Delving Into The Autistic Brain - Part 5

What happens in our bodies if there is an enzyme or hormone deficiency?

The deficiency of a single enzyme or hormone can wreak serious metabolic havoc, because even a partial deficiency in catalytic activity can cause a harmful accumulation of metabolites. Beyond this, enzymatic reactions do not occur in isolation. Rather, they are part of multi-step sequences (pathways) in which the product of one reaction serves as the substrate of a subsequent reaction, and reactions build upon each other.70 If a single enzyme or hormone is missing or deficient, whole sequences of chemical reactions can go awry or fail to take place altogether.

How might a specific hormone, such as secretin, become deficient or defective?

Secretin is a polypeptide, meaning that it is comprised of several amino acids linked together in a specific linear sequence by peptide bonds. If there is a problem with secretin function, it could be that the structure of this hormone (the sequence of amino acids) has somehow been altered or denatured, resulting in reduced efficiency. Or, a shortage of a specific amino acid needed to synthesize secretin could result in a shortage of secretin.

What might be the secretin connection to glucose supply and energy metabolism?

If pancreatic enzymatic activity is short-circuited due to insufficient secretin secretion, carbohydrates might not be fully degraded into monosaccharides. And since only monosaccharides (glucose, fructose and galactose) can be absorbed into the mucosal cells of the intestine, this might result in insufficient glucose entering the bloodstream. Also, if amino acids are not being properly broken down and absorbed, due to a reduced release of bicarbonate, the glucose forming process of gluconeogenesis could not take place. This would mean that the bulk of glucose supplying cellular and brain function would have to come from liver and muscle stores of glycogen.

But there is a problem here too. The release of secretin helps to stimulate the production and release of another very important pancreatic hormone--insulin. This hormone acts to decrease the production of glucose in the liver by inhibiting gluconeogenesis and the breakdown of stored glycogen.71 The less secretin, the less insulin, the more glucose the liver produces. The problem is that a lack of secretin also causes the incomplete digestion of proteins and carbohydrates resulting in the poor absorption of amino acids and glucose into the bloodstream. And low levels of plasma amino acids and glucose serve to stimulate the production of insulin, countering or balancing out the glucose producing effects of another pancreatic hormone, glucagon.72

All this is to say that in cases where secretin isn’t working effectively, neither are the hormones responsible for regulating and coordinating energy metabolism.

How does energy metabolism affect brain function and how might an uneven supply of glucose contribute to autism?

Unlike the liver and muscles, the brain contains no stores of glycogen, so it is completely dependent upon a steady and healthy supply of blood glucose (eight to ten times more than needed by any other organ).73 This being the case, any shortage of glucose would affect the brain more severely than other organs because it has such a high rate of metabolism. If the brain is not getting enough energy, or if that energy is delivered in spurts rather than in a smooth flow, mental function and information processing would invariably be affected.

The sluggish or uneven delivery of glucose to the brain could account for mood alternations between hyperactivity or heedless impulsivity and the spaciness or dream-like state characteristic of individuals with autism. In this respect, autism could be akin to hypoglycemia, “a state that occurs between consciousness and unconsciousness, in which sufferers commonly report aggressive feelings and loss of self-control, free will and the ability to follow any sort of reasoning-symptoms not unlike those of schizophrenia.”74 In his book, The Biological Causes of Autism, Dr. William Shaw cites several instances of hypoglycemia, which he attributes to the overgrowth of yeast byproducts causing pancreatic damage, which in turn results in the deficient production of digestive enzymes.75

In cases where there is no damage to the pancreas, poor enzyme function is most likely the result of the high acidity of intestinal contents that have not been properly neutralized by bicarbonate. If the pancreatic enzymes (peptidases) are not doing their job, proteins and carbohydrates cannot be properly broken down to form glucose and amino acids and this, along with an increase in insulin (due to low blood levels of these glucose precursors) could result in impaired delivery of glucose to the brain causing hypoglycemic symptoms and neuro-chemical impairment. The lack of sufficient amino acids could also result in the formation of fewer hormones or neurotransmitters, and this shortage of metabolic and neural regulators could critically impact both the delivery of glucose to fuel brain processes and the relaying of information within the brain.

Ordinarily the hypothalamus responds to a sharp or sudden decline in the amount of glucose reaching the brain by releasing the neurotransmitter epinephrine or by instructing the pituitary gland to release glucagon and the cortisol hormones that counter the hypoglycemic state.76 But, if the problem is a fluctuating or gradual glucose decline, the resultant anxiety might fail to trigger this epinephrine or endocrine response.

How does secretin tie into neurotransmitters?

Secretin may influence the synthesis of key neurotransmitters through the activation of the enzymes tyrosine hydroxylase and tryptophan hydroxylase. The catecholamines--dopamine, norepinephrine and epinephrine are made from tyrosine. Tyrosine is first hydroxylated (through the action of tyrosine hydroxylase) to form dopa, which is then broken down to form dopamine. Dopamine is further hydroxylated to yield norepinephrine, and epinephrine is formed from norepinephrine.77

Serotonin is hydroxylated from tryptophan in a similar fashion. These reactions could not take place efficiently if secretin and other polypeptide hormones failed to activate the intermediate steps. In fact, there was a significant increase in blood serotonin after secretin injection in several autistic children, validating the connection.78 If secretin does have a circulatory effect on the brain as well as the gut, it may well be due to its role in the synthesis and activation of these key neurotransmitters.

To sum up, what are some of the ways in which secretin might affect the central nervous system?

First of all, if it is working properly, secretin facilitates the complete digestion of proteins, lipids and carbohydrates, which results in the formation of glucose and amino and fatty acids. The glucose and amino acids are then broken down to form ATP, a high energy molecule that fuels the processes of most cells, including neural cells. The hyperactivity reaction (as well as the increased awareness) many autistic children have shown for a short while after the infusion of secretin might well be explained by a sudden surge in glucose supply and neural energy.

Second, by facilitating the release and efficacy of pepsin in the stomach and peptidase in the pancreas and intestines, secretin insures that polypeptides will be completely decomposed into amino acids that can then be used as substrates for the formation of chemical messengers, such as hormones and neurotransmitters. Actually, by activating the breakdown of tyrosine to dopa and the hydroxylation of tryptophan, secretin plays a direct role in the biosynthesis of the neurotransmitters most frequently linked to autism--dopamine, norepinephrine and serotonin.

Third, secretin may act indirectly to increase blood flow and message transmission in areas of the brain containing secretin receptors (hippocampus, hypothalamus and cortex) or by the activation of serotonin and norepinephrine.

Finally, by helping to stimulate and regulate pancreatic enzyme secretion and bile production secretin acts to normalize gastrointestinal function insuring that food particles are completely and properly digested before being passed into the bloodstream, thereby eliminating peptides or other compounds that might have a toxic or opiate effect on the central nervous system.

How might a lack of secretin cause or contribute to gastrointestinal problems?

If the digestion and absorption of dietary carbohydrates, fats or proteins is incomplete, due to a deficiency of secretin induced enzyme or bicarbonate function, undigested food particles will pass into the large intestine. If these particles are osmotically active, they will draw water from the mucosa cells as they make their way to the bowel, resulting in loose stools or chronic diarrhea. If they are not osmotically active, or if fermentation of sugars to yeast and bacterial overgrowth has interfered with intestinal function, constipation may result.

Secretin deficiency might also contribute to lactose intolerance, as lactate is obtained from the metabolism of glycogenic amino acids. A hold up in this metabolism due to enzymatic dysfunction would result in a shortage of cellular lactate, causing problems with the digestion of lactose.

What about infections and allergies?

Many children with autism have abnormalities with their immune system and are highly susceptible to colds and infections. My daughter certainly got more than her fair share of colds and fevers during her childhood, and she suffered from strep throat at least three times a year from the age of three until she turned nine or ten.

One explanation for this susceptibility might be that a large part of the immune system is located in or near the intestinal tract.79 If the enzymes and hormones in this tract are not functioning up to par to keep abnormal microbials from entering the bloodstream, germs might well be among those poorly filtered particles. Also, the immune system works through the action of B-cells (that produce antibodies) and T-cells (that kill tissue virus).80 These cells and cell products are protein-based, composed of a particular combination of amino acids. If any of these amino acids happens to be in short supply, due to a problem with the breakdown of proteins, this could account for an insufficiency of immune cells.

A problem in the breakdown of nitrogen-based amino acids might account for a shortage of histamines as well, the chemical messengers that regulate cellular response to allergens and inflammation. If fewer histamines are produced, allergic reactions would be more pronounced, as they often are in autism. Histamines also play a role in gastric acid secretion and neurotransmission in parts of the brain,81 which might help to explain the abnormal behaviors that often accompany these reactions.

What are some alternative biological factors that might cause or contribute to autism?

It is Dr. William Shaw’s contention that, because of some inborn impairment to their immune system, young autistic children suffer recurrent infections, primarily ear infections. These infections are treated with antibiotics, which eliminate the normal bacteria of the gastrointestinal tract resulting in a proliferation of yeast. This yeast produces abnormal sugars and enzymes, which interfere with carbohydrate and protein metabolism, particularly the metabolism of wheat and milk proteins.

The major proteins in wheat and milk are gluten and casein respectively. These proteins are supposed to be broken down in stages to peptides and then to amino acids, which are then absorbed through the intestinal lining into the bloodstream. But, because of a deficiency in the activity of pancreatic enzymes (due to yeast induced pancreatic atrophy) incompletely digested gluten and casein peptides are absorbed into the bloodstream. These abnormal protein byproducts pass into the brain and react with opiate receptors in the temporal lobe causing a “morphine-like effect” and interfering with speech and auditory integration.82

I’m not sure what role the accumulation of abnormal (possibly toxic) metabolites plays in autism, whether or not these molecules can even make it through the tightly packed endothelial cells that constitute the “blood-brain” barrier.83 If they can get through, they may well have a detrimental effect on the function of key brain structures. But I suspect that the core problem with autism has more to do with the way crucial biochemical catalysts (glucose and certain hormones and neurotransmitters) reach and react in the brain than with the actions of extraneous ones.

70 Susan A. Greenfield, The Human Mind Explained, New York (1996) Henry Holt and Company, p. 66.

71 Susan A. Greenfield, The Human Mind Explained, p. 60.

72 Susan A. Greenfield, The Human Mind Explained, New York (1996) Henry Holt and Company, p. 67.

73 William Shaw, PhD, Biological Treatments for Autism and PDD, Shaw (1998) p. 130.

74 Pamela Champe; Richard Harvey, Lippincott’s Illustrated Reviews: Biochemistry, Philadelphia (1994) J.B. Lippincott Company, p. 277.

75 Pamela Champe; Richard Harvey, Biochemistry, p. 272.

76 Pamela Champe; Richard Harvey, Biochemistry, p. 252.

77 William Shaw, PhD, Biological Treatments for Autism and PDD, Shaw (1998) pp. 295-96.

78 Susan A. Greenfield, The Human Mind Explained, New York (1996) Henry Holt and Company, p. 66.

80 Pamela Champe; Richard Harvey, Lippincott’s Illustrated Reviews: Biochemistry, Philadelphia (1994) J.B. Lippincott Company, p. 265