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December 2010, Volume 60, Issue 12


Genetics in paediatric liver disease

Sina Aziz  ( Lyari General Hospital, Paediatric Unit IV, Dow University of Health Sciences, Karachi. )

Genetics (genetic constitution of an individual, group, or class) is a branch of biology that deals with heredity, especially the mechanisms of hereditary transmission and the variation of inherited characteristics among similar or related organisms.1 Genetic professionals include medical geneticist, genetic counselor, laboratory geneticist and nurse geneticist.2
Clinical geneticist tries to identify the etiology, mode of inheritance and the risk that a similar disorder may occur in the affected childs’ siblings. Five different categories are required for classification of the patients\' disorder. Single gene mutations account for 6% of the children with congenital anomalies, chromosomal disorders 7.5%, multifactorial inheritance 20%, and disorders with unusual pattern of inheritance 2 to 3%, while teratogenically caused conditions are 6%.3 Hence, prenatal diagnosis is necessary when familial, maternal or foetal conditions, may result in malformations, chromosomal abnormality or genetic disorders.
There are studies related to the degeneration of the retina such as in the syndromic entity of BBS (Bardet-Biedl syndrome) and other ciliopathies.4 However, studies on genetic disorders of paediatric liver disease from Pakistan are few if any.
Disorders of the liver are common causes of chronic illness in childhood, affecting approximately one of every 8,000 children. Most childhood liver diseases are congenital (present at birth), and may be caused by a variety of genetic abnormalities, structural malformations, or prenatal infections. In addition, older children and teenagers may be affected by some acquired disorders seen in adults. Paediatric patients account for about 12.5% of liver transplant recipients.2,3
Genetics in liver disease is an important topic. Various paediatric liver diseases in our setup, remain undiagnosed and are managed symptomatically and a diagnosis based on clinical suspicion, radiology, and lab parameters only, rather than a confirmatory diagnosis based on scientific evidence such as genetic analysis of liver tissue, blood/serum etc.
Over the years importance of genetic diagnosis of various diseases especially related to hepatology is shown in the table. However, we have had to face serious deficiencies in our lab analysis, as very few experts and labs are available to do the special diagnosis, required for genetic evaluation in Pakistan. Various diseases have been highlighted in the table, they are but a few which have been documented in literature. We may miss out on all of them due to which diagnosis given to patients is incorrect and awareness among the general population regarding specific disease related to inheritance is missed.
A group of children has been identified with Bile canalicular transport disorders (Bylers disease or syndrome. Another term used for this condition is Progressive familial intrahepatic cholestais (PFIC). Three types have been described PFIC 1, 2 and 3. Genetic diagnosis and differentiation is possible (Table).

The two infantile disorders with low serum GGT are ATP8B1(FIC-1) deficiency PFIC-1 and bile salt export pump (BSEP) deficiency (PFIC-2). However, in PFIC-3 with MDR3 deficiency have intrahepatic cholestasis, but an elevated GGT.5,6
Patients with biliary atresia comprise 50% of the paediatric patients who require a liver transplant. Other disease states that progress to end-stage liver disease in paediatric patients include metabolic disorders and progressive intrahepatic cholestasis. Examples of metabolic derangements include Wilsons disease, alpha 1-antitrypsin deficiency, tyrosinaemia, and haemochromatosis. Other metabolic disease states leading to hepatic dysfunction include Crigler-Najjar syndrome, glycogenosis, hyperoxaluria, metabolic respiratory chain deficiencies, familial hypercholesterolaemia, and methylmalonyl aciduria.7
The need of the hour is to establish full fledged genetic lab with appropriate facilities conducive to the need of the general public and not private, only. This can initially only be achieved in collaboration with international institutes and funded by NGOs or government. Our research is centered on HCV, HBV and communicable disease to name a few. However, as the Table indicates innumerable liver diseases are genetic born and hence future pregnancies can be prevented by appropriate counseling to the parents.
Confidentiality should be maintained in genetic testing and keeping in mind the child\'s interest at the foremost. Guidelines regarding genetic testing are available by the American society of human genetics and American college of medical genetics.2
Hence, we as clinicians/researchers in collaboration with Medical and laboratory geneticist should focus on prevention. This can be achieved by counseling families with affected children so that future affected children can be avoided. In the long run, this will save the budget of the individual families and the government. Genetic counseling sessions with the family should include a discussion of the specific diagnosis/condition, various differential diagnosis when a specific diagnosis cannot be made, knowledge of the natural history of the condition, genetic aspects of the condition and recurrence risk, prenatal diagnosis and prevention, therapies and referral, support groups to help the affected family and follow up to keep up to date with new developments of the particular disease. Counseling should be non directive i.e. family should have a choice about reproduction and to determine what is right for them.8 Above all, the information is provided in understandable terms and outlines the range of options available to them.


1.The Free Dictionary by Farlex. Genetics. (Online) (Cited 2010 July 14). Available from URL:
2.Korf BR. The genetic approach in pediatric medicine. In: Kleigman RM, Behrman RE, Jenson HB, Stanton BF (eds). Nelson text book of pediatrics. 16th ed. Philadelphia Saunders, 2007; pp 485-92.
3.Levy PA, Marion RW Patterns of inheritance. Human genetics and dysmorphology. In: Kleihman RM, Marcdante KJ, Jenson HB Behrman RE (eds). Nelson Essential of pediatrics. Philadelphia: Saunders, 2007; pp 217-28.
4.Riazuddin SA, Iqbal M, Wang Y, Masuda T, Chen Y, Bowne S, et al. A splice-site mutation in a retina-specific exon of BBS8 causes nonsyndromic retinitis pigmentosa. Am J Hum Genet 2010; 86: 805-12.
5.Mirza R, Abbas Z, Luck NH, Azam SM, Aziz S, Hassan SM et al Progressive familial intrahepatic cholestasis. J Coll Physicians Surg Pak 2006; 16: 673-5.
6.Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects. Semin Liver Dis 2010; 30: 134-46.
7.Evrard V, Otte JB, Sokal E, Rochet JS, Haccourt F, Gennari F, et al. Impact of surgical and immunological parameters in pediatric liver transplantation: a multivariate analysis in 500 consecutive recipients of primary grafts. Ann Surg 2004; 239: 272-80.
8.Wolff G, Jung C. Nondirectiveness and genetic counseling J Genet Couns 1995; 4: 3-25.

Journal of the Pakistan Medical Association has agreed to receive and publish manuscripts in accordance with the principles of the following committees: