Alanine amino transferase_concentrations_are.17

Journal of Pediatric Gastroenterology and Nutrition
43:234Y239 August 2006 Lippincott Williams Wilkins, Philadelphia
Alanine Amino Transferase Concentrations Are Linked to
Folate Intakes and Methylenetetrahydrofolate Reductase
Polymorphism in Obese Adolescent Girls
*†Marie-Laure Frelut, ‡Nathalie Emery-Fillon, §Jean-Claude Guilland, kHunh Han Dao,
and ¶Genevie`ve Potier de Courcy
*Pediatric Therapy Center, 95580 Margency, France; ÞPediatric Endocrinology, Saint Vincent de Paul Hospital, University of
Paris 5, Paris, France; þBiochemistry Department, University Hospital, Vandoeuvre-le`s-Nancy, France; §Physiology Department,
University Hospital, Dijon, France; kRheumatology Department, Pitie´ Salpeˆtrie`re University Hospital, AP-HP, Paris, France;
and ¶INSERM U557, Scientific and Technical Institute for Food and Nutrition, ISTNA-CNAM, Paris, France
ABSTRACT
Objective: The objective of this study was to investigate the
consequences of low dietary folate intake and the impact of
the 677 CYT methylenetetrahydrofolate reductase (MTHFR)
common mutation on liver function in obese adolescents.
Methods: Fifty-seven obese girls (BMI = 36.1 T 6.0 kg/m2)
aged 14.1 T 1.5 years were included before starting a weight
reduction program. Dietary intakes for folate were assessed by
means of an adapted food frequency questionnaire (n = 50).
Liver enzymes, plasma lipids, glucose metabolism parameters,
ferritin, homocysteine and erythrocyte folate content were
measured in plasma or blood obtained under fasting con-ditions.
The MTHFR 677 CYT polymorphism, which is
associated with decreased enzyme activity, was determined
using PCR. Body composition was assessed using dual x-ray
absorptiometry.
Results: Twenty-three subjects were heterozygote (CT) for the
mutation and 5 were homozygote (TT). An increase in alanine
amino transferase (ALT) and ALT/aspartate aminotransferase
ratio was associated with the mutation (F = 4.46, P = 0.016 and
F = 5.92, P = 0.0049, respectively). Alanine amino transferase
was correlated negatively to folate intake (r = j0.32, P =
0.024) (n = 50) and positively to homocysteine concentrations
(r = 0.30, P = 0.025). Body composition was similar among
the 3 genotypic groups. Ferritin was also correlated to ALT
concentrations of the entire group (P = 0.009).
Conclusion: Our data suggest that folate intake and the
MTHFR polymorphism represent a part of the link between
antioxidant status and liver disease in obese adolescent girls.
JPGN 43:234Y239, 2006. Key Words: ObesityVAdolescentsV
LiverVFolateVHomocysteineVMethylenetetrahydrofolate
reductase. 2006 Lippincott Williams Wilkins
INTRODUCTION
The risk of nonalcoholic fatty liver disease (NAFLD)
is 4.6-fold higher in obese adults with a BMI more than
30 kg/m2 (1). In children and adolescents, 6% of
overweight and 10% of obese adolescents have been
reported to have elevated serum alanine aminotransfer-ase
(ALT) levels (2), whereas up to 35% of the whole
group have steatosis when assessed by ultrasound (3).
The fatty liver condition is thus acknowledged as an
increasing clinical problem in childhood obesity (4).
Magnetic resonance imaging revealed that abnormalities
in serum ALT occur exclusively in the most severe
cases of fatty liver (5), which could lead to severe
fibrosis and end-stage liver disease, even in children
(5Y13). Thus far, however, weight reduction is the only
clearly identified factor that leads to liver function
improvement in children (14,15) and adults (16),
although supplementing vitamin E (17) may also play
a role. The molecular events that result in hepatic
steatosis and liver injury are thought to result from a
Btwo hit^ phenomenon. The first hit consists of
deposition of triglycerides (TG) in the hepatocytes. For
the disease to progress, a Bsecond hit^ is required that
promotes inflammation, cell death and fibrosis that are
the hallmark of nonalcoholic steatohepatitis (NASH).
Antioxidants are therefore putative protective factors
against the progression from simple fat accumulation
to more severe conditions (18). However, conflicting
results have been published regarding a link with
glucose and lipid metabolism: Elevated TG and gly-cated
haemoglobin (2) and hyperinsulinemia (12,13)
have been reported by some authors, whereas responses
to oral glucose tolerance tests were found similar among
obese children with or without increased ALT concen-trations
(3). Ferritin has also been reported to be a major
Received March 9, 2005; accepted April 5, 2006.
Address correspondence and reprint requests to Marie-Laure Frelut,
MD, Pediatric Therapy Center, Obesity Unit, 18 rue Roger Salengro,
PO Box 6 95580, Margency, France (e-mail: frelut@club-internet.fr).
234
Copyr ight © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

ALT ARE LINKED TO FOLATE INTAKES AND MTHFR POLYMORPHISM 235
determinant of NAFLD in association with insulin
resistance in apparently healthy obese adults (19).
Nutritional factors that could contribute to increasing
the risk level in children are decreased plasma concen-trations
of vitamins E, A-carotene, vitamin C with
antioxidant properties and even modest alcohol consump-tion
(2). In animal models, folate depletion and elevated
plasma homocysteine (Hcy) promote oxidative stress in
the liver (20), whereas in adults suffering liver cirrhosis,
Hcy has been shown to induce cellular toxicity and to
play a role in the development of liver fibrosis (21).
Food consumption patterns in the general population
of French children and adolescents are currently shifting
toward higher fat and sugar intakes (22). Obese
adolescents often report a dislike of fruits and vegeta-bles
and a preference for high-carbohydrateYhigh fat
diets (23). Fruit and vegetables bring significant
amounts of not only antioxidants and fibers but also
folic acid (24).
Tetrahydrofolate and its derivatives are the biolog-ically
active forms of folic acid. They function as
cosubstrates for a variety of enzymes associated with
one-carbon metabolism. 5,10-Methylenetetrahydrofolate
(MTHF) is a hydroxyl methyl group donor for thymi-dylate
synthase and hence plays an important role in cell
division through nucleic acid (purines and pyrimidine)
synthesis. The 677 CYT missense mutation of the
MTHF reductase (MTHFR) decreases its activity by
approximately 20% and enhances the accumulation of
Hcy (25), an independent cardiovascular risk factor
(26). We previously reported that in France, approxi-mately
16% of the population living in the suburbs of
Paris is homozygote (TT) for this mutation (27).
We hypothesized that liver damage in obese adoles-cents
might be enhanced by poor folate status or altered
folate metabolism. The objective of this study was to
examine whether folate consumption and biological
status may be determinants of altered liver function in
severely obese adolescents.
MATERIALS AND METHODS
Fifty-seven girls who were admitted in our unit to inves-tigate
their health status before entering a weight reduction
program were included. Investigations were performed accord-ing
to the Helsinki 2 declaration. All participants were
provided a detailed information on the purpose of the study.
The parents and the adolescent signed an informed consent
form approved by the Medical Ethics Committee of Robert
Debre´ University Hospital. Folate intakes were evaluated in 50
out of 57 subjects using an adapted food questionnaire
developed by our team as previously detailed. In 5 subjects,
for whom no parental control was obtained, data were not
used. Data were also missing in 2 other subjects. In the survey,
the folate content of edible portions of 7 categories of food
(vegetables, fruit, starchy foods, fish and meat, eggs, cheese,
other dairy products) was analyzed and an adjustment made
according to the average food patterns of the French
population. This allowed us to estimate folate intakes and to
detect high-risk subjects, that is, those who eat food with high
folate content less than twice per week (28). Blood samples
were taken by venous puncture in fasting conditions after an
overnight fast. Erythrocyte folate (EF) content, which reflects
folate body stores, was measured by a microbiological
method, as previously detailed (27,28). Methylenetetrahydro-folate
reductase polymorphism was determined by PCR as
previously reported (27,29). Plasma Hcy was measured by
HPLC (Biorad laboratories, Marnes-la-Coquette, France).
Liver damage was evaluated by serum levels of aspartate
aminotransferase (AST), ALT, gamma glutamyl transferase
(FGT), alkaline phosphatase (AP) and 5¶ nucleotidase (30),
and lipids were measured using a Hitachi 911 automat.
Alanine amino transferase and AST were measured using
Randoxi, FGT and AP using Roche Diagnostici and 5¶
nucleotidase was measured using BioMe´rieuxi respective
methods. Total cholesterol and TG were measured by
enzymatic methods (CHOD PAP and GPO PAP, respectively,
Rochei). High-density lipoprotein cholesterol (HDL-C) was
measured using a corresponding nonprecipitating method.
Low-density lipoprotein cholesterol (LDL-C) concentrations
were calculated using the Friedewald formula (LDL-C = Total
cholesterol - HDL-C - TG/5) (31). Plasma glucose concen-trations
were measured using the glucose oxidase method and
fasting insulin concentration by radioimmunoassay using a
double antibody method. Insulin resistance was estimated
using the homeostasis model assessment of insulin sensitivity
(HOMA IR = insulin (U/mL) glycemia (mmol/L)/22.5),
which has been shown to mirror the glucose clamp technique
in the assessment of insulin sensitivity. A higher HOMA IR
score reflects a greater degree of insulin resistance (32).
Glycated haemoglobin (HbA1c) was measured by chromato-graphic
method. Ferritin was measured by immunological
assay (TINA QUANT Ferritin, Roche). Body composition was
assessed using dual x-ray absorptiometry by means of a
Hologic QRD 1000/Wi device (version 5.11, Hologic, Inc.,
Waltham, Mass). Statistics were performed using Statview 5
(Abacus Concept, Inc., Berkeley, Calif). The effect of MTHFR
was analyzed using ANOVA. P values for trends were
calculated using the post hoc Bonferroni/Dunn test. Correla-tions
were calculated using Fisher r coefficient, and unpaired
comparisons were performed using Student t test. Significance
level was set at 0.05.
RESULTS
Age, anthropometrical characteristics and body com-position
data are shown in Table 1 as a function of the
genotype of the MTHFR polymorphism. Five subjects
were homozygote (TT) and 23 were heterozygote (CT)
for the mutation. Mean ages, anthropometrical and body
composition measures did not differ between the 3
genotypes. Biological characteristics are shown in Table
2. Parameters of the lipid metabolism and of glycore-gulation
did not differ among the 3 groups. As expected,
mean insulin values were slightly above the reference
value of our laboratory (15 IU/mL), whereas all other
mean values remained within normal range.
J Pediatr Gastroenterol Nutr, Vol. 43, No. 2, August 2006

236 FRELUT ET AL.
Mean folate intake, which ranged from 104 to 412Kg/d,
did not differ (P = 0.12) among the 3 groups and are
below national recommended allowances (300 Kg/d) in
43 (80%) subjects (33). Erythrocyte folate was corre-lated
neither to BMI (P = 0.18) nor to ferritin (P = 0.23).
Alanine amino transferase levels were above the
upper limit of 50 IU/mL in 3 subjects (1 CC, 2 CT
subjects). Mean ALT concentrations were increased
significantly in subjects displaying the mutation TT (F =
4.46, P = 0.016). 5¶ Nucleotidase was also marginally
increased (F = 3.11, P = 0.054), whereas AP plasma
concentrations did not differ. Alanine amino transferase
concentrations were not correlated to abdominal fat
mass (FM) (P = 0.50). Ferritin concentrations were
G200 ng/mL in all subjects and did not differ among the
3 groups. However, calculation of P for trend showed
that mean insulin levels were higher in the TT than in
the CC group (P = 0.012), and ferritin levels were
higher in the CT than in the CC subjects (P = 0.011).
Antibodies to hepatitis A or C and cytomegalovirus
were checked only in patients with elevated ALT and
found to be negative in all cases. We also verified
individual records on the absence of any past vacci-nations
against hepatitis B before entering the program.
No patient had a history of liver dysfunction.
Erythrocyte folate (P = 0.12) and Hcy (P = 0.15)
were similar in the 3 groups, with the exception that EF
was significantly lower in TT subjects when compared
with CC subjects (t = 2.28, P = 0.027). Alanine amino
transferase concentrations were negatively correlated to
folate intake (r = j0.32, P = 0.024) as shown in Figure
1, positively correlated to both Hcy (Fig. 2; r = 0.30,
P = 0.029) and ferritin concentrations (data not shown;
r = 0.57, P = 0.0007). When multiple regression is
performed between ALT on one hand and ferritin, Hcy
and EF on the other, as shown in Table 3, ALT is linked
with ferritin (P = 0.009) and Hcy (P = 0.039), whereas a
nonsignificant trend is found with EF (P = 0.16). Simple
regression shows that ferritin and insulin are marginally
correlated (r = 0.33, P = 0.052).
DISCUSSION
This is the first report in obese girls of high levels of
ALT associated not only with a low intake of folate, a
major methyl donor nutrient with antioxidant properties,
but also with a common mutation in a key enzyme of
folate metabolism, the 677 CYT mutation of MTHFR.
The frequency (9%) of the TT genotype, slightly below
that reported for a large sample (16%) of adults in the
same area (27), is likely to be due to our sample size.
Anthropometrical measurements and folate intake did
not differ between the 3 genotypes. Obese adolescents
have been shown to often underreport low-quality food
(34). Our food frequency questionnaire did not focus on
energy intake, but rather on categories of foods
classified according to their folate content, and were
completed with the help of a dietician and of the mother
of the adolescent, all of whom were advised of the
purpose of the study. Underreporting is thus unlikely to
provide an explanation for these findings. Careful
attention had also been paid to alcohol consumption,
which could be ruled out in this population of girls.
Gamma GT was normal in all and did not differ among
the genotypes (data not shown).
Alanine amino transferase concentrations reveal liver
injury in a more consistent way than do AST, which is
also present in striated muscle. 5¶ Nucleotidase reveals
TABLE 2. Biological characteristics of obese girls as
a function of the MTHFR polymorphism for the
677 CYT mutation
CC (n = 29) CT (n = 23) TT (n = 5)
ALT, IU/mL 20 T5 23 T8 34 T 11*
AST, IU/mL 22 T5 23 T8 26 T 11
AP, IU/mL 131 T 78 146 T 77 127 T 56
5¶ Nucleotidase, IU/mL 3.0 T 1.7 3.6 T 1.6 5.2 T 2.3†
Insulin, IU/mL 17.0 T 12.4‡ 19.6 T 9.3 24.2 T 17.0
Glycemia, mmol/L 4.42 T 0.53 4.53 T 0.48 4.62 T 0.81
HOMA IR 3.53 T 2.87§ 4.01 T 2.13 4.73 T 3.17
HbA1c, % 5.3 T 0.5 5.2 T 0.6 5.2 T 0.5
Triglycerides, mmol/L 0.93 T 0.37 0.96 T 0.30 1.14 T 0.50
Cholesterol, mmol/L 4.60 T 0.34 4.42 T 0.83 5.27 T 1.60
HDL-C, mmol/L 1.60 T 0.78 1.37 T 0.36 1.09 T 0.13
LDL-C, mmol/L 2.61 T 0.57‡ 2.73 T 0.620 3.46 T 1.73
EF, Kg/L 264 T 65 263 T 104 177 T 80
Hcy, Kmol/L 6.3 T 1.8 5.7 T 2.0 7.9 T 4.6
Ferritin, ng/mL 38 T 20 60 T 38 46 T 14
Results are expressed as mean T SD.
*ANOVA for ALT: F = 4.46, P = 0.016.
***ANOVA for ALT/AST: F = 5.92, P = 0.0049.
†ANOVA for 5¶ nucleotidase: F = 3.11, P = 0.054.
‡P for trend: P = 0.012 between CC and TT subjects for insulin and
LDL-C.
§P for trend: P = 0.067 for HOMA IR.
P for trend: P = 0.011 between CC an CT subjects for ferritine.
ALT, alanine amino transferase; AP, alkaline phosphatase; AST,
aspartate aminotransferase; EF, eythrocytic folate; HOMA IR,
homeostasis model assessment of insulin sensitivity; Hcy,
homocysteine.
TABLE 1. Characteristics and body composition data in
obese girls as a function of the polymorphism of the MTHFR
for the 667 CYT mutation
CC (n = 29) CT (n = 23) TT (n = 5)
Age, y 14.5 T 1.2 14.2 T 1.7 14.7 T 1.3
Weight, kg 100.9 T 20.2 95.8 T 23.6 96.3 T 18.1
Height, m 1.65 T 0.08 1.62 T 0.12 1.64 T 0.05
BMI, kg/m2 37.8 T 6.7 36.4 T 7.1 35.9 T 6.2
Total FM, kg 40.1 T 15.3 39.9 T 17.2 36.1 T 8.7
Total LM, kg 51.5 T 8.3 47.8 T 8.4 51.2 T 13.7
Abdominal FM, kg 17.5 T 8.0 17.4 T 7.3 15.7 T 4.4
Folate intakes, Kg/d 242 T 78 240 T 76 218 T 75
Results are expressed as mean T SD. All comparisons (ANOVA)
were not significant.
FM, fat mass; LM, lean mass.

cholestasis or biliary obstruction in a highly specific
way (30). The increase in ALT beyond the upper
references of our laboratory in 3 subjects is consistent
with the slight increase in the 5¶ nucleotidase (P =
0.054) in CT and TT genotypes, although the concen-trations
of the latter enzyme remained within normal
range. Increased ALT concentrations in obese children
(3) and in adults with ALT/AST ratio 91 (1) have been
reported as a criteria of risk of severe fibrosis in NASH.
However, ALT is the key liver enzyme that allows the
reversible transamination of alanine to pyruvate, which
can be further degraded to acetyl CoA. Alanine acts,
therefore, as a source of carbon and energy within the
glucose-alanine cycle that allows gluconeogenesis.
Intracellular concentrations of ALT may thus be
modulated by the metabolic conditions. Obesity is
characterized by an insulin resistant state. Patients
suffering NAFLD have been shown to have specific
metabolic abnormalities, namely, a more marked hyper-insulinemia
and resistance to the insulin-mediated
suppression of lipolysis (12). An enhanced production
of glucose and a conversion rate of glucose to pyruvate
under the action of increased concentrations of insulin
may, in turn, result in an increased ALT activity.
Cysteine, which derives from Hcy, can also be con-verted
to pyruvate. Intracellular concentrations of ALT
may be further modulated by the accumulation of Hcy
that results from the MTHFR 677 CYT mutation. The
link between a hypothesized alteration of intracellular
and plasma ALT concentrations would still have to be
fully demonstrated (35).
Therefore, additional studies that would include
histopathological assessment, follow-up and assessment
of the impact of weight loss are required to determine the
predictive value and sensitivity of the early elevation of
each criteria (1) and to improve the biological assess-ment
of liver disease severity in this population as has
been recently stated (36).
Similar levels of obesity and similar total and
segmental body compositions strongly suggest that
neither increased total FM nor trunk FM is sufficient
to individually explain the degree of abnormal liver
function, although dual x-ray absorptiometry has shown
some limitations in analyzing body composition in this
population of severely obese adolescents, as we have
shown previously (37).
Although the increase in insulin levels and HOMA IR
values were similar among the 3 genotypes, basal
insulin concentrations tended to be higher in TT than
in CC subjects (P = 0.01). Insulin resistance has been,
thus far, identified in obese adults as a major risk factor
of NASH (1,19). The reduction of the ability of insulin
to suppress lipolysis and the release of VLDL by the
liver(1,18) would lead to higher free fatty acid and TG
content in hepatocytes. However, additional factors are
required to explain the heterogeneity of the disease such
as oxidative stress and its modulation.(1,2,4,17Y19,21)
We also found that ferritin was highly correlated to
ALT (P = 0.009), but not to BMI (P = 0.70) nor to EF
(P = 0.16), whereas its correlation with insulin was only
marginal (P = 0.053). Plasma ferritin concentrations are
not only directly proportional to intracellular ferritin
concentrations and iron stores (38) but also a marker of
inflammation (39). Indeed, obesity can be considered an
inflammatory condition (40). In rats fed diets varying in
folate concentrations, the Fe2+-induced lipid peroxida-tion
of liver homogenates had the strongest correlation
with folate-depletion variables (20). Whether increased
ferritin concentrations would enhance liver damage
because of increased oxidant stress of iron is still a
matter of debate (36,39). Recent data suggest that in a
group of adults with a low prevalence of obesity, who
are suffering NASH, increased ferritin levels are
markers of severe histological damage but not of iron
overload (39). In obese but otherwise healthy adults,
FIG. 1. Correlation between folate intakes and plasma ALT
concentrations (r = j0.32, P = 0.024). ALT, alanine amino
transferase.
FIG. 2. Correlation between plasma ALT and Hcy concentrations
(r = 0.30, P = 0.025). ALT, alanine amino transferase; Hcy,
homocysteine.

238 FRELUT ET AL.
both insulin resistance and ferritin are independent
major contributors to NAFLD (19). In this group of
obese but otherwise healthy population of adolescents,
we did not measure other markers of inflammation.
Blood counts were within normal range and the food
frequency questionnaire was indicative of standard meat
consumption for all subjects.
Therefore, focusing on antioxidant consumption and
status has a major potential interest in the young. Data
in children are scarce and still conflicting but underline
the protective effect of vitamins E and C, which have
strong antioxidant properties (2,17).
Nevertheless, folate metabolism in humans remains
poorly understood (41). In animals, folate depletion and
elevated plasma Hcy have been shown to promote
oxidative stress in the liver by decreasing Zn-Cu super-oxide
dismutase and gluthatione peroxidase activities.
This results in an increased lipid peroxidation in the liver
(20). The links between folate and glucose metabolism
are derived, so far, from 2 sets of data obtained in
animals that need to be confirmed: as stated before,
intracellular methylation seems to be important to allow
the neoglucogenesis derived from the reutilization of Hcy
(40). Low folate intakes markedly alter exocrine pancre-atic
function (41), but no data are available on pancreatic
endocrine function. The conversion of Hcy into methio-nine
requires the methyl group to be transferred from
MTHF after its reduction by MTHFR (42). Higher levels
of serum Hcy had been reported in the general
population in children with low serum levels of folic
acid and among nonusers of multivitamin supplements
(43). In adults, mean Hcy levels were 18% lower among
persons who used vitamin B supplements (44). In obese
girls, insulin seems to also be an independent risk factor
of hyperhomocysteinemia (45). Data from animal
studies also suggest that Hcy could play an additional
role in oxidative stress instead of being a simple
indicator of decreased MTHF production (20).
Children suffering strokes have also been found to
have lower folate intakes. This group was shown to
have a higher frequency of TT genotype for the 677
CYT mutation of the MTHFR. A negative correlation
between Hcy and folate intake was also reported in this
study (46).
In conclusion, our data suggest that in this population
of young obese girls, low folate intakes and MTHFR
polymorphism are additional factors that may increase
the relative contribution of oxidant stress on liver
alteration. Further studies are required to confirm this
hypothesis both from a histological point of view and
also on a long-term basis. So far, only weight reduction
(14Y16) and vitamin E (17) have been demonstrated to
reduce ALT levels in obese children, whereas ursodeox-ycholic
acid therapy proved to be unsuccessful (47).
These data also provide arguments for a potential
additional link that should be further explored between
cardiovascular risk, eating pattern and genetic back-ground
(26). Folate intakes and the impact of the
common 677 C Y T MTHFR mutation require further
investigation for the understanding and management of
obesity and its short- and long-term complications in
children and adolescents.
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TABLE 3. Multiple regression analysis of the influence of
ferritin, Hcy and EF on ALT in obese girls
N = 57 A (slope) SE P Adjusted R2
Dependent variable
ALT 0.27
Independent variable
Ferritin 0.40 0.062 0.008
Hcy 0.29 0.78 0.040
EF 0.20 0.020 0.16
ALT, alanine amino transferase; EF, eythrocytic folate; Hcy,
homocysteine.

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