DISCUSSION
Caroli’s Syndrome (CS), originally reported by Jacques Caroli, is a rare
congenital disorder characterized by cystic dilatation of the
intrahepatic biliary ducts (IHBD) with congenital hepatic portal
fibrosis.5There is a distinction between the CS and CD, the latter is
characterized by isolated dilatation of large IHBD, the absence of
congenital liver fibrosis, and only one portion of the liver
affected.6
This disease is a developmental condition with probable autosomal
recessive inheritance pattern thought to be caused by the complete or
partial arrest of ductal plate remodeling (Ductal Plate Malformation)
leading to persistence of embryonic biliary ductal
structures.7It can affect large as well as small intrahepatic bile ducts that
surround the portal tracts which result in cysts surrounding the portal
triad.8Various other mechanisms like neonatal occlusion of hepatic artery and
prenatal hepatic vascular accident have also been
proposed.9Cytogenetic studies revealed the mutations of PKHD-1 gene on the
chromosome 6p21, which is involved in the synthesis of fibrocystin
protein is responsible for major structural abnormalities of the liver
and
kidneys.7Studies have indicated that the presence of polycystic kidney disease in
a young adult with hepatic fibrosis or Caroli’s disease is highly
suggestive of Autosomal Recessive Polycystic Kidney Disease
(ARPKD).10Typically, CHF and portal hypertension (PH) do not occur in Autosomal
Dominant Polycystic Kidney Disease
(ADPKD).11However, CHF complicated by PH is a rare but potentially
life-threatening complication of
ADPKD.12Genetic analysis could not performed in our case because of financial
constraints, thus the heritance pattern of the cystic kidney couldn’t be
identified.
There is high variation in the clinical progression and presentation of
Caroli’s syndrome, and symptoms may appear early or late during life.
Although present from birth, the disease usually remains asymptomatic
during the first two decades of life and may also remain so throughout
life, necessitating high index of suspicion for its
diagnosis.13,
14 As mentioned, Caroli
syndrome presents a clinical syndrome, a combination of Caroli’s disease
(bouts of cholangitis, hepatolithiasis, and gallbladder stones) and
those of
CHF/PH.15A study of 30 patients with congenital IHBD dilatation showed the most
frequent initial symptoms of the disease included right upper quadrant
pain, fever, anorexia, variceal bleeding (haematemesis, melaena or
hematochezia), fatigue, and jaundice in decreasing order without any
difference in frequency of these symptoms between patients with CD and
CS.14This shows that variceal bleeding is not an uncommon symptom of the
disease condition. However, in CS the clinical presentation is dependent
upon the predominant pathology, cholangitis if duct dilatation
predominates and haematemesis/melaena if portal hypertension
predominates.16In our patient portal hypertension predominated with an episode of
variceal bleeding and splenomegaly as suggested by history, physical,
and endoscopic examination. Associated involvement of kidney (renal
tubular ectasia, medullary sponge kidney, cortical cyst, recessive
polycystic kidney disease or rarely autosomal dominant polycystic kidney
disease) is usually asymptomatic or may present in infancy
(nephrolithiasis, pyelonephritis or hypertension) while cholangitis and
manifestation of portal hypertension is more so in early
childhood.3Our patient had no overt signs/symptoms suggestive of kidney involvement
except for elevated blood pressure even in the presence of bilateral
multiple cysts.
Findings on physical examination include none to hepatosplenomegaly,
ascites, jaundice, peripheral edema, hepatomegaly or splenomegaly,
features of hepatic insufficiency and/or portal
hypertension.17,
18 Apart from
hepatosplenomegaly and mild abdominal distension, our patient had
dilated veins around umbilicus which suggest the presence of portal
hypertension for a considerable time period before she was diagnosed.
The laboratory findings are non-specific. Liver function tests are
normal except for moderately elevated alkaline phosphatase and gamma
glutamyl-transpeptidase. Our case had elevated alkaline phosphatase
level. Also, Transaminases levels may be slightly elevated. Findings of
splenomegaly or cytopenias secondary to hypersplenism are indicative of
portal hypertension as evident in our case. Elevated white blood cell
count or erythrocyte sedimentation rate may indicate cholangitis.
Associated renal disease can be detected by measuring Blood Urea
Nitrogen (BUN) and creatinine
values.4Our patient had normal renal function despite the presence of multiple
cysts.
Ultrasound or computed tomography is often the first studies to
demonstrate an abnormally dilated biliary
system.9On sonography, the dilated biliary channels are anechoic and on CT
(Computed Tomography) are hypodense. The diagnosis rests on the
demonstration of continuity of these saccular dilatations with the
biliary
tree.19Magnetic Resonance Imaging (MRI) provides better information regarding
location, severity, and extent of the disease. The so-called ‘central
dot sign’, defined as small foci of strong contrast enhancement within
dilated intrahepatic ducts, is often found on MRI or CT scan and is
considered highly specific for Caroli
syndrome.20The central dot sign along with CT scan and clinical features described
helped us make the diagnosis of Caroli’s Syndrome. Magnetic Resonance
Cholangiopancreatography (MRCP) is considered the most specific and
non-invasive examination to depict the multiple ductal dilatations seen
in Caroli’s disease, called the “lollipop tree” aspect (T2 and most
notably T1 sequences after contrast
injection).21It shows diverticulum-like saccule of intrahepatic bile duct ectasia of
varying sizes, shapes and distribution, which communicate freely with
the bile duct. Conversely, in Caroli’s syndrome, the cystic bile duct
ectasia are always smaller (<2cm) and periportal hepatic
fibrosis is seen on T2 – weighted sequences as high signal areas among
the portal veins. These both tests couldn’t be performed due to
financial constraints of the
patient.18However, the histopathological examination of the resected specimen is
the definitive investigation and is characterized by hepatic and dense
portal fibrosis, along with dilated bile ducts and secondary cirrhosis
in some patients with more severe disease.14 No
invasive procedure was performed in our case.
The differential diagnoses of this entity include Von Meyenburg complex,
primary sclerosing cholangitis, polycystic liver disease, and
choledochal cyst. Von Meyenburg complex is a rare condition that usually
does not cause symptoms or disturbances in liver function, diagnosed by
chance in MRCP, showing multiple small-size cystic nodules
(<1.5 cm) that do not communicate with the biliary
tree.22
Complications of Caroli’s syndrome are cholangitis, sepsis,
choledocholithiasis, hepatic abscess, cholangiocarcinoma, and portal
hypertension.23After cholangitis occurs, a large number of patients die within 5-10
years.19The CS patients have more than a hundredfold increase of the risk of
developing
cholangiocarcinoma.24,25Death is often related to liver failure or complications of portal
hypertension.23,
26
The treatment of CS is largely supportive and conservative especially in
resource-limited settings like ours. The aim is to treat infections of
the biliary tree, complications of portal hypertension, and prevent
morbidity. These include antibiotics for infections, stenting, and
ursodeoxycholic acid for cholestasis. Measures to treat the portal
hypertension include prophylactic beta-blockers for significant varices
and endoscopic banding, sclerotherapy, and shunting for
bleeding.3The same (banding and prophylactic therapy) was done in our case.
Shunting is generally required for recurrent bleeding episodes not
amenable to treatment with sclerotherapy and esophageal
tamponade.27In the case of abnormalities located in one lobe, lobectomy may be the
best option, which also reduces the risk of developing hepatic
malignancy. In diffuse Caroli’s disease, treatment options include
conservative or endoscopic therapy, internal biliary bypass procedures,
and liver transplantation on carefully selected cases. However, Liver
transplantation represents an uncommon indication for CD or
CS.28 In
addition, If concomitant renal failure ensues from the dysplastic
kidneys, liver transplantation combined with renal transplantation might
be warranted and is the only curative option. Other complications of
Polycystic kidney disease like urinary tract infections can be managed
with support, and hypertensions tend to respond well to
angiotensin-converting enzyme
inhibitors.8