Association Between Nephronophthisis (NPHP) and Intrahepatic Stones
There is no established association between nephronophthisis (NPHP) and intrahepatic stones. NPHP is associated with hepatic fibrosis and congenital hepatic fibrosis, but not with intrahepatic stone formation 1, 2.
NPHP-Associated Hepatic Manifestations
Hepatic fibrosis, not intrahepatic stones, is the documented liver complication in NPHP:
- NPHP can present with associated hepatic fibrosis in approximately 10-15% of patients, particularly in syndromic forms 3, 4
- Mutations in NPHP3 specifically cause nephronophthisis with associated hepatic fibrosis or tapeto-retinal degeneration 1
- Hypomorphic mutations in MKS3/TMEM67 cause NPHP with liver fibrosis (NPHP11), where congenital liver fibrosis is a recognized feature 2
- The mouse ortholog Nphp3 is expressed in liver and biliary tract tissues, explaining the hepatobiliary involvement 1
Distinction from Other Ciliopathies
NPHP is classified as a ciliopathy with specific extrarenal manifestations that do not include cholelithiasis:
- NPHP-related ciliopathies (NPHP-RC) involve retina (Senior-Løken syndrome), CNS (Joubert syndrome), liver fibrosis (Boichis and Arima syndromes), or bone abnormalities 3, 5
- The liver involvement in NPHP manifests as fibrosis, not as stone formation or cholestasis 4
- NPHP is explicitly listed among syndromic ciliopathies that can mimic ADPKD, with hepatic fibrosis being the recognized hepatic phenotype 6
Clinical Pitfall to Avoid
Do not confuse hepatic fibrosis with intrahepatic stones:
- If a patient with NPHP presents with intrahepatic stones, investigate alternative etiologies unrelated to the NPHP diagnosis 1, 2
- Intrahepatic stones are associated with conditions like recurrent cholangitis, parasitic infections, or primary sclerosing cholangitis—not ciliopathies 6
- The presence of intrahepatic stones in an NPHP patient should prompt evaluation for concurrent, independent hepatobiliary pathology 2