A review of the recent advances in the knowledge of the pathology of the liver and their clinical application

A REVIEW

OF THE RECENT

ADVANCES

PATHOLOGY

IN THE KNOWLEDGE

OF THE

OF THE LIVER

AND THEIR CLINICAL

APPLICATION

FERDINAND C. HELWIG, M.D. KANSASCITY, MO. URING the past ten years, gigantic strides have been made in advancing our knowIedge of the anatomy, physioIogy and pathology of the Iiver. There has been no subiect during this period which has received more attention nor about which more has been written. manifestIy impossibIe It is, therefore, to give more than a sketchy outhne of the more important contributions which seem to have some bearing on actuaI cIinica1 probIems. The morphoIogic variations produced in the Iiver by disease are we11 known, but in many instances their pathogensis is IittIe understood. However, recent studies of the structure and function, as appIied to actua1 perverted anatomy, are daiIy bearing fruit; and many diseases, whose expIanation was previousIy enigmatic, are graduahy being cIarified.

D

ANATOMICALADVANCES StructuraIIy speaking, the Iiver is a reIativeIy simpIe organ ahhough it has many unusua1 features. Aside from the entire mass of skeIeta1 muscIe, the Iiver comprises the Iargest singIe homogeneous tissue in the body. Another characteristic possessed by no other organ in the body is the unique double bIood suppIy of the liver; nameIy, the porta bIood suppIy from the intestines, stomach and spIeen, and the arteria1 bIood suppIy from the hepatic arteries. The porta bIood flow is controIIed IargeIy by nerves outside the Iiver; hence, the Iatter has no direct inffuence over the quantity of bIood entering it, which fact may be of considerabIe cIinica1 importance in certain pathoIogica1 aIterations in the Iiver. l

The cehular anatomy of the Iiver is simpIe in the extreme. OnIy three types of ceIIs are present: the parenchymatous or Iiver ceIIs, the ceIIs of the biIe ducts, and the stehate ceIIs of Kupffer which Iine the Iiver sinusoids. AI1 of these ceIIs are arranged into IobuIes of which two distinct varieties are recognized; namely, the “centra1 vein” IobuIe and the “porta space” IobuIe. In the former, the centraI vein forms the center of the IobuIe, and the porta spaces, which are composed of connective tissue in which are embedded the porta vein, hepatic artery and biIe duct, form the periphery of the IobuIe. In the Iatter type of IobuIe, the “porta space ” forms the center of the IobuIe and the centra1 veins form the periphery. Some of the recent advances which have an important bearing upon diseases of the Iiver have been made through investigations of the anatomy of heaIthy and diseased Iivers. McIndoe and CounseIIor2 injected the biIiary tree, porta system and hepatic arteries with ceIIoidin, digested out the parenchymatous tissue and thus obtained cases of the bIood and biIe systems. Their work has demonstrated that the Iiver has a biIatera1 nature which may be of significance in expIaining the pathogenesis of certain Iesions confined to one or the other haIf of the Iiver. These investigators, by their models thus prepared, showed that the right and Ieft branches of the porta vein remain separate and do not anastomose at aI1. This fact hoIds true, Iikewise, for the right and Ieft bile ducts and the hepatic arteries. The previous conception of the gross anatomy of the Iiver Iobes had to be revised. The oId division of right and Ieft Iobes divided by

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the faIciform Iigament does not hoId true, but now we fee1 that the Iine which divides the right and Ieft haIves of the Iiver is one drawn from the fossa of the gaI1 bIadder to the point of entrance of the hepatic vein into the inferior vena cava. McIndoe and CounseIIor,2 by their injection experiments, Iikewise demonstrated the extent of restriction of the porta circuIation in cirrhosis of the Iiver, which studies are of great importance from the standpoint of their bearing on coIIatera1 circuIation. Their preparations proved that the hepatic ceIIs were aImost compIeteIy removed from the porta bIood. In the norma Iiver preparations, it was seen that the space reIations between the portal spaces and the centra1 vein were just one-haIf the diameter of the IobuIe, but in the Iivers in which atrophic cirrhosis was present, it was found that the reIation of the IobuIe was compIeteIy distorted and the two vascuIar systems tended to Iie together, “assuming a basket-Iike arrangement.” The regenerated noduIes of liver parenchyma were found to contain no venous suppIy, which fact may have some bearing upon the question of ascites without liver insufficiency. In the Iivers of cases of obstructive jaundice which were injected, an aImost unbeIievabIe diIatation of the biIiary tree was seen. This enormous dilatation must unquestionabIy have some bearing on certain functiona changes encountered in obstructive jaundice. Moreover, a marked intertwining of the porta and biliary systems was Iikewise seen, which fact may heIp to cIarify the pathogenesis of certain mixed types of cirrhosis.2 Another interesting and remarkabIe piece of research work which seems to have clinica appIication was done by Copher and Dick,3 who observed what they caIIed “ stream Iines ” in the fIowing bIood of the portal vein. They showed that there were three such stream Iines, which Iines corresponded to the*organs from which the bIood flows. First, the porta bIood, coIIected from the stomach and spIeen, is found to pass to the Ieft Iobe of the Iiver;

Pathology whiIe the second stream, or that bIood coIIected from the upper part of the duodenum, head of the pancreas and jejunum, passed to the right Iobe; and the third stream, whose bIood arose from the coIon, was distributed to a11 parts of the liver, more particuIarIy to the Ieft Iobe. Moreover, they found that there w-as IittIe OI no intermingIing of these three streams. Copher and Dick made their experiments by injecting trypan bIue into the different dista1 ramifications of the porta vein and by means of strong transiIIumination they were abIe to observe where this dye was carried. When the liver was Iater removed, it was found that that part of the Iiver to which the bIood flowed was deepIy stained by the dye. PHYSIOLOGICAL

AND

CHEMICAL

PATHOLOGY

Function: For many years, this great organ, the Iiver, was thought of as one which excreted biIe, stored glycogen, and acted as a sort of a fiIter for a11 kinds of poisons brought in by the porta bIood. Manv other hazy functions or pseudofunctions were aIso ascribed to it, but accurate knowIedge was extremeIy Iimited. To Mann,4 of the Mayo CIinic, we owe a great debt, not onIy because he is one of the foremost investigators of Iiver physioIogy but because he has aroused an unusual genera1 interest in this organ. Total Removal of Liver: Mann saw that one way to get an insight into the function of the Iiver was to remove it compIeteIy and see what happened. This, of course, had been tried many times previousIy, but had aIways presented tremenduous technica diffIcuIties. PreviousIy, a11 the work had been carried out with so-caIIed “acute experiments”; that is, animaIs under anesthesia which did not recover. Moreover, previous investigators had been forced to remove so much other functioning anatomy that no data of great vaIue had been obtained prior to Mann’s work. By an extremeIy ingenious though simpIe method, Mann overcame these pre\-ious diffIcaIties

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in compIete Iiver extirpation by simpIy performing a so-caIIed reverse Eck f%tuIa. He then waited for coIIatera1 circuIation to be estabIished, and then compIeteIy removed the Iiver. He found that the animaIs (dogs) recovered quickIy from the operation, and he was thus abIe to observe their actions as had never before been done. In about an hour, these animaIs appeared aImost normaI. They wouId even eat, take an interest in their surroundings, and appeared in every way simiIar to other dogs. This condition, however, did not Iast very Iong for symptoms of Iiver deficiency soon appeared. We can do no better than to quote Dr. Mann who makes the foIIowing interesting cIinica1 observation of these IiverIess animaIs : The first symptom noted is muscuIar weakness; the animaI can not hoId itseIf erect or avoid swaying when waIking, and prefers to Iie down. The muscuIar weakness deveIops quickIy and in a short time the anima1 is unabIe to move any of his muscIes except those necessary for respiration. Coincident with this deveIopment of muscuIar weakness is a decrease in and subsequent Ioss of reflexes. UsuaIIy within an hour after evidence of muscuIar weakness is first noted, the anima1 Iies quietIy breathing with muscIes flaccid and reIaxed. This period of fIaccidity may be short, but rareIy it may Iast for severa hours. After a variabIe period, usuaIIy not more than an hour, there is a rather sudden return and exaggeration of the reffexes, muscuIar twitchings appear, first invoIving separate muscIes or smaI1 groups of muscIes, then genera1 convuIsions occur in one of which the anima1 dies. In typica experiments, the animaI vomits a few seconds before death. The average anima1 dies within two hours aft& the first appearance of muscuIar weakness. Mann aIso observed that certain changes invariabIy occurred in the urine and bIood

of dehepatized animaIs. In the bIood, there was a progressive decrease in sugar, the appearance and progressive increase of a pigment, the progressive increase in uric acid, and the characteristic changes noted in the urine were the appearance of a heavy fIoccuIence ar,d of a yeIIow pigment.

PathoIogy Sugar Metabolism in Total Hepatectomy: Mann then investigated the cause of the symptoms noted above and made many thriIIing observations. As regards the hypogIycemia, it was found that there was aIways a decrease in bIood sugar after tota remova of the Iiver and, after convuIsions set in, the bIood sugar feI1 very rapidIy and one of the most constant and remarkabIe facts was the direct reIationship between the bIood sugar IeveI and the cIinica1 symptoms. Mann then suppIied sugar to these dying animaIs in the form of intravenous gIucose, and he was abIe, by so doing, to compIeteIy restore the dying anima1 to a norma condition. These animaIs, which just before receiving sugar were comatose and “unabIe to contract any muscIes but those of respiration,” wouId, within a haIf minute after the sugar injections, starid up and even waIk about, wag their taiIs and drink water. If the animaIs were permitted to have convuIsions, which in the untreated animaIs were aIways foIIowed by death, the resuIts of intravenous sugar injections were even more spectacuIar. The convuIsions wouId cease as if by magic and the animaIs wouId rise and waIk about normaIIy. It was even possibIe to Iet the heart stop beating, and give the anima1 artificia1 respiration and then an injection of sugar. Mann IiteraIIy recaIIed such an anima1 from death. After using up the injected sugar, the dogs wouId again Iapse into the same state of hypogIycemia from which they couId be restored numerous times, aIthough the same amount of sugar did not suffice with the ensuing attacks, and soon the characteristic symptoms of sugar deficiency began to appear at higher bIood sugar IeveIs. At Iast, after numerous revivaIs, the animaIs wouId reach the stage where sugar injections were of no avai1. They became restIess, vomited, breathed with diffIcuIty, couId neither see nor hear and, finaIIy, Iapsed into u&onsciousness and died a sIow quiet death which was usuaIIy preceded by anuria. Sugar did not aIter the course of this set of symptoms but it

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was necessary to keep up the injections in order to prevent death from hypogIycemia. Sugar couId be given by mouth or rectum, at intervaIs or continuousIy, with the same resuIts as those obtained by repeated or continuous intravenous administration. When the pancreas was removed in a dog, the anima1 deveIoped a high bIood sugar and died in severa days with hypergIycemia. Now, if the pancreas was removed at the same time as the Iiver, there was no difference observed from those animaIs where the Iiver aIone was removed. If the pancreas was removed at some prior time and hypergIycemia was present, when this excess sugar was used up the dog deveIoped the same characteristic hypogIycemic symptoms as if the Iiver aIone had been removed. Those experiments proved that the Iiver aIone was responsibIe for the maintenance of the bIood sugar IeveI, even in the hypergIycemia of diabetes. Mann aIso observed that gIycogen was decreased in the development of hypoglycemia in the IiverIess dog, but no matter how much gIycogen was present in the muscIes it in no way influenced the deveIopment of symptoms of hypogIycemia since it evidentIy couId not be utiIized for maintenance of bIood sugar IeveI and never Ieft the muscIe as bIood sugar but was utiIized by the muscIe and changed into Iactic acid in situ. Hence, it was apparent that the Iiver gIycogen aIone comprised and was present as the bIood and muscIe gIycogen was not sugar, utiIizabIe. He showed that there couId be more than sufficient gIycogen in the muscle to maintain even a hypergIycemia for a Iong time, yet the anima1 wouId deveIop its characteristic hypogIycemia and typical accompanying symptoms Iike an anima1 with IittIe stored muscIe gIycogen. Alann aIso investigated many substances in connection with the bIood sugar IeveI, but of most importance was insuIin. Since both hepatectomy and insuIin injections produce a hypogIycemia, and both are accompanied by CharacteristicaIIy identica1

PathoIogJ

Americ;rn Jo,,rr>:dof Suraery

4%

symptoms, Mann wondered what the effect of insuIin wouId be in the hepatectomized dog. He found that insuIin mereIy acted as if the Iiver were present; nameIy, it caused a rapid deveIopment of hypogIycemia, and the onIy difference between dogs with and without Iivers was that insulin caused hypogIycemia much more quickIy in the Iatter case than in dogs with intact Iivers. The symptoms of hypogIycemia in the IiverIess dog which was given insuIin were the same as if insuIin had not been administered. Giucose produced the same response as if insuIin had not been given. Hence, he concIuded that: AIthough the Iiver is not necessary for the production of the hrpogIycemic action of insulin, it is absoluteIy necessary for a permanent recovery of the blood sugar Ievel, and this did not mean that the liver pIayed no part in the production of the hypogIycemia of insuIin. However, the fact that the liver is essentia1 for the restoration of the norma bIood sugar IeveI proved that the liver is affected either directIy or indirectIy by the ins&n. Protein Metabolism in Total Hepatectomy: The question of protein metabolism

was next studied. In catabolism, protein is broken up into aminoacids and these have been the subject of many experiments. Mann showed that the Iiver is probabIy the soIe source of urea formation, since in the IiverIess dog he noted a striking and progressive decrease of urea in the urine, and in a few hours scarceIy any was present in the bIood, urine or tissues. If he took out the dog’s kidneys at the time he removed the Iiver, the urea content of the bIood remained the same throughout and showed no increase. If the kidneys were removed before taking out the Iiver, there was an increase in bIood urea and after hepatectomy this high IeveI was maintained but not accentuated in the Ieast. Mann aIso noted a marked increase in aminoacids in the bIood when the Iiver was absent and no sphtting of the amino-

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acids into nitrogen with urea formation. Hence, it seems to be definiteIy proved that both urea formation and deamidization of aminoacids are functions of the Iiver. Creatine and ammonia formation did not seem to be materiaIIy affected by Iiver extirpation. The protein metaboIism experiments have Ied to a test for Iiver function. In Leipzig, according to SneII,5 the foIIowing is used as a test for hepatic activity: 50 gm. of geIatine are administered to a patient and, during the next two periods of four hours each, the urine is examined for aminoacids. At Ieast 200 mg. of aminoacid are found to be present in the urine of patients with diseased Iivers after the first period of four hours, and in the earIier specimns a marked decrease in output is found. Mann showed that in the dog, uric acid destruction depends entireIy on the Iiver. He noted an excretion of as much as 1500 mg. in twenty-four hours in some of his animals. UnfortunateIy, this substance has littIe cIinica1 significance in the human. Bile Studies in Total Hepatectomy: BiIe is another substance which for many years has been the subject of heated controversy. Naunyn and Minkowsk? many years ago, when experimenting with geese, removed the Iiver and then poisoned these birds by injecting arseniuretted hydrogen which is a powerfu1 hemoIysing agent, and were unabIe to observe any biIe formation. From this work arose the oId dictum, “Without the Iiver, no jaundice.” However, this did not expIain such jaundice as is seen in hemoIytic icterus, and some other conditions where no reIative Iiver damage or biIiary obstruction can be demonstrated. About eighteen years ago McNee,? working in Aschoff’s Iaboratory in Freiburg, repeated Naunyn’s and Minkowski’s experiments and aIso destroyed dogs’ Iivers with specific poisons. He noted that the steIIate ceIIs of Kupffer were Ioaded with biIe pigment. After much investigation, he was Ied to beheve that the biIe pigments were manufactured in or by the

PathoIogy endotheIia1 reticuIar ceIIs, and he overcame the arguments of Naunyn and Minkowski in regard to jaundice being caused onIy by the Iiver by showing that in the goose most of the endotheIia1 reticuIar ceIIs are in the Iiver. As a resuIt of this investigation, there has been an enormous amount of work done on this subject. In such investigations, the names of WhippIe and Hooper,8 ArnoId Rich,g and McNee are outstanding. Many contradictory experiments foIIowed these observations of McNee and then Mann started his experiments with reference to biIe production. He injected hemogIobin intravenousIy into IiverIess animaIs. The spIeen was removed both before and after the Iiver was removed and, in another set of animaIs, a11 the abdomina1 organs as weI1. He noted that in the IiverIess dog, biIe was readiIy produced and increased progressiveIy, which was aIso true in the dehepatized, spIeenIess anima1. It was necessary to prove that squeezing the Iiver at the time of operation did not cause biIe to ffow into the circuIation, but since none was encountered in the pIasma of the IiverIess anima1 immediateIy after operation, the possibihty of squeezing biIe into the circuIation evidentIy was not a factor. Mann aIso showed by removing the gastrointestina1 tract aIong with the Iiver that biIe was not absorbed from the intestine when a progressive increase in the pigment in the pIasma was obtained in dogs prepared in this manner. The amount of biIe present in the bIood was too Iarge for any other viscera to hoId or manufacture after the spIeen and gastrointestina1 tract had been eIiminated. Hence, it was concIuded that there must be some extraabdomina1 origin of biIe, and this Iocation was found to be the bone marrow. AIthough the Kupffer ceIIs of the Iiver may make some biIe pigment, it is defmiteIy proved that the bone marrow is the main important site of its formation. Among other biIe constituents beside pigment, choIestero1 and biIe saIts were

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investigated. As to the choIestero1, it was not proved to be manufactured in the Iiver. AIthough the Iiver excretes it in the bile, its origin is stiI1 hazy. The origin of biIe salts is Iikewise stiI1 unsolved. There is some evidence to show, however, that the salts may be manufactured in the Iiver. One investigator, Forsgren,‘O noted acidophiIe granules in the hepatic ceIIs near the periphery of the IobuIe which he thought were biIe saIts. Greene and SneII’l found a rapid and marked increase in bile acids in the bIood in obstructive jaundice. This is accompanied, of course, by bilirubin retention, as we11 as retention of dyes. The animals recovered from a11 of these retentions, except in their abiIity to excrete dyes. The cIinica1 importance of dye retention is, therefore, considerabIe. The relationship of biIe acid retention to the slow puIse, itching, and sIow bIood cIotting is important since, contrary to the older teachings, it has been shown that the increase in biIe acids in the bIood has no such reIationship. Instances of hemorrhage and deIayed coaguIation have frequentIy been observed where the biIe acid IeveI had returned to normaI. The consideration of bile pigments in their reIationship to the liver are of enormous importance to the clinician from the standpoint of diagnosis, and everyone now uses the Van den Bergh test to estimate the origin of jaundice. There is no doubt that the direct reaction depends on the hepatic activity which can be proved by mere Iigation of the common duct and the appearance of a quantitative increase of biIirubin in the serum. Mann removed the Iivers of these dogs with Iigated common ducts after a few hours, and he noted the same progressive increase in biie pigments in the bIood; but, instead of giving the direct reaction, a11 of the bile that accumuIated after hepatectomy gave the indirect reaction. This observation is of tremendous cIinica1 importance although its physioIogica1 significance is stiI1 obscure.

PathoIogy

American

Journal
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Detoxijying Action of the Liver: The Iiver as a detoxifying agent has been carefuIIy studied. Drinker and Shaw” showed that in the Iiver the stellate ceIIs of Kupffer remove foreign particles from the bIood stream. FIexner and Sweet’” found that the Iiver excreted the toxins of dysentery, mercury and ricin in the bile and it is probabIy true that many of the heavy metals are strained out of the bIood and eIiminated in this manner. Mann noted that dogs whose Iivers had been removed couId not stand injections of phenol, benzoic acid, pheno1 tetrachIorphthaIein, and other substances which the norma could withstand, and the quantity ivhich had no effect on norma dogs kiIIed liveriess dogs. RecentIy, PriestIy, Markowitz and Mann’-’ have demonstrated that the Iiver possesses a highIy speciaIized abiIit\- immediateIy to arrest and subsequentlv to destroy strychnine, and at this time many experiments are being carried out with other substances. Fibrinogen Formation: The origin of fibrinogen has aIways been obscure, and many investigators have attacked the subject. The question of bIeeding in the jaundiced patient, slow cIotting of bIood in patients with a damaged liver, and similar questions are of great clinical importance. Mann has concluded, after much experimentation, that al1 the evidence for the liver being the site of formation of fibrinogen is not concIusive aIthough the most important fact of clinical importance is that injury or remova of the Iiver does actuaIIy7 affect the formation of a norma bIood cIot. Whether Iack of fibrinogen production is the most important factor in this case, however, is not dehniteIy decided. Brandes,‘” by mechanica constriction of the hepatic veins, noted a definite decrease in bfood coagulation time, ranging from 2j to -50 per cent during constriction which was folIowed by an increase on release. There was a sIight decrease in fibrinogen during constriction and an increase of 25 per cent or more on reIease.

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Partial Hepatectomy: AI1 of these foregoing experimenta works of Mann’s were performed on animaIs where the entire Iiver had been extirpated, but the question arises as to what happens when some functioning Iiver tissue remains. How much Iiver is needed to carry on Iife and what happens when Iarge quantities of the Iiver are removed? These are a11 matters of great importance. The first observation made after surgica1 remova of great portions of the Iiver was its stupendous power of regeneration. It has been shown that if 70 per cent of the functioning liver in a rat is removed, in four weeks the Iiver wiI1 be regenerated to norma size. Even if 83 per cent of the Iiver of a dog is surgicaIIy removed, the Iiver apparentIy can carry on reIativeIy norma function. AIthough its detoxifying functions are seriousIy impaired, the maintenance of the bIood sugar IeveI, formation of urea, and deaminization are not in the Ieast disturbed. Fat Metabolism: The roIe pIayed by the Iiver in fat metaboIism has aIso been the subject of considerabIe study. Wendt16 records a marked disturbance of fat resorption in cirrhosis. Biirger and Habsl’ noted and absence of Iipemia in a patient with atrophic cirrhosis, who had been given Iarge doses of oIive oi1 and choIestero1. ‘This administration aIways produced Iipemia in norma individua1.s. They aIso noticed such an absence of Iipemia in any person with extensive porta stasis. EImer and Scheps,18 however, did not find this dependabIe. Wendt Iikewise observed in patients with severe icterus that there was a diminution of choIestero1 esters in the pIasma. Cassanolg found a marked disturbance of fat metaboIism in liver disease. There is an increase in fatty acids in the bIood, indicating an increase in neutra1 fats and a decrease in phosphatids. Cassano feIt that the fatty acids were partIy bound with choIesteroI forming choIestero1 esters. Drury and McMaster,20 on the other hand, found that fat combustion is carried on ade-

PathoIogy quateIy in animaIs deprived of their Iivers, or those with extreme Iiver insuffIciency. They observed no change in fat combustion as Iate as twenty-four hours after compIete hepatectomy, and they beIieve that the Iiver pIayed no essentia1 part in the breaking down of fat. Derman and Leites2’ found by feeding experiments and chemica1 studies that the Iiver pIayed an active part in Iipoid metaboIism. They thought that metaboIites may be buiIt up into other fats and Iipoids. An actua1 infiItration of anistrophic fat into the Iiver can be accompIished by injecting chIoroform and feeding choIestero1. Whether this proves anything of importance is, however, yet to be demonstrated. Of cIinica1 importance is the function test. The choIestero1 function test is the test empIoyed by Manckez2 who observed that there was a marked increase of choIestero1 in the bIood in obstructive jaundice of Iong duration; but in the toxic or infectious types of icterus, the choIestero1 may be norma whiIe the esters of choIesteroI are found to be greatIy decreased. Hepatic Poisons and Cirrhosis: Many studies have been carried out by the use of hepatic poisons. Of these, carbontetrachIoride has recentIy been used extensiveIy. The dosage of the drug can be so reguIated as to produce a Iiver cirrhosis cIoseIy simuIating that found in man. Such cirrhosis is the basis of many current experiments of interest. Obstruction to the outflow of biIe is a time-honored experimenta procedure. Some remarkabIe experiments were performed at the Mayo CIinic. It was found that the animaIs so treated, which usuaIIy died after a few weeks, couId be kept aIive for many months by mereIy reguIating their diet. They were given a diet high in carbohydrate, whiIe the feeding of meat usuaIIy kiIIed them. Some of these animaIs with biIiary obstruction were fed biIe in an attempt to stimuIate biIe secretion, and it was observed that cirrhosis was more marked in these animaIs than in those not fed the biIe. Ascites was an interesting compIication which deveIoped in some of the

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dogs maintained on carefuI diet for a period of months. It was shown by BoIImanz3 that in some of the animaIs ascites couId be brought on quite suddenIy by feeding a meat diet. Functional and Clinical Tests: Tests for Iiver function have been tried and discarded over and over, and there is more discord on this subject than on aImost any other functiona test. We have aIready discussed the aminoacid test, tests with the administration of biIe acids, and the Van den Bergh and choIestero1 tests. The dye tests have a11 been the subject of considerabIe controversy, aIthough in some conditions they may prove usefu1. The two dye tests being most used are the phenoItetrachIorphthaIein and the bromsuIphaIein. Graham and CoIe24 now are using phenoItetraiodophthaIein iisoidokon) which is good not onIy for gaII-bIadder visuaIization but aIso imparts a purpIe stain to the serum after it has been sIightIy aIkaIinized. A dose of about 2.3 gm. to the average aduIt is used and it is beIieved that this method of estimating the excretory function is of great benefit in determining the operative risk. Moreover, these men beIieve that shouId Iarger doses of the bromsuIphaIein or phenoItetrachIorphthaIein be used, equaIIy good resuIts couId be obtained with these two dyes. The gaIactose test of Iiver function is advanced by some as being very usefu1. The principIe of this test is that gaIactose is stored immediateIy by the undamaged Iiver, but in a diseased Iiver it wiI1 not be stored. Forty grams are given by mouth to the fasting patient, and the urine and bIood are studied for a period of two hours afterward. If more than 3 gm. is excreted in the urine, or if there is a rise in bIood sugar of over 30 mg. per IOO c.c., the Iiver is thought to be definiteIy damaged. It is said to give uniformIy positive resuIts in cases of intrahepatic icterus, and is usuaIIy not positive in obstructing jaundice. In addition to tests, SneI125 mentions a new method now being empIoyed at Leipzig where patients with hepatic disease are studied with a laparoscope. The

PathoIogy Iaparoscope is a modification of Jacoben’s thoracoscope and is used to study obscure ascites. It is possible to insert this instrument into the paracentesis incision after evacuation of the fluid and make a direct inspection of the Iiver and peritoneum. Therapeutic Suggestions: The therapeutic appIication of many of the foregoing chemica1, physioIogic and pathologic observations and many experiments has had and wiI1 have far-reaching significance. BoIImanz6 has shown that the Iiver is Iess apt to be damaged by chIoroform and other hepatic poisons when it is we11 fiIIed with gIycogen, and that in the diseased Iiver the gIycogen content is Iowered. Most of the common anesthetics cause an increase in bIood sugar at the expense of Iiver sugar. The cIinica1 appIication is apparent where the question of preoperative treatment and diet are of utmost importance. Ravdin2’ thinks that morphine shouId not be given in cases where there is a disease of the Iiver, because of its tendency to produce hypergIycemia and depIete the Iiver gIycogen. BoIIman and his co-workers have aIso shown that the detoxifying action of the Iiver is enhanced when it is fIIIed with gIycogen. A high diet of carbohydrate shouId be considered in a11 cases of preoperative preparation of patients with diseased Iivers. EIimination of proteins may be indicated in cases of cirrhosis and caIcium shouId be administered to the patient, with or without jaundice, who is suspected of having Iiver damage, or in whom such a possibiIity may transpire. Lamson, MinotZh and Robbins have shown in experimenta Iiver damage with carbon tetrachIoride that repair is greatIy speeded up by caIcium administration. SneII,23 reporting from t.he pharmacoIogica1 cIinic in Vienna, states that extensive experiments are now being carried on regarding the reIation of the Iiver to water metaboIism. Here it is feIt that the Iiver contains some hormone which stimuIates diuresis. These investigations are particuIarIy appIicabIe in cases of cirrhosis,

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and these workers are trying to prepare an active extract from the Iiver which has a diuretic action. CO-RELATIONSHIPS

WITH

OTHER

ORGANS

AI1 of the previous data which have been reviewed has deaIt aImost excIusiveIy with the Iiver and its diseases aIone, and has not taken into consideration its remote pathoIogic and cIinica1 reIationships. It was noted that the bone marrow manufactured the biIe pigment, that the portal blood from various areas had certain pecuIiar areas of distribution, that spIenectomy and even remova of the gastrointestina1 tract had IittIe effect on biIe production, and we have discussed the question of the pancreas and Iiver in sugar metaboIism. But in addition to these functiona reIationships aIready Iisted, others of a fairIy definite character have aIso been noted as seeming to exist between the Iiver and other organs. There is some reIation which is present in Banti’s disease between the spIeen and Iiver ; and in atrophic cirrhosis, aIso, a certain reIationship of a rather constant character is observed. Many theories have been propounded regarding the frequent concomitant changes seen in the spIeen and Iiver in these two conditions, as we11 as in some others, and on this basis a new treatment was suggested for the ascites of atrophic cirrhosis, nameIy spIenectomy. As was previousIy mentioned, the work of Copher and Dick showed a definite physioIogicaIanatomica basis for inter-reIationship between the pancreas, Iiver, spIeen and the bowe1. Reineck29 has shown an apparent inter-reIationship between the suprarenaIs and the Iiver. In his experiments in proIonged choIestero1 feeding, he noted that there was an apparent reguIatory function of choIestero1 metabohsm in the adrenaIs, and that the Iiver acted as a secondary storage depot. The use of Iiver extract in pernicious anemia has caIIed forth much specuIation about the reIationship between the bIood formation and the Iiver. WhippIe thinks

PathoIogy that there is an increase in iron pigment in the form of hemogIobin in the body in cases of pernicious anemia, and he beIieves that the red ceIIs are deficient in some constituents of their stroma, which deficiency is suppIied by the Iiver. Therefore, since there is a superabundance of hemogIobin in these cases, the immediate formation of red ceIIs takes pIace with the suppIying of these Iiver constituents. Feeding of Iiver extract seems to cause the immature red celIs of the marrow to mature rapidly. Simmons, Becker and McCoIIum31 have apparentIy demonstrated that vitamin E is essentiaI to the assimiIation of iron; and, since both vitamin E and iron are abundant in fresh Iiver, it wouId seem that there is a possibiIity that pernicious anemia may be a nutritiona deficiency in which there is some interference in the proper formation of hemogIobin. T. Fahr,32 after a Iong series of experiments and necropsy studies, aIso concIuded that the anemia couId not be due to a toxic factor acting on the bIood and that Iiver feeding was mereIy suppIying a vitamin deficiency as in vitamin feeding reaction in persons with scurvy. RecentIy, West and Howe33 have isoIated, from purified Iiver extract, the crystaIIine saIt of an acid which is effective in producing the remissions of pernicious anemia and anaIysis of this substance indicates that the acid may be betahydroxygIutanic acid. This probIem may not be entireIy settIed but there does seem to be defmite reIationship existing between the Iiver and bone marrow in pernicious anemia. In 1924, AIIen, Bowie, MacLeod and Robinson34 of Toronto were observing depancreatized dogs that had been kept aIive with insulin for the purpose of measuring their gIucose equivaIent. They found that not infrequentIy such animaIs died after periods ranging from one to seven months. At necropsy, an extensive fatty degeneration of the Iiver was observed in these dogs. In spite of the insuIin injections, the animaIs died after showing some very interesting cIinica1

manifestations such as depression, apathy, anorexia and jaundice. BiIe pigments were found in the urine and a progressive oliguria was always present. Vomiting was frequent and diarrhea and blood in the stoo1 were often observed. In 1889, *Mehring and Minkowski”” had noted that animals that were partiaIIy depancreatized were greatIy benefited by adding raw pancreas to their diets. Since the advent of insuIin, it has been found that depancreatized animaIs faiIed to Iive more than about seven months at a maximum unIess raw pancreas was aIso added to their diets, even though the bIood sugar IeveI was controIIed by insuIin injections. In the expIanation of this phenomenon, it was thought that the pancreas contained an enzyme which was essentia1 for fat digestion. Penau and Simonet,3” however, were abIe to keep depancreatized animaIs ah\-e as Iong as two years with no raw pancreas in their diets. The resuIt of these Intter studies was to start an investigation to find the factor responsibIe for the maintenance of heaIth in these animaIs who were deprived of the raw pancreas feedings. Since, as was formerIy mentioned, these animaIs at times died with extensive fatt>- changes in the Iiver without other notable anatomic aIterations, it was considered probabIe that the Iiver might pIay an important roIe in fat metaboIism in these dogs. Some of Fisher’s37 depancreatized dogs that died were not given insulin in the Iast few days prior to their death because their urine had been sugar free and they died, not in diabetic coma but in hypogIycemic convuIsions. Hedon3s Iiken-ise observed in simiIar experiments which he was carrying out that when the feeding of raw pancreas was discontinued the dogs became very sensitive to insulin and it was necessary greatly to reduce the insuIin dosage in order to avoid Such physiodangerous hypogIycemia. IogicaI observations strongIy suggested an inabiIity of the Iiver to maintain a norma bIood sugar IeveI and the presence in these animaIs of a remarkabIy extensive

fatty metamorphosis would seem to indicate that the disturbance in fat metaboIism was possibIy responsibIe for the Iiver dysfunction. Most observers beIieve that the liver does pIay a Ieading roIe in desaturation of fats, thus preparing them for use in the body, and it is generaIIy conceded that the phosphoIipins are quite important factors in fat metaboIism. In an attempt to account for the disturbance in fat metabolism encountered in depancreatized dogs, Hershey and Soskin”” concIuded that it might be due to some faiIure in the desaturation of fats and, since the phosphoIipins were so important in fat metaboIism, it seemed to these workers that the Iiver deficiency might be due to an insufficiency of this substance. They, therefore, used Iecithin in the form of egg yoIk and were abIe, through feeding of this product, to keep depancreatized animaIs aIive indefiniteIy on a diet of Iean beef muscIe, cane sugar, insuIin and “egg yoIk Iecithin.” The cIinica1 appIication of this investigation is stiI1 uncertain, but I have observed in juveniIe diabetics, dying in coma, liver changes which are hIstoIogicaIIy indistinguishabIe from those obtained in the animals which were necropsied by AIIen, Bowie, MacLeod and Robinson. It seems to me that it might be interesting to try out egg yolk feeding in certain recarcitrant cases of juvenile diabetes wherein fat metaboIism is obviousIy disturbed. In concIusion, it may be of interest to mention some observations which have been made by Drs. Schutz, Kuhn, Orr and myseIf regarding a rather definite interreIationship which we have found to exist between the Iiver and kidney in hepatic disease. In a case of traumatic puIpification of the Iiver without rupture of the capsuIe,40 we observed the progressive deveropment of anuria with striking retention of bIood nitrogen. The patient died after eIeven days in a cIinica1 state of uremia, and at necropsy a high grade nephrosis and extensive mucous and serous surface bIeeding

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were observed. FoIIowing this case, we were impressed by a somewhat simiIar cIinica1 and pathoIogic picture observed in gaIIfour patients with Iong-standing bIadder disease. FoIIowing operation and varying periods of convaIescence (two to eight days), these individuaIs suddenIy deveIoped miId deIirium, an increase in puIse and temperature with abdomina1 distention and progressive oIiguria. The deIirium progressed to coma, the urinary output became even more scanty, hemorrhages occurred from the mucous membranes, particuIarIy the gastrointestina1 tract, and finaIIy the patients died in profound coma. Kidney function, bIood and urinary findings prior to operation had a11 been within normaI Iimits. In no instances were the patients jaundiced during their entire sickness. Necropsy examination in a11 of these cases reveaIed both inffammatory and degenerative changes in the Iiver of a marked degree. In every instance, the kidneys showed advanced degenerative tubuIar changes. The cIose simiIarity, both cIinicaIIy and pathoIogicaIIy, in a11 of these cases Ied us to the concIusion that we were deaIing with a definite cIinica1 and pathoIogic entity which, so far as we have been abIe to find, has heretofore not been described. Frequent aIIusions in the Iiterature to an inter-reIationship between the Iiver and kidney in disease have been made. CompIicating nephritis in common duct obstruction has often been observed, and biIe nephrosis is a weII-estabIished pathoIogic entity. Such investigators as FitzHugh,41 Zaffagnini,42 LeNoir,43 FurthwaengIer,d4 Narath,45 StaehIi,46 Haberer,47 Gunderman,48 WhippIe and Speed,4g Lederer,50 Barkers1 and others have noted co-existing Iiver and kidney Iesions, but have made no particuIar study of the mechanism or significance of this reIationship. The kidney Iesions seen in patients with Iiver damage in the pregnancy toxemias have been the subject of much specuIation and investigation by such authors as SchmorI,52 Ben-

PathoIogy

MARCH, 19%

ecke,53 Shriver and OerteI,54 and many others. Dieckman,55 after experimentaIIy producing the pathoIogic picture of ecIampsia in the Iivers of dogs by the injection of fibrinogen into the porta vein, observed typica ecIamptic kidney Iesions, and numerous other experimenta studies have been conducted which strongIy suggest a definite inter-reIationship between the Iiver and kidney. The afore-reIated observations stimuIated us in an attempt to reproduce this syndrome experimentaIIy.56 We were abIe to do this in part in animaIs by extensive crushing injuries to the Iiver and aIso by Iigation of the hepatic artery. UnfortunateIy, it was impossibIe exactIy to dupIicate the cIinica1 and pathoIogic picture as observed in the human subjects but the bIood chemica1 and urinary findings couId be reproduced at wiI1. At present, further studies are being carried out aIong these Iines. A detaiIed expIanation of the possibIe mechanism of this curious reIationship is impossibIe due to Iack of space. However, we beheve that there is some potent toxin eIaborated by damaged Iiver tissue which acts more or Iess specificaIIy on the kidney. The subject of so-caIIed “Iiver death” is one of greatest importance to surgeons doing operations on the biIe tract. Therefore, we beIieve that the recognition of this syndrome as a distinct and definite cIinica1 and pathoIogic entity is of some importance. Prevention of this condition may possibIy be brought about through carefu1 Iiver function tests and preoperative gIucose administration. The use of caIcium in the postoperative course may be heIpfu1 in hastening hepatic repair. In our cases, we found that the greatest degree of damage in the Iiver was in that portion surrounding the gaII-bIadder fossa and it was suggested by Mann5’ that suturing of the gaII-bladder fossa at operation might Iead to additiona Iiver necrosis, thus possibIy furnishing the necessary added toxic product to cause fata kidney damage.

NEW SERIES VOL. XIX, No. 3

HeIwig-Liver

We have observed severa patients who did not succumb after operation but did show some evidence of renaI impairment which was insuffrcient to resuIt in the profound uremic picture seen in our fata cases, and we beIieve that his syndrome, at Ieast in part, is a common accompaniment of gaII-bIadder surgery in the presence of a Iong-standing ChoIecystitis with concomitant hepatitis.

PathoIogy CONCLUSIONS

Some of the most outstanding advances in the study of the Iiver which seem to have some definite or potentia1 cIinica1 appIication have been reviewed, and a Iiver-kidney syndrome which we beIieve to be a not infrequent compIication foIIowing surgical procedures on the gaII-bIadder and biIe ducts is briefIy described.

REFERENCES I. 2.

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MANN, F. C. Medicine, 6: 375-5 I I, 1927 (excellent bibhography). SNELL, A. M. Proc. .%a$ Meetings Mayo Clin., 6: 406, 1931. MINKOWSKI, O., and NAUNYN, B. Arch. j. exper. Path. u. Pbarmakol., 21: I-33, 1866. 7. MCNEE, J. W. Quart. J. Med., 16: 3go-42o,Ig22-23. 8. WHIPPLE, G. II., and HOOPER, C. W. J. Exper. Med., 17: 593-611, 1913; also J. Exper. Med., 17: 612-635, 1913. 9, RICH, A. Bull. Johns Hopkins Hosp., 34: 321-329, 1923; also Bull. Jobns Hopkins Hosp., 36: 233-247. ‘925. IO. FORSGREN,E. Anat. Anz., 51: 309-314, x918-1919. II. GREEN, C. H., and SNELL, A. M. Arch. Int. Med., 40: 471-487, 1927. 12. DRINKER,C. K., and SHAW, A. J. Exper. Med., 33: 7738, 1921; aIso J. Exper. Med., 38: 829-850, 1923. 13. FLEXNER, S., and SWEET, J. E. J. Exper. Med., 8: 514-535, 1906. 14. PRIESTLY,MARKOWITZand MANN. Am. J. Pbysiol., 96: 696708, 1931. 15. BRANDES,W. W. Arch. Int. Med., 44: 676, 1929. 16. WENDT, H. Klin. Wcbnscbr., 8: 1566, 1929; aIso Klin. Wcbnscbr., 8: 1215, 1929. 17. B~~RCERand HABS. Quoted by Wendt. 18. ELMER,A. W., and SCHEPS,M. Klin. Wcbnscbr., 7: 1083, 1928.

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374, 1927. NARATH. Quoted by Furthwaengler. STAEHLI,E. Beitr. z. klin. Cbir., 123: 103-121, rgzr. HABERER.Ouoted bv FurthwaeneIer. GUNDERMA;, W. I?uncben medy tvcbnscbr., 60:

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55. DIECKMANN.W. J. Proc. Sot. Exp. Biol. F Med., 26: 230-241, 1928. 56. HELWIG. F. C.. and SCHUTZ.C. B. A Iiver kidnev syndrome, cIinica1, pathokgic and experiment;1 studies. Surg. Gynec. Obst., 55: 570-580, 1932. 57. ~IANN, F. C. Persona1communication. ~I

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