Nutritional neuropathies

13. Diagnostic Evaluation
Thiamin deficiency may be assessed by the transketolase assay. Because the carbohydratemetabolizing enzyme transketolase requires thiamin pyrophosphate, a deficiency will lead to an elevation in the red blood cell transketolase. The assay is most sensitive when performed with and without a thiamin pyrophosphate challenge. Serum thiamin levels are unreliable due to low sensitivity and specificity. MRI of the brain will occasionally show an abnormal signal in the periaqueductal gray matter and midline structures. Cobalamin deficiency may be due to a variety of disorders, most commonly pernicious anemia. Approximately 78% of patients with cobalamin deficiency will be found to have a proven or probable defect of intrinsic factor production from the gastric parietal cell (pernicious anemia). Perhaps 10% of patients have food-cobalamin malabsorption due to hypo- or achlorhydria, a disorder that affects from 16-40% of the elderly ( Hurwitz et al, 1997). The rest are due to a variety of causes including malabsorption from inflammatory bowel disease, tape worm infestation, blind loop syndrome, chronic H2 blocker therapy, gastric bypass, and serum binding protein abnormalities. In a patient with signs and symptoms of cobalamin deficiency, one should begin with a cobalamin assay. If the serum cobalamin assay result is less than the lower normal limit, a measurement of intrinsic factor antibodies should be taken. If this test is positive, the diagnosis of pernicious anemia is confirmed, and a Schilling test is not necessary. In pernicious anemia, some laboratory evidence of an autoimmune process is often found. Anti- parietal cell antibodies are present in 90% and intrinsic factor antibodies in 60% of patients with pernicious anemia. Antiparietal cell antibodies have a 10% false positive rate. Though it lacks sensitivity, the test for intrinsic factor antibodies is much more specific.

In patients with serum cobalamin levels in the lower normal range, but in whom one still
suspects clinical cobalamin deficiency, one should measure levels of homocysteine and
methylmalonic acid (Snow, 1999; Kinsella and Green, 1995). Methylmalonic acid may be
measured in serum or urine. The urinary assay is more specific in patients with renal
insufficiency. If either metabolite is elevated, then serum intrinsic factor antibodies and gastrin
should be measured. The serum gastrin level is often elevated in pernicious anemia and is a
marker for achlorhydria, a cause of food- cobalamin malabsorption.

The presence of hypersegmentation may be a sensitive marker for cobalamin deficiency, even in
the absence of anemia or macrocytosis. If metabolites or the serum gastrin are elevated, a
Schilling test may be performed to identify cobalamin absorption, which is usually the result of
autoimmune parietal cell dysfunction that occurs in pernicious anemia. Technically, patients with
classic pernicious anemia have an abnormal test result when radioactive cobalamin alone is given
by mouth (Part I). This abnormality is corrected when the test is repeated with intrinsic factor
(Part II). Abnormally low secretion of cobalamin in the Part II Schilling test indicates an
intestinal cause for the cobalamin malabsorption, such as inflammatory bowel disease. The Part II
Schilling test may be repeated, after giving antibiotics or vermacides to exclude bacterial
overgrowth ("blind loop syndrome") or fish tapeworm infestation due to diphyllobothrium latum,
rare causes of cobalamin deficiency through competition for intraluminal cobalamin.
A normal Part I test in a patient with cobalamin deficiency may be observed in total vegetarians.
It may also occur in patients with food-cobalamin malabsorption who show normal absorption of
crystalline cobalamin but are unable to digest and absorb cobalamin present in food due to
achlorhydria. This defect can be identified using a modified Schilling test in which radioactive
cobalamin is administered with food (Carmel, 1990).
Pyridoxine deficiency will cause elevations in serum homocysteine and cystathionine, and assays
are commercially available. Urinary assays for xanthurenic acid and other pyridoxine metabolites
may be performed following tryptophan loading.
Vitamin E deficiency can be reliably investigated using the serum alpha- tocopherol level. Adult
patients without malabsorption and a clinical picture consistent with Friedrich’s ataxia and
neuropathy should be investigated for an autosomal recessive defect in the tocopherol transporter
protein gene of chromosome 8. Tocopherol transporter protein incorporates tocopherol into
chylomicrons. The serum tocopherol levels in these patients may be in the normal range;
however, they respond to high dose supplementation.