Metabolic Diseases

Metabolic Diseases. All disease is primarily due to alterations (Gr. pera i 30X11, change), quantitative or qualitative, in the chemical changes in the protoplasm of some or all of the tissues of the body. But while in some pathological states these modifications lead to structural changes, in others they do not produce gross lesions, and these latter conditions are commonly classified as Functional Diseases. When such functional disturbances affect the general nutrition of the body they have been termed Metabolic Diseases (Stoffwechselkrankheiten). It is impossible to draw a hard and fast line between functional and organic disease, since the one passes gradually into the other, as is well seen in gout. Nor is it always easy to decide how far the conditions are due merely to quantitative alterations in the metabolism and how far to actual qualitative changes, for it is highly probable that many of the apparently qualitative alterations are really quantitative disturbances in one part of the protoplasmic mechanism, leading to an apparent qualitative change in the total result of the activity.

	In Grms. per Diem.
	Proteid.	Fat.	Car- hydrates.	Calories.
Banting's cure	172	8	81	1 112
Oertel's „. .	156-170	2 5-45	75- 120	1 180-1608
Ebstein's „. .	102	85	47	1401

Obesity

It is as fat that the surplus food absorbed is stored in the body; but the power of storing fat varies enormously in different individuals, and in some it may be considered pathological. The reasons of this are very imperfectly understood. One undoubted cause of obesity is taking a supply of food in excess of the energy requirements of the individual. The amount of food may be absolutely large, or large relatively to the muscular energy evolved in mechanical work or in heat-production; but in either case, when fat begins to be deposited, the muscular activity of the body tends to diminish and the loss of heat from the surface is reduced; and thus the energy requirements become less, and a smaller diet is sufficient to yield the surplus for further storage of fat. Fat is formed from carbohydrates, and possibly indirectly from proteids (see Nutrition). Individuals probably vary in their mode of dealing with these substances, some having the tendency to convert them to fat, some to burn them off at once. Carl von Noorden, however, who has studied the metabolism in cases of obesity, finds no marked departure from the normal. It may be that in some persons there is a very perfect absorption of food, but so far no scientific evidence for this view is forthcoming. In all cases the fat stored is available as a source of energy, and this circumstance is taken advantage of in the various fat "cures," which consist in giving a diet containing enough proteids to cover the requirements of the body, with a supply of fats and carbohydrates insufficient to meet the energy requirements of the individual. This is illustrated by the dietaries of some of the best known of these "cures": - In a normal individual in moderate muscular activity about 3000 Calories per diem are required (see Dietetics), and therefore under the diets of these "cures," especially when accompanied by a proper amount of muscular exercise, the fats stored in the body are rapidly used up.

Diabetes, as distinguished from transitory glycosuria, is produced by a diminution in the power of the tissues to use sugar, which thus accumulates in the blood and escapes in the urine. One great source of energy being unavailable, the tissues have to use more fats and more proteids to procure the necessary energy, and hence, unless these are supplied in very large quantities, there is a tendency to emaciation.

The power of storing and using sugar in the tissues is strictly limited, and varies considerably in healthy individuals. Normally, when about 200 grms. of glucose are taken at one time, some of it appears in the urine within one hour. In some individuals the taking of even ioo grms. leads to a transient glycosuria, while others can take 250 grms. or more and use it all. But even in the same healthy individual the power of using sugar varies at different times and in different conditions, muscular exercise markedly increasing the combustion. Again, some sugars are more readily used than others, and therefore have a less tendency to appear in the urine when taken in the food. Milk-sugar and laevulose appear in the urine more readily than glucose. This power of using sugar possessed by an individual may depend to a small extent on the capacity of the liver to store as glycogen any excess of carbohydrates absorbed from the food, and some slight cases of transient glycosuria may be accounted for by a diminution of this capacity. But the typical form of diabetes cannot be thus explained. It has been maintained that increased production of sugar is a cause of some cases of the disease, and this view has been supported by Claude Bernard's classical experiment of producing glycosuria by puncturing the floor of the fourth ventricle in the brain of the rabbit. But after such puncture the glycosuria occurs only when glycogen is present in the liver. It is transient and has nothing to do with true diabetes. The fact that various toxic substances, e.g. carbon monoxide, produce glycosuria has been used as an argument in support of this view, but they too seem to act by causing a conversion of glycogen to glucose, and are effective only when the liver is charged with the former substance. At one time it was thought that the occurrence of glycosuria under the administration of phloridzin proved that diabetes is due to a poison. But the fact that, while sugar appears abundantly in the urine under phloridzin, it is not increased in the blood, shows that the drug acts not by diminishing the power of the tissues to use sugar, but by increasing the excretion of sugar through the kidneys and thus causing its loss to the body. Hence the tissues have to fall back upon the proteids, and an increased excretion of nitrogen is produced. This, however, is a totally different condition from diabetes.

Anything which produces a marked diminution in the normally limited power of the tissues to use sugar will cause the disease in a lighter or graver form. As age advances the activity of the various metabolic processes may diminish irregularly in certain individuals, and it is possible that the loss of the power of using sugar may be sooner impaired in some than in others, and thus diabetes be produced. But Minkowski and von Mering have demonstrated, by experiments upon animals, that pathological changes in the pancreas have probably a causal relationship with the disease. They found that excision of that organ in dogs, &c., produced all the symptoms of diabetes - the appearances of sugar in the urine, its increased amount in the blood, the rapid breaking-down of proteids, and the resulting emaciation and azoturia. At the same time the absorption from the intestine of proteids, fats and carbohydrates was diminished. How this pancreatic diabetes is produced has not been explained. It has been suggested that the pancreas forms an internal secretion which stimulates the utilization of sugar in the tissues. Though in a certain number of cases of diabetes disease of the pancreas has been found, other cases are recorded where grave disease of that organ has not produced this condition. But the apparent extent of a lesion is often no measure of the depth to which the functions of the structure in which it is situated are altered, and it is very possible that the functions of the pancreas may in many cases be profoundly modified without our methods of research being able to detect the change. The pancreas consists of two parts, the secreting structure and the epithelial islets, and one or other of these may be more specially involved, and thus alteration in digestion and absorption on the one hand, and changes in the utilization of carbohydrates on the other, may be separately produced. The subcutaneous injection of large doses of extracts of the supra-renal bodies causes glycosuria and an increase of sugar in the blood, but the relationship of this condition to diabetes has not yet been investigated.

The disease may be divided into two forms: T T. Slight Cases. - The individual can use small quantities of sugar, but the taking of larger amounts causes glycosuria. Supposing that the energy requirements of an individual are met by a diet of Proteid. loo grms.. 410 Calories.

Fat. loo „. 930 Carbohydrate 400 „ . 1640 2980 „ then if only Too grms. of glucose can be used, the energy value of 300 grms., i.e. 1230 Calories, must be supplied from proteids and fats. To yield this, 300 grms. of proteids or 132 grms. of fats would be required. If these are not forthcoming in the diet, they must be supplied from the tissues, and the individual will become emaciated; hence a diabetic on an ordinary diet is badly nourished, and hence the huge appetite characteristic of the disease.

2. Grave Cases. - From the products of the splitting of proteids sugar can be formed, probably in the liver, and in the more serious form of the disease, even when carbohydrates are excluded from the food, a greater or lesser quantity of the sugar thus formed escapes consumption and may be excreted. Theoretically, too grms. of proteid can yield 113.6 grms. of glucose, i.e. i grm. of nitrogen will be set free for each 7.5 grms. of glucose formed. In the urine of grave cases of diabetes on a proteid diet, the proportion of nitrogen to sugar is about I to 2. This may mean that the theoretically possible amount of sugar is not yielded, or that some of the sugar formed is used in the economy. Both hypotheses may be correct, but the latter is supported by the fact that even in grave cases the decomposition of proteid may be diminished by giving sugar, and that in muscular exercise the proportion of sugar may fall.

In the course of the disease the amount of sugar which the tissues can use varies from day to day. It is in the utilization of glucose - the normal sugar of the body - that the tissues chiefly fail. Many diabetics are able to use laevulose, or the inulin from which it is derived, and lactose (milk-sugar) to a certain extent. It has, however, been observed that under the administration of these sugars the excretion of glucose may be increased, the tissues, apparently by using the foreign sugar, allowing part of the glucose which they would have consumed to escape.

The increased decomposition of proteid, rendered necessary to supply the energy not forthcoming in the sugar, leads to the appearance of a large quantity of nitrogen in the urine - azoturia - and it also leads to the formation of various acids. Sulphuric acid and phosphoric acid are formed by oxidation of the sulphur and phosphorus in the proteid molecule. Organic acids of the lower fatty acid series # oxybutyric and aceto-acetic acid with their derivative acetone also appear in the course of diabetes. They are in part formed from the disintegration of proteids and in part from fats, as the result of a modified metabolism induced by the withdrawal of carbohydrates. To neutralize them ammonia is developed and hence the proportion of ammonia in the urine is increased. By the development of these various acids the alkalinity of the blood is diminished. The development of these acids in large quantities is associated with extensive decomposition of proteid, and is sometimes indicative of the onset of a comatose condition, which seems to be due rather to an acid intoxication than to the special toxic action of any particular acid.

Myxoedesna

The thyroid gland forms a material which has the power of increasing the metabolism of proteids and of fats; and when the thyroid is removed, a condition of sluggish metabolism, with low temperature and a return of the connective tissues to an embryonic condition, supervenes, accompanied by the appearance of depression of the mental functions and by other nervous symptoms. The disease myxoedema, which was first described by Sir William Gull in 1873, was shown by Ord in 1878 to be due to degenerative changes in the thyroid gland. It affects both sexes, but chiefly females, and is characterized by a peculiar puffy appearance of the face and hands, shedding of the hair, a low temperature, and mental hebetude. The symptoms are similar to those produced by removal of the thyroid, and are indicative of a condition of diminished activity of metabolism. The nervous symptoms may be in part due to some alteration in the metabolism, leading to the formation of toxic substances. The administration of thyroid gland extract causes all the symptoms to disappear.

Cretinism may now be defined as myxoedema in the infant, and it has been definitely proved to be associated with nondevelopment or degeneration of the thyroid gland. The characters of the disease are all due to diminished metabolism, leading to retarded development, and the treatment which has proved of service, at least in some sporadic cases, is the administration of various thyroid preparations.

Exophthalmic Goitr

Graves's Disease or Basedow's Disease. - This disease chiefly affects young women, and is characterized by three main symptoms: increased rate and force of the heart's action, protrusion of the eyeballs, and enlargement of the thyroid gland. The patient is nervous, often sleepless, and generally becomes emaciated and suffers from slight febrile attacks. The increased action of the heart is the most constant symptom, and the enlargement of the thyroid gland may not be manifest. Various theories as to the pathology of the condition have been advanced, but in the light of our knowledge of the physiology of the thyroid the most probable explanation is an increased functional activity of that gland or of changes in the parthyroids.

Gout has often been divided into the typical and atypical forms. The first is undoubtedly a clinical and pathological entity, but the second, though containing cases of less severe forms of true gout, is largely constituted of imperfectly diagnosed morbid conditions. The accumulation of urate of soda in the tissues in gout formerly led physicians to believe in a causal relationship between an increased formation of that substance and the onset of the disease. Sir A. Garrod's investigations, however, seemed to indicate that diminished excretion rather than increased production is the cause of the condition. He found an accumulation of uric acid in the blood and a diminution in its amount in the urine during the attack. That uric acid is increased in the blood is undoubted, but the changes described by Garrod in the urine, and considered by him as indicative of diminished excretion and retention, are rendered of less value by the imperfections of the analytic method employed. More recent work with better methods has thrown still further doubt upon the existence of such a relationship, and points rather to the accumulation of uric acid being, like the other symptoms of the condition, a result of some unknown modification in the metabolism, and a purely secondary phenomenon. The important fact that in leucaemia (von Jaksch), in lead-poisoning (Garrod), and in other pathological conditions, uric acid may be increased in the blood and in the urine without any gouty symptoms supervening, is one of the strongest arguments against the older views. That the gouty inflammation is not caused by the deposit of urate of soda, seems to be indicated by the occurrence of cases in which there is no such deposition. The source of the uric acid which is so widely deposited in the gouty is largely the phosphorus containing nucleins of the food and tissues. These in their decomposition yield a series of di-ureides, the purin bodies, of which uric acid is one. Their excretion is increased when substances rich in nuclein, e.g. sweetbreads, &c., are administered. While uric acid itself has not been demonstrated to have any injurious action, the closely allied adenin has been found to produce toxic symptoms. After the discovery of this source of uric acid, physiologists for a time inclined to regard it as the only mode of production. But it must be remembered that in birds uric acid is formed from the ammonia compounds coming from the intestine and muscles, just as urea is formed from the same substance in mammals. Uric acid is a di-ureide - a body composed of two urea molecules linked by acrylic acid - an unsaturated propionic acid. It is therefore highly probable that in many conditions the conversion of ammonia compounds to urea is not complete, and that a certain amount of uric acid is formed apart from the decomposition of nucleins.

Sir William Roberts has adduced evidence to show that uric acid circulates in the blood in a freely soluble combination or quadurate - that is, a compound in which one molecule of an acid salt BHC T is linked to a molecule of the acid BHU. H 2 U. These compounds are said to be readily decomposed and the bi-urates formed, which are at first gelatinous but become crystalline. The deposition of urate of soda in joints, &c., has been ascribed to this change. Francis Tunnicliffe, however, has published the results of certain investigations which throw doubt upon this explanation. The most recent investigations on the metabolism of the gouty have shown that there is undoubtedly a slowing in the rate of elimination of uric acid and also of the total nitrogen of the urine with occasional sudden increases sometimes connected with a gouty paroxysm, sometimes independent of it. Whether this is due to the action of some toxin developed in the body or is caused by a constitutional renal inadequacy is difficult to decide. Certain it is these renal diseases often develop in the course of gout.

Rheumatism

Rheumatic fever was formerly regarded as due to some disturbance in the metabolism, but it is now known to be a specific micro-organismal disease. The whole clinical picture is that of an infective fever, and it is closely related to gonorrhoeal rheumatism and to certain types of pyaemia. A number of independent observers have succeeded in isolating from cases of rheumatic fever a diplococcus which produces similar symptoms in the rabbit to those which characterize the disease in man.

Excluding the peculiar changes in the joints which occur in rheumatoid arthritis and in Charcot's disease, and which are almost certainly primary affections of the nervous system, it is found that a large number of individuals suffer from pain in the joints, in the muscles, and in the fibrous tissues, chiefly on exposure to cold and damp or after indiscretions of diet. This so-called chronic rheumatism appears to be a totally distinct condition from rheumatic fever; and although its pathology is not determined, it looks as if it were due either to a diminished elimination or an increased production of some toxic substance or substances, but so far we have no evidence as to their nature.

Rickets is undoubtedly a manifestation of a profound alteration of the metabolism in childhood, but how far it is an idiopathic condition and how far a result of the action of toxins introduced from without is not yet definitely known. Kassowitz long ago showed that the bone changes are similar to those which can be produced in animals by chronic phosphorus poisoning, and that they are really irritative in nature. Spillmann, in his work Le Rachitisme, discusses the evidence as regards the action of various conditions, and comes to the conclusion that there is no evidence that it is due to a mere primary disturbance of the metabolism, or to excessive production of lactic acid, or to any specific micro-organismal poisoning. But he adduces evidence, perhaps not very convincing, that in the disease there is a specific intoxication derived from the alimentary canal and provoking inflammatory lesions in the bones.

See generally Carl von Noorden, Metabolism and Practical Medicine (1907). (D. N. P.)