Question: A woman aged 18 years, who had undergone splenectomy and had liver cirrhosis, was admitted to the hospital. Her splenectomy was carried out two years ago as a treatment for severe thrombocytopenia, portal hypertension, and several formations of collateral vessels, and the postoperative pathologic findings revealed chronic congestive splenomegaly. On admission, there were not any apparent clinical signs of liver disease, and silybin was used as the drug treatment in the meantime. Regular laboratory tests revealed the patient’s red blood cell count was 4.15 × 1012/L, hemoglobin level 126.00 g/L, white blood cell count 8.42 × 109/L, and platelet count 442.00 × 109/L, which supported the spleen’s resection. In addition, the patient’s bleeding and coagulation functions were examined, and there were no abnormal outcomes. The result of biochemical tests revealed mild liver dysfunction and normal renal function with alanine transaminase (ALT) of 48 U/L, aspartate transaminase (AST) 24 U/L, AST/ALT 0.50, glutamyl transpeptidase 150 U/L, alkaline phosphatase 80 U/L, total bilirubin 12.8 μmol/L, total protein 64.2 g/L, albumin 37.1 g/L, international normalized ratio 1.03, glomerular filtration rate 184 mL/min, and creatinine 40 μmol/L. In contrast, no antinuclear antibodies, autoimmune antibodies, or hepatitis viruses were detected. An autoimmune liver disease test was also negative. Contrast-enhanced computed tomography (CECT) exhibited multiple open collateral circulations and dilated branches of the portal vein in the hepatic hilar region, both of which are suggestive of portal hypertension. The right-left and caudate lobes were also proliferated. The coronal CECT simultaneously highlighted the columnar dilation of the intra- and extra-hepatic bile ducts. There were multiple bilateral renal cysts in the patient. In addition, owing to splenectomy, there was no spleen in these images (Figure A). A percutaneous liver biopsy was done, and the results showed enlarged portal areas, broad fibrous septa, a few highly dilated interlobular veins, and a significantly increased number of small biliary ducts of various shapes. Mallory bodies and overt hepatic steatosis were not seen, nor was there any apparent cholestasis. There was a variable amount of fibrosis around the small bile ducts. The fibrosis in the portal sites was emphasized by both Masson and Sirius red staining. There were few CD68+ Kupffer cells in the hepatocyte immunohistochemistry, and CK7 immunohistochemical staining revealed bile ducts that were proliferating (Figure B). What is the most likely cause of having liver fibrosis for 2 years? Look on page 342 for the answer and see the Gastroenterology website (www.gastrojournal.org) for more information on submitting to Gastro Curbside Consult. Laboratory studies confirmed the CECT results of this patient, which included cirrhosis, dilated bile ducts, and multiple renal cysts. After eliminating the common causes of cirrhosis, such as viruses, drugs, alcohol, and cholestasis, the results of pertinent examinations may still be attributed to congenital hepatic fibrosis (CHF) even though this patient was a female adolescent, and the majority of patients with CHF are neonates. Consequently, a liver biopsy was required as the criterion standard for diagnosing CHF. Liver biopsy revealed a significant amount of fibrosis in the portal areas, normal hepatic lobules structure, and proliferation of biliary ducts consistent with CHF. However, autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and Caroli’s disease frequently coexist with CHF.1Hasbaoui B.E. Rifai Z. Saghir S. et al.Congenital hepatic fibrosis: case report and review of literature.Pan Afr Med J. 2021; 38: 188Crossref PubMed Scopus (2) Google Scholar Imaging results showed that the intrahepatic bile ducts had columnar dilation rather than cystic dilation, which could rule out Caroli’s disease. In the meantime, we found polycystic kidney disease (PKD) in line with CT imaging of the kidney. Regarding CHF, there are 4 clinical forms: portal hypertensive, cholangitic, mixed, and latent. Based on her clinical symptoms, which included portal hypertension and dilation of extra- and intra-hepatic bile ducts, this girl was diagnosed as having mixed CHF. A genetic study should always be performed when CHF potential is present because it will help to determine the risk and even guide treatment decisions. Genetic analysis of this patient’s family revealed 2 distinct mutations in the PKHD1 gene, which were determined to be compound heterozygous mutations consisting of a paternally inherited mutation (c.3629-6C>G) and a maternally inherited mutation (c.5117T>A, p.V1706D). The former mutation upstream of exon 32 may affect the correct splicing of PKHD1 before mRNA (Figure C). The latter mutation in exon 32 results in an amino acid change from valine to aspartate (Figure D). Both her elder brother and niece carried the mutation c.3629-6C>G inherited from her father, whereas her younger brother had no mutation in the PKHD1 gene. In the meantime, all of the families, with the exception of the patient, had a negative phenotype, suggesting that this disease was compatible with autosomal recessive rules and avoiding the probability of ADPKD. As a result, this patient was diagnosed with CHF coexisting with ARPKD. The majority of CHF and ARPKD diagnoses occur during the neonatal period, with an estimated prevalence of 1 in 20,000 live births.2Turkbey B. Ocak I. Daryanani K. et al.Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF).Pediatr Radiol. 2009; 39: 100-111Crossref PubMed Scopus (87) Google Scholar The 2 novel positions of mutation, including a missense and a noncanonic splice-site variant, were not previously reported in the literature, and the case was distinguished by the maturity onset. In contrast to the families with only 1 genetic mutation, this patient had a genetic condition caused by compound heterozygous variants at 2 different genetic loci, which may suggest that the interaction of multiple types of gene variants should be further investigated. With the exception of PKHD1, other gene mutations leading to CHF, including ZFYVE19, NPHP3, etc, were also analyzed, and the results were negative. Mutations in PKHD1, which encodes fibrocystin localized to primary cilia/basal body, could cause PKD and ductal plate malformation. To increase the accuracy of the identification of various congenital diseases, especially those without neonatal onset, we should focus on CHF that manifests in adolescents. Meanwhile, it is important to note that other rare genetic mutations could cause similar clinical manifestations in addition to the homozygous mutations that have been reported to cause CHF in PKHD1.3Xiao F.F. Wang Y.Z. Dong F. Li X.L. et al.Congenital hepatic fibrosis in a young boy with congenital hypothyroidism: a case report.World J Clin Cases. 2021; 9: 1475-1482Crossref PubMed Scopus (1) Google Scholar Compound heterozygous mutations can also present with the identical clinical presentations, which might result from the interaction of different variant positions in PKHD1.
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Feb 13, 2024
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