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Clin Chem Lab Med 2007;45(11):xxx-xxx  2007 by Walter de Gruyter Berlin New York. DOI 10.1515/CCLM.2007.334

2007/287

Letter to the Editor

The systemic inflammatory response syndrome C-reactive


protein and transthyretin conundrum

Larry H. Bernstein*
New York Methodist Hospital Brooklyn, Brooklyn,
NY, USA

Keywords: C-reactive protein; cytokines; hypermetabolism; protein-energy malnutrition; systemic inflammatory response syndrome; transthyretin.

I am surprised by the transthyretin (TTR) document


published in the March 2007 issue (1) with the
endorsement of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Scientific Division Committee on Plasma Proteins (C-PP).
The view reported is that TTR is a poor indicator of
nutrition, imprecise, poorly reliable, having nothing to
do with nutrition, with outcome, length of hospital
stay or with its financial burden. According to this
paper, the fluctuations of TTR are mainly explained
by underlying inflammatory disorders. The effect of
protein-energy malnutrition in kwashiorkor and
marasmus reported by Ingenbleek and Carpentier (2)
in the late 1960s was a basis for another 30 years of
solid investigation of this subject, because of the
short half-life of this protein. The use of the protein
provided a fix to the problem of using serum albumin
(20 day half-life), which though inexpensive, is more
of an osmotic protein and measure of severity of illness. As a result of for-profit managed care the complete metabolic panel, which includes serum albumin,
is severely restricted in favor of the basic metabolic
panel, with significant risk to patient care. This makes
the use of TTR more justified than ever in an acute
care population that enters the hospital with multiple
comorbidities and at an average age of over 65 years.
The conclusion that classical clinical examination
and measurement of C-reactive protein (CRP) is sufficient to follow the nutritional status of a patient is
easily challenged by the peer-reviewed literature. I
consider that the paper contains errors and misconceptions. For instance, it is said that TTR is normal
in anorexia nervosa or in restriction of protein alone;
in contrast, TTR concentrations are decreased in
childhood and old age, confusing pediatric reference
values and that found in the adult; there exists no
indication that the thyroid dysfunction characterizing
goitrous patients might per se depress TTR concen*Corresponding author: Larry H. Bernstein, MD, New York
Methodist Hospital Brooklyn, Brooklyn, NY 11215-9008,
USA
E-mail: larryberns@earthlink.net

trations which are, in fact, the result of underlying


malnutrition; further, the problem of nutritional status
in the geriatric population and the problems with
wound care are too well substantiated. Then, we have
the statement that there exists a high level of uncertainty of TTR values which may be as much as 50%
or more above or below the true value. That is
indeed not the case.
The authors of the paper should be reminded that
in the most severe protein-depleted states, TTR values may drop to one-third or one-fourth of the normal
level, whereas in the most severe inflammatory conditions CRP values may exceed 100 times the starting
level. In that context, the methodological problems
and the level of uncertainty associated with the measurement of CRP are certainly very much higher than
with TTR. I agree with the view that plasma TTR may
be artefactually increased or decreased by some
extra-nutritional or extra-inflammatory factors, such
as corticosteroid medications or renal insufficiency,
as it is also the case for all other plasma proteins,
including CRP. Nevertheless, in the case of TTR, this
interpretation drawback may be circumvented using
appropriate corrections. Such is the approach
currently used in nephrology and explains why TTR
is now regarded as the gold standard of nutritional
status in most renal disorders, in kidney transplantation and hemodialysis. Many other medical disciplines notably in intensive care rehabilitation units,
in geriatrics and oncology are close to adopting the
same attitude and are using the TTR test on a routine
basis in monitoring patients receiving enteral and parenteral nutritional support. The benefit of good use of
the test in monitoring patients is not in doubt.
If the issue is that TTR is an inflammatory marker
and not a nutritional marker, the criticism is misleading. Nutritional status and hypermetabolism cannot
be separated and are closely interwoven features. In
both chronic and acute stressful conditions, the
depressed synthesis of plasma TTR and the exhaustion of body nitrogen stores evolve along parallel
curves due to the combined cytokine-induced effects
on the hepatic and muscular tissues (3). The decrease
of plasma TTR in most inflammatory disorders indicates that the endogenous nitrogen stores become
depleted through the urinary output of nitrogenous
compounds. Regardless of the causal nutritional and/
or inflammatory factor(s) and whatever the initial
plasma TTR plasma level, the follow-up of TTR values
is of utmost importance in the course of any disease.
TTR elevation means that the N reserves are on the
upslope of being restored as a result of effective nutri-

Article in press - uncorrected proof


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Bernstein: The systemic inflammatory response syndrome C-reactive protein and transthyretin conundrum

tional management and/or successful anti-inflammatory therapy. TTR decline means that the nutritional
support is insufficient or unadapted and/or that the
morbid situation further deteriorates. The TTR
decrease with SIRS, directly influenced by interleukin6 and tumor necrosis factor a, is proportional to the
severity of the inflammatory response, as is the
increase in CRP, and the magnitude of the response
is a cause for delayed return to anabolic status (3).
This knowledge actually ties in with the use of TTR
in managing patients and in the intensive care unit
setting. The increase in TTR with re-feeding can be
delayed several days because of the excessive catabolic response. Nutritional therapy for the intensive
care unit patient has been designed to shorten the
period of hyper-catabolic N losses. This implies that
the serial measurement of TTR gives the direction of
the N balance when all available physiological and
biochemical indicators still remain unresponsive.
Owing to its short half-life, TTR is the sole plasma
protein fulfilling this predictive task, and therefore
being of invaluable help to guide on a daily basis the
clinicians therapeutic decisions with significantly
improved impact on the patients outcome and the
length of hospital stay.
What about the impact of timely nutritional intervention on shortened length of hospital stay and
return to anabolic status? Work going back to 1975 by
Bistrian and coworkers (4) showed the impact of protein-energy malnutrition on hospital morbidity for
surgical and medical patients. The study by Reilly et
al. (5) showed that the direct variable costs for surgical and medical patients associated with malnutrition-related comorbidities is increased by delayed
nutritional intervention associated with a 3- to 5-day
extended length of stay. The Veteran Affairs Cooperative Study (6) showed a benefit for total parenteral

feeding with medically significant malnutrition. The


study by Brugler et al. (7) showed a significant savings from systematic surveillance and timely nutritional support in the acute care setting. Owing to the
variability of serum albumin associated with dehydration and re-hydration, the serum TTR has proved to
be a more reliable measure of malnutrition risk than
serum albumin, and it is generally accepted that a
serum albumin measurement reflects the nutritional
status 3 weeks prior to the corresponding change in
serum albumin levels.

References
1. Johnson AM, Merlini G, Sheldon J, Ichihara K. Clinical
indications for plasma protein assays: transthyretin (prealbumin) in inflammation and malnutrition: International
Federation of Clinical Chemistry and Laboratory Medicine
(IFCC): IFCC Scientific Division Committee on Plasma Proteins (C-PP). Clin Chem Lab Med 2007;45:41926.
2. Ingenbleek Y, Carpentier YA. A prognostic and inflammatory and nutritional index scoring critically ill patients.
Int J Vitam Nutr Res 1985;55:91101.
3. Bernstein LH, Ingenbleek Y. Guest editorial: nutrition-disease interactions: malnutrition and stress hypermetabolism. J Clin Ligand Assay 1999;22:2538.
4. Bistrian BR, Blackburn GL, Vitale J, Cochran D, Naylor J.
Prevalence of malnutrition in general medical patients. J
Am Med Assoc 1976;235:156770.
5. Reilly JJ, Hull SF, Albert N, Waller A, Bringardner S. Economic impact of malnutrition: a model system for hospitalized patients. J Parenter Enteral Nutr 1988;12:3716.
6. The Veteran Affairs TPN Cooperative Study Group. Perioperative TPN in surgical patients. N Engl J Med 1991;325:
52532.
7. Brugler L, DiPrinzio MJ, Bernstein L. The five-year evolution of a malnutrition treatment program in a community
hospital. Joint Commission J Quality Improvem 1999;25:
1916.