CONSENSUS CONFERENCE REPORT ON LIVER* TRANSPLANTATION

SUMMARY

Liver transplantation has been developed to the point of a service operation, the exploitation of which depends upon the establishment of multiple regional centers. The increased use of this procedure will permit the delivery of optimum health care to victims of end stage liver disease.

Supported by research grants from the Veterans Administration; by project grant AM-29961 from the National Institutes of Health and by grant RR-000084 from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health.

To be a service, a new surgical procedure must be within the capability of more than the occasional surgeon. In addition the indications for its use should be clear, and the results should be good enough to justify the effort and expense. In this communication we will indicate that orthotopic liver transplantation has met all three of these criteria.

METHODS

Two hundred and ninety-six patients were treated from March 1963 through April 1983. Until the end of 1979, “conventional” immunosuppression was used with azathioprine and prednisone to which ALG was added in almost all cases (1,2). In 16 patients treated in 1971 and 1972 cyclophosphamide was substituted for azathioprine. From early 1980 onward, immunosuppresion was with cyclosporine and steroids. The surgical and medical techniques have been described elsewhere (1,2).

The results were analyzed before and after the introduction of cyclosporine-steroid therapy. In the post-1980 era the impact was assessed of a greatly expanded volume of cases, the use of veno-venous bypasses with and without heparin, and the systematic training of younger surgeons whose objective could be to set up new centers. In all of the case material, the influence of original disease upon the results also was examined.

RESULTS

Survival With Conventional Immunosuppression (1963 – 1979)

From 1963 to the end of 1979,170 consecutive patients were treated, an average case load of less than a dozen per year. Fifty-six (32.9%) of the recipients lived for at least one year, and 32 (18.8%) are still alive with followups of 3 1/2 to 13 1/2 years. Six of the residual group are more than 10 years postoperative, and 26 are more than 5 years. Only one patient who lived for as long as 5 years has subsequently died.

The patient survival during the first 18 months is summarized in Table 1. The predominant mortality was in the first three postoperative months and was due mainly to technical surgical accidents, acceptance of recipients with hopelessly advanced disease, the use of damaged liver grafts, the inability to control rejection, and a variety of infections (1,2). Most of the deaths in the first half of the second year (Table 1) were due to chronic rejection (2).

TABLE 1.

ACTUAL EIGHTEEN MONTH SURVIVAL OF 210 CONSECUTIVE RECIPIENTS

TREATMENT	NO.	TIME IN MONTHS
		1	2	6	12	18
Triple Drug Conventional (1963 – 1979)	170	120 (58%)	95 (55.9%)	65 (33.2%)	56 (32.9%)	47 (27.6%)
Cyclosporine - Steroids (1980 – 1981)	40	32 (80%)	31 (77.5%)	29 (72.5%)	28 (70%)	26 (65%)

Survival With Cyclosporine-Steroid Therapy (1980 – 1981)

Fourteen patients were treated in 1980 and 26 in 1982; follow ups of 18 to 38 months are available for those still living. The one year survival was 28/40 (70%) (Table 1). Three of the one year survivors died in the 13th, 16th, and 20th months of recurrent cholangiocarcinoma, recurrent Budd-Chiari syndrome, and chronic rejection (with an unsuccessful attempt at retransplantion) respectively. The actual 18 month survival (Table 1) was 65% and the actuarial 2 year survival is projected at 60%.

The Breakout Year of 1982

Until 1982, virtually all of the liver transplantations in our series over a span of almost 19 years were performed by a single surgeon (Table 2). The same surgeon also had carried out all of the donor operations in the earliest years of these efforts and in all cases since 1979. The image created was of a procedure that was too difficult to be taught easily to other teams. Thus, policy changes were instituted upon which it was thought that the practicality of liver transplantation would hinge.

TABLE 2.

THE SHARING OF PRIMARY OPERATIVE RESPONSIBILITY BY MULTIPLE SURGEONS

	1963–1979	1980–1981	1982	1983 (4 months)
New Patients	170	40	62	24
Total Transplantations	191	45	80	34
Transplantations by Single Surgeon (TES)	187 (97.9%)	45 (100%)	48 (60%)	10 (29.4%)
Donor Operations by Single Surgeon (TES)	Minority*	100%	0%	0%

^*The majority of these donor operations at the University of Colorado were by Dr. Charles Halgrimson.

The donor operations

Beginning on 1 January 1982, organ harvest teams which had been trained throughout the preceding year assumed responsibility for 100% of the procurement procedures (Table 2). Any one of 5 faculty members (2 were urologists and 3 were general surgeons) headed the teams. In addition, training of other teams was begun in distant cities with the eventual objective of promoting graft hepatectomies by local surgeons instead of by mobile Pittsburgh teams.

Recipient operations

The diffusion of recipient operative responsibility from one to several surgeons also began in 1982 during which 40% of the patients were treated by young faculty members or fellows (Table 2).

High case volume

The foregoing changes led to a considerable expansion of the clinical efforts. In addition to the 62 primary transplantations, 18 retransplantations were carried out bringing the total number of liver replacements in 1982 to 80 (Table 2).

A trial of veno-venous bypasses

Bypasses were used 2 decades ago in the original trials of liver transplantation for decompression of the portal vein and inferior vena cava which must be obstructed during the hepatectomy and actual transplantation (1). The practice was abandoned for many years but tried again in 12 cases during the summer of 1982 using pump driven bypasses under systemic heparinization. Cannulas were placed into the vena cava (via the femoral vein) and into the portal vein. The physiologic condition of the recipients during the anhepatic phase and the ease of vascular suturing of the grafts were enormously improved, but it was difficult or impossible to reverse the heparin effect which was responsible for 3 deaths in the operating room. Of 12 recipients who had 14 such bypasses (two were at retransplantation), only 3 became long term survivors.

Subsequently pump driven veno-venous bypasses without heparin were perfected in the laboratory and in 1983 bypasses have been used for most of the adult patients. This technique has been satisfactory in 14 recent transplantations and should place the operation of liver replacement within the grasp of a much greater number of surgeons.

The results in 1982

Half of the recipients treated during this time of major change are alive with follows of 5 to 16 months. The survival of the 1982 pediatric recipients ( < 18 years) in 16/28 (57.1) a figure higher than the 15/34 (44.1%) achieved during 1982 in the adults.

The Pace in 1983

During the first four months, 24 primary and 10 retransplantation procedures were carried out, a rate which if sustained will total 100 for the year. The new conditions developed in 1982 have continued with more than 70% of the transplantations now performed by young faculty members and fellows (Table 2) and with almost all adults having veno-venous bypasses. The present survival of new patients is 17/24 (70.8%), including 8/10 children and 9/14 adults.

The Influence of Disease Upon Results

None of the diseases for which transplantation has been performed can be categorically excluded from future trials in spite of a very high incidence of recurrence of the original disease which has been documented with primary hepatic malignancies (1,2) and with chronic active hepatitis in B-virus carriers

(2). Recurrence of Budd-Chiari syndrome (2,3) and primary biliary cirrhosis (3) have been less commonly seen.

The one year and current patient survival before and after the introduction of cyclosporine-steroid therapy is summarized in Table 3 for each of the main disease categories; 237 consecutive patients were included whose transplantations were at least one year ago with the assumption that this followup period would permit detection of aggressively evolving recurrences. The only obvious conclusion is that the results have improved after the introduction of cyclosporine-steroid therapy no matter what the original diagnosis. It is noteworthy that no patients with alcoholic cirrhosis have been included in the cyclosporine series, a selection bias that will not be acceptable in the future. Alcoholic recipients from our earlier experience have been followed for as long as a decade.

TABLE 3.

INFLUENCE OF DISEASE UPON ONE YEAR AND SUBSEOUENT SURVIVAL IN 237 PATIENTS^*

	CONVENTIONAL THERAPY			CYCLOSPORINE-STEROIDS
	NO.	1 YEAR	NOW**	NO	1 YEAR	NOW***
Biliary Atresia	51	14 (27%)	7 (14%)	11	6 (54.5%)	6 (54.5%)
Non Alcoholic Cirrhosis	46	16 (34.8%)	10 (21.7%)	16	9 (56.3%)	8 (50%)
Primary Liver Malignancy	18	5 (27.8%)	1 (5.6%)	9	6 (66.7%)	4 (44.4%)
Alpha-1-Antitrypsin
Deficiency	11	6 (54.5%)	5 (45.5%)	6	3 (50%)	3 (50%)
Other Inborn Errors****	4	2 (50%)	1 (25%)	4	4 (100%)	4 (100%)
Alcoholic Cirrhosis	15	4 (26.7%)	3 (20%)	0	-	-
Primary Biliary
Cirrhosis	6	1 (16.7%)	1 (16.7%)	6	5 (83.3%)	5 (83.3%)
Sclerosing Cholangitis	7	2 (28.6%)	0 (0%)	3	2 (66.7%)	1 (33.3%)
Secondary Biliary
Cirrhosis	4	3 (75%)	2 (50%)	5	1 (20%)	1 (20%)
Budd-Chiari Syndrome	1	1 (100%)	1 (100%)	3	3 (100%)	1 (33.3%)
Miscellaneous*****	7	2 (28.6%)	1 (14.3%)	4	3 (75%)	3 (75%)

^*The same case material was analyzed in detail elsewhere (2) but with shorter followups.

^**Followups 3 1/2 to 13 1/2 years.

^***Followups 1 to 3 1/4 years.

^****Wilson’s Disease (3 examples), Tyrosinemia (2 examples), Glycogen Storage Disease (2 examples), Sea Blue Histiocyte Syndrome (1 example).

^*****Neonatal Hepatitis (3 examples), Congenital Hepatic Fibrosis (2 examples), Byler’s Disease (2 examples), Adenomatosis, Hemachromatosis, Protoporphyria, Acute Hepatitis B (1 example each).

The Influence of Disease Stage Upon Results

The stage of the original disease was of greater prognostic importance than its nature. The stage factor was examined in 114 consecutive patients treated in the cyclosporine-steroid era from 3 to 38 months ago. Patients who were not continuously hospitalized prior to operation were called Class I. Those who were hospitalized most of the time but not in Intensive Care Unit to the operating room were termed Class III. These last patients usually were mentally obtunded or unconscious. Many had the hepatorenal syndrome and most were ventilator dependent. The majority had active gastrointestinal bleeding.

The perioperative mortality was almost 60% in the Class III patients (Table 4). In contrast, the mortality in the first 6 weeks was only 16% in Class II patients. The somewhat higher mortality (32%) in Class I patients was partly explained by the fact that many of these recipients had undergone the kinds of operations in or around the hepatic hilum (such as portacaval shunt or biliary tract reconstruction) that greatly increase the technical risk (2). Such patients could be accepted for candidacy only if they were in the kind of reasonable metabolic state that tended to place them in the Class I category.

TABLE 4.

EFFECT OF DISEASE STAGE ON 6-WEEK SURVIVAL (114 CONSECUTIVE PATIENTS)

CLASS	DEFINITION	NO	SURVIVAL
I	Outpatient Care Dependent	63	68%
II	Hospital Care Dependent	25	84%
III	Intensive Care Unit Dependent	26	42%

DISCUSSION

With the better immunosuppression that became available almost 3 1/2 years ago came a revitalization of interest in hepatic transplantation. In spite of its use in most cases for pathologic conditions which will someday be viewed as unrealistically advanced, the number of successful liver replacements has sharply increased.

Continuing observation of the first patients treated with cyclosporinesteroid therapy has dispelled scepticism about the ability to use cyclosporine chronically. Forty-two patients have now been followed for at least one year after liver transplantation under cyclosporine-steroid therapy. Six deaths have occurred after one year and all but two have been caused by recurrence of the original disease (2 examples of metastases from primary hepatic malignancies, 1 each of recurrent Budd-Chiari syndrome and chronic B-virus hepatitis). One patient died of probable airway obstruction secondary to acute tonsillitis. Only one patient lost a graft to chronic rejection. The degree of rehabilitation of long term survivors has been essentially complete.

The mystique surrounding liver transplantation largely has been dispelled by the events of the last 2 years at our institution and elsewhere. Other units in the United States and in other countries have been able to mount effective programs. In Pittsburgh, more than two thirds of the liver transplantation operations are now being done by young faculty members and by surgeons in training. The ease which with the admittedly difficult operation can be performed is being reduced with the pump driven non-heparin bypasses that are being used this year for the first time.