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Biomedical subjects

Saul J Karpen

Publications and source records attributed to Saul J Karpen.

At least 19 recordsLinked to original sources
PubMed2006

Rosiglitazone attenuates suppression of RXRalpha-dependent gene expression in inflamed liver.

BACKGROUND/AIMS: A recently determined target of lipopolysaccharide (LPS) and cytokine signaling in liver is the central Type II nuclear receptor (NR) heterodimer partner, retinoid X receptor alpha (RXRalpha). We sought to determine if Rosiglitazone (Rosi), a peroxisome proliferator activated receptor gamma (PPARgamma) agonist with anti-inflammatory properties, can attenuate LPS and cytokine-induced molecular suppression of RXRalpha-regulated genes. METHODS: In vivo, mice were gavage-fed Rosi for 3 days, prior to intraperitoneal injection of LPS, followed by harvest of liver and serum. In vitro, HepG2 cells were treated with IL-1beta, +/- short-term Rosi pretreatment. RNA was analyzed by quantitative RT-PCR, while nuclear and cytoplasmic proteins were analyzed by immunoblotting and gel shifts. RESULTS: Rosi attenuated LPS-mediated suppression of RNA levels of several Type II NR-regulated genes, including bile acid transporters and the major drug metabolizing enzyme, Cyp3a11, without affecting cytokine expression, suggesting a novel, direct anti-inflammatory effect in hepatocytes. Rosi suppressed the inflammation-induced nuclear export of RXRalpha, in both LPS-injected mice and IL-1beta-treated HepG2 cells, leading to maintenance of nuclear RXRalpha levels and heterodimer binding activity. CONCLUSIONS: Rosi directly attenuates the suppressive effects of inflammation-induced cell signaling on nuclear RXRalpha levels in liver.

Active Transport, Cell Nucleus↗
PubMed2006

Nuclear export of retinoid X receptor alpha in response to interleukin-1beta-mediated cell signaling: roles for JNK and SER260.

As the obligate heterodimer partner to class II nuclear receptors, the retinoid X receptor alpha (RXRalpha) plays a vital physiological role in the regulation of multiple hepatic functions, including bile formation, intermediary metabolism, and endobiotic/xenobiotic detoxification. Many RXRalpha-regulated genes are themselves suppressed in inflamed liver via unknown mechanisms, which constitute a substantial component of the negative hepatic acute phase response. In this study we show that RXRalpha, generally considered a stable nuclear resident protein, undergoes rapid nuclear export in response to signals initiated by the pro-inflammatory cytokine interleukin-1beta (IL-1beta), a central activator of the acute phase response. Within 30 min of exposure to IL-1beta, nuclear levels of RXRalpha are markedly suppressed in human liver-derived HepG2 cells, temporally coinciding with its appearance in the cytoplasm. The nuclear residence of RXRalpha is maintained by inhibiting c-jun N-terminal kinase (JNK, curcumin or SP600125) or CRM-1-mediated nuclear export (Leptomycin B). Pretreatment with the proteasome inhibitor MG132 blocks IL-1beta-mediated reductions in nuclear RXRalpha levels while increasing accumulation in the cytoplasm. Mutational studies identify one residue, serine 260, a JNK phosphoacceptor site whose phosphorylation status had an unknown role in RXRalpha function, as critical for IL-1beta-mediated nuclear export of transfected human RXRalpha-green fluorescent fusion constructs. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear RXRalpha levels, via a multistep, JNK-dependent mechanism involving Ser260, nuclear export, and proteasomal degradation. Thus, inflammation-meditated cell signaling targets RXRalpha for nuclear export and degradation; a potential mechanism that explains the broad suppression of RXRalpha-dependent gene expression in the inflamed liver.

Active Transport, Cell Nucleus↗
PubMed2006

Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure.

BACKGROUND: Orthotopic liver transplantation (OLT) is an effective treatment for fulminant hepatic failure (FHF), but postOLT mortality is higher for patients with FHF than for patients with other indications for OLT. In the current study, a large cohort of patients who underwent OLT for FHF was evaluated to develop and validate a system useful for estimating postOLT patient survival. METHODS: The 1,457 patients who underwent OLT for FHF in the United States between 1988 and 2003 were enrolled through the UNOS database. This group was divided into a modeling group (n=972) and a crossvalidation group (n=486). With a multivariate regression analysis, the modeling group was used to identify clinical parameters that had a significant association with postOLT survival. This regression analysis was used to create a scoring system that was subsequently assessed in the crossvalidation group. RESULTS: Four risk factors were identified with the multivariate analysis: 1) body mass index > or = 30 kg/m2; 2) serum creatinine > 2.0 mg/dL; 3) recipient age > 50 years old; and 4) history of life support. By assigning points based on the number of risk factors present, the scoring system was able to differentiate between low-risk patients (5-year survival, 81%) and high-risk patients (5-year survival, 42%). The relative risk of postOLT mortality increased by approximately 150% for each additional point. CONCLUSION: The scoring system risk-stratified the crossvalidation group and accurately predicted postOLT survival. A scoring system utilizing clinical and demographic information readily available prior to OLT may help predict the probability of survival after OLT for FHF.

Adult↗
PubMed2006

The pediatric end-stage liver disease (PELD) model as a predictor of survival benefit and posttransplant survival in pediatric liver transplant recipients.

The pediatric end-stage liver disease (PELD) model accurately estimates 90-day waitlist mortality for pediatric liver transplant candidates, but it has been unclear if PELD can identify patients who will derive survival benefit from undergoing liver transplantation (LT), if it correlates with posttransplant survival, or if it can identify patients for whom LT would be futile. Pediatric patients who underwent LT between 2001 and 2004 were enrolled through the United Network for Organ Sharing Organ Procurement and Transplant Network database. Survival benefit was measured in terms of life-years gained during the first year after LT. Complete data were available for 1,247 patients: 53% were listed as Status 1 at the time of orthotopic liver transplantation (OLT), while the remaining 47% had PELD scores. Only in patients with a PELD of 17+ or those designated as United Network for Organ Sharing Status 1 derived a survival benefit within 1 year of LT; patients with a PELD score of < or = 16 did not. In addition, a statistically significant association was seen between 1-year post-OLT survival and PELD at LT (P = 0.03). No "threshold" PELD score, beyond which risk of post-LT mortality increased dramatically, was apparent. In conclusion, pediatric patients with a PELD score of 17+ derive survival benefit early after LT, and increasing PELD scores are associated with increasing transplant benefit after liver transplantation. PELD does correlate with posttransplant survival but should not be used as a marker for futility.

Algorithms↗
PubMed2006

The natural history of hepatitis C virus in pediatric liver transplant recipients.

Although rare in the pediatric population, the natural history of hepatitis C virus (HCV) recurrence in pediatric patients undergoing orthotopic liver transplantation (OLT) for end-stage liver disease secondary to HCV has not been well described. We performed an analysis of all 67 pediatric patients (< 17 years old) who have undergone OLT for HCV in the United States between 1/1988 and 6/2005. The 67 pediatric patients received a total of 83 OLTs for HCV. Following initial OLTs performed for HCV, the patient and allograft survival rates were 71.6% and 55.0%, respectively, at 5 years. Following retransplantation these rates decreased to 55.0% and 33.8%, respectively, following retransplantation. Recipients were listed for retransplantation after 31.3% of all OLTs, and overall recipients were retransplanted after 19.3% of OLTs. The overwhelming majority of retransplants were performed for HCV recurrence. A mean of 1.2 OLTs were performed per patient for HCV. The median time between OLTs for HCV was 290 days. In conclusion, the risk of HCV recurrence in pediatric OLT recipients is high and is associated with a high rate of retransplantation. Still, OLT represents the only treatment option that may achieve long-term survival in pediatric patients with end-stage liver disease secondary to HCV that is recalcitrant to medical management.

Adolescent↗
PubMed2006

Resolution of medically resistant hypothyroidism after liver transplantation for hepatic hemangioendothelioma.

Hepatic hemangioendothelioma (HHE) is a rare vascular tumor in neonates and may cause high-output cardiac failure and coagulopathy, and rarely has been associated with hypothyroidism. Hepatic hemangioendothelioma treatment options consist of corticosteroids, alpha-interferon, surgical resection, and liver transplantation. Herein, we report the case of a 6-week-old female neonate that presented with an HHE that involved all segments of the liver, resulting in respiratory failure and severe hypothyroidism that was recalcitrant to exogenous L-thyroxine therapy. After failure of medical and supportive therapy for the HHE, the patient underwent a cadaveric orthotopic liver transplantation that resulted in successful treatment of the severe hypothyroidism, respiratory failure, and cardiac symptoms. The patient is currently 1-year posttransplantation and disease free with normal thyroid function.

Female↗
PubMed2006

Impact of pretransplant growth retardation in pediatric liver transplantation.

OBJECTIVE: Malnutrition frequently complicates end-stage liver disease and orthotopic liver transplantation (OLT) in pediatric patients. Pretransplant malnutrition has been associated with increased post-OLT mortality and length of stay in adults. The relationship between pre-OLT nutritional status and post-OLT outcomes in pediatric liver transplant recipients, however, is not well studied. METHODS: The records of 65 pediatric patients who underwent OLT at a single institution were reviewed. Univariate analyses were used to investigate the relationship between anthropomorphic data (expressed as z-scores) and post-OLT hospital length-of-stay, hospital costs and clinical outcomes. A multivariate model was then used to identify peri-OLT variables independently correlated with post-OLT length-of-stay. RESULTS: A decreased height z-score was correlated with an increased post-OLT hospital length-of-stay (r = -0.30; P = 0.015) and increased hospital costs (r = -0.49; P = 0.0004). The mean length-of-stay was 20.5 days for patients with a height z-score of <-1.5 and 10.7 days for patients with a height z-score of >1.5 (P = 0.038). Likewise, hospital costs were about $40,000 higher (25% increased) for patients with growth retardation. A weak direct correlation was seen between weight z-score and post-OLT length-of-stay (r = 0.18; P = 0.15). Height z-score, biliary atresia and pre-OLT protime were independently and significantly correlated with post-OLT length-of-stay in a multivariate model. CONCLUSIONS: Height z-score is a better indicator of pretransplant malnutrition than weight z-score. Pretransplant growth retardation is associated with increased post-OLT hospital length-of-stay and increased hospitalization costs.

Adolescent↗
PubMed2006

Evaluation and management of patients with propionic acidemia undergoing liver transplantation: a comprehensive review.

Propionic acidemia is a rare metabolic disorder that often results in episodic hyperammonemia, basal ganglia infarction, mental retardation, and cardiomyopathy. OLT has been used as a treatment for propionic acidemia, but its benefit in patients with this disease is unclear. The current study was undertaken to clarify the role of OLT in the management of this disease. The medical literature, a national registry of US OLT recipients, and a single institution liver transplant experience were reviewed for cases of OLT for propionic acidemia. Accumulated cases demonstrate that OLT has resulted in clear evidence of clinical improvement in several patients, often obviating the need for dietary restriction or other forms of medical management. OLT appears to halt the decline in neurocognitive function often associated with propionic acidemia. In total, 12 patients with propionic acidemia have undergone a total of 14 OLTs. A quantitative analysis of outcomes shows an overall patient survival rate of 72.2% at one year after OLT. In conclusion, OLT should be considered a treatment option for patients with propionic acidemia who continue to experience episodes of hyperammonemia in spite of maximal medical therapy. Early OLT may limit the development of mental retardation and/or cardiomyopathy.

Adult↗
PubMed2005

Combined lung and liver transplantation: the United States experience.

BACKGROUND: Combined transplantation of the lungs and liver is indicated for patients who would not be expected to survive transplantation of either organ alone. No single center has accumulated a significant experience, and as a result the expectations for this operation in the current era are unknown. METHODS: Patients that have undergone combined lung-liver transplantation in the United States were enrolled through the United Network for Organ Sharing Organ Procurement and Transplantation Network database. In addition, the English-language literature was searched for additional cases of combined lung-liver transplantation. RESULTS: Eleven patients have undergone combined lung and liver transplantation in the United States at different centers. The 1- and 5-year patient survival rates are of 79% and 63%, respectively, and no patient has required retransplantation. These patient survival rates are equivalent to similar a combined lung-liver case series from the United Kingdom (P=0.37, log-rank test) and isolated orthotopic liver transplantation in the United States (P=0.59, log-rank test), and are comparable to patient survival rates following isolated lung transplantation in the United States. CONCLUSIONS: Patient survival of combined lung-liver transplantation is comparable to that of isolated liver and isolated bilateral lung transplantation. This option should be considered for patients with end-stage lung disease and liver disease when transplantation of a single organ transplantation is precluded by severe disease in the other organ system.

Adolescent↗
PubMed2005

Liver transplantation for severe hepatic graft-versus-host disease: an analysis of aggregate survival data.

Graft-versus-host disease (GVHD) often occurs after bone marrow transplantation (BMT). GVHD may lead to cirrhosis or complete destruction of the bile ducts, and few effective treatment options exist for such cases. Orthotopic liver transplantation (OLT) has been described as an option, but to date the patient survival, graft survival, and GVHD recurrence rates after OLT have been unknown. Cases of OLT for GVHD were accumulated from several sources: (1) cases of OLT performed at a single institution, (2) the English-language medical literature, and (3) the United Network for Organ Sharing (UNOS) liver transplant registry. Descriptive data were derived from pre- and post-OLT information; survival analysis was performed using the Kaplan-Meier method. One case of OLT for GVHD after BMT was found at our institution, and another 6 cases were previously reported in the literature. Extrahepatic GVHD recurred in 2 cases, but no recurrence of hepatic GVHD was reported. The UNOS registry contained an additional 73 patients who underwent OLT for hepatic GVHD. The 1- and 5-year actuarial patient survival rates were 72.4% and 62.9%, respectively. Although 4 patients required retransplantation, no deaths or retransplants were attributed to the recurrence of hepatic GVHD. OLT is an effective treatment for hepatic GVHD after BMT or non-liver organ transplant. Long-term disease-free survival is obtainable in these cases, and recurrence of hepatic GVHD has not been reported. These findings suggest that OLT should be considered as an effective treatment option for cases of hepatic GVHD recalcitrant to medical treatment.

Adolescent↗
PubMed2005

Orthotopic liver transplantation for biliary atresia: the U.S. experience.

Biliary atresia is the most common indication for orthotopic liver transplantation (OLT) in the pediatric population. The outcomes of liver transplantation for biliary atresia, however, have not been formally examined on a national scale. The objective of this study was to identify pretransplant variables that predict patient survival after primary liver transplantation for biliary atresia. A cohort of 1,976 pediatric patients undergoing primary liver transplantation for biliary atresia between 1/1988 to 12/2003 was enrolled from the United Network for Organ Sharing database after excluding patients with a history of multiorgan transplant or previous liver transplant. Follow-up data up to 16 years post-OLT was available. The 5- and 10-year actuarial survival rates of patients that underwent liver transplantation for biliary atresia in the United States are 87.2% and 85.8%, respectively, and the 5- and 10-year graft actuarial survival rates are 76.2% and 72.7%, respectively. Early deaths (< or =90 days post-OLT) were more often caused by graft failure (P = 0.01), whereas late deaths (>90 days post-OLT) were more often due to malignancy (P < 0.01). An analysis of outcomes over time demonstrated a decrease in post-OLT survival and an increase in the number of OLTs done for biliary atresia at an increasing number of centers. A multivariate analysis revealed that cadaveric partial/reduced liver grafts, a history of life support at the time of OLT, and decreased age were independent predictors of increased post-OLT mortality. In conclusion, OLT is an effective treatment for biliary atresia. Certain pretransplant variables may help predict patient survival following liver transplantation for biliary atresia.

Age Distribution↗
PubMed2005

Kupffer cell depletion with liposomal clodronate prevents suppression of Ntcp expression in endotoxin-treated rats.

BACKGROUND/AIMS: In sepsis-associated cholestasis, expression of many genes involved in bile acid transport, including Ntcp, is suppressed by cytokines. Kupffer cells (KC) are an important source of cytokines in sepsis. To assess the consequences of KC depletion on hepatic Ntcp expression in endotoxemic rats. METHODS: Sprague-Dawley rats received liposomal clodronate (CLO) or vehicle (PBS) to deplete KC prior to lipopolysaccharide (LPS) exposure. Plasma and liver samples were taken 1 and 16 h after LPS exposure. RESULTS: Complete CLO-depletion of KC by was demonstrated by immunohistochemistry. Hepatic gene expression of IL-1beta and TNFalpha as well as TNFalpha plasma levels in CLO/LPS-injected animals were significantly reduced to a mean of 41, 36 and 23% of controls injected with LPS only. Ntcp RNA- and protein expression was significantly higher whereas plasma bile salt concentration was lower in CLO/LPS animals vs. animals injected with LPS only. Binding activity of transcription factors RXR:RAR and HNF1alpha was decreased in LPS only controls but preserved in CLO/LPS treated animals. CONCLUSIONS: Clodronate-depletion of KC blocks cytokine-mediated Ntcp suppression upon endotoxin exposure. KC may represent pharmacological targets for treatment of sepsis-associated cholestasis.

Animals↗
PubMed2005

Treatment of acute tacrolimus whole-blood elevation with phenobarbital in the pediatric liver transplant recipient.

The toxicities associated with the chronic use of tacrolimus are well described in the literature; however, little is known about the management during an acute overdose. Phenobarbital is a long-acting barbiturate metabolized in the liver by the cytochrome p450 3a4 system. It is known to enhance the rate of metabolism of itself and the clearance of drugs metabolized by p450 3a4. Because tacrolimus is a substrate of this particular isoenzyme, phenobarbital can be considered a potential option when rapid decreases in tacrolimus whole-blood levels are desired. We hereby report our experience using intravenous phenobarbital in the management of two infants with acute elevations in their tacrolimus whole-blood concentration following liver transplantation. Phenobarbital, through its up-regulation of hepatic cytochrome p450 system increases the elimination of whole-blood tacrolimus concentration in acute overdose situations.

Biliary Atresia↗
PubMed2005

Split-liver transplantation using the left lateral segment: a collaborative sharing experience between two distant centers.

Split-liver transplantation (SLT) increases the pool of organs for pediatric orthotopic liver transplantation (pOLT). With increased collaboration and organ sharing, transplant centers can fully maximize the use of all split donor allografts. Herein, we report the collaborative results between two distant centers involved in a sharing alliance. The current study consists of a retrospective review of 56 pediatric LLS transplants performed at two collaborating centers between 9/1997 and 10/2003. Fifty-three patients (41% Status 1) were transplanted using 56 left lateral segment (LLS) grafts. Sixteen percent of LLS grafts were shared between the two institutions. Overall patient survival at both 1 and 3 years was 90% and 90%, respectively. Overall graft survival at both 1 and 3 years was 82% and 82%, respectively. Shared patient and graft survival was 89% and 89%, respectively. There was an 11% biliary complication and 18% vascular complication rate. Five patients required retransplantation. In conclusion, SLT increases the number of available allografts for pOLT. While SLT is technically demanding, with a significant learning curve, patient and graft survival rates compare favorably with United Network Organ Sharing (UNOS) averages. Sharing of grafts between centers is a safe and effective way to maximize organ usage and should be actively pursued through collaborative networks.

Adolescent↗
PubMed2005

Adult liver transplant candidate attitudes toward graft sharing are not obstacles to split liver transplantation.

Split liver transplantation (SLT) benefits society by increasing the total number of transplants that can be performed, but it is yet unknown if a decreased post-transplant survival (in comparison to whole liver transplantation) would make participation in SLT less appealing to adult liver transplant candidates. A 20-item questionnaire was administered to 50 adult candidates to assess attitudes toward SLT and organ sharing. The overall attitudes of 60% of participants were classified as utilitarian (maximizing benefit to greatest number of candidates), while 26% were classified as self-preserving (maximizing individual benefit) and 14% were undecided. Ninety percent of participants would be willing to share even if expected survival was less than that of whole liver transplantation, and 69% felt that pediatric candidates should have priority over adult candidates. In conclusion, attitudes toward graft sharing and the possibility of compromised survival benefit are not barriers to SLT for most adult liver transplant candidates.

Adult↗