in operated HL is 2.4% for 1978 to 1987 and rises to 13.7% for 1988 to 1990, the overall incidence being 5% for the entire period.26,49 In an autopsy series of 3526 cases from Japan, the incidence of cholangiocarcinoma in HL was 10%.14 In Hong Kong, with the progressive decreasing incidence of clonorchiasis and clonorchiasis-associated cholangiocarcinoma, the association of RPC with cholangiocarcinoma becomes more apparent, at a rate of 7.7%.50 These patients usually present after the age of 50 years after having 10 to 30 years history of recurrent cholangitis. The sex ratio is equal or with slight female predominance. Asymptomatic cholangiocarcinoma may develop even after complete clearance of HL because bile stasis, bacterial infections, and concomitant Clonorchis sinensis infestation are known etiologic factors.51,52 Preoperative diagnosis of cholangiocarcinoma arising in livers with HL is difficult and hence the survival rate is significantly poor.
Grossly, the carcinoma is topographically related to the biliary tree containing stones and showing chronic fibrotic inflammation. It tends to spread along the stone-bearing bile ducts followed by cancerous thickening of the bile duct walls and variable parenchymal invasion. The gross differentiation of such cancerous bile ducts from the fibrous thickened bile ducts without carcinoma is, however, difficult (Fig. 7A). Tumor masses or nodules are also formed around the bile ducts in addition to the spread along the portal tracts in advanced cases. Cholangiocarcinoma associated with HL is basically adenocarcinoma showing various differentiation. Occasionally, squamous differentiation and mucinous change are encountered in the cancer foci. They show stromal invasion of the bile duct walls and periductal tissue and also into the hepatic parenchyma, in addition to the intraluminal spread and peribiliary glandular involvement (Fig. 7B). There is variable degree of associated stromal fibroplasia and perineural invasion. Basically, these histologic features are not different from those of cholangiocarcinoma arising in nonhepatolithiatic livers.14
Carcinogenesis in biliary epithelium in livers with stones is a multistep process through hyperplasia, dysplasia, and in situ adenocarcinoma to invasive adenocarcinoma. The dysplasia, affecting surface and/or glandular epithelium (Fig. 8), is mainly found in stone-bearing ectatic ducts in which periductal gland proliferation and papillary hyperplasia of surface epithelium are regularly seen.50,53 The incidence of biliary epithelial dysplasia (mainly low grade) is as high as 42.3% in our series,50 similar to that quoted in the Japanese literature.14,53 The time sequence suggests a long transition time (approximately 15 y) from dysplasia to carcinoma.50 The term “biliary intraepithelial neoplasia” and the diagnostic criteria have been proposed for such lesions.54 Their molecular and genetic alterations related to cholangiocarcinogenesis have been extensively studied.55–57
Intraductal papillary neoplasm (IPN) (formerly called biliary papillomatosis) is a less frequent neoplastic complication of HL.58–60 It is characterized by multiple papillary adenomas involving extensive areas of the biliary tree and showing varying degree of dysplasia and different epithelial types.61 It is also preceded by epithelial dysplasia of papillary type (Fig. 9). Owing to similar clinical presentations as and overlapping radiologic features with HL, a preoperative diagnosis of IPN is usually difficult. Diagnosis is possible by means of endoscopic retrograde cholangiopancreatogram and endoscopic biopsy for extrahepatic cases, and percutaneous transhepatic cholangioscopy and fine needle aspiration for intrahepatic tumors.62–64 IPN is not infrequently associated with invasive carcinoma, in particular the mucinous subtype.60
PATHOLOGIC DIFFERENTIAL DIAGNOSIS
HL is frequently mistaken for several other diseases in which there may be secondary stone formation (Table 2). To distinguish from stones that migrate from extrahepatic bile ducts, when stones are located in dilated intrahepatic ducts proximal to a stricture, it is presumed that they are formed in the primary site. Extrahepatic biliary obstruction and other causes of acute cholangitis should also be entertained in the differential diagnosis.
Caroli disease should be distinguished because of the presence of cholangiectasis and similar clinical presentation in both diseases (Table 3). In fact, primary HL is mistaken for Caroli disease in early literature.16 In Japan, of the 273 cases of intrahepatic stones, congenital anomalies of the biliary tree were noted in 17 cases (6.2%); these included choledochal cysts, Caroli disease, solitary cystic dilatation of intrahepatic duct, and compression of common hepatic duct by an overriding right hepatic artery.65 They should be considered especially in young patients. In primary HL, there is a predominant involvement of the left lobe and no evidence of ductal plate malformation. Bilirubinate stones and chronic proliferative cholangitis are not observed in uncomplicated Caroli disease (Fig. 10).
Cholangiectasis and even stone formation have also been observed in primary sclerosing cholangitis (PSC) which may be mistaken for HL, especially if only the peripheral liver parenchyma is examined (Table 4).66 In fact, changes of sclerosing cholangitis are observed in the interlobular bile ducts in all cases of HL, as detailed above.47 The degree of ductopenia is never as significant as PSC and ductular proliferation is only rarely observed. The portal inflammation is not diffuse and chronic hepatitis-like with interface hepatitis as in PSC. There is no chronic cholestasis or progression to biliary cirrhosis. The imaging features and clinical course are also different.
Western pathologists often have the misconception that HL results from liver fluke infestation and consider peribiliary glandular proliferation as a feature indicating clonorchiasis, another liver disease of the eastern world.67 Intrahepatic stones are not regular features in pure Clonorchis infestation. In patients with Clonorchis infestation, the intrahepatic bile ducts are slightly enlarged with thickened wall and do not show marked dilatations and stenoses. The wall thickening is due to florid intramural mucinous glandular hyperplasia (so-called adenomatous hyperplasia) and tissue eosinophilia (Fig. 11), quite different from the chronic proliferative cholangitis in HL. It is only rarely complicated by acute suppurative cholangitis.
ETIOLOGY AND PATHOGENESIS
The stones are said to develop primarily in the lumen of the intrahepatic biliary tree. However, the mechanism of stone formation, the bile duct pathology, and alterations of hepatic bile preceding the stone formation remain speculative.
Judging from a high incidence of HL throughout East Asia and its rarity in the western world, ethnic and environment factors may be implicated. When HL is encountered in the west, they are mainly in the Asian immigrants. However, gallstones in individuals of Chinese and Japanese descent in the United States showed no difference from gallstones in the United States population in general.68 Despite a common ethnic origin, there are marked differences in relative incidence of HL among the Chinese patients in various Asian countries.69 These findings suggest that environmental rather than ethnic factors are important in the pathogenesis.
Bacterial Infection and Dietary Factors
The prevalent theory is that smoldering bacterial infection, particularly E. coli, coming from portal blood is responsible for the formation of stone as a result of deconjugation of bilirubin glucuronide by bacterial β-glucuronidase activity.70,71 The unconjugated bilirubin thus formed precipitates as calcium bilirubinate. This is also accompanied by increased hydrolysis of lecithin by bacterial phospholipases, accounting for the high content of fatty acid-calcium soaps in calcium bilirubinate stones. A low-protein, low-fat oriental diet contributes to decreased level of glucaro-1:4-lactone in the bile that normally inhibits β-glucuronidase.72 The role of the diet can account for the higher prevalence of HL observed in rural areas of Japan and a steady decline in the incidence in recent years.13,32 With the formation of biliary sludge, transient otherwise innocuous portal bacteremia is converted into pathogens in biliary system as a result of bile stasis which is further enhanced by the ensuing uneven dilatation and stricture of bile ducts. Once infection is established in the biliary tract, the concentration of glucuronidase of bacterial origin in the bile is increased. Further, hydrolysis of bilirubin glucuronide results with more stone formation and recurrent infection, producing a vicious cycle (Fig. 12). There is a argument whether bacterial infection is the cause or the result of stone formation. It has been shown that, at least in some patients with HL, bile infection preceded rather than followed stone formation.73
Early Korean studies have proposed chronic infestation of the biliary tree with endemic parasites such as C. sinensis and Ascaris lumbricoides as initiating factor, based on high incidence of infestation in HL and finding of dead parasites or ova within stones.21 The parasites can induce ductal injury, cause bile stagnation, and serve a nidus for stone formation. Thus, the term “oriental infestational cholangitis” was proposed and the route of infection was believed to be ascending.21
Although this may be true in some cases, it is not statistically convincing. Indeed in the olden days, evidence of C. sinensis infestation could be detected in 30% to 40% of the HL livers in Hong Kong, yet only 5% higher than that of general outpatients.2,8 With decreasing incidence of both diseases, HL and clonorchiasis nowadays are mostly seen as separate entities. Furthermore, there is continued presence of HL in spite of eradication of the intestinal parasites in Japan.69 A recent Korean nationwide survey also shows no significant positive correlation between clonorchiasis and choledocholithiasis or cholangitis,74 although there are still modern studies claiming evidence to the contrary.75 Anyway, the current consensus is that parasitic infestation is mostly likely a coincidental finding, and yet it does contribute to the severe clinical manifestations in these cases with double pathologies.
Local Bile Duct Factors
Japanese investigators drew attention to the proliferated peribiliary glands which produce much neutral and acid mucin with a different mucin profile.14,76 The mucin alters hepatic bile composition, changes the pH, increases the viscosity, and acts as nucleating agent (mucin glycoprotein), thus playing an important role in the sludge and stone formation and growth of calculi. It remains, however, unsettled what the initiating event of stone formation is: whether bacterial infection occurs first or glandular proliferation and mucus hypersecretion is responsible.
In the cases of cholesterol stones, the intrahepatic biliary tree showed neither remarkable stricture nor much inflammation of the duct wall.43–45 Culture of bile showed no bacteria, and there was an apparent increase in the lithogenic index of hepatic bile. It is presumed that the formation of intrahepatic cholesterol stones requires both the secretion of supersaturated bile and the presence of bile stasis, a mechanism different from bilirubinate stones. Alterations in bile acid synthesis and phospholipid secretion are also implicated,77 and a decrease activity of apolipoprotein A-1, an inhibiting factor of cholesterol nucleation in bile, has been shown.44 Stone dissolution can be considered in the treatment of these type of stones.78,79
In summary, HL is a sort of endemic disease of the far east. This diagnosis should also be considered in the Asian immigrants with biliary tract diseases.71 It is a complex disease characterized by its intractable nature and frequent recurrence, often requiring repeated medical, surgical, and radiologic treatment, and a multidisciplinary team approach. Understanding the underlying pathology avoids confusion with other diseases more prevalent in the western world, so that correct selection of the appropriate treatment can be offered for the best outcome.
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