Iron deficiency in adolescent boys

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  • Journal of Internal Medicine 1996; 239 : 8994

    L E T T E R S T O T H E E D I T O R

    Psycho-neuro-immune-endocrine system: athree-phase-old response

    Dear Sir, in the editorial Integrative biology (physi-

    ology) a necessity ! (J Intern Med 1995; 237:

    3457), Bo$ ttiger explains that we need integrativebiology and integrative physiology to integrate all

    new knowledge into an understanding of whole

    tissues, organs and individuals [1].

    In this respect, we have recently proposed that the

    local and systemic response of the organism to stress,

    represented as the mechanical trauma, is based on

    the successive functional predominance of the ner-

    vous, immune and endocrine systems. In relation to

    this hypothesis, the final and prevalent functions of

    these systems may represent the consecutive phases

    of the response to stress developed by a single system:

    the psychoneuroimmuneendocrine [2].

    These successive functions not only are expressed

    by the mentioned systems, but also by the rest of the

    components of the organism. These make up a

    systemic response integrated by the functions of the

    nervous, immune and endocrine systems.

    So, this functional concept of the nervous, immune

    and endocrine systems is not only limited to those

    systems, but the whole organism is involved, i.e. the

    epithelial, endothelial and mesothelial barriers as

    well as the structures with supporting function

    (osseous, muscular and connective tissues) and

    storage function (adipose tissue), whose functional

    expression is modified in the successive phases of the

    organic response produced by the mechanical trauma


    The succession in the functional expression by the

    organism of the nervous, immune and endocrine

    systems could represent the meaning of an ancestral

    response whose effectiveness makes it possible for the

    organism to persist on the level of cells, tissues, organ

    and individuals, in both physiological as well as

    pathological situations.

    L. Lorente, J. A. Aller & G. J. Arias

    Departamento de CirugU a I, Hospital Universitario SanCarlos, Facultad de Medicina, Universidad

    Complutense de Medicina, Spain


    1 Bo$ ttiger LE. Integrative biology (physiology) a necessity ! JIntern Med 1995; 237: 3457.

    2 Lorente L, Aller MA, Rodr!guez-Fabian G, Alonso MS, Dura! nHJ, Arias JL et al. Psycho-neuro-immune-endocrine system

    behavior in mechanical trauma. Psicothema 1995; 7.

    Received 12 July 1995, accepted 15 August 1995.

    Correspondence : Jaime Arias MD, Departamento de Cirug!a I,Hospital Universitario San Carlos, C} Martin Lagos s.n., 28040Madrid, Spain.

    Familial neurosarcoidosis

    Dear Sir, neurological manifestations are rare in

    sarcoidosis, with an estimated frequency of 56%

    [1, 2]. To our knowledge, no case of familial neuro-

    sarcoidosis has been previously described. We report

    here the cases of a father and his daughter, both

    exhibiting meningeal involvement in the course of

    histologically proved sarcoidosis.

    In 1968, neurosarcoidosis was diagnosed in a 25-

    year-old man. Diagnosis was based on chronic aseptic

    meningitis, positive Kwe$m test and exclusion ofother confounding disease. Sarcoidosis was diag-

    nosed in his daughter, a 17-year-old girl, in May

    1993 on the association of fever and bilateral hilar

    and retroperitoneal lymphadenopathies. Histological

    examination of a mediastinal adenopathy demon-

    strated a noncaseating granuloma. Persistent fever

    responded to steroid therapy at the initial dosage of

    12 mg kg" day". Clinical improvement occurred

    rapidly. Steroid dosage was rapidly decreased because

    of a severe cushingoid syndrome. Fifteen days after

    reducing steroid therapy, fever and headache re-

    curred. The patient was then hospitalized. At pres-

    entation, body temperature was 38C. Clinical exam-ination was normal except for cushingoid appear-

    ance. Biological data only revealed a fibrinogen at

    5 g L", a sedimentation rate at 48 mm and a C-

    reactive protein at 288 mg dL". Seven days afteradmission, she suddenly presented a right facial palsy

    and aphasia. Cranial computed tomography was

    # 1996 Blackwell Science Ltd 83


    normal. CSF evaluation showed pleocytosis

    (180 cells mm$) with 60% of polymorphonuclear

    leukocytes and 40% of lymphocytes, protein at

    35 g L" and glucose at 19 mmol L". Direct exam-ination of CSF was negative and cultures remained

    sterile. Resonance magnetic imagery demonstrated a

    basal meningitis. Amoxicillin therapy was instituted.

    Clinical improvement occurred promptly. Amoxi-

    cillin was continued for 3 weeks and steroid therapy

    was not modified. One month after discharge, clinical

    relapse occurred. CSF evaluation showed

    110 cells mm$ with 90% of lymphocytes, protein at

    35 g L" and glucose at 23 mmol L". Steroid dosagewas increased to 12 mg kg" day" and rapid im-

    provement occurred.

    Our two patients met the diagnostic criteria of

    neurosarcoidosis. Indeed, clinical presentation was

    compatible, no other neurological disease could be

    demonstrated and histological confirmation of sar-

    coid tissue was available. Sarcoidosis may affect two

    or more members of the same family. Previous

    studies provided many arguments to support a

    genetic contribution, including an excess of mono-

    zygotic over dizygotic twins concordant for sar-

    coidosis, ethnic variations in prevalence and HLA

    associations [3, 4]. Moreover, it has been suggested

    that genetic markers could influence both clinical

    expression and prognosis of sarcoidosis. Patients

    with HLA B8 and sarcoidosis are more likely to

    develop arthritis and erythema nodosum, and have

    good prognosis [4]. The occurrence of the same rare

    complication in two members of a family provides

    new arguments for genetic determinism in sarcoid-


    D. Ducloux, Y. Welker, K. Lassoued"

    & J. Modai

    Departments of Infectious Disease and "Immunology,

    HoW pital Saint-Louis, Paris, France


    1 Chretien J, Stanislas-Leguern G, Saltiel JC. Sarcoidose. In:

    Kahn JF, Peltier AP Flammarion, eds. Maladies Systemiques.

    1991; 85788.

    2 Chapelon C, Ziza JM, Piette JC, Levy Y, Raguin G, Wechsler B

    et al. Neurosarcoidosis : signs, course and treatment in 35

    confirmed cases. Medicine 1990; 69: 26176.

    3 Brennan NJ, Crean P, Long JP, Fitzgerald MX. High prevalence

    of familial sarcoidosis in an irish population. Thorax 1984;

    39: 1418.

    4 Gardner J, Kennedy HG, Hamblin A, Jones E. HLA associations

    in sarcoidosis : a study of two ethnic groups. Thorax 1984; 39:


    Received 27 February 1995, accepted 15 August 1995.

    Correspondence : Dr Yves Welker, Clinique des Maladies Infectieuses,

    Ho# pital Saint-Louis, 75475 Paris Cedex 10, France.

    Iron deficiency in adolescent boys

    Dear Sir, in a recent paper in this journal, Olsson et

    al. [1] critically examined a report from a study [2] in

    which, among other things, we found that 15% of

    boys aged 1516 years were iron deficient. They

    found it remarkable that iron deficiency should be so

    prevalent in adolescent boys in this country since the

    prevalence of iron deficiency in children was mark-

    edly reduced between 1930 and 1980 [3], and since

    flour has been fortified with iron for several years.

    Therefore, they undertook a study [1] to confirm or

    reject recent findings indicating a high prevalence of

    iron deficiency in Swedish male adolescents . It is

    certainly important that unexpected findings are

    carefully controlled by other research groups. How-

    ever, it is crucial that such comparative studies are

    adequately controlled and that adequate compari-

    sons are made. The assay methods should be

    adequate, and, whenever possible, their performance

    should be checked through sufficiently large external

    quality assessment programmes. The choice of di-

    agnostic criteria is essential, and in studies on

    adolescents, the choice of age group investigated is


    Choice of age group

    In boys, iron is required to cover basal iron losses

    from skin and so on, growth including blood volume

    increase, and not least, iron required to cover the

    increase in haemoglobin concentration associated

    with sexual maturation. Therefore, iron require-

    ments are markedly different at different ages.

    Figure 1 is based on growth data from Swedish

    and English boys and girls [46], and data on

    haemoglobin changes in adolescents [7]. It is quite

    obvious that iron requirements in boys are very high

    for some years up to the age of 16 years and then are

    suddenly markedly decreased. Our study [2]

    comprised 1516-year-old boys, whereas the control

    study [1] used 18-year-old boys. It is evident that it

    # 1996 Blackwell Science Ltd Journal of Internal Medicine 239 : 8388


    Fig. 1 Iron requirements in adolescents. In the girls,

    consideration is taken to fraction at different ages that had

    reached menarche: (*) seventy-fifth percentile ; (^) sixtiethpercentile ; (D) fiftieth percentile. Boys : (E) fiftieth percentile.*Fiftieth percentile for adult menstruating women. Based on

    growth data from Tanner et al. (1966) and Karlberg et al.

    (1966). Hb changes derived from Dallman & Siimes (1979) and

    FAO}WHO report (1988).

    is not possible to confirm or reject our findings of a

    high prevalence of iron deficiency in 1516-year-old

    boys who have the highest iron requirements in

    comparison with boys}men who had had consider-ably lower iron requirements for a period of at least

    23 years.

    Choice of diagnostic criteria

    The clinical diagnosis of iron deficiency in patients

    with anaemia is usually simple. However, it is difficult

    to establish a diagnosis of mild iron deficiency in

    epidemiological studies, and thus, to estimate the

    true prevalence of iron deficiency in a population.

    The main reason is the marked overlap of all simple

    laboratory measurements used to study iron status

    between normal and iron-deficient subjects. There-

    fore, several models have been used to define iron

    deficiency in laboratory terms. In the recent N-

    HANES II study in the USA, for example, three

    models giving widely different results were used to

    estimate the prevalence of iron deficiency [8, 9].

    Thus, it is not correct to say that the criteria used by

    Olsson et al. [1] were the ones generally accepted for

    20 years . Actually, the facts that many different

    criteria were used by different authors and that the

    validity of these have never been thoroughly tested

    was the reason why we recently addressed this

    problem in a sample of women [10]. This sample

    consisted of 203 women and the study was unique in

    several respects because not only usual haemato-

    logical tests were done, but also measurements of

    menstrual blood losses, degree of iron absorption and

    particularly careful examinations of bone marrow

    smears. In this way, an independent valid classi-

    fication of the iron status of the subjects could be

    made. Two groups of women were defined, one iron-

    replete group with stainable iron in the smears (n105) and one iron-deficient group (n69) withoutstainable iron. The diagnosis of iron deficiency could

    be validly established in these subjects because two

    smears containing generous amounts of stroma were

    examined in each subject and because recent acute

    bleeding (which might give a false diagnosis of iron

    deficiency) could be excluded. The access to this

    material made it possible to examine the overlap for

    different methods between iron-replete and iron-

    deficient subjects, and thus, having an independent

    key to determine the specificity and sensitivity of

    different measurements of iron status for the first


    Serum ferritin (SF) turned out to be the method

    that most efficiently separated iron-replete and iron-

    deficient subjects, and a cut-off value of !16 lg L"showed the best diagnostic efficiency. Olsson et al.

    use a SF of !12 lg L" as one of their combinedcriteria for iron deficiency. If this cut-off value had

    been used in our sample of women, only 61% of

    those with no stainable iron in smears would have

    been classified as iron deficient. It is important to

    emphasize that the cut-off value of !12 lg L" for SFwas proposed at a time before the international

    standard for SF was established and at a time when

    individual laboratories had their own standards

    which turned out to vary considerably.

    Transferrin saturation (TS) was the other criterion

    used by Olsson et al. [1]. It is a widely used measure

    of iron status. Its value to establish a mild iron

    deficiency is limited by the marked diurnal fluctua-

    tions of plasma iron. This is a probable reason for our

    finding of a marked overlap for this variable between

    iron-deficient and iron-replete women. Only 26% of

    the iron-deficient women had transferrin saturation

    below 16%, and 28% of the iron-replete women

    # 1996 Blackwell Science Ltd Journal of Internal Medicine 239 : 8388


    were below 16%. In patients with iron deficiency,

    anaemia TS is usually !16% [11], but this factcannot be transferred to epidemiological studies on

    mild iron deficiency.

    Different multiple criteria were tested in the N-

    HANES II study in the USA, as mentioned above.

    Theoretically, using independent criteria, the di-

    agnostic specificity will increase, but at the cost of a

    reduced sensitivity, thus leading to an under-

    estimation of the prevalence of iron deficiency. As an

    example, by just applying the condition of a TS!16% together with a SF!16 lg L", only 23% of thewomen with no stainable bone marrow iron would

    be classified as iron deficient. Olsson et al. [1] were

    using the combined criteria of SF!12 lg L" and TS!16% for iron deficiency. According to our study inwomen, the use of combined criteria will dramatically

    reduce the diagnostic efficiency and lead to a marked

    underestimation of the prevalence of iron deficiency.

    Using the criteria by Olsson et al. [1] in our sample of

    207 boys, only three (14%) would be considered asiron deficient instead of the 31 (15%) reported in our


    The balance of evidence from studies on animals

    and in man indicate that it is important to get good

    estimates of the prevalence of mild iron deficiency

    and this may be especially important in still-devel-

    oping adolescents. It is difficult to establish effects of

    mild iron deficiency. However, two recent and well-

    controlled studies in iron-deficient but nonanaemic

    adolescent girls showed that iron deficiency had

    statistically significant effects. One study in Israel

    showed that iron deficiency markedly influenced

    mood, concentration and lassitude [12], and one

    study in the USA showed that physical endurance

    was clearly affected [13].

    In their discussion, Olsson et al. [1] indicate that

    their lower prevalence figures are well in agreement

    with findings in two previous studies, one in Canada

    [14] and the other in the USA, referring to the N-

    HANES II study [15]. This interpretation is greatly

    misleading because 30% of adolescents were con-

    sidered to have greatly reduced iron stores in the

    Canadian study, and in the US study the difficulty

    was emphasized in identifying mild iron deficiency

    based on results obtained utilizing different labora-

    tory criteria as already discussed.

    In conclusion, th...


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