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Patients post liver transplant (LT) with progressive familial intrahepatic cholestasis type 1 (PFIC-1) often develop progressive graft steatohepatitis, intractable diarrhea, and growth failure. A total internal biliary diversion (TIBD) during an LT may prevent or reverse these adverse events. Children with PFIC-1 who underwent an LT at our institute were divided into 2 groups, A and B based on the timeline where we started offering a TIBD in association with LT. Pre-LT parameters, intraoperative details, and posttransplant complications like graft steatosis and diarrhea were also analyzed between the 2 groups, and their growth velocity was measured in the follow-up period. Of 550 pediatric LT performed between 2011 and 2022, 13 children underwent LT for PFIC-1. Group A had 7 patients (A1-A7) and group B had 6 (B1-B6). Patients A1, A4, B4, and B5 had a failed partial internal biliary diversion before offering them an LT. Patients A1, A2, and A6 in group A died in the post-LT period (2 early allograft dysfunction and 1 posttransplant lymphoproliferative disorder) whereas A3, A4, and A5 had graft steatosis in the follow-up period. A4 was offered a TIBD 4 years after LT following which the graft steatosis fully resolved. In group B, B1, B2, B5, and B6 underwent TIBD during LT, and B3 and B4 had it 24 and 5 months subsequently for intractable diarrhea and graft steatosis. None of the patients in group B demonstrated graft steatosis or diarrhea and had good growth catch-up during follow-up. We demonstrate that simultaneous TIBD in patients undergoing LT should be a standard practice as it helps dramatically improve outcomes in PFIC-1 as it prevents graft steatosis and/or fibrosis, diarrhea, and improves growth catch-up., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Autophagy is important for hepatic homeostasis, nutrient regeneration, and organelle quality control. We investigated the mechanisms by which liver injury occurred in the absence of autophagy function. We found that mice deficient in autophagy because of the lack of autophagy-related gene 7 or autophagy-related gene 5, key autophagy-related genes, manifested intracellular cholestasis with increased levels of serum bile acids, a higher ratio of tauromuricholic acid/taurocholic acid in the bile, increased hepatic bile acid load, abnormal bile canaliculi, and altered expression of hepatic transporters. In determining the underlying mechanism, we found that autophagy sustained and promoted the basal and up-regulated expression of farnesoid X receptor (Fxr) in the fed and starved conditions, respectively. Consequently, expression of Fxr and its downstream genes, particularly bile salt export pump, and the binding of FXR to the promoter regions of these genes, were suppressed in autophagy-deficient livers. In addition, codeletion of nuclear factor erythroid 2-related factor 2 (Nrf2) in autophagy deficiency status reversed the FXR suppression. Furthermore, the cholestatic injury of autophagy-deficient livers was reversed by enhancement of FXR activity or expression, or by Nrf2 deletion. Conclusion: Together with earlier reports that FXR can suppress autophagy, our findings indicate that autophagy and FXR form a regulatory loop and deficiency of autophagy causes abnormal FXR functionality, leading to the development of intracellular cholestasis and liver injury., (© 2018 by the American Association for the Study of Liver Diseases.)

β-Catenin, the downstream effector of the Wnt signaling, plays important roles in hepatic development, regeneration, and tumorigenesis. However, its role at hepatocyte adherens junctions (AJ) is relatively poorly understood, chiefly due to spontaneous compensation by γ-catenin. We simultaneously ablated β- and γ-catenin expression in mouse liver by interbreeding β-catenin-γ-catenin double-floxed mice and Alb-Cre transgenic mice. Double knockout mice show failure to thrive, impaired hepatocyte differentiation, cholemia, ductular reaction, progressive cholestasis, inflammation, fibrosis, and tumorigenesis, which was associated with deregulation of tight junctions (TJ) and bile acid transporters, leading to early morbidity and mortality, a phenotype reminiscent of progressive familial intrahepatic cholestasis (PFIC). To address the mechanism, we specifically and temporally eliminated both catenins from hepatocytes using adeno-associated virus 8 carrying Cre-recombinase under the thyroid-binding globulin promoter (AAV8-TBG-Cre). This led to a time-dependent breach of the blood-biliary barrier associated with sequential disruption of AJ and TJ verified by ultrastructural imaging and intravital microscopy, which revealed unique paracellular leaks around individual hepatocytes, allowing mixing of blood and bile and leakage of blood from one sinusoid to another. Molecular analysis identified sequential losses of E-cadherin, occludin, claudin-3, and claudin-5 due to enhanced proteasomal degradation, and of claudin-2, a β-catenin transcriptional target, which was also validated in vitro., Conclusion: We report partially redundant function of catenins at AJ in regulating TJ and contributing to the blood-biliary barrier. Furthermore, concomitant hepatic loss of β- and γ-catenin disrupts structural and functional integrity of AJ and TJ via transcriptional and posttranslational mechanisms. Mice with dual catenin loss develop progressive intrahepatic cholestasis, providing a unique model to study diseases such as PFIC. (Hepatology 2018;67:2320-2337)., (© 2017 by the American Association for the Study of Liver Diseases.)

Cholangitis lenta, also known as ductular cholestasis, cholangiolar cholestasis, or subacute nonsuppurative cholangitis, is an uncommon type of cholangitis characterized by ductular reaction with inspissated bile in dilated ductules. The literature on this unique entity has been limited to only a few studies based on a very limited number of cases, which importantly suggest an association with sepsis and/or intra-abdominal infection. The clinical, laboratory, and histologic features of 28 cases of cholangitis lenta are herein investigated. Twenty-five (89.3%) patients were liver transplant recipients. Most notably, the majority of patients showed clinical signs and symptoms of sepsis, and positive microbiology cultures were demonstrated in 24 (85.7%) patients. Significantly, 15 (53.6%) patients died during their hospitalization, ranging from 2 days to 5 months after the initial liver biopsy that showed histologic features of cholangitis lenta. Among the 13 discharged patients, including 2 who received retransplantation, 4 (14.3%) subsequently died of pneumonia, graft dysfunction, or fungal infection within 7 months to 9.3 years. Only 9 (32.1%) patients were alive at the last follow-up, with the follow-up time ranging from 3.8 to 10.4 years. Our data show that the finding of cholangitis lenta on liver biopsy is thus frequently associated with sepsis and with a high mortality rate. Therefore, accurate diagnosis of this condition on liver biopsy is imperative as it is an indication that the patient may have a potentially life threatening condition that requires immediate medical attention and management.

Unlabelled: The intercellular adhesion molecule 1 (ICAM-1) is induced in mouse liver after bile duct ligation (BDL) and plays a key role in neutrophil-mediated liver injury in BDL mice. ICAM-1 has been shown to interact with cytoskeletal ezrin-radixin-moesin (ERM) proteins that also interact with the PDZ protein, Na(+) /H(+) exchanger regulatory factor 1 (NHERF-1/EBP50). In NHERF-1(-/-) mice, ERM proteins are significantly reduced in brush-border membranes from kidney and small intestine. ERM knockdown reduces ICAM-1 expression in response to tumor necrosis factor alpha. Here we show that NHERF-1 assembles ERM proteins, ICAM-1 and F-actin into a macromolecule complex that is increased in mouse liver after BDL. Compared to wild-type (WT) mice, both sham-operated and BDL NHERF-1(-/-) mice have lower levels of activated ERM and ICAM-1 protein in the liver accompanied by significantly reduced hepatic neutrophil accumulation, serum alanine aminotransferase, and attenuated liver injury after BDL. However, total bile acid concentrations in serum and liver of sham and BDL NHERF-1(-/-) mice were not significantly different from WT controls, although hepatic tetrahydroxylated bile acids and Cyp3a11 messenger RNA levels were higher in NHERF-1(-/-) BDL mice., Conclusion: NHERF-1 participates in the inflammatory response that is associated with BDL-induced liver injury. Deletion of NHERF-1 in mice leads to disruption of the formation of ICAM-1/ERM/NHERF-1 complex and reduction of hepatic ERM proteins and ICAM-1, molecules that are up-regulated and are essential for neutrophil-mediated liver injury in cholestasis. Further study of the role of NHERF-1 in the inflammatory response in cholestasis and other forms of liver injury should lead to discovery of new therapeutic targets in hepatic inflammatory diseases., (© 2015 by the American Association for the Study of Liver Diseases.)

The histopathologic distinction between posttransplantation fibrosing cholestatic hepatitis C (FCH-C) and biliary obstruction (BO) is challenging. We sought to identify histopathologic features that could be useful in the differential diagnosis between these 2 entities. A total of 38 cases of hepatitis C virus (HCV)-negative, cholangiography-proven BO (including 16 posttransplant and 22 nontransplant patients) and 13 patients with posttransplantation FCH-C were included. FCH-C patients were characterized by cholestatic disease, high HCV viral load, no evidence of biliary tract obstruction on imaging, and typical histopathologic findings (≥3 of the following: 1, prominent ductular reaction; 2, hepatocyte swelling with lobular disarray; 3, periportal sinusoidal fibrosis, and 4, cholestasis). Biopsies were evaluated with hematoxylin and eosin, Masson trichrome, Victoria blue, and rhodanine stains. Cytokeratin 7 (CK7) immunohistochemistry was used to assess for the presence of CK7+ intermediate hepatobiliary cells. We found that portal edema (63.1% vs. 7.6%; P<0.0001), bile duct dilatation (26.3% vs. 0%; P=0.0003), acute cholangitis (15.7% vs. 0%; P=0.008), bile infarcts (10.5% vs. 0%; P=0.03), periductal fibrosis (23.6% vs. 0%; P=0.0007), and periportal copper deposition (60.5% vs. 15.3%; P=0.0006) are significantly more common in BO, whereas hepatocellular swelling with lobular disarray (84.6% vs. 5.2%; P<0.0001) and periportal sinusoidal fibrosis (34.2% vs. 100%; P<0.0001) are seen more frequently in FCH-C. Furthermore, marked ductular reaction with rare or absent CK7+ intermediate cells is highly suggestive of FCH-C in this context (73.6% vs. 7.6%; P<0.0001). In summary, this study offers a comprehensive characterization of the histologic features discriminating FCH-C from BO.

Unlabelled: Intrahepatic cholangiocarcinoma typically presents in an advanced stage in which treatment options are limited. In an effort to recapitulate key biological and clinical features of the progressive disease, we established a novel rat model based on bile duct inoculation of rat cholangiocyte cell lines in different stages of tumor progression. Our BDEneu cell line, which is highly tumorigenic, originated from an immortalized rat cholangiocyte cell line (BDE1 cells) that was stably transfected to constitutively overexpress mutationally activated rat neu oncogene. Our less aggressive tumorigenic BDEsp cholangiocyte cell line was derived from the spontaneous in vitro neoplastic transformation of the same parent BDE1 cell line. Unlike BDEneu cells, BDEsp cells expressed wild-type c-neu and exhibited in vitro growth rates intermediate between those of BDEneu and BDE1 cholangiocytes. Cyclooxygenase-2 and activated Akt were significantly overexpressed in BDEsp cells over those of BDE1 cells, and at higher levels than those expressed in BDEneu cells. Only BDEneu cells overexpressed activated p185(neu), which was associated with a significant increase in phospho-p44/42 mitogen-activated protein kinase (MAPK). Mucin 1 (MUC1) messenger RNA (mRNA), an indicator of cholangiocarcinoma cell progression, was also significantly overexpressed in BDEneu cells over that of BDEsp cells. BDEneu cells inoculated into the bile duct of isogenic rats resulted over a 21- to 26-day period in rapid exponential cholangiocarcinoma tumor growth within liver, paralleled by increases in bile duct obstruction and gross peritoneal metastases. Under comparable conditions, BDEsp cells yielded only small nonmetastatic intrahepatic cholangiocarcinomas without bile duct obstruction., Conclusions: A novel model of cholangiocarcinoma progression mimicking progressive development of the advanced human disease has been established, which may serve as a powerful preclinical platform to study cholangiocarcinoma progression and for rapidly testing treatment approaches.

Predictive factors for intrahepatic cholestasis after orthotopic liver transplantation (OLT) have not yet been established. We sought to identify the incidence and risk factors associated with prolonged severe intrahepatic cholestasis (PSIC) after OLT. We assessed 428 consecutive patients undergoing their first OLT. PSIC was diagnosed if a serum bilirubin concentration was greater than 100 micromol/L and/or a 3-fold increase of alkaline phosphatase occurred within the first month after OLT and was sustained for at least 1 week in the absence of biliary complications. Multivariable logistic regression identified factors independently associated with PSIC. PSIC developed in 107 patients (25%). Independent risk factors by multivariable analysis were intraoperative transfusion of cryoprecipitate and platelets; nonidentical blood group status; suboptimal organ appearance; inpatient status before transplantation; and bacteraemia in the first month after transplantation. In contrast, acute liver failure, older age, and higher levels of serum sodium and serum potassium were all associated with a reduced likelihood of developing PSIC in the first month. There were 47 deaths in the PSIC group (44%) as opposed to 65 deaths in the non-PSIC group (20%) after OLT. A poor preoperative clinical status in conjunction with a suboptimal graft was associated with PSIC after OLT. Avoidance of suboptimal livers and ABO nonidentical grafts for young patients with poor synthetic function and for pretransplant inpatients may lessen this complication and reduce the associated early mortality., ((c) 2006 AASLD)

Proteomic techniques promise to improve the diagnosis of cholangiocarcinoma (CC) in both tissue and serum as histological diagnosis and existing serum markers exhibit poor sensitivities. We explored the use of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) to identify potential protein biomarkers of CC. Twenty-two resected CC samples were compared with adjacent noninvolved bile duct tissue. Serum from patients with CC (n=20) was compared with patients with benign disease (n=20), and healthy volunteers (n=25). Samples were analyzed on hydrophobic protein chips via SELDI-TOF MS, and classification models were developed using logistic regression and cross-validation analysis. Univariate analysis revealed 14 individual peaks differentially expressed between CC and bile duct tissue, 4 peaks between CC and benign disease, and 12 peaks between CC and sera of healthy volunteers. The 4,462 mass-to-charge serum peak had superior discriminatory ability to carbohydrate antigen 19.9 (CA19.9) and carcinoembryonic antigen (CEA) (P=.004; receiver operating characteristic [ROC] area under the curve [AUC]=0.76, 0.73, and 0.70, respectively). The training models developed panels of peaks that distinguished CC from bile duct tissue (92.5% sensitivity, 92.3% specificity; ROC AUC=0.96), CC from benign serum (65.0% sensitivity, 70.0% specificity; ROC AUC=0.83), and CC from sera of healthy volunteers (75.0% sensitivity, 100% specificity; ROC AUC=0.92). Serum results were further improved with the inclusion of CA19.9 and CEA (ROC AUC=0.86 and 0.99 for CC vs benign and healthy volunteer serum, respectively). In conclusion, biomarker panels are capable of distinguishing CC from nonmalignant tissue; serum markers have important diagnostic implications for unknown bile duct stricture.

Increased gastrointestinal permeability has been demonstrated in several liver diseases. It may facilitate the absorption of gut-derived endotoxin-stimulating Kupffer cells to release proinflammatory cytokines or other potentially hepatotoxic compounds. We examined gastrointestinal permeability, plasma levels of anti-lipopolysacharides (anti-LPS), and four proinflammatory cytokines in 20 patients with intrahepatic cholestasis of pregnancy (ICP) compared with 22 normal pregnant and 29 non-pregnant women. Urinary excretion of sucrose and the urinary lactulose/mannitol (L/M) ratio after a standard oral load were used to assess gastrointestinal permeability. Anti-LPS (IgA, IgM, and IgG) were measured in peripheral blood by Human EndoCAb test kit; TNF-alpha, IL-1beta, IL-6, and IL-10 by Quantikine HS human immunoassays. Sucrose urinary excretion was similar in the three groups, indicating normal gastric permeability. The urinary L/M ratio was significantly higher in ICP than in the other groups [median (interquartile range): 0.018% (0.011-0.023) in ICP, 0.012% (0.009-0.016) in normal pregnancies, and 0.009% (0.008-0.012) in non-pregnant women, P < .01]. No significant differences were found in anti-LPS or cytokines plasma levels except slightly higher levels of IL-6 in ICP patients than in non-pregnant women (P < .05). Four of five women with abnormal urinary L/M ratio during ICP continued to show abnormalities in tests up to 2 years after delivery. In conclusion, an increased intestinal permeability was detected in ICP patients during and after pregnancy. A "leaky gut" may participate in the pathogenesis of ICP by enhancing the absorption of bacterial endotoxin and the enterohepatic circulation of cholestatic metabolites of sex hormones and bile salts.

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.

A histologic pattern comprising centrilobular cholestasis and portal changes including edema, predominantly neutrophil polymorph infiltration, cholangiolar proliferation, and cholangiolitis is well known to correspond to biliary obstruction. This pattern, referred as biliary tract pathology (BTP) in this text, remains unclear in terms of its clinical significance. We aimed to assess the incidence, timing, and diagnostic accuracy of BTP after liver transplantation. All 248 liver biopsies and clinical records, from 94 patients, including 30 living donor, 17 split, 15 domino, and 32 cadaveric full-size primary liver transplantation, were reviewed. BTP was diagnosed in 21% of biopsies from 31% of patients at a median of 28 days after transplantation (range, 5-763 days). When radiologic imaging of the biliary tree was taken as the gold standard, biopsy was found to have a sensitivity of 87% (95% confidence interval, 73%-100%) and a specificity of 87% (95% confidence interval, 80%-95%) for the diagnosis of biliary complications. An underlying clinical condition was found in 86% of cases, which included biliary complications (69%), arterial thrombosis (3%), sepsis (10%), and recurrent disease (3%). In 14% of cases, BTP remained unexplained. In conclusion, BTP after liver transplantation has clinical significance in most cases, with a particular emphasis for true biliary complications. This pattern must incite radiographic verification of the biliary tract.

Fibrosing cholestatic hepatitis (FCH) is a peculiar variant of hepatitis B virus (HBV) infection in immunocompromised patients characterized by rapid viral replication. Posttransplant patients receiving lamivudine for prophylaxis or treatment of HBV infection may develop drug resistance due to viral mutants, but FCH is rare because escape mutants are usually replication deficient. We report the development of FCH due to lamivudine-resistant HBV mutants in 2 patients at 12 and 13 months after liver transplantation. Rapidly progressive graft failure, accompanied by an escalating HBV DNA level, developed within weeks of onset. Analysis of gene sequence variation by polymerase chain reaction (PCR) and direct sequencing showed that both had a core promoter variant A1762T/G1764A and 1 had a concomitant precore stop codon G1896A variant in prelamivudine and postrecurrence serum samples. Comparison of the HBV polymerase gene in the 2 serum samples revealed a single mutation with methionine-to-isoleucine substitution at codon 552 (M552I) in both patients. "Add-in" treatment with adefovir dipivoxil resulted in a more than 2 to 3log10 reduction in HBV DNA level within 2 weeks and retransplantation was performed with adefovir dipivoxil and hepatitis B immunoglobulin (HBIG) prophylaxis. Both patients were alive at 15 months and 48 months after retransplantation, with normal graft function and serum negative for HBsAg and HBV DNA by quantitative PCR (< 200 copies/mL). The current report demonstrates that recurrent graft infection by precore/core promoter variant with lamivudine-resistant escape mutation may result in FCH. With combination of adefovir and high-dose HBIG, however, long-term survival can be achieved after retransplantation.

Cholestasis is a common sequela of liver transplantation. Although the majority of cases remain subclinical, severe cholestasis may be associated with irreversible liver damage, requiring retransplantation. Therefore, it is essential that clinicians be able to identify and treat the syndromes associated with cholestasis. In this review, we consider causes of intrahepatic cholestasis. These may be categorized by time of occurrence, namely, within 6 months of liver transplantation (early) and thereafter (late), although there may be an overlap in their causes. The causes of intrahepatic cholestasis include ischemia/reperfusion injury, bacterial infection, acute cellular rejection, cytomegalovirus infection, small-for-size graft, drugs for hepatotoxicity, intrahepatic biliary strictures, chronic rejection, hepatic artery thrombosis, ABO blood group incompatibility, and recurrent disease. The mechanisms of cholestasis in each category and the clinical presentation, diagnosis, treatment, and outcome are discussed in detail.

Cholestatic liver injury is associated with an increased susceptibility toward endotoxin-induced toxicity. To determine the role of interleukin 1 (IL-1) herein, extrahepatic cholestasis was induced by bile duct ligation (bdl) in IL-1 receptor type I gene-deficient (IL-1R(-/-)) mice, which are unresponsive to IL-1alpha and IL-1beta, and normal IL-1R(+/+) mice. Bdl elicited increases in hepatic IL-1alpha and IL-1beta messenger RNA (mRNA) and protein. Hepatocellular injury at 2 weeks after bdl was similar in IL-1R(-/-) and IL-1R(+/+) mice as shown by clinical chemistry and histopathology. Administration of endotoxin to cholestatic mice at 2 weeks after bdl was associated with enhanced cytokine release, more severe liver damage, and occurrence of death when compared with sham-operated mice. Endotoxin effects in sham-operated IL-1R(-/-) and IL-1R(+/+) mice were largely similar, but cholestatic IL-1R(-/-) mice were better protected against toxic effects of endotoxin, as reflected by lowered cytokine release, less profound liver injury, and reduced mortality. These data indicate that IL-1alpha and IL-1beta are produced in the liver after bdl, but that these cytokines do not play a significant role in cholestatic liver damage; however, endogenous IL-1 activity is an important denominator of enhanced endotoxin sensitivity that is observed during cholestasis induced by bdl.

Inducing positive nitrogen balance and weight gain in patients fed exclusively parenterally was documented first by Dudrick et al. in 1968. Since that time, total parenteral nutrition (TPN) has become commonplace both in acutely ill patients and in those with severe chronic gastrointestinal disease. Clear nutritional benefits accrue, but certain complications associated with TPN have become apparent. In the following discussion we review clinical, biochemical, and pathophysiologic abnormalities of the hepatobiliary system associated with TPN, particularly hepatic dysfunction and gallbladder disease and their management.

A syndrome of idiopathic intrahepatic cholestasis occurs in some patients with Hodgkin's lymphoma. The underlying mechanism is poorly understood. In this paper we describe three patients with Hodgkin's lymphoma in whom severe intrahepatic cholestasis of unknown pathogenesis developed. In two cases jaundice was the presenting symptom; all three patients died with intractable liver damage. The three patients were initially thought to have idiopathic Hodgkin's-associated cholestasis, but subsequent review of histological material revealed advanced vanishing bile duct syndrome in addition to severe cholestasis. Ten liver specimens were obtained from 4 to 97 wk after the onset of jaundice (seven needle biopsies, one wedge biopsy, two postmortem livers). In seven liver specimens taken within 30 wk of the onset of jaundice, portal tracts characteristically had a "burned-out" appearance without secondary periportal changes related to chronic cholestasis. Three biopsy specimens obtained from one of the patients more than 1 yr after the onset of jaundice showed evidence of progressive periportal damage in the form of fibrous expansion, marginal ductular proliferation and copper-associated protein deposition. More than 80% of small portal tracts lacked recognizable bile ducts in the final liver specimens obtained from the three patients. These observations suggest that Hodgkin's lymphoma should be included in the list of diseases associated with loss of intrahepatic bile ducts. The possibility of a vanishing bile duct syndrome should be considered in the differential diagnosis of unexplained intrahepatic cholestasis in patients with Hodgkin's disease.

Although prolonged survival after liver transplantation is now common, the condition of allografts after prolonged survival has not been widely discussed. We reviewed 86 biopsy samples from 38 patients. The samples were obtained between 366 and 1,622 days after transplant. Thirteen patients' biopsy samples were normal or showed minor changes. Six patients' samples showed rejection. Four patients, including two with rejection, demonstrated ischemic change. Three patients showed focal fibrosis, polymorphonuclear infiltration and bile duct proliferation simulating biliary obstruction, although biliary stones were found in only one patient. Three patients had acute hepatitis. Seven patients had a pattern of chronic persistent hepatitis; four had chronic active hepatitis. Follow-up biopsy samples were obtained in seven chronic hepatitis patients. Two of the patients with chronic hepatitis patients. Two of the patients with chronic active hepatitis have shown slight progression of the disease. None has progressed to cirrhosis, but neither has the chronic active hepatitis resolved. It is likely that some of these cases represent non-A, non-B hepatitis. Although histological abnormalities are common after successful transplantation, the clinical significance of many of the changes remains to be determined. Only patients with rejection or vascular thromboses required new transplants.

A woman developed severe cholestatic jaundice and progressive renal failure secondary to amyloid deposition. The amyloid protein was of AL type, consisting of IgG-related kappa chains. This form of amyloidosis is classified as immunocyte-related, not associated with myeloma.

Liver biopsies and/or autopsy specimens from 17 children (ages 1 week to 5 years) with nonsyndromatic paucity of the interlobular bile ducts were studied by light and electron microscopy. Initial biopsies were obtained before 90 days of age from all patients, and two or more specimens were available from nine. No specific underlying condition was found in nine infants. The remaining cases were associated with Down's syndrome (n = 2), hypopituitarism (n = 2), cystic fibrosis (n = 1), alpha 1-antitrypsin deficiency (n = 1), cytomegalovirus (n = 1) and Ivemark syndrome (n = 1). Before 90 days of age, portal changes included duct paucity and fibrosis. Lobular changes were nonspecific, consisting of cholestasis, giant cell transformation, extramedullary hematopoiesis and perisinusoidal fibrosis. Duct paucity, portal fibrosis and perisinusoidal fibrosis persisted after 90 days. Cholestasis was mild or no longer apparent. Portal changes before 90 days of age appear to be sufficiently distinctive to microscopically distinguish nonsyndromatic from syndromatic paucity. Electron microscopic findings suggest that paucity in nonsyndromatic patients may result from a primary ductal insult: ultrastructural studies revealed bile duct destruction characterized by undulation and breaks in the basal lamina and infiltration of the epithelium by lymphocytes. Bile canalicular dilatation with blunting of microvilli and electron-dense material in the lumen, predominantly seen before 90 days, also reinforces the hypothesis of a primary ductal defect.

Three patients with metastatic colorectal adenocarcinoma developed bile duct strictures after treatment of liver metastases by hepatic artery infusion of 5-fluorodeoxyuridine (5-FUDR). All underwent decompression and drainage via endoscopically placed biliary stents, a treatment approach not previously reported in this setting. One patient with recurrent hepatic metastases did not benefit, but two patients with bile duct strictures and tumor regression profited from stent placement and died of nonbiliary tumor-related complications. Stent placement may be helpful in treating patients with persistent and unremitting cholestasis and bile duct strictures in whom tumor regression has followed regional chemotherapy.

The case of a 53-year-old man with idiopathic cholestasis due to Hodgkin's disease illustrates the difficulty in making a definitive diagnosis and the limitations of noninvasive imaging studies. Hodgkin's disease should be considered in the differential diagnosis of profound intrahepatic cholestasis.

We have studied five long-term survivors of allogeneic bone marrow transplantation. All exhibited prolonged serum biochemical evidence of hepatic dysfunction during 2- to 5-year periods of follow-up. Two patients developed chronic cholestasis without pruritus. The serum of a third patient became chronically positive for HBsAg. A fourth patient developed an acute hepatic syndrome and high titers of antibody to cytomegalovirus. Nuclear, mitochondrial, and smooth muscle antibodies were not detected. Seven liver biopsies, obtained from three of the patients, all revealed a hepatocellular necroinflammatory lesion suggestive of chronic active hepatitis, a paucity of interlobular bile ducts, and intrahepatic cholestasis. Possible etiologies for these hepatic changes include reactivation of chronic non-A, non-B hepatitis and chronic graft-versus-host disease per se. Our study emphasizes the diagnostic problems posed by hepatic dysfunction occurring in an immunosuppressed multiply-transfused patient after bone marrow transplantation.

Differentiating intrahepatic cholestasis from extrahepatic biliary tract obstruction may be difficult. Four patients with intraoperative cholangiographic evidence of extrahepatic ductal atresia who underwent hepatoportoenterostomy are described. All were ultimately shown to have arteriohepatic dysplasia with hypoplastic but patent extrahepatic ductal systems. The difficulty in establishing an accurate diagnosis, hazards associated with hepatoportoenterostomy, and suggestions for evaluation and management are discussed.

Cholestasis and injury of interlobular bile ducts occur during rejection of human hepatic allografts. However, knowledge of the nature and progression of bile duct injury during rejection remains incomplete. To define the role of inflammation in bile duct damage, we assessed the light microscopic appearance of hepatic tissue from selected patients in whom allograft failure was solely due to rejection. Nine patients with rejection were easily separated into two groups based on the duration of the allograft survival. The first group (early rejection) consisted of five patients in whom rejection occurred between 13 and 36 days. The second group (late rejection) consisted of four patients in whom rejection occurred between 170 and 912 days. Early rejection was characterized by distortion of bile ducts by adjacent inflammatory cell infiltrates, cytological changes of bile duct epithelial cells and occasionally by frank mononuclear cell inflammation of the epithelium with destruction of the duct. Late rejection was characterized by nonsuppurative destructive cholangitis culminating in the disappearance of interlobular bile ducts. Both groups exhibited histological cholestasis, intact limiting plates, preservation of hepatocytes and positive orcein stains for copper-binding protein. We conclude that the dominant histopathological feature of hepatic allograft rejection is progressive, nonsuppurative destructive cholangitis.