studies

1046A AASLD ABSTRACTS HEPATOLOGY, October, 2015
1718
Autosomal Recessive Polycystic Kidney Disease: Not just
a Renal Disease
Sarika Rohatgi 1 , William E Sweeney 2 , Emma Schwasinger 2 , Nicholas
Kampa 2 , Ellis D. Avner 2 ; 1 Pediatric Gastroenterology, Medical
college of Wisconsin, Milwaukee, WI; 2 Pediatric Nephrology,
Medical college of Wisconsin, Wauwatosa, WI
Introduction: Autosomal Recessive Polycystic Kidney Disease/
Congenital Hepatic Fibrosis (ARPKD/CHF) is an inherited hepatorenal
fibrocystic disease with a wide spectrum of dual organ
developmental abnormalities, secondary to PKHD1 mutations.
Renal pathophysiology of ARPKD/CHF is well understood and
clinical trials targeting renal disease are near. CHF is not well
studied and warrants investigation due independent disease
progression in the two organs. We hypothesize that proliferation
and fibrosis are two separate but overlapping processes
and identification of the ‘Critical stage’ of disease is important
to achieve goal therapeutic results in CHF. Aim and Methods:
PCK rat, an orthologous model with PKHD1 mutation, consistently
develops dual organ abnormalities as in human disease,
providing the best model for investigation. We performed a
systematic characterization of morphological changes in development
and progression of CHF in PCK Rats, correlating them
with biliary ductal ectasia, proliferation, apoptosis and periportal
fibrosis at progressive stages of disease. Our goal was to
identify ‘critical stages’ of the disease to develop liver specific
therapies. Five male rats each at 0, 30, 60, 90, 120 and
150 days of age were evaluated and physiologic data (body,
liver, kidney, intestine and spleen weights) collected. Serial
sections of these livers were stained with Masson’s Trichrome
stain to score fibrosis and immunohistochemistry (IHC) was
done to identify cholangiocytes, proliferation and apoptosis.
Morphometric analysis was done using ImageJ to quantitate
disease progression. Results: Liver weight to body weight ratios
increased as disease progressed. Morphometric analyses of
liver tissues show consistent enlargement and deformation of
biliary ducts with increasing age. A 50% increase in cyst numbers
and cyst area per surface area of the liver with increased
proliferation of cholangiocytes and mesenchymal cells was
observed between ages of 30 and 90 days. Thereafter, proliferation
gradually decreased to negligible by day 150. Periportal
fibrosis index increased to 39% at day 90 and to 47%
at 150 days. Fibrosis score increased from 0 to 2 between
30 and 90 days and to 4 at 150 days. Fibrosis was more
prominent in hilum around larger cysts. Apoptosis increased
steadily with age. Conclusion: Rapid increase in proliferation
and fibrosis at day 90 and decrease thereafter suggest that
‘critical stage’ of the disease is before 90 days. Given the wide
variability in rate of disease progression in CHF, therapies
aimed at reducing proliferation will require a histopathological
assessment of the liver disease to provide maximum benefit.
Disclosures:
The following authors have nothing to disclose: Sarika Rohatgi, William E Sweeney,
Emma Schwasinger, Nicholas Kampa, Ellis D. Avner
1719
Recurrent recessive mutation in DGUOK causes non-cirrhotic
intrahepatic portal hypertension in the absence of
liver synthetic dysfunction
Silvia Vilarinho 4,1 , Sinan Sari 2 , Guldal Yilmaz 3 , Buket Dalgic 2 ,
Richard P. Lifton 1,5 ; 1 Department of Genetics, Yale University
School of Medicine, New Haven, CT; 2 Department of Pediatrics,
Gazi University - Faculty of Medicine, Ankara, Turkey; 3 Department
of Pathology, Gazi University - Faculty of Medicine, Ankara,
Turkey; 4 Department of Internal Medicine, Section of Digestive
Diseases, Yale University School of Medicine, New Haven, CT;
5 Department of Internal Medicine, Yale University School of Medicine,
New Haven, CT
Liver cirrhosis is the most frequent cause of portal hypertension,
but a variety of other diseases may cause elevated pressure
in the portal venous system. However, when all known causes
of portal hypertension have been ruled out, the diagnosis of
idiopathic non-cirrhotic intrahepatic portal hypertension is
established. In the literature, the terminology of this medical
condition is ambiguous and several other terms such as hepatoportal
sclerosis, obliterative venopathy, idiopathic portal
hypertension, incomplete septal cirrhosis and nodular regenerative
hyperplasia are used interchangeably. Despite progress
in the diagnosis and management of this clinical entity,
its etiopathogenesis remains elusive. Interestingly, idiopathic
non-cirrhotic intrahepatic portal hypertension has also been
reported in infancy and childhood, occasionally affecting more
than one family member, suggesting that an unrecognized
Mendelian trait may underpin the onset and development of
portal hypertension in a subset of these subjects. To investigate
this hypothesis, we applied unbiased whole-exome capture
and DNA sequencing, in contrast to a hypothesis-driven
approach, to nine Turkish subjects with onset of intrahepatic
portal hypertension of indeterminate etiology during infancy
or early childhood. Whole-exome sequencing allows us to
determine the existence of recurrent mutations across samples
and to assess the burden of rare variants in individual gene(s)
greater than expected by chance. We found three individuals,
in two unrelated families, that shared an identical rare
homozygous mutation in deoxyguanosine kinase, encoded by
the DGUOK nuclear gene, at a highly conserved amino acid
position (p.Asn46Ser). The probability of finding two unrelated
instances of this identical homozygous variant in DGUOK by
chance is conservatively estimated to be 5.2x10 -12 , providing
extremely strong statistical support for the role of this mutation
in non-cirrhotic intrahepatic portal hypertension. DGUOK is an
enzyme responsible for phosphorylation of purine deoxyribonucleosides
in the mitochondrial matrix and its dysfunction has
been previously associated with mitochondrial depletion syndrome
type 3. In contrast to this syndrome, none of our index
cases demonstrated signs of hepatic synthetic dysfunction for
a follow-up period of 6 to 17 years. In conclusion, our study
provides a new insight into the mechanisms mediating non-cirrhotic
intrahepatic portal hypertension, defines a previously
unrecognized form resulting from recessive N46S mutation in
DGUOK, and expands the phenotypic spectrum of DGUOK
deficiency beyond our current understanding.
Disclosures:
The following authors have nothing to disclose: Silvia Vilarinho, Sinan Sari,
Guldal Yilmaz, Buket Dalgic, Richard P. Lifton