Roger L. Jenkins

Liver transplantation for primary hepatic cancer.

Although early survival following transplantation for primary hepatic cancer is excellent, previously reported high recurrence rates have generally discouraged liver replacement for this indication. Since the inception of the Boston Center for Liver Transplantation (BCLT) in 1983, 33 of 383 (8.6%) liver allograft recipients have undergone orthotopic transplantation as definitive treatment for otherwise unresectable cancer. Diagnoses included hepatocellular carcinoma (HCCA) in 24 patients (73%), and cholangiocarcinoma (CHCA) in 9 patients (27%). Actuarial survival rates for patients with hepatocellular carcinoma were 71%, 56%, and 42% at 1, 2, and 3 years, respectively. The actuarial survival rates for patients with cholangiocarcinoma were 89% at 6 months, and 56% at 1, 2, and 3 years. Of the nine patients with cholangiocarcinoma, 56% (5/9) developed recurrent disease. Although this recurrence rate is disheartening, because of the lack of other morbidity, long-term survival in these patients is comparable to patients with HCCA. In contrast, recurrent hepatocellular carcinoma developed in 25% of recipients (5/20) who survived longer than 3 months posttransplantation. Other causes of death in patients with hepatocellular carcinoma included perioperative complications, 16.6% (4/24); sepsis, 8.3% (2/24); coronary artery disease, 4.2% (1/24); and lymphoma, 4.2% (1/24). Favorable prognostic factors included: primary tumor less than 3 cm in size and absence of associated cirrhosis. These results emphasize that orthotopic liver transplantation can provide a long-term cure for approximately 50% of patients whose primary hepatic malignancy is unresectable by conventional procedures.

Surgical management of nonparasitic cystic liver disease

We report clinical features, surgical management, recurrences, and follow-up study of 12 patients with simple hepatic cyst, 11 patients with polycystic liver disease, and 19 patients with cystadenoma who were surgically treated over a 25-year period. The median age of patients was 48 years, and 37 women and 5 men were in the series. The most common presenting symptom and physical finding were chronic abdominal pain and tenderness in the right upper quadrant. The most commonly associated disease was polycystic kidney disease, which was an associated finding in 5 of the 11 patients with polycystic liver disease (45%). The most valuable diagnostic studies in all groups were computed tomography and ultrasonography. The location of the disease was bilobar in patients with polycystic liver disease, with a right lobe predominance in 18% of patients. The right lobe was also predominant in 83% of patients with simple hepatic cyst and 58% of patients with cystadenoma. Of all solitary cystic lesions in the left lobe, 75% of them were cystadenomas. Of the 66 surgical procedures performed, aspiration was associated with a failure rate of 100%; partial excision, a failure rate of 61%; and total excision and liver resection, a failure rate of 0%. Orthotopic liver transplantation was performed in three patients and was associated with two early deaths. Partial excision relieved symptoms in three patients (43%) with polycystic liver disease. Total excision, enucleation, or liver resection with cyst(s) is the treatment of choice for non-parasitic cystic lesions of the liver.

Graft Function And Outcome Of Older (≥60 Years) Donor Livers

Livers from donors > or = 60 years of age are often considered inadequate for transplantation by many centers. With waiting times exceeding 1 year in our region, we have aggressively used livers from this donor age group. Between 1990 and 1994, 209 patients received 223 liver grafts at our institution. Of these, 29 (13%) were from donors > or = 60 years of age (group A) and 194 (87%) were from donors < 60 years of age (group B). The two groups were matched for recipient diagnosis and severity of disease. Group A and B donors had similar liver, renal, and hematologic studies prior to donation. Weight, sex, race and vasopressor requirement were also similar. Postoperative alanine aminotransferase, aspartate aminotransferase,and prothrombin time were not significantly different over the first 10 postoperative days. Group A grafts were significantly more cholestatic than group B grafts on postoperative days 6-10. The retransplantation rate for primary graft nonfunction was not significantly different from group A (6.7%) and group B (3.4%; P=0.04). Patient and graft survival rates at 1 year were 58.6 % and 44.8% for group A and 79.2% and 74.5% for group B (P<0.001 for both). Four of 12 deaths in the first year in group A were completely unrelated to graft function. If these are excluded, patient and graft survival rates were 68% and 52%, which are better but still significantly less than in group B. Initial graft function of older donor livers are similar to that of the matched younger group. However, patient and graft survival rates were significantly worse for the older donors, even when corrected for unrelated deaths. Livers should not be discarded based on age alone without inspection and/or biopsy to rule out significant steatosis. Prompt retransplantation for primary graft nonfunction of older donors are generally more cholestatic than those from the younger donor age group; however, many of them function quite well. At the present time, given the inability to identify donor variables associated with decreased recipient survival, we recommend cautious use of older liver grafts in healthier recipients.

Nutrition in Patients Undergoing Orthotopic Liver Transplant

Thirteen patients with severe liver disease had nutritional assessment in the weeks prior to orthotopic liver transplantation. Parameters measured included height and weight, upper arm anthropometry, delayed cutaneous hypersensitivity, total lymphocyte count, serum levels of albumin and transferrin, and plasma amino acids. Weight, when expressed as a percentage of ideal body weight, was greater than 85%, considered the normal lower limit, in all but two patients. However, mean triceps skinfold and arm muscle circumference were 49 +/- 25 and 78 +/- 9% standard, respectively. Mean serum albumin was 2.7 +/- 0.6 g/dl and although mean serum transferrin level was 184 +/- 86, eight patients had levels less than normal. Seven patients were anergic to Multitest CMI (58%) and 12 patients had depressed total lymphocyte count. All these later measurements in the aggregate support a diagnosis of protein-calorie malnutrition. High preoperative levels of amino acids, especially aspartate, phenylalanine, tyrosine, and methionine, were returned to normal by transplantation. We conclude that protein-calorie malnutrition is common in the group of patients likely to require liver transplant, although individual nutritional assessment parameters may lack sensitivity and specificity in determining nutritional status.

Hepatic retransplantation in New England - A regional experience and survival model

Hepatic retransplantation (reTx) offers the only alternative to death for patients who have failed primary hepatic transplantation (PTx). Assuming a finite number of donor organs, reTx also denies the chance of survival for some patients awaiting PTx. The impact of reTx on overall survival (i.e., the survival of all candidates for transplantation) must therefore be clarified. Between 1983 and 1991, 651 patients from the New England Organ Bank underwent liver transplantation, and 73 reTx were performed in 71 patients (11% reTx rate). The 1-year actuarial survival for reTx (48%) was significantly less than for PTx (70%, P < 0.05). This survival varied, dependent on the interval of time following PTx in which the reTx was performed (0-3 days, 57% survival; 4-30 days, 24%; 30-365 days, 54%; and > 365 days, 83%). Patients on the regional waiting list had an 18% mortality rate while awaiting transplantation. These results were incorporated into a mathematical model describing survival as a function of reTx rate, assuming a limited supply of donor livers. ReTx improves the 1-year survival rate for patients undergoing PTx but decreases overall survival (survival of all candidates) for liver transplantation. In the current era of persistently insufficient donor numbers, strategies based on minimizing the use of reTx, especially in the case of patients in whom chances of success are minimal, will result in the best overall rate of patient survival.

L-[1-13C] phenylalanine oxidation as a measure of hepatocyte functional capacity in end-stage liver disease**

Background Liver disease is associated with impaired metabolism of these amino acids phenylalanine and tyrosine. Decreased metabolism of these amino acids leads to abnormal plasma elevations and impaired clearance rates. We have developed a noninvasive breath test that measures hepatic cytosolic enzyme activity. Methods The rate of hepatic phenylalanine metabolism was quantitatively calculated from the appearance of 13 CO 2 in the breath using the non-radioactive tracer L-[1- 13 C]phenylalanine. Results Normal controls (n = 47) oxidized phenylalanine more than twice that of end-stage liver disease patients (n = 117). Significant differences in the percent of phenylalanine oxidized per hour (mean ± SEM) were found between controls (7.08% ± 0.33%, 95% Cl: 6.42%–7.74%) and Child Pugh classification patients, class A (4.96% ± 0.69%, 95% Cl: 3.50%–6.42%), class B (2.88% ± 0.13, 95% Cl: 2.39%–3.38%) and class C (1.75% ± 0.13, 95% Cl: 1.50%–2.01%). The phenylalanine breath test score significantly correlated with albumin levels, prothrombin time and total bilirubin. Conclusion We have demonstrated that phenylalanine oxidation is significantly decreased with end-stage liver disease and is correlated with the best clinical measures of liver disease.

Whole body leucine, phenylalanine, and tyrosine kinetics in end-stage liver disease before and after hepatic transplantation

The kinetics of leucine, phenylalanine, and tyrosine metabolism following orthotopic human liver transplantation in end-stage liver disease in hospitalized patients were evaluated and compared to controls. The investigation was carried out by protein turnover studies using 13C leucine, D5-phenylalanine, and [U-14C] tyrosine by continuous infusion and employing a stochastic model in 32 patients with end-stage liver disease, 17 of whom went on to receive an hepatic allograft, and 7 controls without significant liver disease who underwent elective abdominal surgery. Mean tyrosine flux in the liver disease group was 3,242 +/- 811 (n = 32) v 2,899 +/- 688 mumol/h in controls (n = 7) (P less than .001), while the tyrosine oxidation was 328 +/- 179 v 422 +/- 185 mumol/h (P less than .001). Tyrosine clearance in pretransplant patients was 719 +/- 345 (n = 17) v 1,193 +/- 568 mL/min (P less than .005) in posttransplant patients (n = 17) with virtually no overlap. There was a significant correlation between serum albumin levels and the tyrosine clearance (r = .60, P less than .05), but correlations with other conventional liver function tests were of a low order. Leucine and phenylalanine kinetics in liver disease patients did not show any significant differences from controls. Leucine and tyrosine fluxes in controls did exhibit a significant correlation (r = .70, P less than .05), but no correlation was observed in patients with liver disease. These findings indicate that the kinetics of the amino acid tyrosine are substantially altered by end-stage liver disease, with the most profound effect on tyrosine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Experience with transplantation in the treatment of liver cancer

SummaryThirteen patients with hepatic tumors, from the Boston Center for Liver Transplantation, have been transplanted among a total of 169 recipients. Ten were transplanted primarily for tumor, while three other patients harbored incidental tumors. Two perioperative deaths occurred (15%). Eight patients had hepatocellular carcinoma, one hepatoblastoma and four bile duct (Klatskin) tumors. Two of the bile duct cancers recurred with patient deaths at 9 and 10 months. The remaining nine patients are alive from between 1 month and 36 months postoperatively. A selected review of the literature allowed analysis of followup on 185 patients transplanted for tumor. Overall, the proportion of patients transplanted for tumor was 16%. Fifty-two percent of patients had hepatocellular carcinomas (HCC), 24% cholangiocarcinomas, 10% other primary liver tumors, and 14% metastatic hepatic tumors. Median survival for HCC was 1 year; 90-day mortality was 30%. Actuarial survival for 1, 2 and 3 years was 49%, 37% and 30% respectively. Fibrolamellar HCC and incidental HCC had significantly better results than other HCC. Tumor recurrence was present in 72% of autopsies after 90 days. Transplantation for HCC has satisfactory results in selected patients and may be improved by adjuvant chemotherapy. The median survival with cholangiocarcinomas was 8 months; 90-day mortality was 40%. Actuarial survival for 1 year was 36%. Recurrence was present in 100% of autopsies after 90 days. Survival after transplantation for this tumor was similar to that observed in patients not undergoing surgical treatment. Median survival for 18 other primary hepatic tumors was 16 months. Transplantation in carefully selected patients with these other primary tumors appears warranted. Although experience overall with transplantation for metastatic disease has been relatively unfavorable, each histological type must be considered independently.

Human hepatocyte isolation and transplantation into an athymic rat, using prevascularized cell polymer constructs

Human hepatocyte viability and function in vivo in an athymic rat was assessed after transplantation on prevascularized polymer constructs with hepatotrophic stimulation. Sixteen liver biopsy specimens, weighing 5 to 12 g, were obtained from the New England Organ Bank and from the operating room after liver resection. In the laboratory they were catheterized and perfused to obtain liver cell suspensions. From eight of the 16 cell suspensions, only in vitro studies were performed. They showed 40% cell attachment 24 hours after initial cell plating. For patients aged 2, 35, and 60 years, they showed a 20% increase, a 1% decrease, and a 57% decrease (respectively) in cell number from day 2 to day 4, after cell plating. Eight cell suspensions were transplanted into athymic rats. On sections examined histologically, implanted hepatocytes were seen within the fibroblast ingrowth, in the space of the polymer device, until day 21 after cell injection. On day 9 after hepatocyte injection, reorganized hepatic parenchyma was seen on the tissue section. Implanted hepatocyte areas, quantitated through morphometric analysis on days 0, 3, and 7, showed a 36% increase in engraftment 3 days after injection, and a 42% decrease 7 days after injection. At the same time-points, immunoperoxidase staining visualized intracellular albumin, which was specific for the implanted hepatocytes. In conclusion, the authors demonstrated the feasibility of their technique (prevascularized polymer device with hepatotrophic stimulation), using human hepatocytes. Further studies are underway, before implementation of human clinical trials.

Effectiveness of orthotopic liver transplantation on the restoration of cholesterol metabolism in patients with end-stage liver disease

The effects of end-stage liver disease and orthotopic liver transplantation on components that modulate cholesterol esterification in plasma were assessed. In comparison with healthy controls, patients with end-stage liver disease had significantly decreased concentrations of lecithin-cholesterol acyltransferase mass, apolipoprotein A-1, total phospholipids, and both total and esterified cholesterol. Elevated phosphatidylcholine and reduced lysophosphatidylcholine fractions indicated impairment of cholesterol esterification by lecithin-cholesterol acyltransferase. Constituent fatty acids of the patients phospholipids and cholesterol esters manifested increased saturation and a concomitant reduction of polyunsaturated fatty acids, indicative of impaired hepatic elongation and desaturation of essential fatty acids. By the third month after hepatic replacement, the plasma concentrations of total cholesterol, phospholipids, lecithin-cholesterol acyltransferase, and apolipoprotein A-1 were comparable to those of the healthy subjects. Despite the improvement in cholesterol esterification and the rapid normalization of the enzyme and cofactor involved in this process, the percentage of phosphatidylcholine remained significantly higher and the percentages of lysophosphatidylcholine and esterified cholesterol remained significantly lower than in the healthy subjects at 6 mo. Phospholipid and cholesterol ester fatty acid patterns attained normalcy by the sixth month after transplant. We conclude that hepatic transplantation effectively restores cholesterol and essential fatty acid metabolism in patients with end-stage liver disease.