Introduction
Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous
group of genetic autosomal recessive disorders which cause defects in
the formation and secretion of bile components and bile acids [1].
Progressive Familial Intrahepatic Cholestasis consists of five different
variant forms numbered 1 through 5 based on the gene involved [2].
Most of these disorders present in infancy and early childhood as signs
of growth failure vitamin K deficiency (i.e., easy bruising, epistaxis,
coagulopathies) due to impaired vitamin K absorption and progressive
liver disease leading to cirrhosis before adulthood [1. 2].
Progressive Familial Intrahepatic Cholestasis type 3 is an autosomal
recessive disorder arising from mutations in the ATP-binding cassette
subfamily B member 4 (ABCB4) gene located on chromosome 7 [3]. This
gene encodes multidrug resistance protein-3 (MDR3). This 12-domain
transmembrane plasmalemmal translocator actively transports
phosphatidylcholine from the inner to the outer canalicular membrane to
neutralize bile salts and prevent injury to biliary epithelial and bile
canaliculi [4].
The PFIC-3 patients are homozygous or compound heterozygous for ABCB4
pathogenic variants; however, monoallelic ABCB4 variants may also result
in cholestatic liver disease [5]. Genetic testing confirms the
diagnosis of PFIC syndromes for all types, and immunostaining can
confirm the diagnosis of PFIC types 2 and 3 [6. 7].
There were no approved pharmacological treatment options to treat PFIC
that may lead to symptom relief or even limit the disease progression.
Ultimately, liver failure would be the definitive result and may
indicate a need for liver transplantation [6].
Case report
A 6 years old girl presented to the internal medicine clinic in King
Saud medical city due to yellow discoloration of the sclera and skin and
abdominal distension. The parents reported that their child has recently
complained of tiredness, mild abdominal pain, itching, frequent
bleeding, and epistaxis. Her parents have noticed the abdominal
distension earlier. However, they have not sought any medical
consultation until they noticed the yellow discoloration of the skin and
mucous membranes at four. She was diagnosed with hepatic cirrhosis of
unknown etiology at the time. Her family history was unremarkable, but
the parents have mentioned that they were second-degree relatives.
The physical examination revealed a yellow discoloration of the skin
sclera and the mucous membranes, failure to thrive, hepatosplenomegaly,
moderate ascites, and ecchymosis in both legs.
Her vital signs were normal, and the physical examination was otherwise
normal.
The abdominal ultrasonography examination reported that the liver was of
average size measuring 11.5 cm coarse parenchymal echo pattern, with
multiple small variable sizes ill-defined hypoechoic lesions (Fig. 1),
the gallbladder had a thick wall yet no stones or biliary sludge were
seen inside (Fig. 2), and splenomegaly was also reported. The
examination was otherwise normal. The complete blood count test revealed
mild normocytic normochromic anemia, mild leukopenia, and neutropenia,
Thrombocytopenia, as hemoglobin levels were 11.2 g/dl (normal g/dl),
hematocrit of 32.0 percent (normal percent), mean corpuscular volume of
white blood cell count 4.47 10^3/ul (normal 10^3/ul), platelet
count of 92 10^3/ul. Other laboratory tests revealed elevated serum
AST of 223 U/L (normal < 40 U/L), ALT of 115 U/L (normal
< 50 U/L), and total bilirubin levels of 4.14 mg/dl (normal
0.2-1.3 mg/dl), alkaline phosphatase levels of 647 U/L (normal 38 - 126
U/L) whereas serum GGT was not measured. Thyroid-stimulating hormone was
also measured and revealed a serum level of 6.54 mIU/l (normal
0.465-4.68 mIU/L), the measurement of endomysial autoantibodies was
positive. Other laboratory tests were in the normal range. The diagnosis
of PFIC-3 was confirmed via detecting pathogenic variants in the ABCB4
gene. The patient has been listed as a candidate for liver
transplantation, as the patient showed signs of portal hypertension in
ultrasonography examination after a one-year follow-up.