II. COLLAGEN DISEASES, COMMON CHARACTERISTICS 449
In a case of scleroderma collagenous fibrils of hand derma were examined a t the electron microscope; these fibrils had a period and a size markedly greater than in the controls. A second biopsy performed in the same patient on the other hand (in symmetric position) after ACTH treatment revealed a decrease of abnormal fibrils. The authors suppose that the morphological changes of fibrils are due to biochemical alterations of ground substance; the improvement induced by ACTH renders possible a normal fibrogenesis.
1. HALL, C. E., JAKUS, M. A. et SCIIMITT, F. 0.: J. Am. Chem. Soc. 64, 1234, 1942. 2. GROSS, J. et SCHMITT, F. 0.: J. Exper. Med. 88, 555, 1948. 3. TARANTA, A. et MAROTTA, U.: Rend. 1st. Sup. San. 16, 248, 1953. 4. BASSI, G.: La malattia sclerodermica. 1st. Ed. Med., Bologna, 1951. 5. RANDALL, J. T.: Nature and Structure of Collagen. Butterworths Scient. Publ.,
6. MAHAUX, J.: Ann. SOC. Royale Sc. MBd. et Natur. de Bruxellee 7, 65, 1954. London 1953.
The Nodular Symmetrical Liposclerosis as Collagen Disease
BY C. ALEXANDRIDES Thessaloniki, Greece
Under the name of collagen diseases there have been grouped together diseases of which the common characteristic is the fibrinoid change of the collagen system and mainly of its intercellular part) the collagen fibres and the ground substance. Bio- chemically the mucinous ground substance of the collagen tissue is the acid poly- saccharide hyaluronic acid present in loose combination with protein substances. An enzymatic system of hyaluronidases and anti-hyaluronidases regulates this combination in the tissues.
The pathological change observed in the collagen diseases is the fibrinoid degenera- tion or hyalinosis of the collagen system. It is manifested in the swelling of the fibres and in the alteration of the ground substance which becomes an amorphous mass. There also exists an alteration of the blood proteins, a so-called dysproteinemia, an increase of the globulin fraction. It is probable that there also exists a disturbance of the selective permeability of the capillaries which permits the passage of abnormal proteins and their precipitation into the ground substance. Another common charac- 28 - 666198 Medicinkongreaeens fkhandlingar
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teristic of the collagen diseases is that they respond to the treatment with cortico- surrenal and adrenocorticotropic hormones.
However there are essential deviations from these common features. In some diseases of the group not only the collagen but also the reticular and elastic fibres are involved as well as the muscular coat of the vessels, the capillaries of the renal glomeruli and the muscle fibres of the heart. Among the various diseases of this group there are also important clinical and aetiological differences. This is the reason why some authors propose other terms to replace the term collagen diseases. The names proposed are: hyalinosis, hyperglobulinosis, paramyloidosis, fibrinoid degener- ation, collagenosis, pararheumatic diseases or dysoria. I believe that these terms are even more unfit, because each of them means pathohistological or histochemical changes or change of the blood proteins or of the permeability of the capillaries, or they even use an unsuitable clinical term (pararheumatic diseases). For this reason, in my opinion, the term collagen diseases is more appropriate if used with the meaning of diseases which show extensive hyalinosis, dysproteinaemia and dysoria and which respond to treatment with corticosurrenal and adrenocorticotropic hormones.
To the group of collagen diseases belong the rheumatic arthritis, the systemic lupus erythematosus, the periarteritis nodosa, the scleroderma and the clermatomycosis. To these diseases others add the rheumatic fever, the serum sickness, the throm- bangieitis obliterans and the malignant nephrosclerosis.
I n my opinion, the lipophagic granuloma and particularly its special form of the nodular symmetrical liposclerosis is a disease which shows all the above-mentioned characteristics of collagen diseases.
Lipophagic granuloma belongs to the steatonecroses. The fat tissue, a part of the connective tissue, is characterised by great fragility and vulnerability. It easily undergoes necrosis, the so-called liponecrosis or steatonecrosis, which shows a ten- dency to chronicity, extension and sclerosis.
The fat which is liberated from the fat cells after their death is metabolised in the intercellular spaces. The products of this metabolism are highly irritating and cause inflammatory, productive and degenerative reactions. Similar reactions are also caused by the introduction of fatty substances by injection. In both cases the degree and form of the reaction depend on the speed with which the decomposition of the fat takes place, the quantity of the produced subproducts and their chemical nature. The strongest reactions are caused by the non-saturated acid fats.
The steatonecrosis begins with a cellular reaction, that is with an accumulation of lymphocytes, monocytes and histiocytes some of which become lipophagic or giant cells. The fibroblasts also increase in number and produce collagen fibres.
The tendency to expansion of the steatonecrosis is due first to reactions which take place far from the original focus and this is called distant reaction, and secondly to a chain reaction. The explanation for these reactions which cause expansion is that on one hand the water soluble subproducts of the extracellular decomposition of the
II. COLLAGEN DISEASES, COMMON CHARACTERISTICS 451
fat are transferred by the lymph vessels away from the original focus and on the other hand the formed subproducts are phagocytized by the lipophatic cells and transferred to distant sites.
The tendency to sclerosis is due to the multiplication of the fibroblasts, the produc- tion of collagen and its degeneration to hyaline substance, as well as to the presence of dysproteinaemia and dysoria permitting the passage of abnormal proteins in the intercellular spaces and their precipitation and degeneration. I n the steatonecrosis we meet considerable changes of the blood vessels affecting all layers of the wall, especially of the intima, and in this way a stenosis or obliteration of the vessels may occur. So a circulus vitiosus takes place, the steatonecrosis causing obliteration of the vessels and the obliteration in its turn causing steatonecrosis. When the stea- tonecrosis is considerable then microcysts are formed through the confluence of many fat cells. The steatonecrosis causes reactional processes and formation of gran- ulomatous tissue which contains histiocytes, epithelioid and giant cells, many of which have lipophagic properties. The farther evolution of the process depends on many factors such as: the chemical composition of the products of the extracellular fat decomposition, their quantities and physicochemical composition of the tissue- and blood-humors and many other unknown factors.
I will not attempt a discussion of the classification of the different forms of stea- tonecrosis, as it does not concern my subject. I will only state the classification by William Blanc as being, in my opinion, the most correct.
William Blanc distinguishes: (1) small steatonecroses, (2) microcystic steatonecroses, (3) diffuse steatonecroses which include (a) the Rothmann-Makai syndrome and (b ) the Weber-Christian syndrome, (4) massive cheloid liposclerosis, (5) the progressive forms of liponecrosis which include (a) the nodular symmetric liposclerosis of the limbs and (b) the prevertebral dysproteinic liposclerosis (mediastinal and retroperi- toneal) .
Blancs classification is, in my opinion, the best one because it is based on mor- phological, anatomo-histological and clinical signs. It only disregards the aetiological part and for this reason, I think, it can be complemented by the addition of the aetiological factors which would divide all the various forms into (a) of known aetiol- ogy (trauma, injection, infection etc.) and (6) of unknown aetiology (spontaneous or idiopathic).
The forms belonging to the collagen diseases are the progressive forms and partic- ularly the nodular symmetric liposclerosis of the arms. Four cases of the nodular symmetric liposclerosis were published until the year 1951. Blanc in his book Syndro- mes nouveaux de pathologie adipeuse, published in 1951, speaking of the Forme Brachiale of the Progressive forms of steatonecrosis, apart from the above four cases also cites two other cases which he alleges I had communicated t o him orally. Thus the total number of cases became six.
However, as Blancs description of my cases is incomplete and to a certain extent inexact, I wish to make here a full statement of these cases. Out of the six cases, four
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Fig. 1. Fig. 2.
are idiopathic. The remaining two, one of Oppenheim and one of the speaker, may be attributed to injection given in the arms. In Oppenheims case the injection is said to have been of a ferroarsenical preparation and in my case of a medicine called paratoxin.
The disease begins with the appearance of nodules in symmetrical sites of the arms progressively increasing in size and forming hard compact masses movable on the basis and strictly adherent to the skin having continuous tendency to expan- sion. From time to time the tumor shows inflammatory reactions with redness of the skin and tenderness to pressure, a general malaise, and slight fever. The colour of the skin is greyish melanotic becoming reddish when inflammation takes place. The histological examination shows numerous microcysts whose walls are like onion peels and a very extensive hyalinosis. The localisation is strictly symmetrical in both arms but in one of my cases i t was symmetrical in both arms and thighs. To my knowledge no other similar case has so far been made known. A particular feature of this last case is that all four limbs are successively affected by inflammatory exacer- bations.
The strict symmetry and the successive appearance of the inflammatory process in the four extremities, make it probable that nervous factors play some r61e in the pathogenesis of this case. Vascular damages are also observed, as well as dyspro-
II. COLLAGEN ~ I S E A S E S , COMMON CHAFCACTERISTICS 453
teinaemia with an increase of the globulin fraction of the proteins. The electrophoretic analysis shows an increase of the p and y globulins.
For the pathogenesis of the microcysts in the shape of onion peels the following interpretation may be given. Through the confluence of many dead fat cells a cyst containing a mixture of fat and protoplasmatic proteins is formed. In the surrounding tissues multip1icat)ion of the fibroplast and collagen fibres takes place which later on undergoes hyaline degeneration. Lipophagic histiocytes penetrate into the cysts. Some of them digest the fat but others die and liberate fat which diffuses out of the cyst and imbues the hyaline substance or causes new reactions contributing in this way to the expansion of the process. The membrane of the cyst as well as its content and the surrounding connective fibres undergo hyaline degeneration. In this way successive layers of hyaline are deposited in the inner and outer surface of the cyst like rings. Some of them are separated from each other by fat drops. It is thus that the onion peels, resembling layers, are formed. Other authors compare them with Liesegangs rings in the formation of stones.
Nothing is known about the aetiology of the nodular symmetrical liposclerosis. In the speakers two cases however tuberculosis of the lungs is recorded in the pa- tients history.
I now proceed to the description of these two cases:
Case 1: M. R., female, 58 years old, 30 years before haemoptysis with negative sputum and slight shadow on the left subclavicular region. Since then repeated haemoptyses
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without disturbance of well being. Constant rllcs in the apex of the right lung. Three children, one of them had died 15 years before from tuberculosis of the lungs a t tfhe age of twenty. One of the two living daughters has been suffering for two years from a very severe form of pemphigus vegetans. Two brothers died suddenly from heart cliseasc. Mother 97 years old lives in good health.
The present disease started 25 years ago with the appearance of small tumors on the outer side of both arms, size of peanut increasing gradually, symmetrical, hard and
painless (Figs 1 and 2). Now and then appearance of inflammation with redness of the skin and slight malaise. In a short time similar tumors appeared on the outer side of both thighs (Figs. 1 and 2).
The inflammatory exacerbations occur usually in the spring and autumn and attack successively the four extremities. Before the attack of one limb ends the attack of the other one begins so that within the space of a certain time all four extremitios are under inflammation. Since menopause, the attacks of inflammation havc been less frequent and less intense.
Preaent atutw: Obese porson, rdes in the left apex, blood pressure: systolic 180, diastolic 80. Physical examination reveals no abnormality. On the outer side of the lower third of the upper arms and in the middle of the thighs we observe hard tumors, of about 6 x 9 cm size, with irregular surface and shape, adherent to the skin, movable on the basis, painless. Some of the nodules seem to be independent of the rest of the tumor but lying very near it. The consistency of the tumor is very hard in some parts, likc bone. The colour of the skin over the tumor is greyish mclanotic, when inflammation nccurs the skin becomes hot, reddish and oedematous.
The record of the histological examination (Prof. Elephtheriou) is as follows: Very dense fibrous connective tissue, with thick collagen bundles which in many places show hyaline degeneration. In the tissue numerous fatty drops are seen, many of which are surrounded by a connective tissue, rich in cells and less hyaline degenerated. Inflamma- tory infiltrations, consisting mainly of lymphocytes aro also encountered. Some of the fat drops are surrounded by polynuclear phagocytic giant cells. The hyaline degenerated
II. COLLAGEN DISEASES, COMMON CHARACTERISTICS 455
connective tissue presents calcification in a diffuse or circumscripted form. In some places the calcificated hyaline degenerated tissue has the form of concentric rings (Fig. 3) .
Blood sedimentation rate always accelerated, 20 to 40 mm in the 1st hour (Westergreen). Blood cholesterol in repeated examinations 2.5-3 %,,. The electrophoretic analysis of the blood proteins shows: Total proteins 5.99 %, Albumin 44.2 %, Globulin a1 5.2 yo, a2 11.8 %,