Diagnosis of primary sclerosing cholangitis

Primary sclerosing cholangitis is a progressive chronic hepatobiliary disorder of unknown aetiology for which no effective medical therapy currently exists. This syndrome occurs most commonly in young men and is frequently associated with ulcerative colitis. Primary sclerosing cholangitis should be considered in the differential diagnosis of all patients presenting with chronic cholestasis. The diagnosis is based on a combination of the clinical features and cholestatic biochemical profile accompanied by typical cholangiographic abnormalities and is supported by liver histology findings. The major diagnostic criterion is the finding at cholangiography of irregularly distributed multifocal strictures within both the intrahepatic and extrahepatic bile ducts. The most characteristic histological feature of primary sclerosing cholangitis is periductal concentric obliterative fibrosis of small interlobular bile ducts with or without proliferation of bile ducts in portal tracts, but liver biopsy findings alone are infrequently diagnostic. Nevertheless, liver histology remains important to exclude other causes of chronic cholestasis and in staging the disease. Received for publication on March 29, 1999; accepted on April 30, 1999     

Peripheral bile duct paucity and cholestasis in the liver of a patient with Alagille syndrome: further evidence supporting a lack of postnatal bile duct branching and elongation

Alagille syndrome (AGS) is a developmental, multiorgan disease caused by mutations of the Jagged1 gene. The liver is one of the major organs affected in AGS, and the hallmark of liver pathology in AGS is an age-related increase in the proportion of portal tracts that have no bile duct, but without evidence of prominent bile duct damage. The pathogenesis of this bile duct paucity is currently not well understood. (Immuno)histochemical and molecular analyses were performed on several liver biopsies that were taken during macroscopic examination of the explant liver of a 17-year-old AGS patient. The liver periphery was macroscopically pale and was microscopically characterized by complete absence of bile ducts and presence of severe cholestasis, but there was no ductular reaction. Conversely, the central, hilar portion contained normally developed bile ducts showing no or minimal damage and cholestasis. A missense mutation in the Jagged1 gene was present in both parts of the liver, indicating that mosaicism did not cause this peculiar picture. There was also a hypertrophy of the hepatic arterial branches in the liver periphery. Together with previous indirect findings, the current study of the explant liver of an AGS patient strongly suggests that a lack of branching and elongation of bile ducts during postnatal liver growth is the mechanism by which peripheral bile duct paucity and cholestasis develops in AGS. Our findings also suggest that anomalies of the intrahepatic arterial branches may be part of AGS in some patients.     

The Importance of Portal Venous Blood Flow in Ischemic‐Type Biliary Lesions after Liver Transplantation

Ischemic‐type biliary lesions (ITBL) are the most frequent cause of nonanastomotic biliary strictures after liver transplantation. This complication develops in up to 25% of patients, with a 50% retransplantation rate in affected patients. Traditionally, ischemia‐reperfusion injury to the biliary system is considered to be the major risk factor for ITBL. Several other risk factors for ITBL have been identified, including the use of liver grafts donated after cardiac death, prolonged cold and warm ischemic times and use of University of Wisconsin preservation solution. In recent years however, impaired microcirculation of the peribiliary plexus (PBP) has been implicated as a possible risk factor. It is widely accepted that the PBP is exclusively provided by blood from the hepatic artery, and therefore, the role of the portal venous blood supply has not been considered as a possible cause for the development of ITBL. In this short report, we present three patients with segmental portal vein thrombosis and subsequent development of ITBL in the affected segments in the presence of normal arterial blood flow. This suggests that portal blood flow may have an important contribution to the biliary microcirculation and that a compromised portal venous blood supply can predispose to the development of ITBL.     

高位胆管良性狭窄的原因和治疗

目的探讨高位胆管良性狭窄的原因和防治。方法回顾性总结分析高位胆管良性狭窄460例的病因和治疗方法。结果病因依次为肝胆管结石(383例)、高位胆管损伤(54例)、胆囊结石Mirizzi综合征(21例)、单纯良性狭窄(2例)。分别行肝叶或肝段切除；经肝剖开狭窄胆管，肝胆管或肝门胆管空肠吻合；肝门胆管狭窄切开整形后与空肠大口吻合；吻合口狭窄切开扩大吻合；肝门胆管狭窄切开整形后T管支撑等手术。效果满意，优良率为90．1％。结论高位胆管良性狭窄的主要原因是肝胆管结石(83．3％)和高位胆管损伤(11．7％)。肝叶或肝段切除，或联合肝内胆管或肝门胆管空肠大口吻合是治疗肝胆管结石并肝胆管狭窄的有效方法。高位胆管损伤初期修复后较易发生胆管或吻合口狭窄，再次修复以胆管空肠Roux-en-Y大口吻合术效果最好。强调重在预防，在行胆道手术时避免胆管损伤。     

Prevention of biliary lesions that may occur during radiofrequency ablation of the liver: study on the pig

OBJECTIVE: To prevent bile duct injury by using a cold 5% glucose isotonic solution cooling in the bile ducts when radiofrequency (RF) is performed in a porcine model. SUMMARY BACKGROUND DATA: Complications that may arise during liver RF ablation include biliary stenosis and abscesses. METHODS: The RITA 1500 generator was used for the experiments. Two lesions were performed in the left liver. The pigs were killed 1 or 3 weeks after the procedure. An ex vivo cholangiogram was obtained by direct injection into the main bile duct. Samples of RF lesions, of liver parenchyma near and at a distance from the RF lesions, underwent pathologic studies. Two groups of 20 pigs each were treated: one without perfusion of the bile ducts and the other with perfusion of cold 5% glucose isotonic solution into the bile ducts. The Pringle maneuver was used in 50% of the RF procedures. Radiologic lesions were classified as biliary stenosis, complete interruption of the bile duct, or extravasation of the radiologic contrast liquid. RESULTS: Histologic lesions of the bile ducts were observed near the ablated RF lesion site and at a distance from the RF lesions when a Pringle maneuver was performed. Radiologic and histologic lesions of the bile ducts were significantly reduced (P < 0.0001) when the bile ducts were cooled. CONCLUSIONS: Cooling of the bile ducts with a cold 5% glucose isotonic solution significantly protects the intrahepatic bile ducts from damages caused by the heat generated by RF when performed close to the bile ducts.     

腹腔镜胆囊切除术中胆管损伤防治分析

目的探讨腹腔镜胆囊切除术（laparoscopic cholecystectomy,LC）术中胆管损伤原因,总结处理经验。方法回顾性分析1998年10月-2006年8月1 528例LC术中9例（0.59%）胆管损伤的资料。结果本组7例术中发现胆管损伤,4例予局部压迫处理,1例术中置入T管引流,2例中转开腹手术。另有2例术后出现胆汁性腹膜炎而二次手术,术中发现胆总管损伤,予T管支撑引流治愈。开展LC的前500例中发生胆管损伤6例（1.20%）,其中中转开腹手术2例（0.40%）;500例以后的LC,胆管损伤率为0.29%（3/1 028）,中转开腹率为0。结论LC术中胆管损伤多发生在复杂病理改变的病例,强化对解剖变异、高危病例及高危技术的认识是避免胆管损伤的关键;一旦发生LC术中不能良好处理的胆管损伤,及时中转开腹手术是理性的选择。     

Reconstructive surgery for ischemic-type lesions at the bile duct bifurcation after liver transplantation.

OBJECTIVE: To assess the feasibility, morbidity, mortality, and clinical success rate of surgical reconstruction of the biliary system in patients with ischemic-type biliary lesions in their liver graft. SUMMARY BACKGROUND DATA: After liver transplantation, strictures in the biliary tree with secondary sludge formation can occur in the absence of vascular problems. Jaundice, pruritus, and recurrent cholangitis are predominant clinical features leading to considerable morbidity. Interventional measures are the first-line treatment but are frequently only of transient success. Retransplantation is usually considered when interventional treatment is not effective. METHODS: Surgical exploration and reconstruction was performed in 17 patients with ischemic-type biliary strictures at a median of 2 years after liver transplantation. Findings during surgery, surgical strategies, and postsurgical courses are described. Clinical symptoms and biochemical parameters of cholestasis and liver function were analyzed in the postsurgical course. RESULTS: During surgery, all 17 patients were found to have strictures or sclerotic changes involving the hepatic bifurcation and extrahepatic bile duct. Sludge or stones were present in nine patients. In 14 patients with viable bile ducts proximal to the bifurcation, surgical reconstruction was performed by resection of the bifurcation and hepaticojejunostomy. In three patients with more extensive biliary destruction, portoenterostomy with or without peripheral hepatojejunostomy was performed. The prevalence rate of biliary infection at surgery was 93%; the predominant organisms were Candida and enterococci. The perioperative mortality rate was 0%. Clinical symptoms and biochemical parameters became normal or were considerably improved in 14 of 16 patients (88%). CONCLUSIONS: The hepatic bifurcation seems to be a predominant site for ischemic-type biliary changes after liver transplantation. Surgical treatment by resection of the bifurcation and reconstruction by high hepaticojejunostomy is a safe and highly effective approach leading to cure or persistent major improvement in most patients.     

Presence of multiple bile ducts in the liver graft increases the incidence of biliary complications in pediatric liver transplantation.

We studied the impact of multiple bile duct anastomosis on the development of biliary complications after liver transplantation in children. A total of 101 patients received a primary liver transplant and were divided into 2 groups: those with a single bile duct (n = 77) and those with multiple bile ducts (n = 24). Mean follow-up was 39.8 +/- 20.8 months. A total of 27 patients presented with biliary complications (26.7%), 18 patients (18.7%) presented with early complications (12 leaks and 6 strictures), and 9 patients (8.9%) had late strictures. Hepatic artery thrombosis (HAT) and multiple bile ducts were significant risk factors for the development of biliary complications, and the presence of multiple bile ducts was an independent risk factor. Patients with multiple bile ducts had a significantly greater incidence of total biliary complications compared to those with single ducts. Patients with multiple ducts had a higher incidence of leaks when compared to those in the single duct group, but the incidence of strictures, both early and late, was similar in both groups. One-year patient and graft survivals were not statistically different in the 2 groups. In conclusion, the presence of more than one bile duct in the graft is an independent risk factor for the development of biliary complications after pediatric liver transplantation.     

Vanishing bile-duct syndrome following liver transplantation--is it reversible?

Loss of bile ducts is a characteristic feature of chronic rejection in the liver allograft (also known as irreversible rejection and vanishing bile-duct syndrome). Typically, this occurs as a progressive lesion resulting in irreversible damage and graft failure requiring retransplantation. In this study, we describe 6 patients who developed a transient loss of bile ducts following liver transplantation. This occurred in a series of 138 patients who underwent the first 160 liver transplant operations in the Birmingham Liver Transplant Programme (incidence = 4.4% of patients, 3.7% of grafts). Forty needle biopsies were obtained from the 6 patients between 6 and 1303 days after transplantation. Thirteen specimens, taken between 8 and 1253 days posttransplant (median 98 days) showed an absence of bile ducts in more than 50% of portal tracts. Other histologic features of chronic rejection, inflammatory bile-duct lesions, perivenular cholestasis, and hepatocyte dropout were also seen in these biopsies, and severe cholestasis was present biochemically (median serum bilirubin level 240 mumol/L). The histologic and biochemical changes were thought to be compatible with a diagnosis of chronic/irreversible rejection, but the decision to carry out retransplantation was deferred on the basis of stable and, subsequently, improving biochemistry. Follow-up biopsies showed recovery of duct loss and other histologic abnormalities. All 6 patients are currently alive and well with good graft function. It is concluded that a transient, reversible bile-duct loss can occur after liver transplantation and that cases with this condition are indistinguishable from those who subsequently develop irreversible graft damage. In view of the risks associated with additional immunosuppression and/or retransplantation, caution is advocated in the interpretation of ductopenia in posttransplant liver biopsies. We suggest that the term "early chronic rejection" might be appropriate to describe cases in which a definite diagnosis of irreversible graft damage cannot be made.     

Retrograde reperfusion via vena cava lowers the risk of initial nonfunction but increases the risk of ischemic-type biliary lesions in liver transplantation – a randomized clinical trial

Initial nonfunction (INF) and biliary complications such as ischemic-type biliary lesion (ITBL) remain two major complications in clinical orthotopic liver transplantation (OLT). The influence of ischemia and reperfusion injury (I/R) as a significant risk factor for both complications is widely unquestioned. A new reperfusion technique that reduces I/R injury should lead to a reduction in both INF and ITBL. One hundred and thirty two OLT patients were included in this study and randomized into two groups. Group A underwent standard reperfusion with anterograde simultaneous arterial and portal reperfusion and group B received retrograde reperfusion via the vena cava before sequential anterograde reperfusion of portal vein and hepatic artery. Serum transaminase level as a surrogate parameter for I/R injury and serum bilirubin level as a parameter for graft function were significantly reduced during the first week after OLT in group B. INF rate was 7.7% in group A and 0% in group B (P = 0.058). ITBL incidence was 4.55% in group A versus 12.3% in group B (P = 0.053). Retrograde reperfusion seemed to be beneficial for hepatocytes, but was detrimental for the biliary epithelium. The unexplained increased incidence of ITBL after retrograde reperfusion will be focus of further investigation.     

Cancer of the bile ducts associated with ulcerative colitis.

Thirteen patients with bile duct cancer (excluding gallbladder) and associated chronic ulcerative colitis (CUC) were seen at the Mayo Clinic from 1935 through 1973. Most patients had initial symptoms of severe diarrhea and bleeding, followed by a pattern of mild-to-moderate disease with exacerbations and remissions. Three patients had especially severe symptoms and underwent total colectomy (1 patient) or proctocolectomy (2 patients) an average of 15.7 years from onset of CUC symptoms. Anorexia, followed rapidly by the development of progressive jaundice (or a sudden deterioration when liver disease was already present), marked the onset of symptoms of bile duct cancer in the 13 patients. The overall mean duration from onset of CUC to development of symptoms of bile duct cancer was 19 years. The patients in whom colitis was managed by proctocolectomy or total abdominal colectomy developed symptoms of bile duct cancer an average of 9.4 years after colectomy. When cancer was diagnosed, the tumor had spread beyond the bile ducts in 10 patients. The tumors were difficult to identify and often infiltrated the hepatic hilus. The present series and review of the literature suggest that the relationship between CUC and bile duct cancer is more than a chance occurrence. The carcinoma has an onset approximately 3 decades earlier than does carcinoma of the bile ducts without CUC. Surgical removal of the diseased colon and mode of medical management of the unresected colon have no relationship to the subsequent development of carcinoma of the bile ducts; neither does the extent or severity of the colonic disease. The prognosis of carcinoma of the bile ducts unfortunately continues to be dismal.     

Agenesis of the extrahepatic bile ducts: report of five cases

Five patients were encountered in whom agenesis either of the proximal extrahepatic biliary ducts (four patients) or total absence of the extrahepatic bile ducts and gall bladder (one patient) were evaluated. Jaundice was diagnosed from at birth to 3 weeks of age (average, 1.2 weeks of age) in these five patients. The patients' ages ranged from 2 to 8 weeks at the time of surgical exploration. Findings at surgery showed either absence of the entire extrahepatic biliary ducts or proximal bile duct remnants, no evidence of an inflammatory process, and no fibrous mass present at the portahepatis. Liver biopsy specimens showed histological evidence of cholestasis, minimal bile duct proliferation and fibrosis, and nearly complete absence of inflammation. In three patients in whom a portocholecystostomy was performed, no bile flow was obtained. Two patients underwent surgical exploration and liver biopsy only. One patient died as a result of severe congenital heart disease at 3 months of age. Four patients have undergone successful hepatic transplantation. These patients are now 10 months to 6 years of age. In our review of the literature, we were unable to find any reports of bile duct agenesis despite the fact that it appears to be a known phenomenon. We conclude that patients with biliary agenesis have early onset of jaundice when compared with patients with biliary atresia, absence of inflammation at the portahepatis at the time of surgical exploration, as well as on biopsy of the liver. Portoenterostomy or portocholecystostomy are likely to fail. We believe that liver transplantation is the treatment of choice for this rare entity.     

Dearterialization of the liver causes intrahepatic cholestasis due to reduced bile transporter expression

BACKGROUND: Bile duct injury after hepatic artery thrombosis (HAT) in liver transplantation is believed to be caused by ischemia predominantly. We aimed to define the involvement of bile secretory dysfunction in the pathogenesis of liver injury after HAT. METHODS: In a murine model, the main hepatic artery, the extrahepatic peribiliary plexus, or both arterial connections to the liver were interrupted (n=5 for each group). After 1, 14, or 28 days, hepatobiliary function was assessed by analysis of bile transporter expression, serum bile acids and bilirubin, and hepatic ATP content. In addition, cellular injury was assessed by light microscopy and biochemical markers. RESULTS: There were no signs of hepatobiliary dysfunction or injury in sham-operated animals or in mice with interruption of the hepatic artery or the extrahepatic peribiliary plexus alone. However, as early as 24 hr after complete dearterialization, bile transporter expression was significantly reduced and intrahepatic cholestasis started to progress the following weeks. Histologic studies at 28 days after complete dearterialization showed severe hepatobiliary injury. CONCLUSIONS: This study indicates that arterial blood supply is critical for normal bile secretion. Bile duct injury after complete arterial deprivation is preceded by a loss of bile secretory function and subsequent intrahepatic cholestasis.     

Choledocho-Choledochostomy in Deceased Donor Liver Transplantation

Biliary complications following deceased donor liver transplantation occur with an incidence of approximately 5–10%. The most common type of biliary reconstruction in whole-organ deceased donor liver transplantation remains the choledocho-choledochostomy, which creates an anastomosis between the donor and recipient common bile ducts or common hepatic ducts. Key elements in performing a successful choledocho-choledochostomy include ensuring that bile ducts have adequate blood supply and avoiding mechanical trauma or tension on the anastomosis. Techniques including ductoplasty and spatulation can be used to fashion an anastomosis even in the face of significant size mismatch between donor and recipient bile ducts. This article describes the technique of choledocho-choledochostomy in deceased donor liver transplantation.     

Progressive familial intrahepatic cholestasis

Progressive familial intrahepatic cholestasis (PFIC) is an important cause of cholestatic liver disease and biliary cirrhosis in pediatric population. Three cases of PFIC are described that were diagnosed on the basis of family history, pruritus, cirrhosis and / or paucity of interlobular bile ducts on liver biopsy and presence of extrahepatic biliary tree on imaging. These patients were initially labeled as suffering from extra-hepatic biliary atresia and neonatal hepatitis. PFIC-1 and 2 could not be differentiated on histological grounds, since these patients presented late and process of fibrosis was advanced.     

Successful heterotopic segmental liver transplantation from a live donor to a patient with Alagille syndrome

Alagille syndrome is characterized by a paucity of bile ducts in the liver. The syndrome is associated with some or all the features of chronic cholestasis, cardiac disease, skeletal abnormalities, ocular defects and a distinctive facial appearance. The most common finding is chronic cholestasis, which causes intractable pruritus, xanthoma, deficiency of certain metabolic nutrients and growth retardation. Cardiac abnormalities are the most common cause of death in these patients. It is unusual to see the clinical picture of hepatic failure resulting in cirrhosis and requiring transplantation, but liver transplantation is indicated in Alagille syndrome patients who have chronic cholestasis. If the disease is diagnosed in childhood, transplantation can improve significantly the patient's prognosis and the quality of life. In recent years, auxiliary liver transplantation has gained popularity for treating both acute and chronic liver disease. Heterotopic segmental liver transplantation is an alternative treatment modality for patients who do not require native liver removal. Individuals with Alagille syndrome are good candidates for this type of treatment. J Pediatr Surg 36:667-671.     

Cholostase und Leberinsuffizienz beim Intensivpatienten

Cornerstones of the diagnostic investigations of disturbances in liver function are analysis and sophisticated evaluation of serum liver enzymes, bilirubin and ammonia. Coagulation factors, serum albumin and cholinesterase levels are indicators of the hepatic metabolic capacity. Dynamic assessment of complex liver functions allows quantification of the hepatic metabolic activity and excretory function. Imaging techniques permit visualization of the size and texture of the liver, the vascular supply and perfusion as well as an assessment of the gall bladder and the extra-hepatic and intra-hepatic bile ducts. Manifold causes for cholestasis and/or liver dysfunction are known, such as ventilation with high pressure, total parenteral nutrition, shock, hypoxia and certain drugs. Obstructive cholestasis requires reconstitution of bile duct drainage, while non-obstructive cholestasis primarily requires treatment of the causative disease. The symptomatic therapy of liver insufficiency is rarely possible via direct treatment of the cause, but mostly requires specific management of secondary organ dysfunctions related to hepatic dysfunction including circulatory failure, hepatorenal syndrome and hepatic encephalopathy. In rare cases a temporary liver surrogate is necessary. The molecular absorbent recirculating system (MARS), a form of extracorporeal albumin dialysis, is introduced as a modality for the treatment of liver failure.     

Diagnosis and treatment of cicatricial strictures of the extrahepatic bile ducts

On the basis of the assessment of the results of treatment of 73 patients with cicatricial bile duct strictures, it was established that duration and degree of the pronouncement of cholestasis, presence of infection in the bile ducts influenced its early and long-term results. Adequate correction of cholestasis with carcass drainage of anastomoses permits to achieve a stable positive effect in 78.6% of the patients operated on.     

Bile duct apoptosis and cholestasis resembling acute graft-versus-host disease after autologous hematopoietic cell transplantation

BACKGROUND: Acute graft-versus-host disease (GVHD) of the liver is a frequent complication of allogeneic hematopoietic cell transplantation. This report describes hepatic GVHD following autologous transplantation. METHODS: We reviewed 116 consecutive autologous transplant recipients. A diagnosis of GVHD was based on histology (segmental to subtotal destruction of bile ductal epithelial cells with apoptosis and lymphocytic infiltrates), clinical criteria (elevated serum alkaline phosphatase), a response to immunosuppressive therapy, and finding no other cause for cholestatic liver disease. RESULTS: Two patients developed cholestatic liver disease (alkaline phosphatase levels over five times the normal upper limit) and had liver biopsies showing apoptotic and dysmorphic ductular epithelial cells typical of GVHD. Three additional patients developed cholestasis and intestinal symptoms but had gastric biopsies only, showing apoptotic crypt epithelial cells and crypt cell drop-out typical of GVHD. CONCLUSION: Two recipients of autologous hematopoietic cells developed histologic abnormalities of small bile ducts and cholestatic liver disease resembling GVHD of the liver after allogeneic transplant. The mechanisms of bile duct damage in this setting may involve immune dysregulation related to reconstitution of immunity with peripheral blood stem cells.     

Biliary complications following liver transplantation: single-center experience

Biliary complications (BC) following orthotopic liver transplantation (OLT) remain one of the major causes of postoperative complications and treatment failures. The list of common BC consists of biliary stricture, fistula, ischemic type biliary lesions (ITBL), cholangitis, and bile leakage following T-drain removal. Between July 2000 and December 2004, 101 consecutive cadaveric OLTs were performed in our institution. All but three were first full-size grafts. Seventeen patients were transplanted from the urgent list, the remaining 84 (83.16%) from the elective list. All but three patients had a choledochocholedochostomy over a straight drain. Bile cultures were taken routinely. The bile drain was removed following cholangiography 6 weeks after OLT. All patients received antibiotic prophylaxis. Ursodeoxycholic acid was used in selected cases. During the first 6 weeks positive bile cultures in absence of clinical and biochemical symptoms of cholangitis were found in 61 (60.4%) cases. Symptomatic cholangitis requiring antibiotic treatment was observed in 19 (18.8%) patients during the first 6 weeks. Two patients required endoscopic sphincterotomy and temporary stenting due to anastomotic stricture (1) or papilla of Vater fibrosis (1). Bile leakage following drain removal was observed in 8 (7.9%) patients. Five of them were treated conservatively, the remaining 3 (2.9%) required surgery (lavage) and stenting. In one case extrahepatic bile duct necrosis was diagnosed requiring reconstruction of the biliary anastomosis. No case of ITBL, bile leak at the anastomostic site, or stricture requiring surgical repair was noted. Despite the high incidence of positive bile cultures most likely related to use of a drain, the overall number of BC was low.