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