Abstract
Purpose
Congenital hepatic fibrosis (CHF) and/or autosomal recessive polycystic kidney disease (ARPKD) represent rare and complex clinical conditions in childhood. Diagnostic challenges often arise due to heterogeneity in clinical manifestations.
Methods
This study included pediatric patients diagnosed with CHF and/or ARPKD who were followed by the Pediatric Gastroenterology and Pediatric Nephrology Departments. Patient records were reviewed retrospectively.
Results
A total of 23 patients were included in the study. The median age of the cohort was 12.7±4.8 years, and the median age at diagnosis was 0.6±3.4 years. Thirteen patients had combined CHF and ARPKD, while 10 had isolated ARPKD. The diagnosis was incidental in 13 patients (56.5%), whereas five patients (21.7%) presented with an abdominal mass. Most patients had mutations in the polycystic kidney and hepatic disease 1 gene. Bilateral kidney enlargement and multiple millimetric cysts were identified in the majority of cases. Three patients required organ transplantation during follow-up. Two patients who underwent liver or kidney transplantation experienced no complications, whereas the patient who received combined liver and kidney transplantation developed kidney failure secondary to reflux nephropathy. Except for one patient who died in infancy, disease progression was generally mild in the cohort.
Conclusion
Although kidney involvement is often predominant, hepatic complications may develop over time, particularly in patients with combined disease. A collaborative, multidisciplinary approach is essential for effectively managing the complex manifestations of these ciliopathies.
Keywords: Autosomal recessive polycystic kidney, Congenital hepatic fibrosis, Pediatric
INTRODUCTION
Congenital hepatic fibrosis (CHF) is a rare fibrocystic liver disease characterized by autosomal recessive inheritance and abnormal ductal structures arising from fibrosis of the interlobular and septal bile ducts within the portobiliary system. Progressive peribiliary fibrosis results in portal hypertension, and the disease may remain unrecognized in its early stages if patients are asymptomatic. Diagnosis is typically established when complications such as cholangitis or signs of portal hypertension occur. Ciliopathies caused by defects in proteins located in the non-motile cilia of cholangiocytes and renal tubular epithelial cells lead to ductal dysgenesis and cystic lesions [1,2,3,4]. The most common genetic defect involves mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene, which encodes fibrocystin. PKHD1 mutations result in autosomal recessive polycystic kidney disease (ARPKD), characterized by renal cyst formation. Although more than 300 PKHD1 gene mutations have been reported, a genotype–phenotype correlation has not been established [5,6]. Fibrocystin is a multifunctional protein essential for proper ductal development, and the hallmark pathological feature of CHF is ductal plate malformation.
Since patients often remain asymptomatic until complications develop, CHF is frequently diagnosed during adolescence. Biochemical tests of liver function typically remain within normal limits. Radiological evaluation of the liver and kidneys using ultrasonography is a valuable diagnostic tool. Liver biopsy may further assist in demonstrating fibrosis and cystic dilatation. Management focuses on treating complications, while liver transplantation remains the only curative option. In some cases, sequential or simultaneous liver and kidney transplantation may be indicated [4].
This study aims to evaluate the clinical course of patients diagnosed with CHF and/or ARPKD who were followed at our center.
MATERIALS AND METHODS
This study included patients with CHF comorbid with ARPKD and those with isolated ARPKD who were followed at the Pediatric Gastroenterology and Pediatric Nephrology Departments of Erciyes University Faculty of Medicine. A diagnosis of CHF was confirmed through liver biopsy showing ductal plate malformation, portal and periportal fibrosis, and cystic dilatation [7]. ARPKD was diagnosed based on renal ultrasonography findings of cyst formation and genetic analysis [8]. The Schwartz formula was used to estimate glomerular filtration rate (GFR), with values >100 mL/min/1.73 m2 considered normal [9]. Proteinuria was defined as a spot urine total protein/creatinine ratio >0.2 mg protein/mg creatinine [10]. Hypertension was defined according to the 2017 American Academy of Pediatrics guidelines [11].
Transplantation indications were as follows: liver transplantation was considered in cases of liver failure or signs of decompensated cirrhosis, including refractory ascites, encephalopathy, variceal bleeding, or coagulopathy [12]; kidney transplantation was indicated for patients with a GFR <15 mL/min/1.73 m2 [13].
Demographic data—including age, sex, weight, height, and body mass index (BMI) standard deviation scores (SDS)—were recorded. Additional clinical variables such as age at diagnosis, presenting symptoms, liver and kidney function tests, ultrasonographic findings, need for liver and/or kidney transplantation, complications, GFR values, and the presence of proteinuria or hypertension were recorded. Genetic analysis results were also documented.
This study was approved by the Ethics Committee of Erciyes University Faculty of Medicine (Decision No: 2019/549, Date: July 24, 2019).
Statistical analysis
Data normality was assessed using histograms and the Shapiro–Wilk test. Continuous variables were compared using a two-sided Welch’s t-test or the Mann–Whitney U-test, as appropriate. Categorical variables were analyzed using the Pearson chi-square test or the Fisher–Freeman–Halton exact test. Values are presented as frequencies and percentages for categorical variables and as mean±standard deviation or median with interquartile range for continuous variables. A p-value <0.05 was considered statistically significant.
RESULTS
A total of 23 patients (10 female, 13 male) were included in the study. The median age was 12.7±4.8 years (range: 3.8–22 years), and the median age at diagnosis was 0.6±3.4 years (range: 0–11 years). The mean SDS values were −0.80±0.80 for weight, −0.58±1.05 for height, and −0.55±0.98 for BMI. Incidental diagnosis occurred in 13 patients (56.5%), including seven who received an intrauterine diagnosis via fetal ultrasonography. Five patients (21.7%) presented with an abdominal mass, two (8.7%) with hematuria, one with upper gastrointestinal bleeding, one with cholestasis, and one with impaired kidney function tests. The clinical characteristics of the patients are summarized in Table 1.
Table 1. Clinical features of the patients.
| Patients/sex | Current age/age at diagnosis (yr) | Main complaint | AST/ALT (U/L) | BUN/Cre (mg/dL) | First pathology:liver or kidney | Liver and/or kidney involvement | Time interval between two diagnoses (yr) | Consanguinity/hypertension/portal hypertension | Genetic analysis result |
|---|---|---|---|---|---|---|---|---|---|
| 1/M | 14/4 | GI bleeding | 43/20 | 12/0.3 | Liver | Liver and kidney | 5 | +/−/+ | PKHD1/NM_138694/exon 61 c.310207 T<C p.(Phe3403Leu) homozygous |
| 2/F | 13/0 | Incidental | 23/16 | 18.5/0.8 | Kidney | Liver and kidney | 0.25 | +/+/+ | PKHD1 exon 57/32 heterozygous |
| 3/F | 20/2.5 | Hematuria | 32/15 | 18/0.7 | Kidney | Liver and kidney | 3 | −/+/+ | PKHD1/NM_138694/exon 14 c.1068dup p.(Asn357) nonsense heterozygous |
| 4/F | 22/2 | Hematuria | 26/17 | 17/0.6 | Kidney | Liver and kidney | 5 | −/−/+ | 4 |
| 5/M | 16/11 | Cholestasis | 42/87 | 4.5/0.4 | Liver | Liver and kidney | 4 | +/−/− | No mutation |
| 6/F | 14.5/10 | Incidental | 28/15 | 21.4/0.8 | Kidney | Liver and kidney | 2 | −/+/+ | No mutation |
| 7/M | 3.8/0.02 | Abnormal KFT | 67/10 | 15.8/1 | Kidney | Liver and kidney | 0 | −/+/− | PKHD1 exon 32 c.4256.4257 del p.(Arg141911efs *5) heterozygous |
| 8/F | 10/0.6 | Abdominal mass | 29/15 | 15/0.17 | Kidney | Liver and kidney | 0.3 | −/+/+ | PKHD1 NM_138694 exon 64 c.11501C>T p.Pro3834Leu homozygous |
| 9/M | 9.5/0 | Incidental | 52/14 | 7/0.3 | Kidney | Liver and kidney | 3 | +/+/+ | PKHD1 c.2278C>T Arg760cys homozygous |
| 10/F | 12.5/0.16 | Incidental | 76/29 | 3/0.15 | Kidney | Liver and kidney | 4 | −/+/− | PKHD1/NM_138694 (p.Asn711), c.11310+4A>T |
| 11/F | 17/0.6 | Incidental | 32/14 | 13.1/1.83 | Kidney | Liver and kidney | 1 | +/+/− | PKHD1 c.6268A>G, p.Ile2090Val missense heterozygous |
| 12/M | 8.5/0 | Incidental | 19/12 | 32/0.97 | Kidney | Liver and kidney | 2 | +/−/− | No mutation |
| 13/M | 0.3/0 | Incidental | 33/23 | 86.3/1.42 | Kidney | Kidney | - | +/−/− | - |
| 14/M | 16/9 | Incidental | 42/31 | 9.6/0.53 | Liver | Liver and kidney | 0.66 | +/−/+ | TMEM67 NM_153704.5 c.2461 G>A |
| 15/F | 10.5/1 | Incidental | 30/13 | 6/0.14 | Kidney | Kidney | - | −/−/− | PKHD1 exon 32/NM_138694 c4870 C>T p.(Arg162Trp) heterozygous |
| 16/F | 13.5/0.5 | Abdominal mass | 24/16 | 13.9/0.48 | Kidney | Kidney | - | +/−/− | PKHD1 exon 34 c.5480C>T, p.Thr1827 homozygous |
| 17/M | 12/2 | Abdominal mass | 31/15 | 16/0.4 | Kidney | Kidney | - | −/+/− | PKHD1/NM_138694/exon 23 c.2341C>T p.(Arg781) nonsense heterozygous |
| 18/M | 9.5/0 | Incidental | 28/10 | 16.5/2.02 | Kidney | Kidney | - | −/−/− | No mutation |
| 19/F | 16/0 | Incidental | 34/14 | 20/0.7 | Kidney | Kidney | - | +/+/− | HNF1β mutation |
| 20/M | 13.5/0 | Incidental | 34/7 | 4/0.6 | Kidney | Kidney | - | −/−/− | HNF1β.c 434T>A,p.leu145GI |
| 21/M | 10/5 | Abdominal mass | 18/8 | 5/0.5 | Kidney | Kidney | - | −/−/− | COL4A3 NM_000091 exon 28 c.2072A>T p.(Asp691Val) missense heterozygous |
| 22/M | 7/0 | Abdominal mass | 48/12 | 13.8/1.17 | Kidney | Kidney | - | −/−/− | No mutation |
| 23/F | 10/3 | Incidental | 36/18 | 10/0.3 | Kidney | Kidney | - | −/+/− | PKHD1(NM_001009944.3):c.10280dupC (p.Ser3428ValfsTer5) |
M: male, F: female, AST: aspartate aminotransferase, ALT: alanine aminotransferase, BUN: blood urea nitrogen, Cre: creatinine, GI: gastrointestinal, KFT: kidney function test.
In three patients, CHF was diagnosed prior to ARPKD; in the remaining patients, ARPKD was diagnosed first. Kidney and liver ultrasonography findings are presented in Table 2. Bilateral renal enlargement with millimetric cysts was observed in most cases. Eleven patients with ARPKD (47.8%) had hypertension and were treated with single-pill angiotensin-converting enzyme inhibitors. Echocardiography in patients with hypertension revealed no evidence of left ventricular hypertrophy. Parental consanguinity was present in 10 cases (43.5%).
Table 2. Kidney–liver ultrasonography findings throughout the process and support requirements of the patients.
| Patient | Kidney | GFR | Proteinuria | Liver | KRT/Tx/operation |
|---|---|---|---|---|---|
| 1 | Bilateral moderately enlarged kidneys | 150 | 0.06 | Pre-tx: Left liver lobe hypertrophy, heterogeneity and granularity in the liver, and splenomegaly | Liver tx |
| Post-tx: Normal | |||||
| 2 | Bilateral moderately enlarged kidneys and multiple millimetric cysts | 65 | 0.15 | Intrahepatic cystic dilatations (Caroli disease), splenomegaly | - |
| 3 | Bilateral multiple millimetric cysts | 84 | 0.19 | Heterogeneity in liver parenchyma, cavernous transformation in the portal vein, and splenomegaly | - |
| 4 | Bilateral multiple millimetric cysts | 100 | 0.18 | Heterogeneity in liver parenchyma, cavernous transformation in the portal vein, and massive splenomegaly | Splenectomy |
| 5 | Bilateral enlarged kidneys and multiple millimetric cysts | 140 | 0.14 | Heterogeneity in liver parenchyma, Mirizzi syndrome | Cholecystectomy |
| 6 | Bilateral multiple millimetric cysts | 80 | 0.57 | Heterogeneity in liver parenchyma, splenomegaly | - |
| 7 | Bilateral enlarged kidneys and multiple millimetric cysts | 71 | 0.27 | Heterogeneity in liver parenchyma | - |
| 8 | Bilateral enlarged kidneys and multiple millimetric cysts | 53 | 0.12 | Intrahepatic cystic dilatations (Caroli disease), splenomegaly | - |
| 9 | Bilateral enlarged kidneys and multiple millimetric cysts | 45 | 0.13 | Heterogeneity in liver parenchyma, splenomegaly | - |
| 10 | Bilateral enlarged kidneys and multiple millimetric cysts | 89 | 0.19 | Intrahepatic cystic dilatations (Caroli disease) | - |
| 11 | Pre-tx: Bilateral enlarged kidneys and multiple millimetric cysts | 10 | 3.90 | Pre-tx: Heterogeneity in liver parenchyma, massive ascites | Simultaneous liver and kidney tx followed by hemodialysis |
| Post-tx: Reflux nephropathy | Post-tx: Normal | ||||
| 12 | Pre-tx: Bilateral enlarged kidneys and multiple millimetric cysts | 56 | 0.26 | Heterogeneity and cysts in liver parenchyma | Kidney tx |
| Post-tx: Normal | |||||
| 13 | Bilateral enlarged kidneys and multiple millimetric cysts | - | - | Normal | Death (at 4 mo) |
| 14 | Increased echogenicity of the kidneys | 99 | 0.42 | Heterogeneity and granularity in the liver, splenomegaly | - |
| 15 | Bilateral multiple millimetric cysts | 200 | 0.27 | Normal | - |
| 16 | Increased echogenicity of the kidneys | 122 | 0.14 | Normal | - |
| 17 | Increased echogenicity of the kidneys | 148 | 0.11 | Normal | - |
| 18 | Bilateral multiple millimetric cysts | 60 | 0.18 | Normal | - |
| 19 | Bilateral multiple millimetric cysts | 128 | 0.26 | Normal | - |
| 20 | Bilateral multiple millimetric cysts and increased echogenicity of the kidneys | 55 | 0.11 | Normal | - |
| 21 | Bilateral multiple millimetric cysts and increased echogenicity of the kidneys | 133 | 0.16 | Normal | - |
| 22 | Bilateral multiple millimetric cysts and increased echogenicity of the kidneys | 86 | 0.32 | Normal | - |
| 23 | Bilateral multiple millimetric cysts | 160 | 0.22 | Normal | - |
KRT: kidney replacement therapy, Tx: transplantation, GFR: glomerular filtration rate (GFR and proteinuria are the current values of the patients).
Thirteen patients had combined CHF and ARPKD, while 10 had isolated ARPKD. Three patients with CHF also had Caroli syndrome. Upper gastrointestinal endoscopy identified esophageal varices in eight patients with CHF (61.5%), and three required variceal band ligation. All patients with liver involvement also had kidney disease; however, not all patients with cystic kidney disease exhibited liver pathology. Table 3 compares clinical outcomes between patients with combined CHF and ARPKD and those with isolated ARPKD. More severe renal impairment was observed in the combined group.
Table 3. Comparison of the groups according to clinical outcomes.
| Prognostic parameters | CHF+ARPKD 13 (56.5) | Isolated ARPKD 10 (43.5) | p-value |
|---|---|---|---|
| GFR | 80.15±37.74 | 135.85±42.54 | 0.010* |
| Creatinine | 1.10 (0.60–5.90) | 0.67 (0.37–0.85) | 0.003* |
| Proteinuria | 0.19 (0.06–3.90) | 0.18 (0.11–0.27) | 0.660 |
| Hypertension | 8 (61.5) | 3 (30.0) | 0.360 |
| Portal hypertension | 8 (61.5) | 0 (0.0) | - |
Values are presented as mean±standard deviation, mean (range), or number (%).
CHF: congenital hepatic fibrosis, ARPKD: autosomal recessive polycystic kidney disease, GFR: glomerular filtration rate.
*p-values that are significant are indicated.
Three patients required organ transplantation. One patient (Patient 1) underwent liver transplantation at age 12 (8 years after diagnosis) due to recurrent esophageal variceal bleeding. Patient 12 received a kidney transplant at age 4 (4 years after diagnosis), and Patient 11 underwent simultaneous liver and kidney transplantation at age 4 (3.5 years after diagnosis). Post-transplantation outcomes were generally favorable; however, the patient who underwent simultaneous liver and kidney transplantation developed reflux nephropathy and has been undergoing hemodialysis for 10 months. All three transplant recipients were in the combined CHF and ARPKD group.
All patients except one underwent genetic testing. PKHD1 mutations were detected in most cases. Patients 12 and 13 were siblings; Patient 13 died from respiratory failure at 4 months of age, and genetic testing could not be performed. Genetic analysis of Patient 14 revealed heterozygosity for an ATP7B variant, indicating carrier status for Wilson disease. Patient 21 had a concurrent diagnosis of familial Mediterranean fever. Patient 19 carried an HNF1β mutation associated with diabetes. Overall, PKHD1 mutations were found in 13 patients (62%), while no mutations were identified in five patients. Clinical outcomes were compared between patients with and without PKHD1 mutations, but no statistically significant differences were observed. The mean follow-up duration was 9±5.2 years.
DISCUSSION
This study provides valuable real-world data on the clinical spectrum of these rare ciliopathies. Our primary finding is that patients with combined CHF and ARPKD exhibit a more severe clinical phenotype, characterized by a significantly higher burden of portal hypertension and an exclusive need for organ transplantation compared with those with isolated ARPKD. This finding highlights that while renal disease often dictates the initial diagnosis, progressive liver involvement is a key determinant of long-term morbidity [14].
Our clinical findings are consistent with and expand upon existing literature. The mortality observed in one infant due to respiratory failure from massively enlarged kidneys aligns with outcomes reported in the most severe neonatal forms of ARPKD [14]. The prevalence of hypertension in our cohort (43.5%) is below the reported rates in pediatric ARPKD populations, which often range from 55% to 100% [15]. This lower rate may be attributable to the relatively small sample size. The pathophysiology of hypertension in ARPKD is multifactorial, with volume overload and activation of the renin–angiotensin–aldosterone system considered major contributors. The need for liver or kidney transplantation due to recurrent variceal bleeding or end-stage kidney disease in our patients is also consistent with reports from other pediatric cohorts, such as the series published by Dorval et al. [16].
The genetic findings of our cohort underscore the complexity of genotype–phenotype correlations in these conditions. As expected, PKHD1 mutations were most prevalent, particularly among patients with combined CHF and ARPKD. The identification of HNF1β mutations in two patients with isolated kidney involvement is consistent with its recognized association with renal cysts and diabetes [17,18]. Similarly, the detection of a TMEM67 mutation in a patient with hepatic fibrosis aligns with its known role in ciliary function and ductal plate malformation [19]. The presence of a heterozygous COL4A3 mutation in one patient—typically associated with Alport syndrome—is noteworthy. Recent studies have reported an increased prevalence of kidney cysts in COL4A3/COL4A4 carriers, indicating potential overlapping pathogenic pathways [20]. The absence of identifiable mutations in five patients highlights the limitations of current genetic testing, which may fail to detect deep intronic variants or mutations in novel genes not yet associated with these disorders.
A critical clinical implication of our findings is the confirmation that normal liver enzyme levels and radiological imaging do not exclude underlying CHF, particularly in the early stages. Liver involvement may remain silent for years before progressing to portal hypertension. This reinforces the need for routine, long-term hepatobiliary surveillance in all patients diagnosed with ARPKD [6]. Furthermore, while advanced imaging plays a central role in diagnosis and monitoring, the importance of a comprehensive physical examination—especially for detecting subtle signs such as hepatosplenomegaly—cannot be overstated. This step is particularly relevant as clinical practice increasingly incorporates telemedicine and imaging-based assessments [21].
This study has some notable strengths, including its long-term follow-up within a single center, which ensured the use of consistent diagnostic criteria, imaging protocols, and management strategies across all patients. This uniformity enhances the reliability of the clinical and genetic data and enables meaningful comparison between patient subgroups. Moreover, the inclusion of detailed phenotypic, genetic, and longitudinal outcomes offers valuable real-world insight into the natural history of CHF and ARPKD. However, certain limitations should be acknowledged. The retrospective study design and small sample size limit the statistical power of our comparative analyses and preclude definitive conclusions regarding genotype–phenotype correlations. Future prospective, multi-center studies with larger cohorts are needed to enable more robust statistical evaluation and to further elucidate the natural history of these conditions. Additionally, advanced genomic techniques, such as whole-genome sequencing, may help identify the genetic basis in patients who currently lack detectable mutations.
Conclusion
Patients with combined CHF and ARPKD experience a greater disease burden, driven primarily by complications related to portal hypertension. Although renal involvement may be the initial presenting feature, vigilant and lifelong surveillance for liver disease remains essential. A collaborative, multidisciplinary approach involving pediatric nephrologists and gastroenterologists is critical for effectively managing the complex and varied manifestations of these challenging ciliopathies.
Footnotes
Funding: None.
Conflict of Interest: The authors have no financial conflicts of interest.
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