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THE GASTROINTESTINAL SYSTEM

Tryptophan Transport Dysfunction¡ªHartnup's Syndrome

A 12-year-old boy is referred to a dermatologist because of a skin rash reminiscent of pellagra. The rash
appears occasionally and is exacerbated by exposure to the sun. The rash is confined to the face, back of
the neck, backs of the hands and wrists, external surfaces of arms and legs, anterior surfaces of knees,
and dorsal surfaces of the feet. The patient's diet contains sufficient niacin and calories, but is low in
protein. The patient is not frankly malnourished. The parents of the patient have not reported similar skin
rashes, but a sister of the patient has suffered from similar photosensitive skin rashes. The urine of the
patient contains most of the neutral amino acids in levels from 5 to 20 times their levels in the urine of
normal individuals. These amino acids include alanine, asparagine, glutamine, histidine, isoleucine,
leucine, phenylalanine, serine, threonine, tyrosine, and valine. The patient's urine does not contain
elevated levels of basic or acidic amino acids, nor elevated levels of the neutral amino acids glycine,
methionine, or cystine. The patient's plasma levels of individual amino acids are not abnormal. When the
patient is fed partially hydrolyzed casein (polypeptides), the plasma levels of the neutral amino acids rise
in the plasma several hours later, as is the case for normal individuals. However, when the patient is fed a
mixture of amino acids, there is only a very small rise in the plasma levels of those neutral amino acids
that are elevated in the patient's urine. The patient is treated daily with oral doses of niacin (200 mg/kg)
and the episodic skin rash disappears. With this regimen, the patient is asymptomatic.

1. What might account for the higher concentrations of neutral amino acids found in the patient's urine?

2. What might account for the failure of the plasma levels of these same amino acids to rise after feeding
the patient a mixture of all the amino acids?

3. Why do the plasma levels of these neutral amino acids rise after the patient is fed partially hydrolyzed
casein?

4. Why does the patient apparently have a deficit of niacin, despite having an amount of niacin in his diet
that would be sufficient for a normal individual?

5. What bearing might the patient's low-protein diet have on his condition?

6. Why is the patient not malnourished?

7. Because the symptoms of this disorder resemble pellagra, and the symptoms are alleviated by feeding
the patient elevated doses of niacin, why is the patient's problem not simply called pellagra?

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1. The brush border plasma membranes of the proximal renal tubule and the jejunum contain similar
transport proteins that couple the downhill transport of Na+ ions into the cells with the active
transport of amino acids into the cell. The amino acids present at high concentrations in the patient's
urine are primarily those that are transported by the neutral brush border (NBB) amino acid transport
system. These data are explained by a defect in the NBB transporter in the proximal tubule brush
border plasma membrane. Thus, most filtered neutral amino acids cannot be reabsorbed
quantitatively by the proximal tubule, in contrast to normal individuals.

2. This observation is consistent with the explanation that the same NBB amino acid transporter that is
deficient in the renal proximal tubule is also deficient in the jejunal brush border. Thus the ability to
absorb these neutral amino acids as free amino acids from the intestinal lumen is diminished.

3. Dipeptides and tripeptides are absorbed avidly in the jejunum by a peptide transporter. Oligopeptides
fed to the patient are reduced to dipeptides and tripeptides by the combined action of pepsins,
pancreatic proteases, and brush border peptidases. The various individual neutral amino acids are
then absorbed in the form of mixed dipeptides and tripeptides.

4. A fraction of a normal individual's niacin (nicotinamide) is provided by its synthesis from tryptophan.
The major pathway for degradation of tryptophan ends in the production of nicotinamide. Because
the patient cannot reabsorb tryptophan from his urine, levels of this amino acid fall and, as a result,
less conversion of tryptophan to nicotinamide occurs. This problem may be exacerbated because the
degradation of 60 mg of tryptophan is required to produce 1 mg of nicotinamide. Thus the diminished
availability of tryptophan causes the patient to be deficient in niacin, despite having an amount of
niacin in his diet that would be adequate for a normal individual.

5. Patients with this disorder (as judged from high concentrations of neutral amino acids in urine) are
much more likely to have symptoms if they also have poor diets. A patient with a high-protein diet is
believed to compensate somewhat for the loss of tryptophan by increasing absorption of tryptophan
(from dipeptides and tripeptides) in the jejunum. A patient with a high intake of niacin is also less
likely to be symptomatic.

6. The patient is not malnourished, because sufficient amounts of those neutral amino acids that are
transported by the NBB system can be absorbed in the jejunum as dipeptides and tripeptides to
supply the requirement of protein synthesis for the essential amino acids.

7. Pellagra is the disease that results from dietary deficiency of niacin. There is no deficiency in the
conversion of tryptophan to niacin in pellagra. This patient has Hartnup syndrome in which the
deficiency is in the renal and intestinal transport of tryptophan, which diminishes the conversion of
tryptophan to nicotinamide.