The 12-year-old brother (III-2) of case III-1 also had multiple macrocysts on both kidneys (Fig. 2B). On USG, the liver was mildly hyperechogenic. Spleen volume, calculated based on MRI imaging, was at the upper end of normal at 258 mL (Fig. 2B). Serum chemistries were normal (Table 1).
The NIH evaluation of the 14-year-old boy (III-3) revealed a healthy-appearing teenager with normal growth. He had multiple cysts in both kidneys (Fig. 2C). On USG, liver was hyperechogenic. MRI-based liver and spleen volumes were increased at 1899 and 931 mL, respectively (20–22) (Fig. 2C). Liver enzymes and synthetic functions were normal (Table 1).
All of the coding exons of the PKD1 and PKHD1 genes were sequenced in the father and the 3 children. All of the 4 patients were heterozygous for a 7-bp deletion at position g.17554 in exon 5 of the PKD1 gene (Fig. 1, family 1). Sequencing of the 66 coding exons of the PKHD1 gene revealed no mutations.
In Family 2 (Fig. 1), 4 individuals including the mother (II-2), both of her children (III-1, III-2), and the maternal grandfather (I-1) had typical renal findings of ADPKD. The mother had CHF complicated by PH, whereas 3 other individuals with ADPKD had normal-sized spleens (Table 2, Fig. 2D and E).
The mother (II-2) presented with splenomegaly at age 6 months. Liver biopsy was consistent with CHF. She developed esophageal varices that required banding throughout childhood and into adulthood. In addition, she had 3 episodes of cholangitis. The NIH evaluation at age 33 revealed a distended abdomen. The liver was palpable 13 cm below the xiphoid with firm consistency. The spleen was 12 cm palpable below the left costal margin. Based on MRI images, liver and spleen volumes were markedly increased at 2310 and 908 mL, respectively (20–22). USG showed increased liver echogenicity with 3 cysts in the posterior right lobe; on magnetic resonance cholangiopancreatography (MRCP) these cysts were in continuity with the bile tree. The kidneys were markedly enlarged with multiple macrocysts (Fig. 2D). Liver function tests were normal. The patient had thrombocytopenia and leukopenia due to hypersplenism (Table 1).
Her 16-year-old daughter (III-1) (Fig. 2E) and 14-year-old son (III-2) both had multiple renal cysts. Their liver ultrasound pattern, biliary system, and spleen size were normal, and serum chemistries were unremarkable (Table 1). The mother and both children had a missense mutation at position g425323 in exon 61 of the PKD1 gene, replacing a conserved serine with arginine (Fig. 1, family 2). Sequencing of the PKHD1 gene did not reveal any mutations.
In this family, the proband (II-2), a 36-year-old female with ADPKD, was diagnosed with CHF at age 33, based on a liver biopsy prompted by splenomegaly (Table 2, Fig. 2F). Her mother died of renal complications of ADPKD; she did not have PH. At the NIH Clinical Center, USG of patient II-2 showed moderately echogenic liver with coarsening of the echotexture and several small cysts. MRCP showed no dilatation of the bile ducts. There was extensive collateral formation. Based on MRI imaging, the liver and spleen volumes were increased at 1687 and 1090 mL, respectively (20,22). The kidneys contained multiple cysts. Leukocyte and platelet counts were low due to hypersplenism (Table 1). The patient had mild postprandial hyperammonemia; other liver function tests and liver enzymes were normal. She had a missense mutation at position g.26918 in exon 15 of the PKD1 gene, replacing a conserved phenylalanine with cysteine (Fig. 1, family 3). Sequencing of the PKHD1 gene did not reveal any mutations.
In Table 2, we listed the characteristics of liver disease and family history of 19 patients with ADPKD associated with CHF complicated by PH, from 14 ADPKD families, reported in 7 publications between 1984 and 2010 (13–19). Other reports were reviewed but not included because the evidence for autosomal dominant inheritance of PKD was not convincing (23–27). All of the 19 patients had family histories of ADPKD. There were 9 boys and 10 girls. Age at the time of evaluation ranged from 3 to 36 years (mean ± SD, 18.7 ± 10.5) (Table 2). All of the 19 patients had splenomegaly; in many patients, an enlarged spleen was first noted at birth or in early childhood. Five patients had portosystemic shunt placement and 2 had splenectomy. Histopathological evaluation of the liver showed CHF in all of the 17 patients who underwent liver biopsy (Table 2). Age at the time of the liver biopsy ranged from 1 to 33 years (14.9 ± 11.1) in 14 patients for whom this information was available. Thirteen of the 15 patients evaluated had esophageal varices; 7 had bleeding from esophageal varices, the youngest at age 4 years (Table 2). The majority of the patients had decreased platelet and white blood cell counts due to hypersplenism. Synthetic function of the liver was preserved and liver enzymes were normal or midly elevated (Table 2). In all of the 14 families, there were one or more family members with ADPKD but without CHF/PH; 2 fathers and a mother with ADPKD from 3 families had liver biopsies that did not show CHF (Table 2).
Although both ADPKD and ARPKD are associated with liver involvement, the characteristics of liver disease in these 2 types of PKD are quite different. The liver disease of ARPKD involves CHF that is often complicated by PH (28,29) and its consequent hypersplenism and esophageal varices. Many patients with ARPKD also have cystic dilatations of the intrahepatic bile ducts that are continuous with the biliary system; a combination referred to as Caroli syndrome (30,31). In contrast, the liver cysts of ADPKD originate from biliary microhamartomas (von Meyenburg complexes) that are embedded in fibrous tissue; hence, they are not in continuity with the intrahepatic biliary tree (32–34). Imaging of the intrahepatic biliary system, preferably performed using MRCP because endoscopic pancreatiocholangiography increases the risk for cholangitis, is useful in the differential diagnosis (33). In ADPKD, enlarged liver cysts cause complications that are largely due to a mass effect, including chronic upper abdominal pain and distension, early satiety, nausea and dyspnea, and rare cases of hepatic venous outflow obstruction (2,35,36). PH caused by CHF is not typical for ADPKD.
The proteins encoded by the PKD genes (polycystin-1, polycystin-2, and fibrocystin) localize to the primary cilia. Intact cilia–based signaling via the PKD proteins is required for normal development of the portobiliary system (37,38) and renal tubules (39). Dysfunction of cholangiocyte cilia results in defective remodeling of the developing biliary system that is referred to as “ductal plate malformation” (DPM) (28,40,41). DPM is the main pathology that underlies the liver disease in ciliopathies (28). It is characterized by retention of excessive numbers of primitive bile duct remnants in their original, peripheral, interrupted ring-like position. Depending on the level of the affected portobiliary tree, DPM results in a spectrum of abnormalities ranging from CHF (microscopic bile ducts), to CHF/CS (microscopic and medium-size bile ducts), to Caroli disease (CD) (medium and large bile ducts) (40). Liver biopsy in CHF shows abnormal portal tracts with an excessive number of abnormally shaped embryonic bile ducts, abnormal portal vein, and periportal fibrosis without inflammation (29). The severity of DPM and the level of the portobiliary tree affected by DPM vary within and among individual ciliopathies. The isolated liver cysts in the PLD associated with ADPKD probably represent DPM affecting the most peripheral end of the biliary system (40,42).
Typically, kidney and liver disease of ADPKD becomes symptomatic in adulthood. However, many patients with ADPKD-CHF presented with PH at birth or in early childhood (Table 2). Out of the 13 patients for whom age at the time of liver biopsy was available, 9 were younger than 18 years, including patients at ages 1 and 3 years (Table 2). Three of the 7 patients with esophageal variceal bleeding were at ages 4, 12, and 16 years at the time of the bleed. Histopathological and other clinical characteristics of CHF in ADPKD were similar to those of CHF in ARPKD (Table 2). Thrombocytopenia and neutropenia caused by hypersplenism were common. Synthetic function of the liver was preserved and liver enzymes were normal or only mildly elevated (Table 2).
The presence of CHF in these rare ADPKD families raises the question whether the PKD in these families is caused by one of the known genes of ADPKD (PKD1 or PKD2 that typically cause ADPKD associated with PLD) or by another yet to be identified gene(s). The first indirect molecular data on this came from the linkage of ADPKD-CHF to chromosome 16, where PKD1 gene resides (15) (Table 2). By documenting that all of the affected individuals in our 3 families had pathogenic mutations in PKD1, we show for the first time that the PKD in families with ADPKD-CHF is due to PKD1 mutations (Table 2). Given that only some affected individuals develop CHF, despite the fact that all of them (those with PKD and typical liver disease in the form of PLD and those with PKD and CHF) carry the same mutation in PKD1, suggests that the atypical nature of liver disease in these families is not explainable by the location or type of the PKD1 mutation. In all of the 14 families with ADPKD-CHF, the parents of the index cases had PKD but did not have CHF; liver biopsies of 2 fathers and a mother with PKD did not show CHF (Table 2).
There were several families in which several siblings had ADPKD with CHF (Table 2). This suggests contribution of modifier mutation(s) in other gene(s). Given that CHF is observed in both boys (9) and girls (10) with ADPKD, these modifier genes are probably located on autosomal chromosomes and less likely X-linked. PKHD1 and other ciliopathy genes are likely candidates for such modifiers. We sequenced PKHD1 in our 3 families and did not identify any pathogenic mutations. However, it remains possible that a variant in the noncoding parts of PKHD1 or a single-nucleotide polymorphism can be contributing.
In summary, CHF complicated by PH is a rare but potentially life-threatening complication of ADPKD. Increased liver echogenecity on USG, decreased platelet count, enlarged left lobe of liver, or enlarged spleen should alert physicians to this possibility. Upon diagnosis of an index case, other family members, especially siblings, should be evaluated for CHF/PH. We recommend abdominal ultrasound and platelet count on siblings at the time of diagnosis of the proband. Repeat of these tests every 2 years would be warranted especially early in life, as some patients may progress slower than others. Abnormalities in these tests should prompt further work-up. Early diagnosis of CHF/PH in other family members with ADPKD can be lifesaving with appropriate monitoring and treatment of esophageal varices.
We thank the patients with ADPKD and families who generously participated in this investigation.
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Keywords:Copyright 2012 by ESPGHAN and NASPGHAN
autosomal dominant polycystic kidney disease; autosomal recessive polycystic kidney disease; congenital hepatic fibrosis; polycystic liver disease; portal hypertension