Three brothers with progressive hepatic dysfunction and severe hepatic steatosis due to a patent ductus venosus

Uchino, Tetsuya; Endo, Fumio; Ikeda, Shinji; Shiraki, Kazuo; Sera, Yoshihisa; Matsuda, Ichiro

doi:10.1053/gast.1996.v110.pm8964424

Cited by 85 publications

(79 citation statements)

References 2 publications

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“…These data identify the Ah locus as the first gene reported to be associated with patent DV, a condition that can be congenital in humans (40,41) and in dogs (42). These results also provide evidence that the AHR plays a role in the resolution of a number of vascular structures.…”

Section: Discussionsupporting

confidence: 52%

Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice

Lahvis

Lindell

Thomas

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

340

267

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A physiological examination of mice harboring a null allele at the aryl hydrocarbon (Ah) locus revealed that the encoded aryl hydrocarbon receptor plays a role in the resolution of fetal vascular structures during development. Although the aryl hydrocarbon receptor is more commonly studied for its role in regulating xenobiotic metabolism and dioxin toxicity, a developmental role of this protein is supported by the observation that Ah null mice display smaller livers, reduced fecundity, and decreased body weights. Upon investigating the liver phenotype, we found that the decrease in liver size is directly related to a reduction in hepatocyte size. We also found that smaller hepatocyte size is the result of massive portosystemic shunting in null animals. Colloidal carbon uptake and microsphere perfusion studies indicated that 56% of portal blood flow bypasses the liver sinusoids. Latex corrosion casts and angiography demonstrated that shunting is consistent with the existence of a patent ductus venosus in adult animals. Importantly, fetal vascular structures were also observed at other sites. Intravital microscopy demonstrated an immature sinusoidal architecture in the liver and persistent hyaloid arteries in the eyes of adult Ah null mice, whereas corrosion casting experiments described aberrations in kidney vascular patterns.T he aryl hydrocarbon receptor (AHR) is a member of the per-arnt-sim (PAS) superfamily of proteins. The AHR regulates biological responses to a variety of environmental contaminants, such as the polycyclic aromatic hydrocarbons found in cigarette smoke, the polychlorinated dioxins that contaminate industrial chemicals, and the wartime defoliant Agent Orange (1-5). These chemical ligands bind to the AHR, leading to receptor dimerization with another PAS protein known as the aryl hydrocarbon nuclear translocator (ARNT). This heterocomplex interacts with genomic enhancer elements upstream of a battery of target genes that encode xenobiotic metabolizing enzymes (1, 6, 7). The observation that the up-regulated enzymes often have metabolic activity toward AHR agonists has led to the idea that this pathway represents an adaptive metabolic response that protects an organism from exposure to certain classes of toxic environmental contaminants. Although this adaptive role has considerable experimental support, this pathway is not always protective. Exposure to high-affinity AHR agonists, like the chlorinated dioxins, can result in cancer (8), immunosuppression (9), liver damage (10), and birth defects (11). The mechanisms underlying these toxic effects are unknown but appear to be AHR mediated.Because of its role in mediating responses to environmental contaminants, the biology of the AHR has been extensively characterized from a toxicological viewpoint. However, several observations suggest an additional role for the AHR in vertebrate development. First, a phylogenetic survey indicates that the AHR arose over 450 million years ago, with functional orthologs found in species that have evolved in vario...

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Section: Discussionsupporting

confidence: 52%

Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice

Lahvis

Lindell

Thomas

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

340

267

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“…When symp- toms cannot be conservatively controlled, however, interventional treatment must be performed. Therapeutic approaches to patent DV with portosystemic encephalopathy include conservative treatment, occlusion of the shunt and liver transplantation 4,5,8) . In previous reports, 15 of 25 patients with patent DV were complicated by absence or hypoplasia of the intrahepatic portal venous system with or without partial nodular transformation or focal nodular hyperplasia 3,6) .…”

Section: Discussionmentioning

confidence: 99%

“…Large caliber patent DV is a rare congenital anomaly, and depending on the shunt ratio and decreased tolerance to ammonia [3][4][5][6][7][8][9][10][11][12] , and patients may suffer symptoms of portosystemic encephalopathy.…”

Section: Introductionmentioning

confidence: 99%

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Transvenous Embolization of Patent Ductus Venosus in Two Adult Cases

2009

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Although the patent ductus venosus is congenital, the symptoms due to hyperammonemia vary, possibly depending on the shunt ratio and individual tolerance to ammonia. We have experienced two adult patients with large caliber patent ductus venosus and compensated liver cirrhosis. In one case, the ductus venosus simply communicated to the portal vein, but in the other case there were multiple short communicating vessels between the ductus venosus and left portal vein. Both cases were successfully treated by the transvenous embolization with steel coils and ethanolamine oleate, which has an expansive nature.

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“…The most prominent vascular abnormality reported in these nulls is the presence of a patent ductus venosus (DV) throughout life (53). The DV is a porto-systemic shunt that allows blood to bypass the hepatic circulation during embryogenesis (55)(56)(57). In the Ahr Ϫ/Ϫ mouse, the DV allows a significant fraction of the portal blood supply to bypass liver perfusion and exit through the inferior vena cava.…”

Section: Discussionmentioning

confidence: 99%

A Maternal Ahr Null Genotype Sensitizes Embryos to Chemical Teratogenesis

Thomae

Glover

Bradfield

2004

Journal of Biological Chemistry

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The aryl hydrocarbon receptor (encoded by the Ahr locus) is a ligand-activated transcription factor that mediates the toxicology and teratology of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). In an effort to understand the role of the maternal compartment in dioxin teratology, we designed a breeding strategy that allowed us to compare the teratogenic response in embryos from Ahr ؊/؊ (null) and Ahr ؉/؉ (wild-type) dams. Using this strategy, we demonstrate that embryos from the Ahr ؊/؊ dams are 5-fold more sensitive to dioxin-induced cleft palate and hydronephrosis as compared with embryos from an Ahr ؉/؉ dam. Moreover, this increased teratogenic sensitivity extends beyond dioxin, because embryos from Ahr ؊/؊ dams exhibited a 9-fold increase in their sensitivity to the fetotoxic effects of the glucocorticoid, dexamethasone. In searching for an explanation for this increased sensitivity, we found that more dioxin and dexamethasone reached the embryos from Ahr ؊/؊ dams as compared with embryos from Ahr ؉/؉ dams. We propose that increased deposition of teratogens/fetotoxicants to the embryonic compartment is the result of porto-systemic shunting and/or blocked P4501A induction in Ahr ؊/؊ dams. In addition to demonstrating the importance of maternal AHR in teratogenesis, these data may have implications that reach beyond the mechanism of action of dioxin. In this regard, the Ahr ؊/؊ mouse may provide a system that allows pharmacological agents and toxicants to be more easily studied in a model where first pass clearance is a significant obstacle.Chemical teratogens can perturb normal mammalian development through direct action on the embryo, indirectly through maternal toxicity, or as the result of a combination of both of these mechanisms. The maternal compartment can afford protection by functioning as a metabolic or physical barrier that reduces embryonic exposure to a given agent (1). The maternal compartment also holds the potential to serve as a site of teratogen bioactivation and may serve to increase the concentrations of active metabolites that directly perturb normal embryonic development (2, 3). Understanding the relative contributions of maternal and embryonic physiology for a given teratogen can be difficult, especially when chemical agents induce a variety of teratogenic end points or display remarkable pharmacological potency.One approach to understanding the relative contributions of the maternal and embryonic physiology is to define these two compartments via their respective genotypes. Such an approach is particularly powerful when working with null alleles that have been generated via gene targeting. In such cases, the dominance order is clear, as is the functional relationship between one or two copies of the wild-type allele. Through appropriate genetic crosses one can then generate informative combinations of maternal and embryonic genotypes that can help identify when maternally or embryonically expressed loci play a differential role in the teratogenic response to a specific chemical (4).Based...

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Three brothers with progressive hepatic dysfunction and severe hepatic steatosis due to a patent ductus venosus

Cited by 85 publications

References 2 publications

Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice

Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice

Transvenous Embolization of Patent Ductus Venosus in Two Adult Cases

A Maternal Ahr Null Genotype Sensitizes Embryos to Chemical Teratogenesis

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