Part 5

[Footnote 18: Professor Hoppe tests for bile-acids in the following manner:--The urine is boiled with an excess of milk of lime for about half an hour, and filtered to free it from the precipitate thus formed. The filtrate is evaporated to dryness, decomposed with hydrochloric acid, washed with water, and then extracted with alcohol. The alcoholic extract contains the bile-acids, which are recognised by Pettenkofer's test.]

The readiest mode by which the biliary acids may be detected is the following: To a couple of drachms of the suspected urine add a small fragment of loaf-sugar, and afterwards pour slowly into the test-tube about a drachm of strong sulphuric acid. This should be done so as not to mix the two liquids. If biliary acids be present, there will be observed at the line of contact of the acid, and urine--after standing for a few minutes--a deep purple hue.[19] This result may be taken as a sure indication that the jaundice is due to obstructed bile-ducts. On the other hand, the absence of this phenomenon, and the occurrence of merely a _brown_ instead of a _purple_ tint, although, in the earlier stages of jaundice, equally indicative of suppression, is of course, for the reasons already given, no indication of the cause of the suppression. That must be gleaned from other circumstances.

[Footnote 19: The immediate formation of a reddish coloured line is due to the acid setting free urohæmatine, the normal colouring matter of the urine.]

It is seen that I have taken no notice of {62} Frerichs' theory regarding the bile-acids being changed into bile pigment. I have done so advisedly, feeling as I do, that when that observer investigates the subject more fully, he will himself abandon such an untenable doctrine, founded as it is, on an erroneous view regarding the nature of bile pigment. The colour induced by sulphuric acid on the acids of the bile, is as different in its chemical nature from animal pigment, as any two substances can possibly be. Indeed, they have no bond of connection whatever, except the mere tint. All animal pigments, whether they be green, like bile-colouring matter, or red, like hæmatine, spring from the same source, and contain iron. Besides this, the mere fact of an increase of animal pigment being found in the urine after the bile-acids have been injected into the circulation, to which Frerichs attaches such importance, in reality proves nothing more, as Kühne pointed out, than that an increased destruction of blood corpuscles has taken place. I have found the urine of dogs loaded with dark colouring matter after injecting chloroform, and other stimulants into their portal veins, in order to establish artificial diabetes; and, assuredly, in these cases the presence or absence of bile-acids in the blood had nothing to do with the result.

{63} _Diagnostic Value of the presence of Tyrosine, and Leucine in Urine._

There are two other abnormal products occasionally met with in the urine of jaundice, namely, tyrosine, and leucine. These substances, although for many years known to chemists, attracted comparatively little attention until Frerichs discovered their diagnostic value in hepatic disease.

In that peculiar form of complaint, described as acute or yellow atrophy of the liver, the {64} urine is said invariably to contain tyrosine, and leucine. The presence of these substances may therefore assist us in diagnosing the case. When tyrosine, and leucine are present in quantity, they are very readily detected, all that is required being slowly to evaporate an ounce of urine, to the consistency of syrup, put it aside during a few hours to crystallize, and then examine it with the microscope. The tyrosine is recognised by being in fine stellate groups of needle-like crystals, as represented in fig. 4, or spiculated balls not unlike a rolled-up hedgehog, with the bristles sticking out in all directions.

{65} Tyrosine may be obtained in a pure state by adding to four ounces of urine a solution of acetate of lead, till a precipitate ceases to form, filtering, and freeing the liquid from the excess of lead by a current of sulphuretted hydrogen, again filtering, and evaporating the clear solution. The tyrosine is now colourless, and crystallizes with the microscopic characters above alluded to, but still better marked. Tyrosine may be further recognised by putting a few crystals on a platinum spatula, adding a drop or two of nitric acid, and evaporating to dryness. If present, the yellow residue thus obtained assumes a pumpkin hue on the addition of potash, and leaves on incineration a dark greasy stain. Frerichs recommends another test, namely, the following:--Put the suspected substance into a watch-glass, along with some sulphuric acid, and after they have been in contact about half an hour, dilute the mixture with water. Next boil, and then neutralize with carbonate of lime. Filter, and to the clean filtrate add a few drops of perchloride of iron, devoid of free acid. The formation of a dark violet blue colour indicates the presence of tyrosine.

Leucine is known by its flat, circular, oily-looking discs, without any crystalline structure. At the first glance, a globule of leucine might be mistaken for oil, not only on account of its {66} microscopical characters, but also on account of its being lighter than water. The globules of leucine are distinguished from those of oil by their being soluble in water, and boiling alcohol, and insoluble in ether. Besides this, the discs are occasionally opaque and laminated like the granules of potato starch. They are then not at all unlike microscopic crystals of the carbonate of lime; but the carbonate of lime crystals sink in water.

Both tyrosine, and leucine are usually deeply impregnated with the colouring matter of the urine.

Since Frerichs' views were first published I have found tyrosine, and leucine in the urine of cases of chronic, as well as of acute atrophy of the liver. Their presence may therefore aid in diagnosing the latter as well as the former condition of the hepatic organ.

{67} I have little doubt that future research will discover other conditions of the liver, besides those just mentioned, in which tyrosine, and leucine, may appear in the urine; for, as will be subsequently pointed out at page 96, I have been successful in producing them artificially in the urine of animals in which there was no evidence either of acute or chronic atrophy of the liver having taken place. In the cases cited, indeed, it will be seen that the jaundice was the result of suppression, consequent upon congestion of the liver, produced by blood poisoning.

It may be added that since these observations were made I have found in the artificially concentrated urine of a case of jaundice from obstruction consequent upon impacted gall-stone, a few balls closely resembling leucine in shape, and size, but differing from it in being excessively dark in colour. No tyrosine crystals were observed, and unfortunately there was not sufficient of the leucine-like substance present in the urine to admit of its being chemically tested. I have thought it my duty to record this fact for the benefit of other observers, as there can be little doubt that we are gradually verging towards some important discovery in a diagnostic point of view.

{68} _Melanine in the Urine._

Four years ago (1858), Dr. Eiselt of Prague called attention to the fact that in cases of melanotic cancer of the liver, melanine appears in the renal secretion.[20] When the urine is passed it is usually quite clear; but after standing it becomes of a dark colour, even as dark as porter, without, however, losing its transparency. This deepening of the colour is no doubt due to the oxidation of the melanotic pigment, as the employment of an oxidizing agent, such as nitric or chromic acid, causes the same change to occur instantly.

[Footnote 20: Dr. Eiselt states that he also found melanine in the urine in a case of melanotic cancer of the eyeball.]

In addition to the cases related by Dr. Eiselt, I am able to add one of considerable importance, as it not only offers a striking illustration of the correctness of his views, but has the double advantage of being an unbiassed record of facts, in consequence of its having been observed, and recorded long before Dr. Eiselt's views were published, and therefore at a time when the author had no idea of its significance. The case occurred about thirteen years ago, in the wards of the Royal Infirmary of Edinburgh. The history of the case I extract from my private note-book. It is briefly as {69} follows:--In the month of May a sailor was admitted into the clinical wards of the Royal Infirmary with symptoms of jaundice from enlarged liver. He stated that he had been a great deal abroad, in hot climates, and admitted that he had been a hard drinker. On admission his skin was of a dusky yellow colour, and had been so since the month of February. The liver was considerably enlarged, and he complained of sudden violent pains in the neighbourhood of the umbilicus. The pain was usually most severe during the night. The urine was of a dark colour, and on the addition of nitric acid, became nearly quite black. It contained no albumen. The patient died ten days after admission. On post-mortem examination, the hepatic duct was found blocked up with malignant deposit, and the liver of a dark green colour. There was also a considerable amount of malignant deposit in the mesentery. This patient, as frequently happens in such cases, became delirious before death.

In jaundice arising from melanotic cancer of the liver, the recognition of the presence of melanine in the urine would be an important aid to the diagnosis. Care must be taken not to confound the dark olive-green urine occasionally met with in other forms of jaundice, with the melanotic urine just described, or both {70} patient and doctor may become unnecessarily alarmed.[21]

[Footnote 21: While I was Resident Physician in the Royal Infirmary of Edinburgh, in 1850, a woman, aged 28, was admitted with a universal and bright jaundice of three weeks' standing. Her urine was high coloured, and of a specific gravity of 1022. It contained a small quantity of albumen, and became perfectly black on being boiled with nitric acid. In this case there was no reason to suspect malignant disease of the liver; the colour of the urine was, therefore, most probably due to the bile pigment being more than usually oxidized. After a six weeks' stay in the hospital, I dismissed the patient as cured.]

_Urea, Uric Acid, and Sugar._

The presence, and quantity of certain other substances met with in the urine of jaundice, although not peculiar to that condition, nevertheless afford us important information, not only as to its cause, but also as to its probable mode of termination.

Firstly, a correct knowledge of the quantity of urea, and of uric acid passed in the twenty-four hours is of great value; and, secondly, the presence, or absence of sugar is a fact which ought never to be lost sight of. The value of this statement, as well as of several of the preceding, will, I think, be better appreciated by giving a short account of a case of obscure disease (where a correct diagnosis, and prognosis could not have been arrived at without the application of the chemical knowledge referred to), than by any mere abstract {71} treatment of the question. I shall, therefore, at once proceed to relate the brief history of the case.

A gentleman, aged fifty, who had been a remarkably healthy man, observed, within eighteen months of his death, that his skin gradually assumed a more and more jaundiced tint without any assignable cause. The stools were clay-coloured, the urine loaded with bile pigment. Soon afterwards, the patient began to lose flesh. The liver became enlarged, and somewhat tender to the touch; the gall-bladder being at the same time so distended that it could be seen, as well as felt, projecting from under the false ribs. As the case resisted the usual remedies, the patient was recommended to try change of air. During his absence from town, he suddenly passed a large quantity of yellow matter by stool (supposed to be bile), and immediately afterwards the fulness in the abdomen disappeared. On the patient's return to town, the gall-bladder could no longer be seen or felt, and it was naturally supposed that it had emptied itself on the occasion referred to. As, notwithstanding this, the jaundice continued, and the health and strength gradually declined, Dr. Prance, under whose care the patient was, sought the assistance of a physician of distinguished reputation in these affections. At this period, {72} however, the entire absence of physical signs beyond the clay-coloured stools, and those directly referrable to the jaundice, rendered it impossible for any decided opinion to be arrived at. The liver had now resumed its natural size, and the only thing detectable was slight tenderness on pressure, with a doubtful fulness in the pancreatic region. These signs, associated as they were with gradually increasing emaciation and debility, led to the suspicion of malignant disease, either in the course of the bile-ducts, or at the head of the pancreas. About this time it was discovered that the patient occasionally passed a considerable amount of a fatty-looking matter by stool--not mixed with the motion, but separate, though upon it. After the passage of this matter, there in general appeared to be a slight improvement in the patient's condition. The substance in question, on cooling, solidified into a firm pale-brown matter, resembling Windsor soap, and not at all unlike some of the biliary products. This led to the idea that it might be composed of the fatty acids of the bile. On one occasion a portion of it was forwarded to me for analysis, and on subjecting it to chemical examination it proved to be, strangely modified fish-oil, the oleine of which had entirely disappeared. In fact, it was nothing but the sparingly soluble fatty acids of cod-liver oil, which had {73} been transformed in the stomach, and from which all the liquid principles had been absorbed. This was considered an important discovery, as it not only negatived the idea of the bile still reaching the intestines, but also proved that the _pancreas_, as well as the _liver_, was affected. Having thus learned that the pancreatic juice, as well as the bile, failed to reach the intestines, an effort was made to counteract the pernicious effect on the system caused by the absence of the former secretion, by giving 1½ grains of pancreatine in the form of pill three times a day. During the period that the patient was taking this medicine, the quantity of fat passed by stool was supposed to diminish. No decided improvement in the patient's condition took place, however, and on the 2nd of November the gentleman was brought to me by his medical attendant. At this time the patient was much in the state already described,[22] and after a careful physical examination, I failed to elicit any new fact of importance. The hepatic dulness was perfectly natural; there was no tenderness to speak of, no history of gall-stones, and {74} no evidence of any tumour beyond the doubtful fulness in the pancreatic region. The digestive, and other functions of the body, except those already mentioned, seemed unimpaired, and yet the patient's strength daily declined. As physical as well as symptomatical diagnosis proved inadequate to unravel the mystery of this obscure case, and as chemical means had already, in as far as it had been tried, been of advantage, it was resolved to subject the excretions to a rigid chemical examination. The patient was accordingly desired to collect all the urine he passed during twenty-four hours, and while I analysed it, Dr. Prance examined the stools, in order to ascertain their composition--especially as regarded the amount of fatty and albuminous matters contained in them. The urine yielded on analysis the following result:--

24 HOURS' URINE. Quantity (55 oz.) . . . . . . . . . . . . . . . . . . 1705 c.c. Reaction . . . . . . . . . . . . . . . . . . . . . . Acid. Specific gravity . . . . . . . . . . . . . . . . . . 1018. Colour . . . . . . . . . . . . . . . . . . . . . . Greenish yellow. Urea . . . . . . . . . . . . . . . . . . . . . . . . 27·28 grammes. Uric acid (crystals large, and of a dark-green colour) 0·511 " Bile acids[23] . . . . . . . . . . . . . . . . . . . Abundant. {75} Bile pigment[24] . . . . . . . . . . . . . . . . . . Abundant. Albumen . . . . . . . . . . . . . . . . . . . . . . . None. Sugar . . . . . . . . . . . . . . . . . . . . . . . . None.

[Footnote 22: I noted his state to be as follows:--Skin of a black jaundiced tint (dark green). Eyes deeply stained. Lips anæmic. Considerable emaciation and debility. Extreme languor. Appetite good. Tongue, and pulse not remarkable. Slight pain on pressure over the gall-bladder. Indistinct fulness in pancreatic region, and to the left of middle line.]

[Footnote 23: On the addition of sulphuric acid, and white sugar to the urine, a very marked, and beautiful purple hue was obtained.]

[Footnote 24: Nitric acid at first turned the urine green, but on the application of heat it became red, and after prolonged boiling, of a pale straw colour. Hydrochloric acid changed the colour of the urine immediately to a deep olive-green tint.]

The facts here elicited were interpreted as follows:--

1st,--The quantity of urea which might be said to be normal, was considered a favourable sign, as it indicated that the stomachal digestion was unimpaired.

2nd,--The quantity of uric acid being below the average, was likewise regarded as favourable, tending as it did to negative the idea of cancerous disease of the liver; the uric acid being in such cases usually increased.

3rdly, and lastly, the presence of the biliary acids, as well as the bile pigment, in the urine, showed that bile was still being secreted, but re-absorbed, and this led at once to the diagnosis that the case was one of jaundice from obstruction.

Here, then, was an important step gained. The next point was, if possible, to ascertain the cause of the obstruction. Taking into account the absence of any tumour, and any history of gall-stones, together with the fact of the sudden disappearance of the enlarged gall-bladder, my {76} first idea was that it might be a case of hydatids blocking up the common gall-duct, and that on one occasion, some large cyst had ruptured, and discharged itself through the intestines. On talking the case over with Dr. Prance, however, that idea was abandoned, and we were forced to content ourselves with the simple fact that the case was one of jaundice from obstruction of the common bile-duct, complicated with occlusion of the pancreatic duct, which fact had been previously ascertained by the discovery of the fatty acids in the fæces. About this time the patient took three grains of benzoic acid, in the form of pill thrice a day, and it was thought, with the advantage of slightly diminishing the jaundiced state of the skin. But no permanent benefit was obtained, and after a time this remedial agent had to be discontinued, in consequence of its having induced slight dyspepsia. In the letter I received informing me of this fact, it was also noted that there was much less both of the oily matter, and albumen in the stools. There was, at the same time, a considerable deposit of urates in the urine. The specific gravity continued to be about 1018. The quantity in twenty-four hours about forty ounces. On the 29th of November, the patient was again brought to me, and we made a careful examination of the size, shape, and exact position of the {77} hepatic organ. The measurements were found to be 5 inches at the extreme right, 4 inches at a line drawn perpendicularly to the nipple, and 2¾ inches midway between nipple and sternum. Beyond the centre of the sternum the liver did not reach. As regards the size of the liver then, there was still nothing very remarkable.

On this occasion it was observed, that the patient's memory was not so good as formerly, and that there was a certain amount of mental as well as bodily languor. His hearing was likewise sluggish, the words having occasionally to be repeated before they made an impression on the cerebral organ. This, no doubt, arose from the poisonous effects of the bile circulating in his blood.

It may be here mentioned, that in cases of jaundice from suppression we seldom or never meet with those extreme symptoms of cerebral disturbance which are so common in cases of jaundice from obstruction. I believe the reason of this difference in the two forms of jaundice arises from the circumstance that the really poisonous parts of the bile are the biliary acids, and that they, like urea, are powerful narcotic poisons. The results of the experiments on artificial jaundice (page 95) led me to this conclusion.

As neither the symptoms nor physical signs threw any additional light on this interesting case, {78} it was determined once more to bring chemistry and the microscope to bear upon it, with the view of, if possible, extending the information these methods of investigation had already yielded. Accordingly, a specimen of the urine was again obtained for analysis, and it yielded the following results:--

24 HOURS' URINE. Quantity, (43 oz.) . . . . 1333 c.c. Specific gravity . . . . . 1016. Reaction . . . . . . . . . Acid. Urea . . . . . . . . . . . 23·994 grammes. Uric acid . . . . . . . . 0·266 " Bile pigment . . . . . . . Abundant. Bile acids . . . . . . . . Small quantity. Sugar . . . . . . . . . . A little. Solids (total) . . 41·989 Organic matter . . . . . . 31·992 Inorganic . . . . . . . . 9·997

A marked change is here seen to have occurred in the constitution of the renal secretion. First--the quantity of urea has notably diminished (from 27·28 to 23·99 grammes, or in other words, from 423·84 to 370 grains.) The amount of uric acid has also fallen (from 0·511 to 0·266 grammes, or in other words, from 8 to 4 grains); while at the same time the biliary acids have considerably decreased. These changes are also seen to be accompanied by another, which I at once regarded {79} as a most unfavourable sign,--namely, the appearance of sugar in the urine. Although the quantity of sugar was as yet small, and it was associated with a diminution in the bile acids, it nevertheless made me look forward with gloomy forebodings, for as far as my experience goes, when the urine becomes saccharine in the course of a chronic, and exhausting disease, it has generally been the forerunner of a fatal termination. This case, I am sorry to say, proved no exception to the rule. There was, indeed, but one consolatory fact in the analysis, and that was the diminution of the uric acid, which, as I before remarked, tended to negative the idea of malignant disease of the liver, and this was a great source of satisfaction to the patient.

Eight days later, 12th November, a qualitative, and quantative analysis of the urine was again made, with the following result:--