PFIC Newsletter
Winter
Welcome Cade Charles
Cade Charles and his Mom Erin joined our group in October
. “ He is 18
months old --funny and outgoing-- we just want to see this awesome personality shine
all the time.”
Cade ’s story is on our Kids page. He has a working diagnosis
of PFIC II, and had a PEBD in May 2005.
CLiC is one of the most exciting things to happen for the study of PFIC.
The Rare Disease Act of 2002, created the funding for the Rare Diseases
Clinical Research Network (RDCRN). The Cholestatic Liver Disease Con-
sortium (CLIC) is one of ten consortiums at the RDCRN.
The CLiC consists of eleven Clinical and Research Centers that will be
working together to investigate five genetic causes of intrahepatic choles-
tasis and to train the next generation of clinical researchers. These five
diseases are:
• Alpha-1-antitrypsin (a-1AT) deficiency
• Alagille syndrome (AGS)
• Progressive familial intrahepatic cholestasis (PFIC)
• Bile acid synthesis and metabolism defects
• Mitochondrial hepatopathies “
Recently CLIC added a PFIC information page to their site. There is also
a patient contact registry. The Patient Contact Registry is completely pri-
vate, free of charge, and does not commit you to joining any studies. For
more information or to join the PFIC Registry please visit the CLiC PFIC
page at:
http://rarediseasesnetwork.epi.usf.edu/clic/learnmore/pfic.htm
What is CLiC?
Volume 1, Issue 1
Welcome Cade
Charles
Robin’s Notes
I decided to e-mail out The
PFIC Newsletter to help us
all stay in touch. For now it
will be a quarterly newslet-
ter, that may change as we
grow. To date we have 5
PFIC families. Considering
the rarity of the disease, that
is a pretty good start. With
our group being small I
thought we could make the
PFIC Newsletter a little
more personal. So please e-
mail with birthdays, trans-
plant anniversaries, and any
other special occasions you
would like to share. This
newsletter is a way for us to
celebrate, share, and support
each other.
New on the web-site. I have
added a Guest book, a Live
Chat area, a Forum area, a
link to the new CLIC web-
site, and a new Immu-
nostaining explanation page.
I am still learning to build
web-sites, so if you experi-
ence problems with the site
please let me
know.
Kayli Renee was born Dec 2004. She was a healthy baby at birth, but by
2 months she was very jaundice and rubbing her ears all the time. We
took her to the Pediatrician, who didn't know why Kayla was yellow or the
fact she did not have any type of ear infection. She sent us to a number
of specialists, who ran blood work, ultrasounds, and physical exams. All
of the normal liver diseases were ruled out. Finally in June 2005 we met
with a liver specialist from Children's Healthcare of Atlanta. He did a
liver biopsy and diagnosed her with PFIC Type 2. He had already diag-
nosed 5 others, so he knew what to look for.
Kayli was put on a number of medications: Rafampin, Actigal, Vit E, Vit K,
Vit D,and Polyvisol. She started them the beginning of July and has done
well with them. She has had 3 check-ups since then and her lab tests are
getting better. Kayli still itches her ears and stomach, but for now it is not
too bad. We just have to wait it out, see how fast the disease progresses.
It is comforting to know that we have others to confide in, and to let us
know what to expect.
Kayli Renee Kayli is a very happy baby, and laughs all the time. We can't
believe she is almost a year old. Her favorite toys are Care Bears, Dora,
and peek-a-boo blocks.
Brad & Kari
(Parents to Kayli)
Happy Birthday Kayli
Make a Wish Foundation
grants the wishes of children
with life-threatening medical
conditions to enrich the hu-
man experience with hope,
strength, and joy. Zoe’s wish
was to go to Disneyland.
Here Zoe and her sister
Sharamarie meet the princess.
Kayli Renee’s Story
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Zoe’s Make a Wish
Indoor Kids Fun
With cold winter days fast ap-
proaching if you are looking for
some indoor fun try this recipe for
play dough. This is the best play
dough I’ve made. It is very quick
and easy to make. The dough is
very soft and smooth and they can
even play with it when it is still
warm. For a little extra fun I
sometimes mix in a drop of mint
extract or other scent extract to
make is smell good. Little hands
love the good smelling warm
dough on a cold winter day. I think
it can also be baked to make orna-
ments.
1 Cup all purpose flour
1 Cup water
½ Cup of salt
1 teaspoon vegetable oil
½ teaspoon cream of tartar
Food coloring (optional)
Mint or scented extract (optional)
Mix the flour, water, salt, oil, and
cream of tartar in a saucepan.
Cook over medium heat until it
holds together, a non-stick pan is
ideal (keep mixing or it will stick to
the bottom of the pan). When the
dough is cool enough knead in
food colorings and scent extract.
Store in an air tight container. It
will keep for a few weeks .
Recipe from the Disney Family
Cookbook
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Doctor’s Notes
Immunostaining in PFIC – how does it help in diagnosis?
By Dr. Alex Knisley
(go to foot of section for affiliation and contact details. Related biopsy
slides are on line at www.PFIC.org under Immunostaining PFIC-2)
Everyone whose child has been diagnosed with PFIC, “progressive familial intrahepatic cholesta-
sis”, immediately wants to know: What does that mean?
Not “What does PFIC stand for?”, but “What does this diagnosis mean for my baby, and for our
family?”
(Please let me be clear: When I write “PFIC”, I mean a disorder in which, despite jaundice
[“conjugated hyperbilirubinemia”], serum concentrations of gamma-glutamyl transpeptidase [GGT]
activity do not rise. “Low-GGT PFIC” is a very different kettle of fish from “high-GGT PFIC. Check
with your child’s doctors if you are not clear on this point, it is worth the telephone call.)
Two different kinds of PFIC are well-defined. That is, the gene responsible is known for each of
them, even if all the interactions and functions of the protein encoded by that gene are not yet
sorted out. One of these is a disorder limited to the liver. One of these is a disorder that affects
many body systems.
That in itself is a good reason to know which sort of PFIC your child has; down the road, most chil-
dren with PFIC will come to liver transplantation. Will the transplant “cure” your child’s disorder?
(By “cure”, I mean: “Replace one disease with another one that is much easier to deal with”, not
“return-to-absolute-and-total-health”.) Or will the transplant unmask a new set of problems in or-
gans other than the liver?
This is one example of why exact diagnosis, that is, disease identification, can be important: It
helps give a more specific prognosis, that is, forecast of what your child and you can expect.
A Special Anniversary
December is a special Month for our Family. It is Anna’s transplant anni-
versary. This will be her two year anniversary. When you have a day so
special it is hard to decide just how to celebrate it. For us it became a way
we could celebrate and help others by encouraging organ donor aware-
ness. Last year we passed out over 200 green organ donor lapel pins with
organ donor cards, and asked people to wear them on Dec 21st to help us
celebrate. The response was over whelming . We ran out of cards and
pins. I also heard wonderful stories on how organ donation had touched
so many families . This year we ordered a lot more pins, about 1,000! I
don’t know if we will manage to give them all out, but we are going to try. If
you think about it , join on Dec 21st, by wearing a green ribbon . Now as
for Anna, she liked the green ribbon pins, but she liked the cake we got her
even better.
Robin
How can immunostaining be used to help your child’s doctors toward an exact diagnosis?
Immunostaining uses antibodies to mark a specific antigen, in this case a protein, within cells or tissues.
Immunostaining for BSEP is one way to try to distinguish between the two kinds of PFIC. In PFIC, type 1
(PFIC-1), bile salt export pump is normally expressed within the liver – at least as far as immunostaining
can discern! But in PFIC, type 2 (PFIC-2), BSEP is not detectable by immunostaining (in almost every
instance that our team, and other groups of researchers, have studied to date).
This observation is particularly helpful because PFIC-1 and PFIC-2 can look remarkably like each other,
both in how the sick child behaves and under the microscope. Indeed, PFIC-1 and PFIC-2 were
separated and distinguished only within the last ten years.
A bit of information about BSEP and its role in bile formation: BSEP moves bile salts from inside the liver
cell, or hepatocyte, into the tiniest twigs of the “biliary tree”. These are called “bile canaliculi”. They lie
among hepatocytes, forming a sort of network. Their contents, which are the earliest form of bile, drain
into bile ducts and, through bile ducts, into the small bowel. If BSEP does not work, or is absent, bile
salts accumulate within hepatocytes and cause damage. This damage then leads to failure of
hepatocytes to carry out other normal processes – such as moving bile pigment (very different from bile
salts!) into bile. Body-wide, jaundice (back-up into the blood plasma of bilirubin, that is, bile pigment) and
itching (back-up into the blood plasma of bile salts) result. Within the liver, inflammation, cell death, and
scarring result.
The canaliculus is lined, and defined, by a particular region of the cell membrane of the hepatocyte.
BSEP passes back and forth through that region much as a shoelace passes through the eyelets of your
shoe, from one instep to the other, back and forth across the tongue. If the lace is not fed through the
eyelets properly (if the gene encoding BSEP is mutated in a way that leads to abnormal handling of
BSEP within the hepatocyte), the shoe fits poorly (“hepatocellular injury”). Immunostaining is a very
specific tool that lets a microscopist see how well, if at all, the hepatocyte’s shoelace is threaded and
tied.
The process of synthesizing, and transporting, and folding, and inserting BSEP into the canalicular
membrane is monstrously complicated. Our team believes that mutation in ABCB11, the gene encoding
BSEP, is thus very likely to lead to absence of BSEP at the canaliculus – just because so many things
can go wrong. With ABCB11 mutation, if you look at the tongue of the shoe (the canaliculus) to find the
criss-cross of the lace (BSEP) above it, as a rule you find nothing; the lace never makes it to the insteps.
(BSEP is expressed only in the liver. PFIC-2 is thus a liver-limited disease, and liver transplantation in
PFIC-2 can provide a “cure” – defined as above. PFIC-1, however, is a multi-system disorder.)
What if immunohistochemical study finds no BSEP in a liver biopsy specimen from a child with PFIC,
although other, similar proteins are detected in a normal pattern? This means that PFIC-2 is more likely
than PFIC-1 in the child from whom the specimen came. In turn, ABCB11 is the gene likely to be
abnormal in that child. Immunostaining can tell doctors: “Check here first!” Without demonstrable
BSEP, ABCB11 is the gene toward which that child’s doctors should direct mutational analysis if a family
wants absolute security in diagnosis. Mutational analysis also is of value if antenatal diagnosis is an
option for other children in that family: To look for mutations known to be present in an affected child can
give information on whether or not an unborn child will have the same disorder.
Finally, to demonstrate that BSEP is normally expressed in a liver biopsy specimen from a child with
P a ge 4
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Inside Stor y Headline
Caption describing picture
or graphic.
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PFIC generally means that PFIC-1 is more likely in that child than is PFIC-2. As with many things
in medicine, this interpretation is not absolutely certain. Absolute certainty requires mutational
analysis of genes. But to see normal BSEP expression will point mutational analysis toward
ATP8B1, the gene mutated in PFIC-1. As with PFIC-2, to know the results of immunostaining can
save much effort and time, and can get a family the hoped-for answer faster.
** Related Biopsy slides can be viewed on line at www.PFIC.org under Immunostaining PFIC-2
Alex Knisely, MD
Consultant Histopathologist
Institute of Liver Studies
King’s College Hospital
Denmark Hill
London SE5 9RS United Kingdom
alex.knisely@kcl.ac.uk e-mail for comments or
questions, please
Season’s
Greetings