Prochlorperazine-induced chronic cholestasis

A patient with prochlorperazine-induced cholestasis that persisted for more than 2 years is reported. The timing of the onset of jaundice, the clinical, biochemical and histological findings and the subsequent course of this patient were typical of chlorpromazine-induced chronic cholestasis. Despite subsequent resolution of jaundice, liver biopsy performed 2 years after the onset of clinical disease showed fibrous expansion of the portal tracts with focal porto-portal and centro-portal bridging fibrosis, and paucity of inter-lobular bile ducts, a picture simulating that of primary biliary cirrhosis. Long-term follow-up is required to determine whether this patient will progress to frank cirrhosis.     

Idiopathic biliary ductopenia in adults: a report of five cases

The clinical and pathological findings of five adult cases of idiopathic nonsyndromatic paucity of interlobular bile ducts are reported. Patients were 18-32 years old at the onset of the disease; four presented with pruritus and/or jaundice and one with bleeding of the esophageal varices. Two patients were siblings. Serum alkaline phosphatase counts ranged from 1 to 16 times the upper normal value, and total bilirubin counts ranged from 0.6 to 8.8 mg/dL (10 to 150 mumol/L). Initial liver biopsy showed portal and periportal fibrosis with cholangiolar proliferation and reduction in the number of interlobular bile ducts. Antimitochondrial antibodies were absent, and bile ducts were normal after opacification. The patients were observed for 3-11 years. Repeated liver biopsies in the five patients showed progression of the lesions, with development of biliary type cirrhosis in four. Two of the four patients with cirrhosis died of hepatic failure 3 and 11 years after onset of the disease. In the two other cases, liver transplantation was performed successfully. These cases suggest that chronic cholestasis with marked ductopenia resembling the nonsyndromatic paucity described in infancy and childhood may reveal itself at an adult age. This disorder, possibly familial, may rapidly progress to severe and even fatal liver disease and could be a new indication for liver transplantation.     

Familial intrahepatic cholestatic cirrhosis in young adults

Two siblings with intrahepatic cholestatic cirrhosis and their brother, who had a potentially related disease at the time of accidental death, are presented. The onset of disease occurred during adolescence in all 3 cases. The initial sign was mild jaundice or portal hypertension. There was no abnormality in the countenance, cardiovascular system, or vertebral column. Except for the brother who died from an accident, jaundice gradually increased. Death followed due to cirrhosis. Liver biopsy specimens of these 2 patients showed diminution of interlobular bile ducts with no significant cholangitis. At autopsy, the livers of the 2 patients showed biliary cirrhosis without extrahepatic biliary obstruction. In both cases there was an accessory lobe on the right hepatic lobe. Histologically, septal bile ducts showed pronounced papillary proliferations of the epithelium; there was also a decrease in the number of small interlobular bile ducts. Excess copper accumulation in the liver was ascertained. It is suggested that the disease in the 2 autopsied cases is intrahepatic cholestatic cirrhosis due to hypoplasia of the intrahepatic biliary trees.     

Idiopathic adulthood ductopenia: case report and review of the literature

The clinical and pathological findings of idiopathic ductopenia were studied in a 30-year-old woman who initially manifested jaundice and pruritus. Serum biochemical tests of liver function indicated severe and progressive cholestasis. Viral hepatitis markers and circulating autoantibodies were absent. The patient had a normal cholangiogram and lacked evidence of inflammatory bowel disease. Histological examination of a liver specimen showed severe cholestasis and absence of interlobular bile ducts. Severe jaundice and intractable pruritus developed in the patient and served as the indications for liver transplantation 4 months after initial examination. Transplantation resulted in prompt and complete resolution of the jaundice and pruritus. Two types of idiopathic adulthood ductopenia associated with different prognoses are recognized. Patients with type 1 idiopathic adulthood ductopenia are asymptomatic or manifest symptoms of cholestatic liver disease. They tend to have less destruction of the intrahepatic bile ducts on liver biopsy specimens. Their clinical course ranges from spontaneous improvement to progression to biliary cirrhosis. In contrast, patients with type 2 idiopathic adulthood ductopenia generally manifest initial symptoms of decompensated biliary cirrhosis, have extensive destruction of the intrahepatic bile ducts on liver biopsy, and frequently require orthotopic liver transplantation.     

Medical treatment of primary sclerosing cholangitis

Until 1970, primary sclerosing cholangitis (PSC) was considered to be a medical curiosity. With the development of endoscopic cholangiography, PSC is now recognized more frequently and is a common indication for liver transplantation. PSC is usually progressive, leading to cirrhosis, portal hypertension, and liver failure. The manifestations of disease may be clinically similar to those of other causes of bile duct obstruction and must be distinguished from gallstone disease, bile duct carcinoma, primary biliary cirrhosis, and secondary biliary cirrhosis due to bile duct stricture. Medical management of PSC must take into account the likelihood that destroyed bile ducts do not regenerate as hepatocytes do. Hence, PSC should be treated early in its course. The goal of therapy is to prevent further damage and destruction of bile ducts. In this article, we will present relevant data concerning the medical management of primary sclerosing cholangitis.     

IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver

Inflammatory destruction of intrahepatic bile ducts is a common cause of vanishing bile duct syndrome and cholestasis, often progressing to biliary cirrhosis and liver failure. However, the molecular mechanisms underlying the pathogenesis of inflammatory biliary disease are poorly understood. Here, we show that the two IkappaB kinases, IKK1/IKKalpha and IKK2/IKKbeta, display distinct collaborative and specific functions that are essential to protect the liver from cytokine toxicity and bile duct disease. Combined conditional ablation of IKK1 and IKK2, but not of each kinase alone, sensitized the liver to in vivo LPS challenge, uncovering a redundant function of the two IkappaB kinases in mediating canonical NF-kappaB signaling in hepatocytes and protecting the liver from TNF-induced failure. Unexpectedly, mice with combined ablation of IKK1 and IKK2 or IKK1 and NEMO spontaneously developed severe jaundice and fatal cholangitis characterized by inflammatory destruction of small portal bile ducts. This bile duct disease was caused by the combined impairment of canonical NF-kappaB signaling together with inhibition of IKK1-specific functions affecting the bile-blood barrier. These results reveal a novel function of the two IkappaB kinases in cooperatively regulating liver immune homeostasis and bile duct integrity and suggest that IKK signaling may be implicated in human biliary diseases.     

Case Report: Secondary biliary cirrhosis possibly related to congenital hepatic fibrosis. Evidence for decreased number of portal branch veins and hypertrophic peribiliary vascular plexus

A 30-year-old man with presinusoidal portal hypertension was transplanted for cryptogenic cirrhosis. On the explanted liver, few intrahepatic stones, biliary cirrhosis, chronic cholangitis of the large bile ducts and a peculiar proliferation of small dilated bile ducts at the periphery of the portal tracts led to the diagnosis of secondary biliary cirrhosis and cholangitis, possibly linked to ductal plate malformation, including congenital hepatic fibrosis associated with a minor form of Caroli's disease. Ex vivo portogram and histology showed the paucity of portal vein branches and the hypertrophy of the peribiliary vascular plexus. This hypertrophy, which has been reported in livers with presinusoidal hypertension, is another indirect argument to suggest the diagnosis of congenital hepatic fibrosis.     

Hepatic disease in erythropoietic protoporphyria.

Two sisters had erythropoietic protoporphyria and a spectrum of liver disease. One (F.B.) died in hepatic failure within 3 months after the development of jaundice. Only 10 months before she died, she had exhibited only bromsulfalein retention and a borderline increase in serum transaminase. Surgical exploration because of the jaundice revealed patency of the bile ducts which was confirmed at autopsy. Wedge biopsy and autopsy specimens of liver showed an active cirrhosis with massive amounts of protoporphyrin in Kupffer cells, portal histiocytes, bile canaliculi and parenchymal cytoplasm. The other sister (L.R.) had never had symptomatic liver disease and only a slight increase in serum transaminase and bromsulfalein retention. On needle biopsy, the liver specimen showed portal inflammation with erosion of limiting plates, occasional bridging between triads and central areas of cell dropout. Protoporphyrin pigment was present in portal histiocytes, areas of central collapse and, more rarely, in parenchymal cytoplasm. These studies demonstrate that significant, progressive hepatic disease may occur insidiously in erythropoietic protoporphyria, and that once jaundice appears it may be followed rapidly by fatal hepatic failure.     

A case of biliary cast syndrome after cadaveric liver transplantation]

We experienced one fatal case of biliary cast syndrome after cadaveric liver transplantation involving both intrahepatic ducts. A 58-year-old man underwent cadaveric liver transplantation because of hepatitis B virus related liver cirrhosis and concomitant hepatocellular carcinoma. Five weeks after the liver transplantation, postoperative course was complicated by development of acute cholangitis. Subsequent endoscopic retrograde cholangiography revealed diffuse intrahepatic bile duct strictures without filling defects. Percutaneous liver biopsy, which was done to exclude rejection, revealed biliary cast. Successful endoscopic removal was precluded due to its diffuse involvement. Because of the deterioration of patient's condition by refractory biliary obstruction and cholangitis, retransplantation from cadaveric donor was performed. Debridement of the biliary tree after graft removal yielded a near-complete cast of the intrahepatic ductal system. Biliary cast syndrome should be suspected when jaundice or cholangitis is associated with dilated ducts on abdominal imaging studies in cadaveric liver transplantation recipients. Initial therapeutic options include removal of biliary cast after endoscopic or percutaneous cholangiography. Although endoscopic retrieval of biliary cast by endoscopic retrograde cholangiopancreatography could be employed as a first-line management, other modalities such as endoscopic nasobiliary drainage, percutaneous transhepatic drainage, or retransplantation should be considered when complete removal is not feasible and the condition of the recipient deteriorates.     

Expression of major histocompatibility complex class II antigens on bile duct epithelium in patients with hepatic graft-versus-host disease after bone marrow transplantation

We studied the expression of major histocompatibility complex (MHC) class II antigens in liver biopsies taken from ten patients with clinical and biochemical evidence of liver damage after bone marrow transplantation. In all six patients who had histologically confirmed graft-versus-host disease, MHC class II antigens were detected on intrahepatic bile ducts. In four patients with no histological features of graft-versus-host disease, MHC class II antigens were not detected. In controls, a positive reaction for bile duct MHC class II antigens was only detected in the patients with primary biliary cirrhosis. Characterisation of the lymphocytes surrounding the bile ducts showed a prevalence of Leu 3+ cells in graft-versus-host disease and primary biliary cirrhosis. We propose that the aberrant expression of class II antigens on bile duct epithelium cells may play a role in the pathogenesis of graft-versus-host disease. A similar pattern in primary biliary cirrhosis may suggest a common pathogenetic mechanism.     

Hepatic sarcoidosis with vanishing bile duct syndrome, cirrhosis, and portal phlebosclerosis. Report of an autopsy case

A few cases of sarcoidosis are associated with progressive liver disease, with a wide variety of clinicopathologic features. Herein, we report an autopsy case (65-year-old man). During an examination for liver dysfunction, cirrhosis with cholestatic dysfunction and splenomegaly were found. Needle liver biopsy revealed cirrhosis with lymphocytic piecemeal necrosis, dense septal fibrosis, and ductopenia. In addition, noncaseating epithelioid granuloma was also seen in the periportal region. Ductal enzymes and immunoglobulin M (IgM) levels were elevated, although antimitochondrial antibodies were negative. Instead, angiotensin-converting enzyme was elevated. He died of pulmonary failure and lung cancer. The autopsy liver (1,220 g) showed multinodular cirrhosis with broad and dense septa that divided the parenchyma. Mild lymphoid cell infiltration was seen in the periportal region. About a half of the interlobular bile ducts were lost, and the remaining bile ducts showed prominent periductal fibrosis, resembling sclerosing cholangitis. Interestingly, a few interlobular bile ducts showed chronic nonsuppurative cholangitis with epithelioid granulomas. Intrahepatic portal veins showed luminal narrowing with prominent phlebosclerosis. Hepatobiliary pathologies that resemble primary biliary cirrhosis and primary sclerosing cholangitis and that are followed by vanishing bile duct syndrome, chronic active hepatitis-related cirrhosis, and intrahepatic portal venous phlebosclerosis occur in a single case of sarcoidosis.     

Advanced cholangiocarcinoma in a patient with stage I primary sclerosing cholangitis

A 29‐year‐old woman presented with jaundice and fever in May 2001. Cholangiography showed multiple strictures and beading of the biliary tree, with a large stricture in the common bile duct and marked dilatation of the hilar bile ducts. Typical cholangiography findings and elevated hepatobiliary enzymes suggested primary sclerosing cholangitis (PSC). At the same time, computed tomography detected a 2‐cm tumor in the common bile duct, and angiography showed an encasement in the portal vein. Tumor markers, cytology, and biopsy were all negative for cancer. Although laparotomy showed a healthy liver and no lymph node metastasis was found, suggesting early‐stage PSC and a low likelihood of accompanying cholangiocarcinoma (CCA) reported so far, the tumor in the resected common bile duct was subsequently diagnosed as CCA. Therefore, pancreatoduodenectomy was performed combined with partial resection of the portal trunk. Histology also revealed invasion of the wall of the portal vein by cancer cells. The patient had a recurrence 5 months later and died 12 months after her operation. This is a rare case in which stage I PSC was complicated by advanced CCA.     

Intrahepatic bile duct loss in biliary atresia despite portoenterostomy: a consequence of ongoing obstruction?

The histological and immunohistochemical characteristics of the liver in 44 children (28 boys, 16 girls) with extrahepatic biliary atresia at different stages of the clinical course were studied. Thirty-four wedge liver biopsy specimens taken during Kasai operations (25 specimens) and relaparotomy (9 specimens) and 20 hepatectomy explants taken at the time of transplantation were examined. Routine histological stains and monoclonal antibodies against different molecular weight cytokeratins and HLA-DR were used. The histopathological changes and the pattern of cytokeratin expression observed during the course of the disease were suggestive of persistent or recurrent extrahepatic biliary obstruction that occurred despite the Kasai operation and eventually led to cirrhosis and liver failure. Quantitative studies showed a progressive loss of intrahepatic bile ducts over the time course of the disease. This destruction of bile ducts had a geographic anatomical distribution in hepatectomy specimens, and in two livers it occurred predominantly in only one lobe. This geographic distribution of the vanishing bile ducts probably indicates an unpredictable and uneven obliteration of bile ducts in the porta hepatis during portoenterostomy wound healing and scarring.     

Rapid progression of intrapulmonary arteriovenous shunting in polysplenia syndrome associated with biliary atresia

This report describes a patient with biliary atresia (BA) associated with polysplenia syndrome who showed a rapid progression of intrapulmonary arteriovenous shunting (IPS), resulting in a fatal outcome. Intrauterine ultrasonography at 36 weeks of gestation revealed fetal abnormalities, including situs inversus, absent retrohepatic inferior vena cava, and azygous connection. She was diagnosed postnatally as BA because of persistent acholic stool and neonatal jaundice. She underwent hepatic portoenterostomy at age 158 days. The gallbladder and the hepatic ducts were hypoplastic, and the common bile duct was absent. Magnetic resonance image and operative findings also identified polysplenia and an absent portal trunk. Liver histology showed cirrhotic changes and bile duct proliferation. Postoperatively, she achieved good bile secretion, with gradual decrease of total bilirubin. However, she had repeated febrile episodes, and computerized tomography at age 7 months showed multiple liver cysts. Thereafter, she presented with exertional dyspnea. Contrast-enhanced echocardiography showed IPS with a degree of 2/III at age 8 months and 3/III at 10 months. (99m)Technetium-labeled macroaggregated albumin ((99m)Tc-MAA) scintigraphy revealed a shunt ratio of 25.5% at 9 months and 39.7% at 10 months. Percutaneous transhepatic drainage of the bile cysts was performed without success. Sludged bile was obtained. However, respiratory distress rapidly progressed, and she died at age 11 months. In the present patient, the association of polysplenia syndrome and absent portal vein with BA, as well as liver cirrhosis, seemed to be contributing factors to rapid progression of IPS in early life.     

Rapid development of cirrhosis secondary to squamous cell carcinoma of the common bile duct

Summary A 68-year-old male underwent cholecystectomy with a normal operative wedge liver biopsy. Five months later he presented with secondary biliary cirrhosis and signs of portal hypertension and hepatocellular failure. At autopsy, a squamous cell carcinoma of the bile duct was found. This case represents an unusually rapid development of cirrhosis secondary to extrahepatic biliary obstruction with documentation of normal liver histology five months prior to his last admission.     

Living-related liver transplantation in a patient with end-stage hepatolithiasis and a biliary-bronchial fistula

Liver transplantation in patients with end-stage hepatolithiasis is complicated by the high incidence of the suppurative cholangitis and systemic infection. A 43-year-old Korean-Japanese woman with hepatolithiasis, biliary cirrhosis, suppurative cholangitis, and biliary-bronchial fistula underwent living-related liver transplantation (LRLT) using a right lobe graft of her sister. The risk of infection was minimized by preoperative percutaneous transhepatic biliary drainage initiated 2 months before transplantation. The native liver was resected en bloc with the extrahepatic bile ducts and the infected section of the right hemidiaphragm. Opportunistic infection was prevented by limiting antimicrobial therapy to the interval from preoperative day 3 to postoperative day 4. Immunosuppressive agents were given below standard dose. The postoperative course following LRLT was uncomplicated, and hepatic function was good. Careful management of infection and adequate graft size are essential for successful LRLT in patients with end-stage hepatolithiasis.     

Lipids and lipid-activated vitamins in chronic cholestatic diseases

Primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune cholangiopathy are cholestatic liver diseases of unknown cause. Destruction of small to medium bile ducts (in primary biliary cirrhosis and autoimmune cholangiopathy) and large bile ducts (in primary sclerosing cholangitis) leads to progressive cholestasis, liver failure and end-stage liver disease. A variety of abnormalities in lipid metabolism have been described in primary biliary cirrhosis, and range from alterations in serum lipid levels and lipoprotein subsets to deranged metabolism of cholesterol. Progressive cholestasis and, consequently, decreased small intestinal bile acid concentrations in these cholestatic liver disease can also lead to impaired absorption of fats and fat-soluble vitamins, resulting in steatorrhea and deficiencies in vitamins A, D, E, and K. This article focuses on abnormalities in lipid metabolism in primary biliary cirrhosis and primary sclerosing cholangitis, and on lipid-activated vitamin deficiencies in these disorders.     

Histometric and serial section observations of the intrahepatic bile ducts in primary biliary cirrhosis.

Histometric examinations, based on the assumption that hepatic arterial branches and bile ducts run parallel within the portal tracts, suggest that in primary biliary cirrhosis bile ducts with a lumen (the smallest diameter between the subepithelial basal membranes) below 70--80 micron are destroyed. The smaller the ducts, the more they destroyed. Extensive destruction of the ducts was seen more frequently in the nonfibrotic stage of primary biliary cirrhosis than in later stages. Serial sections of the intrahepatic bile ducts in primary biliary cirrhosis revealed three types of periductal lesions preceding the disappearance of bile ducts: (A) periductal cellular reaction including features of chronic nonsuppurative destructive cholangitis, (B) periductal edema, and (C) periductal fibrosis. In the nonfibrotic stage, types A and C were frequent, whereas in the fibrotic stage types A and B were increased, and type C was predominant in the cirrhotic stage.     

Pathology and pathogenesis of intrahepatic bile duct loss

In recent years, the pathology and pathogenesis of bile duct loss have been extensively studied, and a num‐ber of hepatobiliary diseases have been added to the list of ductopenic diseases. In addition, the biology of biliary epithelial cells is now being studied with respect to bile duct loss, as well as biliary epithelial neoplasia. In this review, recent advances in pathogenetic and pathological studies of intrahepatic bile duct loss are described, with an emphasis on immune‐mediated cholangiopathies. The bile duct loss, an acquired and pathologic process that occurs in the biliary tree, is recognizable as an absence of bile duct in an individual portad tract, and also as such absence in the vicinity of parallel running hepatic arterial branches that constitute the portal triad. Immunostaining with biliary cytokeratin and other carbohydrate materials is useful for the identification of biliary elements in the inflamed portal tracts or fibrous septa. The underlying processes responsible for bile duct loss include immunological, ischemic, infectious, metabolic, and toxic processes. Bile duct loss in primary biliary cirrhosis and primary sclerosing cholangitis is immune‐mediated, that in interventional radiology using hepatic arterial branches is related to biliary ischemia, while that in hepatic allograft rejection is related to both immunological and ischemic insults. Bacterial and viral cholangitis with bile duct loss is an example of infectious cholangitis. The biliary tree maintains its homeostasis by renewal and dropout, and bile duct loss occurs mainly via biliary apoptosis. In some patients with bile duct loss, such as occurs in drug‐induced injuries, the bile ducts regenerate and finally redistribute in the liver, while in other types of bile duct loss, the loss is progressive and is followed by vanishing bile duct syndrome, leading to biliary cirrhosis or liver transplantation. More analysis of the biology of biliary epithelial cells is mandatory for the evaluation of the pathobiology of bile duct loss, as well as for the effective restoration of biliary epithelial cells, in ductopenic liver diseases.     

The liver in biliary obstruction due to chronic pancreatitis

Biliary obstruction is an important complication of chronic calcifying pancreatitis. In this study, liver biopsies were examined to determine the nature and severity of hepatic complications in 23 such cases. The most striking changes were portal tract expansion due to oedema and fibrosis, with proliferation of bile ducts. Although common, these changes were not severe, and no patient had developed secondary biliary cirrhosis. Other features of note were intrahepatic cholestasis, iron overload (56.5%), copper-associated protein stained with the orcein technique (34.7%) and mild fatty change or perivenular sclerosis in 13%. It is concluded that no serious, irreversible pathological changes occurred in the liver despite clinically marked biliary obstruction.