Langerhans cell histiocytosis and choledocholithiasis: is there an association?

Langerhans cell histiocytosis (LCH) is a rare disease characterized by clonal proliferation of pathologic cells that have the characteristics of Langerhans cells.1 Langerhans cells are bone marrow–derived dendritic cells that normally reside in the skin and lymph nodes.2 The etiology of LCH remains unknown. The clinical presentation of LCH is heterogeneous and can involve single or multiple organs. Patients with LCH have infiltration with abnormal cells, which eventually results in organ dysfunction. Depending on the extent of organ involvement, LCH can range from benign disease to multisystem life-threatening disease.3 It remains unknown whether LCH is a reactive disorder or a neoplastic disorder. Clonal histiocytes have been detected in most patients with LCH, which suggests a neoplastic disorder.4 However, the alternative hypothesis is that LCH is a reaction against an infective agent that results in immune dysregulation.4 LCH is classified as single-system or multisystem disease. Single-system LCH is characterized by involvement of a single site (unifocal bone, skin, or lymph node) or involvement of multiple sites within the same organ system (multifocal bone or multiple lymph nodes). Multisystem LCH is characterized by involvement of 2 or more organ systems at diagnosis, with or without organ dysfunction.3 Involvement of the liver, lungs, spleen, or hematopoietic system is often associated with a poor prognosis and a high mortality rate.3 Liver involvement is usually seen in the disseminated form of LCH and presents with hepatomegaly related to infiltration of histiocytes into the sinusoids and portal tracts. Biliary involvement secondary to LCH can also occur but only in the disseminated form of the disease; in these cases, the prognosis is uniformly poor.5,6 Fortunately, biliary involvement, which can present as infiltration of intrahepatic and extrahepatic bile ducts, is a rare occurrence. The occurrence of jaundice is considered to be a bad prognostic sign, as biliary involvement is usually progressive. Langerhans cell infiltration of the bile ducts can present with progressive destruction and secondary sclerosing cholangitis, ultimately leading to secondary biliary cirrhosis.7 In fact, some authors have suggested that some cases of primary sclerosing cholangitis (PSC) are related to biliary involvement in patients with LCH. In advanced cases, differentiating these 2 conditions would be difficult. However, in contrast to patients with PSC, the involvement of extrahepatic ducts is rarely seen in patients with LCH.7 The patient reported by Krishnan and coauthors presented with a 1-year history of jaundice with no abdominal pain.8 He had been diagnosed with LCH and was on maintenance therapy with cyclosporine. An upper endoscopy revealed esophageal varices indicative of portal hypertension. Further evaluation revealed elevations in serum bilirubin, aminotransferases, and serum alkaline phosphatase levels. An ultrasound of the abdomen showed a dilated biliary system (common bile duct of 16 mm) with multiple large calculi, the largest of which was 3.8 cm in diameter and required sphincterotomy, mechanical lithotripsy, and stone removal. Krishnan and coauthors suggest a possible relationship between LCH and choledocholithiasis.8 However, their report does not make clear whether there was infiltration of Langerhans cells into the bile ducts nor whether jaundice improved and bilirubin normalized after stone removal. Whether the cholangiogram showed any evidence of secondary sclerosing cholangitis would also be interesting to note. The question we are facing with this case is whether choledocholithiasis was an incidental finding or related to LCH. One explanation is that, since bile duct stones are common in the general population, it would not be surprising to have cases of bile duct stones coexisting with essentially any other medical condition, including LCH. However, the rarity of bile duct stones in a pediatric patient would make this explanation less likely. Another explanation, which is also discussed by the authors, is that long-term maintenance treatment with cyclosporine could be responsible for biliary stone formation. Studies in animal models have shown that cyclosporine causes a significant decrease in bile flow and bile salt secretion without changes in biliary cholesterol and phospholipids.9 These changes alter the composition of bile and predispose patients to stone formation. In addition to the effects of cyclosporine, some reports have suggested a direct relationship between LCH and concomitant biliary sludge or stones. In a case series of 10 children with LCH and biliary involvement, evidence of biliary sludge and/or cholelithiasis was seen in 6 children (60%).10 Similar associations of bile duct stones with LCH have also been reported by other researchers.11,12 Yet another explanation for the observed association is that bile duct stones could be related to biliary stasis secondary to the sclerosing cholangitis–like condition seen in LCH patients. Patients with LCH may have cholestatic jaundice due to biliary ductular proliferation secondary to involvement of intrahepatic or extrahe-patic bile ducts, potentially resulting in portal triaditis and fibrosis. In an initial study of PSC patients, nearly 50% of patients had common bile duct stones on endo-scopic retrograde cholangiography, and these patients were 50% more likely to have ascending cholangitis compared to patients without stones.13,14 These stones likely contribute to the chronic inflammation, stricturing, cholestasis, and cholangitis seen in PSC patients. Similar to stone formation in PSC patients, LCH patients with secondary sclerosing cholangitis could be predisposed to stone formation, particularly when they are treated with agents such as cyclosporine, which alters the biliary milieu toward a prolithogenic state. To conclude, the report by Krishnan and coauthors suggests an interesting association.8 We believe that a multitude of coexisting factors can explain their patient’s predisposition to biliary stone formation. Biliary stasis secondary to bile duct inflammation, cyclosporine use, and a possible direct relationship between LCH and bile duct stones could have contributed, either alone or in combination, to cholecocholithiasis in this patient. Until future studies show the underlying pathophysiologic mechanism of biliary sludge/stone formation in patients with LCH, a possible relationship between LCH and biliary stones will remain hypothetical.