Do salt cravings in children with autistic disorders reveal low blood sodium depleting brain taurine and glutamine?

Abstract

Because boys are four times more likely than girls to develop autism, the role of male hormones (androgens) has received considerable scrutiny. Some researchers implicate arginine vasopressin, an androgen-dependent hormone from the pituitary gland that elicits male behavior. Elevated vasopressin is also the most common cause of low blood sodium (hyponatremia) – most serious in the brains of children. Hyponatremia causes astrocytes to swell, then release the amino acids taurine and glutamine and their water to compensate. Taurine – the brain osmolyte/inhibitory neurotransmitter that suppresses vasopressin – was the amino acid most wasted or depleted in urine of autistic children. Glutamine is a critical metabolic fuel in brain neurons, astrocytes, endothelial cells, and the intestines, especially during hypoglycemia. Because glutamine is not thought to cross the blood–brain barrier significantly, the implications of low blood glutamine in these children are not recognized. Yet children with high brain glutamine from urea cycle disorders are rarely diagnosed with autistic disorders. Other common events in autistic children that release vasopressin are gastrointestinal inflammation, hypoglycemia, and stress. Signs of hyponatremia in these children are salt cravings reported online and anecdotally, deep yellow urine revealing concentration, and relief of autistic behavior by fluid/salt diets. Several interventions offer promise: (a) taurine to suppress vasopressin and replenish astrocytes; (b) glutamine as fuel for intestines and brain; (c) arginine to spare glutamine, detoxify ammonia, and increase brain blood flow; and (d) oral rehydration salts to compensate dilutional hyponatremia. This hypothesis appears eminently testable: Does your child crave salt? Is his urine deep yellow?

Introduction

High levels of ammonia in the blood of children with autistic disorders (ASD) were first detected in the early 1980s [2]. Cohen subsequently found high plasma ammonia in one autistic boy [3]; Filipek et al. detected significantly elevated plasma ammonia in a majority of 100 autistic children [4]. Wakefield et al. suggested their diseased intestines generate more ammonia than their impaired liver can clear, which reaches the brain, provoking a form of hepatic encephalopathy [5].

Most ammonia (NH3) is generated as a byproduct of bacteria digesting proteins in the large intestine, and degrading the amino acid glutamine in the small intestine [6]. The liver uses the amino acid arginine to detoxify ammonia to urea, excreted in urine [7]. Ammonia that reaches the brain is trapped by astrocytes combining ammonia and the amino acid transmitter glutamate to form glutamine, with no transmitter activity but much osmotic activity [8]. Excessive glutamine causes astrocytes to swell, inducing compensatory release of the amino acid taurine and other solutes and their water to restore normal cell volume [9]. Persons with high brain ammonia from liver disease (e.g. cirrhosis) or inborn urea cycle disorders (UCD) have high concentrations of glutamine in astrocytes [10], inducing swelling and intracranial pressure, e.g. hepatic encephalopathy [8].

Plasma ammonia concentrations in children with UCD are five times greater than plasma ammonia in liver failure [11], elevating brain glutamine and impairing cognition. Yet children with UCD are rarely diagnosed with autistic disorders or mood disorders [12], [13], [14]. This striking observation corroborates Wakefield’s speculation that glutamine is low in autistic brains [5] – based on low serum levels [15] and evidence that liver dysfunction impairs the astrocyte glutamate transporter. But if glutamine is low in autistic brains, why are astrocytes swollen [16]? Ammonia and other neurotoxins implicated in autistic disorders, e.g. organic mercury and arsenic, cause astrocytes to swell [17], [18]. A more productive explanation may be chronic hyponatremia (low blood sodium), which drives water into astrocytes, inducing compensatory release of taurine, glutamine, and their water [19]. Why would children with autistic disorders be chronically hyponatremic? One obvious explanation is recurring diarrhea [20]. Another is high concentrations of water-conserving arginine vasopressin (AVP) [21]. A third is depletion of taurine, the inhibitory neurotransmitter that suppresses vasopressin [22].