Nicholas N. Nissen

Race, ethnicity, and socioeconomic status influence the survival of patients with hepatocellular carcinoma in the United States

Racial, ethnic, and socioeconomic disparities in the survival of patients with hepatocellular carcinoma (HCC) continue to exist. The authors of this report hypothesized that these differences result from inequities in access to care and in response to therapy.

Predictors of Survival After In Vivo Split Liver Transplantation: Analysis of 110 Consecutive Patients

ObjectiveTo determine the factors that influence patient survival after in vivo split liver transplantation (SLT). Summary Background DataSplit liver transplantation is effective in expanding the donor pool, and its use reduces the number of deaths in patients awaiting orthotopic liver transplantation. Early SLTs were associated with poor outcomes, and acceptance of the technique has been slow. A better understanding of the factors that influence patient and graft survival would be useful in widening the application of SLT. MethodsDuring a 3.5-year period, 55 right and 55 left lateral in vivo split grafts were transplanted in 102 pediatric and adult recipients. The authors’ in vivo split technique has been previously described. Median follow-up was 14.5 months. Recipient, donor, and surgical variables were analyzed for their effect on patient survival after SLT. ResultsOverall survival rates of patients who received an SLT were not significantly different from those of patients who received whole organ transplants. Survival of left lateral segment recipients, at median follow-up time, was 76% versus 80% in patients receiving a trisegment. Fifty of 102 patients (49%) were high-risk urgent recipients (United Network for Organ Sharing [UNOS] status 1 and 2A) and 52 (51%) were nonurgent recipients (UNOS status 2B, 3). High-risk recipients had a survival rate significantly lower than that of nonurgent recipients. By univariate comparison, two variables—UNOS status and number of transplants per patient—were significantly associated with an increased risk of death. Preoperative recipient mechanical ventilation, preoperative prothrombin time, donor sodium level, donor length of hospital stay, and warm ischemia time approached significance. The type of graft (right vs. left) did not reduce the survival rate after transplantation. Multivariate logistic regression analysis identified UNOS status and length of donor hospital stay as independent predictors of survival. ConclusionsPatient survival of in vivo SLT is not significantly different from that of whole-organ orthotopic liver transplantation. The variables affecting outcome of in vivo SLT are similar to those in whole-organ transplantation. in vivo SLT should be widely applied to expand a severely depleted donor pool.

Homozygous P86s Mutation of the Human Glucagon Receptor Is Associated With Hyperglucagonemia, α Cell Hyperplasia, and Islet Cell Tumor

Objective: The goal of the study was to investigate the genetic and molecular basis of a novel syndrome of marked hyperglucagonemia and pancreatic &agr; cell hyperplasia without glucagonoma syndrome. Methods: The glucagon receptor (GCGR) gene and the glucagon gene were sequenced in a patient with hyperglucagonemia and pancreatic &agr; cell hyperplasia without glucagonoma syndrome. Enhanced green fluorescent protein-conjugated wild type (WT) and mutant GCGR were used to characterize the functions of the mutant GCGR. Results: The glucagon gene sequence was normal, but the GCGR sequencing uncovered a homozygous missense mutation, c.256C>T, p.P86S in the extracellular domain of GCGR. When expressed in human embryonic kidney 293 cells, GCGR P86S localized to the plasma membrane but bound 96% less radiolabeled glucagon than WT GCGR. The median effective concentration of glucagon-induced cyclic adenosine monophosphate production was 24 nmol/L for GCGR P86S but 2.4 nmol/L for WT GCGR. The patients &agr; cells also express glucagonlike peptide 1 and pancreatic polypeptide. Conclusions: We hereby report the first homozygous missense mutation in the human GCGR, which is associated with &agr; cell hyperplasia and hyperglucagonemia. This mutation lowers the receptors affinity to glucagon and decreases cyclic adenosine monophosphate production with physiological concentrations of glucagon. Thus, the P86S mutation in GCGR likely causes &agr; cell hyperplasia and hyperglucagonemia.

Phosphorus ans an early predictive factor in patients with acute liver failure1

Background. This study analyzes the prognostic significance of serum phosphorus in patients with acute liver failure (ALF). Methods. We performed a retrospective analysis of 112 patients with ALF. Univariate and bivariate analyses based on Kaplan-Meier recovery curves and a multivariate Classification Tree Structure Survival Analysis were performed to identify independent predictors of outcome. The variables analyzed were age, gender, race, ABO blood group, etiology of liver disease, grade of encephalopathy, serum bilirubin, prothrombin time, creatinine, serum phosphorus, phosphorus administered, phosphorus binders, and hemodialysis. Results. The median follow-up time was 5 days, the median age was 28 years, and 62% of the patients were female. The patients’ outcomes were as follows: 28% recovered, 52% required orthotopic liver transplantation, and 20% died. White patients showed the best prognosis (58% recovered in the first week), and Hispanics showed the worst prognosis (0.3% recovered at 1 week) (P =0.0001). Encephalopathy and bilirubin were significant predictors of recovery (P <0.0001 and P =0.004). The analysis of the serum phosphorus showed a statistically significant better prognosis in patients with low phosphorus (P <0.001). The recovery rate at 1 week was 74% in patients with serum phosphorus less than 2.5 mg/dL, 45% if phosphorus ranged between 2.5 to 5 mg/dL, and 0% if phosphorus was more than 5 mg/dL. The bivariate analysis on the effects of phosphorus administration showed that phosphorus replacement was associated with a significant improvement in recovery in patients with low (P <0.004) or normal serum phosphorus levels (P <0.017) Conclusions. Hypophosphatemia and early phosphorus administration are associated with a good prognosis in ALF, whereas hyperphosphatemia is predictive of poor recovery.

Fructose Induces Transketolase Flux to Promote Pancreatic Cancer Growth

Carbohydrate metabolism via glycolysis and the tricarboxylic acid cycle is pivotal for cancer growth, and increased refined carbohydrate consumption adversely affects cancer survival. Traditionally, glucose and fructose have been considered as interchangeable monosaccharide substrates that are similarly metabolized, and little attention has been given to sugars other than glucose. However, fructose intake has increased dramatically in recent decades and cellular uptake of glucose and fructose uses distinct transporters. Here, we report that fructose provides an alternative substrate to induce pancreatic cancer cell proliferation. Importantly, fructose and glucose metabolism are quite different; in comparison with glucose, fructose induces thiamine-dependent transketolase flux and is preferentially metabolized via the nonoxidative pentose phosphate pathway to synthesize nucleic acids and increase uric acid production. These findings show that cancer cells can readily metabolize fructose to increase proliferation. They have major significance for cancer patients given dietary refined fructose consumption, and indicate that efforts to reduce refined fructose intake or inhibit fructose-mediated actions may disrupt cancer growth.

Hepatocellular carcinoma: the high-risk patient.

Hepatocellular carcinoma (HCC) is the most common hepatic malignancy worldwide. The primary risk factor for the development of HCC is cirrhosis. Even patients without cirrhosis who develop HCC are typically found to have some underlying hepatic abnormality, such as steatohepatitis or chronic viral hepatitis. Although cirrhosis of any cause increases the risk of developing HCC, cirrhosis associated with chronic hepatitis B or C virus infection or hemochromatosis carries the greatest risk. Additional factors such as patient age and sex, duration and severity of liver disease, concurrent alcohol or aflatoxin exposure, liver histology, and alpha-fetoprotein levels also contribute to the relative risk of developing HCC. Vaccination programs aimed at preventing hepatitis B virus infection have been very successful in lowering the incidence of HCC in some areas of the world. Interferon-based therapy, which may control the inflammatory activity in chronic hepatitis C, also holds promise in preventing HCC. Other novel chemopreventative agents, such as glycyrrhizin and polyprenoic acid, may also have a role in preventing HCC, but they require further study before they can be recommended for widespread use.

Virologic and Clinical Outcomes of Hepatitis B Virus Infection in HIV-HBV Coinfected Transplant Recipients

Liver transplantation (LT) is the treatment of choice for end‐stage liver disease, but is controversial in patients with human immunodeficiency virus (HIV) infection. Using a prospective cohort of HIV‐hepatitis B virus (HBV) coinfected patients transplanted between 2001–2007; outcomes including survival and HBV clinical recurrence were determined. Twenty‐two coinfected patients underwent LT; 45% had detectable HBV DNA pre‐LT and 72% were receiving anti‐HBV drugs with efficacy against lamivudine‐resistant HBV. Post‐LT, all patients received hepatitis B immune globulin (HBIG) plus nucleos(t)ide analogues and remained HBsAg negative without clinical evidence of HBV recurrence, with a median follow‐up 3.5 years. Low‐level HBV viremia (median 108 IU/mL, range 9–789) was intermittently detected in 7/13 but not associated with HBsAg detection or ALT elevation. Compared with 20 HBV monoinfected patients on similar HBV prophylaxis and median follow‐up of 4.0 years, patient and graft survival were similar: 100% versus 85% in HBV mono‐ versus coinfected patients (p = 0.08, log rank test). LT is effective for HIV‐HBV coinfected patients with complications of cirrhosis, including those who are HBV DNA positive at the time of LT. Combination HBIG and antivirals is effective as prophylaxis with no clinical evidence of HBV recurrence but low‐level HBV DNA is detectable in ∼50% of recipients.

Living donor liver transplantation : Histological abnormalities found on liver biopsies of apparently healthy potential donors

Objective:  With the continued shortage of deceased donor grafts, living donor liver transplantation has become an option for adult liver transplant candidates. In the non‐transplant setting, liver biopsy is typically carried out to evaluate clinical or biochemical hepatic dysfunction. In living donor liver transplantation, assessment of histological abnormalities that are undetectable by serological, biochemical and radiological methods might play an important role in donor and recipient outcome.

MELD Score Is an Important Predictor of Pretransplantation Mortality in HIV-Infected Liver Transplant Candidates

BACKGROUND & AIMS Human immunodeficiency virus (HIV) infection accelerates liver disease progression in patients with hepatitis C virus (HCV) and could shorten survival of those awaiting liver transplants. The Model for End-Stage Liver Disease (MELD) score predicts mortality in HIV-negative transplant candidates, but its reliability has not been established in HIV-positive candidates. METHODS We evaluated predictors of pretransplantation mortality in HIV-positive liver transplant candidates enrolled in the Solid Organ Transplantation in HIV: Multi-Site Study (HIVTR) matched 1:5 by age, sex, race, and HCV infection with HIV-negative controls from the United Network for Organ Sharing. RESULTS Of 167 HIVTR candidates, 24 died (14.4%); this mortality rate was similar to that of controls (88/792, 11.1%, P = .30) with no significant difference in causes of mortality. A significantly lower proportion of HIVTR candidates (34.7%) underwent liver transplantation, compared with controls (47.6%, P = .003). In the combined cohort, baseline MELD score predicted pretransplantation mortality (hazard ratio [HR], 1.27; P < .0001), whereas HIV infection did not (HR, 1.69; P = .20). After controlling for pretransplantation CD4(+) cell count and HIV RNA levels, the only significant predictor of mortality in the HIV-infected subjects was pretransplantation MELD score (HR, 1.2; P < .0001). CONCLUSIONS Pretransplantation mortality characteristics are similar between HIV-positive and HIV-negative candidates. Although lower CD4(+) cell counts and detectable levels of HIV RNA might be associated with a higher rate of pretransplantation mortality, baseline MELD score was the only significant independent predictor of pretransplantation mortality in HIV-infected liver transplant candidates.

Ki-67 proliferative index predicts progression-free survival of patients with well-differentiated ileal neuroendocrine tumors

Ki-67 proliferative index (Ki-67 index) is suggested to be an important prognostic variable and is included as one of the grading parameters for neuroendocrine tumors. The present study was undertaken to determine the usefulness of the Ki-67 index and the corresponding tumor grade in predicting progression-free survival (PFS) of patients with ileal well-differentiated neuroendocrine tumors (wNETs). Tumors from 57 patients with ileal wNETs were studied. Immunohistochemical staining for Ki-67 was performed on the primary as well as selected metastatic tumors and quantitated by computer-assisted image analysis using the Ariol system. The tumors were graded based on mitotic activity and Ki-67 index. Clinical and pathological variables affecting the PFS were analyzed. There were 29 women and 28 men, with a mean age of 59 years. At the time of initial presentation, 8 patients (14%) had localized disease (stages I and II), 29 patients (51%) had regional (nodal/mesenteric) spread (stage III), and 20 patients (35%) had distant metastasis (stage IV). Twelve patients experienced disease progression during subsequent follow-up. Patients with initial stage IV disease were more likely to experience disease progression (P = .005). Additionally, higher histological grade (as determined by Ki-67 index >2%) was associated with a decreased PFS (P = .001). Ki-67 index greater than 2% at either the primary site or the metastatic site was found to be the only significant predictor of PFS after consideration of all other variables in an adjusted analysis. In conclusion, the Ki-67 index predicts PFS of patients with ileal wNETs.