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.")

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.