A recent NIH study (A Strongin et al. JPGN 2018; 66: 428-35) provides prospectively-collected data from 100 individuals (mean age 9.1 years) with Joubert syndrome (JS). ( of the patients were >20 years old.
Background: JS is classified as a ciliopathy as mutations in JS genes result in nonmotile cilia. Clinical features in this autosomal recessive condition include the following:
- MRI finding of a “molar tooth sign” caused by cerebellar vermis hypoplasia, horizontally-oriented cerbellar peducles, and a deep interpeduncular fossa
- Ocular features: retinal dystrophy, colobomas
- Renal: nephronophthisis, polycystic kidneys
- Skeletal abnormalities including polydactaly
- Hepatic: congenital hepatic fibrosis (CHF). CHF typically causes noncirrhotic portal hypertension and generally maintain synthetic function and do not progress to cirrhosis
Study Key Findings:
- 43 (43%) had liver involvement indicated by elevated liver enzymes, and/or liver hyperechogenicity and/or splenomegaly
- 13 (13%) developed probable portal hypertension; this group had more significant elevations in alkaline phosphatase (269 vs 169), ALT (92 vs 42), AST (77 vs 40) and GGT (226 vs 51)
- The portal hypertension group were much more likely to have TMEM67 gene mutation
- Probable portal hypertension was associated with renal involvement (P=0.001)
- None of the patients with JS had macrocystic liver disease (which likely indicates a low risk of cholangitis)
The authors note that previous estimates of liver disease with JS of 10-15% are likely an underestimate and that “hepatic disease becomes more noticeable later in life.” In their discussion, they describe the limitations of their study which includes ascertainment bias as their cohort may differ significantly from those who have not bee brought to the attention of the NIH.
My take: JS patients are at increased risk for hepatic disease/portal hypertension, particularly at older ages. The optimal surveillance strategy remains undefined.
Related blog posts:
Tanyard Creek Park
In a previous blog entry (Hepatic ciliopathies), I briefly discussed congenital hepatic fibrosis (CHF). A more detailed review and handy reference: Srinath A, Shneider BL. JPGN 2012; 54: 580-87.
This invited review details information related to 1230 CHF patients from 155 articles (available at http://links.lww.com/MPG/A88). Median and mean age of diagnosis were 2 and 11.2 years respectively.
Distribution of CHF cases/associated conditions: 118 isolated CHF, 788 autosomal recessive polycystic kidney disease, 315 with Caroli disease/syndrome, 9 with type V choledochal cyst
- Sequelae of portal hypertension in 409 patients: 164 with varices, 74 with bleeding varicose, 81 underwent portosystemic shunting. Portal hypertension itself was identified in 71-97% depending on the patient subset examined.
- Cholangitis in 152 patients –often recurrent. This was fatal in 3 of 23 children after renal transplantation.
- Malignancy in 21 patients (2%). 19 were cholangiocarcinoma. Of these cases, 10/19 had Caroli disease/syndrome, 7 had isolated CHF, 1 had ARPKD, and 1 had Type V choledochal cysts. Youngest patient with cholangiocarcinoma was 33 years, all other cases involved patients >40 years.
Transplantation: Isolated kidney 91 (95% in ARPKD), Isolated liver 173 (87% had Caroli), Combined 23. Three renal patients subsequently had combined transplantation.
Other important points:
- CHF is not ‘typically associated with progressive hepatic insufficiency.’ Only rarely is hepatic synthetic function compromised
- Predisposition to cholangitis may affect transplantation decisions and timing
As our understanding of pathophysiology improves, frequently this results in reclassification of diseases. Perhaps the best example in pediatric hepatology is gestational alloimune liver disease/congenital alloimmune hepatitis, formerly called neonatal hemochromatosis (see previous post). Hepatic ciliopathies are less commonly discussed and thus far have not resulted in abandoning previous nomenclature. These hepatic ciliopathies are related to fibrocystic disease proteins which localize to the primary cilia. Ductal plate malformation is the main pathology that underlies the liver disease in ciliopathies. The characteristics of one of these disorders, congenital hepatic fibrosis (CHF) in autosomal dominant polycystic kidney diseae (PKD) involving 19 patients is described in this month’s JPGN (JPGN 2012: 54: 83-89). Portal hypertension was the main manifestation. “Hepatocellular function was preserved and liver enzymes were largely normal.” In patients with AD-PKD-CHF, this was due to PKD1 mutations with probable contributions from modifier genes. One interesting finding was that in the identified families, the parents who were affected by polycystic kidney disease did not have CHF.
Although this study demonstrates that CHF and portal hypertension can occur with AD-PKD, CHF and portal hypertension are a characteristic finding with AR-PKD. With AD-PKD, the liver cysts originate from biliary microhamartomas (von Meyenburg complexes) and are not in continuity with the biliary tree. In contrast, patients with AR-PKD have cystic dilatations of the biliary system; this combination is called Caroli syndrome. Due to these differences, unlike AR-PKD, AD-PKD does not typically result in portal hypertension.
Additional references on congenital hepatic fibrosis:
- -Hepatology 2010; 52: 2223. Review. Medical/Surgical & Tx options.
- -Am J Med Genet C Semin Med Genet 2009; 151C: 296-406. Liver disease and kidney disease in ciliopathies.
- -NEJM 2008; 359: 1477. Review of autosomal dominant polycystic kidney disease. ~80% develop liver cysts.
- -NEJM 2007; 356: 1560. Nice pic of resected liver with polycystic liver disease in 51 year old.
- -J Pediatr 2006; 149: 159. Review and NIH protocol for enrolling patients. Clinical GI issues: recurrent cholangitis, portal htn, cholelithiasis, and cholangiocarcinoma.
- -Pediatr Transplantation 2005; 9: 634-9.
- -Hepatology 2004; 40: 774-82.
- -Surg Endosc 2005; 19: 130-32.
- -Gastorenterol Clin N Am; 2003; 32: 857-75. “Heritable disorders of the bile ducts”