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

Abstract

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;

Clinical manifestations of autosomal recessive polycystic kidney disease (ARPKD): kidney-related and non-kidney-related phenotypes

“…2) [13,16,17]. Although these pathological changes are present at the microscopic level at birth, the significance of these findings is variable, and clinical and radiographic complications of CHF may become apparent at any time between birth and adulthood ( Fig.…”

“…Complications of liver disease: portal hypertension, esophageal varices, and variceal bleeding Although PH in ARPKD was not systematically studied in the past, it starts early in life and progresses over time [12,13,17]; 40-50 % of infants surviving the first year of life will develop evidence of PH over time [9,11]. While renal disease diagnosed during the first year of life is most severe in neonates, many of the surviving patients develop sequelae from congenital hepatic fibrosis later in life, including hypersplenism, PH, and variceal bleeding [13].…”

“…While renal disease diagnosed during the first year of life is most severe in neonates, many of the surviving patients develop sequelae from congenital hepatic fibrosis later in life, including hypersplenism, PH, and variceal bleeding [13]. Despite these hepatobiliary complications, hepatocellular function is usually preserved for a long time, and patients are more likely to present with hematemesis or melena resulting from bleeding esophageal varices.…”

“…PH can only be diagnosed clinically by the presence of splenomegaly, hypersplenism, or esophageal varices, the latter leading to acute variceal bleeding. Platelet count is a good surrogate marker of PH severity [13]. Sonographic evidence of PH is characterized by visualization of the portal vein, decreased blood flow in the portal vein with minimal undulation, splenomegaly, and the presence of varices (Fig.…”

“…Almost 30 % of affected newborns that present with large, echogenic kidneys die within the neonatal period owing to respiratory insufficiency [2,3,9,11]. Some patients that survive the neonatal period present with complications primarily associated with liver disease, such as portal hypertension (PH) [3,4] and esophageal bleeding [9,12,13], later in childhood and adulthood; others may progress to end-stage renal disease (ESRD) within the first decades of life [3]. Other associated comorbidities, such as systemic hypertension [4], renal failure [3,14,15], or chronic lung disease [11], can also occur when the children get older.…”