Phillip Harrison

Improvement by Acetylcysteine of Hemodynamics and Oxygen Transport in Fulminant Hepatic Failure

BACKGROUND When administered early after an overdose of acetaminophen, intravenous acetylcysteine prevents hepatic necrosis by replenishing reduced stores of glutathione. How acetylcysteine improves the survival of patients with established liver damage induced by acetaminophen, however, is unknown. This study was undertaken to determine whether the beneficial effect of acetylcysteine under such circumstances could be due to enhancement of oxygen delivery and consumption. METHODS We studied the effect of acetylcysteine on systemic hemodynamics and oxygen transport in 12 patients with acetaminophen-induced fulminant hepatic failure and 8 patients with acute liver failure from other causes. The acetylcysteine was given in a dose of 150 mg per kilogram of body weight in 250 ml of 5 percent dextrose over a period of 15 minutes and then in a dose of 50 mg per kilogram in 500 ml of 5 percent dextrose over a period of 4 hours; measurements were made before treatment began and after 30 minutes of the regimen. RESULTS In the patients with acetaminophen-induced liver failure, the infusion of acetylcysteine resulted in an increase in mean oxygen delivery from 856 to 975 ml per minute per square meter of body-surface area (P = 0.0036), due to an increase in the cardiac index from 5.6 to 6.7 liters per minute per square meter (P = 0.0021). Mean arterial pressure rose from 88 to 95 mm Hg (P = 0.0054) despite a decrease in systemic vascular resistance from 1296 to 1113 dyn.sec.cm-5 per square meter (P = 0.027). There was an increase in oxygen consumption from 127 to 184 ml per minute per square meter (P = 0.0007) associated with an increase in the oxygen-extraction ratio from 16 to 21 percent (P = 0.022). The effects in the patients with acute liver failure from other causes were similar. CONCLUSIONS The increase in oxygen delivery and consumption in response to acetylcysteine may account for its beneficial effect on survival in patients with fulminant hepatic failure induced by acetaminophen.

Hepatitis delta virus

Hepatitis delta virus (HDV) is a small, defective RNA virus that can infect only individuals who have hepatitis B virus (HBV); worldwide more than 15 million people are co-infected. There are eight reported genotypes of HDV with unexplained variations in their geographical distribution and pathogenicity. The hepatitis D virion is composed of a coat of HBV envelope proteins surrounding the nucleocapsid, which consists of a single-stranded, circular RNA genome complexed with delta antigen, the viral protein. HDV is clinically important because although it suppresses HBV replication, it causes severe liver disease with rapid progression to cirrhosis and hepatic decompensation. The range of clinical presentation is wide, varying from mild disease to fulminant liver failure. The prevalence of HDV is declining in some endemic areas but increasing in northern and central Europe because of immigration. Treatment of HDV is with pegylated interferon alfa; however, response rates are poor. Increased understanding of the molecular virology of HDV will identify novel therapeutic targets for this most severe form of chronic viral hepatitis.

Eliciting cytotoxic T lymphocytes against acute myeloid leukemia-derived antigens: evaluation of dendritic cell-leukemia cell hybrids and other antigen-loading strategies for dendritic cell-based vaccination

Abstract. Dendritic cells (DC) have been successfully used in clinical pilot studies to induce tumor-specific immunity as well as clinical response in selected patients. However, DC-based immunotherapy remains a challenge and several parameters need to be examined in order to optimize the induction of anti-tumor immune responses. This study focuses on DC vaccination for leukemia and evaluates the in vitro efficacy of three different strategies for generating antigen-loaded DC-based vaccines for the induction of major histocompatibility complex (MHC) class I-restricted anti-leukemia cytotoxic T lymphocyte (CTL) responses. These included direct fusion of DC with leukemia cells to generate DC–leukemia cell hybrids, and DC pulsed with either apoptotic leukemia cell fragments or whole tumor cell lysates. Using either the U937 cell line or primary human acute myeloid leukemia blasts (AML), DC–leukemia cell hybrids were found to be the most potent in vitro inducers of CTL activity. DC pulsed with apoptotic tumor cell fragments were less efficient, but induced a more potent CTL response compared to tumor lysate-pulsed DC. The CTL responses were both MHC class I-restricted and antigen-specific, as shown by the inability of the CTL to lyse other control targets. The data presented here suggest that the method of antigen loading onto DC may be critical in the design of tumor vaccines.

Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: Implications for follow-up and screening.

Hepatocellular carcinoma (HCC) has traditionally been considered a rare complication of cirrhosis secondary to autoimmune hepatitis (AIH), yet the true incidence remains unknown due to a lack of published data. Consequently, some professional guidelines do not mandate routine surveillance for HCC in this condition. Our aims were to evaluate the rate at which HCC develops among a large, prospectively obtained cohort of patients with AIH at a single center. Demographic, clinical, and laboratory indices associated with the development of HCC were also identified. HCC was discovered in 15 of 243 patients with AIH, all of whom had type 1 AIH equating to 1090 cases per 100,000 patient follow‐up years. HCC occurred in the same proportion of females as males, 6.1% versus 6.4%, P = 0.95. HCC occurred more frequently in patients who had cirrhosis at presentation, 9.3% versus 3.4%, P = 0.048, or who had a variceal bleed as the index presentation of AIH, 20% versus 5.3%, P = 0.003. The median duration from time of confirmed cirrhosis to a diagnosis of HCC was 102.5 months, range 12‐195 months. Median survival in patients whose HCC was diagnosed on surveillance was 19 months (range 6‐36 months) compared with 2 months (range 0‐14 months) for patients presenting symptomatically (P = 0.042). Conclusion: Cirrhosis in AIH is the sine qua non for HCC development, which subsequently occurs at a rate of 1.1% per year and affects men and women in equal proportions. (HEPATOLOGY 2008.)

Characteristics of autoimmune hepatitis in patients who are not of European Caucasoid ethnic origin

Background: Significant diversity in disease severity has been identified for autoimmune disorders among different ethnic groups but there is a lack of data on autoimmune hepatitis (AIH) in populations other than those of European Caucasoid (EC) or Japanese extraction. Aims: To assess the clinical features, response to therapy, and eventual outcome in AIH patients of non-EC ethnicity. Methods: A retrospective review of a regularly updated database of patients with AIH referred to liver outpatient clinics at Kings College Hospital, London, since 1983. Results: Twelve patients were identified (10 female; six African, five Asian, one Arabic; median age at presentation 30 years (range 12–58)) who satisfied international criteria for type 1 (11 cases) or type 2 (one case) AIH. Nine (75%) had cholestatic serum biochemistry and three (25%) had mild biliary changes on liver biopsy without definitive features of primary biliary cirrhosis or cholangiographic evidence of primary sclerosing cholangitis. Four showed a complete biochemical response to standard prednisolone with or without azathioprine therapy, three partial, and five no response. Four have required liver transplantation for intractable disease. By comparison with 180 EC patients with definite AIH attending during the same period, the non-EC patients were younger (p<0.05), presented with cholestatic biochemistry (p=0.014), and morphological biliary features more frequently (p<0.0005) and showed a poorer initial response to standard therapy (p<0.0005). Conclusions: Clinical expression of AIH in non-EC patients seems to differ in important respects from that in EC or Japanese patients. Management of such patients is challenging and may require alternative or more aggressive treatment strategies.

An open pilot study of the effects of a human fibrin glue for endoscopic treatment of patients with acute bleeding from gastric varices

BACKGROUND Optimal treatment for gastric variceal bleeding remains to be determined. The use of conventional sclerosing agents is associated with high rates of recurrent bleeding. Other agents, such as cyanoacrylate, have significant complication rates and can damage endoscopic equipment. The risk of prior-associated disease has caused concern regarding the use of bovine thrombin. METHODS Beriplast-P (human thrombin) forms a fibrin clot at the needle tip immediately upon injection through a double lumen needle. In 10 patients with gastric variceal bleeding, a median dose of 6 mL of Beriplast-P was injected into gastric varices. OBSERVATIONS Immediate hemostasis was achieved in 7 of 10 patients (70%) with a single injection. At a median follow-up of 8 months, there was no recorded episode of recurrent bleeding from gastric varices. CONCLUSIONS These results suggest that Beriplast-P is useful in the treatment of gastric variceal bleeding. Refinements in the design of the injection needle may improve the efficacy of this novel therapy.

King's Score: an accurate marker of cirrhosis in chronic hepatitis C

Objectives Histological assessment of patients with chronic hepatitis C infection is no longer performed routinely; consequently, a simple test is needed to identify patients with significant hepatic fibrosis. Methods Data were collected, retrospectively, on 923 consecutive patients undergoing percutaneous liver biopsy for chronic hepatitis C at Kings College Hospital between 1 January 2000 and 30 June 2006; 602 patients were accepted to form the training set and a further 105 patients to form the validation set. Results On liver biopsy, 132 (22%) had cirrhosis (Ishak F5–6) in the training set and 19 (18%) in the validation set. Factors found by multivariate analysis to be associated with fibrosis in the training set were used to construct the Kings Score: age×aspartate aminotransferase×international normalized ratio ÷ platelets. Area under receiver operating characteristic curves for predicting cirrhosis and significant fibrosis (F3–6) were 0.91 and 0.79, respectively. A Kings Score of greater than or equal to 16.7 predicted cirrhosis in 34% of patients (odds ratio 36.2, 95% confidence interval, 22.0–59.6; P<0.0001) with sensitivity 86%, specificity 80% and a high negative predictive value of 96%; a score greater than or equal to 12.3 predicted F3–6 (odds ratio 33.9, 95% confidence interval, 15.2–34.4; P<0.001). The validation set confirmed the utility of this index, area under receiver operating characteristic curves 0.94 and 0.89 for cirrhosis and F3–6, respectively. Conclusion The Kings Score is a simple and accurate index for predicting cirrhosis in chronic hepatitis C. Patients with a score of less than 16.7 have a low risk of cirrhosis.

Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: results from two randomised controlled trials

Gastrin has been shown to be a growth stimulant in pancreatic cancer cells. Gastrazole is a potent and selective gastrin receptor antagonist. Two randomised blinded trials were conducted to assess the effect of gastrazole in advanced pancreatic cancer. Patients with biopsy-proven, inoperable pancreatic carcinoma were recruited. Trial A compared protracted venous infusion (PVI) gastrazole with PVI placebo, whereas trial B compared PVI gastrazole with PVI fluorouracil (5-FU). Eighteen patients were randomised in trial A. Gastrazole produced significantly better survival compared to placebo (median 7.9 months vs 4.5 months; 1-year survival: 33 vs 11%, respectively; log rank P=0.02). No difference in toxicity was seen between gastrazole and placebo, except central venous catheter and pump complications. Ninety-eight patients were randomised in trial B. No significant survival difference was detected between gastrazole and 5-FU (median: 3.6 vs 4.2 months; 1-year survival: 13.2 vs 26.2%, respectively; log rank P=0.42). Toxicity of gastrazole was mild with significantly less diarrhoea (P=0.03), stomatitis (P<0.001) and hand– foot syndrome (P<0.001) compared to 5-FU. Quality of life (QoL) assessment showed similar QoL between gastrazole and 5-FU at baseline and no significant differences occurred with treatment either between arms or within arms. Compared to placebo, patients with advanced pancreatic cancer treated with gastrazole appeared to live longer, albeit in a very small trial and will require confirmation with large-scale randomised data. However, it did not produce survival advantage over PVI 5-FU. Lack of toxicity for gastrazole may allow its combination with cytotoxic drugs.

The impact of hepatic steatosis on the natural history of chronic hepatitis C infection

Summary.  Since patients with hepatitis C virus (HCV) often have hepatic steatosis, this retrospective analysis aimed to assess whether steatosis influences fibrosis progression. We studied 112 HCV RNA positive subjects (median age 44, IQR 39–51 years), who had two liver biopsies performed (median biopsy interval 50, 34–74 months). Fibrosis was staged using the Ishak method and steatosis by the Kleiner system (<5% steatosis = S0, 5–33% = S1, 33–66% = S2, and >66% = S3). The subjects were untreated because they had mild fibrosis (n = 59), declined therapy (n = 48), or had co‐existing disease precluding treatment (n = 5). On first liver biopsy, 60 (54%) had S0, 34 (30%) had S1, 12 (11%) had S2, and 6 (5%) had S3. Steatosis was associated with genotype 3, odds ratio 4.8 (95% CI 1.3–16.7, P = 0.02). Twenty‐three patients (21%) had disease progression on the second biopsy, defined as an increase in Ishak score by ≥1 stage. On univariate analysis, fibrosis progression was associated with older age (P = 0.004), higher AST (P = 0.04), and steatosis (P = 0.005) but on multivariate analysis, only baseline steatosis was significant, odds ratio 14.3 (2.1–111.1, P = 0.006). Kaplan‐Meier analysis demonstrated that steatosis impacted on time to progression to both significant fibrosis (Ishak ≥F3) and cirrhosis (Ishak F5‐6) (P = 0.001 and P = 0.049, respectively). The finding that steatosis was significantly associated with fibrosis progression indicates that, independent of baseline fibrosis stage, patients should be considered for anti‐viral treatment if steatosis is present. Furthermore, strategies to reduce steatosis may have a beneficial effect on fibrosis progression and, therefore, patient outcome.

Prospective comparison of Fibroscan, King’s score and liver biopsy for the assessment of cirrhosis in chronic hepatitis C infection

Summary.  Historically, liver biopsy (LB) was the sole method to evaluate the severity of hepatic fibrosis in patients with chronic hepatitis C infection. However, LB is expensive and associated with a risk of severe complications. Therefore, noninvasive tests have been developed to assess the severity of liver fibrosis. The accuracy of Fibroscan (FS) and King’s score (KS) was evaluated individually and in combination using liver histology as the reference standard. One hundred and eighty‐seven patients were identified who had undergone a biopsy with a diagnosis of chronic hepatitis C virus (HCV) mono‐infection (HCV RNA‐positive by RT‐PCR), attending King’s College Hospital (n = 88) or the Royal Free Hospital (n = 99) (London) between May 2006 and December 2007. Liver fibrosis was scored using the Ishak method; significant fibrosis was defined as Ishak fibrosis stage F3–F6, and cirrhosis defined as Ishak fibrosis F5–F6. The diagnostic accuracy of each test was assessed by area under receiver operator characteristic curves (AUROC). Median age was 49 years (43–54) and 115 (61%) were male. The AUROC for FS, KS and FS + KS for the diagnosis of Ishak F3–F6 were 0.83, 0.82 and 0.85, respectively and for the diagnosis of cirrhosis (≥F5) were 0.96, 0.89 and 0.93, respectively. The negative predictive values for the diagnosis of cirrhosis using the optimal cut‐off results for fibrsocan (10.05 kPa), KS (24.3) and the two combined (26.1) were 98%, 91% and 94%, respectively. The noninvasive markers and, particularly, FS were effective tests for the prediction of cirrhosis in chronic hepatitis C. Both KS and FS also had clinical utility for the prediction of Ishak fibrosis stages F3–F6.