Andres Cardenas

The management of ascites and hyponatremia in cirrhosis.

Ascites is the most common complication of cirrhosis and is associated with an increased risk for the development of infections, dilutional hyponatremia, renal failure, and mortality. Cirrhotic patients who develop ascites and associated complications have a low probability of long-term survival without liver transplantation, and therefore should be referred for evaluation of liver transplantation. While the initial management of uncomplicated ascites with low-sodium diet and diuretic treatment is straightforward in the majority of patients, there is a group of patients who fail to respond to diuretics and develop refractory ascites. The development of specific associated complications such as dilutional hyponatremia may further challenge the management of patients with ascites. New pharmacological agents such as the V2 receptor antagonists, drugs that directly antagonize the effects of elevated plasma antidiuretic hormone levels, induce solute-free water diuresis and seem to be promising in the management of patients with cirrhosis, ascites, and dilutional hyponatremia. This article focuses on the pathophysiology, clinical consequences, current management, and new treatment modalities for ascites and dilutional hyponatremia in cirrhosis.

Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood

Prenatal arsenic exposure is associated with increased risk of disease in adulthood. This has led to considerable interest in arsenic’s ability to disrupt fetal programming. Many studies report that arsenic exposure alters DNA methylation in whole blood but these studies did not adjust for cell mixture. In this study, we examined the relationship between arsenic in maternal drinking water collected ≤ 16 weeks gestational age and DNA methylation in cord blood (n = 44) adjusting for leukocyte-tagged differentially methylated regions. DNA methylation was quantified using the Infinium HumanMethylation 450 BeadChip array. Recursively partitioned mixture modeling examined the relationship between arsenic and methylation at 473,844 CpG sites. Median arsenic concentration in water was 12 µg/L (range < 1- 510 µg/L). Log10 arsenic was associated with altered DNA methylation across the epigenome (P = 0.002); however, adjusting for leukocyte distributions attenuated this association (P = 0.013). We also observed that arsenic had a strong effect on the distribution of leukocytes in cord blood. In adjusted models, every log10 increase in maternal drinking water arsenic exposure was estimated to increase CD8+ T cells by 7.4% (P = 0.0004) and decrease in CD4+ T cells by 9.2% (P = 0.0002). These results show that prenatal exposure to arsenic had an exposure-dependent effect on specific T cell subpopulations in cord blood and altered DNA methylation in cord blood. Future research is needed to determine if these small changes in DNA methylation alter gene expression or are associated with adverse health effects.

Esophageal balloon tamponade versus esophageal stent in controlling acute refractory variceal bleeding: A multicenter randomized, controlled trial

Balloon tamponade is recommended only as a “bridge” to definitive therapy in patients with cirrhosis and massive or refractory esophageal variceal bleeding (EVB), but is frequently associated with rebleeding and severe complications. Preliminary, noncontrolled data suggest that a self‐expandable, esophageal covered metal stent (SX‐ELLA Danis; Ella‐CS, Hradec Kralove, Czech Republic) may be an effective and safer alternative to balloon tamponade. We conducted a randomized, controlled trial aimed at comparing esophageal stent versus balloon tamponade in patients with cirrhosis and EVB refractory to medical and endoscopic treatment. Primary endpoint was success of therapy, defined as survival at day 15 with control of bleeding and without serious adverse events (SAEs). Twenty‐eight patients were randomized to Sengstaken‐Blakemore tube (n = 15) or SX‐ELLA Danis stent (n = 13). Patients were comparable in severity of liver failure, active bleeding at endoscopy, and initial therapy. Success of therapy was more frequent in the esophageal stent than in balloon tamponade group (66% vs. 20%; P = 0.025). Moreover, control of bleeding was higher (85% vs. 47%; P = 0.037) and transfusional requirements (2 vs 6 PRBC; P = 0.08) and SAEs lower (15% vs. 47%; P = 0.077) in the esophageal stent group. TIPS was used more frequently in the tamponade group (4 vs. 10; P = 0.12). There were no significant differences in 6‐week survival (54% vs. 40%; P = 0.46). Conclusion: Esophageal stents have greater efficacy with less SAEs than balloon tamponade in the control of EVB in treatment failures. Our findings favor the use of esophageal stents in patients with EVB uncontrolled with medical and endoscopic treatment. (Hepatology 2016;63:1957‐1967)

Type‐1 hepatorenal syndrome associated with infections in cirrhosis: Natural history, outcome of kidney function, and survival

Type‐1 hepatorenal syndrome (HRS) is a common complication of bacterial infections in cirrhosis, but its natural history remains undefined. To assess the outcome of kidney function and survival of patients with type‐1 HRS associated with infections, 70 patients diagnosed during a 6‐year period were evaluated prospectively. Main outcomes were no reversibility of type‐1 HRS during treatment of the infection and 3‐month survival. Forty‐seven (67%) of the 70 patients had no reversibility of type‐1 HRS during treatment of the infection. [Correction to previous sentence added March 10, 2014, after first online publication: “Twenty‐three (33%)” was changed to “Forty‐;seven (67%).”] The main predictive factor of no reversibility of type‐1 HRS was absence of infection resolution (no reversibility: 96% versus 48% in patients without and with resolution of the infection; P < 0.001). Independent predictive factors of no reversibility of type‐1 HRS were age, high baseline serum bilirubin, nosocomial infection, and reduction in serum creatinine <0.3 mg/dL at day 3 of antibiotic treatment. No reversibility was also associated with severity of circulatory dysfunction, as indicated by more marked activity of the vasoconstrictor systems. In the whole series, 3‐month probability of survival was only 21%. Factors associated with poor prognosis were baseline serum bilirubin, no reversibility of type‐1 HRS, lack of resolution of the infection, and development of septic shock after diagnosis of type‐1 HRS. Conclusion: Type‐1 HRS associated with infections is not reversible in two‐thirds of patients with treatment of infection only. No reversibility of type‐1 HRS is associated with lack of resolution of the infection, age, high bilirubin, and no early improvement of kidney function and implies a poor prognosis. These results may help advance the management of patients with type‐1 HRS associated with infections. (Hepatology 2014;59:1505‐1513)

Differential DNA methylation in umbilical cord blood of infants exposed to mercury and arsenic in utero

Mercury and arsenic are known developmental toxicants. Prenatal exposures are associated with adverse childhood health outcomes that could be in part mediated by epigenetic alterations that may also contribute to altered immune profiles. In this study, we examined the association between prenatal mercury exposure on both DNA methylation and white blood cell composition of cord blood, and evaluated the interaction with prenatal arsenic exposure. A total of 138 mother-infant pairs with postpartum maternal toenail mercury, prenatal urinary arsenic concentrations, and newborn cord blood were assessed using the Illumina Infinium Methylation450 array. White blood cell composition was inferred from DNA methylation measurements. A doubling in toenail mercury concentration was associated with a 2.5% decrease (95% CI: 5.0%, 1.0%) in the estimated monocyte proportion. An increase of 3.5% (95% CI: 1.0, 7.0) in B-cell proportion was observed for females only. Among the top 100 CpGs associated with toenail mercury levels (ranked on P-value), there was a significant enrichment of loci located in North shore regions of CpG islands (P = 0.049), and the majority of these loci were hypermethylated (85%). Among the top 100 CpGs for the interaction between arsenic and mercury, there was a greater than expected proportion of loci located in CpG islands (P = 0.045) and in South shore regions (P = 0.009) and all of these loci were hypermethylated. This work supports the hypothesis that mercury may be contributing to epigenetic variability and immune cell proportion changes, and suggests that in utero exposure to mercury and arsenic, even at low levels, may interact to impact the epigenome.

Estimating Effects of Arsenic Exposure During Pregnancy on Perinatal Outcomes in a Bangladeshi Cohort

Background: The relationship between arsenic and birth weight is not well understood. The objective was to evaluate the causal relationship between prenatal arsenic exposure and birth weight considering the potential mediation effects of gestational age and maternal weight gain during pregnancy using structural equation models. Methods: A prospectively enrolled cohort of pregnant women was recruited in Bangladesh from 2008 to 2011. Arsenic was measured in personal drinking water at the time of enrollment (gestational age <16 weeks, N = 1,140) and in toenails collected ⩽1 month postpartum (N = 624) using inductively coupled plasma mass spectrometry. Structural equation models estimated the direct and indirect effects of arsenic on birth weight with gestational age and maternal weight gain considered as mediating variables. Results: Every unit increase in natural log water arsenic was indirectly associated with decreased birth weight (&bgr; = −19.17 g, 95% confidence interval [CI]: −24.64, −13.69) after adjusting for other risk factors. This association was mediated entirely through gestational age (&bgr; = −17.37 g, 95% CI: −22.77, −11.98) and maternal weight gain during pregnancy (&bgr; = −1.80 g, 95% CI: −3.72, 0.13). When exposure was modeled using toenail arsenic concentrations, similar results were observed. Every increase in natural log toenail arsenic was indirectly associated with decreased birth weight (&bgr; = −15.72 g, 95% CI: −24.52, −6.91) which was mediated through gestational age (&bgr; = −13.59 g, 95% CI: −22.10, −5.07) and maternal weight gain during pregnancy (&bgr; = −2.13 g, 95% CI: −5.24, 0.96). Conclusion: Arsenic exposure during pregnancy was associated with lower birth weight. The effect of arsenic on birth weight appears to be mediated mainly through decreasing gestational age and to a lesser extent by lower maternal weight gain during pregnancy.

Lin28 regulates BMP4 and functions with Oct4 to affect ovarian tumor microenvironment

Emerging evidence suggests that the tumor microenvironment plays a critical role in regulating cancer stem cells (CSCs) and tumor progression through both autocrine and paracrine signaling. Elevated production of bone morphogenetic proteins (BMPs) from human ovarian cancer cells and stroma has been shown to increase CSC proliferation and tumor growth. Here, we report that Lin28, a stem cell factor, binds to BMP4 mRNA in epithelial ovarian carcinoma cells, thereby promoting BMP4 expression at the post-transcriptional level. As co-expression of Lin28 and Oct4 (another stem cell factor) has been implicated in ovarian cancer CSCs, we also determined that high levels of Lin28 are associated with an unfavorable prognosis when co-expressed with high levels of Oct4. Together, these findings uncover a new level of regulation of BMP4 expression and imply a novel Lin28/Oct4/BMP4-mediated mechanism of regulating ovarian tumor cell growth, thus holding potential for the development of new strategies for the diagnosis and treatment of ovarian cancer.

Effect of Native American Fish Smoking Methods on Dietary Exposure to Polycyclic Aromatic Hydrocarbons and Possible Risks to Human Health

Although it is known that polycyclic aromatic hydrocarbons (PAHs) can be found in smoked meats, little is known about their prevalence in Native American smoked fish. In this work, the effect of traditional Native American fish smoking methods on dietary exposure to PAHs and possible risks to human health has been assessed. Smoking methods considered smoking structure (tipi or shed) and wood type (apple or alder). Neither smoking structure nor wood type accounted for differences in smoked salmon content of 33 PAHs. Carcinogenic and noncarcinogenic PAH loads in traditionally smoked salmon were 40-430 times higher than those measured in commercial products. Dietary exposure to PAHs could result in excess lifetime cancer risks between 1 × 10(-5) and 1 × 10(-4) at a daily consumption rate of 5 g d(-1) and could approach 1 × 10(-2) at 300 g d(-1). Hazard indexes approached 0.005 at 5 g d(-1), or approximately 0.3 at 300 g d(-1). Levels of PAHs present in smoked salmon prepared using traditional Native American methods may pose elevated cancer risks if consumed at high consumption rates over many years.

Therapy Insight: management of hepatorenal syndrome

Hepatorenal syndrome (HRS), a feared complication of advanced cirrhosis, is characterized by functional renal failure, secondary to renal vasoconstriction in the absence of underlying kidney pathology. Extreme underfilling of the arterial circulation, caused by arterial vasodilation of the splanchnic circulation, activates vasoconstrictor systems, which lead to intense renal vasoconstriction and HRS. Factors predictive for the development of HRS include intense urinary sodium retention, dilutional hyponatremia, low blood pressure, decreased cardiac output, and increased activity of systemic vasoconstrictors. The prognosis for patients with HRS is extremely poor, especially for those with the acute, progressive (type 1) form. Liver transplantation is the best treatment for suitable candidates and should always be the management option considered first. Pharmacologic therapies are aimed at improving renal function to enable patients to survive until transplantation is possible. These therapies are based on plasma expansion with albumin, combined with the use of either vasopressin analogs or α-adrenergic agonists. Other nonpharmacologic therapies, such as transjugular intrahepatic portosystemic shunts and albumin dialysis show promise, but experience with these treatments is limited. For prevention of HRS, albumin infusion is recommended in patients with spontaneous bacterial peritonitis, and pentoxifylline treatment is recommended in patients with acute alcoholic hepatitis.

Validation of a DNA methylation reference panel for the estimation of nucleated cells types in cord blood

ABSTRACT Cord blood is widely used as surrogate tissue in epigenome-wide association studies of prenatal conditions. Cell type composition variation across samples can be an important confounder of epigenome-wide association studies in blood that constitute a mixture of cells. We evaluated a newly developed cord blood reference panel to impute cell type composition from DNA methylation levels, including nucleated red blood cells (nRBCs). We estimated cell type composition from 154 unique cord blood samples with available DNA methylation data as well as direct measurements of nucleated cell types. We observed high correlations between the estimated and measured composition for nRBCs (r = 0.92, R2 = 0.85), lymphocytes (r = 0.77, R2 = 0.58), and granulocytes (r = 0.72, R2 = 0.52), and a moderate correlation for monocytes (r = 0.51, R2 = 0.25) as well as relatively low root mean square errors from the residuals ranging from 1.4 to 5.4%. These results validate the use of the cord blood reference panel and highlight its utility and limitations for epidemiological studies.