ABSTRACT
BACKGROUND: Cftr(-/-tm1Unc) mice develop progressive hepato-biliary pathology. We hypothesize that this liver pathology is related to alterations in biliary bile hydrophobicity and bile salt metabolism in Cftr(-/-tm1Unc) mice. METHODS: We determined bile production, biliary and fecal bile salt- and lipid compositions and fecal bacterial composition of C57BL/6J Cftr(-/-tm1Unc) and control mice. RESULTS: We found no differences between the total biliary bile salt or lipid concentrations of Cftr(-/-) and controls. Compared to controls, Cftr(-/-) mice had a ~30% higher bile production and a low bile hydrophobicity, related to a ~7 fold higher concentration of the choleretic and hydrophilic bile salt ursocholate. These findings coexisted with a significantly smaller quantity of fecal Bacteroides bacteria. CONCLUSIONS: Liver pathology in Cftr(-/-tm1Unc) is not related to increased bile hydrophobicity. Cftr(-/-) mice do however display a biliary phenotype characterized by increased bile production and decreased biliary hydrophobicity. Our findings suggest Cftr dependent, alterations in intestinal bacterial biotransformation of bile salts.
Subject(s)
Bile Acids and Salts/metabolism , Bile Ducts/pathology , Bile/physiology , Cystic Fibrosis/metabolism , Cystic Fibrosis/pathology , Liver/pathology , Animals , Cystic Fibrosis Transmembrane Conductance Regulator , Disease Models, Animal , Feces/chemistry , Feces/microbiology , Female , Hydrophobic and Hydrophilic Interactions , Male , Mice , Mice, Congenic , Mice, Inbred C57BLABSTRACT
We used a congenic C57Bl/6J cystic fibrosis transmembrane conductance regulator (Cftr)(-/-) mouse model, which develops cystic fibrosis (CF)-like pathology in all organs, to evaluate the short- and long-term therapeutic effects of dietary docosahexaenoic acid (DHA). Thirty-day-old Cftr(-/-) mice and wild-type littermates were randomized to receive a liquid diet with or without DHA (40 mg/day). Animals were killed for histological and lipid analysis after 7, 30, and 60 days of therapy. DHA had no significant therapeutic or harmful effect on the lung, pancreas, or ileum of the Cftr(-/-) mice or their wild-type littermates. In contrast, dietary DHA resulted in highly significant amelioration of the severity of liver disease in the Cftr(-/-) mice, primarily a reduction in the degree of peri-portal inflammation. Additionally, these detailed measurements confirm our previous findings that Cftr(-/-) mice have significant alterations in the pancreas (except external acinar diameter), ileum, liver, lung, and salivary (except sublingual) glands at all ages compared with their age-matched wild-type littermates. In conclusion, inhibition of cytokines and/or eicosanoid metabolism and release of endogenous inhibitors of inflammation by DHA may account for the anti-inflammatory effects in the liver of this congenic murine model of CF. The potential therapeutic benefits of DHA in severe CF-associated liver disease remain to be explored.
Subject(s)
Cystic Fibrosis/drug therapy , Docosahexaenoic Acids/therapeutic use , Administration, Oral , Age Factors , Animals , Arachidonic Acid/analysis , Arachidonic Acid/blood , Bile Ducts/drug effects , Bile Ducts/pathology , Cystic Fibrosis/pathology , Disease Models, Animal , Docosahexaenoic Acids/administration & dosage , Docosahexaenoic Acids/blood , Erythrocytes/chemistry , Ileum/drug effects , Ileum/pathology , Liver/drug effects , Liver/pathology , Lung/drug effects , Lung/pathology , Mice , Mice, Congenic , Mice, Inbred C57BL , Mice, Inbred CFTR , Pancreas/drug effects , Pancreas/pathology , Random Allocation , Salivary Glands/drug effects , Salivary Glands/pathology , Treatment OutcomeABSTRACT
OBJECTIVE: To evaluate the role of serum enzymes for defining the pancreatic phenotype in Shwachman-Diamond syndrome (SDS), an inherited multisystem condition. STUDY DESIGN: Serum pancreatic trypsinogen and isoamylase were measured in 164 patients known or presumed to have SDS. The diagnosis was confirmed in 90 patients. Among 74 unconfirmed cases, 35 ("probable SDS") had hematologic dysfunction but lacked documented pancreatic dysfunction, whereas 39 patients ("improbable SDS") lacked both documented pancreatic and hematologic dysfunction. Classification and regression tree (CART) analysis was performed in 90 patients with SDS and 134 control patients to establish a rule for defining the pancreatic phenotype of SDS; the rule was then applied to the patients with unconfirmed diagnosis. RESULTS: In the control patients, serum trypsinogen showed little variation with age, whereas serum isoamylase values rose from birth on, attaining adult values by 3 years. For patients with SDS, serum trypsinogen values were low in young patients and tended to increase with age, whereas serum isoamylase values remained low at all ages. The CART rule combined results from both enzymes and classified the pancreatic phenotype in all but one SDS patient, who was <3 years of age. Excluding patients <3 years of age, CART identified the pancreatic phenotype in 82% and 7% of the "probable SDS" and "improbable SDS" cases, respectively. CONCLUSIONS: Serum pancreatic enzymes are useful for determining the pancreatic phenotype and confirming the diagnosis of SDS.
Subject(s)
Abnormalities, Multiple/enzymology , Abnormalities, Multiple/genetics , Chromosome Aberrations , Chromosomes, Human, Pair 7/enzymology , Chromosomes, Human, Pair 7/genetics , Exocrine Pancreatic Insufficiency/enzymology , Exocrine Pancreatic Insufficiency/genetics , Isoamylase/blood , Isoamylase/genetics , Pancreas/blood supply , Pancreas/enzymology , Trypsinogen/blood , Trypsinogen/genetics , Abnormalities, Multiple/blood , Adolescent , Adult , Biomarkers/blood , Child , Child Welfare , Child, Preschool , Clinical Laboratory Techniques , Exocrine Pancreatic Insufficiency/blood , Female , Hematologic Diseases/blood , Hematologic Diseases/diagnosis , Hematologic Diseases/enzymology , Humans , Infant , Infant Welfare , Intracranial Hemorrhages/blood , Intracranial Hemorrhages/enzymology , Intracranial Hemorrhages/mortality , Male , Phenotype , Retrospective Studies , SyndromeABSTRACT
OBJECTIVES: To evaluate the role of fecal elastase 1 (E1) as a marker of exocrine pancreatic insufficiency (PI). STUDY DESIGN: Fecal E1 was measured in patient groups with (1) failure to thrive but no pancreatic or intestinal disease (disease control patients); (2) PI; (3) pancreatic sufficiency; and (4) steatorrhea caused by a variety of intestinal diseases. RESULTS: Fecal E1 in all disease control patients exceeded 200 microg/g stool. Only 1 (2%) of 50 patients with PI exceeded the minimum reference value of 100 microg/g stool. In contrast, 3 (11%) of 28 patients with pancreatic sufficiency (with Shwachman-Diamond syndrome) had fecal E1 concentrations <100 microg/g stool, as did 5 (20%) of 25 patients with steatorrhea from intestinal causes, all of whom had diluted feces caused by short gut. CONCLUSIONS: Fecal E1 is a useful noninvasive screening test of PI in childhood. A negative test (>100 microg/g stool) had 99% predictive value for ruling out PI. However, a positive test in those with short gut or Shwachman-Diamond syndrome must be interpreted with caution.
