Morphological aspects of the duodenojejunal mucosa in protein

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					Morphological                                      aspects                              of the duodenojejunal
mucosa        in                           protein-calorie                                malnourished      children
and    during                                recovery”2’3
Roberto             E.      Schneider,4              M.D.,             and         Fernando              E.   Viteri,5        M.D.,           D.Sc.



      Protein-calorie                    malnutrition                 (PCM)          is as- The              morphological                 investigations                consisted          of
sociated              with         various           degrees             of intestinal the stereoscopical                          and light             microscopy             study        of
                                                                                             the duodenojejunal                      mucosa          obtained          by suction           bi-
malabsorption                      (1,     2). Morphological                        altera-
                                                                                             opsies.         At      the      same        time,        different          studies         were
tions       in the intestinal                  mucosa           are also present, performed                         to measure               and        characterize             the      mal-
but       their        relationship               to PCM               has     not       beenabsorption            present          in these          children.          The micellar
elucidated            as yet (3-5).                Previous            work        of the capacity             and the bile salts                  composition              of the duo-
                                                                                        and denal         content          during        fat stimulation                 were      studied;




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Institute         of Nutrition               of Central             America
                                                                                             stool-fat         balances,          d-xylose          absorption,            and Schill-
Panama              (INCAP)               has shown              that,      in general,
                                                                                             ing tests were also done. The results                                      of these stud-
the        malabsorptive                     state         disappears               as      the will be reported
                                                                                             ies                                   elsewhere.
child        recovers             (6),     but       some        of the morpho-                    The        children             were         investigated              at      different
logical         changes             persist         despite          improved                stages of recovery
                                                                                           nu-                                   as follows:
tritional          status         (7).                                                             1) On         admission,          any time            between           admission
                                                                                             and the 4th hospital day.
      A longitudinal                   study        was carried               out in 11 2) During                      stabilization,       between          the 9th and             12th
children           with        severe         PCM          from         admission             to
                                                                                             days of hospitalization.                        From         admission           until that
full recovery,                  in order            to obtain             information        time,        the     children            were        placed         on      a therapeutic
on the           role        that      malnutrition,                 infection,              regimen,
                                                                                           and                  which        improved            their protein             and calorie
diarrhea             play       in the pathogenesis                        of some           nutrition
                                                                                               of                only       slightly,         but       water        and       electrolyte
                                                                                             disturbances              were       corrected.           Antibiotics            were       used
the gastrointestinal                        alterations             observed.            The
                                                                                             when         indicated.           Any       child       requiring           antimicrobial
present          paper          covers          the morphological                      stud- therapy           was        excluded            from         the       microbiological
ies      of     the        duodenojejunal              mucosa              of    these       study.        The diet contained                      0.7 high
                                                                                                                                                     g               quality        pro-
patients.            The        microbiological                    alterations               tein
                                                                                           ob-         and      70 kcal/kg               body         wt;     20 to 30%                of the
served          in their             GI      tract        are      presented              in totala calories             were        derived         from        fat. The          children
                                                                                             also       received           vitamins          andminerals              in amounts
separate             communication                      (8).                                 adequate           to fulfill daily               recommended                 allowances.
                                                                                               After    the studies  were   completed,         intake    of protein
Material           and           methods                                                       and  calories     was raised    progressively          to reach,     in
                                                                                               6 to 8 days,    3 to 4 g protein/kg          per day and        120 to
     Besides        the         11 malnourished              subjects         previously       150 kcal/kg           per day,         30%         of which        came       from       fat.
mentioned,               four  clinically       healthy     children                        with
normal        growth      patterns,       whohad been followed                         in          Paper    presented                 at    the     National           Academy             of
well      baby     clinics and       who    had      always   been                     well- Science     Workshop   on Malabsorption                and Nutrition
nourished,      were also studied.                                                  held in Washington,              D.C., April 29-30,               1971.
    The age of the malnourished                           children varied                 Funds      2from       the National            Institutes        of Health
from 23 to 61 months.               They were             kept under          close(NIH)        of the U. S. Public                   HealthService (Grant
observation        at the Clinical        Center            of INCAP            dur-No. 5R22          AM       12105-03),          through        the U. S. Japan
ing the full duration        of the study.               All had severe Cooperative                      Medical       Science       Program.
PCM       of the edematous type; none                    presented         evi-           Publication        1-594 of the Institute                  of Nutrition
dence of gluten enteropathy.                                                        of Central         America         and Panama,             Guatemala,          C.A.
    The degree         of malnutrition         and         of recovery          was       Research          Associate,          Biomedical            Division,        In-
assessed     clinically,    and by means                of serial         meas- stitute         of Nutrition           of Central           America          and Pan-
urements        of weight     for      height,           height       for      age, ama;     Associate          Professor         of Medicine,             University
creatinine/height             index    (CHI)      (9), total       serum        pro-of San         Carlos        School        of Medicine,               Guatemala,
tein,     and     serum       albumin       concentrations.             Some         of
                                                                                    C.A.,     and Chief            of the Research                 Division,        Insti-
the characteristics              of the children            at the different tute           of Social           Security        of Guatemala.              Chief,        6

stages when              the     morphological             and      functional Biomedical              Division,        Institute       of Nutrition            of Cen-
studies      were     performed       are shown          in Table       1.          tral America          and Panama.
1092                      The     American         Journal        of    Clinical       Nutrition          25:
                                                                                                         OCTOBER      1972, pp. 1092-1102.                Printed in U.S.A.
                                                       MORPHOLOGY                     OF DUODENOJEJTJNAL                 MUCOSA            IN     PCM                                                    1093

TABLE                1
Characteristics                        of   the       PCM            children            on   admission           and      at     different             periods       of         study

                                                                                                                                                                      Diarrhea

                                                                           Hospital           Percent        of                     Serum
    Child’s      name             months     Period         of    study                                           CHI5            protein,                                 Indez         of diarrhea
                                                                             days             wt/ht6                              g/100    ml           At the
                                                                                                                                                        time of
                                                                                                                                                         study
                                                                                                                                                                      Partial                Cumulative


          NG                      37                  Adc                         2               84              0.41               3.8                   0
                                                      Stab’                      10               84                0.57             4.5                   +               25
                                                      R±e                       34                81              0.79               7.0                   0                8
                                                      Rec1                      118                105                 1.10                       6.5      0               19                    17
          GZ                      41                  Ad                          2               74                0.47             5.6                   +
                                                      Stab                       13               74                0.56             4.8                   0               70
                                                      Rec                       161                110                 1.10                       7.1      0               17                    2
          RS                      42                  Ad                          4               84                0.58             4.0                   +
                                                      Stab                       13                     84               0.58                     4.1      0                 0
                                                      R±                        41                88              0.78               6.3                   0               11
                                                      Rec                       75                98                0.90                        7.0        0                 9                       8




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          LC                      19                  Ad                          2               67              0.57               4.0                   0
                                                      Stab                       14               67                0.57                        4.0        0                     46
                                                      R±                        62                75              0.69               6.0                   0                8
                                                      Rec                       156               94                0.90             6.2                   0               18                    18
          EP                      26                  Ad                         4               85               0.59               4.5                   0
                                                      R±                        39               90               0.80               7.0                   0               29
                                                      Rec                       121             100               1.05               7.0                   0                9                    13
          BM                      23                  Stab                        9               72                 0.46            3.5                   0               80
                                                      Rec                       105                100                  1.04                      7.2      0                 5                       8
          VB                      69                  Stab                       12               82                 0.53            4.8                   0                 0
                                                      Rec                        67               90                 0.97            7.0                   0                 5                       4
          DM                      35                  Stab                       10               72                 0.44                       3.5        0                     40
                                                      Rec                       107               99                 1.04                       7.0        0              5                          8
          DS                      34                  Stab                        9               82                 0.56             3.3                  +           100
                                                      Rec                       147                110                  1.06                      7.5                 + 41                       44
          AC                      26                  Ad                          4               70              0.58               4.8                   +
                                                      R±                         39               65                0.63              6.8                  +               79
                                                      Rec                       107               92                0.96                        7.0               +        86                    83
          AS                      24                  Ad                          4               98                0.52             4.5                   +
                                                      R±                        42                79              0.80                6.8                  +               96
                                                      Rec                       82                  100           1.02                7.1                  +               93                    94

          Percent           wt/ht     =    percent                  of weight      for height    (on admission        and at stabilization,                                                  edema            was   pres-
ent).            b   CHI      =    creatinine                    height    index.     c Ad = admission.        d Stab   = stabilization                                          period.                R±
                                                                                                                                                                                                     #{149}
=       during           recovery.           / Rec               =    full recovery.

This     intake      was      maintained         until                       nutritional carefully
                                                                                  full                          screened            for      thepresence        of Giardia
recovery        was    attained.         The    protein                 sources         usedlamblia.        Stool        cultures       for enteropathogens                  were
were      Incaparina         (10)     and    casein;               adequate           nutri-made         in the         majority           of children          who       presented
tional recovery              was attained          with either source.                      diarrhea.           The       degree         of intestinal          parasite         infec-
     3) During               recovery,      when       the       CHI         was       be- tion       and protozoa                present in the children                on ad-
tween        0.65      and        0.80, which      was usually achieved mission                              and      their       evolution          during      the          of
                                                                                                                                                                         period
around         the 35th          to 60th      day of hospitalization.                       study       are presented                in Table 2; the            number            of
      4) After         full recovery,          when        all the measure-                 treatments            administered              during      this period         of time
ments        used        to evaluate           recovery          were      within           is
                                                                                         nor- also stated.
mal      limits;        this      usually       occurred          between          75 and
 150 days after              admission.                                                      Characterization               of diarrhea
      Direct        fresh stool           examinations              for      ova       and       Diarrhea           was defined                by the number,                weight,
parasites,         as well         as for ova counts                (Stoll’s      concen- and          consistency            of the          stools      every      24 hr.           The
tration          method),            were        done        periodically.             Freshnumber           was       considered            abnormal          when       the     child
stool      examinations                 were      also      performed            for the    had       four       or more            bowel        movements;            when        stool
detection         of protozoa,              and the histological                 sections weight           was greater             than       150 g; and         consistency            of
of all duodenojejunal                     mucosa        biopsies taken were the                     stools        was      considered            abnormal         if more           than
 1094                                                                                   SCHNEIDER                  AND         VITERI


TABLE          2                                                                                                     areas        of the sections                         showing                muscularis                 mucosa
Estimates        of expected       errors                               in counting                   different were            favored              for this study.                     A coefficient                  of varia-
types     of nuclear      cells   in the                              lamina             propria             of Lion of 6%                        was          obtained                when             the       results         were
duodenojejunal           biopsies                                                                                   evaluated              by analysis                   of variance                      techniques              with
                                                                                                                    appropriate             variance              component                    models.
                                                 Ex-                                                                      The        following                 aspects              were           specifically               evalu-
                                Mean            pected                                                              ated:
         Item                   count           error            Coeffici      ent of variability
                             (n         3S4) (no.       of                                                               Mucosa              thickness,           expressed                  as the            average            of
                                               cells)                                                                10 random                measurements                         performed                  at a magnifi-
                                                                                                                    cation        of 125 (12).
 Plasma cells                    24.36              1.62                6.65                                              Epit/ielial              cell         and          brush             border            height,           and
 Lympho.                         6.22             1.07              17.20                                           nuclear          size, expressed                  as the mean                     value         of 10 dif-
    cytes                                                                                                           ferent        random                measurements                        done          at a magnifica-
                                                                                                    1
 PMN                             4.60          1.15             25.00             EE           X                    lion      of 1,250.                 The         nuclear               size       is determined                    by
 Otherb                        40.36           2.63               6.52                                              multiplying                the longitudinal                         axis        by the transverse
        Total                      75.34              2.99                 3.97                                     axis of one                 randomly                chosen              epithelial             cell nuclei.
                                                                                                                   The approximate                           thickness               of the brush                  border         was
     a PMN          =     polymorphonuclear                            cell.            b Other           =
                                                                                                                    measured              in PAS-stained                        sections;            at the magnifica-
all cells not specifically                                 defined.                                                 lion      used,         a minimal                   difference                of 0.3                could         be
                                                                                                                    consistently               differentiated.




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 50%        were          liquid,           semiliquid,                   or contained                      mucus         Mitotic           figures present                      in well-oriented                         crypts
                                                                                                                    were       counted              in every               10th         section            of each           biopsy
or blood.                Diarrhea               was diagnosed                          when least
                                                                                             at
                                                                                                                    taken.        The        mitotic            activity            is expressed                 as the num-
two       of the above-mentioned                                      criteria            were          present.
The        incidence                 was        calculated                  using           an        index         ber of mitoses
                                                                                                                      of                                present            in 100 crypts.                       This        method
                                                                                                                    (to be published)                           has        a correlation                       coefficient             of
diarrhea,              in percent,                   resulting                from           dividing              the
                                                                                                                    0.957       with the usual                     mitotic            index.
number            of days that the child                               had         diarrhea              by the
                                                                                                                          Nuclear              cell        counts            of       the       infiltrate            present            in
days        of hospitalization.                          In this             way,         both          cumula-
                                                                                                                    the      epithelium.               All        nuclei            clearly              different           from
live      and       partial             diarrhea!                indices            were          calculated.
The former                  assessed             the overall incidence                         of diar-             those        of the epithelial                           cells         were           counted            in two
                                                                                                                   areas         of 700-               to 900-p               length.             These           nuclei         were
rhea during                 the whole                 hospitalization,                      whereas              the
latter          was          calculated                  for         each            period              between not identified                     further,           and thealues   v                 reported            rep-
studies.        It was considered                           that a child had chronic resent                                       the average                    of the two                    counts,           expressed             as
                                                                                                                    the number                 of nuclei             in l00-j             length.
diarrhea              when            the        cumulative                      index           was          above
                                                                                                                         Nuclear               cell          counts               in        the          lamina            propria,
 50%.
                                                                                                                    counted           in two areas                    of 0.06 mm2 each.                             Depending
Morphological                     studies                                                                           on nuclear                characteristics,                      the cells              were        classified
                                                                                                                    as: 1) lymphoplasmocytic                                  cells          (lymphocytes                    and
      Suction            biopsies            of the               duodenojejunal                        mucosa plasma                cells); 2) polymorphonuclear                                     cells,        and 3)
were         obtained                after         6 hr of fasting.                             A modified other                cells.
suction          tube          and        a capsule                (1 1), which                   can        be in- To estimate                         the contribution                         of varioussources
troduced                following                  nasogastric                      intubation,                   was error,
                                                                                                                    of                  repeated               counts            of all groups                   of cells         con-
used         for        this        purpose,                and          two         specimens                  weresidered         were         carried           out in randomly                           selected          slides
obtained             in each                session.              Failure             to obtain                  ade-
                                                                                                                    on      two         different               occasions                  one         month            apart.          A
quate          specimens                 with          this        capsule             was . 21%       No           total       of 308 counts                      were            performed.                  A summary
bleeding           or other              complications                      have         occurred.              The of the           net        expected               error             of the              different           items
capsule           was        located           fluoroscopically,                         and the biop-counted                           is presented                      in Table                    2. Although                    the
sies were             taken           at the level                  of the angle                    of Treitz.coefficient                   of variation                    is elevated                   in some             of the
The properly                     oriented              specimens                   were          placed            on
                                                                                                                    cell groups                 counted, it actually varies around                                           the
a    Marlex            mesh           and immediately                         fixed        in Bouin’s minimal                         expected               error        of one cell.
solution.         After           6 to 8 hr the secretions                                    and         mucus
that       clouded              the       appearance                     of the mucosa                          were
rinsed.          The           biopsies             were            photographed                         at         Results
                                                                                                                 15.6
magnifications                     and       all the viii                    present             in the two
specimens                were          counted.               The          former             were          classi-Morphology
fied into three                   groups: a) finger-like,                      b) leaf-shaped,
                                                                                                                          Table             3 shows                     the           degree                 and         type           of
and c) ridged.
     Serial 5-is sections, stained with hematoxylin- parasite
                                                                                                                                           load             and          protozoa                      found            in       these
eosin        and with               Schiff’s          periodic               acid        were         used          children
                                                                                                                  for                    upon              admission,                    as well as their                        evo-
histological               studies.            Besides              the general                    configura- lution               during                the study                  period.               On admission
tion       of the             villi,       several               measurements,                         and        cell was found that
                                                                                                                    it                                          all patients                     had          a moderate
counts           were           performed                    at      random                in a double-
                                                                                                                    degree             of parasitic                      infection                    except             for       one
blind        fashion            using         a Seitz             ocular           micrometer                   with
appropriate                  scales.          Areas              showing               any         degree           who had 50,000
                                                                                                                      of                                        eggs Ascaris  of                    lu,nbricoides
trauma           or other              artifacts             were          avoided;             the central per              gram             of feces.                No correlation                              was        found
                                                      MORPHOLOGY                           OF        DUODENOJEJUNAL                  MUCOSA            IN    PCM                                                    1095

TABLE             3
Intestinal             parasite              load,          on        admission                     and       during         treatment,                of    11 PCM              childrent




                                                     T.t.                            Al.
                                                                                            Xematodes5

                                                                                                          ,      Na.                        S.s.
                                                                                                                                                             No. of
                                                                                                                                                             treat-
                                                                                                                                                             ments
                                                                                                                                                                          E.h.
                                                                                                                                                                                 Protozoab


                                                                                                                                                                                      Stool        biopsy
                                                                                                                                                                                                              No. of
                                                                                                                                                                                                              treat-
                                                                                                                                                                                                              mta



Admission    and                     sta-                        5c                             7                        5                         1            0          2            5                7          2
  bilization                                     5  2,6001                  5     2,000k                      fl,000                  (14,000)
                                                 12,800J                     5l,200j                          4,000J
During           recovery                               4                                       3                        1                   1                 10          2           0                 3          4
                                                 I   800k                    f 2,000                           (2,400)                (10,000)
                                                 l2,400J                    5l,200J
Fully          recovered                                4                          2                                     1                         1           12          0           0                 4          1
                                                    f300                     5  400                                  (200)             (2,000)
                                                       400J                     l,000J

         Studied             longitudinally                      from    admission       to complete      nutritional                                           recovery.
     b   T.t.    =       Trichuris               tric/liura;         Al.   =     Ascaris    lumbricoides;    Na.                                        =     Necator             americaizus;               S.s.
                                                     E. h. = Eiztamoeba




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Strongyloides                 stercoralis;                                                            histolytica.
         Number               of     children.          Range     of stool                            egg      count         in parentheses.


between                 the         kind and                degree                of            intestinal             the   viffi         was    noted             within             an    area 52 to of
parasitic             load         and      any             of the  morphological                                      100      j.    It      was     not           unusual                   to observe        the
characteristics                    studied.                 This   was    also        true presence               of very         long        villi,                                    some       fused the at
when            protozoa                  were          present                 in    stoolstips,
                                                                                           either       giving         origin         to wider                                           formations         (Figs
or     histological              sections.                                                  2A,        2B,        2C).
     Practically             all the children                 had experienced                     A significant                  and        progressive              increase            in
frequent              episodes             of     diarrhea              for         several the      thickness          of the         duodenojejunal               mucosa
months           before          admission;               in many              cases         its
                                                                                            the       epithelial            cell       height,         and        brush         border
beginning              could       be traced             back        to the wean- thickness                      was      observed             in all children                as nu-
ling     period.           During           hospitalization                  diarrheal tritional                recovery           progressed              (Fig.       3). Never-
episodes            varied         widely          in frequency                   and       theless,
                                                                                            se-                in the two children                     with       chronic          diar-
verity.       Even         so, children             AC and AS were                          rhea
                                                                                          the             (circled           points)            these        three          measure-
only       two       patients         who       fulfilled          the      criteria        ments
                                                                                               of          were        significantly              smaller        than       in those
chronic           diarrhea,            with       cumulative                       o
                                                                            indices f       without             diarrhea.
84     and        96% , respectively.                      Information            re-             A close            correlation              was      also      observed             be-
garding          the severity              of the diarrhea                   observed tween                  the      increase            in thickness                 of the          du-
at the time                 of thestudy             in each            patient           is odenojejunal                    mucosa               and        the        creatinine/
given        in Table            1.                                                         height          index,        the      correlation             coefficient           being
     The       duodenojejunal                     mucosa             of these            pa-0.767.            No significant                 changes           were        noted         in
tients        showed            a homogeneously                          ridged             the size of the epithelial
                                                                                          ap-                                                     cell nucleus             through-
pearance             on stereoscopy,                    irrespective                of the  out       recovery.
degree         of malnutrition                    present           on      admission             Figure          4 shows           the evolution               of the mitotic
or       the         stage           of      nutritional                    recovery                         during activity.              This         is    expressed                 as         the       number        of
which        the     biopsy          was      taken        (Figs.       1A,         mitoses
                                                                                 1B).               in 1 00 crypts                 of the duodenojejunal
Furthermore,             its persistence               in the       recovered       mucosa           during         different          stages        of nutritional
groups          was       not      associated            with       any      degree recovery,            as well           as with           the     presence and
of malabsorption,                      as a battery                of tests         degree
                                                                                    for            of diarrhea,               expressed            by the          partial
malabsorption               revealed          no     abnormality.              Be- index        between          biopsy          periods.        No change              was
sides       the      marked              predominance          of     ridged        observed           with      nutritional            recovery.           However,
villi,    the general              distribution      of the different               children         with       a partial         index       higher        than      20%
forms        of villi observed              remained         unchanged              had       less      mitotic          activity         than        those         a
                                                                                                                                                                    with
during       nutritional        recovery          (Table        4). Marked          smaller         partial        index          of diarrhea,               regardless
variation        in the length,           shape,        and contour         of      of the          degree         of nutritional                  recovery.             Dc-
1096                                                            SCHNEIDER       AND      VITERI


      A




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  B




      FIG.        IA,      lB. Stereoscopical      appearance        of the   duodenojejunal      mucosa   from   patient   NG   on   admission   (A),
and       fully         recovered      (B). X75.
                                                            MORPHOLOGY                            OF      DUODENOJEJUNAL                      MUCOSA              IN     PCM                                          1097

TABLE                 4
Average               mucosal                  thickness                 and     villi             configuration (%)                of the duodenojejunal                                mucosa
of PCM                children                 at different                 stages                of nutritional                     recovery

                                                                                                                                                                           Villi   configuration,    %
                                                                                                                  Average          mucosal
        Nutritional               status              Percent          wt/ht#{176}              CHI
                                                                                                                                                     Convoluted                        Leaves               Fingers


        Admission                                               80.0                        #{216}53c                  380.7c                             63.8c                        29.0c                 73c

             (n = 7)                                            10.7                        0.07                        30.0                               8.8                          7.7                  5.2
        Stabilization                                           77.1                        0.50                       392.2                              61.5                         29.8                  8.8
             (n = 8)                                             6.6                        0.05                            40.0                           8.2                          6.0                  4.3
        Recovery                                            82.2                            0.80                       429.5                              59.2                         33.3                  7.5
             (n = 6)                                          5.7                           0.08                         23.2                              6.0                          5.4                  5.1
        Full    recovery                                   102.1                            1.00                       487.1                              66.9                         25.6                  7.5
             (n = 11)                                         7.9                           0.07                         27.1                              2.7                          3.5                  4.3
        Control                                            100.4                                                       472.3                              60.0                         31.6                  8.4
             (n = 4)                                             2.4                                                    26.2                                5.7                         2.8                  2.3

        Percent    of                       weight         for       height                index      (edema                was              present            on      admission           and     during      stabilization).




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        The average                          mucosal             thickness                   of children                without                 chronic              nonspecific           diarrhea             495.9
                                                                                                                                                                                                           was 20.8.
                                                                                                                                                                                                            ±
The       average                   mucosal               thickness                   of        children             with           chronic            nonspecific                 diarrhea 447.5 was ± 4.9. The
difference                  is statistically                     significant         (t     =     2.95;       P      < 0.05).                      ±      SD.



pressed                   mitotic              activity                was           also    wheninteraction
                                                                                                      noted                  between              PCM          and        diarrhea              was
diarrhea                    was             present              at          the    of biopsy observed.
                                                                                          time
(mean         ± SD mitotic                activity            30.50           ± 6.54,                    The        evolution           of the morphological                             altera-
and 5 1.87             ±               respectively).
                                    8.24,                                                           tions determined                      in our           patients             led       to      the
     Although              the      epithelial               infiltrate            (Table 5)        definition             of three            categories.      a) Those               that
tended          to be higher                     in children                 upon          admis- persisted               unchanged                  even        when            full        nutri-
sion      and         during        the stabilization                         period           thantional        recovery            was       attained,           and       were          unre-
at other          stages         of recovery,                   significant               differ- lated           to diarrhea;                 these        include            the        stereo-
ences       (P        < 0.001)             were             obtained               between          scopical              appearance                   of      the         mucosa,                 the
the     children             with       and            without           diarrhea,               andpopulation              of cells             present            in      the        lamina
between            children           with           PCM          and normal                  con-propria,               and       the       size       of the           epithelial               cell
trols.                                                                                              nuclei.         b) Those             that        improved               with         nutri-
     Finally           (Fig. 5), the number                           of cells           pres- tional                recovery            but         which           were           adversely
ent       in       the        lamina                 propria             remained                  un-
                                                                                                    affected            by chronic                 diarrhea;             these          include
changed              throughout                    recovery,              whether              diar-the      mucosal            thickness              and      the epithelial                   cell
rhea       existed           or not.                                                                and         brush         border            heights. c) Lastly,                  those
     It     is       important                  to        note          that          the        only
                                                                                                    that        were         more         related           to the            presence                of
morphological                 difference                  between               the       biop- diarrhea                 than       to nutritional                 status;          these          in-
sies     from          the    four       healthy              children              and       thosedude            the mitotic          activity           of the           epithelium
recovering               or fully          recovered                  from          malnutri- and              its degree             of cellular             infiltrate.             None           of
tion was          the degree              of cellular                 infiltrate           at the   the morphological                       alterations            could          be related
epithelium.                                                                                         to the presence                     or degree              of intestinal                 para-
                                                                                                    sitic infection.
Discussion
                                                                                                         For        many         years         malnutrition                 was         consid-
     From           the previous                     data       it is evident                   thatered            responsible                  for        the          morphological
protein-calorie                 malnutrition                     cannot             be      con- changes                observed             in the          proximal               small          in-
sidered          the only            cause             for the morphological                        testinal           mucosa           of children                 and        adults          with
alterations                         observed                      in          the      intestine.                          protein-calorie
                                                                                                                         The                                           malnutrition.                Nevertheless,
presence                    and        frequency                        of       “nonspecific                         diar-many          ofthese      changes,                               especially        the      pres-
rhea”          seems       to                     be    more                       closely                associated         ence   of leaf       and   ridged                            villi,     mild    alterations
with       many     of these                      changes,               and          often             afrank               of the    epithelial        cell,                           and       the    presence            of
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                                        C)
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                           -
                                                            MORPHOLOGY                             OF          DUODENOJEJUNAL                         MUCOSA                      IN              PCM                                                                         1099


                                               .UCCSOL         THICKI453                                                      propria         in our                                        normal                    controls                            coming                          from
                                                                                                                              poor       environments                                                          further        point                         to the                        non-
                                                                                                                              specificity         of                                        these                  alterations.                               They                           also
                                                                                                                              suggest                         that               they                         are          very         common                             mdi-in
                                                                                                                              viduals                          living                        in               poor                hygienic                               conditions,
                                                                                                                              and     that malnutrition          is not directly            responsi-
       450
                                                                              A
                                                                                                                              ble   for them.       Ther     presence           in normal         adult
                                                                                                                              populations          from     developing            countries           (16)
       400
                                                                              50
                                                                                                                              with       otherwise       normal         absorptive            capacity
                                                                                                                              ( 1 7) corroborates           this     possibility.          A geneti-
                                                                                                                              cally                   induced                               change                         is      unlikely,                             as         the       im-
                             5)
                                                                                                                              mediate                          postmortem                                            examination                                    of        the         small
                                              EPITHELIAL            CELL       HEIGHT                                         intestinal                               mucosa                             of         fetuses                      and          stillborns                         of
                                                                                                                              similar                         background                                             to          that               of          patients
                                                                                                                                                                                                                                                               our
                                                                                                                              revealed                                   predominantly                                            finger-like                                 villi.
                                                                                                                              Finally,       the presence          of these       changes        in bi-
                                                                                                                              opsy       specimens         of     adults       from       developed




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                                                                                                                              countries,        obtained      after      they    had    lived     for a
                                                                                                                              few months         in Pakistan         (18)     and     Viet      Nam

                                                                                                                                                      A
                                                                                                                                         60                        .


                                                                                                                               0
                                                                                                                               0


                                                                                                                                         ::                                                               ;                               .                                         ‘
                                                                                                                                                                                                                                          .
                                                                                                                                            30                     .

                                                                                                                                   B
                                                                                                                                            20


                                                                                                                                            IC
                                                                                                                               B
                                                                                                                               z                                                        -                                                     -           -
                                                                                                                                                 0
                                                                                                                                                              ADMI55IO                  STABILIZATION                           RECOVERY                      RECOVERED
                                                                                                                                                      ON




                                                                                                                                                                         a       S3                             CC

                                                                                                                                                                         A

                                                                                                                                                                             .   Re:c

                  C      C              =   Pa?eC?             cO=:           CCOeC                                                                                                ‘S             C’CC’                   ‘CC      ctde             ?i’       CCO             LOIChCS
                                                                                                                                                                         6         N’               -



     FIG.     3. Mucosal           thickness,          epithelial          cell     and
brush         border      heights        of     duodenojejunal                  mucosa                                                        70          B
from       11 children         with     PCM        followed           from       admis-
                                                                                                                                                 60
sion to complete            nutritional         recovery.          Circled       points
                                                                                        =
=    patients        with    chronic        diarrhea;          stars           normal -                                                       Sc’
children.
                                                                                                                                   S          40               A


                                                                                                                                                                                  a                  #{149}                         a                                *
                                                                                                                               _:                3c
cellular     infiltrate                              in       the           lamina                     propria,               are
not specific         and                          probably                         reflect               the        limited
ways              in    which               the       small                intestinal                     mucosa               re-               10

acts         to        different               noxae.                 The            above-mentioned
alterations                          have            been             observed                           not        only               in
PCM               but             in association                      with              certain                 intestinal                                                                          CIARPHEA                    INDEX

parasites                         and        protozoa                        (13,                 14),           after             the
                                                                                                                                FIG.     4.                            Number        of mitoses      of the duodenojeju-
administration                              of certain                       drugs          and
                                                                                         (15),                           in
                                                                                                                           nal mucosa                                     of 1 1 children      with    PCM      followed         lon-
many        other                       conditions.                        The     presence                          of thegitudinally,                                   from    admission      to complete         nutritional
same               stereoscopical                         alterations                            and            the    de- recovery.                                   (A)     Changes      observed       with      nutritional
gree              of         cellular                 population                   in            the           lamina      status,      and                             (B) with diarrhea       index.
TABLE             5
Intestinal               epithelial                    infiltrate                       in      PCM                 children                                on      admission                  and       at    different                    stages          of    recovery

                                                                                                                                                                                                              I)iarrhea
                                                                                                          All           cases
                                                                                                                                                                                     Present                                                      Absent


On admission                     and             stabilization                                    5.95          ±            0.42a                                         7.00 ±               0.37                                  4.81 ±               0.43
                                                                                                     (n =                      15)                                             (n =               6                                         (ii       =    9)
During            recovery                  and         recovered                                 5.18 ±                       0.41                                        6.63 ±                 0.23                                4.73 ± 0.46
                                                                                                     (n =                      17)                                             (n =               4                                      (n = 13)
Normal                children                                                                                                                                                                                                        1.78 ± 0.23
                                                                                                                                                                                                                                         (n = 4)

    a   Number               of           cells         in100       ,      of           epithelium                             (mean ±                       SE).




                                                             I              ()n         ad-      ssion              N
                                           240               II                   StoHlzoon                        0
                                                                                                                #{149}N\
                                                             III                  Durrq            rccoerv                    N
                                          230                Iv                 F51l          recovered                  N        11
                                                                                Normal’              N=         4
                                           220


                                           210
                                                                                    1T1                      1 S.D.                                                                                               I1




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                                           200

                                           190


                                           130


                                           170

                                           160

                                           150

                                            140

                                             130

                                     .(     120


                                             110

                                 -          100


                                             90




                                                70                                       #{149}

                                             60

                                             50


                                                40

                                                30




                                                 10



                                                                     I     II                                     I
                                                                                        Ii I’J #{149}‘N#{149}#{149} II
                                                                                                                        rFw             III           l’’    #{149}l’’          I    II    I’EJ                    I
                                                                                                                                                                                                                       -


                                                                                                                                                                                                                           II   ill    \‘         r

                                                                LYmphoplasma.                                           Poly’orplonu.                                           Other                             T’:           Ces

                                                                   cvtic        CellS                                        dect             ce1is


     FIG.    5.     Number                   of         cells in                the        lamina propria                              of             I I children                  with        ICM           followed                longitudinally                 from    ad-
mission           to complete                         nutritional                       recovery.

                                                                                                                                              1100
                                                          MORPHOLOGY                     OF       DUODENOJEJUNAL                   MUCOSA             IN      PCM                                        1101

(19),       and       the tendency                   for lesions              to regress the            mucosa            and        the      cell        population                of the
when        these       individuals               returned            to their          origi- lamina            propria,             remained                unchanged                   and
nal      environment                   (19)        suggest          that        “nonspe- showed                 no relation              to nutrition                or diarrhea.
cific”     or “tropical                jejunitis,”            as it is called,                  is The         morphological                    characteristics                   of the
conditioned               by ecological                  factors.         A common upper                     GI mucosa                 of normal,                  well-nourished
denominator                  in the majority                    of these            entities children,              were         no      different             from         those          ob-
is the presence                   of variable              degrees           of nonspe- served                in the recovered                    patients.
cific     diarrhea.                                                                                  PCM         cannot          be considered                   the only            cause
      The      increase             in mucosal                thickness              and       for the alterations
                                                                                                in                                    found,          as the presence                    and
cell      and        brush           border           heights           probably               re-
                                                                                               frequency             of nonspecific                    diarrhea             were        also
flects      protein        repletion,             which         also       correlates           associated           with       several          of those            alterations;              a
with       improvement                    in mucosal                 function.             The frank        interaction             between             PCM           and      diarrhea
epithelium               of the            proximal               small          intestinal was          frequently             observed.              It appears               that       the
mucosa            is one           of the           most        active          tissues          in
                                                                                               ecological            situation            characteristic          of environ-
the body             (20);       for this reason,                   the nutritional ments                      where          poor         hygienic              conditions              and
status        of the patient                    is expected                to affect            diarrhea
                                                                                                 it.               prevail          plays         an important                    role        in
      Nonspecific               diarrhea              is associated                  with the genesis
                                                                                                 a                     and       persistency                of the         GI      altera-




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decrease            in mucosal                thickness            and        in mitotic tions              observed            in children                with        and       without
activity,         as well as with                    an increase              in epithe- clinically                 evident PCM. [
hal cell infiltrate.                   Alterations               of the small                 in-
testinal        fluxes        of water,           electrolytes,              and nutri- References
ents resulting               in decrease               absorption,              and low-
                                                                                                  1. Vrrniu,          F. E., M.BHAR,                 G. ARROYAVE                  AND
ered energy             and protein availability                         (21)       have
                                                                                                      N. S. SCRIMSHAW.                 Clinical          aspects         of protein
been       noticed           also in nonspecific                     diarrhea.             The        malnutrition.            In: Mammalian                 Protei,z        Metabo-
mechanisms                  involved             in the genesis                   of all of lism, edited                    by H. N. Munro                       J
                                                                                                                                                              and. B. Allison.
these           changes                  remain                unknown.                                                      New       York:          Academic,           1964,        vol. chapt.
                                                                                                                                                                                         II,               22,
                                                                                                                             p. 523.
                                                                                                                        2.   G6MEz,             F.,        R. Rio   GALvAN,             J.     CRAVIOTO,
Summary                                                                                                                      S.   FRENK,        J.    VELAZQUEZ           AND     C.   PEtA.       Fat     ab-
                                                                                                                             sorption     in          chronic  severe             malnutrition             in chil-
     The characteristics                 and evolution                of differ-                                             dren. Lancet             2: 121, 1956.
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present      in the proximal                   small      intestine           of I 1 NICLIFFE.          Intestinal        biopsy        in    kwashiorkor.
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                                                                                      4. BuRMAN,       D. The jejunal          mucosa      in kwashiorkor.
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status,    diarrhea,          and      intestinal          parasitic           infec- 5. BRUNSER,       0.,     A. Riom,         F. M6NCKEBERG,         A.
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ished              children               whose                    background                    was            simi-        in infant    malnutrition.             Am.           J.   Clin.      Nutr. 21:
                                                                                                                             976,   1968.
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                                                                                                6. VITERI,    F. E., J. M. FLORES                  AND M. B/CHAR.
studied.               None         of             the     morphological             charac-       Intestinal     absorption        inprotein-calorie          malnu-
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presence                 or degree                     of intestinal        parasitic          or Hamburg,         August    1966, p. 46.
protozoa                 infection.                                                             7. SCHNEIDER,       R. E., F. E. VITERI               AND J. ALVA-
                                                                                                                             RADO.   Histopathological                  study     of the intestinal
      Morphologically,                             the          thickness                of       the       du-
                                                                                                                             mucosa       in malnutrition.                 A preliminary       report.
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well     as the                  heights                 of         the epithelial                  cell          and        Macy       Conference.)                 Santiago,        Chile,    March
its     brush              border           increased                    with          nutritional                  re-      1969, p. 34.
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adversely                     affected                 improvement               and          was         as-            PRERA.            Gastrointestinal     floraof children           with
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      for human      feeding.     Ill. Development           of INCAP      opsy    of the small         bowel     of Thai          Am.
                                                                                                                              people.
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1 1 . SCHNEIDER,      R. E., AND R. CHANG.            A modified       17. TRONCALE,     F. J., G. T. KEUSCH,           L. H. MILLER,
       pediatric        tube         and     capsule      for  suction         biopsy         R.     A. OLssoN         AND      R.     D. BUCHANAN.      Normal        ab-
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12.    REID,       A., AND0. BRUN5ER.      Pathogenesis            of                   18.   LINDENBAUM,               J.,     T.    H. KENT        AND    H.    SPRINZ.
    small                 changes
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       THOMPSON,      JR. Relationship         of infestation     with 21. BANWELL,       J. G.,      S. L. GORBACH,        N. F. PIERCE,
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Discussion

Dr.    Lindenbaum:               Dr.  Schneider,                  did   you       say dude    the data         in the       paper      presented          here,    the
that    increased              or decreased               crypt              a
                                                                       mitotic c-     study  of rectal         biopsies       obtained        simultaneously
tivity was noted               during  diarrhea?                                      with  the upper            intestinal       biopsies       revealed       that
                                                                                      the mitotic      activity        of the rectal        mucosa         also de-
Dr.     Schneider:        Decreased.           Although            I did not in- creased         during       diarrhea.

				
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