Hepatocellular Carcinoma Arising in an HNF-1α-Mutated Adenoma in a 23-Year-Old Woman with Maturity-Onset Diabetes of the Young: A Case Report.

Hepatocyte nuclear factor-1α mutated hepatocellular adenomas (H-HCA) are thought to have no to minimal malignant potential. This report describes a 23-year-old woman with maturity-onset diabetes of the young who developed a 12.5-cm hepatic mass with a radiographically and pathologically distinct 3.0-cm region. Histologically and immunohistochemically, the bulk of the mass was an H-HCA with extensive pseudoglandular formation and only focal steatosis. The 3.0-cm nodule showed small cell change, thickened hepatocyte plates, pleomorphic and hyperchromatic nuclei, reticulin loss, and stromal and vascular invasion, diagnostic of hepatocellular carcinoma (HCC). Immunohistochemically, increased expression of glutamine synthetase in tumor cells and CD34 expression in sinusoidal endothelial cells were seen in the HCC component. Nuclear expression of ß-catenin, and exon 3 of CTNNB1 and TERT promoter mutations were absent in this case. Thus, we report a HCC arising in an H-HCA; although cases appear exceedingly rare, they reinforce the potential of H-HCA for malignant transformation.

Pre-transplant left ventricular diastolic dysfunction is associated with post transplant acute graft rejection and graft failure.

INTRODUCTION: Acute cellular rejection (ACR) is a significant cause of morbidity and graft failure in liver transplant recipients (LTR). Diastolic dysfunction (DD) is frequently present in patients with cirrhosis undergoing liver transplantation. However, it is unclear if DD leads to ACR. METHODS: Data was collected retrospectively for consecutive LTR between January 2000 and December 2010. Demographic data and mortality related data was obtained from social security index. Primary outcome was biopsy proven ACR. Graft failure and all-cause mortality were also evaluated. DD was evaluated as a predictor of these outcomes. Other echocardiographic indices were also assessed as predictors of ACR by using Cox proportional hazard modeling adjusted for covariates. RESULTS: A total of 970 LTR (mean age 53.2 ± 10 years, women 34.6 % and white 64.5 %) were followed for 5.3 ± 3.4 years. Patients with DD (n = 145, 14.9 %) were significantly more likely to develop ACRs (HR 10.56; 95 % CI 6.78-16.45, p value = 0.0001) as well as graft failure (HR 2.09; 95 % CI 1.22-3.59, p value = 0.007) and all-cause mortality (HR 1.52; 95 % CI 1.08-2.13, p = 0.01). There was an increase in the risk of these outcomes with worsening of DD, when adjusted for various risk factors such as donor and recipient age, gender, race, Framingham risk score, pre-transplant MELD, transplant etiology and cold ischemia time. CONCLUSION: Pre-transplant DD is significantly associated with increased risk of allograft rejection, graft failure and mortality. This signifies the importance of cardiac evaluation during the pre-transplant period.

Decision making in liver transplant selection committees: a multicenter study.

BACKGROUND: To receive a liver transplant, patients must first be placed on a waiting list-a decision made at most transplant centers by a multidisciplinary committee. The function of these committees has never been studied. OBJECTIVE: To describe decision making in liver transplant committees and identify opportunities for process improvement. DESIGN: Observational multicenter study. SETTING: 4 liver transplant centers in the United States. PARTICIPANTS: 68 members of liver transplant committees across the 4 centers. MEASUREMENTS: 63 meetings were observed, and 50 committee members were interviewed. Recorded transcripts and field notes were analyzed by using standard qualitative sociologic methods. RESULTS: Although the structure of the meetings varied by center, the process was uniform and primarily involved inductive reasoning to review possible reasons for patient exclusion. Patients were excluded if they were too well, too sick (in the setting of advanced liver disease), or too old or had nonhepatic comorbid conditions, substance abuse problems, or other psychosocial barriers. Dominant themes in the discussions included member angst over deciding who lived or died, a high correlation between psychosocial barriers to transplantation and the patient's socioeconomic status, and the influence of external forces on decision making. Unwritten center policies and confusion regarding advocacy versus stewardship roles were consistently identified as barriers to effective group decision making. LIMITATIONS: The use of qualitative methods provides broad understanding but limits specific inferences. The 4 centers may not reflect the practices of every transplant center nationwide. CONCLUSION: The difficult decisions made by liver transplant committees are reasonably consistent and well-intentioned, but the process might be improved by having more explicit written policies and clarifying roles. This may inform resource allocation in other areas of medicine. PRIMARY FUNDING SOURCE: The Greenwall Foundation and the National Institutes of Health.

Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory or intolerant to conventional therapy.

BACKGROUND: Autoimmune hepatitis is characterized by hepatocellular inflammation often progressing to cirrhosis. Standard treatment consists of corticosteroids and azathioprine. For the 20% of patients with refractory disease or those who are intolerant to medication, there is no standardized treatment. OBJECTIVE: To evaluate mycophenolate mofetil (MMF) as an alternative therapy for autoimmune hepatitis.  METHODS: The present retrospective study identified all patients with autoimmune hepatitis who were treated with MMF over a 10-year period at the Henry Ford Hospital (Michigan, USA). These patients were evaluated for tolerance and response. RESULTS: Of the 90 patients participating in the study, 48% had a complete response, 32% experienced relapses and 21% were refractory. MMF was initiated in 21 patients - 12 (57%) for refractory disease and nine (43%) for medication intolerance. Of the 12 patients converted for refractory disease, all showed biochemical improvement but none had a complete response. Of the patients converted due to intolerance, 88% maintained complete remission. For all patients converted to MMF, there was a mean decrease in steroid dose from 18.9 mg/day to 7.8 mg/day (P=0.01). CONCLUSIONS: In patients with autoimmune hepatitis who were intolerant to conventional therapy, MMF was well tolerated, with 88% of patients maintained in remission. MMF did not induce remission in those refractory to conventional therapy; however, it resulted in a significant decrease in steroid use. Prospective studies are needed to better assess the role of MMF as an alternative therapy.

Renal insufficiency after liver transplantation in the MELD era compared to the pre-MELD era.

Because the model for end-stage liver disease (MELD) system for liver allocation gives priority to patients with a higher creatinine, and because pre-transplant renal function is one determinant of post-transplant renal function, this study compares the burden of renal insufficiency in the pre-MELD and MELD eras. Two hundred and eleven patients, at our institution, transplanted in the pre-MELD era, were compared to 143 in the MELD era. The GFR (mL/min/1.73 m2) was significantly higher in the MELD cohort than the pre-MELD cohort at time of transplant, discharge, and 12 months post-transplant (95.5 vs. 85.3, p = 0.039; 90.4 vs. 77.4, p = 0.002; 66.8 vs. 60.3, p = 0.026). There was no difference between the two groups in time to renal failure. There was a higher rate of sirolimus use in the MELD era (27% vs. 18%: p = 0.042) and a slightly higher use of kidney-liver transplant in the MELD era (p = 0.056). We did not identify greater renal insufficiency in the MELD era. There was greater renal function in the MELD era at time of transplant, discharge and month 12. Potential explanations include: absence of an increase in renal insufficiency prior to transplant in the MELD era, greater use of renal sparing immunotherapy and growing use of kidney-liver transplant.

Natural history of hepatitis B and outcomes after liver transplantation.

HBV infection is the single most common cause of cirrhosis globally although the prevalence rate is influenced by geographic region. The natural course of HBV infection and the clinical outcome is dependent on the interplay between host, virus, and environmental factors. Understanding the natural history of HBV infection is important in determining treatment strategies. OLT is the ultimate cure for patients with HBV-related liver failure or HCC. The use of HBIG and new antiviral agents has resulted in significant decrease in HBV re-infection rate and survival of patients transplanted for hepatitis B in recent years is comparable to that of patients transplanted for other liver disease.

High rates of false-positive hepatitis C antibody tests can occur after left ventricular assist device implantation.

Hepatitis C virus (HCV) screening is routine before cardiac transplantation, and virus presence is an exclusion at most centers. Left ventricular assist devices (LVADs) are often used as a bridge to transplantation and cause immune activation. We collected data on 32 consecutive patients undergoing LVAD placement between January 2006 and February 2008 at a single center. Of the 23 potential bridge-to-transplant patients with HCV testing before and after LVAD, seven (30%) turned positive for HCV antibody but did not have true HCV infection on confirmatory testing. Cardiac transplant care providers should be aware of possible false-positive HCV antibody tests in this setting.

Significance of complement split product C4d in ABO-compatible liver allograft: diagnosing utility in acute antibody mediated rejection.

Diagnosis of liver allograft antibody-mediated rejection (AMR) is difficult and requires a constellation of clinical, laboratory and histologic features that support the disease and exclude other causes. Histologic features of AMR may intermix with those of biliary obstruction, preservation/reperfusion injury, and graft ischemia. Tissue examination for complement degradation product 4d (C4d) has been proved to support this diagnosis in other allografts. For this reason, we conducted a retrospective review of all ABO compatible/identical re-transplanted liver patients with primary focus on identifying AMR as a possible cause of graft failure and to investigate the utility of C4d in liver allograft specimens. We reviewed 193 liver samples obtained from 53 consecutive ABO-compatible re-transplant patients. 142 specimens were stained with C4d. Anti-donor antibody screening and identification was determined by Luminex100 flow cytometry. For the study analysis, patients were stratified into 3 groups according to time to graft failure: group A, patients with graft failure within 0-7 days (n=7), group B within 8-90 days (n=13) and C >90 days (n=33). Two patients (3.7%) met the diagnostic criteria of acute AMR. Both patients experienced rapid decline of graft function with presence of donor specific antibodies (DSA), morphologic evidence of humoral rejection and C4d deposition in liver specimens. C4d-positive staining was identified in different medical liver conditions i.e., acute cellular rejection (52%), chronic ductopenic rejection (50%), recurrent liver disease (48%), preservation injury (18%), and hepatic necrosis (54%). Univariate analysis showed no significant difference of C4d-positive staining among the 3 patients groups, or patients with DSA (P>.05). In conclusion, AMR after ABO-compatible liver transplantation is an uncommon cause of graft failure. Unlike other solid organ allografts, C4d-positive staining is not a rugged indicator of humoral rejection, thus, interpretation should be done with caution to avoid diagnostic dilemmas.

Risk for renal cell carcinoma in chronic hepatitis C infection.

BACKGROUND: Chronic infection with hepatitis C virus (HCV) confers increased risk for chronic renal disease, and numerous reports suggest an association with renal cell carcinoma (RCC), a cancer with rapidly rising global incidence. We sought to determine whether HCV infection confers an increased risk for developing RCC. METHODS: With the use of administrative data from a large, integrated, and ethnically diverse healthcare system, we did a cohort study of 67,063 HCV-tested patients between 1997 and 2006 who were followed for the development of RCC until April 2008. RESULTS: A search of the health system cancer registry for patients with the diagnosis of kidney cancer showed that RCC was diagnosed in 0.6% (17 of 3,057) of HCV-positive patients versus 0.3% (177 of 64,006) of HCV-negative patients. The mean age at RCC diagnosis was much younger in HCV-positive individuals (54 versus 63; P < 0.001). The univariate hazard ratio for RCC among HCV patients was 2.20 (95% confidence interval, 1.32-3.67; P = 0.0025). In a multivariate model that included the risk factors age, African-American race, male gender, and chronic kidney disease, the overall hazard ratio for RCC among HCV patients was 1.77 (95% confidence interval, 1.05-2.98; P = 0.0313). CONCLUSION: Chronic HCV infection confers a risk for the development of RCC. IMPACT: Clinicians should consider newly identified renal lesions in patients with chronic HCV infection with a heightened suspicion for neoplasm, and newly diagnosed cases of RCC may require more careful surveillance for the presence of HCV infection. Additional studies are required to confirm these findings and to explore potential mechanisms of oncogenesis.

One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study.

BACKGROUND AND AIM: In individuals with biopsy-proven non-alcoholic steatohepatitis (NASH), short-term weight loss has been shown to improve biochemical abnormalities; however, its effect on liver histology is largely unknown. The aim of the article is to determine if dietary intervention is effective in improving histological features of steatohepatitis in patients with biopsy-proven NASH. METHODS: Twenty-three patients (11M/12F) with BMI >25 kg/m(2) and biopsy-proven NASH received standardized nutritional counseling aimed at reducing insulin resistance (IR) and weight. Blood tests were checked at baseline and every 1-4 months, and liver biopsy was repeated at month 12. IR was assessed by the homeostasis model assessment (HOMA). Liver biopsies were scored according to modified Brunt criteria for NASH. "Histologic response" was defined as a reduction in total NASH score of >/=2 points with at least one point being in the non-steatosis component. RESULTS: Sixteen patients (8M/8F) completed 12 months of dietary intervention, and 15 underwent repeat liver biopsies. At month 12, mean weight decreased from 98.3 to 95.4 kg. Mean waist circumference, visceral fat, fasting glucose, IR, triglycerides, AST, ALT, and histologic score were all reduced but the difference was not significant. Nine patients had a histologic response, six had stable scores, and none had a worsened score. Compared to patients with unchanged histologic scores, patients with improved scores had significantly greater reduction in weight, waist circumference, AST, ALT, steatosis grade, and total NASH score. CONCLUSION: Among patients who successfully completed 1 yr of intense dietary intervention, nine of 15 patients with NASH displayed histologic improvement. This pilot study suggests that dietary intervention can be effective in improving histology in patients with biopsy-proven NASH.

Hepatocellular carcinoma.

The number of papers published regarding hepatocellular carcinoma increased remarkably over the previous year. The 1-year survival for hepatocellular carcinoma has only improved slightly over the past 20 years, while the overall survival has remained unchanged. Hepatitis B genotypes, specifically genotype B, correlate with better response and survival in patients with hepatocellular carcinoma caused by this chronic infection. A consensus conference recommended that patients with Child-Turcotte-Pugh class A or B cirrhosis should be screened with ultrasound and alpha-fetoprotein measurement every 6 months. Using microarray technology, several groups established the gene expression for human hepatocellular carcinoma including the identification of potential genes involved in hepatic carcinogenesis. Dynamic gadolinium MRI is the preferred imaging of choice for the evaluation of hepatocellular carcinoma, but contrast-enhanced power Doppler ultrasound is a new imaging technique able to differentiate neoplastic from nonneoplastic liver lesions. Overall, transplantation is the best long-term therapeutic option, but in patients without portal hypertension and well-preserved liver function, resection may be preferable.