Hepatic stellate cell activation in nonalcoholic steatohepatitis and fatty liver.

Factors associated with the development of fibrosis in nonalcoholic steatohepatitis (NASH) are largely unknown, although an association with increased hepatic iron has been suggested. Hepatic stellate cells are the principal collagen-producing cells in many liver diseases and when activated express alpha-smooth muscle actin (alpha-SMA). Hepatic stellate cell activation and association with fibrosis, necroinflammatory activity, steatosis, and stainable iron in 60 cases of NASH and 16 cases of steatosis were evaluated. All 76 patients were obese or had other risk factors for NASH. All biopsy specimens were stained for alpha-smooth muscle actin to evaluate the pattern of hepatic stellate cell activation and were evaluated for inflammatory activity (0 to 3), fibrosis (0 to 4), and stainable iron stores (0 to 4). The zonal location of activated stellate cells was recorded, and the degree of activation was graded as high-grade or low-grade based on the percentage of lobular alpha-SMA+ cells. Activated stellate cells were identified in the hepatic lobule in 74 of 76 biopsy specimens and graded as low-grade in 26 and high-grade in 48. Zone 3 was involved in 72 of 74 positive cases, and in 33 cases, the activated stellate cells were preferentially located in zone 3. The degree of stellate cell activation correlated with fibrosis but not with inflammatory activity, severity of steatosis, or stainable iron. In most cases, the degree of stellate cell activation paralleled the degree of hepatic fibrosis, but in 25 cases, the degree of hepatic stellate cell activation was greater than expected, raising the question of whether such patients are at risk for disease progression.

A comparison of reverse transcription-polymerase chain reaction and branched-chain DNA assays for hepatitis C virus RNA in patients receiving interferon treatment. Consensus Interferon Study Group.

Measurement of hepatitis C virus (HCV) RNA may be beneficial in managing the treatment of patients with chronic HCV infection. In a phase 3 study comparing consensus interferon (IFN) and IFN-alpha2b treatment in patients with chronic HCV infection, serum samples were assayed for HCV RNA using two different assays: a quantitative multicycle reverse transcription-polymerase chain reaction (RT-PCR) method and the Quantiplex branched-chain DNA (bDNA) method. Lower and upper detection limits were 100 copies ml-1 and 5 x 10(6) copies ml-1, respectively, for the RT-PCR method, and 3.5 x 10(5) and 4 x 10(7) genome equivalents ml-1, respectively, for the bDNA method. The two assays were generally concordant over the common range of detectability. The major discrepancy was where PCR still indicated detectable virus in the sample but the bDNA result was negative. Assessment of serum samples during IFN treatment demonstrated that 37% of samples were negative for HCV RNA by bDNA but positive by RT-PCR. Differences were also noted in the quantification of baseline HCV RNA by genotype. These data suggest that HCV patients could be categorized as treatment responders by the bDNA assay when the more sensitive RT-PCR assay indicates lack of complete viral response.

Bromfenac (Duract)-associated hepatic failure requiring liver transplantation.

Bromfenac sodium (Duract) is a phenylacetic acid-derived nonsteroidal anti-inflammatory agent introduced in the United States in 1997 and withdrawn in 1998. We describe the first case of fulminant hepatic failure associated with this agent treated successfully with liver transplantation. Similarities to hepatotoxicity with related agents is discussed.

Pulmonary vascular morphological changes in cirrhotic patients undergoing liver transplantation.

Cirrhosis and portal hypertension may be associated with pulmonary hypertension and pulmonary dysfunction. However, morphological pulmonary vascular lesions in patients with cirrhosis have not been well characterized morphometrically. We morphometrically evaluated pulmonary vessels in liver transplant recipients with pretransplantation cirrhosis and correlated our findings with pretransplantation cardiopulmonary function, postoperative course, and postmortem cardiopulmonary findings. Autopsy lung slides from 23 transplant recipients with pretransplantation cirrhosis were examined. External vessel diameter, intimal thickness, and arterial medial thickness were measured with a micrometer after pentachrome staining. The percent of total diameter comprised by intima or media was calculated for each vessel. Medical records were reviewed for smoking history, pretransplantation cardiopulmonary function testing, and postoperative course. Autopsy cases without liver or significant cardiopulmonary diseases, matched for age, sex, and smoking history, served as controls. Transplant recipients had significantly more pulmonary venous intimal thickening than matched controls (P <.0001). Sixty-five percent (15 of 23) of these patients had some degree of pretransplantation pulmonary dysfunction, defined by abnormalities in pulmonary function tests, oxygen saturation, and/or increased pulmonary artery pressures. However, the severity of venous intimal thickening did not correlate with the severity of pretransplantation pulmonary dysfunction. Arterial intimal and medial thickness were not statistically significantly different from controls. Pulmonary venous intimal thickening and resultant luminal impingement are morphological findings not previously described in this population. The arterial lesion, when present, is similar to that seen in pulmonary hypertension from other causes. These pulmonary vascular lesions may be implicated in pulmonary dysfunction in patients with cirrhosis and may be associated with increased posttransplantation cardiopulmonary morbidity and mortality.

Experience with neoral versus sandimmune in primary liver transplant recipients.

We compared results using Neoral versus Sandimmune, each in combination with steroid and azathioprine immunosuppression, in primary liver transplantation recipients. There were 15 patients in each group with similar demographic distributions. Intravenous cyclosporine was stopped at 4.3 +/- 1.9 days in the Neoral group vs 7.8 +/- 4.9 days in the Sandimmune group. (P < 0.025). Cyclosporine levels in the first 10 days were higher (mean 306 ng/ml vs 231 ng/ml) in the Neoral group than the Sandimmune group (P < 0.05). The Neoral dose was less than the Sandimmune dose (mean 5.5 ng/kg per day vs 7.9 ng/kg per day) to achieve these levels in that time period (P < 0.05). Two patients (13%) experienced three episodes of biopsy-proven rejection in the Neoral group compared to nine patients (60%) with 12 episodes of rejection in the Sandimmune group (P < 0.025). Incidences of neurological and renal complications were similar between the groups. Infections requiring treatment were also similar. Liver function, renal function, and marrow function, evaluated at days 7, 14, 21, 28, and 2, 4, 6, and 12 months post-transplant, were not different between the groups. In summary, shorter use of intravenous cyclosporine and quicker stabilization of trough cyclosporine levels was achieved with Neoral than with Sandimmune. In the early post-transplant period, higher levels with lower doses were achieved with Neoral than with Sandimmune. In our experience, the incidence of rejection was lower with Neoral than with Sandimmune. There were similar lengths of hospitalization, mortality, adverse events, retransplantation, and similar liver, renal, and marrow function up to 1 year post-transplantation. Because of this experience, we continued to use Neoral in a total of 59 primary liver transplant recipients. We have not used intravenous cyclosporine in the last 44 patients. Follow-up was a mean of 11.4 months, ranging from 1 to 27 months. The incidence of rejection was 24% in these 59 patients compared to our historical experience of 70% using Sandimmune.

Outcomes analysis in 100 liver transplantation patients.

BACKGROUND: There is an increasing demand for outcomes analysis, including quality of life and financial analysis, following medical interventions and surgical procedures. We analyzed outcomes for 100 consecutive patients undergoing liver transplantation during a period of case management revision. METHODS: Patient survival was calculated by Kaplan-Meier actuarial methods. The Karnofsky performance status was objectively assessed for surviving patients up to 6 years after transplantation and was evaluated by repeated measures analysis of variance and covariance. Subjective evaluation of quality of life over time was obtained using the Psychosocial Adjustment to Illness Scale. The correlations between time and scale were calculated. Financial data were accumulated from billing records. RESULTS: Six-month, 1-year, 2-year, and 3- through 5-year survival was 86%, 84%, 83%, and 78%, respectively. Karnofsky performance status confirmed poor functional status preoperatively with a mean of 53 +/- 2, but significantly improving to 72 +/- 2 at 3 months, 80 +/- 2 at 6 months, 90 +/- 1 at 1 year, 92 +/- 1 at 2 years, 94 +/- 1 at 3 years, 96 +/- 1 at 4 years, and 97 +/- 1 at 5 years (P <0.001). Psychosocial Adjustment to Illness Scale scores demonstrated significant improvement following transplantation overall (r = -0.33), improving most in sexual relationships (r = -0.41), and domestic environment (r = -0.35; P <0.001). Median length of stay for the first half of the patients was 19 days declining to 11 days for the second half. Median hospital charges declined from $105,000 to $90,000. CONCLUSIONS: Quality of life parameters assessed both by care givers (Karnofsky) and by patients (Psychosocial Adjustment to Illness Scale) improved dramatically following transplantation and over time, demonstrating that liver transplantation effectively restores a good quality of life. Outcomes can be improved while reducing length of stay and charges through modifications in case management.

Nashville experience with liver transplantation in Veterans Administration patients.

In this study, we compared results of 28 liver transplants performed in 25 patients referred through the Veterans Administration with 82 transplants performed in 75 nonveteran patients. The evaluation and follow-up care was provided by the same team of physicians and nurses and the transplant procedure performed in the same hospital for both patient groups. There was a significantly greater incidence of hepatitis C and/or previous alcohol abuse in veteran compared with non-VA patients [23/25 (92%) vs 29/75 (39%); P < 0.05] and a greater incidence of native portal vein thrombosis [6/25 (24%) vs 2/75 (2.6%); P < 0.01], but no difference in Child's-Pugh score (10.8 vs 9.9) or UNOS listing status (mean status 2.7 vs 2.8). The increased incidence of native portal vein thrombosis did not appear to be solely related to previous alcohol abuse or hepatitis C, since only 1 of 29 (3.4%) non-VA patients with these etiologies had this finding. There was no difference in patient or graft survival between the VA and non-VA groups with overall actuarial 6-, 12-, and 18-month patient survival of 86, 84, and 83% and graft survival of 80, 78, and 77%. There was no difference in major complication rates but there was a significantly longer average hospital stay (27 +/- 31 vs 18 +/- 12 days; P < 0.05) in the VA compared with non-VA group. One patient with native portal vein thrombosis in the non-VA group developed portal vein thrombosis in the postoperative period. There was no documented recidivism in any patient with a history of prior substance abuse in either group. This study confirms that veteran patients have a higher incidence of hepatitis C and previous alcohol abuse as causes of liver disease, have a higher incidence of native portal vein thrombosis, and have longer mean hospital stays, but experience the same survival in the first 18 months compared with nonveteran patients.

Outcomes analysis for 50 liver transplant recipients: the Vanderbilt experience.

Healthcare reform has mandated scrutiny of the fiscal aspects of patient care as well as medical outcomes. Therefore, we reviewed our experience with 50 liver transplant recipients from a multidisciplinary collaborative transplant team. From February 1991 to July 1994, of 175 patients referred, 75 were formally evaluated for transplantation; 56 (76%) of these patients were accepted for transplantation; 50 patients underwent 53 transplants. Operative mortality of 6 per cent, retransplantation rate of 6 per cent, 6-month actuarial survival of 88 per cent, 1-year survival of 86 per cent, and the 2 and 3-year survival of 83 per cent were unchanged over time. Quality of life evaluated by the Karnofsky Performance Status was a mean of 55 pretransplant, 72 at 3 months, 79 at 6 months, 84 at 1 year, 88 at 2 years, and 95 at 3 years, demonstrating improved general health and functional rehabilitation after transplantation. Psychosocial Adjustment to Illness Scale scores demonstrated significant improvement following transplantation, improving most dramatically in the vocation environment, domestic environment, and sexual relationship domains. Postoperative length of stay has declined with an average of 28 days in 1991, 22 days in 1992, 19 days in 1993, and 14 days in 1994. Average total hospital, organ procurement, and physician charges for the transplantation hospitalization was $165,000. Average 91-92 hospital charges were $154,000 and were reduced in 93-95 to $103,000 (P < .05). We found that charges and length of stay decreased over time, while the outcome and quality of patient care was maintained. We believe the collaborative practice, case management, and revised patient care protocols are responsible.

Safety of the blood supply. Surrogate testing and transmission of hepatitis C in patients after massive transfusion.

OBJECTIVE: To define a risk profile for post-transfusion hepatitis C in patients receiving massive transfusion. SUMMARY BACKGROUND DATA: Hepatitis C accounts for more than 90% of post-transfusion hepatitis. METHODS: Two-hundred twenty-one of 8,765 consecutive trauma admissions to a Level I trauma center received more than 20 units of erythrocytes. Sixty-nine survivors had positive viral serologic tests at least 1 year after transfusion. Surrogate testing for hepatitis C using alanine aminotransferase (ALT) levels and antibodies to hepatitis B core antigen (Core) began in October 1986 and January 1987, respectively. Donor blood for group 1 (pre-ALT/Core) was transfused before surrogate screening was introduced. Donor blood for group 2 (post-ALT/Core) was transfused after surrogate screening. RESULTS: Sixty-nine patients received blood products from 4,987 donors (mean, 72.3 units of exposure). No patient tested positive for antibodies to hepatitis B surface antigen, human immunodeficiency virus, or human T-lymphotrophic virus type 1. However 23.2% tested positive for hepatitis C virus (HCV) as measured by a second-generation enzyme immunoassay (HCV 2.0) and a recombinant immunoblot assay (RIBA), and 21.7% tested positive by HCV 1.0. Antibodies to Core were found in 8.7% of patients. The risk for post-transfusion hepatitis C per unit of exposure is estimated to be 1.52% group 1 (pre-ALT/Core) and 0.239% for group 2 (post-ALT/Core). CONCLUSIONS: The introduction of ALT/Core donor screening by a blood bank reduced the incidence of post-transfusion hepatitis C by 84%. The risk for post-transfusion hepatitis C depends on units of exposure, screening techniques, and prevalence of hepatitis C in the donor population. In our community, the risk for post-transfusion hepatitis C is less than 0.2% per unit of exposure. The population of massively transfused patients may serve as our effective resource for monitoring the safety of the blood supply.

Physicochemical determinants in hepatic extraction of small peptides.

Although the liver is known to extract amino acids and organic anions by well-characterized transport systems, the factors that regulate the hepatic uptake of small, circulating peptides are poorly understood. We previously reported that cholecystokinin octapeptide, a biologically active form of cholecystokinin, is efficiently cleared by the liver and that uptake depends on its carboxyl-terminal tetrapeptide (Trp-Met-Asp-PheNH2). Here we further define the physicochemical determinants for hepatic clearance of cholecystokinin. A series of 13 tetrapeptides, including eight analogs of the carboxyl-terminal tetrapeptide of cholecystokinin-8 with different charges, hydrophobicity and amino-acid sequences, were prepared by solid-phase synthesis, purified by high-performance liquid chromatography and characterized by amino-acid analysis and mass spectrometry. Radioiodination was performed by oxidative or nonoxidative techniques. Hydrophobicity of individual radiolabeled peptides was calculated using published hydrophobicity data or measured directly by determining their partition between octanol and aqueous triethylammonium acetate. First-pass hepatic extraction of radiolabeled peptides was determined with a nonrecirculating, isolated, perfused rat liver model. First-pass hepatic extraction of injected, labeled peptides varied from 4% to 86% and correlated significantly (r = 0.85; p less than 0.0002) with hydrophobicity. Hydrophobic peptides with positive, neutral or negative charges were avidly extracted (30% to 86%) by the liver; first-pass clearance of hydrophobic peptides with similar charges varied with amino-acid sequence. In contrast, the first-pass hepatic extraction of positively or negatively charged hydrophilic tetrapeptides was negligible (less than 10%). These results suggest that hydrophobicity and amino-acid sequence--but not anionic or cationic nature--are the major determinants of hepatic extraction of cholecystokinin, and perhaps other small, circulating peptides.

Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis.

The natural history of primary sclerosing cholangitis was assessed in 174 patients; 37 were asymptomatic and 137 had symptoms related to underlying liver disease. At the time of diagnosis, the mean age was 39.9 years, 66% of the primary sclerosing cholangitis patients were male and 71% had associated inflammatory bowel disease, most commonly chronic ulcerative colitis. Long-term follow-up (mean: 6.0 years; range: 2.7 to 15.5 years) was available in all patients. During follow-up, 59 (34%) of the patients died: 55 in the symptomatic group and four in the asymptomatic group. Median survival from the time of diagnosis of primary sclerosing cholangitis at the Mayo Clinic was 11.9 years. Survival in the asymptomatic group was significantly decreased compared with that in a control population matched for age, race and sex. Multivariate analysis (Cox proportional hazards regression modeling) revealed that age, serum bilirubin concentration, blood hemoglobin concentration, presence or absence of inflammatory bowel disease and histologic stage on liver biopsy were independent predictors of high risk of dying. The development of a multivariate statistical survival model is a major step in identifying individual primary sclerosing cholangitis patients at low, moderate and high risk of dying. Such models will be useful for stratifying patients in therapeutic trials, in patient counseling and in patient selection and timing of liver transplantation.

Endocarditis and infections of intravascular devices due to Eikenella corrodens.

Eikenella corrodens, a microaerophilic gram-negative rod, is a normal inhabitant of human mucosal surfaces. Infections involving Eikenella have been reported with increasing frequency during the past 10 years. Despite a demonstrated ability to invade the blood stream, Eikenella has rarely been implicated in endocarditis or other vascular space infections. Two patients are reported with prolonged illness due to infection of peripheral vascular prostheses with E. corrodens and prior reports of Eikenella vascular space infections are reviewed. When Eikenella is the sole infecting organism, vascular space infections tend to be indolent. However, removal of vascular prostheses may be required for cure.