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Fatal Folic Acid Toxicity in Humans

Authors:
  • ALL INDIA INSTITUTE OF MEDICAL SCIENCES MANGALAGIRI
  • REGIONAL FORENSIC SCIENCE LABORATORY, VILLUPURAM

Abstract

Folic acid is B-9 vitamin. Folic acid is prescribed commonly for pregnant women to prevent neural tube defects in the fetus,patients under chemotherapy, pernicious anemia and to reduce the risk of stroke and cardiovascular disease. Acute or chronic ingestion of a large dose of folic acid generally manifests as neurological complications, which are reversible. In this present case, a 23-year-old pregnant woman committed suicide by consuming folic acid tablets and succumbed to death within 36 h. Postmortem toxicological analysis detected folic acid in viscera. Death following acute consumption of folic acid is rare and has been not reported in the literature, to the best of our knowledge
CASE REPORT
PATHOLOGY/BIOLOGY; TOXICOLOGY
Gerard Pradeep Devnath,
1
M.B.B.S., M.D.; Senthil Kumaran,
1
M.B.B.S., M.D.; R. Rajiv,
2
M.Sc., M.Phil.;
Kusa Kumar Shaha,
1
M.B.B.S., M.D.; and Ashok Nagaraj,
1
M.B.B.S., M.D.
Fatal Folic Acid Toxicity in Humans
ABSTRACT: Folic acid is B-9 vitamin. Folic acid is prescribed commonly for pregnant women to prevent neural tube defects in the fetus,
patients under chemotherapy, pernicious anemia and to reduce the risk of stroke and cardiovascular disease. Acute or chronic ingestion of a
large dose of folic acid generally manifests as neurological complications, which are reversible. In this present case, a 23-year-old pregnant
woman committed suicide by consuming folic acid tablets and succumbed to death within 36 h. Postmortem toxicological analysis detected
folic acid in viscera. Death following acute consumption of folic acid is rare and has been not reported in the literature, to the best of our
knowledge.
KEYWORDS: forensic science, folic acid, pregnant woman, suicide, toxicological analysis, histopathology
Suicide among pregnant women is not an uncommon scenario.
Expectant mothers who commit suicide are mostly likely juve-
nile, single, belonging to the low socioeconomic status, or drug
addicts. Suicides commonly noted in their second trimester of
first pregnancy. Poisoning is the most common method adopted
by the pregnant women (1).
Folic acid is prescribed for pregnant women in their first tri-
mester to prevent neural tube defects in the fetus (2). Folic acid
tablets are relatively safe with wide therapeutic margin. Acute
toxicity is uncommon due to consumption of large doses, which
manifest as gastrointestinal disturbance and central nervous sys-
tem features, which are reversible (25). Chronic toxicity is seen
in patients with pernicious anemia on folic acid drugs. However,
neither acute nor chronic toxicity is rarely fatal. Death due to
consumption of large doses of folic acid has not been reported
in the literature (2,3). We highlight a case of death in pregnant
women due to folic acid poisoning and its complication.
Case Report
A 23-year-old female consumed 3040 white-colored tablets
following a family dispute. The patient presented in a state of
shock with the rigid abdomen. There was no history of the
deceased suffering from typhoid, tuberculosis or cancer, or use
of any medications such as NSAIDs. The patient was clinically
diagnosed to have gastrointestinal perforation with metabolic aci-
dosis. However, the exact details of the drug consumed were not
available; the victim was treated for an iron overdose, based on
clinical and laboratory investigation. The patient survived for
36 h in total and expired despite treatment.
At autopsy, there was no evidence of any external injury. The
abdomen had one liter of blood-tinged fluid mixed with pus.
Two ileal perforations of size 1 cm diameter, separated by a dis-
tance of 4 cm, and placed 42 cm proximal to the ileocaecal
junction with the intestinal mucosa being hemorrhagic were
found (Fig. 1). The stomach contained 100 mL of brown-colored
fluid along with an intact white-colored tablet; the gastric
mucosa is hemorrhagic (Fig. 2). The tablet was recovered and
preserved for toxicological analysis. The liver showed yellowish
discoloration, and the kidneys were congested. A male fetus with
a crown-heel length of 29 cm and weight 650 g with red,
wrinkled skin was present in the uterine cavity.
Sections from the liver, kidney, gastric mucosa, loop of the
intestine with the perforation site, and mesentery were sent for
histopathological examination. Histopathology reports of liver
showed submassive hepatic necrosis. Kidney showed massive
acute tubular necrosis (50%), with inflammatory infiltrate in
interstitium evident of subcortical infarction. Gastric wall
showed erosion of lining epithelium with lympho-plasmacytic
infiltrate. Perforation site showed extensive ulceration of the lin-
ing epithelium with dense fibrinous exudates involving the full
thickness of intestinal wall and areas of ischemic infarction.
Mesentery shows areas of hemorrhagic infarction. Toxicological
analysis report of the viscera (stomach, intestine, liver, and kid-
ney) detected folic acid. Half of tablet recovered from the stom-
ach was found to be folic acid tablet. When the clinical,
pathological, and histopathological findings were suggestive of
iron poisoning, toxicology analysis was positive for folic acid.
Hence, the above-reported histopathological features may be due
to the unique toxic effects of folic acid, with no literature data
available to substantiate, may be first of its kind to be reported
in the literature.
Discussion
Folic acid is available as monocomponent tablets or in combi-
nation with other vitamins and minerals. Strengths usually
1
Department of Forensic Medicine and Toxicology, Jawaharlal Institute of
Postgraduate Medical Education and Research (JIPMER), Puducherry
605006, India.
2
Scientific Officer, Regional Forensic Science Laboratory (Villupuram),
605602, Tamil Nadu, India.
Received 20 Jan. 2017; and in revised form 2 Feb. 2017; accepted 6 Feb.
2017.
1©2017 American Academy of Forensic Sciences
J Forensic Sci,2017
doi: 10.1111/1556-4029.13489
Available online at: onlinelibrary.wiley.com
available are 100 lg, 250 lg, 400 lg, 800 lg, 1 mg, and
5 mg. Folic acid is absorbed in the proximal portion of the
small intestine following oral administration. (6) Blood folate
level reaches peak activity after oral administration within
3060 min. Average folate concentrations in plasma range
from 9 to 45 nmol/L, and concentrations below 9 nmol/L are
considered folate deficient (6). Enterohepatic circulation of
folate has been demonstrated and is mainly concentrated in
the liver (7).
Oral folic acid usually is not toxic. Even with doses as high
as 15 mg/day, there have been no substantiated reports of side
effects. There are few reported cases of severe allergic reactions
characterized by nausea, vomiting, itching, erythema bron-
chospasm, hypotension, and shock. Undesirable gastrointestinal
and central nervous system effects have also reported. But in
none of the above cases, the fatality was not reported. (25)
From 1998 to 2003, Texas Poison Centre received 650 cases
involving folic acid as a single-ingredient product. Of which,
55% were human exposure and 94.8% had no adverse effects
(8). There is only one reported case of pregnant women who
committed suicide by consuming folic acid at the dose of 120
150 mg. However, there were no toxic effects reported in either
the mother or the fetus in the above case (9). In this instance,
the fatality was following consumption of 3040 tablets, lead-
ing to small intestine perforation, substantiated by the fact that
folic acid absorption is maximum in the small intestine. There
is one reported case of small intestine perforation following
folic acid tablet consumption according to FDA (10). In this
case, the perforation is mostly likely due to the local effect of
the drug. Submassive hepatic necrosis was present which is
due to enterohepatic circulation of folic acid and its metabo-
lism in the liver (8). Common cause for acute hepatic necrosis
is drugs/toxins, and folic acid was detected in liver, strongly
supporting that hepatic necrosis is due to folic acid. Acute
tubular necrosis has been demonstrated in experimental mice
following administration of folic acid in various studies, coin-
ciding with the finding of massive acute tubular necrosis in
this case (11,12).
Toxicological analysis was extensively carried out in this sam-
ple. Initial tests were carried out in line for iron, and all tests
were negative for iron, including atomic absorption spectrometry
(AAS) being the confirmatory test for iron. Subsequently, the
test sample in UV spectrophotometer gave a peak at 283 nm
indicative of folic acid. Following which a thin-layer chromatog-
raphy was performed, and the plate viewed under UV and folic
acid appeared as dark zone under 254 nm. There are many ana-
lytical data regarding folic acid detection in pharmaceutical folic
acid preparation and samples. The results of these many analyti-
cal data matched with our test results (13). With all the available
toxicological technique, the tests were carried out, and folic acid
was detected in stomach, liver, kidney, blood, and in the tablet
recovered from the stomach. Based on the clinical features,
autopsy findings, and histopathological features of this case, sup-
ported by a toxicological analysis report, we concluded that the
death was due to fatal folic acid poisoning and complications
thereof.
Conclusion
The present case, after a complete workout, turned out to be a
case of folic acid poisoning. With a scant literature available to
back up the folic acid poisoning, we conclude that acute folic
acid ingestion can also be fatal, based on this case findings.
Hence, the above-reported histopathological findings and autopsy
findings may be unique manifestations of folic acid poisoning in
humans.
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FIG. 2–– Stomach containing an intact white-colored tablet even after
stomach wash, with hemorrhagic mucosa.
FIG. 1–– Perforation site shows extensive hemorrhage and ulceration.
2JOURNAL OF FORENSIC SCIENCES
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Additional information and reprint requests:
Gerard Pradeep Devnath, M.B.B.S.
Department of Forensic Medicine and Toxicology
Jawaharlal Institute of Postgraduate Medical Education and Research
(JIPMER)
Puducherry-605006
India
E-mail: drgerardfm@gmail.com
G. P. DEVNATH ET AL. .FOLIC ACID TOXICITY IN HUMANS 3
... In many countries, during maternal/fetal health programs; medicines such as iron, folic acid, vitamin D are given free of charge. Although many of these drugs are given as replacement therapy, they are known to have serious effects at toxic doses [12,18,26]. Acute iron and folic acid toxicity in pregnancy are relatively well-known because they are more common, and cases with a different course from asymptomatic to mortal course have been reported [12,21,26]. ...
... Although many of these drugs are given as replacement therapy, they are known to have serious effects at toxic doses [12,18,26]. Acute iron and folic acid toxicity in pregnancy are relatively well-known because they are more common, and cases with a different course from asymptomatic to mortal course have been reported [12,21,26]. The fact that these drugs are free and easy to access may cause them to be preferred frequently for SA, and it was observed that they were used at a high rate (20%) in our series too. ...
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