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Biomedical subjects

Emmet B Keeffe

Publications and source records attributed to Emmet B Keeffe.

At least 37 records · Page 2Linked to original sources
PubMed2005

Survival after liver transplantation in patients with hepatic iron overload: the national hemochromatosis transplant registry.

BACKGROUND & AIMS: Previous uncontrolled studies have suggested that patients with hepatic iron overload have a poor outcome after liver transplantation. We examined the effect of HFE mutations on posttransplantation survival in patients with hepatic iron overload. METHODS: Two hundred sixty patients with end-stage liver disease and hepatic iron overload were enrolled from 12 liver transplantation centers. Hepatic iron concentration (HIC), hepatic iron index (HII), HFE mutation status, and survival after liver transplantation were recorded. RESULTS: HFE-associated hemochromatosis (HH) defined as homozygosity for the C282Y (n = 14, 7.2%) mutation or compound heterozygosity for the C282Y/H63D (n = 11, 5.6%) mutation was identified in 12.8% of patients. Survival postliver transplantation was significantly lower among patients with HH (1-, 3-, and 5-year survival rates of 64%, 48%, 34%, respectively) compared with simple heterozygotes (C282Y/wt or H63D/wt) or wild-type patients. Patients with HH had a hazard ratio for death of 2.6 (P = .002) after adjustment for age, United Network for Organ Sharing status, year of transplantation, and either elevated HII or HIC. Non-HH patients with hepatic iron overload also had significantly decreased survival when compared with the overall population undergoing liver transplantation (OR = 1.4, 95% CI: 1.15-1.61, P < .001). CONCLUSIONS: One- and 5-year survivals after liver transplantation are significantly lower among patients with HFE-associated HH. Our data also suggest that hepatic iron overload may be associated with decreased survival after liver transplantation, even in patients without HH. Early diagnosis of hepatic iron overload using HFE gene testing and iron depletion prior to liver transplantation may improve posttransplantation survival, particularly among patients with HH.

Adult↗
PubMed2005

Chronic hepatitis C: management of treatment failures.

Forty percent to 50% of patients undergoing initial treatment of chronic hepatitis C with peginterferon plus ribavirin fail to achieve a sustained virologic response (SVR), thus prompting consideration of retreatment with alternative regimens. Patients may fail to respond to initial therapy secondary to an inadequate therapeutic regimen, host factors such as African American race, disease characteristics such as cirrhosis, or viral factors including genotype 1 and a high viral load. The decision to re-treat should be based on the presence of advanced fibrosis and the presence of clinical and virologic factors that predict the possibility of a successful outcome with further therapy. Retreatment of patients who were prior nonresponders to interferon monotherapy with interferon plus ribavirin results in overall SVR rates of 13%-15%, which can be increased to 16%-28% with the use of peginterferon plus ribavirin. Retreatment of patients who were prior nonresponders to interferon plus ribavirin with peginterferon plus ribavirin achieves overall SVR rates of 6%-15%; SVR rates are higher with favorable clinical or virologic factors. Prior relapsers to interferon plus ribavirin achieve SVR rates of 32%-50% after retreatment with peginterferon plus ribavirin. There is a limited experience with retreatment of patients who failed peginterferon plus ribavirin, but the use of interferon alfacon-1 plus ribavirin and higher doses of peginterferon and/or a longer duration of peginterferon plus ribavirin therapy are under study. Because therapy has improved in recent years, there are more patients who have been treated and failed initial therapy, highlighting the need for the development of more efficacious antiviral agents for the treatment of chronic hepatitis C.

Antiviral Agents↗
PubMed2005

Prevalence and treatment of hepatitis C virus genotypes 4, 5, and 6.

Infection with hepatitis C virus (HCV) genotypes 4-6 (with the previously named genotypes 7-9 included as subtypes of genotype 6) is distributed and studied less widely than genotypes 1-3. However, genotypes 4-6 are very common in geographic areas where chronic hepatitis C is highly prevalent. In fact, the majority (87%) of the 169.7 million HCV-infected individuals worldwide are from western Pacific countries (62.2 million), southeast Asia (32.3 million), Africa (31.9 million), and eastern Mediterranean countries (21.3 million). It is among this large population outside of the Americas and Europe that these less well known genotypes are found: genotype 4 in Egypt and Africa, genotype 5 in South Africa, and genotype 6 in southeast Asia. The existing literature, although limited, suggests that patients with chronic hepatitis C genotypes 4-6 may exhibit different clinical courses and treatment outcomes. Ethnicity-related factors may contribute to the presence of more advanced disease in patients with genotype 4, who also tend to have a poor response to interferon-based therapy. HCV genotype 5 appears to be an easy-to-treat virus with response rates similar to those of genotypes 2 and 3 after a 48-week course of therapy. Response to treatment in patients with HCV genotype 6 may be at an intermediate level between that seen with genotype 1 and genotype 2 or 3. The optimal duration of treatment (24 vs 48 wk) for HCV genotype 6 is unclear and currently is under investigation.

Antiviral Agents↗
PubMed2005

Advances in gastrointestinal pharmacotherapy.

The medical management of patients with gastrointestinal diseases is advancing rapidly. At a recent symposium held during Digestive Disease Week in Chicago in May of 2005, specific attention was given to the future prospects for medical management of 3 common gastrointestinal disease areas: antisecretory therapy, chronic hepatitis C, and inflammatory bowel disease. Antisecretory approaches include drug combinations including a proton pump inhibitor, potassium competitive acid blockers, and antigastrin agents. The latter two classes are still experimental, but the former combinations have potential to enhance the highly effective agents currently available. The focus of treatment advances in chronic hepatitis C in the immediate future is the discovery of more effective treatment regimens for nonresponders to prior therapy, who are becoming the largest group of patients seeking treatment of hepatitis C. The combination of peginterferon with ribavirin results in 6%-15% sustained virologic response rates in patients who were prior nonresponders to standard interferon plus ribavirin. Newer strategies to eradicate hepatitis C virus infection using different interferons, such as interferon alfacon-1 or higher doses of peginterferon, or long-term maintenance peginterferon, are undergoing study and show promise based on data from preliminary studies. Several immunomodulators have promise in inflammatory bowel disease, although the risk-benefit ratio and costs of therapy require evaluation. Nevertheless, the success of new biologics such as anti-TNFalpha agents augurs well for effective future therapies.

Chicago↗
PubMed2005

Keratins as susceptibility genes for end-stage liver disease.

BACKGROUND & AIMS: Keratins 8 and 18 protect the liver from stress. Keratin 8 and 18 variants in 17 of 467 liver disease explants and 2 of 349 blood bank controls were previously reported in 5 analyzed exonic regions. We asked whether mutations were present in the remaining 10 exons of keratins 8 and 18. METHODS: Exonic regions were polymerase chain reaction-amplified from genomic DNA, isolated from the above-mentioned 2 cohorts, and analyzed for the presence of mutations. Mutant keratins were also studied biochemically. RESULTS: We identified 10 novel keratin 8 and 18 heterozygous variants in 44 of 467 explants and 11 of 349 controls: keratin 18 deletion (delta64-71), a keratin 8 frameshift that truncates the last 14 amino acids; 8 missense keratin 8 and 18 alterations; and several new polymorphisms. The most common variant, keratin 8 R340H, at the highly conserved R340 was found in 30 of 467 explants and 10 of 349 controls (P = .02) and was confirmed in the diseased livers by generation of an R340H-specific antibody. Germline transmission and variant protein expression were verified. The mutations involved a variety of liver diseases, and some variants had an ethnic background preponderance. Mutations that introduced disulfide bonds (keratin 8 G61C or R453C) decreased keratin solubility, particularly after oxidative stress, whereas others decreased keratin 8 phosphorylation (keratin 8 G433S). CONCLUSIONS: The overall frequency of keratin 8 and 18 variants was 12.4% in 467 liver disease explants and 3.7% in 349 blood bank controls (P < .0001). Variants can alter keratin solubility or phosphorylation and may render individuals susceptible to end-stage liver disease, depending on their genetic background and exposure to other insults, such as alcohol or viral infection.

Female↗
PubMed2005

Fulminant hepatic failure secondary to neoplastic infiltration of the liver.

Two patients with previously normal liver function, who presented with fulminant hepatic failure (FHF) of unknown etiology despite an extensive evaluation, are described. No etiology for FHF was apparent with initial evaluation. One patient was found to have nearly complete replacement of hepatic parenchyma by metastasis from an occult small cell lung carcinoma identified postmortem. The other patient had lymphomatous infiltration of the liver detected by a liver biopsy. Imaging studies were performed in the patients and did not reveal any evidence of neoplastic infiltration of the liver. Neoplastic involvement of liver should be considered in the differential diagnosis of FHF of unknown etiology. The imaging studies in this setting can be misleading.

Aged↗
PubMed2005

Portal hypertensive hemorrhage from a left gastroepiploic vein caput medusa in an adhesed umbilical hernia.

Caput medusa is a frequent incidental finding in patients with portal hypertension that usually represents paraumbilical vein portosystemic collateral vessels draining into body wall systemic veins. A symptomatic caput medusa was seen in a morbidly obese patient after an umbilical hernia repair, which was fed not by the left portal vein but by the left gastroepiploic vein, in a recurrent adhesed umbilical hernia that likely contained herniated omentum. Refractory hemorrhage from this caput medusa was successfully treated by transjugular intrahepatic portosystemic shunt creation and balloon-occluded variceal sclerosis.

Hemorrhage↗
PubMed2005

Erythropoietic response to anemia in chronic hepatitis C patients receiving combination pegylated interferon/ribavirin.

OBJECTIVES: In hepatitis C virus (HCV)-infected patients receiving pegylated interferon (PEG-IFN)/ribavirin (RBV) combination therapy, anemia is a well-known side effect. The purpose of this study was to describe the time course and extent of hemoglobin (Hb) changes and the erythropoietic response to PEG-IFN/RBV-induced anemia. METHODS: In this multicenter, observational, 8-wk study, laboratory parameters were measured weekly for 8 wk or until early withdrawal. Primary endpoints included changes in Hb and serum erythropoietin (sEPO) from baseline to week 8; other measures were changes in reticulocytes and RBV dose. The predictive value of baseline factors for maximum Hb decline was assessed. RESULTS: In the 97 evaluable patients, mean Hb decreased from 14.4 +/- 1.4 g/dl (baseline) to 11.9 +/- 1.3 g/dl (week 8). Twenty-one percent of patients withdrew before week 8. The estimated erythropoietic response was lower than that seen in two historic control populations of iron deficiency anemia patients. Mean RBV dose decreased from 986 +/- 190 mg/day (baseline) to 913 +/- 228 mg/day (week 8). Fifty-seven out of 77 (74%) patients who completed the study maintained their initial prescribed RBV dose. Patients maintained on the initial dose of RBV who had a higher baseline Hb and viral load showed a trend toward larger Hb declines. Platelets and white blood cells (WBCs) also declined during the study. CONCLUSIONS: HCV-infected patients receiving PEG-IFN/RBV therapy have reductions in Hb, platelets, and WBCs, possibly due to bone marrow suppression. They also have diminished endogenous sEPO production for their degree of anemia.

Anemia↗
PubMed2005

Role of liver biopsy in the management of chronic liver disease: selective rather than routine.

Liver biopsy has historically played a central role in the diagnosis and management of a variety of chronic liver diseases. However, as the understanding of disease pathology has progressed, and laboratory diagnostics, imaging technology, and clinical algorithms to determine both the etiology and presence of fibrosis have advanced, the role of liver biopsy has become more circumscribed. In chronic liver disease, liver biopsy is now more often used selectively, rather than routinely, for diagnostic purposes. Newer treatment of chronic hepatitis B and C has become more effective and thus reduced the routine need to acquire tissue. Risk factors for nonalcoholic fatty liver disease are readily identified and suggest the diagnosis after exclusion of alternative considerations, and there is no specific treatment for this condition; thus there is little role for the routine use of liver biopsy to guide treatment. Only in select cases of chronic hepatitis C, especially in patients with genotype 1, an indeterminate stage and grade of disease on noninvasive evaluation, or in those with human immunodeficiency virus coinfection, for whom the risks and benefits of treatment are less clear, is there a role for routine pretreatment biopsy.

Biopsy↗
PubMed2004

Older age and liver transplantation: a review.

Patients older than 60 are undergoing transplantation with increasing frequency. Reports from several transplant centers document that overall short-term patient survival rates in seniors undergoing liver transplantation are comparable to survival rates of younger adults. However, specific subgroups of older patients may not fare as well. Seniors with far-advanced end-stage liver disease are high-risk for liver transplantation and have poor survival rates. In addition, seniors older than 65 have worse outcomes than those who are 60 to 65, and studies have shown increased mortality with increasing age as a continuous variable. On the other hand, the majority of seniors who survive liver transplantation have full or only minimally limited functional status. Preoperative evaluation of older patients for transplantation requires careful screening to exclude cardiopulmonary disease, malignancy, and other diseases of the aged. Paradoxically, seniors may benefit from a senescent immune system, which results in decreased requirements for immunosuppressive drugs, and possibly a lower rate of acute allograft rejection. Despite good overall short-term survival in the elderly, long-term survival may be worse because of an increased rate of long-term complications, such as malignancy and heart disease. In conclusion, although advanced age is a negative risk factor, advanced age alone should not exclude a patient from liver transplantation; however, it mandates thorough pretransplant evaluation and careful long-term follow-up with attention to usual health maintenance issues in the elderly.

Aged↗
PubMed2004

Liver transplantation for alcoholic liver disease: current concepts and length of sobriety.

1. The 1-year and 5-year actuarial survival rates following liver transplantation for patients with alcoholic liver disease are 82% and 68%, respectively, in the United States and 85% and 70%, respectively, in Europe. These survival rates are similar to the outcomes of patients who undergo transplantation for other types of chronic liver disease. 2. Posttransplant improvements in health-related quality of life are similar in patients who undergo transplantation for alcoholic liver disease compared to those who undergo transplantation for other causes of end-stage liver disease. 3. Approximately 20% of patients who undergo transplantation for alcoholic liver disease use alcohol posttransplant, with one-third of these individuals exhibiting repetitive or heavy drinking. Surprisingly, little evidence exists to document a significant detrimental effect on graft or patient survival associated with resumption of drinking. 4. There are few reliable predictors of relapse in alcoholic patients after liver transplantation. Although not supported by all studies, abstinence of fewer than 6 months prior to transplantation may be a reasonable predictor of recidivism and is widely employed as a criterion for listing for liver transplantation. There are no good data to determine if some patients with sobriety fewer than 6 months might benefit from liver transplantation.

Alcohol Drinking↗
PubMed2004

Hepatitis B vaccines.

Immunization is the most effective way to prevent transmission of HBV and, hence, the development of acute or chronic hepatitis B. The national strategy to eliminate transmission of the virus in the United States includes vaccination of all newborn infants, children, adolescents, and high-risk adults. Postexposure prophylaxis is also advocated, depending on the vaccination and anti-HBs status of the exposed person. Seroprotection after vaccination, defined as anti-HBs > or = 10 mIU/mL, is achieved in over 95% of all vaccinees. The hepatitis B vaccines are very well tolerated with usually minimal adverse effects. Predictors of non-response include increasing age, male gender, obesity, tobacco smoking, and immunocompromising chronic disease. For those who remain nonresponders after the second series of vaccination, adjuvants such as GM-CSF may be considered, but their results are variable.

Adolescent↗
PubMed2004

A treatment algorithm for the management of chronic hepatitis B virus infection in the United States.

BACKGROUND AND AIMS: Chronic hepatitis B is an important public health problem worldwide and in the United States. A treatment algorithm for chronic hepatitis B virus (HBV) infection was developed by a panel of US hepatologists based on new developments in the understanding of the virology of HBV, availability of more sensitive molecular diagnostic testing, and advantages and disadvantages of currently approved therapies. METHODS: This algorithm is based on available evidence, but where data are lacking, the panel relied on clinical experience and consensus expert opinion. RESULTS: Serum HBV DNA can be detected at levels as low as 100-1000 copies/mL by using molecular assays and should be determined to establish a baseline level before treatment, monitor response to antiviral therapy, and survey for the development of drug resistance. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to the lowest level possible. The threshold level of HBV DNA for determination of candidacy for therapy is >/=10(5) copies/mL for patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. A lower serum HBV DNA threshold is appropriate for patients with HBeAg-negative chronic hepatitis B and those with decompensated cirrhosis, and the panel recommends thresholds of 10(4) copies/mL and 10(3) copies/mL, respectively. CONCLUSIONS: Interferon alfa-2b, lamivudine, and adefovir dipivoxil are all approved as initial therapy for chronic hepatitis B and have certain advantages and disadvantages. Issues for consideration include efficacy, safety, incidence of resistance, method of administration, and cost. Studies are under way to explore the safety and efficacy of combination therapy, which may prove to be more effective than monotherapy in suppressing viral replication and may decrease or delay the incidence of drug resistance.

Algorithms↗
PubMed2004

Role of ethnicity in risk for hepatocellular carcinoma in patients with chronic hepatitis C and cirrhosis.

BACKGROUND AND AIMS: In the United States, hepatocellular carcinoma (HCC) is more common among Asians and African Americans than Caucasians, with chronic hepatitis C virus (HCV) infection accounting for up to half of the patients. Our study examined ethnicity as a potential risk factor for HCC among patients with chronic hepatitis C. METHODS: We conducted a case-control study of 464 patients with chronic hepatitis C and cirrhosis (207 cancer patients and 257 controls) using medical records and pathology records at 4 medical centers. We estimated odds ratios with 95% confidence intervals by using conditional logistic regression on case-control sets, matched within study centers and study period on sex and age groups (< or =45, 46-55, 56-65, >65 yr). To control for potential confounding caused by severity of cirrhosis and residual confounding caused by age, we also included Child-Turcotte-Pugh (CTP) scores and age (continuous variable) in all regression analyses. RESULTS: Compared with Caucasians, the cancer risk was increased significantly among Asians (adjusted odds ratio, 4.3; 95% confidence interval, 2.1-9.0 for men, and 4.6; 1.2-18.5 for women) and somewhat increased among African-American men (adjusted odds ratio, 2.4; 95% confidence interval, 0.9-6.3). CONCLUSIONS: This study suggests that, among patients with chronic hepatitis C and cirrhosis, liver cancer risk is increased 4-fold in Asians and may be doubled in African-American men, compared with Caucasians. These results need confirmation in larger studies from racially diverse populations, but, if confirmed, these results point to high-risk populations that should be targeted for screening and preventive efforts.

Black or African American↗