Abstract
OBJECTIVE
To examine the effects of age, sex, breed, liver histopathology, and year of death/sample collection on liver copper concentrations in dogs fed various commercial dog foods throughout their lives.
SAMPLE
During necropsy, 336 samples were collected between the years 2006 and 2022 from dogs that were fed a variety of commercial dog foods on the market. This study utilized all liver samples available and did not require specific criteria for sample selection.
METHODS
Liver samples (n = 336) were analyzed as dry weight for copper concentration by inductively coupled plasma-optical emission spectrometry. The potential effects of animal age and year of death/collection (scatterplots and linear regression), sex, liver histopathology (t test), and breed (ANOVA) on liver copper concentration were assessed.
RESULTS
Labrador Retrievers had lower liver copper concentrations than Beagles, but mixed breeds did not differ from Beagles or Labrador Retrievers. Analysis of year of death showed that liver copper concentrations decreased from 2006 through 2011, increased in 2012, decreased in 2013, and peaked in 2016, decreasing thereafter. Mean copper concentration of abnormal liver histopathology samples was lower than mean copper concentrations of normal liver histopathology samples. Age (12.9 ± 2.6 years) and sex had no effect on liver copper concentrations. Of note, some samples showed abnormal hepatic pathology.
CLINICAL RELEVANCE
Liver copper concentrations varied significantly with breed and year of death; however, average liver copper concentrations of each year were within normal. However, this was a retrospective population study and diet histories of the dogs were unknown, requiring further investigation.
Introduction
Over the past 20 years, some internists have perceived an increase in copper-associated hepatopathy incidences in dogs.1 Copper is an essential nutrient in canine diets and involved in numerous biological functions such as, but not limited to, serving as a cofactor for enzymes, hemoglobin formation, cardiac function, bone formation, immune function, myelin formation, pigmentation, and cellular respiration. Due to copper’s crucial role in biological systems, copper deficiencies can be detrimental to animal health and can result in anemia, hair growth disruption and depigmentation, bone lesions, reproductive failure, and neuromuscular disorders. Conversely, copper toxicity can lead to hepatic injury and increased liver enzyme activity.2 To prevent copper deficiencies, the Association of American Feed Control Officials (AAFCO) recommends that diets for dogs contain a minimum of 7.5 ppm on a dry-matter basis.3 However, there is currently no recommendation on the maximum dietary copper concentration for dogs3 and, as such, concerns have surfaced surrounding a potential direct causal relationship between dietary copper concentration and increased dog copper hepatopathy cases.
The normal physiological hepatic copper concentration for dogs is 150 to 400 μg/g dry weight (ppm),4,5 and hepatic copper concentrations exceeding 1,000 ppm can result in hepatic histopathological changes and/or damage; however, liver damage may vary for each individual on the basis of environmental, genetic, or physiological factors.6 In 1997, the AAFCO revised copper recommendations in dog foods to calculate only bioavailable forms of copper toward the minimum requirement, which copper oxide is not. The revised copper recommendation by the AAFCO was prompted from research that showed decreased serum copper and hemoglobin concentrations in dogs fed a diet that utilized copper oxide instead of copper sulfate, likely due to the low bioavailability of copper oxide (approx 5%) compared to copper sulfate (approx 60% to 100%).7–9 Concurrently, increases in hepatic copper concentrations in both purebred and mixed-breed dogs with chronic hepatitis have since been reported.10 Previous studies have demonstrated increases in liver copper concentrations from < 10 ppm in 1929 to 200 ppm in 1982 and 453 ppm in 1995, mostly in predisposed breeds such as Bedlington Terriers, West Highland White Terriers, and Labrador Retrievers.10–22 In addition to this observation, some investigators have drawn conclusions that high hepatic concentrations in dogs reflect high copper content in commercial dog food that may be greater than the biological requirement for dogs.1 However, the exact cause for the increase in copper-associated hepatopathy incidences is unknown. Therefore, the goal of the present retrospective study was to examine liver copper concentrations in dogs fed a representative sampling of commercially available dog foods throughout their lives and to determine the effects of age, sex, breed, liver histopathology, and year of death on liver copper concentrations.
Methods
Animals
A total of 336 liver samples were analyzed as dry weight for copper concentration in ppm from necropsied dogs. In a similar manner to another study,23 samples were from 336 dogs that were euthanized by a veterinarian when quality of life was declined and prior to the planning of this study. Of the samples collected, 90% were obtained from Hill’s internal colony dogs and 10% were obtained from external private veterinary clinics with owner consent as mentioned in a previous study.23 This study utilized all liver samples available and did not require specific criteria for sample selection. Dogs from which liver samples were obtained are representative of a population being fed a variety of commercial diets; however, exact diet histories are unknown. Dogs from the internal colony were involved in various palatability and digestibility studies compiled of diets from Hill’s Pet Nutrition and a range of other brands. Diets of privately owned dogs are unknown. Of the 336 samples, 55 samples were collected and analyzed in a previous study, which were selected on the basis of liver histopathology; although, 16 of the 55 samples were considered normal.23 The additional 281 samples were retrieved from Hill’s internal archived biological samples and were included to obtain a larger sample size. Of the remaining 281 samples, 43 samples were considered abnormal, 237 samples were considered normal, and 1 sample was unable to be evaluated. The 336 samples were obtained from 289 Beagles, 24 Labrador Retrievers, 10 Labrador mixes, and 13 mixed breeds (Table 1). Additionally, of the 336 samples, 176 were spayed females, 154 were neutered males, 4 were intact males, and 2 were intact females. Average age at death was 12.9 ± 2.6 years for the 336 samples. Demographic information and year of death/collection ranging from 2006 to 2022 from all 336 samples are shown (Table 2).
Demographic information and liver copper concentrations of necropsied liver samples from dogs.
| Variable | n1 | Liver copper concentrations (ppm)5 |
|---|---|---|
| Age (y) | 12.9 ± 2.62 | |
| < 1 | 3 | 185 ± 84 |
| 1 | 1 | 196 ± 146 |
| 2 | 2 | 451 ± 103 |
| 4 | 2 | 94 ± 103 |
| 5 | 1 | 144 ± 146 |
| 6 | 1 | 75 ± 146 |
| 7 | 7 | 219 ± 55 |
| 8 | 6 | 305 ± 60 |
| 9 | 14 | 238 ± 39 |
| 10 | 20 | 216 ± 33 |
| 11 | 21 | 185 ± 32 |
| 12 | 59 | 219 ± 19 |
| 13 | 63 | 229 ± 18 |
| 14 | 70 | 215 ± 17 |
| 15 | 50 | 211 ± 21 |
| 16 | 16 | 231 ± 37 |
| Sex | ||
| Female | 178 | 215 ± 10 |
| Male | 158 | 223 ± 13 |
| Breed | ||
| Beagle | 289 | 232a ± 8 |
| Labrador Retriever/Labrador mix3 | 34 | 108b ± 24 |
| Mixed breed | 13 | 222ab ± 39 |
| Liver histopathology4 | ||
| Normal | 253 | 246 ± 9 |
| Abnormal | 82 | 139 ± 14 |
1n = 336. 2Value represents the average ± SE age at death. 3Labrador Retriever and Labrador mix breeds were combined. 4One sample was unable to be evaluated. 5Values represent the least-square mean ± SEM, and values with different letters indicate differences (P ≤ .05) in liver copper concentrations.
Year of death/collection and liver copper concentrations of necropsied liver samples from dogs.
| YOD/Collection | n1 | Liver copper concentrations (ppm)2 |
|---|---|---|
| 2006 | 20 | 102 ± 28 |
| 2007 | 22 | 81 ± 27 |
| 2008 | 11 | 84 ± 38 |
| 2009 | 6 | 60 ± 52 |
| 2010 | 3 | 72 ± 72 |
| 2011 | 7 | 49 ± 47 |
| 2012 | 5 | 208 ± 56 |
| 2013 | 3 | 66 ± 72 |
| 2014 | 36 | 207 ± 21 |
| 2015 | 19 | 200 ± 29 |
| 2016 | 18 | 308 ± 30 |
| 2017 | 23 | 296 ± 26 |
| 2018 | 31 | 293 ± 23 |
| 2019 | 34 | 247 ± 22 |
| 2020 | 42 | 249 ± 19 |
| 2021 | 30 | 291 ± 23 |
| 2022 | 26 | 246 ± 25 |
YOD = Year of death.
1n = 336. 2Values represent the least-square mean ± SEM, and values with different letters indicate differences (P ≤ .05) in liver copper concentrations.
Sample analysis
The entire liver sample, approximately 0.5 to 2.5 g, was weighed in an aluminum pan and dried for 3 to 4 hours at 104 °C. The dried sample was then weighed back and crushed. A portion of the dried sample, approximately 0.25 g or the entire sample if < 0.25 g, was digested by use of nitric acid and a microwave digestion system (Multiwave 7000; Anton Paar GmbH). The sample was diluted to 50 mL using 18.2MΩ deionized water. Inductively coupled plasma-optical emission spectrometry was used to analyze the solution with a 5-point calibration line for copper concentration in the 55 liver samples in a previous study, plus an additional 23 samples that were analyzed but not used in the final analysis of a previous study23 (Optima 4300 DV; PerkinElmer Instruments), and the remaining 258 samples (5100 ICP-OES; Agilent Technologies).
Statistical analysis
The effect of age was evaluated using scatterplots and linear regression. Linear, quadratic, and cubic models were used to identify statistically and clinically meaningful relationships between age and liver copper concentration. The same approach was used for the assessment of year on liver copper concentrations. However, with year, yearly means were calculated and the regression models were run using the yearly means. The effects of sex and liver histopathology on liver copper concentration were assessed using a 2-sample t test. The effects of breed were assessed using a heterogeneous variance ANOVA model. The Tukey mean comparison test was used to compare the means for each breed. All analyses were performed in SAS (version 9.4; SAS Institute Inc). A P ≤ .05 was considered significant. Yearly mean concentrations were calculated for samples collected from 2006 to 2022. Data were analyzed using a linear regression model for linear, quadratic, and cubic trends with year as the only term in the model. The cubic model was selected as the final model on the basis of both the statistical significance of the model and various diagnostic criteria. With the linear and quadratic models, the residuals were not randomly distributed about zero and showed significant lack of fit. In contrast, with the cubic model, the residuals were randomly distributed around zero and showed no lack of fit in the model.
Results
Average liver copper concentration was 219 ± 145 ppm (data not shown). There were 126 (38%) liver tissue samples below the normal reference range for copper concentration (< 150 ppm) and 27 (8%) samples above the normal reference range (> 400 ppm) ranging from 401 to 891 ppm (Table 3).4,5 Of the samples above the normal reference range, 4 had abnormal pathologies consistent with moderate multifocal nodular hyperplasia, chronic lymphoplasmacytic cholecystitis with associated lymphoplasmacytic cholangiohepatitis and ductular reaction, severe multifocal lymphoplasmacytic and suppurative fibrosis with vacuolar degeneration and biliary hyperplasia, and multifocal to coalescing cytoplasmic vacuolarization. Of the samples below the normal reference range, 59 had abnormal pathologies. The remaining 183 (54%) samples had copper concentrations within normal reference range (150 to 400 ppm).4,5 Of note, all liver copper concentration results are represented as dry matter.
Liver samples above the normal copper reference range and pathology type of abnormal samples.
| Copper concentration (ppm) | n1 | Abnormal pathology (n) | Pathology type | Significance | Primary cause of death |
|---|---|---|---|---|---|
| 400.1–499.9 | 15 | 3 | 1. Moderate multifocal nodular hyperplasia | No clinical significance, incidental findings | Chronic kidney disease |
| 2. Chronic lymphoplasmacytic cholecystitis with associated lymphoplasmacytic cholangiohepatitis and ductular reaction | Likely a chronic gallbladder infection and/or obstruction | Chronic kidney disease | |||
| 3. Severe multifocal lymphoplasmacytic and suppurative fibrosis with vacuolar degeneration and biliary hyperplasia | Inflammatory hepatitis with lymphosarcoma | Inflammatory bowel disease | |||
| 500.0–599.9 | 5 | 0 | |||
| 600.0–699.9 | 2 | 0 | |||
| 700.0–799.9 | 2 | 1 | |||
| 1. Multifocal to coalescing cytoplasmic vacuolarization | Incidental findings | Acute hemorrhagic gastroenterocolitis | |||
| 800.0–899.9 | 3 | 0 |
1n = 27.
Age (P = .8; Figure 1) and sex (P = .6) had no effect on liver copper concentrations of dogs (Table 1). Breed had an effect (P < .0001) on liver copper concentrations such that Labrador Retrievers had lower liver copper concentrations when compared to Beagles. Although, mixed breeds were not different (P > .05) from Beagles or Labrador Retrievers. Mean copper concentration of abnormal liver histopathology samples (139; SE = 15) was lower (P < .0001) than mean copper concentrations of normal liver histopathology samples (246; SE = 9). There was a significant cubic trend between year of death/collection (R2 = 0.78; P < .001) and liver copper concentrations. Liver copper concentrations decreased from 2006 through 2011 below the normal liver copper reference range, averaging around 75 ppm per year, then increased in 2012, decreased in 2013, peaked in 2016 with a mean liver copper concentration of 308 ppm, then decreased until 2022 when the average liver copper concentration was around 270 ppm (Table 2; Figure 2).
Hepatic copper concentrations of dogs aged < 1 to 16 years old from the years 2006 to 2022. Red lines represent the lower (150 ppm) and upper (400 ppm) limits of the normal copper range.4,5
Citation: Journal of the American Veterinary Medical Association 2025; 10.2460/javma.23.11.0621
Average yearly hepatic copper concentrations of dogs from the years 2006 to 2022 fitted to a cubic model. Red lines represent the lower (150 ppm) and upper (400 ppm) limits of the normal copper range.4,5
Citation: Journal of the American Veterinary Medical Association 2025; 10.2460/javma.23.11.0621
Discussion
The present study demonstrates that liver copper concentrations decreased from 2006 through 2011 and were below the normal liver copper range, then increased in 2012, decreased below the normal range in 2013, peaked in 2016, and decreased thereafter. Additionally, average liver copper concentrations of each year were within normal copper limits, suggesting that although there was a periodic increase in copper concentrations, it was not clinically significant. Samples were collected from dogs without chronic hepatitis and had an average liver copper concentration of 219 ppm. Likewise, others showed that liver samples collected and analyzed between 1980 and 2010 from dogs without chronic hepatitis had an average copper concentration of 299 ppm.10 Similarly, the majority of the dogs in the present study represented a population being fed various dog foods from the pet food industry.
On the basis of the relationship between year of death and liver copper concentration, corresponding trends in the pet food industry must be considered, including increased use of chelated minerals (copper chelate) and avoidance of cereal grains, GMO, and gluten-associated ingredients becoming popular around 2010. From 2012 to 2016, diets marketed as grain-free experienced significant growth, with sales increasing by 221% during this time.24,25 Some investigators observed that cereal-free diets contained significantly more copper, iron, zinc, and manganese than cereal diets in addition to other significant differences in the nutritional profiles.25 In the present study, samples collected from 2009 to 2022 were Hill’s Pet Nutrition internal colony dogs that were fed in-market grain-free diets on occasion; however, there may be a correlation between the spike in grain-free diet sales around 2012 and the results of other studies. For example, in one study,26 hepatic biopsy specimens from dogs were submitted to a diagnostic center between 2010 and 2015 and 51% (2,149) of total samples had hepatic copper concentrations of > 400 ppm.
While further research is required, one could hypothesize that the popularity of grain-free diets over the past decade and the higher concentrations of copper found in grain-free diets compared to grain diets in the European study may suggest an association between the increase in copper concentrations in liver samples.25 However, other ingredient use and diet trends should be investigated to further determine the effects of diet type on liver copper concentrations such as incorporation of chelated minerals and mineral content and forms from popular ingredients used, such as meat, poultry, and fish meals.
Some have hypothesized that the observed increased liver copper accumulation may be associated with increased dietary copper intake, especially after the 1997 AAFCO revision of copper to utilize more bioavailable forms of copper, such as copper sulfate, in place of copper oxide, a largely nonbioavailable form of copper.1 However, prior to the 1997 revision, copper sulfate had been the more commonly used source of copper in pet foods.27–29 Additionally, some investigators have suggested that mineral premixes may be related to increased liver copper concentrations because addition of mineral premixes to the diet is a common practice in the commercial pet food industry.30 While some investigators have concluded that the increase in copper concentration in dogs is associated with dietary intake,1 many emphasize that the true cause-and-effect relationship is unknown and that this investigational topic could have potentially raised awareness due to other reasons.10,30 Similarly, while the present study showed an increasing trend in liver copper concentrations over time, a direct cause-and-effect relationship cannot be established. As such, other factors such as mineral-mineral interactions, mineral routes of digestion, and bioavailability should be considered.
A potential explanation for increased copper concentrations in dog liver samples is mineral-to-mineral interactions. If the dietary supply and/or body reserve of a nutrient are low, the intestine adapts to improve the efficiency of uptake or similar minerals have enhanced absorption.31 For example, hepatic or overall copper concentrations may be increased due to deficiency or low concentrations of dietary iron; as such, dietary copper may be decreased due to the increase of other nutrients.32 Additionally, the liver is involved in functions and deposits of various nutrients such as iron, zinc, and copper.31 If excess or deficiency of one of these minerals occurs, compensation of another mineral will arise to help counter the lack of balance, which may result in hepatic dysfunction.31
Zinc therapy is known to help lower hepatic copper concentrations. However, in a study33 of Labrador Retrievers fed a low-copper diet, hepatic copper concentrations decreased and stabilized to the high normal range but no additional benefits were seen with zinc supplementation. Zinc is metabolized in the liver, and excess zinc content is associated with a greater concentration of metallothionein, a cysteine-rich protein that binds metals such as zinc, copper, and cadmium to help facilitate storage and detoxification of metals.2,34 Metallothionein is associated with the kidney, liver, and intestines and changes with dietary zinc; administration of other metals, like copper and cadmium; and other factors.34 When zinc is the primary metal bonded to the protein, metallothionein degrades quickly unless copper or cadmium is bound to the protein as well.34 In humans with Menkes and Wilson diseases, copper accumulation in various tissues may be a result of altered metallothionein turnover.34 This may be true for other mammals, but further research is required.
Copper, zinc, and iron are mostly available in the organic form found in meat ingredients, especially organ meat, compared to inorganic mineral supplements.2 Copper is also more readily available to the liver and other tissues when loosely bound to albumin or certain amino acids compared to ceruloplasmin-bound copper.2 Tissue damage associated with copper accumulation may be a result of availability associated with the lack of the ceruloplasmin transport protein, which is seen in Bedlington Terriers, a predisposed breed.11
In addition to the year of death, the present study demonstrated that liver copper concentrations were impacted by dog breed. Similar to a previous study that observed an increase in median liver copper concentrations in both predisposed and nonpredisposed breeds over a 34-year period,30 liver copper concentrations in the present study rose in both nonpredisposed and predisposed breeds over the 16-year period. Copper-associated hepatopathy is commonly observed in breeds such as Bedlington Terriers, Labrador Retrievers, Doberman Pinschers, and other suspected predisposed breeds due to a defect in copper metabolism.35 Ten percent of the liver samples in the present study contained Labrador Retrievers or Labrador mixes, a predisposed breed, while 90% of the samples came from breeds that are not considered to be predisposed to copper-associated hepatopathy such as Beagles and mixed breeds. In the present study, liver copper concentrations differed between breeds, such that Labrador Retrievers had lower liver copper concentrations than Beagles. Even though Labrador Retrievers are a predisposed breed, these data indicate that Labrador liver samples from this population contained a lower copper concentration than nonpredisposed breeds. Although, dogs from the Hill’s internal colony may have higher activity factors than client-owned dogs. As such, since the majority of the samples were obtained from the internal colony, the observation of Labrador Retrievers having a lower copper concentration than Beagles may be related to the increased food intake to meet the resting energy requirements of the internal colony dogs.
A limitation of this retrospective study was the limited knowledge around diets fed to the dogs in the study, especially toward end of life. However, dogs from the Hill’s internal colony were likely fed various commercialized diets including both Hill’s and a range of competitors’ diets during palatability and digestibility studies, as is typical of pet partners, but may have been limited to an array of therapeutically intended diets associated with mitigation of chronic diseases if indicated.
This study demonstrated that breed and year of death impact liver copper concentrations, while age and sex appeared to have no effect on liver copper concentrations of the dogs assessed. Due to the low number of intact and overweight animals, the effect of neutering and excess body fat could not be assessed. Analysis of breed demonstrated that Labrador Retrievers have lower liver copper concentrations than Beagles. Mixed breeds were not different from Beagles or Labrador Retrievers. Of the 336 samples, 18% were considered abnormal and had a lower copper concentration than normal liver histopathology samples. In the 4 samples above the normal reference range with pathologies, liver disease was not the cause of death and pathologies were often incidental findings of little to no clinical significance. Assessment of year of death showed that liver copper concentrations decreased from 2006 through 2011, then increased dramatically in 2012, decreased in 2013, and peaked in 2016, while decreasing thereafter. Overall, these data indicate that liver copper concentrations appear to be impacted by breed and year of death; however, average liver copper concentrations of each year were below the hepatic copper concentration suggesting that although there is an increase in copper concentrations, it is not clinically significant and changes in AAFCO copper recommendations are not resulting in hepatic copper toxicity. Additional research on a larger and more diverse population of dogs is needed to further understand liver copper concentration trends.
Acknowledgments
The authors would like to greatly acknowledge Regina Hollar, Joseph Greitl, Kiran Panickar, and Dale Scherl for their assistance in sample analysis and review.
Disclosures
Madison D. Amundson, Laura A. Motsinger, and Leslie Hancock are current employees of Hill’s Pet Nutrition Inc.
No AI-assisted technologies were used in the generation of this manuscript.
Funding
This work was funded by Hill’s Pet Nutrition Inc.
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