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KPU / Cryptopyrroluria

The relatively unknown, yet now widespread, multi-metabolic detoxification disorder

This page has been written following the workshop training 'Feed Your Horse Fit', by Dr Christina Fritz, Oct'21

KPU is the abbreviation for the metabolic disorder "cryptopyrroluria". It’s not a disease – it’s a growing, and very complex, metabolic detoxification disorder in horses.

Put simply, the liver’s natural detoxification talents have gone seriously wonky, meaning dangerous circulating toxins escape into the body, triggering a whole range of metabolic disorders, manifesting in a multitude of unspecific symptoms - often several at a time concurrently, with our horse never seeming to get better from one issue to the next.

The root cause? A disturbed hindgut intestinal biome. Normally, a healthy hindgut microbiome happily beavers away, day in and day out, digesting the forage cellulose fibre in our grasslands and hay, creating the main energy source for the horse as well as many of the important nutrients, including many amino acids, vit.K and two B-vitamins in an ‘activated’ form, specifically B12 and B6, and it’s this activated B6 that the liver needs to effectively metabolise – correct term biotransform – the body’s waste and toxins and convert them into a water-soluble, excretable state for the kidneys to eliminate.

Cryptopyrroluria/KPU happens when the hindgut biome is far from happy due to either not being fed enough fibre, usually due to too much neon-green grass and not enough stemmy, cellulose-fibre-rich hay, or when haylage is fed. Cue hindgut dysbiosis/acidosis, which causes the multiplication of putrefactive bacteria, which disrupts the production of the activated form of vit.B6 – pyridoxal-5-phosphate, aka P5P, so the liver is unable to deactivate those harmful toxins. P5P acts as the catalyst for the equine liver’s biotransformation process to function correctly.

KPU underlies many of the well-known metabolic diseases we see, i.e. IR/EMS, laminitis, recurrent colic, a constant chronic cough, sweet itch, mallenders/sallenders, persistent diarrhea, loss of performance – it’s said that all have underlying KPU, and there’s a reason why it’s called ‘the disease of a thousand faces’.

The good news is that it’s not genetic, but it can be inherited by a foal from its mother. That said, it can be reversed but be prepared for an almighty marathon with no sprint in sight. Basically, we have to regenerate the hindgut microbiome to get the liver start working properly again.

The How&Why

KPU can be triggered from birth. That first year of the foal is crucial, and very much depends on how the mother was fed, because a foal eats its mother’s faeces to build its own microbiome.

We now know that if the dam has a disturbed microbiome, the foal will end up with same poor-quality microbiome; new breeding practices are now putting mares with disturbed hindgut function in with other mares known to have a healthy microbiome, so the foal will eat mixed faeces to give its hindgut a better chance for good colonisation. Otherwise, if the foal is unable to establish a healthy microbiome, you have a metabolic-risk patient for life because if a healthy microbiome isn’t there to start with, it’s very difficult to restore and recreate.

In that strange perfect parallel world, it would all be so much easier to simply feed healthy microbes to the horse to then outgrow the bad bugs, but such a thing doesn’t exist – all probiotics out there either include lactic-acid bacteria or yeast, neither of which are a recognized colony member of the equine microbiome. We know the dangers of lactic-acid bacteria residing in the large intestine, but science is now showing that yeasts also negatively disturb the equine hindgut biome, meaning that current probiotics do the very opposite to what we want them to do. In that perfect world we need to install cellulose-digesting microbes in the hindgut when there’s a biome disturbance, to outgrow the bad guys – this way we’d come back to a natural microbiome that the equine gut system is evolved for.

So, if it’s possible to check the history of our horse back to birth, we’d have more of a clue as to how they were fed, and that hopefully no antibiotics or haylage were fed in the first 6-months of their life, or that the mare unknowingly already had hindgut dysbiosis.

How to diagnose

So, we know that KPU is caused by dysbiosis in the gut microbiome, which disrupts the B6 production, so by reinstalling the natural biome we’ll restore liver function and we’ll have a healthy horse again. Until then, it’s the usual rule – fix the gut, fix everything - we have to follow a nutrient-support programme.

There’s also good and kind-of-bad news - KPU can be diagnosed via a urine test. It’s not an indepth test yet as it’s still early days, but it will show you whether the fermentation process in the hindgut is right or wrong. The downside? This test is currently only available in Germany and a further issue is that the urine test needs to be tested within 3-days, which is problematic from the UK with the current courier situation. Rest assured avenues are being explored to get the test more readily available in the UK.

The test results show a numbered gradient – a result of 1 = not perfect but not bad either, change feeding and focus on gut restoration. Between 2-4 = there’s plenty gone wrong; severe dysbiosis with major therapeutic help to restore the hindgut biome.

The other important factor to be aware of is that this is no sprint fix – KPU takes an almighty marathon to repair. Not wishing to alarm anyone, but a result of 1 = 1-2 years. 2-4 and you're looking at 2-3 years of therapy to get back to normal. A super high reading? 5-years at least, because the body needs time to excrete what’s been collected and stored over months/years.

KPU is also seasonal dependent, perfectly matching the well-known metabolic symptoms we’re well aware of – during spring-autumn grass, KPU symptoms go up; during winter they go down.

The liver connection

So, we know now it starts with the hindgut dysbiosis, but what actually happens in the liver? Reminder – probably the liver’s most important task is the biotransformation of waste products/toxins, converting them to a state where the kidneys can excrete them. And it’s this vital biotransformation process that’s affected.

It breaks down to 2 phases :

Phase 1 – the attachment of a Functional Group (FG) molecule.

Picture a 4x4 jeep, and a separate trailer you’ve filled with hay for your horse. Without a towbar to attach the trailer to the jeep, you’re not going to get your hay to the yard. The towbar is the grouping-mechanism, aka the ‘functional group’. And this is what toxins need when they arrive in the liver – the liver cells attach a ‘functional group’ molecule to the toxin, in order to prepare it in a form that the kidneys need for excretion.

Phase 2 – So, the liver’s added the ‘towbar’, the FG, to the waste molecule. Now it needs a catalyst to attach the hay trailer, aka, a 2nd molecule attachment which is highly water-soluble – remember, the kidneys only excrete water-solubles. And the catalyst? P5P. This Phase-2 molecule attachment then makes the whole waste molecule water-soluble. This now signals to the kidney that the whole complex needs to be excreted via the urine.

So, Phase-1 - the attachment of a FG; Phase-2 - the conjugation of a water-soluble molecule courtesy of the activated form of vit.B6 – pyridoxal-5-phosphate, aka P5P.

Now to Vit.B6 - P5P

Normally in a healthy horse this process runs smoothly 24hrs/day so we don’t need to even think about it, because a healthy horse has a healthy gut microbiome which produces many different trace elements the metabolism needs, including the activated form of vit B6.

We know that horses don’t get deficient in vitamins normally as the small intestinal biome produces most of them (other than vit.C which the liver produces). This includes most of the very diverse B-family, with B6 and B12 produced in the hindgut. These last two are also the only two B-vits that can go into deficiency – B12, which builds hemoglobin and red blood cells – isn’t found in plants so can only come from the microbiome; and B6 – you’ll often see this included in some processed feeds and mineral balancers, labelled as ‘Piridoxine’, which is the inactive form that the small intestine has no activation pathway for. Thus, it neither recognises, or knows what to do with; therefore, as it can’t be used it’s automatically ignored and sent off for excretion.

The activated form of B6 is called P5P – pyridoxal 5 phosphate ; quick Science Alert - the ‘5’ meaning that in the 5th position of the molecule it needs phosphate attached. Science Alert over 😉

This active form – P5P - is essential to start phase 2 of the liver transformation process (Christina spent hours and hours of reading through chemistry books to discover this fact!.

P5P is needed to catalyse this reaction, and without it, Phase 2 simply cannot start. So … back to our jeep and trailer example – you’ve attached the towbar but without a person (P5P) to attach the trailer to the towbar, the hay won’t get to the yard.

Long and short? If there’s a disturbed gut biome, there’s no activated B6 – P5P - for the liver biotransformation to work properly. Without P5P the detoxification/biotransformation reaction stops after Phase 1, leaving highly toxic agents in the body.

So what happens if it doesn’t work?

The liver still filters toxins from the bloodstream, and still attaches the FG, but if there’s no P5P, the liver literally says, “F***, what do I do now?!”

The good news is that the body has emergency pathways to keep functioning until the environment changes, then the body can go back to its normal metabolic pathways. So, the body continues to constantly produce waste products and absorbing into the bloodstream, but as the liver cant transform them anymore, they get stored.

Water-soluble toxins get stored in the connective tissue – we’re talking tendons/ligaments – this is a completely natural emergency process to store dangerous toxins, but it means … water retention! This is why some horses swell up. Now cue Serious Misunderstanding No.1 because – this is also where we can now get confused, because we think it’s fat.

Serious Misunderstanding No.1

We put our horses on a diet! Except it’s not fat – it’s lymph fluid sent to dilute the waste products – when waste product concentration gets too high, the connective tissue starts to die off so the body needs to dilute the waste products, hence why there’s water retention.

And where does it happen? The typical neck crest and what we think are fat pads on the flanks, all signs of EMS/IR, yet it’s the lymphatic system trying to dilute the stored waste products.

Meanwhile, back to water-soluble waste to the connective tissue – what about fat-soluble waste? This one’s easy – they go to fat tissue, which also creates is big problem! Cue Serious Misunderstanding No.2.

Serious Misunderstanding No.2

So again, we think our horse has overindulged so we skinny down their rations to make them drop some weight. Wrong. What we’re actually doing is releasing fat-soluble toxins, which now triggers a vicious cycle – if there’s less fat in the body, there’s less storage room for the fat-soluble toxin storage, so they simply circulate back into the body. And this leads us back to the How&Why of the liver biotransformation process.

When liver biotransformation works properly, there’s no problem because the waste molecules are made water-soluble so they can be excreted via the kidneys, but without P5P we can’t do this. So by endeavouring to skinny our horse down means an overload of circulating toxins in the body, which as we all know induce laminitis due to re-toxification. So, the body has a really good reason to try and hold onto those fat or lymph pads while the toxins are stored there.

Which means … when we’re faced with a fat-pad/lymph-pad horse, it’s vital that we fix the liver biotransformation process, so when available we should get the KPU test done before considering any weight reduction, otherwise retoxification will occur. If the test proves positive, we must address liver function first before starting a s-l-o-w weight reduction process, so circulating toxins can be biotransformed.

Meanwhile, there is another emergency pathway, but it comes at a price.

Trace element deficiency

There’s another emergency pathway for some Phase-1 toxins to still be excreted by the kidneys, because if P5P is missing, the liver can couple certain minerals to certain toxins, depending on the toxin molecule, to excrete at least some of it.

We’re talking certain Phase 1 toxins being coupled to zinc, selenium and sulphur, but manganese and iron can also be used. There is a price though – these minerals themselves can go into false deficiency.

Zinc

Zinc deficiency is historically rare; copper, yes, certainly in Europe, but not zinc. However, zinc deficiency is now being seen in bloodworks. This is interesting as both zinc and copper counteract each other – when zinc goes up copper goes down, when copper’s up zinc is down – if you look at hay analyses you’ll often find high zinc/low copper. This is normal as our soils/forage don’t have much, hence why we have to supplement to the NRC RDAs, but despite this it’s rare to see a zinc deficiency.

However, over the last 3-5 years we’re seeing many horses with zinc deficiency but not copper, now thought to be due to metabolism changes due to the faulty liver biotransformation process using zinc to bind to toxin molecules for excretion.

There’s a suggestion that we can check this by feeding extra zinc, and if bloods show better levels, stop feeding extra zinc and see if the problems reoccur. However, it shouldn’t be about compensating with extra zinc, it should be about repairing the liver biotransformation so the horse can regulate back to their normal zinc levels.

NB. A side effect of this is that because the labs aren’t aware of KPU, they’re now reducing what’s thought of as ‘normal’ zinc parameters so we should always question this, and request previous ‘normal’ reference values from the literature and not necessarily what the labs are now saying.

Selenium

And this is interesting because until the mid-1980s, everyone thought selenium was toxic to horses so it was never fed. This was apparently based on American thinking because in America soil selenium levels were so high that horses were literally dying of selenium toxicity, so the thinking was that ‘selenium is toxic’.

Cut to the mid-80s and the first research into selenium began with dairy cows – there was a condition known as white muscle disease and calves were dying. A connection was found between selenium and feed for white muscle disease, so the thinking was that cows with low selenium levels meant there wasn’t enough selenium in their forage so, therefore – and here’s where it got ridiculous – there must be the same problem for horses too!

Thus, reference blood work values for horses were established and selenium began to be measured in every horse. Thing is, the blood parameters were set too high, and many horses were found to have alleged ‘selenium deficiency’ because of where the labs chose to set their reference parameters.

The fact is that horses aren’t normally selenium-deficient. Over the years, the parameters were gradually reduced towards more normal (should be around 40-micrograms per litre), so these days we simply don’t see selenium deficiency.

There’s a connection with zinc though. When either zinc or selenium levels are low, the other is as well. Stop feeding zinc, both levels lower; supplement zinc and selenium levels rise. And … it’s all connected through KPU.

When horses have KPU, not only is large amounts of zinc used to couple to the waste toxins, but selenium is also used. As soon as you top up zinc, the body uses less selenium to excrete waste and this is why higher selenium levels can be seen.

So, we always need to be careful feeding selenium as it can trigger IR, EMS, Cushings – selenium is highly toxic to horses so we should never feed more than in a mineral feed as if there’s selenium-deficiency - always look at zinc levels first. Address the KPU, and the selenium levels will rise by themselves.

Sulphur

Again, good and not-so-good news here - in a healthy horse, sulphur is usually sufficiently available through forage/roughage as there are plentiful levels of sulphur-containing amino acids in grass/hay.

However, a KPU horse will use up too much of its sulphur reserves attaching to waste molecules which can lead to sulphur deficiency. This is apparently not identifiable in bloods, but we can visibly see the symptoms of sulphur deficiency in skin, hair and hooves – all kidney markers.

Typically we’ll see poor skin regeneration, poor coat change/shedding, which could be related to sulphur deficiency. Over time they’ll lose long hair so develop a thinner mane/tail. As for hooves, they’re built from keratin which has very high content of sulphur amino acids. Typical signs are very slow hoof growth, i.e. not needing your hoof professional for ages. Weak/soft soles, footy response, poor hoof horn quality – all likely a sulphur deficiency/likely KPU as this doesn’t happen in healthy horses.

We can supplement with MSM (true sulphur) with many horses being fed MSM; if your horse has had these symptoms which then mysteriously improve, perhaps we should ask Why, and consider if they have KPU.

Manganese

Manganese is rarely deficient as our UK forage already has way too high levels of manganese, so a horse should never become deficient, unless they have KPU – like sulphur, a manganese deficiency can also not be traced in bloods. Be aware – a new ‘myth’ hitting the headlines is horse feed companies saying there’s an epidemic of manganese-deficiency – they’re always on the lookout for some new spin to buy their products, so bear this in mind.

To conclude, we have zinc, selenium, sulphur and manganese involved in this KPU/liver emergency pathway. We should never, ever feed supplementary manganese or selenium, but if we see our horses improve with added sulphur (via MSM) and/or zinc, we should always test for KPU.

The symptoms

It’s known as 'the disease with a thousand faces', as there’s such a wide range of symptoms. This section also goes hand-in-hand with liver/kidney issues, so check this page as well.

  • Always check for continuous gut disturbance, i.e. if you’ve got faecal water, continual diarrhea, excess gas, it follows logically that there’s hindgut dysbiosis so P5P deficiency is a given. If you put a healthy horse on fresh grass and they get the squits for a few days, no worries, but continuous?
  • Skin problems – sweet itch, eczema, mud fever, cellulitis, continual itching.
  • Hooves – poor hoof quality, thrush, WLD, frequent absessing, permanently footy.
  • Susceptible to - or unexplained - tendon/ligament injury.
  • Chronic ongoing cough, resistant to meds yet not always allergic. Always ask Why is your horse coughing? The wild horse is naturally used to dry, dusty environments – a horse can manage this perfectly well as normally, the cellular epithelium level in the airways is covered with a thick mucous layer which binds to the dust and shifts it out again – no cough required. To build this mucus layer the horse needs enough cysteine – an amino acid that contains sulphur – so to build up enough cysteine the body needs enough sulphur. When there’s KPU the horse goes into sulphur-deficiency so the airways can’t build up enough cysteine; thus they can’t build up the mucous layer so the airway is dry. Dust is inhaled and the horse coughs. Cue Serious MisUnderstanding No.3. One method us carers do is turn to haylage instead of hay – well, it’s dust-free innit! Well, yes, but … while this is our well-meaning attempt at alleviating the symptoms, haylage significantly damages the gut microbiome, which completely runs the immune system, so it triggers the autoimmune response which increases allergic reactions – moulds, pollens, insect bites … This is always a secondary reaction – we should always track back to the root cause – is it hindgut dysbiosis causing B6 disruption, causing liver biotransformation disfunction, causing KPU?
  • Musculoskeletal issues that can’t be explained – there’s intermittent lameness so you call the vet, yet the horse is fine when the vet arrives and for a few days then goes lame again – the carer can’t explain it. Or constant back tension that the physio can’t explain, where the horse needs 30-40 minutes to warm up the muscles to work comfortably again. This could be KPU because remember, the connective joint tissue around the muscles stores the waste toxins as well as its own waste toxins.
  • Mineral disorders – exostosis (a benign growth of new bone on top of existing bone), bone/tooth demineralization (EOTRH), brittle bones, various lamenesses.
  • A whole range of continuous illnesses/condition, aka Multi Morbid. Here at EquiNatural we see this repeatedly, where ‘everything’s wrong’. Usually starting several years previously with, say, a tendon rupture, then soon after the permanent coughing started, followed by repeat tendon issues, then laminitis, and so on and so on … The symptoms seem to have simply shifted around the body, and as soon as one gets under control, something else pops up; we now have a horse with several different issues, and nothing’s helping. Again in the perfect world we need that test, but meanwhile we can make a positive, yet gentle start with our OptimaCARE detox program.
  • Non-responsive to any therapy – doesn’t respond or responds unexpectedly, too weak a response, i.e. pain meds not working. Many pharma meds have to be activated in the body by design – they absolutely have to run through the biotransformation process but without P5P they can’t be activated. Hence, those pharma components are either automatically excreted without working, or they remain in the body as a toxin. Typical examples are a horse suddenly developing laminitis following chemical worming, or going into toxic shock from a vax – both typical of the final straw that breaks the camel’s back, all due to the disturbed biotransformation process.
  • Even headshaking has been listed.
  • Finally, the Big One – what we know as EMS – Equine Metabolic Syndrome – laminitis, IR, pseudo Cushings, yet no matter what we do, how we supplement, and how we change the feed/forage to shift the weight, nothing works!

What to do meanwhile

Yep, we know the test is still currently only available in Germany, so meanwhile what to do now? The key is to restore the natural microbiome in the colon; only a horse with a healthy gut biome can produce enough activated P5P to have a normal liver biotransformation function. And the only way to fix the hindgut biome? Hay, 24/7, 365-days/year, for the cellulose fibre to restore the beneficial microbe population. If you continue to feed your horse haylage, forget it. If you let your horse run out of hay, especially if stabled overnight, forget it.

So, feed hay, hay, and more hay, and for the feedbowl feed a basic grass-fibre cob as the base carrier, to add in a mineral balancer with extra zinc, salt, micronized linseed for the omega-3 EFA, and B-vitamins in P5P form. Currently P5P is not available as a supplement so you’ll need to buy them in human form – Amazon has loads.

If haylage was fed, the gut also needs to deacidify, so feed Spirulina for a couple of weeks which is an excellent toxin-binder and is mainly excreted via the liver-bile-intestine, thus relieving the kidneys.

Meanwhile, what not to feed. No beet, no alfalfa, no sugars, no pectins, no muslis, no pellets, no treats, and definitely no feedbags with wheatfeed, oatfeed, soya, NIS in any form for at least 6-months, basically anything listed in our ‘The Feedbowl – what’s really in those feedbags’ page. The more basic the feeding program – in other words, the more species-appropriate, as in what a horse is meant to eat and what a horse’s gut is meant to digest – the faster the hindgut environment will be restored to normal.

This is all covered in our ‘Feeding our Horses’ section off the main menu, and specifically the ‘Why what we feed has to be right’ page.

Now we need to clean up the gut, liver and kidney function, so head to our Detoxification page and our OptimaCARE detox program. Take a 1-week break then feed our WildFed for 1-month, as it’s vital to support the horse's natural eating behaviour.

Take another week off to assess, then come back to us for advice on long-term support, as KPU horses will benefit from constant metabolic support until the body is back in balance.