Liver / Hepatic Disorders of the
Cavalier King Charles Spaniel

The predominance of disorders of the canine liver appear to vary depending upon the breed. The most common liver disorder in dogs is chronic hepatitis. Overall, the cavalier King Charles spaniel does not stand out as having a higher incidence of any form of hepatitis, hepatic cancer, of other severe disorders involving the liver.

Below is a listing of liver disorders of which the CKCS tends to be predisposed. 

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List of Disorders

Dog's LiverThe disorders include:

Hepatic lesions

Liver lesions are groups of abnormal cells in the dog's liver. They occur as a result of any of a variety of hepatic diseases which involve inflammation of the liver. Canine hepatic diseases are divided into two main types: primary and secondary. "Primary" means that the liver is directly affected by the disorder and consists of chronic hepatitis, acute hepatitis, fibrosis, cirrhosis, and neoplasia. "Secondary" means that the disorder is ancillary to some other bodily disorder and consist of hepatic congestion, hepatic vacuolation, and reactive hepatitis.

In a January 2016 article about the prevalence of hepatic lesions in cavalier King Charles spaniels, the livers of 54 deceased CKCSs were examined. Of those, 13 were found to have no liver disorders, and the remaining 41 had hepatic lesions associated with a combined total of 7 liver disorders. Only two of the cavaliers had been diagnosed with hepatic disorders prior to their deaths. The breakdown of hepatic disorders appears on the study's Table 3 below.

Table 3 

Secondary hepatic lesions were detected in 64.8% of the cavaliers in the study, while only 11.1% of them had primary hepatic lesions. The investigators stated:

"Hepatic lesions were commonly detected in this study, but the majority of cases were diagnosed as secondary to other diseases. For instance, congestion was assumed to be related to chronic heart disease. Although this supposition was not supported by the relative risk statistics, the sample size was small, and the power to detect these associations was weak. The finding of hepatocyte vacuolation is likely to be a secondary reactive change of the liver to a variety of other diseases."
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Hepatic mineralization

Hepatic mineralization describes the appearance of mineral "opacities" in any of a variety of patterns in the liver in x-rays. In a December 2017 article, its researchers assessed the prevalence and clinical significance of linear branching mineralization of dogs' livers on x-rays from one referral veterinary hospital over a period off 30 years. They report that of 17 dogs with branching mineralization in their livers, 7 (41%) were cavalier King Charles spaniels. While they found that the prevalence of branching hepatic mineralisation in dogs appears to be very low, the CKCS was "over-represented" in the study and have an increased prevalence compared with other breeds or crossbreed dogs, since they accounted for only 5.2% of dogs seen at the hospital and only 4.1% of x-rays which included the liver.

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Hepatocutaneous syndrome (HCS)

Hepatocutaneous syndrome (HCS) produces lesions on the surface of the liver, giving it a "honeycomb"
 appearance on ultrasound images. It usually is accompanied by a skin disorder, superficial necrolytic dermatitis (SND), which is discussed on our Skin Disorder webpage. HCS is a progressive disorder which usually is fatal. HCS is marked by extremely low plasma amino acids (hypoaminoacidemia) and elevated concentrations of liver enzymes, particularly serum alka ne phosphatase. Cavaliers occassionally have been diagnosed with HCS (see this January 2016 article and this January 2022 article and this January 2023 article), but overall it is not a common disorder. Diabetes mellitus reportedly tends to develop during the later stages of HCS.

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Portal hypertension

The portal vein is the source of blood which flows into the liver from the gastrointestinal tract, which includes the pancreas, gallbladder, and spleen. Portal hypertension (PH) occurs if the blood pressure in the portal vein reaches a high level (e.g., 10 mm Hg) . This type of high blood pressure may be due to any of several causes, particularly increased blood flow to the liver or increased resistance to that flow (such as due to a clot or narrowing of the vessel). PH may be the result of shunts whereby the excess blood is diverted from the arteries serving the liver. Other causes include pre-existing illnesses, such as pancreatitis, cancer, other liver disorders, or complications following surgical repair of portosystemic shunts.

While this form of hypertension is not commonly reported in cavaliers, it has been found to occur in the breed occasionally. See this May 2008 article, this January 2020 article, this September 2022 article, and this February 2023 article.

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Portosystemic (liver) shunt

In a normal dog, blood from the gastrointestinal tract enters the portal vein, which then takes blood to the liver, which then metabolizes and detoxifies this blood before sending it back into the circulatory system to the heart. A portosystemic shunt is a blood vessel present at the fetal stage, carrying toxified blood directly from the gastrointestinal tract to the heart, bypassing the liver and shunting the blood directly into the circulatory system. These shunts are classified as either intrahepatic (inside the liver) and extrahepatic (outside the liver) shunts. An intrahepatic portosystemic shunt (IHPSS) represents a normal embryologic shunt which normally closes at birth, allowing the liver to take over its filtering, storage, and production functions. However, in some cases the intrahepatic shunt does not close down properly and the liver is unable to grow or function properly. An extrahepatic portosystemic shunt (EHPSS) is an abnormal embryonic connection between to venous systems, which completely bypasses the liver. Most portosystemic shunts are congenital, but in some cases, shunts may be acquired due to another problem with the liver, such as portal hypertension.

Yorkshire terriers and Cairn terriers reportedly appear to have an inherited basis for EHPSS. Breeds which are predisposed to EHPSS are Jack Russell terriers, Dachshunds, Miniature schnauzers, and Maltese. EHPSS have been observed mainly in small breeds. Cavaliers do not appear to be predisposed to EHPSS, but some CKCSs have been diagnosed with the disorder. See this July 2012 article and this December 2015 article and this November 2017 article for additional information regarding cavaliers with this condition.

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Copper associated hepatopathy (CAH)

Copper PenniesThe cavalier breed has been found to be predisposed to copper associated hepatopathy (CAH). CAH describes excessive quantities of the metal copper (Cu) in the dog's liver. Copper normally is processed by the liver into bile by certain proteins. When the dog's liver is unable to convert copper, it accumulates in the liver and causes inflammation, scarring of the liver, and death of liver cells. Symptoms of CAH rarely are evident before permanent damage to the liver's cells occur.

The primary cause of CAH in cavaliers and other predisposed breeds is excessive quantities of copper found in many commercial dry dog foods. Beginning in 1998, the Association of American Feed Control Officials (AAFCO) recommended that minimum copper concentrations in dry foods be increased to 2.1 mg/1,000 kcal ME. In a 2013 article, investigators reported finding that the median concentration of copper in maintenance commercial dry foods was 4.4 mg/1,000 kcal ME, with a range from 2.3 to 9.0 mg/1,000 kcal ME.

In a February 2021 article, a panel of veterinary nutritionists and hepatic specialists reported observing "Over the past 15 to 20 years, we have seen what we believe to be an increased incidence of copper-associated hepatopathy in dogs." They suggested that "The onset of this increase appears to have coincided with a change in the type of copper used in premixes added to commercial dog foods." They warned that the AAFCO's "current recommendations for copper content in adult maintenance canine diets are too high and may exceed the upper tolerability limit for some dogs, resulting in hepatic disease."

In a November 2022 article, a team of Colorado State University researchers studied dogs diagnosed with "copper associated hepatopathy" (CAH), a build-up of copper in the liver due to the liver's inability to fully process copper ingested by the dogs in their food. The researchers examined the concentrations of copper in the livers ("hepatic Cu") of 1,490 dogs in the Colorado State University Diagnostic Veterinary Laboratory database between 2010 and 2020. They report finding that the cavalier King Charles spaniel ranked sixth (after Doberman pinscher, corgi, Dalmatian, Labrador retriever, and West Highland white terrier) among all breeds with abnormally high hepatic Cu. They describe the CKCS as predisposed to CAH. Abnormally high hepatic Cu symptoms are severe inflammation (necroinflammatory disease) of the liver, necrosis, and apoptosis (self-destruction of cells). They attribute the CAH to excessively high quantities of copper in commercial dry dog foods. They concluded:

"Therefore, high Cu in commercial dog foods and the connection to abnormally high hepatic Cu warrants reconsideration of the current regulations for dietary Cu."

In a January 2023 article, a team of Angell Animal Medical Center (Boston, Mass.) clinicians diagnosed a cavalier with superficial necrolytic dermatitis and successfully treated him with copper chelation therapy. The dog intially had high liver enzymes. Ultimately the CKCS was diagnosed with copper-associated hepatitis.  A month after the diagnosis of CAH, the dog developed hyperkeratosis (a thickening of the outer layer of the skin) on his foot pads and ulcers on his feet, legs, and rectum. Superficial necrolytic dermatitis was diagnosed at that point. They clinicians treated the dog with the copper chelation agent penicillamine designed to remove excess copper from the blood system. This drug was successful in improving the skin lesions over a period of a few months, after which the lesions returned. The dog was switched from penicillamine to stonger copper chelation agent, trientine, followed by the addition of zinc acetate, and the skin conditions improved.

 In a November 2023 article, a team of Israeli researchers and Dr. Penny J. Watson reported finding copper-associated chronic hepatitis (CuCH) in 12 cavaliers. They listed a variety of common symptoms, including decreased appetite, diarrhea, vomiting, portal hypertension, ascites, increased transamination (degradation of essential amino acids), and elevated biliary enzyme concentrations. Six of the dogs (50%) had 3 or more abnormalities in measures of liver function, including hypocholesterolemia, hypoalbuminemia, hyperbilirubinemia, decreased urea concentration and hyperammonemia. All of the dogs were homozygous negative for the COMMD1 deletion mutation reported in Bedlington terriers, but 9 of them (75%) were homozygous positive or heterozygous for the ATP7B mutation reported in Labrador retrievers. The median copper score was 3/5. They found "marked architectural distortion by regenerative nodules, severe, often bridging, fibrosis, moderate inflammatory infiltrate, biliary ductular reaction and rare necrosis." Where liver fibrosis was significant, copper accumulation was most conspicuous within regenerative nodules. They treated the dogs with copper chelation, and anti-inflammatories and antioxidants, which resulted in normalization of alanine transaminase activity in 5 of 6 dogs, including resolution of ascites and liver function abnormalities in one dog. The remaining 7 dogs died despite or without chelation therapy. They concluded:

"In conclusion, we report an apparent breed-related CuCH in CKCS in which copper seemed to be a primary trigger of CH, rather than an epiphenomenon. Histochemical staining and quantitative copper measurements were significant, there was an apparent response to chelation therapy and there was a dearth of evidence to support cholestasis/inflammation-induced HCA in these dogs. An insidious onset of disease is suspected, which can be recognised by elevations in ALT activity. Notwithstanding a normal history in some dogs, or mild, nebulous clinical signs in others, significant architectural changes, fibrosis and differential copper staining within regenerative nodules were common in many cases. All affected dogs were homozygous negative for the COMMD1 and ATP7A variants but homozygous positive or heterozygous for the ATP7B variant reported in LRs, alluding to a possible genetic breed predisposition. However, the occurrence of the ATP7B variant in the control dogs demonstrates that the ATP7B variant is not singularly causative in the pathogenesis of CuCH in CKCS. Resolution of haematological and biochemical changes and clinical signs is feasible, even in the presence of previously reported negative prognostic markers. Future studies in a larger cohort of CKCS are warranted to ascertain heritability, the significance of currently found and additional genetic mutations, and the efficacy of chelation therapy and diet."
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Xylitol toxicosis

In an October 2009 article, a clinician reported that a cavalier which had eaten 2 or 3 pieces of chewing gum containing xylitol subsequently developed jaundice, severe lethary, anorexiz, and vomiting over a 5-day period. Laboratory testing indicated several adnormalities indicating liver damage. Helatic lymphadenopahty was detected on abdominal ultrasound. Xylitol toxicosis was presumed. LIver support therapy was started, and the dog recovered following several weeks of treatment. 

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Symptoms

The symptoms of liver disorders tend to progress from non-specific ones (increase in thirst, vomiting, diarrhea, weight loss) during the early stages to much more specific signs, such as:

• Jaundice – yellowish color of the skin, gums, and eyes
• Enlargement of the liver, resulting in noticeable swelling of the abdomen
• Blood in urine and feces
• Blindness
• Seizures
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Diagnosis

Blood tests, including the liver function test, are necessary to check the levels of liver enzymes and proteins. Urinalysis likewise will indicate the levels. The major enzymes associated with hepatic injury or altered function include ALP (alkaline phosphatase), ALT (alanine transaminase) , and AST (aspartate transaminase).

 Alkaline phosphatase (ALP) is an enzyme that’s found throughout the dog's body, but particularly in the liver, intestines, and bones. ALP blood tests measure the level of ALP in the blood that comes from the liver and bones. The range of normal levels of ALP in the blood are from 15 to 140 IU/L. High levels of ALP produced in the liver and detected in the blood may indicate liver disease or certain bone disorders. Witness Lepto is a brand name (by Zoetis) antibody test to detect IgM antibodies against Leptospra.

Alanine transaminase (ALT) is an enzyme found in the liver that in involved in converting proteins into energy for the liver cells. When the liver is damaged, ALT is released into the bloodstream and ALT levels increase. The test for ALT leels is referred to as SGPT (serum glutamic-pyruvic transaminase).

Aspartate transaminase (AST) is an enzyme that helps the body break down amino acids. AST usually is present in the blood at low levels. An increase in AST levels may mean liver damage, liver disease, or muscle damage. The AST test is referred to as SGOT (glutamic-oxaloacetic transaminase).

X-rays (radiographs) of the liver and surrounding ograns, as well as ultrasound scans are appropriate, to determine if the liver is enlarged and if cysts or tumors appear to be present.

Computed tomography angiography (CTA) is a combination of a CT scan with a contrast dye injected into a vein, to highlight blood vessels and organs, the liver in this case. CTA is used to diagnose intrahepatic portosystemic shunts (IHPSS).

Biopsies of the liver may be necessary, depending upon what is observed in the x-rays and ultrasound scans.

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Treatment

Standard forms of treatment of liver disorders include intravenous fluid therapy to treat or avoid dehydration, and medications to control symptoms, such as vomiting and inflammation. Vitamin K (potassium) may be injected.

Canine Hepatic SupportThe dog's glutathione, an antioxidant which is produced by the liver, may have to be replaced or supplemented. Medications include SAMe (S-Adenosylmethionine) and milk thistle (silybin). Denamarin is a combination of SAMe and silybin. Also, ursodiol (Actigall, Urso, Ursofalk), a choleretic bile acid, may be administered.

Standard Process offers its Canine Hepatic Support as a supplement to suppor the dog's liver.

Surgery may be necessary to remove cysts or tumors.

Copper chelation agents, for removing copper and other heavy metals from the dog's blood system, include penicillamine (d-Penicillamine) and trientine. d-Penicillamine is the sulfhydryl-containing amino acid cysteine but substituted with 2 methyl groups. It reportedly significantly increases urinary excretion of copper, but with potentially serious side effects, including neurological symptoms and hypothyroidism, proteinuria, leukopenia, and thrombocytopenia. Alternative copper chelation agents include the previously mentioned trientine and zinc.

Dry dog foods with high dietary copper (Cu) content should be avoided.

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What You Can Do

Milk ThistleConsider adding milk thistle (50 mg. per 10 lbs. body weight) as a supplement to your cavaier's daily diet once any liver disorder is suspected. Milk thistle is a flower in the aster family. It contains an active ingredient called silymarin, an antioxidant which supports the bodily systems that control inflammation and stimulate new cell production. Silymarin is a combination of three biochemicals found in milk thistle -- silychristine, silydanin, and silybin (silibinin).

In a June 2021 article, a team of Polish researchers studied the effect of silybin on nutrients digestibility, liver function indices, and the overall health status in 18 healthy laboratory beagles and then in 15 client-owned dogs diagnosed with idiopathic hepatic disorders. They reported finding that:

"[I]n healthy dogs, supplementation with silybin, at 12.75 mg per 10 kg BW, or with a commercial hepatoprotectant containing silybin, at the same dose, does not interfere with the nutrient’s digestion, and subsequently exerts no detrimental effect on liver function indices, health, or blood parameters."

In dogs with liver disorders, they found that:

"[S]upplementation with commercial hepatoprotectant containing silybin, at a dose of 12.75 mg per 10 kg BW [body weight], decreased the activity of serum liver markers, which hence was accompanied by a decrease in the concentration of liver-specific miRNA molecules (mainly miR-122). Liver function was thus improved. Overall, silybin supplementation has no adverse impact on healthy dogs and supports liver function in dogs with hepatopathies."

MiR-122 (the blood molecule MicroRNA-122), has been found in an August 2018 study, to be a biomarker for liver injury in dogs, with very high levels of miR-122 in dogs diagnosed with liver disorders. Those researchers concluded that, "Liver disease can be sensitively and specifically diagnosed in dogs by measurement of miR-122."

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Research News

November 2023: Copper-associated chronic hepatitis is found in cavalier King Charles spaniels. Dr. Ran NivyIn a November 2023 article,  a team of Israeli researchers (Ran Nivy [right], S. Kuzi, I. Gajanayake, A. Berkowitz) and Dr. Penny J. Watson reported finding copper-associated chronic hepatitis (CuCH) in 12 cavalier King Charles spaniels. They listed a variety of common symptoms, including decreased appetite, diarrhea, vomiting, portal hypertension, ascites, increased transamination (degradation of essential amino acids), and elevated biliary enzyme concentrations. Six of the dogs (50%) had 3 or more abnormalities in measures of liver function, including hypocholesterolemia, hypoalbuminemia, hyperbilirubinemia, decreased urea concentration and hyperammonemia. All of the dogs were homozygous negative for the COMMD1 deletion mutation reported in Bedlington terriers, but 9 of them (75%) were homozygous positive or heterozygous for the ATP7B mutation reported in Labrador retrievers. The median copper score was 3/5. They found "marked architectural distortion by regenerative nodules, severe, often bridging, fibrosis, moderate inflammatory infiltrate, biliary ductular reaction and rare necrosis." Where liver fibrosis was significant, copper accumulation was most conspicuous within regenerative nodules. They treated the dogs with copper chelation, and anti-inflammatories and antioxidants, which resulted in normalization of alanine transaminase activity in 5 of 6 dogs, including resolution of ascites and liver function abnormalities in one dog. The remaining 7 dogs died despite or without chelation therapy. They concluded:

"In conclusion, we report an apparent breed-related CuCH in CKCS in which copper seemed to be a primary trigger of CH, rather than an epiphenomenon. Histochemical staining and quantitative copper measurements were significant, there was an apparent response to chelation therapy and there was a dearth of evidence to support cholestasis/inflammation-induced HCA in these dogs. An insidious onset of disease is suspected, which can be recognised by elevations in ALT activity. Notwithstanding a normal history in some dogs, or mild, nebulous clinical signs in others, significant architectural changes, fibrosis and differential copper staining within regenerative nodules were common in many cases. All affected dogs were homozygous negative for the COMMD1 and ATP7A variants but homozygous positive or heterozygous for the ATP7B variant reported in LRs, alluding to a possible genetic breed predisposition. However, the occurrence of the ATP7B variant in the control dogs demonstrates that the ATP7B variant is not singularly causative in the pathogenesis of CuCH in CKCS. Resolution of haematological and biochemical changes and clinical signs is feasible, even in the presence of previously reported negative prognostic markers. Future studies in a larger cohort of CKCS are warranted to ascertain heritability, the significance of currently found and additional genetic mutations, and the efficacy of chelation therapy and diet."

January 2023: Cavalier with copper-associated hepatitis is successfully treated with copper chelation for necrolytic dermatitis. Dr. Shawn KearnsIn a January 2023 article, a team of Angell Animal Medical Center (Boston, Mass.) clinicians (Cynthia Talbot, Shawn Kearns [right], Pamela J. Mouser) diagnosed a cavalier King Charles spaniel with superficial necrolytic dermatitis and successfully treated him with copper chelation therapy. The dog intially had high liver enzymes. Ultimately the CKCS was diagnosed with copper-associated hepatitis. Cavaliers as a breed have been found to be predisposed to copper associated hepatopahty (CAH). CAH describes excessive quantities of the metal copper (Cu) in the dog's liver. Cavaliers appear to be less capable of processing copper by the liver into bile. When the dog's liver is unable to convert copper, it accumulates in the liver and causes inflammation, scarring of the liver, and death of liver cells. A month after the diagnosis of CAH, the dog developed hyperkeratosis (a thickening of the outer layer of the skin) on his foot pads and ulcers on his feet, legs, and rectum. Superficial necrolytic dermatitis was diagnosed at that point. They clinicians treated the dog with the copper chelation agent penicillamine designed to remove excess copper from the blood system. This drug was successful in improving the skin lesions over a period of a few months, after which the lesions returned. The dog was switched from penicillamine to stonger copper chelation agent, trientine, followed by the addition of zinc acetate, and the skin conditions improved.

November 2022: Copper-associated chronic hepatitis is found in cavalier King Charles spaniels. Dr. Ran NivyIn a September 2022 abstract presented at the 32d European College of Veterinary Internal Medicine – Companion Animals (ECVIM-CA) Congress, a team of Israeli researchers (Ran Nivy [right], S. Kuzi, I. Gajanayake, A. Berkowitz) and Dr. Penny J. Watson reported finding copper-associated chronic hepatitis in 12 cavalier King Charles spaniels. They listed a variety of common symptoms, including decreased appetite, diarrhea, vomiting, portal hypertension, ascites, increased transamination (degradation of essential amino acids), and elevated biliary enzyme concentrations. Six of the dogs (50%) had 3 or more abnormalities in measures of liver function, including hypocholesterolemia, hypoalbuminemia, hyperbilirubinemia, decreased urea concentration and hyperammonemia. All of the dogs were homozygous negative for the COMMD1 deletion mutation reported in Bedlington terriers, but 9 of them (75%) were homozygous positive or heterozygous for the ATP7B mutation reported in Labrador retrievers. The median copper score was 3/5. They found "marked architectural distortion by regenerative nodules, severe, often bridging, fibrosis, moderate inflammatory infiltrate, biliary ductular reaction and rare necrosis." Where liver fibrosis was significant, copper accumulation was most conspicuous within regenerative nodules. They treated the dogs with copper chelation, and anti-inflammatories and antioxidants, which resulted in normalization of alanine transaminase activity in 5 of 6 dogs, including resolution of ascites and liver function abnormalities in one dog. The remaining 7 dogs died despite or without chelation therapy. They concluded:

"Considering the findings herein, CuCH should be considered in CKCS with suspected liver disease. Long-term prognosis, albeit based on a small number of dogs, seems favorable in dogs receiving chelation therapy, notwithstanding the presence of previously reported negative prognostic markers."

November 2022: Cavaliers are found predisposed to copper associated hepatopathy, due to increases in copper content in commercial dry dog foods. Dr. David C. TwedtIn a November 2022 article, a team of Colorado State University researchers (Tarini Vedantham Ullal, Steven Lakin, Brooke Gallagher, Nick Sbardellati, Zaid Abdo, David C. Twedt [right]) studied dogs diagnosed with "copper associated hepatopathy" (CAH), a build-up of copper in the liver due to the liver's inability to fully process copper ingested by the dogs in their food. The researchers examined the concentrations of copper in the livers ("hepatic Cu") of 1,490 dogs in the Colorado State University Diagnostic Veterinary Laboratory database between 2010 and 2020. They report finding that the cavalier King Charles spaniel ranked sixth (after Doberman pinscher, corgi, Dalmatian, Labrador retriever, and West Highland white terrier) among all breeds with abnormally high hepatic Cu. They describe the CKCS as predisposed to CAH. Abnormally high hepatic Cu symptoms are severe inflammation (necroinflammatory disease) of the liver, necrosis, and apoptosis (self-destruction of cells). They attribute the CAH to excessively high quantities of copper in commercial dry dog foods. They observe that, beginning in 1998, the Association of American Feed Control Officials (AAFCO) recommended that minimum copper concentrations in dry foods be 2.1 mg/1,000 kcal ME. A prior study reported finding that the median concentration of copper in maintenance commercial dry foods was 4.4 mg/1,000 kcal ME, with a range from 2.3 to 9.0 mg/1,000 kcal ME. The investigators in the present study conclude:

"Therefore, high Cu in commercial dog foods and the connection to abnormally high hepatic Cu warrants reconsideration of the current regulations for dietary Cu."

June 2021: Silybin in milk thistle improved liver function in dogs with hepatopathies, in Polish study. Dr. Małgorzata Szumacher-StrabelIn a June 2021 article, a team of Polish researchers (Maciej Gogulski, Adam Cieślak, Julia Grabska, Marie Ardois, Małgorzata Pomorska-Mól, Paweł A. Kołodziejski, Kacper Libera, Viola Strompfová, Małgorzata Szumacher-Strabel [right]) studied the effect of silybin on nutrients digestibility, liver function indices, and the overall health status in 18 healthy laboratory beagles and then in 15 client-owned dogs diagnosed with idiopathic hepatic disorders. They reported finding that:

"[I]n healthy dogs, supplementation with silybin, at 12.75 mg per 10 kg BW, or with a commercial hepatoprotectant containing silybin, at the same dose, does not interfere with the nutrient’s digestion, and subsequently exerts no detrimental effect on liver function indices, health, or blood parameters."

In dogs with liver disorders, they found that:

"[S]upplementation with commercial hepatoprotectant containing silybin, at a dose of 12.75 mg per 10 kg BW [body weight], decreased the activity of serum liver markers, which hence was accompanied by a decrease in the concentration of liver-specific miRNA molecules (mainly miR-122). Liver function was thus improved. Overall, silybin supplementation has no adverse impact on healthy dogs and supports liver function in dogs with hepatopathies."

August 2018: UK Researchers find blood molecule microRNA-122 is marker for liver disease in dogsDr. James DearIn an August 2018 article, a team of researchers (W. Oosthuyzen, P.W.L. Ten Berg, B. Francis, S. Campbell, V. Macklin, E. Milne, A. G. Gow, C. Fisher, R.J. Mellanby, J.W. Dear [right]) at the University of Edinburgh's Royal (Dick) School of Veterinary Studies examined the blood of 250 dogs (120 healthy dogs, 100 dogs with non-liver diseases, and 30 dogs with confirmed liver disease) to determine if the blood molecule MicroRNA-122 (miR-122) can be a biomarker for liver injury in dogs, as it already has shown to be in humans and rodents. They found no difference between healthy dogs and those with non-liver disease. However, they found very high levels of miR-122 in dogs diagnosed with liver disorders. They concluded that, "Liver disease can be sensitively and specifically diagnosed in dogs by measurement of miR-122."

December 2017: Cavaliers are "over-represented" in a study of hepatic mineralization. Dr. Michael HerrtageHepatic mineralization describes the appearance of mineral "opacities" in any of a variety of patterns in the liver in x-rays. In a December 2017 article, its researchers (M.-A. Genain, A. Barbosa, M. Herrtage [right], P. Watson)  assessed the prevalence and clinical significance of linear branching mineralization of dogs' livers on x-rays from one referral veterinary hospital over a period off 30 years. They report that of 17 dogs with branching mineralization in their livers, 7 (41%) were cavalier King Charles spaniels. While they found that the prevalence of branching hepatic mineralisation in dogs appears to be very low, the CKCS was "over-represented" in the study and have an increased prevalence compared with other breeds or crossbreed dogs, since they accounted for only 5.2% of dogs seen at the hospital and only 4.1% of x-rays which included the liver.

January 2016: Secondary hepatic lesions were found in 64.8% of post-mortem samples of cavaliers in UK study. Dr. P. J. WatsonIn a January 2016 article, UK researchers (Kent, Andrew C. C.; Constantino-Casas, Fernando; Rusbridge, Clare; Corcoran, Brendan; Carter, Margaret; Ledger, Tania; Watson, Penny J. [right]) searched for pancreatic, hepatic (liver) and renal (kidney) lesions in post-mortem samples from Cavalier King Charles Spaniels (CKCSs). Primary hepatic lesions were present in only 11.1% of cases, but secondary hepatic lesions were more common and were present in 64.8%. The researchers report that cavaliers have similar rates of hepatic disease as the general population.

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Related Links

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Veterinary Resources

Control of Canine Genetic Diseases. Padgett. G.A., Howell Book House 1998, pp. 198-199, 222.

Use of transcolonic portal scintigraphy to evaluate efficacy of cellophane banding of congenital extrahepatic portosystemic shunts in 16 dogs. B.P. Landon, L.A. Abraham, J.A. Charles. Australian Vet. J. May 2008; doi: 10.1111/j.1751-0813.2008.00278.x. Quote: Objective: To evaluate the efficacy of cellophane banding of single congenital extrahepatic portosystemic shunts in dogs using transcolonic portal scintigraphy. To investigate the portal circulation of those dogs with elevated postoperative shunt fractions to determine the cause of the persistent shunting. Further, to evaluate whether presenting signs, clinical pathology findings and liver histopathology are predictive of outcome. Design: Prospective study of 16 dogs presenting with single congenital extrahepatic portosystemic shunts [including one cavalier King Charles spaniel]. Procedure: Dogs with single extrahepatic portosystemic shunts attenuated by cellophane banding underwent portal scintigraphy and bile acids tolerance testing pre- and post-operatively. Dogs identified with elevated shunt fractions at 10 weeks post-operatively underwent mesenteric portovenography. Qualitative hepatic histopathology from all dogs was reviewed by a veterinary pathologist and assigned a semi-quantitative score to identify any abnormalities that may predict surgical outcome. Results: At 10 weeks post cellophane banding, 10 of 16 cases (63%) had normal shunt fractions, whilst six dogs (37%) had increased shunt fractions and seven dogs (44%) had increased serum bile acids. Of these dogs, mesenteric portovenography revealed incomplete closure of the shunt in three dogs (18.6%) and multiple acquired shunts in three dogs (18.6%). Liver histopathology findings were similar for all dogs, regardless of outcome. Conclusions: Cellophane banding is an efficacious method for complete gradual occlusion of single extrahepatic shunts when the shunt vessel is attenuated to ≤ 3 mm. Transcolonic portal scintigraphy is a reliable method for assessment of shunt attenuation and, unlike serum bile acids, is not influenced by other causes of liver dysfunction.

Acute hepatic necrosis following xylitol ingestion in a 2-year-old dog. Hillary Wentworth. Cornell Univ. eCommons. October 2009. Quote: A 2-year-old intact female Cavalier King Charles Spaniel presented to the triage service at the Cornell University Hospital for Animals (CUHA) with a 5-day history of icterus, severe lethargy, anorexia, and vomiting. The patient had a history of eating 2-3 pieces of xylitol-containing chewing gum 8 days before presentation to her referring veterinarian (48 hours before the onset of her clinical signs). Multiple laboratory abnormalities referable to liver damage were observed. Hepatic lymphadenopathy was detected on abdominal ultrasound. A presumptive diagnosis of xylitol toxicosis was made based on the patient's history and laboratory findings. Supportive and hepatoprotective therapy was instituted and the patient recovered after a treatment course of several weeks. Principals of the pathogenesis, diagnosis, treatment, and prognosis of canine xylitol toxicosis are discussed.

Distribution of extrahepatic congenital portosystemic shunt morphology in predisposed dog breeds. Lindsay Van den Bossche, Frank G van Steenbeek, Robert P Favier, Anne Kummeling, Peter AJ Leegwater, Jan Rothuizen. BMC Vet. Research. July 2012;8:112. Quote: "Background: An inherited basis for congenital extrahepatic portosystemic shunts (EHPSS) has been demonstrated in several small dog breeds. If in general both portocaval and porto-azygous shunts occur in breeds predisposed to portosystemic shunts then this could indicate a common genetic background. This study was performed to determine the distribution of extrahepatic portocaval and porto-azygous shunts in purebred dog populations. Results: Data of 135 client owned dogs diagnosed with EHPSS at the Faculty of Veterinary Medicine of Utrecht University from 2001 – 2010 were retrospectively analyzed. The correlation between shunt localization, sex, age, dog size and breed were studied. The study group consisted of 54 males and 81 females from 24 breeds. ... Additional breeds diagnosed with EHPSS were the Lhasa Apso, Miniature Poodle, Norfolk terrier with two cases, and single cases of a Basset Hound, Bolognese, Cavalier King Charles Spaniel, Epagneul Nain Papillon, Flat Coated Retriever, Fox terrier, Giant Spitz, Great Dane, Miniature Pinscher, Norwich terrier and Welsh terrier. ... Twenty-five percent of dogs had porto-azygous shunts and 75% had portocaval shunts. Of the dogs with porto-azygous shunts only 27% was male (P = 0.006). No significant sex difference was detected in dogs with a portocaval shunt. Both phenotypes were present in almost all breeds represented with more than six cases. Small dogs are mostly diagnosed with portocaval shunts (79%) whereas both types are detected. The age at diagnosis in dogs with porto-azygous shunts was significantly higher than that of dogs with portocaval shunts (P < 0.001). Conclusion: The remarkable similarity of phenotypic variation in many dog breeds may indicate common underlying genes responsible for EHPSS across breeds. The subtype of EHPSS could be determined by a minor genetic component or modulating factors during embryonic development."

Evaluation of calcium, phosphorus, and selected trace mineral status in commercially available dry foods formulated for dogs. Jason W. Gagné, Joseph J. Wakshlag, Sharon A. Center, Michael A. Rutzke, Raymond P. Glahn. J.A.V.M.A. September 2013; doi: 10.2460/javma.243.5.658. Quote: Objective: To evaluate concentrations of calcium, phosphorus, zinc, iron, copper, manganese, and selenium in several commercially available dry dog foods and compare these with current Association of American Feed Control Officials (AAFCO) recommendations for maintenance of healthy dogs. Design: Descriptive study. Sample—45 over-the-counter dry foods formulated for maintenance of healthy dogs (ie, maintenance foods) and 5 therapeutic dry foods formulated for dogs with hepatic or renal disease. Procedures: Mineral concentrations were measured via inductively coupled plasma mass spectrometry or inductively coupled plasma atomic emission spectroscopy and compared with AAFCO-recommended minimum and maximum values. ... With the exception of therapeutic foods, no products had copper concentrations below the AAFCO-recommended minimum of 2.1 mg/1,000 kcal ME; none exceeded the recommended maximum value. The median concentration of copper in maintenance foods was 4.4 mg/1,000 kcal ME (range, 2.3 to 9.0 mg/1,000 kcal ME). Copper concentrations in 2 therapeutic foods for dogs with hepatic disease were 1.3 and 1.7 mg/1,000 kcal ME. Considering that these diets were formulated to maintain neutral copper balance in Bedlington Terriers with copper-storage hepatopathy, maintenance food copper concentration was also compared with that standard. Copper concentrations in 29 of 45 (64%) maintenance foods were approximately 2 times the median value for these 2 therapeutic foods (1.5 mg/1,000 kcal ME), and copper concentrations in 4 maintenance foods were 3 times this value.

A Retrospective Histopathological Survey on Canine and Feline Liver Diseases at the University of Tokyo between 2006 and 2012. Naoki Hirose, Kazuyuki Uchida, Hideyuki Kanemoto, Koichi Ohno, James K. Chambers, Hiroyuki Nakayama. J. Vet. Med. Sci. July 2014;76(7): 1015–1020. Quote: "To determine the incidence of hepatic diseases in dogs and cats in Japan, a retrospective study was performed using data of 463 canine and 71 feline liver biopsies at the Veterinary Medical Center of the University of Tokyo. The most common canine hepatic disease was microvascular dysplasia (MVD) and occupied 29.4% of all diagnoses. This terminology might contain “real” MVD and primary portal vein hypoplasia, because these two conditions were difficult to be clearly distinguished histopathologically. Parenchymal and interstitial hepatitis and primary hepatic tumors accounted for 23.5% and 21.0% of the diagnoses, respectively. Parenchymal and interstitial hepatitis occupied 34.1% of non-proliferative canine hepatic diseases, while hepatocellular adenoma and carcinoma were 26.6% and 24.5% of roliferative hepatic diseases, respectively. Breed-specificity was seen in MVD for Yorkshire terrier, Papillon and Toy poodle, in hepatitis for Doberman pinscher and Labrador retriever, in cholangiohepatitis for American cocker spaniel, Miniature schnauzer and Pomeranian, in hepatocellular adenoma for Golden retriever and Shiba and in hepatocellular carcinoma for Shih Tzu. Among 25 cases of canine chronic hepatitis, Labrador retrievers and Doberman Pinschers ranked the first (8 cases, 32.0%) and the second (3 cases, 12.0%), respectively. Females were more susceptible than males in both breeds [Labrador retrievers (male/female=1:7) and Doberman pinschers (male/female=1:2)]. The median age of the hepatitis cases was 8 years and 7 months old. Eight of the 25 canine chronic hepatitis cases had copper deposition. Two of the 8 cases were Doberman pinschers, and 1 was Labrador retriever, Bedlington terrier, Welsh corgi, Cavalier King Charles spaniel or a mixed breed."

Lipopolysaccharide and toll-like receptor 4 in dogs with congenital portosystemic shunts. M.S. Tivers, V.J. Lipscomb, K.C. Smith, C.P.D. Wheeler-Jones, A.K. House. Vet. J. December 2015;404-2015;206(3):303-413. Quote: "Surgical attenuation of a congenital portosystemic shunt (CPSS) results in increased portal vein perfusion, liver growth and clinical improvement. Portal lipopolysaccharide (LPS) is implicated in liver regeneration via toll-like receptor (TLR) 4 mediated cytokine activation. The aim of this study was to investigate factors associated with LPS in dogs with CPSS. Plasma LPS concentrations were measured in the peripheral and portal blood using a limulus amoebocyte lysate (LAL) assay. ... We included paired peripheral and portal plasma samples from 13 CPSS dogs of the following breeds: Bichon Frise (n = 2), Labrador (n = 2), Border terrier (n = 1), Cavalier King Charles spaniel (n = 1), crossbreed (n = 1), Dogue de Bordeaux (n = 1), German shepherd dog (n = 1), Miniature Schnauzer (n = 1), Springer spaniel (n = 1), West Highland White terrier (n = 1), Yorkshire terrier (n = 1). The median age was 295 days (range, 125–1835 days). Nine dogs (69.2%) had an extrahepatic CPSS and four (30.8%) had an intrahepatic CPSS. ... LPS concentration was significantly greater in the portal blood compared to peripheral blood in dogs with CPSS (P = 0.046) and control dogs (P = 0.002). LPS concentrations in the peripheral (P = 0.012) and portal (P = 0.005) blood of dogs with CPSS were significantly greater than those of control dogs. The relative mRNA expression of cytokines and TLRs was measured in liver biopsies from dogs with CPSS using quantitative PCR. TLR4 expression significantly increased following partial CPSS attenuation (P = 0.020). TLR4 expression was significantly greater in dogs that tolerated complete CPSS attenuation (P = 0.011) and those with good portal blood flow on pre-attenuation (P = 0.004) and post-attenuation (P = 0.015) portovenography. Serum interleukin (IL)-6 concentration was measured using a canine specific ELISA and significantly increased 24 h following CPSS attenuation (P < 0.001). Portal LPS was increased in dogs with CPSS, consistent with decreased hepatic clearance. TLR4 mRNA expression was significantly associated with portal blood flow and increased following surgery. These findings support the concept that portal LPS delivery is important in the hepatic response to surgical attenuation. Serum IL-6 significantly increased following surgery, consistent with LPS stimulation via TLR4, although this increase might be non-specific."

Prevalence of pancreatic, hepatic and renal microscopic lesions in post-mortem samples from Cavalier King Charles Spaniels. Kent, Andrew C. C.; Constantino-Casas, Fernando; Rusbridge, Clare; Corcoran, Brendan; Carter, Margaret; Ledger, Tania; Watson, Penny J. J. Small Animal Practice, January 2016. Quote: "Objectives: To describe the prevalence of pancreatic, hepatic and renal microscopic lesions in post-mortem samples from Cavalier King Charles Spaniels (CKCS) presented to a UK post-mortem collection scheme. Methods: Histopathology was performed on the organs of interest and the prevalence of microscopic lesions described, this was related back to the clinical signs shown ante-mortem. Results: Evidence of chronic pancreatitis was seen in 51.9% of the cases, and age correlated with severity of disease, suggesting that chronic pancreatitis is a progressive condition. Evidence of renal lesions was present in 52.2% of cases, most commonly inflammatory disease. The rate of ante-mortem diagnosis was low for both pancreatic and renal disease, at 25% and 16.7% respectively. Primary hepatic lesions were present in only 11.1% of cases, but secondary hepatic lesions were more common and were present in 64.8%. Clinical Significance: Pancreatic and renal lesions are common in Cavalier King Charles Spaniels and clinicians should be aware of this when presented with clinical cases, they have similar rates of hepatic disease as the general population."

Morphology of splenocaval congenital portosystemic shunts in dogs and cats. R. N. White, A. T. Parry. J.S.A.P. January 2016;57(1):28-32. Quote: "Objective: To describe the anatomy of congenital portosystemic shunts involving the splenic vein communicating with the caudal vena cava at the level of the epiploic foramen. Materials and Methods: A retrospective review of a consecutive series of dogs and cats managed for congenital portosystemic shunts. Results: Ninety-eight dogs and eight cats met the inclusion criteria of a congenital portosystemic shunt involving the splenic vein communicating with the prehepatic caudal vena cava plus recorded intra-operative mesenteric portovenography or computed tomography angiography and gross observations at surgery. All cases (both dogs and cats) had a highly consistent shunt that involved a distended gastrosplenic vein that communicated with the caudal vena cava at the level of the epiploic foramen via an anomalous left gastric vein. Clinical Significance: The morphology of the shunt type described appeared to be a result of an abnormal communication between the left gastric vein and the caudal vena cava and the subsequent development of preferential blood flow through an essentially normal portal venous system. The abnormal communication (shunt) was through the left gastric vein and not the splenic vein, as might have been expected. This information may help with surgical planning in cases undergoing shunt closure surgery."

Clinical relevance of radiographic linear branching mineral opacities in the canine liver. M.-A. Genain, A. Barbosa, M. Herrtage, P. Watson. J. Sm. Anim. Pract. December 2017. DOI: 10.1111/jsap.12797. Quote: Various conditions have been reported to cause mineral opacities within the liver or biliary system in dogs, including parenchymal mineralisation or linear branching mineralisation. Hepatic parenchymal mineral opacification has been described in different patterns: a densely mineralised lesion, a curvilinear ring of calcification or large centrally located coarse mineralisation pattern or multiple or solitary foci of mineralisation located eccentrically within a complex heterogeneous mass. ... Branching mineralisation within the hepatic parenchyma of the dog has been reported occasionally in older small breed dogs and is the focus of this study. ... Objectives: To assess the prevalence, clinical significance and breed distribution of linear branching mineralisation superimposed on the hepatic radiographic silhouette in dogs. Materials and Methods: Retrospective review of radiographs or ultrasound images of dogs showing branching mineralisation in the liver. Results: Over the 30-year review period, 17 cases were identified and the mineralisation had a predominantly ventral distribution. Seven of the 17 were cavalier King Charles spaniels, and four of the total 17 dogs were diagnosed with hepatobiliary system disease. Five dogs had repeat radiographs, of which four showed no change in the pattern and one developed the pattern 6 years after being diagnosed with cholangiohepatitis. Serum calcium concentrations were normal in all patients. Liver enzymes were markedly elevated only in the dog diagnosed with cholangiohepatitis. Histology performed on three patients showed no convincing evidence of primary liver disease. Clinical Significance: ... Hepatic linear branching mineralisation is uncommon in dogs. CKCS appear to have an increased prevalence compared with other breeds or crossbreed dogs. Biopsy of the liver of affected dogs with no clinical or clinicopathological evidence of liver disease is unlikely to be helpful in these cases.

Intrahepatic congenital portosystemic shunts in dogs: short- and long-term outcome of suture attenuation. M. S. Tivers, V. J. Lipscomb, P. Bristow, D. J. Brockman. J. Sm. Anim. Pract. April 2018;59(4):201-210. Quote: Objectives: To report the short- and long-term outcomes of one- or two-staged suture attenuation for complete closure of intrahepatic congenital portosystemic shunts in dogs. Materials and Methods: Retrospective cohort study of dogs surgically treated for intrahepatic congenital portosystemic shunts between February 2000 and March 2015. Long-term follow-up was conducted by telephone conversations with the referring veterinary surgeon, owner, or both. Results: In total, 55 dogs [including 2 cavalier King Charles spaniels] had suture attenuation of their intrahepatic congenital portosystemic shunt; 10 dogs (18·2%) tolerated complete attenuation, whilst 45 dogs (81·8%) tolerated partial attenuation. Postoperative complications occurred in 24 dogs [including one CKCS] (43·6%), and six dogs (10·9%) died. Repeat surgery was performed in 33 of 39 dogs [including one CKCS] (84·6%) that had previously undergone partial attenuation, and 27 [including one CKCS] of these (84·9%) ultimately achieved complete shunt attenuation. One dog (3·0%) died following second surgery, resulting in an overall postoperative mortality of seven of 55 (12·7%). Detailed follow-up was available for 22 dogs that were still alive at a median of 29 months after surgery (7·4 to 103·1) with a subjectively good quality of life. Of 17 dogs (82·4%), 14 with complete attenuation in one or two surgeries had an excellent outcome compared with one of five dogs (20%) with persistent shunting. Clinical Significance: Staged suture ligation resulted in a high proportion of complete attenuation and reduced persistent shunting compared with a single surgery. Repeat surgery was associated with fewer complications than the first surgery. The proportion of dogs with an excellent outcome was greater for those that had complete attenuation in one or two surgeries compared with those with persistent shunting.

Sensitivity and specificity of microRNA-122 for liver disease in dogs. W. Oosthuyzen, P.W.L. Ten Berg, B. Francis, S. Campbell, V. Macklin, E. Milne, A. G. Gow, C. Fisher, R.J. Mellanby, J.W. Dear. J. Vet. Int. Med. August 2018; doi: 10.1111/jvim.15250. Quote: Background: Current tests for diagnosing liver disease in dogs are sub-optimal. MicroRNA-122 (miR-122) is a sensitive and specific biomarker of liver injury in humans and rodents. Circulating miR-122 could have utility in identifying dogs with liver disease. Objective: Establish the reference interval for miR-122 in healthy dogs and determine performance in a range of dog breeds with liver disease and control animals with non‐liver disease. Animals: Stored serum from 120 healthy dogs, 100 dogs with non‐liver diseases, and 30 dogs with histologically confirmed liver disease was analyzed. Methods: Retrospective study. Medical records of dogs with liver disease, non-liver disease and healthy dogs were reviewed. Serum miR-122 concentrations were measured by PCR and compared with the characteristics of the dogs and their conventional clinical measurements. Results: In healthy dogs the 2.5th, 50th, and 97.5th quartiles of miR‐122 were 110 (90% CI 80-114), 594 (505-682), and 3312 (2925-5144) copies/μL, respectively. There was no difference between healthy dogs and dogs with non-liver disease (median ± IQR: healthy dogs 609 [327-1014] copies/μL; non-liver disease 607 [300-1351] copies/μL). miR-122 was higher in dogs with liver disease (11 332 [4418-20 520] copies/μL, P < .001 compared to healthy dogs). miR-122 identified dogs with liver disease with high accuracy (receiver operating characteristic area under curve for comparison with healthy dogs: 0.93 [95% CI 0.86-0.99]). The upper limit of normal for healthy dogs (3312 copies/μL) had a sensitivity of 77% and specificity of 97% for identifying liver disease. Conclusion and Clinical Importance: Liver disease can be sensitively and specifically diagnosed in dogs by measurement of miR-122.

Plasma renin activity and aldosterone concentration in dogs with acquired portosystemic collaterals. Yumi Sakamoto, Manabu Sakai, Keita Sato, Toshihiro Wata. J. Vet. Intern. Med. January 2020; doi: 10.1111/jvim.15661. Quote: Background: The renin-angiotensin-aldosterone system (RAAS) is activated in humans with portal hypertension (PH) associated with liver disease. However, involvement of RAAS in dogs with intrahepatic PH is not clear. Objective: To measure plasma renin activity (PRA) and plasma aldosterone concentration (PAC) in dogs with PH (chronic hepatitis [CH] and primary hypoplasia of the portal vein [PHPV]), dogs with extrahepatic congenital portosystemic shunt (EH-CPSS) [including one cavalier King Charles spaniel], and healthy dogs and to determine whether the RAAS is activated in dogs with PH. Animals: Twenty-seven dogs with acquired portosystemic collaterals (APSCs; 15 dogs with CH, 12 dogs with PHPV), 9 dogs with EH-CPSS, and 10 healthy dogs. Methods: Retrospective study. Plasma renin activity and PAC were measured by radioimmunoassay. Results: Plasma renin activity was significantly higher in the CH group (median, 4.4 ng/mL/h) than in the EH-CPSS (median, 1.0 ng/mL/h; P < .01) and the healthy (median, 1.1 ng/mL/h; P < .01) groups. No significant differences were found between the PHPV group (median, 2.2 ng/mL/h) and other groups. Plasma aldosterone concentration was significantly higher in the CH (median, 111.0 pg/mL) and PHPV (median, 89.5 pg/mL) groups than in the EH-CPSS (median, 1.0 pg/mL; P < .001, P < .01, respectively) and healthy (median, 14.5 pg/mL; P < .001, P < .05, respectively) groups. Conclusions and Clinical Importance: Activation of the RAAS contributes to the pathophysiology of intrahepatic PH in dogs, suggesting that spironolactone may not only be effective for the treatment of ascites but also for the suppression of intrahepatic PH.

Breed-related expression patterns of Ki67, γH2AX, and p21 during ageing in the canine liver. Laura J. A. Hardwick, Andre J. Kortum, Fernando Constantino-Casas, Penny J. Watson. Vet. Res. Commun. December 2020; doi: 10.1007/s11259-020-09784-x. Quote: Cellular senescence is a molecular hallmark of ageing that is associated with multiple pathologies, and DNA damage marker γH2AX, together with cell cycle inhibitor p21, have been used as senescence markers in multiple species including dogs. Idiopathic canine chronic hepatitis has recognised breed-related differences in predisposition and prognosis, but reasons behind this are poorly understood. This retrospective study using archived post mortem tissue aimed to provide insight into liver ageing in 51 microscopically normal canine livers across seven breed categories [including 10 cavalier King Charles spaniels (19.6%) aged from 1 to 14 years], including those with and without increased risk of chronic hepatitis. Immunohistochemistry was conducted for γH2AX, p21, and cell proliferation marker Ki67, and the mean number of positive hepatocytes per high power field was determined. All three markers were strongly correlated to each other, but no age-dependent expression was seen in the combined study population. ... Age-dependence of marker expression was analysed within each breed group and ... CKCS showed a positive correlation between Ki67 and age. ... Overall expression levels were low in most dogs, with median values representing less than 1.5% of hepatocytes, but this increased to 20–30% in individual dogs at the upper end of the range. Individual breed differences were noted in two breeds that have increased risk of chronic hepatitis, with English Springer Spaniels having lower expression of Ki67 than other dogs, and Labradors having higher expression of Ki67 and γH2AX than other dogs. These results warrant further investigation in these breeds and highlight a need to validate reliable markers of cellular senescence in dogs.

Is it time to reconsider current guidelines for copper content in commercial dog foods? Sharon A. Center, Keith P. Richter, David C. Twedt, Joseph J. Wakshlag, Penny J. Watson, Cynthia R. L. Webster. JAVMA. February 2021; doi: 10.2460/javma.258.4.357. Quote: Over the past 15 to 20 years, we have seen what we believe to be an increased incidence of copper-associated hepatopathy in dogs. The onset of this increase appears to have coincided with a change in the type of copper used in premixes added to commercial dog foods. And, more recently, the increased incidence may have been exacerbated by consumer-driven desire for pet foods formulated with a high content of animal-based ingredients (eg, evolutionary diets), including certain organ meats, that might introduce additional copper and by trends favoring foods containing vegetables with a high copper content (eg, sweet potatoes). In light of the increased incidence of copper-associated hepatopathy in dogs, the association between dietary copper and hepatic injury, and the higher copper content of current commercial dog foods, compared with foods marketed prior to the revised guidelines for dietary copper, we believe that it would be prudent to reexamine dietary copper recommendations for dogs and reconsider current guidelines for copper content in commercial dog foods. ... In agreement with suggestions by several previous authors,1,2,3,4,5,6,7 we suspect that copper contents of many commercial dog foods are greater than the biologic requirement of dogs and exceed the tolerance limit for some of them. ... Conclusions: We understand that AAFCO recommendations are intended to broadly meet the needs of all dogs while allowing for the complex interactions that might influence bioavailability of certain ingredients and accounting for differences in energy needs and food intake. Nevertheless, we believe that the current recommendations for copper content in adult maintenance canine diets are too high and may exceed the upper tolerability limit for some dogs, resulting in hepatic disease. Therefore, we recommend that copper requirements for dogs be reconsidered and that the AAFCO consider establishing an upper tolerability limit. We believe that doing so would reduce the incidence of copper-associated hepatopathy in dogs and enhance canine welfare.

Effects of Silybin Supplementation on Nutrient Digestibility, Hematological Parameters, Liver Performance, and Liver-specific mi-RNA Concentration in Dogs. Maciej Gogulski, Adam Cieślak, Julia Grabska, Marie Ardois, Małgorzata Pomorska-Mól, Paweł A. Kołodziejski, Kacper Libera, Viola Strompfová, Małgorzata Szumacher-Strabel. BMC Vet. Res. June 2021; doi: 10.1186/s12917-021-02929-3. Quote: Background: Hepatopathies are an important group of disorders in dogs where proper nutritional care is crucial. Supplementation with a hepatoprotectant like silybin can improve liver function and should not interfere with nutrient digestibility. The purpose of this study was to investigate the effect of both pure silybin and commercial hepatoprotectant on nutrients digestibility, liver function indices and health status in healthy dogs (EXP1). Moreover, the second experiment (EXP2) investigated the effect of commercial hepatoprotectant on liver function tests and liver-associated miRNAs concentration in dogs with idiopathic liver disorder. Results: Nutrient digestibility was not affected by treatment in EXP1. Supplementation did alter the serum fatty acid profile, with no clinical relevance. The levels of liver markers such as ALT, AST and GGT significantly decreased. In EXP2, supplementation with commercial hepatoprotectant containing silybin improved liver function tests. A decrease was observed in liver serum markers such as ALT, AST and miR122 concentration. Conclusions: EXP1 confirmed that silybin (whether pure or as a commercial hepatoprotectant) does not interfere with digestion which subsequently exerts no detrimental effect on dogs’ health and metabolism. In EXP2, dietary supplementation with commercial hepatoprotectant containing silybin resulted in a decreased activity of serum liver markers, accompanied by a decrease in the concentration of liver-specific miRNA molecules. Liver function indices were consequently improved. Silybin supplementation can thus serve as an effective therapeutical tool in dogs with hepatopathies.

Clinical features and amino acid profiles of dogs with hepatocutaneous syndrome or hepatocutaneous-associated hepatopathy. John P. Loftus, Sharon A. Center, Michael Astor, Adam J. Miller, Jeanine Peters-Kennedy. J. Vet. Intern. Med. January 2022; doi: 10.1111/jvim.16259. Quote: Background: Superficial necrolytic dermatitis (SND), hepatocutaneous-associated hepatopathy (HCH), aminoaciduria, and hypoaminoacidemia define hepatocutaneous syndrome (HCS) in dogs. Dogs without SND but that possess all other syndrome components are not well described. Hypothesis/objectivesz: To define an inclusive syndrome, aminoaciduric canine hypoaminoacidemic hepatopathy syndrome (ACHES) for dogs with HCH or HCS. Compare clinical features, salient clinicopathologic variables, and plasma and urine amino acid (AA) profiles among ACHES cases by skin lesion status. Animals: Dogs of various breeds and ages diagnosed with ACHES (n = 41) [including one cavalier King Charles spaniel]. A control (CON) cohort (n = 12) provided AA profile data. Methods Retrospective case series. Available medical records of previously identified cases were reviewed for salient clinical features and clinical pathology data. Plasma and urine AA profiles were performed. Cutaneous lesion status was classified as none, mild, or fulminant. Results Thirty cases (73%) developed SND at some time. Dogs with fulminant skin lesions at diagnosis (n = 22/41, 54%) had significantly lower hematocrit (P = .05) and mean corpuscular volume (P = .01) than dogs without SND. Principal component analysis of plasma AA profiles identified distinct clustering of CON from ACHES dogs, but not by skin lesion status. Plasma 1-methylhistidine (<7 nmol/mL) and cystathionine (<7.5 nmol/mL) were robust ACHES biomarkers. Urine lysine (>344 nmol/mg creatinine) and methionine (>68 nmol/mg creatinine) also were useful ACHES biomarkers. Conclusions and Clinical Importance Specific AA biomarkers provide additional diagnostic utility in ACHES. Data suggests that HCH is an early stage, and SND a later stage manifestation of ACHES.

Copper-associated chronic hepatitis in Cavalier King Charles Spaniels. R. Nivy, S. Kuzi, I. Gajanayake, A. Berkowitz, P.J. Watson. Society of Comparative Hepatology. 32d ECVIM-CA Congress; SCH-O-1. September 2022; doi: 10.1111/jvim.16559 (pg 20). Quote: Abnormal hepatic copper accumulation engenders oxidative stress and might culminate in the development of copper-associated chronic-hepatitis (CuCH). Twelve Cavalier King Charles Spaniels (CKCS) with CuCH were recruited. Clinical presentation highly varied and included decreased appetite (n=7) and diarrhea/vomiting (n=7). Portal hypertension and ascites were documented in 5 (41%) dogs. Increased transaminase activities (11 dogs, 92%) and elevated biliary enzyme concentrations (8 dogs, 70%) were common. Six dogs (50%) had ≥3 abnormalities in measures of liver function, including hypocholesterolemia, hypoalbuminemia, hyperbilirubinemia, decreased urea concentration and hyperammonemia. All tested dogs were homozygous negative for the COMMD1 deletion mutation reported in Bedlington terriers, but homozygous positive (n=5) or heterozygous (n=4) for the ATP7B mutation reported in Labrador retrievers. The median copper score was 3/5. Salient histological findings included marked architectural distortion by regenerative nodules, severe, often bridging, fibrosis, moderate inflammatory infiltrate, biliary ductular reaction and rare necrosis. Centrilobular copper accumulation characterized early cases with minimal fibrosis, but in most cases, where fibrosis was significant, copper accumulation was most conspicuous within regenerative nodules. Copper chelation, in addition to anti-inflammatory and antioxidant therapy, resulted in normalization of alanine transaminase activity in 5/6 dogs, including resolution of ascites and liver function abnormalities in one dog. The remaining dogs died despite (n=1) or without (n=6) chelation therapy. Considering the findings herein, CuCH should be considered in CKCS with suspected liver disease. Long-term prognosis, albeit based on a small number of dogs, seems favorable in dogs receiving chelation therapy, notwithstanding the presence of previously reported negative prognostic markers. (See, also, this November 2023 article.)

Demographic and histopathologic features of dogs with abnormally high concentrations of hepatic copper. Tarini Vedantham Ullal, Steven Lakin, Brooke Gallagher, Nick Sbardellati, Zaid Abdo, David C. Twedt. J. Vet. Intern. Med. November 2022; doi: 10.1111/jvim.16580. Quote: Background: Copper associated hepatopathy (CAH) has become an important and prevalent disease since the 1990's, coincidental with changes in copper (Cu) content in commercial dog foods. Knowing the demographic and histopathologic features related to hepatic Cu concentrations might aid in diagnosing CAH in dogs. Hypothesis/ Objectives: The primary aim was to identify demographic and histopathologic features associated with abnormally high hepatic Cu concentrations. Animals: Dogs that underwent liver histopathology and Cu quantification at a veterinary diagnostic laboratory between July 2010 and February 2020. Methods: Data was retrospectively collected from an electronic database. A Gaussian multiple regression model on the log scale was used to evaluate associations between hepatic Cu and a set of demographic and histologic features selected with machine learning methods. Results: Of 4559 cases meeting criteria, 50% had hepatic Cu > 400 and 19% had Cu > 1000 ppm (parts per million) dry weight (reference range 120-400). ... Of the 1490 cases where breed information was available, a select subset of breeds (Doberman pinscher, corgi, Dalmatian, Labrador retriever, West Highland white terrier, Cavalier King Charles spaniel, and Great Dane) were the most predictive of abnormally high hepatic Cu. ... Additionally, the following breeds had significant correlations with abnormally high hepatic Cu level: Doberman Pinscher, Labrador retriever, West Highland White Terrier, Dalmatian, Corgi, and Cavalier King Charles spaniel. ... Age was negatively associated with hepatic Cu, but select breeds (Doberman pinscher, Labrador retriever, West Highland white terrier, Dalmatian, Corgi, Cavalier King Charles spaniel), presence and severity of inflammation in the liver, and necrosis or apoptosis were associated with abnormally high hepatic Cu. ... Severity of inflammation (mild, moderate, and severe) and necrosis/ apoptosis were associated with abnormally high hepatic Cu. ... In conclusion, younger dogs and predisposed breeds such as the Labrador retriever, Doberman pinscher, and West Highland white terriers had abnormally high hepatic Cu. New breed associations were documented in the Corgi and Cavalier King Charles spaniel. Hepatic inflammation of increasing severity and necrosis or apoptosis were the strongest predictors of abnormally high hepatic Cu. Cholestasis, nodular regeneration, or cirrhosis were not significantly associated with hepatic Cu levels, suggesting these processes do not increase hepatic Cu and therefore might not affect the diagnosis of CAH.

Treatment of Superficial Necrolytic Dermatitis with Copper Chelationina Dog with Copper-Associated Hepatitis. Cindy Talbot, Shawn Kearns, Pamela J. Mouser. J. Am. Hosp. Assn. January 2023; doi: 10.5326/JAAHA-MS-7217. Quote: A 7 year old castrated male Cavalier King Charles spaniel presented for evaluation of liver enzyme elevations. Abdominal ultrasound revealed a small liver with mixed echogenicity, small hypoechoic nodules, and an irregular surface. Histologic examination and copper quantification of the liver obtained by laparoscopy diagnosed copper-associated hepatitis. One month later the dog developed hyperkeratosis of all four foot pads and ulcerations of feet, legs, and rectum. Punch biopsies confirmed superficial necrolytic dermatitis. After a total of 2 mo of chelation with no changes to medications, skin lesions began to improve, continuing over the following 6 wk to almost complete resolution. At this point the skin lesions returned and had minimal response to four amino acids infusions. The dog was switched from penicillamine to trientine. Zinc acetate was initiated 6 wk after the switch to trientine, and skin improvement was noted soon thereafter. At the time of death, skin lesions were improving and the dog was clinically comfortable. Copper-associated hepatitis should be considered as a possible etiology for superficial necrolytic dermatitis. Treatment of superficial necrolytic dermatitis is often unrewarding, and copper chelation, when copper-associated hepatitis has been confirmed, represents another therapeutic option.

Prognostic indicators in dogs with intra-hepatic portal hypertension. Shaun Calleja, Robert Shiel, Laura Bree, Paolo Silvestrini, Mary Trehy, Lucy McMahon, Kevin Murtagh. Canadian Vet. J. February 2023;vol.64:174-189. Quote: Objectives: The primary goals of this retrospective study were to describe a population of dogs with portal hypertension secondary to liver disease, and to assess whether prognosis could be inferred from historical, clinical, and clinicopathological data. Animals and procedures: Dogs (N = 76) diagnosed with intrahepatic portal hypertension between 2011 and 2020 were included [including 2 cavalier King Charles spaniels]; dogs with known congenital hepatic anomalies were excluded. Effect on survival was assessed using univariable and multivariable Cox proportional hazards models for historical, clinical, and clinicopathological variables. Results: Dogs survived for a median of 14 d (range: 0 to 2028 d), with 31.6% being euthanized within 2 d of diagnosis and 23.7% surviving longer than 2 mo. Presence of jaundice and duration of clinical signs, expressed in days, were significantly associated with outcome in the univariable analysis. However, only presence of jaundice was significantly associated with increased hazard of death in the multivariable analysis. Conclusion: Results of this study show that portal hypertension is associated with a poor prognosis; however, some dogs can show prolonged survival. Clinical relevance Clinical data can guide decision-making for clinicians and owners.

Copper-associated chronic hepatitis in Cavalier King Charles spaniels. Ran Nivy, Sharon Kuzi, June Swinburne, Fernando Constantino-Casas, Isuru Gajanayake, Yaron Bruchim, Asaf Berkowitz, Penny Watson. Vet. Rec. November 2023; doi: 10.1002/vetr.3561. Quote: Background: Copper-associated chronic hepatitis (CuCH) is poorly characterised in Cavalier King Charles spaniels (CKCS). Methods: Hepatic copper accumulation was qualitatively and quantitatively assessed, and blood samples were used for genetic testing to screen for known CuCH-associated genetic variants. Results: The study included 13 CKCS with CuCH and eight unaffected controls. Increased transaminase activities, elevated biliary enzyme concentrations and portal hypertension were documented in 100%, 73% and 38% of dogs with CuCH, respectively. Five dogs had three or more abnormalities in measures of liver function. All 11 dogs with CuCh that underwent genetic testing were homozygous negative for the COMMD1 deletion and ATP7A variant but homozygous positive (n = 7) or heterozygous (n = 4) for the ATP7B variant. Liver histology often demonstrated marked architectural distortion by severe, bridging fibrosis and regenerative nodules with lymphoplasmacytic inflammation. Centrilobular copper accumulation characterised early cases with minimal fibrosis. When fibrosis was significant, copper was often differentially concentrated within regenerative nodules. Chelation therapy resolved laboratory derangements and portal hypertension in five of seven dogs. Of the 7 non-surviving dogs with CuCH, 6 had not received chelation therapy. Limitations: Limitations include a small cohort size and the lack of pedigree analyses to corroborate heritability. Conclusions: CuCH should be considered in CKCS with suspected liver disease. Long-term prognosis seems favourable in dogs receiving chelation therapy, notwithstanding the presence of previously reported negative prognostic markers. (See, also this September 2022 abstract.)

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