Navigating Prognostic Factors and Long-Term Outcomes in Caroli’s Disease and Syndrome - A Prospective Observational Cohort Study

Navigating Prognostic Factors and Long-Term Outcomes in Caroli’s Disease and Syndrome - A Prospective Observational Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Navigating Prognostic Factors and Long-Term Outcomes in Caroli’s Disease and Syndrome - A Prospective Observational Cohort Study Amr Shaaban Hanafy, Eslam Kamal Fahmy, Rania Naguib, Moaz Abulfaraj, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7353511/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Mar, 2026 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Background Caroli’s disease (CD) and Caroli’s syndrome (CS) are rare congenital disorders of the intrahepatic bile ducts associated with significant morbidity and risk of malignant transformation. Differentiating the clinical course between CD and CS remains critical for tailoring surveillance and management. Aim To compare the clinical characteristics, complications, and outcomes of patients with CD and CS and identify potential predictors of biliary malignancy. Methods This cross-sectional observational study included 19 patients diagnosed with CD (n = 7) or CS (n = 12) at Zagazig University Hospitals between November 2015 and December 2022. Diagnosis was confirmed via MRCP. Clinical, biochemical, endoscopic, and imaging assessments were performed. Patients were followed longitudinally for 85 months. Outcomes included incidence of cholangitis, liver decompensation, variceal bleeding, malignancy, and mortality. Statistical comparisons were conducted using nonparametric tests, and correlations were assessed using Spearman’s rank. Results Patients with CS exhibited significantly higher bilirubin (p = 0.018), INR (p = 0.014), and CA 19 − 9 (p < 0.001), and lower albumin and platelet counts (p = 0.028, 0.016) compared to CD. Portal hypertension and esophageal varices were observed exclusively in CS. Three CS patients developed cholangiocarcinoma after a mean of 28.3 ± 5.7 months and died within 3.3 ± 2.3 months of diagnosis. Correlation analysis revealed strong associations between malignancy and AST (ρ = 0.642), number of cholangitis episodes (ρ = 0.735), platelet count (ρ=–0.753), and CA 19 − 9 (ρ = 0.754). Kaplan–Meier analysis demonstrated significantly reduced survival in CS vs. CD (median survival 45.0 vs. 59.0 months, p = 0.020). Conclusion Caroli’s syndrome is associated with a more severe clinical phenotype, higher complication rate, and increased risk of malignancy compared to Caroli’s disease. Identifying predictors of poor outcomes may guide individualized surveillance and management. Regular monitoring, even in asymptomatic patients, is essential for early detection of complications and malignancy. Biological sciences/Cancer Health sciences/Diseases Health sciences/Gastroenterology Health sciences/Oncology Caroli’s disease cholangiocarcinoma Cholangitis Figures Figure 1 1. Introduction Caroli’s disease (CD) is a rare congenital disorder characterized by segmental, non-obstructive saccular dilatation of the intrahepatic bile ducts. It is classified into two distinct forms: the simple form, referred to as Caroli’s disease (type I), and the more complex form known as Caroli’s syndrome (CS or type II), which is associated with congenital hepatic fibrosis and often renal cystic diseases such as autosomal recessive polycystic kidney disease (ARPKD) or autosomal dominant polycystic kidney disease (ADPKD) [ 1 , 2 ]. Both CD and CS are part of the fibropolycystic disease spectrum and are often caused by mutations in the PKHD1 gene on chromosome 6p12, which encodes fibrocystin/polyductin — a protein expressed in bile ducts, renal tubules, and pancreatic ducts [ 3 , 4 ]. These mutations disrupt the normal remodeling of the ductal plate during embryogenesis, resulting in malformed intrahepatic bile ducts and periportal fibrosis [ 5 ]. Clinically, Caroli’s disease presents with recurrent episodes of cholangitis, abdominal pain, and hepatobiliary complications. In Caroli’s syndrome, progressive fibrosis may lead to portal hypertension and upper gastrointestinal bleeding, especially from esophageal varices [ 6 , 7 ]. Imaging plays a central role in diagnosis, with hallmark features such as the “central dot sign” on ultrasonography and MRCP [ 8 ]. Despite being described decades ago, the natural history, prognostic factors, and malignant potential of CD and CS remain incompletely understood due to their rarity and clinical heterogeneity. Notably, patients with these conditions are at increased risk of developing hepatobiliary malignancies, including cholangiocarcinoma. In this study, we aimed to evaluate the prognostic factors, survival outcomes, and risk of cholangiocarcinoma in patients with Caroli’s disease and Caroli’s syndrome. We also examined the clinical correlates of recurrent cholangitis, portal hypertension, and relevant laboratory biomarkers in this challenging patient population. 2. Patients and Methods This was a cross-sectional observational study conducted at the Gastroenterology and Hepatology Clinic, Zagazig University Hospitals, between November 2015 and December 2022. The study was approved by the Institutional Review Board of Zagazig University [ZU-IRB # 85-28-1-24], and written informed consent was obtained from all participants in accordance with the Declaration of Helsinki. 2.1. Patient Selection Nineteen patients diagnosed with Caroli’s disease or Caroli’s syndrome were enrolled. Inclusion criteria included confirmed radiological diagnosis of Caroli’s disease or syndrome via MRCP and clinical presentation suggestive of biliary pathology. Exclusion criteria were solid organ transplantation, diabetes mellitus or obesity, non-alcoholic fatty liver disease, chronic alcohol use, presence of other congenital hepatic cysts, refusal to participate. The cohort included 12 patients with Caroli’s Syndrome and 7 with isolated Caroli’s Disease. 2.2. Clinical Assessment Patients presented with a combination of right upper quadrant abdominal pain, recurrent fever, vomiting, and signs of cholangitis. Initial evaluation included thorough history, physical examination, and baseline laboratory and imaging studies. 2.3. Diagnostic Workup 2.3.1. Laboratory Investigations Routine laboratory investigations were conducted, including comprehensive liver and renal function panels, as well as serum alkaline phosphatase levels. A complete blood count (CBC) was performed to assess for thrombocytopenia, a potential marker of portal hypertension, and leukocytosis. The neutrophil-to-lymphocyte ratio (NLR) was also calculated, given its reported association with severe acute cholangitis and septic shock [ 9 ]. Coagulation profiles were obtained to evaluate hepatic synthetic function and bleeding risk. Additionally, an extensive panel of serological tests was performed to exclude infectious, autoimmune, and neoplastic etiologies. These included serologies for fascioliasis, ascariasis, and hydatid disease, as well as autoimmune markers such as antinuclear antibodies (ANA), antimitochondrial antibodies (AMA), and anti–liver-kidney microsomal (anti-LKM) antibodies. Viral hepatitis screening was conducted via Hepatitis B surface antigen (HBsAg) and Hepatitis C virus antibody (anti-HCV). The tumor marker CA 19 − 9 was measured to assess for potential cholangiocarcinoma. 2.3.2. Abdominal Ultrasonography Abdominal ultrasonography was employed to evaluate hepatic architecture, screen for complications, and assist in the diagnosis of Caroli’s disease and its associated syndromic features. The presence of ascites or ultrasonographic signs of liver cirrhosis including coarse hepatic echotexture, nodular liver contour, and reduced hepatic size were documented. Portal hypertension was diagnosed based on the presence of portal venous collaterals, a portal vein diameter > 13 mm, a splenic diameter > 130 mm, or the presence of splenomegaly and ascites, in accordance with established sonographic criteria [ 10 ]. Segmental intrahepatic bile duct dilatation a hallmark of Caroli’s disease was observed, often with associated intraductal stones. Additional findings included cholelithiasis, cystic lesions of the pancreas, and cystic renal abnormalities, consistent with the fibropolycystic spectrum seen in Caroli’s syndrome. In cholangiocarcinoma, ultrasonography revealed suspicious features such as an infiltrative or compressive mass, biliary tract obstruction, or intraductal lesions with irregular margins. These were further evaluated with cross-sectional imaging and tumor markers when indicated. 2.3.3. Magnetic Resonance Cholangiopancreatography (MRCP): It effectively detected dilated segmental intrahepatic biliary radicles, as well as associated hepatic cysts and intrahepatic abscesses, which are common complications in Caroli’s disease. A hallmark finding on MRCP is diffuse intrahepatic bile duct (IHBD) dilatation, which is considered diagnostic of Caroli’s disease. One of the characteristic MRCP signs in Caroli’s disease is the peripheral “funnel-shaped” appearance of the bile ducts, often accompanied by both saccular and fusiform dilatations. These features are typically distributed throughout the liver and help distinguish Caroli’s disease from other biliary disorders. In contrast, localized IHBD dilatation particularly without associated cystic or fibrotic changes may suggest isolated primary intrahepatic lithiasis rather than true Caroli’s disease [ 11 ]. 2.3.4. Upper GI Endoscopy: Esophageal varices were identified and graded according to the Paquet classification system, which categorizes varices from Grade I to Grade IV based on their size and protrusion into the esophageal lumen [ 12 ]. 2.3.5. Outcome Measures The primary efficacy outcomes were defined as the clinical control of disease manifestations, including resolution or improvement of fever, right upper quadrant abdominal pain, vomiting, jaundice, and a reduction in the frequency of cholangitis episodes. Safety outcomes were defined as the occurrence of significant complications, specifically: Major gastrointestinal bleeding attributable to portal hypertension (e.g., variceal hemorrhage), Abnormalities in liver function tests (AST, ALT, bilirubin, INR), All-cause mortality, with a specific focus on the development of cholangiocarcinoma confirmed by imaging and/or histopathology. 2.3.6. Secondary Outcomes Secondary outcomes were included to provide a broader understanding of disease progression and included: Incidence of hepatic decompensation (hepatic encephalopathy). Radiologic progression, defined by increased intrahepatic bile duct dilatation, new cyst formation, or liver fibrosis on imaging. Development of extrahepatic complications, including cystic renal or pancreatic involvement. 2.3.7. Follow-up Duration Patients were followed prospectively from November 2015 to December 2022. The median follow-up duration was XX months (range: XX–XX), allowing for evaluation of both short- and long-term outcomes. 2.3.8. Statistical Analysis Statistical analysis was performed using IBM SPSS Statistics version 25.0 (IBM Corp., Armonk, NY, USA). The distribution of continuous variables was assessed using the Shapiro–Wilk test, given the small sample size. Continuous variables were summarized as median and interquartile range (IQR), and group comparisons were performed using the Mann–Whitney U test. Categorical variables were summarized as frequencies and percentages, and comparisons were made using the Fisher’s exact test. Spearman’s rank correlation was used to assess associations between clinical variables and outcomes such as development of cholangiocarcinoma and mortality. Due to the limited sample size, logistic regression analysis was not performed to avoid model overfitting and unstable estimates. A p-value < 0.05 was considered statistically significant. To account for the increased risk of type I errors due to multiple hypotheses testing, we applied a Bonferroni correction using the adjusted pvalue approach: each unadjusted p-value was multiplied by the number of tests, and statistical significance was assessed at the nominal α = 0.05 level. This ensures control of the family-wise error rate at 5%. 2.3.9. Sample Size Due to the rarity of Caroli's disease and syndrome, our sample size was limited. While this allows for valuable descriptive insights, findings from subgroup or regression analyses should be interpreted with caution. 3. Results The study enrolled 19 patients from November 2015 to December 2022 (73 months), with one group consisted of 7 patients with CD and the other group enrolled 12 patients with CS, the first patient was enrolled in December 2015 and the last patient in May 2018. Table 1 compares the baseline demographic, clinical, laboratory, and endoscopic characteristics between patients with Caroli’s disease (CD) and Caroli’s syndrome (CS). The mean age was higher in the CS group (37.1 ± 7.4 years) compared to the CD group (33.3 ± 3.9 years), though not statistically significant (p=0.351). Abdominal pain was frequently reported in both groups; however, fever, jaundice, gastrointestinal bleeding (hematemesis and melena), liver cell failure, cholangiocarcinoma, and death were observed exclusively in the CS group, though statistically non-significant differences. Laboratory values revealed that patients with CS had significantly higher total bilirubin (2.03 ± 0.63 vs. 1.36 ± 0.17 mg/dL; p=0.018) and INR (1.47 ± 0.3 vs. 1.1 ± 0.09; p=0.014), along with lower albumin (3.3 g/dL vs. 4.1 g/dL; p=0.028), suggesting more advanced liver dysfunction. Moreover, the CS group exhibited lower platelet counts and elevated CA19-9 levels, both associated with more severe disease and higher risk of malignancy (p=0.016, <0.001 respectively). The presence of esophageal varices was reported in 41.7% of CS patients and none of the CD group (p=0.106), consistent with portal hypertension being more common in CS. Notably, a significantly increased odds ratio for fever (OR: 14.7, 95% CI: 1.2–185) and jaundice (OR: 8.4, 95% CI: 0.76–93.3) in the CS group, Using Haldane-Anscombe correction for sparse data, patients with CS had an estimated odds ratio of 5.53 for both cholangiocarcinoma and death compared to those with CD, though these differences were not statistically significant (p=0.263 for both). Similarly, the odds of having esophageal varices were 11-fold higher in the CS, but this also did not reach statistical significance (p=0.106). These findings underscore the more severe clinical phenotype and worse prognosis associated with Caroli’s syndrome compared to Caroli’s disease alone (Table 1). In CD group, abdominal ultrasound had revealed segmental dilation of intrahepatic bile ducts with ductal stones formation, central dot sign ( Image 1A, Image 2 ) with no evidence of cystic pancreatic, or cystic renal diseases or splenomegaly. However, in CS, in addition to the previously mentioned features, splenomegaly, pancreatic and cystic renal disorders were present ( Image 1B ). MRCP confirmed segmental cystic dilation, which was in continuity with the biliary tree. It revealed complications such as biliary stricture in 2 patients and cholangiocarcinoma in 3 patients, either as a focal stricture involving the duct bifurcation with dilatation of the intrahepatic ducts (n = 1) or intraductal mass-forming cholangiocarcinoma (n = 2). It was important to rule out differential diagnoses by serological testing for fascioliasis, ascariasis, and hydatid disease was negative in all patients. Autoimmune markers including antinuclear antibodies (ANA), anti-mitochondrial antibodies (AMA), and anti-liver kidney microsomal antibodies (anti-LKM) were also negative. Viral hepatitis screening revealed negative results for hepatitis C virus antibodies and hepatitis B surface antigen. Complete blood counts were assessed to evaluate for thrombocytopenia as a surrogate marker of portal hypertension, which was identified in 8 patients within the Caroli’s syndrome (CS) group. Upper gastrointestinal endoscopy was performed in all patients, revealing esophageal varices (EV) in the CS group: grade 1 EV in 1 patient and grade 3 EV in 4 patients. Four patients in the CS group experienced hematemesis during follow-up (at 17, 20, 9, and 13 months, respectively), and all were successfully managed with endoscopic variceal band ligation. Leukocytosis was evident in case of biliary cholangitis and leukocytic count was non- significantly higher in CS group (p = 0. 091) also NLR was significantly higher in CS group (p=0.03) when compared to CD group (Table1 ). During the follow-up period, a total of 94 medically supervised episodes of biliary cholangitis were recorded among all patients, with a mean of 4.95 ± 1.8 episodes per patient. Antibiotic regimens varied according to clinical severity. Ciprofloxacin 500 mg twice daily was administered in 33 episodes, and cefixime 400 mg twice daily was used in 40 episodes. In 21 episodes presenting with signs of sepsis—defined by fever, hypotension, and elevated procalcitonin levels—meropenem was prescribed. Intravenous metronidazole was administered in all episodes as adjunct therapy. Supportive treatments including ursodeoxycholic acid, spasmolytics, and antipyretics were consistently utilized. Patients were monitored regularly with liver function tests and abdominal ultrasonography every three months in accordance with the follow-up protocol. Liver cell failure had occurred in 3 patients (25%) in CS group after a significant attack of hematemesis (n = 1) and severe cholangitis (n = 2). Serum total bilirubin, transaminases, albumin were significantly higher in CS group ( Table 1 ), one patient in CS group developed left kidney pyelonephritis with severe sepsis and managed with nephrectomy. Three patients in the CS group after 28.3±5.7 months respectively from enrollment had developed cholangiocarcinoma with increased CA19-9, rising bilirubin and managed with ERCP and metallic stents were deployed, the clinical condition was not suitable for chemotherapy and only provided symptomatic treatment, death occurred 3.33±2.31 months after initial diagnosis of cholangiocarcinoma ( Image 2 ). In CS subgroup (n = 12, 3 deaths/cholangiocarcinoma), strong monotonic associations were observed between death/cancer and AST (ρ = 0.642, p =0 .024), number of episodes (ρ = +0.735, p = 0.006), and platelet count (ρ = -0.753, p = 0.005), with a moderate-to-strong correlation for CA19‑9 (ρ = +0.754, p = 0.005), after applying Bonferroni adjusted p value, CA19-9 was excluded. Among those with esophageal varices (n = 5) and GI bleeding (n = 4), age, sex. NL, albumin and frequency of episodes were significantly correlated, however, Bonferroni adjusted p value excluded age variable. The number of episodes correlated especially strongly with platelet count (ρ = +0.93, p < .001) and CA19‑9 (ρ = +0.91, p < .001), and moderately with other liver function tests and mortality, after Bonferroni adjusted p value, platelet count, CA19-9, LCF and death holding significant. These exploratory findings are based on small sample sizes and limited event counts. Correlations should be interpreted as hypothesis-generating and not as evidence of causality or predictive utility ( Table2 ). Survival analysis using Kaplan–Meier estimates revealed a notable difference in both the mean and median survival times between the two groups. Patients in CD group demonstrated a mean survival time of 58.1 months (95% CI: 51.5–64.8) and a median survival of 59.0 months (95% CI: 56.4–61.6), indicating a generally favorable prognosis. In contrast, CS had a significantly lower mean survival time of 45.3 months (95% CI: 39.6–51.1) and median survival of 45.0 months (95% CI: 39.9–50.1) ( Figure 1 ). Overall, the cohort had a mean survival time of 50.1 months and a median of 50.0 months, suggesting that the survival disparity between the two groups materially affects the aggregate outcome. The non-overlapping or narrowly overlapping confidence intervals, especially for the medians, support a potentially meaningful difference in survival distribution. The log-rank test revealed a statistically significant difference in survival distributions between the two groups (χ² = 5.407, p = 0.020). This indicates that the observed difference in survival times—where Group 1 had a median survival of 59 months and Group 2 had a median survival of 45 months—is unlikely due to chance. During the follow up period no evidence of radiologic progression, defined by new cyst formation or development of extrahepatic complications, including cystic renal or pancreatic involvement. 4. Discussion Caroli’s disease is a rare congenital disorder marked by segmental, non-obstructive saccular dilatation of the intrahepatic bile ducts, often resulting from a ductal plate malformation during embryogenesis. It may occur in isolation or in conjunction with congenital hepatic fibrosis and renal cystic disease, in which case it is termed Caroli’s syndrome. Both entities are now understood to lie within the spectrum of fibropolycystic liver disease and are genetically linked to PKHD1 mutations, also implicated in autosomal recessive polycystic kidney disease. Bile stasis within the dilated ducts predisposes patients to recurrent cholangitis, intrahepatic lithiasis, and an elevated lifetime risk of cholangiocarcinoma. Recent literature underscores the importance of regular imaging surveillance and timely surgical or transplant referral in cases of progressive or complicated disease [ 13 , 14 ]. The differential diagnosis of Caroli’s disease includes von Meyenburg complexes (also known as biliary hamartomas), which are typically small, multiple cystic lesions that do not communicate with the biliary tree. These lesions are often asymptomatic, incidentally discovered on imaging—particularly magnetic resonance cholangiopancreatography and do not usually affect liver function. However, rare cases of malignant transformation to cholangiocarcinoma have been reported. Other conditions to consider in the differential diagnosis include polycystic liver disease and primary sclerosing cholangitis, both of which may present with hepatic cystic or biliary abnormalities [ 15 ]. In the present study, three patients (25%) with Caroli’s syndrome developed cholangiocarcinoma within a mean follow-up period of 28.3 ± 5.7 months, a notably higher incidence than that reported in the literature, which estimates the risk of cholangiocarcinoma in Caroli's disease to be up to 14% [ 17 ]. This striking difference highlights the substantial malignant potential in this population. Caroli’s disease and Caroli’s syndrome are known to predispose patients to biliary tract malignancies, primarily due to the underlying congenital cystic dilatation of intrahepatic bile ducts, which creates a microenvironment conducive to carcinogenesis. Several pathophysiological mechanisms have been proposed, including chronic biliary stasis, stone-related inflammation, and prolonged exposure of biliary epithelium to potentially carcinogenic bile constituents. These factors synergize to induce chronic epithelial injury, dysplasia, and eventually malignant transformation. Additionally, long-standing disease, older age, and inefficient bile drainage have been associated with increased risk of neoplastic progression [ 18 , 19 ]. Recent insights also suggest that chronic inflammation, driven by recurrent cholangitis and fibrosis, plays a key role in the activation of oncogenic pathways in biliary epithelium. Although rare, mutations in oncogenes and tumor suppressor genes (e.g., KRAS, TP53) have been detected in cholangiocarcinomas arising in this context, further supporting the neoplastic potential of this congenital biliary disorder. The diagnosis of malignancy in patients with Caroli’s syndrome (CS) or Caroli’s disease (CD) remains particularly challenging. Detecting neoplastic transformation within dilated and distorted biliary tracts is technically demanding, and current imaging modalities often fail to identify early malignant changes. Consequently, routine screening for cholangiocarcinoma in these patients has shown limited success. However, the present study identified several clinical and biochemical parameters that may help in risk stratification for malignancy. These include severe thrombocytopenia, elevated AST, furthermore, a high frequency of cholangitis episodes and elevated CA 19 − 9 levels were associated with an increased risk of malignancy. Previous studies have reported that cholangiocarcinoma in CS or CD tends to occur more frequently in older patients and those with long-standing disease, with reported incidences ranging between 2.7% and 37.5% [ 20 , 21 ]. Notably, a CA 19 − 9 level of ≥ 103 U/L has been suggested as a prognostic marker for metastatic potential and overall survival in this patient population [ 22 ]. These findings underscore the potential utility of combining clinical and laboratory indicators for earlier identification of high-risk patients and tailoring surveillance strategies accordingly In the current study, females accounted for 26.3% of the cohort in both the Caroli’s syndrome (CS) and Caroli’s disease (CD) groups, a lower proportion than previously reported, where female representation has been noted at approximately 53% [ 21 ]. This discrepancy may reflect sample size limitations, referral patterns, or regional demographic differences [ 21 ]. Liver cell failure occurred in three patients within the Caroli’s syndrome (CS) group, each following an episode of hematemesis attributed to portal hypertension; a complication that is well-documented in the clinical course of CS and consistent with previously reported observations [ [ 23 , 24 ]. Treatment selection in patients with CD or CS should be tailored to the extent and severity of disease involvement. In localized disease, particularly unilobar involvement—hepatic resection (e.g., segmentectomy or lobectomy) provides symptom relief and may diminish the long-term risk of cholangiocarcinoma; retrospective studies suggest malignancy rates drop to approximately 7% following surgical removal of affected segments [ 25 ]. In diffuse or bilateral disease, particularly when accompanied by portal hypertension or recurrent cholangitis, orthotopic liver transplantation remains the only definitive curative option and should be considered when resection is not feasible. For patients who are not surgical candidates or are awaiting transplantation, conservative management focuses on aggressive treatment of complications: prompt antibiotic therapy for cholangitis, endoscopic or radiologic drainage (ERCP or PTC) to relieve biliary obstruction, endoscopic band ligation or nonselective beta-blockers for variceal bleeding, and ursodeoxycholic acid to manage cholestasis and hepatolithiasis [ 26 ]. Several pharmacologic agents have been explored for their potential disease-modifying effects. Octreotide, a somatostatin analog, has been proposed to reduce hepatic cyst volume and fibrosis by suppressing cyclic AMP-mediated cholangiocyte proliferation; however, evidence is limited and largely preclinical or anecdotal Europe. Similarly, pioglitazone, a PPARγ agonist, has been hypothesized to mitigate future bile duct dilation, fibrosis, and renal cystogenesis, but data supporting its use in CD/CS are minimal and extrapolated primarily from animal models and related fibrocystic disorders [ 27 ]. Thus, while promising in theory, neither octreotide nor pioglitazone has become standard of care; large prospective clinical trials are lacking. At present, definitive decision-making should rely on disease distribution, symptom severity, and risk of malignancy, with surgical resection for localized disease and transplantation for diffuse symptomatic disease being the mainstays of treatment. This study presents one of the most detailed clinical characterizations of Caroli’s disease and Caroli’s syndrome in a single-center cohort over an extended follow-up period. Key strengths include: the study enrolled a carefully selected group of patients with radiologically confirmed Caroli’s disease or syndrome, enhancing diagnostic accuracy and clinical relevance, comprehensive diagnostic workup with detailed diagnostic protocol, including MRCP, extensive serological screening, and tumor marker evaluation, allowing for precise differentiation from mimicking conditions, rigorous follow-up and survival analysis Longitudinal follow-up (up to 7 years) allowed for meaningful evaluation of disease progression, complications (e.g., cholangitis, variceal bleeding, and cholangiocarcinoma), and survival outcomes, the study highlights clinically measurable predictors (e.g., platelet count, CA19-9, INR, number of cholangitis episodes) associated with adverse outcomes in CS patients, which may guide risk stratification in future clinical practice. However, the limitations that should be acknowledged including a small sample size due to the rarity of the condition, single-center, observational design, Exploratory correlations should be interpreted with caution: Given the limited number of events (e.g., deaths and cancer diagnoses), significant associations should be viewed as hypothesis-generating rather than confirmatory. 5. Conclusion Simple Caroli’s disease typically follows a benign clinical course, whereas Caroli’s syndrome represents a more complex entity with significant risk for hepatic decompensation and biliary malignancy. These findings underscore the importance of rigorous clinical monitoring and proactive management of complications, particularly recurrent cholangitis, portal hypertension, and variceal bleeding, to improve outcomes and delay liver failure. Furthermore, the study identifies several potential predictors of malignancy, offering valuable insight for risk stratification. Given the risk of cholangiocarcinoma even in asymptomatic individuals, regular clinical and radiological surveillance is essential for early detection and intervention. Declarations Author Contributions: Conceptualization, A.S.H.; methodology, A.S.H. and H.A.E.; software, E.K.F, R.N., and H.N.; validation, A.S.H. and H.A.E.; formal analysis, M.A.; investigation, A.S.H.; resources, A.S.H. and H.A.E; data curation, A.A.M., and M.M.A.; writing—original draft preparation, A.S.H. and H.A.E.; writing—review and editing, ALL; supervision, R.N., H.N.; project administration, E.K.F.; funding acquisition, E.K.F. All authors have read and agreed to the published version of the manuscript. Funding: The study was funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2025R774), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. Institutional Review Board Statement: The study was approved by the Zagazig University—Faculty of Medicine Ethical Committee (ZU-IRB # 85-28-1-24). The study followed the ethical standards of the ethical committees on human experimentation and the Helsinki Declaration of 1964 and its amendments. We only used clinical data, with no invasion or harmful intervention to the patient. The purpose of the research was explained, and participants were given the choice to decline participation. Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Data Availability Statement: Data from the present study can be obtained from the corresponding author upon reasonable request. Acknowledgments: We would like to thank AlMaarefa University, Riyadh, KSA, for supporting this research. 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Caroli's disease: report of surgical options and long-term outcome of patients treated in Argentina. Multicenter study. J Gastrointest Surg 2011; 15:1814–1819. Fahrner R, Dennler SG, Inderbitzin D. Risk of malignancy in Caroli disease and syndrome: A systematic review. World J Gastroenterol 2020 Aug 21;26(31):4718-4728. Coelho R, Silva M, Rodrigues-Pinto E, Cardoso H, Lopes S, Pereira P, et al. CA 19-9 as a Marker of Survival and a Predictor of Metastization in Cholangiocarcinoma. GE Port J Gastroenterol 2017; 24:114-121. Tzoufi M, Rogalidou M, Drimtzia E, Sionti I, Nakou I, Argyropoulou M et al. Caroli’s disease: Description of a case with a benign clinical course. Ann Gastroenterol 2011;24(2):129-133. Raut A, Shrestha S, Homagain S, Jayswal A, Ghimire B. Portal hypertension: An uncommon presentation of Caroli's syndrome. Clin Case Rep 2020; 8: 3133– 3137. Taylor AC, Palmer KR. Caroli's disease. Eur J Gastroenterol Hepatol 1998 Feb;10(2):105-8. Masyuk TV, Masyuk AI, Torres VE, Harris PC, Larusso NF. Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3',5'-cyclic monophosphate. Gastroenterology. 2007 Mar;132(3):1104-16. Yoshihara D, Kurahashi H, Morita M, Kugita M, Hiki Y, Aukema HM, et al. PPAR-gamma agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. Am J Physiol Renal Physiol. 2011 Feb; 300(2): F465-74. Tables Table 1 and 2 are available in the Supplementary Files section. Images Image 1 and Image 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files image1.jpg Image 1. A: Saccular dilation of intrahepatic ducts with central dot sign (white arrow) and surrounded dilated biliary radical (pink arrow); B: multiple renal cysts image2.jpg Image 2 A: Saccular dilation of intrahepatic ducts; B: Saccular dilation of intrahepatic ducts, pancreatic cysts, hypoechoic mass with compressing effects (white arrow) cause dilation of intrahepatic biliary radicals; C: Triphasic CT confirming intrahepatic cholangiocarcinoma Cite Share Download PDF Status: Published Journal Publication published 26 Mar, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 21 Jan, 2026 Reviews received at journal 17 Jan, 2026 Reviewers agreed at journal 13 Jan, 2026 Reviewers agreed at journal 18 Nov, 2025 Reviews received at journal 17 Oct, 2025 Reviewers agreed at journal 23 Sep, 2025 Reviewers invited by journal 22 Sep, 2025 Editor assigned by journal 22 Sep, 2025 Editor invited by journal 20 Aug, 2025 Submission checks completed at journal 14 Aug, 2025 First submitted to journal 14 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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1","display":"","copyAsset":false,"role":"figure","size":64693,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier survival curve showing higher survival in CD \u0026amp; CS groups.\u003c/p\u003e","description":"","filename":"fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7353511/v1/e0de3ce45e9366398700978e.jpg"},{"id":105755862,"identity":"16b9eb66-335b-44e8-a8af-b78019349c52","added_by":"auto","created_at":"2026-03-30 16:31:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":784636,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7353511/v1/5dd11925-5738-42c7-8974-9e6eccac69c8.pdf"},{"id":92846890,"identity":"6261cdcb-7a68-4002-90e9-1cf66d00ef71","added_by":"auto","created_at":"2025-10-06 09:42:32","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":49629,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImage 1. \u003c/strong\u003eA:\u003cstrong\u003e \u003c/strong\u003eSaccular dilation of intrahepatic ducts with central dot sign (white arrow) and surrounded dilated biliary radical (pink arrow); B: multiple renal cysts\u003c/p\u003e","description":"","filename":"image1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7353511/v1/2693fe6ad5db0eacfd7f02a4.jpg"},{"id":92847289,"identity":"21c11d67-2287-4753-9a21-bcb5933c51b4","added_by":"auto","created_at":"2025-10-06 09:50:32","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":88702,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImage 2 \u003c/strong\u003eA: Saccular dilation of intrahepatic ducts; B: Saccular dilation of intrahepatic ducts, pancreatic cysts, hypoechoic mass with compressing effects (white arrow) cause dilation of intrahepatic biliary radicals; C: Triphasic CT confirming intrahepatic cholangiocarcinoma\u003c/p\u003e","description":"","filename":"image2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7353511/v1/3ff933cf5a042bfdccd795bc.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Navigating Prognostic Factors and Long-Term Outcomes in Caroli’s Disease and Syndrome - A Prospective Observational Cohort Study","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCaroli\u0026rsquo;s disease (CD) is a rare congenital disorder characterized by segmental, non-obstructive saccular dilatation of the intrahepatic bile ducts. It is classified into two distinct forms: the simple form, referred to as Caroli\u0026rsquo;s disease (type I), and the more complex form known as Caroli\u0026rsquo;s syndrome (CS or type II), which is associated with congenital hepatic fibrosis and often renal cystic diseases such as autosomal recessive polycystic kidney disease (ARPKD) or autosomal dominant polycystic kidney disease (ADPKD) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eBoth CD and CS are part of the fibropolycystic disease spectrum and are often caused by mutations in the \u003cem\u003ePKHD1\u003c/em\u003e gene on chromosome 6p12, which encodes fibrocystin/polyductin \u0026mdash; a protein expressed in bile ducts, renal tubules, and pancreatic ducts [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. These mutations disrupt the normal remodeling of the ductal plate during embryogenesis, resulting in malformed intrahepatic bile ducts and periportal fibrosis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eClinically, Caroli\u0026rsquo;s disease presents with recurrent episodes of cholangitis, abdominal pain, and hepatobiliary complications. In Caroli\u0026rsquo;s syndrome, progressive fibrosis may lead to portal hypertension and upper gastrointestinal bleeding, especially from esophageal varices [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Imaging plays a central role in diagnosis, with hallmark features such as the \u0026ldquo;central dot sign\u0026rdquo; on ultrasonography and MRCP [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDespite being described decades ago, the natural history, prognostic factors, and malignant potential of CD and CS remain incompletely understood due to their rarity and clinical heterogeneity. Notably, patients with these conditions are at increased risk of developing hepatobiliary malignancies, including cholangiocarcinoma.\u003c/p\u003e\u003cp\u003eIn this study, we aimed to evaluate the prognostic factors, survival outcomes, and risk of cholangiocarcinoma in patients with Caroli\u0026rsquo;s disease and Caroli\u0026rsquo;s syndrome. We also examined the clinical correlates of recurrent cholangitis, portal hypertension, and relevant laboratory biomarkers in this challenging patient population.\u003c/p\u003e"},{"header":"2. Patients and Methods","content":"\u003cp\u003eThis was a cross-sectional observational study conducted at the Gastroenterology and Hepatology Clinic, Zagazig University Hospitals, between November 2015 and December 2022. The study was approved by the Institutional Review Board of Zagazig University [ZU-IRB # 85-28-1-24], and written informed consent was obtained from all participants in accordance with the Declaration of Helsinki.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Patient Selection\u003c/h2\u003e\u003cp\u003eNineteen patients diagnosed with Caroli\u0026rsquo;s disease or Caroli\u0026rsquo;s syndrome were enrolled. Inclusion criteria included confirmed radiological diagnosis of Caroli\u0026rsquo;s disease or syndrome via MRCP and clinical presentation suggestive of biliary pathology. Exclusion criteria were solid organ transplantation, diabetes mellitus or obesity, non-alcoholic fatty liver disease, chronic alcohol use, presence of other congenital hepatic cysts, refusal to participate. The cohort included 12 patients with Caroli\u0026rsquo;s Syndrome and 7 with isolated Caroli\u0026rsquo;s Disease.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Clinical Assessment\u003c/h2\u003e\u003cp\u003ePatients presented with a combination of right upper quadrant abdominal pain, recurrent fever, vomiting, and signs of cholangitis. Initial evaluation included thorough history, physical examination, and baseline laboratory and imaging studies.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Diagnostic Workup\u003c/h2\u003e\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\u003ch2\u003e2.3.1. Laboratory Investigations\u003c/h2\u003e\u003cp\u003eRoutine laboratory investigations were conducted, including comprehensive liver and renal function panels, as well as serum alkaline phosphatase levels. A complete blood count (CBC) was performed to assess for thrombocytopenia, a potential marker of portal hypertension, and leukocytosis. The neutrophil-to-lymphocyte ratio (NLR) was also calculated, given its reported association with severe acute cholangitis and septic shock [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Coagulation profiles were obtained to evaluate hepatic synthetic function and bleeding risk. Additionally, an extensive panel of serological tests was performed to exclude infectious, autoimmune, and neoplastic etiologies. These included serologies for fascioliasis, ascariasis, and hydatid disease, as well as autoimmune markers such as antinuclear antibodies (ANA), antimitochondrial antibodies (AMA), and anti\u0026ndash;liver-kidney microsomal (anti-LKM) antibodies. Viral hepatitis screening was conducted via Hepatitis B surface antigen (HBsAg) and Hepatitis C virus antibody (anti-HCV). The tumor marker CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 was measured to assess for potential cholangiocarcinoma.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\u003ch2\u003e2.3.2. Abdominal Ultrasonography\u003c/h2\u003e\u003cp\u003eAbdominal ultrasonography was employed to evaluate hepatic architecture, screen for complications, and assist in the diagnosis of Caroli\u0026rsquo;s disease and its associated syndromic features. The presence of ascites or ultrasonographic signs of liver cirrhosis including coarse hepatic echotexture, nodular liver contour, and reduced hepatic size were documented. Portal hypertension was diagnosed based on the presence of portal venous collaterals, a portal vein diameter\u0026thinsp;\u0026gt;\u0026thinsp;13 mm, a splenic diameter\u0026thinsp;\u0026gt;\u0026thinsp;130 mm, or the presence of splenomegaly and ascites, in accordance with established sonographic criteria [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Segmental intrahepatic bile duct dilatation a hallmark of Caroli\u0026rsquo;s disease was observed, often with associated intraductal stones. Additional findings included cholelithiasis, cystic lesions of the pancreas, and cystic renal abnormalities, consistent with the fibropolycystic spectrum seen in Caroli\u0026rsquo;s syndrome. In cholangiocarcinoma, ultrasonography revealed suspicious features such as an infiltrative or compressive mass, biliary tract obstruction, or intraductal lesions with irregular margins. These were further evaluated with cross-sectional imaging and tumor markers when indicated.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section3\"\u003e\u003ch2\u003e2.3.3. Magnetic Resonance Cholangiopancreatography (MRCP):\u003c/h2\u003e\u003cp\u003eIt effectively detected dilated segmental intrahepatic biliary radicles, as well as associated hepatic cysts and intrahepatic abscesses, which are common complications in Caroli\u0026rsquo;s disease. A hallmark finding on MRCP is diffuse intrahepatic bile duct (IHBD) dilatation, which is considered diagnostic of Caroli\u0026rsquo;s disease. One of the characteristic MRCP signs in Caroli\u0026rsquo;s disease is the peripheral \u0026ldquo;funnel-shaped\u0026rdquo; appearance of the bile ducts, often accompanied by both saccular and fusiform dilatations. These features are typically distributed throughout the liver and help distinguish Caroli\u0026rsquo;s disease from other biliary disorders. In contrast, localized IHBD dilatation particularly without associated cystic or fibrotic changes may suggest isolated primary intrahepatic lithiasis rather than true Caroli\u0026rsquo;s disease [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\u003ch2\u003e2.3.4. Upper GI Endoscopy:\u003c/h2\u003e\u003cp\u003eEsophageal varices were identified and graded according to the Paquet classification system, which categorizes varices from Grade I to Grade IV based on their size and protrusion into the esophageal lumen [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section3\"\u003e\u003ch2\u003e2.3.5. Outcome Measures\u003c/h2\u003e\u003cp\u003eThe primary efficacy outcomes were defined as the clinical control of disease manifestations, including resolution or improvement of fever, right upper quadrant abdominal pain, vomiting, jaundice, and a reduction in the frequency of cholangitis episodes.\u003c/p\u003e\u003cp\u003eSafety outcomes were defined as the occurrence of significant complications, specifically:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eMajor gastrointestinal bleeding attributable to portal hypertension (e.g., variceal hemorrhage),\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAbnormalities in liver function tests (AST, ALT, bilirubin, INR),\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAll-cause mortality, with a specific focus on the development of cholangiocarcinoma confirmed by imaging and/or histopathology.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section3\"\u003e\u003ch2\u003e2.3.6. Secondary Outcomes\u003c/h2\u003e\u003cp\u003eSecondary outcomes were included to provide a broader understanding of disease progression and included:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eIncidence of hepatic decompensation (hepatic encephalopathy).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eRadiologic progression, defined by increased intrahepatic bile duct dilatation, new cyst formation, or liver fibrosis on imaging.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDevelopment of extrahepatic complications, including cystic renal or pancreatic involvement.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section3\"\u003e\u003ch2\u003e2.3.7. Follow-up Duration\u003c/h2\u003e\u003cp\u003ePatients were followed prospectively from November 2015 to December 2022. The median follow-up duration was XX months (range: XX\u0026ndash;XX), allowing for evaluation of both short- and long-term outcomes.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section3\"\u003e\u003ch2\u003e2.3.8. Statistical Analysis\u003c/h2\u003e\u003cp\u003eStatistical analysis was performed using IBM SPSS Statistics version 25.0 (IBM Corp., Armonk, NY, USA). The distribution of continuous variables was assessed using the Shapiro\u0026ndash;Wilk test, given the small sample size. Continuous variables were summarized as median and interquartile range (IQR), and group comparisons were performed using the Mann\u0026ndash;Whitney U test. Categorical variables were summarized as frequencies and percentages, and comparisons were made using the Fisher\u0026rsquo;s exact test. Spearman\u0026rsquo;s rank correlation was used to assess associations between clinical variables and outcomes such as development of cholangiocarcinoma and mortality. Due to the limited sample size, logistic regression analysis was not performed to avoid model overfitting and unstable estimates. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. To account for the increased risk of type I errors due to multiple hypotheses testing, we applied a Bonferroni correction using the adjusted pvalue approach: each unadjusted p-value was multiplied by the number of tests, and statistical significance was assessed at the nominal α\u0026thinsp;=\u0026thinsp;0.05 level. This ensures control of the family-wise error rate at 5%.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\u003ch2\u003e2.3.9. Sample Size\u003c/h2\u003e\u003cp\u003eDue to the rarity of Caroli's disease and syndrome, our sample size was limited. While this allows for valuable descriptive insights, findings from subgroup or regression analyses should be interpreted with caution.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eThe study enrolled 19 patients from November 2015 to December 2022 (73 months), with one group consisted of 7 patients with CD and the other group enrolled 12 patients with CS, the first patient was enrolled in December 2015 and the last patient in May 2018.\u003c/p\u003e\n\u003cp\u003eTable 1 compares the baseline demographic, clinical, laboratory, and endoscopic characteristics between patients with Caroli\u0026rsquo;s disease (CD) and Caroli\u0026rsquo;s syndrome (CS). The mean age was higher in the CS group (37.1 \u0026plusmn; 7.4 years) compared to the CD group (33.3 \u0026plusmn; 3.9 years), though not statistically significant (p=0.351). Abdominal pain was frequently reported in both groups; however, fever, jaundice, gastrointestinal bleeding (hematemesis and melena), liver cell failure, cholangiocarcinoma, and death were observed exclusively in the CS group, though statistically non-significant differences.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLaboratory values revealed that patients with CS had significantly higher total bilirubin (2.03 \u0026plusmn; 0.63 vs. 1.36 \u0026plusmn; 0.17 mg/dL; p=0.018) and INR (1.47 \u0026plusmn; 0.3 vs. 1.1 \u0026plusmn; 0.09; p=0.014), along with lower albumin (3.3 g/dL vs. 4.1 g/dL; p=0.028), suggesting more advanced liver dysfunction. Moreover, the CS group exhibited lower platelet counts and elevated CA19-9 levels, both associated with more severe disease and higher risk of malignancy (p=0.016, \u0026lt;0.001 respectively). The presence of esophageal varices was reported in 41.7% of CS patients and none of the CD group (p=0.106), consistent with portal hypertension being more common in CS.\u003c/p\u003e\n\u003cp\u003eNotably, a significantly increased odds ratio for fever (OR: 14.7, 95% CI: 1.2\u0026ndash;185) and jaundice (OR: 8.4, 95% CI: 0.76\u0026ndash;93.3) in the CS group, Using Haldane-Anscombe correction for sparse data, patients with CS had an estimated odds ratio of 5.53 for both cholangiocarcinoma and death compared to those with CD, though these differences were not statistically significant (p=0.263 for both). Similarly, the odds of having esophageal varices were 11-fold higher in the CS, but this also did not reach statistical significance (p=0.106). These findings underscore the more severe clinical phenotype and worse prognosis associated with Caroli\u0026rsquo;s syndrome compared to Caroli\u0026rsquo;s disease alone (Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn CD group, abdominal ultrasound had revealed segmental dilation of intrahepatic bile ducts with ductal stones formation, central dot sign (\u003cstrong\u003eImage 1A, Image 2\u003c/strong\u003e) with no evidence of cystic pancreatic, or cystic renal diseases or splenomegaly. However, in CS, in addition to the previously mentioned features, splenomegaly, pancreatic and cystic renal disorders were present (\u003cstrong\u003eImage 1B\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eMRCP confirmed segmental cystic dilation, which was in continuity with the biliary tree. It revealed complications such as biliary stricture in 2 patients and cholangiocarcinoma in 3 patients, either as a focal stricture involving the duct bifurcation with dilatation of the intrahepatic ducts (n = 1) or intraductal mass-forming cholangiocarcinoma (n = 2).\u003c/p\u003e\n\u003cp\u003eIt was important to rule out differential diagnoses by serological testing for fascioliasis, ascariasis, and hydatid disease was negative in all patients. Autoimmune markers including antinuclear antibodies (ANA), anti-mitochondrial antibodies (AMA), and anti-liver kidney microsomal antibodies (anti-LKM) were also negative. Viral hepatitis screening revealed negative results for hepatitis C virus antibodies and hepatitis B surface antigen. Complete blood counts were assessed to evaluate for thrombocytopenia as a surrogate marker of portal hypertension, which was identified in 8 patients within the Caroli\u0026rsquo;s syndrome (CS) group. Upper gastrointestinal endoscopy was performed in all patients, revealing esophageal varices (EV) in the CS group: grade 1 EV in 1 patient and grade 3 EV in 4 patients. Four patients in the CS group experienced hematemesis during follow-up (at 17, 20, 9, and 13 months, respectively), and all were successfully managed with endoscopic variceal band ligation.\u003c/p\u003e\n\u003cp\u003eLeukocytosis was evident in case of biliary cholangitis and leukocytic count was non- significantly higher in CS group (p = 0. 091) also NLR was significantly higher in CS group (p=0.03) when compared to CD group \u003cstrong\u003e(Table1\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring the follow-up period, a total of 94 medically supervised episodes of biliary cholangitis were recorded among all patients, with a mean of 4.95 \u0026plusmn; 1.8 episodes per patient. Antibiotic regimens varied according to clinical severity. Ciprofloxacin 500 mg twice daily was administered in 33 episodes, and cefixime 400 mg twice daily was used in 40 episodes. In 21 episodes presenting with signs of sepsis\u0026mdash;defined by fever, hypotension, and elevated procalcitonin levels\u0026mdash;meropenem was prescribed. Intravenous metronidazole was administered in all episodes as adjunct therapy. Supportive treatments including ursodeoxycholic acid, spasmolytics, and antipyretics were consistently utilized. Patients were monitored regularly with liver function tests and abdominal ultrasonography every three months in accordance with the follow-up protocol.\u003c/p\u003e\n\u003cp\u003eLiver cell failure had occurred in 3 patients (25%) in CS group after a significant attack of hematemesis (n = 1) and severe cholangitis (n = 2). Serum total bilirubin, transaminases, albumin were\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003esignificantly higher in CS group (\u003cstrong\u003eTable 1\u003c/strong\u003e), one patient in CS group developed left kidney pyelonephritis with severe sepsis and managed with nephrectomy.\u003c/p\u003e\n\u003cp\u003eThree patients in the CS group after 28.3\u0026plusmn;5.7 months respectively from enrollment had developed cholangiocarcinoma with increased CA19-9, rising bilirubin and managed with ERCP and metallic stents were deployed, the clinical condition was not suitable for chemotherapy and only provided symptomatic treatment, death occurred 3.33\u0026plusmn;2.31 months after initial diagnosis of cholangiocarcinoma (\u003cstrong\u003eImage 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eIn CS subgroup (n = 12, 3 deaths/cholangiocarcinoma), strong monotonic associations were observed between death/cancer and AST (\u0026rho; = 0.642, p =0 .024), number of episodes (\u0026rho; = +0.735, p = 0.006), and platelet count (\u0026rho; = -0.753, p = 0.005), with a moderate-to-strong correlation for CA19‑9 (\u0026rho; = +0.754, p = 0.005), after applying Bonferroni adjusted p value, CA19-9 was excluded. Among those with esophageal varices (n = 5) and GI bleeding (n = 4), age, sex. NL, albumin and frequency of episodes were significantly correlated, however, Bonferroni adjusted p value excluded age variable. The number of episodes correlated especially strongly with platelet count (\u0026rho; = +0.93, p \u0026lt; .001) and CA19‑9 (\u0026rho; = +0.91, p \u0026lt; .001), and moderately with other liver function tests and mortality, after Bonferroni adjusted p value, platelet count, CA19-9, LCF and death holding significant. These exploratory findings are based on small sample sizes and limited event counts. Correlations should be interpreted as hypothesis-generating and not as evidence of causality or predictive utility (\u003cstrong\u003eTable2\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSurvival analysis using Kaplan\u0026ndash;Meier estimates revealed a notable difference in both the mean and median survival times between the two groups. Patients in CD group demonstrated a mean survival time of 58.1 months (95% CI: 51.5\u0026ndash;64.8) and a median survival of 59.0 months (95% CI: 56.4\u0026ndash;61.6), indicating a generally favorable prognosis. In contrast, CS had a significantly lower mean survival time of 45.3 months (95% CI: 39.6\u0026ndash;51.1) and median survival of 45.0 months (95% CI: 39.9\u0026ndash;50.1) (\u003cstrong\u003eFigure 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eOverall, the cohort had a mean survival time of 50.1 months and a median of 50.0 months, suggesting that the survival disparity between the two groups materially affects the aggregate outcome. The non-overlapping or narrowly overlapping confidence intervals, especially for the medians, support a potentially meaningful difference in survival distribution.\u003c/p\u003e\n\u003cp\u003eThe log-rank test revealed a statistically significant difference in survival distributions between the two groups (\u0026chi;\u0026sup2; = 5.407, p = 0.020). This indicates that the observed difference in survival times\u0026mdash;where Group 1 had a median survival of 59 months and Group 2 had a median survival of 45 months\u0026mdash;is unlikely due to chance.\u003c/p\u003e\n\u003cp\u003eDuring the follow up period no evidence of radiologic progression, defined by new cyst formation or development of extrahepatic complications, including cystic renal or pancreatic involvement.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eCaroli\u0026rsquo;s disease is a rare congenital disorder marked by segmental, non-obstructive saccular dilatation of the intrahepatic bile ducts, often resulting from a ductal plate malformation during embryogenesis. It may occur in isolation or in conjunction with congenital hepatic fibrosis and renal cystic disease, in which case it is termed Caroli\u0026rsquo;s syndrome. Both entities are now understood to lie within the spectrum of fibropolycystic liver disease and are genetically linked to PKHD1 mutations, also implicated in autosomal recessive polycystic kidney disease. Bile stasis within the dilated ducts predisposes patients to recurrent cholangitis, intrahepatic lithiasis, and an elevated lifetime risk of cholangiocarcinoma. Recent literature underscores the importance of regular imaging surveillance and timely surgical or transplant referral in cases of progressive or complicated disease [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe differential diagnosis of Caroli\u0026rsquo;s disease includes von Meyenburg complexes (also known as biliary hamartomas), which are typically small, multiple cystic lesions that do not communicate with the biliary tree. These lesions are often asymptomatic, incidentally discovered on imaging\u0026mdash;particularly magnetic resonance cholangiopancreatography and do not usually affect liver function. However, rare cases of malignant transformation to cholangiocarcinoma have been reported. Other conditions to consider in the differential diagnosis include polycystic liver disease and primary sclerosing cholangitis, both of which may present with hepatic cystic or biliary abnormalities [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn the present study, three patients (25%) with Caroli\u0026rsquo;s syndrome developed cholangiocarcinoma within a mean follow-up period of 28.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7 months, a notably higher incidence than that reported in the literature, which estimates the risk of cholangiocarcinoma in Caroli's disease to be up to 14% [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This striking difference highlights the substantial malignant potential in this population. Caroli\u0026rsquo;s disease and Caroli\u0026rsquo;s syndrome are known to predispose patients to biliary tract malignancies, primarily due to the underlying congenital cystic dilatation of intrahepatic bile ducts, which creates a microenvironment conducive to carcinogenesis. Several pathophysiological mechanisms have been proposed, including chronic biliary stasis, stone-related inflammation, and prolonged exposure of biliary epithelium to potentially carcinogenic bile constituents. These factors synergize to induce chronic epithelial injury, dysplasia, and eventually malignant transformation.\u003c/p\u003e\u003cp\u003eAdditionally, long-standing disease, older age, and inefficient bile drainage have been associated with increased risk of neoplastic progression [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Recent insights also suggest that chronic inflammation, driven by recurrent cholangitis and fibrosis, plays a key role in the activation of oncogenic pathways in biliary epithelium. Although rare, mutations in oncogenes and tumor suppressor genes (e.g., KRAS, TP53) have been detected in cholangiocarcinomas arising in this context, further supporting the neoplastic potential of this congenital biliary disorder.\u003c/p\u003e\u003cp\u003eThe diagnosis of malignancy in patients with Caroli\u0026rsquo;s syndrome (CS) or Caroli\u0026rsquo;s disease (CD) remains particularly challenging. Detecting neoplastic transformation within dilated and distorted biliary tracts is technically demanding, and current imaging modalities often fail to identify early malignant changes. Consequently, routine screening for cholangiocarcinoma in these patients has shown limited success.\u003c/p\u003e\u003cp\u003eHowever, the present study identified several clinical and biochemical parameters that may help in risk stratification for malignancy. These include severe thrombocytopenia, elevated AST, furthermore, a high frequency of cholangitis episodes and elevated CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 levels were associated with an increased risk of malignancy.\u003c/p\u003e\u003cp\u003ePrevious studies have reported that cholangiocarcinoma in CS or CD tends to occur more frequently in older patients and those with long-standing disease, with reported incidences ranging between 2.7% and 37.5% [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Notably, a CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 level of \u0026ge;\u0026thinsp;103 U/L has been suggested as a prognostic marker for metastatic potential and overall survival in this patient population [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. These findings underscore the potential utility of combining clinical and laboratory indicators for earlier identification of high-risk patients and tailoring surveillance strategies accordingly\u003c/p\u003e\u003cp\u003eIn the current study, females accounted for 26.3% of the cohort in both the Caroli\u0026rsquo;s syndrome (CS) and Caroli\u0026rsquo;s disease (CD) groups, a lower proportion than previously reported, where female representation has been noted at approximately 53% [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This discrepancy may reflect sample size limitations, referral patterns, or regional demographic differences [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Liver cell failure occurred in three patients within the Caroli\u0026rsquo;s syndrome (CS) group, each following an episode of hematemesis attributed to portal hypertension; a complication that is well-documented in the clinical course of CS and consistent with previously reported observations [ [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTreatment selection in patients with CD or CS should be tailored to the extent and severity of disease involvement. In localized disease, particularly unilobar involvement\u0026mdash;hepatic resection (e.g., segmentectomy or lobectomy) provides symptom relief and may diminish the long-term risk of cholangiocarcinoma; retrospective studies suggest malignancy rates drop to approximately 7% following surgical removal of affected segments [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In diffuse or bilateral disease, particularly when accompanied by portal hypertension or recurrent cholangitis, orthotopic liver transplantation remains the only definitive curative option and should be considered when resection is not feasible.\u003c/p\u003e\u003cp\u003eFor patients who are not surgical candidates or are awaiting transplantation, conservative management focuses on aggressive treatment of complications: prompt antibiotic therapy for cholangitis, endoscopic or radiologic drainage (ERCP or PTC) to relieve biliary obstruction, endoscopic band ligation or nonselective beta-blockers for variceal bleeding, and ursodeoxycholic acid to manage cholestasis and hepatolithiasis [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSeveral pharmacologic agents have been explored for their potential disease-modifying effects. Octreotide, a somatostatin analog, has been proposed to reduce hepatic cyst volume and fibrosis by suppressing cyclic AMP-mediated cholangiocyte proliferation; however, evidence is limited and largely preclinical or anecdotal Europe. Similarly, pioglitazone, a PPARγ agonist, has been hypothesized to mitigate future bile duct dilation, fibrosis, and renal cystogenesis, but data supporting its use in CD/CS are minimal and extrapolated primarily from animal models and related fibrocystic disorders [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThus, while promising in theory, neither octreotide nor pioglitazone has become standard of care; large prospective clinical trials are lacking. At present, definitive decision-making should rely on disease distribution, symptom severity, and risk of malignancy, with surgical resection for localized disease and transplantation for diffuse symptomatic disease being the mainstays of treatment.\u003c/p\u003e\u003cp\u003eThis study presents one of the most detailed clinical characterizations of Caroli\u0026rsquo;s disease and Caroli\u0026rsquo;s syndrome in a single-center cohort over an extended follow-up period. Key strengths include: the study enrolled a carefully selected group of patients with radiologically confirmed Caroli\u0026rsquo;s disease or syndrome, enhancing diagnostic accuracy and clinical relevance, comprehensive diagnostic workup with detailed diagnostic protocol, including MRCP, extensive serological screening, and tumor marker evaluation, allowing for precise differentiation from mimicking conditions, rigorous follow-up and survival analysis Longitudinal follow-up (up to 7 years) allowed for meaningful evaluation of disease progression, complications (e.g., cholangitis, variceal bleeding, and cholangiocarcinoma), and survival outcomes, the study highlights clinically measurable predictors (e.g., platelet count, CA19-9, INR, number of cholangitis episodes) associated with adverse outcomes in CS patients, which may guide risk stratification in future clinical practice.\u003c/p\u003e\u003cp\u003eHowever, the limitations that should be acknowledged including a small sample size due to the rarity of the condition, single-center, observational design, Exploratory correlations should be interpreted with caution: Given the limited number of events (e.g., deaths and cancer diagnoses), significant associations should be viewed as hypothesis-generating rather than confirmatory.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eSimple Caroli\u0026rsquo;s disease typically follows a benign clinical course, whereas Caroli\u0026rsquo;s syndrome represents a more complex entity with significant risk for hepatic decompensation and biliary malignancy. These findings underscore the importance of rigorous clinical monitoring and proactive management of complications, particularly recurrent cholangitis, portal hypertension, and variceal bleeding, to improve outcomes and delay liver failure. Furthermore, the study identifies several potential predictors of malignancy, offering valuable insight for risk stratification. Given the risk of cholangiocarcinoma even in asymptomatic individuals, regular clinical and radiological surveillance is essential for early detection and intervention.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e Conceptualization, A.S.H.; methodology, A.S.H. and H.A.E.; software, E.K.F, R.N., and H.N.; validation, A.S.H. and H.A.E.; formal analysis, M.A.; investigation, A.S.H.; resources, A.S.H. and H.A.E; data curation, A.A.M., and M.M.A.; writing\u0026mdash;original draft preparation, A.S.H. and H.A.E.; writing\u0026mdash;review and editing, ALL; supervision, R.N., H.N.; project administration, E.K.F.; funding acquisition, E.K.F. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e The study was funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2025R774), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement:\u0026nbsp;\u003c/strong\u003eThe study was approved by the Zagazig University\u0026mdash;Faculty of Medicine Ethical Committee (ZU-IRB # 85-28-1-24). The study followed the ethical standards of the ethical committees on human experimentation and the Helsinki Declaration of 1964 and its amendments. We only used clinical data, with no invasion or harmful intervention to the patient. The purpose of the research was explained, and participants were given the choice to decline participation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement:\u0026nbsp;\u003c/strong\u003eInformed consent was obtained from all subjects involved in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u003c/strong\u003e Data from the present study can be obtained from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e We would like to thank AlMaarefa University, Riyadh, KSA, for supporting this research. The authors appreciate the Deanship of Scientific Research at Northern Border University, Arar, KSA for funding this research work through the project number \u0026ldquo;NBU-FFR-2025-3105-03\u0026rdquo;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare no conflicts of interest.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSummerfield JA, Nagafuchi Y, Sherlock S, Cadafalch J, Scheuer PJ. Hepatobiliary fibropolycystic diseases. A clinical and histological review of 51 patients. J Hepatol 1986; 2:141.\u003c/li\u003e\n\u003cli\u003eDesmet VJ. What is congenital hepatic fibrosis? Histopathol 1992; 20:465\u0026ndash;77.\u003c/li\u003e\n\u003cli\u003eMadjov R, Chervenkov P, Madjova V, Balev B. Caroli\u0026apos;s disease. Report of 5 cases and review of literature. Hepato-Gastroenterol 2005; 52(62):606\u0026ndash;609. \u003c/li\u003e\n\u003cli\u003eHoyer PF. Clinical manifestations of autosomal recessive polycystic kidney disease. Curr Opin Pediatr. 2015 Apr. 27 (2):186-92\u003c/li\u003e\n\u003cli\u003eTodani T, Watanabe Y, Narusue M, Tabuchi K, Okajima K. Congenital bile duct cysts: Classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst. Am J Surg 1977; 134: 263-269.\u003c/li\u003e\n\u003cli\u003eAwasthi A, Das A, Srinivasan R, Joshi K. Morphological and immunohistochemical analysis of ductal plate malformation: correlation with fetal liver. Histopathology 2004; 45:260\u0026ndash;267\u003c/li\u003e\n\u003cli\u003eZhu L, Zhao G, Jia CF, Li Y. A Case of Congenital Hepatic Fibrosis Associated With Medullary Sponge Kidney-Radiologic and Pathologic Features. Gastroenterol Res 2012 Apr;5(2):63-66. \u003c/li\u003e\n\u003cli\u003eWang ZX, Li YG, Wang RL, Li YW, Li ZY, Wang LF, et al. Clinical classification of Caroli\u0026apos;s disease: an analysis of 30 patients. HPB (Oxford). 2015 Mar; 17(3):278-83.\u003c/li\u003e\n\u003cli\u003eLee SH, Lee TY, Jeong JH, Cheon YK. Clinical Significance of the Neutrophil-Lymphocyte Ratio as an Early Predictive Marker for Adverse Outcomes in Patients with Acute Cholangitis. Medicina (Kaunas). 2022 Feb 9;58(2):255. \u003c/li\u003e\n\u003cli\u003eGonz\u0026aacute;lez-Ojeda A, Cervantes-Guevara G, Ch\u0026aacute;vez-S\u0026aacute;nchez M, D\u0026aacute;valos-Cobi\u0026aacute;n C, Ornelas-C\u0026aacute;zares S, Mac\u0026iacute;as-Amezcua MD, et al. Platelet count/spleen diameter ratio to predict esophageal varices in Mexican patients with hepatic cirrhosis. World J Gastroenterol 2014;20: 2079-2084.\u003c/li\u003e\n\u003cli\u003eLewin M, Desterke C, Guettier C, Valette PJ, Agostini H, Franchi-Abella S, et al. Diffuse Versus Localized Caroli Disease: A Comparative MRCP Study. AJR Am J Roentgenol 2021 Jun. 216 (6):1530-1538.\u003c/li\u003e\n\u003cli\u003ePaquet KJ. Prophylactic endoscopic sclerosing treatment of esophageal wall in varices: A prospective controlled trial. Endoscopy 1982; 14:4-5.\u003c/li\u003e\n\u003cli\u003eIssar P, Issar SK. Caroli\u0026apos;s disease. Indian J Gastroenterol. 2014 Sep;33(5):500\u003c/li\u003e\n\u003cli\u003eTorra R, Badenas C, Darnell A, Br\u0026uacute; C, Escorsell A, Estivill X. Autosomal dominant polycystic kidney disease with anticipation and Caroli\u0026apos;s disease associated with a PKD1 mutation. Rapid communication. Kidney Int. 1997 Jul;52(1):33-8.\u003c/li\u003e\n\u003cli\u003eMamone G, Carollo V, Cortis K, Aquilina S, Liotta R, Miraglia R. Magnetic resonance imaging of fibropolycystic liver disease: the spectrum of ductal plate malformations. Abdom Radiol (NY). 2019 Jun;44(6):2156-2171.\u003c/li\u003e\n\u003cli\u003eXu AM, Xian ZH, Zhang SH, Chen XF. Intrahepatic cholangiocarcinoma arising in multiple bile duct hamartomas: report of two cases and review of the literature. Eur J Gastroenterol Hepatol 2009;21 (5): 580-4.\u003c/li\u003e\n\u003cli\u003eLai Q, Lerut J. Proposal for an algorithm for liver transplantation in Caroli\u0026apos;s disease and syndrome: putting an uncommon effort into a common task. Clin Transplant. 2016; 30:3\u0026ndash;9\u003c/li\u003e\n\u003cli\u003ePetrick JL, Yang B, Altekruse SF, Van Dyke AL, Koshiol J, Graubard BI, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: A population-based study in SEER-Medicare. PLoS One 2017 Oct 19;12(10):e0186643.\u003c/li\u003e\n\u003cli\u003eFahrner R, Dennler SG, Inderbitzin D. Risk of malignancy in Caroli disease and syndrome: A systematic review. World J Gastroenterol 2020 Aug 21;26(31):4718-4728.\u003c/li\u003e\n\u003cli\u003eLendoire JC, Raffin G, Grondona J, Bracco R, Russi R, Ardiles V, et al. Caroli\u0026apos;s disease: report of surgical options and long-term outcome of patients treated in Argentina. Multicenter study. J Gastrointest Surg 2011; 15:1814\u0026ndash;1819.\u003c/li\u003e\n\u003cli\u003eFahrner R, Dennler SG, Inderbitzin D. Risk of malignancy in Caroli disease and syndrome: A systematic review. World J Gastroenterol 2020 Aug 21;26(31):4718-4728.\u003c/li\u003e\n\u003cli\u003eCoelho R, Silva M, Rodrigues-Pinto E, Cardoso H, Lopes S, Pereira P, et al. CA 19-9 as a Marker of Survival and a Predictor of Metastization in Cholangiocarcinoma. GE Port J Gastroenterol 2017; 24:114-121. \u003c/li\u003e\n\u003cli\u003eTzoufi M, Rogalidou M, Drimtzia E, Sionti I, Nakou I, Argyropoulou M et al. Caroli\u0026rsquo;s disease: Description of a case with a benign clinical course. Ann Gastroenterol 2011;24(2):129-133.\u003c/li\u003e\n\u003cli\u003eRaut A, Shrestha S, Homagain S, Jayswal A, Ghimire B. Portal hypertension: An uncommon presentation of Caroli\u0026apos;s syndrome. Clin Case Rep 2020; 8: 3133\u0026ndash; 3137.\u003c/li\u003e\n\u003cli\u003eTaylor AC, Palmer KR. Caroli\u0026apos;s disease. Eur J Gastroenterol Hepatol 1998 Feb;10(2):105-8.\u003c/li\u003e\n\u003cli\u003eMasyuk TV, Masyuk AI, Torres VE, Harris PC, Larusso NF. Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3\u0026apos;,5\u0026apos;-cyclic monophosphate. Gastroenterology. 2007 Mar;132(3):1104-16. \u003c/li\u003e\n\u003cli\u003eYoshihara D, Kurahashi H, Morita M, Kugita M, Hiki Y, Aukema HM, et al. PPAR-gamma agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. Am J Physiol Renal Physiol. 2011 Feb; 300(2): F465-74. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"},{"header":"Images","content":"\u003cp\u003eImage 1 and Image 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Caroli’s disease, cholangiocarcinoma, Cholangitis","lastPublishedDoi":"10.21203/rs.3.rs-7353511/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7353511/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eCaroli\u0026rsquo;s disease (CD) and Caroli\u0026rsquo;s syndrome (CS) are rare congenital disorders of the intrahepatic bile ducts associated with significant morbidity and risk of malignant transformation. Differentiating the clinical course between CD and CS remains critical for tailoring surveillance and management.\u003c/p\u003e\u003ch2\u003eAim\u003c/h2\u003e\u003cp\u003eTo compare the clinical characteristics, complications, and outcomes of patients with CD and CS and identify potential predictors of biliary malignancy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis cross-sectional observational study included 19 patients diagnosed with CD (n\u0026thinsp;=\u0026thinsp;7) or CS (n\u0026thinsp;=\u0026thinsp;12) at Zagazig University Hospitals between November 2015 and December 2022. Diagnosis was confirmed via MRCP. Clinical, biochemical, endoscopic, and imaging assessments were performed. Patients were followed longitudinally for 85 months. Outcomes included incidence of cholangitis, liver decompensation, variceal bleeding, malignancy, and mortality. Statistical comparisons were conducted using nonparametric tests, and correlations were assessed using Spearman\u0026rsquo;s rank.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003ePatients with CS exhibited significantly higher bilirubin (p\u0026thinsp;=\u0026thinsp;0.018), INR (p\u0026thinsp;=\u0026thinsp;0.014), and CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and lower albumin and platelet counts (p\u0026thinsp;=\u0026thinsp;0.028, 0.016) compared to CD. Portal hypertension and esophageal varices were observed exclusively in CS. Three CS patients developed cholangiocarcinoma after a mean of 28.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7 months and died within 3.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3 months of diagnosis. Correlation analysis revealed strong associations between malignancy and AST (ρ\u0026thinsp;=\u0026thinsp;0.642), number of cholangitis episodes (ρ\u0026thinsp;=\u0026thinsp;0.735), platelet count (ρ=\u0026ndash;0.753), and CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 (ρ\u0026thinsp;=\u0026thinsp;0.754). Kaplan\u0026ndash;Meier analysis demonstrated significantly reduced survival in CS vs. CD (median survival 45.0 vs. 59.0 months, p\u0026thinsp;=\u0026thinsp;0.020).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eCaroli\u0026rsquo;s syndrome is associated with a more severe clinical phenotype, higher complication rate, and increased risk of malignancy compared to Caroli\u0026rsquo;s disease. Identifying predictors of poor outcomes may guide individualized surveillance and management. Regular monitoring, even in asymptomatic patients, is essential for early detection of complications and malignancy.\u003c/p\u003e","manuscriptTitle":"Navigating Prognostic Factors and Long-Term Outcomes in Caroli’s Disease and Syndrome - A Prospective Observational Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-06 09:42:27","doi":"10.21203/rs.3.rs-7353511/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-21T09:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-17T14:56:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"112228139562796326192241213641107842377","date":"2026-01-13T12:18:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"89844145865411377308824266997297055180","date":"2025-11-18T12:59:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-17T04:26:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"198268298219059888995096030047653950706","date":"2025-09-24T00:25:32+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-22T21:08:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-22T10:46:28+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-20T08:03:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-14T15:51:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-08-14T15:48:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"efc2f61f-ecf6-4bbd-a2c6-2763ca208a46","owner":[],"postedDate":"October 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":55690291,"name":"Biological sciences/Cancer"},{"id":55690292,"name":"Health sciences/Diseases"},{"id":55690293,"name":"Health sciences/Gastroenterology"},{"id":55690294,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-03-30T16:25:45+00:00","versionOfRecord":{"articleIdentity":"rs-7353511","link":"https://doi.org/10.1038/s41598-026-42855-8","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-03-26 16:12:21","publishedOnDateReadable":"March 26th, 2026"},"versionCreatedAt":"2025-10-06 09:42:27","video":"","vorDoi":"10.1038/s41598-026-42855-8","vorDoiUrl":"https://doi.org/10.1038/s41598-026-42855-8","workflowStages":[]},"version":"v1","identity":"rs-7353511","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7353511","identity":"rs-7353511","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}