Congenital aflatoxicosis, mal-detoxification genomics & ontogeny trigger immune-mediated Kotb disease biliary atresia variant: SANRA compliant review

Abstract

Biliary atresia (BA) is the most common indication for pediatric liver transplantation. We describe The BA variant: Kotb disease. Liver tissue in the Kotb disease BA is massively damaged by congenital aflatoxicosis resulting in inflammation, adhesions, fibrosis, bile duct proliferation, scarring, cholestasis, focal syncytial giant cell transformation, and typical immune response involving infiltration by CD4+, CD8+, CD68+, CD14+, neutrophil infiltration, neutrophil elastase spill, heavy loads of aflatoxin B1, accelerated cirrhosis, disruption of p53 and GSTPi, and have null glutathione S transferase M1 (GSTM1). All their mothers are heterozygous for GSTM1. This inability to detoxify aflatoxicosis results in progressive inflammatory adhesions and obliterative cholangiopathy early in life. The typical disruption of both p53 and GSTPi causes loss of fidelity of hepatic regeneration. Hence, regeneration in Kotb disease BA typically promotes accelerated cirrhosis. The immune response in Kotb disease BA is for damage control and initiation of regeneration, yet, this friendly fire incurs massive structural collateral damage. The Kotb disease BA is about actual ongoing hepatic entrapment of aflatoxins with lack of ability of safe disposal due to child detoxification-genomics disarray. The Kotb disease BA is a product of the interaction of persistent congenital aflatoxicosis, genetic lack of GSTM1 detoxification, ontogenically impaired activity of other hepatic detoxification, massive neutrophil-elastase, immune-induced damage, and disturbed regeneration. Ante-natal and neonatal screening for aflatoxicosis, avoiding cord milking, and stringent control of aflatoxicosis content of human, poultry and live-stock feeds might prove effective for prevention, prompt diagnosis and management based on our recent understanding of its patho-genomics.

Low-dose biliatresone treatment of pregnant mice causes subclinical biliary disease in their offspring: Evidence for a spectrum of neonatal injury

“…Placental tissue was not collected. Although in utero exposure is the most likely route of biliatresone toxicity in pups, we could not rule out transfer in milk [33] and therefore kept nursing mothers with pups until P21, then euthanized both.…”

Editorial: Elimination of biliary atresia

“…Many factors have been flagged as the initial trigger of bile duct wall inflammation in the susceptible host: these include viral, vascular, immune, toxins as biliatresone ( 3 ), and aflatoxins. The aflatoxin-induced cholangiopathy in glutathione S transferase (GST) M1 deficient Egyptian neonates born to GST M1 heterozygous mothers is a known etiology of BA, namely, Kotb disease ( 4 – 6 ).…”

“…The known susceptibility factors include the congenital detoxification detect ( 4 – 6 ), the degree, severity and rate of the massive immune response, the genetic susceptibility to fibrosis and scaring, maternal microchimerism , co-existing viral infections as cytomegalovirus ( 7 ), or bacterial infection as E coli and others ( 5 ). The immune response involves neutrophil elastase ( 6 , 8 ), CD4+, CD68+, CD8+2, CD14+, and others ( 2 ).…”

“…Immune involvement is fundamental to the development of the BA phenotype ( 4 , 16 ), yet the immune modulatory therapies remain adjuvant to the surgical intervention ( 17 ). And despite the central role of immune pathogenesis, the roles of current immune modulatory therapies as steroids ( 18 ), immunoglobulins ( 19 ), colchicine ( 20 ), etc.…”

Medical-grade Spore-free Natural Honey is an Effective Choleretic in Neonatal Cholestasis: A Pilot Single-center Trial

“…4,5 Congenital aflatoxicosis-induced cholangiopathy also has been reported as a cause of biliary atresia; Kotb disease that has been observed in infants with the null glutathione S-transferase mu 1 genotype with disrupted p53 and glutathione S-transferase pi to mothers heterozygous for the glutathione S-transferase mu 1 polymorphism. [6][7][8] There is no known treatment for cholestasis. 9 Bile acids are known to be hepatotoxic, yet ursodeoxycholic acid (UDCA) is used off-label as a choleretic to treat neonatal cholestasis even though there is poor evidence for its safety or effectiveness.…”