IRON DEPOSITS IN THE BODY AND THEIR
PATHOLOGIC SIGNIFICANCE
A
REVIEW
GEORGE S. STRASSMANN, M.D.
Department of Pathology, Metropolitan State Hospital, Waltham, Massachusetts
This review is concerned with a discussion of the pathologic importance of
iron deposits in human tissues insofar as they can be demonstrated by histochemical methods. The review pertains to the interrelationships between iron
deposits, iron metabolism, diseases and injuries. Further related details may be
found in the papers by Harm,83 Granick, 78,79 Finch,67 Hegstedt, 91 Kinney and
his co-Avorkers,108 the symposium by Sunderman and his associates208 and in
the German reviews by Lintzel121 and by Schmidt.185
HISTORY
218
In 1847, Virchow published the first gross and microscopic descriptions of
hematogenous pigments visible in human autopsy material. His observations
contributed much to our present knoAvledge of these deposits. He distinguished
2 different blood pigments derived from effused red cells in hemorrhagic areas.
Grossly, both pigments presented brown or yelloAV discoloration of the tissues.
Microscopically, in the center of the hemorrhage, yelloAV rhomboid crystals or
globules were found, and these were termed hematoidin. They reacted with
strong acids in a manner similar to bile pigment. The other pigment appeared
as brown granules within phagocytic cells at the periphery of the hemorrhage.
It was believed to be related to hemin or hematin. Virchow also described the
brown discoloration of the lungs in mitral stenosis,.used the expression "brown
induration of lungs," and observed many pigmented phagocytes within the
alveoli. According to Virchow, cellular activity was essential for the production
of the granular intracellular blood pigment, but not for hematoidin which, he
believed, appeared only in dead tissue.
In 1867 Perls159 introduced the Prussian blue reaction as a means of demonstrating iron in microscopic sections. Both pigments could be differentiated by
this method. The granular intracellular pigment stained blue, indicating the
presence of compounds of ferric oxide; the yellow hematoidin pigment remained
unstained. Occasionally, hematoidin was also found in phagocytic cells. In such
instances, it was believed that having been formed in the dead tissue, it was
later taken up by mesenchymal phagocytes.45, 101,113, 123, 185
The term "hemosiderin" was proposed by Neumann in 1888 for the ironReceived for publication August 10, 1953.
Dr. Strassmann is Pathologist.
Review articles in the Journal are under the direction of E. A. Gall, M.D., Associate
Editor.
453
454
STRASSMANN
VOL.
24
containing intracellular pigment that appears brown and granular in unstained
material and with ordinary stains.146 Quincke164"166 introduced ammonium sulfide
in the staining technic. By this means the ferric salts are reduced to ferrous iron
and black ferro sulfide (FeS) is formed. A combination of ammonium sulfide
and potassium ferricyanide in acid solution, a method known as Tumbull's
reaction, is preferred by many pathologists because it demonstrates free ferrous
and ferric protein compounds at the same time.101
Recently, Rich170"173 demonstrated hematoidin (bilirubin) in tissue cultures
of mesenchymal cells. It thus appears that hematoidin may be produced by the
activity of living cells and is not formed in dying or dead tissue alone as had
formerly been believed. 42 ' 44 ' 146,150 In animal experiments, Quincke164"166 demonstrated both hemosiderin and hematoidin in tissues by the injection of blood.
He gave the name "siderosis" to the accumulation of iron deposits in the organs
under varying conditions (anemias). Duerck42 (1892) investigated the time necessary for the formation of hematoidin and hemosiderin after hemorrhage into
tissues. Iron-carrying phagocytes were named "siderophages" or "siderophoric
cells" by Arnold4 in 1900.
Bronze diabetes, the combination of cirrhosis of the liver, diabetes and pigmentation of the skin28'89 was recognized by Trousseau214 as early as 1865 but was
first described in detail by Chauffard and Hanot in 1881. Von Recklinghausen216 coined the name "hemochromatosis" for this entity in 1889. He recognized that an excess of 2 different pigments was present in the tissues of patients
with this disease. The liver and many parenchymatous organs were overloaded
with hemosiderin and in some tissues a non-iron-containing pigment also appeared. This, Von Recklinghausen called "hemofuscin." The latter pigment
appears not to be of hematogenous origin, and is similar either to the wear-andtear pigment, lipofuscin, or to melanin. 101 ' 186 ' 228 Incidentally, it had long been
known that iron is normally stored in the spleen, liver, bone marrow, lymph
nodes and other organs.235
HISTOCHEMICAL DEMONSTRATION OF IRON DEPOSITS
With specific iron stains only a small amount of body iron becomes visible in
the gross or in microscopic sections of tissues. The largest amount of body iron
(60-70 per cent) is combined with protein in a form that cannot be demonstrated
by staining methods. 57 ' 121,156 In this category is the iron of hemoglobin and
myohemoglobin.78'83 Warburg's 220,221 functional cellular iron attached to
cytochrome or catalase is not stainable, nor is storage iron (ferritin) in liver,
spleen, bone marrow or lymph nodes ordinarily demonstrable. Ferritin gives
the iron reaction, only if it is present in excess.76"80 In order to calculate the exact
iron content of organs, chemical methods are necessary.16 Some relation frequently exists between the increased amount of iron, demonstrated by histochemical methods and that by chemical methods. 69, 121
The successful use of any histochemical stain for iron depends on the skill of
the technician. TurnbuU's reaction was recommended by Hueck.101 Bunting
used equal parts of 20 per cent potassium ferricyanide and 1 per cent hydro-
APR. 1954
IRON DEPOSITS IN BODY
455
chloric acid for the demonstration of the ferrous iron and an equal mixture of
2 per cent potassium ferrocyanide and 2 per cent hydrochloric acid to demonstrate ferric iron. He preferred not to use ammonium sulfide nor any counterstain ;21 more iron can certainly be demonstrated in tissues without any counterstain. The diffuse blue discoloration obtained with either the Perls or the
Turnbull reaction in some organs (spleen, lentiform nucleus of brain) disappears or
is obscured by any counterstain. Most demonstrable iron deposits of the body
consist of hemosiderin and are free ferric and not ferrous iron protein compounds.
For many years I have used Gomori's74 modification of the Prussian blue reaction. The sections are stained with equal amounts of 10 per cent potassium ferrocyanide and 20 per cent hydrochloric acid. 120 1 prefer a counterstain with lithium
carmine followed by 1 per cent acid alcohol, distilled water, dehydration and
mounting.
Hemosiderin, a ferric hydroxide protein, cannot be demonstrated by potassium
ferricyanide alone.30 In order to unmask138 more iron, Liilie recommended the
use of hot acid alcohol or hydrogen peroxide prior to the iron stain.120 The Gillmans found these procedures or even slight putrefaction of value in iron staining.67"70 Unfortunately, the blue stain of the Prussian blue and Turnbull reactions
fades, often in a relatively short time. Quincke's166 ammonium sulfide is not a
specific stain for iron, since it forms black precipitates also with other metals
such as lead and silver. Formaldehyde slowly dissolves the iron.119'207 Often in
autopsy material preserved in formaldehyde for long periods neither hemosiderin
nor similarly reacting iron compounds can be demonstrated.192 In critical determination iron-free instruments (glass needles), iron-free distilled water and
freshly prepared stains should be used to prevent false-positive precipitates.
Ferritin, the usual form of storage iron is ordinarily invisible in microscopic
sections. It can be demonstrated as ferritin crystals in tissue extracts of organs
by means of 20 per cent cadmium sulfate.75"80 Hemosiderin is more readily demonstrable although its chemical composition is similar to that of ferritin. This
is probably the case because hemosiderin consists of larger clusters of concentrated, free, ferric hydroxide-protein compounds. 30 ' 7S
IRON METABOLISM
The investigations of Granick,75"80 Finch and his co-workers,67 and many
others83' 98' 121' 185t 1 9 7 - 1 9 9 > 2 0 8 have confirmed earlier studies that iron is absorbed
via the intestinal (duodenal) mucosa usually in the form of ionizable ferrous
iron. Ferrous iron is more readily absorbed than ferric iron and better from
acid than alkaline medium. It is more soluble in the presence of bicarbonate or
as a loose complex with amino acids. In the presence of oxygen the ferrous iron
is oxidized in the mucosa to ferric iron and deposited as ferritin. If the mucosal
cells are saturated with ferritin no additional iron is absorbed from the intestine. Ferritin regulates the uptake of iron by the mucosa and prevents the absorption of an excess. Beyond the intestine the reducing mechanism of the body cells
reconverts ferric iron into the ferrous state.76"80 Therefore, in the body a frequent
change occurs from ferrous to ferric and from ferric to ferrous iron. From the
456
STHASSMANN
VOL. 24
intestinal mucosa iron is released and enters the blood stream. It is there combined with beta globulin and transported as siderophilin, a ferric compound.
It reaches the liver by way of the portal circulation and is stored in the Kupffer
and parenchymatous cells as ferritin. Some iron may reach the bone marrow
directly for formation of hemoglobin.208 Ferritin is also stored in other cells of
the reticuloendothelial system (RES), i.e., bone marrow, spleen and lymph nodes.63
The absorption, transportation, storage, mobilization, utilization and excretion
of the ingested iron has been traced recently by numerous investigators with the
aid of radioactive iron isotopes.26,31~38, 64"58, 63"65, 133-135, 157 Hemoglobin is formed
in the bone marrow after the iron has been liberated from serum globulin. In
combination with pyrrol pigment (protoporphyrin) and native globin, iron is
utilized for the synthesis of hemoglobin. 175208224 The life span of hemoglobin
iron in the erythrocytes is limited and varies.6*7, m Red cells are periodically
destroyed, and the iron liberated from hemoglobin is stored as ferritin or hemosiderin in the spleen and other reticuloendothelial components.
There is, thus, daily destruction and new formation of hemoglobin.208 As new
hemoglobin synthesis is required, the iron may be mobilized from the storage
organs. Iron is excreted only in minimal amounts through the mediums of bile,
urine or stool. Iron metabolism is relatively independent of absorption or excretion of iron, as long as enough storage iron is present. After blood loss, the storage
iron is mobilized for hematopoiesis. The rapidity of this process depends on the
amount of storage iron and is slowed down after depletion of the iron
depots. 36, 54"68, 60, 63'66 A large amount of storage iron is usually found in the
liver of newborns.185 Serum and plasma also contain small amounts of iron. 9, 133-135
The uptake of iron by the body varies and depends on the manner of its administration (by mouth or intravenously, in ferrous or ferric form or as inorganic
or organic compounds).60, 162,197-199 Iron introduced parenterally is stored essentially by the cells of the RES.162 Localized iron deposits resulting from hemorrhages are utilized only to a limited degree and very slowly for hematopoiesis.
Many phagocytes laden with hemosiderin remain in hematomas for months or
years. The amount of stainable iron in the storage organs varies greatly. Many
factors (age, disease, nutrition, anemia, poisoning, rapid or prolonged blood
destruction, blood loss, blood transfusions, administration of iron) influence
the iron content of the organs.186
If the RES and the parenchymatous cells are overloaded with iron, some iron
may be released, enter the blood stream and be stored in the form of hemosiderin.
This occurs not only in the storage areas but in many other parenchymatous and
glandular organs as well (hemosiderosis and hemochromatosis).
Normally, the total amount of iron in the body of an adult person is estimated
to be 4-5 Gm., of which iron porphyrin (heme compound) comprises 3 Gm.,
myohemoglobin, 0.13 Gm. and the heme enzymes (cytochrome, catalase, peroxidase), 0.004 Gm.78 Nonheme iron is composed of monomolecularly dispersed
ferrous iron and siderophilin (a ferric iron compound), 0.004 Gm. and of micelles
of ferric hydroxide units (ferritin, noncrystallizable ferritin, hemosiderin) comprising 0.4 to 0.8 Gm.78 The total heme iron, therefore, constitutes 75 per cent
APR. 1954
IRON DEPOSITS IN BODY
457
of body iron and the nonheme iron represents 15 per cent. About 10 per cent
of the total body iron is not accounted for.75"80 The ferric hydroxide units (ferritin and hemosiderin) tend to aggregate in clusters and are used for the replacement of lost or destroyed iron. Ferritin also regulates the iron absorption of the
intestinal mucosa and the placenta. It inhibits adrenal function and may play a
role in the production of shock.210 Large clusters of ferritin form hemosiderin.
Hahn83 calculates that in the dog 65 per cent of the total body iron is represented
by hemoglobin and myohemoglobin iron, 20 per cent by both storage and available iron and 15 per cent by cellular and parenchymatous iron. In the body,
hemoglobin is formed from liberated iron in combination with protoporphyrin
and globin. Later the hemoglobin is broken down and split into globin, ferritin
(hemosiderin) and bilirubin. The transformation from iron beta globulin to
ferritin and from ferritin to iron beta globulin may occur in either direction. 37 ' 67,78
IRON IN BRAIN
Basophilic incrustations of capillaries and arterioles and similar perivascular
deposits in the globus pallidus and the granular layer and dentate nucleus of
the cerebellum of adults are not rare. Their nature and origin are still doubtful.
In the globus pallidus these incrustations usually contain free iron compounds
that are demonstrable by iron stains. In the cerebellum, on the other hand, the
incrustations frequently may be free of iron. Perusini160 first described iron
deposits in the region of the extrapyramidal system (1912). Later, Spatz 192,194, 196
studied them in greater detail. In the human adult and in old, large animals, in
gross sections of the globus pallidus, the striate body and the substantia nigra,
he often found a diffuse bluish hue on staining with the Perls and Turnbull
methods, indicating the presence of large amounts of free iron compounds. Also,
the pineal body and the amyloid bodies of the choroid plexus often contain free
iron.47, 66
In some patients exhibiting progressive rigidity and mental deterioration,
Hallervorden and Spatz observed at autopsy a brown color of the globus pallidus
and the substantia nigra. These areas gave a strong iron reaction, both grossly
and microscopically. The disease has been named Hallervorden-Spatz disease or
progressive pallidal degeneration. 48 ' 87, 9 2 ' 1 0 5 , 1 0 6 ' 2 1 6 ' 2 2 7 Benda found similar
accumulations of iron in patients with torsion dystonia."
In routine examinations of brains of psychotic patients large amounts of ironcontaining incrustations are frequently found in vessel walls and in perivascular
spaces in the globus pallidus. 46 ' 82 ' 103 ' 155 They have been reported in psychotic
patients with cerebral arteriosclerosis but also in elderly persons with schizophrenia, in general paresis, and following CO poisoning, electrocution and
encephalitis.192, 194' 196,201,203,204 -p n e deposits are not specific for any form of
mental disease.192,201 Increased iron deposits in the lenticular nucleus are sometimes but not always found in hepatolenticular degeneration (Wilson's disease).33, ° 6 ' 212,22e In kernicterus, with or without associated erythroblastosis
fetalis, the yellow discoloration of the lenticular nucleus is not the result of
iron deposition but of a bilirubin-like iron-free substance that fades easily during
458
STRASSMANN
VOL. 24
the procedures of fixation and embedding. This staining is seen also in the hippocampus and in pontine and medullary nuclei. 10,39,40, 186,217,236,237
Bunting 21 demonstrated ferrous as well as ferric compounds in the cerebral
vascular incrustations and deposits by using either potassium ferrocyanide or
potassium ferricyanide without counterstain. He believed that there was a
fluctuating transition from ferrous to ferric loose protein compounds. However,
in routine iron stains of these areas usually much more iron deposit is found in
staining with ferropotassium cyanide than with ferripotassium cyanide. This
indicates that most of the deposits are in the nature of ferric oxide. If large
amounts of iron are present in these areas, even the neuroglia and the nerve
cells contain demonstrable iron. 192,194,196 This ferrugination of nerve cells can
also be found occasionally in various portions of the brain at the sites of older
contusions or hemorrhages.167 In these regions the iron is identical with hemosiderin and is seen also within phagocytes. Hemosiderin-laden phagocytes are
often observed around areas of cerebral infarction, where they may enter both
the perivascular spaces and the blood vessel wall.204 Increased iron deposits in
the extrapyramidal areas, the choroid plexus, the pineal body and the ependymal
layers of the ventricle have been observed in hemochromatosis.24, 97, 118,228
Sheldon183"190 found increased amount of iron in the brain in this disease, using
histologic and chemical technics.212 Isolated leptomeningeal hemochromatosis
or hemosiderosis without involvement of the viscera was described by Neumann.147 The nature and origin of the iron deposits and the vascular incrustations in the extrapyramidal areas of the brain have been widely discussed.21, 82> 123, 192,201 The deposits stain in a manner similar to hemosiderin and
consist of free ferric hydroxide-protein combinations. More rarely they contain
ferrous iron compounds, apparently prior to oxidation to ferric iron.21 They are
different from hemosiderin insofar as they are frequently invisible in unstained
sections or with routine stains. If the incrustations are combined with a basophilic substance, they stain dark blue with hematoxylin and eosin and with Nissl
stains. Rarely, they contain calcium. The Kossa stain is usually negative 156, 194,203
but Bunting21 found evidence of calcium on staining with alizarin red. With the
Perls or Turnbull reaction the brain deposits stain blue. They appear, in
contrast to hemosiderin, as blue extracellular perivascular globules or granules
or as more or less diffuse blue incrustations of capillary or arteriolar walls or
as blue deposits in the neuroglia and nerve cells. The material rarely is noted in
mesodermal phagocytes. 194,201 As a rule, no damage to the nervous elements
appears and there are no evidences of preexisting hemorrhages or glial reactions
near the iron deposits or incrustations. Only patients with hypertension, cerebral arteriosclerosis, meningovascular syphilis or other vascular disturbances
may show cystic cavities, perivascular gliosis, endarteritis, softenings, arteriolosclerosis and phagocytes with blood pigment in relation to the incrustations.
This appears to be coincidental, since impairment of the vascular supply and
resulting anoxemia usually affect the same areas. It is felt that the iron deposits
in adult human brains in the extrapyramidal region are not of hematogenous
origin. They probably represent products of disintegration or degradation of
APR. 1954
IRON DEPOSITS IN BODY
459
the cellular or functional iron of nerve and glial cells. A common, underlying,
damaging factor could be a temporary or recurrent anoxemia, hypoxemia or
ischemia, leading to liberation and degradation of the cellular iron. 155 ' 206 The
vulnerability of these areas to anoxemia makes such a hypothesis probable. Krai
and Lehmann110, " 4 found an increased iron content in the spinal fluid of deteriorated patients with schizophrenia and in patients with organic brain disease.
They believed that a disturbance of the iron metabolism of the nervous system
was responsible for this increase and that it was not attributed to a lowering of
the barrier between blood and spinal fluid for the passage of iron.
In patients with general paresis perivascular iron deposits are found in the
cortex, the striate body, the globus pallidus and in other brain areas. These
deposits usually contain hemosiderin but there are also frequently large deposits
of cellular iron in the caudate and lenticular nuclei. Gross sections Mill give a
diffuse blue stain in general paresis with the Prussian blue or Turnbull reaction.
The pars nervosa of the pituitary gland also exhibits increased iron deposits in
this disease.122,195 It is of interest that the brain of paretic patients treated with
malaria or penicillin not only reveals less perivascular inflammation but the iron
deposits are also less conspicuous than in untreated patients.
Old hemorrhages in the brain appear brown or yellow and are often cystic.
Microscopically, there are always phagocytes containing hemosiderin at the
periphery of these lesions. Indeed, often phagocytes containing hematoidin and
incrustations of the vascular wall with hemosiderin or hematoidin are also evident. Such findings indicate hemorrhage of long standing with phagocytosis of
red cells and breakdown of hemoglobin into hemosiderin and hematoidin. 42 ' 113 ' 204
Phagocytes containing hemosiderin may be found in the subarachnoid space or
in subdural membranes for a long time after spontaneous or traumatic subarachnoid or subdural hemorrhages.
LOCALIZED DEPOSITS OF HEMOSIDERIN
Quincke was one of the first to demonstrate hemosiderin and hematoidin by
the injection of blood into animals.165 The formation of hemosiderin is a vital
reaction depending on the activity of living mesenchymal cells after phagocytosis
of erythrocytes in effused blood. No hemosiderin is formed from fluid or dried
blood outside of the body by either physical or chemical processes. 113,123,2l9
Rapid lysis of red cells in certain poisonings or transfusion reactions may result
in the intravascular formation of hemosiderin without the action of extravascular phagocytes.139"141,143, 153 The presence of red cells or granules of hemosiderin
or hematoidin within phagocytes proves that an injury or hemorrhage has occurred during life and not after death. After the introduction of blood into subcutaneous tissue of animals, phagocytes with hemosiderin appear within 24 to
48 hours. Hematoidin does not become manifest before 7 days. 42,113, 123,142,204
In the lungs of rabbits hemosiderin-laden phagocytes were found within the
alveoli 36 hours after intratracheal injection of blood.126,202 In brain injuries of
mice similar phagocytes were not apparent until 72 hours had elapsed. Phagocytes with hematoidin occurred not before 7 to 14 days after the injury and were
460
STRASSMANN
VOL. 24
less common than those with hemosiderin. 202204 Phagocytized hematoidin has
never been observed in the lungs.145 • 146' 151'182
Phagocytes with hemosiderin from hemorrhagic areas migrate early to regional lymph nodes.136'142 They are found frequently in the bronchial lymph
nodes of animals and persons after hemorrhage into the lung tissue. The time
relation found in animal experiments is not always applicable to human material. Cellular reactions, including hemosiderin formation, are often slower in the
tissues and organs of man than in animals.142'204 In the brain and most organs
of man phagocytized hemosiderin becomes visible after 5 to 7 days; 8 phagocytes
containing hematoidin, if they appear at all, after 11 to 14 days.204 A similar
time interval elapses before hemosiderin or hematoidin formation occurs in man
after hemorrhages into subcutaneous tissue, lungs, kidneys, spleen, adrenal
glands and myocardium. Walcher219 found phagocytes with hemosiderin 9 days
after contusions of the human skin. Wartman and Laipply223 observed this in
dogs 7 clays after the injection of blood into arterial Avails.
In mitral stenosis "brown induration of the lungs" is the result of repeated
small hemorrhages into the alveoli. Many siderophages are visible in the lumen
and walls of alveoli and in regional lymph nodes in such instances. 4,145 Pulmonary
accumulation of hemosiderin in chronic passive congestion of the lungs may be
followed by pulmonary fibrosis. Imbibition of elastic and reticulum fibers with
iron, granulomas with giant cells and crystals containing iron have been observed
in pulmonary hemosiderosis. 1 ' 49 ' U5 ' 116> 156> 158 ' 209 ' 232
The rapidity and degree with which iron-containing and iron-free blood pigments are formed after hemorrhage vary greatly, as mentioned, in animal and in
human tissues. It depends probably on the number of mesenchymal phagocytic
cells that can be activated and mobilized in a given area as a reaction to the
effusion. In the subarachnoid space phagocytes appear faster and earlier than in
the brain itself.8'88'204
The brown discoloration of the tissues and granular pigment within phagocytes
need not represent blood pigment. Its nature should be confirmed by special
iron stains. The dark brown pigment of melanin or carbon may resemble hemosiderin in routine stains.145' 182 Examinations of tissue and organs for iron will
often show accumulations of hemosiderin-containing phagocytes unsuspected
with routine stains. In addition to the usual storage depots, such phagocytes
are frequently found in the lungs, brain, ovaries, blood vessel Avails, old contusions, hemorrhagic ulcerations of gastrointestinal tract, certain tumors, vascular
malformations and in areas of infarction.
ENDOGENOUS HEMOSIDEROSIS AND HEMOCHROMATOSIS
Hemosiderosis indicates an excess of hemosiderin deposits in the cells of the
RES, in parenchymatous and glandular organs and in other tissues of the body.
Hemochromatosis is hemosiderosis combined Avith abnormal pigmentation by
hemofuscin, lipofuscin or melanin. 2 ' 3 ' 1 7 , 2 8 ' 1 7 5 ' 1 9 0 ' 2 1 6 ' 2 2 S Two kinds of hemosiderosis are recognized, an endogenous idiopathic variety and an exogenous
type.187 Hemosiderosis of liA'er and kidneys Avas early described by Quincke164
APK.
1954
IRON DEPOSITS IN BODY
461
in patients with pernicious anemia. Blood destruction or hemorrhage into the
tissues in any type of anemia may lead to hemosiderosis, as in hemolytic anemia,
aplastic anemia, refractory anemia, Cooley's anemia, sickle-cell disease or in
porphyria. 17,26,107,124,144,169,229,234 Hemosiderosis also occurs in infants or
adults suffering from malnutrition and deficiency diseases.41, 67~69 Several factors
may be responsible for the abnormal accumulation of hemosiderin in the storage
and other organs of the body. These are:
1. Rapid and continued destruction of erythrocytes with erythrophagia,
breakdown of hemoglobin and its conversion into hemosiderin,
2. A hemorrhagic diathesis,
3. Anemic anoxia with damage to the respiratory activity and iron metabolism
of cells,
4. Increased excretion of iron by the cells and organs or inability to excrete
iron by the body,
5. Abnormal absorption of large amounts of iron by way of the intestinal
mucosa and
6. Repeated administration of large amounts of blood, hemoglobin or iron
parenterally. 15 ' 64 " 68,71,73
Each of these factors or a combination of them may lead to increased deposits
of hemosiderin. In patients with hemosiderosis and hemochromatosis, the iron
content of the plasma is generally high.3' 14, 5 5 , 7 8 , 176'190
Hemosiderosis of the spleen follows rapid and prolonged blood destruction in
hemolytic anemia but is less conspicuous than the hemosiderosis of liver and
kidneys in pernicious anemia.180, 181, 185 Brown discoloration of the splenic capsule with perisplenitis is often found in elderly people, and is characterized by
the presence of many macrophages with hemosiderin in and beneath the capsule. On the other hand, in routine examinations of the spleen the amount of
hemosiderin in the capsule and pulp varies greatly. 181,200 There is no regular
increase of hemosiderin in the spleen in elderly people. Localized hemosiderosis is
found in or near splenic infarctions. Another type of hemosiderosis is the siderofibrosis associated often with calcium deposits and Gamma-Gandy bodies. This
is believed to be the result of impairment of the portal circulation and passive
congestion of the spleen. 43,72, U1 Elastic fibers in areas of infarction generally
have the tendency to take up iron and calcium.47, 66,109
The spleen as a storage organ always contains ferritin in relatively large
amounts. Only part of the storage iron is visible in iron stains and still less is
seen with routine stains.
In hemosiderosis and hemochromatosis the Kupffer and the parenchymatous
cells of the liver are overloaded with hemosiderin. 18,71,176 Hemosiderosis of the
liver also occurs in many other conditions, such as anemia, poisonings, infections,
deficiency diseases and after repeated transfusions.41, 68,124,132, 181,200 It is often
evident in the newborn.185 Gillman and Gillman68, 69 suggest the term "cytosiderosis" for the abnormal deposits of hemosiderin in liver and parenchymatous organs. They frequently observed cytosiderosis in malnourished South
African natives and found by chemical and histochemical methods an associated
462
STRASSMANN
VOL. 2 4
increased amount of iron in the liver and other organs of such patients. Hemosiderosis of the liver has been produced experimentally.20 •85 •94 •130 •136 •149 •166 •178 •181
The true idiopathic hemochromatosis first described by Hanot and Chauffard 28,89 and by Von Recklinghausen216 is a pathologic entity with excessive
deposits of 2 different pigments and is associated with liver cirrhosis, skin pigmentation and diabetes. 2, s. is, 22,23.190,22s j n ^ n ; s condition much ferritin and
hemosiderin are stored in all cells of the RES, the Kupffer cells of the liver, the
macrophages of the spleen, the endothelial cells of bone marrow, periportal and
other lymph nodes, in the parenchymatous cells of liver, pancreas, lungs,
in the adrenal, salivary, thyroid, parathyroid and pituitary glands and in
the pineal body, blood vessel walls, bile ducts, synovial membranes, gastroinintestinal mucosa, myocardium, sweat glands, skin, testes, choroid plexus and
urethra. Biopsies of skin and liver show a large amount of hemosiderin. Frequently, the hemosiderin deposits are less conspicuous in the spleen, bone marrow
and convoluted tubules of kidneys than in the liver and parenchymatous organs
of the body. On the other hand, the iron-free brown pigment is accumulated in
skin, connective tissue and reticulum fibers, smooth musculature of intestine,
and to a lesser degree in epithelial cells. This pigment originally called "hemofuscin" by Von Recklinghausen is either related to lipofuscin or to
melanin. 17 - 101,19 °- 228 The accumulation of both pigments is responsible for the
pigmentation of the skin. 3,69 Biopsies of the skin and liver may confirm the
diagnosis.59 Chemically, the iron content of the liver is 10 times higher than
normal. Sheldon188"190 found 40 Gm. of iron in the body, most of it in the liver,
in hemochromatosis. The role of an increased amount of copper in the liver in
the production of hemochromatosis is still doubtful. Mallory and Parker and
Hall and Butt, 8 5 , 8 6 , 126,127 produced changes in animals similar to those in hemochromatosis by experimental copper poisoning. Other investigators have not
been able to confirm the results of these experiments. 6195154161 ' 163 ' 178 Relatively
often an association of hemochromatosis with cirrhosis and primary carcinoma
of the liver has been observed.12,222 Occasionally, sudden death under shocklike
symptoms occurred in patients with hemochromatosis and was attributed
to the large amount of ferritin and its vasodepressor action. 129 ' 174 ' 210 One or
more of several factors may be connected with the development of hemochromatosis.3, 29' 131 The well-known hypothesis that an inborn, perhaps familial disorder
of liver and pancreatic cells is responsible, has been emphasized by Sheldon.196
Anoxemia resulting in impaired cellular iron metabolism has been suggested by
the Gillmans.69 However, the newest investigations by Granick, Finch and his
co-workers, and others 55,78 make it probable that hemochromatosis results
from a faulty blocking mechanism and absorption of abnormally large amounts
of iron by the intestinal mucosa over a long period of time.3 • 57 •187 •229-231 Apparently the regulatory and blocking mechanism of the mucosal cells after saturation with ferritin becomes ineffective for unknown reasons. There is thus an
excessive iron absorption over a period of years. Overloading of the Kupffer and
parenchymatous cells of the liver with ferritin and hemosiderin results in excess
iron introduced into the blood stream with distribution throughout the whole
APR.
1954
463
I R O N D E P O S I T S I N BODY
body and storage in many organs.65 The accumulation of iron in the cells of
liver, pancreas and the RES either has a toxic action directly upon the cells
(which is doubtful) or mechanically obstructs blood and lymph channels and
glandular ducts. 3 1 4 4 1 8 7 ' 2 3 1 Resulting anoxemia probably leads to damage or
necrosis of liver and pancreatic cells and is followed by fibrosis. There is also the
possibility that several unrelated damaging factors, still not quite understood
(anoxemia, nutritional deficit, metabolic disturbances), are responsible for the
combination of hemochromatosis, hepatic cirrhosis and diabetes. 3 ' 19
After repeated withdrawal of blood by phlebotomy, rapid hematopoiesis
occurs in patients with hemochromatosis. This is related to the large iron deposits. The patients do not develop significant anemia.35 In those instances in
which storage iron had been depleted after blood loss or in some types of anemia,
hematopoiesis after phlebotomy is retarded. It is concluded that the rapidity
of hematopoiesis after blood loss depends on the amount of available storage
iron.57 Not all the problems concerning hemochromatosis have been solved. The
iron is stored in excess apparently for a long time before liver cirrhosis and diabetes develop.3
E X O G E N O U S H E M O S I D E R O S I S AND
HEMOCHROMATOSIS.
TRANSFUSION
SIDEROSIS
In animal experiments exogenous hemosiderosis has been produced by many
methods. This has been accomplished by injections of blood and hemoglobin,
by the administration of iron compounds, by poisonings and by the addition of
iron to restricted diets.67, 108' 23° In patients with different types of anemia many
of the symptoms characteristic of endogenous hemochromatosis have occurred
after repeated blood transfusions for anemia (pernicious anemia, sickle-cell
anemia, Cooley's anemia, dystrophic anemia).187 Hemosiderosis, together with
fibrosis of liver and pancreas and skin pigmentation, has sometimes been observed in such instances.144,187>231 Nevertheless, true hemochromatosis with the
accumulation of iron-containing and iron-free pigment in the organs, combined
with liver cirrhosis and bronze diabetes, has not been produced by experimental
means and has rarely occurred in persons after repeated blood transfusions.100, 117'229 Indeed, in severe chronic anemia the storage of iron may be quite
marked in the absence of transfusion. It is probable, however, that the intravenous administration of whole blood or of iron compounds may lead to still
greater deposits of iron. It is entirely possible also that abnormal amounts of
iron in patients with anemia may be absorbed through the intestinal mucosa as
the result of a faulty blocking mechanism.
Hemoglobin iron is taken up by the kidneys. These organs always contain
iron on chemical examination. Microscopically, demonstrable hemosiderin in the
kidneys (renal siderosis) is found under abnormal conditions in connection with
some types of anemias (pernicious anemia, hemolytic anemia and blackwater
fever).13, 16, 60 ' 81 ' 163' 177,180 It is found also after hemorrhages, injuries, infarctions, intoxications, infections or tumors of the kidney.152 In animals injections
of hemoglobin lead to renal siderosis.112,149 Most conspicuous are iron deposits in
the kidney after transfusion of incompatible blood. 6 0 , 8 1 1 5 3 ' 2 3 3 Transfusion
464
STRASSMANN
VOL. 2 4
reaction results in intravascular hemolysis, filtration of hemoglobin through the
glomeruli and formation of hemoglobin and methemoglobin casts in the tubular
lumen. The casts rarely give a positive reaction, since the iron in them is firmly
attached to the hemoglobin. Increased absorption of hemoglobin by the tubular
epithelium, however, results in secondary formation and deposits of hemosiderin
in the cells of the proximal convoluted tubules. The kidneys reabsorb large
amounts of blood pigment, and the iron is then redistributed to the liver and
reticuloendothelial system.57
In anemias, iron is frequently transferred from the circulating blood to other
tissues without change of the total body iron. Only in anemias with iron deficiency may storage of iron be decreased.90
BIBLIOGRAPHY
1. AHVENAINEN, E . K . , AND CALL, J . D . : Pulmonary hemorrhage in infants. Am. J .
Path., 28: 1-23, 1952.
2. ALTHAUSEN, T . L., AND K E R R , W. J . : Hemochromatosis; report of 3 cases with results
of insulin therapy in 1 case. Endocrinology, 11: 377-422, 1927.
3. A L T H A U S E N , T . L., D O I G , R. K . , W I D E N , S., M O T T E R A M , R., T U R N E R , C. N . , AND
4.
5.
6.
7.
M O O R E , A . : Hemochromatosis; investigation of 23 cases with special reference to
etiology, nutrition, iron metabolism and studies of hepatic and pancreatic function.
Arch. I n t . Med., 88: 553-570, 1951.
ARNOLD, J . : Uber Siderosis unci siderofere Zellen; die Rolle der Zellgranula bei der
hiimatogenen Pigmentierung. Virchows Arch. f. p a t h . Anat., 161: 284-310, 1900.
ASHBY, W.: The determination of the length of life of transfused blood corpuscles in
man. J . Exper. Med., 29: 267-281, 1919.
ASHBY, W.: Stud}' of transfused blood. I . T h e periodicity in eliminative activity shown
by the organism. J . Exper. Med., 34: 127-146, 1921.
ASHBY, W.: Red cells, the span of life of t h e red blood cell. In George R . Minot Symposium on Hematology. New York: Grune & S t r a t t o n , I n c . , 1949, p p . 637-651;
Blood, 3 : 486-500, 1948.
8. BAC.O.ENSTOSS, A. H . , K E R N O H A N , J . W., AND D R A P I E W S K I , J . F . : T h e healing process
in wounds of t h e brain. Am. J . Clin. P a t h . , 13: 333-348, 1943.
9. BARKAN, G., AND SCHALES, O . : Chemischer Aufbau und physiologische Bedeutung
des "leicht a b s p a l t b a r e n " Bluteisens. Ztschr. f. physiol. Chem., 248: 96-116, 1937.
Bildungsmoglichkeiten und Eigenschaften der Pseudohamoglobine. Ztschr. f.
physiol. Chem., 253: 83-104, 1938.
10. BECKER, P . F . L., AND VOCEL, P . : Kernicterus; review with report of findings in s t u d y
of 7 cases. J . Neuropath. & Exper. Neurol., 7: 190-215, 1948.
11. B E N D A , C : Chronic rheumatic encephalitis, torsion dystonia and HalleivordenSpatz disease. Arch. Neurol. & Psychiat., 61: 137-163, 1949.
12. B E R K , J . , AND L I E B E R , M.: Primary carcinoma of t h e liver in hemochromatosis. Am.
J. M . S c , 202: 708-714, 1941.
13. BLACK, R. H . : Resorption of haemoglobin by renal tubules in hemoglobinuria. Ann.
T r o p . Med., 42: 90-94, 1948.
14. BLANTON, W. B . , AND HEALY, W . : Hemochromatosis; report of 4 cases. Arch. I n t .
Med., 27:406-120, 1921.
15. BLOOM, D . , WESTMAN, L. H . , AND LALICH, J . J . : Renal siderosis in rabbits following
injections of hemoglobin and organic iron. Arch. Path., 53: 331-338, 1952.
16. BOONIARD, R. P . , AND W H I P P L E , G. H . : Iron content of blood-free tissues and viscera;
variations due to diet, anemia and hemoglobin injections. J . Exper. Med., 55: 653665, 1932.
17. BOMFORD, R. R., AND RHOADS, C. P . : Refractory anemia; clinical and pathologic
aspects. Quart. J . Med., 10: 235-281, 1941.
18. BORK, K.: Zur Lehre von der allgemeinen Hamoehromatose. Virchows Arch. f. p a t h .
Anat., 269:,178-208, 1928.
19. BOULIN, R . : Etude statistique de 70 cas de diabete bronzed Presse m6d., 53: 326-327,
1945.
20. BROWN, W. H.: Changes in t h e hemosiderin content of t h e rabbit's liver during autolysis. J . Exper. Med., 12: 623-637, 1910.
21. BUNTING, H.: Histochemical analysis of pathological mineral deposits a t various sites.
Arch. Path., 52: 458-469, 1951.'
22. B U T T , H. R., AND WILDER, R. M.: Hemochromatosis; report of 30 cases in which diagnosis was made during life. Arch. P a t h . , 26: 262-273, 1938.
APR. 1 9 5 4
IRON DEPOSITS IN BODY
465
23. C A I N , J. C : Hemochromatosis; report of 6 cases. Texas State J. Med., 36: 356-363,
1940.
24. CAMMERMEYER, J . : Deposition of iron in paraventricular areas of t h e human brain in
hemochromatosis. J. Neuropath. & Exper. Neurol., 6: 111-127, 1947.
25. CAPPELL, D . F . : T h e late results of intravenous injection of colloidal iron. J. P a t h .
& Bact., 33: 175-196, 1930.
26. CAUTWRIGHT, G.,
H U G U L E Y , C., ASHENBRUCKER, H . ,
F A Y , J.,
AND W I N T R O B E ,
M.:
Studies on free erythrocyte protoporphyrin, plasma iron and plasma copper in
normal and anemic subjects. In George Minot Symposium of Hematology. New
York: Grune & S t r a t t o n , I n c . , 1949, p p . 918-942.
27. CARTWRIGHT, G., L A U R I T S E N , M., J O N E S , P . , M E R R I L L , 1., AND W I N T R O B E , M . :
28.
29.
30.
31.
32.
33.
34.
35.
The
anemia of infections. I. Hypoferremia, hypercupreniia and alterations in porphyrin
metabolism in patients. J. Clin. Investigation, 25: 65-80, 1946.
CHAUFFARD, A., AND H A N O T , V.: Cirrhose hypertrophique pigmentaire dans le diabete
sucrc. R e v . de Med., 12: 385, 1882.
CHESNER, C : Hemochromatosis; review of literature and presentation of a case without pigmentation or diabetes. J. L a b . & Clin. Med., 31: 1029-1036, 1946.
COOK, S. F . : T h e structure and composition of hemosiderin. J . Biol. Chem., 82: 595609, 1929.
Coi'i', D . H . , AND GREENBERG, D . : Tracer study of iron metabolism with radioactive
iron; methods: absorption and excretion of iron. J. Biol. Chem., 164: 377-3S7, 1946.
CRUZ, W. 0 . , H A H N , P . F . , AND B A L E , W. F . : Hemoglobin radioactive iron liberated by
erythrocyte destruction (acetvlphenylhydrazine) promptly reutilized to form new
hemoglobin. Am. J. Physiol., 135: 595-599, 1942.
CUMINGS, J. N . : T h e copper and iron content of brain and liver in the normal and in
heptolenticular degeneration. Brain, 71: 410-415, 1948.
DAVIDSON, W. M., AND JENNISON, R. F . : T h e relationship between iron storage and
anaemia. J. Clin. P a t h . , 5: 281-285, 1952.
D A V I S , W. D . , J R . , AND ARROWSMITH, W. R. F . : T h e effect of repeated bleeding in
hemochromatosis. J. L a b . & Clin. Med., 36: 814-815, 1950.
36. DUBACH, R., CALLENDER, S. T., AND M O O R E , C. V . : Studies in iron t r a n s p o r t a t i o n and
metabolism; absorption of radioactive iron in patients with fever and with anemias
of varied etiology. Blood, 3 : 526-540, 1948.
37. D U B A C H , R., CALLENDER, S. T . , AND M O O R E , C. V . : Studies in iron t r a n s p o r t a t i o n and
metabolism. In George Minot Symposium of Hematology. New York: Grune &
S t r a t t o n , I n c . , 1949, p p . 903-917."
38. D U B A C H , R., M O O R E , C. V., AND M I N N I C H , V.: Studies in iron t r a n s p o r t a t i o n and
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
metabolism. V. Utilization of intravenously injected radio-active iron for hemoglobin synthesis and an evaluation of t h e radio-active iron method for studying iron
absorption. J. L a b . & Clin. Med., 31: 1201-1222, 1946.
D U B L I N , W.: Pathogenesis of kernicterus. J. Neuropath. & Exper. Neurol., 8: 119-120,
1949.
D U B L I N , W. B . : Neurologic lesions of erythroblastosis fetalis in relation to nuclear
deafness. Am. J. Clin. P a t h . , 21: 935-939, 1951.
D U B O I S , M . : Die Hiimosiderosis bei den Erniihrungsstorungen der Siiuglinge. Virchows
Arch. f. path. Anat., 236: 493-503, 1922.
DUERCK, H . : Beitrag zur Lehre von den Veriinderungen und der Altersbestimmung von
Blutungen im Centralnervensystem. Virchows. Arch. f. p a t h . Anat., 130: 29-93,
1892.
D U E R R , R.: Bantimilz und hepatolienale Fibrose. Beitr. z. path. Anat. u. z. allg.
P a t h . , 72: 418-455, 1924.
D U N N , T . B . : Hematoidin crystals in reticulum cell sarcoma of the mouse and in newborn human tissues. Mil. Surgeon, 109: 350-359, 1951.
DUNZELT, H . : tlber das Auftreten von Haematoidininkristallen beim Icterus E r wachsener. Centralbl. f. allg. P a t h . u. p a t h . Anat., 20: 966-970, 1909.
E A V E S , E . C : A contribution to the study of deposits containing calcium and iron in
the brain. Brain, 49: 307-332, 1926.
EHRLICH, S.: Eisen- und Kalkimpriignation in menschlichen Geweben, insbcsondere
den elastischen Fasern. Centralbl. f. allg. P a t h . u. p a t h . Anat., 17: 177-180, 1906.
E I C K E , W. J . : Neue Beobachtungen iiber die Hallervorden-Spatzsche Krankheit.
Arch. f. Psychiat., I l l : 514-546, 1940.
ELLMAN, P., and G E E , A.: Pulmonary haemosiderosis. Brit. Med. J., 2 : 384-390, 1951.
ELVEHJEM, C. A., AND SHERMAN, W. C.: T h e availability of iron from different sources
for hemoglobin formation. J. Biol. Chem., 95: 363-370, 1932.
ELVEHJEM, C. A., AND SHERMAN, W. C : T h e action of copper in iron metabolism. J.
Biol. Chem., 98: 309-319, 1932.
E N G L E , R. L., J R . : T h e association of iron-containing crystals with Schaumann bodies
in t h e giant cells of granulomas of sarcoid type. Am. J . Path., 27: 1023-1035, 1951.
466
STRASSMANN
VOL. 2 4
53. F A H R , T . : Lymphatischer Portalring und Hamoglobinstoffwechsel. Virchows Arch.
f. p a t h . Anat., 246: 89-105, 1923.
54. F I N C H , S., H A S K I N S , D . M., AND F I N C H , C. A . : Iron metabolism. Hematopoiesis following phlebotomy. Iron as limiting factor. J . Clin. Investigation, 2 9 : 1078-1086, 1950.
55. F I N C H , C . A . : Iron metabolism in hemochromatosis. J . Clin. Investigation, 28: 780781, 1949.
56. F I N C H , C. A., G I B S O N , J. G., I I , PEACOCK, W. C , AND F L U H A R T Y , R. G.: Iron m e t a b -
olism; utilization of intravenous radioactive iron. Blood, 4: 905-927, 1949.
57. F I N C H , C. A., H E G S T E D T , D . M . , K I N N E Y , T . D . , T H O M A S , E . , R A T H , C. E . , H A S K I N S ,
D . , F I N C H , S., AND FLUHARTY, R. G . : Iron metabolism; pathophysiology of iron
storage. Blood, 5: 983-1008, 1950.
5S. F I N C H , C. A., W O L F F , J . A., R A T H , C. E . , AND F L U H A R T Y , R. G . : I r o n m e t a b o l i s m ;
erythrocyte iron turnover. J . L a b . & Clin. Med., 34: 1480-1490, 1949.
59. FISHBACK, H . : Clinical demonstration of iron in skin in hemochromatosis. J . L a b . &
Clin. Med., 25: 9S-99, 1929.
60. F L I N K , E . : Blood transfusion studies; relationship of hemoglobinemia and of p H of
urine to renal damage produced bv injections of hemoglobin solutions into dogs.
J. L a b . & Clin. Med., 33: 223-261, 1947.
61. F L Y N N , F . , AND VON GLAHN, W . : A chemical and pathologic study of t h e effects of
copper on t h e liver. J . Exper. Med., 49: 5, 1929.
62. FREEMAN, W.: Deficiency of catalytic iron in the brain in schizophrenia. Arch. Neurol.
& Psychiat., 24: 300-310, 1940.'
63. G I B S O N , J . G., I I , A U B , J., E V A N S , R., AND PEACOCK, W . t T h e post-transfusion survival
of preserved human erythrocytes stored as whole blood or in resuspension after removal of plasma, bv means of 2 isotopes of radioactive iron. J . Clin. Investigation,
26: 715-73S, 1947.
64. G I B S O N , J . G., I I , PEACOCK, W., E V A N S , R., SACK, T . , AND A U B , J . : T h e r a t e of post-
transfusion loss of non-viable stored human erythrocytes and t h e re-utilization of
hemoglobin derived radioactive iron. J . Clin. Investigation, 26: 739-746, 1947.
65. G I B S O N , J. G., I I , W E I S S , S., E V A N S , R., PEACOCK, W., I R V I N E , J., G O O D , W., AND K I P ,
A.: T h e measurement of t h e circulating red cell volume by means of 2 radioactive
isotopes of iron. J . Clin. Investigation, 25: 616-626, 1946. •
66. G I E R K E , E . : tlber den Eisengehalt verkalkter Gewebe unter normalen und p a t h o logisehen Bedingungen. Virchows Arch. f. p a t h . Anat., 167: 318-351, 1902.
67. GILLMAN, J . , AND GILLMAN, T . : Structure of t h e liver in pellagra. Arch. P a t h . , 40:
239-263, 1945.
68. GILLMAN, J., AND GILLMAN, T . : T h e pathogenesis of cytosiderosis (hemochromatosis)
as evidenced in malnourished Africans. Gastroenterology, 8: 19-23, 1947.
69. GILLMAN, J . , MANDELSTAM, J . , AND GILLMAN, T . : Comparison of chemical and histo-
logical estimations of iron and copper content of livers of Africans in relation to
pathogenesis of cvtosiderosis and cirrhosis (hemochromatosis). South African J .
M. S c , 10: 109-136, 1945.
70. GILLMAN, T . , AND IVY, A.: Histological study of participation of intestinal epithelium,
reticulo endothelial system a n d lymphatics in iron absorption and t r a n s p o r t ; preliminary report. Gastroenterology, 9: 162-169, 1947.
71. GLADSTONE, S.: Iron in liver and spleen after destruction of blood and transfusions.
Am. J . D i s . Child., 41: 81-105, 1932.
72. GLASSUNOW, M . : Uber die sidero-fibrosen Knotchen der Milz. Virchows Arch. f. p a t h .
Anat., 278: 110-124, 1930.
73. GOETSCH, A. T . , M O O R E , C. V., AND M I N N I C H , V . : Observation on t h e effect of massive
74.
75.
76.
77.
78.
79.
80.
SI.
doses of iron given intravenously t o patients with hyperchromic anemia. Blood,
1: 129-142, 1946.
GOMORI, G.: Microtechnical demonstration of iron; a criticism of its methods. Am.
J . P a t h . , 12: 655-664, 1936.
GRANICK, S.: Personal communication to author.
GRANICK, S.: Ferritin; its properties and significance for iron metabolism. Chem. R e v . ,
38: 379-403, 1946.
GRANICK, S.: Ferritin; increase of t h e protein apoferritin in t h e gastrointestinal
mucosa as a direct response to iron feeding. Function of ferritin in the regulation of
iron absorption. J . Biol. Chem., 164: 737-746, 1946.
GRANICK, S.: Iron metabolism and hemochromatosis. Bull. New York Acad. Med.,
25: 403-428, 1949.
GRANICK, S.: S t r u c t u r e and physiological functions of ferritin. Physiol. R e v . , 3 1 :
489-511, 1951.
GRANICK, S., AND MICHAELIS, L . : T h e presence of ferritin in the duodenal mucosa and
liver in hemochromatosis. Proc. Soc. Exper. Biol. & Med., 66: 296-29S, 1947.
D E G O W I N , E . L., WARNER, E . D . , AND RANDALL, W. L.: Renal insufficiency from blood
APR.
1954
I R O N D E P O S I T S I N BODY
467
transfusion; anatomic changes in man compared with those in dogs with experimental hemoglobinuria. Arch. I n t . Med., 6 1 : 609-630, 193S.
82. HADEIELD, G . : Sidcrosis of globus pallidus; its relation to bilateral necrosis. J . P a t h .
& Bact., 32: 135-148, 1020.
83. I-IAHN, P . F . : Metabolism of iron. Medicine, 16: 249-266, 1937.
84. H A H N , P. F . , B A L E , W. F . , R O S S , J . F . , H E T T I G , R., AND W H I P P L E , G. H . : R a d i o iron
85.
86.
87.
88.
89.
90.
in plasma does not exchange with hemoglobin iron in red cells. Science, 92: 131-132,
1940.
H A L L , E . M., AND B U T T , E . M . : Experimental pigment cirrhosis due to copper poisoning; its relation to hemochromatosis. Arch. P a t h . , 6: 1-25, 1928.
H A L L , E . M., AND MACKAY, E . M . : Experimental hepatic pigmentation and cirrhosis.
Am. J. P a t h . , 7:327-342, 1931.
HAI.LEHVORDEN, J . , AND SPATZ, H . : Eigenartigo E r k r a n k u n g im extrapyramidalen
Svsfem m i t besonderer Beteiligung des Globus pallidus und der Substantia nigra.
Ztschr. f. d. ges. Neurol, u. Psychiat., 79: 254-302, 1922.
HAMMES, E . M . , J R . : Reaction of the meninges to blood. Arch. Neurol. & Psychiat.,
52: 505-514, 1944.
H A NOT, V., AND SCHACHMANN, M . : Sur la cirrhose pigmentairo dans le diabete sucre\
Arch, de physiol. norm, et p a t h . , 7: 50-87, 1886.
H E A T H , C. W., AND PATEK, A. J . , J R . : T h e anemia of iron deficiency. Medicine, 16:
267-350, 1937.
91. H E G S T E U T , D . M., FINCH, C. A., AND K I N N E Y , T . D . : T h e influence of diet on iron a b -
sorption; interrelation of iron and phosphorus. J . Exper. Med., 90: 147-156, 1949.
92. HELEAND, M . : Status pigmentatus; its pathology and its relation to HallervordenSpatz disease. J . Nerv. & Ment. Dis., 8 1 : 662-675, 1935.
93. H E R B U T , P . A., AND T A I I A K I , H . T . : Cirrhosis of the liver and diabetes as related to
hemochromatosis. Am. J . Clin. Path., 16: 640-650, 1946.
94. H E R B U T , P . A., WATSON, J . S., AND P E R K I N S , E . : Alloxan in experimental hemochro-
matosis. Am. ,1. Clin. Path., 16: 506-511, 1946.
95. H E R K E L , W.: Ueber die Bedeutung des Kupfers (Zinks und Mangans) in dor Biologie
und Pathologic. Bcitr. z. path. Anat. u. z. allg. P a t h . , 85: 513-554, 1930.
96. H E R Z , E., AND D R E W , A. L . , J R . : Hepaticolenticular degeneration; analysis of d y s kinetic phenomena. Arch. Neurol. <fe Psychiat., 63: 843-S74, 1950.
97. HEKZENBERG, H . : t l b e r Hamochromatose (mit besonderer Beriicksichtigung des F e Pigments im Gchirn). Virchows Arch. f. p a t h . Anat., 260: 110-129, 1926.
98. HociiiiAus, H . , AND QUINCKE, H . : tlber Eisen-Resorption und Auscheidung im D a r m kanal. Arch. f. exper. P a t h . u. pharmakol., 37: 159-182, 1896.
99. H O R N S , II. L . : Hemochromatosis; cardiac failure associated with extensive hemosiderosis of myocardium. Am. J . Med., 6: 272-274, 1949.
100. H O W E L L , J . , AND WYATT, J . F . : Development of pigmentary cirrhosis in Cooley's
anemia. Arch. P a t h . , 55: 423-431, 1953.
101. H U E C K , W.: Pigmentstudien. Beitr. z. p a t h . Anat. u. z. allg. P a t h . , 54: 68-232, 1912.
102. H U R S T , .IS. W.: On the so-called calcification in the basal ganglia of t h e brain. J . P a t h .
& Bact., 29: 65-85, 1926.
103. H U R S T , E . W.: Calcification in the brains of equidae and bovidae. Am. J . P a t h . , 10:
795-798, 1935.
104. JAGER, E . : Milzbau und Kreislaufstorung; ein Beitrag zur Entstehung von Milzveranderungen bei Stauungszustanden im Pfortadersystem. Virchows Arch. f. p a t h .
Anat., 299: 531-551, 1937.
105. JISRVIS, G . : Hallervorden-Spatz disease associated with atypical amaurotic idiocy.
J. Neuropath. & Exper. Neurol., 1 1 : 4-18, 1952.
106. KALINOWSKY, L . : Familiare Erkrankung m i t besonderer Beteiligung der Stammganglicn. Monatschr. f. Psychiat. u. Neurol., 66: 16S-190, 1927.
107. K A R K , R. M . : TWO cases of aplastic anemia; one with secondary hemochromatosis
following 290 transfusions in nine years, t h e other with secondary carcinoma of t h e
stomach. Guy's Hosp. R e p . , 87: 343-353, 1937.
108. K I N N E Y , T . D . , H E O S T E D , D . M., AND F I N C H , C. A.: T h e influence of diet on iron a b -
sorption. 1. T h e pathology of iron excess. J . Exper. Med., 90: 137-146, 1949.
109. KLOTZ, O.: Iron impregnation and incrustation of various tissues. Bull. Johns Hopkins
Hosp., 27: 363-366, 1916.
110. K R A L , V. A., AND LEHMANN, H . E . : F u r t h e r studies on t h e iron content of t h e cerebrospinal fluid in psychoses. Arch. Neurol. & Psychiat., 68: 321-32S, 1952.
111. K R A U S S , E . J . : Zur Frage der Eiseninkrustation in der menschlichen Milz. Virchows
Arch. f. path. Anat., 278: 284-289, 1930.
112. LALICII, J . J., AND SCHWARTZ, S. I.: T h e role of aciduria in t h e development of hemoglobinuric nephrosis in dehydrated rabbits. J . Exper. Med., 92: 11-2S, 1950.
113. LANGHANS, T.: Bcobachtungen fiber Resorption der E x t r a v a s a t e und Pigmentbildung in
denselben. Virchows. Arch. f. p a t h . Anat., 49: 66-116, 1S70.
468
VOL. 2 4
STRASSMANN
114. LEHMANN, H . E . , AND K R A L , V. A.: Studies on t h e iron content of cerebrospinal fluid
in different psychotic conditions. Arch. Neurol. & Psychiat., 65: 326-336, 1951.
115. LENDRUM, A. C : Pulmonarv haemosiderosis of cardiac origin. J. P a t h . & Bact., 62:
555-561, 1950.
116. L E N D R U M , A. C , SCOTT, L. D . W., AND P A R K , S. D . S.: P u l m o n a r y changes due to
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
cardiac disease with special reference to haemosiderosis. Quart. J . Med., 19: 249262, 1950.
LEVINSON, S., AND LIMARZI, L . : Agnogenic myeloid metaplasia of the spleen; report of
case with necropsy findings. Am. J . Clin. Path., 17: 449-461, 1947.
L E W E Y , F . H . , AND GOVONS, S. R . : Hemochromatotic pigmentation of t h e central
nervous system. J . Neuropath. & Exper. Neurol., 1: 129-138, 1942.
L I L L I E , 11. D . : Experiments on the solubility of hemosiderin in acids and other reagents during and after various fixations. Am. J . P a t h . , 15: 225-239, 1939.
L I L L I E , R . : Histopathologic Technic. Philadelphia: T h e Blakiston Co., 194S, p . 124.
LINTZEL, W.: Neuere Ergebnisse der Erforschung des Eisenstoffwechsels. Ergebn. d.
Physiol., 31:844-919, 1931.
LUBARSCH, 0 . : t l b e r die Ablagerung eisenhaltiger Pigmente im Gehirn und ihre Bcdcutung bei der progressiven Paralyse. Arch. f. Psychiat., 67: 1-12, 1923.
LUBARSCH, 0 . : tlber die hiimoglobinogenen Pigmentierungen. Klin. Wchnschr., 4:
2137-2143, 1925.
M A C K A Y , R . : An unusual case of aplastic anemia with organ changes resembling
hemochromatosis. Med. J . Australia, 1: 172-173, 1942.
MAGAREY, F . R . : Experimental pulmonary hemosiderosis. J . P a t h . & Bact., 63: 729734,1951.
MALLORY, F . B . , AND P A R K E R , F . , J R . : Experimental copper poisoning. Am. J . P a t h . ,
7: 351-364, 1931.
MALLORY, F . , P A R K E R , F . , Jr., AND N Y E , R . : Experimental pigment cirrhosis due to
copper and its relation to hemochromatosis. J . Med. Res., 42: 461-4S2, 1921.
MARINESCO, C , AND DRAGINESCO, S.: Iron metabolism in nervous centers. R e v .
Neurol., 2 : 385-398, 1923.
MCCLATCHIE, S., TAYLOR, H . E . , AND H E N R Y , A. T . : Acute abdominal pain and shock
associated with haemochromatosis. Canad. M . A. J . , 63: 485-488, 1950.
M E N K I N , V . : Experimental hemosiderosis. Proc. Soc. Exper. Biol, it Med., 3 1 : 755757, 1933.
M I L L S , E . : Hemochromatosis with special reference to frequency and occurrence in
women. Arch. I n t . Med., 34: 292-300, 1924.
M I N K O W S K I , O., AND NAUNYN, B . : Beitr&ge zur Pathologic der Leber und des Icterus.
Arch. f. exper. P a t h . u. Pharmakol., 2 1 : 1-33, 1886.
133. M O O R E , C , ARROWSMITH, W., D O A N , C , Q U I L U G A N , J . , AND R E A D , J . : Studies in iron
transportation and metabolism. J . Clin. Investigation, 16: 613-626, 1937.
134. M O O R E , C. V., D O A N , C. A., AND ARROWSMITH, W. R . : Studies in iron t r a n s p o r t a t i o n
135.
136.
•137.
138.
139.
140.
141.
142.
143.
and metabolism. I I . Mechanism of iron transportation—its significance in iron
utilization in anemic states of varied etiology. J . Clin. Investigation, 16: 627-64S,
1937.
MOORE, C. V., MINNICH, V., AND WELCH, J . : Studies in iron transportation and m e t a b olism. I I I . T h e normal fluctuations of serum and "easily-split-off" blood iron in
individual subjects. J . Clin. Investigation, 18: 543-580, 1939.
M O R I T Z , A.: T h e Pathology of T r a u m a . Philadelphia: Lea & Febiger, 1942. p . 33.
M U E L L E R , M . : tlber physiologisches Vorkommen von Eisen im Zentralncrvcnsystem.
Ztschr. f. d. ges. Neurol, u. Psychiat., 77: 519-535, 1922.
MUHLMANN, M . : Hematoxylin als Reagens auf Eisen. (tlber Lipoidsiderose.) Virchows
Arch. f. path. Anat., 266: 697-711, 1928.
M U I R , R., AND D U N N , J . S.: T h e iron content of the organs in bronzed diabetes (haemochromatosis). J . P a t h . & Bact., 19: 226-238, 1914.
M U I R , R., AND D U N N , J . S.: T h e retention of iron in the organs in haemolvtic anaemia
J. P a t h . & Bact., 19: 417-428, 1914.
M U I R , R., AND D U N N , J . : T h e absorption of iron from organs after haemolysis. J .
P a t h . & Bact., 20: 41-49, 1916.
M U I R , R., AND N I V E N , J . S. F . : T h e local formation of blood pigments. J . P a t h . &
Bact., 4 1 : 183-197, 1935.
M U I R , R., AND YOUNG, J . S.: T h e relation of t h e liver to t h e disposal of haemoglobin.
J . P a t h . & Bact., 35: 113-125, 1932.
144. M U I R H E A D , E. E., CRASS, C , J O N E S , F . , AND H I L L , J . M . : Iron overload
(hemosider-
osis) aggravated b y blood transfusions. Arch. I n t . Med., 8 3 : 477-501, 1949.
145. N E U M A N N , E . : Beitriige zur Kenntniss der pathologischen Pigmente. Virchows Arch.
f. p a t h . Anat., I l l : 25-47, 1888.
146. NEUMANN, E . : Nochmals die Pigmentfrage. Virchows. Arch. f. p a t h . Anat., 177: 401425, 1904.
APR.
1954
IRON DEPOSITS IN BODY
469
147. NEUMANN, M.: Hemochromatosis of central nervous svstem. J. Neuropath. & Exper.
Neurol., 7 : 10-34, 1942.
148.
N E T S K Y , M . G., S P I R O , D . , AND ZIMMERMAN, H . M . : H a l l e r v o r d e n - S p a t z disease and
dystonia. J . Neuropath. & Exper. Neurol., 10: 125-141, 1951.
149. N E W M A N , W. V., AND W H I P P L E , G. H . : Hemoglobin injections and conservation of
pigment by kidney, liver, and spleen; influence of diet and bleeding. J . Exper. Med.,
55: 637-652, 1932.
150. N I V E N , J . S. F . : The Formation of haematoidin in vitro from mammalian erythrocytes.
J . P a t h . & Bact., 41: 177-181, 1935.
151. OHERNDORFER, S.: Die pathologischen Pigmente. Ergebn. d. allg. P a t h . u. p a t h .
Anat., 19: 47-146, 1921.
152. O ' D O N N E L L , W. M . : Postabortal oliguria. J . A. M. A., 140: 1201-1205, 1949.
153. O ' D O N N E L L , W. M . : Renal siderosis in hemoglobinuric nephropathy. Am. J . Path., 26:
899-909, 1952.
154. OSIIIDA, F . , AND S I E B E R T , P . : Experimentelle chronische Kupfervergiftung, ein
Bcitrag zur Frage dor Pathogenese der Hiimochromatose. Beitr. z. path. Anat., u. z.
allg. Path., 84: 107-110, 1930.
155. OSTBRTAO, B . : Die a n bestimmte Lokalisation gebundenen Konkremente des Zentralnervcnsystcms und ihre Beziehung zur Verkalkung intracercbraler Gefiisso "bei gewissen" enclokrinen Erkrankungen. Virchows Arch. f. p a t h . Anat., 275: 82S-S59,
1930.
156. PALMER, W. W.: The determination of haemoglobin. Proc. Soc. Exper. Biol. & Med.,
14: 175-176, 1917.
157.
PEACOCK, W. C , E V A N S , R . D . , I R V I N E , J . W., G O O D , W. M . , K I P , A. F . , W E I S S , S.
AND GIBSON, J . G.: T h e use of 2 radioactive isotopes of iron in tracer studies of
erythrocytes. J . Clin. Investigation, 25: 605-615, 1946.
158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
P E N D E R G R A S S , E . P., L A M E , E. L., AND OSTRUM, H . W . : Hemosiderosis of lung due to
mitral disease; a report of 6 cases simulating pneumoconiosis. Am. J . Roentgenol.,
61: 443-456, 1949.
P E R L S , M . : Nachweis von Eisenoxyd in gewisson Pigmenten. Virchows Arch. f. p a t h .
Anat., 39: 42-48, 1867.
P E R U S I N I , G.: Uber cinige eisengierige, nichtkalkhaltige Inkrustierungen im Zentralnervensvstem. Folia neuro-biol., 6: 465-488, 1912.
POLSON, C. J . : Chronic copper poisoning. Brit. J . Exper. P a t h . , 10: 241-245, 1929.
POLSON, C . J . : F a t e of colloidal iron administered intravenously. J . P a t h . & Bact.,
31: 445-460, 1928; 32: 247-260, 1929.
POLSON, C. J . : Failure of prolonged administration of iron to cause haemochromatosis.
Brit. ,1. Exper. P a t h . , 14: 73-76, 1933.
QUINCKE, H . : Zur Pathologic des Blutes, Siderose. Arch. f. klin. Med., 25: 567-5S5;
27: 193-217, 1880.
QUINCKE, H . : Beitriige zur Lehre von Ikterus. Virchows Arch. f. path. Anat., 95:
125-139, 1884.
QUINCKE, H . : tlber directe Fe-Reaktion in tierischen Geweben. Arch. f. exper. P a t h . u.
Pharmakol., 37: 182-190, 1896.
R A N D , C. W., AND COURVILLE, C. B . : Histologic changes in the brain in cases of fatal
injury to the head; alterations in nerve cells. Arch. Neurol. & Psvchiat., 55: 79-110,
1946."
R A T H , C. E., AND F I N C H , C. A.: Sternal marrow hemosiderin; method for determination
of available iron stores in man. ,1. L a b . & Clin. Med., 33: Sl-86, 1948.
R A V I D , J . M., AND CIIESNER, C : A fatal case of hemolytic anemia and nephrotic uremia
following sulfapyridine administration. Am. J . M. S c , 199: 3S0-3S5, 1940.
R I C H , A.: The formation of bile pigment from haemoglobin in tissue cultures. Bull.
Johns Hopkins Hosp., 34: 321-329, 1923.
R I C H , A.: The formation of bile pigment from hemoglobin in tissue cultures. Bull.
Johns Hopkins Hosp., 35: 415-416, 1924.
R I C H , A.: T h e formation of bile pigment. Physiol. Rev., 5 : 182-224, 1925.
R I C H , A., AND BUMSTEAD, J . : On the identity of hematoidin and bilirubin. Bull. Johns
Hopkins Hosp., 36: 225-232, 1925.
R O G E R S , W. F . , J R . : Familial hemochromatosis; with comments on adrenal function in
hemochromatosis. Am. J . M . S c , 220: 530-537, 1950.
R o s s , J . F . : Metabolism of inorganic and hemoglobin iron. J . Clin. Investigation, 25:
933, 1946.
R O T H , O . : Zur Pathologenese und Klinik der Hamochromatose. Deutsohes Arch. f.
klin. Med., 117: 224-249, 1915.
R o u s , P . : Urinary sidcrosis; hemosiderin granules in the urine as an aid in the diagnosis
of pernicious anemia, hemochromatosis and other diseases causing siderosis of t h e
kidney. J . Exper. Med., 28: 645-659, 1918.
470
VOL. 2 4
STRASSMANN
178. R o u s , P . , AND OLIVER, J . : Experimental hemochromatosis. J. Exper. Med., 28: 629645, 1918.
179. RUTLEDGE, E., AND NEUBUERGER, K.: Icterus of the adult brain; report of case. Am. J .
P a t h . , 18: 153-157, 1942.
180. R Y F F E L , J . : Amount of iron in organs in cases of pernicious anemia. J. P a t h . & Bact.,
14: 411-413, 1910.
1S1. SANDBERG, M., GROSS, H., AND HOLLY, 0 . M . : Changes in retention of copper and iron
in liver and spleen in chronic diseases accompanied by secondary anemia. Arch.
Path., 33: 834-844, 1942.
182. SCHMIDT, M. B . : Uber die Verwandtschaft der hiimatogenen und autochthonen Pigmente und deren Stellung zum sogenannten Hiimosiderin. Virchows Arch. f. p a t h .
Anat., 115: 397-459, 1889.
183. SCHMIDT, M. B . : Ueber Pigmentbildung in den Tonsillen und im Processus vermiformis. Verhandl. d. deutsch. p a t h . Gesellsch., 11: 24-29, 1908.
184. SCHMIDT, M. B . : Ueber die Organe des Eisenstoffwechsels und die Blutbildung bei
Eisenmangel. Verhandl. d. deutsch. p a t h . Gesellsch., 15: 91-96, 1912.
185. SCHMIDT, M. B . : Storungen des Eisenstoffwechsels und ihre Folgen. Ergebn. d. allg.
P a t h . u. p a t h . Anat., 35: 105-208, 1940.
186. SCHMORL, G.: Kernikterus. Verhandl. d. deutsch. p a t h . Gesellsch., 6: 109-115, 1904.
187. SCHWARTZ, S. O., AND BLUMENTHAL, S. A.: Exogenous hemochromatosis resulting from
blood transfusions. Blood, 3 : 617-640, 1948.
188. SHELDON, J. H.: The iron content of the tissues in haemochromatosis; with special
reference to the brain. Quart. J. Med., 21: 123-137, 1927.
189. SHELDON, J. H . : Haemochromatosis. Lancet, 2: 1031-1036, 1934.
190. SHELDON, J. H . : Haemochromatosis. London: Oxford University Press, 1935, 382 pp.
191. SHEMIN, D., AND R I T T E N B E R C , D . : T h e life span of the human red blood cell. J. Biol.
Chem., 166: 627-636, 1946.
192. SPATZ, H . : Ueber den Eisennachweis im Gehirn, besonders in Zentren des cxtrapyramidal-motorischen Systems. Ztschr. f. d. ges. Neurol, u. Psychiat., 77: 261-390, 1922.
193. SPATZ, H . : Zur Eisenfrage, besonders bei der progressiven Paralyse. Ztschr. f. d. ges.
Neurol, u. Psychiat., 7: 171-176, 1.922.
194. SPATZ, H . : Ueber Stoffwechseleigentumlichkeiten in don Stammganglien. Ztschr. f. d.
ges. Neurol, u. Psychiat., 78: 641-648, 1922.
195. SPATZ, H . : Zur anatomischen Schnelldiagnose der progressiven Paralyse. Centralbl.
f. allg. u. p a t h . Anat., 33: 313-320, 1923.
196. SPATZ, H . : Untersuchungen iiber Stoffspeicherung und Stofftransport im Nervensystem. Ztschr. f. d. ges. Neurol, u. Psychiat., 89: 130-137, 1924.
197. STARKENSTEIN, E . : Uber die Resorbierbarkeit von Eisenverbindungen aus dem Verdauungskanal. Arch. f. exper. P a t h . u. Pharmakol., 127: 101-124, 1927.
198. STARKENSTEIN, E., AND W E D E N , H.: t)ber das anorganische Eisen des Organismus. Arch.
f. exper. P a t h . u. Pharmakol., 134: 274-287, 1928.
199. STARKENSTEIN, E., AND W E D E N , H . : t l b e r das Schicksal des Eisens im Organismus
nach Zufuhr von komplexen Verbindungen mit anorganisch und organisch gebundenem Eisen. Arch. f. exper. P a t h . u. Pharmakol., 150: 354-380, 1930.
200. STASNEY, J . : Erythrophagocytosis and hemosiderosis in liver and spleen in sickle cell
disease. Am. J. P a t h . , 19: 225-237, 1943.
201. STRASSMANN, G.: Hemosiderin and tissue iron in the brain—its relationship, occurrence
and importance. J. Neuropath. & Exper. Neurol., 4: 393-401, 1945.
202. STRASSMANN, G.: Formation of hemosiderin in the lungs; experimental study. Arch.
P a t h . , 38: 76-81, 1944.
203. STRASSMANN, G.: Iron and calcium deposits in the brain, their pathologic significance.
J. N e u r o p a t h . & Exper. Neurol., 8: 428-135, 1949.
204. STRASSMANN, G.: Formation of hemosiderin and hematoidin after traumatic and spontaneous cerebral hemorrhages. Arch. P a t h . , 47: 205-210, 1949.
205. STRASSMANN, G.: Die Rolle der Blutpigmente fur die Altersbestimmung von Hirnblutungen. Ztschr. ger. Med., 39: 561-565, 1949.
206. STRASSMANN, G.: Iron deposits in the brain compared with similar deposits in spleen,
liver, lungs, and other organs, and their relationship to mental diseases and age.
Am. J. P a t h . , 28: 540, 1952.
207. SUMITA, M . : Zur Frage der Eisenreaktion kalkhaltiger Gewebe, insbesondere des
Knochens. Virchows Arch. f. p a t h . Anat., 200: 220-258, 1910.
208.
SUNDERMAN, P . W.,
M A C F A T E , R.
P., MACFADYEN, D.
A.,
S T E V E N S O N , G.
F.,
AND
COPELAND, B . E . : Symposium on Clinical Hemoglobinometry. Am. J. Clin. P a t h . ,
23: 519-598, 1953.
209. T A I T , G. B . , AND CORRIDAN, M. M . : Idiopathic pulmonary haomosideiosis. Thorax,
7: 302-304, 1952.
210. TAYLOR, H . E . : T h e possible role of ferritin in t h e production of shock in hemochromatosis. Am. J. Clin. P a t h . , 21: 530-535, 1951.
APR. 1 9 5 4
IRON DEPOSITS IN BODY
471
211. TAYLOR, J., S T I V E N , D . , AND R E I D , E . VV.: Experimental and idiopathic siderosis in
cats. J . P a t h . & Bact., 4 1 : 397-405, 1935.
212. TiNOBY, A.: T h e iron content of t h e human brain. J . Ment. S c , 84: 9S0-9S4, 193S.
213. T O P P , J . H . , AND L I N D E R T , M . C . F . : T h e diagnosis of hemochromatosis by means of
needle biopsy of t h e liver. Gastroenterology, 10: 813-821, 194S.
214. TROUSSEAU, A . : Clinique M6dicale de l'H6te!-Dieu de Paris. E d . 2. Paris, F r a n c e :
J. B . Bailliere e t his, 1S65, p p . 672-673.
215. VON BOGAERT, L . : Sur une affection heredo-familiale apparentde a la maladie d'HalIcrvorden-Spatz. Monatschr. f. Psychiat. u. Neurol., 113: 183-214, 1947.
216. VON RECKLINGHAUSEN, F . : tlber Hiimochromatose. Tagbl. d. Vers. Deutsch. Naturf.
unci Aerate, p . 324, 1889.
217. VAUGHAN, V. C : Kernicterus in Erythroblastosis fetalis. J . Pediat., 29: 462-473, 1946.
218. VIRCHOW, R.: Die pathologischen Pigmente. Virchows Arch. f. p a t h . Anat., 1: 379-4S6,
1847.
219. WALCHER, K . : D i e vitale Reaktion bei d e r Beurteilung des gewaltsamen Todes.
Deutsche Ztschr. f. d. ges. gerichtl. Med., 26: 193-211, 1936.
220. WARBURG, 0 . : Ubcr E isen, den Saucrstoff "iibertragendon Bestandteil des Atmungsfermentes. Biochem. Ztschr., 152: 479-494, 1925.
221. WARBURG, 0 . : Obcr die Koncentration des Fermenteisens in der Zelle. Biochem. Ztschr., 203: 95-98, 192S.
222. WARREN, S., AND D R A K E , W. L., J R . : Primary carcinoma of the liver in hemochromatosis. Am. J . P a t h . , 27: 573-609, 1951.
223. WARTMAN, W. B . , AND LAIPPLY, T . C.: T h e fate of blood injected into the arterial wall.
Am. J . Path., 25: 383-388, 1949.
224. W H I P P L E , G. II., AND ROBSCHEIT-ROBBINS, F . S.: Hemoglobin production factors in the
human liver. 111. Anemias—primary, aplastic and secondary—leukemias. J . Exper.
Med., 57: 671-687, 1933.
225. W H I P P L E , G. H . , AND ROBSCHEIT-ROBBINS, F . S.: Blood regeneration in severe anemia.
Am. .J. Physiol., 79: 260-288, 1926.
226. WILSON, S. A. K . : Progressive lenticular degeneration: a familial nervous disease
associated with cirrhosis of the liver. Brain, 34: 295-509, 1912.
227. WINKELMAN, N . W.: Progressive pallidal degeneration; new clinicopathologic syndrome. Arch. Neurol. & Psychiat., 27: 1-21, 1932.
228. WOIILWILL, F . : Uber bronze Diabetes. Verhandl. d. deutsch. p a t h . Gesellsch., 20:
207-211, 1925.
229. WYATT, J . P., AND GOLDENBERG, H . : Hemosiderosis in refractory anemia. Arch. I n t .
Mod., 8 3 : 67-76, 1949.
230. WYATT, J . P., AND H O W E L L , J . : Experimental induction of iron overload in t h e r a t .
Arch. Path., 55: 466-474, 1953.
231. WYATT, J., M I G H T O N , l i . , AND M O R A G U E S , W.: Transfusional siderosis. Am. J . P a t h . ,
26: 863-894, 1950.
232. W Y L L I E , W. G., SHELDON, W., B O D I A N , M., AND B A R L O W , A.: I d i o p a t h i c p u l m o n a r y
233.
234.
235.
230.
237.
haemosiderosis (essential brown induration of t h e lungs). Quart. J . Med., 17: 2 5 48, 1948.
Y U I L E , C. L.: Hemoglobinuria. Physiol. Rev., 22: 19-31, 1942.
ZELTMACHBR, K., AND BEVANS, M . : Aplastic anemia and its association with hemochromatosis. Arch. I n t . Med., 75: 395-403, 1945.
ZIEGLER, F . : Zur Kenntniss der Eisenablagerungen in verschiedenen Organen des
mcnschlichen und tierischcn Organismus. Centralb. f. allg. P a t h . u. p a t h . Anat.,
5: S47-S49, 1S94.
ZIMMERMAN, H . M., AND Y A N N E T , H . : Kernicterus; jaundice of t h e nuclear masses of
the brain. Am. J . D i s . Child., 45: 740-759, 1933.
ZUELZER, W. W., AND MUDOETT, R . T . : Kernicterus; etiologic s t u d y based on analysis
of 55 cases. Pediatrics, 6: 452-474, 1950.