Congenital Hepatic Fibrosis and Portal Hypertension in Autosomal Dominant Polycystic Kidney Disease

O’Brien, Kevin; Font–Montgomery, Esperanza; Lukose, Linda; Bryant, Joy; Piwnica–Worms, Katie; Edwards, Hailey; Riney, Lauren C.; Garcia, Angelica; Daryanani, Kailash; Choyke, Peter L.; Mohan, Parvathi; Heller, Theo; Gahl, William A.; Gunay‐Aygun, Meral

doi:10.1097/mpg.0b013e318228330c

Cited by 40 publications

(21 citation statements)

References 39 publications

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“…In addition to the identified NPHP1 full gene deletion, the patient was also shown to harbor heterozygous substitutions in PKD1, BBS1, and INPP5E . The PKD1 substitution (p.Phe2132Cys) (dbSNP: rs150154235, https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=150154235, https://www.ncbi.nlm.nih.gov/clinvar/variation/431936/) identified in this patient was previously reported in the PKD Mutation Database as a “likely pathogenic mutation” . Although the detected BBS1 substitution (p.Val303Ala) (rs750668484 in NCBI (https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=750668484) has been previously reported as a heterozygous mutation (AGVGD class, C25; SIFT prediction, deleterious; MAPP prediction, good), its pathological significance is not yet clear .…”

Section: Discussionmentioning

confidence: 67%

PKD1 mutation may epistatically ameliorate nephronophthisis progression in patients with NPHP1 deletion

Watanabe

Ino

Fujimaru

et al. 2019

Clinical Case Reports

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Key Clinical Message We report a patient with adult‐onset nephronophthisis (NPHP) that was identified a homozygous full gene deletion of NPHP1 and a heterozygous PKD1 mutation. We suggest that the PKD1 mutation may have epistatically ameliorated NPHP disease progression and that the screening of larger cohorts for similar possible epistatic effects is needed.

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Section: Discussionmentioning

confidence: 67%

PKD1 mutation may epistatically ameliorate nephronophthisis progression in patients with NPHP1 deletion

Watanabe

Ino

Fujimaru

et al. 2019

Clinical Case Reports

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“…This model presents unique features compared to other experimental models of portal fibrosis, such as bile duct ligation, sclerosing cholangitis caused by multidrug resistance‐2 deficiency, or toxicants. In fact, in Pkhd1 del4/del4 mice, fibrosis is not related to a necroinflammatory or obstructive process and the evolution of biliary fibrosis is slow: it resembles that of human CHF, in which portal hypertension occurs in the absence of cirrhosis and is generally diagnosed only late in youth …”

Section: Discussionmentioning

confidence: 99%

Macrophage recruitment by fibrocystin‐defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis

et al. 2016

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Congenital Hepatic Fibrosis (CHF) is a disease of the biliary epithelium characterized by bile duct changes resembling ductal plate malformations and by progressive peribiliary fibrosis, in the absence of overt necroinflammation. Progressive liver fibrosis leads to portal hypertension and liver failure, however the mechanisms leading to fibrosis in CHF remain elusive. CHF is caused by mutations in PKHD1, a gene encoding for fibrocystin, a ciliary protein expressed in cholangiocytes. Using a fibrocystin-defective (Pkhd1del4/del4) mouse, which is orthologous of CHF, we show that Pkhd1del4/del4 cholangiocytes are characterized by a β-catenin-dependent secretion of a range of chemokines, including CXCL1, CXCL10 and CXCL12, which stimulate bone marrow-derived macrophage recruitment. We also show that Pkhd1del4/del4 cholangiocytes, in turn, respond to proinflammatory cytokines released by macrophages by up-regulating αvβ6 integrin, an activator of latent local TGFβ1. While the macrophage infiltrate is initially dominated by the M1 phenotype, the profibrogenic M2 phenotype increases with disease progression, along with the number of portal myofibroblasts. Consistent with these findings, clodronate-induced macrophage depletion results in a significant reduction of portal fibrosis and portal hypertension as well as of liver cysts. Conclusion our results show that fibrosis can be initiated by an epithelial cell dysfunction, leading to low-grade inflammation, macrophage recruitment and collagen deposition. These findings establish a new paradigm for biliary fibrosis and represent a model to understand the relationship between cell dysfunction, parainflammation, liver fibrosis and macrophage polarization over time.

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“…19 Proteins defective in other diseases associated with fibrocystic pathology, such as autosomal dominant polycystic kidney disease, nephronophthisis, Joubert syndrome, and Bardet–Biedl syndrome, also localize to the primary cilium; these disorders, along with ARPKD, are referred to as “ciliopathies.” 7,19 CHF also occurs in other ciliopathies, including Bardet–Biedl syndrome, Joubert syndrome, Meckel–Gruber syndrome, Jeune syndrome 7 and rare cases of autosomal dominant polycystic kidney disease. 20 …”

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confidence: 99%

Characteristics of Congenital Hepatic Fibrosis in a Large Cohort of Patients With Autosomal Recessive Polycystic Kidney Disease

et al. 2013

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BACKGROUND & AIMS Autosomal recessive polycystic kidney disease (ARPKD), the most common ciliopathy of childhood, is characterized by congenital hepatic fibrosis and progressive cystic degeneration of kidneys. We aimed to describe congenital hepatic fibrosis in patients with ARPKD, confirmed by detection of mutations in PKHD1. METHODS Patients with ARPKD and congenital hepatic fibrosis were evaluated at the National Institutes of Health from 2003 to 2009. We analyzed clinical, molecular, and imaging data from 73 patients (age, 1–56 years; average, 12.7 ± 13.1 years) with kidney and liver involvement (based on clinical, imaging, or biopsy analyses) and mutations in PKHD1. RESULTS Initial symptoms were liver related in 26% of patients, and others presented with kidney disease. One patient underwent liver and kidney transplantation, and 10 others received kidney transplants. Four presented with cholangitis and one with variceal bleeding. Sixty-nine percent of patients had enlarged left lobes on magnetic resonance imaging, 92% had increased liver echogenicity on ultrasonography, and 65% had splenomegaly. Splenomegaly started early in life; 60% of children younger than 5 years had enlarged spleens. Spleen volume had an inverse correlation with platelet count and prothrombin time but not with serum albumin level. Platelet count was the best predictor of spleen volume (area under the curve of 0.88905), and spleen length corrected for patient’s height correlated inversely with platelet count (R2 = 0.42, P < .0001). Spleen volume did not correlate with renal function or type of PKHD1 mutation. Twenty-two of 31 patients who underwent endoscopy were found to have varices. Five had variceal bleeding, and 2 had portosystemic shunts. Forty-percent had Caroli syndrome, and 30% had an isolated dilated common bile duct. CONCLUSIONS Platelet count is the best predictor of the severity of portal hypertension, which has early onset but is underdiagnosed in patients with ARPKD. Seventy percent of patients with ARPKD have biliary abnormalities. Kidney and liver disease are independent, and variability in severity is not explainable by type of PKHD1 mutation;

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Congenital Hepatic Fibrosis and Portal Hypertension in Autosomal Dominant Polycystic Kidney Disease

Abstract: 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.

Cited by 40 publications

References 39 publications

PKD1 mutation may epistatically ameliorate nephronophthisis progression in patients with NPHP1 deletion

PKD1 mutation may epistatically ameliorate nephronophthisis progression in patients with NPHP1 deletion

Macrophage recruitment by fibrocystin‐defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis

Characteristics of Congenital Hepatic Fibrosis in a Large Cohort of Patients With Autosomal Recessive Polycystic Kidney Disease

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