Disturbance of Liver Function and Changes in Its Nucleic Acids

In the pathogenesis of the severe disorders that determine the irreversibility of terminal states and cause the symptom complex known as ‘postreanimation disease’, disorders of liver function play an important role. 

The functional state of the liver during resuscitation and the beginning of the restorative period is of primary importance for the final outcome of reanimation, since the liver, as the main or­gan responsible for detoxication of the organism, must at this time cope with an enormous quantity of the various toxic products that flood the organism after the severe hypoxia it has experienced. The role of the liver in restoring homeostasis, severely disturbed during dying, is also far from inconsiderable.

Lesions of this organ most frequently develop during slow dying on a background of the previous protracted hypotension as a result of centralization of the circulation.

No less important in the pathogenesis of hepatic insufficiency during prolonged hypotension, and in cases of shock, is the dis­turbance of regional and microcirculation.

Fluid constriction and the slowing of blood flow are particularly marked in the portal system. Whereas, in normal conditions, 75 per cent of the blood reaches the liver through the portal vein system, in cases of lengthy hypo­tension and shock, it flows principally through the hepatic artery.

When capillary spasm develops and a considerable part of the sinusoids are excluded from the circulation because of the conglo­meration of formed blood elements in them hepatic circulation goes through the system of shunts in these conditions, which leads to an in­crease in the portal gradient and a jump in venous potential. Oxygenation of venous blood decreases, par­ticularly in the hepatic vein; oxygen tension drops in hepatic tissue as early as the erectile stage of shock.

The disturbances in liver function that arise in conditions of hypoxia can cause dilation of the peripheral vessels and so main­tain the state of hypotension. This is apparently associated with the fact that the iron-containing protein ferritin, which is synthe­sized in the reticulo-endothelial hepatic cells, is not oxidized in conditions of oxygen starvation. Entering the blood stream the protein catalyses the oxidation of adrenalin to adrenochrome. As hepatic cells are highly sensitive to hypoxia, disturbance of gas exchange has an extremely unfavourable effect on the functional state of the liver. Particularly severe al­terations, not infrequently reaching states of necrosis, are observed in terminal states developing during slow dying in conditions of prolonged hypotension.

Earlier research has shown that severe hypoxic states lead to a disturbance of nucleic acid metabolism in the organism. And it is well known that nucleic acids, like proteins, are irreplaceable ele­ments for maintaining cell structure and functions and are conse­quently of particular importance in the processes of restoring cell structures after damage. There are no data in the literature, however, on the changes in nucleic acid content during dying, let alone after resuscitation of the organism. Yet it is the damage to macromolecular metabolism that occurs during the postreanima­tion period that is of the greatest interest in reanimatology. The new data obtained in our Laboratory have enabled us to extend our notions considerably about the processes that occur in the liver during dying from loss of blood and also in the postreani­mation period.

It has been established that there is a drop in RNA concentration in hepatic tissue in cases of rapid dying due to loss of blood and during the first nine hours after resuscitation. On the second or third day of the restorative period, the RNA level becomes normal. DNA concentration does not alter during the extinction of functions or after reanimation. Correlation of these findings with the favourable course of restorative processes allows us to say that the alterations in the liver in these animals are reversible.

In dying from blood loss on a background of prolonged hypo­tension the changes in nucleic acid content are greater. Then, it must be noted, DNA content changes as well as RNA. After a two-hour period of hypotension there is a statisti­cally reliable drop from the original level in the RNA and DNA content of hepatic tissue. DNA concentration in the liver, after two hours of hypotension, is much lower than the level found at the end of agony with acute haemorrhage.

Study of the dynamics of RNA and DNA content in hepatic tissue during the postreanimation period in animals that have ex­perienced lengthy dying and one or two minutes of clinical death presents special interest. In animals resuscitated but that later died, in which autopsy revealed wide spread necrotic regions in the liver, the loss of DNA and RNA progressed during the post hypoxic period. Thus a progressive decrease in nucleic acid content, above all of DNA which is a component of the cell nucleus, indicates considerable damage to the nuclear substance of hepatic cells during terminal states. These alterations reflect severe functional and structural damage to the liver, and its degree is of considerable importance in determining the gravity of the course of the postreanimation period and the outcome of resuscitation. Despite the fact that cardiac activity and respiration had been restored in these animals, catabolic processes predo­minated over anabolic processes.

At the same time the content of nucleic acids of the liver of animals that survived after dying on a background of lengthy hypotension and the same period of clinical death was not notably different from that found in the last period of hypo­tension. During the fifth or sixth day, nucleic acid level increased in these dogs and was close to the initial value.

Elucidation of the differences in the dynamics of nucleic acid content in the liver during the restorative period in accordance with the outcome of resuscitation of the animals, and the greater resistance of the surviving dogs to posthypoxic disorders, hint that these biological macromolecules are actively involved in the processes taking place in the organism during terminal states.

The considerable accumulation of uric acid in the blood that is particularly typical of the postreanimation period confirms that a catabolic effect predominates in nucleoprotein metabolism during terminal states. Thus nine hours after cardiac activity was res­tored, the blood level of uric acid in animals that subsequently died was almost double that found in the blood of those animals that survived. Study of nucleic acid metabolism in the liver, kidneys, and heart in the remote postreanimation period of animals who have endured clinical death or acute total cerebral ischaemia revealed that RNA level in these organs did not depend solely on the gravity of the hypoxia, but also on the completeness of the restoration of their neurological state.

Further investigation of the biochemical processes closely as­sociated with functional and morphologic alterations in the or­ganism will, we expect, elucidate the mechanism of damage to the liver and other organs that occurs in the conditions of terminal states.

Studies of hepatic function after clinical death of three to five minutes provoked by electric shock have not revealed any consi­derable impairment of proteinogenic and prothrombinogenic func­tions. On the other hand, after clinical death followed prolonged hypotension, hypoproteinaemia develops, with a drop in albumin content and both a relative and an absolute increase in alpha-globulin content. This is possibly a result of proteins entering the blood from hepatic tissue. The level of prothrombin in the blood flowing from the liver both during hypotension and immediately after resuscitation decreases con­siderably.

Hepatic secretion is considerably depressed in all dogs that have suffered clinical death but these disturbances are much more severe in animals that have experienced a prolonged hypotension than in those that experienced three to five minutes of clinical death provoked by electric shock. The results of tests involving intravenous injection of bromsulphalein in a dose that in normal conditions maintains a constant level in the blood confirm that the secretory functions of the liver are depressed in the early postreanimation period. Analysis of the bromsulphalein level of the blood flowing to and from the liver revealed an increase in the evacuation threshold by a factor of two to eight.

In experiments with prolonged hypotension, the ratio between the curves of the bromsulphalein level in arterial blood and the blood in the hepatic vein, which reflects the rate of blood flow in the liver, varied widely and altered sharply throughout the resto­rative period.

Most of the experimental animals showed an increase in the difference in bromsulphalein level in the arteries and veins during the first five or ten minutes after reanimation. This could have been due to a slowing of hepatic blood flow. Subsequently the artero-venous difference decreased and sometimes became normal after 20 to 25 minutes. At the same time the excretion threshold of bromsulphalein remained considerably above normal, indicating continued depression of the functioning of hepatic cells. Occa­sionally, on the contrary, there was a sharp decrease in the artero-venous difference with a high bromsulphalein excretion threshold, a state that was rapidly altered by an increase in the artero-venous difference with the excretion threshold of bromsulphalein remaining high. In view of the high lability of these parameters and the rapid change from one state to the other, it seems likely that disturbances of regional circulation in the liver play a leading role in the pathogenesis of its functional impairment. The reason for this state of affairs is apparently centralization of hepatic cir­culation with the blood flow being diverted through the shortest shunts.

In studying the functional state of the liver during the restora­tive period we found a direct dependence between the severity of its functional impairment and the prognosis of resuscitation. It has been shown that 70 per cent of the dogs in which considerable impairment of hepatic secretion was discovered, and in particular a considerable, lengthy delay in excretion of bromsulphalein, proved inviable and died after various intervals following resusci­tation. On the other hand complete restoration of vital functions was observed in all animals with a favourable picture of hepatic function.

Isolated perfusion of the liver with oxygenated blood was found to be a most effective measure to avoid severe, irreversible altera­tions in the liver in cases of shock. Injecting such blood into the portal vein of a dog raised the oxygen saturation of the blood of the hepatic vein from 3-6 to 71 per cent, and the dogs died less often.

Preliminary experiments carried out in our Laboratory with isolated perfusion of the liver with oxygenated blood by means of an artificial circulation apparatus during 12 minutes of clinical death from electric shock, established the possibilities of this me­thod for treating terminal states. Evidence of this was the complete restoration of vital functions in most of the animals and more rapid restoration of circulation, respiration, and corneal reflexes than in the controls.

Attempts at treating severe hepatic insufficiency by means of cross circulation in order to allow the donor’s healthy liver to compensate the functional insufficiency of the recipient’s undoubt­edly also present interest.

In recent years more and more works have appeared devoted to the employment of homologous or heterologous liver transplants in cases of hepatic insufficiency. It is expected that this method will prove useful for treating the hepatic insufficiency that arises as a result of the development of a terminal state.