Relationship between immunosuppression and osteoporosis in an outpatient liver transplant clinic.

BACKGROUND: The aim of this study is to determine the relationship between immunosuppression, disease state, and osteoporosis in an outpatient liver transplant clinic. METHODS: All liver transplant recipients visiting an outpatient transplant clinic received bone density scanning with a dual-energy X-ray absorptiometry (DEXA) device of the calcaneal bone after completing a questionnaire assessing risk and medications currently being used. RESULTS: Of the 137 liver transplant (OLT) recipients completing questionnaires and receiving DEXA screening, patients with low bone density (n = 50) were older (56.6 +/- 12.7 years vs 50.2 +/- 10.1 years; P = .02) compared with normal density patients (n = 87) and were predominately female (64.0% vs 35.6%; P = .01). Based on disease state, patients with cholestatic liver failure had lower bone calcaneal area (17.3 +/- 1.3 cm2 vs 18.9 +/- 1.57 cm2; P < .01). Patients taking tacrolimus (n = 112), as compared with cyclosporine (n = 25), had a tendency toward fewer findings of low bone density (37.5% [42 of 112] vs 56.0% [14 of 25]; P = .08) but had more risk factors (3.1 +/- 1.2 vs 2.1 +/- 0.8; P = .001) and a higher prednisone dose (4.4 +/- 5.9 mg/d vs 2.1 +/- 3.8 mg/d; P = .026). For patients weaned from prednisone, the tacrolimus patients were less likely to have low bone density (36.2% vs 68.8%; P = .02). Mycophenolate mofetil did not influence bone density or area measured. CONCLUSIONS: After liver transplantation, patients taking cyclosporine were more likely to have low bone density compared with those taking tacrolimus.

Procurement and preparation of human isolated small intestinal grafts for transplantation.

We have developed a donor operation that incorporates en bloc removal of the liver and intestine with a limited surgical resection in vivo. Over the past 18 months, we have used the following technique for the retrieval and preparation of seven isolated small intestinal allografts. The donor operation and bench preparation can be divided into three phases. During the first phase, the small intestine is removed with the liver, pancreas, and an aortic segment. In the second phase performed ex vivo, the donor liver can be separated from the specimen. The third phase involves additional bench dissection to yield an isolated intestinal allograft. The principle advantage of this technique is that it reduces potential liver injury by minimizing the surgical dissection required in vivo. Also, dividing the liver from the intestine ex vivo allows the organs to be separated in a bloodless field under controlled conditions that may be especially important when two different surgical teams are involved.

Transfusion-induced graft-versus-host disease after liver transplantation. Documentation using polymerase chain reaction with HLA-DR sequence-specific primers.

Graft-versus-host disease (GVHD) occurring after liver transplantation can pose a difficult diagnostic dilemma. Similar clinical and pathologic skin and gastrointestinal manifestations can result from other causes (i.e., drugs, infections). Treatment for each of these entities differs, and the high mortality associated with GVHD makes this distinction critical. GVHD has been assumed to result from the cotransplantation of donor lymphoid tissue along with the allograft. In most instances, the patient also receives blood products during the operation, and occasionally during the postoperative period, and the lymphoid cells in these products are also a potential source of concern. In this report, we describe a patient who developed GVHD after liver transplantation. Using molecular diagnostic techniques, we determined that the source for this GVHD was not the organ donor, but was most likely nonirradiated blood products received during the hospital course. Our results suggest that transplant recipients with concomitant hematopoietic dysfunction would benefit from irradiated blood products to reduce the likelihood of this complication.

Interferon-alpha and ribavirin for the treatment of recurrent hepatitis C after liver transplantation.

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.

Combined liver/small bowel transplantation using a blood group compatible but nonidentical donor.

A successful liver/small intestinal transplantation with a blood group O donor to a blood type A recipient is described. Mild graft versus host disease developed, manifested by hemolysis, but did not result in graft loss or patient mortality. This suggests that minor ABO incompatibility may be tolerated with intestinal transplantation, despite the transplantation of large amounts of lymphoid tissue.

Improved results of living-related liver transplantation with routine application in a pediatric program.

Living related liver transplantation (LRT) was introduced as a response to the shortage of donor organs that has existed for small children. Results were promising in the initial experience, with a one-year patient survival of 80% and a graft survival of 75%. Since the completion of the protocol, LRT has been considered routinely in the management of children in our center. We present here our experience with 45 consecutive transplants in which LRT accounts for 40% of grafts with an overall patient survival of 90%. Between 4/91 and 4/92, 45 OLT were performed in 41 children. Median age was 2.7 years (3 months to 13 years) and weight was 10.4 kg (3.5-60 kg). Thirty-five were primary grafts, 10 were retransplants. One patient received 2 grafts in the orthotopic auxiliary position. Cholestatic disorders including biliary atresia accounted for 60%, metabolic diseases for 15%. Grafts were obtained from cadaver donors in 27/45 (60%) cases; reduction was required in 12/27 (44%). LRT was performed in 18 cases. Fifty-two percent of recipients of cadaver grafts were UNOS status 4, while 16% of LRT recipients met these criteria. Actual patient survival for cadaver grafts is 21/24 (88%) and graft survival is 20/27 (74%). Patient survival in 18 LRT was 94%. Two grafts were lost to arterial thrombosis for a graft survival of 83%. All donors have been discharged and are well. One patient, a teenager with fulminant hepatitis, was successfully transplanted with a left lobe from his father. This experience demonstrates the programmatic flexibility accorded by use of LRT. Since 40% of grafts were LRT, more livers were available for urgent use for patients who did not have a donor available, as reflected in the 73% incidence of cadaver recipients on status 3 or 4. Therefore, patients are more likely to receive a transplant at the optimal time. We are now prepared to offer LRT for fulminant hepatic failure since the benefit of graft availability appears to outweigh concerns about coerced donation. The successful treatment of a teenaged patient may herald extension of LRT to adults. We conclude that the use of LRT should be expanded.

Biliary complications in pediatric liver transplantation. A comparison of reduced-size and whole grafts.

One of the major changes in liver transplantation has been the application of reduced-size liver transplants(RLT). RLT has the great advantage of expanding the donor pool up to ten times the weight of the recipient, thereby decreasing pretransplant mortality in the pediatric age group. It has been suggested that RLT is a risk factor for biliary complications. To analyze the role of RLT and biliary complications, the results of 213 consecutive liver transplants in 164 pediatric patients over a 6-year period will were reviewed. These included 113 whole-liver transplants and 100 reduced-size liver transplants (49 reduced cadaveric liver transplants (RCLT), 38 split-liver transplants (SLT) and 13 living-related liver transplants (LRLT). The average weight and age were significantly higher in recipients receiving whole-size grafts (average weight 18.4 mg, average age 4.9 years) than in those receiving reduced size grafts (average age 2.3 years, average weight 11.1 kg). Biliary reconstruction consisted of Roux-en-Y, cholangiojejunostomy (n = 203) or choledochocholedochostomy (n = 10). There were 29 total biliary complications, (13.6%) with no significant difference in the complication rate between the whole (n = 13, 11.5%) or reduced livers (n = 16, 16%). Biliary leakage was the most common complication (n = 20), and it occurred at the biliary enteric anastomoses (n = 10), the roux limb (n = 7), or at the cut edge (n = 3). Of the leaks occurring at the biliary enteric anastomoses, 50% were caused by hepatic artery thrombosis. Biliary obstruction accounted for their remaining complications (n = 9) or 4.2%. Actuarial survival from 6 years to a minimum of two months of follow-up was 73% in the whole-size and 70% in reduced-size liver transplants. This series demonstrates that the incidence of biliary complications is similar in reduced-size and full-size grafts. No grafts were lost to biliary complications in the absence of hepatic artery thrombosis.

Hepatic artery thrombosis in infants. A comparison of whole livers, reduced-size grafts, and grafts from living-related donors.

Hepatic artery thrombosis (HAT) is a major cause of patient morbidity and graft loss in pediatric liver transplantation (OLT). Although some grafts may be salvaged by arterial thrombectomy and reconstruction, many patients require retransplantation. Patient survival is reduced by HAT. It has been suggested that the incidence of HAT may be altered by the use of reduced-size grafts (RSG). We analyzed our series of infants receiving OLT to determine the frequency of HAT in full-size OLT, cadaveric RSG, and living-related RSG. The role of arterial anastomotic technique in the development of HAT was also examined. Between 10/1/84 and 12/7/90 433 liver transplants were performed. During this period 100 patients between 3 months and 2 years of age (mean 13 months) received 134 liver grafts. The mean weight at the time of transplant was 7.9 kg. (range: 1.9-15 kg). Of the 134 grafts, 60 were whole livers, 61 were cadaveric RSGs, and 13 were living-related RSGs. The cadaveric RSGs were 9 right lobe grafts, 21 left lobe grafts, and 31 left lateral segment grafts. Twenty-seven of the cadaveric RSGs were from split livers, while the other 34 were simple reductions. All 13 living-related RSGs were left lateral segments. HAT occurred in 15 of 60 (25%) whole livers, 9 of 61 (15%) cadaveric RSGs, and 3 of 13 (23%) of the living-related-donor RSGs (P = NS). Subdividing the cadaveric RSGs revealed that HAT occurred in 3 of 9 (33%) right lobe grafts, 3 of 21 (14%) left lobe grafts, and 3 of 31 (10%) left lateral segment grafts (P = NS). The site of the arterial anastomosis in the recipient correlated with the incidence of HAT (hepatic artery 21/86 [24%], celiac axis 1/9 [11%], aorta 2/32 [6%], P = 0.06). In conclusion, it appears that use of a cadaveric left lobe or left lateral segment graft and an aortic arterial anastomosis reduces the risk of hepatic artery thrombosis in liver transplant recipients less than 2 years of age.

Preliminary experience with intestinal transplantation in infants and children.

OBJECTIVE: This report discusses the preliminary experience with intestinal transplantation in children at the University of Nebraska Medical Center. PATIENTS: During the past 4 years, 16 intestinal transplants have been performed in infants and children. Thirteen have been combined liver and bowel transplants, and the reminder were isolated intestinal transplants. Nearly half of the patients were younger than 1 year of age at the time of surgery, and the vast majority were younger than 5 years of age. All but one had short bowel syndrome. RESULTS: The 1-year actuarial patient and graft survival rates for recipients of liver and small bowel transplants were 76% and 61%, respectively. Eight of 13 patients who received liver and small bowel transplants remain alive at the time of this writing, with a mean length of follow-up of 263 (range, 7 to 1223) days. Six patients are currently free of total parenteral nutrition. All three patients receiving isolated intestinal transplants are alive and free of parenteral nutrition. The mean length of follow-up is 384 (range, 330 to 450) days. Major complications have included severe infections and rejection. Lymphoproliferative disease, graft-versus-host disease, and chylous ascites have not been major problems. CONCLUSIONS: Although intestinal transplantation is in its infancy, these preliminary results suggest combined liver and bowel transplants and isolated intestinal transplantation may be viable options for some patients with intestinal failure caused by short bowel syndrome or other gastrointestinal disease in whom long-term total parenteral nutrition is not an attractive option.

Resection of primary schwannoma of the liver not associated with neurofibromatosis.

A 38-year-old woman developed right upper quadrant pain due to a mass in the left lobe of the liver. The tumor was resected along with segment 3 of the left lobe. Histologic examination and immunochemistry supported a diagnosis of benign schwannoma. No metastatic disease was present, and the patient has been well for more than 18 months after surgery without recurrence. This is the first reported case of successful resection of a schwannoma of the liver in a patient without von Recklinghausen's disease.

Living-related pediatric liver transplantation.

Living-related liver transplantation (LRLT) was developed to reduce preoperative mortality in the small pediatric patient. It has now been successfully used for recipients ranging in size from 0.3 to 50 kg. Besides reducing preoperative mortality, LRLT offers the ability to electively schedule transplantation at the optimal time for the child's survival, evidenced by recent series with greater than 90% recipient survival coupled with 0% donor mortality or long-term complications. Living-related transplantation (LRT) should be made available at centers with experience to all children with end-stage liver disease.

Can current technology be integrated to facilitate laparoscopic living donor hepatectomy?

BACKGROUND: Living donor hepatectomy (LDH) is a technically demanding procedure that is an alternative for providing livers for transplantation. Unlike liver resections for other pathology, LDH requires preservation of the major vessels and biliary tree. This study was performed to determine if current technology can be integrated to perform laparoscopic LDH. METHODS: Six adult sheep underwent laparoscopic LDH of the left lateral segment under general anesthesia. Instruments utilized included standard dissecting instruments, ultrasound, ultrasonic dissectors, CUSA, the TissueLink Floating Ball, and endoscopic staplers. RESULTS: LDH-harvested liver grafts were 44% of whole liver weight. Estimated blood loss was 300 cc. Warm ischemia time was 5-7 min. Grafts were delivered through 18-cm abdominal wounds. Major vessels and biliary anatomy were positively identified in the grafts. CONCLUSIONS: Laparoscopic LDH can be performed with available technology. Theoretical advantages include reduced liver manipulation and smaller wound size.

Hepatic artery thrombosis in pediatric liver transplantation.

PURPOSE: Children have been reported to be at greater risk for hepatic artery thrombosis when compared to adults due to small arterial size, nonuse of intraoperative microscope, and postoperative hypercoagulable state. METHODS: We evaluated arterial anastomosis type, intraoperative field magnification, and hepatic artery complications and how they were managed. All patients underwent ultrasound, anticoagulation consisted of 41 mg aspirin once a day, and 35 patients received alprostadil (PGE) for the first 7 days after transplantation. No patients were administered intravenous heparin following liver transplantation. RESULTS: Of the 74 livers transplanted, 36 grafts (48.6%) were whole organ transplants and 38 grafts (51.4%) were partial livers. We observed HAT in 1 of 74 (1.35%) transplants in our pediatric liver transplant population. The only patient with HAT was a young girl with a history of biliary atresia. The occurrence of a hepatic artery thrombosis on day 7 was caused by the migration of an intimal plaque dissection within the artery graft. She was emergently taken back into the operating room for graft revision. This individual currently has a survival time of 426 days following her last transplant. CONCLUSIONS: Hepatic artery thrombosis may be minimized in pediatric liver transplantation without the use of microsurgery. Anticoagulation utilizing ASA and alprostadil is sufficient to avoid HAT. Accurate use of ultrasound is crucial to avoid this complication. Graft and patient salvage is possible with expedient surgical treatment; microsurgery, anticoagulant therapy, site of arterial inflow, and recipient size and weight.

Biliary complications after pediatric liver transplantation revisited.

BACKGROUND: Biliary complications in pediatric liver transplantation (PLT) are associated with increased morbidity and mortality. METHODS: Prospectively, data was collected on 89 consecutive liver transplants performed in 82 children. Eighty-nine consecutive PLTs were tracked for transplant type (partial versus whole), recipient age/weight, duct anastomosis type, surgical technique, and biliary complications. Treatments of biliary complications (surgical versus interventional radiology) were also evaluated. RESULTS: Forty-six children (51.7%) received partial transplants and 43 (48.3%) children received whole organs. The average age for whole liver transplanted children was 8.95 +/- 6.62 years and average weight was 36.2 +/- 28.7 kg; for those receiving partial livers, 3.19 +/- 3.52 years and 14.1 +/- 13.0 kg. Duct-to-duct anastomosis was performed for 26 grafts and Roux-en-Y choledochojejunostomy for 63 grafts. Biliary complications occurred in 10 of 89 (11.2%) grafts. Complications included anastomotic strictures in four (40%), bile leak in five (50%), intraparenchymal biloma in one (10%). The complication rate for whole organs was 1/43 (2.3%) and 9/46 (19.6%) for partial organ (P =. 015). No difference in complication rates were seen in type of ductal anastomosis (7.7% vs 12.7%, P = NS). Reoperation for biliary complication was necessary in only 2/10 (20%) of grafts. CONCLUSIONS: Technical advances have reduced the incidence of biliary complications in PLT. Partial liver grafts have a statistically higher risk of biliary complication than whole grafts. Most biliary complications can be managed with radiological intervention without surgical exploration. Pediatric biliary complications are not associated with graft loss.

Nonresponders of interferon/ribavirin treatment for recurrent hepatitis C following liver transplantation.

BACKGROUND: Treatment of recurrent hepatitis C (HCV) following liver transplant currently includes alpha-interferon with ribavirin. OBJECTIVE: The aim of this study is to evaluate nonresponder protocols for patients failing current treatment for recurrent hepatitis C following liver transplantation. METHODS: From February 1998 through November 2002, 67 patients, all serum RNA-positive for hepatitis C with histological evidence of recurrent hepatitis C, underwent treatment with alpha-interferon and ribavirin. For patients who failed initial treatment, patients were begun on either amantadine along with interferon/ribavirin or peginterferon with ribavirin. RESULTS: Of the initial 67 patients, there was a complete viral clearance in only 14.9% (10/67). Of the 57 remaining patients not clearing the virus, 30 (52.6%) were taken off treatment due to adverse events associated with bone marrow or hemoglobin suppression. In the amantadine group (n = 12), three (25%) had to discontinue due to CNS side effects of slurred speech, dizziness, and increased depression. In the amantadine group, no patients cleared the virus but there was a one log drop in viral load (1.6 x 10(6) vs 0.9 x 10(6); P =.4). In the peginterferon group, there were three (20%) patients with complete viral clearance during treatment with similar drops to amantadine. There was also seen a biochemical response by month 3 with peginterferon, which was not seen with amantadine. CONCLUSIONS: Peginterferon with ribavirin appears to be superior to amantadine with interferon/ribavirin when used in nonresponders for hepatitis C viral clearance.

Duct-to-duct biliary anastomosis for patients with sclerosing cholangitis undergoing liver transplantation.

BACKGROUND: Due to the association of strictures within the biliary ductal system, Roux-en-Y choledochojejunostomy has been the preferred method of anastomosis for liver transplant recipients with primary sclerosing cholangitis (PSC). The aim of this study was to evaluate duct-to-duct anastomosis in patients with PSC who undergo liver transplantation. METHODS: Data were collected and evaluated based on demographics, type of anastomosis preformed, malignancies, outcomes comparisons, and survival. RESULTS: Of the 60 patients transplanted for PSC, 58 were diagnosed PSC prior to transplantation and 2 were diagnosed on explant. The Roux-en-Y group (n = 38) were similar in age, gender, and race when compared to the duct-to-duct (d-d) group (n = 22). There were similar rates of anastomotic revisions when comparing d-d anastomosis with Roux-en-Y (2 [9.1%] versus 2 [5.3%], P = NS) owing to bile leaks. Based on radiologic interventions of the bile ducts, seven (18.4%) in the Roux-en-Y group had interventions compared to two (9.1%) in the duct-to-duct group (P = NS). There was also no difference in recurrence of PSC: three (7.9%) in the Roux-en-Y group compared to two (5.3%) in the duct-to-duct group (P = NS). Survival at 4 years were similar between each group (76.5% [+/- 0.07] Roux-en-Y versus 84.9% [+/- 0.08] duct-to-duct, P = NS). CONCLUSION: Duct-to-duct anastomosis at the time of liver transplantation is both safe and efficacious when used in patients with PSC. Outcomes as described by surgical interventions, radiologic interventions, retransplantation, and survival were similar between groups.

Adult and pediatric liver transplantation for autoimmune hepatitis.

BACKGROUND: Due to the early age that pediatric patients with autoimmune hepatitis (AIH) are transplanted, it is theorized that older AIH patients may have different outcomes than pediatric patients following liver transplantation. METHODS: This is a retrospective review of both the adult and pediatric liver transplant programs consisting of 56 patients. Rejection and recurrence of AIH were determined by biopsy. RESULTS: The autoimmune patient having rejection episodes had a 1.76-fold increase in relative risk to develop autoimmune recurrence when compared to patients without rejection [RR = 1.76; 95% CIRR (1.08, 2.86)]. The pediatric group had a 6.62-fold increase in relative risk to develop colitis following liver transplantation [RR = 6.62; 95% C.I.R.R. (1.36, 32.13); P =.02]. Mean days to recurrence of AIH were similar in both groups (1364 +/- 1074 vs 936; P = NS). There were more hospitalized days in the pediatric group compared to the adults (20.5 +/- 13.3 days vs 51.7 +/- 22.2 days, P =.039). OKT-3 was rarely used (n = 5) in either group (9.3% vs 7.7%, P = NS) and was not correlated with which patients would be weaned from steroids or recurrence. CONCLUSIONS: Based on this review, pediatric patients were more likely to develop ulcerative colitis following liver transplantation and they incurred longer hospital stays than adults. The adult group was more likely to be weaned from steroids, with AIH recurrence unrelated to weaning.

Hypothyroidism following treatment for head and neck cancer.

One hundred ninety-six head and neck patients were studied to determine the effects of radiation therapy and surgery on thyroid function. Serum thyroid-stimulating hormone (TSH) levels were obtained as a screening test for primary hypothyroidism. Elevated TSH levels were found in 57 of the 196 patients (29.1%). The highest incidence of abnormal TSH values (66%) occurred in the group treated with combination radiation therapy and surgery, including partial thyroidectomy. TSH levels rose early in the posttreatment period with 60% of the abnormal values occurring within the first three posttreatment years. Posttreatment thyroid dysfunction was twice as common in women (48.6%) as in men (25.4%). When serum thyroxine levels by radioimmunoassay (T4RIA) were correlated with the elevated serum TSH levels, a similar pattern was seen with 65% of the patients in Group 3 having a decreased T4RIA level indicating overt hypothyroidism. Pretreatment levels of thyroid function including thyroid antibody studies should be established for all patients. Serial TSH levels should be done every three months during the first three posttreatment years and semiannually thereafter as long as the patient will return for follow-up care. All patients treated with combination radiation therapy and surgery who develop elevated TSH levels should be treated with thyroid replacement therapy. Patients receiving radiation therapy alone should receive replacement thyroid therapy if they develop a depressed T4RIA value or a pattern of gradually increasing TSH levels.

Stress conditioning: a novel approach to organ preservation.

Effective stress conditioning can extend the safe cold storage time of rat kidneys to 48 hours. We demonstrated that planned induction of the stress response, by heat shock, can be used to stress condition the transplant organ and protect it against the damages of cold storage. A powerful and useful protective mechanism exists in a latent form in all cells. This mechanism can be rapidly activated in a controlled and planned way to allow tissues temporarily to resist injury. Through stress conditioning it is possible to provide a high level of protection in situations in which stress can be anticipated and planned for.

Secondary carcinoma of the liver from parotid gland tumor.

Secondary tumors of the liver from primary tumors arising in organs of the head and neck are rarely diagnosed during the patient's lifetime, though they should be suspected. A case of parotid mucoepidermoid carcinoma with liver metastases, treated by liver resection, is described. The clinical features and biological behavior of this secondary tumor are similar to those of the rare primary mucoepidermoid carcinoma of the liver. This case is unique because it is such a very rare occurrence.