Jessica L. Mueller

Circulating Soluble CD163 is Associated with Steatohepatitis and Advanced Fibrosis in Nonalcoholic Fatty Liver Disease

OBJECTIVES:Soluble CD163 (sCD163), a marker of Kupffer cell activation detectable in serum, correlates with inflammation and fibrosis in chronic viral hepatitis, but its role in nonalcoholic fatty liver disease is unknown. We hypothesized that sCD163 would correlate with nonalcoholic fatty liver disease activity and fibrosis.METHODS:Liver biopsies and serum were obtained from 145 obese subjects undergoing gastric bypass surgery. Subjects were divided into four groups based on fibrosis stage and nonalcoholic fatty liver disease activity score (NAS); Group 1: F0, NAS=0; Group 2: F<2, 0<NAS<5; Group 3: NAS≥5, F<3; or Group 4: F≥3, any NAS. Serum sCD163 and the monocyte/macrophage marker sCD14 were measured by enzyme-linked immunosorbent assay. Relationships between sCD163, sCD14, fibrosis stage, and NAS were examined. Area under the receiver operating charateristic for the diagnosis of nonalcoholic steatohepatitis based on the Clinical Research Network definition was calculated.RESULTS:sCD163 increased with progressive liver histology, with lowest values in normal histology and highest levels in those with nonalcoholic steatohepatitis and advanced fibrosis (Group 1: 552 ng/ml, Group 2: 721 ng/ml, Group 3: 803 ng/ml, and Group 4:1,031; P=0.001). sCD14 also differed significantly across groups (Group 1: 1,877 ng/ml, Group 2: 1632 ng/ml, Group 3: 1,706 ng/ml, and Group 4: 2111; P=0.008, respectively). sCD163 correlated with steatosis grade (P<0.001), lobular inflammation (P=0.033), and hepatocyte ballooning (P<0.001). In a multivariable ordered logistic regression model, there was a significant association between every 100 ng/ml increase in sCD163 and higher fibrosis stage, with an odds ratio of 1.16 (95% confidence interval 1.02–1.31), P=0.020. The odds ratios of the association between every 100 ng/ml increase in sCD163 and higher NAS was 1.17 (95% confidence interval 1.04–1.32), P=0.010. A sCD163-based predictive score demonstrated an area under the receiver operating charateristic of 0.70 (95% confidence interval: 0.58–0.82) for the diagnosis of nonalcoholic steatohepatitis. Soluble CD14 did not correlate with fibrosis stage or NAS.CONCLUSIONS:In obese subjects, serum sCD163, but not sCD14, correlated with fibrosis stage and NAS. These data support a role for activated Kupffer cells in the pathogenesis of nonalcoholic steatohepatitis and fibrosis, and suggest potential clinical utility for assessment of sCD163 levels.

Most ApoL1 Is Secreted by the Liver

Two coding sequence variants in the APOL1 gene (G1 and G2) explain much of the increased risk for FSGS, HIV-associated nephropathy, and hypertension-attributed ESRD among people of recent African ancestry. The ApoL1 protein is expressed in a wide variety of cell tissues. It has been assumed that the majority of circulating ApoL1 is produced by the liver, but this has not been shown. Using mass spectrometry, we genotyped and quantified the circulating ApoL1 in two liver transplant recipients whose native APOL1 genotype differed from the genotype of the deceased donors, allowing us to differentiate liver- from nonliver-produced ApoL1. Our findings confirm that the liver is indeed the main source of circulating ApoL1. However, the liver is not the sole source of circulating ApoL1, because we found that residual amounts of native ApoL1 continued to circulate in the blood, even after the liver transplant.

Metastatic renal cell carcinoma to the small bowel: three cases of GI bleeding and a literature review

Approximately 25–30% of patients with renal cell carcinoma (RCC) have metastatic disease at the time of diagnosis, where the most common sites of metastasis are the lung (50–60% of patients with metastatic disease), bones (30–40%), liver (30–40%), and brain (5%). Although RCC metastasis to the small intestine is thought to be exceedingly rare, with predominantly isolated case reports and a few case series in the literature, we present below three additional cases at our institution of metastatic RCC to the small bowel presenting as GI bleeding. A literature review demonstrates that the number of published case reports has been increasing in recent years. We hypothesize that in the era of targeted chemotherapy and VEGF inhibitors to treat RCC that patients are living longer and have more time for their primary tumors to metastasize to the small bowel and become symptomatic, causing metastatic RCC to the small bowel to be less rare than previously thought.

Nature Versus Nurture: The Impact of Nativity and Site of Treatment on Survival for Gastric Cancer

BackgroundThe prognosis of gastric cancer patients is better in Asia than in the West. Genetic, environmental, and treatment factors have all been implicated. We sought to explore the extent to which the place of birth and the place of treatment influences survival outcomes in Korean and US patients with localized gastric cancer.MethodsPatients with localized gastric adenocarcinoma undergoing potentially curative gastrectomy from 1989 to 2010 were identified from the SEER registry and two single institution databases from the US and Korea. Patients were categorized into three groups: Koreans born/treated in Korea (KK), Koreans born in Korea/treated in the US (KUS), and White Americans born/treated in the US (W), and disease-specific survival rates compared.ResultsWe identified 16,622 patients: 3,984 (24.0%) KK, 1,046 (6.3%) KUS, and 11,592 (69.7%) W patients. KK patients had longer unadjusted median (not reached) and 5-year disease-specific survival (81.6%) rates than KUS (87 months, 55.9%) and W (35 months, 39.2%; p < 0.001 for all comparisons) patients. This finding persisted on subset analyses of patients with stage IA tumors, without cardia/GEJ tumors, with > 15 examined lymph nodes, and treated at a US center of excellence. On multivariable analysis, KUS (HR 2.80, p < 0.001) and W (HR 5.79, p < 0.001) patients had an increased risk of mortality compared to KK patients.ConclusionsBoth the place of birth and the place of treatment significantly contribute to the improved prognosis of patients with gastric cancer in Korea relative to those in the US, implicating both nature and nurture in this phenomenon.

Impact of EGF, IL28B, and PNPLA3 polymorphisms on the outcome of allograft hepatitis C: a multicenter study.

Hepatitis C virus (HCV) infection is accelerated following liver transplantation (LT). Single nucleotide polymorphisms (SNPs) near the epidermal growth factor (EGF) (rs4444903), IL28B (rs12979860), and PNPLA3 (rs738409) loci are associated with treatment response, fibrosis, and hepatocellular carcinoma in non‐transplant hepatitis C, but allograft population data are limited. We sought to determine the role of these SNPs in 264 patients with HCV who underwent LT between 1990 and 2008. Genotypes were determined from donor wedge/allograft biopsies and recipient explants. Cox proportional hazards model was used to assess time to cirrhosis, liver‐related death, and retransplantation, adjusting for donor age and sustained virological response (SVR). Over a median follow‐up of 6.3 yr, a trend toward increased progression to graft cirrhosis was observed among recipients of an EGF non‐AA vs. AA donor liver (adjusted HR 2.01; 95% CI 0.93–4.34; p = 0.08). No other genotypes predicted cirrhosis development or graft survival. The CC IL28B variant in both recipients and donors was associated with increased rate of SVR (R‐CC/D‐CC 8/12[67%], R‐non‐CC/D‐CC or R‐CC/D‐non‐CC 23/52[44%], R‐non‐CC/D‐non‐CC 12/45[27%], p linear trend = 0.009). Recipient EGF, IL28B, and PNPLA3, and donor IL28B and PNPLA3 genotypes do not predict adverse outcomes in HCV LT recipients. A potential association exists between donor EGF genotype and cirrhosis.