Ron Hines DVM PhD
Links To Other Articles On Liver Problems
I want to make it clear from the start that veterinarians do not have any medications that will cure chronic liver disease in your dog or cat. At best, we are trying to stabilize your pet or slow its decline. That goes for all the possible options I mention here as well. They are basically some of the treatments I would consider for my pet if current conventional treatments were not working. I cannot tell you what the best doses would be or that they are all safe. But I can tell you that what veterinarians have in their black bags now to treat liver disease leaves much to be desired.
Until better treatments arrive, try feeding your dog or cat very frequent, very small meals of a high-quality, easily-digested diet so that its remaining liver processing ability is not exceeded. Next to laboratory tests, the best judge of diet adequacy is keeping close watch on your cat or dog’s weight.
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When veterinarians runs blood work that shows abnormally high ALT, Alkaline Phosphatase, Bilirubin and/or GGT, your vet is likely to inform you that there is a good chance that your pet has a liver problem.
At that point the vets might suggest an ultrasound examination and a liver biopsy. They might suggest a bile acid test as well, measure prothrombin time and check for low blood albumin levels if their diagnosis remains in doubt.
In many cases, they still will not de able to tell you why the animal’s liver is failing. If your pet is a cat, they might suggest that the problem is part of triad disease (cholangiohepatitis) or hepatic lipidosis. If a dog, perhaps secondary to Cushing’s disease, toxin or drug exposures (eg corticosteroids or cyclosporin/Atopica® . Read more about that here They might mention that gall bladder obstruction, portal shunts or hepatic microdysplasia are sometimes at fault or that rare genetic copper storage disease underlies the problem. You see, as in humans, in the great majority of pets liver problems are a sign of some other underlying health issue. (read here)
Only a very few of those underlying issues have a quick or simple fix. Liver shunts , gallstones and gall bladder issues can sometimes be corrected surgically. Antibiotics sometimes cure a liver infection and liver damage due to toxins ingested sometimes resolve with time and good supportive care. (read here) But we veterinarians have no products to offer your dog or cat that have been scientifically proven to extend your pet’s life and nothing that will grow new liver cells. Yet. That is particularly true when no specific underlying cause for the liver problem can be identified. Humans in that situation would be offered a liver transplant. That has been done experimentally in dogs, I know of no attempts in cats. But I know of no one attempting a liver transplant in a pet. (read here)
Your veterinarian will probably put your dog or cat on a “liver diet” , send you home with some “liver support” product like SAMe, dispense some antibiotics (eg metronidazole and ampicillin) and perhaps a thiamine (vitamin B 1) supplement and advise you that your pet’s blood work needs to be checked periodically.
If you consulted an “alternative medicine” veterinarian or checked out paid product ads online (like the ones at the top and bottom of this page), there is no telling what advice or products will be suggested. The products they sell are only limited by the expanse of the marketer’s imagination. Such is the marketplace situation of today. But had you, yourself had those same liver issues, your physician might have advised small, frequent meals, a shift from meat to plant protein or a lower protein diet when the buildup of toxins began to cause you other health issues. Your doctor like your veterinarian, would also have recommended periodic monitoring. But your physician would also have the ability to comfort you that a liver transplant was an option if things got worse down the road. Veterinarians like me can’t offer you that – at least not yet.
Your pet’s liver has many duties – it is a highly complex organ. Its complexity means that it can fail in a large variety of ways. In some situations, the organ is still capable of some of its tasks but deficient in performing others. Since blood tests are often unable to pin point the problem, veterinarians generally try a number of medications and dietary changes and wait to see which appear to give your dog or cat the most relief. When one can afford it, ultrasonically often tells us more and a liver biopsy, more clues to what is going on. But a more precise diagnosis of the problem does not necessarily add more treatment options.
This article is more about chronic, long-term liver disease than sudden liver injury. Livers often rebound better from acute (sudden) short-term liver problems. As I mentioned, acute liver problems are more likely to be due to infections, ingestion of toxic substances or perhaps a bad reaction to a medication. With supportive care, those situations often resolve. But chronic liver problems are something your veterinarian can only manage – they are progressive and the best your veterinarian can hope for is to give your pet as extended and comfortable life as he or she can. When cancer underlies the problem, comfort, not cure or time is the most we have to offer you.
What Are Bile Acids And Why Are They Important In Many Forms Of Liver Disease?
Your pet’s liver cells (hepatocytes) form bile acids from cholesterol. Tiny channels (bile canaliculi) transport this product to its gall bladder where the acids are stored and periodically sent through the bile duct into the intestine to aid digestion and food nutrient absorption. Much of those bile acids are reabsorbed in transformed forms through the final sections of your pet’s small intestine and eventually recycled as new bile by the liver. (read here)
In many forms of liver disease (chronic hepatitis), there is a breakdown in the processes that form, excretes and then reabsorbs bile acids. (read here ) In those animals, blood bile acid levels become too high. Many believe that those high blood bile acid levels cause many of the symptoms of liver disease. Measuring your pet’s blood bile acid levels – particularly after a meal (postprandial) is a very sensitive test for liver disease. But the test not particularly helpful to your veterinarian in determining its cause.
The standard liver function tests on an ordinary veterinary blood panel are high during active liver cell destruction. That is because they measure intracellular compounds that are leaked when liver cells are actively being damaged. Those measured compounds often go down again after the damage has occurred. Blood bilirubin and bile acid levels are the two that don’t. And of the two, the bile acid assay is the more sensitive.
There is another important reason for looking at your pet’s bile acid level. In higher than normal concentrations, certain bile acids and their breakdown products (metabolites) are toxic to your pet in their own right. These are all secondary bile acids made by bacteria in your pet’s intestine from the original bile acids formed in its liver. Lithocholic and deoxycholic acid appear the most toxic. (read here & here)
Medications That Might Be Helpful:
Many believe that the best way to decide if a liver medication is actually helping is to track your pet’s alkaline phosphatase level to see if it is going down while on the medication. In mature dogs and cats, elevated AP is often a sign of liver damage. Blood levels of AP drop rapidly when a liver drug is effective because the half-life of AP is only seven days.
Ursodeoxycholic Acid – Ursodiol
Ursus is the Latin name for a bear. Back in the early 1990s, a bile acid that was originally isolated from the bile of a bear (ursodeoxycholic acid, aka ursodiol, UDCA) seemed to be helpful in the long-term treatment of chronic liver disease. Liver test results appeared to improve on that medication. (read here) A few years later veterinarians at Cornell found that ursodeoxycholic acid appeared to be non- toxic to cats too (at the dose they used). (read here) Veterinarians at the veterinary school in Florida found it helpful in treating dogs with liver disease as well. (read here) The medication was also tried in some healthy dogs in Australia to see what its effects on bile acid levels might be. (read here) Ursodiol is not a cure for liver disease, but it might help restore or improve bile flow in situations where bile flow is restricted (= cholestasis). (read here) Those benefits might only be moderate or perhaps short-term because ursodiol supplementation is unlikely to fully compensate for the liver damage that has already occurred. Its primary use in medicine today is to dissolve gallstones although it is also dispensed for a number of liver problems in humans, dogs and cats.
Ursodiol is an FDA approved treatment for chronic liver disease in humans when it is suspected that bile is not flowing through the liver properly. But its effectiveness in human is controversial. (read here & here) However, the Merck Veterinary Manual still lists ursodiol as an effective treatment for liver disease in cats. Many veterinarians prescribe it for dogs and cats with various forms of liver issues. The BVA suggests the drug as well. Veterinarians in the Netherlands did not find it to be as helpful as simple oral prednisolone when treating liver and gall bladder disease in cats. (read here)
Most researchers believe that when ursodiol is helpful in liver obstructive liver disease, it is so because it activates a system that limits bile acids production. Bile acid production in the liver relies on sensors (monitors) found in the liver and intestine. They are called the FXR or farnesoid X receptors. (read here) When these sensors are activated, processes down the line that form bile acids are switched off. That is not something that pet owner – or veterinarians for that matter – are likely to care about. But understanding how ursodiol might work led to a search for more powerful alternative meds that might accomplished the same thing. Switching on the FXR receptor might also be important in moderating other diseases such as IBD . (read here & here )
Obeticholic Acid OCA Oclavia™
Better understanding of the FXR switch led to a search for something that might be more efficient in turning the FXR switch to the on position (FXR-agonists). A medicinal chemist at the University of Perugia, Italy successfully synthesized a potent FXR agonist in 2002. All new drugs need a test group and one was readily available. Unfortunately, there are more people with failing livers in Italy than there are potential liver donors. So it is common for patients to have to wait a considerable amount of time before one becomes available. Several studies gave some of those waiting patients OCA and others none. Those receiving OCA did considerably better and lived longer. Seeing those impressive results, the FDA quickly approved the drug in May of 2016. There is no reason to believe that some dogs and cats with liver disease might not also benefit from this medicine. But veterinarians and pet owners have a big problem here. Medication breakthroughs can be the pot of gold at the end of the rainbow for their discoverer – particularly for liver disease because there are so few, proven treatment options. The chemist patented his discovery and with venture capital formed a NY based company, Intercept Pharmaceuticals, to market obeticholic acid under the trade name Oclavia™. The cost of those 5 mg tablets is likely to be more than the vast majority of pet owners could afford (~$252.66/ 5 mg tablet)- although I did find what claimed to be a generic version at $12.37/ 5 mg tablet. An equal amount of obeticholic acid ,sold for “scientific research purposes”, sells for $1 – $3.60.
The obeticholic Acid that I just discussed reduces bile acid synthesis (production) by inhibiting an enzyme called CYP7a1. Another group of human medications, primarily used to control cholesterol, fibrates also inhibit the same CYP7a1 enzyme. A commonly used one, gemfibrozil (Lopid®), also has the ability to lower bile acid levels. (read here) A study in people found its to be safe in humans with bile flow problems. (read here) The same drug has been used successfully in dogs that had abnormally high blood triglyceride levels. Angell Memorial lists it and other fibrates in their treatments plans for high blood triglycerides in pets as well. I have never personally dispensed this medication and, to the best of my knowledge, no one has yet to give any of the fibrates to dogs or cats for their bile acid lowering abilities. If you have please let me know. All medications that affect the CYP7a1 enzyme have the potential to interfere with the action of other drugs your pet is taking simultaneously. Those drug interactions are even more likely if your pet was diagnosed with liver shunts .
Colestipol And Cholestyramine – Bile Acid Sequestrants
Unlike Obeticholic Acid or the fibrates, these two medications do not reduce your pet’s bile acid production. Instead they increase bile acid elimination from the body. Colestipol (Colestid®, etc.) and cholestyramine (Questran®, etc.) are bile acid sequestrants used in humans, and occasionally dogs, to lower blood cholesterol and triglycerides or in an attempt to bind and remove ingested toxins. Colestipol also binds to (traps and neutralizes) bile acids in the intestine, making them unavailable for bacterial fermentation into more toxic secondary bile acids. (abstract here) I’ll send you the article if you ask me to. I do not know of veterinarians who have suggested giving either of these medications to dogs or cats to lower their bile acid levels. But the medications might be capable of doing so. If other treatments are not bringing your pet’s bile acid levels down, your veterinarian might want to consider them – particularly since the price of obeticholic acid is so high. Very little colestipol or cholestyramine is absorbed into the body and both are thought to be relatively safe medications. Some pharmacies sell have added flavors that your pet might find objectionable. Also, the normal dose size is rather large – similar to bran, Miralax™ or Metamucil™. Not all pets are going to put up with that.
With any of the medications I mentioned, you need to keep track of your pet’s weight every few days to be sure it is getting adequate nutrition. If it is loosing weight, drugs, dose and diet need to be reviewed. A lot of pets with liver issues have poor appetites. Medications that lower the level of bile acids in the intestine can negatively effect vitamin and fat absorption. So a multivitamin supplement for your pet is a probably a good idea. In cats, colestipol is thought to interfere with taurine absorption. Taurine is an essential amino acid for cats and a deficiency has been associated with heart problems in dogs. (read here) Both colestipol and cholestyramine can also interfere with the absorption of a number of drugs and require a drug dose increase.
Sevelamer is sold under the trade names, Renagel® and Renvela®. It is a phosphate binding drug used to help lower the abnormally high blood phosphorus levels found in kidney disease. Dialysis patients commonly take it. Like colestipol and cholestyramine, it is not absorbed into the body but instead binds to compounds in the digestive tract and in doing so prevents their absorption. Besides binding to undesirable phosphorus, sevelamer binds strongly to bile acids in the intestine. That enhances their elimination from the body and, through the same FXR mechanism that obeticholic acid/Oclavia utilizes, lowers the amount of bile acids produced by the liver. Sevelamer has been used safely to lower blood phosphorus levels in dogs. Perhaps it would also be useful in dogs and cats with liver issues for its bile acids lowering and anti-inflammatory abilities. Because sevelamer binds so well to bile acids, pets that receive it may need a fat soluble vitamin supplement (A,D,E&K) and their blood calcium levels need to be monitored from time to time (sequestrants can lower vitamin D/calcitriol absorption). If your veterinarian decided to give this medication to your dog or cat, let me know if it seemed helpful.
Long Term Antibiotics
Many veterinarians give pets with liver disease antibiotics like metronidazole and/or ampicillin in an attempt to reduce the production of ammonia by the resident bacteria of the animal’s intestines. That is because high ammonia levels in the blood are thought to be one of the causes of mental decline in dogs whose livers are failing. If your veterinarian suspects that some type of liver infection is involved, that might be a reason for giving your pet antibiotics as well. However, giving antibiotics has other possible consequences. The same bacteria that liberate ammonia have important feedback functions that limiting the amount of bile acids formed in the liver. Suppressing them with antibiotics might, in some cases, actually increase bile acid levels. (read here) I wish things weren’t so complex. It is just another reason why every liver treatment plan needs to be individualized and why periodic blood liver enzyme tests need to be run to see if your pet’s health is stabilizing or improving.
What Is The Best Diet For Dogs With liver Problems?
Since veterinarians (and physicians) can’t agree as to the best medications for dealing with liver disease, you might already have guessed that there is considerable disagreement as to what diets pets with liver problems should eat. Pet food companies market “liver diets” and sell them exclusively through veterinarians (Hills Prescription Diet Liver Care and id Hepatic feline, Royal Canin Canine or Feline HEPATIC™, PURINA® Canine or Feline HP Hepatic, etc.). To the best of my knowledge there are no studies that show that pets with liver disease who are fed these diets live longer or have improvement in their liver function tests. They are formulated on guesswork alone. These brands run ~ 17.8 – 19.0% protein and 18-24% fat for dog formulas and ~ 28% – 31.4% protein and ~ 22 – 23.1 % fat for their feline formulas (cats cannot survive on as low a protein food content as dogs). They are supplemented with two amino acids, L-carnitine and L-arginine that were reported to help humans with NASH and rat liver regeneration respectively. (read here) A newer study disputes that. (read here) If you cook for your pet, beef has the highest L-carnitine level and turkey breast the most L-arginine. These commercial diets often contain higher levels of omega-3 fatty acids than the companies regular diets – based on other human studies. (read here) Many also have higher levels of zinc than the regular diets they sell and lower copper levels based on a rare form of liver disease that occasionally occurs in dogs. (read here) They are formulated to be tasty because sick pets have poor appetites. Of course, your dog or cat would prefer the beef and turkey breast. They are all marketed as “nutrient dense”. So the pets don’t have to eat much of it to maintain their body weight. However browsing over the sac analyses does not really support that claim. Other than the lower copper and higher zinc, the formulas are all quite similar to an OTC premium beef- based dog food, since l-carnitine and zinc are highest in choice cuts of beef. Many of the producers of these prescription diets attain lower protein content through the addition of added amounts of carbohydrates (such as brewers rice) and fat.
The 2016 protocol of the University of California veterinary school at Davis saw no need to change your dog or cat’s diet when liver enzyme results were only moderately high. They did suggest an antioxidant supplement that contains Vitamin E, Vitamin C, S-adenosyl-methionine (SAMe) and/or silymarin (Milk Thistle). They noted that the benefits of those supplements and dose size were not known with certainty. UC Davis did not suggest a lower than normal protein intake until signs of hepatic encephalopathy occurred (spacey looks, star gazing, mental decline or seizures).
If you have been feeding the pet a lower cost supermarket brand, purchase something of higher quality. Despite the Davis protocol, you can try one of those premium commercial formulations for a few months to see if your pet’s situation improves. Just be sure your pet’s body weight, blood albumin level and RBC count do not go below normal or decrease. Be sure to track its alkaline phosphate level as well. Some dogs and cats actually need more, not less, protein during the majority of their time living with liver problems in order to keep their blood albumen levels normal. Low blood albumen is a common cause of fluid pooling in the abdomen (dropsy). We also want to be sure that copper restriction is not causing anemia.
Just as in people, many smaller meals given throughout the day might put less stress on your pet’s liver. A normal liver stores energy in the form of glycogen to be released when needed. A weakened liver is not very good at doing that. If you pet’s appetite is poor and you cannot improve the situation with home cooked meals, consider Entyce®.
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