Barry Rosser

Fatty infiltration of liver in hyperlipidemic patients

Hyperlipidemia is a known risk factor for fatty infiltration of the liver, a condition that can progress to cirrhosis and liver failure. The objectives of this study were to document the prevalence of fatty infiltration in the livers of hyperlipidemic patients and to identify the predictor variables associated with this condition. Over an 18-month recruitment period, clinical, biochemical, and radiologic assessments were performed in a cross-sectional manner in 95 adult patients referred to an urban hospital-based lipid clinic for evaluation and management of hyperlipidemia. The mean (±sd) age of the patients was 55 ± 13 years. Forty-eight (51%) were male. Fifty-two patients (55%) had hypercholesterolemia, 25 (26%) severe hypertriglyceridemia, 14 (15%) mixed hyperlipidemia, and 4 (4%) moderate hypertriglyceridemia. Obesity and diabetes were present in 36 (38%) and 12 (12%) of cases, respectively. A total of 61 (64%) patients had elevated liver enzyme tests. The most common enzyme abnormalities were an elevated serum ALT in 45 (47%) and GGT in 43 (45%) of patients. Ultrasound findings revealed diffuse fatty liver in 47 patients (50%), of which 21 cases (22%) were mild, 18 (19%) moderate, and 8 (9%) severe. The majority of patients with hypercholesterolemia [35/52 (67%)] had normal ultrasounds, whereas severe hypertriglyceridemia and mixed hyperlipidemia were frequently associated with radiologic evidence of fatty liver (odds ratios 5.9 and 5.1 respectively, P < 0.01). Independent predictors of fatty liver were; AST (P = 0.001), hyperglycemia (P = 0.02), and age (P = 0.04). In a model incorporating known risk factors for fatty liver, diabetes was the only risk factor other than hypertriglyceridemia that was significantly associated with fatty infiltration. No such effect was seen with age, gender, obesity, or alcohol consumption. In conclusions, the results of this study indicate that ultrasonographic evidence of fatty infiltration of the liver is evident in approximately 50% of patients with hyperlipidemia. Hypertriglyceridemia is the lipid profile most often associated with this condition. Serum AST values, hyperglycemia, and age independently predict the presence of fatty infiltration, while hypertriglyceridemia and diabetes are the only risk factors that significantly increase the risk of fatty infiltration in hyperlipidemic patients.

Risk of sedation for upper GI endoscopy exacerbating subclinical hepatic encephalopathy in patients with cirrhosis

BACKGROUNDnThe risk of exacerbating subclinical hepatic encephalopathy associated with the administration of sedative drugs in patients with cirrhosis undergoing diagnostic upper gastrointestinal (GI) endoscopy for portal hypertension remains to be determined.nnnMETHODSnTen adult patients with cirrhosis completed number connection tests before sedation for endoscopy and at discharge from the endoscopy unit 2 hours post-procedure. Control patients consisted of five patients with cirrhosis undergoing the same procedure for the same indication who did not receive sedation and 12 patients with no evidence of liver disease who received sedation before diagnostic endoscopy for a variety of GI complaints. The control populations were age, gender, education level, and, in the case of patients with cirrhosis, Child Pugh s score matched to the patients with cirrhosis who received sedation.nnnRESULTSnThe mean (+/- SEM) age of patients with cirrhosis who received sedation was 59.6 +/- 3.8 years. Seven of the ten (70%) were men. Their mean Child Pugh s score was 7.2 +/- 1.5. Nine of the ten (90%) had abnormal baseline number connection tests results (mean for the group 52.3 +/- 6.7 seconds) the extent of which correlated with Child Pugh s scores (p < 0.005). Individually, the baseline number connection tests results were normal in one (10%), mild in six (60%), moderate in one (10%), and severe in two (20%). After the procedure (before discharge) the mean number connection tests result was 61.5 +/- 7.9 seconds (p = 0.01 when compared with baseline). The results were now normal in none (0%), mild in four (40%), moderate in four (40%), and severe in two (20%). Pre- and post-procedure number connection tests results did not change in the non-sedated cirrhotic or sedated non-liver disease control patients.nnnCONCLUSIONSnThe results of this study indicate that (1) the majority of patients with cirrhosis and suspected portal hypertension have evidence of subclinical hepatic encephalopathy, (2) the extent of encephalopathy correlates with the Child Pughs score, (3) sedation with midazolam for upper GI endoscopy exacerbates the encephalopathy, and (4) this adverse effect is still evident 2 hours after the procedure.

Outcomes Following Liver Transplantation for Patients with Alcohol- Versus Nonalcohol-Induced Liver Disease

OBJECTIVEnTo document and compare the outcomes of adult patients who received liver transplants for alcohol- and nonalcohol-induced liver diseases who attended a liver transplantation follow-up clinic in an urban, nontransplantation centre at a time when no formal alcohol abuse program for transplant candidates and/or recipients was offered.nnnPATIENTS AND METHODSnThe study population comprised 10 alcoholic patients and 48 nonalcoholic patients followed for an average of 41 months (range five to 79 months) and 46 months (range two to 116 months), respectively. Primary outcome variables included rates of recidivism, duration of abstinence after transplantation and compliance with post-transplant medical follow-up visits. Time to discharge after transplantation, episodes of graft rejection, liver and renal biochemical abnormalities, diabetes, hypertension, sepsis, strictures, complications unrelated to transplantation and changes in psychosocial status were secondary outcome variables.nnnRESULTSnSignificant differences were found with respect to a higher incidence of recidivism (50% for alcoholic patients compared with 2% for nonalcoholic patients, P<0.0001), a shorter period of abstinence after transplantation (14.7+/-17.2 months for alcoholic patients compared with 26.3+/-23.0 months for nonalcoholic patients, P<0.05) and more missed office visits (2.7+/-3.5 for alcoholic patients compared with 1.0+/-1.9 for nonalcoholic patients, P=0.05) in the alcoholic group. The alcoholic group also had a lower incidence of rejection episodes (10% for alcoholic patients compared with 44% for nonalcoholic patients, P<0.05) but higher rates of post-transplantation diabetes (40% for alcoholic patients compared with 2% for nonalcoholic patients, P<0.05), more nontransplantation-related complications (20% for alcoholic patients compared with 0% for nonalcoholic patients, P<0.05), and higher serum creatinine but lower bilirubin and cyclosporine A levels (P<0.05, respectively). Marital separations were also more common in the alcoholic group (20% for alcoholic patients compared with 0% for nonalcoholic patients, P<0.05).nnnCONCLUSIONSnIn the absence of formal alcohol abuse programs, the post-transplantation outcome in alcoholic patients generally does not compare well with that of patients who undergo transplantation for nonalcohol-related liver diseases.

The effects of various organ preservation solutions on hepatocyte membrane potentials, intracellular calcium concentrations, and outcome following liver transplantation.

BACKGROUNDnHepatocyte membrane potential differences (PDs) may be altered by the preservation solutions used in liver transplantation. Such alterations could impact on the survival of the donor liver, extent of biochemical injury, and flux of important ionic compounds. The purpose of the present study was to document these outcomes in the presence of four different preservation solutions.nnnMETHODSnLivers of adult male Sprague-Dawley rats (N = 3 to 4 per group) were impaled with intracellular microelectrodes prior to and at various time periods for 6 hours following complete hepatic resection. Just prior to resection, each liver was perfused with preservation solutions associated with high (normal saline [NS]), moderate (Euro-Collins [EC]), and low (University of Wisconsin solution [UW]) risks of reperfusion injury.nnnRESULTSnBaseline (in situ) PDs were similar in all groups (-37 +/- 4 mV, mean +/- SD). Ten minutes postresection, hepatic PDs were as follows: NS, -23.8 +/- 3.5 mV; EC, -11.4 +/- 0.4 mV; and UW, -8.7 +/- 0.3 mV (P <0.01 for all groups). Maximum depolarization occurred at 6 hours postresection (NS, -8.1 +/- 1.1 mV; EC, -7.7 +/- 1.3 mV; and UW, -8.6 +/- 1.0 mV). To determine whether these changes are of pathophysiologic importance, the NS solution was modified (addition of 0.1% ethanol) to achieve similar PD changes as those observed with UW. Liver transplants were then performed where the donor livers had been perfused and preserved for 6 hours with either NS or the modified NS (MNS) solution. Posttransplant (10 day) survival was 1 of 6 (17%) in the NS group and 4 of 6 (67%) in the MNS group (P <0.05). Regarding the effects of PD changes on ionic flux, intracellular calcium levels were documented for up to 4 hours by fluorescence video microscopy using Fura-2 in isolated hepatocytes exposed to NS, UW, and MNS solutions. Intracellular calcium levels were similar in all solutions at each time point studied.nnnCONCLUSIONSnThe results of this study indicate that hepatocytes undergo prompt and marked depolarization following hepatic resection, and the extent of the depolarization correlates with survival following transplantation.

Altered transmembrane ionic flux in hepatocytes isolated from cirrhotic rats

BACKGROUND/AIMSnAlthough cirrhosis is known to be associated with many hepatocyte abnormalities, there is no well-established model to study the cellular drug uptake process independent of hemodynamic effects. The purpose of the present study was to test the following hypothesis: hepatocytes isolated from cirrhotic animals may be used as a model to study the cellular abnormalities associated with cirrhosis. Our hypothesis was tested by comparing the membrane potential (PD) of hepatocytes in anesthetized healthy and cirrhotic animals, and the PD and [3H]palmitic acid clearance rate of hepatocytes isolated from healthy and cirrhotic animals.nnnMETHODSnMild to moderate cirrhosis was induced in female Sprague-Dawley rats by CCl4 administration. PD was recorded in anesthetized animals using intracellular microelectrodes. Hepatocytes from those livers were subsequently isolated by collagenase perfusion for further determinations of PD and [3H]palmitic acid uptake.nnnRESULTSnThe mean (+/-SEM) hepatocyte PD from intact rat livers was 38+/-1 mV (control) and -32+/-1 mV (cirrhosis; n=6/group, p<0.01). The PD (mean+/-SEM) in isolated hepatocytes was -21+/-1 mV (control) and -15+/-1 mV (cirrhosis, n=13/group, p<0.01). The clearance rate of [3H]palmitic acid was lower in hepatocytes isolated from cirrhotic animals (26%) than in those isolated from healthy control animals (p<0.01).nnnCONCLUSIONnThe results of this study indicate that hepatocytes isolated from cirrhotic animals may be used to study the cellular abnormalities associated with cirrhosis.

Early changes in hepatitis C virus (HCV) RNA levels predict response to interferon treatment in noncirrhotic HCV patients.

UNLABELLEDnThe role of hepatitis C virus (HCV) RNA quantification in determining ideal interferon (IFN) treatment of noncirrhotic HCV liver disease is uncertain. The specific aim of this study was to determine whether measurement of baseline HCV RNA or changes in HCV RNA levels (DHCV RNA) early during therapy predict response to IFN alpha in noncirrhotic HCV patients.nnnPATIENTS AND METHODSnTwenty-one noncirrhotic patients with chronic HCV were treated with 3 MU IFN alpha-2a three times per week. HCV RNA levels were determined at baseline and after two, four, six, eight and 12 weeks of treatment. Baseline HCV RNA and DHCV RNA during therapy were compared with treatment response results at six months. Data were expressed as mean +/- SE, and differences were assessed using Students t test.nnnRESULTSnTwenty-one patients initiated IFN alpha therapy. Two patients were noncompliant and lost to follow-up. One patient discontinued IFN alpha due to side effects. Apart from age, where responders tended to be younger than nonresponders, the baseline clinical characteristics and alanine aminotransferase (ALT), aspartate aminotransferase, bilirubin and HCV RNA levels did not differ between IFN alpha responders and nonresponders. Levels of HCV RNA were significantly lower after both two and four weeks of therapy in IFN alpha responders compared with nonresponders (P<0.001). Changes in log HCV RNA levels after both two and four weeks of therapy were significantly greater in IFN alpha responders compared with nonresponders (P<0.001). Changes in log HCV RNA of more than 1.0 after two weeks of IFN alpha therapy identified all six-month responders, with a sensitivity of 100% and a specificity of 89%. Potential financial impact of these findings on patients management was also calculated. Decisions regarding discontinuation of therapy based on early changes in HCV RNA levels would result in a 40% to 50% reduction in IFN alpha cost.nnnCONCLUSIONSnIn noncirrhotic HCV patients, the change in quantitative HCV RNA after the first two weeks of IFN alpha therapy identifies responders. This finding would result in a 40% to 50% cost savings if decisions about continuing IFN alpha were based on early changes in HCV RNA levels rather than ALT or HCV RNA assessment after the completion of three months of IFN alpha treatment.

Sa1023 Liver Transplantation for Hepatocellular Carcinoma Outside of Both Milan and UCSF Criteria: Does Etiology of Liver Disease Impact Outcomes?

Background: Liver transplantation (LT) is the optimal treatment for selected patients with hepatocellular carcinoma (HCC). Survival of >80% at 4 years has been demonstrated for patients with HCC meeting Milan criteria. The UCSF group reported acceptable outcomes using a specific protocol for patients beyond Milan criteria. Proceeding with LT for HCC outside UCSF criteria is very controversial given the concern for recurrent HCC affecting longterm outcomes. Underlying viral disease may influence post-transplant immunosuppression. However, the impact of a viral etiology on patients with HCC at higher risk of recurrence is unknown. We sought to examine the impact of underlying etiology of liver disease on recurrence and outcomes in patients who had explants with HCC beyond Milan and UCSF criteria. Methods: We reviewed 87 patients after LT for HCC from 1998-2009 with explant tumor beyond Milan UCSF criteria. We compared outcomes of patients with cirrhosis due to chronic hepatitis B or C to those from non-viral etiology, with recurrence data up to 11/ 2012. Results: The viral hepatitis group (n=58) had a mean LT age of 56.7 years. Hepatitis C (HCV) was present in 86%, with eleven achieving SVR after transplant and one before. Mean biological MELD and mean alfa-fetoprotein (AFP) at LT were 14.4 and 537.9ng/mL, respectively. Pre-LT locoregional therapy with transarterial chemoembolization (TACE) or radiofrequency ablation (RFA) was given in 81% and 12%, respectively. At explant, mean tumor count (MTC) was 4.3, mean largest tumor size (mLTS) was 4.92cm, and 46.6% had vascular invasion. HCC recurrence occurred in 50%, with a mean patient survival time (PST) of 3.41 years. 10 of the 12 HCV patients with SVR had HCC recurrence. Patient survival at 1 year (1yPS) and 3 years (3yPS) was 81% and 48%, respectfully, both lower than the 2005-2010 Surgical Registry of Transplant Recipient (SRTR) national averages. The non-viral group (n=29) had a mean LT age of 61.3 years. Mean MELD and AFP were 17.3 and 1190.1ng/mL, respectively. Pre-LT TACE and RFA were performed in 85% and 7%, respectively. MTC was 4.7 and mLTS was 4.95cm. 65.5% had vascular invasion. HCC recurrence occurred in 55.2%, with a mean PST of 3.76 years. 1yPS and 3yPS was 79% and 48%, respectively, again lower than the national averages from the 2005-2010 SRTR. Conclusion: In our cohort of patients who had HCC outside of Milan and UCSF criteria that underwent LT, the cause of liver disease did not impact recurrence of HCC or patient survival. Both viral and non-viral groups had similar disease burden, AFP levels, and vascular invasion in the explant as well as cancer recurrence rates. HCV SVR did not appear to impact HCC recurrence. Longer term survival was less favorable for patients transplanted beyond Milan and UCSF criteria and was lower than the national average for the same time period.

Mo1906 Anti-Thymocyte Globulin (ATG) in Severe Acute Cellular Graft Rejection (ACGR) After Liver Transplantation (LT)

Background/Aims: Hepatitis B virus (HBV) genotypes B and C are common in Japan and have been demonstrated as one of the predictive factors associated with the progression of liver diseases. The aim of this study was to examine the changes over time in genotypes of HBV carriers in the hyperendemic area for HBV genotype B infection in Japan as well as in genotypes responsible for acute hepatitis B. Methods: We evaluated HBV genotypes in 430 HBsAg-positive HBV carriers and 34 patients with acute hepatitis B who had a medical examination at our university hospital between 1990 and 2010. The subjects were divided into two time-period groups (1990-1999 and 2000-2010) and analyzed the distribution of genotypes. In addition, the clinical and virological characteristics; ALT value, HBeAg, antiHBe antibody, IgM-HBc antibody, HBVDNA, were compared between subjects with genotype A infection and those with non-genotype A infection. Results: Of the 430 HBsAg-positive carriers, 45% had genotype B and 35% had genotype C in both time-period groups, indicating no changes in genotypes over time. Among 34 acute hepatitis B patients, the prevalence of genotype B was lower in the 2000-2009 group (1/17; 5.9%) than in the 1990-1999 group (10/17; 58.8%, p=0.012), while that of genotype A tended to have increased from 11.8% (2/17) to 29.4% (5/17) in the last 10 years. One of 7 patients with acute HBV genotype A infection did not clear HBsAg and developed to chronic infection. When Kaplan-Meier analysis was used to compare HBsAg clearance phase between the patients with or without genotype A infection, the phase was significantly longer in the genotype A patients (49 wks vs. 8 wks; p < 0.05). HBV DNA negative phase was also significantly longer in the genotype A patients (45 wks vs. 4.9 wks; p < 0.05), while the both groups showed no difference in HBeAg negative phase, anti-HBe positive phase, IgM-HBc antibody negative phase, and ALT normalization period. Conclusion: In a hyperendemic area for HBV genotype B infection in Japan, there was no large change of HBV genotypic distribution in carriers, while genotype A infection was increased in acute hepatitis B in the last 10 years. Compared to patients with acute HBV non-genotype A infection, patients with genotype A infection took a longer duration for HBsAg clearance and for achievement of HBV DNA negative status. Infection became chronic in some of the patients with infected with genotype A, suggesting that genotype distribution in HBV carriers will change in Japan in the future. It is necessary to re-examine the nation-wide study of clinical course of acute hepatitis B patients, especially infected with genotype A.

An institutional review of fulminant hepatic failure in an urban Canadian centre

Abstract This study describes the demographic, etiologic, biochemical, and outcome features of 20 adult patients admitted to an urban intensive care unit with fulminant hepatic failure (FHF) from January 1989 to November 1994. The mean age of the group was 46±16 years (range: 18–70) with the majority (12/20, 60%) female. Fifteen (75%) of the 20 patients were encephalopathic prior to admission to the ICU while the remaining five (25%) developed encephalopathy during their ICU stay. The mean ICU stay was 5±4.6 days (range: 1–17 days). Acetaminophen toxicity was the most common cause of FHF (9/20, 45%) followed by hepatic ischemia (5/20, 25%), viral hepatitis (2/20, 10%), and miscellaneous or undiagnosed causes (4/20, 20%). The mortality rate was 95%. These findings indicate that in this Canadian centre the most common cause of FHF admissions to the intensive care unit is acetaminophen toxicity rather than viral hepatitis (British rather than American pattern) and is associated with an unexpectedly high mortality rate.