Cholangitis resembling Caroli’s syndrome in a patient with autosomal dominant polycystic kidney disease: Case report

Abstract

Caroli’s syndrome is a rare autosomal recessive disorder characterized by segmental cystic dilation of the intrahepatic bile ducts and congenital hepatic fibrosis. It is associated with autosomal recessive polycystic kidney disease. Here, we report a 63-year-old male known with polycystic kidney disease, who was admitted to our hospital with intermittent fever, accompanied by weight loss. Magnetic resonance cholangiopancreatography suggested the presence of Caroli’s syndrome, characterized by cystic dilation of the intrahepatic proximal bile ducts on both the right and left lobes of the liver. Shear wave elastography revealed the presence of mild liver fibrosis. The patient recovered with broad-spectrum antibiotics. Genetic testing found no evidence of variation in the PKHD1 gene. However, a heterozygous deletion of the PKD1 gene was identified, a deletion that has not previously been linked to disease, and therefore the patient’s family was offered genetic analysis. The patient has since remained free of cholangitis and icterus and continues to be followed in the nephrology department.

Introduction

Caroli’s disease is a rare autosomal recessive disorder characterized by segmental cystic dilation of the intrahepatic ducts. Caroli’s syndrome presents as Caroli’s disease and the presence of congenital hepatic fibrosis characterized by periportal fibrosis and irregularly shaped proliferating bile ducts, and portal vein hypoplasia.^1,2

It is an extremely rare congenital disorder with an estimated prevalence of 1/1,000,000 in the general population and is equally distributed between sexes. ³ It is considered a part of group V of the Todani classification of biliary tract cystic diseases.

Phenotypically, Caroli’s syndrome presents a combination of aspects related to Caroli disease (cholestasis, cholangitis attacks, hepatolithiasis, and gallbladder stones) and of those related to congenital hepatic fibrosis and cirrhosis (portal hypertension and its complications such as liver and spleen enlargement, ascites, and esophageal varices). ⁴ The disease may be intermittent, with the potential for deteriorating toward chronic complications. It is insidious in nature and several years/decades may elapse before index symptoms appear in a patient.

The genetic pattern of Caroli’s disease and syndrome is autosomal recessive. The conditions are strongly associated with cystic kidney lesions, including autosomal recessive polycystic kidney disease (ARPKD); in some case series, almost half of the patients have associated cystic kidney lesions. ³

The genetic basis of ARPKD differs from that of autosomal dominant polycystic kidney disease (ADPKD). In ARPKD, PKHD1 is affected, whereas PKD1 or PKD2 is affected in ADPKD. ⁵ Additionally, while ADPKD is typically diagnosed in adulthood, ARPKD is usually identified in the neonatal or fetal state and is associated with a high mortality rate in early life. In the case of ARPKD, all patients present with or develop congenital liver fibrosis, some of whom also exhibit the characteristics of Caroli’s syndrome. Conversely, only a few cases of Caroli’s Syndrome and concomitant ADPKD have been previously reported.

Case

The patient, a 63-year-old male with a known diagnosis of polycystic kidney disease since 2011, presented to our infectious disease clinic with complaints of intermittent fever for a duration of 2–5 days, accompanied by a weight loss of ~6 kg. The patient reported no night sweats and maintained a good appetite.

A review of the family history revealed that the patient’s father, uncles, and brothers had all been diagnosed with polycystic kidney disease.

Laboratory studies revealed elevated levels of C-reactive protein (CRP; 13–61 mg/l (ref: <8.0)), amylase (80 U/l (ref: 10.0–65.0)), and leukocyte count (10.5 × 10⁹/l (ref: 3–10)). Alanine transaminase (ALT), bilirubin, and alkaline phosphatase (ALP) were normal, as was the international normalized ratio. Blood culture was negative.

A positron emission tomography scan was requested to identify the source of infection. It revealed the presence of the previously identified multiple kidney cysts and a cystic process measuring ~3 cm in diameter in the right liver lobe, exhibiting increased fluorodeoxyglucose activity. An abdominal ultrasound revealed no abnormalities in the gallbladder or the biliary tract. A wide-bore needle biopsy of the cyst revealed significant inflammation. The final diagnosis was that the cyst was infectious. The patient was not administered antibiotics since his temperature was within the normal range.

Two months later, the patient was admitted to the emergency room with a 3-day history of acute abdominal pain, diarrhea, and vomiting. Additionally, the patient presented with a fever, with a temperature between 38.5°C and 40°C, and low blood pressure.

Laboratory studies revealed markedly elevated levels of CRP (238 mg/l), creatinine (344 µmol/l, reference range: 45–90 µmol/l), ALT (161 U/l, reference range: 10–45 U/I), and ALP (112 U/l, reference range: 35–105 U/l). The bilirubin level was within the normal range (see Table 1).

Table 1.

Summary of lab results during the patient’s outpatient follow-up and on admission.

Test	Normal range	Outpatient follow-up	On admission
Amylase (U/l)	10–65	80	58
CRP (mg/l)	<8	13–61	238
Leukocyte (109 /l)	3.50–10.0	10.5 × 109	15
Creatinine (µmol/l)	45–90	110	344
ALT (U/l)	10–45	40	161
Bilirubin (µmol/l)	5–25	10	17
ALP (U/l)	40–120	81	112
INR	0.8–1.2	<1.0	<1.0

ALP: alkaline phosphatase; ALT: alanine transaminase; CRP: C-reactive protein; INR: international normalized ratio.

A new ultrasound scan of the abdomen revealed mild dilation of the biliary duct of the left liver lobe. Subsequently, magnetic resonance cholangiopancreatography suggested the presence of Caroli’s syndrome, characterized by cystic dilation of the intrahepatic proximal bile ducts on both right and left liver lobes without the involvement of the extrahepatic bile duct (Figure 1). Shear wave elastography revealed the presence of mild liver fibrosis, with a stiffness value of 1.35 m/s and an interquartile range/median of 0.13.

Figure 1.

MRI (T2-weighted transverse on the left; coronal T2-weighted MRCP on the right): there are multiple multifocal cystic dilations associated with the intrahepatic bile ducts in both the right and left liver lobes, with no concurrent dilation of the extrahepatic bile ducts.^10,11 These findings are consistent with Caroli disease (type V in the Todani classification). ¹² Additionally, bilateral polycystic kidneys are noted, consistent with ADPKD. ¹³

ADPKD: autosomal dominant polycystic kidney disease; MRCP: magnetic resonance cholangiopancreatography.

Furthermore, the “central dot sign,” pathognomonic for Caroli’s syndrome, was observed on the initial contrast-enhanced CT of the abdomen ¹⁴ (see Figure 2).

Figure 2.

Furthermore, the “central dot sign,” (Blue arrow) pathognomonic for Caroli’s syndrome, was observed on the initial contrast-enhanced CT of the abdomen. ¹⁴

The patient was treated with broad-spectrum antibiotics and intravenous fluids with a good outcome.

Genetic testing revealed a deletion in the heterozygous form of exons 32–34 of the PKD1 gene (NM_001009944.3:c.10167+11_10499+1289del). The variant assessed the pathogen. PKD1 is associated with autosomal dominant polycystic kidney disease (OMIM #173900). There was no evidence of variants in PKHD1.

The patient was suspected of having Caroli’s syndrome, and the patient’s family was offered a genetic analysis.

The patient has since remained free of cholangitis and icterus and continues to be followed in the nephrology department.

Discussion

Caroli’s syndrome is primarily associated with ARPKD and variants in the PKHD1. In this case, a patient with a known diagnosis of ADPKD presented with a recurrent cholangitis, distinctive cystic lesions of the gall tree, and elastography findings indicative of early hepatic fibrosis, suggestive of Caroli’s syndrome. Moreover, a heterozygous deletion of the PKD1 gene was identified – a deletion that has not previously been linked to disease.^6,7

The coexistence of Caroli’s syndrome and ADPKD is an exceedingly rare occurrence. To our best knowledge, only a small number of case reports have previously been published.^8,9

The potential implications of a possible Caroli’s syndrome-like condition in this patient are significant. The risk of cholangiocarcinoma is markedly elevated in individuals with Caroli’s syndrome, and the potential for developing decompensated liver cirrhosis later in life can have a profound impact on clinical decision-making regarding the ongoing management of the patient. ¹

Conclusion

The identification of an additional genetic deletion with potential clinical implications for the association between Caroli’s syndrome and polycystic kidney disease may support the hypothesis that congenital hepatic fibrosis may encompass a wide range of hepatic and renal lesions.