SEVERAL different views on the function of the gall-bladder are now current, but the following are those which have been more or less generally accepted :—
1. The gall-bladder is the temporary container of bile coming from the liver.
2. T h e gall-bladder concentrates the bile received from the liver.
3. T h e gall-bladder is able to eject the concentrated bile into the duodenum.
4. Oddi’s muscle acts as an intermittent sphincter, closing the papilla of Vater against the intestine.
The so-called law of Meitzer-Lyon is widejy accepted. According to this law, there is an antagonistic innervation between the muscles of the gall-bladder and those of Oddi’s sphincter. When the muscle-layer of the gall-bladder con­ tracts, a newly discovered sphincter between the neck of the gall-bladder and the cystic duct (Berg, Luetkens), and the sphincter of Oddi opens, which enables the bile from the gall­ bladder and from the liver to enter the duodenum. Accord­ ing to Rost, the filling and emptying is dependent on sympathetic and parasympathetic innervation.
In 1923, at a lecture in Philadelphia on The Gall-Bladder, its Past, Present, and Future Sweet expressed the opinion that bile, having entered the gall-bladder, is not under physio­ logical conditions ejaculated again. He believes that bile which has entered the gall-bladder is absorbed, and enters the liver using the lymphatic vessels as the way of exit.
In 1928 Blond published a paper ” A New Hypothesis to explain the Problems of the Function of the Bile-ducts ‘\ A number of writers took part in the discussion which followed
THE LIVER
this pubHcation (v. Bergmann, Westphal, Rosenthal and Licht, Körte, Brenner, Kalk and Schoendube, Bronner, Bronner and Schneller, Eisler and Kopstein, Taiman, Gassman, and others).
T h e main point of controversy was the problem of the cystic duct, which, it was then thought, must certainly be the inlet as well as the outlet of the gall-bladder. But no other duct in the body functions both as inlet and outlet under
physiological conditions.
Hepatic Ducts
Physiologists have never satisfactorily answered the question : at what time does bile flow into or out of the gall-bladder ? According to Lepehne and Schoen­ dube, the gall-bladder is capable of concentrating bile excreted from the liver some 20-30 times. McMaster and Rous
Gall Bladder (sectioned)
Fig. I.—Gall-bladder and extrahepatic ducts. Experiments with carbol-fuchsine.
Duodenum
estimate the power of concentration of the dog’s gall-bladder at y-i-io-S.
Tobias, Iwanaga, and Blond have, by experi­ ment, proved the absorp­ tion of sodium iodide, sodium ferrocyanate, alka­ loids, and dyes by the gall-bladder. Blond found
that the dyes, absorbed through the mucous membrane, do not pass through the lymphatic vessels as Sweet and Halpert believed, but re-enter the portal vein through the cystic vein, the public vas efferens.
According to the prevailing theories regarding the emptying mechanism of the gall-bladder, we should expect to see a difference in colour between the hepatic ducts and that part of the system which is distal to the confluence with the cystic duct, i.e., the common bile-duct. If the gall-bladder were to empty its highly concentrated bile through the common bile-duct into the duodenum, we should expect to find a
EXTRAHEPATIC BILE-DUCTS 13
change in the colour of the mucosa at the junction of the cystic and common bile-ducts. Such an occurrence has never been observed, neither has it been recorded in the literature. {Fig. I.)
Moreover, Blond has carried out experiments which showed that this picture is not changed, even when dyes are injected into the gall-bladder. A striking difference always remains between the staining of that part of the biliary system con­ cerned with concentration (gall-bladder), and the colour of the conducting system. The cystic vein does not drain into the hepatic veins, but is a tributary of the portal vein. Dyes absorbed by the wall of the gall-bladder are thus carried into the liver by the cystic vein via the portal vein. This serves as a fresh argument in favour of the theory that bile reaches the gall-bladder through the cystic duct, the vas afferens, but that it does not leave it again by the same route.
These observations induced Blond to carry out, twenty years ago, a critical analysis of the current teaching of the physiology and pathology of the gall-bladder. Surgical failures after operations on the biliary tract are, themselves, sufficient reason to doubt the value of physiological and pathological theories, some of which have almost become dogmas. It is quite strange to observe how little use is made of the results of modern methods of investigation to revalue the old theories, and how results are made to fit into the old framework.
Each new method of investigation appears to try to gain recognition by suppressing evidence contradictory to the preva­ lent teaching, and by stressing observations which appear to agree with it. In this way hypotheses become theories which are maintained even if they hardly conform to the facts [suppressio vert).
This attitude is also demonstrated by the teaching which postulates that the gall-bladder can actively empty itself. Although this has not been proven by direct observation, the doctrine has been staunchly upheld until a recent date. Quite recently a number of authors have begun to doubt the active contractility of the gall-bladder (Auster and Crohn, Martindale, Haberland, Blond). In contradiction to them.
14 THE LIVER
Doyen, Duetmann, Bainbridge, and Dale, among others, claim definitely to have observed contraction. Loehner, by reason of physiological studies, and Luetkens, on pathological grounds, both regard it as proved that the gall-bladder actively empties its contents into the duodenum.
Blond, on the contrary, as a result of specially planned experiments on dogs, failed to observe the slightest motility of the gall-bladder, even following large doses of morphine (ο·2 g. of morphine was given pre-operatively to twenty dogs). It is well known that, with such a dosage, the slightest touch of the gut with a pair of forceps will cause vigorous contractions. Methylene blue or indigo-carmine were injected into the gall­ bladders of these animals. On opening the duodenum, the outflow of dye from the papilla of Vater was not once observed, even after a cannula had been introduced into the papilla, and suction applied. Frequently observations were continued for almost an hour, and these are in accord with the results of cholecystography.
Between the extremes of Hutchinson’s and Harvey’s conception of the gall-bladder as a functionless and rudimen­ tary organ, and the teaching of Westphal and Luetkens, which stresses the importance of various reflexes between the sphincter of Oddi and a newly discovered sphincter at the neck of the gall-bladder and the muscle of the gall-bladder itself, there is a wide field filled with many conflicting theories.
As already mentioned, some regard the gall-bladder merely as a reservoir which is able to empty itself actively (SchiflF), whereas others take it to be a regulator of bile-flow and pres­ sure (Berg, Murphy, Rutherford). According to Aschoff and his collaborators, the gall-bladder regulates the tone of the biliary passages, and Mayo and Denver assume that it also acts Hke a rubber suction ball.
Luetkens described the folds in the cystic duct as semilunar in shape, arranged in an irregular spiral one behind the other, and forming a little cul-de-sac with its open end towards the gall-bladder. Even when applying the strongest suction to the biliary system, Aschoff never succeeded in aspirating even thin fluid bile from the gall-bladder, and neither Winkelstein
EXTRAHEPATIC BILE-DUCTS 15
nor Halpert achieved any success in obtaining bile from the gall-bladder by suction.
In order to test the physiological properties of the valve, Loehner carried out perfusion experiments, and affirms that under moderate pressure from the common hepatic duct, the gall-bladder at once becomes tensely filled, but, when attemp­ ting to empty it, he experienced appreciable resistance.
” When perfusing the empty duct system under moderate pressure, it is found that the current ascends the spiral of Heister’s valve, and while opening up the lumen of the cystic duct and the neck of the gall-bladder, it pushes the free margins of the valves a little towards the wall. Perfusing in the opposite direction, i.e. as would occur during emptying of the gall­ bladder, the current is held and completely stopped by the valve cusps billowing before it and complete apposition of the valves takes place.”
Demel confirms these results by experiments which show that bile finds relatively great difficulty in passing from the gall-bladder through the cystic duct.
On probing the cystic duct in cadavers, Halpert’s view was confirmed by showing that the arrangement of the cusps is favourable for an inflow of bile, but unfavourable for an out­ flow. According to him, the cystic duct is the aflferent but not the eflFerent route of bile from the gall-bladder. Blond has carried out experiments with gall-bladders freshly removed at operation. Up to 40-50 c.c. of warm normal saline were injected into the fundus, but no outflow from the unligatured cystic duct could be observed. Each time the duct was opened up subsequently, and proved to be normal. It is impossible, as Haler has proved in many hundreds of gall­ bladders in situ and in cadavers, to express bile through the cystic duct by firm digital pressure on ihe fundus of the gall­ bladder.
In further experiments on 15 dogs under ether anaes­ thesia, with pre-dosage of 0-2 g. of morphine, 10-20 c.c. of methylene blue were injected into the gall-bladder with a fine needle, and the duodenum opened up subsequently. Drops of unstained liver bile were seen to come from the papilla of Vater in 2 cases ; in the remaining 13 no outflow from the
i6 THE LIVER
common bile-duct could be observed. In all 15 animals a cannula was easily introduced into the common bile-duct, and connected to a 20-c.c. syringe with a piece of closely fitting rubber tubing. In no single case could one drop of the dye be aspirated.
In all the dogs experimented on, subsequent exploration of the biliary system showed that the cystic duct was normally patent. Emptying the gall-bladder by compression was suc­ cessful only when relatively strong pressure was applied. In the literature no plausible explanation for this state of affairs is to be found.
Although Luetkens admits that it is easier to pass a probe through the cystic duct via the common bile-duct than vice versa, he maintains, with little conclusiveness, that only secondary importance should be attached to the finding that the position of the folds [of Heister’s valve] makes the flow into the gall-bladder easier than out of it.”
The muscular bundles in the valves are regarded by Westphal as dilators. To us, however, it appears that, under physio­ logical conditions, the muscles of the cystic duct and in Heister’s valves serve to place the cusps in such a position as to render impossible any outflow from the gall-bladder. They assist the rigidity of the valves, and prevent incom­ petence of the valve, which might come about when the elasticity of the cystic duct reaches its limit owing to any over-distension.
The experiments on gall-bladders freshly removed at operation were compared with those removed post mortem, but the lack of muscle tone in this material, after a certain time, led to a relative insufficiency of the flaps causing slow dribbling of fluid from the cystic duct. It is unphysiological to work upon gall-bladders removed from their normal sites. Post-mortem work should be done on gall-bladders in situ.
T h e results of duodenal aspiration have formed the main support for the hypothesis that the gall-bladder contracts actively, and that there exists an antagonism between it and the sphincter of Oddi. It is well known that bile of diflFerent colouring is produced on passing an Einhorn duodenal tube into the duodenum. In this way it has been possible
EXTRAHEPATIC BILE-DUCTS 17
to differentiate between less concentrated ‘ A ‘ bile and more concentrated ‘ Β ‘ bile. T h e very nomenclature of the bile thus produced indicates clearly that there is no finality envisaged as to the source of the different biles. T h e more concentrated bile is supposed to originate from the gall­ bladder, and is thought to be ejaculated into the duodenum during the relaxation of Oddi’s sphincter. This ‘ Β ‘ bile is then followed by less concentrated bile from the common bile-duct. This course of events is said to become more strikingly evident following a dose of 15-25 per cent magnesium sulphate solution (Meltzer-Lyon), or a dose of Witte-Peptone (Stepp). Bassler and Luket, Crohn, Reitz, and Bodin con­ tradict the view of Meltzer-Lyon and Stepp, as they have been able to obtain ‘ Β’ bile also from patients who had under­
gone cholecystectomy ; more recently the statement of these American workers was confirmed by Hechtmann.
Meltzer-Lyon’s hypothesis thus becomes untenable if subjected to critical analysis ; in addition, the results of chole­ cystography seem to point to the fact that liver bile enters the duodenum only in response to a stimulus produced by food substances supplied by the portal vein to the liver cells.
The variation in the qualitative composition of bile (whether thin or thick. A, B, or C bile) can only be the result of liver- cell function. No direct part can possibly be played by the gall-bladder, since, even following cholecystectomy, fluctua­ tions in the concentration of bile can still be observed.
Lintz published a case which provided striking disproof of Meitzer-Lyon’s view and that of Stepp : A woman, aged 45, had been suffering from colicky pain in the right upper abdomen for two years, and had twice been operated upon by well- known surgeons, who had both failed to demonstrate the presence of a gall-bladder. Cholecystography, too, failed to produce a shadow of the organ ; in spite of this, Meltzer-Lyon’s test gave the same result as is found in people with normal gall­ bladders, i.e., three differently coloured and concentrated types of fluid which could be aspirated from the duodenal tube.
According to Heidenhain, the production and concentration of saliva and bile increase directly with the intensity of this food stimulus.
i8 THE LIVER
The pancreas is not only anatomically similar to the parotid gland, but its function also, so far as its external secretion is concerned, is almost identical with that of the parotid. The secretion of pancreatic juice occurs only after intake of food, according to Dolinsky, Pavlow, Cohnheim, and Klee, who think that the stimulus is provided by acid gastric contents entering the intestine. The concentration of pancreatic juice varies according to the nature of the stimulus, whether it be of a chemical or a different nature (Babkin and Sawitsch). The analogy goes still further, and, according to Narbut, psychological stimuli take part in the production of pancreatic
juice even to the same extent as they do in salivation.
We must remind ourselves of the fact that the common bile- duct and the pancreatic duct have a common exit into the duodenum at the papilla of Vater. It would be illogical to assume that the sphincter of this common opening could not influence the outflow of pancreatic juice if, on the other hand, it is supposed to have a certain antagonistic relation to the gall­ bladder and the secretion of bile, determining the time at
which bile is discharged into the duodenum.
We have seen that not only is the existence of a sphincter
regulating external pancreatic secretion superfluous, but that it would, however, be a disadvantage, because other factors regulate this secretion. Thus we appear to be justified in doubting any physiological significance of the common sphincter for the secretion of bile into the duodenum.
Steinmetzer gave experimental proof (in animals) of the assumption that the secretion of different types of bile, as demonstrated by duodenal aspiration, is a function of the liver cells, and not of the gall-bladder. By suitable experimental arrangements to exclude the gall-bladder, he was able to show that natural cholagogues, such as Carlsbad salts, will produce bile of twenty-fold concentration. Walzel and Weltmann demonstrated that bile obtained from a fistula of the common bile-duct following cholecystectomy normally showed great fluctuation of pigment concentration in hourly specimens.
During duodenal aspirations. Stepp sometimes obtained 200 c.c. in one hour, whereas, on other occasions, only 30-50 c.c. of bile could be collected. It was impossible says
EXTRAHEPATIC BILE-DUCTS 19
this author, to explain the cause of this difference This fluctuation of biliary secretion well agrees with that found in the function of other glands, e.g., the parotid.
In this connexion, an observation by Schiff is significant. He found that, on tying the common bile-duct, the secretion from a previously formed gall-bladder fistula will diminish. SchiflF then reintroduced the bile thus obtained through a duodenal fistula, and, again, an increase of biliary secretion was produced. The same observation can be made if, instead of its own bile, bile of another individual is introduced into the experimental animal. This fact demonstrates the impor­ tant part played by the absorption of bile in biliary metabolism. If animals suffer from a constant drain of bile they finally become cachectic and die.
It is probable that no bile whatever enters the duodenum during fasting, and the normal tone of the duodenal muscle is apparently higher than the maximum pressure of excretion of bile by the liver.
Bile is produced during fasting, but, instead of reaching the duodenum, it enters the gall-bladder. An external circulation of bile-salts, which is of the greatest importance to the digestive process, would appear to be uneconomical if it were to take place also during the intervals between meals.
T h e gall-bladder should be regarded as an organ for resorbing and not for pouring out bile. Its veins, like those of the intestines, drain into the portal system, whereas the veins from secreting or emptying organs, such as the kidneys, bladder, and ovaries, are tributaries of the vena cava.
According to Eppinger, the liver has a daily output of 10 g. of solid biliary constituents, and of these only i g. is lost from the organism by excretion. T h e investigations of Schiff, and also those of Stransky, show that the small intestines can and do reabsorb any excess bile-salts. As long as the gall­ bladder is able to function, it mainly appears to effect re- absorption ; if it is removed, or if it ceases to function, reabsorption from the mucosa of the small intestines takes its place.
Hammarsten found, as a result of analysing human bile- salts, that the mucous membrane of the gall-bladder absorbs
20 THE LIVER
salts from the bile. He has demonstrated a threefold con­ centration of different salts in the bile coming from the liver, in spite of the fact that bile in the gall-bladder is of ten times higher concentration. Until lately very little was known about reabsorption of other constituents of the bile. T h e existence of a shrunken gall-bladder in pathological conditions, however, proves that the gall-bladder is capable of active absorption. As a rule, such a gall-bladder is almost empty of fluid, and has a stone in the cystic duct which obstructs the inflow of bile from the liver. It is quite obvious that the bile content of such a gall-bladder has been absorbed by the mucous membranes. Another pathological finding, which proves that the gall-bladder is capable of absorption, is the so-called hydrops of the gall-bladder. The bilirubin from such a bladder undoubtedly has disappeared by absorption. T h e most satisfactory proof of absorption is the lack of all constituents of bile in a shrunken gall-bladder ; colorimetric methods to test the quantity of bilirubin are not considered reliable.
Rosenthal and Licht were able to prove the reabsorption of biliary acids. According to Hosokawa, reabsorption of bile acids increases in an inflamed gall-bladder. Rosenthal and Licht accepted Blond’s view of reabsorption in the gall­ bladder via the cystic veins, and, in their experiments, they tied the cystic ducts ; for the first timé in such an experiment the cystic vein was avoided. T h e y came to the conclusion that a healthy gall-bladder is able to reabsorb considerable amounts of bile acids. After causing inflammation of the mucous membrane of the gall-bladder by the injection of turpentine, they were able to increase the absorbability of biliary acids. They conclude: One can assume that constant physiological impulses reach the liver via the cystic veins and portal vein by reabsorption of bile acids from the bladder (Blond) a process similar to the reabsorption of bile acids in the entero-hepatic circulation (Schiff), thus constantly regulating the secretion of the liver. Bile secretion is regulated by the continual supply of bile reabsorbed from the intestine via the portal vein. The supply of fats, protein, and the other products of metabolism, such as insuHn, haemoglobin, and
EXTRAHEPATIC BILE-DUCTS 21
bile, through the portal system to all liver cells is the most reliable regulator of the function of the liver cells.
In spite of the care taken by Rosenthal and Licht to avoid all possible mistakes in their experiments, their conclusions some­ times show how difficult, or even impossible, it is to avoid such mistakes. Even perfect experiments must lead to wrong conclusions, because one cannot possibly establish physio­ logical conditions. We must realize that :—
1. Under physiological conditions pure biliary acids are present neither in the healthy nor in a pathological gall-bladder. 2. By the introduction of turpentine or Dakin’s solution into a gall-bladder, a so-called inflammation may be produced which is similar to that caused after the use of tetra-iodo- phenolphthalein in cholecystography. But the pathological changes in the mucous membrane, which followed in this experiment, are neither identical nor comparable with the well- known acute or subacute chronic bacterial inflammation of
the gall-bladder.* Surely they can hardly have any similarity to those pathological conditions in which complete destruc­ tion of the mucous membrane of the gall-bladder has already occurred. For instance, a chemical poison may be able to produce an intermittent dilatation of the capillaries in the mucosa ; bacterial inflammation of some duration may lead to a thrombosis of parts of the capillary system. Faster re- absorption may be occasioned by acutely inflamed epithelium. On the other hand, a chronically inflamed mucous membrane may, to some extent, have lost its power to absorb.
3. Ligature of the cystic duct will completely change the physiological condition of reabsorption from within the gall-bladder.
T h e constituents for the formation of bile and reabsorbed bile are supplied to the liver via the portal system. In addition, the contents of the gall-bladder pass to the liver, fat metabolites passing the same channels. If it happens but once, for example after cholecystectomy, the loss of 50 ml. of bile in a human being (or 5-10 ml. in dogs), which is equivalent to the
* It is, however, extremely improbable that so-called inflammation in the gall-bladder is even bacterial in primary origin. The bacterial theory for this has never been satisfactorily explained. (Haler.)
22 THE LIVER
capacity of the gall-bladder, is of no importance to bile metabolism.
The liver is supplied from the portal system with sufficient haemoglobin for the formation of bile. The whole amount of bile produced by the liver enters the intestine, and, after a
loss of about one-tenth, is reabsorbed, and again carried to the liver via the portal system. After removal of the gall-bladder the intestinal mucosa takes over this function. Constant inflow of bile into the storehouse is a stimulus for reabsorption by the gall-bladder. Once the continuous inflow of bile into the storehouse has been stopped by ligature of the cystic duct, this stimulus ceases to have effect. Therefore such experi­ ments cannot lead to valid conclusions concerning the rate of absorption under physiological or pathological conditions.
In human so-called cholecystitis, completely different conditions prevail in comparison with experiments on animals after ligature of the cystic duct, because in cholecystitis this remains open.
After ligature of the cystic duct, the entero-hepatic circula­ tion of bile is, at one stroke, deprived of its reservoir. It is doubtful whether we can achieve a real picture of the function of this reservoir by experiments on dogs. Probably only the surgeon, constantly watching the results of his work on human beings, will be able to solve these problems of human physiology and pathology ; that is, if in the future he becomes a research worker and does not remain a technician only.
Until recently reabsorption of bilirubin from the gall­ bladder has been denied. Reabsorption of bilirubin by the mucous membrane of the gall-bladder was at first denied by von Bergmann and his pupil (Gassman) ; later (1931) they confirmed Blond’s view, but with the reservation that ” although bilirubin reabsorption occurs in the storehouse, it is never to such a degree as e.g. Blond supposes
The results of Einhorn’s duodenal tube test entirely upset a certain group of German research workers. It had been stated that, even after cholecystectomy, the so-called ‘ Β ‘ bile (supposed to come from the gall-bladder) could be produced by using Einhorn’s tube. Thus a new theory had to be produced to explain the contradiction. Von Bergmann
EXTRAHEPATIC BILE-DUCTS 23
and his workers tried to produce an explanation within a short time. ” T h e common bile-duct gets the ‘ vicarious power ‘ to concentrate the * A ‘ bile (supposed to come from the liver-cells). But it is well known that the bile-ducts do not possess a mucous membrane capable of absorption.” Soon von Bergmannes pupil, Westphal, knew the explanation.
The mucous membrane of the common bile-duct after re­ moval of the bladder simply develops similar villi to those of the intestine.” His co-worker, Mann, could prove the truth of Westphal’s views by producing the necessary specimens.
In spite of all such proofs, colic following cholecystectomies still had to be explained. Another pupil of the same school, Leutkens, discovered a new, and so far unknown, sphincter between the neck of the gall-bladder and the cystic duct.
According to the American pathologist Halpert, such a coUum-cysticus sphincter does not exist. Halpert did, how­ ever, still believe in the function of Oddi’s sphincter. Experi­ mental evidence, which will be discussed later, seems to us to rule out the existence of such a sphincter, because the influx of bile into the storehouse is regulated by the absorptive power of the gall-bladder and the pressure of bile being excreted from the liver. The pressure of bile secretion from the liver is higher than the muscle tone of the duodenum at the time of metabolism. As we shall be able to understand later, the pressure in the efferent bile-duct depends on the pressure in the aflFerent vessel, the portal vein {see Chapter I).
Fluids may be injected into the human gall-bladder, to a degree of distension exceeding the normal capacity of the organ, before Heister’s valve starts to leak. The main function of the thin muscle-layer of the gall-bladder is solely to counter­ act such an over-distension.
Assuming that rapid absorption of water and salts only occurs in the gall-bladder, it ought to be emphasized that, in spite of absorption by the storehouse, the constant flow of bile from the liver is not interrupted. Such a function can only be explained by presuming that bile is sucked into the storehouse from the extrahepatic ducts, as the internal pressure in the storehouse decreases by absorption. The pressure in the common bile-duct increases as a result of liver secretion.
24 THE LIVER
The gall-bladder, therefore, represents a kind of suction pump. As bile is concentrated in the gall-bladder a simul­ taneous dilution is caused by the aspiration of fresh bile from the extrahepatic ducts and from the liver. It has been gener­ ally accepted that the gall-bladder concentrates bile coming from the liver, but, so far, no satisfactory explanation has been given as to how such a concentration is possible, seeing that diluted bile constantly flows in from the liver, and that concentrated bile is expelled. In addition, the following facts must be taken into account. Comparing a section (plain cut) between the hepatic veins and the portal vein leads to the conclusion that the amount of blood which passes the portal vein is much larger than that which leaves the liver by the hepatic veins and enters the general circulation.
Molitor and E. P. Pick, using dogs for their experiments, studied the water diuresis of hepatic origin by performing an anastomosis between the inferior caval vein and the portal vein (Eck’s fistula). After 50-60 minutes a normal dog begins to excrete water taken by mouth. Diuresis begins after 20-30 minutes in dogs with Eck’s fistula. The liver in a healthy dog excretes water only slowly into the general circulation. According to Molitor and Pick, a healthy dog stores part of the water intake in the liver. It seems more likely, however, that the greatest amount of the water is excreted as bile into the entero-hepatic circulation. T h e red blood-count in a healthy dog decreases slowly by about 500,000-1,000,000 per c.mm. after intake of water; the decrease is about 2,000,000 per c.mm. in a dog with Eck’s fistula. It is believed by some authors (Array and Simmonds, JaflFe) that a kind of sphincter within the hepatic veins regulates water diuresis from the liver. But, as before mentioned, con­ siderable amounts of water are kept back in the entero-hepatic circulation to be used as a solvent of bile-salts and acids, whereas only a small proportion of water passes through the liver and enters the general circulation. There is no need to assume the existence of a hypothetical sphincter in the veins. An amount of bile fluid equal to the whole amount of blood in the general circulation constantly circulates through liver.
EXTRAHEPATIC BILE-DUCTS 25
extrahepatic bile-ducts, the gall-bladder, and in the intestinal villi—in the entero-hepatic circulation.
In considering the potentialities of absorption shown by the mucous membrane of the gall-bladder, it would seem that all experiments based on the fistula of the gall-bladder method to ascertain the amount of bile produced by the liver are at fault, and therefore misleading, because they overlook the quantity of fluids reabsorbed by the storehouse and circulating between the liver and intestinal mucosa.
The method of draining bile from the storehouse outwards is even more misleading, since Rosenthal and Licht were able to prove a rapid increase in reabsorption of bile acids once the mucous membrane of the gall-bladder had become inflamed as a result of irritation. A person with a healthy liver begins secretion of 2 ml. of a i per cent indigocarmine solution after 15-45 niinutes. In cases of liver dysfunction, the secretion of such a dye does not take place, or, if it does occur, more than 30 minutes elapse before secretion begins.
After total extirpation of the duodenum in dogs, and after transplantation of the papilla of Vater into the jejunum, a constant flow of bile from the papilla can be observed ; the bile trickles regularly, drop by drop (Blond). It is important to avoid over-distension of the gall-bladder when such experi­ ments are being made. By introducing two injection needles through the liver parenchyma (thus sealing the puncture in the gall-bladder), the same amount of bile should be removed before the dye (indigocarmine) is injected in such experiments to avoid over-distension of the gall-bladder.
In spite of the papilla being patent (because sympathetic nerves have been cut), no dye comes from the storehouse during the time of observation. No change can be noted after injection of pituitary extract or intake of magnesium sulphate.
As the portal blood carries polypeptides, fats, sugar, haemo­ globin, bile, insulin, etc., to the liver cells, no other stimuli for bile secretion and reabsorption are necessary to regulate bile pressure. As long as the liver cells are not poisoned by toxins, secretion and reabsorption are in a state of balance. Any disturbance of the physiological balance leads to disorder and disease of the organs drained by the portal system.

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