Ursodeoxycholic Acid Improves Cholestasis in Infants with Cystic Fibrosis

Scher, Herschel; Bishop, Warren P.; McCray, Paul B.

doi:10.1177/106002809703100909

Cited by 17 publications

(10 citation statements)

References 19 publications

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“…This finding is similar to children with cystic fibrosis, who often have abnormally elevated liver enzymes in the blood in the absence of liver histopathology [41]. Interestingly, oral administration of ursodeoxycholic acid (a hydrophilic dihydroxylated bile acid) normalizes liver function tests in neonatal cystic fibrosis ferrets [4 •• ] similarly to what has been observed in cystic fibrosis infants [42]. These findings suggest similar pathophysiologic mechanisms in the processing of bile acids between cystic fibrosis humans and ferrets.…”

Section: Liver and Gallbladdersupporting

confidence: 66%

New animal models of cystic fibrosis

Keiser¹,

Engelhardt

2011

Current Opinion in Pulmonary Medicine

115

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Purpose of review Cystic fibrosis is the first human genetic disease to benefit from the directed engineering of three different species of animal models (mice, pigs, and ferrets). Recent studies on the cystic fibrosis pig and ferret models are providing new information about the pathophysiology of cystic fibrosis in various organ systems. Additionally, new conditional cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice are teaching unexpected lessons about CFTR function in surprising cellular locations. Comparisons between these animal models and the human condition are key to dissecting the complexities of disease pathophysiology in cystic fibrosis. Recent findings Cystic fibrosis pigs and ferrets have provided new models to study the spontaneous development of disease in the lung and pancreas, two organs that are largely spared overt spontaneous disease in cystic fibrosis mice. New cystic fibrosis mouse models are now interrogating CFTR functions involved in growth and inflammation at an organ-based level using conditional knockout technology. Together, these models are providing new insights on the human condition. Summary Basic and clinical cystic fibrosis research will benefit greatly from the comparative pathophysiology of cystic fibrosis mice, pigs, and ferrets. Both similarities and differences between these three cystic fibrosis models will inform pathophysiologically important mechanisms of CFTR function in humans and aid in the development of both organ-specific and general therapies for cystic fibrosis.

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Section: Liver and Gallbladdersupporting

confidence: 66%

New animal models of cystic fibrosis

Keiser¹,

Engelhardt

2011

Current Opinion in Pulmonary Medicine

115

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“…As CF ferrets age, they require pancreatic enzyme supplementation to retain growth, similar to CF infants. CF kits are born with elevated markers of liver pathology, as occurs in human CF infants (41), and oral ursodeoxycholic acid (UDCA) therapy normalizes these markers in both species (40,42,43). Thus, the CF ferret model has several characteristics similar to the human CF phenotype.…”

Section: Resultsmentioning

confidence: 99%

“…However, it remains unclear whether neonatal liver pathologies in CF influence glucose and insulin regulation. Elevated levels in liver function tests (LFTs: alanine transaminase, aspartate transaminase, γ-glutamyltransferase, and bilirubin) are commonly observed in the majority of newborn CF infants (41,42,57) and newborn CF ferrets (40). Neonatal elevations in LFTs observed in CF infants are generally thought to reflect cholestasis due to thickening of bile (42,57,58).…”

Section: Discussionmentioning

confidence: 99%

Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets

Olivier¹,

Yi²,

Sun³

et al. 2012

J. Clin. Invest.

120

143

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Diabetes is a common comorbidity in cystic fibrosis (CF) that worsens prognosis. The lack of an animal model for CF-related diabetes (CFRD) has made it difficult to dissect how the onset of pancreatic pathology influences the emergence of CFRD. We evaluated the structure and function of the neonatal CF endocrine pancreas using a new CFTR-knockout ferret model. Although CF kits are born with only mild exocrine pancreas disease, progressive exocrine and endocrine pancreatic loss during the first months of life was associated with pancreatic inflammation, spontaneous hyperglycemia, and glucose intolerance. Interestingly, prior to major exocrine pancreas disease, CF kits demonstrated significant abnormalities in blood glucose and insulin regulation, including diminished first-phase and accentuated peak insulin secretion in response to glucose, elevated peak glucose levels following glucose challenge, and variably elevated insulin and C-peptide levels in the nonfasted state. Although there was no difference in lobular insulin and glucagon expression between genotypes at birth, significant alterations in the frequencies of small and large islets were observed. Newborn cultured CF islets demonstrated dysregulated glucose-dependent insulin secretion in comparison to controls, suggesting intrinsic abnormalities in CF islets. These findings demonstrate that early abnormalities exist in the regulation of insulin secretion by the CF endocrine pancreas. IntroductionCystic fibrosis (CF) is caused by defects in the CF transmembrane conductance regulator (CFTR) chloride channel. Cystic fibrosisrelated diabetes (CFRD) is a common complication of CF and affects 20%-25% of adolescents and 40%-50% of individuals over 30 years of age (1,2). CFRD is associated with worsening clinical status, including reduced pulmonary function, increased frequency of pulmonary exacerbations, and a decline in nutritional status (3-7). Furthermore, CFRD leads to increased mortality compared with CF patients without diabetes (4,8). Thus, early diagnosis and treatment are vital to improving clinical outcome of CFRD patients.While the pathophysiology of CFRD is multifactorial, delayed insulin secretion appears to be a key hallmark of disease progression (9-12), and the health of CF patients is improved by insulin therapy prior to and following diagnosis of overt diabetes (13,14). Partial insulin deficiency occurs in part due to islet loss associated with exocrine pancreas disease (15-18). However, CF pancreata at CFRD autopsy demonstrate that remaining islets contain roughly half the number of insulin-positive cells found in non-CF controls (17,18), and this degree of β cell loss is thought to be insufficient to explain diabetes (19). Thus, insulin deficiency in CFRD is relative and not absolute. All stages of CFRD are characterized by abnormalities in circulating insulin levels (10,12,20,21). Impaired first-phase insulin (IFPI) responses are common in CFRD patients, but also occur in approximately 50% of CF children with normal glucose tolerance (9). Cu...

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“…Gross necropsy demonstrated that although there was no intestinal obstruction in the CFTR -/-kits, fat stores throughout the animals were depleted, consistent with sustained malnutrition ( Figure 4B and Supplemental Figure 4C). UDCA treatment normalized serum ALT and bilirubin levels, as is the case in CF infants (27), but failed to normalize serum cholesterol levels, which remained low in comparison with treated controls ( Figure 4C). Three out of the four CFTR -/-kits developed respiratory distress and showed signs of multifocal bronchopneumonia - with the lungs demonstrating intralesional neutrophils, macrophages, hemorrhage, fibrin, and bacterial colonies ( Figure 4B and Supplemental Figure 4).…”

Section: Cftr-knockout Kits Exhibit MI Of Variable Penetrance Eight mentioning

confidence: 94%

“…Our findings of reduced serum cholesterol levels in 2- to 4-day-old CFTR -/-kits that escaped MI are consistent with impaired bile acid absorption by the gut and the depletion of cholesterol pools through defective fat absorption by the gut. Oral administration of the hydrophilic dihydroxylated bile acid ursodeoxycholic acid (UDCA) has been shown to normalize LFTs (including serum ALT and bilirubin levels) and to improve the nutritional status in patients with CF (26,27).…”

Section: Cftr-knockout Kits Exhibit MI Of Variable Penetrance Eight mentioning

confidence: 99%

Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis

Sun

Sui²,

Fisher³

et al. 2010

J. Clin. Invest.

331

409

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Cystic fibrosis (CF) is a recessive disease that affects multiple organs. It is caused by mutations in CFTR. Animal modeling of this disease has been challenging, with species-and strain-specific differences in organ biology and CFTR function influencing the emergence of disease pathology. Here, we report the phenotype of a CFTR-knockout ferret model of CF. Neonatal CFTR-knockout ferrets demonstrated many of the characteristics of human CF disease, including defective airway chloride transport and submucosal gland fluid secretion; variably penetrant meconium ileus (MI); pancreatic, liver, and vas deferens disease; and a predisposition to lung infection in the early postnatal period. Severe malabsorption by the gastrointestinal (GI) tract was the primary cause of death in CFTR-knockout kits that escaped MI. Elevated liver function tests in CFTR-knockout kits were corrected by oral administration of ursodeoxycholic acid, and the addition of an oral proton-pump inhibitor improved weight gain and survival. To overcome the limitations imposed by the severe intestinal phenotype, we cloned 4 gut-corrected transgenic CFTR-knockout kits that expressed ferret CFTR specifically in the intestine. One clone passed feces normally and demonstrated no detectable ferret CFTR expression in the lung or liver. The animals described in this study are likely to be useful tools for dissecting CF disease pathogenesis and developing treatments.

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Ursodeoxycholic Acid Improves Cholestasis in Infants with Cystic Fibrosis

Cited by 17 publications

References 19 publications

New animal models of cystic fibrosis

New animal models of cystic fibrosis

Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets

Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis

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