OF NUTRITIONAL DEFICIENCY.

*
(Abstract of the Gordon Wilson Lecture which was illustrated
with 25 lantern slides.)

ANEMIAS

By GEORGE R. MINOT,
BOSTON , MIASS.

In recent years it has become possible to.aagreater extent than

before to classify anemias on the basis of etiological considerations.
In manv instances anemia is dependent on defective or deficient nutrition. Nutrition implies the act of using substances. Nutritional
dleficiency disease is still likely to be thought of as arising only from
d'ietary defect. Nutrition depends', however, not only on what man
decides to eat, but on numerous other factors, such as digyestion, absorption, and proper utilization of the thirty-six or more food-derived
substances required for health.
The anemias due to deficiency, of material effective in pernicious
anemia are macrocytic, but not all cases with red blood cells averaging, larger than normal are due to shortage of this material. If the
miaterial is crude enough, it will alleviate not only the anemia but other
dlisordiers arisingy in pernicious anemia, such as those referable to the
g-astro-intestinal tract and neural system.
The nuitritional disturbance that occurs in pernicious anemia and
r.ome related macrocytic anemias has been shown by Castle to be condlitioned by the state of the gastro-intestinal tract. The normal person
c-an derive from food, by means of gastric digestion, the material
nieeded to prevent pernicious anemia. Deficiency of the gastric factor
(intrinsic factor), of the dietary factor (extrinsic factor), or of the
mnaterial within the body proper originating from the interaction of
these two factors leads to macrocytic anemia. Intestinal impermeabi-'I
itx and faulty internal metabolism may play a r6le. Faulty storage
of liv,,er extract" in the liver alone is probably not a cause of the con(lition. Acid does not destroy the gyastric factor, but heating to 70' C.
or boiling will do so, in contrast with 'liver extract, which withstands
"From the Thorndike TMemnorial Laboratory, Second andi Fourth Mledical
Service_; (Harvard), Boston Citv Hosipital, andi the Department of M,Nedicine, HarVard Mledical School, Boston.

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~~~~GEORGE

R. MINO'f

boiling. T'he stumach after death cuntains buth the intrinsic factor
and the extrinsic factor. "Liver extract' (fraction G of Cohn) contains the extrinsic factor, so that its potency may be enhanced ten or
more times by incubating with the gastric factor, making a very s-uitable preparation for oral use.
The very small volume of gastric secretion in pernicious anemia
makes studies concerning the in, z,itro activity of the gyastric factor
difficult. The factor is probablyI a proteolvtic enzyme. The extrinsic
factor is, present in a number of natural souirces of the vitamin B1

complex.
Tropical macrocvtic anemia respondls, as Wlills and Evans have
shown, to autolyzed yeast (pernicious anemia does not respond to
this) and crude liver extract, but not to the more higyhly purified liver
extracts (such as the preparation of Dakin and WAest) effective in pernicious anemia. WNintrobe considers that dehydrated yeast contains
anti-perniciouis anemia material, but Heinle and Miller and others
believe that the effect of feedingy large doses of yeast is due to the fact
that it is a rich source of extrinsic factor. Since residual amounts of
the gyastric factor are present in many cases of pernicious anemia, a
continuously progressive decrease of the blood to the vanishing point
does not occur.
Mleulengracht has shown the relatively high potency of the
pyloric portion of the stomach and of the duodenum for the intrinsic
factor, and Uotila has shown that the ileum, and Schemenskv that the
colon of hogs are effective when fed. Castle and his associates have
dlemonstrated that the effectiveness of ileum. and thus by inference of
colon, can be accounted for by the absorption of gastric factor. Their
studies suggest that the activity of duodenum may be due also to absorption of intrinsic factor rather than to its secretion.
The conditions causing failure of secretion of the intrinsic factor
must be sought fuirther. PigYs on diets defective in the B., complex, as
s.hown by Miller and Rhoads, lose this factor.
Important observations by Rhoads and associates suggest that
l1iver extract" acts to cause cessation of abnormal blood destruction
rather than to supply a building stone for blood formation. They sugg,est that abnormal blood destruction of the type seen in pernicious
anemia operates in the presence of nutritional deficiency and that

ANL.\EMIAS OF NUTRITIONAL DEFICIENCY17

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-liver extract'! acts to allow aromatic compounds, wxhich can cause

anemia in the presence of a deficiency, to detoxify such injurious
suibstances.
In diagnosis, aplastic anemia of various pathological types must
be excluded. At a given level of red blood cells, the variation in their
-,zize in bloodls with increasedl mean corpuscular volume will be distinctIlv greater in pernicious anemia than in aplastic anemia.
The fundamental principle of treatment of pernicious anemia is
the administration of adequate amounts of potent material for the
-iven indlividual case. An aim must be not onlyr to return the number
of redl blood cells to normal, but to return them to normal size and
k,eep them there. Neural signs will not develop nor will they progress
in the adequately treated case. A U.S.P. unit of liver extract is not
orecessarilv the minimal or averag-e effective amount per day. It is
-the amouint of material when given daily to patients with pernicious
ainemia which has produced satisfactory hematopoietic response."
TFhe effectiveness of liver extract upon the grastro-intestinal tract and
neuiral manifestations mav differ from that on the bloodl upon which
Ithe unit is based.
Strauss has shown that if one stops the treatment of patients in
toull remnission who have been adequately treated with liver extract
intramuscuilarly, at intervals of one to four weeks over a period of
three ylears or more, they will usually relapse in from two to twelve
mnonths, but sometimes not for more than two years. If then the
l)atients are given in a week a little more liver extract than they
p)reviouslv received in a year they will relapse in a similar period of
time. It is thus unwise to give treatment at too infrequent intervals.
S ome cases may be successfully treated at monthly intervals, but in
niany cases weekly injections are wise.
Hemoglobin deficiency is the feature of hypochromic anemia.
The dleficiency may arise from lack of material other than iron, but
p harmacopeial preparations of iron supply in largye part the metabolic
needs of these cases. Iron-deficiency anemia is common, and names
have tendled to obscuire the close etiological relationship of the various
types of hypochromic anemia. The basic causes of iron deficiency are
loss of bloodl and growth. Woman requires about four times as much
ir-on as man up to the age of the mienopause. which explains why the

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~~~~GEORGE

R. 'MINOT

condition is very much more common in wxomen. A w\oman may be

born with poor iron endowment and have a poor diet leading to iron
dieficiency in the first years of life. WAith growth and the onset of
menstruation, iron deficiency may develop and the condition known
as chlorosis, appear. Infection and severe damage to organs may act
to impair the utilization of iron in the s,,ame way that such conditions
act to inhibit the utilization of other minerals and vitamins. Achlorhydria and digestive disturbances as well as a diet poor in iron prevent a suitable replacement of iron. In pregynancy iron deficiency is
common, in part owing to the bodyv's extra demands, and it is especially likely to develop when causes of iron deficiency have been
operative before pregnancy. The condition known as "idiopathic"
hypochromic anemia can be accounted for by the cumulative effects
of the factors mentioned, of which chronic blood loss is particularly
significant. In some chronic cases of iron deficiency other deficiencies
exist, and probably slight degrees of deficiency of other minerals and
vitamins occur frequently. The possible r6le of some factor of the
vitamin B3 complex in chroniic iron deficiency needs study.
In the therapy of iron-deficiency anemia there is no quiestion of
the gyreater effectiveness of an excess of iron rather than "just enough."
It is the case of long standing iron deficiencv with achlorhvdria which
needs the largest doses. The important thing in the treatment is to
administer enough of a given kind of iron rather than to debate on
what is the smallest dose of iron in some particular form that gives
maximal effects. In human disease it seems that ferrous salts are more
effective than ferric salts. V'ery rarely will there he need to glive iron
parenterally, and the margin between effective doses and toxic doses
is small. Iron given during pregnancy can prevent manyT cases of
hvpochromic anemia.
There is much to be learned about the mechanism of iron metabolism. Only very small amounts of iron are required to keep the
organism in positive iron balance. The work of MIcCance and Wlidowson and others indicates that there is a negligible and nonregulatory
excretion of iron. Storage of iron may be large and yet the patient
may remain anemic until iron is fed, as suggested by the w'ork of
McCance, Brock, and others. It is possible that the amount of iron in
the body, is regulated by controlled absorption. Wlhipple's and Hahn's

ANEMNIAS OF NUTRITIONAL DEFICIENCY17

179

stiudies with radioactive iron indicate that more iron is absorbed by

iLhe anemic dog than by the normal dogy. Hawkins and WVhipple have
dlearly shown the importance of a continuous cycle of secretion and
absorption of bile from the gastro-intestinal tract for the normal
>~vnthesis of hemoglobin.
The relation of the gastro-intestinal tract and its contents to
iron deficiency is a significant one. Whatever leads to rapid gastric
and small intestine evacuation andI loss of tone diminishes the amount
of iron taken into the body from the amount available in the diet.
Iron in food is present as ferric iron, but it is absorbed as ferrous iron.
An abundance of readily oxidizable substances in the gut and an
acid reaction provide conditions in which conversion of ferric to
ferrouis iron is likelv to occur. Certain mixtures of food and an excess
of mucus may handicap absorption of iron. Iron is absorbedI particularly in the upper part of the small intestine, and its absorption is
favored by a lower rather than a higher pH.
Achlorhydria can act in several ways to hinder the absorption of
iron. The action of achlorhydlria to antagonize the absorption of
iron is reflected from therapeutic studies in man. Cases of 'idiopathic" hvpochromic anem-ia with achlorhydria usually require distinctly largyer (loses of iron for the regeneration of hemogylobin at a
maximal rate than do cases of hvpochromic anemia without achlorhydlria. Small doses of iron often have essentiallyT no effect in the
achlorhydric individual, but frequently, they can cause a (listinctive
hemoglobin increase when the g,astric acidityvi about normal.
It is rare to see untreated cases with both 'liv7er extract" and
iron (leficiency. Protein (leficiencyT is perhaps a partial cause of some
cases of anemia, especially, in pregnancy, as l3ethell has pointed out.
However, hemoglobin can be formed in iron deficiency anemia when
there is a negative nitrogen balance. P'atients with scurvy may have
iron deficiency and other types, of anemia. However, in scurvy with
anemia the administration of food rich in vitamin C wiill often cause a
reticulocyte response and quick regyeneration of the bloodl.
The establishment of early (liagnosis followedi by proper treatmient for each and every aspect of the given individlual's case will lead
to the prevention of many severe cases of anemia andI serious dlamage
to the spinal cord in pernicious anemia. Careful observations with the

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GEORGE R. MINOT

aid of a stomach tube, tuning fork, and blood smear of close relatives
of individuals with pernicious anemia will lead to the prevention of a
number of "full blown" cases of pernicious anemia. Attention to
proper diet, slight recurrent blood loss, and factors acting to inhibit
nutrition and to impair digestion will aid in preventing the types of
anemia mentioned, namely, those of deficiency of material derived
from food.
The many gaps in our knowledge concerning the blood and nutritional deficiency in man will be filled primarily by continued study of
patients by investigators who recognize that science is unstable and
that art is uncertain.