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Hepatic Encephalopathy (HE)
AKA:  Portosystemic Encephalopathy In Your Dog Or Cat

 

Ron Hines DVM PhD

Not all cases are the portosystemic type

Liver Metabolism

Hepatic  encephalopathy describes a situation in your dog or cat that results from a failing liver. When you pet’s liver is no longer healthy, it looses its ability to detoxify waste materials (eg ammonia, glutamine, ɣ-aminobutyric acid agonists, benzodiazepine-like substances as well as proinflamatory cytokines). Ammonia levels becoming too high in your dog or cat’s blood stream are a major marker for this problem. Ammonia  is normally produced by the bacteria in your pet’s intestines and as a normal byproduct of everyday metabolism within your pet's body. Its the liver's job to convert that ammonia into less toxic urea. The traditional explanation of HE is that ammonia buildup in you pet’s blood stream affects the animal’s brain, leading to confusion and mental dysfunction.

The most common cause of HE in younger dogs and cats  is an abnormal blood flow from the veins that drain their intestines. The major vein that does that (the pet’s portal vein) normally leads to the animal’s liver where these wastes are detoxified or re-excreted into the pet’s bile for elimination. These abnormal vein channels that circumvent the liver are called portosystemic shunts. You can read my rather complex article through the link at the top of this page or just look at a simplified diagram of the problems here. Most are birth defects, but some occur as a result of chronic liver inflammation. Hepatic encephalopathy can also occur when the pet’s liver has been damaged by medications such as Tylenol, sulfa antibiotics, moldy food, toxic mushrooms, artificial sweetener (just xylitol) and a number of poisonous plants. Hepatic encephalopathy can also result from liver damage caused by canine hepatitis, FIP in cats, toxoplasmosis, leptospirosis and neospora infections. It is also occasionally seen in very severe cases or the end-stage results of hepatic microdysplasia. In many older dogs and cats, HE is just another sign of age-related liver failure.

In dogs, heavy burdens of heartworms (caval syndrome) have been known to cause HE. In cats, HE has been associated with abnormally low levels of the amino acid arginine. In some dog breeds HE is due to a genetically based problem storing copper. (copper storage disease ref1, ref2). In pets with copper storage disease, restricting dietary copper sources can slow the disease's progression.

You can read an extensive review of the many things that have been linked to the liver failure that can bring on HE here.

Hepatic encephalopathy is somewhat more common in the breeds of dogs and cats that are the most prone to liver problems (portosystemic shunts are a predisposing factor in toy and small breeds of dogs and in Persian cats; English cockers, Labs, Westies and dobies because of their increased susceptibility to liver disease of other sorts).

Humans suffer from hepatic encephalopathy too. The most common cause in humans is cirrhosis of the liver. A common cause for that is alcoholism. (ref)

 

What Signs Would I See If  My Cat or Dog Had This Disease ?

Hepatic encephalopathy is a disease that usually begins gradually. Generally, the first sign that owners notice is the pet’s lack of interest - a sort of preoccupation or fog – as if the dog or cat was contemplating things far away. That can progress to confusion when decisions need to be made and even snappiness when urged to move or perform some task.

Because you know your pet so well, none of these early signs are likely to be apparent to visitors or even to your veterinarian.  But as liver damage increases, some pets become unsteady on their feet and disoriented or “spacey”. That can progress to getting trapped in corners, pressing their heads against objects, blindness, drooling, and even aggression when handled or disturbed. In middle-aged to old dogs and cats, those signs need to be sorted out from early onset dementia. Other owner descriptions of their pet’s changed behavior with HE include wandering, circling, stargazing, pacing, sleepiness, apathy, dementia and compulsiveness. 

Signs can progress to prolonged seizures/ convulsions and a semi-comatose condition. Pets with these more critical signs are approaching the end of life.   In some, heroic emergency treatments might restore a semblance of normalcy and gain time. But in many cases they will not.

In some cats with HE, the iris color of their eyes are said to assume a lighter metallic color. 

Near-normal  liver function is essential for many of your pet's critical body processes; so a lot of other, non-specific symptoms such as poor hair coat, diarrhea, weight loss and vomiting can occur as well.

It is common for the signs of hepatic encephalopathy to come and go – becoming worse at one time getting better at another. That is not the case with other things that affect the brain - things like brain tumors, brain deterioration (encephalomalacia) or hydrocephalus - all of which can result in symptoms similar to HE. Sometimes owners notice that symptoms of HE are the worst soon after their pets have eaten.

Are There Things That Might Make The Symptoms Of Hepatic Encephalopathy Worse In My Pet From Time To Time ?

Any form of stress tends to make the symptoms of hepatic encephalopathy worse. As I mentioned earlier, a recent meal sometimes triggers an episode – perhaps because the pet’s body has to deal with more free ammonia released (indirectly) from the food it ate.  Ammonia ions are liberated through the breakdown (hydrolysis) of the digested amino acids in the proteins your dog or cat consumes as well as during the construction and deconstruction of its own body proteins. (ref) Ammonia (NH3) at low levels is a normal constituent of all your pet's body fluids. Ammonia's ionized form, ammonium (NH4+), is most prevalent in your dog or cat's muscles - the chief non-dietary source of free ammonia in its body.

What Test Will My Veterinarian Use To Diagnosis This Disease ?

As I mentioned earlier, there are a number of non-liver health problems that could explain some or all of your pet's symptoms. Some of the tests your veterinarian might suggest are designed to rule out those other issues. 

Things that pet owners describe that might bring HE to their veterinarian’s mind are a history of unusually strong or persistent effects of tranquilizers and anesthetics (prolonged recovery) or sensitivity to flea and tick products, or to medications used to control epilepsy. That is because many of those (and other) medications are eliminated/detoxified by your dog or cat's liver and a weakened liver is inefficient in doing that.

Liver function tests (ALT, Total bilirubin, Alkaline Phosphatase, GGT ) are indicated. But normal results do not rule out HE. Those tests tend to be high early in liver disease when liver cells are inflamed (leaking) or destroyed, but the test results can be normal when liver problems are long-standing. 

Many dogs and cats with failing livers will also have lower than normal blood albumin levels because their liver can no longer synthesize sufficient albumin. Some have reduced blood-clotting factors in tests that measure their blood clotting ability (CT, PT,CTG, etc.) because blood clotting also relies on compounds produced by a healthy liver.

Measuring your pet's blood ammonia levels directly might be helpful in diagnosing hepatic encephalopathy. But the test is quite difficult to perform because ammonia is so volatile (evaporates quickly). So it is a test best performed at advanced institutions familiar with this difficult assay procedure. Even then, the test suffers from poor repeatability (two identical samples sent to different labs give different results). When your pet's plasma ammonia level is substantially elevated, it is a suggestion that HE underlies your pet's problems. But some pets with normal reading still have the disease. Also, the degree (amount) that the pet's ammonia level is above the lab's normals does not appear to directly influence the severity of the symptoms the animal is experiencing. (ref)

Because of the difficulties in accurately testing for blood ammonia, many veterinarians rely on the pet's blood bile acid levels instead. However, like ammonia, normal bile acid results do not entirely rule out HE either.

X-ray, Ultrasound And Other Imaging Techniques

Many pets with HE have a smaller-than-normal liver or liver tissue that has an abnormal texture (echogenicity) when viewed with an ultrasound machine. That is due to fibrosis (scaring). There are advanced imaging methods that are excellent for identifying abnormal liver blood flow (as in portosystemic shunts) which account for a large portion of the younger pets with HE. You can read about them here.

Dogs and cats with HE are also at an increased risk of developing urinary tract stones and crystals composed, in part, of ammonia compounds (ie ammonium biurate urolithiasis = calculi = “stones”). They can be detected and are generally checked for during imaging exams whenever chronic liver disease is suspected.

Immediate Stabilization

Dog and cats brought to their veterinarian in hepatic encephalopathy crisis often need intravenous fluids to rehydrate them. They may also need products to coat inflamed intestines - another common finding. Any other life threatening symptoms will be addressed appropriately. Some dogs and cats with HE are thought to have increased pressure upon their brain. Those pets are often given manitol in an attempt to alleviate that.

Dogs experiencing seizures are often given levetiracetam or sodium bromide. Both are anti-epileptic drugs. Both medications tend to have the potential to cause more worrisome side effects when given to cats than when given to dogs.

If constipation is thought to be a contributing factor (and even if it is not), enemas are useful to solve that immediate problem. Ammonia can leave the body with the stool and some ammonia is also produced by the microbes that normally inhabit your pet's colon. That exit rout for ammonia needs to be preserved and fully utilized.

What Long Term Treatments Are Available For My Dog Or Cat ?

The best hope for dogs and cats with hepatic encephalopathy are for those in which the underlying cause of their problem is a surgically-correctable hepatic shunt. That surgery is quite expensive. It can only be performed by a limited number of trained veterinary surgeons. It is not always successful and some cases do not lend themselves to surgical correction.  Read about that in another article of mine I mentioned before. (rptref)

If your veterinarian suspects that a liver infection might be the cause of your pet's liver failure, antibiotics are indicated. Antibiotics (like neomycin and metronidazole) are also thought to be helpful when no infection exists because they  reduce the number of ammonia-forming bacteria in your pet’s intestine. So in almost every case of hepatic encephalopathy, antibiotics will be part of your veterinarian's long-term treatment plan.

Pets with hepatic encephalopathy should avoid medications used to sedate them or they should be given those drugs in reduced doses and the pets then closely monitored. Those medications include benzodiazepines (like Valium®), barbiturates (like phenobarbital given for epilepsy or various compounds used to anesthetize or tranquilize pets) as well as narcotics and pain-control medications of any kind. Bouts of constipation, dehydration or prolonged fasting can precipitate (cause) an HE attack in dogs with the problem. 

Lactulose, a non-absorbable sugar, is one of the most widely used medications to lessen the symptoms of hepatic encephalopathy.  An alternative is lactitol. Both work only in the pet’s intestine and are not absorbed. Added dietary fiber (soluble and insoluble) is also thought to be beneficial. Fiber and fiber fermentation in the dog or cat's intestine might allow more ammonia to leave as ammonium via the feces. Be prepared for looser stools and/or bloating on all three of these products. Oral neomycin might reduce bloating and/or diarrhea problems.

Folks generally believe that neomycin is not absorbed into the body when it is given orally.... But that is not entirely correct. Drugs of that class have the potential to cause kidney harm and hearing problems. So pets on long-term neomycin need to be monitored (kidneys, hearing, etc.). When neomycin can not be given, metronidazole (Flagyl®) at a reduced dose has been used to keep intra-intestinal bacterial ammonia production as low as possible. In humans, rifaximin (Xifaxan®) is sometimes given for HE [rifampin as well [ref]. I am told that rifaximin has been given successfully to dogs and cats when neither neomycin nor metronidazole were effective in keeping the pet’s blood ammonia levels under control.
 
Some veterinarians give or suggest zinc supplements or additional levocarnitine in the diet. But the benefits of either are uncertain. Others suggest probiotics for a wide array of health issues including hepatic encephalopathy. Although they are not harmful, there is little science to suggest that they will be helpful either. You are certainly welcome to give live-culture yogurt to your pet if it handles it well. You can read one veterinarian's suggested case treatment plan here.

Omega-3 polyunsaturated fatty acids (PUFAs) are thought to reduce inflammation throughout the body. (ref) In experimental systems, these PUFAs also appeared to protect liver cells from the toxic damage caused by abnormally high bile acid levels. (ref) So a krill or cold water fish oil supplement, marketed for humans, might be a helpful addition to your pet's diet as well - particularly if its bile acid test results are high.

You might recall that earlier I mentioned that some veterinarians use high blood ammonia levels to confirm that your pet has HE - but that normal ammonia levels do not rule the disease out. I also gave you a link to a recent article that found that the level of ammonia detected in your pet's blood stream does not correlate well with the severity of the symptoms the pet is experiencing. (rptref) That led some of us to question if high blood ammonia was really the cause (or only cause) of the mental problems your pet is experiencing or if other toxic substances that build up in the blood stream of pets with failing livers might also be involved. One of those other substances are the bile acids your veterinarian used to confirm the diagnosis. Abnormally high blood bile acid levels are also toxic. An interesting experiment was performed in 2016. Mice were intentionally given compounds that caused their livers to fail. Some were fed supplemental bile acids and some where given medications that lowered blood bile acid levels. Those authors reported that the mice fed supplemental bile acids developed mental problems early than mice that did not. They also reported that the medication (cholestyramine aka Questran®, Prevalite®) delayed or minimized those problems. (ref) Cholestyramine is one of a group of medications called bile acid sequestrants used in human medicine to lower cholesterol - but also to treat the itching that commonly occurs in chronic liver disease in humans. I do not know of any veterinarians who have attempted to use cholestyramine or similar medications to lower high bile acid levels in HE pets or if they were helpful. If you do, please let me know.

There are other medications that sometimes help humans facing hepatic encephalopathy issues similar to those your pet is facing. You can read about some of those medications and suggestions here and here.

What Would Be The Best Long Term Diet For My Dog Or Cat With Hepatic Encephalopathy ?

Many veterinarians believe that reducing your pet’s protein intake and upping its carbohydrate intake might reduce the symptoms of hepatic encephalopathy. That is because protein breakdown is the source of much of the blood ammonia that is thought to play a part in your dog or cat’s symptoms. But other veterinarians (and human physicians [rptref]) avoid low protein diets because pets (and humans) can develop malnutrition when fed low protein diets. The actual protein requirements of ill pets can be even greater than the protein requirements of healthy ones. Those veterinarians simply suggest that the pet’s protein intake not be “excessive”. Pets would probably also benefit from frequent small meals rather than one or two large ones. The reduced number of healthy cells in your pet's liver might be able to manage the ammonia produced by small more frequent meals easier than by large less frequent meals. Once you dog or cat is on medications like lactulose, its ability handle protein should also improve. Physicians have observed that their human patients with hepatic encephalopathy seem to do better when plant protein rather than animal protein is the main source of protein in their diets. I have known that to be the case in some HE dogs as well.

Veterinarians will often also suggest you give your pet antioxidants, supplements with added vitamin E and/or C, silymarin (milk thistle) and/or s-adenosyl-methionine (SAMe). There is no harm in doing that but there is minimal hard data that they are helpful. Give them a try long enough to see if they are beneficial.

Humans, in a similar hepatic encephalopathy situation to your dog or cat would be place on a liver transplant waiting list . Your pet does not currently have that option. But there are visionary veterinarians pioneering other options right now. (ref1, ref2)

My personal believe is that it is quackery for anyone to offer to “regenerate” your pet’s liver with fat-derived stem cells. There are companies currently marketing those "treatments" for pets. Although it is the current rage, others (including me) have no faith in those procedures. (ref)

What Is The Long Term Outlook For My Dog or Cat ? What Does The Future Hold ?

You have to realize that many of the suggested treatments for HE that veterinarians have today are of unproven value in extending a pet’s life. Veterinarians and physicians have nothing that will regrow or regenerate a failing liver in man or beast. When veterinarians locate a particular, correctable anatomical reason for your pet’s liver failure, its surgical options for a long life greatly increase. My favorite places to have those decisions made are the AMC in Manhattan, Angell Memorial in Boston, Penn Vet and the U. of C., Davis. In Europe, Utrecht, in the UK, the RVC. I have had clients happy with the objectivity of all of them. Even if you utilize corporate services like the VCA, a second opinion from one of the above is prudent.

If you go to this human Wikipedia entry. you will see than several of the standard treatments we veterinarians still use in confirmed cases of HE have been laid aside in human medicine as being ineffective. But if you pet can be stabilized, its time progression (speed) of liver function decline is quite variable. I have two of the more current diagnostic and treatment guidelines for dogs and cats with HE but I can not post them here. I mentioned most, if not all, of the therapies they suggest in this article; but Email me if they are of interest to you and I will send them.