Significance of ductal plate malformation in the postoperative clinical course of biliary atresia

Purpose

Ductal plate malformation (DPM) is one of the etiologic theories for the development of biliary atresia (BA). In this study, we investigated the significance of DPM in the postoperative clinical course of BA, especially as a predictive factor of jaundice clearance.

Methods

Between 1988 and 2005, 31 patients with uncorrectable BA underwent hepatoportoenterostomy and steroid therapy. Immunohistochemistry was used to characterize biliary structures using cytokeratin 19. Specimens were defined as DPM-positive if a concentric cellular arrangement was detected. This retrospective study included comparisons of preoperative characteristics, the postoperative jaundice period, and cumulative steroid doses between patients with and without DPM.

Results

Of the 31 patients with uncorrectable BA, 25 (80.6%) became jaundice-free. Ductal plate malformation was detected in 11 (35.5%) of the 31. Between the 2 groups, there were no differences in preoperative characteristics or in the postoperative jaundice-free rate. Among those who became anicteric, the postoperative jaundice period was 145.3 ± 69.9 days in the DPM-positive group (n = 9) and 81.8 ± 44.7 days in the DPM-negative group (n = 16) (P < .05). The total administered steroids were 149.7 ± 78.2 and 95.0 ± 60.2 mg/kg, respectively (P = .09).

Conclusion

Ductal plate malformation may disturb bile flow and require more steroid to improve bile drainage. Therefore, the presence of DPM in the liver predicts poor bile flow after hepatoportoenterostomy in infants with BA.     

The etiology of "white bile" in the biliary tree

"White bile" is the colorless fluid occasionally found in occluded biliary systems. The absence of pigments in this "bile" was not satisfactorily explained. The objectives of this study were to assess its etiology. In dogs, "white bile" developed whenever both the common bile duct and the cystic duct were ligated. In comparison, dark green ("black") bile occurred when only the common bile duct was ligated leaving the gallbladder in communication with the obstructed ducts. The pressure in extrahepatic ducts containing "white bile" was significantly higher than in those filled with "black bile." Flow in the extrahepatic ducts was assessed by the aid of radioiodinated human serum albumin (RIHSA). When "black bile" was present, the direction of flow was from the extrahepatic ducts into the gallbladder. Whenever "white bile" developed, a reverse flow from the extrahepatic ducts into the liver was observed. Thus, the role of the gallbladder appears to be decompression of the biliary system allowing bile flow from the liver even in obstruction. In the absence of the gallbladder water absorption activity, the colorless secretion of the bile ducts seems to "back wash" into the liver and replace the bile present in the ducts at the time of occlusion.     

High-dose steroids,ursodeoxycholic acid,and chronic intravenous antibiotics improve bile flow after Kasai procedure in infants with biliary atresia

Background/Purpose: Early reports suggest that the use of steroids after Kasai portoenterostomy may improve bile flow and outcome in infants with biliary atresia. Methods: Of 28 infants with biliary atresia, half received adjuvant high-dose steroids, and half received standard therapy. Infants in the steroid group (n = 14) received intravenous solumedrol (taper of 10, 8, 6, 5, 4, 3, 2 mg/kg/d), followed by 8 to 12 weeks of prednisone (2 mg/kg/d). The steroid protocol also included ursodeoxycholic acid indefinitely and intravenous antibiotics for 8 to 12 weeks followed by oral antibiotic prophylaxis. Infants in the standard therapy group (n = 14) received no steroids, occasional ursodeoxycholic acid, and perioperative intravenous antibiotics followed by oral antibiotic prophylaxis. The infants were not assigned randomly, but rather received standard therapy or adjuvant steroid therapy according to individual surgeon preference. Results: Eleven of 14 (79%) in the steroid group and 3 of 14 (21%) in the standard therapy group had a conjugated bilirubin level less than 1.0 within 3 to 4 months of surgery (P [lt ] .001). Fewer patients in the steroid group (21% v 85%) required liver transplantation or died during the first year of life (P [lt ] .001). Infants in the steroid group did better despite the fact that this group included 5 infants with biliary atresia-polysplenia-heterotaxia syndrome, a subgroup that might have been expected to have a poor prognosis. Neither bile duct size nor liver histology was a reliable predictor of success or failure in either group. Conclusions: Adjuvant therapy using high-dose steroids, ursodeoxycholic acid, and intravenous antibiotics may accelerate the clearance of jaundice and decrease the need for early liver transplantation after Kasai portoenterostomy. J Pediatr Surg 38:406-411.     

Bile flow--an index of ischemic injury

Bile formation is an active secretory process involving bile salt-dependent and -"independent" mechanisms. This study was performed to determine the effect of selected periods of warm ischemia on biliary secretion. Rats were studied using an in situ liver perfusion system after stabilization of bile flow with intravenous sodium taurocholate. Bile flow remained stable in control livers and ceased during ischemic periods of 15 or 25 min. After reperfusion of 15-min ischemic livers, bile flow was depressed but returned to normal by 45 min of reperfusion. After 25 min of ischemia, bile flow remained depressed. A similar depression in bile salt secretion was observed. These studies indicate that both bile flow and bile salt secretion reflect the degree of ischemia in this isolated perfused system, and further use of this model for the investigation of biliary flow as an index of ischemic injury is warranted.     

Usefulness of Steroid Administration for Diagnosis of IgG4-Related Sclerosing Cholangitis

Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is one of the IgG4-related systemic sclerosing diseases and responds well to steroid therapy. A 58-year-old male was admitted with hilar bile duct stenosis revealed by computed tomography. We performed percutaneous transhepatic right portal vein embolization (PTPE) and scheduled a right hepatectomy because a hilar cholangiocarcinoma was first suspected. However, there was no cytologic evidence of malignancy and serum IgG4 was elevated. Steroid therapy was initiated after PTPE. There was no evidence of bile duct stenosis after 4 weeks. Improving diagnostic technique, IgG4-SC was diagnosed and treated with steroid therapy. In some cases, we couldn''t deny the malignancy and performed unnecessary resection. We recommend that steroid administration while waiting for the liver volume to increase after PTPE is useful. The therapy aids in the diagnosis of bile duct stenosis, which has value for a hilar bile duct limit type of IgG4-SC, as in the case reported here.     

Hepatobiliary scintigraphy after hepatic portoenterostomy

Hepatobiliary scintigraphy with 99mTc-E-HIDA was carried out in 10 patients who had undergone hepatic portoenterostomy for "non-correctable" biliary atresia. In all the patients there was an active bile flow and disappearance of jaundice, post-operatively. Elimination of 99mTc-E-HIDA from the liver was slow during the first 3 post-operative months despite active bile flow and disappearance of jaundice. The elimination rate of the radioactive agent from the liver in most long-term survivors was comparable with findings in controls.     

Hydrolytic activities of human pancreatic phospholipase A2 and endotoxin-stimulated endogenous phospholipase A2 toward membrane phospholipids of erythrocytes

Previous experiments have demonstrated the cholestatic effects of somatostatin administration in several animal species. These effects were confirmed in the rat. Nine pairs of intact awake rats received intravenous sodium taurocholate (23 mg hr-1) to stabilize bile flow, and half were later given somatostatin at doses of 185 micrograms hr-1. After 1 hr of somatostatin the experimental group showed a significant decrease in bile flow compared to the control group. Cholestasis reversed when somatostatin infusion was stopped. An in situ isolated perfused rat liver technique was used to assess the direct effects of somatostatin on biliary flow. In 10 pairs of rat livers, after achieving stable bile flow, half of those perfused (the "experimentals") received continuous (370 micrograms hr-1) somatostatin infusion, while the controls received saline. The percentage change in bile flow from baseline in the somatostatin group was not significantly different from that in controls for any test period. Bile analysis revealed no significant differences between groups for cholesterol, phospholipid, or bile salt concentrations or outputs. These data suggest that somatostatin inhibits bile secretion by some mechanism other than direct inhibition of bile secretory mechanisms.     

Bile acids analysis: a tool to assess graft function in human liver transplantation

The expanding use of sub-optimal grafts due to donor organ shortage increases the importance of accurate graft assessment before liver transplantation. Bile secretion is an early sign of recovering hepatic function post-transplant. The role of bile acid analysis in assessing graft function before and immediately after liver transplantation has been investigated. Two hundred and sixteen samples of hepatic bile were collected from 35 donors and 13 recipients. Clinical data, bile flow, total bile acid concentration, apparent choleretic activity and bile acid composition were assessed. Sub-optimal donor livers showed a low apparent choleretic activity and a different bile acid composition when compared to normal grafts. In recipients, the pattern of recovery of bile secretion immediately after reperfusion was a useful predictor of graft function. This study characterises bile acid secretion of liver grafts and remarks the potential value of bile acid analysis to assess donor liver quality and early post-transplant graft function.     

IgG4相关硬化性胆管炎的CT和磁共振胰胆管成像表现

目的观察IgG4相关硬化性胆管炎(IgG4-SC)的CT和磁共振胰胆管造影(MRCP)影像表现。方法回顾性分析9例IgG4-SC患者的临床及影像资料,观察IgG4-SC初始病变的CT和MRCP特征及随访变化。结果初始病变:6例CT扫描显示肝外胆管胰腺段管壁增厚,其中2例伴有胰上段胆管壁偏心性增厚,增厚的胆管壁呈渐进性强化;7例MRCP检查中,6例显示肝外胆管胰腺段狭窄,1例肝内胆管狭窄和肝外胆管胰腺段狭窄,狭窄近侧的胆管呈中度至重度扩张。随访:5例未接受类固醇治疗以及2例治疗后复发的患者胆管病变均较初始加重。8例随访患者中,无论治疗及时与否,或是病变复发后再治疗,应用类固醇后胆管病变均显著好转。结论 IgG4-SC的CT和MRCP表现为胆管壁增厚、管腔狭窄和近侧胆管扩张,类固醇治疗后病变明显好转。     

Bile CXC Motif Chemokine 10 Levels Correlate With Anti-donor Cytotoxic T Cell Responses After Liver Transplantation

Background

CXC motif chemokine 10 (CXCL10), known as interferon-γ−induced protein 10, is an inflammatory cytokine secreted by various cells in response to interferon-γ. CXCR3, the receptor of CXCL10, is predominantly expressed on activated T, B, natural killer, and dendritic cells, as well as macrophages. CXCR3 promotes chemotaxis upon binding CXCL10. Serum CXCL10 levels have recently attracted attention as a post-transplantation biomarker for graft rejection. However, the correlation between the degree of T cell response to allostimulation and CXCL10 levels remains unclear. In this study, we investigated the serum and bile CXCL10 levels of patients who underwent living donor liver transplantation (LDLT) and compared them with the T cell responses to allostimulation.

Patients and Methods

Between February 2009 and August 2012, 41 patients underwent LDLT at Hiroshima University Hospital. Serum and bile CXCL10 levels were measured weekly for 4 weeks after surgery, while the T cell responses to allostimulation were evaluated using a mixed lymphocyte reaction with an intracellular carboxyfluorescein diacetate succinimidyl ester−labeling technique that we regularly use to monitor the immune response to anti-donor and anti−third-party stimulation after liver transplantation. The stimulation index (SI) and CD25 expression of the CD4+ and CD8+ T cell subsets in response to allostimulation were then analyzed using flow cytometry.

Results

Serum CXCL10 levels were significantly correlated with the SI values for CD8+ T cells in response to both types of allostimulation. Bile CXCL10 levels were significantly correlated with CD25 expression of CD8+ T cell subsets, especially in response to anti-donor stimulation. Patients with higher bile CXCL10 levels suffered from severe acute cellular rejection that was refractory to steroid pulse.

Conclusion

Measurements of bile CXCL10 levels could predict anti-donor cytotoxic T cell responses in liver transplant recipients.     

Immunoglobulin G4–Related Sclerosing Cholangitis Mimicking Hilar Cholangiocarcinoma Diagnosed With Following Bile Duct Resection: Report of a Case

We report a rare case of immunoglobulin G4 (IgG4)–related sclerosing cholangitis without other organ involvement. A 69-year-old-man was referred for the evaluation of jaundice. Computed tomography revealed thickening of the bile duct wall, compressing the right portal vein. Endoscopic retrograde cholangiopancreatography showed a lesion extending from the proximal confluence of the common bile duct to the left and right hepatic ducts. Intraductal ultrasonography showed a bile duct mass invading the portal vein. Hilar bile duct cancer was initially diagnosed and percutaneous transhepatic portal vein embolization was performed, preceding a planned right hepatectomy. Strictures persisted despite steroid therapy. Therefore, partial resection of the common bile duct following choledochojejunostomy was performed. Histologic examination showed diffuse and severe lymphoplasmacytic infiltration, and abundant plasma cells, which stained positive for anti-IgG4 antibody. The final diagnosis was IgG4 sclerosing cholangitis. Types 3 and 4 IgG4 sclerosing cholangitis remains a challenge to differentiate from cholangiocarcinoma. A histopathologic diagnosis obtained with a less invasive approach avoided unnecessary hepatectomy.Key words: Immunoglobulin G4, Cholangitis, Cholangiocarcinoma, Autoimmune pancreatitis, Hepatectomy, DiagnosisSerum immunoglobulin G4–related sclerosing cholangitis (IgG4-SC) is a type of autoimmune pancreatitis associated with elevated serum IgG4 levels.^1,2 Types 3 and 4 IgG4-SC are difficult to differentiate from bile duct cancer, and hepatectomy has been reported sporadically in such situations.^3,4 We describe a rare case of a patient with IgG4-SC but without pancreatic lesions. Accurate diagnosis was made, without the need for performing a partial hepatectomy.     

Effects of cyclosporine and corticosteroids on bile secretion in the rat.

In order to study their effects on the bile secretion, cyclosporine and methylprednisolone were injected intravenously into rats at a dose of 10 mg/kg b.w. for 30 min. Methylprednisolone had no effect on bile secretion. Cyclosporine led to transient intrahepatic cholestasis characterized by decreased bile flow as well as a decrease of bile salts and cholesterol in bile. Phospholipid levels were not affected. Liver biopsy showed no particular anomaly. These findings suggest that the observed cholestatic reaction may be due to impairment of the metabolism of cholesterol into bile salts or of the conjugation of bile salts rather than to disturbances in bile secretion. After liver transplantation in humans, cholestasis associated with acute rejection or nonspecific cholestasis cannot be attributed directly to the effect of cyclosporine. Cholestasis can be offset by administering taurocholate at a dose of 10 mumol/min/kg b.w. in order to maintain bile salt and phospholipid levels high enough to ensure proper "vectorization" of cholesterol to bile.     

Effectiveness of Endoscopic Nasobiliary Drainage for Postoperative Bile Leakage after Hepatic Resection

The effectiveness of endoscopic nasobiliary drainage (ENBD) for postoperative bile leakage after hepatic resection was investigated retrospectively. Between 1997 and 2002 a series of 486 hepatectomies without biliary reconstruction were performed. Bile leakage was divided into two categories. Type A was defined as bile leakage communicating with the main bile tree fistulographically or endoscopic cholangiographically, and type B was bile leakage without such a patency of bile flow. Bile leakage developed in 31 patients (6.4%) (types A/B = 16/15). Type A frequently occurred at the major Glissons sheath. In contrast, most type B cases occurred at the peripheral bile duct at the cut surface of the liver. Among the type A patients, 10 of 11 were effectively treated with ENBD. For the type B patients, 12 of 15 patients were successfully treated with intraabdominal drainage via surgical drains inserted during the operation or percutaneous tubes newly inserted for biliary fluid collection. ENBD was effective in two of three type B patients. The duration of bile leakage significantly shortened after initiation of ENBD in type A patients (15.3 ± 6.9 vs. 25.8 ± 13.2 days, p < 0.05). The classification based on communication with the main bile tree is useful for determining therapeutic strategy. Type A leakage has a good indication for ENBD, whereas type B can be treated with intraabdominal drainage in most cases, although ENBD may be effective in some intractable type B cases. It is preferable to initiate ENBD as early as possible to shorten the duration of bile leakage and the subsequent hospital stay.     

The perinatal transition of the hepatobiliary cyst size provides information about the condition of bile flow in biliary cystic malformation cases

Purpose

The aim of this study was to understand the level of bile flow by perinatal transitions of the hepatobiliary cyst size in biliary cystic malformation (BCM) cases and to examine the association between the transitions of the cyst size, cholangiographic images of the intrahepatic bile ducts (IHBDs), and histological features of the liver specimens in BCM.

Methods

We measured perinatal size of the hepatobiliary cyst in 7 BCM cases, composed of 1 case with choledochal cyst and 6 cases with biliary atresia (BA). Bile excretion was inferred from the transition of cyst size and the postoperative course. The IHBD cholangiographic images were also examined. In addition, histology of liver specimens obtained at the time of initial surgery was evaluated for IHBD maturity and fibrosis.

Results

The size of the small cyst in 2 BA cases remained almost unchanged throughout gestation. These cases required longer postoperative period for the clearance of jaundice. Their IHBD images were indistinct, and histology showed severe fibrosis. The ratio of bile ducts to portal tracts was 0.5 in 1 of the cases. However, in other BCM cases where the cysts grew large perinatally, bile excretion was good postoperatively, and their jaundice cleared in shorter period. Their cholangiographic images demonstrated clearer periphery of the IHBDs, and their histology showed mild or moderate fibrosis, if any.

Conclusions

The perinatal transition of the cyst size in BCM cases can be helpful in assessing the level of bile flow. BCM with a small cyst during gestation can include some BAs with poorer bile flow, vaguer IHBD images, and prominent liver fibrosis. For the treatment of BCM cases, especially patients with a small biliary cyst, prompt response may be required after birth.     

The role of cyclic AMP in canine secretin-stimulated bile flow.

Cyclic nucleotide secretion rates in bile during the physiologic stimulation of ductular bile flow in dogs was evaluated by measurement of bile cyclic AMP concentration during the stimulation of secretin release by infusion of acid into the duodenum of dogs with chronic bile fistulas. The effects of PGA₁ and theophylline on secretin-stimulated bile flow and cyclic AMP secretin rates were also evaluated. Endogenous secretin stimulated bicarbonate-rich bile flow and decreased bile cyclic AMP concentration. PGA₁ significantly decreased secretin-stimulated bile flow but not bile cyclic AMP secretion. Theophylline did not alter secretin-stimulated bile flow or cyclic AMP secretion rates. These data indicate that based on cyclic AMP content in bile, secretin-stimulated ductular bile flow is unrelated to cyclic AMP metabolism.     

Inhibition of bile flow by intravenous arginine hydrochloride

One proposed mechanism for the cholestasis associated with total parenteral nutrition is infusion of amino acids. Arginine, 19 mumol/kg/min, was infused for a short time in healthy dogs with a biliary fistula to test the effect of endogenous hormone release on bile flow and composition. Both plasma glucagon and blood glucose levels increased. Despite the release of the choleretic hormone, glucagon, bile flow decreased 30%. The suppression of bile flow was attributed to a decrease in the bile acid-dependent fraction of bile flow. Bile acid, cholesterol, and phospholipid output were all depressed.     

Formation and fate of fibrin clots in the biliary tract: a clinical and experimental study.

Fibrin clots may form in the biliary tract from hemobilia or in inflammatory disease. There is a wide variation in the clinical course of such clots which is exemplified by 9 patients. They may either dissolve through fibrinolysis, get ejected into the intestine, remain and obstruct the biliary tract, or may even transform into gallstones. In order to elucidate the mechanisms involved, the behavior of blood clots in bile was studied in vitro. A model was constructed of the biliary tract and, drained by a T-tube, where human bile circulated with a flow rate resembling that in vivo. When a small amount of human blood was injected, it flowed immiscibly to the lowest level, displaced the bile, and formed a clot of pure blood. Even a minor bleeding may thus form a coagulum. This is different from the mixed clot of blood and bile that forms in experiments simulating major hemorrhage. These findings are related to clinical experience and especially to the disappearance of "retained stones" with or without the use of dissolving agents.     

Compliance with oral corticosteroids during steroid trials in chronic airways obstruction.

BACKGROUND: Corticosteroid trials are an important part of the assessment of patients with chronic airways obstruction, but false negative results will occur if the treatment is not taken. To determine compliance low dose phenobarbitone has been used as a marker. METHODS: Thirty six patients referred to a chest clinic for assessment of their airways obstruction were studied. They were instructed to take eight capsules (each containing 5 mg prednisolone and 0.5 mg phenobarbitone) per day for two weeks. The response was assessed by home peak flow monitoring and clinic spirometric tests. Plasma phenobarbitone levels were measured after the trial to enable calculation of the dose to plasma concentration ratio (level to dose ratio, LDR) and the result was compared with the reference range for fully compliant individuals. RESULTS: Five patients defaulted from follow up, 23 had LDR values within the expected range, and eight had low LDR values consistent with poor compliance. The nine patients with steroid responsive disease (> 20% improvement in peak flow or spirometric parameters) all had LDR values in the expected range. CONCLUSION: Excluding those who defaulted whose compliance must be questionable, eight (26%) patients did not fully comply with the steroid trial. Not all patients who fail to respond to a two week home steroid trial have a steroid "unresponsive" disease.     

Minor hemobilia. Clinical significance and pathophysiological background.

Profuse hemorrhage into the biliary tract--major hemobilia,--is an alarming condition which attracts much attention. Minor hemobilia, often caused by gallstones or operative injury, is much more frequent, yet often neglected. Clinical observations indicate that minor hemobilia is not always an innocent condition with the blood remaining fluid and unobtrusively flowing into the intestine. Examples are given where clots from occult hemobilia have caused diagnostic errors or obstructed the bile flow, thus imitating gallstones for which they may be mistaken. Experiments have been performed to elucidate the pathophysiology of this clot formation: 1) A model of the biliary tract was constructed with bile flowing through it. When blood was injected forcefully to simulate a major hemorrhage, mixed clots of blood and bile were formed. When introduced gently, as in minor hemobilia, the blood flowed immiscibly to the lowest level where it formed a clot of pure blood. The clots dissolved under the influence of flowing bile, but remained intact when protected from the flow. 2) Mixed clots were mushy and dissolved spontaneously, while pure clots remained solid and stable. When clots containing increasing amounts of bile were incubated, increasing amounts of cleavage products of fibrinogen and fibrin were formed. 3) Blood clots were produced in gallbladders of 33 dogs. Pure clots remained solid and floating while mixed clots formed a mushy layer, strongly adherent to the mucosa. Both kinds of clots disappeared after two-four weeks, but remained if bile flow was diverted. These findings explain why under certain circumstances minor hemobilia acquires clinical significance by forming clots that may obstruct the flow or cause diagnostic errors. Successful dissolution of "retained stones" may occasionally have the simple explanation that blood clots, mistaken for calculi, have been fibrinolysed. Consequently, in biliary obstruction or when defects are found on cholangiography, the possibility of blood clots in the ducts should be considered even in the absence of overt gastrointestinal hemorrhage.     

Influence of liver transplantation and cyclosporin on bile secretion —an experimental study in the rat

Bile secretion is reduced after liver transplantation. It has been suggested that this is due either to the effect of cyclosporin or to the damage to the liver graft during preservation and reperfusion. The aim of this study was to explore the influence of cyclosporin as well as of liver transplantation on bile secretion. Bile flow was studied in an experimental model in the rat. In syngeneic liver-transplanted animals, the bile flow was increased compared to the bile flow in the control group (1.29±0.09 ml/h vs 0.66±0.03 ml/h; P<0.01), mainly due to an increased bile acid-independent flow (0.76 ml/h vs 0.50 ml/h; P<0.01). The findings in the livertransplanted rats contrasted with those in a group of nontransplanted animals treated with cyclosporin. Cyclosporin treatment resulted in a reduced bile acid-independent fraction (0.37 ml/h vs 0.50 ml/h, P<0.05) of the bile flow, although no biochemical signs of hepatotoxicity were present. This reduction in the bile acid-independent fraction could, however, not be demonstrated when cyclosporin was given to a group of liver-transplanted rats, although a reduced total bile flow was recorded in the 1st hour measurements. In contrast to previous studies, we found that the cyclosporin vehicle (Cremophor EL), when administered chronically, induced a higher bile flow than that in the control rats. This effect was not seen in the transplanted rats. Our findings in this experimental rat model indicate that cyclosporin will influence and reduce bile secretion and bile acid secretion even if no other signs of liver dysfunction are present. On the other hand, the preservation and reperfusion in this model resulted in an increased bile flow, while bile acid secretion remained constant.