5th Amino Acid Assessment Workshop

Adequate Range for Sulfur-Containing Amino Acids and Biomarkers for

Their Excess: Lessons from Enteral and Parenteral Nutrition1
Marcel C. G. van de Poll,2 Cornelis H. C. Dejong,2 and Peter B. Soeters3
Department of Surgery, University Hospital Maastricht and Nutrition and Toxicology Research Institute
Maastricht (NUTRIM), University Maastricht, Maastricht, the Netherlands

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ABSTRACT The adequacy range of dietary requirements of specific amino acids in disease states is difficult to
determine. In health, several techniques are available allowing rather precise quantification of requirements based on
growth of the organism, rises in plasma concentration, or increases in the oxidation of marker amino acids during
incremental administration of the amino acid under study. Requirements may not be similar in disease with regard to
protein synthesis or with regard to specific functions such as scavenging of reactive oxygen species by compounds
including glutathione. Requirements for this purpose can be assessed only when such a function can be measured
and related to clinical outcome. There is apparent consensus concerning normal sulfur amino acid (SAA) re-
quirements. WHO recommendations amount to 13 mg/kg per 24 h in healthy adults. This amount is roughly doubled
in artificial nutrition regimens. In disease or after trauma, requirements may be altered for methionine, cysteine, and
taurine. Although in specific cases of congenital enzyme deficiency, prematurity, or diminished liver function, hy-
permethionemia or hyperhomocysteinemia may occur, SAA supplementation can be considered safe in amounts
exceeding 2–3 times the minimal recommended daily intake. Apart from some very specific indications (e.g.,
acetaminophen poisoning), the usefulness of SAA supplementation is not yet established. There is a growing body of
data pointing out the potential importance of oxidative stress and resulting changes in redox state in numerous
diseases including sepsis, chronic inflammation, cancer, AIDS/HIV, and aging. These observations warrant con-
tinued attention for the potential role of SAA supplementation. In particular, N-acetylcysteine remains promising for
these conditions. J. Nutr. 136: 1694S–1700S, 2006.

KEY WORDS:  glutathione  deficiency  N-acetylcysteine supplementation

The importance of adequate amino acid intake is unequiv-
ocal. Insufficient intake of specific amino acids can lead to
functional deficiencies, but high plasma levels of some amino
acids may have detrimental effects. To furnish an optimal amino
acid mixture remains a challenge also because the requirements
for amino acid intake are determined by many factors including
age, liver function, renal function, and catabolism caused by
disease or trauma. Moreover, amino acids are generally not in-
gested or administered as free amino acids but rather as protein
or short-chain peptides after protein hydrolyzation. Adequacy of
amino acid intake is not simply determined by the amount that
actually enters the body.
1
Published in a supplement to The Journal of Nutrition. Presented at the
conference ‘‘The Fifth Workshop on the Assessment of Adequate Intake of Dietary
Amino Acids’’ held October 24–25, 2005 in Los Angeles. The conference was
sponsored by the International Council on Amino Acid Science (ICAAS). The
organizing committee for the workshop and guest editors for the supplement were
David H. Baker, Dennis M. Bier, Luc Cynober, Yuzo Hayashi, Motoni Kadowaki,
and Andrew G. Renwick. Guest editors disclosure: all editors received travel
support from ICAAS to attend workshop.
2
MCGvdP (920-03-317 AGIKO) and CHCD (907-00-033 Clinical Fellowship)
are recipients of grants from The Netherlands Organization for Health Research
and Development.
3
To whom correspondence should be addressed. E-mail: PB.Soeters@ah.
unimaas.nl.
The balance among protein, carbohydrates, trace elements,
and other macronutrients in the feed, as well as the feeding
frequency and modus (bolus feeding or continuous artificial
feeding), determine to a large extent the efficacy of amino
acid utilization to serve protein synthesis and maintenance or
growth of cellular mass (1). After enteral ingestion, protein is
broken down to its constituent amino acids within the gut.
While still in the gut, these amino acids can be utilized for
protein resynthesis, which facilitates a gradual release of amino
acids in the portal vein (2). Protein thus residing in the gut is
referred to as the labile protein pool. Protein with an amino acid
composition that allows resynthesis of protein after digestion
to amino acids while still in the gut is considered to be of high
biological value because it releases its constituent amino acids
to the liver and the rest of the body more gradually than protein
with a low biological value (1–5). The more gradual this
‘‘autoinfusion’’ of amino acids from the labile protein pool, the
more efficiently the amino acids can be used in functional met-
abolic processes, and less amino acids are ‘‘lost’’ to ureagenesis
(2,6).
After enteral administration most amino acids are subject to
first-pass extraction (7,8). The supposed influence of splanch-
nic extraction on sulfur amino acid requirements in enteral
versus parenteral nutrition (9) remains unclarified because
amino acids extracted by the gut may actually serve intestinal

0022-3166/06 $8.00 Ó 2006 American Society for Nutrition.

1694S
 SULFUR AMINO ACID ADEQUACY
metabolism; likewise, parenterally administered amino acids
may be extracted similarly after reaching the gut through the
circulation.
Various methods to assess requirements of specific amino
acids have been proposed (10). Obviously recommendations based
on these different approaches are variable, and the external
validity of these experiments may be hampered by the small
sample size that is generally applied, leading to large confidence
intervals (11). Most importantly, these experiments are conducted
in healthy volunteers and are aimed at the general population.
However, specific amino acid requirements are altered in
disease (12), and recommendations for the general population
may not be valid in situations in which the adequacy of the
amino acid or protein component of the diet may be crucial to
sustain body composition and function. Because there is no
tailor-made recipe for amino acid supplementation in various
disease states, biomarkers for the adequacy of specific amino
acids are needed to monitor amino acid supply. Such biomarkers
should be based on physiological functions of the amino acid in
question and should preferably be suitable to reflect excess as
well as deficiency.
This review concerns the adequacy of dietary provision of
the sulfur-containing amino acids (SAA)4 methionine and
cysteine with a special focus on potential biomarkers of
their deficiency or excess.
SAA metabolism
Methionine and homocysteine. Methionine breakdown
occurs by transmethylation to homocysteine (13). The first
step in this pathway is the conversion of methionine to
S-adenosylmethionine, which can donate its methyl group for
numerous methylation processes including DNA methylation.
Separation of the methyl group yields S-adenosylhomocysteine,
which can be converted to homocysteine. Homocysteine can
be remethylated to methionine by the folate- and vitamin
B-12-dependent enzyme methionine synthetase or enter the
irreversible transsulfuration pathway.
Transsulfuration. Homocysteine can donate its sulfur
group to serine, forming cystathionine under influence of the
vitamin B-6-dependent enzyme cystathionine synthetase. Cyst-
athionine can subsequently be broken down to cysteine and
a-ketobutyrate. During this 2-step process the homocysteine
sulfur group is transsulfurated to the serine carbon skeleton,
forming cysteine. Transsulfuration occurs preferentially in the
liver and the kidney (13). The plasma cysteine pool is quite
distinct from the intracellular cysteine pool. More than 95% of
protein-free cysteine in plasma is found in cysteine-cysteine di-
peptides (cystine) at a total cysteine concentration ([cysteine] 1 2
[cystine]) of ;180 mmol/L (14). Reduced cysteine in plasma is
primarily found in albumin that contains 1 free cysteine residue
with a free thiol group per molecule and accounts for 80% of the
free thiols in plasma (15). Cysteine (or cystine) is transported
into the cell by several sodium-dependent transporters with
a Km that exceeds the normal plasma level of cysteine ;2.5-
fold (16). Intracellular cysteine pools and fluxes can therefore
readily be modulated by supplemental cysteine (17,18). Intra-
cellularly most cyst(e)ine is found in its reduced form.
Intracellular total cyst(e)ine ([cysteine] 1 2[cystine]) concen-
trations range from 20 to 300 mmol/kg wet weight (19),
dependent on the affinity of the various transporters on
different cells (20). Cells with active cyst(e)ine metabolism
4
Abbreviations used: GSH, glutathione, GSSG, glutathione disulfide; SAA,
sulfur-containing amino acids.
1695S
such as intestinal, hepatic, and renal tubular cells generally
express high-affinity transporters and have higher cyst(e)ine
levels. Uptake of cyst(e)ine is also dependent on the extracel-
lular redox state.
GSH synthesis and metabolism. Most cysteine within the
cell is found in the tripeptide glutathione (GSH), which is
synthesized from glutamate, glycine, and cysteine and is found
in millimolar ranges. Its concentrations are highest in the
gastrointestinal tract and the liver (14). GSH can reduce
reactive oxygen species on oxidation to its disulfide GSSG and
form S-conjugates with electrophilic foreign compounds by the
GSH-S-transferase enzymes (21). In fact, all intracellular thiols
can form disulfide bridges, forming numerous redox couples,
but GSH:GSSG is by its abundance the most representative
and therefore most widely studied intracellular redox couple
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(22). Increased oxidative stress induces a right shift in the
GSH:GSSG ratio. GSSG can be reduced by the NADPH/
NADP1-dependent enzyme glutathione reductase to GSH to
restore the redox potential, but this activity can be inhibited by
decreased NADPH/NADP1 redox level, whereafter GSSG is
exported from the cell, to restore GSH redox state (23). This
leads to reduction of the cellular GSH pool, and hence the
cellular reductive potential becomes dependent on glutathione
de novo synthesis (24). Other GSH-S conjugates are also ex-
ported from the cell.
Taurine. Taurine is formed from cysteine via several en-
zymatic steps, of which the action of cysteine sulfonic acid
decarboxylase is believed to be rate limiting (25). Taurine is
involved in conjugation of bile acids and is as such subject
to enterohepatic cycling (26). Intracellular taurine levels are
maintained 50- to 100-fold higher than extracellular concen-
trations by active membrane transport through the taurine
transporter (25). This osmotic gradient contributes to the main-
tenance of cellular hydration state.
Normal daily sulfur amino acid requirements
Methionine is the only essential SAA and can provide sulfur
for cysteine and taurine synthesis. Animal protein is generally
considered to be a better source of SAA than vegetable protein.
This is primarily because the biological value of animal protein
is higher than that of vegetable protein (2,6). Soy, which is the
only vegetable protein used for artificial enteral nutrition, is also
low in absolute SAA content (6,27).
Increasing cysteine intake can reduce methionine require-
ments (28). From the classical experiments of Rose (29) in
healthy men, it was calculated that the minimal intake of
methionine required to maintain nitrogen balance is 1.10 g/d,
which comes down to ;13 mg/kg. This number was reproduced
TABLE 1
Daily sulfur amino acid requirements
Infants Preschool children Adults
Millward (30) 29 19 16
Di Buono (11) 13
Dewey (31) 27
Young (32) 13
FAO/WHO/UNU (33) 58 27 13
Mean daily requirement of sulfur amino acids (methionine1cysteine)
(mg/kg) according to different estimations. NB population safe require-
ments exceed the mean requirements by statistical definition of 2
standard deviations.
1696S SUPPLEMENT
in several other attempts to define SAA requirements (11,30–33)
(Table 1). In a recent study it was shown that this intake also is
sufficient to maintain glutathione synthesis in healthy volunteers
(34). In infancy and childhood, the dietary requirement for SAA
is higher (Table 1). The SAA derivative taurine is considered
(conditionally) indispensable in neonates and in growing chil-
dren, although this indispensability may (partly) depend on (lack
of) intestinal function. This issue is addressed below. At present,
taurine is a standard component in infant feeding formulas.
SAA requirements in elderly subjects are unknown, but it has
been suggested that the altered redox state reported in the elderly
(35–38) requires increased ingestion of SAA. In contrast, the safe
upper limit of chronic SAA supplementation may be reached
earlier in the elderly because of accumulation of homocysteine,
which is considered a risk factor for the development of athero-
sclerosis (36). Hyperhomocysteinemia may, however, be prevented
by adequate vitamin B and folate supplementation.
Biomarkers for adequate supply
A prerequisite for the definition of biomarkers for SAA
deficiency or toxicity is the definition of SAA deficiency and
toxicity themselves. This requires clinical trials that prove the
presence of SAA deficiency by counteracting the clinical con-
sequences of SAA deficiency by SAA supplementation. Only
in this way can potential biomarkers be linked to adequacy of
SAA supplementation.
Unfortunately, most potentially interesting areas for SAA
supplementation have not been investigated in larger clinical
trials. Consequently, no proven valid biomarkers for potential
sulfur-containing amino acid deficiency are at hand. Nevertheless,
the plasma concentration and redox state of GSH are presently
important surrogate endpoints of clinical studies. However, the
intracellular localization of GSH metabolism, and the discrepancy
between intra- and extracellular GSH concentration and redox
state, together with the dynamic and rapid intercoversion of thiols,
makes the redox status of the GSH:GSSG and other redox
couples very difficult to interpret (39).
Even when deficiencies are established, it is uncertain
whether this will lead to clinically applicable biomarkers. This
is exemplified by glutamine, a nonessential amino acid that has
clearly been shown to become deficient in catabolic states (40).
Glutamine is especially of interest in the present context because
its tissue and plasma concentrations have been found to closely
correspond with GSH concentrations (41–43), although this
obviously does not necessarily means that there is an actual
glutamine or glutathione deficiency. Low tissue glutamine con-
centrations are generally believed to reflect a deficiency of
glutamine supply despite the fact that these concentrations can
not be increased by ample exogenous glutamine supply (up to
40 g/d) (44). Therefore, the clinical benefits of glutamine supple-
mentation do not appear to be related to increased intracellular
glutamine levels. The uphill gradient of glutamine (low in
plasma, high in the cell) most likely is maintained by active ATP-
driven Na1-linked transport, which may fail in conditions of
severe inflammatory activity. Therefore, low tissue glutamine
levels may reflect disease state rather than glutamine depletion.
This probably explains why administration of glutamine increases
glutamine plasma flux and plasma concentrations of glutamine
but does not increase tissue concentrations. The regulation of
tissue GSH levels may be subject to similar mechanisms. The
close connection with tissue glutamine concentrations, the steep
uphill gradient between plasma and tissue concentrations, and
the variable success of trying to raise levels by supplementing
precursors suggests that low tissue levels reflect inflammatory
activity rather than depletion.
In the case of glutathione, this view is substantiated by the
fact that, in renal tubular cells, mitochondrial glutathione con-
centration almost exclusively relies on transport because GSH
is synthesized in the cytoplasm and not in the mitochondria.
This transport is carrier linked, which may be influenced by
different disease states (45). It is therefore not yet established
which of the intermediates and products, or which of the
kinetic characteristics of GSH metabolism, may serve as a bio-
marker or as a marker of depletion or sufficiency. Identification
of a biomarker is further complicated by the fact that free thiols
exist as cysteinylglycine, as cysteine, as GSH and as protein
bound cysteine or GSH. All these thiols can readily intercon-
vert to form disulfide bridges with other thiols and most likely
do so at different speeds, hampering simple establishment of a
status parameter or biomarker.
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Ideally, a biomarker should reflect adequacy of a biological
function in a precise manner. In the case of GSH, most at-
tention is paid to its potential to scavenge reactive oxygen
species. Subsequently, this function should closely correspond
with other surrogate markers such as malondialdehyde,
peroxynitrite, superoxide dismutase, and, most importantly,
clinical outcome. One of the few evidence-based indications
for N-acetylcysteine (N-acCys) supplementation is acetamin-
ophen intoxication. This acute situation, however, may not be
optimal to study intermediate metabolism of GSH and to
monitor potential biomarkers. More promising (because
predictable) fields to study biomarkers for cysteine adequacy
in relation with GSH metabolism may be found in standard-
ized human situations of increased GSH oxidation. Promising
examples in this context are the administration of radioactive
iodine in radiology (46) or the application of hepatic inflow
occlusion in liver surgery, which induces ischemia of a large
part of the healthy liver for a fixed period of time, giving rise to
oxidative stress (Fig. 1). Another, more general approach to
monitor amino acid adequacy has been proposed by Bérard
et al. and involves the assessement of changes in amino acid
levels during artificial nutrition. If changes in amino acid
levels reflect their over- or undersupply, a tailor-made mixture
could be offered based on these changes. This approach
improved nitrogen balance in a small population of surgical
patients (47).
FIGURE 1 (Intermittent) Hepatic pedicle clamping during liver
surgery provides a standardized human ‘‘model’’ of oxidative stress. In
10 patients hepatic inflow was occluded for 15 min, and splanchnic
malondialdehyde release (hepatic venous minus arterial concentration)
was assessed. Establishment of the induction of oxidative stress in such
a standardized model opens the possibility of studying the effect of
antioxidant therapies such as modulation of SAA and GSH levels (M. C.
G. van de Poll, C. H. C. Dejong, A. Bast, and G. H. Koek. unpublished
data).
 SULFUR AMINO ACID ADEQUACY
Potential SAA deficiencies and rationale
for supplementation
Methionine. As for any essential amino acid, inadequate
methionine intake impairs protein synthesis (29,48). Chronic
dietary folate insufficiency causing methionine deficiency, and
DNA hypomethylation has been implicated in carcinogenesis
(49,50) This theory is circumstantially supported by large lon-
gitudinal epidemiologic studies showing that low intake
of methionine, and more frequently of folate is related to the
development of colorectal cancer (49,50) and breast cancer
(51). An accumulation of methionine is likely to occur in
patients with disturbances in the transmethylation and trans-
sulfuration pathways as a result of genetic polymorphisms or or
hepatic dysfunction (52). Burn patients may have an increased
demand for methionine to maintain nitrogen balance (53).
Cysteine. Cysteine deficiency may occur as a result of insuf-
ficient intake, transsulfuration defects, and in cases of increased
demand (increased need for GSH synthesis). Cysteine defi-
ciency has been suggested to occur and to lead to changes in
GSH metabolism (17,18,35,38,39,54–58) (Table 2). Also, gly-
cine and glutamate depletion have been implicated in dimin-
ished glutathione synthesis (42,57), but based on its pool size,
cysteine is most frequently named as the rate-limiting constit-
uent (59). In a previous part of this article we already indicated
that free cysteine has a very small pool size, but cysteine thiol is
abundantly available in di-, tri-, and polypeptides and in pro-
tein, both as thiols and as disulfides.
Because GSH metabolism is an almost exclusively intracel-
lular process that does not equilibrate with the plasma com-
partment, disturbances in GSH and cysteine metabolism are
difficult to assess in vivo. GSH synthesis can be assessed in vivo
by measuring the rate of incorporation of precursors during
stable isotope infusion. Human data on glutathione synthesis
exclusively concern erythrocyte metabolism. Decreased synthesis
rates in erythrocytes have been found in healthy volunteers re-
ceiving an SAA-free diet (59), in weight-losing obese patients (60),
in septic children (18,56), and in HIV-positive patients (17).
It has been shown in several studies that short-term sup-
plementation of N-acCys leads to an increase in GSH synthesis
(17,18) as well as to an improved redox state (38). Interest-
ingly, erythrocyte glutathione synthesis decreased transiently
when protein intake was reduced from habitual intake to the
recommended amount (34). This may reflect substrate-induced
TABLE 2
Conditions potentially associated with disturbances in GSH metabolism
Condition Tissue
HIV Erythrocytes
Inflammatory bowel disease Intestinal mucosa
Elective surgery Muscle
Critical illness Muscle
Erythrocytes
Ischemia reperfusion Liver
Aging Plasma
Cancer PBMCs
Acetaminophen poisoning Liver
Burns Leukocytes
1697S
down-regulation of GSH-synthesizing enzymes and cast some
doubt on the long-term effects of cysteine supplementation.
Human data concerning GSH concentrations and GSH:
GSSG ratio indicate that tissue GSH concentrations and redox
state are depressed in inflammatory bowel disease (39), fol-
lowing abdominal surgery (57), as well as in critical illness (42),
aging, and cancer (38) (Table 2). In addition, it has been sug-
gested that maintenance of GSH concentration and redox status
coincides with maintenance of functional performance in elderly
people and with a delay the process of aging.
Interesting data from the group of Dröge (38) suggest that
the plasma and intracellular redox state is causally related to a
decrease in body cell mass and functional capacity in cancer
patients. Oral administration of N-acCys improved redox state.
This change was related to an increased body cell mass and
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decreased inflammatory activity in some selected patient groups
and improved quality of life. However, confirmation of these
findings by other groups is necessary to establish their value.
A few well-designed trials concerning children with protein-
energy malnutrition (61) and patients undergoing abdominal
surgery (62) failed to show significant effects on clinical end-
points. In a recent meta-analysis it was shown that N-acCys may
reduce contrast-induced nephrotoxicity (46), but in several
subsequent large randomized clinical trials this conclusion was
disregarded again (63–65).
Currently the only robust indication for N-acCys use is in
the treatment of acetaminophen-induced hepatotoxicity (54).
Taurine. It has been shown that children receiving par-
enteral nutrition without supplemental taurine developed low
taurine plasma levels and neuronal (especially retinal) dys-
function, which could be counteracted by addition of taurine to
the feed (66). The indispensability of taurine in this condition is
generally ascribed to low expression of taurine biosynthestic
enzymes, which can account for only a very slow renewal of the
total body pool of taurine. Consequently, adequate mechanisms
should operate to conserve the body pool of taurine including
enterohepatic cycling of taurine (26). Most children on long-
term parenteral nutrition suffer from intestinal malabsorption
inducing substantial losses of bile acids and taurine in their
stools. In children with healthy intestines and normal enter-
ohepatic cycling, taurine may not be indispensable. Similarly
adult patients with intestinal malabsorption, for example
choleric diarrhea, may suffer substantial losses of taurine. No
data, however, are available on this subject.
Methods Reference
Stable isotopes (17)
GSH concentration (39)
GSH:GSSG ratio
GSH concentration (57)
GSH:GSSG ratio
GSH concentration (18, 56)
GSH:GSSG ratio
Stable isotopes
GSH concentration (55)
GSH:GSSG ratio
GSH concentration (35)
GSH:GSSG ratio
GSH concentration (38)
GSH:GSSG ratio
N-Acetylcysteine supplementation (54)
GSH concentration (58)
1698S SUPPLEMENT
TABLE 3
SAA content of commercially available feeding solutions
Protein source, g/1000 mL
Specific indication Whey Soy
General TPN/EN
General TPN/EN 0.6
Ventilated ICU patients
Metabolic stress 2.9
Malnourished cancer patients
Typical SAA content of some commercially available feeding solutions based on SAA content of
protein source.
The particularly high abundance of taurine in lymphocytes
suggests an important role in the immune system. Taurine
further has been suggested to be involved in stabilization of cell
membrane potential and regulation of Ca21 transport through
several calcium-ion channels and to control cardiomyocellular
contraction, which provides a rationale for addition of taurine
to commercially available energy drinks. Although taurine is
not considered essential in human nutrition, it has been
suggested that subjects on strictly vegetarian diets run the risk
of developing taurine deficiency because taurine is primarily
found in animal protein (67). Convincing data supporting this
claim are lacking, however (68).
SSA supplementation and toxicity
Methionine. As an essential amino acid, methionine is a
standard component of artificial feeding formulas. According to
the reported methionine amount and dose recommendation of
standard tube feeds (Table 3), the daily amount of methionine
administered to enterally or parenterally fed patients is ;26
mg/kg per day, which apparently is twice the minimally required
amount. Disease-specific feeds for malnutrition or metabolic
stress are even higher in total protein and SAA content and
provide ;4 times the recommended daily dose of SAA.
Amino acid concentrations of pediatric protein and hydroly-
sate-based enteral formulas exceed that of breast milk, leading
to a moderate increase of plasma levels of amino acids and urea
nitrogen in enterally fed children (69). The consequences of
this mild elevation of blood nitrogen concentration are difficult
to assess in the light of the other differences between formula
feeds and mother milk. However, no clinical data indicating
specific amino acid toxicity in formula-fed children without
errors in metabolism are known.
Methionine intake in infants at 14–28 d with various for-
mulas may reach up to 120 mg/kg per day (70). A methionine-
fortified hydrolysate providing up to 260 mg/kg per day to
newborn healthy children was shown to induce only moderate
elevations in methionine plasma level and no signs of methi-
onine toxicity (71). In a retrospective case study of 10 children
without enzyme deficiencies receiving the same methionine-
fortified formula, however, severe hypermethionemia was found,
which may have induced brain edema in 2 patients (70). References
70 and 71 are summarized in Figure 2. A conclusive explanation
for the increased sensitivity to high methionine intake was not
given, but these findings led the authors to suggest that precaution
is especially warranted in premature children, children with a very
low birth weight, and children with liver disease.
Toxicity of methionine in liver disease was established half-
way through the twentieth century by Dame Sheila Sherlock,
who recognized that high methionine intake (;10 g per day or
Sulfur amino acids, mg/100 mL
Casein Methionine Cysteine Total SAA
4 133 12 145
3.1 112 17 129
6.3 207 19 226
6.1 209 19 228
6.3 263 27 290
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133 mg/kg per day for a 75-kg person) in patients with impaired
liver function resulted in hyperammonemia and a deterioration
of neurological functions, which could be alleviated with
antibiotics (72). In addition, high levels of methionine may be
directly hepatotoxic, and it has been suggested from results of
animal studies that high amounts of methionine in feeding
formulas are causally related to the onset of cholestasis during
tube feeding or parenteral feeding (73,74). It has been shown
that there is no relation between methionine intake and
hyperhomocysteinemia, provided that vitamin status is optimal.
In most cases hyperhomocysteinemia can be treated by vitamin
B-12, B-6, and/or folate supplementation (75). In the old lit-
erature it is mentioned that methionine restriction and cysteine
supplementation can prevent cognitive retardation in children
with inborn errors of SAA metabolism (76).
Cysteine. The typical dosage of N-acCys that is generally
used in clinical trials ranges from 300 to 600 mg/d when given
as a chronic nutritional supplement, up to 2400 mg/d to treat
acute acetaminophen poisoning and to prevent contrast-
induced nephrotoxicity. In a study in severely septic patients
receiving up to 100 mg/kg N-acCys per day, no adverse events
were found that could directly be ascribed to the N-acCys
supplementation, although it must be noted that the treatment
group showed a decrease in cardiovascular performance (77).
Intravenous infusion of 160 mg/kg per day in healthy volunteers
induced significant changes in vitamin K–dependent coagula-
tion factors without actually compromising coagulation itself
FIGURE 2 Summary of 2 studies describing the effects of high
methionine intake in formula-fed children. The solid line represents a
histogram of methionine intake in 58 children receiving a methionine-
fortified protein hydrolysate without experiencing any side effects or
hypermethioninemia (71). The circles represent individual methionine
intake in selected cases receiving the same formula that did experience
hypermethioninemia without (open circles) or with (closed circles)
adverse effects that could be directly ascribed to methionine toxicity (70).
 SULFUR AMINO ACID ADEQUACY
(78). Two patients developed epileptic states after high-dose
N-acCys administration, 1 with a fatal course after the erro-
neous administration of 2450 mg/kg N-acCys in 11.5 h (intended
dose 208 mg/kg) to an acetaminophen-poisoned child (79).
Taurine. The metabolic value of supplemental taurine in
nondepleted adult subjects is doubtful because it has been
shown that 70% of supplemental taurine is excreted in the urine
unchanged and another 25% is degraded by enteral bacteriae
(80). Because of its supposed positive inotropic effects, taurine
has been added to commercially available energy drinks in large
amounts (1000 mg/L) with no untoward side effects. Although
the true benefit of taurine on cardiovascular and mental per-
formance is doubtful, it underlines the safety of high-dose taurine
supplementation.
Summary
The adequacy range of dietary requirements of specific
amino acids in disease states is difficult to determine. In health,
several techniques are available that allow rather precise
quantification of requirements either on the basis of growth of
the organism or on the basis of rises in oxidation of a specific
amino acid during its incremental administration. These re-
quirements may not be similar in disease with regard to protein
synthesis or with regard to specific functions such as scavenging
of reactive oxygen species by glutathione. Requirements for
such specific functions can be assessed only when such func-
tions or sensitive surrogate markers can be measured and re-
lated to clinical outcome.
SAA supplementation can be considered safe in amounts
exceeding 2–3 times the minimal recommended daily intake,
and apart from methionine toxicity in liver disease, true SAA
toxicity has been reported only anecdotically or in patients with
inborn enzyme deficiencies. Apart from some very specific indi-
cations, the usefulness of SAA supplementation is not yet es-
tablished. There is, however, an ever-growing body of data
pointing out the potential importance of disturbances in redox
state in numerous disease states including sepsis, chronic in-
flammation, cancer, AIDS/HIV, and aging. These observations
warrant continued attention for the potential role of SAA
supplementation. In particular, N-acetylcysteine remains a po-
tentially promising drug for a variety of conditions in which
redox state is disturbed.
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