Indian Pediatr 2017;54: 589-592
Fibrosis with Polycystic Kidney Disease: An Unusual Cause of
Vani Bharani, *G Vybhav
Venkatesh, #Uma Nahar Saikia
and $BR Thapa
From Departments of Pathology,*Pediatrics, #Histopathology and
$Gastroenterology, PGIMER, Chandigarh, Punjab, India.
Correspondence to: Dr Uma Nahar Saikia, Department of Histopathology,
5th floor, Research Block A, Postgraduate Institute of Medical Education
and Research, Sector 12, Chandigarh, India.
Received: June 23, 2016;
Initial Review: October 13, 2016;
April 25, 2017.
Congenital hepatic fibrosis is characterized by hepatic fibrosis, portal
hypertension, and renal cystic disease. Typical presentation of
congenital hepatic fibrosis is in the form of portal hypertension, in
adolescents and young adults. We present an unusual case of neonatal
cholestasis with rapid deterioration within first 4 months of life, who
was diagnosed to have congenital hepatic fibrosis with polycystic kidney
disease on autopsy.
Keywords: Autopsy; Cholestatic Jaundice; Neonate.
History and examination: A 4-month-old child was
admitted with complaints of jaundice since day 10 of life, passage of
clay colored stool and dark colored urine. He had intermittent high
grade fever with dry cough and respiratory distress for 4 days duration.
In addition, there was progressive abdominal distension, decreased urine
output, irritability, poor feeding and lethargy since 2 days.
Examination revealed pallor, icterus, facial
puffiness, and pedal edema. He was febrile with a pulse rate of 128/min.
He weighed 4.3 kg, was 59 cm in length and occipitofrontal circumference
was 40 cm. There were visible dilated veins over abdomen with presence
of free fluid. Liver was palpable 4 cm below right costal margin and was
firm, non-tender with smooth surface and irregular borders. Spleen tip
was also palpable. Cardiovascular system was unremarkable. The
respiratory rate was 58/min, with subcostal retractions and crepitations
in bilateral infra-axillary areas. The child was drowsy; however,
central nervous system examination was normal. There was no cataract or
Kayser–Fleischer ring on ophthalmic examination. The child was
developmentally normal and had two elder asymptomatic siblings. He was
immunized as per National immunization schedule.
Investigations: He was anemic (Hb 7.9 g/dL), had
neutrophilic leukocytosis (WBC count 18,900/µL, 90% polymorphs and 10%
lymphocytes) and persistent thrombocytopenia (platelet count 35,000/µL).
The coagulogram was deranged (INR 6.8, aPTT >2 min). He had conjugated
hyperbilirubinemia (total bilirubin 16.1 g/dL, direct bilirubin 11 g/dL)
and transaminitis (AST 774 U/L, ALT 284 U/L). Persistent hyponatremia
was recorded (115 meq/L). Random blood sugar was low at 48 mg/dL.
No focus of infection could be identified and
peritoneal fluid, urine and blood cultures were sterile. Ultrasonogram
(USG) of abdomen showed altered liver echo texture with gross ascites.
Gall bladder was mildly distended with edematous wall. No intrahepatic
biliary radical dilatation was seen.
Course and management: Lactulose and N acetyl
cysteine, intravenous Meropenem and vancomycin were started and
Amphotericin B was added later. Hypoglyc3emia was corrected and child
was maintained on glucose infusion. An ascitic tap was performed thrice,
for symptomatic relief. Albumin could not be administered to correct
hypoalbuminemia, due to economic constraints. He received 10 mL/kg of
fresh frozen plasma. There was decreased urine output with prerenal
azotemia, for which he received slow normal saline bolus. Hyponatremia
and hypokalemia were corrected. On day 8 of admission, infant was
ventilated due to poor respiratory efforts with falling oxygen
saturation. There was a profuse endotracheal tube bleed and the child
succumbed to his illness soon after.
Clinical analysis: The infant had cholestatic
jaundice, ascites, altered sensorium along with hepatospleno-megaly,
deranged liver function tests, deranged coagulogram, anemia and
thrombocytopenia. The causes of cholestasis in infancy can be broadly
classified as extrahepatic causes like biliary atresia, choledochal
cysts and intrahepatic causes including infections, metabolic and
genetic conditions. Of the causes of neonatal cholestasis in north
Indian population, biliary atresia is the commonest 34.6 %, followed by
idiopathic neonatal hepatitis 24.7 %, sepsis/UTI 19.8 %, metabolic
disease like galactosaemia 10.8% and TORCH infections 1.9% . The
relevant possibilities are discussed.
The classic features of biliary atresia including
jaundice, pale stools and high colored urine along with firm liver 
were noted in the index case. However, gall bladder was normal on
ultrasound. USG has a high overall accuracy in diagnosing biliary
atresia  whereas clinical signs like persistent clay colored stools
have a modest accuracy . A confirmatory Tc99HIDA scan could not be
performed to confirm the diagnosis. The infantile variety of choledochal
cyst  and Caroli’s disease  can have similar presentations,
but were ruled out on imaging.
Infants with metabolic disorders like galactosemia
typically present with failure to thrive, vomiting, diarrhea, lethargy,
jaundice and cataracts. Edema, ascites, and bleeding can be seen in
severe cases. There is an increased risk of overwhelming sepsis, most
commonly related to Escherichia coli . The present case had
acute liver failure with sepsis, encephalopathy and hypoglycemia.
However, there was no cataract and urine was negative for reducing
Congenital hepatic fibrosis (CHF) usually presents
with signs and symptoms of portal hypertension, although cases
presenting in infancy with cholestasis are well known . The rapid
deterioration, deranged coagulogram, no intrahepatic biliary tree
dilation in the index case is unusual for typical CHF. Synthetic
dysfunction of the liver can explain the persistently deranged
coagulogram in the index case.
The likely cause of death was overwhelming sepsis,
along with acute on chronic liver failure. There was evidence of
disseminated intravascular coagulation with pulmonary hemorrhage
Open house discussion
Treating unit resident: Clinical scenario is
suggestive of a metabolic disease, probably galactosemia. An untreated
infant with Classic galactosemia presents as failure to thrive, hepatic
injury and sepsis, as seen in the index case. Child was off-milk for few
days, which could explain absence of reducing substances in urine. The
GALT assay was not preformed due to economic constraints.
Pediatrician 1: In a 4-month-old child,
Galactosaemia presenting as cirrhosis with ascites is rather unusual.
Biliary atresia has a vast spectrum with varying degrees of obstruction
and must be kept as a possibility. Tyrosinemia can also be considered
with the clinical picture.
A complete autopsy was performed with examination of
brain. There was peritoneal (200 ml straw colored fluid), pleural (50 ml
clear fluid each) and pericardial (40 ml hemorrhagic fluid) effusion.
The liver was enlarged (450 gm) and firm to hard in
consistency. The capsular surface showed pin point to pin head sized
vague nodules. A fine reticular pattern of fibrosis was seen on cut
surface (Web Fig. 1a). Gall bladder, biliary
tree, portal and splenic vein were within normal limits. Multiple vague
nodules with diffuse periportal fibrosis were seen microscopically (Web
Fig. 1b, 1c). There was extensive bile ductular
proliferation with circumferential interrupted ring like arrangement,
highlighted on CK 7 immunostain, reminiscent of embryonic ductal plate (Web
Fig. 1d). Few Von myenberg complexes were also seen. Extensive
intrahepatic and intracanalicular cholestasis along with giant cell
transformation and pseudoacinar transfor-mation of hepatocytes was
noted. Sinusoids showed extramedullary hematopoiesis. There was no
evidence of cirrhosis or biliary atresia. No steatosis or significant
inflammation was seen. The spleen was enlarged (weight 180 gms) with no
significant pathology on microscopy.
The kidneys weighed 110 g with persistent fetal
lobulation and numerous pin head sized cysts (Web Fig.
2a, 2b). Numerous cystically dilated tubules arranged perpendicular
to the cortex, lined by flattened cells were seen on microscopy (Web
Fig. 2c). Glomerulocystic change was seen in <5%
glomeruli. Few glomeruli revealed collections of cells with abundant
bubbly cytoplasm (Web Fig. 2d), which were
positive for CD68 immunostain. Tubules showed bile casts and there was
no significant inflammation or fibrosis noted in the interstitium.
The lungs weighed 188 g and showed hemorrhagic
consolidation with dull pleura. No thrombi were seen in pulmonary artery
and secretions were present in the tracheobronchial tree. Pulmonary
hemorrhage was confirmed on microscopy with evidence of hyaline membrane
formation. Several bone marrow emboli were noted.
The stomach and esophagus were grossly within normal
limits; however, dilated submucosal vessels were seen at
gastroesophageal junction on microscopy.
Stress involution changes were seen in the thymus.
Lymph nodes revealed sinus histiocytosis. The bone marrow showed
adequate representation of all lineages. The brain weighed 620 g and
showed mild cerebral edema. Remaining organs did not reveal any
The final autopsy diagnosis was offered as:
• Congenital hepatic fibrosis, portal
hypertension with evidence of splenomegaly, ascites and esophageal
• Polycystic kidney disease, possibly Autosomal
recessive polycystic kidney disease (ARPKD)
• Bile cast nephropathy
• Diffuse alveolar damage with pulmonary
• Stress involution of thymus
Open house discussion
Pathologist 1: The liver morphology is typical of
CHF, though the findings in kidney are more in favor of Autosomal
dominant polycystic kidney disease (ADPKD). Short of genetic testing,
the parents can be screened to rule out the possibility.
Pathologist 2: The radial cyst arrangement,
association with CHF, absence of hepatic cysts and lack of other system
involvement are suggestive of ARPKD.
Pediatric gastroenterologist: The index case
looks to be the mixed portal hypertensive-cholangitic form of CHF. The
usual cholangitic form of CHF has a more protracted course. The cause of
persistently elevated INR still remains unclear. Also no source of
sepsis could be identified at autopsy.
CHF is characterized by persistence and/or aberrant
remodeling of embryonic ductal plate along with abnormal intrahepatic
portal vein branching and progressive portal fibrosis. The age at
presentation is highly variable, and most cases are diagnosed in
adolescents and young adults. Four clinical forms have been described,
portal hypertensive (most common), cholangitic, mixed and latent .
Portal hypertension related splenomegaly, hypersplenism and
gastrointestinal bleeds are the most common presenting features.
Cholestasis and recurrent cholangitis are noted in the cholangitic form,
while patients are largely asymptomatic in the latent form with delayed
presentation. Liver histology with diffuse periportal fibrosis,
irregular islands of hepatic parenchyma and interrupted circumferential
arrangement of bile ducts, suggestive of an embryonic ductal plate are
diagnostic. Few of the ducts are variably ectatic with intraluminal
bile. Collection of acute inflammatory cells can be seen in cholangitic
form. The number of portal vein radicals may be reduced. Multiple bile
duct hamartomas, von Meyenburg complexes can also be present . In
the index case, the morphology of liver was typical of CHF; however the
clinical presentation was unusual.
The index case had polycystic kidney disease in
association with CHF. The possibilities considered include ARPKD,
early-onset ADPKD, Glomerulocystic kidney disease (GCKD), juvenile
nephronophthisis and renal dysplasia. ARPKD is characterized by renal
enlargement with numerous small cysts in the parenchyma and maintained
reniform shape. The cysts originate from collecting ducts, run
perpendicular to the cortex and are lined by flattened cells . Most
cases are attributed to mutations in the PKHD1 gene that encodes
for fibrocystin/polycystin proteins, involved in maintaining the tubular
architecture . PKHD1 is an exceptionally large gene with over
300 mutations. Four clinicopathological subtypes of ARPKD have been
described: perinatal, neonatal, infantile and juvenile, depending on age
at presentation and severity of renal and liver disease. In infancy,
there is renal enlargement accompanied by oligohydramnios and subsequent
pulmonary hypoplasia. In older patients the presenting symptoms are
related to liver including hepatosplenomegaly, hypersplenism, variceal
bleeding, and cholangitis . A review of 1230 CHF cases showed
associated ARPKD in 64% cases .
Early-onset ADPKD is a close morphologic differential
of ARPKD. Cylindrical cysts lying perpendicular to cortex are typical of
ARPKD, and not seen in other cystic renal diseases. The cysts in ADPKD
can originate from the entire nephron and are oval in shape. The lining
may be cuboidal or flat with intracystic epithelial micropolyps.
Glomerulocystic change can be seen in ADPKD and ARPKD, though is more
characteristic for ADPKD. The liver shows cysts in cases of ADPKD, while
liver fibrosis is common with ARPKD. Glomerulocystic kidney disease
(GCKD) is another morphologic differential in the index case. However,
glomerulocystic change was seen in <5% glomeruli with renal enlargement,
hence GCKD was ruled out. Juvenile nephronophthisis and renal dysplasia
were ruled out on morphology . Thus the features were suggestive of
ARPKD, based on enlarged kidneys and several cylindrical cysts lying
perpendicular to the cortex and associated CHF. Further confirmation by
genetic evaluation and parental imaging were not available for the case.
Glomerular foam cells have been demonstrated in
hyperlipoproteinemia type III, LCAT deficiency, Lipoprotein
glomerulopathy and lysosomal storage disorders, as well as secondary to
focal segmental glomerulosclerosis, diabetic glomerulosclerosis, HIV
associated nephropathy and osmotic nephrosis . A lipidogram was done
on post mortem serum sample which revealed markedly elevated
triglycerides 801mg/dl and low HDL 15 mg/dL. Total cholesterol was 102
mg/dL and LDL was 47 mg/dL. Since the secondary causes can be excluded,
these cells could be attributed to dyslipidemia.
This was a case of cholestasis of infancy with
deterioration within first 4 months of life found to have CHF with
polycystic kidney disease on autopsy. Presentation in infancy with
cholestasis and features of portal hypertension were the unusual
features in this case. The associated cystic kidney disease was
identified only at autopsy, which could have been identified antemortem
if a complete rather than a limited abdominal imaging were performed.
Also findings of glomerular foam cells, associated with dyslipidemia
have not been seen in the above clinical setting before.
Contributors: VB, UN: Pathological evaluation at
autopsy, preparation of manuscript, VV and BRT: Clinical management of
the patient and clinical discussion.
Funding: None; Competing interest: None
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