Grace L. Su

Prognosis of hepatocellular carcinoma: Comparison of 7 staging systems in an American cohort

Currently there is no consensus as to which staging system is best in predicting the survival of patients with hepatocellular carcinoma (HCC). The aims of this study were to identify independent predictors of survival and to compare 7 available prognostic staging systems in patients with HCC. A total of 239 consecutive patients with cirrhosis and HCC seen between January 1, 2000, and December 31, 2003, were included. Demographic, laboratory, and tumor characteristics and performance status were determined at diagnosis and before therapy. Predictors of survival were identified using the Kaplan–Meir test and the Cox model. Sixty‐two percent of patients had hepatitis C, 56% had more than 1 tumor nodule, 24% had portal vein thrombosis, and 29% did not receive any cancer treatment. At the time of censorship, 153 (63%) patients had died. The 1‐ and 3‐year survival of the entire cohort was 58% and 29%, respectively. The independent predictors of survival were performance status (P < .0001), MELD score greater than 10 (P = .001), portal vein thrombosis (P = .0001), and tumor diameter greater than 4 cm (P = .001). Treatment of HCC was related to overall survival. The Barcelona Clinic Liver Cancer (BCLC) staging system had the best independent predictive power for survival when compared with the other 6 prognostic systems. In conclusion, performance status, tumor extent, liver function, and treatment were independent predictors of survival mostly in patients with cirrhosis and HCC. The BCLC staging system includes aspects of all of these elements and provided the best prognostic stratification for our cohort of patients with HCC. (HEPATOLOGY 2005.)

Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis: A case-control study

Folate deficiency has been associated with dysplasia in human cancer models. Patients with ulcerative colitis commonly have decreased folate levels, which are partially due to sulfasalazine, a competitive inhibitor of folate absorption. To study the effect of folate supplementation on the risk of dysplasia or cancer (neoplasia) in ulcerative colitis, records from 99 patients with pancolitis for greater than 7 yr and enrolled in a surveillance program were reviewed. Thirty-five patients with neoplasia were compared with 64 patients in whom dysplasia was never found to determine the effect of folate supplementation on the rate of development of neoplasia using case-control methodology. At the time of the index colonoscopy, patients with neoplasia were older (43 +/- 11 vs. 39 +/- 12 yr) and had disease of longer duration (20 +/- 8 vs. 15 +/- 7 yr, p less than 0.05). Folate supplementation was associated with a 62% lower incidence of neoplasia compared with individuals not receiving supplementation (odds ratio, 0.38; 95% confidence interval, 0.12-1.20). There was no appreciable change in this effect when models were fit to adjust for sulfasalazine dose, duration of disease, age at symptom onset, prednisone dose, sulfa allergy, sex, race, or family history of colon cancer. The statistical power of the association between folate supplementation and neoplasia was 72%. Correction of risk factors before the development of neoplasia may prevent this serious complication. Pending a larger case-control study, folate supplementation during sulfasalazine administration is recommended to possibly prevent the complication of dysplasia or cancer in ulcerative colitis.

Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C.

This study determined the utility of a panel of serum fibrosis markers along with routine laboratory tests in estimating the likelihood of histological cirrhosis in a cohort of prior nonresponders with chronic hepatitis C. The relationship between serum markers and quantitative hepatic collagen content was also determined. Liver biopsy samples from 513 subjects enrolled in the HALT‐C trial were assigned Ishak fibrosis scores. The collagen content of 386 sirius‐red stained, nonfragmented biopsy samples was quantified using computerized morphometry. Serum tissue inhibitor of matrix metalloproteinase‐1 (TIMP‐1), amino‐terminal peptide of type III procollagen (PIIINP), hyaluronic acid (HA), and YKL‐40 levels were determined using commercially available assays.Sixty‐two percent of patients had noncirrhotic fibrosis (Ishak stage 2‐4) whereas 38% had cirrhosis (Ishak stage 5,6). Multivariate analysis identified a 3‐variable model (HA, TIMP‐1, and platelet count) that had an area under the receiver operating curve (AUROC) of 0.81 for estimating the presence of cirrhosis. This model was significantly better than that derived from the cirrhosis discriminant score (AUROC 0.70), the AST‐to‐platelet ratio (AUROC 0.73), and a prior model developed in HALT‐C patients (AUROC 0.79). Multivariate analysis demonstrated that the serum fibrosis markers correlated substantially better with Ishak fibrosis scores than with the log hepatic collagen content (AUROC 0.84 versus 0.72). Conclusion: A 3‐variable model consisting of serum HA, TIMP‐1, and platelet count was better than other published models in identifying cirrhosis in HALT‐C Trial subjects. The stronger correlation of the serum markers with Ishak scores suggests that serum fibrosis markers reflect the pattern of fibrosis more closely than the quantity of hepatic collagen. (HEPATOLOGY 2008.)

Effectiveness of Hepatocellular Carcinoma Surveillance in Patients with Cirrhosis

Background: Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis, but the effectiveness of a surveillance program in clinical practice has yet to be established. Aims: To evaluate the effectiveness of a surveillance program with ultrasound and alpha-fetoprotein (AFP) to detect early HCCs. Methods: Four hundred and forty-six patients with Child A/B cirrhosis were prospectively enrolled between January 2004 and September 2006 and followed until July 2010. HCC surveillance using ultrasound and AFP was conducted per the treating hepatologist, although the standard was every 6 to 12 months. HCC was diagnosed using American Association for the Study of Liver Disease (AASLD) guidelines and early HCC defined by Barcelona Clinic Liver Cancer (BCLC) staging. Performance characteristics were determined for surveillance using AFP, ultrasound, or the combination. Results: After a median follow-up of 3.5 years, 41 patients developed HCCs, of whom 30 (73.2%) had early HCCs. The annual incidence of HCC was 2.8%, with cumulative 3- and 5-year incidence rates of 5.7% and 9.1%, respectively. Surveillance ultrasound and AFP had sensitivities of 44% and 66% and specificities of 92% and 91%, respectively, for the detection of HCCs. Sensitivity significantly improved to 90%, with minimal loss in specificity (83%) when these tests were used in combination. Conclusions: When used as a surveillance program in a real-world clinical setting, combination of ultrasound and AFP is the most effective strategy to detect HCC at an early stage. Impact: Our results differ from the guidelines of the AASLD. Cancer Epidemiol Biomarkers Prev; 21(5); 793–9. ©2012 AACR.

Comorbid Illness Is an Important Determinant of Health-Related Quality of Life in Patients With Chronic Hepatitis C

OBJECTIVES:Chronic hepatitis C (CHC) patients selected for entry into treatment trials have been reported to have impaired health-related quality of life (HRQOL). However, these trials have an inherent selection bias, and HRQOL in CHC patients may have been underestimated because of the exclusion of patients with comorbid illness. The aim of this study was to assess HRQOL in an unselected group of CHC patients and to identify factors associated with impairment in HRQOL.METHODS:A total of 220 consecutive eligible CHC patients were enrolled from a hepatology clinic. HRQOL was assessed by the short form 36 (SF-36) and comorbid illnesses were assessed by an interview.RESULTS:CHC patients had significantly lower SF-36 scores in all subscales and in the summary scales when compared to those of the healthy general population in the United States (p < 0.001). Compared to CHC patients entering treatment trials, our patients had lower SF-36 scores on five subscales (p < 0.001). The presence of comorbid illness was the most important predictor of HRQOL in CHC patients. However, CHC alone resulted in significantly lower SF-36 scores in all subscales and summary scales (p≤ 0.003) compared to those of the healthy U.S. population. There was no correlation between SF-36 scores and history of i.v. drug use or dependence, alcohol dependence, and serum aminotransferase levels.CONCLUSIONS:We conclude that unselected CHC patients presenting for medical evaluation have a reduced HRQOL, which is lower than that reported for CHC patients entering treatment trials. CHC alone is associated with significant impairment in HRQOL, but the presence of comorbid illness leads to further diminution in HRQOL.

Emotional distress in chronic hepatitis C patients not receiving antiviral therapy

BACKGROUND/AIMS The aim of our study was to determine the prevalence, type, and severity of emotional distress in a large group of consecutive chronic hepatitis C (CHC) patients not receiving anti-viral therapy. METHODS The brief symptom inventory and a 67-item questionnaire with the SF-36 embedded within it were used to study 220 outpatients with compensated CHC. RESULTS Seventy-seven (35%) participants reported significantly elevated global severity index (GSI) T-scores compared to an expected frequency of 10% in population controls. In addition, significantly elevated depression, anxiety, somatization, psychoticism, and obsessive-compulsive subscale T-scores were reported in 28-40% of subjects. Subjects with an active psychiatric co-morbidity had significantly higher GSI and subscale T-scores compared to subjects with active medical co-morbidities and subjects without medical or psychiatric co-morbidities (P<0.01). However, patients with CHC alone also had a higher frequency of elevated GSI T-scores compared to population controls (20 versus 10%). GSI and subscale T-scores were strongly associated with SF-36 summary scores (P<0.001). CONCLUSIONS Clinically significant emotional distress was reported in 35% of CHC patients not receiving antiviral therapy. In addition to depression, a broad array of psychological symptoms were observed. Further investigation into the etiopathogenesis and treatment of emotional distress in CHC patients is warranted.

An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction

Defective cardiac function during sepsis has been referred to as “cardiomyopathy of sepsis.” It is known that sepsis leads to intensive activation of the complement system. In the current study, cardiac function and cardiomyocyte contractility have been evaluated in rats after cecal ligation and puncture (CLP). Significant reductions in left ventricular pressures occurred in vivo and in cardiomyocyte contractility in vitro. These defects were prevented in CLP rats given blocking antibody to C5a. Both mRNA and protein for the C5a receptor (C5aR) were constitutively expressed on cardiomyocytes; both increased as a function of time after CLP. In vitro addition of recombinant rat C5a induced dramatic contractile dysfunction in both sham and CLP cardiomyocytes, but to a consistently greater degree in cells from CLP animals. These data suggest that CLP induces C5aR on cardiomyocytes and that in vivo generation of C5a causes C5a–C5aR interaction, causing dysfunction of cardiomyocytes, resulting in compromise of cardiac performance.

Sustained virologic response to therapy of recurrent hepatitis C after liver transplantation is related to early virologic response and dose adherence

Sustained virologic response (SVR) after antiviral therapy for recurrent hepatitis C virus (HCV) infection in liver transplant (LT) recipients is consistently lower than that achieved in non‐LT patients. We evaluated efficacy and safety of pegylated interferon (IFN) and ribavirin (RBV) therapy in LT recipients with recurrent HCV and factors associated with SVR. All subjects with histologic evidence of recurrent HCV were intended to be treated for 48 weeks with full‐dose pegylated IFN; target dose of RBV was 800 mg/day. Thirty‐five LT recipients with recurrent HCV, median age 48.5 years, 77% genotype 1, and median pretreatment HCV RNA 6.4 log10 IU/mL were treated between January 2000 and February 2006. Antiviral therapy was discontinued prematurely in 15 subjects as a result of adverse events. Median overall treatment duration was 46 weeks. Early virologic response at week 12 was seen in 17 (49%) and an end‐of‐treatment virological response in 19 (54%) patients. SVR was achieved in 13 patients (37%), and all 9 patients followed for >1 year after treatment had durable response. Patients with SVR had significantly lower pretreatment HCV RNA (5.7 vs. 6.5 log10 IU/mL, P = 0.003), more likely to have a week 12 virological response (85% vs. 27%, P = 0.0009) and received higher cumulative doses of pegylated IFN (75% vs. 33%, P = 0.029) and RBV (90% vs. 26%, P = 0.016) compared with patients whose disease did not respond to therapy. In conclusion, SVR was achieved in 37% of patients with recurrent hepatitis C after LT. Similar to non‐LT patients, those with lower pretreatment HCV RNA, a week 12 virological response, and pegylated IFN and RBV dose adherence were more likely to achieve SVR. Liver Transpl, 2007.

Risk factors for hepatocellular carcinoma may impair the performance of biomarkers: a comparison of AFP, DCP, and AFP-L3.

Current surveillance strategies for hepatocellular carcinoma (HCC) are applied uniformly in patients with cirrhosis, regardless of their cancer risk. The aim of this study was to compare the performance characteristics of the biomarkers alpha-fetoprotein (AFP), des-gamma carboxyprothrombin (DCP), and lectin-bound AFP (AFP-L3) in the diagnosis of HCC, and to determine the effect of risk factors for HCC on test performance. Eighty-four patients with HCC and 169 patients with cirrhosis were enrolled and their serum analyzed for total AFP, AFP-L3 and DCP. Receiver-operating characteristic (ROC) curves were constructed to determine the performance characteristics. DCP was significantly better than total AFP or AFP-L3 in differentiating HCC from cirrhosis, with a sensitivity of 86% and specificity of 93%. When subjects were divided into two groups by their risk for HCC, all 3 markers had a lower sensitivity and area under the ROC curve in the high-risk group compared to the low-risk group. In conclusion, DCP has the best performance characteristics of all 3 serum markers for the diagnosis of HCC. Serum biomarkers may be less sensitive and specific in the highest risk patients.

CD14 expression and production by human hepatocytes

BACKGROUND/AIMS CD14 has been identified as a receptor for LPS and is present both in a membrane-bound and a soluble form. Membrane CD14 (mCD14) is predominantly expressed on monocytes, macrophages and granulocytes. The source of soluble CD14 (sCD14) is as yet unclear. Previous investigation using monocytes has shown that sCD14 can be derived either from the shedding of mCD14 or from direct secretion by monocytes. Whether the monocyte is the sole or even the major source of sCD14 is as yet uncertain. Clearance of LPS from the bloodstream is thought to be primarily mediated by the liver. Production of CD14 by hepatocytes would potentially provide a powerful mechanism by which the liver could clear LPS, and therefore we examined the ability of human hepatocytes to produce CD14. METHODS Human hepatocytes were isolated using collagenase perfusion. RESULTS Human hepatocytes were found to have CD14 mRNA by Northern blot analysis. Western blot analysis and immunohistochemical staining confirmed CD14 protein in primary hepatocyte cultures. Further studies showed that a liver epithelial-like cell line AKN-1 is capable of producing CD14. Comparisons of the size of hepatocyte-derived CD14 protein with the sCD14 protein from the human monocytic leukemia cell line HL60 suggested that a slightly larger form of CD14 is expressed by human liver cells. CONCLUSION This is the first study to demonstrate production of CD14 by human hepatocytes.