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Liver Disease Treatment Options On The Horizon

 

Other Articles On Liver Problems:

Ron Hines DVM PhD ..........................

Lots of my articles are plagiarized and altered on the web to market products and services. There are never ads running or anything for sale with my real articles. Try to stay with the ones that begin with http://www.2ndchance.info/ in the URL box or find all my articles at ACC.htm.

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.

I appreciate all feedback that you send me. They will get posted here, without your name or contact information unless you ask me not to post them. None of these options should be attempted without the guidance of a health care professional.

When veterinarians runs blood work that shows abnormally high ALT, Alk Phos, 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 too, measure prothrombin time and check for low 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 Atopica. (ref) 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, in the great majority of pets, liver problems are a sign of some other underlying health issue. (ref)

Only a very few of those underlying issues have a quick fix. Liver shunts can sometimes be corrected surgically and antibiotics sometimes cure a liver infection; but we veterinarians have few products to offer you that have been proven to extend a pet’s life and nothing that will grow new liver cells. That is particularly true when no specific underlying cause for the liver problem can be identified.

The veterinarian will probably put the pet on a “liver diet” send you home with some “liver support” products like SAMe, antibiotics (eg metronidazole and ampicillin) and vitamins and advise that the pet’s blood work needs to be checked periodically.

If you consulted an “alternative medicine” veterinarian or checked out products online, there is no telling what advice or products were suggested. The products they sell are only limited by the expanse of one's imagination.

That is the marketplace situation in 2016. But had you, yourself had those same liver results, 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 mental issues. Your doc, like your vet, would also have recommended periodic monitoring. But your physician would also have comforted you that a liver transplant was an option if things got worse down the road.  Veterinarians like me can’t off that – at least not in 2016.

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 about chronic, long-term liver disease. Liver’s often rebound better from acute (sudden) short-term liver problems. 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 I hope for is to give a pet as extended and comfortable life as I can.  When cancer underlies the problem comfort, not cure or time is the most I have to offer. 

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 the gall bladder where the acids are stored and periodically sent into the intestine to aid digestion and food nutrient absorption. Much of those bile acids are reabsorbed in the final section of the pet's small intestine and eventually recycled as new bile by the liver.

In many forms of liver disease (chronic hepatitis), there is a breakdown in the process that forms, excretes and then reabsorbs bile acids. (ref) In those animals, blood bile acid levels are too high. Many believe that those high blood bile acid levels cause some 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 (hepatocellular dysfunction) but not particularly helpful in determine its cause (not for differential diagnosis).

Many of the liver tests on a standard 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 but go down after the damage has occurred. Blood bilirubin and bile acid levels are two that don’t. And of the two, bile acid assay is the more sensitive.

There is another important reason for looking at your pet’s bile acid levels. In higher than normal concentrations, certain bile acids and their breakdown products (metabolites) are toxic to your pet (eg the secondary bile acids made by bacteria in the intestine from liver bile acids, lithocholic and deoxycholic acids appear the most toxic). (ref)

Ursodeoxycholic Acid Ursodiol

Ursus is a bear. Back in the early 1990s, a bile acid that was isolated from the bile of bears (ursodeoxycholic acid, aka Ursodiol, UDCA) that seemed to be helpful in the long-term treatment of chronic liver disease. Liver test results appeared to improve on that medication. (ref) A few years later vets at Cornell found that ursodeoxycholic acid appeared to be non- toxic to cats too (at the dose they used). (ref) Veterinarians at the veterinary school in Florida found it helpful in treating dogs with liver disease as well. (ref)  The medication was also tried some healthy dogs in Australia as well to see what its effects on bile acid levels might be. (ref) Ursodiol is not a cure for liver disease in humans or pets, but it may help restore some improve bile flow in situations where flow is restricted (= cholestasis). (ref)

Those benefits might only be moderate or short-term because ursodiol supplementation can not compensate for the liver damage that has already occurred. Its primary use today is to dissolve gallstones although it is also dispensed for a number of liver problems in humans and pets.

Ursodiol is an FDA approved treatment for chronic liver disease in humans when it is suspected that bile does not flow through the liver properly. (ref), But its human use for that is controversial. (ref1, ref2)

However, the 2016 online Merck Veterinary Manual still lists ursodiol as an effective medication for liver disease in cats and many veterinarians administer it to dogs and cats with various forms of liver disease. The BSAVA suggests it as well. (ref) Others did not find it as helpful as simple oral prednisolone. (ref)

Most researchers believe that when ursodiol is helpful in liver cirrhosis, it is because it activates a system that limits other bile acids production. Bile acid production in the liver relies on a sensors or monitors found in the liver and intestine called the FXR or the farnesoid X receptors. (ref)  When it activates, 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 . (ref1, ref2)

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. (ref1, ref2) All new drugs need a test group and one was readily available. Unfortunately, there are more people with failing livers than there are new donor livers. So it is common for patients to have to wait a considerable 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. (ref1, ref2, ref3)
Seeing those impressive results, the FDA quickly approved the drug in May of 2016. (ref)

There is no reason to believe that some dogs and cats with liver disease might not benefit from this medicine too. But vets and pet owners have a big problem here. Medication breakthroughs in 2016 are a pot of gold at the end of the rainbow for their discoverers - particularly for liver disease because there are so few, proven treatment options. The chemist patented his discovery and, with others promptly formed a NY based company, Intercept Pharmaceuticals to market obeticholic acid under the trade name Oclavia ™. The cost of those tablets is likely to be much more than the vast majority of pet owners could afford (~$20 - $40/day). Sold for "scientific research purposes", that amount goes for about $1 - $3.60 per day. (ref)
 
Fibrates

Obeticholic Acid that I just discussed reduces bile acid synthesis (production) by inhibiting an enzyme called. CYP7a1.

Another group of  human medications, used to control cholesterol, fibrates , also inhibit that CYP7a1 enzyme. A commonly used one, gemfibrozil (Lopid®), also has the ability to lower bile acid levels. (ref) A 2010 study found its use safe in human patients with bile flow problems. (ref)

That drug has been successfully used in dogs that had abnormally high blood triglyceride levels. (ref) Angell Memorial lists it and other fibrates in their treatments plans for high blood triglycerides as well. (ref). 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 info on that, please let me know.

All medications that affect the CYP7a1 enzyme have the potential to interfere with the action of other drugs taken simultaneously (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 lower 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 sequestrant used in humans, and occasionally dogs, to lower blood cholesterol and triglycerides or in an attempt to bind and remove ingested toxins. (ref1, ref2)

Colestipol also binds to (traps) bile acids in the intestine, making them unavailable for bacterial fermentation into the more toxic secondary bile acids. (ref)

I do not know of veterinarians that suggest giving either of these medications to dogs or cats to lower their bile acid levels. But these medications might be capable of doing so. If other treatments are not bringing your pet’s bile acid levels down, your vet 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 medication. Some pharmacy forms have added flavors that pets might find objectionable. Also, 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 discussed, 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 their vitamin and fat absorption. So a pet multivitamin supplement is a probably a good idea.  In cats, colestipol is thought to interfere with taurine absorption. Taurine is an essential amino acid for cats. (ref) Both colestipol and cholestyramine can also interfere with the absorption of a number of drugs, requiring a drug dose increase.

One of the major used of cholestyramine by physicians is to relieve the itch that is sometimes associated with reduced bile flow in pregnancy. A study that compared cholestyramine to ursodeoxycholic acid use found that ursodeoxycholic acid did a better job at that than cholestyramine. (ref)

Sevelamer

Sevelamer is sold under the trade names, Renagel® and Renvela®. It is another 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 preventing their absorption. Besides binding to undesirable phosphorus, sevelamer binds strongly to bile acids in the intestine, enhances their elimination from the body and through the same FXR mechanism that obeticholic acid/Oclavia utilizes, lowers the amount of bile acids produced in the liver. (ref1, ref2, ref3)

Sevelamer has been used safely to lower blood phosphorus levels in dogs. (ref) Perhaps it would also be useful in dogs and cats with liver issues for its bile acids lowering and anti-inflammatory abilities as well. Because it binds so well to bile acids, pets that receive it may need a fat soluble vitamin supplement and their blood calcium levels monitored from time to time (sequestrants can lower vitamin D/calcitriol. absorption) . If your veterinarian decides 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 were thought to be one of the causes of mental problems in dogs with failing livers. If some type of liver infection is suspected, antibiotics might be given as well.

Doing so may not always be beneficial. First, blood ammonia levels do not correlate well with the mental confusion failing livers can cause in pets. (ref) Second, those same bacteria have important functions in limiting the amount of bile acids formed in the liver. Suppressing them with antibiotics might, in some cases, actually increase bile acid levels. (ref) That is just one more reason why every liver treatment plan needs periodic re-checks to see if it is improving your pet’s health. There is no one plan that will fit all pets.

What Is The Best Diet For Dogs With liver Problems ?

Since  physicians and veterinarians can not 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 these problems should eat.

Many pet food companies market “liver diets” sold 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 improved liver function tests.

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. (refA newer study disputes that. (ref) If you cook for your pet, beef has the highest L-carnitine levels and turkey breast the most L-arginine.

These commercial diets also contain higher levels of omega-3 fatty acids based on other human studies. (ref)  Many have higher levels of  zinc than their regular diets and lower copper levels because of a rather rare form of liver disease that occasionally occurs in dogs. (ref)

These diets are formulated to be tasty because sick pets have poor appetites. They are marketed as very "nutrient dense" so the animals don’t have to eat much to maintain themselves. However their analyses do not really support that claim. Other than the lower copper and higher zinc, the formulas are quite similar to a premium beef- based dog food, since l-carnitine and zinc are highest in choice cuts of beef. But many of the prescription diets are lower in protein through the addition of added carbohydrates (like brewers rice) and fat.

The 2016, the University of California veterinary school in Davis liver disease protocol sees no need to change your pet’s diet when liver enzyme results are only moderately high. They do suggest an antioxidant supplement that contains Vitamin E, Vitamin C, S-adenosyl-methionine (SAMe) and/or silymarin (Milk Thistle), although they note that the benefits of those supplements and dose size are not known with certainty. They do not suggest lower than normal protein intake until signs of hepatic encephalopathy might occur (spacy looks, star gazing or seizures).

If you have been feeding the pet a supermarket brand, purchase something of higher quality. Despite the Davis protocol, you can try one of the commercial formulations for a few months to see if your pet’s situation improves (none of the "liver support" diets are that low in protein that they should cause weight loss). Just be sure the pet's body weight, blood albumin and RBC levels do not go below normal. Some pets 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. We also want to be sure that copper restriction is not causing anemia.

Just as in humans, many small meals given throughout the day might put less stress on your pet's liver. (ref) A normal liver stores energy in the form of glycogen to be released when needed. A weakened liver is not as good at doing that. (ref)