Enhancing Safety and Minimizing Idiosyncratic Effects By Titration of Physiological Compounds

The author of this letter [Giesecke, 1990: (http://www.ncbi.nlm.nih.gov/pubmed/2316743)] discusses a strategy for taking small amounts of a compound, in this case fluoxetine hydrochloride, and thereby helping to avoid idiosyncratic hypersensitivities to the physiological effects of the compound. In this case, the doctor told the person to dissolve a 20-mg capsule of fluoxetine HCl into 100 mL of water or "apple juice" and then take 5 mL (i.e. ~1 tsp.) of the solution at a time (providing a 1-mg dose). The author contacted the manufacturer and was told that the solution of fluoxetine could be refrigerated and would exhibit a "shelf life" of 14 days. One wouldn't need to get into refrigeration, and, cumbersome as this approach might seem to be, it is one approach to maximizing safety in the use of over-the-counter nutrients or the like, even under a doctor's supervision. Assuming the nutrient is water-soluble, dissolving the nutrient in 100 or 500 mL, or whatever, of water will form a solution (meaning that the nutrient will be dissolved "homogeneously" throughout the liquid). Drinking a small amount of the water will then provide a fraction of a dosage form. It tends to be the case that there are physiological adaptations to some of the idiosyncratic and initial effects that "physiological" compounds or medications can have. The rationale for using that type of approach, even under a doctor's supervision, has to do with safety, in a general sense, and individual differences in physiology.

In the case of the article by Giesecke (1990), the idiosyncratic effect was that the drug had been producing prolonged periods of insomnia that had prevented the person from adjusting to the therapeutic effects of the medication. Fluoxetine, like many drugs and even nutrients, can produce initial effects that differ from the long-term effects. Belzung et al. (2001) [Belzung et al., 2001: (http://desco.univ-tours.fr/Psychobio%20Emotions/Public/CBarticle%2047.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/11485052)] found that haloperidol antagonized this type of initial, stimulant-like effect that fluoxetine has been reported to have had in some people, and the effect of fluoxetine is thought to be due to either a transient action of fluoxetine as a dopamine-receptor agonist or some indirect effect that causes dopamine release [such as interaction with postsynaptic serotonin-1A (5-HT1A) receptors on ventral-tegmental-area (VTA) neurons receiving serotonergic inputs [Amargos-Bosch et al., 2004: (http://cercor.oxfordjournals.org/cgi/reprint/14/3/281)(http://www.ncbi.nlm.nih.gov/pubmed/14754868?dopt=Abstract)]. Belzung et al. (2001) actually discuss some articles that imply that fluoxetine could transiently decrease the firing rates of dopaminergic neurons in parts of the striatum and simultaneously increase the firing rates of neurons in the prefrontal cortex (PFC) that receive dopaminergic inputs from other parts of the striatum, and that's essentially the type of thing that one would expect to see in response to stimulant-like effects (dopamine release in the PFC and the high-Km, phosphorylated form of tyrosine hydroxylase, in dopaminergic neurons that project to the PFC, are less susceptible to feedback inhibition in response to ongoing dopaminergic stimulation than dopamine release, by neurons whose cell bodies are in the VTA, in the striatum is, etc.). Glutamatergic pyramidal neurons in the PFC project back to the VTA and dorsal raphe nuclei (containing the cell bodies of serotonergic neurons) and interact with serotonergic inputs to the VTA, etc. The idea is that there could be an initial, dopaminergic effect and a subsequent, usually-rapid downregulation of the responsiveness of the receptor or receptors that are initially activated by fluoxetine and that may be unusually sensitive in some people. It's possible that there could just be hypersensitivity, in the face of a fluoxetine-induced increase in extracellular serotonin, of 5-HT1A or 5-HT2 receptors on VTA neurons or pyramidal neurons in the PFC, etc.

Glutamine-Induced Protection Against Secondary White-Matter Injury Following Experimental Spinal Cord Injury

The authors of this article [Golding et al., 2006: (http://jap.physiology.org/cgi/reprint/101/4/1045)(http://www.ncbi.nlm.nih.gov/pubmed/16778003?dopt=Abstract)] found that exogenous glutamine reduced some of the abnormalities in the skeletal muscles that had begun to occur in response to spinal cord injury in rats. The authors also referred to their past research showing that glutamine had reduced the secondary damage to the white matter (myelin) that had occurred in response to spinal cord injuries in an animal model. Golding et al. (2006) suggested that the effects of glutamine on the muscles, following the spinal cord injuries, may have partially been the result of effects, such as the restoration of glutathione levels or the ATP that is required for glutathione biosynthesis, on the nerve fibers (i.e. motor neurons) innervating the muscles. In previous research, this group of researchers found that the restoration of glutathione levels by glutamine had occurred in association with improvements in the outcomes of spinal cord injuries in animal models.

Inhibition of Nitric-Oxide-Dependent Vasodilation by High Levels of Glutamine in Endothelial Cells: Relevance of Arginine Availability and Exercise

This article [Kawaguchi et al., 2005: (http://ajpregu.physiology.org/cgi/reprint/288/6/R1612)(http://www.ncbi.nlm.nih.gov/pubmed/15705802?dopt=Abstract)] shows that exogenous glutamine, without concomitant hyperammonemia (abnormal elevation of ammonia) can inhibit the dilation of cerebral arterioles (the smaller-diameter branches of the pial arteries that run along the outer surface of the brain) in rats, and exogenous arginine can block the effect, to some extent. There are lots of articles that show the same thing, and, in my opinion, this shows that elevating the plasma glutamine levels would only be expected to be beneficial up to a point. There's quite a bit of evidence, discussed by Kawaguchi et al. (2005), that the effect of glutamine is the result of its competition with citrulline for transport into endothelial cells or perivascular nerve fibers (fibers that induce nitric-oxide-dependent vasodilation). Citrulline is converted into arginine, and arginine is then used as a substrate for nitric oxide biosynthesis by eNOS. The citrulline formed as a product is then recycled, and an excess of glutamine is thought to inhibit the recycling (or the transport of citrulline into cells from the blood) of citrulline. The authors also noted that glucosamine, formed from glutamine, could have produced the impairment in vasodilation. I think only a small percentage, about 3 percent, of glutamine is converted into glucosamine in the liver, but I don't know what percentage is converted into glucosamine in endothelial cells or neurons (i.e. perivascular neurons, etc.).

Although a person could, in my opinion, conceivably help to minimize this type of effect by taking glutamine with meals (thereby preventing spikes in plasma glutamine and deliberately limiting its bioavailability) and spreading the dosages out across the day, it's important to consider the drastic reductions in plasma glutamine that can occur, for example, during and after intense exercise or in catabolic disease states. Keast et al. (1995) [Keast et al., 1995: (http://www.ncbi.nlm.nih.gov/pubmed/7845291)] found that high-intensity exercise depleted plasma glutamine levels by more than half, and more than 6 days were required for the restoration of pre-"overtraining" plasma glutamine to occur in some of the athletes. For some reason, there's been an obsessive focus on controversy about the role of glutamine depletion in the immunosuppressive effects that high-intensity exercise can have. I don't know why there has been so much focus on that aspect of glutamine metabolism, but it doesn't matter if glutamine depletion is not a major role in exercise-induced immunosuppression. By definition, someone who can exercise at high intensities is going to be fairly "healthy," and this makes the entire debate, surrounding that specific issue, seem bizarre to me. For example, Walsh et al. (1998) [Walsh et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9562294)] found not-very-drastic reductions in plasma glutamine following exercise (of poorly-defined intensity) but took the measurements in "well-trained" athletes. In my mind, the capacity of an athlete to replenish glutamine levels in his or her blood or muscles or heart or endothelial cells is going to be fairly robust. A major point of the hundreds of articles showing immunostimulatory effects of glutamine in trauma patients, etc., is that one cannot, in my opinion, look at the results of studies in elite athletes and then generalize or apply those results to a discussion or analysis of glutamine or cell-energy metabolism in the context of disease states.

That's unrelated to the original topic, and it's still important, in my opinion, to take seriously the possibility of a nitric-oxide-suppressive effect of excessively-high glutamine intakes, particularly in the absence of arginine. It's worth noting that significant portion of glutamine is converted into citrulline and alanine in the intestinal tract, and the blood-borne citrulline can then be converted into arginine in the kidneys or, locally, in endothelial cells. So that would tend to oppose or counteract the supposed vasoconstrictive effects of abnormal elevations in plasma glutamine. But the idea, in my opinion, is not really to induce supraphysiological levels of plasma glutamine. Other approaches, besides limiting the dosage of glutamine and taking the glutamine in smaller dosages with meals, would be to use arginine simultaneously, as I've discussed in past postings. The first article I linked to (together with other articles) suggest to me that the ratio of arginine to glutamine, in approaches to supplementation, would be an important factor in limiting some of these effects. But, for this and other reasons, in my opinion, the dosage of glutamine at which this type of effect might occur would be different for every person and would depend on his or her activity level. It's always good for a person to talk to his or her doctor about this type of issue. As with anything, there tends to be a therapeutic dosage range and a range at which side effects begin to occur. It's interesting that Spolarics et al. (1991) [Spolarics et al., 1991: (http://www.ncbi.nlm.nih.gov/pubmed/1872392)] found evidence that glutamine, along with fatty acids, is a major energy source for endothelial cells in blood vessels perfusing the liver. Free fatty acids (FFAs), similarly, can be major energy sources for cells in some tissues, under some circumstances, but also can inhibit mitochondrial functioning and interfere with insulin sensitivity and cause other problems, etc. The roles of glutamine in cellular energy metabolism aren't as murky as the roles of FFAs are, but the point is that physiological substrates and compounds tend to not simply be either "good" or "bad."

Metabolism of Arginine to Agmatine; Psychopharmacological Effects of Agmatine

This is an interesting article [Halaris and Pleitz, 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17927294)], and the authors discuss the effects that the administration of exogenous agmatine, an arginine metabolite, can have on the brain. Apparently, significant amounts of agmatine can be made from arginine, either outside the brain or in the brain, by the decarboxylation of arginine by arginine decarboxylase (ADC). ADC converts arginine into agmatine in a single enzymatic step. The authors discuss some of the research showing antidepressant or anxiolytic (anti-anxiety) effects of agmatine in animal models of depression or chronic stress, etc. (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=agmatine+psychiatric+OR+antidepressant+OR+anxiety+OR+anxiolytic+OR+neuroprotective+OR+pain+OR+antinociceptive). I have no idea if agmatine actually has antidepressant effects in people, and it's important to remember that these types of physiological substances are not a substitute for medical treatment for anxiety or mood disorders. Even under a doctor's supervision, the uses of some of these things would, in my opinion, only potentially have value as adjunctive treatments, etc. None of them has been proven or approved to treat any condition or disorder.

Some people have also suggested that agmatine could be responsible, at least in part, for the growth hormone (GH) releasing effects of arginine. I can't immediately find an article in which someone suggests that, but I'm sure various people have suggested it. Agmatine exerts, among other actions, alpha2-adrenoreceptor (alpha2-AR) agonism, meaning that it activates alpha2-AR's, in a manner similar to clonidine. Clonidine is known to release GH by acting as an alpha2-AR agonist. The anxiolytic effects of agmatine could also be the result of its alpha2-AR agonism. Yohimbine, an alpha2-AR antagonist, is sometimes referred to as an "anxiogenic" drug and has been shown to block or reverse many of the effects of agmatine (the alpha2-AR agonism can contribute to the potentiation by agmatine of the morphine-induced antinociceptive effects, etc.) (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=clonidine+agmatine). Agmatine also exerts antagonism at NMDA receptors (NMDA-R), and that action could account for the anxiolytic, antidepressant, and antinociceptive effects. Halaris and Pleitz (2007) noted that agmatine evidently doesn't bind to a polyamine binding site (there are multiple polyamine binding sites on different NMDA-R subunits) on the NMDA receptor. I'm not sure which polyamine binding site the authors are referring to, but presumably they mean the ifenprodil-sensitive binding site. Agmatine is also an agonist at imidazoline receptors (I1 and I2 imidazoline receptors) (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=imidazoline+agmatine).

Halaris and Pleitz (2007) had suggested that agmatine might be useful in treating anxiety disorders or depression but subsequently began to favor the use of agmatinase inhibitors in the treatments of those conditions. Agmatinase is an amine oxidase enzyme that degrades agmatine to putrescine and urea. Thus, the idea would be that inhibition of agmatinase would slow the breakdown of agmatine and prolong its actions. This sounds rational, on a superficial level, given that agmatine does appear to have a short duration of action (even though its formation from endogenous arginine pools would presumably be somewhat ongoing). But agmatine aldehyde (AGALD) is known to be an inhibitor of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS). The slowing of agmatine turnover could increase the extent of the AGALD-mediated inhibition of nNOS. The inhibition of iNOS would tend to be desirable but could conceivably be undesirable under some circumstances. As a rationale for the use of agmatinase inhibitors and not agmatine itself, the authors note that agmatine may have a narrow therapeutic window and may begin to enhance glutamate release, an effect that would tend to be undesirable, at dosages slightly higher than the dosages that are neuroprotective and that produce therapeutic effects. At 50-100 mg/kg, given intraperitoneally, agmatine was shown to be neuroprotective. In contrast, a dose of 150 mg/kg did not produce neuroprotection. The authors also noted that 80-100 mg/kg, which are in the higher range of dosages used in animal studies, can cause transient uremia in animals (they mean an elevation in serum urea that is not (likely to be) associated with kidney toxicity; this is a misuse of the term, really, given that, in the true uremia that occurs in people with renal failure, there are elevations in the serum concentrations of urea and also of other metabolites that are excreted renally or that have accumulated abnormally, such as in response to metabolic toxicity from uremic toxins, etc.). The urea is formed from the degradation of agmatine by agmatinase. The authors discuss similar effects associated with uremia, such as lethargy and loss of appetite, in a primates given 30 mg/kg by intravenous injection [Piletz et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/15028571)]. At dosages approaching 200 mg/kg, given intravenously, in rodents, Piletz et al. (2003) noted that large (dangerous) reductions in mean arterial blood pressure had been noted. If one scales those dosages (http://hardcorephysiologyfun.blogspot.com/2008/12/equations-for-animal-food-intake-and.html) using the scaling factor of 7.14, for young rats, or the most conservative, blanket scaling factor of 10, one gets 7-14 mg/kg bw or 5-10 mg/kg bw for a human (given intraperitoneally). The monkey weighed 12 kg (Piletz et al., 2003), and that gives a scaling factor of 1.70 (17.65 mg/kg bw i.v. for a human). Those translate into potentially-therapeutic, intraperitoneal dosages, for a 70-kg human, of 350-700 mg or 490-980 mg. The scaled monkey dosage of 1235.5 mg (i.v.), for a human, was associated with lethargy and adverse effects. The upper range of dosages, approaching 100 mg/kg i.p. in animals (which is the range of 700-980 mg per dose, scaled to humans), were associated with adverse effects in some studies, according to Halaris and Pleitz (2007). Those dosages are by parenteral routes of administration, and the Cmax and AUC values would be expected to be lower in response to oral dosing (due to a higher first-pass effect in the liver or even the lungs (the lungs exert a first-pass limitation of bioavailability following i.v. dosing)). That would theoretically mean that oral doses could be higher, but the point is no one knows what the oral dosage range would be. Additionally, the urea issue would still be a dose-limiting factor, regardless of bioavailability.

I do that kind of analysis to get a sense of things for myself and to hopefully discourage anyone from being reckless with something like agmatine, given its complex pharmacological effects. There might be tachyphylaxis to the central hypotensive effects, but the transience of that type of effect wouldn't necessarily show up in everyone to the same degree. A person taking any number of medications could have serious complications from something that has strong hypotensive effects. I give these warnings because I see that agmatine is being sold as a supplement, although it's evidently not widely available. But this is the type of thing that could be especially problematic without a doctor's supervision, even though one should always discuss these things with one's doctor before one takes any supplement. I'm not saying agmatine is necessarily likely to have any usefulness at all (it may not, and I have no idea if it would or not), but I will say that lots of drugs have narrow therapeutic windows. It's worthwhile to take that information, provided by Halaris and Pleitz (2007), seriously, though, because an excess of urea can elevate serum sodium (and an excess of glutamate release would probably not be desirable). Agmatine has also been shown to be capable of lowering blood pressure, an effect that could be the result of its activation of imidazoline or alpha2-ARs. I was going to discuss agmatine in relation to polyamine metabolism, more broadly, but I don't have time at the moment.

Arginine Hydrochloride and Hyperchloremic (Normal-Anion-Gap) Metabolic Acidosis: Relevance to Nonclassical Renal Tubular Acidosis and CSF Production

The authors of this article [Sugiura et al., 2000: (http://www.ncbi.nlm.nih.gov/pubmed/10758360)] discuss the capacity of arginine hydrochloride to induce hyperchloremic metabolic acidosis (so-called normal anion gap metabolic acidosis), partly by the excess intake (or infusion, during an intravenous infusion) of chloride and partly, in theory, by the metabolism of arginine per se (this second mechanism is essentially the same as the mechanism discussed in an article I discussed recently, whereby the "activation" of the urea cycle by arginine produces an increase in the consumption of bicarbonate and can reduce plasma bicarbonate). One approach would be to use free-form L-arginine, which is negatively-charged, as opposed to the neutral L-arginine hydrochloride. Usually, the amount of HCl (which would be absorbed as Cl-) provided by hydrochloride salts of medications or other compounds is so small as to have no effect on the plasma anion gap (the plasma sodium concentration, in mEq/L, minus the sum of the plasma concentrations, in mEq/L, of the chloride and bicarbonate anions). [The plasma potassium concentration is sometimes included and added to the plasma sodium concentration, but the plasma potassium concentration is normally low (most potassium is present intracellularly)]. But when a person takes an amino acid as an amine salt, such as in the case of arginine hydrochloride, the intake of chloride can be large and can cause metabolic acidosis that is not reflected in the anion gap (the excess of chloride decreases the anion gap, which would usually be elevated by metabolic acidosis). But, to some extent, Sugiura et al. (2000) are saying that cutting out the excess of chloride might not prevent the acidosis. It's worth noting that some articles have noted the potential for hyperchloremic metabolic acidosis from oral L-arginine hydrochloride, and so the problem may not be confined to situations in which the arginine HCl is infused intravenously (parenterally, such as during total parenteral nutrition) [Soriano, 2002: (http://jasn.asnjournals.org/cgi/reprint/13/8/2160)(http://www.ncbi.nlm.nih.gov/pubmed/12138150?dopt=Abstract)].

Pedrinelli et al. (1995) [Pedrinelli et al., 1995: (http://www.ncbi.nlm.nih.gov/pubmed/7589041)] also found that the infusion of arginine hydrochloride caused acidemia, and both Pedrinelli et al. (1995) and Sugiura et al. (2000) found significant decreases in the urinary anion gap. A decrease in the urinary anion gap is generally thought to be accompanied by an increase in the urinary ammonium concentration [Battle et al., 1988: (http://www.ncbi.nlm.nih.gov/pubmed/3344005)]. Arginine HCl therefore has the potential, according to those articles (and in my opinion), to acidify the urine, by increasing ammonium excretion, and decrease the serum bicarbonate level. In contrast, L-glutamine has sometimes been shown to increase the urinary ammonium level, thereby acidifying the urine, and increase serum bicarbonate (see past postings). In my opinion, this means that taking L-glutamine would not be expected to counteract or balance out the acid-base disturbances that arginine HCl could potentially cause. It might to some extent (to the extent that the effect of arginine occurs via an increase in ureagenesis), but these are the types of things that are worth discussing with one's doctor and being aware of.

Part of the reason these types of things are of interest to me is that the secondary effects of some of these acid-base disturbances can, under some circumstances, in my opinion, lead to elevations (or pathological decreases) in intracranial pressure. The rate of cerebrospinal fluid production can be altered in pathological ways by acid-base dysequilibria between "compartments," such as between the blood and CSF. Carbonic anhydrase inhibitors, for example (inhibitors of enzymes that interconvert bicarbonate and dissolved carbon dioxide gas), such as acetazolamide, are used to reduce CSF production and decrease intracranial pressure, in the context of intracranial hypertension from a variety of causes. Maren and Broder (1970) [Maren and Broder, 1970: (http://www.ncbi.nlm.nih.gov/pubmed/5441150?dopt=Abstract)] found that both chloride and bicarbonate transport from the blood to the CSF can influence the rate of CSF production, and severe disturbances in systemic acid-base balance could, in some people, in my opinion, conceivably lead to intracranial hypertension or hypotension and produce serious complications involving the brainstem, etc. (brainstem herniations can result from intracranial hypotension, and intracranial hypertension can produce serious problems). Also, hypophosphatemia or reductions in the serum ionized calcium (hypercalcemia, more commonly) can accompany increases in the serum bicarbonate level, under some circumstances, and have sometimes been shown to produce intracranial hypertension. It's not my opinion that many or most people would experience any of these effects, even in the presence of a mild acid-base disturbance/dysequilibrium. But it's the type of thing that's worth discussing with one's doctor. The potential for these types of problems to occur in some contexts is, in my opinion, something that is worth taking seriously and being cognizant of.

Nonalcoholic Fatty Liver Disease (NAFLD): Relevance to Public Health "Concepts" of Causation and to the Study of Energy Metabolism in General

This article [Cave et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17296492)] provides a general overview of nonalcoholic fatty liver disease (NAFLD), and the authors discuss the fact that 20-30 percent of Americans have NAFLD. The percentages are higher when one considers the numbers of people with alcohol-induced fatty liver disease. Cave et al. (2007) discuss some of the therapeutic approaches that have been used in human studies, but most of the approaches the authors discuss are not likely to be very effective, in my opinion. There's a great deal of validity to the role of aberrant one-carbon metabolism in NAFLD, as the authors discuss. In my opinion, however, the use of betaine in NAFLD should be abandoned. Uridine, reduced folates, such as levoleucovorin or L-methylfolate, with methylcobalamin, purine nucleotides, magnesium, and arginine would, in my opinion, be more rational as therapeutic strategies. Ethyl pyruvate could conceivably have some usefulness in NAFLD, and I know sodium pyruvate has been researched in alcohol-associated FLD. There's one on the use of ethyl pyruvate in alcoholic FLD [Yang et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/14647036)]. Ethyl pyruvate would have advantages over pyruvate, as someone noted, in a recent comment to the posting on pyruvate in the context of neuroprotection (http://hardcorephysiologyfun.blogspot.com/2009/02/pyruvate-and-ethyl-pyruvate-in.html), and pyruvate itself could, in my opinion, conceivably increase urinary phosphate excretion, by its conversion into alpha-ketoglutarate in the distal tubule cells of the kidneys [(http://hardcorephysiologyfun.blogspot.com/2009/02/potential-for-hypophosphatemia-or.html); (http://hardcorephysiologyfun.blogspot.com/2009/02/urea-cycle-renal-glutaminase-activity.html)], etc. Ethyl pyruvate could be used in low dosages and could conceivably be used in a manner that would more specifically target the liver (or at least not be subject to renal clearance en masse, due to poor transport across cell membranes, as the pyruvate anion would, as noted by the person who commented). If one were going to research one or more of those things, it would be necessary to choose the dosages rationally and not be afraid to increase them to dosages in the adequate or therapeutic ranges. I'm forgetting to mention some other things, and a person would obviously want to talk to his or her doctor before taking anything in the context of NAFLD or any other liver disease. I could go into all the mechanisms and research, but I've discussed most of those things in past postings.

It's worth reading about NAFLD, in my opinion, because, as Cave et al. (2007) discuss, the condition generally goes along with insulin resistance and prediabetes and with obesity. The numbers of articles, both in the context of animal models and in relation to humans, are very large, and the research on animal models of NAFLD provide a framework for learning about mitochondrial disorders and energy metabolism. Abnormalities in cellular energy metabolism play an important role in lots of different disease states, in my opinion, and the research on mitochondrial functioning in NAFLD is relevant to the study of disease states outside the liver. NAFLD is generally viewed as being both a cause and a consequence of obesity, but some of these articles don't quite give the reader a sense of the way in which, for example, drug-associated or drug induced fatty liver disease can cause large amounts of weight gain or even obesity in short periods of time, in association with liver damage. I came across one case report, a few months ago, of drug-associated NAFLD in which a person gained 10 kg (22 lbs) over several months (Shuster, J. Hospital Pharmacy 2008; 43(3): 172-176). There are many similar and more extreme examples. NAFLD is not simply an excess of free fatty acids in the liver or something vague. It's a set of relatively specific pathological abnormalities, such as enlarged mitochondria, triglyceride accumulation in cytoplasmic micelles, and paracrystalline inclusions, which are abnormal patterns in the cristae (structures formed by the infoldings of the inner mitochondrial membrane) of the mitochondria ("prismatic" cristae, hexagonal cristae, and other "atypical cristae"). It's also worthwhile to note that NAFLD is often difficult to diagnose with liver function tests (with blood tests). Mofrad et al. (2003) [Mofrad et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/12774006)] found that significant percentages of people with NAFLD had severe liver damage and no elevation in serum liver enzymes, in a commonly-used blood test. I talked about that article in a previous posting (http://hardcorephysiologyfun.blogspot.com/2008/12/sensitivity-issues-with-blood-tests-for.html). It's often necessary to use a transabdominal ultrasound to diagnose NAFLD. I think CT or MRI scans are also used, but I'm not sure which diagnostic approaches are used most frequently.

Note On Psychiatric Symptoms From Vitamin A and Related Compounds

I was going to mention that, in reference to my last two postings, that an excess of vitamin A and some retinoic acid derivatives could, in my opinion and in the opinions of others, produce psychiatric symptoms without elevating the intracranial pressure. But using lumbar punctures to test the CSF pressure is a crude and, from a clinical or "diagnostic" standpoint, relatively insensitive approach to discerning the phenotypic state of the choroid plexus epithelial cells that constitute the blood-CSF barrier. The mechanisms underlying the apparent psychiatric side effects of retinoids (and, in my opinion, there is clearly a link) are almost totally unknown, totally mysterious. There's evidence that an excess of vitamin A can antagonize and derange the actions of vitamin D, but I don't know that that effect could account for the extreme qualities of some of these case reports with vitamin A or related compounds. They're absolutely appalling, in my opinion, and I think there's a danger of thinking of these things in excessively rigid terms. It's necessary to remember the whole "normal-pressure hydrocephalus" spectrum of neurological symptoms. As nebulous as some of those types of diagnostic categories are, there's a multitude of mechanisms that could conceivably account for the symptoms and manifestations, psychiatric or other, that characterize those "categories."