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Peter L Choyke - One of the best experts on this subject based on the ideXlab platform.
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prospective evaluation of kidney and liver disease in autosomal recessive polycystic kidney disease Congenital Hepatic Fibrosis
Molecular Genetics and Metabolism, 2020Co-Authors: Nehna Abdul Majeed, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Theo Heller, Peter L Choyke, Peter Veppumthara, Ismail B Turkbey, William A Gahl, Meral GunayaygunAbstract:Abstract Background and objectives We have previously published the characteristics of kidney and liver disease in a cohort of 73 individuals with molecularly confirmed autosomal recessive polycystic kidney disease-Congenital Hepatic Fibrosis, based upon cross-sectional data. Here, we present prospective data on the same cohort. Design, setting, participants, and measurements Comprehensive biochemical and imaging data on progression of kidney and liver disease in 60 of the 73 patients were prospectively collected at the NIH Clinical Center on multiple visits between 2003 and 2019. Results and conclusions Of the 73 patients, 23 received a renal allograft at an average age of 17.5 years and 10 underwent liver transplantation at an average age of 20.3 years. Patients who presented perinatally and those who had corticomedullary disease required kidney transplantation significantly earlier. The mean eGFR slope in patients with corticomedullary disease was −1.6 ml/min/1.73 m2/y, in comparison to −0.6 ml/min/1.73 m2/y in those with medullary disease. Kidney size remained the same over time and normalized to the upper limit of normal by 20–25 years of age. The extent of renal disease on ultrasound remained largely unchanged; no patient progressed from the “medullary” to the “corticomedullary” group. There was no correlation between eGFR slope and kidney size. The synthetic function of the liver remained largely intact even in patients with advanced portal hypertension. Based on spleen length/height ratio, two thirds of patients had portal hypertension which remained stable in 39% and worsened in 61%. Patients with portal hypertension had lower platelet counts and relatively higher levels of AST, GGT, direct bilirubin and ammonia. The progression rates of kidney and liver disease were independent of each other. Patients with bi-allelic non-truncating PKHD1 variants had similar progression of kidney and liver disease in comparison to those who were compound heterozygous for a non-truncating and a truncating variant.
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characteristics of Congenital Hepatic Fibrosis in a large cohort of patients with autosomal recessive polycystic kidney disease
Gastroenterology, 2013Co-Authors: Meral Gunay Aygun, Baris Turkbey, Kailash Daryanani, Linda Lukose, Esperanza Font Montgomery, Maya Gerstein, Katie Piwnica Worms, Peter L Choyke, Roxanne Fischer, Isa BernardiniAbstract: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 ( R 2 = 0.42, P 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; ClinicalTrials.gov number, NCT00068224.
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Congenital Hepatic Fibrosis and portal hypertension in autosomal dominant polycystic kidney disease
Journal of Pediatric Gastroenterology and Nutrition, 2012Co-Authors: Kevin Obrien, Kailash Daryanani, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Katie Piwnicaworms, Hailey Edwards, Lauren Riney, Angelica Garcia, Peter L ChoykeAbstract: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.
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autosomal recessive polycystic kidney disease and Congenital Hepatic Fibrosis summary statement of a first national institutes of health office of rare diseases conference
The Journal of Pediatrics, 2006Co-Authors: Meral Gunayaygun, Lisa M Guaywoodford, Theo Heller, Peter L Choyke, Ellis D Avner, Robert Bacallao, Joseph T Flynn, Gregory G Germino, Peter C Harris, Julie R IngelfingerAbstract:Researchers and clinicians with expertise in autosomal recessive polycystic kidney disease and Congenital Hepatic Fibrosis (ARPKD/CHF) and related fields met on May 5-6, 2005, on the National Institutes of Health (NIH) campus for a 1.5-day symposium sponsored by the NIH Office of Rare Diseases, the National Human Genome Research Institute (NHGRI), and in part by the ARPKD/CHF Alliance. The meeting addressed the present status and the future of ARPKD/CHF research.
Meral Gunayaygun - One of the best experts on this subject based on the ideXlab platform.
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prospective evaluation of kidney and liver disease in autosomal recessive polycystic kidney disease Congenital Hepatic Fibrosis
Molecular Genetics and Metabolism, 2020Co-Authors: Nehna Abdul Majeed, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Theo Heller, Peter L Choyke, Peter Veppumthara, Ismail B Turkbey, William A Gahl, Meral GunayaygunAbstract:Abstract Background and objectives We have previously published the characteristics of kidney and liver disease in a cohort of 73 individuals with molecularly confirmed autosomal recessive polycystic kidney disease-Congenital Hepatic Fibrosis, based upon cross-sectional data. Here, we present prospective data on the same cohort. Design, setting, participants, and measurements Comprehensive biochemical and imaging data on progression of kidney and liver disease in 60 of the 73 patients were prospectively collected at the NIH Clinical Center on multiple visits between 2003 and 2019. Results and conclusions Of the 73 patients, 23 received a renal allograft at an average age of 17.5 years and 10 underwent liver transplantation at an average age of 20.3 years. Patients who presented perinatally and those who had corticomedullary disease required kidney transplantation significantly earlier. The mean eGFR slope in patients with corticomedullary disease was −1.6 ml/min/1.73 m2/y, in comparison to −0.6 ml/min/1.73 m2/y in those with medullary disease. Kidney size remained the same over time and normalized to the upper limit of normal by 20–25 years of age. The extent of renal disease on ultrasound remained largely unchanged; no patient progressed from the “medullary” to the “corticomedullary” group. There was no correlation between eGFR slope and kidney size. The synthetic function of the liver remained largely intact even in patients with advanced portal hypertension. Based on spleen length/height ratio, two thirds of patients had portal hypertension which remained stable in 39% and worsened in 61%. Patients with portal hypertension had lower platelet counts and relatively higher levels of AST, GGT, direct bilirubin and ammonia. The progression rates of kidney and liver disease were independent of each other. Patients with bi-allelic non-truncating PKHD1 variants had similar progression of kidney and liver disease in comparison to those who were compound heterozygous for a non-truncating and a truncating variant.
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pkhd1 sequence variations in 78 children and adults with autosomal recessive polycystic kidney disease and Congenital Hepatic Fibrosis
Molecular Genetics and Metabolism, 2010Co-Authors: Meral Gunayaygun, Esperanza Fontmontgomery, Linda Lukose, Maya Tuchman, Katie Piwnicaworms, Hailey Edwards, Angelica Garcia, Surasawadee Ausavarat, Shira G Ziegler, Joy BryantAbstract:PKHD1, the gene mutated in autosomal recessive polycystic kidney disease (ARPKD)/Congenital Hepatic Fibrosis (CHF), is an exceptionally large and complicated gene that consists of 86 exons and has a number of alternatively spliced transcripts. Its longest open reading frame contains 67 exons that encode a 4074 amino acid protein called fibrocystin or polyductin. The phenotypes caused by PKHD1 mutations are similarly complicated, ranging from perinatally-fatal PKD to CHF presenting in adulthood with mild kidney disease. To date, more than 300 mutations have been described throughout PKHD1. Most reported cohorts include a large proportion of perinatal-onset ARPKD patients; mutation detection rates vary between 42% and 87%. Here we report PKHD1 sequencing results on 78 ARPKD/CHF patients from 68 families. Differing from previous investigations, our study required survival beyond 6 months and included many adults with a CHF-predominant phenotype. We identified 77 PKHD1 variants (41 novel) including 19 truncating, 55 missense, 2 splice, and 1 small in-frame deletion. Using computer-based prediction tools (GVGD, PolyPhen, SNAP), we achieved a mutation detection rate of 79%, ranging from 63% in the CHF-predominant group to 82% in the remaining families. Prediction of the pathogenicity of missense variants will remain challenging until a functional assay is available. In the meantime, use of PKHD1 sequencing data for clinical decisions requires caution, especially when only novel or rare missense variants are identified.
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mutations in 3 genes mks3 cc2d2a and rpgrip1l cause coach syndrome joubert syndrome with Congenital Hepatic Fibrosis
Journal of Medical Genetics, 2010Co-Authors: Dan Doherty, Melissa A Parisi, Meral Gunayaygun, M Almateen, Daniel Bates, Carol L Clericuzio, H Demir, Michael O Dorschner, Laura S Finn, A J Van EssenAbstract:Objective To identify genetic causes of COACH syndrome Background COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic Fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD). Methods In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced. Results 19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the Congenital Hepatic Fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%). Conclusions Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L.
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autosomal recessive polycystic kidney disease and Congenital Hepatic Fibrosis summary statement of a first national institutes of health office of rare diseases conference
The Journal of Pediatrics, 2006Co-Authors: Meral Gunayaygun, Lisa M Guaywoodford, Theo Heller, Peter L Choyke, Ellis D Avner, Robert Bacallao, Joseph T Flynn, Gregory G Germino, Peter C Harris, Julie R IngelfingerAbstract:Researchers and clinicians with expertise in autosomal recessive polycystic kidney disease and Congenital Hepatic Fibrosis (ARPKD/CHF) and related fields met on May 5-6, 2005, on the National Institutes of Health (NIH) campus for a 1.5-day symposium sponsored by the NIH Office of Rare Diseases, the National Human Genome Research Institute (NHGRI), and in part by the ARPKD/CHF Alliance. The meeting addressed the present status and the future of ARPKD/CHF research.
Linda Lukose - One of the best experts on this subject based on the ideXlab platform.
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prospective evaluation of kidney and liver disease in autosomal recessive polycystic kidney disease Congenital Hepatic Fibrosis
Molecular Genetics and Metabolism, 2020Co-Authors: Nehna Abdul Majeed, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Theo Heller, Peter L Choyke, Peter Veppumthara, Ismail B Turkbey, William A Gahl, Meral GunayaygunAbstract:Abstract Background and objectives We have previously published the characteristics of kidney and liver disease in a cohort of 73 individuals with molecularly confirmed autosomal recessive polycystic kidney disease-Congenital Hepatic Fibrosis, based upon cross-sectional data. Here, we present prospective data on the same cohort. Design, setting, participants, and measurements Comprehensive biochemical and imaging data on progression of kidney and liver disease in 60 of the 73 patients were prospectively collected at the NIH Clinical Center on multiple visits between 2003 and 2019. Results and conclusions Of the 73 patients, 23 received a renal allograft at an average age of 17.5 years and 10 underwent liver transplantation at an average age of 20.3 years. Patients who presented perinatally and those who had corticomedullary disease required kidney transplantation significantly earlier. The mean eGFR slope in patients with corticomedullary disease was −1.6 ml/min/1.73 m2/y, in comparison to −0.6 ml/min/1.73 m2/y in those with medullary disease. Kidney size remained the same over time and normalized to the upper limit of normal by 20–25 years of age. The extent of renal disease on ultrasound remained largely unchanged; no patient progressed from the “medullary” to the “corticomedullary” group. There was no correlation between eGFR slope and kidney size. The synthetic function of the liver remained largely intact even in patients with advanced portal hypertension. Based on spleen length/height ratio, two thirds of patients had portal hypertension which remained stable in 39% and worsened in 61%. Patients with portal hypertension had lower platelet counts and relatively higher levels of AST, GGT, direct bilirubin and ammonia. The progression rates of kidney and liver disease were independent of each other. Patients with bi-allelic non-truncating PKHD1 variants had similar progression of kidney and liver disease in comparison to those who were compound heterozygous for a non-truncating and a truncating variant.
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characteristics of Congenital Hepatic Fibrosis in a large cohort of patients with autosomal recessive polycystic kidney disease
Gastroenterology, 2013Co-Authors: Meral Gunay Aygun, Baris Turkbey, Kailash Daryanani, Linda Lukose, Esperanza Font Montgomery, Maya Gerstein, Katie Piwnica Worms, Peter L Choyke, Roxanne Fischer, Isa BernardiniAbstract: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 ( R 2 = 0.42, P 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; ClinicalTrials.gov number, NCT00068224.
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Congenital Hepatic Fibrosis and portal hypertension in autosomal dominant polycystic kidney disease
Journal of Pediatric Gastroenterology and Nutrition, 2012Co-Authors: Kevin Obrien, Kailash Daryanani, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Katie Piwnicaworms, Hailey Edwards, Lauren Riney, Angelica Garcia, Peter L ChoykeAbstract: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.
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pkhd1 sequence variations in 78 children and adults with autosomal recessive polycystic kidney disease and Congenital Hepatic Fibrosis
Molecular Genetics and Metabolism, 2010Co-Authors: Meral Gunayaygun, Esperanza Fontmontgomery, Linda Lukose, Maya Tuchman, Katie Piwnicaworms, Hailey Edwards, Angelica Garcia, Surasawadee Ausavarat, Shira G Ziegler, Joy BryantAbstract:PKHD1, the gene mutated in autosomal recessive polycystic kidney disease (ARPKD)/Congenital Hepatic Fibrosis (CHF), is an exceptionally large and complicated gene that consists of 86 exons and has a number of alternatively spliced transcripts. Its longest open reading frame contains 67 exons that encode a 4074 amino acid protein called fibrocystin or polyductin. The phenotypes caused by PKHD1 mutations are similarly complicated, ranging from perinatally-fatal PKD to CHF presenting in adulthood with mild kidney disease. To date, more than 300 mutations have been described throughout PKHD1. Most reported cohorts include a large proportion of perinatal-onset ARPKD patients; mutation detection rates vary between 42% and 87%. Here we report PKHD1 sequencing results on 78 ARPKD/CHF patients from 68 families. Differing from previous investigations, our study required survival beyond 6 months and included many adults with a CHF-predominant phenotype. We identified 77 PKHD1 variants (41 novel) including 19 truncating, 55 missense, 2 splice, and 1 small in-frame deletion. Using computer-based prediction tools (GVGD, PolyPhen, SNAP), we achieved a mutation detection rate of 79%, ranging from 63% in the CHF-predominant group to 82% in the remaining families. Prediction of the pathogenicity of missense variants will remain challenging until a functional assay is available. In the meantime, use of PKHD1 sequencing data for clinical decisions requires caution, especially when only novel or rare missense variants are identified.
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autosomal recessive polycystic kidney disease and Congenital Hepatic Fibrosis arpkd chf
Pediatric Radiology, 2009Co-Authors: Baris Turkbey, Iclal Ocak, Kailash Daryanani, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Maya Tuchman, Parvathi Mohan, Theo HellerAbstract:ARPKD/CHF is an inherited disease characterized by non-obstructive fusiform dilatation of the renal collecting ducts leading to enlarged spongiform kidneys and ductal plate malformation of the liver resulting in Congenital Hepatic Fibrosis. ARPKD/CHF has a broad spectrum of clinical presentations involving the kidney and liver. Imaging plays an important role in the diagnosis and follow-up of ARPKD/CHF. Combined use of conventional and high-resolution US with MR cholangiography in ARPKD/CHF patients allows detailed definition of the extent of kidney and hepatobiliary manifestations without requiring ionizing radiation and contrast agents.
Joy Bryant - One of the best experts on this subject based on the ideXlab platform.
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prospective evaluation of kidney and liver disease in autosomal recessive polycystic kidney disease Congenital Hepatic Fibrosis
Molecular Genetics and Metabolism, 2020Co-Authors: Nehna Abdul Majeed, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Theo Heller, Peter L Choyke, Peter Veppumthara, Ismail B Turkbey, William A Gahl, Meral GunayaygunAbstract:Abstract Background and objectives We have previously published the characteristics of kidney and liver disease in a cohort of 73 individuals with molecularly confirmed autosomal recessive polycystic kidney disease-Congenital Hepatic Fibrosis, based upon cross-sectional data. Here, we present prospective data on the same cohort. Design, setting, participants, and measurements Comprehensive biochemical and imaging data on progression of kidney and liver disease in 60 of the 73 patients were prospectively collected at the NIH Clinical Center on multiple visits between 2003 and 2019. Results and conclusions Of the 73 patients, 23 received a renal allograft at an average age of 17.5 years and 10 underwent liver transplantation at an average age of 20.3 years. Patients who presented perinatally and those who had corticomedullary disease required kidney transplantation significantly earlier. The mean eGFR slope in patients with corticomedullary disease was −1.6 ml/min/1.73 m2/y, in comparison to −0.6 ml/min/1.73 m2/y in those with medullary disease. Kidney size remained the same over time and normalized to the upper limit of normal by 20–25 years of age. The extent of renal disease on ultrasound remained largely unchanged; no patient progressed from the “medullary” to the “corticomedullary” group. There was no correlation between eGFR slope and kidney size. The synthetic function of the liver remained largely intact even in patients with advanced portal hypertension. Based on spleen length/height ratio, two thirds of patients had portal hypertension which remained stable in 39% and worsened in 61%. Patients with portal hypertension had lower platelet counts and relatively higher levels of AST, GGT, direct bilirubin and ammonia. The progression rates of kidney and liver disease were independent of each other. Patients with bi-allelic non-truncating PKHD1 variants had similar progression of kidney and liver disease in comparison to those who were compound heterozygous for a non-truncating and a truncating variant.
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Congenital Hepatic Fibrosis and portal hypertension in autosomal dominant polycystic kidney disease
Journal of Pediatric Gastroenterology and Nutrition, 2012Co-Authors: Kevin Obrien, Kailash Daryanani, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Katie Piwnicaworms, Hailey Edwards, Lauren Riney, Angelica Garcia, Peter L ChoykeAbstract: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.
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pkhd1 sequence variations in 78 children and adults with autosomal recessive polycystic kidney disease and Congenital Hepatic Fibrosis
Molecular Genetics and Metabolism, 2010Co-Authors: Meral Gunayaygun, Esperanza Fontmontgomery, Linda Lukose, Maya Tuchman, Katie Piwnicaworms, Hailey Edwards, Angelica Garcia, Surasawadee Ausavarat, Shira G Ziegler, Joy BryantAbstract:PKHD1, the gene mutated in autosomal recessive polycystic kidney disease (ARPKD)/Congenital Hepatic Fibrosis (CHF), is an exceptionally large and complicated gene that consists of 86 exons and has a number of alternatively spliced transcripts. Its longest open reading frame contains 67 exons that encode a 4074 amino acid protein called fibrocystin or polyductin. The phenotypes caused by PKHD1 mutations are similarly complicated, ranging from perinatally-fatal PKD to CHF presenting in adulthood with mild kidney disease. To date, more than 300 mutations have been described throughout PKHD1. Most reported cohorts include a large proportion of perinatal-onset ARPKD patients; mutation detection rates vary between 42% and 87%. Here we report PKHD1 sequencing results on 78 ARPKD/CHF patients from 68 families. Differing from previous investigations, our study required survival beyond 6 months and included many adults with a CHF-predominant phenotype. We identified 77 PKHD1 variants (41 novel) including 19 truncating, 55 missense, 2 splice, and 1 small in-frame deletion. Using computer-based prediction tools (GVGD, PolyPhen, SNAP), we achieved a mutation detection rate of 79%, ranging from 63% in the CHF-predominant group to 82% in the remaining families. Prediction of the pathogenicity of missense variants will remain challenging until a functional assay is available. In the meantime, use of PKHD1 sequencing data for clinical decisions requires caution, especially when only novel or rare missense variants are identified.
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autosomal recessive polycystic kidney disease and Congenital Hepatic Fibrosis arpkd chf
Pediatric Radiology, 2009Co-Authors: Baris Turkbey, Iclal Ocak, Kailash Daryanani, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Maya Tuchman, Parvathi Mohan, Theo HellerAbstract:ARPKD/CHF is an inherited disease characterized by non-obstructive fusiform dilatation of the renal collecting ducts leading to enlarged spongiform kidneys and ductal plate malformation of the liver resulting in Congenital Hepatic Fibrosis. ARPKD/CHF has a broad spectrum of clinical presentations involving the kidney and liver. Imaging plays an important role in the diagnosis and follow-up of ARPKD/CHF. Combined use of conventional and high-resolution US with MR cholangiography in ARPKD/CHF patients allows detailed definition of the extent of kidney and hepatobiliary manifestations without requiring ionizing radiation and contrast agents.
Yusuf Bayraktar - One of the best experts on this subject based on the ideXlab platform.
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experience of a single center with Congenital Hepatic Fibrosis a review of the literature
World Journal of Gastroenterology, 2010Co-Authors: Ali Shorbagi, Yusuf BayraktarAbstract:Congenital Hepatic Fibrosis (CHF) is an autosomal recessive inherited malformation defined pathologically by a variable degree of periportal Fibrosis and irregularly shaped proliferating bile ducts. It is one of the fibropolycystic diseases, which also include Caroli disease, autosomal dominant polycystic kidney disease, and autosomal recessive polycystic kidney disease. Clinically it is characterized by Hepatic Fibrosis, portal hypertension, and renal cystic disease. CHF is known to occur in association with a range of both inherited and non-inherited disorders, with multiorgan involvement, as a result of ductal plate malformation. Because of the similarities in the clinical picture, it is necessary to differentiate CHF from idiopathic portal hypertension and early liver cirrhosis, for which a liver biopsy is essential. Radiological tests are important for recognizing involvement of other organ systems. With regards to our experience at Hacettepe University, a total of 26 patients have been diagnosed and followed-up between 1974 and 2009 with a diagnosis of CHF. Presentation with Caroli syndrome was the most common diagnosis, with all such patients presenting with symptoms of recurrent cholangitis and symptoms related to portal hypertension. Although portal Fibrosis is known to contribute to the ensuing portal hypertension, it is our belief that portal vein cavernous transformation also plays an important role in its pathogenesis. In all patients with CHF portal vein morphology should be evaluated by all means since portal vein involvement results in more severe and complicated portal hypertension. Other associations include the Joubert and Bardet-Biedl syndromes.
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is portal vein cavernous transformation a component of Congenital Hepatic Fibrosis
World Journal of Gastroenterology, 2007Co-Authors: Ozlem Yonem, Yusuf BayraktarAbstract:Congenital Hepatic Fibrosis (CHF) is an autosomal recessive disorder that belongs to the family of fibropolycystic liver diseases. This family includes a spectrum of disorders which are usually found in combination with each other and are usually inherited. Clinically fibropolycystic diseases have three effects being present in different proportions, those of a space occupying lesion, of portal hypertension and of cholangitis. In most patients, the first manifestations of CHF are signs and symptoms related to portal hypertension such as splenomegaly and varices. Portal hypertension in these patients has been attributed to the hypoplasia or compression of the portal vein radicles in the fibrous bands. Cavernous transformation of the portal vein (CTPV) is a relatively rare condition resulting from extraHepatic portal vein obstruction with recanalization or collateral vein formation to bypass the obstruction. It has been found that patients with CHF having an accompanying CTPV have relatively large splenomegaly and suffers more frequent episodes of bleeding from esophageal varices.We believe that CTPV is a Congenital component of CHF and also one of the important causative factors of portal hypertension in these patients.
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is Congenital Hepatic Fibrosis a pure liver disease
The American Journal of Gastroenterology, 2006Co-Authors: Ozlem Yonem, Nihal Ozkayar, Ferhun Balkanci, Ozgur Harmanci, Cenk Sokmensuer, Osman Ersoy, Yusuf BayraktarAbstract:Objectives An association between Congenital Hepatic Fibrosis (CHF) and several different conditions is being increasingly recognized. We aimed to investigate, prospectively, these associated disorders and the clinical consequences for patients with CHF. Materials and methods CHF was diagnosed using liver biopsy, abdominal ultrasound (US), Doppler US, upper endoscopy, and abdominal computed tomography (CT) in 19 patients (13 women, 6 men). CT portography and splenoportography with digital subtraction angiography were performed if indicated. Endoscopic retrograde cholangiopancreatography (ERCP) was performed to investigate the extent of portal vein involvement of the common bile duct if it existed, to remove a stone located in the common bile duct when documented, and to confirm the diagnosis of Caroli's syndrome. Cranial MRI was done when clinical findings suggested brain involvement. Results The mean age of the patients was 29.47+/-12.06, ranging from 13 to 57. CHF-associated diseases were Caroli's syndrome, polycystic kidney disease, cavernous transformation of the portal vein, Joubert's syndrome, von Meyenburg complex, polydactyly, medullary sponge kidney, and pancreatic duct atrophy. In two cases, cholangiocarcinoma had developed. There was only one case with pure CHF. Portosystemic shunt, TIPS, or splenectomy were performed in some cases to control bleeding from esophageal varices. Papillotomy and stone extraction from the common bile duct were performed in four patients with Caroli's syndrome complicated by cholangitis. Three patients died of complications of CHF. Two patients with Caroli's syndrome underwent liver transplantation. Conclusion In this prospective study, it seems that CHF is not a pure liver disease but rather a multiorgan disorder involving the brain, portal vein, kidneys, and bile ducts. In most cases, the clinical picture includes other organ involvement, rather than purely the liver parenchyma.
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Congenital Hepatic Fibrosis associated with cavernous transformation of the portal vein
Hepato-gastroenterology, 1997Co-Authors: Yusuf Bayraktar, Ferhun Balkanci, B Kayhan, B Uzunalimoglu, Ahmet Ozenc, Arif Ozdemir, S Dundar, Serap Arslan, Bulent Sivri, H TelatarAbstract:Background/Aims: Congenital Hepatic Fibrosis (CHF), which is one of the fibropolycystic diseases, occurs in various forms. Portal hypertension, a very common clinical feature of this condition, has been attributed to the compression of portal vein radicles in the fibrous bands. We investigated whether there are any other contributing factors in the development of portal hypertension in patients with CHF. Methodology: A total of 1285 patients with portal hypertension of different etiologies were studied using ultrasonography as the screening test. Forty-seven (including portal vein involvement and/or CHF) of these 1285 patients were prospectively studied to evaluate the etiology of the portal hypertension by portography, abdominal computed tomography, exploratory laparotomy, peritonoscopy, liver biopsy and laboratory tests. The patients with CHF were divided into two groups, according to whether or not they had portal vein involvement. Results: Eleven (0.8%) of the 1285 patients with portal hypertension had CHF, and 41 (3.2%) had cavernous transformation of the portal vein (CTPV), resulting from different or unknown etiologies. Five patients had both pathologies (CTPV and CHF). In the 11 patients with CHF, there was CTPV in 5 patients, Caroli's disease in 2 patients, cholangiocarcinoma in 1 patient, inferior vena caval obstruction in 1 patient, and CHF in only 2 patients. There were statistically significant differences in the age ofthe CHFpatients at clinical onset, the incidence ofbleeding from esophageal varices, and laboratory findings between the 2 groups with and without CTPV. Despite a thorough investigation, we could not distinguish any predisposing factor in 25 of the 41 patients with CTPV. The incidence of CTPV was 48% in patients with CHF and 3.2% in patients with portal hypertension. Conclusions: These results suggest that the association of CTPV with CHF is not coincidental, but that CTPV may be associated with CHF and a new possible factor in portal hypertension, and that it can be a major factor in the manifestation of esophageal bleeding from varices.