Osteomalacia hepatica

Acta Medica Scandinavica. Vol. XCIX, fasc. 11-111, 1939.

From the Medical Clinic (Director: Professor Sven Ingvar) of the Royal University at Lund (Sweden),

Osteomalacia hepatica. BY

ERIK ASK-UPMARK, M. D.

(Submitted for publication January 3rd 1939).

The present study will attempt an analysis of the patho-physiology of osteomalacia with special regard to the rBle of the liver.

Definifion of osteomalacia. Osteomalacia may be characterized as a deficiency disease

in adults comparable to rickets in children, the central factor in both conditions being a disorder of the mineral metabolism, brought about by inadequate supply of vitamin D as compared with the utilization.

Occurrence of osfeomalacia. The occurrence of osteomalacia is by no means confined to

the East, although the peculiar social, religious and economic conditions of China and India makes the disease particularly common in these countries, as set forth for example in the excellent review of Hunter, to which may be referred for details. Thus, in China the disease is mainly to be encountered in the high plateaus of the North, where the severe winters and the foot-binding of the women invites to confinement indoors and the diet, mainly being represented by cereals, is thoroughly inadequate particularly with regard to calcium and vitamin D. In India osteomalacia is likewise common in women observing strict purdah (screening from the sun; inten- tionally insufficient food with the idea to facilitate the delivery by keeping the foetus small; severe drain of calcium by repeated

OSTEOMALACIA HEPATICA. 205

pregnancies and lactations, carried on for years a t a time). Among women working in the open air and accordingly exposed to the sun osteomalacia was not to be observed in Kashmiri boat women, whose food is adequate whereas in Punjab osteomalacia is common, the diet here being insufficient with regard to milk and eggs. In Europe the ))hunger-osteopathieso of southern Germany and particularly of Austria and Vienna during and after the war may he quoted as another illustration. In England the remarkable study of Drummond probably represents a connected phenomenon: at an English high school the annual number of fractures during the years 1914-1929 averaged 5-6 except of in 1918- 1922 when margarin was substituted for butter; during this period the number of fractures more than redoubled; i t should be observed that the nutrition, although probably insufficient also in other regards in 1917-1918, was, in 1919-1922, normal in every regard except of the butter. In Denmark osteomalacia has been reported l)y Meulengracht (1938), who points out that the disease is probably much more common than generally anticipated. As a matter of fact two essential conditions makes the appearance of osteomalacia i n the Scandinavian countries reasonable enough: on the one hand the dietary habits are, in several places, rather inadequate (not least so in Denmark, the country of the xerophtalmias), on the other hand the sun is poor for considerable parts of the year (not least so in the far North).

Physiology of vitamin D. The physiology of vitamin D may be briefly recollected. It is

supplied by means of the food and by ultraviolet irradiation of the skin, i t is stored in various organs, particularly the liver, and it is utilised in the mineral metabolism of the bone system.

The intake of vitamin D is liable to occur along three different routes.

1. The food, particularly so egg-yolk, butter, cod liver oil, ccrtain fat fishes; for grazers, hay, dried in the sun.

2. The activation of sterols of the skin, acting as pro-vitamins, I)y ultra-violet light.

3. According to Seyderhelm (1938) there is an endogenous source of vitamin D, represented by the red blood cells: when destroy- cd their vitamin D is excreted with the bile, it is re-absorbed from

206 ERIK A S K - U P M A R K .

the bowels and again utilized in the bone-marrow for the hemo- poietic activities, thus representing a hepato-enteric circle; if this circulation is cut off, for example by means of a hiliary fistula, anemia is liable to occur.

I t will be seen already from these considerations that the liver is holding a certain key-position with regard to the vitamin D. This is substantiated also by the fact that the most important store- house for this vitamin is the liver; other (minor) depbts are reprc- sented by the suprarenals, the kidneys, the brain, the skin (after exposure to light) and the intestinal wall. -

The main function of the vitamin D is the regulation of the calcium and phosphorus metabolism; the absorption of these matters from the bowels, their utilization in the bone system and the control of their faecal excretion being performed along lines preventing the appearance of rickets in children and osteomalacia in adults. Other functions of vitamin D are connected with the elaboration of anli- bodies and the maintenance of the bactericidal abilities of the blood.

Description of case.

‘The following case seems instructive with regard to the pathophysiology of osteomalacia to be discussed later on in. this paper.

Medical Clinic 2654/1938. K. B., man, aged 57. Observed in the surgical clinic Jan. 11th-Febr. 11th 1937, March 1st-March 11th 1937, Oct. 28th-Nov. 4th 1937, observed in the medical clinic Nov. 4th-Dec. 3d 1937, Aug. 19th-Oct. 5th 1938, Oct. 19th-Nov. 18th 1938 (death), observed a t the Spaa of Ronneby (by myself) July-Aug. 1938.

History: Until a few years ago a butcher, last years retired. Well-off from economic point of view. During the period covered by and immediately succeeding the great war he used quite a lot of hard liquors. In 1919 he had a traumatic fracture of the VIIIth dorsal vertebra, otherwise he was prr- viously entirely healthy. He now applied for medical attention because of abdominal pains, diabetes and pains in the back.

a) The abdominal pains firstly appeared in the spring of 1935. They were localized to the very centre of the epigastrium, they had no relation to the intake of food and neither to the kind of food consumed, they did not interfere with the appetite nor with the regularity of the bowels, but they were rather strictly confined to the night, and a t least for the last 6 months appearing about 24 o’clock, continuing for some hour if not dealt with accordingly. At first they were fairly irregular but since the early

O S T E O M A L A C I A H E P A T I C A . 207 spring of 1937 they have been rather continuous although some improvement was noted in the summer. Their severity increased during the last 4 months to a degree sometimes almost compatible with tabic crises (no luetic infection was to be ascertained in the history neither during the clinical observation). No vomiting, no impairment of the bowels, appetite unaf- fected, no emaciation or reduction of weight (except for the last 2 months before death).

b) Diabetes had been present at least since 1936 but was throughout the course of a mild degree, most blood sugar records averaging 0.14-0.15; insulin was only temporarily used, mostly not so; no dietary restrictions were necessitated although the patient did avoid sugar and sweets. On the whole the diabetes was by no means very striking and from clinical point of view only to be looked upon as a n accidental phenomenon.

c) The pains in the back did appear in January 1937, i . e. some 22 months before death. He was then taken ill wih the ordinary symptoms of a lumbago or sciatics, the pains involving the left hip joint region, the lumbar spine and to some extent the left leg. When dismissed from the clinic February 1937 these pains had considerably improved but not entirely subsided and there was also some discomfort to be noted about the left half of the chest, particularly so when the weather changed. I n the subse- quent course the pains in the lower region of the back did return a t several occasions, on the whole with increasing severity. The pains were, then, felt not only in the back but also along the cristae ilei and towards the trochanteric regions as well as the shoulders; when most severe they kept him bedridden, unable to stand or t o move. Originally i t was thought that the pains be due t o static insufficiency, since there were (Jan. 1937) radio- graphic evidences of a spondylosis deformans as well as of an old, well- healed fractura of the dorsal spine and, finally, of a spondylolisthesis of the 4th lumbar vertebra. The increasing and considerable severity of the inimobilizing pains on the one hand, the constantly increased sedimentation rate of the red blood cells on the other made i t however obvious that something more was about. I t should be added that the pains were less severe during the summer, a t least in 1937; in 1938 severe attacks of pain did occur also in July and Aug.

C1 in ical observations : a) General conditiori and physical examination: On all admissions except

of the last the general condition was fairly good, the stature being tall, the colour of the skin approximately normal, occasionally slightly yellowish, the weight constant until Aug. 1938 when a reduction did start, the temperature and the blood pressure normal. Physical examination of heart, lungs, abdomen and nervous system did not reveal any abnormalities. There was however now and then a certain slight tenderness in the midline of the epigastrium and some restriction of the movements of the spine parallel to the pains experienced. The prostata was slightly enlarged, otherwise entirely normal. When admitted in August 1938 his weight had become reduced t o 86 kg from 95 kg as registered 10 months ago; there

208 ERIK A S K - U P M A R K .

was also a definite tenderness of sacrum and when attempting to bow for- wards severe pains were felt in the lumbar spine. During Sept. 1938 his weight again increased to 94.4 kg parallel1 to the appearance of oedema of the legs; it was uncertain whether any ascites was to be registered; later on the weight again reduced, the last registration (Oct. 1st) being 83.3 kg. When, finally, admitted in November 1938 he was in a poor general condition, presenting (since October) increased temperature with chills towards 41" C. from a base line averaging 37.8-38' C; he was pale, emaciated, bedridden and suffering from severe pains in the back and the sacroiliac regions, irradiating down into the thighs; his weight was obviously considerably reduced although i t was impossible t o obtain any registration (on account of his pains); there was a considerable tenderness over the lumbar spine, the sacrum and the left trochanteric region; movements of the spinal column were practically impossible to perform, the patient being unable to stand. A rapidly progressing anemia was present as well as some degree of ascites and a temporary urinary infection. He went continuously down hill and eventually died Nov. 18th.

As already mentioned his diabetes was mild throughout the course, no reducing substances being present in the urine and the level of the blood sugar averaging 0.15. I t should be stressed tha t on no account was there any increased diuresis, the output in 24 hours averaging 1 1. Albumen was never present in the urine, bu t the urobilino- gen test was repeatedly positive, when examined daily (Aug.-Sept. 1938), with negative registrations in between.

As for the stools numerous examinations were made in order to find occult blood: all findings were negative. Gastric analysis was performed Oct. 1937 and (fractionated) Aug. 1938: on both occasions free hydrochloric acid in small amounts was found. Duodenal analysis (Sept. 2d, 1938): bilirubin 20.5/200,000 before and 12.5/200,000 after the injection of 0.5 mgm pituitrin.

Blood: The sedimentation rate was determined on numerous occasions ever since Jan. 1937 and always found to exceed 60; the last determination, Oct. 19th 1938, was 110/138. Bilirubin was Nov. 4th 1937 1.4/200,000, some days later 1.5/200,000, Aug. 20th 1938 0.2/200,000. The non-protein-N was Nov. 1937 = 30, Aug. 1938 = 37. The colloid osmotic tension was determined once only, in Nov. 1938, when it was 309; at the same time the serum protein was 6.29 yo. The calciumlevel of the serum was 10.7 uzz. 9.3 (Oct. viz. Nov. 1938). The citric acid a. mod. Thunberg-Sjostrom was only slightly increased amounting to 29 as well in Nov. 1937 as in Sept. 1938. The blood sugar, as mentioned, averaged 0.15. The Rona test was mode- rately pronounced (Nov. 1937 difference of drops 8 via. 7 for chinin viz. atoxyl; Sept. 1938 difference of drops 11 and 7 respectively). The Takata- Ara test was markedly positive when registered (Nov. 1937, Aug. 1938, Oct. 1938). The galactose-test showed, in Nov. 1937, an excretion of 10 out of 73 grams administered; in Sept. 1938 the corresponding figures were 3.78 and 68.4. The blood morphology, finally, may be briefly summarised in thc- following table.

b) Laboratory records.

OSTEOMALACIA HEPATICA. 207 spring of 1937 they have been rather continuous although some improve- iiient was noted in the summer. Their severity increased during the last 4 months to a degree sometimes almost compatible with tabic crises (no luetic infection was to be ascertained in the history neither during the clinical observation). No vomiting, no impairment of the bowels, appetite unaf- fected, no emaciation or reduction of weight (except for the last 2 months before death).

b) Diabetes had been present at least since 1936 but was throughout the course of a mild degree, most blood sugar records averaging 0.14-0.15; insulin was only temporarily used, mostly not so; no dietary restrictions were necessitated although the patient did avoid sugar and sweets. On the whole the diabetes was by no means very striking and from clinical point of view only to be looked upon as an accidental phenomenon.

c) The pains in the back did appear in January 1937, i. e. some 22 months before death. He was then taken ill wih the ordinary symptoms of a lumbago or sciatics, the pains involving the left hip joint region, the lumbar spine and to some extent the left leg. When dismissed from the clinic February 1937 these pains had considerably improved but not entirely subsided and there was also some discomfort to be noted about the left half of the chest, particularly so when the weather changed. In the subse- quent course the pains in the lower region of the back did return at several occasions, on the whole with increasing severity. The pains were, then, felt not only in the back but also along the cristae ilei and towards the trochanteric regions as well as the shoulders; when most severe they kept him bedridden, unable to stand or to move. Originally it was thought that the pains be due to static insufficiency, since there were (Jan. 1937) radio- graphic evidences of a spondylosis deformans as well as of an old, well- healed fractura of the dorsal spine and, finally, of a spondylolisthesis of the 4th lumbar vertebra. The increasing and considerable severity of the inimobilizing pains on the one hand, the constantly increased sedimentation rate of the red blood cells on the other made it however obvious that something more was about. I t should be added that the pains were less severe during the summer, at least in 1937; in 1938 severe attacks of pain did occur also in July and Aug.

C1 in ical observations : a) General condition and physica2 examination: On all admissions except

of the last the general condition was fairly good, the stature being tall, the colour of the skin approximately normal, occasionally slightly yellowish, the weight constant until Aug. 1938 when a reduction did start, the temperature and the blood pressure normal. Physical examination of heart, lungs, abdomen and nervous system did not reveal any abnormalities. There was however now and then a certain slight tenderness in the midline of the epigastrium and some restriction of the movements of the spine parallel to the pains experienced. The prostata was slightly enlarged, otherwise entirely normal. When admitted in August 1938 his weight had become reduced to 86 kg from 95 kg as registered 10 months ago; there

210 E R I K A S K - U P M A R K .

2. Cholecystograyhy Nov. 1937: no contrast to be identified within the gallbladder.

3. Bone system Jan. 1937: Spondylosis deformans. Spondylolisthesis between L4 and L5. Inveterated fracture of 8th thoracic vertebra. Radio- grams otherwise normal.

4. Bone system Oct. 1938: Thoracic and lumbar spinal column, ribs, pelvis and skull examined. Positive observations on the one hand a diffuse demineralisation, particularly pronounced in the spinal column, the ribs and the pelvis, on the other hand small destructions e. g. of 4th and 5th lumbar vertebra, of the ribs and of pelvis (small punched-out areas); it should also be observed that the general appearance of the various verte- brae is much more ufish-typed, (biconcave) in Oct. 1938 than in Jan. 1937.

Necropsy: This was performed Nov. 19th by Professor E. Sjovall. The following observations were recorded.

1. A most pronounced cirrhosis of the liver, the parenchymatous cells containing ample of iron pigment (haemochromatosis). Some degree of ascites.

2. A moderate sclerosis of the pancreas, which was macroscopically somewhat brown-yellowish and microscopically showed haemochroma- losis as well.

3. An about pea-sized ulcus duodeni, rather callous. 1. A pronounced osteoporosis with a few spontaneous fractures but

5 . No biliary concrements were to be registered. 6. No enlargement of the parathyreoids was to be observed. 7 . Hyperplasia of the red pulp of the spleen.

Briefly summarized the case did concern a man, aged 57, applying for severe pains in the stomach and in the back, presenting clinical evidences of a liver insufficiency and, finally, a severe anemia and clinical and radiographical evidences of a progressive rarefication and destruction of the bone system. The clinical diagnosis was originally cirrhosis hepatis but since it was felt by the roentgenologists that the bone alterations might have been due to metastatic deposits the possibility for malignancy was considered as well. The necropsy, however, eventually confirmed the original diagnosis and beautifully elucidated the hitherto somewhat obscure character of the bone affection.

As for the abdominal pains i t is of course entirely possible that as well the affection of the thoracic spina1 column as the presence of a duodenal ulcer might have been of contributory importance; on the

The liver insufficiency was clearly demonstrated by the laboratory observations already quoted as well as by the result of the cholecystrography, concrements being absent.

with no abnormal tissue present.

OSTEOMALACIA HEPATICA. 21 1

other hand i t should be emphasized that this type of pains may be readily encountered in instances of severe cirrhosis, so tha t no other explanations seem to be necessitated. The presence of a duodenal ulcer cannot be considered as any surprise since i t is well known that such ulcers not infrequently do accompany the type of cirrhosis here in question, and that they, moreover, may be obtained experimentally by means of intoxications of the liver, particularly with cinchophenpreparations; to this interesting relation between the condition of the liver and the presence of duodenal ulcus will be returned in another paper.

With regard to the affection of the bone system the following features should be recollected as particularly instructive.

1. The severe intensity and the general progression of the pains. 2. The fact that the pains were most severe by night. 3. The fact that they did improve during the summer, a t least

so in 1937. As set forth elsewhere (Ask-Upmark 1938) these general charac-

ters furnish strong evidence for the presence of an organic disorder of the bone system, and this was, of course, confirmed by the general evolution of the clinical and radiological symptoms.

The character of the lesion of the bone system did remain, until the necropsy, a matter of discussion. The following possibi- lities were to be considered:

1. Osteitis fibrosa generalisata Engel-Recklinghausen. 2. Multiple myeloma. 3. Metastatic deposits e. g. from a carcinoma. 4. Lymphogranulomatosis maligna. 5. Osteomalacia.

The general appearance of the radiological affections did not favour the assumption of a Recklinghausen or a myeloma, although it should be admitted that the radiographical appearance may, in these conditions, be variable. If the blood calcium level had been elevated, if the diuresis had been pathologically increased or if concrements of the kidneys had been demonstrated these features might have called attention to the possibility of a Recklinghausen; the absence of these characters does of course prove nothing but there was no particular reason why the liver should be involved in this syndrom. If, on the other hand, Bence Jones had been posi- 1 4 - Acta med. scandinau. Vol . X C I X .

212 ERIK ASK-UPMARX.

tive or if the serum protein had been markedly increased a myeloma might have been considered. Metastatic deposits from a malignant growth was an outstanding possibility; no primary tumour had of course been registered, but it should be remembered that certain tumours may remain clinically rather obscure during life, for example several carcinomas of the pancreas or of the medi- astinal part of the bronchial structures, Lymphogranulomatosis maligna might have furnished an explanation since i t is well known that the bone system is particularly liable to become involved by this disorder (for references see Ask-Upmark l). Just as with the metastatic growths the predilection exists that the bones affect- ed are those containing red marrow; the apparent involvement of the liver might well have been compatible with this possibility and the terminal stage with pyrexia would tally as well. On the other hand most instances of lymphogranulomatosis maligna clinically involving the bone system apparently run a more rapid course and although the absence of enlarged lymphatic glands might have been apparent the possibility of Hodgkin’s disease was nevertheless considered less likely. As to osteomalacia this possibility was thought of but the adequately composed food served to obscure the epicritic considerations.

As a matter of fact it seems entirely probable that the cirrhosis of the liver and the osteoporosis of the bone system be functionally connected. The osteoporosis had the general characters described in osteomalacia and the thesis will be marshalled that the case should be considered as an osteomalacia of hepatic origin. This matter will be discussed in the following section of this paper.

Pathophysiology oi osteomalacia. In general, osteomalacia is liable to appear if the adult body is

exposed to a disproportion between utilization of vitamin D and supply of vitamin D. The utilization may be increased, for example during pregnancy, lactation, chronic infections, etc. The supply may be reduced by one or several of the following factors.

I. Insufficient intake of vitamin D. When the amount or compositioii of the food is inadequate and no compensation is offer- ed in activation of the provitamin of the skin by the sun osteomalacia will occur, even if sufficient amounts of calcium and phos-

Acta SOC. Medicor. Suec. 1938, p. 1-93.


phorus are provided. The osteomalacia of China and India, the hungerosteopathies of Central Europe during and after the war, the scattered observations in England and Denmark already quoted all belong to this deficiency group. The observations of osteomalacia also in individuals working in the open air with plenty of sunshine during most of the year (Wilson, women in the Kangra district of Punjab) seem to stress the importance of the alimentary supply of vitamin D. I t should however be remembered that a demineralisation of the spongy skeleton is t o be expected even when the vitamin D is furnished in large amounts, if the supply of calcium be insufficient; under such circumstances the calcium depSts of the bone system will be drained in order to maintain the calciumlevel of the blood; i t is possible that this factor was cooperating in the observations of Wilson since the food of these women apparently was very poor also with regard to calcium.

11. When the intake of vitamin D in adequate disturbances of the resorption from the intestinal tract may establish a vitamin-D- deficiency of the body with osteomalacia eventually resulting if adults and rickets if children are concerned. The resorption may suffer under the following conditions.

1. If there is present in the bowels a substance liable to be connected with the vitamin D, viz. with the calcium of the food, the combination being of a character inappropriated for resorption. As far as the fat-soluble vitamins are concerned the use of paraffin fluid as a laxans represents such a substance: the vitamins will be dissoluted in the paraffin and pass the bowels unresorbed. With regard to vitamin D no observations along this line hitherto seem to have been published; with regard to vitamin A an avitaminosis probably resulting from the fanatic use of paraffin has been described by Ask-Upmark (1938). With regard to calcium, ,attention has been called, by Meulengracht (1938), to the possibility that the extensive use of Sal Carlsbadense as a laxative may result in the appearance o l unsoluble calcium sulphate within the bowel and hence to a calciumdeprivation of the body, eventually resulting in osteomalacic disturbances. Experimentally, stron- tium feeding to dogs and rabbits has been noted as causing rickets, uiz. osteomalacia, also with fractures, it beeing presumed that the condition of the bone system be due to the affections of the phos- phate within the bowel (Huggins 1937).

214 E R I K A S K - U P M A R K .

2. If achylia gastrica is present the resorption of calcium from the intestinal tract is liable to suffer. It should be remembered that the resorption of calcium is facilitated by acid reaction of the intestinal content and also that the hydrochloric acid has to trans- form less soluble calcium salts into more soluble combinations. Meulengracht (1938) has published a series of observations con- cerning osteomalacia which he attributes to this factor (oosteoma- lacia achylicao); in another of his observations no achylia was to be registered but there was a pyloric obstruction of long duration. I t seems uncertain whether the most interesting experimental results achieved in puppies and dogs by gastrectomy (severe homogeneous osteoporosis; Bussabarger et al. 1938) should be looked upon as a connected phenomenon: on the one hand a pronounced demineralisation of the skeleton was obtained, leading to deformities and even to fractures, on the other hand the type of bone lesion was, a t least in the puppies, not identical with rickets but more with a severe osteoporosis; the absence of hydrochloric acid, the increased speed of intestinal transport of food substances when the stomach was removed and the presence of a postcibal acidosis ())acid tide,) tending to decrease calcium retention were considered the factors responsible. It is of course entirely possible, that the affection of the bone may be somewhat different when a calcium deficiency is about as compared with the result of a vitamin D deficiency; in adults the difference may be less conspicuous but in puppies rickets is to be expected from a deficiency of vitamin D.

3. Impairment of the resorption of fat is liable to be connected with a deficiency of fat-soluble vitamins and accordingly also of vitamin D.

a) In steatorrhaea (coeliac disease; sprue, Gee-Herter’s disease) calcium as well as vitamin D will remain in the fat stools unavail- able for the body. In children rickets will be the result, in adults osteomalacia.

b) In affections of the pancreas a similar sequence of events will appear: insufficiency of the pancreatic activities in the bowels will result in fat stools, the resorption of calcium and vitamin D will hence become impaired and osteomalacia will be obtained. This was demonstrated already in 1905 by Pavlov (fistula of the pancreatic duct in dogs) and has since been confirmed clinically (e. g. in pancreatitis).


c) In all conditions where the bile has been prevented to enter the bowels in sufficient amount fat stools will result, thus seriously impairing the resorption as well of calcium (which will form soaps with the fat acids) as of fat-soluble vitamins. If the condition is allowed to persist for sufficiently long time osteomalacia will be obtained.

Experimental evidence to this effect has been furnished mainly by the investigations of Pavlov (1905), Tamman (1928), Heymann (1928), C. L. A. Schmidt and Greaves (1932) and others. Pavlov, draining the bile out of the body by means of a biliary fistula (in dogs), observed the appearance, after a few months, of a typical osteomalacia. Since calcium is contained in the bile the bone affection might have been ascribed to the mere output of calcium had i t not been for the quantitative relations: in a dog with a fistula of the bile duct during 15 months the loss of calcium by means of the bile was only 13.5 gm (L6wy, quoted by Schmidt 1937), whereas the calcium deficiency of the skeleton did amount, during 7 months, to 490 gm (Tamman). A most important contribution was delivered by Tamman: in dogs with a biliary fistula the resulting osteomalacia was to be healed or prevented by the subcutaneous injections of activated cholesterin (the only preparation available a t that time). Heymann obtained rickets in young dogs with a biliary fistula when the animals were kept in darkness; cure was obtained by vigantol; control animals (without fistula) did not get any rickets. Schmidt and Greaves made a fistula between the bile duct and the renal pelvis, and obtained a negative balance of calcium and phosphorus; if vitamin D was injected subcutaneously the calcium balance turned positive. The experimental evidence hence obtained represents an important contribution to our knowledge of osteomalacia; the blood calcium level was, in these experiments, never elevated but sometimes depressed and enlargement of the para- thyroids was noted repeatedly (compensatory adjustment).

Clinical correlations are to be expected from instances where the admission of the bile to the bowels has been prevented for a sufficiently long period of time. Such may be the case in biliary fistulas, draining the bile from the duct out of the body: instructive cases of this kind have been published by Seidel (1910, 2 cases) and by Wangensteen (1927, 2 cases). Such may, further, be the case in long-standing jaundice where the stools remain acholic (Schmidt,

216 ERIK ASK-UPMARK.

1937). Thus, one of the cases of Seidel had a fistula since 4 years, with pains and impaired gait since 2 years; when, then, the fistula- tion was improved the symptoms of osteomalacia improved as well; the second case of Seidel died, presenting a t the necropsy soft long bones and broken ribs.

111. With regard, finally, to the storage of vitamin D it has already been mentioned that the most importante store-house is represented by the liver. Yet has nobody, to the best of my knowledge, hitherto attempted to connect osteomalacia with disturbances of the liver functions (cfr. below p. 217). It has been maintained, however, that the present case may represent a syndrom characterized by the connection of cirrhosis with osteomalacia, the most likely explanation being that impairment of the functional abilities of the liver have made the storage (possibly also the elaboration) of vitamin D inadequate. I t should be readily admitted that the investigations of the patient here in question might have been more complete: the serum phosphorus level was not determined, the intake and excretion of calcium and phosphorus was not controlled with regard to the quantitative relations and no attempt was made to influence the condition by parented administration of sufficiently large doses of vitamin D. Even if such an attempt had been made its failure could not have been used as anargument against the interpretation here mentioned. Nevertheless it was felt that the following topics might represent suggestive evidence for the pathophysiological relations between liver disease and bone disorder here assumed:

1. The clinical particulars were in all essential regards in con- formity with the presumed correlation. Thus, there could be no doubt but that the severe cirrhosis was the older disease, that the affection of the bone system mainly developed during the last two years and particularly during the last year, that the amount and composition of the food was entirely adequate and that there was an improvement of the bone pains during the summer when the man enjoyed exposure to the sun. It should be emphasized that bile was present in the stools all the time (cfr. the result of the duodenal test).

2. it is tempting to refer to the pathophysiology of the anemias as analogy. If the hypochromic anemias be seIected as example they may be due to deficient intake of iron (food deficiencies), to deficient elaboration of the food in the ventricle (achylia, resec-

OSTEOYALACIA HEPATICA 217

tions etc.), to deficient resorption of iron from the bowels (instances of intestinal hurry etc.) and to damages to the store-house (liver- cirrhosis). There seems to be no reason why not a similar sequence of events might be applied to the vitamin D. As far as the liver is concerned i t should also be mentioned that, although I have been unable to find any osteomalacia in connection with liver disorders in the literature, a condition termed brachitis hepaticab has been described by Gerstenberger (1933): in 3 infants a pronounced rickets was to be registered in connection with a severe cirrhosis of the liver; blood calcium level essentially normal; hypophosphatemia was present; no therapeutical results whatsoever were to be achieved; all instances proved fatal. Since in two of these infants a con- genital atresia of the bile duct was present these cases were not entirely compatible with my own observation but should perhaps rather be considered as due, a t least in part, t o insufficient intestinal digestion (the resorption of fat in these two cases was considered to be reduced to a degree of 50 Oleo). In the third case, however, the bile had entirely free accession to the bowels and the resorption of fat was fulfilled to some 80-90 yo; this case, as the only one apparently hitherto reported in the literature, seems to be fairly comparable with my own, although the difference of course was present that Gerstenberger’s observation did concern an infant the bone affection hence obtained being rickets whereas my own observation did concern an adult with osteomalacia resulting. The only observation hitherto reported in the literature which possibly might have represented an osteomalacia hepatica, has been published by Decourt (1937): in a woman, aged 63, a severe osteomalacia was present since several years and since no therapeutic results whatsoever were to be achieved by oral ingestion of vitamin D and the food and the exposure to sunlight were entirely adequate, intramuscular injections with vitamin A and vitamin D were administered and considerable improvement obtained. I t was concluded that these facts daissent entrevoie I’existence probable d’une forme spkciale d’osteomalacie, secondaire, non plus a une carence d’origines alimentaires, mais h un trouble interne du mkta- bolisme, lie par exemple a un trouble hbpatique ou endocrinien)). The hypothetical character of this explanation is thus readily admitted by the author himself but i t may be said in favour of the hepatic conception, that in the earlier history of the patient several

218 E R I K ASK-UPMARK.

Fig. 1. Radiogram of the skull Sept. 30th 1938. Some degree of osteoporosis may be present but otherwise the

picture is essentially normal.


Fig. 2 a. The lumbar spine Jan. 13th Fig. 2 b. The lumbar spine Sept. 29th 1937. Normal conditions. 1938. Pronounced osteomalacia.

220 ERIK A S K - U P M A R H .

Fig. 3 a. The lumbar spine in another projection Jan. 13th 1937.

O S T E O M A L A C I A H E P A T I C A .

Fig. 3 b. The lumbar spine Sept. 29th 1938.

22 1

222 E R I K A S K - U P M A R K ,

U S T E O M A L A C I A H E P A T I C A , 223

Fig. 5 a. The promontorial region Jan. 13th, 1937.

OSTEOMALACIA H E P A T I C A . 225

biliary attacks as well as dyspeptic disorders were to be noted; although considered, by the author, to be due to chronic cholecys- titis, i t is obviously entirely possible that a hepatic disorder might have been present.

3. From theoretical point of view i t would only be natural-if a damage to the liver might result in an affection of the vitamin D metabolism, since the liver has a central position in this regard. Not only is the liver the main depBt of vitamin D but the produc- tion of the bile is of essential importance for the intestinal resorption of the fat-soluble vitamins; another evidence is represented by the observations of Seyderhelm already quoted about the nhepato- enteric circulations of the vitamin D of the red blood cells. It is of considerable interest, moreover, to remember that liver oil has antirachitic activities only if the liver is derived from a teleost, i. e. a fish with bone skeleton, whereas the livers are valueless from antirachitic point of view if obtained from selachians, i. e. fishes where the skeleton is only cartilaginous. A profound biological difference is thus present between these two groups of fishes and i t may be added that the parathyroid glands make their first appearance in the animal kingdom in the teleosts, i. e. when bone appears in the evolution of the skeleton. The close connection between parathyroid glands, bone system and vitamin D storage in the liver is thus firmly established phylogenetically. It is instructive to note, in this connection, the living habits of the socalled ,sun shark, (Gunnerus maximus), who spends several hours a day a t the surface of the sea exposed to the radiant energy of the sun; nevertheless, the liver does not contain any antirachitic factors the fish being just a shark and accordingly not equipped with a bony skeleton.

Considering the evidence here marshalled it will appear reasonable to look upon the case here described as representing a syndrom which perhaps most conveniently might be termed nosfeomalacia hepatica,. It is entirely possible that this condition may be less unusual than may be anticipated from the analysis here conducted. Thus, as an example, further research will have to demonstrate whether perhaps the osteoporosis to be encountered in thyreotoxi- cosis might be ascribed, in part a t least, to the damage of the liver so common in this disease. The close connection between the stomach and the liver makes i t tempting to investigate whether perhaps extensive resections of the stomach may be able to in-

226 E R I K ASK-UPMARK.

fluence the mineralisation of the bone system. Certain instances of hitherto obscure osteoporosis may become elucidated by a con- sideration of the sequence of events in the vitamin D metabolism here described. At any rate the present observation seems to stress the importance in disorders of the liver also to direct the attention towards the bone system and its metabolic mechanisms.

Summary and conclusions. 1. A brief review is given of our present knowledge about osteo-

malacia, its occurrence and aetiology. 2. A case is described of a man, aged 57, who did present a

severe cirrhosis of the liver in connection with osteomalacia. No biliary retention being present and the food being adequately composed the conclusion was derived that the cirrhosis was the primary condition, responsible for the osteomalacia by means of the damage to the storage function of the liver for vitamin D.

3. A survey is presented of the various ways by means of which a vitamin D deficiency may be brought about: deficient supply, deficient resorption from the intestinal tract, deficient storage function of the liver.

4. Attention is called to the observation of Gerstenberger of an infant presenting severe cirrhosis of the liver together with severe incurable rickets: rachitis hepatica. The present condition may accordingly be termed osteomalacia hepatica.

5. The phylogenetic evolution of the connection between the parathyroid glands, the bony skeleton and the vitamin D storage in the liver is briefly recollected.

6. Some further problems are briefly outlined and the importance is stressed in disorders of the liver also to attend to the condition of the bone system and in generalized disorders of the skeleton also to remember the liver.

Bibliography. 1. Ask-Upmark, E.: 1) 1938, Acta Med. Scand. 96: 390. 2. Ask-Upmark,

E.: 2) 1938, Rapports Congrbs Franc. de MBd. Marseille 1938. 3. Bussa- barger, A. and Smith Freeman and A. C. Ivy: 1938, Am. J . Physiol. 1 2 1 : 137. 4. Christiansen, J.: 1938, Ugeskrift f. Laeg. 100: 692. 5. Decourt, J.: 1937, Bull. et MBm. SOC. m6d. d. hap. de Paris 63: 248. 6. Drummond: Quoted by Willstaedt, Rapports Congrh Franc. de Med. Marseille 1938.

O S T E O M A L A C I A HEPATICA. 227

7. Fromme, A.: 1937, Arch. f . klin. Chir. 189: 240. 8. Gerstenberger: 1937, Monatsschr. f. Kinderheilk. 56: 217. 9. Heymann, W.: 1933, Monatsschr. f . Kinderheilk. 66: 216. 10. Huggins, C.: 1937, Physiol. Reviews 17: 119. 11. Hunter, D.: 1931, Brit. J. Surg. 19: 203. 12. Meulengracht, E. and A. Rothe Meyer: 1936; Ugeskrift f . Laeg. 98: 961. 13. Meulengracht, E.: 1938, ibid. 100: 1091. 14. Pavlov, J.: 1905, quoted by M. B. Schmidt. 15. Schmidt, C. L. A. and Greaves: 1932, Proc. SOC. Exp. Biol. Med. 29: 373. 16. Schmidt, M. B.: 1937, Textbook of Henke-Lubarsch in Pathology. 17. Seidel: 1910, MU. Med. Woch.schr. p. 2034. 18. Seyderhelm, R.: 1938, Die Hypovita- minosen, Barth, Leipzig. 19. Tarnman: 1928, Bruns Beitr. z. klin. Chir. 142: 83. 20. Wangensteen: 1929, J. Am. Med. Ass. 93: 1199. 21. Wilson, D. C.: 1931, Indian J. Med. Res. 16: 951, 969.

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Osteomalacia hepatica