Introduction
Copper is an essential trace mineral and is 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.1 Due to copper’s crucial role in biological systems, copper deficiencies in puppies have been shown to result in lameness, anemia, hair growth disruption and depigmentation, and poor growth.2–5 Furthermore, a study6 of puppies showed that giving an oral dose of a copper absorption inhibitor and systemic copper chelator, ammonium tetrathiomolybdate, decreased active osteoblast number, and subsequent osteoporosis was observed. Conversely, copper toxicity can lead to hepatic injury and increased liver enzyme activity.1 Over the past 20 years, some investigators have reported an increase in incidences of copper-associated hepatopathies in dogs.7–9 To prevent copper deficiencies, the Association of American Feed Control Officials (AAFCO) recommends that diets for adult dogs contain a minimum of 7.3 ppm of copper on a dry matter basis (DMB) for adult dogs and 12.4 ppm DMB for canine growth and reproduction.10 However, there is currently no recommendation on the maximum dietary copper concentration for dogs10; as such, concerns have surfaced surrounding a potential direct causal relationship between dietary copper concentration and increased incidences of copper-associated hepatopathies.
The normal physiological hepatic copper concentration range for dogs is 150 to 400 μg/g (ppm) on a DMB,11,12 and hepatic copper concentrations exceeding 1,000 ppm can result in hepatic histopathologic changes and/or damage13; however, recent studies have shown that histological changes can occur when copper concentrations exceed 400 ppm13–16 and may vary for each individual on the basis of environmental, genetic, or physiological factors.13 In 1997, AAFCO revised the 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 AAFCO was prompted from research showing the low bioavailability of copper oxide (approx 5%) compared to copper sulfate (approx 60% to 100%).17,18 Additionally, increases in hepatic copper concentrations in both purebred and mixed-breed dogs with copper-associated hepatopathy have since been reported.14 Previous studies5,7,14–16,19–27 have demonstrated increases in mean liver copper concentrations in dogs from < 10 ppm in 1929 to 200 ppm in 1982 to 453 ppm in 1995. In addition to these observations, some investigators have drawn conclusions that high hepatic concentrations in dogs reflect high copper content in commercial dog foods that may be greater than their biological requirement.7 Some breeds, such as Bedlington Terriers, Labrador Retrievers, Doberman Pinschers, Dalmatians, and West Highland White Terriers, are predisposed to copper-associated hepatopathy.13,28 On the other hand, for nonpredisposed breeds and mixed breeds, the exact cause for the observed increase in incidences of copper-associated hepatopathies is unknown. Therefore, the goal of the present retrospective study was to examine liver copper concentrations in a population of colony dogs—predominately Beagles—fed a wide variety of commercially available dog foods throughout their lives and to determine the effects of age, sex, year of death/collection, and liver histopathology on liver copper concentrations.
Methods
Population
Copper concentration was analyzed on a DMB in 296 canine liver samples that were collected from the left lateral lobe at necropsy from dogs, predominately Beagles and solely from the internal feeding colony at Hill’s Pet Nutrition, that were humanely euthanized by a veterinarian when quality of life had declined and prior to the planning of this study. Some dogs were bred at our facility and others were acquired externally. This study utilized liver samples available as a census and did not require specific criteria for sample selection. Dogs from which liver samples were obtained were representative of a population being fed a wide variety of commercial foods, and therefore exact diet histories were not evaluated. These dogs participated in various studies, including palatability and digestibility studies. The 296 dogs utilized in this study consumed 19,331 foods (76% dry, 22% wet, 2% other forms), including those from Hill’s Pet Nutrition (88% of foods fed) and a range of other commercially available foods from other brands (12% of foods fed). On average, the cohort of 296 dogs utilized in this study consumed 744 different foods per year and individual dogs consumed 111 different foods per year.
Sample analysis
At necropsy, liver samples were flash frozen in liquid nitrogen and transferred to a –80 °C freezer for long-term storage. The entire liver sample, approximately 0.5 to 2.5 g obtained from the left lateral lobe, was weighed into an aluminum pan and dried to completion at 104 °C, approximately 4 hours. The dried sample was then ground to uniform size. A known portion of approximately 0.25 g (entire sample if < 0.25 g was available) was digested to completion with nitric acid in a microwave digestion system (Multiwave 7000 Microwave Digestion System; Anton Paar GmbH). The digested sample was then diluted to 50 mL with deionized water and analyzed with inductively coupled plasma-optical emission spectrometry (5100 ICP-OES; Agilent Technologies) with a 5-point calibration line for copper quantification. Each individual sample was analyzed 3 times for copper concentration, and the 3 replicates were averaged to determine the reported results. Additionally, multiple control samples were prepared and analyzed, including a National Institute of Standards and Technology–certified beef liver sample to ensure that the sample preparation and instrumentation stayed consistent between runs and were within acceptable limits of expected values on the certificate of analysis. All hepatic copper concentration results are reported as ppm on a DMB.
The sample pathology reports were completed by board-certified veterinary pathologists at Kansas State Veterinary Diagnostic Laboratory, an American Association of Veterinary Laboratory Diagnostician–accredited laboratory. Pathologists classified liver conditions as normal or abnormal, with additional comments if the sample was deemed abnormal.
Statistical analysis
The effect of sex and liver histopathology on liver copper concentrations was assessed by 2-sample t tests with PROC TTEST in SAS (version 9.4; SAS Institute Inc). Two regression methods were used to assess the effect of age at death and year of death on liver copper concentrations. The first approach was to calculate the mean for each year of death and use the means to assess linear, quadratic, and cubic trends in liver copper concentrations. This approach has the advantage in that the central limit theorem states that the sampling distribution of the means will always be normally distributed if the sample size is large enough, regardless of the underlying distribution. Thus, it meets many of the statistical assumptions underlying linear regression. These analyses were performed with PROC REG in SAS. The lack of statistically significant differences in liver copper concentrations between dogs of different ages and liver histopathology indicated there was no benefit in dividing or categorizing the data for the regression analyses.
In many environmental and public health studies, there is interest in not only the average change but changes in the upper or lower tails of a distribution. Quantile regression is used where upper limits of quantiles of pollution levels are critical from a public health perspective. Quantile regression makes no distributional assumption about the data or the error term in the model, can be used for modeling data with heterogeneous conditional distributions, and is very robust to extremes in the response variable.29 Therefore, quantile regression was used to assess trends over age and year of death for selected quantiles. For this analysis, 5 quantiles of 0.05, 0.25, 0.50 (median), 0.75, and 0.95 were selected to examine trends in both the extremes of the tails (0.05 and 0.95) and middle of the distribution in liver copper concentrations. PROC QUANTREG in SAS was used to perform quantile regression. The ALGORITHM=INTERIOR option was used to estimate the regression parameters, and the CI=RESAMPLING option was used to estimate the CI around the slope coefficients. All analyses were performed with SAS (version 9.4; SAS Institute Inc). A P value ≤ .05 was considered statistically significant.
Results
Of the 296 samples, on the basis of histopathology, 213 samples were considered abnormal, 82 samples were considered normal, and 1 sample was unable to be evaluated. The 296 samples were obtained from 283 Beagles and 13 mixed-breed dogs (Table 1). Additionally, of the 296 samples, 155 were spayed females and 141 were neutered males, and the mean age at death was 13.1 (SE = 0.1) years for the 296 samples. Demographic information and year of death/collection ranging from 2006 to 2022 are provided in Table 1 and Table 2, respectively. Of note, 1 sample with a liver copper concentration of 2,670 ppm was identified as an extreme outlier because it was > 7 SDs outside the population mean and > 6 times greater than the upper limit of reference or normal range for dogs and thus was excluded in the analysis. This dog was an 8-year-old neutered male Beagle with a liver histopathology report of normal.
Demographic information and liver copper concentrations of necropsied liver samples from dogs.
| Variable | n* | Liver copper concentrations (ppm)† |
|---|---|---|
| Age (y) | 13.14 ± 0.142 | |
| < 1 | 1 | 204 ± — |
| 1 | 1 | 196 ± — |
| 2 | 2 | 451 ± 361 |
| 4 | 1 | 186 ± — |
| 7 | 5 | 224 ± 44 |
| 8 | 4 | 241 ± 86 |
| 9 | 12 | 271 ± 49 |
| 10 | 18 | 245 ± 39 |
| 11 | 15 | 267 ± 27 |
| 12 | 51 | 259 ± 17 |
| 13 | 62 | 244 ± 13 |
| 14 | 64 | 244 ± 18 |
| 15 | 46 | 254 ± 16 |
| 16 | 14 | 309 ± 35 |
| Sex | ||
| Female | 155 | 254.2 ± 9.6 |
| Male | 141 | 253.9 ± 11.7 |
| Breed | ||
| Beagle | 283 | 255.5 ± 7.7 |
| Mixed breed | 13 | 222.4 ± 25.8 |
| Liver histopathology‡ | ||
| Normal | 82 | 241.3 ± 11.4 |
| Abnormal | 213 | 259.5 ± 9.4 |
*N = 296.
†Values represent the mean liver copper concentration ± SE.
‡One sample was unable to be evaluated.
Year of death (YOD)/collection and liver copper concentrations of necropsied liver samples from dogs.
| YOD/collection | n* | Liver copper concentrations (ppm)† |
|---|---|---|
| 2006 | 4 | 221 ± 33 |
| 2007 | 6 | 219 ± 36 |
| 2008 | 7 | 220 ± 43 |
| 2009 | 4 | 259 ± 74 |
| 2010 | 3 | 255 ± 41 |
| 2011 | 7 | 217 ± 43 |
| 2012 | 3 | 208 ± 30 |
| 2013 | 3 | 219 ± 74 |
| 2014 | 36 | 212 ± 23 |
| 2015 | 19 | 200 ± 26 |
| 2016 | 18 | 308 ± 44 |
| 2017 | 23 | 297 ± 21 |
| 2018 | 31 | 293 ± 28 |
| 2019 | 34 | 247 ± 23 |
| 2020 | 42 | 249 ± 16 |
| 2021 | 30 | 291 ± 24 |
| 2022 | 26 | 246 ± 17 |
*N = 296.
†Values represent the mean liver copper concentration ± SE.
The average liver copper concentration for all samples was 254.1 (SE = 7.5) ppm. There were 61 liver tissue samples (21%) below the normal reference range for copper concentration (< 150 ppm), with a mean copper concentration of 111.4 (SE = 5.0) ppm, and 27 samples (9%) above the normal reference range (> 400 ppm) ranging from 421 to 891 ppm, with a mean copper concentration of 538.1 (SE = 25.5) ppm. Liver tissue samples within the reference range had a mean copper concentration of 259.1 (SE = 4.6) ppm.
Of the 61 samples below the normal reference range, 46 had abnormal pathologies. The pathology reports of these 46 samples had findings consistent with 1 or more of the following: hepatocellular degeneration (n = 19), hyperplasia (17), hemosiderin pigmentation (7), neoplasia (6), fibrosis (5), vacuolation (5), inflammation (4), bile stasis (3), lipofuscin pigmentation (3), unspecified pigmentation (1), cysts (1), necrosis (1), and hemorrhage (1; Supplementary Table S1). Of note, some dogs had > 1 hepatic pathology finding and humane euthanasia was elected for 2 dogs with hepatic copper concentrations of 90.7 and 93.9 ppm due to declined quality of life associated with hepatic and renal disease.
Of the 27 samples above the normal reference range, 23 had reported abnormal hepatic pathology with the following findings: hepatocellular hyperplasia (n = 8), degeneration (8), inflammation (5), hemosiderin pigmentation (5), neoplasia (4), fibrosis (4), necrosis (3), lipofuscin pigmentation (2), vacuolation (2), bile stasis (2), unspecified pigmentation (1), thrombosis (1), lipogranulomas (1), granulomas (1), ductular reaction (1), hepatitis (1), and cholangitis (1; Supplementary Table S2). Of note, some dogs had > 1 hepatic pathology finding and humane euthanasia was elected for 3 dogs with hepatic copper concentrations of 463.3, 484.3, and 638.8 ppm due to declined quality of life associated with hepatic disease. The remaining 208 samples (70%) had copper concentrations within the normal reference range (150 to 400 ppm), with 144 samples having abnormal pathology.
The pathology reports of these 144 samples had primary findings consistent with 1 or more of the following: hepatocellular hyperplasia (n = 34), degeneration (32), unspecified pigmentation (16), neoplasia (13), fibrosis (13), lipofuscin pigmentation (10), vacuolation (9), inflammation (9), congestion (3), necrosis (2), cholestasis (2), ductular reaction (1), lobular atrophy (1), cord atrophy with suspected fibrosis (1), cyst (1), thrombosis (1), and erosion (1).
Age (P = .85; r2 = 0.004) and sex (P = .99) had no effect on liver copper concentrations of dogs (Table 1). Mean copper concentration of abnormal liver histopathology samples (259.5 ppm; SE = 9.4) was not different (P = .22) from mean copper concentrations of normal liver histopathology samples (241.3 ppm; SE = 11.4). However, liver copper concentrations increased linearly during the years used in this study (slope = 3.41 ppm, SE = 1.53, P = .0415; Figure 1). Quantile linear regression analysis of age at death (Table 3) and year of death (Table 4) in quantiles 0.05, 0.25, 0.5 (median), 0.75, and 0.95 showed that the linear increase in liver copper concentrations with year of death was statistically significant (P = .0495) only in the 0.25 quantile, indicating that there was a slight increase in liver copper concentrations on the lower side of the median. There was no significant increase (P > .05) in liver copper concentrations in either of the tails of the distribution (0.05 and 0.95 quantiles), meaning that the lowest 5% and highest 5% of liver copper concentrations analyzed in the present study were not changing, nor did the median value change with years. Quadratic and cubic trends were not statistically significant (P > .05) for the means or any of the 5 quantiles when age at death and year of death were assessed by quantile regression analysis. In summary, the lower and upper extremes were not changing and only a slight increase (3.7 ppm per year) was observed in the lower 25% of samples.
Mean yearly hepatic copper concentrations of dogs from the years 2006 to 2022. Red lines represent the lower (150 ppm) and upper (400 ppm) limits of the normal copper range.11,12
Citation: Journal of the American Veterinary Medical Association 2025; 10.2460/javma.24.09.0634
Regression equations, 95% CI around the slope, and P value for trends in liver copper concentration with age at death for the mean age values (one-tenth–year intervals) and selected quantiles.
| Parameter | Equation | 95% CI | Pr > |t|* |
|---|---|---|---|
| Mean age | Cu = 258 + 0.7 X age | –6.4 to 7.7 | 0.8517 |
| 0.05 quantile | Cu = 86 + 1.4 X age | –9.8 to 12.5 | 0.8100 |
| 0.25 quantile | Cu = 103 + 4.9 X age | –0.7 to 10.5 | 0.0858 |
| 0.50 quantile | Cu = 201 + 2.8 X age | –3.7 to 9.3 | 0.3948 |
| 0.75 quantile | Cu = 277 + 3.3 X age | –8.0 to 14.7 | 0.5630 |
| 0.95 quantile | Cu = 668 – 14.0 X age | –43.9 to 15.9 | 0.3578 |
*Pr > |t| is the probability of observing a value equal to or greater than the calculated t statistic.
Regression equations, 95% CI around the slope and P value for trends in liver copper concentration with year of death for regression by use of the means and selected quantiles.
| Parameter | Equation | 95% CI | Pr > |t|* |
|---|---|---|---|
| Yearly means | Cu = 214 + 3.4 X year | 0.15 to 6.7 | 0.0414 |
| 0.05 quantile | Cu = 54 + 3.8 X year | –5.1 to 12.8 | 0.4013 |
| 0.25 quantile | Cu = 117 + 3.7 X year | 0.009 to 7.4 | 0.0495 |
| 0.50 quantile | Cu = 201 + 2.6 X year | –0.7 to 5.9 | 0.1274 |
| 0.75 quantile | Cu = 278 + 3.2 X year | –1.5 to 8.0 | 0.1837 |
| 0.95 quantile | Cu = 366 + 9.5 X year | –5.3 to 24.2 | 0.2088 |
*Pr > |t| is the probability of observing a value equal to or greater than the calculated t statistic.
Discussion
There have been reports of an increase in hepatic copper concentrations over the past 2 decades, but it has not been confirmed whether dietary copper is the sole cause. As such, the goal of this retrospective study was to contribute to the larger body of scientific evidence surrounding this topic by assessing liver copper concentrations in available samples from internal colony dogs, which mostly consisted of Beagles, in the Hill’s bioarchive. The present study demonstrated no effect of age, sex, or histopathology on liver copper concentrations, and mean copper concentration increased linearly, specifically concentrated in the 25th lower quantile, over time but remained within normal ranges.
Liver samples utilized in the present study were from necropsies performed over a span of 16 years (2006 to 2022) and had a mean copper concentration of 254.1 (SE = 7.5) ppm. Likewise, 1 study14 showed that liver samples collected and analyzed between 1980 and 2010 from Labrador Retrievers without chronic hepatitis had an average copper concentration of 299 ppm. Additionally, this study14 investigated Labrador Retrievers with and without copper-associated hepatopathy in 2 different time periods and identified an increase in hepatic copper concentration in all dogs over time and acknowledged that the direct cause of this increase was unknown. In that same study,14 Labrador Retrievers with chronic hepatitis had an average copper concentration of 614 ppm, which was significantly higher than dogs without chronic hepatitis. Another study8 showed that copper concentrations increased in both predisposed and nonpredisposed breeds over time. Some investigators 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 the largely nonbioavailable copper oxide.7
While conclusions have been made that the increase in liver copper concentration in dogs is associated with dietary intake,7 other investigators have emphasized that the true cause-and-effect relationship is unknown and that this investigational topic could have potentially raised awareness because of other reasons.8,14 The present study showed that liver copper concentrations of the population assessed increased linearly by an average of 3.41 (SE = 1.53) ppm per year; however, mean liver copper concentration for each year assessed remained within normal copper ranges. In addition, the linear increase observed could be due to the limited number of samples for the years 2006 to 2013 as compared to the remaining years. Further, on the basis of the quantile regression analysis, which is insensitive to outlier values and non-normality in the data, no increase or decrease in copper concentration over time was observed in the most extreme values including the lowest quantile (5%) and highest quantile (95%). The increase in liver copper concentration over time was concentrated in the 25th quantile, which increased over time by 3.7 ppm per year. The clinical significance of these results is that there is no evidence that the lower limit of exposure to copper in dogs has increased over time and there is no evidence that the upper limit of exposure to copper in dogs has changed over time, so the statistically significant change in the mean appears to be caused by shifts within the population rather than by overall movement of the population (ie, the tails did not move). Of the 297 samples, 30% were outside of the normal reference range for liver copper, and there are other factors that could have contributed to these findings.
Other factors such as mineral-to-mineral interactions, mineral routes of absorption, and mineral bioavailability should be considered. Mineral-to-mineral interactions, which can be direct or indirect, may also play a role in bioavailability.30 Direct mineral interactions occur when minerals compete for receptor binding in the intestine, affecting absorption of the minerals.30 Indirect mineral interactions occur when one mineral affects the metabolism of another due to its overabundance or deficiency.30 If the dietary supply and/or body reserve of a nutrient are low, the intestine adapts to improve the efficiency of uptake of that nutrient with concomitant enhancement to the absorption of similar minerals.31 For example, hepatic and intestinal copper concentrations may be increased due to iron deficiency or low concentrations of dietary iron.32 Although, additional studies are warranted to examine whether mineral interactions may play a role in copper accumulation in the liver. Additionally, since the liver is involved in functions and deposits of various minerals such as iron, zinc, and copper, excesses or deficiencies of one of these minerals could result in compensation of using another mineral, which may result in hepatic dysfunction.31
As an example, zinc has been prescribed to help lower hepatic copper concentrations. In predisposed breeds with hepatic copper toxicosis—Bedlington Terriers and West Highland White Terriers—zinc acetate, initially provided at 200 mg per day and later reduced to 50 to 100 mg per day, was shown to decrease hepatic copper concentrations over a 2-year period.33 However, in a study34 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 largely 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.1,35 Metallothionein is associated with the kidney, liver, and intestines and changes with dietary zinc, the administration of other metals like copper and cadmium, stress, glucocorticoids, infection, food restriction, and endotoxin treatment.35 When zinc is the primary metal bonded to the protein, metallothionein degrades quickly unless copper or cadmium is bound to the protein as well.35 In humans with Menkes and Wilson diseases, copper accumulation in various tissues may be a result of altered metallothionein turnover.35 This may be true for other mammals, but further investigation is warranted.
Copper, zinc, and iron are mostly available in the organic form found in meat ingredients, especially organ meat, compared to inorganic mineral supplements.1 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.1 Tissue damage associated with copper accumulation in Bedlington Terriers may be a result of ineffective biliary copper excretion from the deletion of exon 2 of the copper metabolism domain containing 1 gene, which is involved in copper transport.36 All of these factors could contribute to deficiency or excess of liver copper accumulation; however, additional investigation is necessary to support these hypotheses.
The present study consisted of 96% Beagles and 4% mixed-breed dogs, and, as such, evaluating the effect of various breeds on liver copper concentrations requires additional research of a more diverse population of breed types. Additionally, further investigation is needed in predisposed breeds, as this study was a starting point for understanding baseline liver copper concentrations in dogs. Copper-associated hepatopathies are commonly observed in breeds such as Bedlington Terriers, Labrador Retrievers, Doberman Pinschers, and other suspected predisposed breeds due to a defect in copper metabolism.37
One limitation of this retrospective study was the limited evaluation of foods and mineral content fed to the dogs in the study. Dogs from the Hill’s internal colony are routinely fed various commercialized foods, including both Hill’s foods and a range of competitors’ foods, but may have also been fed a limited array of therapeutically intended foods. Another limitation of the present study was that the population primarily consisted of Beagles; as such, additional investigation is required in other breed types, especially predisposed breeds. The limited number of samples for years 2006 to 2013 as compared to the remaining years presented another limitation of the present study. Other limitations included the use of a partial sample of each liver from a single region (left lateral lobe) and the lack of histochemical staining and quantification of minerals known to interact with copper. Furthermore, it is unknown whether cases having abnormal liver pathology could have affected the determination of hepatic copper concentrations.
This study demonstrated that age, sex, and histopathologic findings had no effect on liver copper concentrations of the dogs assessed. Analysis of year of death showed that liver copper concentrations of the population assessed increased linearly over time by an average of 3.41 (SE = 1.53) ppm per year; however, mean liver copper concentrations remained within normal limits over the 16-year period. Of the five dogs that were euthanized due to hepatic disease and had hepatic copper concentrations outside of the normal reference range, more information on these specific hepatic disease cases could have provided valuable insight. The present study serves as a starting point for understanding baseline liver copper concentrations in dogs, warranting additional research on a larger and more diverse population of dogs in which diet histories are evaluated.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org.
Acknowledgments
The authors would like to greatly acknowledge Tara Carter, 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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