SUBSTANTIATION OF A NEW WAY OF ORTHOTOPIÑ TRANSPLANTATION OF A CADAVERIC LIVER
Kemerovo State Medical Academy,
Scientific Research Institute of Complex Problems of Cardiovascular Diseases,
Kemerovo, Russia
In 1963 Starzl performed the first liver transplantation for the human. In Europe the first liver transplantation was in 1968. By 1982 about 500 procedures of liver transplantation with 5-7 years of survival were conducted in the world. But the outcomes of the operations were mostly unsatisfactory. In Russia the first liver transplantation was executed by A.K. Eramishantsev only in 1990. Currently, the total amount of transplantations ever made is more than 150,000. The results have significantly improved. Some variants of the intervention have been developed: cadaveric liver transplantation, split liver transplantation, transplantation of liver lobes from a healthy donor [1].
The range of the diseases for liver transplantation is quietly wide. It includes inborn defects of development and function of hepatocytes, the terminal stage of diffuse diseases of the liver, unresectable liver tumors, biliary atresia and primary sclerosing cholangitis, acute liver insufficiency including traumatic origin.
Orthotopic transplantation is one of the most difficult abdominal operations from the perspective of organizational and technical realization. Another intricate moment is postsurgical management, because such surgery is associated with various complications, as well as an injury to the graft, which is restored and reserved with some difficulties. At the present time liver transplantation is widely used in many countries of the world, and its outcomes have been improving constantly. The number of the liver transplantation centers is increasing. Such surgery is now available in the medical facilities in Novosibirsk and Kemerovo. However some complications are still possible. They worsen results of treatment, they are to be considered, and it is necessary to find some measures for prevention. The actuality of the problem has not decreased with experience accumulation.
Hypotensia and hypoxia in the liver donor, cold ischemia during conservation, heat ischemia during implantation and reperfusion with portal and arterial blood lead to absence of primary functioning in 4-10 % of cadaveric grafts and appearance of disordered functioning in 80 % in early postsurgical period. Commonly the inflammatory response develops in the graft. It leads to sinusoidal endothelium damage, activation of Kupffer cells, leukocytes and platelets (adhesion of neutrophils and platelets). Microcirculatory disorders can lead to severe deconstructive changes. All above-mentioned negative influences result in development of postperfusion syndrome. The gradually developing cellular and molecular processes define the clinical picture of transplant rejection syndrome, which develops in acute or chronical variants.
Use of oxycorticosteroids for prevention of graft rejection causes some serious complications: slowing regeneration, osteoporosis, steroidogenic diabetes, erosive ulcer lesions of the gastrointestinal tract, mental disorders and others. Therefore, it is naturally that transplant surgeons decrease dosages and exclude oxycorticosteroids from the protocols of immune suppression.
The range of the drugs is offered for achieving tolerance and decreasing dosages of oxycorticosteroids, but these drugs are not without disadvantages. Azathioprine is a cytostatic drug of toxic action with lymphocyte suppression, but also with toxic influence of the liver. Antilymphocyte globulin (1967) is a derivative from the animal serum with protection against human lymphocytes. It causes decrease in the level of T-lymphocytes. Cyclosporin A (1980) is an inhibitor of calcineurin and a derivative of fungi. It suppresses proliferation of T-cells and interleukin-1. It increases the action of oxycorticosteroids, but it is nephrotoxic, hepatotoxic and neurotoxic. Tacrolimus (1989) is calcineurin inhibitor. Its effects and complications are similar with cyclosporine A. Diabetes mellitus is one of the complications. Rapamycin (1990) is a synergist of tacrolimus and cyclosporine A. It inhibits tumor proliferation. Monoclonal antibodies suppress the recipient’s immune response by means of blocking the receptors of IL-2 on T-cells in peripheral blood.
Cadaveric liver transplantation is associated with the wide range of complications, which are not associated with the graft. Adrenal bleeding is a common complication after ligation and transection of the central vein of the right adrenal gland for achievement of mobility of inferior vena cava. Even if bleeding is absent, venous hypertension inevitably causes blood imbibition in the tissues of the gland with further suppression of its hormone-producing function that is a well-known fact in adrenal surgery.
Deficiency of the factors 1, U, P and HP leads to fibrinolytic bleedings. Vascular thrombosis is common (arterial anastomosis, portal vein [5] and the inferior vena cava). Its rate is 5-10 %. Besides technical errors, arterial thrombosis is favored by ischemic conservation-reperfusion injury to the liver with slowing down the blood flow. Recurrent transplantation is indicated in case of unfavorable restoration of blood flow. Biliary complications are common in 16-34 % of cases within the first 3 months. Virus replication and autoimmune processes may induce rapid development of grafted liver cirrhosis. Also malignant transformation is possible in the liver [1].
Presence of the wide range of complications after orthotopic transplantation of the cadaveric liver can be an incentive for search of new preventive measures. The analysis of pathogenesis of complications after liver grafting and of the sanogenetic mechanisms of surgery with unilateral portalization of paranephric and renal blood according to Torgunakov (As. No.623271) suggested the appropriateness of left-side renoportal venous anastomosis (RPVA) as supplementation to liver transplantation. The essence of the technique consists in preservation of blood outflow from the right adrenal gland and creation of left-side with ligation of splenic vessels (the approval for granting a patent of RF for the invention on the request No.2013103685) – “The method for orthotopic transplantation of cadaveric liver”). Addition of left-side RPVA to liver grafting initiates multiple sanogenetic mechanisms for prevention of the above-mentioned complications.
Our technique for liver grafting is realized as indicated below.
The recipient’s liver is removed after obtainment of the donor liver graft. The left lobe, the ligaments of the right lobe and the subdiaphragmatic department of the inferior vena cava are subsequently mobilized. The central vein of the right adrenal gland is preserved. The elements of the hepatoduodenal ligament are separated: the general and hepatic arteries, the splenic artery in its middle one-third, the cystic duct and the cystic artery. The cystic duct and the cystic artery are ligated and transected. The left renal vein is separated in the region before its connection with the inferior vena cava under the mesenterium of the transverse colon. All flows of the left renal vein are ligated and transected (except for the suprarenal vein). The inferior mesenteric vein is transected. The place of junction of the splenic vein and the superior mesenteric vein is separated. The left renal artery is filopressured. Hepaticocholedochus and the portal vein are transected. The distal end of the portal vein is cannulated. Portal-femoral-axillary shunting is prepared. Arterial blood flow to the liver and blood flow through the inferior vena cava are arrested. From that moment we realize portal-femoral-axillary shunting. Hepatectomy is completed. The subdiaphragmatic department of the inferior vena cava is preserved. The single cava-caval anastomosis is formed. The distal end of the inferior vena cava is ligated. The proximal end is sutured into the side part of the recipient’s inferior vena cava or the side-to-side anastomosis is created. Blood flow from the right adrenal gland is preserved by means of realizing inferior vena cava above the region of connection with the paranephric vein. Portal blood flow is preserved by means of the porto-portal anastomosis (end to end). Portal shunting is ceased, but cava-caval shunting is preserved until portal and caval blood flow restores. Arterial blood flow in the graft is restored with the anastomosis of the common hepatic artery of the graft with the recipient’s general hepatic artery by end to end type. Left-side renoportal venous anastomosis is created. The splenic artery is ligated in the middle one-third (near the entrance). The place for implanting the portal vein entrance to the entrance of the splenic vein and to the side part of the superior mesenteric vein is prepared. Arterial blood flow is arrested in the place of left renal artery. The renal vein is transected from the inferior vena cava. Then the renal vein is implanted to the prepared site. The parietal clip is removed from the root of the portal vein. Blood flow through the renal artery is initiated. The parietal peritoneum is sutured over the anastomosis. Biliary reconstruction is conducted by means of end to end choledocho-choledochoanastomosis. Hemostasis is controlled. The tube drains are placed near the region of creation of the anastomosis (to the small pelvis). The tube drains are drawn through the holes in the abdominal wall. The edges of the laparotomy wound are sutured layer by layer.
Let’s consider some advantageous moments of such combination which may favor decreasing probability of complications and improvement in outcomes of liver grafting.
1. Salvation of the unligated central vein of the right adrenal gland favors the preservation of hormonal functioning of the right adrenal gland and the anti-inflammatory potential of the body. It prevents appearance of such complication as bleeding from the adrenal gland, and it decreases dosage of prednisolone as the immune suppressive drug after surgery.
2. Shunting for oxycorticosteroids of the left adrenal gland through RPVA to the liver graft (passing over the general blood flow) stabilizes cellular membranes, lysosomes, makes the anti-inflammatory and antiedemic effect, decreases release of the antibodies, decreases the possibility of virus replication in the graft and fibrosis progression. The phenomenon of regionary immunosuppression by oxycorticosteroids of the left adrenal gland is reproduced. It decreases the dosage of exogenous prednisolone and other immunosuppressants.
3. The rheologic properties of the blood, microcirculation in the graft and prevention of thrombosis in the portal vein are stimulated by passage of the left kidney venous blood through the liver. The fibrinolytic effect is achieved by means of urokinase. Urokinase is a physiological activator of plasminogen (non-active precursor of fibrinolysis) in the blood plasma. It causes splitting of the internal arginine-valine peptide link in the plasminogen molecule and formation of the plasmin molecule (fibrinolysin). The main function of fibrinolysin is fibrin and fibrinogen lysis. Also it splits U, P and HP factors of blood clotting, glucagon, gamma-globulin and growth hormone. The described biochemical processes provide increasing fibrinolytic activity of the blood of the renal veins. According to E.K. Zhavoronkova [2], antithrombin activity of urine is directly related to renal filtration function. In her experiments with dogs the author showed that the renal vein blood provided more anticoagulation activity (estimated with heparin and thrombin clotting time) in comparison with arterial blood. Our examination of the blood in the peripheral and renal veins showed that the renal venous blood was characterized with lower levels of fibrinogen, higher fibrinolytic activity, lower prothrombin ratio and more long-lasting spontaneous clotting [3]. This feature of the renal blood allowed refusal from specific postsurgical anticoagulant therapy after creation of left-side RPVA. There were no cases of anastomosis obstruction.
4. According to oxygen levels, the left kidney venous blood is close to the arterial blood. Our findings [3] show oxygen saturation of 92.1 % by means of presence of direct arteriovenous anastomoses in the kidney and high rate of blood flow in the organ. It is impossible to make differentiation between the renal venous blood and the arterial blood in the macroscopic examination. The renal venous blood has the same bright red color as the arterial blood. Therefore, left-side RPVA leads to blood arterialization in the liver and makes positive influence on the functional state of the kidneys.
5. Ligation of splenic vessels leads to partial shunting of the splenic blood to common blood flow bypassing the liver. It decreases the splenic immunologic influence on the liver. It is known that splenectomy improves preservation of the liver graft.
6. Such way of blood arterialization in the graft allows prevention of necrotic processes and retransplantation in case of postsurgical obstruction in the arterial anastomosis. Let us remark that the liver is ready to such blood circulation from the perspective of evolution. The fetus liver gets the placental blood through the umbilical vein (oxygen saturation about 80 %), but oxygen saturation is not more than 30 % in the portal vein.
All above mentioned facts provide improvement and prolongation of functioning of the graft at the background of decreasing dosing of immune suppressants and decreasing number of complications and their intensity.
The authors conducted their long term clinical observation for patients with progressing chronic hepatitis and estimated the influence of RPVA on the functional state of the liver [4]. Left-side RPVA was conducted for 50 patients (age of 16-69) with chronic hepatitis (CH) in the general surgery clinic, Kemerovo State Medical Academy. There were 28 men and 22 women. All patients received the complex clinical, laboratory and instrumental examination. Chronic hepatitis was diagnosed in 30 patients, CH with the initial signs of hepatic cirrhosis (HC) – in 10, HC of type A (Child-Pew) – 7, HC of type B – 2, HC of type C – 1. The clinical diagnosis was confirmed by the histologic examination of the liver. Before surgery the patients with recurrent states were repeatedly admitted to the therapeutic departments: 28 patients received hospital treatment 1-3 times, 22 patients – 3-5 times [6].
The postsurgical hospital examination was conducted in early postsurgical period, at 3 months, after a year and after 3 years. The maximal duration of the control examination was 18 years on average, with variations from 15 to 22. The follow-up and the examination showed improvement in the biochemical values of the functional state of the liver in the late postsurgical period. The intensity of cytolysis syndrome decreased after left-side RPVA (decreasing levels of ALT, AST and bilirubin). Also the intensity of cholestasis syndrome (decreasing activity of alkaline phosphatase, decreasing levels of cholesterol and beta-lipoproteins), inflammatory syndrome (decreasing hamma-globulins and flocculation tests) and syndrome of hepatocellular insufficiency (increasing levels of prothrombin, total protein and albumin) decreased. The normalizing influence on glycemia was found.
The positive influence of RPVA on the liver functioning was confirmed by hepatobiliary scintigraphy and liver scanning. Before surgery the significant decrease in absorbing function of the liver was noted in 28 % of the patients. 28 % of the patients had some disorders of bile outflow. However absorption improved after a year in all patients, and less intense disorder of bile outflow persisted only in 12 %. At 3 months after surgery the structure of scanograms normalized in 16 % of the patients, after a year – in 30 %. As for the clinical signs (disappearance of the symptoms or decrease in their intensity), 80 % of good and excellent outcomes were achieved one year after surgery. The ultrasonic examination showed normal functioning of the anastomosis and absent obstruction in all patients (the figure). The sizes of the kidneys and the spleen did not change.
Figure
The echogram and the doppler image of the patient P. (the observation 35) 19 years after surgery with RPVA
The following case shows the efficiency of RPVA in the patient with chronic aggressive hepatitis.
The clinical case No.28. The history disease No.740. The patient G., age of 26, was admitted to the clinic on January 1, 1987. He had some complaints of bursting pain in the right hypochondrium, feeling of weight in this region during walking, general weakness, sweatiness, dry mouth.
In 1967 he suffered from Botkin's disease. In his childhood days he often suffered from cold-related diseases. The disease began on January 10, 1987, after his night shift, when the above mentioned complaints appeared. He addressed to the health unit of the factory. Then he was admitted to the therapeutic department. The diagnosis was: “Chronic persisting hepatitis of mixed origin (viral and toxic), active phase”. After 5 weeks of treatment his condition improved insignificantly. Chronic persisting hepatitis was confirmed by the histological examination of the liver. The patient was transferred to the surgical clinic on February 27, 1987.
The objective examination: the state was satisfactory. The skin surface and visible mucosa were without changes; lungs and the heart – without specific features. AP – 140/90 mm Hg. The dense (painful) edge of the liver was palpated (at the level of the costal arc). The values of clinical blood and urine analyses were without any declinations from the references, increased levels of ALT (up to 0.86 mcM/l) and γ-globulins (up to 26.3 %).
Isotopic hepatography showed some insignificant decrease in absorbing function of the liver. The hepatic scanogram showed the unsmooth distribution of the agent and its decreased accumulation in the left lobe. The spleen was enlarged. Rheohepatography showed decreasing blood filling in the liver, increased tone of intrahepatic vessels and slow venous return.
Fiberoptic gastroduodenoscopy showed some signs of insufficiency of the cardiac and pyloric orifices with duodenogastric reflux, some events of bulboduodenite and gastritis. Staged manometry identified disarrangement of duodenal patency of hypokinetic type. The examination of the kidneys showed presence of chronic left-side pyelonephritis. Intravenous cholegraphy showed the decreasing concentration function of the gall bladder.
The surgery was conducted on March 12, 1987: end to side RPVA, liver biopsy, umbilical vein catheterization. The operation lasted for 4 hours (3 hours for each group on average), renal heat ischemia – 35 min (29 min for each group on average). Portal pressure before anastomosis creation – 160 mm w.g., after the operation – 180 mm w.g., within the following 3 days – 120-160 mm w.g.
The histological examination No.7721, April 10, 1987: lobe structure not disordered, hepatocytes with persistent frame structure; cytoplasm with scarcely noticeable granular structure; bubble-shaped nuclei. Blood congestion in moderately extended intertubular space – clear contours of red blood cells. Portal tracts were moderately extended. Cellular infiltration was beyond the limits of the terminal plate in individual regions. Blood congestion was in the vessels of the portal vein system. The epithelium of bile ducts was swollen and hyperchromic. Proliferation of bile ducts was in some regions. The conclusion: chronic aggressive hepatitis, histologic index of activity – 11-12 points. The weak degree of fibrosis, histological index – 1.
The course of the short term postsurgical period was common. On the second day bilirubin increased to 37.35 mcM/l (indirect – 28.33 mcM/l). ALT increased to 0.90 mcM/l. At 3 days the level of bilirubin normalized. ALT decreased to 0.72 mcM/l only after 2 weeks. On March 30, 1987 the patient was discharged. His condition was satisfactory. The examination was conducted after 3 months and after 9 years from the moment of the operation. All clinical manifestations of CH disappeared within the first year. The patient resumed his professional activity (equipment operator). The examinations showed the normal values of the main indices of the liver function (biochemical parameters of the blood, hepatography, scanning). The ultrasonic examination of the gall bladder, pancreas and the kidneys were without significant changes. Fiberoptic gastroduodenoscopy showed tight closure between the cardial sphincter and the pylorus, absence of duodenogastral reflux, absent signs of bulboduodenitis, presence of some moderate signs of superficial gastritis.
The follow-up showed that left-side RPVA had caused regression of the pathologic process in the liver and almost full recovery of the patient. The follow-up and the associated data from the whole group of the patients with chronic hepatitis testify the feasibility of combination of liver grafting and anastomosis. Chronic aggressive hepatitis presents the model of the changes, which appear in the liver graft. Viral hepatitis B and C is associated with 100 % infectious contamination of the delta liver graft; 79 % of cases are associated with histologic picture of chronic hepatitis or cirrhosis. Acute hepatitis is observed in 9 %. It is known that the key directions in treating the progressing types of chronic hepatitis are oxycorticosteroids, fibrinolytic agents and liver oxygenation. RPVA includes all these components of pathogenetic influence on the liver.
If addition of left-side RPVA to liver grafting is substantiated with pathogenetical direction of the mechanisms of the surgery affecting the liver, then the contraindications should be based on the consistency of such mechanisms. So, absence of the left adrenal gland or pathologic changes of tumoral or destructive pattern defeat the purpose of creation of RPVA. Usually chronic renal insufficiency is a contraindication for addition of RPVA to liver grafting. As a rule, chronic renal insufficiency is associated with sharp decrease in volumetric blood flow in the kidneys, decreasing fibrinolytic activity of renal blood and its oxygenating effect. It is naturally that the contraindication for RPVA is anomal positioning of the vessels preventing formation of the anastomosis.
CONCLUSION
1. The sanogenetic mechanisms of left-side RPVA allow appropriateness of its combination with orthotopic grafting of the liver in absence of contraindications for anastomosis creation.
2. The new offered method for orthotopic transplantation of the liver with preserving the blood flow from the right adrenal gland and formation of left-side RPVA improves the functional state of the grafted liver, decreases the dosages of immune suppressants and the possibility of development of complications.