Hille Fieten

Utrecht University | UU · Department of Clinical Sciences of Companion Animals

OBJECTIVE To identify prognostic indicators and inflammatory markers associated with nonsurvival in dogs with gallbladder mucoceles (GBMs) following cholecystectomy and to evaluate C-reactive protein (CRP) and haptoglobin concentrations in dogs with GBMs compared to healthy controls. ANIMALS 25 dogs that underwent cholecystectomy for removal of GB...

Gastric carcinoma is generally considered to be a rare disease in dogs, carrying a grave prognosis. However, in the Tervueren and Groenendael varieties of the Belgian Shepherd dog breed, the disease is highly prevalent. While histopathology is the gold standard for diagnosing gastric carcinoma, there is no general consensus on the methods for histo...

The Dutch Kooiker dog (het Nederlandse Kooikerhondje) is one of nine Dutch dog breeds. As of 1960, a number of heritable diseases have been noted in this breed. One is an inflammatory myopathy that emerged in 1972, with numbers of affected dogs gradually increasing during the last few decades. The objective of this paper is to describe clinical sig...

Background—Though physiologic regurgitation of the right-sided cardiac valves is well recognized in dogs and other mammals, the prevalence of trace insufficiency of the mitral and aortic valves in clinically healthy, young adult dogs is unknown. Methods—In this observational cross-sectional study, 50 clinically healthy, young adult Labrador retriev...

Cardiac disease is a leading cause of death for both humans and dogs. Genetic cardiomyopathies, including dilated cardiomyopathy (DCM), account for a proportion of these cases in both species. Patients may suffer from ventricular enlargement and systolic dysfunction resulting in congestive heart failure and ventricular arrhythmias with high risk fo...

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This chapter presents the various forms of hepatocellular death: apoptosis and necrosis, the morphological patterns of necrosis in the liver, and the response of the liver to hepatocellular injury. The definition and characteristics of acute and chronic hepatitis and cirrhosis are given, including copper-associated chronic hepatitis, lobular dissec...

Hepatic abscesses and granulomas usually occur by hematogenic spread from the portal vein or in neonates from the umbilical vein and a wide variety of causative organism is given. The various hepatic metabolic storage diseases in dogs and cats mentioned in the literature are summarized including the enzymatic defect, the hepatic cells involved and...

This chapter describes the nature and morphological characteristics of the normal hepatic circulation, consequences of impaired hepatic perfusion, the histological pattern of portal venous hypoperfusion, and the circulatory disorders of the liver in dogs and cats. Impaired hepatic perfusion can result in reduced portal flow, which leads to atrophy...

The biliary disorders can be grouped into four major categories: 1) Biliary cystic disease and biliary atresia, 2) Cholestasis and cholate-stasis, 3) Cholangitis, and 4) Disorders of the gallbladder. The biliary cystic diseases comprise solitary usually acquired cysts and congenital cystic diseases of the liver. The latter are considered ductal pla...

ABSTRACT The normal anatomy of the classical liver lobule and acinus of Rappaport and the constituent elements of the hepatic parenchyma i.e. the hepatocytes, sinusoids, Kupffer cells and hepatic stellate cells are described. The parenchymal disorders of the liver in dogs and cats mentioned in this chapter are hepatic amyloidosis and the various f...

Gallbladder mucocele (GBM) is a common biliary disorder in dogs. Gallbladder hypokinesia has been proposed to contribute to its formation and progression. The specific cause of gallbladder stasis in dogs with GBM as well as viable treatment options to resolve dysmotility remains unknown. Vitamin D deficiency is one of the many potential causes of g...

Abstract Hepatitis E virus (HEV) as an emerging zoonotic pathogen causes a major public health issue. Transmission from domestic, wildlife and zoo animals to human has been widely reported. Whether pets also serve as reservoirs remains an intriguing question. In this study, we found the sero-positive rates of HEV-specific antibodies in pet dogs, ca...

Copper toxicosis is a major cause of hepatitis in dogs. We have shown that variants in ATP7A and ATP7B modulate hepatic copper levels in Labrador retrievers and Dobermans. However, these variants cannot fully explain the observed variation in hepatic copper levels in these dog breeds. Homozygous deletion of exon 2 of COMMD1 causes copper toxicosis...

Copper toxicosis is a complex genetic disorder in Labrador retrievers characterized by hepatic copper accumulation eventually leading to liver cirrhosis. The variation of hepatic copper levels in Labrador retrievers has been partly explained by mutations in ATP7A c.980C>T and ATP7B c.4358G>A. To further elucidate the genetic background of this dise...

Wilson Disease is a rare autosomal recessive liver disorder in humans. Although its clinical presentation and age of onset are highly variable, hallmarks include signs of liver disease, neurological features and so-called Kayser-Fleischer rings in the eyes of the patient. Hepatic copper accumulation leads to liver disease and eventually to liver ci...

Health issues in purebred dogs are currently considered one of the biggest problems in companion animal health. The Labrador retriever (LR) is one of the most popular dog breeds. The aim of this study was to quantify LR breed health in comparison with mixed-breed dogs (MB), by using four different data sources: a veterinary practice management syst...

Gallbladder mucocele (GBM) is a common extra-hepatic biliary syndrome in dogs with death rates ranging from 7 to 45%. Therefore, the aim of this study was to identify the association of survival with variables that could be utilized to improve clinical decisions. A total of 1194 dogs with a gross and histopathological diagnosis of GBM were included...

Background: Hepatic copper accumulation causes chronic hepatitis in dogs. Mutations in the copper transporters ATP7A and ATP7B were, respectively, associated with attenuation and enhancement of hepatic copper concentrations in Labrador Retrievers. There is a predisposition of Dobermanns to hepatitis with increased hepatic copper concentrations. O...

Background Selective breeding in populations with a limited effective population size may result in a loss of genetic diversity, which can cause an increased concentration of specific disease liability genes. The Dutch Shepherd Dog (DSD) in the Netherlands is an example of such a breed with a small effective population. Objective To evaluate the m...

Background Chronic hepatitis (CH) in dogs is common and has the tendency to progress to liver cirrhosis (LC). Circulating microRNAs might have the potential as markers for disease progression. Objectives To investigate whether concentration of specific microRNAs in serum correlate with the stage and grade of CH in Labrador Retrievers. Animals Twe...

Reliable incidence measurement of diseases is necessary for identification of hereditary diseases in companion animal populations. The data collection system ‘PETscan’ was developed to facilitate standardized registration of diagnoses in veterinary practice. In the development, we attempted to counter challenges known from other primary practice da...

Urea cycle enzyme deficiency (UCED) patients with hyperammonemia are treated with sodium benzoate (SB) and sodium phenylacetate (SPA) to induce alternative pathways of nitrogen excretion. The suggested guidelines supporting their use in the management of hyperammonemia are primarily based on non-analytic studies such as case reports and case series...

Background: Biochemical indicators for diagnosing liver disease are plasma alanine aminotransferase activity (ALT), alkaline phosphatase activity (ALP), and bile acid concentration (BA). Objectives: To determine the sensitivity and specificity of ALT, ALP, and BA for detecting primary hepatitis (PH) in clinically healthy Labrador retrievers and...

Copper is an essential trace element, but can become toxic when present in abundance. The severe effects of copper-metabolism imbalance are illustrated by the inherited disorders Wilson disease and Menkes disease. The Labrador retriever dog breed is a novel non-rodent model for copper-storage disorders carrying mutations in genes known to be involv...

Primers and qPCR conditions. (DOCX)

Animal characteristics. (DOCX)

P values qPCR data. (DOCX)

Genes and their biological function. (DOCX)

Current public and professional opinion is that many dog breeds suffer from health issues related to inherited diseases or extreme phenotypes. The aim of this historical comparative observational study was to evaluate the breed-related disease burden in three purebred dog populations (Chihuahua, French bulldog, Labrador retriever) and one purebred...

Copper-associated hepatitis is recognized with increasing frequency in dogs. The disease is characterized by centrolobular hepatic copper accumulation, leading to hepatitis and eventually cirrhosis. The only way to establish the diagnosis is by histologic assessment of copper distribution and copper quantification in a liver biopsy. Treatment with...

Whole transcriptome sequencing (RNA-seq) has become a standard for cataloguing and monitoring RNA populations. One of the main bottlenecks, however, is to correctly identify the different classes of RNAs among the plethora of reconstructed transcripts, particularly those that will be translated (mRNAs) from the class of long non-coding RNAs (lncRNA...

Figure S1. Concentrations of ALT (A), ALP (B) and BA (C) in all Labrador retrievers with known hepatic quantitative copper concentrations (n = 222).

Figure S2. Concentrations of ALT (A), ALP (B) and BA (C) in Labrador retrievers with normal liver histology (n = 69).

Background: Current biochemical indicators cannot discriminate between parenchymal, biliary, vascular, and neoplastic hepatobiliary diseases. MicroRNAs are promising new biomarkers for hepatobiliary disease in humans and dogs. Objective: To measure serum concentrations of an established group of microRNAs in dogs and to investigate their concent...

Hereditary hepatic copper accumulation in Labrador retrievers leads to hepatitis with fibrosis and eventually cirrhosis. The development of a non-invasive blood-based biomarker for copper status in dogs could be helpful in identifying dogs at risk and to monitor copper concentrations during treatment. In this study, two cellular copper metabolism p...

Whole transcriptome sequencing (RNA-seq) has become a standard for cataloguing and monitoring RNA populations. Among the plethora of reconstructed transcripts, one of the main bottlenecks consists in correctly identifying the different classes of RNAs, particularly those that will be translated (mRNAs) from the class of long non-coding RNAs (lncRNA...

The low-density lipoprotein receptor (LDLR) plays a pivotal role in clearing atherogenic circulating low-density lipoprotein (LDL) cholesterol. Here we show that the COMMD/CCDC22/CCDC93 (CCC) and the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complexes are both crucial for endosomal sorting of LDLR and for its function. We find that...

Supplementary Figures 1-12, Supplementary Tables 1-3 and Supplementary References

Copper is an essential trace nutrient metal involved in a multitude of cellular processes. Hereditary defects in copper metabolism result in disorders with a severe clinical course such as Wilson disease and Menkes disease. In Wilson disease, copper accumulation leads to liver cirrhosis and neurological impairments. A lack in genotype-phenotype cor...

Common parenchymal liver diseases in dogs include reactive hepatopathies and primary hepatitis (acute or chronic). In chronic hepatitis, there is usually a long subclinical phase. Specific clinical signs become overt only when liver damage is severe and in this phase, treatment is usually less effective. Limited data are available regarding the sen...

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 toWilson disease, which is characterized by a predom...

Table S2. Increase in microRNA concentrations in dogs with different hepatobiliary diseases compared to control dogs.

The recent development of 3D-liver stem cell cultures (hepatic organoids) opens up new avenues for gene and/or stem cell therapy to treat liver disease. To test safety and efficacy, a relevant large animal model is essential but not yet established. Because of its shared pathologies and disease pathways, the dog is considered the best model for hum...

Document S1. Supplemental Experimental Procedures, Figures S1–S3, and Tables S1 and S2

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 concen...

The detoxification of ammonia occurs mainly through conversion of ammonia to urea in the liver via the urea cycle and glutamine synthesis. Congenital portosystemic shunts (CPSS) in dogs cause hyperammonemia eventually leading to hepatic encephalopathy. In this study, the gene expression of urea cycle enzymes (carbamoylphosphate synthetase (CPS1), o...

Liver diseases are highly prevalent in the general dog population, though the etiology is often unknown. Recently a homolog of human hepatitis C virus was discovered in dogs with respiratory infections. Although this canine hepacivirus (CHV) was detectable in some liver samples, a clear link with liver disease has not been established. A recent stu...

Alternatives for liver transplantation in severe liver disease are urgently needed in view of the limited availability of donor livers. The use of embryonic stem cells (ES) or hepatic progenitor cells (HPC) has been investigated in mice models of acute and chronic liver failure. To extrapolate the findings in inbred mouse strains (weighing around 2...

The One Health principle recognizes that human health, animal health, and environmental health are inextricably linked. An excellent example is the study of naturally occurring copper toxicosis in dogs to help understand human disorders of copper metabolism. Besides the Bedlington terrier, where copper toxicosis is caused by a mutation in the COMMD...

Hereditary copper-associated hepatitis in dogs resembles Wilson’s disease, a copper storage disease in humans. Values for urinary copper excretion are well established in the diagnostic protocol of Wilson’s disease, whereas in dogs these have not been evaluated. The objectives of this study were to characterize both basal and D-penicillamine induce...

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 contin...

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 c...

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 mod...

Nucleotide Sequences of dog specific primers for Quantitative Real-Time PCR. (DOC)

Used antibodies in immunohistochemical experiments. (DOC)

Used antibodies in Western blot experiments. (DOC)

Hereditary forms of copper toxicosis exist in man and dogs. In man, Wilson's disease is the best studied disorder of copper overload, resulting from mutations in the gene coding for the copper transporter ATP7B. Forms of copper toxicosis for which no causal gene is known yet are recognized as well, often in young children. Although advances have be...

Gene expression profiling of spontaneous tumors in the dog offers a unique translational opportunity to identify prognostic biomarkers and signaling pathways that are common to both canine and human. Osteosarcoma (OS) accounts for approximately 80% of all malignant bone tumors in the dog. Canine OS are highly comparable with their human counterpart...

Cox proportional hazard analysis upon stratification for postoperative chemotherapy. Cox proportional hazard analysis (univariate) upon stratification for postoperative chemotherapy revealed no significant influence of the variables assessed on survival time of the dogs in the total population of study (n = 32).

Differential expressed genes categorized based on their molecular functions.

Univariate analysis. a) Univariate analysis of specific variable influences on survival time (ST) among dogs from the entire population of study. b) Variables with P < 0.15 from univariate analysis that were subsequently forced into multivariate model identifies elevation of serum alkaline phosphatase with significantly increased HR for a shorter S...