Gallbladder Scalloping, Mammillated Caudate Lobe, and Inferior Vena Cava Scalloping: Three Novel Ultrasound Signs of Cirrhosis.

PURPOSE: We aimed to present three new ultrasound signs-gallbladder scalloping, mammillated caudate lobe, and inferior vena cava scalloping-and determine their accuracy in diagnosing liver cirrhosis. MATERIALS AND METHODS: A total of 201 consecutive patients with a history of chronic liver disease who had undergone ultrasound imaging and liver biopsy were identified. A senior ultrasound radiologist blindly reviewed the ultrasound examinations. Specificity, sensitivity, positive predictive value, and negative predictive value of diagnosing cirrhosis were calculated for all evaluated ultrasound signs and selected combinations of signs, using the liver biopsy results as the reference standard. RESULTS: Of the 201 patients, 152 (76%) had either pathology-proven cirrhosis or significant fibrosis. Caudate lobe hypertrophy was the most specific (88%) and most positive predictor (90%) for cirrhosis, whereas mammillated caudate lobe was the most sensitive (78%). Inferior vena cava scalloping was the most specific (78%) of the three proposed ultrasound signs. When signs were combined, the presence of either gallbladder scalloping or liver surface nodularity was highly sensitive for cirrhosis (87%), whereas the presence of either gallbladder scalloping or inferior vena cava scalloping with caudate lobe hypertrophy was highly specific (93%). CONCLUSIONS: Gallbladder scalloping, mammillated caudate lobe, and inferior vena cava scalloping are three novel signs that improve the accuracy of ultrasound in diagnosing cirrhosis.

Predicting cancer mortality: Developing a new cancer care variable using mixed methods and the quasi-statistical approach.

OBJECTIVE: To demonstrate the value of using a variable derived from qualitative analysis in subsequent quantitative analyses. DATA SOURCES/STUDY SETTING: Mixed methods data were combined with 10-year mortality outcomes. Participants with cancer were recruited from services at a large teaching hospital, and mortality data were from the Social Security Death Index. STUDY DESIGN: An observational concurrent or convergent mixed methods design was used to collect demographics and structured ratings along with qualitative data from 909 cancer patients at baseline. DATA COLLECTION/EXTRACTION METHODS: Coding rules for qualitative data were defined for open-ended responses from cancer participants speaking about their view of self, and a variable was numerically coded for each case. Mortality outcomes were matched to baseline data, including the view of self variable. PRINCIPAL FINDINGS: Individuals with an improved view of self had a significantly lower mortality rate than those for whom it was worse or unchanged, even when adjusting for age, gender, and cancer stage. CONCLUSIONS: Statistical analysis of qualitative data is feasible and can identify new predictors with health services' implications associated with cancer mortality. Future studies should consider the value of testing coded qualitative variables in relation with key health care outcomes.

Older donor livers show early severe histological activity, fibrosis, and graft failure after liver transplantation for hepatitis C.

BACKGROUND: In hepatitis C virus (HCV)-positive liver transplant recipients, infection of the allograft and recurrent liver disease are important problems. Increased donor age has emerged as an important variable affecting patient and graft survival; however, specific age cutoffs and risk ratios for poor histologic outcomes and graft survival are not clear. METHODS: A longitudinal database of all HCV-positive patients transplanted at our center during an 11-year period was used to identify 111 patients who received 124 liver transplants. Graft survival and histological endpoints (severe activity and fibrosis) of HCV infection in the allografts were compared as a function of donor age at transplantation. RESULTS: By Kaplan-Meier analyses, older allografts showed earlier failure and decreased time to severe histological activity and fibrosis as compared with allografts from younger donors. By Cox proportional hazards analysis, older allografts were at greater risk for all severe histologic features and decreased graft survival as compared with younger allografts (P< or =0.02 for all outcomes). Analysis of donor age as a dichotomous variable showed that donors greater than 60 yr were at high risk for deleterious histologic outcomes and graft failure. An age cutoff of 60 yr showed a sensitivity of 94% and specificity of 67% for worse graft survival by receiver operating characteristics curve. CONCLUSIONS: Advanced donor age is associated with more aggressive recurrent HCV and early allograft failure in HCV-positive liver transplant recipients. Consideration of donor age is important for decisions regarding patient selection, antiviral therapy, and organ allocation.

Treatment of hepatitis C cryoglobulinemia: mission and challenges.

Mixed cryoglobulinemia (MC) is a syndrome resulting from cold-insoluble immunoglobulin complexes or cryoglobulins (CGs) that precipitate in the serum of 40% to 50% of patients with chronic hepatitis C virus (HCV) infection. The pathogenesis of cryoglobulinemia likely occurs due to chronic viremia and generation of rheumatoid factor following continuous presentation of antigen-immunoglobulin complexes to B cells. CGs are thought to be responsible for a variety of extrahepatic manifestations associated with HCV, including vasculitis, glomerulonephritis, arthritis, and neuropathies, which occur in approximately 10% of HCV patients with CGs. CGs also are a powerful predictive factor for progressive liver disease and the aggressive reoccurrence of liver disease in HCV-positive patients after liver transplantation. First-line therapy for MC due to HCV infection is antiviral therapy with pegylated interferon-alpha and ribavirin. Viral eradication usually produces marked reduction of physical complications and arrests end organ damage concomitant with clearance of CG. Additional prospective, controlled studies are necessary to determine whether CG influences patient virologic response and/or its durability to antiviral therapy. Immunomodulators such as corticosteroids and cyclophosphamide are efficacious for palliative treatment of the symptomatology of HCV cryoglobulinemia but may enhance viral replication. Consequently, prolonged therapy with immunomodulatory agents should be limited to severe vasculitis or aggressive glomerulonephritis in patients with MC due to HCV who have failed to respond to antiviral therapy. In acute, fulminant presentations, plasmapheresis may provide temporary relief and arrest the rapid progression of the disease so that additional therapy can be initiated.

Mental and physical symptoms associated with lower social support for patients with hepatitis C.

AIM: To systematically examine the impact of the hepatitis C virus (HCV) diagnosis on patients' level of social support in a large-scale study. METHODS: Patients evaluated and treated for HCV in a tertiary referral center were enrolled in a cross-sectional study. Demographic data, functional and emotional status as measured by the Hospital Anxiety and Depression Scale (HAD) and the Sickness Impact Profile (SIP), severity of liver disease, mode of acquisition, and physical and psychiatric comorbidities were collected from patients or abstracted from the medical record. All participants completed a semi-structured interview, addressing questions of social support. RESULTS: A total of 342 patients (mean age 45.2 years; 37% women) were enrolled. Ninety-two (27%) patients described lower levels of support by family and friends. Nearly half of the participants (45%) noted the loss of at least one relationship due to the disease. Fears related to transmitting the disease (25%) were common and often associated with ignorance or even discrimination by others (19%). Nearly one fifth of the patients did not share information about their disease with others to avoid being stigmatized. Lower levels of social support were significantly associated with living alone, being unemployed, being excluded from antiviral therapy, having psychiatric comorbidities, contracting HCV through intravenous drug use, having high levels of anxiety and depression as measured by the HAD and negative mood state as measured by the SIP. Patients reporting lower levels of social support also noted more physical symptoms as measured by the SIP. CONCLUSION: Patients with hepatitis C often face significant social problems, ranging from social isolation to familial stress. The most common concerns reflect a limited insight of patients and their relatives and friends about the disease, the risk factors for its spread, and about potential consequences. Our data suggest that educational interventions targeting support persons and the stressors identified in our findings may lessen or alleviate the social strains patients with hepatitis C experience.

Majority of patients with hepatitis C express physical, mental, and social difficulties with antiviral treatment.

OBJECTIVE: The hepatitis C virus can be successfully treated in up to 60% of infected patients. However, treatment is long and is associated with significant side-effects. We investigated difficulties with this treatment as it is an important factor in patient adherence. METHODS: Patients receiving hepatitis C treatment in a tertiary referral center were enrolled in a cross-sectional study. Demographic data, functional and emotional status, and co-morbidities were collected from patients or abstracted from the medical records. All participants underwent a semistructured interview, which was analysed by blinded coders. RESULTS: A total of 65 patients (mean age 46.1 years; 38.5% women) were enrolled. Fifty-two (80%) described moderate to severe problems attributed to treatment, with a predominance of physical difficulties (fatigue 74% of cases; flu-like symptoms 32%). Approximately one third of patients (38%) experienced depression during treatment. In 31% of cases, physical or emotional problems forced patients to quit their jobs or reduce employment. One fifth attributed deteriorating relationships with friends and family to adverse treatment effects. Necessary lifestyle adjustments, such as alcohol abstinence, caused frictions with friends in 22% of the participants. CONCLUSIONS: Our findings show a high prevalence of significant adverse effects in patients undergoing antiviral therapy. Whereas the nature and severity of these adverse reactions is consistent with earlier reports, we identified implications with worsening private and professional relationships. To encourage appropriate levels of adherence, healthcare providers should seek information about these indirect treatment effects as they monitor their patients on therapy.

GB virus type C NS5A sequence polymorphisms: association with interferon susceptibility and inhibition of PKR-mediated eIF2alpha phosphorylation.

GB virus type C (GBV-C) causes persistent infection in humans, although the mechanism by which the virus avoids clearance by the host is unknown. To determine if amino acid polymorphisms in the GB virus type C (GBV-C) NS5A and E2 proteins alter response to interferon (IFN) therapy, we studied the sequence of GBVC NS5A and E2 obtained from people receiving IFN therapy. In addition, we expressed recombinant GBVC NS5A protein to determine if it interferes with RNA-activated protein kinase (PKR) function in vitro. GBVC NS5A amplified from a person whose virus was cleared by IFN therapy (IFN sensitive) demonstrated unique amino acid changes occurring in the region that aligns with the hepatitis C virus (HCV) IFN sensitivity-determining region (ISDR) compared with NS5A sequences from individuals who did not clear GBV-C (IFN resistant). There were no differences in the E2 sequences obtained from IFN-sensitive and IFN-resistant isolates. Using a yeast genetic system, IFN-resistant NS5A inhibited PKR-mediated phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) in yeast, whereas IFN-sensitive NS5A did not inhibit PKR function. GBV-C NS5A amino acid polymorphisms appear to be involved in response to IFN therapy, and IFN-resistant GBV-C NS5A inhibited PKR-mediated eIF2alpha phosphorylation in a yeast genetic system, suggesting a mechanism by which GBV-C may evade clearance by naturally occurring host antiviral responses.

T-cell activation after chronic ethanol ingestion in mice.

Chronic excessive consumption of ethanol causes immunodeficiency in human beings and in mice. Immunologic changes have been described in both species, including T-cell and innate immune system cell activation, among others. The features of chronic ethanol-induced activation have similarities in the two species, including an increased effector subset in both CD4+ and CD8+ T cells. There are also features of activation observed in the splenic macrophages of mice consuming ethanol chronically, including increased up-regulation of CD80 and CD86. Because these molecules are involved in T-cell-antigen-presenting cell interactions in vivo, it is of interest to ask whether these and other pathways of interaction are important in the T-cell activation and cytokine skewing described in chronic ethanol abuse. Preliminary findings from comparisons of wild-type, CD40 ligand knock-out, and CD28 knock-out C57BL/6 mice strongly support the suggestion of a critical role for T-cell-antigen-presenting cell interactions in the immune alterations observed in chronic ethanol abuse.

Down-regulation of heme oxygenase-1 by hepatitis C virus infection in vivo and by the in vitro expression of hepatitis C core protein.

Antioxidant enzymes, including heme oxygenase (HO)-1, are an important line of defense against oxidant-mediated liver injury. Because hepatitis C virus (HCV) infection appears to increase the production of oxidants, we evaluated levels of antioxidant enzymes and HO-1 in liver-biopsy samples from HCV-infected patients by immunoblot and semiquantitative reverse-transcriptase polymerase chain reaction. In HCV-infected liver samples, levels of immunoreactive HO-1 and HO-1 mRNA were >4-fold lower than levels in control samples, but levels of superoxide dismutase and catalase were unaffected. Immunohistochemical results confirmed the decreased expression of HO-1 in hepatocytes from liver samples from HCV-infected patients but not in those from patients with other chronic liver diseases. The expression of HO-1 was also reduced in cell lines that stably express HCV core protein, which suggests that core gene products are capable of regulating the expression of HO-1.

A large biloma causing gastric outlet obstruction after a percutaneous liver biopsy.

Biloma formation has not been reported to occur after a routine percutaneous liver biopsy. It is an uncommon yet well known complication of laparoscopic cholecystectomy. We report the development of a biloma within 1 week after a liver biopsy with a Jamshidi needle in a non-cirrhotic patient with hepatitis C. The biloma was large and caused a dramatic alteration of the hepatic contour and displaced the liver medially, resulting in gastric outlet obstruction. The biloma was treated successfully with percutaneous drainage. We believe this to be the first report of a large biloma causing gastric outlet obstruction as a complication of percutaneous liver biopsy.

Liver transplantation for disulfiram-induced fulminant hepatic failure.

Disulfiram has been used as a popular adjunct in programs for alcohol rehabilitation. However, in rare cases, disulfiram has been reported to cause fulminant hepatitis. Disulfiram use and its associated complications in adolescents have received minimal attention in the literature. We report the first pediatric case of successful orthotopic liver transplantation for disulfiram-induced fulminant hepatic failure in a 16-year-old girl, who developed an idiosyncratic reaction associated with short-term, low-dose disulfiram use, as evidenced by her liver biopsy and explanted liver. This case report indicates that a high index of suspicion, and aggressive therapeutic interventions are necessary to recognize and manage disulfiram-induced fulminant hepatic failure in adolescents. Success of this case suggests that transplant centers should consider liver transplantation of an adolescent alcoholic patient with fulminant hepatic failure due to non-alcohol-related causes such as disulfiram. Orthotopic liver transplantation should be considered early in the management of disulfiram-induced fulminant hepatic failure.

Hepatitis C virus-infected patients report communication problems with physicians.

We examined the prevalence and nature of perceived problems in the interaction between physicians and patients diagnosed with hepatitis C virus (HCV) infection. This cross-sectional study included 322 outpatients diagnosed with chronic HCV infection and treated at a tertiary referral hospital's hepatology clinic. Patients were asked to provide demographic information and to complete a semistructured interview, the Sickness Impact Profile (SIP) and Hospital Anxiety Depression (HAD) scale. A team of two blinded coders analyzed the interviews. A total of 131 (41%) study patients reported communication difficulties with physicians involved in their care. The main difficulties were the poor communication skills of physicians (91 [28%]), physician incompetence regarding the diagnosis and treatment of HCV infection (74 [23%]), feelings of being misdiagnosed, misled, or abandoned (51 [16%]), or being stigmatized by their physician (29 [9%]). Patients were twice as likely to report difficulties with subspecialists as compared with generalists. Nonresponse with antiviral therapy correlated with perceived physician conflict even after adjusting for treatment in relation to the time of interview, whereas previous or ongoing substance abuse and mode of acquisition did not. In a multivariate model, patients' psychosocial problems were the best predictors of communication difficulties. In conclusion, a substantial number of patients with HCV infection report difficulties when interacting with physicians, which may be due to coexisting emotional or social problems. However, perceived stigmatization by physicians and a sense of abandonment reflect the need for further educational efforts. These should target both specialists and primary care providers to inform them about the psychosocial challenges facing these patients.

"They treated me like a leper". Stigmatization and the quality of life of patients with hepatitis C.

OBJECTIVE: Hepatitis C virus is the most prevalent chronic blood-borne infection in the United States, typically acquired through contaminated blood products or needle sharing. We hypothesized that patients with chronic hepatitis C infection experience stigmatization independent of mode of acquisition and that it negatively affects quality of life. DESIGN: Cross-sectional observation study. SETTING: Specialty clinic in a tertiary referral hospital. PATIENTS: Two hundred and ninety outpatients diagnosed with chronic hepatitis C infection and seen in a hepatology clinic. Thirty participants were excluded because of missing data. MEASUREMENTS AND MAIN RESULTS: Patients were asked to complete a demographic profile, a semistructured interview, the Sickness Impact Profile, and the Hospital Anxiety Depression Scale. A team of two blinded coders analyzed the interviews. A total of 147 of the 257 study patients experienced stigmatization that they attributed to the disease. Women were more likely to report perceived stigmatization than men (P <.05). Age, education, professional status, and mode of infection did not influence the likelihood of stigmatization. Stigmatization was associated with higher anxiety (P <.01) and depression (P <.01), worsened quality of life (P <.01), loss of control (P <.01), and difficulty coping (P <.01). Individuals who experienced stigmatization also mentioned problems in their health care (P <.01) and work environment (P <.01) as well as with family members (P <.01). CONCLUSION: Stigmatization is a very common emotionally burdensome experience for patients with hepatitis C, which can erode social support. As it penetrates even into the health care environment, physicians and other care providers should be aware of the existence and impact of such negative stereotyping.

Recombinant hepatitis C virus-like particles expressed by baculovirus: utility in cell-binding and antibody detection assays.

Hepatitis C virus (HCV) is difficult to study due to the lack of an efficient cell culture system or small animal model. As a result, HCV-cell interactions are not well-defined. In addition, several studies have identified a subset of patients in whom HCV RNA is present, but HCV antibody is not detected. We produced recombinant baculoviruses that expressed HCV structural proteins (core, E1 and E2, nt 342-2651) or control proteins. The HCV structural protein precursor was processed into immunoreactive proteins of appropriate size, and sucrose density sedimentation and electron microscopy of infected cell lysates demonstrated particle formation. To evaluate HCV antigenicity, particularly in patients who tested negative for HCV antibody in commercial HCV immunoassays but had persistent viremia, we evaluated the virus-like particles (VLPs) in solid-phase immunoassays. VLPs reacted with sera from HCV antibody positive subjects in these solid phase immunoassays, but not with control sera. Plasma samples from 19% (5/26) of HCV antibody negative subjects who were persistently HCV RNA positive also reacted with the HCV VLPs. When incubated with MOLT-4 cells at 4 degrees C, HCV VLPs demonstrated cell binding, and behaved similar to plasma-derived HCV preparations in a flow cytometry-based cell binding assay. These data suggest that recombinant HCV VLPs may allow identification of HCV antibody in patients, including some patients with persistent viremia and who are seronegative with current assays. In addition, HCV VLPs seem useful for evaluating HCV-cell interactions.