Ductal Plate Malformation in the Liver of Boxer Dogs: Clinical and Histological Features.

Ductal plate malformations (DPMs) represent developmental biliary disorders with a wide phenotypic spectrum. This study characterizes DPM in 30 Boxer dogs. Median age was 1.5 (range, 0.3-10.0) years, with 12 dogs <1 year. Clinical features included increased serum levels of liver enzymes (28), gastrointestinal signs (16), poor body condition (14), abdominal effusion (9), and hepatic encephalopathy (2). Additional malformations included gallbladder atresia (8), atrophied left liver (2), absent quadrate lobe with left-displaced gallbladder (1), portal vasculature atresia (left liver, 1), intrahepatic portosystemic shunt (1), and complex intrahepatic arteriovenous malformation (1). All dogs had portal tracts dimensionally expanded by a moderate-to-severe multiple small bile duct phenotype embedded in abundant extracellular matrix; 80% displayed variable portal-to-portal bridging. Quantitative analysis confirmed significantly increased fibrillar collagen and a 3-fold increased portal tract area relative to 6 Boxer and 10 non-Boxer controls. Biliary phenotype was dominated by tightly formed CK19-positive ductules, typically 10 to 15 µm in diameter, with 3 to >30 profiles per portal tract, reduced luminal apertures, and negative Ki-67 immunoreactivity. CK19-positive biliary epithelium intersected directly with zone 1 hepatocytes as a signature feature when considered with other DPM characteristics. Phenotypic variation included a multiple small bile duct phenotype (all dogs), predominantly thin-walled sacculated ducts (4), well-formed saccular ducts (4), and sacculated segmental, interlobular, and intralobular ducts (Caroli malformation, 2 dogs, one with bridging portal fibrosis). Histologic evidence of portal venous hypoperfusion accompanied increased biliary profiles in every case. We propose that this spectrum of disorders be referred to as DPM with appropriate modifiers to characterize the unique phenotypes.

Loss of cilia causes embryonic lung hypoplasia, liver fibrosis, and cholestasis in the talpid3 ciliopathy mutant.

Sonic hedgehog plays an essential role in maintaining hepatoblasts in a proliferative non-differentiating state during embryogenesis. Transduction of the Hedgehog signaling pathway is dependent on the presence of functional primary cilia and hepatoblasts, therefore, must require primary cilia for normal function. In congenital syndromes in which cilia are absent or non-functional (ciliopathies) hepatorenal fibrocystic disease is common and primarily characterized by ductal plate malformations which underlie the formation of liver cysts, as well as less commonly, by hepatic fibrosis, although a role for abnormal Hedgehog signal transduction has not been implicated in these phenotypes. We have examined liver, lung and rib development in the talpid(3) chicken mutant, a ciliopathy model in which abnormal Hedgehog signaling is well characterized. We find that the talpid(3) phenotype closely models that of human short-rib polydactyly syndromes which are caused by the loss of cilia, and exhibit hypoplastic lungs and liver failure. Through an analysis of liver and lung development in the talpid(3) chicken, we propose that cilia in the liver are essential for the transduction of Hedgehog signaling during hepatic development. The talpid(3) chicken represents a useful resource in furthering our understanding of the pathology of ciliopathies beyond the treatment of thoracic insufficiency as well as generating insights into the role Hedgehog signaling in hepatic development.

["Adult form" of congenital liver fibrosis]. / "Adulte Form" der kongenitalen Leberfibrose.

HISTORY AND ADMISSION FINDINGS: During a routine check-up, a 37-year-old woman was found to have elevated levels of serum gamma-glutamyl transferase (gamma GTP) and IgA- and IgM-antibodies. One of the patient's brothers had died at the age of six from acute liver failure. We found a palpably enlarged liver with normal consistency and no particular helpful laboratory results. INVESTIGATIONS: The abdominal ultrasound and computed tomography (CT) showed segmental and saccular dilatations of the biliary tract, hepatofugal flow in the portal vein, multiple collateral vessels as well as a mild splenomegaly. Histopathology revealed fibrotic liver parenchyma, a dilatated and branched biliary tract lined by cubical epithelium. COURSE: Gastroscopy showed lowgrade esophageal varices. Seventeen months after the initial presentation there were no significant changes of the laboratory tests or the ultrasound. CONCLUSIONS: The defective remodelling of the ductal plate ("ductal plate malformation") is associated with dysplasia of the biliary tract. Depending on the localisation of the lesions within the biliary tract and whether it is a more cystic or more fibrotic component, there are different malformations caused by ductal plate malformation. We diagnosed congenital hepatic fibrosis, because of the atypical age of presentation, it could be the "adult form" of congenital liver fibrosis.

Foscarnet therapy for congenital cytomegalovirus liver fibrosis following prenatal ascites.

We report on an infant with multi-system disease including liver fibrosis, right microphthalmia with cataract, interstitial pneumonitis, and hyperechoic lesions in the basal ganglia and in the periventricular and thalamic regions. Prenatal ascites with hepatomegaly concomitantly with detection of cytomegalovirus (CMV) DNA in the amniotic fluid, following recurrent maternal CMV infection, had been shown. Although CMV culture and DNA detection were negative in the urine, the infant was given foscarnet because CMV infection was demonstrated in the liver by DNA detection and immunohistochemical staining. Favorable clinical outcome and absence of CMV in the liver were subsequently shown. Our case suggests that congenital CMV disease following maternal recurrence may not be associated with disseminated infection but only with intracellular infection. The diagnosis should therefore be based on CMV detection in the involved organs. Moreover, this is the first report on the possible efficacy and safety of foscarnet for therapy of immunocompetent infants with congenital CMV disease.

D-propoxyphene and norpropoxyphene kinetics after the oral administration of D-propoxyphene: a new approach to liver function?

In an attempt to design a liver function test which takes into account both portal-systemic shunting and hepatocellular dysfunction, we investigated a group of patients with cirrhosis with or without surgical porta-caval shunt for d-propoxyphene and its major metabolite, norpropoxyphene kinetics. A small dose of d-propoxyphene (0.7 mg/kg body weight) was given orally to seven normal subjects, 15 patients with cirrhosis and seven patients with cirrhosis and surgical portacaval shunt. D-propoxyphene and norpropoxyphene areas under the plasma concentration-time from 0 to 4-h (AUC) were determined by the trapezoidal method. As d-propoxyphene is a high extraction drug and since the production of norpropoxyphene should reflect the amount of d-propoxyphene available to the hepatocytes, we tested the hypothesis that norpropoxyphene/d-propoxyphene AUC ratios should reflect both the degree of portal-systemic shunting and the severity of hepatocyte dysfunction. Norpropoxyphene/d-propoxyphene AUC ratios were significantly lower in patients with cirrhosis (mean +/- S.D.: 0.92 +/- 0.59) than in controls (2.51 +/- 0.45) and also significantly lower in patients with cirrhosis and a surgical shunt (0.53 +/- 0.23) than in patients with cirrhosis but without surgical shunt (1.10 +/- 0.63). Moreover, there was an overall statistically significant correlation between norpropoxyphene/d-propoxyphene AUC ratios and branched to aromatic amino acids ratios (rs = 0.91) and fasting venous NH4 (rs = -0.63). On the other hand, there was only a weak correlation between norpropoxyphene/d-propoxyphene AUC ratios and the 14C-aminopyrine breath test (rs = 0.43). These data suggest that the norpropoxyphene/d-propoxyphene AUC ratio reflects both shunting and reduced hepatocellular function.(ABSTRACT TRUNCATED AT 250 WORDS)

Copper disposition of the fetus and placenta in a patient with untreated Wilson's disease.

A patient with untreated Wilson's disease showed the possibility of fetal liver damage and copper accumulation in the placenta by this disease. This is the first report of copper disposition on the fetus and placenta in a patient with untreated Wilson's disease.