David C. Twedt1, DVM, DACVIM; Marge Chandler2, DVM, DACVN, DACVIM, DECVIM-CA, MANZCVSc, MRCVS
There are many misconceptions on the nutritional management of the dog or cat with liver disease. With progressive liver damage, metabolic function also becomes compromised that could ultimately result in liver failure. Important physiological functions of the liver include intermediary metabolism of nutrients (carbohydrates, lipids, and proteins), coagulation, storage (vitamin K), bilirubin, and xenobiotic (drug) metabolism.
Canine Chronic Liver Disease
The most important and also the most common primary liver disease in the dog is chronic hepatitis. Chronic hepatitis is characterized by hepatocellular apoptosis or necrosis with variable mononuclear or mixed inflammatory infiltrates, regeneration, and fibrosis. The etiology of this chronic inflammatory condition is generally never determined although copper, infectious agents (leptospirosis or viral), and various drugs (phenobarbital, NSAIDs) are implicated. To date, the best described etiology is the copper-associated hepatitis where copper accumulates within hepatocyte to a concentration that then becomes toxic causing hepatocyte death.
The clinical signs tend to parallel the extent of hepatic damage. Early in the disease, there are usually no or minimal clinical signs. Only after the disease progresses considerably, do the clinical signs specific for liver disease become evident. In the late stages of liver disease, ascites, jaundice and hepatic encephalopathy may occur owing to loss of hepatic function. The ability of the liver to maintain albumin, glucose, and clotting factor production decreases. The liver also loses its ability to metabolize ammonia to urea resulting in eventual hepatic encephalopathy.
The four major goals of hepatic therapy should include:
1. Identifying and removing the primary etiology
2. Providing adequate nutritional support
3. Specific therapy (i.e., anti-inflammatory, antifibrotic, copper chelation, etc.)
4. Liver support therapy (i.e., antioxidants, vitamins etc.)
Further management of the specific complications of liver therapy include coagulopathies, GI ulceration, ascites, and hepatic encephalopathy management.
Nutritional Management of Chronic Hepatitis
Dietary Evaluation and Energy
A starving animal catabolizes its own proteins for energy, potentially increasing endogenous ammonia concentrations that can contribute to hepatic encephalopathy (HE) and compound the metabolic disorders already present. Hospitalized patients should be fed initially at resting energy requirement (RER):
RER = 70 (BW kg)0.75 or = 30(BW kg) + 70
Active pets at home are fed at maintenance energy requirements (MER), which is estimated by multiplying RER by 1.1 to 2.0 to account for body condition, age, and activity. These figures are estimates and can vary by as much as 50%. Food intake should be adjusted for the pet's weight and body condition.
Protein is needed to support hepatic regeneration and prevent negative nitrogen balance. In the healthy animal, protein in excess of the body's needs is deaminated, the carbon chain used for energy or stored energy and the nitrogen converted to ammonia. The ammonia is then converted to urea by the liver and urea excreted by the kidneys. In animals with liver failure, the conversion to urea is decreased and excess nitrogen may cause increased ammonia, one of the toxins involved in hepatic encephalopathy (HE).
Protein restriction should be instituted only if signs of HE exist. Reducing dietary protein in all patients with liver disease is not appropriate as it may lead to protein malnutrition. Commercial "liver diets" may not contain enough protein for growing puppies; adding ~ 100 g of cottage cheese per 420 g can of a "liver diet" is often recommended. The pet should be reassessed at 2 to 4 weeks and the protein increased to the highest level possible without signs of HE or when the animal is consuming protein levels equivalent to a maintenance food (~ 20–30% protein calories in dogs, ~ 30–40% protein calories in cats). Vegetable- and milk-based proteins are recommended in preference to meat-based proteins, which worsen signs of HE, possibly due to increased purines in meat proteins. Milk products contain tryptophan, a precursor for endogenous benzodiazepines; however, this has not been shown to worsen signs. Branched-chain amino acids (BCAA), leucine, isoleucine and valine, are preferentially used for energy by muscles when carbohydrates are insufficient. Clearance of the aromatic amino acids (AAA), tyrosine, tryptophan and phenylalanine, is decreased in liver disease and are the precursors to 'false transmitters,' octopamine and B-phenylethanolamine, which can contribute to HE.
Carbohydrate and Fiber
In liver disease there may be a decrease in hepatic glycogen storage, potentially increasing the risk of hypoglycemia and increasing the use of protein catabolism for energy. Feeding small meals frequently may help prevent this metabolic reaction. Colonic bacteria ferment some types of fiber to organic acids, decreasing the colonic luminal pH. A decreased pH converts ammonia to ammonium, which is less absorbable (ion trapping) and is more likely to be excreted in the feces. Bacterial nitrogen fixation also decreases the amount of nitrogen available for ammonia production. The inclusion of some fiber types speeds colonic transit and helps prevent constipation, which gives toxins less time to be absorbed from the colon.
Increased dietary fat content increases caloric density and palatability. Fat is tolerated by most patients with liver disease unless there is severe cholestasis resulting in fat maldigestion.
Water-soluble vitamins. Decreased appetite, polyuria, and decreased hepatic storage contribute to B vitamin deficiencies. Supplementation of vitamin B1 (thiamine) is recommended (especially in cats as they are particularly sensitive to thiamine deficiency). Dosage for cats is 10 to 25 mg SQ or PO q 12–24 h; for dogs is 50–250 mg/dog SQ or PO q 12–24 h. If intravenous fluids are given, a B vitamin complex can be added at 1–5 ml/l. Vitamins are light sensitive and will degrade in hours if not protected from light.
Fat-soluble vitamins. Any disorder that decreases the amount of bile acids entering the intestine, enterohepatic bile acid circulation, or intestinal fat absorption can reduce the uptake of the fat-soluble vitamins A, D, E, and K. Vitamin K and E deficiencies are more common. Vitamin K dosage is 0.5 to 1.0 mg/kg IM or SQ q 12 h for two initial doses. This is often administered prior to surgical biopsy because vitamin K is required for the vitamin K-dependent clotting factors II, VII, IX, X. The succinate alpha-tocopherol form of vitamin E theoretically helps protect the cells' membranes from mitochondrially derived oxidative radicals or reactive oxygen species. Alpha tocopherol acetate has greater water solubility and is more commonly used. Recommended doses are empiric and range from 10 IU/kg PO q 24 h to 100 IU/kg PO q 24 h.
Abnormal hepatic copper accumulation can only be determined based on a liver biopsy and quantitation. Hepatic copper levels of greater than 1000 µg/g dry weight liver (normal 400 µg/g) require therapy to reduce copper to non-toxic levels. It has been demonstrated that copper accumulation is often controlled using short-term penicillamine therapy associated with feeding a low-copper diet. Some dogs following chelation can be maintained only on a low-copper diet. Now evidence suggests that most commercial dog foods may contain too much copper for some dogs resulting in abnormal copper accumulation. Currently, the lowest dietary copper concentrations are found in the prescription liver diets. Dietary zinc can also block intestinal copper absorption and zinc supplementation with low-copper diets may also be beneficial in some patients following chelation therapy.
Antioxidants and Nutraceuticals
Considerable evidence shows that free radicals are generated in chronic liver disease and participate in the pathogenesis of oxidative liver injury in dogs and cats. Nutritional supplementation products, such as S-adenosylmethionine (SAMe), N-acetylcysteine (NAC) and milk thistle, are but a few therapies that are used for their antioxidant properties. SAMe is a nucleotide molecule synthesized by all cells derived from methionine and ATP. It is essential for major biochemical pathways of the liver and the production of glutathione (GSH), the major soluble hepatic antioxidant. N-acetylcysteine, given IV, also replenishes GSH. Silibinin (milk thistle extract) has antioxidant effects, suppresses fibrinogenesis, promotes fibrinolysis, and helps protect against hepatotoxins.
Feline Hepatic Lipidosis
Hepatic lipidosis (HL) is a unique liver disease that is very common in the anorexic cat. Severe lipidosis results in hepatic failure and alteration of many metabolic functions. Feline lipidosis is different in the dog in which severe lipidosis is uncommon. Feline hepatic lipidosis occurs either as a primary idiopathic disorder or secondary to a number of other primary disease conditions (e.g., diabetes, GI disease, pancreatitis, cancer, etc.) causing prolonged anorexia. When lipidosis is identified, an underlying etiology should be completely investigated before making the diagnosis of idiopathic form. The idiopathic form of HL generally occurs in older and obese cats that may have undergone a recent stressful episode followed by a period of complete anorexia. These cats will present with an acute history of rapid weight loss (up to 40–60% body weight over several weeks), depression, and icterus. The weight loss is significant with loss of muscle mass while abdominal and inguinal fat stores are often spared. Hyperbilirubinemia, elevated alkaline phosphatase, hypokalemia, hypercholesterolemia, hyperammoniemia, and coagulopathies are characteristic. The diagnosis is based on clinical findings supported by needle aspirate cytology or preferably histopathology.
The mainstay of therapy for idiopathic or secondary hepatic lipidosis is aggressive nutritional support. In one unpublished study, the author found an 86% survival rate for the idiopathic cats while secondary lipidosis cases had only a 32% survival rate. The poor survival rate for the secondary lipidosis cases was likely based on the primary underlying disease. Force feeding or the use of appetite stimulants, such as mirtazapine, is generally not adequate to meet the caloric needs of the patient. Force feeding can result in food aversion and stress to the patient. Tube feeding is the best way to administer adequate calories in a stress-free setting. Nasogastric tubes can be placed without anesthesia, but due to the small diameter (generally 5 F) feeding is limited to liquid diets. The author's preference is to place either an esophageal or gastric feeding tube. Esophageal feeding tubes are preferred but require anesthesia, are well tolerated and of a large diameter (~ 20 F) that will accommodate a blenderized food or prescription recovery formulations.
As mentioned above, an enteral feeding tube is usually placed as soon as a diagnosis is made, assuming the cat is stable enough for anesthesia. A nasoesophageal tube may be placed but only short term prior to other tube placement if necessary or anesthesia must be delayed.
The provision of adequate energy is one of the keys to the successful management of this condition. Energy requirements should be determined on an individual basis (see above for formula), but most cats should receive at least RER after tube placement and the gradual introduction of food. I usually begin feeding ¼ of the calculated requirements the first day divided into 4 to 6 feedings and then gradually increase the volume to full requirements over 5–7 days. By the time they leave the hospital, many cats are receiving close to MER. The nutritional makeup for feeding a cat with hepatic lipidosis is completely empirical and poorly documented. There are numerous reports in the literature suggesting various diets (with a variety of protein and fat content recommendations) but little consensus as to the best exact type to feed. In general, dietary fat and protein should not be restricted in these cats because calories and protein are so important in providing nutritional balance. Protein and amino acids are particularly important in cats with HL as protein deficiency may play a major role in disease development. Cats are less efficient than other mammals at sparing protein during starvation, and the amino acids methionine and arginine become limiting in obese cats during starvation. It has been hypothesized that protein or amino acid deficiency may induce lipid accumulation in the liver by limiting lipoprotein synthesis needed for lipid metabolism and transport in the normal liver. Supplementation of protein, even at only ¼ of the daily requirement, significantly reduces lipid accumulation in the liver and promotes positive nitrogen balance during long-term fasting in obese cats.
There are also no good data showing the benefit of various dietary supplements although they are often recommended. Some suggest arginine (1000 mg/day), thiamine (100 mg/day) and taurine (500 mg/day) supplementation during the recovery weeks while others believe there is adequate supplementation in most balanced recovery diets. The use of L-carnitine has been proposed to benefit some cats with HL. Carnitine transports long-chain fatty acids across the inner mitochondrial membrane into the matrix for oxidation. Although carnitine deficiency does not appear to be a mechanism for the development of HL, it may protect obese cats from hepatic lipid accumulation during weight loss. A recommended dosage for supplementation of carnitine in cats with HL is 250–500 mg per day. Many veterinarians also supplement the water-soluble B vitamins to their cases (see above).
There is also new evidence to suggest many cats with HL have or will develop cobalamin deficiency. Experimental cobalamin deficiency results in lethargy, anorexia, and weight loss - the signs observed with lipidosis. A suggested dose for B12 in cats is 125–250 µg per cat subcutaneously q 7 days for 4 treatments, then q 2–4 wk as needed. However serum cobalamin concentrations should first be determined to document the presence of a deficiency. Other therapies suggested include S-adenosylmethionine (SAMe), N-acetylcysteine, or silybin (milk thistle) nutraceuticals that may improve the oxidative status of the patient.
The prognosis must be guarded; however, with aggressive nutritional therapy many, if not most, cats recover. Several complications that can occur with therapy include a re-feeding syndrome and vomiting. The re-feeding syndrome is associated with the development of an often life-threatening electrolyte disturbance that occurs within 24 to 48 hours of enteral feeding. This is well described in humans occurring with introduction of nutrition and resultant increased insulin levels driving potassium, phosphorus and magnesium into the cells causing a critical depletion of these electrolytes in the blood. Vomiting is also a frequent complication associated with feeding. To avoid these problems, electrolyte abnormalities should be first corrected and then by feeding small frequent meals usually starting out with 25% of the daily calculated caloric needs and gradually increasing the diet volume over 5 to 7 days. If vomiting occurs, I will sometimes use maropitant (Cerenia®) or other antiemetics. Maropitant is metabolized by the liver and the dose I use in cats with hepatic lipidosis is lower (0.5 mg/ kg SO q 24 h) with my normal cat dose being 1.0 mg/kg SQ q 24 h. We have also used mirtazapine (Remeron®), a tetracyclic antidepressant that has both antiemetic and appetite stimulant effects (approximate dose is 1/8 of a 15-mg tablet every 1–2 days) with encouraging preliminary success.
When the cat is consuming adequate calories without the need for tube supplementation, the feeding tube can be removed. Tube feeding may extend for up to 4–6 weeks. A failure to respond to traditional hepatic lipidosis therapy should signal the need to investigate the likelihood of an underlying condition in the patient.
References are available upon request.