scopic examination was pronounced by Mr. Quekett to have passed
into a corresponding condition.

Whether any or all of these morbid changes are essentialy con-
cerned — as I believe they are — in giving rise to this very remark-
able disease, future observation will probably decide."

Clinically to Addison's description may be added gastric achylia
without stagnation, diminished pancreatic ferment secretion, fre-
quent or intermittent exhausting diarrhea, continuous or intermit-
tent albuminuria, spinal cord changes usually of the spastic type,
disturbances in sensation particularly malfunction of the special
senses and not rarely psychic upsets.

(b) Acute Type of Addisonian Anemia. This occurs infre-
quently. In 107 cases observed by me, it was present but five
times. The following history emphasizes some of the clinical
aspects of the acute form of the affection.

On January 12, 1916, there was brought to our clinic upon a
stretcher a semi-conscious female aged 35. At the time of entry she
exhibited low muttering delirium, lemon yellow, waxy, oily skin,
pale, water logged mucus surfaces, extreme weakness and dyspnoea.
The general body nourishment was moderately well preserved. The
hemoglobin was eighteen per cent., the red cell count 920.000, the
leucocyte count 2,300. The stained blood smear showed a large
celled anemia, marked poikilocytosis and polychromatophilia and
numerous normoblasts with an occasional megaloblast. The lym-



THE AMERICAN CONGRESS ON INTERNAL MEDICINE 77

phocytes were fifty-six per cent, of the total differential count; the
coagulation time was more than eight minutes.

The previous history of this patient is interesting. Up to Octo-
ber, 1915— three months before coming under observation, the
patient was and had been in perfect health. So excellent had her
health been that she was considered somewhat as a prize beauty
in her county. In early October, she was affected with a form of
sore throat with grippe-like sequelae, which lasted for about ten
days and left her much exhausted. The exhaustion continued, a
lemon color pallor became noticeable, a swelling appeared below the
edge of the left ribs, irregular temperature was recorded and five
weeks following the initial illness a blood examination revealed the
quantitative and morphologic picture associated with Addisonian
anemia. The patient was removed to a hospital in one of the large
cities of Iowa and a standard form of treatment instituted by a
very competent internist. The patient made practically no prog-
ress. Anorexia, diarrhea, dyspnea, palpitation of the heart and
mental changes became established. The swelling below the rib
edge was proven to be the spleen, it persisted and increased and
became so painful that deep breathing, lying on the left side or
palpation caused exquisite distress. The blood pictured showed
no change except quantitatively the hemoglobin and red cell mass
slowly and steadily diminished.

In this striking picture, I would emphasize particularly the acute
onset of the ailment in a previously well individual, the disease
being initiated by a sore throat ; the rapidly developing anemia in
every respect that of a pernicious or Addisonian anemia; the clini-
cal appearance of the patient which in the space of a few months be-
came that which is commonly associated with Addisonian anemia of
long standing; the rapid and persistent enlargement of the spleen so
painful as to be described by the patient herself as feeling like a
"large boil." Further examination showed this case to be non-
syphilitic. A haemolytic coccus was isolated from the throat and a
similar organism from the tissue of the gall bladder and the spleen.
This case will be considered in detail with regard to treatment later.

BLOOD FINDINGS IN ADDISONIAN ANEMIA

Emphasis is to be placed upon the statement that the blood
morphology set down by early investigators as indicating essen-
tial or ideopathic anemia or Addisonian anemia may be closely
mimicked in numerous forms of anemia where the cause is known



78 THE AMERICAN CONGRESS ON INTERNAL MEDICINE

or evident and that upon blood morphology alone or even upon
quantitative blood studies alone, absolute diagnosis of the disease
is not possible. The blood studies are only to be taken when con-
sidered with respect to the clinical course of the disease and pos-
sible with regard to evidences of haemolysis.

Usually there are shown a low erythrocyte count (fifteen-fifty
per cent, of normal), the average being 1,200,000 (Cabot) while
Quinke's case of 143,000 holds the record for low counts. The
hemoglobin is decreased, but in lesser degree than the red blood
cell count, thus making the color index greater than one in the
majority of cases.

The fragility of the erythrocytes is increased. The platelets are
diminished, often absent. The normal is 500,000 (J. H. Pratt),
while in pernicious anemia they usually are less than 100,000 per
cu. m.m. The stained smear shows nucleated red blood corpuscles
and multitudes of large and small, misshapen and contorted red
blood cells. Cells measuring from two to twenty microns in diam-
eter (microcytes and marcrocytes), "dumbbells," "doughnuts,"
"pears," "commas," "ovals," "pseudopods" and "rings" (poikilo-
cytes) are common. Nucleated red blood corpuscles are frequently
present at some stage of the ailment. They vary in size and are
designated microblasts, normoblasts and megaloblasts, accordingly.
Cells containing Howells nuclear particles are often seen. These
various blast cells represent the reserve currency of the bone mar-
row and indicate that the demand for erythrocytes is so imperative
that the marrow, being unable to produce matured cells, throws
off their parent form — the erythroblasts. The degree of the mar-
row's embarrassment is probably indicated by the type of blast
found in the circulating blood, the more primitive the nucleated
cell, the more urgent the systemic call for red corpuscles. In very
severe cases, however, no nucleated cells many be seen. This prob-
ably indicates almost complete marrow exhaustion.

Besides nucleation, the circulating red blood corpuscles show
polychromatophilia, reticulation, Ehrlick's "spotting," vacuolation
and rarely basophilic degeneration.

There is a marked leukopenia, usually about 3,500, although
counts as low as 330 and as high as 13,000 have been reported.
Higher leucocyte counts are rare. They probably are associated
with active infection or the free absorption of toxic agents which
temporarily stimulate the defenisve mechanism in the blood making
centers. Evidence suggestive of this is adduced from the prompt



THE AMERICAN CONGRESS ON INTERNAL MEDICINE 79

leucocytosis following blood transfusion with or without associated
splenectomy.

The leucocytes are of smaller size than normal, myelocytes more
numerous and often basophilic granules are seen in the cytoplasm.
The differential counts usually show an increase in the small lympho-
cytes and a decrease in the polymorphonuclear percentages — in
fact, the normal percentages are often reversed, so that lympho-
cytes outnumber polymorphonuclears three to one. Such reversal
of the normal differential leucocyte ration might be interpreted as
indicating diminution of the blood's defensive mechanism.

CHANGES IN THE BLOOD PLASMA

Coagulation time is prolonged, but not so greatly as in hemophilia
and icterus. Our cases ranged from three to ten minutes. The
appearance of the blood is watery, milky or greasy, and sometimes
it is nearly impossible to smear it evenly on a slide. Ehrlich de-
scribes the flow from a puncture wound as "streaked." The volume
of erythrocytes, as determined by the hematocrit of Oliver, is les-
sened out of proportion to the serum, which is often pinkish in
color from the free hemoglobin. The specific gravity of the serum,
freed from corpuscles, is nearer normal.

Nayen and LeNoble say that the fibrin is decreased and that the
clot in pernicious anemia does not retract even after seventy-two
hours. Other observers do not agree to this statement. We have
noticed that the clot is soft and insecure, and is easily dislodged.

Blankenhorn has recently demonstrated an increase in the bile
pigment in the blood in cases of Addisonian anemia. There would
also seem to be variations in the cholestrin and iodine factors. It
has not been constantly shown that the lytic bodies are increased.
In certain cases it has been shown by Eppinger and by King that
the blood serum contains an increase in the unsaturated fatty acids
in the blood some of which have been shown to be highly lytic.

PATHOLOGIC ALTERATIONS

General. The most striking feature of the disease is the general
fatty degeneration of the systemic non-striated and heart muscula-
ture and of the liver, kidneys and bone marrow. All the body tis-
sues are hydraemic except the spleen which is commonly firm and
congested. Multiple small hemorrhages into meninges, brain, spinal



80 THE AMERICAN CONGRESS ON INTERNAL MEDICINE ■

cord and retina are not uncommon. Such lesions are, however,
not especially specific of Addisonian anemia. The researches of
Hunter and others would, however, indicate that in Addisonian
anemia there are specific changes which have been commonly over-
looked by many observers.

Hunter lays particular emphasis upon the lesions in the mouth.
It is a common observation that in many forms of severe anemia
infected gums, tonsils and nasal accessory sinuses are coincident.
Not infrequently the infecting organisms are haemolytic cocci or
bacteria. Decayed, broken teeth are very generally noted. Hunter
emphasizes the importance of these long persisting infections with
respect to a peculiar glossitis which he claims is quite characteristic
for Addisonian anemia. We, ourselves, have noticed the tongue
changes as being practically constant in haemolytic anemias of
Addisonian type, in fact, we have never seen a true case of Addi-
sonian anemia in which the tongue did not show varying degrees
of atrophy of the mucous membrane and hyperplasia of the muscles
of the tongue. Hunter claims that there is no other anemia in
which the glossitis is so constant and persistent. He claims that
the glossitis fluctuates in severity as does the disease and that the
preence of the glossitis accounts for the alterations in the special
senses particularly of taste so characteristic of the disease. Hunter
has shown that while in many severe anemias, superficial inflam-
matory changes of the tongue are quite common, in Addisonian
anemia there is an actual invasion of the lymph spaces and muscle
bundles of the tongue with lytic streptococci. Hunter claims that
the tongue furnished the most important portal of entrance for
these bacteria or their toxins into the general circulation. Tissue
cultures from the tongue would apparently show these organisms
in pure culture. Pathologic changes similar to those observed in
the tongue have been observed in the stomach wall and that of the
large intestine. In the early course of the disease, the gastroin-
testinal lesions are of the ulcerative type, later inflammatory
action results in a scar tissue with atrophy of the mucosa and mus-
cularis. Haemolytic bacteria can often be isolated from the walls
of both stomach and intestine, upon tissue culture after the technic
of Rosenow.

In our clinic, tissue cultures have been made of removed appen-
dices and gall bladders. While grossly all these appendicies and gall
bladders show chronic inflammatory changes with or without evi-
dences of ulceration, in some of the specimens, streptococcus veri-



THE AMERICAN CONGRESS ON INTERNAL MEDICINE 81

dans, lytic staphlococci and organism of the colon group have been
recovered.

Besides fatty change and frequent enlargement, the liver presents
a rather characteristic picture with respect to the distribution of iron
pigment. The deposits of iron pigment are increased from six to
ten times the normal amount. This increased iron is characteris-
tically deposited in the outer and middle zones of the lobules. This
increase of iron pigment does not occur as result of iron medication
nor does it occur in secondary anemias to such extent nor in such
position. By Charnas and Schneider's methods for the estimation
of blood derived pigments, duodenal catheterized fluid appears
characteristically to reveal a great increase in the elimination of uro-
bolin and urobilinigen by the liver. In only the lytic anemias is this
great increase in blood derived pigments constantly found. This
observation is of value in separating instances of true Addisonian
anemia from anemia where the blood morphology indicates a severe
anemia often carelessly called "Addisonian."

Examination of the kidneys in pernicious anemia shows increased
iron deposits. In the urine are demonstrated increased urobiligen
and hetero- and perhaps iso-hemolysins.

BONE MARROW

Smears of the bone marrow reveal in the early stages of perni-
cious anemia megaloblastic hyperplasia in the majority instances.
This is apt to be succeeded by aplasia which represents an over-
work or fatigue. In certain cases of Addisonian anemia aplasia
may be early manifested. Bone marrow cultures have not been
made in sufficient number of cases of Addisonian anemia to enable
one to state definitely whether or not there is actual bone marrow
infection but evidence is accumulating which offers to substantiate
this opinion. It would appear that the bone marrow changes may
represent reactions to the haemolytic agent. It would seem in
Addisonian anemia the bone marrow is not primarily at fault. In-
jections with pure cultures of staphylococcus pyogenes aureus
cause definite bone marrow reactions closely resembling the megalo-
blastic reactions produced in Addisonian anemia. Following the in-
jection of non-bacterial hemolytic agents as has been described by-
Bunting similar changes are observed. It is quite likely that in
Addisonian anemia, widespread infection with hemolytic cocci re-
tards blood formation.



82 THE AMERICAS CONGRESS OX INTERNAL MEDIC IX E

SPLEEN

Spleens removed at laparotomy from cases of Addisonian anemia
in our clinic almost universally show increase in size, blood conges-
tion, chronic peri-splenitis and often increase in weight. On section-
ing the tissue evidences chronic hyperplasia. The iron content is
greatly decreased. In some instances of Addisonian anemia tissue
cultures from the spleen pulp have returned hemolytic cocci and
colon-like bacilli. Spleen extracts have not exhibited increased iso-
or hetero-haemolysins.

It might be well to review certain functions performed by the
spleen. Even though the exact use of the spleen is unknown, it
would appear from its embryology to be an important organ con-
cerned with digestion or assimilation of food. It will be recalled
the blood supply of the spleen comes from the coelio axis as does
that of the stomach, liver and pancreas. The spleen is derived from
the fore gut as are also these organs. Its venous efterents are
direct tributaries to the portal circulation. The chief functions of
the spleen would appear to be those connected with control of blood
formation and with blood destruction. In the human embryo
erythrocytes are produced by the spleen but at birth this produc-
tion ceases and the bone marrow becomes practically the sole course
of the red blood cells. The spleen is, however, intimately con-
cerned with the production of leucocytes. Kolliker and Ebener
found more leucocytes in the splenic vein than in the splenic artery.
The large mononuclears (splenocytes) formed in the spleen prob-
ably do not enter the blood stream but remain and serve as partial
sources of haemolysis. There is reason to believe that even nor-
mally the spleen exercises a certain degree of inhibition upon the
bone marrow, influencing the formation and the addition to the
circulation of both red and white cells. Lethaus, Kuttner, Roetner
and Lagg have noted polycythenia following removal of the spleen
traumatically ruptured. Schupfer, Levison and Muhsan and Mayo
have similarly noted increased red cells following splenectomy in
Banti's disease. The tremendous medullary reaction after splenec-
tomy in pernicious anemia has been commonly noted. Sometimes
the pain in the long bones following the operation is definitely asso-
ciated with this increased medullary activity.

That the spleen bears a direct relation to iron metabolism has
been abundantly proven by the work of Ascher and his pupils, by
Schmidt, Voegel and Baer. It seems probable that the spleen is a



THE AMERICAN COXGRESS OX INTERNAL MEDICINE 83

depot for iron derived from destruction of blood and tissue cells
The liver stores the iron coming to the body in food. After splenec-
tomy Baer has shown a marked reduction in hemoglobin when
animals receive but little iron in the food and rapid improvement
when iron is added. Pearce has emphasized that the iron in un-
cooked food, particularly unboiled food is of greater benefit after
splenectomy than that in cooked or boiled food and from this ob-
servation thinks that the spleen is in some way concerned with the
process of indigestion. Increased siderosis may be an indication,
therefore, of general tissue cell destruction. Increase of iron bear-
ing pigment in the liver and kidneys is, on the other hand, charac-
teristic of active haemolytic processes and especially of active
haemolysis in the spleen. Just what function the spleen has in
digestion is not known. It may have some influence with respect to
stomach and liver hyperemia. It does not seem to be directly con-
cerned with the proper elaboration of pepsin and trypsin. Certainly
after removal of the spleen in Addisonian anemia, Banti's disease,
etc., there is a tremendous improvement in appetite, less gastric dis-
tress and frequently of vomiting. The relation of the spleen to the
ductless glands and the haemolymph nodes is still undetermined.
Certainly after splenectomy, enlargement of the thymus, thyroid
and haemolymph node is not uncommon. Such have been noted
by Tizonni, Mosler, Warthin and Dock, Pearce and Austin and
others. The latter observers have shown that after splenectomy in
dogs there is a great increase of the endothelial cells in the lymph-
nodes and have found that these cells may become phagocytic for
erythrocytes following the injection of haemolytic serum. Eppinger
has pointed out that the failure of splenectomy to benefit certain
cases of pernicious anemia may be referred to the increased hemo-
lytic activity of many newly formed hemolymph glands.

The relation of the spleen to infectious disease has been fre-
quently commented upon. It has been generally supposed that the
spleen acts as a pow r er for good in the struggle against infections.
There is no evidence to show- that immune bodies are more favor-
ably developed in the spleen than they are in other organs. Patients
without spleens have not rarely been shown to survive from severe
infectious disease. It may be that in such circumstances the hemo-
lymph nodes take on the function of the spleen. The relation of
the spleen to neoplasms is worthy of notice, primary cancer of the
spleen is extremely uncommon. The injection of spleen emulsion
into rats has been shown by Osser and Pribam to be followed by



84 THE AMERICAN CONGRESS ON INTERNAL MEDICINE

retrogressive changes in rat tumors. Murphy has shown that rat
sarcoma will grow freely in chick embryos only before the develop-
ment of the spleen. Carroll has found that connective tissue growth
is greatly activated by extract of adult spleen. Eppinger on the
other hand has shown that the removal of the spleen in man may
be followed by greatly accelerated tumor growth.

The Relation of the Spleen to Hemolysis. Under normal con-
ditions there is maintained a delicate balance between blood de-
struction and blood production. The bone marrow reacts sensi-
tively to increased carbondioxide tension of the blood to the prod-
ucts of red blood destruction and to many chemical and infective
agents. It is not to be doubted that normally the spleen prevents
entrance into the blood stream of materials which would stimulate
excessive bone marrow activity. Normally there is little, if any,
active destruction of red blood cells in the general circulation.
Their slow destruction is brought about mainly by the spleen al-
though there is some haemolysis in the liver and bone marrow.
The spleen causes red cell destruction by autolysis and by phagocy-
tosis. The iron of the blood cells is deposited as an albuminate
of iron mainly in the spleen and is used later in the formation of
new red blood cells and hemoglobin. In the absence of the spleen,
Gilbert, Chabrole and Benard have demonstrated that the liver may
transform hemoglobin into bile or bile pigment.

In Addisonian anemia, numerous authors notably Kelliger, Benti,
Minkowski, Hunter and Chauffard and Eppinger assign a very
active role in the hemolysis to the spleen. They maintain that in
this disease, there is a definite hypersplenism and that the red blood
cells are destroyed far in excess of their rate of manufacture by
the bone marrow. Other observers as Ponfick, Goodall and Achard
maintain that the spleen is increased in size in pernicious anemia
as the consequence of the excessive quantity of products of blood
destruction brought to it. It is also maintained that a combination
of the two views is possible, namely, that blood destruction may be'
primarily initiated elsewhere than in the spleen and that as a con-
sequence of the toxic products brought to it the spleen responds
with an overwork hyperplasia with the resultant over-normal hem-
olysis. Under such circumstances it is apparently evident that
removal of the spleen in an ailment such as Addisonian anemia can-
not cure the disease unless the primary haemolytic fault is eradi-
cated.

Effects of Splenectomy. In our clinic, Percy has observed that



THE AMERICAN CONGRESS ON INTERNAL MEDICINE 85

immediately after splenectomy a polymorphonuclear leucocytosis
generally appears, due probably to necrosis of tissue following
operation, being a chemotactic, phagocytic reaction. The nucleated
red blood corpuscles become more numerous at first, especially
Howell's cells, after which they gradually disappear from the cir-
culation.

After a slight fall following the operation, the red blood count
and hemoglobin steadily rise. The stomach symptoms are im-
proved, and there is a decided gain in weight and strength. In some
patients a sensitiveness of the long bones is present. The red cells
tend to lose their misshapen condition and become more uniform in
size. Lee, Vincent and Robertson say that products of red blood
corpuscles destruction (i. e., bile pigments) decrease in the excreta
— the cells become more resistant to hypotonic salt solutions. Plate-
lets appear or increase in numbers — the color-index falls to approxi-
mately one, and the normal ration between polymorphonuclears
and small lymphocytes is gradually established after the initial
polymorphonuclear leucocytosis declines. The abnormal blood cells
generally disappear in from six to twelve, weeks.

The Problem. From the above clinical review of the work of
others and ourselves, it would appear that the problem of treatment
embraces certain fundamental principles. It would seem that in
the proper treatment of true Addisonian anemia the clinical and
therapeutic treatment indicated includes the (a) attempt to bring
the patient's blood serum within the biologic normal by such pro-
cedure as diluting or antagonizing lysins and supplying and stimu-
lating the production of specific protective anti-bodies; (b) the
attempt to remove radically active foci containing lytic bacteria or
to counteract the constant or intermittent absorption of their toxins
or their spread to new localities ; (c) the attempt to simulate normal
red cell production in the bone marrow or to temporarily substitute
an adequate number of normal red blood cells until bone marrow
damage is repaired; (d) the attempt to improve the patient's gen-
eral state by stimulating or supplying normal alimentary secretions,
preventing the absorption of injurious end digestion products from
the digestive tract, stimulating the circulatory mechanism and the
excretory function of the liver, kidneys and surface glands; (e)
to attempt the protection of newly formed and old red blood cells
in selected cases by removal of the hyperlytic spleen and intra-
abdominal infected tissue.



86 THE AMERICAN CONGRESS ON INTERNAL MEDICINE