Biliary atresia

Biliary atresia also known as "Kotb disease", "extra hepatic ductopenia" and "progressive obliterative cholangiopathy",[1] is a childhood disease of the liver in which one or more bile ducts are abnormally narrow, blocked, or absent. Biliary atresia is a congenital aflatoxicosis, in babies who have a congenital specific detoxification defect.[2] As a birth defect in newborn infants, it has an incidence of one in 10,000–15,000 live births in the United States,[3] and a prevalence of one in 16,700 in the British Isles.[4][5] Biliary atresia is most common in East Asia, with a frequency of one in 5,000.

The only known effective treatments are surgeries such as the Kasai procedure and liver transplantation.[6]

Signs and symptoms

A video explanation of biliary atresia

Initially, the symptoms of biliary atresia are indistinguishable from those of neonatal jaundice, a usually harmless condition commonly seen in infants. Distinctive symptoms of biliary atresia are usually evident between one and six weeks after birth. Infants and children with biliary atresia develop progressive cholestasis, a condition in which bile is unable to leave the liver and builds up inside of it. When the liver is unable to excrete bilirubin through the bile ducts in the form of bile, bilirubin begins to accumulate in the blood, causing symptoms. These symptoms include yellowing of the skin, itchiness, poor absorption of nutrients (causing delays in growth), pale stools, dark urine, and a swollen abdomen. Eventually, cirrhosis with portal hypertension will develop. If left untreated, biliary atresia can lead to liver failure. Unlike other forms of jaundice, however, biliary-atresia-related cholestasis mostly does not result in kernicterus, a form of brain damage resulting from liver dysfunction. This is because in biliary atresia, the liver, although diseased, is still able to conjugate bilirubin, and conjugated bilirubin is unable to cross the blood–brain barrier.

Pathophysiology

The cause of biliary atresia remained unknown until recently. Many possible causes have been proposed, such as reovirus 3 infection,[7] congenital malformation, congenital cytomegalovirus infection,[8] and autoimmunity.[9] However, experimental evidence is insufficient to confirm any of these theories.[10]

Abnormal high levels of aflatoxin B1 and to a lesser extent aflatoxin B2 was found in liver tissue and blood of neonates suffering from biliary atresia. These loads of aflatoxins causes extensive damage to the hepatocytes leading to hepatitis and damage to bile ducts causing inflammation, adhesions and final obstruction of bile ducts.[11] The affected neonates have a genetic detoxification defect that does not allow them to detoxify these aflatoxins timely or effectively. The babies have homozygous deficiency of glutathione S transferase (GST) M1. [12] The aflatoxin damaged liver cells and bile duct cells are removed by neutrophil elastase [13] and by involvement of immune system mediators such as CCL-2 or MCP-1, tumor necrosis factor (TNF), interleukin-6 (IL-6), TGF-beta, endothelin (ET), and nitric oxide (NO). Among these, TGF-beta is the most important pro-fibrogenic cytokine that can be seen in progressive cirrhosis.

The cascade of immune involvement to remove damaged hepatocytes and cholangiocytes ushers regeneration. Yet in infants with biliary atresia regeneration is defective, and results in cirrhosis, as these infants have disrupted p53 and disrupted GSTPi. p53 and GSTPi are responsible for DNA fidelity at regeneration. Hence, these infants get accelerated cirrhosis and march to portal hypertension. [14]

Progressive cirrhosis, is associated with signs and symptoms of portal hypertension, such as esophagogastric varix bleeding, hypersplenism, hepatorenal syndrome, and hepatopulmonary syndrome. The latter two syndromes are essentially caused by systemic mediators that maintain the body in a hyperdynamic state.[15]

There are three main types of extra-hepatic biliary atresia:

In approximately 10% of cases, anomalies associated with biliary atresia include heart lesions, polysplenia, situs inversus, absent venae cavae, and a preduodenal portal vein.[16]

Genetics

All infants with biliary atresia have homozygous deficiency of GSTM1, while all their mothers are heterozygous for GSTM1. [17] This genetically determined detoxification defect protects the baby during pregnancy from aflatoxin damage as maternal detoxification is intact, yet after delivery the baby will not be able to detoxify any aflatoxin that passed to its liver via the portal circulation before and during delivery. Thus baby sustains the aflatoxin loads without the ability to detoxify it, with subsequent cascade of liver and bile duct injury leading to biliary atresia and cirrhosis.

An association between biliary atresia and the ADD3 gene was first detected in Chinese populations through a Genome-wide association study, and was confirmed in Thai Asians and Caucasians. A possible association with deletion of the gene GPC1, which encodes a glypican 1-a heparan sulfate proteoglycan, has been reported.[18] This gene is located on the long arm of chromosome 2 (2q37) and is involved in the regulation of inflammation and the Hedgehog gene.

Toxins

Biliary atresia results from exposure to aflatoxin B1, and to a lesser extent aflatoxin B2 during late pregnancy. Intact maternal detoxification protects baby during intrauterine life, yet after delivery the baby struggles with the aflatoxin in its blood and liver. Moreover, the baby feeds aflatoxin M1 from its mom, as aflatoxin M1 is the detoxification product of aflatoxin B1. It is a milder toxin that causes cholangitis in the baby. [19]

Aflatoxins are ranked as the number 1 carcinogen in the world and caused outbreaks of serious hepatitic illness in man.[20][21]

Eating plants that contain a toxin called biliatresone has been implicated in outbreaks of a biliary-atresia-like illness in lambs.[22] Studies are ongoing to determine whether there is a link between human cases of biliary atresia and toxins such as biliatresone. There are some indications that a metabolite of certain human gut bacteria may be similar to biliatresone.[23]

Diagnosis

Diagnosis is made by an assessment of symptoms, physical exam, and medical history, in conjunction with blood tests, a liver biopsy, and imaging. Diagnosis is often made following investigation of prolonged jaundice that is resistant to phototherapy and/or exchange transfusions, with abnormalities in liver enzyme tests. Ultrasound or other forms of imaging can confirm the diagnosis. Further testing may include radioactive scans of the liver and a liver biopsy.[24]

Treatment

If the intrahepatic biliary tree is unaffected, surgical reconstruction of the extrahepatic biliary tract is possible through an operation known as the Kasai procedure (after Morio Kasai, the Japanese surgeon who developed the surgery) or hepatoportoenterostomy. This procedure is not usually curative, but may temporarily alleviate symptoms until the child is fully grown and can undergo liver transplantation. Many individuals are known to have undergone the Kasai procedure and lived for more than a few years without requiring additional surgeries.

If the atresia is complete, liver transplantation is the only option. Timely Kasai portoenterostomy (< 60 postnatal days) has shown better outcomes. Nevertheless, a considerable number of patients undergo liver transplantation within a couple years of the Kasai procedure, even if that procedure was successful.

Recent large-scale studies by Davenport et al. (Annals of Surgery, 2008) show that the age of the patient is not an absolute clinical factor affecting prognosis. The influence of age differs according to the disease etiology—i.e., whether biliary atresia is isolated, cystic (CBA), or accompanied by splenic malformation (BASM).

It is widely accepted that corticosteroid treatment after a Kasai operation, with or without choleretics and antibiotics, has a beneficial effect on postoperative bile flow and can clear jaundice, but the dosing and duration of the ideal steroid protocol are controversial. Furthermore, it has been observed in many retrospective longitudinal studies that corticosteroid treatment does not prolong survival of the native liver or transplant-free survival. Davenport et al. also showed (Hepatology 2007) that short-term, low-dose steroid therapy following a Kasai operation had no effect on the mid- or long-term prognosis of biliary atresia patients.

Epidemiology

Biliary atresia seems to affect females slightly more often than males, and Asians and African Americans more often than Caucasians. It is common for only one child in a pair of twins or within the same family to have the condition. There seems to be no link to medications or immunizations given immediately before or during pregnancy.

Prevention

Biliary atresia is a potentially preventable disease. Designing the prevention would certainly include detection of index cases by screening pregnant ladies prior to delivery. Our food and feeds of poultry and cattle should be strictly monitored for aflatoxins.

References

  1. ↑ Kotb MA. EXTRAHEPATIC BILIARY ATRESIA; KOTB DISEASE IS POTENTIALLY PREVENTABLE. Excellence in Pediatrics Conference 2015 http://www.ineip.org/content/abstract/1582/op-250-2015-extrahepatic-biliary
  2. ↑ Kotb Ma, Kotb A. Extrahepatic Biliary Atresia is an Aflatoxin Induced Cholangiopathy in Infants with Null GSTM1 Genotype with Disrupted P53 and GSTPi to Mothers Heterozygous for GSTM1 Polymorphism: Damage Control is Mediated through Neutrophil Elastase and CD14+ Activated Monocytes: Kotb Disease. Med. J. Cairo Univ., Vol. 83, No. 2, March: 137-145, 2015. http://medicaljournalofcairouniversity.net/home2/images/pdf/2015/march/21.pdf
  3. ↑ Suchy, Frederick J. (2015). "Anatomy, Histology, Embryology, Developmental Anomalies, and Pediatric Disorders of the Biliary Tract". In Feldman, Mark; Friedman, Lawrence S.; Brandt, Lawrence J. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management (10th ed.). Elsevier Health Sciences. pp. 1055–77. ISBN 978-1-4557-4989-8.
  4. ↑ McKiernan, Patrick J; Baker, Alastair J; Kelly, Deirdre A (2000). "The frequency and outcome of biliary atresia in the UK and Ireland". The Lancet 355 (9197): 25–9. doi:10.1016/S0140-6736(99)03492-3. PMID 10615887.
  5. ↑ Hartley, Jane L; Davenport, Mark; Kelly, Deirdre A (2009). "Biliary atresia". The Lancet 374 (9702): 1704–13. doi:10.1016/S0140-6736(09)60946-6. PMID 19914515.
  6. ↑ Wildhaber. Biliary Atresia: 50 Years after the First Kasai ISRN Surgery Volume 2012 (2012), Article ID 132089, 15 pages http://dx.doi.org/10.5402/2012/132089
  7. ↑ Mahjoub, Fatemeh; Shahsiah, Reza; Ardalan, Farid; Iravanloo, Guiti; Sani, Mehri; Zarei, Abdolmajid; Monajemzadeh, Maryam; Farahmand, Fatemeh; Mamishi, Setareh (2008). "Detection of Epstein Barr Virus by Chromogenic in Situ Hybridization in cases of extra-hepatic biliary atresia". Diagnostic Pathology 3: 19. doi:10.1186/1746-1596-3-19. PMC 2424033. PMID 18442403.
  8. ↑ Amer, O. T.; Abd El-Rahma, H. A.; Sherief, L. M.; Hussein, H. F.; Zeid, A. F.; Abd El-Aziz, A. M. (2004). "Role of some viral infections in neonatal cholestasis". The Egyptian Journal of Immunology 11 (2): 149–55. PMID 16734127.
  9. ↑ Wen, Jie; Xiao, Yongtao; Wang, Jun; Pan, Weihua; Zhou, Ying; Zhang, Xiaoling; Guan, Wenbin; Chen, Yingwei; Zhou, Kejun; Wang, Yang; Shi, Bisheng; Zhou, Xiaohui; Yuan, Zhenghong; Cai, Wei (2014). "Low doses of CMV induce autoimmune-mediated and inflammatory responses in bile duct epithelia of regulatory T cell-depleted neonatal mice". Laboratory Investigation 95 (2): 180–92. doi:10.1038/labinvest.2014.148. PMID 25531565.
  10. ↑ Saito, Takeshi; Shinozaki, Kuniko; Matsunaga, Tadashi; Ogawa, Tomoko; Etoh, Takao; Muramatsu, Toshinori; Kawamura, Kenji; Yoshida, Hideo; Ohnuma, Naomi; Shirasawa, Hiroshi (2004). "Lack of evidence for reovirus infection in tissues from patients with biliary atresia and congenital dilatation of the bile duct". Journal of Hepatology 40 (2): 203–11. doi:10.1016/j.jhep.2003.10.025. PMID 14739089.
  11. ↑ Kotb MA. Aflatoxins in Infants with Extrahepatic Biliary Atresia. Med. J. Cairo Univ., Vol. 83, No. 1, March: 207-210, 2015. http://scholar.cu.edu.eg/?q=magdkotb/files/aflatoxins_in_biliary_atresia.pdf
  12. ↑ MA. Glutathione S Transferase M1 Polymorphism in Extrahepatic Biliary Atresia. Med. J. Cairo Univ., Vol. 83, No. 2, March: 109-112, 2015. http://scholar.cu.edu.eg/?q=magdkotb/files/glutathione_s_transferase_m1_polymorphism_in_extrahepatic_biliary_atresia_.pdf
  13. ↑ Kotb MA. Nuetrophil Elastase Mediated Damage in Infants with Extrahepatic Biliary Atresia: A Prospective Cohort Study.Med. J. Cairo Univ., Vol. 82, No. 2, September: 233-23 7, 2014 http://scholar.cu.edu.eg/?q=magdkotb/files/nuetrophil_elastase_mediated_damage_in_infants_with_extrahepatic_biliary_atresia-_a_prospective_cohort_study_.pdf
  14. ↑ MA. Evidence of Disruption of p53 and Glutathione S Transferase Pi in Extrahepatic Biliary Atresia in Association with Neutrophil Elastase Mediated Damage. Med. J. Cairo Univ., Vol. 83, No. 1, March: 201-205, 2015. http://scholar.cu.edu.eg/sites/default/files/magdkotb/files/evidence_of_disruption_of_p53_and_glutathione_s_transferase_pi_in_extrahepatic_biliary_atresia_in_association_with_neutrophil_elastase_mediated_damage_.pdf
  15. ↑ Kotb MA, El Henawy A, Talaat S, Aziz M, El Tagy GH, El Barbary MM, Mostafa W. Immune-mediated liver injury: prognostic value of CD4+, CD8+, and CD68+ in infants with extrahepatic biliary atresia. J Pediatr Surg. 2005 Aug;40(8):1252-7. PubMed PMID: 16080928.
  16. ↑ {Nio M, Wada M, Sasaki H, Tanaka H, Watanabe T. Long-term outcomes of biliary atresia with splenic malformation. J Pediatr Surg. 2015 Dec;50(12):2124-7. doi: 10.1016/j.jpedsurg.2015.08.040. Epub 2015 Nov 21. PubMed PMID: 26613836.
  17. ↑ Kotb MA. Glutathione S Transferase M1 Polymorphism in Extrahepatic Biliary Atresia. Med. J. Cairo Univ., Vol. 83, No. 2, March: 109-112, 2015. http://scholar.cu.edu.eg/?q=magdkotb/files/glutathione_s_transferase_m1_polymorphism_in_extrahepatic_biliary_atresia_.pdf
  18. ↑ Cui, Shuang; Leyva–Vega, Melissa; Tsai, Ellen A.; Eauclaire, Steven F.; Glessner, Joseph T.; Hakonarson, Hakon; Devoto, Marcella; Haber, Barbara A.; Spinner, Nancy B.; Matthews, Randolph P. (2013). "Evidence from Human and Zebrafish That GPC1 is a Biliary Atresia Susceptibility Gene". Gastroenterology 144 (5): 1107–1115.e3. doi:10.1053/j.gastro.2013.01.022. PMC 3736559. PMID 23336978.
  19. ↑ Kotb MA. Aflatoxins in Infants with Extrahepatic Biliary Atresia. Med. J. Cairo Univ., Vol. 83, No. 1, March: 207-210, 2015. http://scholar.cu.edu.eg/?q=magdkotb/files/aflatoxins_in_biliary_atresia.pdf
  20. ↑ Tandon HD. Handling toxicoses of unknown origin. Food Addit Contam. 1993 Jan-Feb;10(1):105-13. PubMed PMID: 8504866.
  21. ↑ Tandon HD, Tandon BN, Ramalingaswami V. Epidemic of toxic hepatitis in India of possible mycotoxic origin. Arch Pathol Lab Med. 1978 Jul;102(7):372-6. PubMed PMID: 580871.
  22. ↑ Waisbourd-Zinman O, Koh H, Tsai S, Lavrut PM, Dang C, Zhao X, Pack M, Cave J, Hawes M, Koo KA, Porter JR, Wells RG. The toxin biliatresone causes mouse extrahepatic cholangiocyte damage and fibrosis via decreased glutathione and SOX17. Hepatology. 2016 Apr 15. doi: 10.1002/hep.28599. [Epub ahead of print] PubMed PMID: 27081925.
  23. ↑ Patman G. Biliary tract: Newly identified biliatresone causes biliary atresia. Nat Rev Gastroenterol Hepatol. 2015 Jul;12(7):369. doi: 10.1038/nrgastro.2015.91. Epub 2015 May 26. PubMed PMID: 26008130.
  24. ↑ Kotb MA, Kotb A, Sheba MF, El Koofy NM, El-Karaksy HM, Abdel-Kahlik MK, Abdalla A, El-Regal ME, Warda R, Mostafa H, Karjoo M, A-Kader HH. Evaluation of the triangular cord sign in the diagnosis of biliary atresia. Pediatrics. 2001 Aug;108(2):416-20. PubMed PMID: 11483808.

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