Dual-Organ Transplantation: Indications, Evaluation, and Outcomes for Heart-Kidney and Heart-Liver Transplantation: A Scientific Statement From the American Heart Association.

Although heart transplantation is the preferred therapy for appropriate patients with advanced heart failure, the presence of concomitant renal or hepatic dysfunction can pose a barrier to isolated heart transplantation. Because donor organ supply limits the availability of organ transplantation, appropriate allocation of this scarce resource is essential; thus, clear guidance for simultaneous heart-kidney transplantation and simultaneous heart-liver transplantation is urgently required. The purposes of this scientific statement are (1) to describe the impact of pretransplantation renal and hepatic dysfunction on posttransplantation outcomes; (2) to discuss the assessment of pretransplantation renal and hepatic dysfunction; (3) to provide an approach to patient selection for simultaneous heart-kidney transplantation and simultaneous heart-liver transplantation and posttransplantation management; and (4) to explore the ethics of multiorgan transplantation.

Excess Mortality Among Solid Organ Transplant Recipients in the United States During the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic is the first sustained respiratory disease pandemic to arise since the start of solid organ transplantation (SOT). Prior studies have demonstrated that SOT recipients are at greater risk for severe complications of infection and are less likely to respond to vaccination. METHODS: The Scientific Registry of Transplant Recipients Standard Analysis Files was used to assess the cumulative excess mortality in SOT recipients during the first 20 mo of the pandemic. RESULTS: Compared with excess mortality rates in the US population (25.9 deaths/10 000; confidence interval [CI], 10.9-41.1), the excess mortality per 10 000 was higher in all SOT groups: kidney (188.5; CI, 150.7-225.6), lung (173.6; CI, 17-334.7), heart (123.7; CI, 56-191.4), and liver (105.1; CI, 64.6-146). The higher rates persisted even with attempts to control for population age structure and renal allograft failure. Excess mortality was also higher in Black (236.8; CI, 186.1-287) and Hispanic (256.9; CI, 208.1-305.2) organ recipients compared with other racial and ethnic groups in the Scientific Registry of Transplant Recipients and compared with the Black and Hispanic populations in the United States. CONCLUSIONS: Studies of excess mortality provide insight into the health and survival of specialized populations like SOT recipients during major health events like the COVID-19 pandemic.

Resolution of Murine Toxic Hepatic Injury Quantified With Ultrasound Entropy Metrics.

Image-based classification of liver disease generally lacks specificity for distinguishing between acute, resolvable injury and chronic irreversible injury. We propose that ultrasound radiofrequency data acquired in vivo from livers subjected to toxic drug injury can be analyzed with information theoretic detectors to derive entropy metrics, which classify a statistical distribution of pathologic scatterers that dissipate over time as livers heal. Here we exposed 38 C57BL/6 mice to carbon tetrachloride to cause liver damage, and imaged livers in vivo 1, 4, 8, 12 and 18 d after exposure with a broadband 15-MHz probe. Selected entropy metrics manifested monotonic recovery to normal values over time as livers healed, and were correlated directly with progressive restoration of liver architecture by histologic assessment (r2 ≥ 0.95, p < 0.004). Thus, recovery of normal liver microarchitecture after toxic exposure can be delineated sensitively with entropy metrics.

A Patient Decision Support Tool for Hepatitis C Virus and CKD Treatment.

RATIONALE & OBJECTIVE: Patient education and decision support tools could facilitate decisions around the timing of antiviral therapy in patients living with both hepatitis C virus (HCV) infection and chronic kidney disease (CKD). We previously developed a tool through the HELP (Helping Empower Liver and Kidney Patients) study. This article evaluates the preliminary efficacy and usability of the tool among participants with both HCV infection and CKD. STUDY DESIGN: Pre-post study pilot evaluation. SETTING & PARTICIPANTS: Participants were at least 18 years old, were English speaking, and had a diagnosis of chronic HCV infection and CKD; they were seen in CKD clinics, dialysis units, and/or hepatology and liver transplantation clinics. INTERVENTION: Electronic patient decision support tool. OUTCOMES: Participants' change in knowledge, certainty about choice, decision self-efficacy, patients' treatment preferences, and tool usability. RESULTS: 70 participants were recruited; 56 of 70 (80.0%) completed study procedures. Nearly all (51/56; 91.1%) requested paper-based study procedures despite the electronic design of the tool. Participants reported that they were most worried about the following treatment factors: (1) cost of drugs to treat HCV infection, (2) how their HCV infection affected their CKD, and (3) wait times for a kidney transplant. After using the decision tool, participants had significantly higher HCV infection and CKD knowledge (mean posttest percent of questions answered correctly = 65.74% vs pretest percent of questions answered correctly = 53.44%; P < 0.001) and more certainty about choice (mean posttest = 3.13 vs pretest = 2.65; P = 0.05). There were no significant changes in decision self-efficacy (mean posttest = 86.62 vs pretest = 84.68; P = 0.48). LIMITATIONS: Single-site pilot study to explore preliminary tool efficacy and usability. CONCLUSIONS: This study suggests that a decision tool may support informed patient-centered choices among patients with HCV infection and CKD. Future studies should evaluate ways to improve care decisions in a larger sample using both paper-based and electronic materials. FUNDING: Merck & Co, Inc, Kenilworth, NJ. TRIAL REGISTRATION: Registered at clinicaltrials.gov with study number NCT03426787.

The burden of hepatorenal syndrome among commercially insured and Medicare patients in the United States.

BACKGROUND: This study evaluated the characteristics, healthcare resource utilization (HCRU), and costs, from the payer perspective, of hepatorenal syndrome (HRS) patients covered by commercial and Medicare insurance. Mortality was assessed as a secondary outcome. METHODS: Patients were identified from claims databases of commercially insured patients (OptumHealth Care Solutions Inc.) in 1998-2014 and Medicare beneficiaries in 2009-2013 (5% Standard Analytic Files). At the time of their first inpatient admission ("index date") with an HRS diagnosis (ICD-9 code 572.4), commercially insured patients must be aged 18-64 and Medicare patients must be aged 65 and older. RESULTS: A total of 784 commercially insured and 1061 Medicare HRS patients met the sample selection criteria. Patients were disproportionately male (commercial: 63.0%; Medicare: 57.9%) with a mean age of 54.1 among commercially insured and 74.1 among Medicare patients. Within the first 30 days, the average hospital length of stay (LOS) was 12.3 days among commercially insured and 10.8 days among Medicare patients. Based on Kaplan-Meier analyses, 36% of commercially insured and 26% of Medicare patients were readmitted within the next 30 days. During follow-up, many patients received dialysis (commercial: 33.0%; Medicare: 22.1%) or liver transplant (commercial: 10.7%; Medicare: 1.6%). Average costs within the 90 day follow-up were $157,665 for commercially insured and $48,322 for Medicare patients, with 68.3% and 78.3% of the costs incurred within the first 30 days. The primary cost driver was inpatient visits (commercial: 90.3% of costs; Medicare: 83.1% of costs), with differences between the populations consistent with lower mortality, higher dialysis rates, and higher transplant rates (both liver and kidney) among the commercially insured. Using US population and prevalence statistics, these results suggest that HRS imposes an annual total direct medical cost burden of approximately $3.0-$3.8 billion to payers over the period. CONCLUSIONS: HRS imposes a significant economic burden.

Older age is associated with increased early mortality after transjugular intrahepatic portosystemic shunt.

INTRODUCTION & AIM: The role of age as a predictor of mortality after transjugular intra hepatic portosystemic shunt (TIPS) is controversial. Age has been found to be an important predictor of post-TIPS mortality in some, but not all, studies and is not a component of the MELD score. The purpose of this study was to compare the 90-day survival of subjects with cirrhosis age ≥ 70 years with younger subjects undergoing TIPS. MATERIAL AND METHODS: A database of adult with cirrhosis undergoing TIPS from 2003-2011 was analyzed. The primary endpoint was survival 90-days post-TIPS. Survival was analyzed by the Kaplan-Meier method and proportional hazard modeling. RESULTS: 539 subjects met study criteria. 474 (88%) were between the ages of 24-69 and 65 (12%) were age 70-89 years. The groups were similar with respect to the indication for TIPS, mean MELD score and distribution of MELD score. Survival 90-days post-TIPS was 60% in the older cohort compared with 85% in the younger cohort (p < 0.001). Proportional hazards modeling controlled for comorbidities identified age ≥ 70 and MELD score as predictors of early post-TIPS survival. The hazard ratio associated with age increased monotonically, became significant at age ≥ 70 years (HR 3.22; 95% CI 1.81-5.74; p < 0.001) and exceeded the effect of MELD on survival. CONCLUSIONS: Age ≥ 70 was associated with reduced survival within 90 days following TIPS. The findings from this study indicate that age is a relevant consideration in assessing the early mortality risk of TIPS.

Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis.

BACKGROUND: As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase. METHODS: We conducted a phase 3, open-label study involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis (classified as Child-Pugh-Turcotte class B). Patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval [CI], 74 to 90) among patients who received 12 weeks of sofosbuvir-velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir-velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir-velpatasvir, 16% of those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir-velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin. CONCLUSIONS: Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis. (Funded by Gilead Sciences; ASTRAL-4 ClinicalTrials.gov number, NCT02201901.).

Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease.

BACKGROUND & AIMS: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. METHODS: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85%-88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. CONCLUSION: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.

Liver volume in the cirrhotic patient: does size matter?

BACKGROUND: While it is established that cirrhosis results in a decrease in liver volume (LV), whether LV itself predicts patient survival is unknown. We hypothesize that estimated LV is an important prognostic indicator in patients with cirrhosis. METHODS: Data was gathered retrospectively from consecutive patients evaluated for a liver transplant from January 2001 to June 2006. Of 500 patients identified, 323 patients met both inclusion and exclusion criteria. LV per ideal body weight (IBW) was used to correct for body size, and LV/IBW was stratified by median split for survival analyses. Patients were classified into one of three clinical groups: hepatocellular disease (n = 229), cholestatic disease (n = 56), and miscellaneous (n = 38). One of three possible clinical outcomes (survival, liver transplantation, or death) was recorded during the 5-year follow-up, the latter two grouped together as "transplant/death." RESULTS: Transplant/death occurred in 283 (88 %) subjects. Overall, there was a significant increase in transplant/death in those with lower LV/IBW (χ(2) = 5.27, p = 0.022). When considering the subset with hepatocellular disease, lower LV/IBW was a robust predictor of transplant/death (χ(2) = 9.62, p = 0.002). In multivariate analyses, the LV/IBW trended toward predicting transplant/death (ExpB = 0.943, p = 0.053) independent of Model for End stage Liver Disease (MELD) (ExpB = 1.13, p = 0.001). DISCUSSION: LV has important predictive value in patients with cirrhosis from hepatocellular disease. This observation appears to be independent of MELD, suggesting LV may impart important prognostic information that is not captured by the MELD score alone. Thus, LV may serve as an important adjunct to the MELD score in patients with hepatocellular disease.

Circulating miR-122 as a potential biomarker of liver disease.

AIM: Expression profiles indicate that miR-122 is specifically and abundantly expressed in liver. This study sought to determine miR-122 plasma concentrations in 15 apparently healthy subjects and 30 patients with liver disease, and clarify whether plasma miR-122 correlates with ALT. MATERIALS & METHODS: miR-122 was measured by quantitative PCR in healthy volunteers and patients with liver disease. RESULTS: ALT was increased in two out of 15 (13%) apparently healthy subjects and 17 out of 30 (57%) liver disease patients. In healthy subjects, median miR-122 plasma concentration was 51.7 copies/20 pg RNA (range 16.0-312.0). In liver disease patients, median miR-122 was significantly elevated to 202.3 copies/20 pg RNA (range 20.9-1160.0; Mann-Whitney test between median concentrations; p = 0.0016). CONCLUSION: This small proof-of-principle study suggests that miR-122 may be a potential plasma biomarker of liver damage.

Evidence for regulated monoacylglycerol acyltransferase expression and activity in human liver.

Intrahepatic lipid accumulation is extremely common in obese subjects and is associated with the development of insulin resistance and diabetes. Hepatic diacylglycerol and triacylglycerol synthesis predominantly occurs through acylation of glycerol-3-phosphate. However, an alternative pathway for synthesizing diacylglycerol from monoacylglycerol acyltransferases (MGAT) could also contribute to hepatic glyceride pools. MGAT activity and the expression of the three genes encoding MGAT enzymes (MOGAT1, MOGAT2, and MOGAT3) were determined in liver biopsies from obese human subjects before and after gastric bypass surgery. MOGAT expression was also assessed in liver of subjects with nonalcoholic fatty liver disease (NAFLD) or control livers. All MOGAT genes were expressed in liver, and hepatic MGAT activity was readily detectable in liver lysates. The hepatic expression of MOGAT3 was highly correlated with MGAT activity, whereas MOGAT1 and MOGAT2 expression was not, and knockdown of MOGAT3 expression attenuated MGAT activity in a liver-derived cell line. Marked weight loss following gastric bypass surgery was associated with a significant reduction in MOGAT2 and MOGAT3 expression, which were also overexpressed in NAFLD subjects. These data suggest that the MGAT pathway is active and dynamically regulated in human liver and could be an important target for pharmacologic intervention for the treatment of obesity-related insulin resistance and NAFLD.

MicroRNAs and liver disease.

Posttranscriptional regulation of gene expression is now recognized as an important contributor to disease pathogenesis, whose mechanisms include alterations in the function of stability and translational elements within both coding and noncoding regions of messenger RNA. A major component in this regulatory paradigm is the binding both to RNA stability as well as to translational control elements by microRNAs (miRNAs). miRNAs are noncoding endogenously transcribed RNAs that undergo a well-characterized series of processing steps that generate short single-stranded (∼20-22) RNA fragments that bind to complementary regions within a range of targets and in turn lead to mRNA degradation or attenuated translation as a result of trafficking to processing bodies. This article will highlight selected advances in the role of miRNAs in liver disease including nonalcoholic fatty liver disease, viral hepatitis, and hepatocellular carcinoma and will briefly discuss the utility of miRNAs as biomarkers of liver injury and neoplasia.

Effect of fenofibrate and niacin on intrahepatic triglyceride content, very low-density lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease.

CONTEXT: Nonalcoholic fatty liver disease is associated with risk factors for cardiovascular disease, particularly increased plasma triglyceride (TG) concentrations and insulin resistance. Fenofibrate and extended release nicotinic acid (Niaspan) are used to treat hypertriglyceridemia and can affect fatty acid oxidation and plasma free fatty acid concentrations, which influence intrahepatic triglyceride (IHTG) content and metabolic function. OBJECTIVE: The objective of the study was to determine the effects of fenofibrate and nicotinic acid therapy on IHTG content and cardiovascular risk factors. EXPERIMENTAL DESIGN AND MAIN OUTCOME MEASURES: We conducted a randomized, controlled trial to determine the effects of fenofibrate (8 wk, 200 mg/d), Niaspan (16 wk, 2000 mg/d), or placebo (8 wk) on IHTG content, very low-density lipoprotein (VLDL) kinetics, and insulin sensitivity. SETTING AND PARTICIPANTS: Twenty-seven obese subjects with nonalcoholic fatty liver disease (body mass index 36 +/- 1 kg/m(2), IHTG 23 +/- 2%) were studied at Washington University. RESULTS: Neither fenofibrate nor Niaspan affected IHTG content, but both decreased plasma TG, VLDL-TG, and VLDL-apolipoprotein B concentrations (P < 0.05). Fenofibrate increased VLDL-TG clearance from plasma (33 to 54 ml/min; P < 0.05) but not VLDL-TG secretion. Niaspan decreased VLDL-TG secretion (27 to 15 micromol/min; P < 0.05) without affecting clearance. Both fenofibrate and Niaspan decreased VLDL-apolipoprotein B secretion (1.6 to 1.2 and 1.3 to 0.9 nmol/min, respectively; P < 0.05). Niaspan reduced hepatic, adipose tissue, and muscle insulin sensitivity (P < 0.05), whereas fenofibrate had no effect on insulin action. CONCLUSIONS: Fenofibrate and Niaspan decrease plasma VLDL-TG concentration without altering IHTG content. However, the mechanism responsible for the change in VLDL-TG concentration is different for each drug; fenofibrate increases plasma VLDL-TG clearance, whereas nicotinic acid decreases VLDL-TG secretion.

Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease is associated with insulin resistance and diabetes. The purpose of this study was to determine the relationship between intrahepatic triglyceride (IHTG) content and insulin action in liver (suppression of glucose production), skeletal muscle (stimulation of glucose uptake), and adipose tissue (suppression of lipolysis) in nondiabetic obese subjects. METHODS: A euglycemic-hyperinsulinemic clamp procedure and stable isotopically labeled tracer infusions were used to assess insulin action, and magnetic resonance spectroscopy was used to determine IHTG content, in 42 nondiabetic obese subjects (body mass index, 36 +/- 4 kg/m(2)) who had a wide range of IHTG content (1%-46%). RESULTS: Hepatic insulin sensitivity, assessed as a function of glucose production rate and plasma insulin concentration, was inversely correlated with IHTG content (r = -0.599; P < .001). The ability of insulin to suppress fatty acid release from adipose tissue and to stimulate glucose uptake by skeletal muscle were also inversely correlated with IHTG content (adipose tissue: r = -0.590, P < .001; skeletal muscle: r = -0.656, P < .001). Multivariate linear regression analyses found that IHTG content was the best predictor of insulin action in liver, skeletal muscle, and adipose tissue, independent of body mass index and percent body fat, and accounted for 34%, 42%, and 44% of the variability in these tissues, respectively (P < .001 for each model). CONCLUSIONS: These results show that progressive increases in IHTG content are associated with progressive impairment of insulin action in liver, skeletal muscle, and adipose tissue in nondiabetic obese subjects. Therefore, nonalcoholic fatty liver disease should be considered part of a multiorgan system derangement in insulin sensitivity.

Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Steatosis in patients with nonalcoholic fatty liver disease (NAFLD) is due to an imbalance between intrahepatic triglyceride (IHTG) production and export. The purpose of this study was to evaluate TG metabolism in adipose tissue and liver in NAFLD. METHODS: Fatty acid, VLDL-TG, and VLDL-apolipoprotein B-100 (apoB100) kinetics were assessed by using stable isotope tracers in 14 nondiabetic obese subjects with NAFLD (IHTG, 22.7% +/- 2.0%) and 14 nondiabetic obese subjects with normal IHTG content (IHTG, 3.4% +/- 0.4%), matched on age, sex, body mass index, and percent body fat. RESULTS: Compared with the normal IHTG group, the NAFLD group had greater rates of palmitate release from adipose tissue into plasma (85.4 +/- 6.6 and 114.1 +/- 8.1 micromol/min, respectively; P = .01) and VLDL-TG secretion (11.4 +/- 1.1 and 24.3 +/- 3.1 micromol/min, respectively; P = .001); VLDL-apoB100 secretion rates were not different between groups. The increase in VLDL-TG secretion was primarily due to an increased contribution from "nonsystemic" fatty acids, presumably derived from lipolysis of intrahepatic and intra-abdominal fat and de novo lipogenesis. VLDL-TG secretion rate increased linearly with increasing IHTG content in subjects with normal IHTG but reached a plateau when IHTG content was >/=10% (r = 0.618, P < .001). CONCLUSIONS: Obese persons with NAFLD have marked alterations in both adipose tissue (increased lipolytic rates) and hepatic (increased VLDL-TG secretion) TG metabolism. Fatty acids derived from nonsystemic sources are responsible for the increase in VLDL-TG secretion. However, the increase in hepatic TG export is not adequate to normalize IHTG content.

Hepatic lipin 1beta expression is diminished in insulin-resistant obese subjects and is reactivated by marked weight loss.

OBJECTIVE: Lipin 1 plays critical roles in controlling energy metabolism. We sought to determine the expression of lipin 1 isoforms (lipin 1alpha and -beta) in liver and adipose tissue of obese subjects and to evaluate cellular mechanisms involved in the regulation of lipin 1 expression by physiologic stimuli. RESEARCH DESIGN AND METHODS: The expression of lipin 1alpha and -beta was quantified in liver and adipose tissue of extremely obese (average BMI 60.8 kg/m(2)) human subjects undergoing gastric bypass surgery (GBS). Second, the expression of lipin 1 was evaluated in HepG2 cells in response to overexpression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha under normal or hyperinsulinemic conditions. RESULTS: The expression of lipin 1beta in liver and adipose tissue was inversely related to BMI, fasting plasma insulin concentration, and the homeostasis model assessment of insulin resistance but was significantly increased by marked weight loss and insulin sensitization following GBS. Hepatic lipin 1beta mRNA levels were strongly correlated with the expression of PGC-1alpha, and overexpression of PGC-1alpha in HepG2 cells increased lipin 1 expression. Conversely, hyperinsulinemic culture conditions downregulated the expression of lipin 1beta, PGC-1alpha, and their known target genes involved in mitochondrial metabolism in HepG2 cells. Finally, overexpression of lipin 1beta or PGC-1alpha reversed the effect of hyperinsulinemia on the expression of their target genes. CONCLUSIONS: These studies suggest that hepatic lipin 1beta and PGC-1alpha expression are downregulated by obesity and obesity-related metabolic perturbations in human subjects, likely due to alterations in insulin concentration or sensitivity.

Disseminated histoplasmosis in a liver transplant recipient.

A 61-yr-old liver transplant recipient presented with abdominal cramping and nonbloody diarrhea resulting in orthostasis. Multiple ulcerations throughout the colon were seen during endoscopy, and biopsies from the ulcer edges revealed histoplasmosis. Treatment with a course of itraconazole improved the diarrhea. The patient later presented with pericarditis and symptomatic pleural effusions, the latter of which was confirmed to be a result of disseminated histoplasmosis. Treatment with amphotericin B led to resolution. Histoplasmosis should be considered in liver transplant patients with diarrhea and large ulcers in the colon. The presence of disseminated histoplasmosis should be ruled out once colonic histoplasmosis has been diagnosed.