E. A. (Edward Albert) Sharpey-Schäfer.

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That extracts of the intestinal mucous membrane have marked
lohysiological properties, there is httle doubt. It is comparatively easy
to make such extracts free from micro-organisms, and it is generally
agreed that these extracts have a considerable power of inverting cane-
sugar and of changing starch, in an intense degree, into dextrose,
probably through the stage of maltose.


By D. ISToEL Paton.

Contents. — Mode of Formation of Bile Constituents, p. 559 — Water, p. 559 —
Inorganic Salts, p. 560 — Nucleo-Proteid, p. 561 — Bile Acids, p. 562— Bile Pig-
ments, p. 563 — Cliolesterin, p. 564 — Lecithin, etc., p. 564 — Influence of various
Factors on the Secretion of Bile, p. 564 — Flow of Blood, p. 565 — Food, p. 565
— Pressure of other Organs, p. 567 — Nerves, p. 567 — Chemical Substances, p.
567 — General Conclusions, p. 569.

In considering the mechanism of bile secretion, it must be remembered
that the formation of l^ile is only one of many functions performed by
the liver.

Placed as it is upon the course of the portal vein, the great channel
of absorption of material from the alimentary canal, the liver regulates
the supply of carbohydrates to the body by storing the surplus sugar
absorbed in the form of glycogen. It also gets rid of any excess of
nitrogen absorbed, by converting it into the innocuous and easily
eliminated urea. In addition to performing these functions, the liver
acts as one of the great storehouses of iron in the body, and in many
animals it is also a situation in which surplus fats are accumulated.

When these numerous functions are considered, the small amount of
bile formed per diem by so large an organ is the less surprising. In man
about 800 or 900 grms. of bile, with about 14 or 15 grms. of solids, are
daily secreted from the liver, an organ which weighs about 1600 grms.

In studying how bile is formed in the liver, it is necessary to
remember that, besides the great mass of liver cells, there are in-
numerable bile passages lined by a living epithelium. In most animals
a saccular diverticulum, the gall bladder, is developed upon these
passages. In this and in the passages the surplus bile accumulates.
How far the liver cells, and how far the cells lining the ducts, act in
producing the various constituents of bile, must be subsequently con-

The bile is a fluid containing many different substances in solution
(see article, " Chemistry of Bile " ), and an investigation of the mechanism
of bile secretion necessitates a consideration of the mode of production
of each of these.

Mode of Foemation of Bile Constituents.

Water. — The water of the bile is in part secreted from the walls
of the bile passages, for it has been found that when the cystic duct
is occluded, and the fundus of the gall bladder opened, a small amount



of fluid, about 70 c.c. per diem, is continually secreted from the walls of
the gall bladder.! How far this fluid is a physiological secretion, and
how far it is due to pathological conditions, is difficult to decide.

That water is secreted by the liver cells, as well as by the cells of
the ducts, is proved by the way in which pigments,^ which are secreted
by the liver cells alone, are washed down into the bile passages.

The elimination of the water of the bile is a process of secretion,
and not of transudation. Heidenhain's observations on the relative
pressures in the bile passages and in the blood vessels passing to the
liver,^ given in the following table, demonstrate very clearly that, though
the pressure of secretion of bile is low, it is nevertheless considerably
higher than the blood pressure in the portal vein.


BiJe Pressure.

Pressure in Vena Mesenterica


220 mm. carbonate of soda sol.

90 mm. carbonate of soda sol.


175 ,,

67 „


204 ,,

90 „


110 ,,

50 ,,


180 „

65 „

The aljsorption of water from the alimentary canal seems under
certain conditions to increase the secretion of water by the liver.

Eohrig,* Bidder and Schmidt,^ and Zalesky,^ noticed that the intro-
duction of water into the stomach and intestine of dogs with bihary
fistulse increased the flow of bile. Eosenberg '^ found that if the intestine
had previously been cleared out by a glycerin enema, the introduction
of 500 c.c. of water into the intestine increased the flow of bile. In a
case of complete l)iliary fistula in a woman,^ the amount of the bile
secretion was greater upon the days on which a large quantity of fluid
was taken, and tliis increase was in the water of the bile, not in the

Inorganic salts. — The analyses of the l)ile of the dog given by
Hoppe-Seyler,'' show that in bile taken from the gall bladder the salts
constitute about 5 per cent, of the solids, while in freshly secreted bile
they amount to about 13 or 14 per cent. The freshly secreted bile
alone need be considered in discussing the mode of formation of these
salts. A comparison of the salts of the bile with the salts of the blood
plasma indicates that the percentage amoimt of salts is smaller in bile
than in blood, and that, while chloride of sodium is the most abundant in

^ Birch and Spoiig, Jour a. Physiol., Cambridge and London, vol. viii. p. 378 ; Mayo
Robson, Proc. Roy. Soc. London, 1890, A'ol. xlvii. p. 499.

- Wertlieimer, Arch, de phy-'^wl. norm, etpath., Paria, 1891, p. 724.

^ Hermann's "Handbuch," Bd. v. S. 269.

^ Med. Jahrh., Wien, 1873, Bd. ii.

" "Die Verdaunngssafte," 1852, S. 166.

" Hofmann and Schwalbe, Jahresb. ii. d. Fortschr. d. Anat. ii. Phyfiiol., Leipzig. 1877,
S. 219.

■^ Arch./, d. yes. Physiol., Bonn, 1890, Bd. xlvi. S. 361.

8 NoiJl i'aton and Balfour, Pep. Lab. Roy. Coll. Phys., Edin., 1891, vol. iii. p. 191.

^ "Physiol. Cheni.," S. 302.


both, in bile the proportion of this salt is not nearly so high as in
plasma. This may possibly be explained by the withdrawal of hydro-
chloric acid in the stomach, leaving the soda to be comljined with the
organic acids of the bile.

A study of the excretion of chlorine in the bile has been made by
Dagnini in Albertoni's laboratory.^ He finds that in dogs with a
permanent fistula the percentage of chlorine varies Httle, and that it
is only slightly raised by the administration of chloride of sodium, or
of potassium. Chlorides, as is well known, are chiefly excreted by
the kidney.

Giovanni Pirri ^ has studied the secretion of sodium and potassium,
and finds that, while the amount of sodium excreted per diem is very
constant in spite of variations in diet, and in spite of the administration
of chloride of sodium, the excretion of potassium varies within wide
limits, and is increased by giving sodium and potassium chloride in the
food. The sodium is in great measure combined with the organic
acids of the bile, and hence these results do not throw light upon the
excretion of sodium in inorganic compounds.

On the secretion of lime salts, work has been done under Naunyn's
direction by Jankau. He shows that the amount of lime in l^ile is very
small, and that it is not increased by the administration of lime salts.^
From the fact that lime salts are present in the secretions from mucous
membranes, Naunyn suggests that the lime of the bile may be formed in
the bile passages.

The very small quantity of iron which exists in the bile (less than
1 mgr. per diem in the dog)* may be derived from the iron stored in the
liver cells, or may be formed from the disintegration of the epithelial
lining of tlie passages. Evidence on the subject is wanting.

How far the other inorganic salts are secreted by the liver cells,
and how far by the cells lining the bile passages, cannot be considered
as established. There is clear evidence to show that they are, in part
at any rate, formed in the latter situation. In a series of analyses of
bile, collected from a woman with a complete biliary fistula, it was found
that during attacks of fever the true biliary constituents, the organic
salts and pigments, were markedly diminished, while the proportion of
inorganic salts remained unaltered, between 0"7 and 0'8 per cent.^

Birch and Spong's analysis of the fluid from the gall bladder showed
the presence of 0-826 per cent, of inorganic salts, of which the chief was
chloride of sodium. Mayo Robson found 0-84 per cent, of inorganic
matter. Analysis of freshly secreted human bile gives about the same
proportion of salts.^ Hence, since the amount of salts is the same in
the small amount of fluid secreted from the bile passages, and in the
total amount of bile poured out from bile passages and liver cells
together, about the same proportion of salts must exist in the secretion
from each.

Nucleo-proteid. — The mucus-like nucleo-proteid of bile is formed in
the bile passages and gall bladder. The amount in bile is small, about
0'2 per cent.

^ Mem. r. Accad. d. sc. d. 1st. di Bologna, 1893, Ser. 5, vol. i. p. 3.

2 Ibid., 1893.

^ Naunjni, "Cholelithiasis," translated by A. E. Garrod, New. Syd. Soc, p. 15.

■* Anselm, Arb. d. pliarmakol. Inst, zii Dorpat, Stuttgart, 1892, Bd. vii.

^ Hep. Lab. Roy. Coll. Fhys., Edin., vol. iv. p. 44.

« Hoppe-Seyler, "Physiol. Chem.," S. 302.

VOL. I. — -;6



In cases of occluded gall bladder this mucin-like substance has been
found to be the chief organic solid of the secretion.^

Mayo Rohson's Analysis.

Organic matter, chiefly mucin . . . •672 per cent.

Chlorides equal to ]N"aCl . . . . '573 ,,

Sodium carbonate ..... "220 ,,
Other salts containing phosphates, potassium

salts, etc. . . . . . . '071 „

The fact that the amount of this substance does not vary with the
true bile constituents either at different periods of the day ,2 or in febrile
conditions,^ indicates very clearly that it is not formed by the liver

Salts of the bile acids.— These are entirely produced in the liver
cells. In Birch and Spong's case, and in the case examined by Mayo
Eobson, they were entirely absent from the secretion of the gall

That they are actually formed by the liver cells, and not merely ex-
tracted from the blood, was demonstrated by Minkowski and Naunyn.'^
These observers found that, while bile salts are normally absent from the
blood, they appear when the bile duct is ligatured. If, however, the
liver be excluded from the circulation, there is no accumulation of bile
salts in the blood.

The source of the cholalic acid moiety of the glycocholic and
taurocholic acids is unknown. The source of the glycine and taurine is
to be sought ultimately in the proteids of the body and of the food,
since these alone can yield the nitrogen and sulphur. Both are amido-
acids of the fatty acid series.

Nencki, Pawlow and Zaleski,^ have shown that the surplus proteid
of the diet is largely broken down into ammonia compounds in the wall
of the intestine, and these compounds pass to the liver. Von Schroder ^
demonstrated that ammonia compounds are readily converted to urea by
the liver. Hence by far the greater quantity of nitrogen in excess of
that required must undergo this transformation, and it is not to be
expected that an additional quantity of proteids in the food will lead to
a markedly increased formation of bile acids. Spiro,'^ by feeding animals
w^ith biliary fistulee upon various kinds of food, found that a proteid diet
increased the nitrogen and sulphur excreted in the bile, but not in
proportion to the amount of proteid taken.

The following figures illustrate Spire's results : —


Sulphur of Bile
in Grms.

Nitrogen of Bile
in Grms.

Fasting ....
125 grms. flesh .
500 „ ...
949 ,, ...



1 Hoppe-Seyler, "Physiol. Chem.," S. 302.

- Rep. Lab. Roy. Coll. Fhys., Edinburgh, vol. iii. p. 204.

'•'Ibid. p. 212. ■^Arch.f. expcr. Path. u. Fharmakol., Leipzig, Bd. xxi. S. 7.

^ Ibid., Bd. xxxvi. S. 26.

'^ Ztschr. f. physiol. Chem., Strassburg, Bd. ii. S. 234.

■^ Arch./, rhysiol., Leipzig, 1880, Siipp. Bd. S. 50.


Kunkel/ from similar experiments on dogs, concluded that a definite
part of tlie sulphur taken in the diet is excreted in the hile, but the
increase in biliary sulphur occurs two or three days after the ingestion,
and not upon the same day, as is the case with the sulphur of the urine.
Of the sulphur of the food, from 8 to 30 per cent, is excreted in taurine.

In man on an ordinary diet, about 33 grms. of urea with 1.5 grms. of
nitrogen are daily formed, while only about 10 grms. of bile acids with
about 0'3 grms. of nitrogen are excreted. The increased ingestion of
proteids leads to a proportionate increased excretion of urea, and any
increase in the bile acids is necessarily so small that it may readily
be overlooked. Similarly, any increased decomposition of the proteids
of the tissues leads to a proportionately increased excretion of the
nitrogen in the form of urea, and any increase in the bile acids which
may occur must be very trifling.

Whether the bile acids which are absorbed from the intestine can
be again excreted by the liver cells, has been investigated by injecting
into the blood of animals a bile salt differing from that which is normally
present. In dogs the taurocholate of soda is the normal salt of the
bile. After injecting giycocholate of soda. Pre vest and Binet,^ and
Weiss ^ found it in the dog's bile. Socoloff,* on the other hand, failed
to detect it after it had been injected. Huppert ^ observed that the
injection of glycocholic acid increases the amount of bile acids in the
bile. The experiments of Eosenberg ^ show that the administration of
bile salts causes an increased secretion of bile with a marked increase
in the solids. They appear to be the only substances which produce
this result, and since the bile salts are the most abundant solids of bile,
it seems fairly certain that they are absorbed, and re-excreted from the
blood by the liver.

Bile pigments. — The pigments must be produced in the liver cells,
since the secretion from the bile passages is entirely destitute of colour-
ing matter.'^ They are formed from the hsematin moiety of the haemo-
globin molecule. The injection of free haemoglobin into the blood,^ or
the setting free of haemoglobin by solution of the red corpuscles,^ rapidly
leads to a great increase of the bilirubin of the bile. Minkowski and
Naunyn, by experiments upon birds,^" have confirmed these observations.
They further found that if the liver is excluded from the circulation
the formation of bilirubin does not take place. They thus showed that
bilirubin is actually produced in the liver cells. The iron-containing
part of the haematin molecule appears to be split off and retained in
these cells, giving rise to the accumulation of iron in the liver, which
follows the disintegration of red corpuscles.^^

Not only do the liver cells manufacture bilirubin, but when this or
any other bile pigment is present in the blood they take it up and eliminate

^ Arch. f. d. ges. Physiol., Bonn, Bd. xiv. S. 344.

" Compt. rend. Acad. d. sc, Paris, 1888, tome cvi. p. 1690.

^ B%dl. Soc. imp. d. nat. de Moscou, 1884.

^Arch.f. d. ges. Physiol., Bonn, 1875, Bd. xi. S. 166.

5 Arch. d. Heilk., Leipzig, 1869, Bd. v.

" Arch./, d. ges. Physiol., Bonn, 1890, Bd. xlvi. S. 334.

■^ Birch and Spong, Journ. Physiol., Cambridge and London, voL viii. p. 378 ; Mayo
Robson, Proc. Poy. Soc. London, 1890, voL xlvii. p. 499.

^ Stadelmann, Arch. f. exper. Path. u. Pharmakol., Leipzig, 1890, Bd. xvii. S. 93.

^ Afanassiew, Ztsclir. f. klin. Med., Berlin, Bd. vi. Heft 4.
1'^ Arch. f. exper. Path. u. Pharmakol., Leipzig, 1886, Bd. xxi. S. 1.
11 Hunter, Lancet, London, 1892, p. 1262.


it. This was definitely proved by Wertheimer/ who injected into the
circulation of dogs the bile of the ox and sheep. The bile of these
animals contains a pigment, cholohsematin, which gives a characteristic
spectrum, and the appearance of this spectrum in the bile of the dog
showed that cholohsematin had been taken up and excreted.

Cholesterin. — Whether cholesterin is formed in the liver cells, or in
the cells lining the bile passages, or in both, is not definitely known.
In the two cases of fistula of the gall bladder already referred to, the
presence or absence of cholesterin is not noted.^

Tliat the cholesterin is formed somewhere within the liver, and not
merely excreted by it, is shown by an experiment by Jankau, performed
in Naunyn's laboratory.^ He injected cholesterin into dogs, and also
gave it in their food, and ascertained that it had been absorbed ; but he
failed to find any increase of cholesterin in the liver tissue, or in the
bile. The analyses of the liver and bile made by Kausch ^ in the same
laboratory show no relationship between the amount of cholesterin in
the gland, and in its secretion. Thomas,^ who also worked in ISTaunyn's
laboratory, found that there is no relationship between the amount of
cholesterin excreted and the kind of food taken. When the dog under
observation suffered from catarrh of the biliary passages, there was a
marked increase in the cholesterin of the bile.

From these experiments, and from the fact that cholesterin is always
found where cells are disintegrating, Naunyn strongly supports the view
that cholesterin is produced, not in the liver cells, but from the cells of
the passages, and that it is a product of the disintegration of their

Lecithin and other compounds of the fatty acids. — The occur-
rence of these bodies in the secretion from the gall bladder has not
been observed. On the other hand, lecithin and fat are constant and
abundant constituents of hver cells. Liver tissue contains about 2 "3 5
per cent, of lecithin, and about 3 or 4 per cent, of fat.^ Thomas found ^
that, while cholesterin was unaltered in amount by the administration
of various diets, the amount of fat in the bile depended largely upon
the amount of fat taken in the food ; and since the fats of the food are
frequently stored in the liver cells, it is probable that the fatty acid
compounds in the bile are derived from this source.

Influence of Various Factors upon the Secretion.

The investigation of the influence of varying conditions upon bile
secretion is a matter of extreme difficulty, for the bile may accumulate
in the gall bladder and passages to be expelled from the liver some time
after secretion.

The flow of bile is governed by —

1. The rate of secretion.

2. The activity of the muscular walls of the passages.

3. The pressure upon the liver of adjacent organs.

^ Arcli. de pkysiol. norm. et2Mth., Paris, 1891, p. 724.

^ In the colourless fluid from a case of hydrops cystidis fellere, I found a considerable
quantity of cholesterin.

3 "Cholelithiasis," translated by A. E, Garrod, New Syd. Soc, 1896.

^ Diss., Strassburg, 1891.

^ Noel Paton, Journ. Physiol., Cambridge and London, 1896, vol. xix. p. 213.

** Loc. cit.


Further, the liver being placed upon the eh'erent vessel of the
alimentary canal, must have its vascular condition altered l)y every
modification in that of the gastro-intestinal tract, and it is impossiljle to
eliminate this element while studying the action of any agency on bile

Influence of the hepatic circulation upon bile secretion. —
The circulation in the liver may he profoundly altered without actual
stoppage of bile secretion. Thus it has been shown, in cases where, by
the method devised by Ore, the portal blood has been directed into the
inferior vena cava, that l)ile is still secreted by the liver ; ^ while
Wertheimer^ has confirmed the results of older investigators, that
ligature of the hepatic artery does not immediately stop the secretion,
although ultimately necrosis of liver tissue supervenes and leads to
abolition of function.

But while these marked disturl;)ances do not at once stop secretion,
there is evidence that its rate depends upon the vascular supply.
Thus Heidenhain has shown ^ that in dogs, section of the splanchnic
nerves, which causes a dilatation of the portal vessels, produces a
marked increase in the flow of bile. If, however, this local dilatation
is accompanied by a general dilatation, such as is produced by section of
the spinal cord in the neck, a fall in the secretion occurs. Munk,"* on
the other hand, has shown that stimulation of the splanchnic nerves,
which produces constriction of the vessels, leads to a diminution in
the rate of bile secretion.

How far this influence of alteration in the blood supply is due to
variation in pressure, and how far to alteration in the rate of blood flow
through the liver, has not been directly investigated. But the observa-
tion of Eohrig,^ that constriction of the vena cava inferior, which raises
the pressure in the liver while decreasing the rate of blood flow,
diminishes bile secretion, seems to indicate that the rate of flow is of
more importance than the mere intravascular pressure. In this con-
nection the relationship of the pressure of secretion to blood pressure
(p. 560) must be borne in mind.

Effects of food. — Starvation, according to Bidder and Schmidt,
causes a diminution in the amount of bile secretion, and a corresponding
fall in the amount of solids.^ Their experiments are unsatisfactory, in
so far that cats were taken at various stages of starvation up to 240
hours after food, a temporary fistula made, and the bile secretion
determined for a short period only. The most recent contribution
to our knowledge of this subject was made by Lukjanow,'' who
determined the changes in the various solids of the bile in guinea-pigs
kept without food or water. He concludes that both the secretion of
water and of solids diminishes throughout the period of fasting.

From the investigations on the relationship of bile secretion to
the flow of blood through the liver, it is obvious that the dilatation
of the abdominal vessels, which occurs in digestion, will of itself
cause an increased secretion of bile. Such an increased flow has

^ Arch. d. sc. hioL, St. Petersbourg, 1892, vol. ii.

" Arch, dephysiol. norm, etpath., Paris, 1892, p. 577.

^ Hermann's "Handbuch," Bd. v. S. 266.

'^ Arch. f. d. ges. Physiol., Bonn, 1874, Bd. viii. S. 151.

5 Med. Jahrh., Wien, 1873, Bd. ii.

*> Bidder and Schmidt, " Die Verdaimngssafte. "

■? Ztschr.f. physiol. Chem., Strassburg, 1892, Bd. xvi. S. 87.



been observed by various investigators. The most careful observations
on the influence of food in bile secretion are those recorded by Hoppe-
Seyler.^ The experiments were made on a dog with a permanent
biliary fistula, and they show that within an hour after food the flow of
bile is slightly and temporarily increased. It is very probable that
this initial increase is simply due to reflex stimulation of the gall bladder
and bile passages, expelling the bile already secreted. Four or five
hours after a meal the flow is enormously increased, the amount of
bile sohds rising with the amount of bile. The extent of this accelerated
flow indicates that it is actually an increased secretion. How far it
is due to the increased vascularity of the abdominal viscera, and
how far to the stimulating action of absorbed material on the liver
cells, is not made manifest by the experiments. About nine or ten

hours after a meal there is a seconda.ry
increase, not so marked as the first, but
lasting for two or three hours, and accom-
panied by a still more marked rise in the
excretion of solids. The cause of this is

As to the special influence of the
various constituents of the food, our know-
ledge is somewhat defective. The re-
searches of Eosenberg^ and of Barbera,^
on dogs with a permanent flstula, show an
increase in the secretion of bile and of the
bile solids after proteid food. The latter
observer states that carbohydrates have
also a certain effect in increasing the secre-
tion of bile, but that their effect is very
small indeed. Both observers find that
the administration of fats very markedly
increases the bile flow ; but while in Eosen-
berg's experiments the flow of bile under
the influence of fats was greater than with
proteids, in Barbera's the increase was most
marked on a diet of flesh.

The accompanying chart (Fig. 48) gives
a summary of Barbera's observations.

Online LibraryE. A. (Edward Albert) Sharpey-SchäferText-book of physiology; (Volume v.1) → online text (page 80 of 147)