Preventing the Pitfalls: Copper-Associated Hepatopathy in Dogs

In 2017, faced with an arduous eight-month journey to uncover a diagnosis for my cherished companion, Riggs, an Old English Sheepdog, I navigated the complexities of his health challenges— copper associated hepatopathy (CuAH).

Confronted with a myriad of responses ranging from uncertainty to disheartening indifference, I persevered in advocating for Riggs, grappling with the emotional toll of navigating an intricate medical landscape for my beloved dog. The challenges encountered during this journey became a catalyst for my pursuit of knowledge and expertise in the realm of veterinary health.

Riggs OVC

Canine associated hepatopathy (copper storage disease) is recognized with increasing frequency, while growing studies are demonstrating it is possible that a dietary ingredient (cu) plays a role due to several industry changes, which may give answers to those with an unknown etiology.

Now, our story, once unique and rare, is not just an isolated case but rather a part of a growing recognition of CuAH. As studies accumulate, shedding light on the possible role of a dietary ingredient (copper) in this condition, our journey has become a shared narrative, offering insights and answers to those who grapple with the same diagnosis.

Where once we faced invisibility, there is now a resounding call for recognition and change. The echoes of advocacy resonate strongly, urging a transformative shift in how we understand and manage CuAH. Renowned veterinarians advocate their evidence to support recommendations to reexamine dietary copper for dogs and reconsider current guidelines for copper content in commercial dog foods.

Copper storage disease occurs when the amount of dietary copper ingested exceeds a dog’s tolerance level and accumulates in the liver.

Copper, an essential trace mineral, plays a crucial role in the physiological processes of dogs as it cannot be endogenously synthesized and must be obtained through dietary intake. Its significance lies in its ability to serve as an activator for various enzymes that are vital for numerous biochemical processes. While copper is indispensable for maintaining canine health, an imbalance or excess can lead to adverse effects, particularly in the liver, where copper metabolism is intricately regulated.

Copper-associated liver injury in dogs manifests insidiously, with a subtle and often covert onset.

The liver has a large regenerative capacity. However, symptoms may not be obvious until 70% of the liver is damaged as the liver has a reasonable ‘reserve’ capacity. Clinical signs are often non-specific and often insidious making the diagnosis of liver disease challenging. You may only notice elevations on routine lab work because the dog’s clinical signs range variably from one individual to the next. However, symptoms usually only occur once the reserve capacity of the liver has been exceeded.

The insidious nature of this condition lies in its ability to develop over time without immediate and overt symptoms. However, with chronicity, the consequences can be severe, even lethal. The slow progression of copper accumulation in the liver underscores the importance of vigilant monitoring and early intervention to mitigate the potential life-threatening outcome.

Copper associated liver injury in dogs is insidious and onset, with chronicity it can be lethal.

The liver, as an organ that adjusts homeostasis, exhibits the most severe and apparent injury with copper accumulation.

FDA Virtual Listening Session on the Oversight of Pet Food- Center -Slides for FDA SA Center Copper Canine Dog Food
FDA Virtual Listening Session on the Oversight of Pet Food- Center -Slides for FDA SA Center Copper Canine Dog Food
FDA Virtual Listening Session on the Oversight of Pet Food- Center -Slides for FDA SA Center Copper Canine Dog Food
FDA Virtual Listening Session on the Oversight of Pet Food- Center -Slides for FDA SA Center Copper Canine Dog Food

“Copper provokes oxidative injury through a complex series of interrelated chemical reactions. Importantly the net reaction is generation of the injurious hydroxyl radical that can independently cause cell death or worsen coexistent diseases.” Dr. Center – FDA Virtual Listening Session on the Oversight of Pet Food.

This condition, when left unchecked and progressing into chronicity, poses a grave threat, ultimately lethal for the pet. The insidious nature of copper-associated liver injury underscores the importance of vigilant monitoring, timely detection, and proactive intervention in canine health care to safeguard against its potentially severe consequences.

Copper-associated hepatopathy (CuAH) found its initial documentation in Bedlington Terriers in 1979, while several other breeds, including Labrador Retrievers, Doberman Pinschers, Dalmatians, West Highland White Terriers, Welsh Corgis, Keeshonds, and others, have been notably affected by this condition. It’s crucial to clarify that an intolerance to dietary copper is now seen as not secondary to a more primary liver disease in dogs, and cannot be assigned to a genetic mutation – with the exception of the COMMD1 in Bedlington Terriers and copper-mediated liver injury in Labrador Retrievers which may be influenced by mutations in ATP7B gene, which predispose to copper accumulation, and mutations in ATP7A gene, the intestinal Cu transporter, which protects against Cu accumulation. It is now well recognized that the surge in CuAH cases transcends traditional breed boundaries. Mixed breed dogs and those often referred to as “designer” dogs, combining various breeds, have emerged as highly susceptible to CuAH as well.

Copper storage disease transcends traditional breed boundaries. This affects all dogs, all breeds, including mixed breed dogs and those often referred to as "designer" dogs.
Copper storage disease transcends traditional breed boundaries. This affects all dogs, all breeds, including mixed breed dogs and those often referred to as "designer" dogs.

Copper Concentration in Commercial Maintenance Dog Food Exceeds Tolerance for Numerous Healthy Dogs

A “White Paper” was published as an Open Access Commentary in JAVMA authored by the Copper Hepatopathy Working Group, which consists of diplomats of Board-certification in veterinary internal medicine, veterinary pathology, veterinary nutrition, and veterinary sports medicine and rehabilitation. J Am Vet Med Assoc 2021 Feb 15;258(4):357-364.

The 2013 manuscript where the Labrador Retriever was used to demonstrate the impact of altered dietary copper regulations, copper was measured in the liver of dogs with and without hepatitis in subsets representing era’s before and after altered copper guidelines. Liver copper concentrations showed a notable increase in alignment with the adjusted dietary copper recommendations.

This objective data validates the concern that allowances for dietary copper mandated by regulatory agencies – the NRC (National Research Council) and AAFCO (Association of American Feed Control Officials), exceed physiologic tolerance for many healthy dogs. This has been since modifications of food grade copper pre mix supplements in approximately 1993.

Dr. Center - FDA Virtual Listening Session on the Oversight of Pet Food
Dr. Center - FDA Virtual Listening Session on the Oversight of Pet Food

While the adoption of commercial dog diets has undoubtedly streamlined canine care and enhanced the well-being of our dog companions, the routine nature of daily feeding may give rise to cumulative effects. An intriguing correlation emerges between dietary formulations and a gradual upswing in hepatic copper concentration in dogs, a trend that has gained momentum since the widespread acceptance of commercial dog foods in the late 1940s. The pinnacle of these liver values becomes particularly pronounced following the most recent alterations in copper supplements.

Available data spans a period of almost 100 years. In 1929, the first study reported mean hepatic liver levels of less than 10 micrograms (μg) per gram of liver (dry weight) in the dogs studied.

A second study in 1982 discovered average liver values had increased to 200 μg/g, an increase of about 20-fold following the introduction and widespread use of commercial pet foods. The average copper concentration increased again to 453 μg/g between 1982 and 1995.

Is it time to reconsider current guidelines for copper content in commercial dog foods?
Hepatic copper concentrations in 546 dogs (1982-2015)
Hepatic copper concentrations in 546 dogs (1982-2015)

Recognizing Copper-Associated Hepatopathy
Early recognition of CuAH is difficult as these dogs do not demonstrate signs of illness. Rather, they display increased serum ALT activity, one of the liver enzymes that vacillates. With more advanced disease, these dogs develop obvious laboratory and physical (ethargy, inappetence, vomiting, jaundice, distended abdomen) and imaging findings (small liver, ± nodules abdominal fluid/ascites) indicative of a severe liver injury. These dogs are more difficult to treat and have a more dismal prognosis.

Diagnosing Copper-Associated Hepatopathy
The cornerstone of this diagnosis hinges upon obtaining a liver biopsy, a procedure meticulously performed through laparoscopic or open surgical methods. Needle biopsies, deemed less accurate, and a mere extraction of liver aspirates proves inadequate for establishing this diagnosis definitively. Definitive diagnosis requires pathological inspection of tissues and reconciliation with the degree of hepatic copper accumulation.

Copper-Specific Staining (rhodanine) Rhodanine is one of the chemical stains that selectively highlights copper deposits in liver tissues. By employing this staining method, veterinary professionals can visually identify and assess the distribution of copper within the liver.

Histological section of canine liver. Rhodanine stain. Magnification
Histological section of canine liver. Rhodanine stain. Magnification

Qualitative Scoring (0-5 scale) A qualitative scoring system ranging from 0 to 5 is employed to subjectively evaluate the extent and severity of copper accumulation within the liver. This scale provides a nuanced assessment, allowing for a qualitative understanding of the degree of hepatic involvement.

Quantification (ppm or µg/gm Dry Weight Liver) The quantification stage involves measuring the actual concentration of copper in the liver tissue. This is typically expressed in parts per million (ppm) or micrograms per gram (µg/gm) of dry weight liver. Quantification provides a precise and quantitative assessment of the copper content, aiding in understanding the severity of hepatic copper accumulation.

Reconciliation The reconciliation phase is a comprehensive analysis that integrates the quantified copper levels, qualitative scoring results, and a histologic correlation. By examining the association between areas of liver injury and copper accumulation, veterinarians can reconcile the various diagnostic components. This step ensures a thorough understanding of the interplay between histological changes, qualitative assessments, and actual copper concentrations, contributing to a definitive diagnosis of CuAH.

Costs Associated with CuAH
Costs associated with CuAH involve the diagnostic and treatment expenses. This can range $2000 – $5000 for just the initial diagnostic phase. The diagnostic process introduces a set of challenges that directly impact pets. The necessity of diagnostic procedures, such as liver biopsies, brings forth surgical and anesthetic risks adding a layer of complexity to their overall well-being. The diagnostic phase, while crucial for identifying and managing CuAH, the biopsy process itself while introduces discomfort, and the subsequent recovery period may involve additional challenges for the affected animals.

Riggs' Pet Insurance Biopsy Claim
Riggs' Pet Insurance Biopsy Claim

Beyond the financial strain, this condition inflicts additional costs, like the emotional toll on pet owners, navigating the challenges of diagnosis and treatment, which further contributes to the multifaceted costs associated with addressing this intricate liver condition. Once your dog is diagnosed with copper storage disease, I can assure you, the unrest never ends, echoing the perpetual worry and heartfelt concern for your cherished companion’s well-being.

Sheepdog Riggs recovering post biopsy
Sheepdog Riggs recovering post biopsy
Sheepdog Riggs recovering post biopsy
Sheepdog Riggs recovering post biopsy
Sheepdog Riggs recovering post biopsy
Sheepdog Riggs recovering post biopsy

This is a lifelong disease that demands continuous management, encompassing a comprehensive approach. This includes regular veterinary monitoring to track the progression of the condition, specialized diets tailored to mitigate copper accumulation, and the administration of medications and supplements designed to support liver health.

Riggs’ lifelong management of copper storage disease - pet insurance reimbursement total example costs
Riggs’ lifelong management of copper storage disease - pet insurance reimbursement total example costs

The multifaceted costs associated with CuAH not only extend to financial expenses but also encompass the emotional toll on pets, pet owners – and the veterinary team, highlighting the importance of a dedicated and supportive care approach for the well-being of affected pets throughout their lifetime.

Treatment
Veterinarians integrate chelation therapy as a crucial component in the comprehensive treatment protocol for CuAH. The chelating agent of choice, D-penicillamine (D-Pen), is meticulously administered to bind with copper and effectively facilitate its removal from the body. D-Pen’s targeted therapeutic action aims to mitigate the toxic effects associated with the accumulation of copper in the liver. Notably, D-Pen enhances metallothionein levels in hepatocytes, contributing to the detoxification of intracellular copper, and in enterocytes, facilitating its elimination through the feces. Additionally, D-Pen exhibits mild anti-inflammatory and anti-fibrotic properties, adding to its multifaceted role in addressing CuAH and supporting liver health in affected dogs.

Predicting the duration of chelation required for individual dogs poses a challenge, necessitating vigilant monitoring by veterinary professionals. D-Pen is compounded at specialty pharmacies, and though these formulations prove effective, the associated costs are notably high.

D-penicillamine proven effective, the associated costs are notably high.
D-penicillamine proven effective, the associated costs are notably high.

In response to oxidative liver injury induced by copper accumulation, the utilization of hepatoprotective medications are used for their anti-inflammatory benefit. This includes S-adenosylmethionine (SAMe) as it generates glutathione (GSH) and vitamin E.

Ursodiol is a bile acid that helps to decrease the amount of cholesterol produced by the liver and absorbed by the intestines. It serves as a multifaceted agent, demonstrating antioxidant, choleretic, immunomodulatory, and anti-inflammatory properties.

Immunosuppressive therapies, such as prednisolone, azathioprine, or cyclosporine, are also used.

Tracing the Trace Mineral | The Evolution of Excessive Copper in Canine Diets

How did this become a problem? Modifications in food-grade copper additives in commercial dog food. The increasing frequency of cases began in the late 1990s.

In 1988, Chelated copper sulfate replaced the use of copper oxide in pigs to improve growth rate in industrial swine farming. This approach became not only exclusive to pigs, but has been explored in various livestock species to optimize nutrient utilization and enhance growth.

This correlated with the change in the premixes used to supplement Cu in commercial dog foods, which resulted in higher amounts of bioavailable Cu in diets.

This was based on a small study in purpose-bred dogs in 1993 published only as an abstract that concluded low bioavailability of copper oxide precluding its use as a dietary supplement. This data was never published as a peer review manuscript. The baseline diet was not distinguished in the abstract. The outcome recommendation was to replace copper oxide with highly bioavailable copper chelates. In application of this recommendation the baseline dietary copper content is not considered and importantly this change was instituted despite no evidence of copper insufficiency in any pet dog that is known to be fed commercial diets before the recommended change.

AAFCO

No additional empirical data has been added to the scientific nutritional literature that bears on what a maximum limit for copper should be in normal dogs in the years since 2006.

Pet food manufacturers are obligated to follow NRC and AAFCO recommendations. The abstract recommendations were inactive regardless of base diet copper content typically not clearly defined by labeling. Currently, standardized premix containing bioavailable copper chelates is added to canine formulated diets. In commercial dog diets, the net impact is an increase in bioavailable copper.

The Cu concentrations in dog foods often exceed NRC recommendations by >2-4.

From the ACVIM consensus statement on the diagnosis and treatment of chronic hepatitis in dogs:

The NRC recommendations were extrapolated for adult dogs based on observations of puppies fed diets containing 0.11-0.19 mg/100 kcal metabolizable energy/day that resulted in reduced serum ceruloplasmin concentrations. Serum ceruloplasmin concentrations however do not reflect copper (Cu) bioavailability and this assumption may be not valid for dietary Cu adequacy and dietary recommendations.

The AAFCO recommendations for adult maintenance require a minimum of 7.3 mg/kg/DM/d with no maximum limit, regardless of the Cu source. This recommended amount of Cu is typically added as a premix but fails to also include the Cu present in the base diet. Changes in premix formulations containing Cu oxide with a bioavailability of ~5% to that of Cu chelates (acetate, sulfate, and carbonate) with ~60%-100% bioavailability significantly increases the amount of Cu absorbed. Consequently, there is a large variation in the Cu concentrations in dog foods and many commercial foods have Cu concentrations that far exceed the NRC recommendations by 2-4 times or even more.

Hepatic diets specifically Royal Canin Hepatic, Hills L/d and Purina HP Hepatic (Europe only) contain Cu concentrations below AAFCO and NRC requirements. These diets approximate the dietary Cu concentration of approximately 5 mg/kg DM that is the concentration that maintained affected Bedlington Terrier in a neutral Cu balance.

What can be done?
Pet food companies cannot independently make these dietary corrective changes to copper without NRC-based FDA recommendations for AAFCO regulation. Unfortunately, AAFCO believes the recommendations for copper in commercial dog food are appropriate, until scientific data shows otherwise. Their expert panel determined there is “insufficient empirical data to establish a safe upper limit or maximum tolerable level in normal dogs” – but this was not a unanimous decision. However, historic data supports copper adequacy without copper additives, when non-bioavailable copper oxide was used before 1993. As tolerated copper intake for many dogs is already being exceeded, copper should be scaled back to estimated intake before the change. Due to copper oxide lacking bioavailablity, it has also been acknowledged that it is probable that base diets deliver biologically adequate copper intake.

The FDA and AAFCO need to empower pet food companies to decline copper additives. The white papers, co-authored by members of the Copper Hepatopathy Working Group, present substantiating evidence in ways to assist with the mitigation of this avoidable and tragic nutritionally provoked canine illness.

A pivotal step in addressing the rising cases of CuAH in dogs is reexamining and determining copper intake in dogs. This is a change that can and should be made, as it is already known we are exceeding the tolerated intake with data that supports copper delivery in base diets is adequate. 

Not only should maintenance diets be revised as an easy preventative to CuAH, but pets living with this disease have limited options to treatment. CuAH, shaping Riggs’ diet, extends beyond preferences; it’s a necessity. The disease doesn’t just affect dogs like Riggs’s health, but dictates what he can eat. This isn’t merely a culinary preference but a crucial element in mitigating copper intake, a vital consideration for CuAH patients.

The challenge magnifies where only two low-copper dietary options exist, Hills L/D and Royal Canin Hepatic, with production interruptions exacerbating the scarcity.

The formulation of the two available hepatic diets on the market is designed to address the needs of various hepatopathies. Specifically, they are crafted to be low in protein, particularly beneficial for cases involving encephalopathy. It’s important to note that while this protein restriction is essential for certain conditions, it is not necessary for the majority of dogs and creates more challenges than it resolves.

Consultations with board certified veterinary nutritionists are a necessary option, where balancing the diet underscores the need for specialized expertise to orchestrate a nutritional strategy that aligns with the unique needs of each individual affected by CuAH. This demands scientific precision to achieve optimal nutritional support while mitigating the risk of exacerbating hepatic copper accumulation. This specialty service is just another critical aspect of disease management.

When faced with a diagnosis of copper-associated hepatopathy, it becomes evident that copper is ubiquitous – it’s in everything. This realization is not an exaggeration; rather, it stems from the profound presence of copper in various aspects of our environment, including food, soil, and water.

Copper in Food, Soil, and Water
Copper is present in a wide array of foods, both of plant and animal origin. The copper content in soil is influenced by geological factors. Certain regions naturally have higher copper levels in the soil, affecting the copper content in crops grown in those areas. Tap water, especially in areas with copper pipes, can contribute to overall copper intake, therefore, it is recommended to give distilled water to a dog diagnosed with CuAH.

The Challenge in Knowing Copper Intake
When it comes to caring for a dog diagnosed with copper-associated hepatopathy, the challenge lies in understanding and controlling copper intake. The complexities arise from:
1. Diverse Sources: Copper comes from various sources, making it difficult to pinpoint the exact amount consumed by your dog.
2. Synergistic and Antagonistic Effects: Interactions with other elements further complicate the scenario, affecting the bioavailability and utilization of copper.
3. Varied Forms: Copper exists in different forms in food, and its bioavailability can be influenced by the cooking process and the specific form of copper present.

Awareness of the pervasive nature of copper is crucial. Scientific understanding of copper’s role, interactions, and the challenges in measurement underscores the need for precise monitoring and management.

The challenge intensifies even more yet: navigating the day-to-day impact of Copper-Associated Hepatopathy (CuAH) on appetite adds a profound layer of concern. Limited dietary options further amplify the gravity of the situation. The disease’s influence on eating habits becomes a critical aspect of daily life, and with limited dietary options for dogs with CuAH, the stakes are elevated. The anxiety of having an ailing dog that won’t eat, coupled with the stark realization that there are scarce options to cater to their specific needs is a scenario that underscores the urgency and importance of expanding low copper dietary choices for affected dogs. Addressing this gap becomes paramount in providing comprehensive care and support for both dogs and their dedicated owners.

Copper-associated hepatopathy can be hard to diagnose, distressing to treat, but it is easy to prevent.

It is paramount to extend heartfelt gratitude to Dr. Sharon Center and the Copper-Associated Hepatopathy working group. Their unwavering commitment and their dedicated efforts in drawing attention to this complex condition have significantly contributed to our understanding, paving the way for enhanced diagnosis, treatment, and preventive measures. By shedding light on the challenges and potential solutions, they’ve empowered pet owners, veterinarians, and researchers alike in the collective mission to ensure the well-being of our cherished canine companions. Through shared knowledge and collaborative endeavors, we strive for a future where Copper-Associated Hepatopathy is not just a concern but a condition effectively managed and, where possible, prevented.

I extend my heartfelt gratitude to Riggs’ dedicated veterinary teams who have been an integral part of his journey through to the end. Your unwavering commitment to Riggs’ well-being and the exceptional care he received have made a significant impact. Your expertise, compassion, and dedication have not only helped Riggs navigate his health challenges but have also provided comfort and reassurance to those who care deeply for him. Thank you for your tireless efforts, compassion, and the invaluable support you’ve extended to Riggs. Your commitment to his well-being is truly appreciated and never forgotten. With sincere thanks and warm regards.

Copper Hepatopathy Working Group
• SA Center, DVM, DACVIM (Cornell University)
• JM Cullen, DVM, PhD, DACVP (North Carolina St. University)
• KP Richter, DVM, DACVIM (Ethos Veterinary Health)
• DC Twedt, DVM, DACVIM (Colorado St. University)
• JJ Wakshlag DVM, PhD, DACVN & DACVSMR (Cornell University)
• PJ Watson, VetMD, DACVIM & DECVIM (University of Cambridge, UK)
• CRL-Webster, DVM, DACVIM (Tufts University)

Source:

Relying on reputable sources in the veterinary industry provides a foundation of credibility and ensures accurate and trustworthy information for pet owners. For a comprehensive list please visit our Copper Storage Disease page.

This page is dedicated to a carefully curated collection providing up-to-date scientific resources and support to ensure you have access to the latest advancements and insights in the field. Our thoughtfully assembled array of research studies ensures you have access to the most recent breakthroughs and valuable insights in the field. As an integral part of this resource, we shed light on the crucial role played by the Association of American Feed Control Officials (AAFCO).

 Join our Group | Canine Copper-Associated Hepatopathy – An Evidence Based Approach

Synergistically Yours

Danielle & Sheepdog Riggs

forever in our hearts

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