About liver metabolism and hepatoprotectors in clinical veterinary medicine of dogs and cats by Dmytro Morozenka
The use of hepatoprotectors in veterinary practice is an urgent problem, as veterinary doctors often cannot choose the necessary treatment for their patients with liver diseases.
There are many reasons for this, for example, inconsistencies in the clinical effectiveness of drugs that affect liver function, insufficient evidence base for the use of this or that drug, the absence of the necessary drug on the market, as well as alternative opinions of more experienced colleagues. However, it should be noted that the main and most justified criterion for the selection of hepatoprotectors for dogs and cats is the availability of modern research conducted within the framework of evidence-based medicine.
Hepatic metabolism in normal and pathological conditions
In order to understand the principles of the use of hepatoprotective drugs, a practitioner of veterinary medicine should know what metabolic processes occur in the liver.
As you know, the liver is involved in the breakdown and synthesis of protein. A lot of proteins are synthesized in the liver, including albumin. A decrease in albumin synthesis, as a rule, indicates severe liver pathology with a chronic course. A decrease in the synthesis of blood coagulation factors (prothrombin) in the liver and a decrease in the level of vitamin K1 can lead to DIC and spontaneous bleeding. A sharp lack of protective proteins in the body leads to the destruction of skeletal muscles and other tissues, which is manifested by cachexia.
If an insufficient amount of an amino acid such as arginine enters the body of a dog or cat, then the level of ammonia in the animal’s blood increases – the reason for the development of hepatic encephalopathy. Deficiency of taurine in food, especially in cats, causes a violation of the synthesis of bile acids and, as a result, a violation of the formation of bile.
Dietary carnitine deficiency leads to the development of liver lipidosis in obese animals, which is more relevant for cats than for dogs. It is also known that feeding patients with liver pathology with liquid food (canned foods) improves the growth of intestinal microflora and the metabolism of bile acids.
The liver is also involved in the synthesis, oxidation and transport of lipids throughout the body. With liver pathology, lipolysis increases, which leads to increased oxidation of fatty acids in the liver. Violation of bile synthesis leads to violation of assimilation of fat-soluble vitamins (A, D, E, K), especially vitamin E (provides antioxidant protection) and K (related to the blood coagulation system).
It is known that cholesterol, an important component of cell membranes, is synthesized in the liver. In acute liver failure and/or porto-systemic shunt, there is a decrease in the level of cholesterol in the blood, and this is an unfavorable prognostic sign in liver pathology. Cholesterol in the body of dogs and cats is transported in the blood, combining with lipoproteins. In dogs and cats, due to the peculiarities of lipoprotein capture and cholesterol removal, primary atherosclerosis is not observed, however, with some endocrine diseases (for example, hypothyroidism), the development of secondary disorders of cholesterol metabolism with the formation of plaques is possible.
Glucose is deposited in the liver in the form of glycogen, but its reserve is small in dogs, and completely insignificant in cats. With the development of liver pathology, glycogen reserves in dogs and cats are quickly depleted, while glucose compensation occurs due to the breakdown of muscle proteins into amino acids (activation of gluconeogenesis), which leads to muscle atrophy, an increase in the level of nitrogen in the blood, hepatic encephalopathy and hypoglycemia . Hyperglycemia develops with pathologies associated with insulin deficiency or resistance.
Soluble fiber reduces the formation of ammonia and its absorption in the large intestine (lowers pH) and improves the growth of acidophilic bacteria (bacteria utilize ammonia).
Water-soluble vitamins are involved in the regeneration of hepatocytes, additional losses of them with urine are also possible in case of accompanying liver pathology. Vitamin C can be formed in the body of dogs and cats, so its addition to the regimen of treatment of hepatopathies is not always justified.
Deficiency of fat-soluble vitamins leads to impaired enterohepatic circulation of bile acids as a consequence of cholestasis. Vitamin E has antioxidant properties, protects cells from oxidation by free radicals, which increases with liver damage. Deficiency of vitamin K leads to blood coagulation disorder, and in cats such a disorder is less common than in dogs.
Iron – plays an important role in erythrocytopoiesis, but in high doses can show hepatotoxicity. Copper is a potential toxin for hepatocytes, some breeds of dogs are prone to liver pathology associated with copper toxicosis (Bedlington terriers, Dalmatians, Dobermans). Copper toxicoses are very rare in cats. The mechanism of this process consists in excessive intake of copper in the body. It is able to damage mitochondria in hepatocytes, which leads to increased formation of free radicals.
Principles of treatment of hepatopathies
First of all, the patient should be offered a therapeutic diet with good palatability, since appetite decreases with hepatopathy.
An adequate energy supply of 50–60 kcal/kg/day is necessary, as well as high-quality protein to prevent tissue breakdown and nutrient deficiencies. Unjustified restriction of protein in the diet will lead to a decrease in muscle mass and hepatic encephalopathy. Carbohydrates and fats are necessary to improve the palatability of the diet and prevent the body from using amino acids as a source of energy. The best option is essential fatty acids.
As a nutraceutical, patients will need L-carnitine – it protects the liver from fatty dystrophy – the accumulation of triglycerides in hepatocytes. Normally, carnitine is formed from lysine and methionine, so their amount in the diet should be sufficient.
Soluble fiber reduces the formation of ammonia and its absorption in the large intestine (lowers pH) and improves the growth of acidophilic bacteria (bacteria utilize ammonia). Feed with a low fiber content can be enriched with plantain seeds – ½ teaspoon per 2.5 kg of body weight at each feeding. Including soluble fiber in the diet – 1-3 teaspoons of plantain seeds per day will increase the volume of feces and prevent constipation.
For long-term anorexia, patients with hepatopathy are indicated for the installation of a probe or esophagostomy for the first 7–10 days, after which the animal can be offered food for independent consumption. In case of blood coagulation disorders, vitamin K1 is administered (0.5–1.5 mg/kg of body weight per 1 dose). In some cases, for example, with a porto-systemic shunt, animals need drugs that reduce the absorption of ammonia in the large intestine, lactulose and antibiotics are indicated.
Thus, despite the fact that the principles of therapy of liver pathology in dogs and cats are widely studied in clinical veterinary practice, the use of hepatoprotective drugs remains a controversial issue in the treatment of dogs and cats. Do dogs and cats need hepatoprotectors? In order to answer this question, it is necessary to analyze a number of hepatoprotective drugs that are present on the modern market of medicines and nutraceuticals.
Ursodeoxycholic acid is a pharmacological drug. It causes a decrease in the intestinal absorption of cholesterol and its synthesis in the liver. Displaces harmful hydrophobic bile acids from the pool, protecting the liver from damage. Provides stimulation of bile secretion. Contraindicated in case of shunts, obstruction of bile ducts.
The drug has an immunomodulatory effect due to the stimulation of the formation of immunoglobulins, inhibition of the synthesis of cytokines and inflammatory factors in liver fibrosis. It is not toxic to dogs and cats, although its effectiveness has not been fully studied. Dosage: dogs, cats – 4–15 mg/kg p/o per day, in 2 doses every 12 hours. Used in dogs for cholangitis together with prednisone.
Ademethionine is a coenzyme, a carrier of methyl groups. It is used for acute and chronic hepatopathies of various genesis. There are foreign studies on the effectiveness in humans, the studies in dogs and cats are very contradictory. For example, methionine deficiency will lead to the formation of gallstones in dogs (one study). The doctor of veterinary medicine independently decides on the use of this drug. The majority of medical practitioners note in their experience the high effectiveness of this drug. Dosage: dogs – 20 mg/kg p/o every 24 hours, cats – 200–400 mg p/o every 24 hours.
Quercetin is a vitamin-like substance, according to its chemical structure, it is a derivative of plant (flavone) glycosides. Antioxidant, stabilizes cell membranes.
The effectiveness of quercetin as an antioxidant is confirmed by research by foreign authors in experiments on rats, there are separate publications on the effectiveness of the drug in cats and dogs. The drug stabilizes hepatocyte membranes, especially with accompanying obesity in dogs. It is also used in humanitarian medicine to eliminate intoxication caused by the use of cytostatics. Dosage: dogs, cats – 4–5 mg/kg PO every 12 hours for 3–4 weeks.
L-carnitine is a vitamin-like substance. It is used for lipidosis, chronic hepatopathies. There are foreign studies on the effectiveness of this substance in humans, as well as rats in an experiment, in dogs and cats – isolated studies of the effectiveness in cardiomyopathy. It is known that with a deficiency of carnitine in the diet, cats develop liver lipidosis. Dosage: for dogs 50 mg/kg of body weight per day, for cats – 250–500 mg/cat per day.
Choline is a nutraceutical. It is used for lipidosis, chronic hepatopathies. There are foreign studies on the effectiveness of people with alcoholic liver disease. Choline is also known to improve liver function in chickens, rats, cows, pigs, and cats. Choline deficiency can lead to liver lipidosis, there are isolated reports of the effectiveness of choline in toxic liver damage in dogs. Dosage: dogs, cats – 10–20 mg/kg PO every 12 hours – 7–10 days.
Vitamin E – tocopherol, fat-soluble vitamin, antioxidant. Used for oxidative stress, liver amyloidosis. Studies on the effectiveness are isolated and mainly refer to experimental animals – rats, single studies in cats and dogs – improves the structure of hepatocyte membranes. Dosage: 5–25 units/kg p/o every 24 hours, add to food within a month.
Vitamin K1 is a fat-soluble vitamin. It is used as an antihemorrhagic factor in hepatopathies of various genesis, poisoning with hepatotropic poisons. The role of vitamin K1 preparations as an antihemorrhagic agent affecting blood coagulation in dogs and cats has been proven. Dosage: dogs, cats – 0.5–1.5 mg/kg of body weight subcutaneously or intramuscularly.
Taurine is a nutraceutical that is part of bile acids. It is used for chronic hepatopathies of various genesis. Improves liver function in rats and mice in an experiment when it is damaged by ethanol and other toxins, improves bile synthesis in cats, has a positive effect on hepatocyte membranes in cats. Dosage: for dogs – 500 mg per dog every 12 hours p/o, for cats – 250 mg per cat every 12 hours p/o.
Ornithine is a nutraceutical, a source of the amino acid arginine. They are used for chronic hepatopathies of various genesis. Only one study was found in which arginine glutamate improved gastric motor function in dogs and rats. Evidence-based studies in dogs and cats with liver pathology have not been found. Dosage: dogs – 10 mg/kg p/o every 24 hours for 1–6 months, cats – 150 mg/cat p/o.
Artichoke extract is a herbal remedy. It is used for liver pathologies accompanied by cholestasis. It is known that in humans, the drug causes a decrease in the level of cholesterol in the blood, has an antioxidant and choleretic effect. In rats, artichoke extract has a hepatoprotective and immunomodulatory effect; there are no studies in dogs and cats.
Silymarin is an antioxidant obtained from milk thistle. There is evidence that it has antioxidant activity in liver diseases, but the level of evidence is low. There are publications about the effectiveness of this substance in liver fibrosis in experimental animals. It can be used for chronic liver pathologies accompanied by fibrosis. Dosage: dogs – 50–200 mg/kg PO every 24 hours.
Zinc is a trace element. It is used for liver fibrosis. In dogs, zinc is effective in copper-associated hepatitis, prevents the development of liver fibrosis. Dosage: dogs: 3 mg zinc gluconate per 1 kg per day or 2 mg zinc sulfate per 1 kg per day p/o. It is better to combine with vitamin E; cats – 1 mg/kg of zinc sulfate or zinc gluconate per day p/o. The drug is prescribed under mandatory monitoring of the level of zinc in the blood!
Vitamin B12 is cyanocobalamin, a water-soluble vitamin. Used for anorexia associated with liver pathology. Cobalamin deficiency must always be eliminated in case of gastrointestinal diseases in dogs and cats. Dosage: for dogs: 100–200 mcg/day p/o or 250–500 mcg/day i/m or s/c; cats: 50–100 mcg/day p/o or 250 mcg i/m or s/c. The drug is used once a week.
Essential phospholipids are used in chronic hepatopathies in human medicine, there are food additives containing this substance in veterinary medicine. However, there are no evidence-based studies in humane and veterinary medicine.
Thus, as can be seen from the conducted analysis of the effectiveness and features of the use of hepatoprotective agents, the use of this group of drugs should be carried out taking into account the results of the diagnostic examination of patients and the established diagnosis, as well as the availability of evidence-based studies. Each pharmaceutical drug or nutraceutical has its own evidence base of use, based on studies of its clinical effectiveness.