638
FOLATE DEFICIENCY SECONDARY TO
DISEASE OF THE INTESTINAL TRACT*
FREDERICK A. KLIPSTEIN
Assistant Professor of Medicine
Columbia University College of Physicians and Surgeons
New York, N. Y.
M/[ALABSORPTION from the intestinal tract is a common cause of deficiency of folate and vitamin B12. Deficiency of either of these
vitamins results in the development of a megaloblastic anemia. Vitamin
B12 is particularly susceptible to defects of absorption since it requires
the elaboration of intrinsic factor from the stomach to facilitate its
absorption and must traverse the length of the small intestine to reach its
specific absorption site, the ileum.' Thus defects in intrinsic factor production, the presence in the upper small intestine of parasitic or bacterial organisms that utilize the vitamin, or disease of the ileum can all
result in malabsorption of vitamin B12. In the United States, with the
exception of rare dietary deficiency occurring in vegetarians, deficiency
of vitamin B12 is always a secondary manifestation of disease of the
gastrointestinal tract. Folate is absorbed principally in the proximal
jejunum2' 3 and disorders of folate absorption are associated with disease
of this segment of the intestine. In addition to malabsorption, folate
deficiency can also result from inadequate dietary intake,4-6 from excessive demand, as sometimes occurs in pregnancy or hemolytic anemia,8
or secondary to the use of folic acid antagonists or anticonvulsant
drugs.9
Although some disorders of the intestinal tract can be associated with
malabsorption and deficiencies of both folate and vitamin B12, this
review will restrict itself to a consideration of malabsorption and deficiency of folate.
TESTS FOR FOLATE DEFICIENCY AND ABSORPTION
For technical reasons, knowledge of the normal physiology and
pathology of absorption and of deficiency states of folate has lagged
*Presented at a meeting of the Society for the Study of Blood, held at The New York Academy
of Medicine, December 1, 1965.
The investigations described in this paper were supported in part by Public Health Service Grant
RIO CA-02332-11 from the National Cancer Institute, Bethesda, Md., the Williams-Waterman Fund
for the Combat of Dietary Diseases, New York, N. Y., and M. J. Ossorio, of Greenwich, Conn.
Bull. N. Y. Acad. Med.
SECONDARY FOLATE DEFICIENCY
63 9
behind that of vitamin B12. The facts that vitamin B12 is absorbed and
circulates in the plasma in a single, unchanged form and that this vitamin
can be labeled with the gamma-emitting isotopes Co5T or Co60 have
made the determination of its serum and tissue concentrations'0 and its
absorption" relatively simple. Folate, on the other hand, is present in
foodstuffs and in the body in a variety of forms, only a small fraction
of which is in the form of folic acid (PGA).12 For this reason, studies
of folate deficiency and absorption have required the use of various
microbiologic organisms. The organism Lactobacillus casei, which measures principally the concentration of the naturally occurring coenzyme,
5-methyltetrahydrofolic acid,13 has been used to assay folate depletion
in tissue,'4 whole blood,'5 or serum,'6 17 and the organism Streptococcus
faecalis, which measures PGA and other reduced monoglutamate forms
of folate not naturally found in the serum, has been used in studies of
folic acid absorption.3 Tritiated PGA is the only form of folate presently
available in radioisotopic form.
Several tests are available to measure the capacity of the small intestine to absorb folic acid. They are based on the assessment, either by
microbiologic or radioisotopic techniques, of the concentration of PGA
in the serum, urine, or stool following an oral test dose of the vitamin.
Each has certain disadvantages; all share the disadvantage that they
measure the absorption of crystalline PGA, a determination which, in
some circumstances, may bear little relevance to the absorption of
dietary folate.
Microbiologic Determination of Urinary Folic Acid Activity
As introduced and extensively used by Girdwood and his associates, 8-21 this procedure consists of determining, with S. faecalis assay,
the sequential 24-hour urinary excretion of PGA following, first, parenteral administration of 5 mg. of PGA and, subsequently, oral administration of a similar dose. Excretion of less than 1.5 mg. PGA after the
oral test dose or an excretion index (urinary excretion after oral administration divided by excretion after parenteral administration, times Ioo)
of less than 75 per cent is interpreted as evidence of malabsorption of
the vitamin. This test has the disadvantage of including the administration of pharmacologic doses of PGA that preclude any further studies
of a therapeutic nature; in addition, it introduces the variable of renal
excretion into the determination of PGA absorption.
Vol. 42, No. 8, August 1966
64 0
640
F. A. KLIPSTEIN
Microbiologic Determination of Serum Folic Acid Activity
A more direct assay of PGA absorption was introduced by Spray
and Witts in I952 when they demonstrated that serum levels of folic
acid, assayed with S. faecalis, fail to rise after an oral test dose in patients
with malabsorption.22 However, a similar situation prevails in vitamin
B12 deficiency states unless patients have received prior saturation with
folic acid to prevent rapid plasma clearance of folic acid causing spuriously low serum levels in the absorption test.22 For this reason, in the
test as modified by Chanarin and his associates,3 patients receive daily
saturating doses of 15 mg. folic acid parenterally for 3 consecutive days;
36 hours after the last parenteral dose, an oral test dose of 40 1Jg. PGA
per kg. body weight is administered. In normal subjects, serum levels
reach peak values of greater than 40 mIxg./ml. at I to 2 hours after the
oral test dose. 23
Determination of Radioactivity in the Urine
Following an oral test dose of 40 M1g. tritium-labeled folic acid
(H3FA) per kg. body weight, accompanied by a parenteral flushing dose
of I5 mg. PGA to prevent tissue retention of the absorbed H3FA, the
24-hour urine excretion of H8FA in normal subjects has been found to
range between 32 and 4I per cent of the oral test dose.2427 Patients with
malabsorption usually excrete less than 26 per cent of the oral test dose.25
As in the previous test, preliminary saturation is essential in patients who
have either folate or vitamin B12 deficiency.215 Thus this test shares the
disadvantage of the previous two tests in that patients receive therapeutic doses of folic acid during the study; in addition, reduced renal
function will compromise the test.25
Determination of Fecal Radioactivity
Fecal radioactivity of an oral test dose of H3FA may be determined
in a 24- or, preferably, a 72-hour stool collection by several techniques.
Anderson and her associates found that control subjects excreted from
9.2 to 59 per cent, with an average of 2 1.3 per cent, of an oral test dose
of 200 ,ug. H3FA.24 Paterson, David, and Baker have reported that normal
subjects excrete less than 40 per cent in a 24-hour collection,28 and in
our experience normal subjects usually excrete between 4o and 6o per
cent in 72-hour collections after an oral test dose of 6o Ktg. H3FA.
Increased fecal excretion in excess of 6o per cent has been observed in
Bull. N. Y. Acad. Med.
SECONDARY FOLATE DEFICIENCY
-~~~~EODR
OAEDFCEC
64 I
4
the majority of patients with malabsorption who have been studied to
date. This test has the advantage that it does not require preliminary
saturation or flushing doses of PGA and hence is the only absorption
study in which patients may be studied without treatment. Further, the
test dose more closely approximates physiologic quantities of PGA. The
limited results available at the present time, however, preclude a final
assessment of its reliability and duplicability.
DIETARY SOURCES AND ABSORPTION OF FOLATE
The majority of naturally occurring dietary folate is in conjugated
form, containing up to 7 y-linked glutamate residues. For this reason,
the determination of total folate in the diet is made after deconjugating
dietary folate, using chick pancreas as the source of conjugase activity. When assayed with L. casei, total daily folate activity has been
found to approximate 1000 MLg.12' 29 It is likely that only a small fraction
of this total folate activity is available for absorption and utilization since
the naturally occurring polyglutamate forms are not readily absorbable
until they have been deconjugated into small units,30 a process that presumably occurs through cleavage at the glutamyl residues by the action of
a y-glutamic acid carboxypeptidase.83 Since the availability of conjugase activity in the human gastrointestinal tract is unknown, it is
thought that values obtained prior to conjugase treatment may be more
representative of the amount of folate that is physiologically available
in the diet.32' 33 When assayed without deconjugation, dietary folate
activity is found to range between 49 and 450 Jug.12' 3.334 Even these
values are considerably in excess of the daily dosage of 50 Ig. crystalline
PGA which has been shown to be effective in the treatment of megaloblastic anemia secondary to folate deficiency.3'537
Little is known concerning the absorptive process of folate either
prior to or after deconjugation. In humans, the rapidity of absorption
of an oral test dose of PGA and the pattern of malabsorption in certain
disorders have suggested that folic acid is absorbed principally in the
proximal jejunum, and studies by Burgen and Goldberg38 and Herbert and Shapiro39 have shown that, in the rat, PGA absorption occurs
principally as an active process in the proximal small intestine. Whether
folate forms are altered during transport through the intestinal epithelium is unknown; one investigation has suggested such to be the case
in one monoglutamate form of folate.40
Vol. 42, No. 8, August 1966
642
F. A. KLIPSTEIN
In humans, folate is secreted in the bile in greater concentration than
is present in the serum,41' 42 suggesting an enterohepatic circulation of
folate similar to that already described for vitamin B12.43 In addition,
studies in mice utilizing H3-labeled folic acid have suggested that parenterally administered folic acid may be concentrated within the epithelial
cells of the upper intestinal tract and then pass out into the intestinal
lumen." The significance of the enteric loss of folate by biliary excretion
and the possible enteric loss by other mechanisms in the depletion of
body stores of folate remain to be elucidated.
CONDITIONS ASSOCIATED WITH MALABSORPTION OF FOLATE
FOLLOWING SUBTOTAL GASTRECTOMY
As a result of atrophy of the gastric remnant with subsequent deficiency of intrinsic factor and malabsorption of vitamin B12, approximately I 5 per cent of patients who have undergone subtotal gastrectomy
eventually develop a megaloblastic anemia secondary to deficiency of
vitamin B12.45-48 Recent studies have indicated that folate deficiency
also occurs commonly in this condition, although only rarely is it
responsible for the development of a megaloblastic anemia. Serum folate
levels have been found to be subnormal in from 12 to 50 per cent of
patients selected randomly following subtotal gastrectomy and in from
54 to 67 per cent of those patients who had a megaloblastic anemia.48~i0
Folate deficiency, however, has been the sole cause of megaloblastic
anemia in only 13 patients reported to date.48-5'
The cause of folate deficiency following subtotal gastrectomy has
not been studied adequately. Suboptimal dietary intake of folate may be
a factor in some patients.48' 50, "5 Folate deficiency does not appear to be
related to the presence of the steatorrhea or abnormalities of jejunal
morphology that may develop following subtotal gastrectomy. Jejunal
biopsies were normal in all eight patients with folate deficiency following subtotal gastrectomy studied by Gough and his associates,50 and the
absorption of folic acid was normal in all of these patients as it has been
in the majority of other patients who have been so studied.2 19 4', 1
However, since these studies were of crystalline PGA, their relevance
to the absorption of dietary folate is uncertain. The possible role of
bacterial overgrowth in the upper small intestine, present in some
patients following the Billroth II procedure,52 also remains to be
evaluated.
Bull. N. Y. Acad. Med.
6 4.
SECONDARY FOLATE DEFICIENCY
j
TABLE I.-STUDIES OF FOLIC ACID ABSORPTION IN PATIENTS
WITH GLUTEN ENTEROPATHY
Patients with
malabsorption
of folic acid
Investigator
Date
Girdwood
Cox et al.
Doig and
Girdwood
Cooke et al.
Chanarin et al.
Chanarin and
Bennett
Cooke et al.
1953
1958
microbiologic, urine
microbiologic, urine
19
1960
microbiologic, urine
microbiologic, urine
microbiologic, serum
1962
1963
Klipstein
Baker et al.
Anderson et al.
Klipstein
Kinnear et al.
Anderson et al.
1964
1964
1960
1963
1963
1960
microbiologic,
microbiologic,
microbiologic,
microbiologic,
1963
1958
Method
H3FA,
H3FA,
H3FA,
H3FA,
serum
serum
serum
serum
urine excretion
urine excretion
urine excretion
stool excretion
6
Total
patients
studied Reference
6
19
18
8
25
31
18
30
20
33
20
53
3
77
15
8
7
7
8
4
9
84
15
9
7
9
8
8
13
54
53
55
56
84
25
26
24
Gluten-Induced Enteropathy (Celiac Disease)
Malabsorption of folic acid occurs in the majority of patients with
this disorder.2, 3, 18, 20, 24-26, "3"56 The results of absorption studies are summarized in Table I. Studies using H3FA have suggested to both Anderson and her co-workers24 and Klipstein25 that a correlation exists between
the severity of jejunal villous atrophy and the degree of impairment of
folic acid absorption. Serum folate levels have been subnormal in the
majority of patients studied,17' 25,55, 57-59 although not all of these patients
have had a megaloblastic anemia.57 In our experience, 12 of I4 patients
with gluten enteropathy have had malabsorption of folic acid (Figure
i) and serum folate levels were subnormal in 9 of IO patients tested
with reduced absorption and normal in 2 patients with normal absorption (Figure 2). Gluten restriction results in reversal of subnormal folic
acid absorption to normal in this condition.26' 53 5
Tropical Sprue
The information available (Table II) suggests that malabsorption of
folic acid is a frequent but not universal occurrence in tropical
sprue.3 15,19,24,25,28,55,60,61 In Puerto Rican subjects, Butterworth and
his associates reported subnormal absorption in IO patients,60 and we
have found reduced absorption in 9 of 12 untreated patients (Figure i).
Vol. 42, No. 8, August 1966
64 4
F. A. KLIPSTEIN
TABLE II.-STUDIES OF FOLIC ACID ABSORPTION IN PATIENTS
WITH TROPICAL SPRUE
Investigator
Date
Girdwood et al.
Chanarin et al.
Butterworth et al.
Klipstein
Klipstein et al.
Klipstein
Anderson et al.
Paterson et al.
1953
1958
1957
1964
1966
1963
1966
1965
Method
microbiologic, urine
microbiologic, serum
microbiologic, serum
microbiologic, serum
microbiologic, serum
H3FA, urine excretion
H3FA, stool excretion
H3FA, stool excretion
Total
Patients with
malabsorption patients
of folic acid studied Reference
3
1
10
7
3
4
1
7
3
1
10
11
12
4
1
20
18,19
3
60
55
61
25
24
28
Fig. 1. Results of absorption studies in patients with tropical sprue ('IS) and gluten
enteropathy (GE). Stippled areas indicate the range of normal values.
In contrast, only 2 of 1 2 patients whom we have studied in Haiti,61 and
7 of 20 patients investigated by Paterson, David, and Baker in India had
subnormal absorption.28 The cause for the varied findings in different
geographic locations remains unexplained. Whether folic acid absorption is related to the severity of the intestinal lesion in tropical sprue as
it appears to be in gluten enteropathy has not been evaluated adequately.
Treatment with pharmacologic doses of folic acid results in improvement in the absorption of this vitamin.55
Megaloblastic anemia is commonly present in the advanced stage of
the disease. This is secondary to vitamin B12 deficiency in nearly all
cases25,5-, 61-63 and due to a combined deficiency of vitamin B12 and folate
Bull. N. Y. Acad. Med.
SECONDARY FOLATE DEFICIENCY
64 5
Fig. 2. Results of serum assays for folate, vitamin B1, and iron in patients with untreated tropical sprue (TS) and gluten enteropathy (GE). Stippled areas indicate the
range of normal values.
in some. Serum folate levels have been subnormal in i8 of 24 Puerto
Rican patients whom we have seen in New York City (Figure 2), in 5
of I3 patients investigated in Haiti,6" in 27 of 32 patients studied by
Paterson and colleagues in India,28 and in all 39 patients reported by
O'Brien and England from Malaya.63 In some instances, folate deficiency
may occur in the absence of demonstrable malabsorption of PGA,28 61
suggesting that defective utilization of dietary folate rather than malabsorption may be responsible for the deficiency in these cases.
Regional Enteritis
Malabsorption of folic acid occurs commonly in this condition. Subnormal absorption has been reported in 6 of 22 patients by Cox and his
associates2 and in 19 of 22 patients studied by Chanarin and Bennett.54
Malabsorption is less severe than in gluten enteropathy and folate
deficiency is rare. Folic acid absorption has been subnormal in two of
four patients with regional enteritis whom we have studied (Figure 3).
Small Intestinal Resection
Distal resection of the small intestine results in malabsorption of
vitamin B12 if the ileum is totally removed;64 however, folate absorption
remains unaltered unless all but a few feet of jejunum are removed.65
Vol. 42, No. 8, August 1966
64 6
646
F. A. KLIPSTEIN
F.
A.
Fig. 3. Results of absorption studies of folic acid and xylose. Stippled areas indicate
the range of normal values. Open circles indicate patients who were folate-deficient.
Three of five patients whom we have studied had subnormal absorption
of folic acid (Figure 3); all three of these patients had had large segments of jejunum removed; one had a megaloblastic anemia on the basis
of folate deficiency.
Subnrucosal Infiltration
Lymphoma. Lymphomatous involvement of the small intestine can
be associated with malabsorption, and it has been postulated that this
disorder may be a sequela to gluten enteropathy in some instances."7
Reduced absorption of folic acid has been reported by Doig and Girdwood in one patient who had overt involvement of the small intestine
with Hodgkins's disease, and by Pitney and his associates in 12 of i8
patients who had either chronic lymphatic leukemia or lymphoma.68
Many of the patients in the latter group did not have overt evidence of
intestinal involvement. In 20 patients with lymphoma whom we have
studied, folic acid absorption was reduced in only the 4 patients in the
group who had clinical and biopsy evidence of lymphomatous involvement of the intestine and was normal in the other i6 (Figure 3). The
urinary excretion of xylose was subnormal in every patient tested.
Bull. N. Y. Acad. Med.
SECONDARY FOLATE DEFICIENCY
64 7
Whether this represents actual malabsorption or reflects increased catabolism of pentose normally absorbed in patients with neoplastic disease
remains to be determined.
Whipple's disease. Folic acid absorption was subnormal in one patient reported by Pitney et al.68 and in one patient, who was folatedeficient in addition, whom we have studied (Figure 3).
Scleroderma and amyloidosis. Malabsorption can occur secondary to
involvement of the small intestinal tract by scleroderma or amyloid.69
Folic acid absorption was subnormal in three such patients with scleroderma and in one of three patients with amyloid whom we have studied
(Figure 3).
Other Conditions
Impaired absorption of folic acid occasionally can occur in conditions not usually associated with malabsorption. Presented are those in
which studies have been reported or in which we have had experience.
Bacterial Overgrowth
Recent evidence has indicated that the small intestine in normal
subjects is not usually sterile,70 as was previously supposed. Little is
known as to whether this bacterial population utilizes or synthesizes
folate forms in either normal or abnormal conditions. Doig and Girdwood have reported that microorganisms isolated from the jejunum of
patients who had bacterial overgrowth of the proximal intestine were
capable of synthesizing a substance that supported the growth of Strep.
faecalis.20 The overgrowth of microorganisms in the proximal small
intestine, which occurs as a result of anatomic disorders producing stasis
of the fecal flow, is frequently associated with steatorrhea and a megaloblastic anemia due to deficiency of vitamin B12.71 72 To date megaloblastic anemia secondary to folate deficiency has not been reported in
this condition. Folic acid absorption has been normal in the majority
of patients studied,3 20 73 with the exception of 6 of 2 I patients with
jejunal diverticulae investigated by Cooke and his associates.72 Malabsorption was corrected by therapy with oral antibiotics in these patients. However, antibiotic therapy does not appear to correct the malabsorption in patients in whom the bacterial overgrowth is secondary to
altered intestinal motility on the basis of submucosal infiltration. In two
such patients whom we have studied, one with a lymphoma, the other
Vol. 42, No. 8, August 1966
64 8
F. A.
A. KLIPSTEIN
F.
with scleroderma, oral antibiotic therapy corrected the diarrhea but not
malabsorption of folic acid and xylose.74
Cirrhosis. Megaloblastic anemia due to folate deficiency is a common
occurrence in alcoholic cirrhosis.7577 Folate deficiency in this condition
is due to inadequate dietary intake coupled, in some instances, with
increased demand for folate by a hyperactive bone marrow.76 Studies of
folic acid absorption have been normal in most instances,2 76 and the
development of folate deficiency does not appear to be related to malabsorption of the vitamin. In our experience, folic acid absorption has
been subnormal in 2 of I 3 patients studied (Figure 3). Folate deficiency
was present in these two patients as well as six others who had normal
absorption. As in patients with lymphoma, xylose absorption is sometimes subnormal in patients with cirrhosis (Figure 3) .7
Hypoparathyroidism. Steatorrhea and malabsorption of vitamin B12
can occur occasionally in hypoparathyroidism, especially during periods
of uncorrected hypocalcemia.79 We have found normal folic acid absorption in five such patients who had normal serum calcium concentrations at the time they were studied. Studies in a sixth patient, conducted
at a time when serum calcium levels were subnormal and the patient
had diarrhea, showed subnormal absorption of both folic acid and
xylose. This patient had a normal jejunal biopsy.
Diabetes mellitus. The steatorrhea that develops in some patients
with diabetes mellitus is thought to occur on the basis of either: i) disease of the autonomic nervous system, with resultant altered intestinal
motility and bacterial overgrowth,80 or 2) secondary to concomitant
gluten enteropathy.81 Disorders of jejunal morphology and absorptive
capacity are usually limited to the latter group. The absorption of both
folic acid and xylose was subnormal in one diabetic patient reported by
Doig and Girdwood20 and in two patients we have studied who had
steatorrhea but normal jejunal biopsies.
Anticonvulsant drug therapy. Over 5o per cent of patients on Dilantin therapy have a subnormal serum folate concentration without
anemia.9' 82 This is due, it is thought, to mild competitive inhibition
of folate metabolism caused by this drug. In some instances, usually in
the presence of an additional factor such as inadequate dietary intake,
overt megaloblastic anemia may occur. Although studies of folic acid
absorption have been normal in patients receiving Dilantin who had a
8'3-85 certain observations raise the possibility
megaloblastic anemia,9,19'23,
Bull. N. Y. Acad. Med.
SECONDARY FOLATE DEFICIENCY
64 9
that this drug may have a deleterious effect on the absorptive capacity
of the small intestine. We have observed subnormal folic acid absorption
in two nonanemic patients taking Dilantin, and other patients taking
this drug have been reported to have a defect in absorption of xylose86
and vitamin B1287 that was reversible by treatment with folic acid.
FOLATE AND THE INTESTINAL MUCOSA
Little is known concerning the role of the folate coenzymes in maintaining the functional and morphologic integrity of the small intestinal
mucosa. Direct assay of folate concentration of the jejunal mucosa in
either normal subjects or in patients with disorders of the intestinal tract
have not been reported. Grossowicz and his associates found the folate
concentration of the rat intestine to be o.6 ,Ag./g., one fifteenth that of
the concentration in the liver.'4 The generation time of the crypt epithelium approximates that of erythropoietic tissue in its rapidity, and it
is on these two tissues that the action of the folic acid antagonists is
initially manifest. However, folate deficiency from other causes-,4-6,'8 as
well as vitamin B12 deficiency,89 has not been found to be associated with
villous atrophy, and it is likely that, with the exception of tropical sprue,
folate deficiency plays no role in the development of malabsorption in
the conditions described in the previous section. In tropical sprue, treatment with pharmacologic doses of either folic acid or vitamin B12 results
not only in a hematologic remission of the megaloblastic anemia but, in
the majority of cases, in reversal of villous atrophy and malabsorption
towards normal.55' 62, This can occur even in the absence of overt
evidence of folate deficiency.91 Therapy with oral antibiotics also results
in a hematologic and intestinal remission in this disease.55' 92-95 In patients
with tropical sprue who have folate deficiency, antibiotic therapy has
been shown to result in folate repletion95 when there is an adequate dietary supply of this vitamin.94 In these patients, folate repletion appears to
be responsible for the hematologic remission as well as for some aspects
of the intestinal improvement.95 Other aspects of the intestinal remission
appear to be unrelated to folate repletion, since the administration of
antibiotics subsequent to treatment with folic acid results in further
improvement in jejunal morphology and function in some patients.93
These therapeutic observations have indicated that in tropical sprue,
folate and vitamin B12 are of importance in restoring intestinal function
and morphology to normal in a previously damaged intestinal mucosa;
however, other environmental factors are thought to be primary in the
Vol. 42, No. 8, August 1966
65o
F. A. KIAPSTEIN
etiology of this disease, and the role of these vitamins in the pathogenesis
of the intestinal lesion remains obscure.
SUMMARY
Disorders of the intestinal tract that can be associated with malabsorption and deficiency of folate have been reviewed. In the majority
of these conditions, folate deficiency results from impaired absorptive
capacity for the vitamin secondary to the basic disease. In some conditions, as in those following subtotal gastrectomy, the situation appears
to be more complex. Investigation of this has been hampered by the
fact that to date absorptive studies have been limited to crystalline folic
acid that in some instances may bear little relevance to the absorption
of dietary folate. Tropical sprue is unique in that folate appears to play
a role, in an as yet unexplained manner, in maintaining the functional
and morphologic integrity of the intestinal mucosa in this condition.
1.
2.
3.
4.
5.
6.
7.
8.
9.
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