Faculty Bibliography

A 15-year-old Caucasian female on human chorionic gonadotropin (HCG) diet presented with fever, cholestasis, coagulopathy, hemolytic anemia, and acute renal dysfunction. Imaging of the biliary system and liver were normal. She responded to intravenous antibiotics, vitamin K and blood transfusions but experienced relapse upon discontinuation of antibiotics. She had remission with reinstitution of antibiotics. Liver biopsy revealed pronounced bile ductular reaction, bridging fibrosis, and hepatocytic anisocytosis and anisonucleosis with degenerative enlarged eosinophilic hepatocytes, suggestive of Wilson disease. Diagnosis of Wilson disease was further established based on the low serum ceruloplasmin, increased urinary and hepatic copper and presence of Kayser-Fleischer rings. The multisystem involvement of the liver, kidney, blood, and brain are consistent with Wilson disease; however, the clinical presentation of cholangitis and reversible coagulopathy is uncommon, and may result from concurrent acute cholangitis and/or the HCG diet regimen the patient was on.

BACKGROUND & AIMS: Pathologists participating in the National Institutes of Health-sponsored Biliary Atresia Research Consortium (BARC) developed and then evaluated a standardized system for histologic reporting of liver biopsies from infants with cholestasis. METHODS: A set of 97 anonymous liver biopsy samples was sent to 10 pathologists at BARC centers. A semiquantitative scoring system that had 16 histologic features was developed and then used by the pathologists, who had no knowledge of clinical history, imaging results, or laboratory data. Interobserver agreement was evaluated statistically. Agreement on scoring of each feature and on the pathologists' diagnosis, compared with the final clinical diagnosis, was evaluated by using weighted kappa statistics. RESULTS: There was moderate to substantial interobserver agreement in identification of bile plugs in ducts, giant-cell transformation, extramedullary hematopoiesis, and bile duct proliferation. The pathologists' diagnosis of obstruction in clinically proven cases of biliary atresia (BA) ranged from 79%-98%, with a positive predictive value of 90.7%. Histologic features that best predicted BA, on the basis of logistic regression, included bile duct proliferation, portal fibrosis, and absence of sinusoidal fibrosis (each P<.0001). CONCLUSIONS: The BARC histologic assessment system identified features of liver biopsies from cholestatic infants, with good interobserver agreement, that might be used in diagnosis and determination of prognosis. The system diagnosed BA with a high level of sensitivity and identified infants with biliary obstruction with reasonable interobserver agreement. However, distinguishing between BA and disorders such as total parenteral nutrition-associated liver disease and alpha(1)-antitrypsin deficiency is not possible without adequate clinical information.

Progressive familial intrahepatic cholestatic diseases encompass a group of autosomal recessive hereditary diseases, which usually present in infancy or childhood, with cholestasis of hepatocellular origin. The currently preferred nomenclature for the three PFIC disorders that have been characterized to date is FIC1 deficiency, BSEP deficiency, and MDR3 deficiency, relating to mutations in the specific genes involved in bile acid formation and transport. Since the first description of these diseases, extensive clinical, biochemical, and molecular studies have increased our understanding of the features specific to each one of them. This review focuses mainly on the liver histology, summarizing their characteristic pathologic features, the correlation to specific genotypes, and complications arising with disease progression.

INTRODUCTION: Biliary atresia (BA) is a progressive obliteration of the extrahepatic bile ducts resulting in hepatic fibrosis. The underlying mechanisms have not been defined. We used an animal model of BA to evaluate mediators of extracellular matrix (ECM) processing to determine which factors may be involved. METHODS: Newborn BALB/c mice received an intraperitoneal injection with rhesus rotavirus or saline within 24 h of birth. Livers were harvested on days 7 and 14 for histology and immunohistochemistry (IHC). RNA expression was determined using quantitative real-time PCR. Human liver from patients with BA and those having a resection for nonfibrosing diseases was also evaluated. RESULTS: In experimental mice, mRNA expression for tissue inhibitor of metalloproteinase (TIMP)-1 and matrix metalloproteinase (MMP)-7 was increased 18-fold and 69-fold, respectively on day 7, with further increases on day 14. On day 14, mRNA expression for plasminogen activator inhibitor (PAI)-1 (38-fold), TIMP-4 (9.5-fold), and MMP-9 (5.5-fold) mRNA was also observed. Furthermore, integrin alpha(v) beta(6) mRNA expression was increased on days 7 (11-fold) and 14 (6-fold). Presence of integrin alpha(v) beta(6) protein was confirmed by IHC in both mouse and human specimens in the proliferating biliary epithelium. CONCLUSIONS: Our data suggest experimental BA is associated with increased mRNA expression of ECM degradation inhibitors, TIMP-1, PAI-1, and TIMP-4. MMP-7 and MMP-9 expression is also elevated in this model. Furthermore, increased gene expression of integrin alpha(v)beta(6) was demonstrated and IHC confirmed protein expression. Integrin alpha(v)beta(6) or the inhibitors of ECM breakdown may be attractive targets for future treatment strategies

A 15-year-old boy who underwent liver transplantation for fulminant Wilson's disease, presented with elevated transaminases 2 months post-transplant. He had recently seroconverted from previous Epstein-Barr virus (EBV) naive status and by polymerase chain reaction (PCR) had increasing viral load copies of EBV in blood. A liver biopsy was obtained 6 weeks post-transplant, which showed isolated central perivenulitis (CP). His immunosuppresion was reduced and antiviral therapy was added with subsequent increase in liver transaminases. A second liver biopsy 6 weeks later again showed isolated CP. Subsequent further reduction in immunosuppression was followed by the appearance of portal-based moderate acute cellular rejection that was resistant to immunosuppressive treatment and rapidly evolved into ductopenic chronic rejection. This case report underlines the difficulties in interpreting isolated perivenulitis, especially in the setting of EBV seroconversion, and suggests that it may not only represent a form of acute rejection but also a predictor of rapidly progressing chronic rejection.

BACKGROUND AND OBJECTIVES: A male infant with a family history of thrombotic microangiopathy developed atypical hemolytic uremic syndrome (aHUS). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Case report. RESULTS: Genetic analysis demonstrated a heterozygous mutation (S1191L) of CFH, the gene coding complement factor H (CFH). The child suffered many episodes of HUS, each treated with plasma exchange. In time, despite initiation of a prophylactic regimen of plasma exchange, his renal function declined significantly. At the age of 4 yr he received a (split liver) combined liver-kidney transplant (LKT) with preoperative plasma exchange and enoxaparin anticoagulation. Initial function of both grafts was excellent and is maintained for nearly 2 yr. CONCLUSIONS: This report adds to the small but growing number of individuals in whom LKT has provided a favorable outcome for aHUS associated with CFH mutation, expands the technique of using a split liver graft, and describes the unique histologic features of subclinical liver disease in HUS.

We report a five-yr-old child, presenting three yr after heart transplant with acalculous cholecystitis. Histology revealed EBV negative T-cell PTLD. The disease involved the gallbladder, liver, lungs, and mesenteric lymph nodes. He was treated with chemotherapy, went into remission, but relapsed after 11 months and died

OBJECTIVES: Esophageal subepithelial fibrosis has been reported in adults with eosinophilic esophagitis (EE). Our goal was to determine the prevalence of esophageal fibrosis in children with EE, to determine whether it is specific for EE, and to correlate it with clinical and pathological features. PATIENTS AND METHODS: Twenty-one children with EE, 7 with eosinophilic gastroenteritis, 6 with gastroesophageal reflux disease, and 17 control children were studied. Distal esophageal biopsy specimens containing lamina propria were evaluated for extent of subepithelial collagen deposition by use of trichrome staining. Fibrosis was defined as abnormally increased collagen deposition, determined after the establishment of normal patterns on sections of esophagus from pediatric autopsies. Maximum numbers of intraepithelial and lamina propria eosinophils per high-power field by hematoxylin and eosin staining and mast cells per high-power field by immunohistochemical staining for tryptase were determined. Eosinophil and mast cell degranulation in epithelium and lamina propria was determined by use of immunohistochemical staining for major basic protein and tryptase, respectively. The patients' records were reviewed. RESULTS: Esophageal subepithelial fibrosis was present in 12 (57%) patients with EE, 1 with eosinophilic gastroenteritis, 0 with gastroesophageal reflux disease, and 1 control patient. Forty-two percent of those with fibrosis had dysphagia, 80% of whom had food impactions; these symptoms were present only in patients with fibrosis. Within the EE group, fibrosis was not associated with duration of symptoms or with increasing numbers of infiltrating eosinophils/mast cells, but it was associated with eosinophil degranulation. CONCLUSIONS: Esophageal subepithelial fibrosis is prevalent in EE and is specific for the disease in children. It is associated with dysphagia, and it may explain and predict future esophageal dysmotility. Fibrosis is related to the extent of esophageal eosinophil activation, as evidenced by eosinophil degranulation.