A large proportion of the fibrine formers are changed in passing through the liver (Lehmann, Bernard), in man as much as 2,690 grammes daily (Brown Sequard), a fact which goes to account for the increase of fibrine in inflammation when the liver is inactive. The change consists mainly in deoxidation and reduction into simpler compounds which can be more readily dissolved and eliminated. Arrest of the liver functions in fever is therefore liable to throw into the blood, products that are little soluble and often poisonous. The end product is largely urea, and this Cyon always found in excess in the hepatic veins of dogs (in the portal veins 0.08 grammes, and in the hepatic veins 0.14 to 0.17 grammes). In man hepatic disorder is at once marked by the lessening or disappearance of urea from the urine, and the increase of the less oxidized uric acid (Parkes). In acute atrophy of the liver, urea disappears from the urine, being replaced by the less oxidized leucin and tyrosin (Frerichs, Murchison). In birds urea is replaced by uric acid and this is always found in the liver.
The increase of urea and allied products bears a direct relation to the activity of the hepatic circulation. Stimulation of the liver by electric current sent through the abdominal walls largely increased the secretion of urea (Sigrist, Stolnikow, Schröder and Salomon). Murchison, Perrin and Bruardel had a great increase of urea by stimulating the circulation in the liver. Certain agents ingested are transformed into urea, among which may be named glycocolle, brucin, asparagin, sarcine, alanine, and ammonia muriate.
Any degeneration of the hepatic cells which impairs or arrests their functions lessens the production of urea. In fevers therefore and in hepatic degenerations the extent of the functional or structural derangement may be to a large extent gauged by the diminution of urea. A simple hyperæmia, without as yet any serious impairment of structure or function, may be attended by a marked increase of urea, whereas any destruction of the liver cells, or any serious modification which interferes with the normal function, brings about a decided decrease. A hepatic disorder accompanied by suppression of urine is always a grave disorder. On the contrary a free secretion of urine during liver disease is a favorable symptom.
There is reason to believe that red blood globules are destroyed in the healthy liver, producing bilirubin and urea (Landois). In diseased states this becomes excessive, and the resulting coloring matter is often modified, giving the strong tints, seen in the urine in fever and certain hepatic disorders.
The secretion of bile is but a small part of the function of the liver, and that is by no means a purely eliminating process. Man secretes in twenty-four hours about 10 parts per 1,000 of body weight, the dog 14 to 15, the cat 15 to 20, the sheep 25, the rabbit 130, the Guinea-pig 170, the goose 12 (Cadeac), the horse 12 (Colin). But the amount varies largely; Scott found that a dog yielded 21, and Kölliker that another yielded 36 per 1,000 of the body weight.
Only about one-fourth of the biliary acids (Bischoff, Voigt), and one-eighth of the sulphur (Bidder and Schmidt) of the bile can be found in the fæces. Most of the bile is re-absorbed from the intestine and secreted anew, so that, in the course of twenty-four hours, the material secreted serves the same purpose again and again. During this repetition of secretion and absorption, it becomes little by little metamorphosed into other products, which are eliminated by the lungs and kidneys (Parkes, Murchison).
The functions of the bile so far as known are:
a. The solution of alimentary matters, and especially of fat, in the intestine, and the hastening of endosmosis, of fats and peptones;
b. The stimulation of peristalsis in the bowel;
c. Antisepsis and deodorization of the contents of the bowels;
d. The determination of the formation of glycogen;
e. The excretion of bile coloring matter, bile acids and cholesterine.
In regard to the glycogenic action it may be said that in cats, the bile ducts of which have been tied, no glycogen was formed, even when the diabetic puncture of the brain was made (Legg). Clinical observation seems to throw some doubt on the formation of bile coloring matter apart from the liver. In diseased liver with suspended secretion of bile (waxy and fatty degeneration, cancer, cirrhosis) the bile pigment was found in neither blood nor urine (Frerichs, Murchison, Haspell, Budd). Even after extirpation of the liver in frogs, neither biliary acid nor pigment could be found in the blood (Müller, Lehmann, Moleschott). These results must, however, be qualified by the observations of Hammersten who found bilirubin as a normal constituent of blood serum in the horse, and by Virchow’s discovery that hæmatoidin (now held to be identical with bilirubin) is constantly found in old blood extravasations into the tissues.
The origin of the bile coloring matters may be traced in part to destruction of red globules in the liver. Quincke has shown that in the hepatic capillaries in post-embryonic life the leucocytes englobe and destroy the old and worn out red blood corpuscles which thus become a source of bile coloring matter. Such destruction is specially likely to occur in badly maintained conditions of the blood, and in hepatitis or other liver disease in which the white cells accumulate in the hepatic capillaries, and when the blood current is retarded. Hence the liability to jaundice in such conditions. The formation of new red blood corpuscles has been observed in the protoplasmic cells of the liver in the embryo, but this has not been established for post-embryonic life (Neumann, Lowit).
The two common coloring matters of the bile are bilirubin which colors the yellow bile of man, omnivora, and carnivora and biliverdin which tints the dark green bile of herbivora. Bilirubin (C32H36N4O6) forms transparent fox red clinorhombic prisms. It is insoluble in water but soluble in chloroform, and may thus be separated from the biliverdin which is insoluble in chloroform. United as a second basic acid with alkalies it is soluble in water. It is easily obtained from the red gall-stones of man or ox, and is chemically identical with hæmatoidin. Biliverdin (C32H36N4O8) is an oxidized derivative of bilirubin and is insoluble in chloroform, slightly soluble in ether and freely soluble in water. In addition to its presence in bile it has been found in the placenta of the bitch. The test for bile coloring matter is made by placing a drop of the suspected liquid on a white porcelain plate and adding a drop of impure, brown, nitric acid (nitric and nitrous acids). If bile is present there is produced a beautiful play of colors passing from the green of biliverdin, through blue, violet, red, and ending in yellow.
With regard to the formation of bile pigments in morbid conditions it may be noted, that agents which dissolve the red blood globules (such as bile acids or water), when injected into the veins determine the appearance of bile pigment in the urine (Frerichs, Kuhne). When we consider that an animal (dog) secretes ¹⁄₅₀ of its body weight daily of bile, and that nearly all of this is re-absorbed from the intestines, we can realize this as an important source of bile and urinary pigments.
Of the bile acids, taurocholic is the most abundant in the bile of man, birds, and of many mammals and amphibians, while glycocholic acid is the more plentiful in the ox and pig. It is absent in sucklings. The taurocholic acid has been found to prove most destructive to red blood corpuscles, and in strong solution is distinctly antiseptic, checking the development of bacteria, of the alcoholic and lactic fermentations and of the tryptic and diastatic action of pancreatic juice.
These are conjugate acids, formed by the union of cholic acid with taurin and glycin respectively, and they are found almost exclusively, in combination with soda in the bile. They are found in the liver and do not accumulate in the blood when the liver has been removed. They increase under an albuminous diet.
The test for bile acid, is to take the suspected liquid from which all albumen has been precipitated, add a few drops of solution of cane sugar, shake into a froth, and pour sulphuric acid, drop by drop, down the side of the test tube. A reddish purple color appears in the froth, and shows two absorption bands at E and F. Any albumen left in the liquid will give the same color, but only one absorption band.
The secretion of bile is more abundant on animal than on vegetable food, and on albuminous than fatty. It ceases during hunger, but is increased by ingestion of water. Its solids are most abundant one hour after feeding. It increases under a copious and rapid blood supply, but is arrested by diminished blood flow, even under increased pressure (in ligature of the vena cava in front of the diaphragm). Vigorous exertion, drawing off blood to the muscles of the trunk, diminishes the secretion of bile, while transfusion of blood, up to a given grade of blood pressure increases it. Nervous conditions, which cause contraction of the portal vessels, increase the secretion by forcing more blood through the liver. Such are strychnia or other stimulation of the valve of Vieussens, of the inferior cervical ganglion, of the hepatic or splanchnic nerves, or of the spinal cord. Fever causes its arrest.
The secretion of bile is further stimulated by the following :
a. The ingestion of bile into the stomach and abdomen. This being absorbed and carried to the liver greatly increases the biliary secretion. It is not necessary that the bile shall be a product of the same genus of animal, the bile of the ox is an active stimulant of the liver of the dog.
b. Of medicinal agents the following increase and liquefy the bile: olive oil in large doses, phosphate of soda, salol, and salicylate of soda.
c. The following not only increase the bile, but through their purgative operation, expel it from the bowels: calomel, mercuric chloride, colocynth, aloes, jalap, rhubarb, podophyllin, and cold rectal injections. These accordingly lessen the secretion later, by removing the stimulus of the absorbed bile.
d. The following are comparatively mild biliary stimulants: benzoic acid, benzoate of soda, oil of turpentine, terpene, terpinol, and euonymus, and still less active are alkaline bicarbonates, bromides, sulphates and chlorides, arsenic and ether.
Secretion of bile is lessened by: starvation, a too fatty dietary, alkaline iodides, atropia, strychina, hepatic degenerations, (fatty, cirrhosis), catarrh of the bile ducts, diseases of the liver, gall duct, or duodenum which interfere with the discharge of bile, the antisepsis of the bowels, or the reabsorption of bile. This work virtually moves in a vicious circle, as the action of septic ferments in the duodenum hinders the reabsorption of bile and of the food products which go to the production of bile, and in its turn the withholding of bile from the intestine removes the normal antiseptic (the bile acids) and favors septic fermentation and the inhibition of duodenal digestion and absorption. Another factor is found in the ptomaines and toxins absorbed from the alimentary canal and arrested in the liver. These debilitate the liver cells, impair the liver functions and lay the gland open to bacteridian infection. The bile in such a case is transformed into a pale or yellow, viscid liquid, with more or less dark colored granular debris, and this proves a favorable culture ground for bacteria especially the golden staphylococcus and the bacterium coli commune. With septic condition of the liver the usual result of ligature of the bile duct is a peri- and intralobular sclerosis and the formation of minute biliary abscesses. In the absence of sepsis, ligature of the biliary duct, produces—not abscess but—necrobiosis, preceded by interlobular connective tissue hyperplasia, and granular or fatty degeneration of the hepatic cells. (Charcot, Legg, Lahousse, Dupre).
The liver in the mature animal, being the one destination of the blood carried in the portal vein, necessarily becomes the recipient of all medicinal and poisonous agents absorbed by the capillaries and venous radicals of the stomach and intestines. This organ retains and lays up for a time the heavier metals, such as the salts of copper and iron, the iodides and bromides, the vegetable alkaloids such as nicotine, quinine, morphia, and curare, the toxic elements of the bile, the ptomaines and toxins produced by gastric and intestinal fermentations, indol, phenol, etc. Some agents it transforms, as peptones (which it renders non-poisonous), casein, the carbonate of ammonia and its salts with vegetable acids, also indol and phenol, which it combines with sulphuric acid as indyxol and phenyl sulphate, thus rendering them much less toxic. The destructions or new combinations established in the cases of the ptomaines and toxins may explain why such agents are usually much less poisonous when taken by the stomach than when generated in tissues or blood, or when injected hypodermically. Another interesting fact in connection with the ingestion of these bacteridian products (ptomaines and albumoses) is that, when the liver functions are normal as evidenced by the production of glycogen, the toxins are largely destroyed, and they fail to produce poisoning, whereas with a functionally deranged liver and no production of glycogen, they retain their potency, almost as if injected subcutem.
MELLITURIA, GLYCOSURIA, DIABETES MELLITUS, SACCHARINE URINE.
Source of glucose in food. Glycogen: Its use: Enlarged liver means more glycogen. Glycosuric centre in medulla. Other glycosuric nerve centres. Reflex action, action of drugs and poisons, phlorizin. Disease of lungs or pancreas. Removal of pancreas in dogs. Removal of thyroid. Diseased, liver, fatty, fibroid, hypertrophy, congestion. Extreme fatty change arrests glycogenesis. In solipeds: 3 cases with liver hypertrophy; 1 case with adenitis; 6 cases with emaciation; 2 cases with hæmoglobinuria. Symptoms: Emaciation, debility, langor, fatigue, breathlessness, hollow flanks, unthrifty skin, ardent thirst, polyuria, urine saccharine, of high density. Diagnosis by analysis of urine, sweet taste, Fehling’s test, Trommer’s test, fermentation test. Prognosis: Grave, diet being carbonaceous, when functional resulting from curable disease is hopeful. Treatment: In poisoning cases, antidotes and eliminants, in curable disorders treat these, in more inveterate cholagogues, antiseptics, codeine, opium, croton chloral, strychnia, phosphoric acid, iodoform, ergot, skim milk or buttermilk, good hygiene, open air, shelter, carminatives, bitters, mineral acids, treat complications.
Grape sugar (glucose, C6H12O6) is undoubtedly formed in the stomach and intestines by the action of saliva and pancreatic juice on starch (C6H10O5), and glucose and laevulose (C6H12O6) are also derived from the transformation of cane sugar (C12H12O11). These sugars are absorbed, transformed into glycogen in the liver and passed into the circulation, where they serve to maintain animal heat through their decomposition into carbonic acid and water. They further assist in nutrition and growth, and if their metamorphosis is imperfect they pass out of the system in the urine, producing a temporary glycosuria. As shown above glycogen is produced in the liver cells, and stored up there, in greatest abundance during digestion of starchy and saccharine food, but it is also formed in animals kept on a purely albuminous diet, (flesh), and in the fœtal calf and unhatched chick to which neither starch nor sugar has been furnished as food. It is produced during the decomposition of albuminoids, along with the other end products, leucin, tyrosin and urea. None of these last three is found in the portal vein nor bile ducts, but all four are found in the liver cells, and in the hepatic veins.
In health a physiological balance is maintained by the oxidation of the glucose, mainly in the lungs, so that in the blood of the pulmonary veins no sugar is found. There is an exception to this observable after a full meal, rich in starch and sugar, which produces such an excess of glycogen that a portion is carried to the kidneys and expelled by them causing temporary glycosuria.
A small amount of glycogen is also produced habitually by the white blood cells and stored up in them, but this is insufficient to determine its appreciable elimination by the kidneys.
In cases of persistent glycosuria the fault may be held to consist in one of three functional derangements:
1st. The failure of the liver to transform the alimentary sugar into glycogen.
or 2d. The excessive production of glycogen in the liver.
or 3d. The arrest of the destructive oxidation of sugar in the lungs and tissues.
In a diabetic patient who died suddenly of apoplexy Bernard found that the liver was enlarged, comparing with the average as 25:14 while the contained sugar bore the ratio of 37.5:22. This enlargement coming from malaria or other poison, such as alcohol, ether (Harley), arsenic, quinia (Aitken), ammonia, chloroform, or phosphoric acid (Murchison), is an established condition of glycosuria. A rich and abundant food (starchy and saccharine especially), or an unusually active hepatic circulation acts in the same way.
Bernard as early as 1849 showed that the glycogenic function of the liver was greatly increased and glycosuria determined by pricking the floor of the fourth ventricle in the median line just in front of the calamus scriptorius and near the root of the vagus nerve, or a few millimeters in front of this.
It follows that irritation of this part of the medulla however produced, whether from local disease, or by reflex action from some distant organ in a state of irritation, may serve as the starting point of diabetes in particular instances. That the cause may be a reflex stimulus is shown by the suspension of the glycogenic function after section of the vagus nerves, and its reappearance when the central end of the cut vagus is galvanized, or, the floor of the fourth ventricle is irritated, the direct or efferent excitation being transmitted through the sympathetic nerve (Bernard). I can cite a case of glycosuria in a man supervening on a severe blow on the head from a falling ledger. Brain injuries which suspend animal functions, but not the nutritive ones, such as apoplexy, concussion of the brain or curare poisoning are liable to induce diabetes.
Traumatic injuries to other parts of the nervous system induce glycosuria. Thus traumatism of the optic thalami; of the cerebral lobes or peduncles; of the pons; of the cerebellum or of its middle or posterior peduncles; transverse section of the medulla or of the spinal cord opposite the second dorsal vertebra; traumatism of the superior or inferior cervical ganglion or the first thoracic (Eckhard); of the sympathetic twig which accompanies the vertebral artery (Pavy); of the brachial plexus; of the solar plexus (Munck, Klebs); or of the sciatic nerve (Schiff).
The explanation of these facts may be sought in a reflex action established by the conveyances of irritation to the true glycogenic centres in the brain and the transference of the efferent nervous impulse through the sympathetic nerve to the liver. It will be borne in mind that in the case of section of the vagus nerve electric stimulation of its detached peripheral part has no glycogenic effect on the liver, while galvanizing the central portion determines glycosuria.
In the case of glycosuria through stimulation of the sympathetic nerve or its ganglia the action may be concluded to be direct. Strangely enough, irritation of the sympathetic between the tenth and twelfth ribs or the splanchnic nerves fails to produce glycosuria, though the hepatic branches of the sympathetic pass through them.
In ordinary cases of reflex glycosuria it may be assumed that the existence of irritation at the peripheral ends of the vagus and of some other nerves, leads to an apparent glycogenic influence passing through these to the brain, and of the distribution of the efferent impulse through the upper portion of the spinal cord, as far as the fourth dorsal vertebra in the rabbit (Cyon, Aladoff, Schiff), and through the sympathetic nerve to the liver. This may account for the appearance of the disorder as a sequel of disease in any part to which the vagus in particular is distributed, and notably in the lungs. A number of poisons (malarial, alcoholic, ether, carbon monoxide, amyl nitrate, curare, or the nitro-propionic acid, methyl delphinin, morphia, chloral hydrate, arsenic, quinia, ammonia, chloroform, phosphoric acid, and phlorizin) produce glycosuria.
The intravenous injection of dilute saline solutions, or frequent blood letting materially increases the sugar, probably by causing solution of the red globules. Phlorizin is the most potent of all these agents. Whether given hypodermically or by the stomach it causes in three hours a marked production of glucose which continues to be eliminated for a period of thirty-six hours. The urine may become charged with glucose to the extent of from 6 to 13 per cent., and without any rise in the body temperature. This artificial glycosuria may be kept up indefinitely by the continued administration of phlorizin, and even in the fasting animal, or one on an exclusively albuminous diet, as well as in those on an aliment rich in saccharine or hydro-carbonaceous matter. In the frog it produces diabetes even after the extirpation of the liver showing that it stimulates other sources of sugar production beside the hepatic or that it inhibits the transformation of sugar derived from the alimentary canal and other sources.
Another suggestive source of mellituria is disease of the lungs, or any condition which interferes with the due æration of the blood and oxidation of the alimentary or hepatic sugar. But it cannot be assumed that the rôle is altogether or mainly chemical. The thoracic organs being supplied by branches of the vagus and sympathetic nerves there is the obvious suggestion of a reflex action through the diabetic centers in the brain. The frequent complication of diabetes with lung diseases (inflammatory, tubercular, syphilitic, and otherwise) is abundantly proved, whether it is to be explained on the above hypothesis or through other unknown changes in the blood.
Diabetes has been repeatedly found in connection with disease of the pancreas, and the complete extirpation of the pancreas in dogs gives rise to glycosuria (Mering and Minkowski, Thiroloix, Lancereaux, Lepine). If a small portion of the pancreas remains glycosuria does not supervene. It has been suggested that the pancreas has a double function, and beside its secretion, produces a glycolytic ferment which passing into the portal blood determines the formation of glycogen in the liver. Arrest of the pancreatic secretions does not cause glycosuria, so it has been suggested that the glycogenic enzyme is a product of the connective tissue cells of the pancreas. Functional as well as structural disease of the pancreas can be conceived of as inhibiting the production of this ferment and the consequent elaboration of glycogen. Chauveau and Kauffmann deduce from their observations that the action is a reflex one established through the glycogenic centres in the medulla. Pancreatic glycosuria is especially fatal (Harley).
Finally extirpation of the thyroid body in dogs has been followed by glycosuria (Falkenberg). This suggests a systematic examination of the urine in all cases of goitre, with extensive glandular changes.
Apart from experimental cases diabetes in the lower animals has been observed to be nearly always associated with diseased liver. Fatty degeneration has been the most frequent lesion, but cirrhosis, hypertrophy and congestion were present in other cases. In a number of cases as the fatty degeneration reached an extreme degree, the sugar disappeared from the urine, the hepatic cells being no longer functionally active, and death speedily followed. The same has been observed in the fatty degeneration attendant on poisoning by arsenic or phosphorus.