Andrei C. Stieber

Abdominal organ cluster transplantation for the treatment of upper abdominal malignancies

Ten patients with primary malignant tumors of the biliary tract, duodenum, or stomach and with secondary involvement of the liver underwent removal of most or all of the stomach, liver, pancreas, spleen, duodenum, proximal jejunum, terminal ileum, and ascending and transverse colon. The void in the upper abdomen was filled with an organ cluster graft consisting of the liver, pancreas, duodenum, and variable segments of proximal jejunum. Eight of the ten patients are alive after 3 to 9 months, all with good liver and pancreas function, and most with satisfactory function of the gastrointestinal tract. One of the surviving patients was in the hospital for 4 months because of multiple enteric fistulas and infections; the other seven survivors were discharged after an average of 43 +/- 17.61 (SD) days. Recurrent tumor has not been proved in any of the surviving recipients and is suspected in only one. The study of such cases should provide insight and guidelines applicable to other visceral transplantation procedures that may be attempted in the future.

Hepatic artery thrombosis after pediatric liver transplantation a medical or surgical event

Hepatic artery thrombosis (HAT) is one of the most serious complications after orthotopic liver transplantation, and is associated with a high morbidity and mortality. This study retrospectively reviewed 66 liver transplants in children under the age of 10 years during a year-long period at a single institution. A total of 28 perioperative variables were analyzed to identify responsible factors of HAT. Of the 66 children, 18 (26%) developed HAT within 15 days after the transplant (HAT group); 29 (42%) had an uneventful postoperative course (control group). To avoid the possible influence of other complications 19 patients were excluded. Of the variables compared between the 2 study groups, three surgical factors (diameter of the hepatic artery--greater or less than 3 mm; type of arterial anastomosis--end-to-end versus the use of an iliac graft or aortic conduit; and number of times the anastomosis was redone--one versus more than one), were found to be significantly different (P less than .05) between HAT and control groups. Two medical factors also were significantly different: the use of intraoperative transfusion of fresh frozen plasma (FFP) and the administration of postoperative prophylactic anticoagulant treatment. A heparin and dextran-40 protocol appeared to be effective in preventing HAT (P less than .02). Moreover, after multivariate analysis, anticoagulation therapy was demonstrated to be the major independent variable influencing HAT. A better definition of factors responsible for the occurrence of HAT is required. This study should help in formulating effective methods to decrease the incidence of this dreaded complication after liver transplantation.

The spectrum of portal vein thrombosis in liver transplantation

Thrombosis of the portal vein with or without patency of its tributaries used to be a contraindication to orthotopic liver transplantation (OLTX) until quite recently. Rapid progress in the surgical technique of OLTX in the last few years has demonstrated that most patients with portal vein thrombosis can be safely and successfully transplanted. Presented here is a series of 34 patients with portal vein thrombosis transplanted at the University of Pittsburgh since 1984. The various techniques used to treat various forms of thrombosis are described. The survival rate for this series was 67.6% (23 of 34 patients). Survival was best for patients who underwent phlebothrombectomy or placement of a jump graft from the superior mesenteric vein. The survival rate also correlated with the amount of blood required for transfusion during surgery. Overall it is concluded that a vast majority of the patients with thrombosis of the portal system can be technically transplanted and that their survival rate is comparable to that of patients with patent portal vein.

A PROSPECTIVE RANDOMIZED TRIAL COMPARING SEQUENTIAL GANCICLOVIR-HIGH DOSE ACYCLOVIR TO HIGH DOSE ACYCLOVIR FOR PREVENTION OF CYTOMEGALOVIRUS DISEASE IN ADULT LIVER TRANSPLANT RECIPIENTS

Cytomegalovirus disease is an important cause of morbidity following liver transplantation. To date there has not been an effective prophylaxis for CMV disease after liver transplantation. One hundred forty-three patients were randomized to receive either high dose oral acyclovir (800 mg 4 times a day) alone for 3 months after transplantation (acyclovir group) or intravenous ganciclovir (5 mg/kg twice a day) for 14 days followed by high dose oral acyclovir to complete a 3-month regimen (ganciclovir group). Of 139 patients available for evaluation, 43 of 71 (61%) patients from the acyclovir group developed CMV infection compared with 16 of 68 (24%) from the ganciclovir group (relative risk, 3.69; 95% confidence interval, 2.07–6.56; P<0.00001). Of those randomized, CMV disease was seen in 20 (28%) of the acyclovir group compared with 6 (9%) of the ganciclovir group (relative risk, 5.11; 95% confidence interval, 2.05–12.75; P=0.0001). The median time to onset of CMV infection was 45 days in the acyclovir group compared with 78 days in the ganciclovir group (P=0.004). The median time to onset of CMV disease was 40 days in the acyclovir group compared with 78 days in the ganciclovir patients (P=0.02). With respect to primary CMV infection, there was no difference in the rates in the 2 groups, but tissue invasive disease and recurrent CMV disease were less frequent in the ganciclovir group. It is concluded that a course of 2 weeks of ganciclovir immediately after transplantation followed by high dose oral acyclovir for 10 weeks is superior to a 12-week course of high dose oral acyclovir alone for prevention of both CMV infection and CMV disease after liver transplantation. However, the lack of significant effect in sero-negative recipients who received grafts from sero-positive donors suggests that other strategies are needed to prevent CMV infection in this high risk population.

INTERFERON-?? AND RIBAVIRIN FOR THE TREATMENT OF RECURRENT HEPATITIS C AFTER LIVER TRANSPLANTATION1

BACKGROUND Initial studies utilizing interferon-alpha and ribavirin for the treatment of recurrent hepatitis C virus (HCV) infection after liver transplantation showed promising results. Here we report our single-center experience using this combination therapy. METHODS Liver transplant recipients with recurrent HCV (elevated serum aminotransferases, positive serum HCV RNA, and biopsy-proven hepatitis without rejection) received interferon-alpha (1.5-3 million units subcutaneously three times a week) and ribavirin (400-1000 mg p.o. daily) for 12 months or more. Serum aminotransferases, HCV RNA, and severity of hepatitis were followed. RESULTS Thirty-two patients have been treated for at least 3 months, including 13 who have been on 12 or more months of therapy. Three died from allograft failure due to recurrent HCV. Dose reductions of interferon-alpha and/or ribavirin occurred in 22 patients. Thirteen had their medications permanently discontinued for severe adverse effects. Twenty-six patients (81%) had a biochemical response (BR; normalization of serum aminotransferases) after 3 months. End-of-treatment and sustained BR were 77% and 71%, respectively. Mean viral loads decreased 68-77%; however, only three patients became serum HCV RNA negative. After 12 months of therapy, no histological improvement was observed in 11 patients who were biopsied. Patients who received mycophenolate mofetil or daclizumab had a less likelihood of achieving a BR. CONCLUSIONS A significant number of patients did not tolerate interferon-alpha or ribavirin. Although BR was excellent and mean viral loads decreased significantly, virological clearance was poor and no histological improvement was noted. A more efficacious treatment with less adverse effects for recurrent HCV after liver transplantation is needed.

Liver transplantation in patients with previous portasystemic shunt

Over a 9-year period, 58 patients who had previous portasystemic shunt procedures underwent orthotopic liver transplantation (OLTx) under a cyclosporine-steroid immunosuppressive regimen. The types of shunt used were distal splenorenal (18 patients), mesocaval (17 patients), end-to-side portacaval (11 patients), side-to-side portacaval (5 patients) and proximal splenorenal (7 patients). The mean interval between shunt and transplantation was 6 years. There was no statistical difference in survival between patients with previous shunts and the entire population of patients with primary liver transplantation performed during the same period of time. Age, sex, shunt patency, status of portal vein, and use of vein or artery graft did not affect survival. Childs classification had a significant influence on graft survival, even though no difference was subsequently observed in patient survival. A progressively improved intraoperative strategy and the use of veno-venous bypass and University of Wisconsin preservation solution had a significant impact on blood loss, length of operation, length of stay in intensive care unit, and ultimately, on survival. Distal splenorenal and mesocaval shunts with no or minimal hilum dissection are safer shunts if subsequent transplantation is planned; in fact, their 9-year survival was 87%, whereas all other shunts were associated with a survival no better than 52% (p less than 0.006).

VENOUS JUMP GRAFTS FOR LIVER TRANSPLANTATION IN PATIENTS WITH PORTAL VEIN THROMBOSIS

When the recipient portal vein (PV) has thrombosed at or above the confluence of the splenic vein (SV) and superior mesenteric (SMV) vein in a liver transplant recipient, grafts of iliac vein or vena cava can be used in the hilum to bridge the gap to the homograft PV (1, 2). A thrombosis that extends down into the SV and SMV can not be dealt with by this hilar approach, and in most centers the more extensive thrombotic occlusion is a contraindication to candidacy. For a number of years, we have used jump vein grafts in such cases and have evolved a technique that, in its final form, is a simple and highly satisfactory resolution to the problem. Since the need for this kind of vein graft is sometimes not evident until the actual transplantation, the donor team should always bring back long segments of donor iliac vein (1, 3). These vein grafts are kept in a standard tissue culture medium in the refrigerator, and can be used for at least a week. The value of this precaution was dramatically demonstrated by Sheil et al. (4) who used a mesoportal vein graft when they encountered an unexpected portal vein thrombosis in the first patient treated with liver transplantation in Australia. When a decision for a jump graft is made, a segment of the SMV to the right of the superior mesenteric artery is skeletonized below the transverse mesocolon at the root of the small bowel mesentery (Fig. 1). The dissection should be as distal as is necessary to find a soft and compressible vessel. Depending on the anatomic circumstances, a partially or completely occluding clamp is placed on the SMV segment, and the angled distal end of the iliac vein graft is anastomosed to the presenting surface of the SMV. The proximal end of the graft is led superiorly through a hole in the transverse mesocolon either to the right or left of the middle colic vessels, the exact location being guided by transillumination. The graft is brought anterior to the pancreas behind the gastric pylorus and into the subhepatic area (Fig. 1). The rest of the transplantation is carried out in the normal way. The vein graft is anastomosed to the portal vein of the liver graft (Fig. 1). FIGURE 1 Position of completed venous jump Graft. The patients who need these procedure are generally high-risk, and usually have intractable ascites. In spite of this, the procedure itself is technically easy and can be carried out with little blood loss. Ultrasound studies postoperatively allow determination of jump graft patency. Thrombosis of a jump graft has not been seen.

Reversal of hypersplenism following orthotopic liver transplantation

The purpose of this study was to clarify the effect of orthotopic liver transplantation on hypersplenism. In a 1-year period from July 1, 1986 to June 30, 1987, 196 adult patients underwent 233 orthotopic liver transplantations. Of the 58 patients with hypersplenism who were analyzed in this study, hypersplenism was more commonly associated with postnecrotic cirrhosis than other kinds of liver disease (55.3% (47/85) vs. 14.5% (11/76); p less than 0.001). Postoperative platelet counts were statistically higher than preoperative values (p less than 0.05). The latest platelet counts were more than 100,000/mm3 in 53 patients (91.4%). Of the eight patients whose preoperative and postoperative spleen volumes could be compared, all showed the reduction in the spleen size (p less than 0.02). We conclude that orthotopic liver transplantation, which is a radical surgical procedure for portal hypertension, reverses hypersplenism.

Intrahepatic bile duct strictures after human orthotopic liver transplantation: Recurrence of primary sclerosing cholangitis or unusual presentation of allograft rejection?

Abstract. One of 55 patients transplanted for sclerosing cholangitis during the cyclosporin‐steroid era (March 1980‐June 1986) developed intrahepatic biliary strictures in the absence of allograft rejection within the 1st year posttransplantation. Although many causes underlie biliary pathology in the postoperative period (i.e., arterial injury, ischemia, chronic rejection, cholangitis), recurrent disease remains a possibility.

Liver transplantation in patients over sixty years of age.

Orthotopic liver transplantation has been considered the accepted form of therapy for a number of end-stage liver diseases for several years (1). Until the early 1980s, the unofficially accepted limit for OLTX candidates was 50 years of age. Although a recent UNOS report seems to suggest that the survival of older patients with OLTX is poorer than that of the general adult transplant population (2), we have previously reported excellent preliminary results with OLTX in patients over 50 years of age (3). We have now expanded our series to 156 patients over 60 years of age at the time they received their transplant, and the results are reported here. Our study indicates that results after liver transplantation in patients over 60 years of age are comparable to the results obtainable in other age groups and that advanced age per se is not a contraindication to liver transplantation. Between January 1, 1985 and November 30, 1989, 1475 patients underwent OLTX at the University of Pittsburgh. There were 125 (8.5%) infants (under 2 years of age), 229 (15.5%) children (between 2 and 18 years of age), 965 (65.4%) adults, and 156 (10.6%) seniors (over 60 years of age) (Fig. 1A). Figure 1 (A) OLTX by age group; (B) senior OLTX population distribution by class; (C) senior OLTX population distribution by graft number; and (D) senior OLTX population distribution by diagnosis. Of the 156 senior patients, 80 were males (51.3%), and 76 were females (48.7%). One hundred fifty-two patients (97.4%) were in the seventh decade of their life, while 4 patients (2.6%) were in the eighth decade. Forty-nine patients (31.4%) were UNOS class 1 (out of hospital) at the time of the operation, 62 (39.7%) were class 2 (in the hospital), 24 (15.4%) were class 3 (in the intensive care unit), and 21 (13.5%) were class 4 (urgent) (Fig. 1B). Of the entire group, 129 patients (82.7%) received one graft, 26 patients (16.7%) 2 grafts, and 1 patient (0.6%) received 3 grafts (Fig. 1C). The indications for transplantation were: postnecrotic cirrhosis (PNC)* 65 (41.7%); primary biliary cirrhosis (PBC) 40 (25.6%); primary hepatic malignancy (CA) 19 (12.2%); alcoholic cirrhosis (ETOH) 17 (10.9%); primary sclerosing cholangitis (PSC) 6 (3.8%); metabolic disorders (MET) 5 (3.2%); acute hepatic failure (AHF) 2 (1.3%); and miscellaneous (OTH) 2 (1.3%) (Fig. 1D). Actuarial survival analysis was performed using the 1L module of BMDP/PC, 1988 release (BMDP Statistical Software, Los Angeles, CA) on an IBM-PC compatible microcomputer. Differences were considered significant if P <0.05 and highly significant if P<0.01. The actuarial survival rates (life-table method) for patients with primary grafts was 71.3% after 1 year and 65.5% after 3 years. By comparison, the adult survival ranges were 78% and 71.4%, respectively (Fig. 2A). Figure 2 (A) Patient survival (primary graft); (B) patient survival (retransplants); and (C) senior OLTX population survival by UNOS class. For retransplantations, the senior survival rates were 50% at 1 year and 30.7% at 3 years. By comparison, the adult survival rates were 56% and 43.1%, respectively (Fig. 2B). When the UNOS status was considered, the survival was significantly worse for class 4 (P <0.02) (Fig. 2C). Of the survivors, 66 (66.7%) are fully functional (status I); 27 (27.3%) are functional with some limitation (status II); 5 (5.0%) are partially disabled and in need of some assistance (status III); and 1 (1.0%) is disabled and needing full-time assistance (status IV) (Fig. 3A). Figure 3 (A) Senior OLTX population; functional status; and (B) senior OLTX population by year. The senior group had characteristics similar to the general adult liver transplant population, with the exception of age. This includes primary liver disease, male/female ratio, and medical urgency status (UNOS class). The overall survival for the senior group compared favorably with that of the infant and adult groups. The adult group was used for comparison as a “standard” for survival, while the infants were used as another “high-risk” group. The positive results with the older age population may come as a surprise at first glance, but to us it is clear that the physiological age is vastly more important than the chronological age toward survival. Our oldest recipient was 76 years old when she was given a transplant for PBC, and is still well and an active grandmother at 4 years later. In fact, over the years, the number of transplants in older patients has proportionally increased, compared to those in the adult population, as we have become more confident of achieving good results in this patient population (Fig. 3B). As anticipated, the survival for the much sicker patients in class 4 was statistically poorer. This is consistent with previous observations of a correlation between preoperative patient condition and survival with OLTX (4,5). The preoperative evaluation of the older OLTX candidates is similar to that of the general population, although sometimes it may be more complex, as it is more frequently necessary to study the cardiopulmonary condition in greater detail. But once severe concurrent conditions have been ruled out, the prognosis is as good as that for the general adult population. Many of these patients, especially those with primary biliary cirrhosis, present with advanced hepatic osteopathy that is often the rate-limiting pathology for recuperation after liver transplantation. This is one of the reasons for which we advocate early referral and transplantation for such patients, before the crippling effects of advanced and irreversible bone disease have set in. It is frequently possible and often important to use less-aggressive steroid regimens for immunosuppression in these older patients, in order to avoid worsening of the osteopathy, onset of steroid-dependent diabetes, and cataracts. As in the rest of the surgical population, early mobilization is extremely important. Otherwise, the postoperative care does not differ significantly from the “standard.” A large percentage of the older patients do recuperate completely or almost completely (93.9% of the survivors in our series have a functional status I or II) and can be active and productive again. Besides assuring them satisfactory quality for the rest of their lives, liver transplantation has the potential to increase the pool of productive population, in an era in which there will be an ever-higher percentage of elderly persons who retire late or reenter the job market. We conclude that advanced age is not a contraindication to liver transplantation. The results after liver transplantation in patients over the age of 60 were comparable to results for the general transplant population. These statistics were in contrast to the recent UNOS report for the calendar year 1988, during which the 1-year mortality rate was 50% for patients 65 years or older (2).