Clinical studies

BILE DUCT DISORDERS

Alagille syndrome

Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder characterized by bile duct paucity and associated syndromic features. The syndromic features are classically defined by the presence of three of five major clinical criteria: cholestatic liver disease, cardiac disease, ocular abnormalities (typically posterior embryotoxon), skeletal abnormalities (most commonly butterfly vertebrae), and characteristic facial features. We have described vascular and renal anomalies as additional disease-defining clinical features.

ALGS is a rare condition and affects between 1:30,000 to 1:70,000 individuals. ALGS is caused by mutations in one of two genes; the Notch signalling Pathway ligand JAGGED1 (in 94 per cent of patients) or the notch receptor, NOTCH2 (in 1 to 2 per cent of patients). The liver disease ranges from mild to very severe with extensive liver damage necessitating liver transplantation.

We are actively conducting clinical and translational studies of patients with Alagille syndrome.

 

In the fall of 2017, we launched the Global ALagille Alliance Study (GALA) in partnership with the Alagille Syndrome Alliance (ALGSA) with financial support from the Lumena Pay It Forward Project. The GALA study is an international effort to pool together available data sources to conduct a comprehensive analysis of an international cohort of patients with ALGS to determine prevalence, natural history, socio-economic burden, patient outcomes, with a focus on extra-hepatic manifestations. By pooling together available datasets, we will increase our understanding of ALGS and identify the unique challenges and needs of this patient population. The Hospital for Sick Children and University of Toronto are leading this multi-centre study.

If you are interested in participating as a site, please contact gala.study@sickkids.ca for more information.

 

Cholestatic liver diseases

Cholestatsis is a condition in which bile is not formed normally in the liver, or its flow from the liver to the intestine is impaired. We are a part of the Childhood Liver Disease Research Network (ChiLDReN), a National Institute of Diabetes and Digestive and Kidney Diseases-(NIDDK) supported consortium for the study and care of children with cholestatic disorders (including Alagille syndrome). ChiLDReN consists of 14 Clinical Centers in the US and Canada. We are the only Canadian site. The goal of ChiLDReN is to understand the causes of liver disease and to discover new approaches to the diagnosis and treatment of liver diseases in infants, children and young adults with cholestasis, and those who undergo liver transplantation. ChiLDReN is currently studying the following diseases:

  • Alagille syndrome
  • Alpha-1-antitrypsin deficiency
  • Bile acid synthesis and metabolism defects
  • Biliary atresia
  • Cystic fibrosis liver disease
  • Idiopathic neonatal hepatitis
  • Mitochondrial hepatopathies
  • Progressive familial intrahepatic cholestasis
We run both natural history and clinical therapy trial ChiLDReN studies at SickKids. For more information on all active ChiLDReN studies, please visit the ChiLDReN website.

FRAILTY

Frailty is a syndrome of decreased reserve and resistance to stressors, resulting from cumulative declines across multiple physiologic systems and causing vulnerability to adverse outcomes.1 Frailty is a validated measure of debilitation in the elderly, which is correlated with significant morbidity and mortality. Adult data reveal that frailty measures elements of morbidity in patients awaiting liver transplantation that are not captured in laboratory evaluations or current organ allocation scoring systems. In collaboration with Dr. Vicky Ng, we have adapted the five elements of the adult Fried frailty phenotype in children utilizing validated paediatric tools.

We have completed a pilot feasibility project to assess frailty in children and have now extended this study to a multi-site collaboration of 16 North American transplant centres, with SickKids as the lead site.

Basic research

Stem cell studies of bile duct disorders; “Biliary Disease in a Dish

In the laboratory, we study rare forms of inherited biliary disease and these studies are fundamental to understanding biliary disease mechanisms that have generalizability to other more common and complex bile duct diseases.

The liver is comprised of two cell types which arise from bipotential cells called hepatoblasts. The first, hepatocytes, account for more than 95 per cent of the cell mass, and have long been characterized and established as playing pivotal roles in physiological processes ranging from detoxification to energy storage. Cholangiocytes, which line the intrahepatic biliary tree, account for only a small fraction of the total liver. Our understanding of cholangiocyte biology and their role in biliary disease is relatively limited due to the difficulty in purifying them from tissue samples and a lack of appropriate culture conditions. This had made assessment of biliary disease, which accounts for more than half of all liver transplants in children, incredibly challenging. To date, very few treatment options outside of transplantation exist to meet this disease burden.

In collaboration with colleagues at the McEwen Regenerative Medicine Centre, we have devised a strategy to generate pure populations of cholangiocytes from both iPS and embryonic stem cells. This process takes roughly 40 days, and has opened a conducive avenue for full characterization of cholangiocyte physiology in vitro. Additionally, with the use of 3D culture, we are able to generate “cholangiod” cysts and tubules which better reflect the in vivo environment.

Using our protocol we aim to better understand both normal cholangiocyte function and contribution to a wide variety of previously enigmatic biliary disease mechanisms.

People

Dr. Binita Kamath
Dr. Binita Kamath, MBBChir, MTR

Physician – Division of Gastroenterology, Hepatology and Nutrition
Senior Associate Scientist – Developmental & Stem Cell Biology Program
Associate Professor –
Department of Paediatrics, University of Toronto

Dr. Binita Kamath was educated at Cambridge University in England and trained at several London hospitals, including Kings College Hospital. She moved to the Children’s Hospital of Philadelphia in 2000 and completed her fellowship in GI, Hepatology and Nutrition. She joined the faculty in 2006 and developed a strong interest in cholestatic liver disease, specifically Alagille syndrome. She joined the faculty at The Hospital for Sick Children (SickKids) in 2009 as a Hepatologist and Clinician-Investigator continuing to work on biliary diseases and utilizing stem cell biology to develop disease models.

Claudia Quammie

Claudia Quammie

Clinical Research Project Manager

Shannon Vandriel

Shannon Vandriel

Clinical Research Project Manager

Elena Reydman

Elena Reydman

Clinical Research Project Assistant

Deepika Sharma

Deepika Sharma

Clinical Research Project Assistant

Matthew Rozycki

Matthew Rozycki, PhD

Lab Research Project Manager

Ruku Ali (Postdoctoral Fellow)

Ruku Ali, PhD

Postdoctoral Fellow

Jane Liu

Jane Liu

Lab Technician

Aishwarya

Aishwarya Parmar

Undergraduate Research Student

Rukhsar Sultana

Rukhsar Sultana

Undergraduate Research Student

Ben Martinez

Ben Martinez

Undergraduate Research Student

Selected publications

Funding

Thanks to the following agencies for their generous support!

Childhood Liver Disease Research Network logo

ChiLDReN

Canadian Liver Foundation logo

Canadian Liver Foundation

Alagille Syndrome Alliance logo

Alagille Syndrome Alliance

SickKids Foundation logo

SickKids Foundation

Contact

For administrative or clinical inquiries

Ms. Ivette Milanes Abreus
Administrative Assistant

Gastroenterology, Hepatology and Nutrition
Black Wing, Room 8263
555 University Avenue
Toronto, ON M5G 1X8

416-813-7654 ext: 207733

For research inquiries

Matthew Rozycki, PhD
Lab Research Project Manager

Developmental & Stem Cell Biology Program
SickKids Research Institute
Peter Gilgan Centre for Research and Learning
686 Bay Street,
Room 16.9400, Aisle S
Toronto, ON M5G 0A4