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.
[Illustration: FIG. 4.--Crystals of pure tyrosine, obtained from the
urine of a case of chronic atrophy of the liver, following upon
obstruction of the bile-duct. _(a)_ Large crystals. _(b)_ The more
common form of the stellate groups of needle-shaped crystals. _(c)_ A
few separate fragments of needle-shaped crystals.]
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.
[Illustration: FIG. 5. Spiculated balls of tyrosine, from the urine of
a case of acute atrophy of the liver. When these were re-dissolved,
purified, and re-crystallized, they assumed the form represented in
Fig. 4 _(b)_.]
{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.
[Illustration: FIG. 6. Dark globules of leucine of various sizes,
resembling in appearance globules of carbonate of lime.]
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:--
24 HOURS' URINE.
Quantity (33 oz.) . . . . . . . 1023 c.c.
Reaction . . . . . . . . . . . Acid.
Specific gravity . . . . . . . 1017.
Urea . . . . . . . . . . . . . 15·345 grammes.
Uric acid . . . . . . . . . . . ?
Bile acids . . . . . . . . . . None.
Bile pigment . . . . . . . . . Abundant.
Sugar . . . . . . . . . . . . . Increased. {80}
Tyrosine, and leucine[25] . . . In small quantity.
Solids (total) . . . . 23·426
Organic matter . . . . . . . . 17·698
Inorganic . . . . . . . . . . . 5·728
[Footnote 25: On precipitating the urine with the acetate of lead,
filtering, and freeing the clear liquid from the excess of that reagent
by means of sulphuretted hydrogen, and again filtering, the liquid, on
evaporation, was found to deposit small crystals of tyrosine, and to
have floating in it, and on its surface, round balls of leucine.]
Here, is now to be observed, the rapid downward progress of the case.
Stomachal digestion, as indicated by the amount of urea, is much
impaired. The general health, as indicated by the sugar, is sadly
affected, and, to crown all, tyrosine, and leucine, the indicators of
atrophy of the liver, have made their appearance. So unfavourable was
the result of this analysis considered, that Dr. Prance felt himself
bound to fulfil a promise he had made to the family some time
previously, of warning them of approaching danger, when we had no
longer any hope of the patient's recovery.
Some time afterwards, in the beginning of December, we again saw the
patient together, and made a physical examination of the hepatic organ,
the result of which only confirmed our suspicions. The liver was
decidedly smaller. The epigastric tenderness was increased. The {81}
jaundiced tint deeper. Petechial spots had now appeared on the trunk,
and arms. The lower extremities were oedematous, and the abdomen
two-thirds filled with fluid.
On the 31st December, I received a sample of urine, and a note saying
that the patient had slightly rallied. But on examining the urine, it
was found to have a neutral reaction--it had previously always been
acid--to be of a specific gravity of 1019, and on standing, to deposit
a copious sediment of lithates, coloured intensely yellow with the bile
pigment. Curiously enough, the bile-acids had reappeared; but only in
quantity sufficient to admit of their being detected. In spite of these
trifling changes for the better, the ominous one of an increased amount
of sugar was still there.
A few days later, and just before his death, the patient had the
benefit of another physician's opinion, which, although it differed
somewhat from the foregoing, was, nevertheless, equally unfavourable,
for he considered it a case of malignant disease.
The gentleman having noticed that his case excited considerable
interest, and some difference of opinion among his medical attendants,
directed that his body should be examined after death; and as this wish
was seconded by his wife, {82} a lady of superior mind and
accomplishments, a post-mortem examination was accordingly made, with
the following results:--
Firstly,--The pancreatic duct, as had been suspected, was found
completely occluded at its outlet, and so distended by the accumulated
secretion, that it readily admitted the point of the little finger.
(Vide Plate I., _g_.)