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KPU / Cryptopyrroluria

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

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

Put simply, Cryptopyrrolura, aka KPU, means 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, despite herioc efforts from the owner.

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 amino acids, vit.K and - here's the important issue - two B-vitamins in an ‘activated’ form, specifically B12 and B6. And here's the critical part - 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 (relating to or causing decay), which disrupts the production of the activated form of vit.B6 – pyridoxal-5-phosphate, aka P5P (Science Alert! 🤓 The number ‘5’ meaning that in the 5th position of the molecule it needs phosphate attached), 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're now seeing, i.e. IR/EMS, laminitis, recurrent colic, a constant chronic cough, sweet itch, mallenders/sallenders, persistent faecal water/diarrhea, loss of performance – even headshaking's being mentioned; it’s said that all have underlying KPU, hence why it’s known as ‘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 completely regenerate the hindgut microbiome to get the liver to 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 a 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 biome 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, the immune system is already compromised before they're barely a yearling. We've got this all covered separately in our Foal's Microbiome page.

In that strange perfect parallel world that none of us live in, 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.

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 raised and fed, and that hopefully no antibiotics or haylage were fed in the first 6-months of their life, or that the mother unknowingly already had hindgut dysbiosis.

How to diagnose

So, we know that KPU is caused by dysbiosis in the gut microbiome, which disrupts the P5P B6 production, so by regenerating the hindgut 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 timescales. Rest assured avenues are being explored to get the test more readily available in the UK.

The other important factor to be aware of is that this is no sprint fix – KPU takes an almighty marathon to repair. The test results show a numbered gradient – a result of 1 = not perfect but not bad either - change feeding and focus on gut restoration and you're looking at 1-2 years. A result of between 2-4 = there’s plenty gone wrong; severe dysbiosis with major therapeutic help to restore the hindgut biome - you're looking at 2-3 years of therapy to get back to normal. A reading over 5+? 5-years at least, because the body needs time to excrete what’s been collected and stored over the 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

Science Alert! 🤓

So, we know now KPU starts with the hindgut dysbiosis and causes liver function dysruption, 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 then 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.

Imagine 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’ (FG). And this is what toxins need when they arrive in the liver – the liver cells attach a ‘functional group’ molecule to the waste toxin molecule, in order to prepare it into a form that the kidneys need for excretion.

Phase 2 – So, the liver’s now added the ‘towbar’, the FG, to the waste molecule. Now it needs a catalyst in order to actually 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 it's just created with a FG and a P5P catalyst now 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 itself - P5P

Normally in a healthy horse the P5P creation 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, aka P5P.

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, as mentioned earlier, 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 ‘Pyridoxine’, which is the inactive form that the small intestine has no absorbing receptor for. Thus, the small intestine neither recognises, or knows what to do with Pyridoxine; therefore, as it can’t be used it’s automatically ignored and sent off for excretion.

This active form – P5P - is essential to start phase 2 of the liver transformation process. 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 someone to attach the trailer to the towbar (P5P), 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 – we get confused because we think it’s fat, so ...

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 this happen? The typical neck crest and what we think are fat pads on the flanks, as in all signs of EMS/IR, yet it’s actually the lymphatic system trying to dilute the stored water-soluble waste products.

Meanwhile, what about actual fat-soluble waste? Simple – they go to fat tissue, which also creates is big problem! Cue 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 (Phase 1 and 2) so they can be excreted via the kidneys, but without P5P this won't happen. So, by endeavouring to skinny our horse down means an overload of circulating toxins in the body, which as we all know induces 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 re-toxification will occur. If the test proves positive, we should 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

Science Alert (again)! 🤓

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 – with the liver utilising these minerals from the stores, they 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 see 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 still 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, this is the sticky-plaster approach - it shouldn’t be about compensating with extra zinc; it should absolutely be about repairing the liver biotransformation process so the horse's system can regulate back to its 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 if we get unusual numbers back from bloods, requesting previous ‘normal’ reference values from the literature be used 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 now thought to be connected with 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 – there's a very fine line between safe selenium and toxic selenium; selenium is highly toxic to horses so we should never feed more than in a mineral feed 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 for us 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 feed supplementary manganese, but if we see our horses improve with added sulphur (via MSM) and/or zinc, we should 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 our Liver&Kidneys 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 abscessing, permanently footy.
  • Susceptible to - or unexplained - tendon/ligament/muscle 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 – you just 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 disordersexostosis (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 start with a gut regeneration programme (see below).
  • 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! 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 scenario, all due to the disturbed biotransformation process.
  • Even headshaking is now being listed; as yet though, we don't have any further info but watch this space.
  • Finally, the Big One – our old friend 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 content to restore the beneficial microbe population. If you feed a horse haylage, forget it. If you soak your hay for a long time, 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.

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 route, 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 pro-inflammatory gut-damaging wheatfeed, oatfeed, soya, NIS ... 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. Or, if you’re stuck, feel free to email me your current feed regime in case there are triggers we can identify here – everything that goes in your feedbowl, so all brands/supplements etc., and forage, so turnout, how long etc., and dried, so hay/haylage and how much.

To summarise

So, we need to clean up the gut, liver and kidney function and restore the P5P production.

  • First up, we need to start with the gut and repair the hindgut acidosis, the dysbiosis/SIBO, and the leaky gut, with a 1-month (1kg) course of our SIBO-CARE blend.
  • Alongside this we reconnect the gut membrane with our GutAminos, a combo of two vital amino-acids for the cellular membrane protein repair, specifically L-Glutamine with N Acetyl L Cysteine (NAC) which is is the precursor to the body's master antioxidant, Glutathione. L-Glutamine is an important part of resolving leaky gut because it’s the preferred food of the cells lining the gut wall, so it helps with their growth and repair. It also supports the mucosal lining in the gut and can help maintain the right pH balance. It’s so important to gut health that low concentrations are linked to gut permeability and inflammation.
  • Meanwhile, we need to feed the activated form of B6 - Pyridoxal-5-Phosphate, aka P5P - we sell it in human-grade pharm powdered form, at half the price of Amazon's capsules.
  • When the gut regeneration programme is finished, take a 1-week break before we start on the liver/kidney function - feed our LKLCARE for 1-month (1kg).
  • We also recommend feeding our WildFed mix as it’s vital to support the horse's natural eating behaviour.

Meanwhile, come back to us for advice on long-term support if needed, as KPU horses may benefit from constant metabolic support until the body is back in balance. For our sweet itch affected horses, feed our SwItchTonic blend during the typical sweet itch season.

NB. It might also be worth getting bloods done - the following is courtesy of Dr Christina Fritz (please bear in mind this is translated from german):

"You can read a lot from the bloodworks. In KPU horses you usually find:

Erythrocytes = low (within normal, but low)

Hemoglobin = low (within normal, but low)

The horses also don’t build up stamina, you can work them to a certain level but then you kind of get stuck = not enough oxygen for more. Don’t confuse this with a normal anemia where horses lack iron. In KPU horses usually iron values are within normal, since horses have more than enough iron in their roughage.

Zinc = low (sometimes still within normal, but low)

Selenium = low (depending on the reference values, Selenium is usually way below normal, but values down to 40µg/l are normal)

Creatinine Kinase (CK) = high (normal value should be below 130U/L)

Lactate Dehydrogenase (LDH) = high (normal value should be below 400U/L)

Potassium = a little elevated when CK and LDH are high

Horses with high CK / LDH often need a very long time to warm up, riders will tell you that it takes 30-45 min for the horse to loose up and get flexible before you can even think about real training, they might tell you that the horse seems stiff every day like having muscle soreness. In sport horses that „stiffness“ is often the only symptom pointing into the direction of waste products being stored in the connective tissue system. In Ponys and other „non-sport“ horses you might also see the lymph pads in the „saddlebag“ area and have a thick neck, full of lymph.

When you take bloodworks, you should also do Glucose from Sodium-fluoride-stabilised blood (beware not to fast the horse! 12h before taking the blood, let the horse consume hay nonstop, but no concentrates, no green pasture, no work) to get reliable results. Glucose should be below 4,9 mmol/l or 83 mg/dl. In sporthorses it is ok when the values are around the upper numbers, in non-sport horses and ponys you want them well below that.

So if everything in the bloodworks points into the KPU direction and also the feeding / health history of the horse (e.g. having been fed haylage in the past or anything like that) you can go ahead and treat for KPU. After all you can't do much harm with this. You supplement with Zinc (you need to feed about 1g/day to achieve over-dosage, you never reach this with normal supplements), organic Sulphur (MSM, you can give up to 15g / day / horse) which is hard to overdose as well. Also you supplement with P5P (active Vitamin B6) and Methylcobalamin (active Vitamin B12), both being watersoluble Vitamins. So if the horse already has plenty, they will be excreted via the kidneys. And a gut restoration in my experience is a good idea for almost every horse, anyways :-)"