Farewell, UCD label

Question: Do all urea cycle disorders result in excess plasma ammonia?

Answer: yes.  Which kind of makes sense, but I had to confirm it.

So, where to from here?  We discard the "UCD" label, and start looking at the broader category of protein metabolism disorders.  That can probably be referred to just as "amino acid disorders", since they describe problems that happen after proteins have been broken down.  Best known is PKU, but I was screened for that at birth.  There is also Maple Syrup Urine Disease (BCKD deficiency), which is an inability to process the valine family (valine, leucine, isoleucine) which is common in animal products.

Those are two of them.  There's a whole host of others; understandable, given how many amino acids we deal with.  These include:

Branched chain amino acid disorders

• Isovaleric acidemia (leucine): creates a sweaty smell
• Propionic acidemia 
• Maple Syrup Urine Disease

Methionine metabolism disorders (homocysteineuria and related sulfur metabolism problems)

Tyrosine metabolism disorders

• Tyrosinemia type I
• Tyrosinemia type II
• Alkaptonuria

D-glyceric aciduria 

Iminoglycinuria (proline, hydroxyproline, glycine)

Guanidinoacetate methyltransferase deficiency

Hyperprolinemia, type I and II; usually benign

Δ1-Pyrroline-5-carboxylate synthetase deficiency (associated with high ammonia levels)

Prolidase deficiency (proline, hydroxyproline)

Hyperlysinemia (lysine)

Glutaric acidemia type I (carnitine, lysine, tryptophan)

Nonketotic hyperglycinemia (Glycine)

γ-Glutamylcysteine synthetase deficiency (glutathione deficiency); tied in with G6PD

Pyroglutamic aciduria (glutathione); tied in with G6PD

Hyper-β-alaninemia (alanine, taurine, GABA, β-aminoisobutyrate)

Methylmalonate/malonate semialdehyde dehydrogenase issues

Pyridoxine dependency

GABA-transaminase deficiency (GABA, β-alanine, carnosine)

4-Hydroxybutyric aciduria (glycine)

Most of these are non-starters, and I don't see any which are explicitly tied to arginine, but it's worth sifting through them to see what might fit.

Every question spawns a hundred more questions.  This is the boring footwork of diagnosis, but it's essential.  Somewhere out there is the answer, all I have to do is sniff it out.

There goes that hypothesis

What a lot of non-scientists don't understand is the role of the hypothesis, and the role of the theory.

I just got my blood tests back from the challenge diet.  My plasma ammonia levels went from a baseline of 42 (normal) to.... 30.  Statistically the same.

What does this mean?  It means that this hypothesis, that my chronic pain was caused by hyperammonemia, has been disproven.  Assuming the lab didn't screw up, that's not what's going on.  When I eat protein, I don't end up with a buildup of ammonia in my blood.

So I'll toss that hypothesis, look at the data again, and form a new one.  But these hypotheses that I'm testing are meant to answer the specific question, "what is the mechanism that connects my diet with my chronic pain?"  They don't address the larger question, "Does my diet affect my chronic pain?", nor the slightly smaller question, "Is protein intake directly related to my pain level?"  Both of those have been answered to my satisfaction.  The evidence I've collected, such as the fact that arginine helps tremendously all on its own, and that my feet are better when I eat less protein *and* elevate them for a period, all fits together.  I can put the pieces together to make a big picture that makes sense.

That big picture is my theory: I have some form of protein-metabolism disorder.  Did the ammonia test disprove my theory?  No.  It just showed me that the picture is more complex than I had first assumed.  All of the other evidence still supports my theory.

I have learned that I was asking the wrong question.  Now I need to find the right one to ask next. 

The broadest swath of protein-metabolism disorders are UCDs, so that's the label I've been using to find information.  The next logical question to ask would be, "Do all UCDs result in elevated plasma ammonia levels?"  If the answer is "No", I may have just narrowed the possibilities dramatically.  If the answer is "Yes", I need to broaden my search terms to other metabolic disorders.

This is what scientists mean when we say that failure is just a different kind of information.  My results weren't what I expected, so now I use that to figure out what to do next.  It's all part of the process.

(But I don't mind telling you, my first reaction was "Damn, we're getting into really deep Zebra territory here.")

Now we're cooking with gas

I must be feeling better... this evening I ended up, without planning to, cooking several things to tide me over the hot couple of days we're heading into, and I was fixing three things at once while rocking out to a remix of RamJam's "Black Betty" which was running in my head.  My feet aren't too happy now, but my energy and good mood are back.  Amazing what eliminating chronic pain will do.

I made a double batch of baba ghanouj, because I'll eat that any and every day, and all I need are some chips.  I made some beet salad for a memorial service I'm attending tomorrow, and I'm sure I'll have leftovers.  I made some marinated potato salad, ostensibly for tonight's dinner, but it was so late by the time I finished it that I knew it would be far better with some time to itself.  And, finally, I came up with a recipe for lime ice pops -- the ones I could find were either blends of lime with something else, or just didn't seem to fit my needs.  We'll see how they come out; still, it's a good start on stuff to eat while it's over a hundred out.

I like simple food as much as complex things, and a lot of my recipes are sort of "Take however much of this you have, and throw in this other ingredient until it looks/tastes/feels right".  So quantifying them for a new person can be a little challenging, as simple as they are.  My beet salad is essentially "cubed cooked beets, a little salt, some dried thyme, and enough balsamic vinegar that it feels like enough, then drizzle with olive oil".  I sort of stumbled on it some years ago, but it turned out to be something that even people who aren't fond of beets think is okay.  It must be something about the balsamic vinegar.

My method of cooking means that I can adapt easily, though.  When making baba ghanouj, I knew that I needed a substitute for tahini that added umami (savory) flavor, but also some bitterness, as I've never met a tahini that wasn't bitter to some degree.  I landed on pureed ripe olives (savory) plus Bragg aminos (umami boost) plus dry mustard, as I remembered that mustard powder or ground mustard seeds has that particular bitter quality.  I'm still working on a substitute for ricotta cheese, but it needs that same savory quality, plus a rich mouthfeel, and a fine-grained but fluffy texture... I'll probably experiment with the same ripe olive puree plus something to add body; possibly moist breadcrumbs.  It may need a little extra oil to give it the same richness, we'll see. 

But that analysis, that tendency to break each food down into its most prominent qualities, is how I can do substitutes which may not be identical, but sometimes result in a food which is equally good.  A similar effect can be seen in the vegan ice cream recipes that use avocado as a base: guess what, a ripe Hass avocado is essentially identical to a plant-based heavy cream, and you can use it as such.  I've done exactly that to make vegan tikka masala sauce (which was marvelous, by the way).  I'll have to post that recipe too, with both dairy and vegan variants.

I like cooking, obviously.  I like taking time to focus on something basic but nourishing, seeing it take shape, and figuring out how to tweak it to be how I want it.  I like food prep, which occupies the hands but leaves the mind free -- to think, to listen to audiobooks, to half-watch television.  I'm good with tools, and I have a finely tuned sense of time and heat and texture.  Practice fills in the rest.

That love of cooking has been a huge source of relief and comfort to me over twenty years of dealing with shifting food sensitivities and dietary needs.  Low-protein has probably been the biggest shift I've ever made, bigger even than doing low-carb (which I did several times, for various reasons). But I'm finding that a lot of my old favorites are still fine, and some others just need a little nudge to bring them into line.  Then there are challenges, like lasagna, or a proper chili.  I'm happy to embrace some of those because I know that I have solid options to fall back on if they don't work.  After all, failure comes with the territory.  Failure is when you really learn.  And by this point, even my failures are almost always edible.  So why not seize the challenge with both hands?

Technical resources

These resources are not the friendly sort that take you by the hand and say gently "We'll teach you how to cope".  These are the technical, professional, hard-science resources that provide the facts necessary to build those friendly guidelines.

If long words and blocks of medical jargon don't make your eyes glaze, you might want to check some of these out; this is the best list I have so far of information available to laypeople.  Most aren't provided by people trying to sell you something.

Rare Diseases Clinical Research Network (from the US National Institutes of Health) has a UCD Consortium.
National Urea Cycle Disorders Foundation (and some links to their partners).
National Organization for Rare Disorders has a Urea Cycle Disorders page.
The NIH Genetics Home Reference.
Hyperammonemia (discovery and treatment of a serious case of late-onset UCD)
Suggested Guidelines for the Diagnosis and Treatment of Urea Cycle Disorders
NAGS deficiency (CarbaGlu sells a pharma treatment, but they have some very useful info on UCDs nonetheless)


NORD's Rare Disease Database has been exceptionally helpful, while RDCRN has a nifty diagram of the urea cycle with accompanying descriptions of how each of the disorders result from a break in the system.  I need to spend some more quality time with both.

Feeling my way around the research

Sweet relief.  I felt better as soon as I took arginine last night, and I'm already 50% improved.

I've been browsing through my research notes again, and realizing how much I still need to pull together.  Genetic tests interpreted by an expert might tell me more (still waiting on a geneticist), but until then I'm collecting everything I can find about the mechanisms of UCDs, to try to ferret out what might be going on.  There aren't a lot of broad sources, but the ones that are have a lot of dense info to comb through.

I want a differential to help narrow down the possibilities, basically a diagnostic key -- I haven't found a comprehensive one yet.  I know that "individuals with OTC deficiency usually have both low levels of citrulline and high glutamine in the blood and high levels of orotic acid in the urine", and that orotic acid is the way to differentiate OTC from NAGS; I know that supplementing with arginine helps just about all UCDs, but that supplementing with citrulline (a slightly simpler, related amino acid) can be counterproductive in Argininosuccinate Lyase (ASL) and Argininosuccinate Synthase (ASS) deficiencies, where both of those show elevated citrulline levels in the urine but ALSD also has elevated argininosuccinic acid levels...  I just want some kind of table so that I can run the yes/no paths and come up with a set of differential tests that would narrow it to one or two possibilities.

(Yes, I have done this kind of thing in a lab, and I do diagnostics in the field for my career.)

Why is such a thing not available?  Who knows, perhaps it is to specialists.  But it needs to be more widely available not just for wonks like me, but for general practitioners, pediatricians, and anybody else who might run into a UCD patient.  We need fewer people in the dark.

I'll post a list of resources a bit later.

Day Three: Fin

This morning I woke up, and it was Day Three.

All of my joints hurt.  I felt vaguely ill.  I was so tired.  And the pain was enough to set my teeth on edge.  When I heard myself whimper as I got ready for my shower, I decided: no more.

I got through the day, partly by virtue of going to see a movie to distract myself.  When I got home, I had two hotdogs and drank a glass of water, then another a half hour later, then a third.  Finally, I took myself to the lab.  As I expected, 90 minutes was about the perfect interval after eating a bunch of protein; my bones had that "dipped in an acid bath" feeling.

I'm a difficult draw, but the water paid off this time.  I went home, still breathing a little hard from the effort of moving, and immediately took two arginine caps.  Then I had dinner.

Now, three hours later, things are a little better.  I expect it'll take the next couple of days to recover, but by the weekend I should feel much more myself.  And I hope, dearly, that this is the last time I ever have to do this.  The psychological toll of deliberately poisoning myself is not a minor thing.

Here's hoping for high numbers.

Day Two: only Tuesday

How can it be only Tuesday?

I started the challenge diet easily enough.  I shrugged into my pain coat like a familiar old pack, ready to carry it for four days.  I spent yesterday mostly at home, nursing a scratched cornea I managed to pick up on Sunday afternoon.  And I woke up this morning and it was only the beginning of Day Two.  It feels like it's been weeks.

The pain coat is heavy, lying across my shoulders like a canvas duster or a full backpacking rig.  It weighs me down, takes the bounce out of my step, makes standing and walking more tiring.  Going through the day with it is an exercise in endurance, like hiking a 15-mile trail.  I expected that.  I've lived with it for four decades.  Likewise, I expected the pain in my feet to get worse, as ammonia collects there and inflames the joints.

What I had forgotten were the other effects.  It's harder to regulate my body temperature; my shower this morning started pleasantly warm, and ended uncomfortably hot.  I had six to eight night sweats last night, waking me up.  I can feel a hot flush after every meal.

I inadvertently stayed up after 1am last night -- the first thing I noticed when I ditched protein was that I got sleepy around 10:30 at night, where I used to be a serious night owl.  Then I slept until after 11 this morning.  I'd forgotten how much of my life I was sleeping away before this.  I did get up rested, but only after ten hours in bed.

All of my joints below the waist feel like they're held together with chewing gum and baling twine.  I have to be careful walking, since it seems like they could slip out of alignment with the slightest provocation.  Past history says that's not far off.

I'd forgotten what the cravings were like.  My body needs something I'm not getting, and only protein sates it even briefly, particularly chicken.  But the food sits heavily, and I'm still hungry, even as the pain kills my appetite.  I know now what's happening: I need arginine to prop up my urea cycle, but the protein that supplies it simultaneously overloads the very system it's supposed to fix.  I'm left restless and uncomfortable.

I figured I could do this week practically standing on my head, but time seems to have slowed to a crawl.  I'll make it, I always do.  But I can't believe it's still only Tuesday.

Twiddling the dials

So apparently, two days of not supplementing with arginine is enough to bring my chronic pain up a couple of notches.  It greeted me this morning for the first time in many weeks.

This week I get to do a challenge diet: high protein (verging on proper low-carb) for several days, then a blood test for plasma ammonia.  Going off of the arginine was to make sure that my system breaks rapidly when confronted with that much protein, and I get to keep it up long enough for the ammonia to accumulate.  I'm figuring four days should do it.

I devised this plan without any real apprehension, and when I look at it a little nervously now, I can remind myself that all the factors are in my control: if it gets to be too bad, I can ease off the protein, or cut the experiment short and go in for the test early.  Most of all, the chronic pain is not something I'm actually afraid of.  I lived with it for forty years, after all; it's a familiar demon.  I cleared my schedule this week so I wouldn't have to worry about commitments if I felt like hell, but really, I'll probably be reasonably functional most of the time.  After I'm done, I can get rid of the pain even faster than I did the first time.

I'm looking forward to the results, too.  I had a baseline taken a week ago, which placed my ammonia squarely in the middle of the normal range.  Given the behavior of my chronic pain in relation to diet, I'm almost completely certain that hyperammoniasis is what's going on, but this is my chance to test that hypothesis.  It could, after all, actually be something even weirder going on... I certainly have a history supporting that.

So here's to being in another medical experiment... wish me luck.