Caroli’s disease (CD) was first described by Jacques Caroli in 1958 [1], as a rare congenital condition characterized by localized or diffuse, non obstructive, saccular or fusiform, multifocal segmental dilatation of the intrahepatic bile ducts. The disease prevalence is one case per 1,000,000, however, with better imaging techniques, such as magnetic resonance cholangiography, CD appears to be more prevalent than previously reported [2,3]. Males and females are equally affected, and more than 80.0% of patients present before 30 years of age [4]. Recurrent cholangitis dominates the clinical course and is the principal cause of morbidity and mortality [5]. Two types of disease have been described: type 1, a simple form or CD without hepatic fibrosis and type 2, a complex form or Caroli’s syndrome (CS; also known as Grumbach’s disease) with the presence of congenital hepatic fibrosis (CHF) [3,6,7].
Caroli’s disease (type 1) consists of pure segmental cystic dilatations of the intrahepatic bile ducts, without cirrhosis and portal hypertension. Caroli’s disease can be diffuse, when it involves both lobes, or localized, when occuring in a single lobe. Increased incidence of biliary lithiasis, recurrent cholangitis, biliary abscesses and septicemia are all its potential complications [4,6]. Caroli’s syndrome (type 2) presents a clinical syndrome that is a combination of CD (bouts of cholangitis, hepatolithiasis, and gallbladder stones) and those of CHF (portal hypertension). Caroli’s syndrome is associated with hepatic fibrosis, or even cirrhosis, portal hypertension and oesophageal varices. Caroli’s syndrome may be accompanied by chol-angiocarcinoma, pancreatic cyst and renal cystic disease [4,6]. These diseases have a close relationship with congenital kidney disorders, notably autosomal recessive polycystic kidney disease (ARPKD) [8,9]. Many investigators believe that the two types of CD are actually different stages of the same disease characterized by periportal fibrosis and ductal dilatation [4,10].
Mutations in the polyductin 1 (
Laboratory analysis showed increased parameters of acute inflammation, liver and kidney function tests (Table 1). Magnetic resonance cholangiopancreatography (MRCP) revealed hepatosplenomegaly, multiple cysts in both kidneys with reduced parenchyma, and diffuse cystic/fusiform dilatation of the intrahepatic bile ducts, which was more evident in the left lobe (Figures 1 and 2).
Laboratory data of the proband on admission to the hospital.
Parameters | M-41 | Reference Ranges |
---|---|---|
Hb (g/dL) | 13.0 | 13.0-17.0 |
WBC (109/L) | 14.71 | 4.00-10.00 |
Platelets (109/L) | 11.9 | 15.0-40.0 |
Urea (mmol/L) | 12.6 | 3.2-7.4 |
Creatinine (μmol/L) | 338.0 | 62.0-106.0 |
Albumin (g/L) | 38.0 | 35.0-52.0 |
ALP (IU/L) | 105.0 | <129.0 |
ALT (IU/L) | 178.0 | <41.0 |
ASP (IU/L) | 99.0 | <37.0 |
GGT(IU/L) | 127.0 | <60.0 |
Total bilirubin (μmol/L) | 22.0 | <20.0 |
CRP (mg/L) | 326.0 | <5.0 |
Fibrogen (g/L) | 4.6 | 1.8-4.0 |
ESR (mm/h) | 40.0 | 1.0-10.0 |
Hb: hemoglobin; WBC: white blood cell count; ALP: alkaline hosphatase; ALT: alanine aminotransferase; ASP: aspartate aminotransferase; GGT: γ-Glutamyl transferase; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate.
The patient had the first episode of pyelonephritis at 9 months of age, when vesicoureteral reflux and enlarged kidneys were also observed. Monitoring by a nephrologist started when patient was at age 20, due to chronic renal insufficiency assumed as a consequence of chronic pyelo-nephritis. Since then, he has been on a conservative treatment for chronic renal insufficiency.
During his thirties, he was treated in hospital several times for recurrent cholangitis. Magnetic resonance
chol-angiopancreatography and endoscopic retrograde chol-angiopancreatography (ERCP) were performed multiple times. First, the differential diagnosis of CD with polycystic kidney disease and PSC with dysplastic kidney disease was established. As part of further examination, a liver biopsy showed the existence of a multiple bile duct hamartomas (MBH), without evidence of CHF and portal hypertension. On the following ERCP and MRCP examinations, changes in bile duct pointing to PSC were described and the diagnosis was leaning towards PSC. Thus, the diagnosis remained unclear after classical imaging studies and additional evidence was required to establish the definitive diagnosis.
In order to resolve the diagnostic dilemma (PSC or CD), we referred the patient for genetic diagnostics, where clinical exome sequencing (CES) using a TruSight One capture kit (Illumina, San Diego, CA, USA) was performed, followed by sequencing on an Illumina MiSeq platform. The bioinformatic analysis was performed according to GATK Best Practices workflow [14,15]. The strategy for exome data interpretation was primarily based on the combined disease and phenotype gene target definition approach we previously described [16]. Considering the observation of multiple renal cysts in the patient, bio-informatic analysis and interpretation of genes associated with polycystic kidney disease was performed (
In the presented patient, we discovered two pathogenic heterozygous variants in the
Two types of CD have been described in the literature, based on the presence of congenital hepatic fibrosis and the severity of the liver impairment. In our patient, CD presented clinically with recurrent cholangitis, which is normally the most common clinical manifestation of the type 1 disease, simply referred to as CD. Other clinical presentation of CD are varied and include right upper quadrant pain, jaundice, recurrent chills and fevers, weight loss, anorexia, nausea and vomiting, most of which were common complaints during several hospitalizations of the patients. On the other hand, CS is a complex clinical syndrome that includes characteristics of CD and CHF, portal hypertension, liver cirrhosis, esophageal varices and ascites. Caroli’s syndrome is mostly comorbid with cystic kidney diseases, and rarely with pancreatic or lineal cysts. Caroli’s syndrome may progress to cholangiocarcinoma due to cirrhosis, chronic inflamation and prolonged exposure of the ductal epithelium to high concentration of un-conjugated secondary bile acids. Hepatobiliary malignant transformation occurs in approximately 7.0-14.0% of cases, and occurrence of cholangiocarcinoma in CD/CS is 100 times greater than that in the general population. However, the division may be arbitrary, as many investigators believe that the two conditions present a continuation of the same disease. Nevertheless, the diagnosis in this patient established after clinical exome sequencing was CD, due to the absence of the hepatic symptoms characteristic of CS. The mild clinical presentation bearing similarities to PSC, contributed to the difficulty of diagnosis in the presented patient as multiple MRCP and ERCP as well as liver biopsy, were insufficient to clearly diagnose CD. In selected groups of patients genetic analysis may thus be helpful to differentiate between genetic and non genetic etiologies, as in our example, where clinical exome sequencing enabled the diagnosis of CD in this patient after the detection of the pathogenic variants in the
We report the discovery of two pathogenic variants on the