Importance of a Rapid and Accurate Diagnosis in Strongyloides Stercoralis and Human T-Lymphotropic Virus 1 Co-infection: A Case Report and Review of the Literature

Strongyloides (S.) stercoralis and Human T-Lymphotropic Virus 1 (HTLV-1) share some endemic regions such as Japan, Jamaica, and South America and are mostly diagnosed elsewhere in immigrants from endemic areas. This co-infection has not been documented in Argentina although both pathogens are endemic in the Northwest. We present a case of S. stercoralis and HTLV-1 co-infection with an initial presentation due to gastrointestinal symptoms which presented neither eosinophilia nor the presence of larvae in stool samples in a non-endemic area for these infections. A young Peruvian woman living in Buenos Aires attended several emergency rooms and finally ended up admitted in a gastroenterology ward due to incoercible vomiting, diarrhea, abdominal pain, fever, and weight loss. Gastrointestinal symptoms started 3 months before she returned to Argentina from a trip to Peru. She presented malnutrition and abdominal distension parameters. HIV-1 and other immunodeficiencies were discarded. The serial coproparasitological test was negative. Computed tomography showed diffuse thickening of duodenal and jejunal walls. At the beginning, vasculitis was suspected and corticosteroid therapy was initiated. The patient worsened rapidly. Skin, new enteral biopsies, and a new set of coproparasitological samples revealed S. stercoralis. Then, HTLV-1 was suspected and infection was confirmed. Ivermectin and albendazole were administrated, until the stool sample remained negative for 2 weeks. Larvae were not observed in fresh stool, Ritchie method, and agar culture 1 week post-treatment. Although she required initial support with parenteral nutrition due to oral intolerance she slowly progressed favorably. It has been highly recommended to include a rapid and sensitive PCR strategy in the algorithm to confirm Strongyloides infection, which has demonstrated to improve early diagnosis in patients at-risk of disseminated strongyloidiasis.Fil: Quintero, Olga. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Berini, Carolina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Waldbaum, Carlos. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Avagnina, Alejandra. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Juarez, María. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Repetto, Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Sorda, Juan. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Biglione, Mirna Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentin

Editorial: bezafibrate in the treatment of patients with primary biliary cholangitis—are we there yet? Authors' reply

We thank Drs Rodrigues and Banales for the interest in our study.1, 2 We aimed to examine the histological effect of the combination of ursodeoxycholic acid (UDCA) and bezafibrate (BZF) in difficult to treat patients with primary biliary cholangitis (PBC). We agree with Dr Rodrigues et al that late-stage PBC is an entity underrepresented in clinical trials, so recruitment of greater number of patients with the cirrhotic disease may be difficult to obtain in future trials. PBC is increasingly diagnosed at a much earlier stage, and more than 60% of patients are asymptomatic at presentation with the majority not having cirrhosis3, 4; this was observed in our study. Thus a key therapeutic challenge in early non-cirrhotic PBC is to prevent progression; and/or if fibrosis exists to promote regression to earlier stages. The early identification of progression based on biomarkers and predictive scores is important for this group of difficult-to-treat patients with PBC who may benefit from therapies beyond UDCA, including obeticholic acid, off-label bezafibrate, as well as clinical trial agents in development.5Our results reinforced previous data on patients with PBC for whom UDCA response is insufficient, where combined UDCA-BZF therapy is associated with significant decreases or even normalization of biochemical markers of cholestasis.6 We observed that normalization of ALP at 12 months was associated with histological benefit at 5 years, but not in those patients without ALP normalization. Moreover, we observed a significant improvement in GLOBE and UK-PBC risk score under UDCA-BZF therapy. However, these results should be considered with caution since these predictive score needs to be validated in combination therapy; furthermore, the impact of BZF on AST values (a component of APRI and the UK-PBC risk score) needs better understanding, recognising extra-hepatic sources for the AST may include fibrate induced myopathy.We want to point out that moderate or severe lymphocytic interface hepatitis (LIH) has been identified as an independent predictive factor of cirrhosis development as well as liver-related morbidity and mortality.7, 8 Notably, LIH evaluation still needs liver biopsy since non-invasive biomarkers are not validated for this histologic finding. As for the POISE trial population where obeticholic acid was studied,9 we observed a high prevalence of LIH in our cohort, which was a marker of low probability of UDCA response.10 However, in our study, a significant reduction in LIH was associated with UDCA-BZF therapy.Finally, we agree with the editorial that the benefit of UDCA-BZF combination treatment needs further studies, especially in long-term controlled studies, in comparison with, and/or in conjunction with other therapies such as obeticholic acid, and from a cost-effectiveness perspective.Fil: Sorda, Juan Antonio. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: González Ballerga, Esteban. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Barreyro, Fernando Javier. Universidad Nacional de Misiones; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Daruich, Jorge. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentin

New evidence for the therapeutic potential of curcumin to treat nonalcoholic fatty liver disease in humans.

INTRODUCTION:The immune system acts on different metabolic tissues that are implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Leptin and linoleic acid have the ability to potentially affect immune cells, whereas curcumin is a known natural polyphenol with antioxidant and anti-inflammatory properties. AIMS:This study was designed to evaluate the pro-inflammatory and pro-oxidant effects of leptin and linoleic acid on immune cells from patients with NAFLD and to corroborate the modulatory effects of curcumin and its preventive properties against the progression of NAFLD using a high-fat diet (HFD)-induced NAFLD/nonalcoholic steatohepatitis mouse model. RESULTS:The ex vivo experiments showed that linoleic acid increased the production of reactive oxygen species in monocytes and liver macrophages, whereas leptin enhanced tumor necrosis factor-α (TNF-α) production in monocytes and interferon-γ production in circulating CD4+ cells. Conversely, oral administration of curcumin prevented HFD-induced liver injury, metabolic alterations, intrahepatic CD4+ cell accumulation and the linoleic acid- and leptin- induced pro-inflammatory and pro-oxidant effects on mouse liver macrophages. CONCLUSION:Our findings provide new evidence for the therapeutic potential of curcumin to treat human NAFLD. However, the development of a preventive treatment targeting human circulating monocytes and liver macrophages as well as peripheral and hepatic CD4+ cells requires additional research

The reversal effects of curcumin on peripheral immunological cells.

<p>Ex vivo curcumin treatment of PBMCs from patients with NAFLD resulted in decreases in <b>(A)</b> linoleic acid-induced reactive oxygen species generation (n = 9, *p = 0.011) and <b>(B)</b> leptin-induced TNF-α production (n = 9, *p = 0.016) by monocytes. <b>(C)</b> Ex vivo curcumin treatment of PBMCs from patients with NAFLD resulted in decreased IFN-γ production in CD4⁺ cells (n = 9, *p = 0.048). Lines connect the “Linoleic acid” and “Linoleic acid+Curcumin” stimulation indexes or the “Leptin” and "Leptin+Curcumin" fold of increase indexes for each patient. A Wilcoxon matched-pairs signed rank test was performed.</p

Effect of leptin on TNF-α and reactive oxygen species production in human monocytes.

<p>(A) The fold of increase index for TNF-α production was higher in monocytes from patients with NAFLD (n = 10) than those from control subjects (n = 10); however, when monocytes were stimulated with leptin, the stimulation index for reactive oxygen species production (B) was similar in patients with NAFLD (n = 10) and control subjects (n = 10). The box and whiskers indicate the non-parametric statistics: median, lower and upper quartiles and confidence interval around the median. A two-tailed Mann-Whitney U test was used, *p = 0.004.</p

Effect of linoleic acid on reactive oxygen species production in human monocytes and liver macrophages.

<p>(A) The stimulation index for reactive oxygen species production in monocytes was higher in patients with NAFLD (n = 12) than in control subjects (n = 10). The box and whiskers indicate the non-parametric statistics: the median, lower and upper quartiles and confidence interval around the median. A two-tailed Mann-Whitney U test was used; *p = 0.036. (B) DCF-MFI, 2', 7’-dichlorofluorescein median fluorescence intensity. Linoleic acid increased reactive oxygen species production in liver macrophages from patients with NAFLD (n = 12). Lines connect the “Basal” and “Linoleic acid” values for each patient. A Wilcoxon matched-pairs signed rank test was performed; *p = 0.001. (C) The stimulation index in monocytes and liver macrophages from patients with NAFLD were positively correlated. Spearman´s rank correlation coefficients test was used.</p

Curcumin effects on linoleic acid- and leptin-induced the production of reactive oxygen species and cytokines as well as the infiltration of CD4⁺ cells in HFD-fed mice.

<p><b>(A)</b> After they were treated with linoleic acid ex vivo, liver macrophages from HFD-fed mice showed a higher stimulation index for reactive oxygen species production (*p<0.05 vs. normal chow-fed mice). In vivo curcumin administration of HFD-fed mice (HFD+curcumin) prevented the increase in the stimulation index (*p<0.05 vs. HFD-fed mice). <b>(B)</b> Ex vivo linoleic acid stimulation of hepatocytes from all the experimental groups resulted in similar stimulation indexes for reactive oxygen species production. <b>(C)</b> TNF-α production induced by ex vivo leptin treatment was higher in liver macrophages from HFD-fed mice (*p<0.05 vs. normal chow-fed mice). In vivo curcumin treatment of HFD-fed mice also prevented the increase in TNF- α production (*p<0.05, HFD+curcumin vs. HFD). <b>(D)</b> The percentage of CD4⁺ cells among the non-parenchymal cell populations was higher in HFD-fed mice (*p<0.01 vs. normal chow-fed mice). In vivo curcumin treatment also prevented the increase in CD4⁺ cell recruitment (*p<0.01, HFD+curcumin vs. HFD). The box and whiskers show the non-parametric statistics: the median, lower and upper quartiles and confidence interval around the median. The Kruskal-Wallis test with Dunn’s post-test was performed.</p

Diagram of the experimental design.

<p>Experimental design using human peripheral blood mononuclear cells (PBMCs), human or mouse liver cells. PMA: phorbol myristate acetate, H₂DCFDA: 2’7’-dichlorofluorescein diacetate.</p