The association between loss of gut wall integrity as measured by ZOnulin and hepatic ischaemia as measured by NIRS and Biliary Atresia development

The aetiology of perinatal biliary atresia is unknown, but the cause is
probably multifactorial. The end result seems an (auto) immunological event
aimed at the cholangiocytes, leading to destruction of the biliary tree during
early infancy. Recent studies demonstrated an association between loss of gut
wall integrity due to a loss of tight junctions between the enterocytes in
early infancy with the development of auto-immune disorders such as type I
diabetes.

Zonulin is a small protein that (partly) regulates tight junction functioning.
Zonulin leads to the release of ZO1, a component of the tight junction complex,
and in that way opens the paracellular pathway. Zonulin can be measured in
blood. As such it is considered a marker for tight junction function. In
patients and in animal experiments a raise in serum Zonulin was associated with
the development of Diabetes Mellitus Type 1 (DM1) later in life. Zonulin levels
were also associated with the development and activity of Celiac Disease (CD).
In animal models, blocking Zonulin could reverse CD symptoms and CD/DM
development. This suggests an association between loss of gut wall integrity
and the development of auto-immune disease.

Furthermore, previous studies showed higher VEGF levels, as an expression of
hypoxia/ischemia, in infants with biliary atresia, which suggest that ischaemia
might be involved in the development of the obstructive cholangiopathy. A
method that can reliable measure tissue oxygenation and hypoxia of an organ is
Near-Infrared Spectroscopy (NIRS). NIRS is a non-invasive method to assess
end-organ perfusion. With NIRS one measures regional tissue oxygen saturation
(rSO2), as surrogate for tissue perfusion. Combined with the arterial oxygen
saturation the fractional tissue oxygen extraction (FTOE) can be calculated
(FTOE = [SpO2-rSO2]/SpO2). FTOE reflects the balance between tissue oxygen
supply (perfusion) and tissue oxygen consumption. Both rSO2 and FTOE thus serve
as an indicator of tissue ischemic hypoxia.

To confirm that loss of gut wall integrity is associated with the development
of biliary atresia and to investigate possible hypoxia in the liver/bile ducts
in children with biliary atresia using NIRS

Prospective single center explorative study

There will be no risk or burden for the children, who will not have to undergo
extra procedures for this research. As biliary atresia is a disease of the
young children, this study can only be performed in this patient group. A small
piece of small bowel will be sampled during the Kasai procedure. This consists
of the most distal part towards the staple line, which is resected anyway prior
to performing the anastomosis. The control group also routinely undergoes
venapuncture for assessment of blood pH and electrolytes, therefore also in the
control group there will not be extra burden.