Congenital hepatic fibrosis and portal hypertension in autosomal dominant polycystic kidney disease

Abstract

Objectives: Autosomal dominant (ADPKD) and recessive (ARPKD) polycystic kidney diseases are the most common hepatorenal fibrocystic diseases (ciliopathies). Characteristics of liver disease of these disorders are quite different. All of the patients with ARPKD have congenital hepatic fibrosis (CHF) often complicated by portal hypertension. In contrast, typical liver involvement in ADPKD is polycystic liver disease, although rare atypical cases with CHF are reported. Our goal was to describe the characteristics of CHF in ADPKD.

Patients and methods: As a part of an intramural study of the National Institutes of Health on ciliopathies (www.clinicaltrials.gov, trial NCT00068224), we evaluated 8 patients from 3 ADPKD families with CHF. We present their clinical, biochemical, imaging, and PKD1 and PKHD1 sequencing results. In addition, we tabulate the characteristics of 15 previously reported patients with ADPKD-CHF from 11 families.

Results: In all of the 19 patients with ADPKD-CHF (9 boys, 10 girls), portal hypertension was the main manifestation of CHF; hepatocelllular function was preserved and liver enzymes were largely normal. In all of the 14 families, CHF was not inherited vertically, that is the parents of the index cases had PKD but did not have CHF-suggesting modifier gene(s). Our 3 families had pathogenic mutations in PKD1; sequencing of the PKHD1 gene as a potential modifier did not reveal any mutations.

Conclusions: Characteristics of CHF in ADPKD are similar to CHF in ARPKD. ADPKD-CHF is caused by PKD1 mutations, with probable contribution from modifying gene(s). Given that both boys and girls are affected, these modifier(s) are likely located on autosomal chromosome(s) and less likely X-linked.

FIGURE 1.

Pedigrees and DNA sequences displaying mutations in the PKD1 gene. Upper panel shows mutations in comparison with the normal control sequence (lower panel). The Sequencher software assigns letters other than A,T,C, or G to indicate heterozygous states. In family 1, the father (II-3) and all of the 3 children (III-1, III-2, and III-3) displayed a 7-base-pair deletion at position g.17554 (arrow) in exon 5, resulting in a frameshift. In family 2, the mother (II-2) and both the children (III-1 and III-2) had a missense mutation at position g.425323 (arrow) in exon 61, replacing a conserved serine with arginine. In family 3, patient II-2 had a missense mutation at position g.26918 (arrow) in exon 15, replacing a conserved phenylalanine with cysteine.

FIGURE 2.

Abdominal MRI images displaying kidney, liver, and spleen findings. All of the patients displayed polycystic kidneys. (A), (B), and (C) belong to the 3 siblings in family 1. Patient III-1, who underwent splenorenal shunt placement, had a mildly enlarged spleen (A). Patient III-2 had a normal-sized spleen (B). Patient III-3 had an enlarged spleen (C). In family 2, patient II-2 had an enlarged spleen (D), whereas her daughter (III-1) had a normal-sized spleen at age 16 (E). In family 3, patient II-2 also displayed splenomegaly (F).