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Peter F Whitington

Publications and source records attributed to Peter F Whitington.

35 records · Page 2Linked to original sources
PubMed2004

Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin.

Obesity and type 2 diabetes are associated with nonalcoholic steatohepatitis (NASH), but an obese/diabetic animal model that mimics human NASH remains undefined. We examined the induction of steatohepatitis and liver fibrosis in obese and type 2 diabetic db/db mice in a nutritional model of NASH and determined the relationship of the expressions of osteopontin (OPN) and leptin receptors to the pathogenesis of NASH. db/db mice and the corresponding lean and nondiabetic db/m mice were fed a diet deficient in methionine and choline (MCD diet) or control diet for 4 wk. Leptin-deficient obese and diabetic ob/ob mice fed similar diets were used for comparison. MCD diet-fed db/db mice exhibited significantly greater histological inflammation and higher serum alanine aminotransferase levels than db/m and ob/ob mice. Trichrome staining showed marked pericellular fibrosis in MCD diet-fed db/db mice but no significant fibrosis in db/m or ob/ob mice. Collagen I mRNA expression was increased 10-fold in db/db mice, 4-fold in db/m mice, and was unchanged in ob/ob mice. mRNA expressions of OPN, TNF-alpha, TGF-beta, and short-form leptin receptors (Ob-Ra) were significantly increased in db/db mice compared with db/m or ob/ob mice. Parallel increases in OPN and Ob-Ra protein levels were observed in db/db mice. Cultured hepatocytes expressed only Ob-Ra, and leptin stimulated OPN mRNA and protein expression in these cells. In conclusion, our results demonstrate the development of an obese/diabetic experimental model for NASH in db/db mice and suggest an important role for Ob-Ra and OPN in the pathogenesis of NASH.

Animals↗
PubMed2004

Biliary atresia is associated with CD4+ Th1 cell-mediated portal tract inflammation.

A proposed mechanism in the pathogenesis of biliary atresia involves an initial virus-induced, progressive T cell-mediated inflammatory obliteration of bile ducts. The aim of this study was to characterize the inflammatory environment present within the liver of infants with biliary atresia to gain insight into the role of a primary immune-mediated process versus a nonspecific secondary response to biliary obstruction. Frozen liver tissue obtained from patients with biliary atresia, neonatal giant cell hepatitis, total parenteral nutrition (TPN)-related cholestasis, choledochal cysts, and normal control subjects was used for fluorescent immunohistochemistry studies of cellular infiltrates, cytokine mRNA expression, and in situ hybridization for localization of cytokine-producing cells. Immunohistochemistry revealed increases in CD8(+) and CD4(+) T cells and Kupffer cells (CD68(+)) in the portal tracts of biliary atresia. Reverse transcription-PCR analysis of biliary atresia tissue showed a Th1-type cytokine profile with expression of IL-2, interferon-gamma, tumor necrosis factor-alpha, and IL-12. This profile was not seen in normal, neonatal hepatitis or choledochal cyst livers but was present in TPN-related cholestasis. In situ hybridization revealed that the Th1 cytokine-producing cells were located in the portal tracts in biliary atresia and in the parenchyma of TPN-related cholestasis. A distinctive portal tract inflammatory environment is present in biliary atresia, involving CD4(+) Th1 cell-mediated immunity. The absence of similar inflammation in other pediatric cholestatic conditions suggests that the portal tract inflammation in biliary atresia is not a secondary response to cholestasis but rather indicates a specific immune response involved in the pathogenesis of biliary atresia.

Bile Ducts, Extrahepatic↗
PubMed2004

Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model.

The pathogenesis of nonalcoholic steatohepatitis (NASH) is poorly defined. Feeding mice a diet deficient in methionine and choline (MCD diet) induces experimental NASH. Osteopontin (OPN) is a Th1 cytokine that plays an important role in several fibroinflammatory diseases. We examined the role of OPN in the development of experimental NASH. A/J mice were fed MCD or control diet for up to 12 wk, and serum alanine aminotransferase (ALT), liver histology, oxidative stress, and the expressions of OPN, TNF-alpha, and collagen I were assessed at various time points. MCD diet-fed mice developed hepatic steatosis starting after 1 wk and inflammation by 2 wk; serum ALT increased from day 3. Hepatic collagen I mRNA expression increased during 1-4 wk, and fibrosis appeared at 8 wk. OPN protein expression was markedly increased on day 1 of MCD diet and persisted up to 8 wk, whereas OPN mRNA expression was increased at week 4. TNF-alpha expression was increased from day 3 to 2 wk, and evidence of oxidative stress did not appear until 8 wk. Increased expression of OPN was predominantly localized in hepatocytes. Hepatocytes in culture also produced OPN, which was stimulated by transforming growth factor-beta and TNF-alpha. Moreover, MCD diet-induced increases in serum ALT levels, hepatic inflammation, and fibrosis were markedly reduced in OPN(-/-) mice when compared with OPN(+/+) mice. In conclusion, our results demonstrate an upregulation of OPN expression early in the development of steatohepatitis and suggest an important role for OPN in signaling the onset of liver injury and fibrosis in experimental NASH.

Alanine Transaminase↗
PubMed2004

Pentoxifylline attenuates steatohepatitis induced by the methionine choline deficient diet.

BACKGROUND/AIMS: Feeding mice a methionine choline deficient (MCD) diet serves as a nutritional model of non-alcoholic steatohepatitis (NASH). NASH and alcohol-induced steatohepatitis are histologically similar, suggesting a similar pathogenesis. Pentoxifylline (PTX) attenuates TNF-alpha production, acts as an antioxidant and decreases mortality in alcoholic steatohepatitis. The aim of our study is to determine if PTX attenuates MCD diet induced steatohepatitis and determine the mechanism of this effect. METHODS: Mice were placed on an MCD or control diet for 2 weeks and were treated with or without PTX. Serum ALT, liver histology, and inflammatory mechanisms were evaluated. RESULTS: PTX attenuates MCD diet induced steatohepatitis, decreasing both serum ALT levels and hepatic inflammation. Serum ALT levels were reduced approximately 50% in the MCD+PTX group compared to the MCD group. Hepatic glutathione levels were significantly higher in the MCD+PTX group compared to the MCD group. There was also a reduction in TNF-alpha mRNA in female mice treated with PTX. MCD+PTX mice had increased hepatic triglyceride content compared to the MCD mice, but less histologic evidence of inflammation despite the increased steatosis. Serum lipid and bile salt levels also were similar in PTX and vehicle control treated mice. CONCLUSIONS: PTX decreases serum ALT levels and hepatic inflammation in the MCD model of steatohepatitis, likely via increasing glutathione levels or reducing TNF-alpha expression.

Alanine Transaminase↗
PubMed2004

Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

For the primary care provider, cholestatic jaundice in infancy, defined as jaundice caused by an elevated conjugated bilirubin, is an uncommon but potentially serious problem that indicates hepatobiliary dysfunction. Early detection of cholestatic jaundice by the primary care physician and timely, accurate diagnosis by the pediatric gastroenterologist are important for successful treatment and a favorable prognosis. The Cholestasis Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has formulated a clinical practice guideline for the diagnostic evaluation of cholestatic jaundice in the infant. The Cholestasis Guideline Committee, consisting of a primary care pediatrician, a clinical epidemiologist (who also practices primary care pediatrics), and five pediatric gastroenterologists, based its recommendations on a comprehensive and systematic review of the medical literature integrated with expert opinion. Consensus was achieved through the Nominal Group Technique, a structured quantitative method. The Committee examined the value of diagnostic tests commonly used for the evaluation of cholestatic jaundice and how those interventions can be applied to clinical situations in the infant. The guideline provides recommendations for management by the primary care provider, indications for consultation by a pediatric gastroenterologist, and recommendations for management by the pediatric gastroenterologist. The Cholestasis Guideline Committee recommends that any infant noted to be jaundiced at 2 weeks of age be evaluated for cholestasis with measurement of total and direct serum bilirubin. However, breast-fed infants who can be reliably monitored and who have an otherwise normal history (no dark urine or light stools) and physical examination may be asked to return at 3 weeks of age and, if jaundice persists, have measurement of total and direct serum bilirubin at that time. This document represents the official recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition on the evaluation of cholestatic jaundice in infants. The American Academy of Pediatrics has also endorsed these recommendations. These recommendations are a general guideline and are not intended as a substitute for clinical judgment or as a protocol for the care of all patients with this problem.

Bilirubin↗
PubMed2004

Simultaneous surgical and interventional radiological approach to treat complicated biliary strictures after pediatric liver transplantation.

Post-transplantation biliary strictures occur in 5-15% of the pediatric liver transplant patients and are conventionally managed by interventional radiological techniques. Failure of this treatment leads to reoperation and sometimes to retransplantation. Herein, we describe a surgical approach and interventional radiologic approach to manage biliary strictures that failed the conventional radiologic treatment, in order to avoid retransplantation. Included in the study were eight children who underwent liver transplantation at our center or referred to our institution for evaluation of the biliary strictures that failed radiological treatment. Biliary strictures were confirmed by a narrowing of the biliary anastomosis on the percutaneous transhepatic cholangiogram. At surgery, a guide wire was introduced into the distal bile system through the use of an enterotomy in Roux limb. Over the guide wire, the stricture was ballooned and the diameter of the biliary tree was determined. A pigtail catheter was introduced on the biliary tree across the abdominal wall, the liver, the stricture and the anastomosis into the enterotomy. A final cholangiogram confirmed the positioning of the catheter. Mean follow-up was 39.8 +/- 20.8 months. All patients had their strictures successfully treated and survived the procedure. Three patients were readmitted to the hospital with fever. It was necessary to revise the hepaticojejunostomy in three patients because of cholangitis and/or recurrence of biliary stricture. Of the eight patients of this study, two required retransplantation and one died. We conclude that an aggressive combined surgical and radiologic approach can avoid retransplantation in patients with complicated post-transplant biliary strictures.

Bile Ducts↗
PubMed2003

Neonatal hemochromatosis.

Neonatal hemochromatosis is a rare gestational condition in which iron accumulates in the fetal tissues in a distribution like that seen in hereditary hemochromatosis. Extensive liver damage is the dominant clinical feature, with late fetal loss or early neonatal death. NH recurs within sibships at a rate higher than that predicted for simple Mendelian autosomal-recessive inheritance, possibly suggesting the role of a maternal factor. Immunomodulation during pregnancy at risk appears to lessen the severity of disease.

Female↗
PubMed2003

Liver transplantation in neonates.

Orthotopic liver transplantation (OLT) has evolved over the past two decades to become the standard of care for end-stage liver disease in infants and children. Technical advances, particularly the use of technical variant allografts, have permitted extension of OLT into a much younger and smaller population than previously possible. Major centers around the world now routinely perform OLT in infants with survival success equivalent to that in older children and adults. We are beginning to see a small population of school-aged children who were infant OLT recipients. The further extension of OLT into neonates is more recent, with only a few pediatric centers reporting survival success. Very little is known about this frontier of transplantation. Our intent is to provide an overview of neonatal OLT using all available data and our experience in the field.

Acute Kidney Injury↗
PubMed2003

Surgical restoration of portal flow corrects procoagulant and anticoagulant deficiencies associated with extrahepatic portal vein thrombosis.

Extrahepatic portal vein thrombosis (EHPVT) is associated with abnormal circulating procoagulants and anticoagulants. Eleven children with EHPVT and abnormal coagulation factors underwent a mesenterico-left portal vein bypass to restore portal flow. Coagulation factors had returned to normal by one year. The data suggest that portal venous flow is essential for maintaining normal coagulation.

Antithrombin III↗
PubMed2003

Recombinant factor VIIa improves coagulopathy caused by liver failure.

OBJECTIVE: Coagulopathy is an important cause of morbidity and mortality in patients with liver failure. The benefit of traditional therapies to correct coagulation is often limited and short-lived. Our aim is to identify indications for rFVIIa use and the outcome of treatment in children with liver failure. METHODS: A retrospective review from July 2000 to December 2001 was performed to identify consecutive patients with acute or chronic liver failure who received rFVIIa. Prothrombin times (PT) before and after therapy were compared by paired t test. RESULTS: Fifteen patients were treated with rFVIIa for coagulopathy caused by liver failure. All were receiving fresh frozen plasma (mean infusion rate, 39.7 mL/kg/day) when rFVIIa therapy was started. The mean PT before rFVIIa was 32.0 +/- 7.0 seconds. One hour after infusion, the PT normalized to 13.7 +/- 2.4 seconds (P < 0.0001) and remained significantly reduced at 6 hours (19.8 +/- 5.3 seconds; P < 0.0001). A sustained improvement was maintained during the subsequent 3 days. Five of seven patients with bleeding complications improved clinically after rFVIIa treatment. Two of the bleeding patients also benefited from improved fluid balance as fresh frozen plasma support was reduced. No thrombotic events were attributed to rFVIIa therapy. CONCLUSIONS: In patients with liver failure, rFVIIa therapy quickly normalizes the PT and maintains improved hemostasis, even when coagulopathy has been refractory to fresh frozen plasma. Therapy subjectively reduces clinical bleeding and can improve fluid balance, without complications.

Adolescent↗
PubMed2002

Molecular basis of neonatal cholestasis.

At present, specific evidence regarding the molecular mechanisms of neonatal cholestasis is limited. The recent explosion in the understanding of the molecular physiology of bile formation has been fueled by the discovery of several genes that are involved in familial cholestasis. The ever-growing understanding of the functional immaturity of the neonatal liver is sure to be enhanced by the study of the ontogeny of important hepatobiliary transporters as they are discovered. The understanding of the functional differences between the immature and mature liver is key to the understanding of neonatal cholestasis.

Bile↗
PubMed2002

Fetal gender and cocaine exposure as determinants of cord blood gamma-glutamyl transferase activity.

OBJECTIVE: The serum activity of the hepatic enzyme gamma-glutamyl transferase (GGT) is elevated in the newborn relative to older age groups. Few reports to date have studied the influence of perinatal factors on neonatal serum GGT and no study has assessed the influence of maternal drug ingestion. STUDY DESIGN: Cord blood was randomly collected from 234 liveborn infants and correlated with a range of maternal and fetal perinatal variables to assess influences on cord blood GGT. RESULTS: Our study showed that the range of cord blood GGT activity in 234 randomly selected term newborns was 22 to 556 IU/l. In a subgroup of 75 newborns, GGT activity was independently influenced by only two of the variables studied - cocaine exposure and fetal gender (p=0.009, r=0.39). Females had a lower GGT than males (95+/-66 vs 130+/-90 IU/l, p<0.001) while GGT activity in cocaine-exposed newborns was lower than in cocaine-nonexposed newborns (96+/-48 vs 142+/-109, p<0.01). Birth weight, race, gestational age, and maternal serum GGT were not found to significantly influence cord blood GGT activity. Maternal GGT was uniformly normal and was not affected by any of the variables tested. CONCLUSION: Our findings demonstrate that the reference range for cord blood GGT activity is wide and appears to be influenced by fetal gender and cocaine exposure.

Cocaine↗
PubMed2002

Partial external biliary diversion for intractable pruritus and xanthomas in Alagille syndrome.

Alagille syndrome (AGS) causes intractable pruritus and disfiguring xanthomas because of retained bile acids and cholesterol. This study was performed to determine whether partial external biliary diversion (PEBD) is effective for relief of pruritus and xanthomas in AGS patients who fail conventional medical therapy. Between the years 1985 and 2001, 9 AGS patients underwent PEBD. Complete follow-up data were available for all patients. The average age at PEBD was 4.8 (range 1.4-10) years. The average duration of follow-up was 7.5 (range 0.5-16.0) years. All 9 patients had severe, mutilating pruritus (grade 4) prior to diversion. At 1 year post-PEBD, the average pruritus score was 1.1; 8 patients had only mild scratching when undistracted. Three patients with extensive xanthomas prior to PEBD had complete resolution within 1 year. Mean serum bile salt levels (n = 5) decreased from 136.5 to 37.1 micromol/L and mean cholesterol (n = 7) from 724 to 367 mg/dL 1 year after PEBD. A single 21-year-old patient with PEBD for 14 years experienced an increase in pruritus from grade 1 to grade 4 within 2 months of elective reversal of PEBD. In conclusion, PEBD is effective for treating severe pruritus and hypercholesterolemia in AGS patients without cirrhosis who did not respond to medical therapy. PEBD should be considered as a therapeutic option for these patients before referral for liver transplantation because of morbid complications.

Alagille Syndrome↗
PubMedDate not supplied

High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis.

BACKGROUND: Neonatal haemochromatosis is a rare disease of gestation that results in severe fetal liver injury. We hypothesised an alloimmune aetiology for the disorder on the basis of its high recurrence rate in sibships. In this study, we assessed the effectiveness in preventing or changing the severity of recurrent neonatal haemochromatosis of administering during pregnancy high-dose intravenous immunoglobulin (IVIG) derived from pooled serum of multiple donors. METHODS: Women whose most recent pregnancy ended in documented neonatal haemochromatosis were treated with IVIG, 1 g/kg bodyweight, weekly from the 18th week until the end of gestation in their subsequent pregnancy. The outcomes of treated pregnancies were compared with those of randomly selected previous affected pregnancies for each woman, which were used as historical controls. FINDINGS: 15 women were treated through 16 pregnancies. All pregnancies progressed uneventfully and resulted in live babies with normal physical examinations and birthweights that were appropriate for gestational age. 12 babies had evidence of liver involvement with neonatal haemochromatosis: 11 had higher than normal concentrations of serum alpha-fetoprotein and ferritin or serum alpha-fetoprotein alone, including four with coagulopathy (international normalised ratio >1.5), and one had coagulopathy alone. All babies survived with medical or no treatment and were healthy at follow-up within the past 6 months. In analysis on a per-mother basis comparing outcomes of treated gestations with those of randomly selected previous affected gestations, gestational IVIG therapy was associated with better infant survival (15 good outcomes vs two in previous pregnancies; p=0.0009). INTERPRETATION: Treatment with high-dose IVIG during gestation appears to have modified recurrent neonatal haemochromatosis so that it was not lethal to the fetus or neonate. These results further support an alloimmune mechanism for recurrent neonatal haemochromatosis.

Female↗