Congenital Hepatic Fibrosis and Portal Hypertension in Autosomal Dominant Polycystic Kidney Disease
ABSTRACT 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.
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.
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.
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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ABSTRACT: BACKGROUND: Dominant polycystic kidney disease is common and usually presents clinically in adulthood. Recessive polycystic kidney disease is much less common and frequently presents antenatally or in the neonatal period with severe renal involvement. These are usually thought of as clinically distinct entities but diagnostic confusion is not infrequent. CASE-DIAGNOSIS/TREATMENT: We describe an infant with antenatally diagnosed massive renal enlargement and oligohydramnios with no resolvable cysts on ultrasound scanning. He underwent bilateral nephrectomy because of respiratory compromise and poor renal function but died subsequently of overwhelming sepsis. Genetic analysis revealed that he had bilineal inheritance of abnormalities of PKD1 and no demonstrable abnormalities of PKD2 or PKHD1. CONCLUSIONS: Biallelic inheritance of abnormalities of PKD1 may cause extremely severe disease resembling autosomal dominant polycystic kidney disease (ADPKD) which can result in diagnostic confusion. Accurate diagnosis is essential for genetic counseling.Pediatric Nephrology 04/2013; DOI:10.1007/s00467-013-2484-x · 2.88 Impact Factor
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ABSTRACT: BACKGROUND & AIMS:: Autosomal recessive polycystic kidney disease (ARPKD), the most common ciliopathy of childhood, is characterized by congenital hepatic fibrosis (CHF) and progressive cystic degeneration of kidneys. We aimed to describe CHF in patients with ARPKD, confirmed by detection of mutations in polycystic kidney and hepatic disease ( PKHD1). METHODS:: Patients with ARPKD and CHF were evaluated at the US National Institutes of Health from 2003 through 2009. We analyzed clinical, molecular, and imaging data from 73 patients (ages 1 to 56 y; average of 12.7 ±13.1 y), 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, others presented with kidney disease. One patient underwent liver and kidney transplantation; 10 others received kidney transplants. Four presented with cholangitis and 1 with variceal bleeding. Sixty nine percent had enlarged left lobes on magnetic resonance imaging, 92 % had increased liver echogenicity upon ultrasound analysis 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. Platelet count was the best predictor of spleen volume (area under the curve=0.88905) and spleen length corrected for patient's height correlated inversely with platelet count (R(2)=0.42, p<0.0001). Spleen volume did not correlate with renal function or type of PKHD1mutation. 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's syndrome and 30 % had isolated dilated common bile duct. CONCLUSIONS:: Platelet count is the best predictor of the severity of portal hypertension, which is early-onset but underdiagnosed in ARPKD. Seventy percent of ARPKD patients have biliary abnormalities. Kidney and liver disease are independent; variability in severity is not explainable by type of PKHD1mutation. ClinicalTrials.gov number, NCT00068224.Gastroenterology 10/2012; 144(1). DOI:10.1053/j.gastro.2012.09.056 · 13.93 Impact Factor
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ABSTRACT: PORTAL HYPERTENSION IN CHILDREN REPRESENTS A PARTICULAR DIAGNOSTIC AND MANAGEMENT CHALLENGE FOR SEVERAL REASONS: (1) treatment outcomes should be evaluated in relationship with a long-life expectancy, (2) pediatric patients with portal hypertension constitute an heterogeneous population, both in terms of individual characteristics and diversity of liver diseases; making comparison between treatment outcomes very difficult, (3) application of techniques and procedures developed in adult patients (v.gr. TIPS) face size limitations in small children, and (4) absence of data from well-controlled trials in children forces pediatric specialists to adapt results obtained from adult cohorts suffering from diseases such as HCV and alcoholic cirrhosis. Despite those limitations, substantial progress in the treatment of children with portal hypertension has been achieved in recent years, with better outcomes and survival. Two main factors influence our therapeutic decision: age of the patient and etiology of the liver disease. Therefore, diagnosis and treatment of complications of portal hypertension in children need to be described taking such factors into consideration. This paper summarizes current knowledge and expert opinion.10/2012; 2012:879163. DOI:10.1155/2012/879163