Enrico Regalia

Liver Transplantation for the Treatment of Small Hepatocellular Carcinomas in Patients with Cirrhosis

BACKGROUND The role of orthotopic liver transplantation in the treatment of patients with cirrhosis and hepatocellular carcinoma is controversial, and determining which patients are likely to have a good outcome after liver transplantation is difficult. METHODS We studied 48 patients with cirrhosis who had small, unresectable hepatocellular carcinomas and who underwent liver transplantation. In 94 percent of the patients, the cirrhosis was related to infection with hepatitis B virus, hepatitis C virus, or both. The presence of tumor was confirmed by biopsy or serum alpha-fetoprotein assay. The criteria for eligibility for transplantation were the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter, in patients with multiple tumors. Thirty-three patients with sufficient hepatic function underwent treatment for the tumor, mainly chemoembolization, before transplantation. After liver transplantation, the patients were followed prospectively for a median of 26 months (range, 9 to 54). No anticancer treatment was given after transplantation. RESULTS The overall mortality rate was 17 percent. After four years, the actuarial survival rate was 75 percent and the rate of recurrence-free survival was 83 percent. Hepatocellular carcinoma recurred in four patients (8 percent). The overall and recurrence-free survival rates at four years among the 35 patients (73 percent of the total) who met the predetermined criteria for the selection of small hepatocellular carcinomas at pathological review of small hepatocellular carcinomas at pathological review of the explanted liver wer 85 percent and 92 percent, respectively, whereas the rates in the 13 patients (27 percent) whose tumors exceeded these limits were 50 percent and 59 percent, respectively (P=0.01 for overall survival; P=0.002 for recurrence-free survival). In this group of 48 patients with early-stage tumors, tumor-node-metastasis status, the number of tumors, the serum alphafetoprotein concentration, treatment received before transplantation, and 10 other variables were not significantly correlated with survival. CONCLUSIONS Liver transplantation is an effective treatment for small, unresectable hepatocellular carcinomas in patients with cirrhosis.

Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: A prospective study

Objective:Determine the histologic response-rate (complete versus partial tumor extinction) after single radiofrequency ablation (RFA) of small hepatocellular carcinoma (HCC) arising in cirrhosis. Investigate possible predictors of response and assess efficacy and safety of RFA as a bridge to liver transplantation (OLT). Background:RFA has become the elective treatment of local control of HCC, although histologic data supporting radiologic assessment of response are rare and prospective studies are lacking. Prognostic impact of repeated RFA for HCC persistence is also undetermined. Methods:Percentage of RFA-induced necrosis and tumor persistence-rate at various intervals from treatment was studied in 60 HCC (median: 3 cm; Milan-Criteria IN: 80%) isolated in 50 consecutive cirrhotic patients undergoing OLT. Single-session RFA was the only treatment planned before OLT. Histologic response determined on explanted livers was related to 28 variables and to pre-OLT CT scan. Results:Mean interval RFA→OLT was 9.5 months. Post-RFA complete response rate was 55%, rising to 63% for HCC ≤3 cm. Tumor size was the only prognostic factor significantly related to response (P = 0.007). Tumor satellites and/or new HCC foci (56 nodules) were unaffected by RFA and significantly correlated with HCC >3 cm (P = 0.05). Post-RFA tumor persistence probability increased with time (12 months: 59%; 18 months: 70%). Radiologic response rate was 70%, not significantly different from histology. Major post-RFA morbidity was 8%. No mortality, Child deterioration, patient withdrawal because of tumor progression was observed. Post-OLT 3-year patient/graft survival was 83%. Conclusions:RFA is a safe and effective treatment of small HCC in cirrhotics awaiting OLT, although tumor size (>3 cm) and time from treatment (>1 year) predict a high risk of tumor persistence in the targeted nodule. RFA should not be considered an independent therapy for HCC.

Regulation of glucose homeostasis in humans with denervated livers.

The liver plays a major role in regulating glucose metabolism, and since its function is influenced by sympathetic/ parasympathetic innervation, we used liver graft as a model of denervation to study the role of CNS in modulating hepatic glucose metabolism in humans. 22 liver transplant subjects were randomly studied by means of the hyperglycemic/ hyperinsulinemic (study 1), hyperglycemic/isoinsulinemic (study 2), euglycemic/hyperinsulinemic (study 3) as well as insulin-induced hypoglycemic (study 4) clamp, combined with bolus-continuous infusion of [3-3H]glucose and indirect calorimetry to determine the effect of different glycemic/insulinemic levels on endogenous glucose production and on peripheral glucose uptake. In addition, postabsorptive glucose homeostasis was cross-sectionally related to the transplant age (range = 40 d-35 mo) in 4 subgroups of patients 2, 6, 15, and 28 mo after transplantation. 22 subjects with chronic uveitis (CU) undergoing a similar immunosuppressive therapy and 35 normal healthy subjects served as controls. The results showed that successful transplantation was associated with fasting glucose concentration and endogenous glucose production in the lower physiological range within a few weeks after transplantation, and this pattern was maintained throughout the 28-mo follow-up period. Fasting glucose (4. 55+/-0.06 vs. 4.75+/-0.06 mM; P = 0.038) and endogenous glucose production (11.3+/-0.4 vs. 12.9+/-0.5 micromol/[kg.min]; P = 0.029) were lower when compared to CU and normal patients. At different combinations of glycemic/insulinemic levels, liver transplant (LTx) patients showed a comparable inhibition of endogenous glucose production. In contrast, in hypoglycemia, after a temporary fall endogenous glucose production rose to values comparable to those of the basal condition in CU and normal subjects (83+/-5 and 92+/-5% of basal), but it did not in LTx subjects (66+/-7%; P < 0.05 vs. CU and normal subjects). Fasting insulin and C-peptide levels were increased up to 6 mo after transplantation, indicating insulin resistance partially induced by prednisone. In addition, greater C-peptide but similar insulin levels during the hyperglycemic clamp (study 1) suggested an increased hepatic insulin clearance in LTx as compared to normal subjects. Fasting glucagon concentration was higher 6 mo after transplantation and thereafter. During euglycemia/hyperinsulinemia (study 3), the insulin-induced glucagon suppression detectable in CU and normal subjects was lacking in LTx subjects; furthermore, the counterregulatory response during hypoglycemia was blunted. In summary, liver transplant subjects have normal postabsorptive glucose metabolism, and glucose and insulin challenge elicit normal response at both hepatic and peripheral sites. Nevertheless, (a) minimal alteration of endogenous glucose production, (b) increased concentration of insulin and glucagon, and (c) defective counterregulation during hypoglycemia may reflect an alteration of the liver-CNS-islet circuit which is due to denervation of the transplanted graft.

Resection versus transplantation for liver metastases from neuroendocrine tumors.

LIVER metastases from neuroendocrine tumors (NET) is the main cause of death for patient with neuroendocrine tumors originating from the intestine and pancreas. In about 90% of patients, the distribution of liver metastases is multifocal and bilateral so that curative liver resection is feasible in no more than 20% of the referred cases. Large liver metastases often cause hormone-related symptoms (carcinoid syndrome) with severe consequences on patient quality of life. Both surgical and medical treatments have been proposed for patients with liver metastases from NET (systemic and intraarterial chemotherapy, somatostatin analogues, interferon therapy) with cumulative patient survival not exceeding 25 to 35% at five years. Resective surgery with curative intent has been associated with an improved 5 year survival in nearly 50% of cases, but the number of eligible patients is low. Total hepatectomy and liver transplantation (OLT) has been advocated for patients with bilateral unresectable symptomatic liver metastases from NET although a clear consensus on stage of disease, pathological subtypes, and patient conditions amenable of transplant candidacy are still lacking. In this report, we describe our experience with 29 patients affected by liver metastases from NET who were treated with either hepatic resections or liver transplantation. Pre-transplantation selection criteria currently applied in our centre are also proposed.

Metabolic effects of liver transplantation in cirrhotic patients.

To assess whether liver transplantation (LTx) can correct the metabolic alterations of chronic liver disease, 14 patients (LTx-5) were studied 5+/-1 mo after LTx, 9 patients (LTx-13) 13+/-1 mo after LTx, and 10 patients (LTx-26) 26+/-2 months after LTx. Subjects with chronic uveitis (CU) and healthy volunteers (CON) were also studied. Basal plasma leucine and branched-chain amino acids were reduced in LTx-5, LTx-13, and LTx-26 when compared with CU and CON (P < 0.01). The basal free fatty acids (FFA) were reduced in LTx-26 with respect to CON (P < 0.01). To assess protein metabolism, LTx-5, LTx-13, and LTx-26 were studied with the [1-14C]leucine turnover combined with a 40-mU/m2 per min insulin clamp. To relate changes in FFA metabolism to glucose metabolism, eight LTx-26 were studied with the [1-14C]palmitate and [3-3H]glucose turnovers combined with a two-step (8 and 40 mU/m2 per min) euglycemic insulin clamp. In the postabsorptive state, LTx-5 had lower endogenous leucine flux (ELF) (P < 0.005), lower leucine oxidation (LO) (P < 0.004), and lower non-oxidative leucine disposal (NOLD) (P < 0.03) with respect to CON (primary pool model). At 2 yr (LTx-26) both ELF (P < 0.001 vs. LTx-5) and NOLD (P < 0.01 vs. LTx-5) were normalized, but not LO (P < 0.001 vs. CON) (primary and reciprocal pool models). Suppression of ELF by insulin (delta-reduction) was impaired in LTx-5 and LTx-13 when compared with CU and CON (P < 0.01), but normalized in LTx-26 (P < 0.004 vs. LTx-5 and P = 0.3 vs. CON). The basal FFA turnover rate was decreased in LTx-26 (P < 0.01) and CU (P < 0.02) vs. CON. LTx-26 showed a lower FFA oxidation rate than CON (P < 0.02). Tissue glucose disposal was impaired in LTx-5 (P < 0.005) and LTx-13 (P < 0.03), but not in LTx-26 when compared to CON. LTx-26 had normal basal and insulin-modulated endogenous glucose production. In conclusion, LTx have impaired insulin-stimulated glucose, FFA, and protein metabolism 5 mo after surgery. Follow-up at 26 mo results in (a) normalization of insulin-dependent glucose metabolism, most likely related to the reduction of prednisone dose, and, (b) maintenance of some alterations in leucine and FFA metabolism, probably related to the functional denervation of the graft and to the immunosuppressive treatment.

The Long-Term Benefit of Liver Transplantation for Hepatic Metastases From Neuroendocrine Tumors

Selection criteria and benefit of liver transplantation for hepatic metastases from neuroendocrine tumors (NETs) remain uncertain. Eighty‐eight consecutive patients with metastatic NETs eligible for liver transplantation according to Milan‐NET criteria were offered transplant (n = 42) versus nontransplant options (n = 46) depending on list dynamics, patient disposition, and age. Tumor burden between groups did not differ. Transplant patients were younger (40.5 vs. 55.5 years; p < 0.001). Long‐term outcomes were compared after matching between groups made on multiple Cox models adjusted for propensity score built on logistic models. Survival benefit was the difference in mean survival between transplant versus nontransplant options. No patients were lost or died without recurrence. Median follow‐up was 122 months. The transplant group showed a significant advantage over nontransplant strategies at 5 and 10 years in survival (97.2% and 88.8% vs. 50.9% and 22.4%, respectively; p < 0.001) and time‐to‐progression (13.1% and 13.1% vs. 83.5% and 89%; p < 0.001). After adjustment for propensity score, survival advantage of the transplant group was significant (hazard ratio = 7.4; 95% confidence interval (CI): 2.4–23.0; p = 0.001). Adjusted transplant‐related survival benefit was 6.82 months (95% CI: 1.10–12.54; p = 0.019) and 38.43 months (95% CI: 21.41–55.45; p < 0.001) at 5 and 10 years, respectively. Liver transplantation for metastatic NETs under restrictive criteria provides excellent long‐term outcome. Transplant‐related survival benefit increases over time and maximizes after 10 years.

Changes in alpha-1 and beta-2 adrenoceptor density in human hepatocellular carcinoma

Catecholamines are involved critically in the mechanisms of liver cell proliferation by acting on hepatic alpha‐1 and beta‐2 adrenoceptors. To identify the role of these receptors in human hepatocellular carcinoma (HCC), the density was examined of alpha‐1 and beta‐2 adrenoceptors with their affinity and coupling of beta‐2 adrenoceptors to adenylate cyclase in HCC tissue and in nonadjacent/nontumor tissue from the same livers. Studies were also done on healthy livers from age‐matched and sex‐matched patients undergoing abdominal surgery for nonhepatic diseases. Twenty‐two HCC had a decrease of about 72% in alpha‐1 adrenoceptor density compared with their nonadjacent/nontumor tissue and a decrease of about 40% compared with healthy controls. Nonadjacent/nontumor tissue from HCC patients had a 125% increase in alpha‐1 adrenoceptor density compared with healthy livers. Twenty‐three of 24 HCC had an increase of about 180% in beta adrenoceptor density compared with their nonadjacent/nontumor tissue and healthy controls. Beta adrenoceptors were coupled to adenylate cyclase, as evidenced by a guanosine triphosphate‐mediated right shift in (–)‐isoproterenol competition isotherms and by cyclic adenosine monophosphate (cAMP) production after stimulation with (–)‐isoproterenol. The HCC tissue yielded a larger increase in cAMP than nonadjacent/nontumor tissue and healthy controls. The authors conclude that a higher density of alpha‐1 adrenoceptors in nonadjacent/nontumor tissue from HCC characterizes the “healthy” part of the liver in HCC patients and that an increase in beta‐2 and a decrease in alpha‐1 adrenoceptor densities characterize the tumor part of the liver in human HCC.

Outcome of pregnancy after organ transplantation: a retrospective survey in Italy

The number of women who decide to have a child after organ transplantation has increased. We determined the outcomes of 67 pregnancies of women who had undergone kidney, liver or heart transplantation. All recipients had been maintained on immunosuppressive therapy before and during pregnancy. Pregnancy complications at term were observed in 17 out of 67 women (25%), hypertension being the most frequent complication (16.17%). Two transplant rejections were reported. Sixty-eight infants were delivered (including one pair of twins); five women had two pregnancies at term. Twenty-eight miscarriages (29.2%) were recorded. Of these 68 babies (including the pair of twins), 40 (58.8%) were born at term and 28 (41.2%) before term. The babies were followed-up for 2 months to 13 years. According to our previous experience, our study shows that patients who have undergone organ transplantation can give birth to healthy infants as long as they are monitored accurately during pregnancy.

Assessment of insulin sensitivity based on a fasting blood sample in men with liver cirrhosis before and after liver transplantation.

Background. Insulin resistance is a key factor in the pathogenesis of hepatogenous diabetes and influences the prognosis of chronic liver diseases. In vivo assessment of insulin resistance in humans is expensive; therefore, surrogate indices based on a fasting plasma glucose and insulin concentrations (HOMA-IS, QUICKI) were proposed. This study aimed to test whether these simple indices are reliable measures of insulin sensitivity in patients with liver cirrhosis before and after liver transplantation (LTx). Methods. HOMA-IS and QUICKI were compared with insulin sensitivity as assessed with the gold standard technique (insulin clamp) in 20 patients with liver cirrhosis, in 36 patients after LTx, and in 25 matched healthy subjects (predominantly men). To test whether these indices may be applied also in prospective studies, 10 patients with liver cirrhosis were studied longitudinally before and 2 years after LTx. Results. Both HOMA-IS and QUICKI were associated with insulin sensitivity in patients with liver cirrhosis (r =0.63, P =0.005 and r =0.60, P =0.009) and in LTx patients (r =0.41, P =0.02 and r =0.46, P =0.05). Both were able to detect the improvement of insulin sensitivity after LTx in the patients studied prospectively. Conclusions. HOMA-IS and QUICKI are simple reliable tools to assess insulin sensitivity in clinical and epidemiologic investigations of chronic liver disease before and after LTx.

Donor safety in living donor liver donation: An Italian multicenter survey

Major concerns about donor morbidity and mortality still limit the use of living donor liver transplantation (LDLT) to overcome the organ shortage. The present study assessed donor safety in LDLT in Italy reporting donor postoperative outcomes in 246 living donation procedures performed by 7 transplant centers. Outcomes were evaluated over 2 time periods using the validated Clavien 5‐tier grading system, and several clinical variables were analyzed to determine the risk factors for donor morbidity. Different grafts were obtained from the 246 donor procedures (220 right lobe, 10 left lobe, and 16 left lateral segments). The median follow‐up after donation was 112 months. There was no donor mortality. One or more complications occurred in 82 (33.3%) donors, and 3 of them had intraoperative complications (1.2%). Regardless of graft type, the rate of major complications (grade ≥ 3) was 12.6% (31/246). The overall donor morbidity and the rate of major complications did not differ significantly over time: 26 (10.6%) donors required hospital readmission throughout the follow‐up period, whereas 5 (2.0%) donors required reoperation. Prolonged operative time (>400 minutes), intraoperative hypotension (systolic < 100 mm Hg), vascular abnormalities, and intraoperative blood loss (>300 mL) were multivariate risk factors for postoperative donor complications. In conclusion, from the standpoint of living donor surgery, a meticulous and well‐standardized technique that reduces operative time and prevents blood loss and intraoperative hypotension may reduce the incidence of donor complications. Transparency in reporting results after LDLT is mandatory, and we should continue to strive for zero donor mortality. Liver Transplantation 23 184–193 2017 AASLD