TCCI Consultancy BV

Utrecht, Netherlands

TCCI Consultancy BV

Utrecht, Netherlands
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PubMed | RAS Institute of Cytology and Genetics, The Center for Pet Nutrition, University Utrecht, University of Groningen and 3 more.
Type: Journal Article | Journal: Disease models & mechanisms | Year: 2016

The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters ATP7A and ATP7B. Menkes disease, involving ATP7A, is a fatal neurodegenerative disorder of copper deficiency. Mutations in ATP7B lead to Wilson disease, which is characterized by a predominantly hepatic copper accumulation. The low incidence and the phenotypic variability of human copper toxicosis hamper identification of causal genes or modifier genes involved in the disease pathogenesis. The Labrador retriever was recently characterized as a new canine model for copper toxicosis. Purebred dogs have reduced genetic variability, which facilitates identification of genes involved in complex heritable traits that might influence phenotype in both humans and dogs. We performed a genome-wide association study in 235 Labrador retrievers and identified two chromosome regions containing ATP7A and ATP7B that were associated with variation in hepatic copper levels. DNA sequence analysis identified missense mutations in each gene. The amino acid substitution ATP7B:p.Arg1453Gln was associated with copper accumulation, whereas the amino acid substitution ATP7A:p.Thr327Ile partly protected against copper accumulation. Confocal microscopy indicated that aberrant copper metabolism upon expression of the ATP7B variant occurred because of mis-localization of the protein in the endoplasmic reticulum. Dermal fibroblasts derived from ATP7A:p.Thr327Ile dogs showed copper accumulation and delayed excretion. We identified the Labrador retriever as the first natural, non-rodent model for ATP7B-associated copper toxicosis. Attenuation of copper accumulation by the ATP7A mutation sheds an interesting light on the interplay of copper transporters in body copper homeostasis and warrants a thorough investigation of ATP7A as a modifier gene in copper-metabolism disorders. The identification of two new functional variants in ATP7A and ATP7B contributes to the biological understanding of protein function, with relevance for future development of therapy.


Mandigers P.J.J.,University Utrecht | Biourge V.,The Royal Canin Research Center | Van Den Ingh T.S.G.A.M.,TCCI Consultancy BV | Ankringa N.,University Utrecht | German A.J.,University of Liverpool
Journal of Veterinary Internal Medicine | Year: 2010

Background: Hydrolyzed protein diets are commonly used to manage canine chronic enteropathies (CE), but their efficacy has not yet been critically evaluated.Hypothesis: A hydrolyzed protein diet is superior to that of a highly digestible (control) diet in the management of CE in dogs.Animals: Twenty-six dogs (18 test diet, 8 control diet) referred for investigation and management of naturally occurring chronic small intestinal disease.Methods: Randomized, open-label, positively controlled trial. After a full diagnostic investigation, which included endoscopy, dogs were assigned either to the test diet or control diet on a 2-:-1 basis (test-:-control). Cases were re-evaluated 3 times (at approximately 3, 6-12 months, and 3 years). Outcome measures included response of clinical signs (complete, partial, none), change in severity of signs (based upon clinical disease activity index; canine inflammatory bowel disease activity index [CIBDAI]), change in body weight, and need for other therapy.Results: There were no significant differences in baseline characteristics (eg, signalment, body weight, and duration of clinical signs), and histopathologic severity between test and control diet groups. However, despite randomization, CIBDAI was significantly higher in the test diet group (P=.013). Most dogs had responded by first evaluation, with no difference between groups (P=.87). However, significantly more dogs on the test diet remained asymptomatic at both the second (P=.0012) and third (P <.001) re-evaluation, and the decrease in CIBDAI was significantly greater (P=.010).Conclusions and Clinical Importance: A hydrolyzed protein diet can be highly effective for long-term management of canine chronic small bowel enteropathy. © 2010 by the American College of Veterinary Internal Medicine.


Fieten H.,University Utrecht | Biourge V.C.,The Royal Canin Research Center | Watson A.L.,The Royal Canin Research Center | Leegwater P.A.J.,University Utrecht | And 2 more authors.
Journal of Veterinary Internal Medicine | Year: 2015

Background: Genetic and environmental factors, including dietary copper intake, contribute to the pathogenesis of copper-associated hepatitis in Labrador retrievers. Clinical disease is preceded by a subclinical phase in which copper accumulates in the liver. Objective: To investigate the effect of a low-copper, high-zinc diet on hepatic copper concentration in Labrador retrievers with increased hepatic copper concentrations. Animals: Twenty-eight clinically healthy, client-owned Labrador retrievers with a mean hepatic copper concentration of 919 ± 477 mg/kg dry weight liver (dwl) that were related to dogs previously diagnosed with clinical copper-associated hepatitis. Methods: Clinical trial in which dogs were fed a diet containing 1.3 ± 0.3 mg copper/Mcal and 64.3 ± 5.9 mg zinc/Mcal. Hepatic copper concentrations were determined in liver biopsy samples approximately every 6 months. Logistic regression was performed to investigate effects of sex, age, initial hepatic copper concentration and pedigree on the ability to normalize hepatic copper concentrations. Results: In responders (15/28 dogs), hepatic copper concentrations decreased from a mean of 710 ± 216 mg/kg dwl copper to 343 ± 70 mg/kg dwl hepatic copper after a median of 7.1 months (range, 5.5-21.4 months). Dogs from a severely affected pedigree were at increased risk for inability to have their hepatic copper concentrations normalized with dietary treatment. Conclusions and Clinical Importance: Feeding a low-copper, high-zinc diet resulted in a decrease in hepatic copper concentrations in a subset of clinically normal Labrador retrievers with previous hepatic copper accumulation. A positive response to diet may be influenced by genetic background. Determination of clinical benefit requires further study. © 2015 The Authors.


PubMed | University Utrecht, TCCI Consultancy BV and The Royal Canin Research Center
Type: Journal Article | Journal: Journal of veterinary internal medicine | Year: 2015

Genetic and environmental factors, including dietary copper intake, contribute to the pathogenesis of copper-associated hepatitis in Labrador retrievers. Clinical disease is preceded by a subclinical phase in which copper accumulates in the liver.To investigate the effect of a low-copper, high-zinc diet on hepatic copper concentration in Labrador retrievers with increased hepatic copper concentrations.Twenty-eight clinically healthy, client-owned Labrador retrievers with a mean hepatic copper concentration of 919 477 mg/kg dry weight liver (dwl) that were related to dogs previously diagnosed with clinical copper-associated hepatitis.Clinical trial in which dogs were fed a diet containing 1.3 0.3 mg copper/Mcal and 64.3 5.9 mg zinc/Mcal. Hepatic copper concentrations were determined in liver biopsy samples approximately every 6 months. Logistic regression was performed to investigate effects of sex, age, initial hepatic copper concentration and pedigree on the ability to normalize hepatic copper concentrations.In responders (15/28 dogs), hepatic copper concentrations decreased from a mean of 710 216 mg/kg dwl copper to 343 70 mg/kg dwl hepatic copper after a median of 7.1 months (range, 5.5-21.4 months). Dogs from a severely affected pedigree were at increased risk for inability to have their hepatic copper concentrations normalized with dietary treatment.Feeding a low-copper, high-zinc diet resulted in a decrease in hepatic copper concentrations in a subset of clinically normal Labrador retrievers with previous hepatic copper accumulation. A positive response to diet may be influenced by genetic background. Determination of clinical benefit requires further study.


Van Sprundel R.G.H.M.,University Utrecht | Van den Ingh T.S.G.A.M.,TCCI Consultancy BV | Guscetti F.,University of Zürich | Kershaw O.,Free University of Berlin | And 5 more authors.
Veterinary Journal | Year: 2013

Many advances have been made in the characterisation of primary liver tumours in humans, in particular relating to the identification and role of hepatic progenitor cells, resulting in a new classification. The aim of the present study was to investigate the presence and relative frequency of morphological types of canine primary hepatic neoplasms and to determine whether a classification similar to the human scheme can be applied to these canine neoplasms. Canine primary liver tumours ( n=. 106) were examined histologically and with the immunohistochemical markers keratin 19, HepPar-1, epithelial membrane antigen/mucin-1, CD10, neuron-specific enolase and chromogranin-A. Eleven nodular hyperplasias and 82 tumours of hepatocellular origin were diagnosed. The latter were subdivided in hepatocellular tumours with 0-5% positivity for K19 ( n=. 62), which were well differentiated and had no evidence of metastasis, tumours with >5% positivity for K19 ( n=. 17), which were poorly differentiated and had intrahepatic and/or distant metastasis, and a scirrhous subgroup ( n=. 3) with an intermediate position with regard to K19 staining and malignancy. Ten cholangiocellular tumours (nine cholangiocellular carcinomas and one cholangiolocarcinoma) were diagnosed and all had intrahepatic and/or distant metastases. Three neuroendocrine carcinomas were also diagnosed. Histopathological and immunohistochemical examination of canine primary hepatic neoplasms can differentiate hepatocellular, cholangiocellular and neuroendocrine tumours, in accordance with the most recent human classification system. © 2013 Elsevier Ltd.


Fieten H.,University Utrecht | Hooijer-Nouwens B.D.,University Utrecht | Biourge V.C.,Royal Canin Research Center | Leegwater P.A.J.,University Utrecht | And 3 more authors.
Journal of Veterinary Internal Medicine | Year: 2012

Background: Copper-associated hepatitis is an inherited disease in the Labrador Retriever. Apart from genetic factors, dietary intake of copper and zinc are suspected to play a role in the pathogenesis. Objectives: To investigate whether dietary copper and zinc levels of commercially available dry diets are associated with hepatic copper and zinc concentrations in Labrador Retrievers. Animals: Fifty-five Labrador Retrievers that were fed a single brand and type of commercial dry food for at least 1 year. Of these, 44 dogs were family members of Labrador Retrievers with copper-associated hepatitis. Methods: Liver biopsies, blood samples, and diet samples were obtained. Liver specimens were scored histologically and copper and zinc concentrations were quantified. Dietary concentrations of copper and zinc were measured. The association between dietary intake of copper and zinc and hepatic copper and zinc concentrations was investigated by linear regression analysis. Results: High dietary copper and low dietary zinc levels were significantly associated with high hepatic copper levels. No association between dietary intake and hepatic zinc was present. Conclusions and Clinical Relevance: Dietary copper and zinc at current levels in commercially available dry dog food can influence hepatic copper and can be a risk factor for the development of copper-associated hepatitis in Labrador Retrievers with a genetic susceptibility to copper. © 2012 by the American College of Veterinary Internal Medicine.


Fieten H.,University Utrecht | Dirksen K.,University Utrecht | van den Ingh T.S.G.A.M.,TCCI Consultancy BV | Winter E.A.,University Utrecht | And 3 more authors.
Veterinary Journal | Year: 2013

d-penicillamine is effectively used in the lifelong treatment of copper toxicosis in Bedlington terriers and Wilson's disease in humans. A complex form of copper-associated hepatitis has recently been characterized in the Labrador retriever. The aims of this study were to evaluate the effectiveness of d-penicillamine treatment for copper-associated hepatitis in this breed, to study the effects on hepatic copper, iron and zinc concentrations, and to evaluate parameters to predict optimal duration of treatment. Forty-three client owned Labrador retrievers that were diagnosed with increased hepatic copper were treated with d-penicillamine and underwent at least one follow-up examination including a liver biopsy for histopathological scoring of inflammatory lesions. Hepatic copper, iron and zinc concentrations were determined in the initial and follow-up biopsies by instrumental neutron activation analysis. The influence of initial hepatic copper concentration, sex, age, d-penicillamine formulation and the occurrence of side effects were investigated for their influence on hepatic copper concentration after a certain period of treatment by generalized mixed modelling. d-penicillamine proved to be effective in reducing hepatic copper concentration and associated inflammatory lesions. Parameters derived from the model can be used to estimate the necessary duration of d-penicillamine treatment for Labrador retrievers with increased hepatic copper concentration. Continuous, lifelong d-penicillamine treatment is not recommended in this breed, as there may be a risk for hepatic copper and zinc deficiency. © 2012 Elsevier Ltd.


Fieten H.,University Utrecht | Biourge V.C.,Royal Canin Research Center | Watson A.L.,Royal Canin Research Center | Leegwater P.A.J.,University Utrecht | And 2 more authors.
Veterinary Journal | Year: 2014

Canine hereditary copper-associated hepatitis is characterized by gradual hepatic copper accumulation eventually leading to liver cirrhosis. Therapy is aimed at creating a negative copper balance with metal chelators, of which d-penicillamine is the most commonly used. d-penicillamine often causes gastro-intestinal side effects and life-long continuous therapy may lead to a deficiency of copper and zinc. The aim of the current study was to investigate the effect of a low-copper, high-zinc diet as an alternative to continuous d-penicillamine treatment for the long-term management of canine copper-associated hepatitis.Sixteen affected Labrador retrievers were followed for a median time period of 19.1. months (range, 5.9-39. months) after being effectively treated with d-penicillamine. The dogs were maintained on a diet containing 1.3. ±. 0.3. mg. copper/1000. kcal and 64.3. ±. 5.9. mg. zinc/1000. kcal. Liver biopsies were taken every 6. months for histological evaluation and copper determination. Plasma alanine aminotransferase (ALT) and alkaline phosphatase, as well as serum albumin were determined.Dietary treatment alone was sufficient to maintain hepatic copper concentration below 800. mg/kg dry weight liver in 12 dogs during the study period. Four dogs needed re-treatment with d-penicillamine. ALT activity and albumin concentration were not associated with hepatic copper concentration, but showed a significant association with the stage and grade of hepatitis respectively. In conclusion, a low-copper, high-zinc diet can be a valuable alternative to continuous d-penicillamine administration for long-term management of dogs with copper-associated hepatitis. The copper re-accumulation rate of an individual dog should be considered in the design of a long-term management protocol and in determining re-biopsy intervals. © 2013 Elsevier Ltd.


Kanemoto H.,University Utrecht | Kanemoto H.,University of Tokyo | Sakai M.,Nihon University | Sakamoto Y.,Nihon University | And 5 more authors.
Journal of Veterinary Internal Medicine | Year: 2013

Background: American Cocker Spaniels are predisposed to chronic hepatitis. Objective: To describe the clinical and histological features of chronic hepatitis in Japanese American Cocker Spaniels. Animals: Thirteen cases examined from 2003 to 2009. Methods: Retrospective study. Medical records were searched for American Cocker Spaniels with chronic liver diseases. History, physical examination, clinicopathologic features, hepatic ultrasonographic findings, hepatic histopathology, and immunohistochemistry were evaluated. Results: The median age was 4.6 (1.9-10.7) years. Clinical signs included inappetence (11/13), ascites (11/13), lethargy (9/13), diarrhea (7/13), and melena (2/13). Only 1/13 dogs was jaundiced. Clinicopathological abnormalities were increased liver enzymes (gamma-glutamyl transpeptidase: 9/12, aspartate aminotransferase: 7/10, alanine aminotransferase: 6/13, alkaline phosphatase: 6/13), increased total serum bile acid concentrations (10/12), and hypoalbuminemia (10/13). The liver had an irregular surface in all dogs and acquired portosystemic collaterals were verified in 11/13 dogs by abdominal ultrasound (2), laparoscopy (4), or both (5). Liver histology revealed severe fibrosis and cirrhosis in all cases, subdivided in lobular dissecting hepatitis (7), periportal fibrosis (1), micronodular cirrhosis (3), and macronocular cirrhosis (2). Inflammatory activity was low to mild. Immunohistochemical stains showed ductular proliferation. The median survival time was 913 (range: 63-1981) days. Conclusion and Clinical Importance: Hepatitis in Japanese American Cocker Spaniels is clinically silent until an advanced stage and is associated with severe hepatic fibrosis leading to cirrhosis, extensive ductular/putative hepatic progenitor cell proliferation, portal hypertension, and acquired portosystemic collateral shunting, but relatively long survival times. Lobular dissecting hepatitis seems more prevalent than in previously reported cases from other countries. © 2013 by the American College of Veterinary Internal Medicine.


Favier R.P.,University Utrecht | Spee B.,University Utrecht | Schotanus B.A.,University Utrecht | van den Ingh T.S.G.A.M.,TCCI Consultancy BV | And 5 more authors.
PLoS ONE | Year: 2012

New therapeutic concepts developed in rodent models should ideally be evaluated in large animal models prior to human clinical application. COMMD1-deficiency in dogs leads to hepatic copper accumulation and chronic hepatitis representing a Wilson's disease like phenotype. Detailed understanding of the pathogenesis and time course of this animal model is required to test its feasibility as a large animal model for chronic hepatitis. In addition to mouse models, true longitudinal studies are possible due to the size of these dogs permitting detailed analysis of the sequence of events from initial insult to final cirrhosis. Therefore, liver biopsies were taken each half year from five new born COMMD1-deficient dogs over a period of 42 months. Biopsies were used for H&E, reticulin, and rubeanic acid (copper) staining. Immunohistochemistry was performed on hepatic stellate cell (HSC) activation marker (alpha-smooth muscle actin, α-SMA), proliferation (Ki67), apoptosis (caspase-3), and bile duct and liver progenitor cell (LPC) markers keratin (K) 19 and 7. Quantitative RT-PCR and Western Blots were performed on gene products involved in the regenerative and fibrotic pathways. Maximum copper accumulation was reached at 12 months of age, which coincided with the first signs of hepatitis. HSCs were activated (α-SMA) from 18 months onwards, with increasing reticulin deposition and hepatocytic proliferation in later stages. Hepatitis and caspase-3 activity (first noticed at 18 months) increased over time. Both HGF and TGF-β1 gene expression peaked at 24 months, and thereafter decreased gradually. Both STAT3 and c-MET showed an increased time-dependent activation. Smad2/3 phosphorylation, indicative for fibrogenesis, was present at all time-points. COMMD1-deficient dogs develop chronic liver disease and cirrhosis comparable to human chronic hepatitis, although at much higher pace. Therefore they represent a genetically-defined large animal model to test clinical applicability of new therapeutics developed in rodent models. © 2012 Favier et al.

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