THE IRON CONTENT OF THE ORGANS IN BRONZED DIABETES (HAMOCHROMATOSIS).'

By ROBERT MUIR, M.D., Sc.D., F.R.S. ; and JOHN SHAW DUNN, M.A., M.D.

(From the PatlmZogieaZ Ldoratories of the University and W&m I@rmary, GZmgm.)

IN this paper we give the results of estimation of the amounts of iron in the organs and tissues in bronzed diabetes, and consider the significance of the changes. We do not propose to enter into an analysis of the various cases of the disease recorded, as this has been done by others in recent times, or to consider in detail the histological changes which have been observed. I t is sufficient for our purpose to recognise that in the condition to be considered, there are the following chief features, namely-(a) a deposit of hzemosiderin in large amounts in the various organs and tissues, leading sometimes to a bronzing of the skin ; (b) cirrhosis of the liver and pancrm ; and (c) diabetes. I t was the association of the pigmentation of the skin with diabetes that first led to the recognition of the disease by Hanot and Chauffard (1882 '), and the same association has since led to the recognition of subsequent cases. With regard to the occurrence of diabetes, the majority of recent writers-nd with these we agree- regard it as simply the result of fibrous atrophy in the pancreas, and as, in fact, a terminal phenomenon. The bronzing of the skin also undoubtedly comes on late in the disease, and is present in very varying degree. So far as its pathological nature is concerned, there is nothing to separate it from the accumulation of iron-containing pigment in the various organs, though the deposit of hsmosiderin in the skin no doubt has a certain significance. Accordingly, the affection is recognised clinically by its late phenomena, and although, up to the present, only about sixty caBes of bronzed diabetes have been recorded, the disease, in the strict sense, is no doubt much commoner than is indicated by these cases. As a matter of fact, cases of hzemo- chromatosis have been described without the presence of diabetes.

We shall first give the chief facts with regard to the case which came under observation, and thereafter the results of our estimation

[Received July 9, 1914. Communicated to the Patliologioel Society of Great Britain and Ireland, July 1913.]--The expenses of this research were defrayed by a Scientific Grant from the Carnegie "rust, for which we have pleasurc in recording our indebtedncss.

IRON CONTENT OF ORGANS IN BRONZED DIABETES. 237

of the iron in the organs. W e are indebted to Professors Beattie, Lorrain Smith, and O'Sullivm for portions of liver from three other cases, and we give the estimations in these also. These cases are marked (a), (3), and (4) respectively in the Table below (p. 231). The portion of liver given to us by Professor Beattie waa from the case already published by him in this Journal (1904 *).

He was admitted to the Western Infirmary on 3rd July 1911. There waa a history of swelling of abdomen and legs of six nionths' duration, and previously there had been symptoms of diabetes. The patient passed an average amount of 1200 grs. of sugar a day; there was a trace of acetone, but no dimetic acid. Symptoms of peritonitis supervened, and the patient died as the result of this on 30th July 1911.

Post-mortem Eramination (twenty-six hours after death).-The body was much emaciated ; the skin had a dusky brown colour, but there was no marked bronzing. The abdomen was somewhat swollen. There waa no jaundice.

'honax.-The pericardial sac was normal. The heart was much atrophied and the muscle had a brownish colour. The valves were healthy and the cavities were slightly dilated.

bDoxEs.-The peritoneal cavity contained 8 pints of slightly turbid fluid with flakes of fibrin. The peritoneum was thickened and opaque and coverod with a thin membranous layer of fibrino-purulent exudate. The liver weighed 3 1b. The surface showed a fine granularity, and it was stained almost black by post-mortem change. The organ was of firm consistence, and on section showed a distinct cirrhosis of it fine multilobular type. The liver tissue waa of a bright rusty brown colour, and on the cut surface one could see small hyperplastic islets where the colour was paler. The gall-bladder contained 2 oz. of dark green bile. The pancreas weighed 2 oz. I t was somewhat attenuated in form and Roft in con- sistence; it shows well-marked fatty infiltration as well as a certain degree of cirrhosis. The substance of the gland had a distinctly brown tint. The spleen neighed 8 oz. I t was distinctly firm in consistence ; the pulp was of a pale reddish colour and the mrlpighian bodies were rather indistinct. There wa5 slight increase of the trabecular tissue. The kidneys were somewhat anemic i n appearance, but there was no brown coloration and no evidence of any lesion. The suprarends were of normal size and colour, the medulla was softened by post-mortem change. Its lining had a slaty colour, and the mucous membrane of the upper part of the small intestine showed a similar coloration, which gradually faded off in a down- ward direction.

LYMPHATIC GLaNDs.--The retro-peritoneal glands, especially round the pancreas, were all enlarged, and on section showed a bright orange-brown colour, like rust in appearance. The glands at the root of the mesentery showed a similar condition, whilst those more peripheral were little affected. Similar changes, though less marked, were found in the bronchial and mediastinal glands. On the other hand, the cervical, axillary, and inguinal glands showed no special coloration.

Naked-eye test for ima (potassium fermcyanide and hydrochloric acid) :-

1. The iron reaction was extremely marked in the liver, pancreas, and the glands with brown coloration, a deep blue colour appearing rrlniost at once.

2. It was fairly well marked in the spleen, suprarenals, lungs and

The patient, C. G., was a inan et . 52, a clerk by occupation.

The lungs showed no lesions of importance.

There was no obstruction of the bile duct.

The sfoiizuch was of normal size.

The rest of the intestine was normal in appearance.

228 ROBERT MUIR AND JOHN SHA W DUNN.

pleura, stomach (mucous and milscular coats), skin from the chest and both legs.

3. It was comparatively slight in the jejunum and heart muscle. 4. The kidneys, ileum and colon gave almost no reaction. No staining was obtained in the case of the cervical and inguinal

glands. The following are the chief results of the microscopic examination,

especially as regards the characters and distribution of the pigment : Liver.-There is a very marked cirrhosis, of mnltilobular type ;

the liver tissue occurs in the form of rounded masses of liver cells, separated from one another by broad bands of cellular fibrons tissue. The fibrous bands are densest in the region of the portal tracts ; there is well-marked new formation of bile-ducts in these areas. The liver cells contain a great abundance of brown granules, which take on an intensely blue colour with the iron reagents. These granules are most abundant in the central parts of the liver cells. The reaction is equally marked with hot and cold hydrochloric acid. Much pigment also occurs in the connective-tissue septa, in the forni of both large and small granules, and also in larger masses which apparently represent dead phagocytic cells. This pigment in the connective tissue colours very imperfectly with cold hydrochloric acid, assnming a greenish- brown tint, while with hot acid it stains intensely blue. Here and there throughout the organ occur hyperplastic nodules of liver tissne, in which the cells are actively proliferating. In these cells the amonnt of pigment is notably less than elsewhere. No brown non-ferruginons pigment is seen anywhere in the liver.

Pancreas.-The glandular tissue is almost destroyed by auto- digestion, and the islets are not definitely recognisable. There is a very marked overgrowth of fibrons tissue, chiefly in the form of coarse bands, but also of finer intralobnlar strands. Pigment is very abundant in the remains of the cells of the parenchyma, occurring in granules and in conglomerate masses. It is also present in considerable amount in the connective tissue and around the blood vessels. With cold hydrochloric acid it mostly gives a greenish tint; with hot acid it appears more abundant and most of it stains dark blue, only a few granules still appearing green.

XpZeen.-Brown pigment is very abundanti through the pulp, occurring both in phagocytes and in stroma cells; in certain cells very large masses occur. The lymph nodules are cornparati\-ely free, only a few interstitial cells containing pigment. The arteries show marked atheroma and arteriosclerosis, and in many of the affected vessels there is seen diffuse impregnation of their walls with iron pigment, irregular in distribution. A similar condition is also seen at places in the general stroma of the organ. In the spleen the iron pigment again appears more abundant with hot than with cold hydro- chloric acid, and with the cold acid the pigment in the pulp stains

IRON CONTENT OF ORGANS IN BRONZED DIA3ETES. 239

green. The cliffuse pstches in the connective tissue, however, stain blue with either hot or cold acid.

A!etro-pq+oneal Lymphtie Glands.-These contain enormous quantities of brown pigment. Of the ordinary gland tissue only a few lymph follicles remain recognisable, the greater part being taken up by masses of phagocytic cells filled with pigment, and also by free granules and maeses. When sections are shined for iron, with cold acid a few granules remain unstained, but most show some degree of greenish staining, while a few are blue. The connective- thsue fibres are, however, coloured an intense blue. With the hot acid, almost all the pigment etains dark blue. The posterior media- stinal glands show similar changes.

Stomcrch.-Without special staining a considerable amount of brown pigment is seen in the muscularis mucosq in certain connec- tive-tissue fibres, and in the muscle fibres of the arteries in the submucosa. With potassium ferrocyanide and cold acid, greenish- blue granules are seen in the epithelial cells of the glands, irregular in distribution ; in the rnuscularis mucosae many granules show varying degrees of greenish staining, but most remain unstained. Some staining occurs in connective-tissue fibres, and in some cells in the subperitoneal coat. With hot acid, more pigment and more intense staining are seen in the epithelial cells of the mucosa ; in the muscularis mucos;E a con- siderable pnrt of the pigment stains dark blue, a part greenish, while a certain proportion still remains unstained. The perivaecular pigment is deeply stained, and that in the subperitoneal coat appears more abundant, and stains more deeply than with cold acid. The pigment in the niuscular coats of the arteries remains quite unstained.

Small Intestine.-A few scattered granules are seen in mucous, submucous, and peritoneal coats; none in the epithelium or in muscular coats. These give an iron reaction both with hot and cold hydrochloric acid. No non-staining granules are seen.

Kkhey.--Yigment occurs only in certain collections of tubules, the greater part of the cortex being unstained. In the affected tubules (convoluted, and also some collecting and Henle’s tubules), the cells contain numerous large granules, staining greenish with cold acid, but intensely blue with hot. Many of the cells in the affected tubules are much degenerated. The glomeruli generally are unaffected, but in one or two there are small blue masses, apparently in the capillnrie~ (? embolic).

Suprct-md+--With cold acid a considerable quantity of pigmen t, staining bluish to bluish-green, is seen in the superficial layer of cortical cells. With hot acid this pigmelit stains very intensely, and also certain iron-containing connective-tissue cells are mado visible throughout the gland. A certain amount of brown pigment, which does not give any iron reaction. is present in cells of the fascicular layer.

Slcin.-With cold acid a considerable quantity of brown p i p e n t

230 ROBERT MUZR AND JOHN SHAW DUNN:

is seen in cells around the sweat glands ; only a few isolated granules have a bluish or even a greenish reaction. No staining is found in the surface epithelium or in the glandular epithelium. With hot acid all the brown pigment mentioned gives an intense blue colour; i t occim chiefly in somewhat elongated corpuscles around the vessels of the corium and around the sweat ducts. Some granules stained deeply blue are found in the deepest layers of the rete Malpighii, but they are comparatively scanty.

Hccart.-Brown pigment is present in nearly all the muscle fibres, varying in amount. It is chiefly central in position, and occurs in the form of granules, mainly arranged in the form of rows along the fibrils. The normal pi,oment is invisible except in a few fibrea. With cold hycirochloric acid the staining is not very intense, having a greenish tinge ; with hot acid, all the pigment stains a very intense blue.

Luizgs.-A few cells of the alveolar epithelium and some cells in the connective tissue show the presence of haemosiderin, more marked with hot than with cold hydrochloric acid.

From a consideration of the above description, it is evident that the iron in the various organs is in different states of combination; and the same observation has been made by Abbott (1901 s, and others. Thus a part readily gives a blue colour if either hot or cold hydrochloric acid is used with the ferrocyanide ; a part appears green with cold acid or remains uncoloured, whilst it gives a deep blue colour with hot acid ; and some granules, for example in the stomach and in the suprarenals, give no iron reaction at all. The last-men- tioned moiety, which corresponds to the so-called “ hamofuscin,” is, however, in amount very small--much smaller than has been recorded in other cases. For example, in Beattie’s case no iron reaction was given by the pigment in the gastro-intestinal tract. Owing to the very small amount of “ ha?mofuscin ” in our case, the estimations of iron given below throw no light on the question as to whether this pigment contains iron or not. With regard to the different reactions given by the haemosiderin when tested by hot and cold hydrochloric acid, we have also no definite opinion to offer. Apparently the piewent which gives a deep blue reaction contains the iron in its simplest combination, or in what might be called the least organic form, and one would accordingly expect that the pigment giving the iron reaction less readily represents the earlier stage. On the other hand, the histological examination makes it probable that the pigment is first elaborated in the cells of organs, e.g., in those of the liver, and is thence carried by the lymphatics to the glands, etc. The pigment in the lymphatic glands would thus be of oldest formation, and we should expect that it would give a blue reaction with cold hydro- chloric acid. As a matter of fact, however, this is not the case, as the pigment in the glands on the whole gives the blue reaction much less readily than that in the liver. At present we have no data

IRON CONTENT OF ORGANS IN BRONZED BIABETES. 231

which enable us to determine the significance of the different reactions mentioned.

ESTIMATIOXS OF IRON. All the estimations of iron were made by means of Neumann's

(1902 ') wet-ash method. In this the dried tissues are incinerated in a mixture of pure sulphuric and nitric acids ; the iron is ultimately got as a solution of ferric chloride, and this is titrated against sodium- thio-sulphate in the usual way. The following are the results, the amounts of iron being expressed as percentages of the tissues dried to constant weight:

Tissue percentage of ! 6-43 iron

I

, I 2-49 10'825 11'64 0 406 I '

- 1- I--- j-- 0.121 10-714 10%8 j 0.14

The percentages of iron in the liver in the other three cases examined were : Professor Lorrain Smith's case, 5-56 ; Professor Beattie's, 2.1 9 ; and Dr. O'Sullivan's, 2.38.

In most of the cases recorded in which the iron has been estimated, this has been done only in the case of the liver. It will be convenient to present these results in tabular form along with our own :

It is to be noted that the estimations of Auscher and Lapicque (1 89 6 b), Jeanselme (1 8 9 76 ), and of Garrod are given as percentages of the fresh organs. As the fresh tissue becomes reduced to about a sixth of its weight, when it is thoroughly dried, on a rough estimate, these figures must be multiplied by six to give the percentage of dried substance, in accordance with the other figures.

We may mention some other results. Jeanaelme found that the percentage of iron in relation to the fresh tissue wm, in the thyroid,

238 ROBERT MUZR AND jOXN SHA W DUNN

0.317, in the spleen, 0.169, aud in the heart, 0.181. Auscher and Lapicque found a percentage of iron, also in relation to the fresh tissue, in the spleen, 042, in the parotid, 0.15, and in a lymphatic glrmd, 1.85 ; in the case of another gland the result was 9 per cent. of the dried substance, a somewhat similar result. Anschutx (1899 found that the amount of iron in the pancreas was 5 per cent. of the dried substance, and in the lymphatic glands, 14.69. liesults of analyses are also given by Roque, Challier, and Nod-Josserand, but the per- centages are considerably lower than those mentioned.

On reviewing all these results, it is manifest that there is a remarkable increase of iron in all the tissues examined. The largest amounts are found in the lymphatic glands, in the liver, and in the pancreas, in the order named. The highest percentage of iron in the pancreas is in the case recorded by Anschutz, being 5 per cent. of dried substance ; in our case it was 2.49 per cent.

The accumulations of iron in the liver are of special iniportance on account of the large size of the organ. The amount in the normal organ varies considerably, but in view of the figures of Stockman (1896 11) and others, 0.3 grru. may be said to be above rather than below the average. The amounts in cases of bronzed diabetes present a marked contrast to this. I n Hess aud Zurhelle’s (1905 lo) case the total amount was 38.7 grms., in Garrod’s, 32.8 grms., and in our case about 18 grms. Anschutz does not give the weight in his case, but states that the amount was a hundred times the normal. It is manifest, in view of the number of analyses actually on record, that such an increase as Anschutz mentions is by no means exceptional. The increase in other organs need not be discussed in detail, but we may refer to the high percentage in the heart muscle, namely, 0.7 in our case, and about 0.9 in the case of Jeanselme; and it may be noted that the enormous amounts of hamosiderin found on micro- scopic examination are in accordance with these figures.

DIscuSSION OF RESULTS.

In the first place, we may consider the amount of iron present in the viscera in relation to the normal amount. The total quantity of iron in the body of a normal adult may be put a t about 5 grms., of which more than half is contained in the hzemoglobin of the blood. Probably this figure represents rather more than the actual amount, but we may take the figure for our present purpose. Estimations of the iron in bronzed diabetes-and it is to be borne in mind that after all these have been comparatively few-show that it is not exceptional for the amount of iron in the liver to amount to 7 per cent. of the dry weight, the total quantity reaching niore than 30 grms., or more than a hundred times the normal amount of iron in the organ. W e cannot say what is the actual amount in the rest of the body, but if

IRON CONTBNT OF ORGANS ZN BRONZED DZABETES. 333

we even take it as 1 0 grms.-and to judge from the microscopic appearances it is probably more-we get as the total amount in the body about 40 grms., or nearly this amount over the normal, as the latter is not more than 2 grms. We have then as an eaaential feature in the disease, that the tissues, apart from the blood, may contain this excess of iron. Now, of course, the only ultimate source of this excess iiiust be the iron of the food-whether the iron after absorption passes through the form of haemoglobin or not is a separate question, which will be discussed later. The amount of iron in an ordinary diet is comparatively small, and the amount excreted in the urine and faeces together exactly corresponds, the greater part being in the latter. Xven when the diet is unusually rich in iron, intake and output are cqual, as Gr6h (191319) has recently shown by feeding pigs with Wutnield; that is, excess of iron in the food does not lead to accumulation in the tissues. Stockman (189513) found that the average amount of iron in an ordinary diet was only about 1 0 mgrms. per day ; though, of course, when certain substances rich in blood are ingested the amount may be considerably greater than this. Even if, for the sake of argument, we take the amount of iron ingested per day as 30 mgrms., it will be seen that with this figure the total amount of iron in the food over a period of more than three years would be necessary to make up the amount which may be present in the tissues in bronzed diabetes ; and this, nioreover, is on the assumption that none is excreted in the faeces and urine. In connection with this we have the very important fact ascertained by Garrod, that in a case of bronzed diabetes no iron could be found in the urine, bile, or in 5 C.C. of the faeces. Further observations on this point, extending over a period of time, are manifestly desirable. We have therefore the all-important fact to deal with, that a complete retention of the food iron over one or two years, or a partial retention for a longer period, would be necessary to account for the accumu- lations of iron found in the tissues. Some writers indicate that the iron accumulations in bronzed diabetes represent merely an extreme degree of a process which is comparatively common, pointing out that an excess of iron is often met with in cases of cirrhosis. This may be perfectly true, but it is only another way of saying that slighter degrees of the change we are considering are not uncommon-it throws no light on the uature of the process underlying the massive accumulations. Moreover, in some cases of cirrhosis, there is no increase of iron in the liver.

The next point for discussion is the possible source of the enormous amount of pigment present. Up till comparatively recently the commonly accepted view waa, that the siderosis in bronzed diabetes was the result of increased haemolysis produced by some toxic agent. Rut when this view is critically examined, certain facts emerge which seem to us to be directly opposed to it. In the great

234 ROBERT MUIR AND JOHN SUA W BUNN.

majority of cases recorded there has been no anemia, no histological changes of importance have been observed in the blood, and, in the cases where the marrow has been examined, no evidence of compen- =tory blood formation or any other alteration has been present; in fact, apart from the accumulation of hsmosiderin, there has been nothing even to suggest the occurrence of excessive blood destruction at all. Some French writers have noted a diminished resistance of the red corpuscles, but this in itself cannot be accepted as proof that the corpuscles have a shorter life than normal. In these respects there is a marked contrast to what is found in pernicious anzemia, and it is to be noted that in the latter disease the siderosis, though a well- marked feature, does not approach in degree that in bronzed diabetes. As a matter of fact, in at least some cases the greater part of the iron in the organs can be accounted for by a simple transference from the blood ; in other words, the total amount of iron in the body may not be much above normal. Another point of importance is the distri- bution of the hsemosiderin. In pernicious ansmia it corresponds, as regards the organs implicated, with what is found after experimental hamolysis, though the degree to which they are involved varies in different cases, as it does with different haemolytic agents. On the other hand, in hamochrornatosis the haemosiderin is abundant in various situations in which it does not occur as the result of hsemolysis by toxic agents, or after the injection of red corpuscles, or of hamo- globin ; among such sites may be mentioned the heart muscle, supra- renal cortex, epithelium of thyroid, ependyma of ventricles of brain, non-striped muscle of the intestine, etc. Nor does it seem likely that this widespread distribution is due to the greater amount of pigment present; it would rather appear as if various cells and tissues, which do not take up hemosiderin to any extent after general hemolysis, havo a marked affinity for it, and become extensively impregnated with it in bronzed diabetes. Another noteworthy point is the enormous amount of pigment in the retro-peritoneal glands, the percentage of iron in these being higher than in any other tissue. This may simply represent an overflow from the organs, especially the liver, but it is curious that nothing corresponding to it occur^ in conditions of known hamolysis.

Again, if we assume that the hemosiderin comes from increased disintegration of red corpuscles, then we must suppose that though compensatory blood formation is practically perfect, the stored iron in the organs is not used up in the process of blood formation-otherwise, of course, the iron would not go on accumulating as it does. It has been supposed by certain French writers, for example, Rope, Chalier, and Nod-Josserand (”>, that granular hemosiderin is not utilisable in blood formation, but no evidence is brought forward in favour of such a view. On the contrary, our own experiments go to show that the deposited iron is readily used up for purposes of blood formation. As we

IRON CONTENT OF ORGANS IN BRONZED DIABETES. 235

havc already said, there must be a retention of the iron supplied by the food, whether this passes through the form of hemoglobin or not; and in either case there would seem to be an abnormal aflinity of certain tissues for iron. The view that the deposited iron is derived from an excessive breaking down of red corpuscles is a t least not supported by facte, and would appear to us to be unnecessary to explain the changes actually present. The retention of iron in the situations mentioned is, in our opinion, due to a special affinity of the tissues for iron, though we cannot explain how this is brought about. It a t least appears difficult to imagine that it should be the result simply of non-excretion, as this would involve failure on the part both of the intestine and of the kidneys to excrete the compounds of the metal. In this connection, however, the suggestion made by Garrod that the iron may be in a form not suitable for excretion is well worthy of con- sideration.

Whilst the great majority of writers regard the source of the pigment to be an excessive destruction of hemoglobin, some have expressed a view of similar nature to that set forth above. So far as we can find, Parker (19O3l4) is the first to question the occurrence of abnormal hemolysis. He suggests that the pigment represents rather the accumulated product of the normal daily mor- tality of the red cells, which is in some way prevented from elimina- tion by the death of the cells whose duty is to remove it. The chief factor is the loss of power of elimination rather than any abnormal amount of hzmolysis. Sprunt (1911 16) also points out that there is no evidence of excessive blood destruction nor of reparative activity of the haemopoietic organs. H e regards hemochromatosis as a meta- bolic disease, implicating many of the body tissues, and manifested especislly by a change in the chromogenic groups of the proteid molecule with the deposition of pigments. The view of Mackenzie Wallis (19147) is somewhat similar. He supposes that the meta- bolism of iron has apparently undergone some error, whereby it is retained in the cells and not excreted. He considers that there is an unusual avidity of the various organs for iron, and that its origin is from some protein, possibly of the nature of a nucleo-protein, and not from hsmoglobin or its derivatives. Garrod (1 914 ') also agrees that the accumulation is not due to any excessive destruction of blood corpuscles, but rather to a failure to excrete iron by the usual channels. He, however, is of opinion that the source of the iron is the normal hrrmolysis constantly going on in the organism, and not the breaking down of proteins other than haemoglobin.

If there is, as we suppose, no abnormal amount of haemolysis, whilst there is still an impregnation of the tissue with iron, the possible source is twofold. I n the first place, there is the iron derived from normal haemolysis. This is split off from the haemoglobin, chiefly in the liver, and is carried by the blood to the bone marrow, where it is

16-~1.. OF PATB.-VOL. IIX.

236 ROBERT MUIR AND JOHN SHA W DUNN.

utilised in the normal formation of red corpuscles. In the second place, there is the iron supplied by the food. This, according to the results of various investigators, is absorbed from the duodenum and upper part of the je~junuiii, and a corresponding amount is escreted by the large intestine and, to a less extent, by the urine. Manifestly if the iron derived from normal hzmolysis is deposited in the tissues, the food iron must be drawn upon to a greater extent than normally for purposes of blood formation. We have a t present, however, no means of distinguishing the iron from these two sources. We cannot say whether the iron from normal hremolysis is in the same form as that derived from the food. It is practically certain, however, that both are available for puryoEes of blood formation, and it is probable that either may be, and probably is, deposited in the tissues in hmno- chromatogis. It is evident, moreover, that in haemochromatosis there is sufficient iron available for purposes of normal blood formation, and that the ultimate source of the iron deposited must be the iron of the food, whether this previously passes through the form of hsmoglobin or not. The retention or the fixation of iron is the all-important phenomenon, and we are inclined to regard i t as the cause rather than the result of deficient elimination.

We have now to consider the relation of the siderosis to the fibrotic lesions in the liver and pancreas which accompany it. We have fuller information with regard to the former, as in many of the earlier caws the condition of the pancreas has not been noted, and we have the outstaiiding fact that in practically all the cases there has been cirrhosis of the liver. In fact, i t is doubtful whether in true cases of bronzed diabetes this lesion of the liver has been absent. The question thus comes to be, whether the cirrhosis or the deposit of pig- ment is the primary factor. Taking all the facts into consideration, we can hardly suppose that the fibrotic changes are due to the presence of the pigment. In many situations in bronzed diabetes we find abundant depositti of pigment without s i p s of irritation, and in per- nicious anzmia and in other conditions there is little or no evidence that hsmosiderin gives rise to fibrosis. The question can only be properly answered by the examination of early cases, and some such cases, which will shortly be published by one of us, show that a t least in the pancreas the fibrosie may precede the deposit of pigment. In some of these early cases also the amount of piepent, to judge from corresponding amounts in pernicious anaemia, seems quite insufficient to account for the degree of fibrosis. An excess of iron in the liver appears to be not uncommon in cases of cirrhosis, but there is no relationship between the degrees of the two conditions. It is therefore only in a very small proportion of cases of cirrhosis that the extreme accumulations of iron occur, and there must be some distinct reason for this. That a large proportion of the pigment is formed in the liver, and that it is carried thence to lymphatic glands and other tissues,

IRON CONTENT OF ORGANS IN BRONZED DIABETES. 237

seems scarcely open to question. But, on the other hand, the character of the pigment in the heart muscle and elsewhere cannot be explained on the supposition that the pigment is carried in a granular form to these tissues and there taken up by the cells. The whole appearance is as if the iron were carried in a soluble form, and then split up by the cells into granular pigment which gives the reaction of iron, there thus occurring a sort of iron impregnation or infiltration. As we have already said, it seems that this does not result simply from retention owing to non-excretion; it would appear to be due rather to an increased affinity of the cells for iron, which leads to its fixation over a long period of time. Beyond this we have nothing definite to go upon, as we are ignorant as to the regulation of iron metabolism. It would appear, however, that we must suppose in this disease some common influence to be at work which affects the various cells, and that this influence arises from one lesion, though we can only conjecture what this niay be. We know that the liver plays the chief part in storing iron, whether this is derived from the food or from blood destruction, and also in the giving up of iron according to the needs of the organism. But apart from this we know nothing of any influence it may have in controlling the iron metabolism of the various tissues of the body. Nevertheless, that it may have some such influence, is not beyond the limits of possibility in view of what is known with regard to internal secretions. If the liver had a controlling influence of this kind, and if this influence Kere disturbed by Borne lesion, usually cirrhosis, we Ehould have a satisfactory explanation of the phenomena in question.

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Journ. dephpiol. et depath. gin., Paris, 1913,

Ztschr. f. klin. Med., Berlin, 1905, Bd. Ivii.

Bd. xxxvii. S. 115.

p. 390.

tome xiv. p. 179.

p. 129.

Bd. lxii. S. 411.

tome xv. p. 361.

s. 34.

238 IRONCONTENT OF ORGANS IN BRONZED DIABBTES.

11. STOCRYAN . . . . . Brit. Hed. Joum., London, 1906, vol. i. p. 1077.

12. GROH . . . . . . . Biochent. Ztsc7~1*., Berlin, 1913, Bd. liii. S. 256. 13. STOCKMAN . . . . . Journ. Physiol., Cambridge, 1896, vol. xviii.

p. 484 ; ibid., 1897, 1-01. rxii. p. 55. 14. PARKER . . . . . . Brit. Med. Journ., London, 1913, vol. ii. p. 1052. 15. SPRUNT . . . . . . Arch. Intern. Med., Chicago, 1911, vol. viii.

p. 75.