Clinical Course and Risk Factors for Infection in Severe Forms of Alcohol-Associated Liver Disease.

BACKGROUND AND AIMS: Infection is a major driver of mortality in patients with advanced alcohol-associated liver disease (ALD). The epidemiology and clinical course of patients infected with life-threatening forms of ALD, including severe alcohol-associated hepatitis (sAH) and decompensated alcohol-associated cirrhosis (DAC), and specific risk factors for infection remain mostly unknown. APPROACH AND RESULTS: In this observational study, we assessed all infectious episodes occurring within a 90-day period from diagnosis in all consecutive patients with biopsy-proven sAH (modified Maddrey's discriminant function ≥ 32, Model for End-Stage Liver Disease [MELD] ≥ 18) and DAC (MELD ≥ 18) without alcohol-associated hepatitis in our tertiary hospital between 2003 and 2016. A total of 207 patients were included: 139 with sAH and 68 with DAC. One hundred seventeen (84%) patients with sAH and 41 (60%) patients with DAC experienced at least one infection episode at 90 days (P < 0.001). In multivariable analysis, factors associated with the development of infection were the presence of sAH and baseline MELD score. Bacterial infections represented the most common infection in the two groups, and only the MELD score was independently associated with the occurrence of bacterial infection. In both groups, pneumonia was the most prevalent bacterial infection, and gram-negative bacilli were the main pathogens. Invasive fungal infections (IFI) occurred in 20 (14.5%) patients with sAH and 3 (4.5%) with patients with DAC (P < 0.05). Multivariable regression showed that younger age, higher MELD, and corticosteroid therapy were independently associated with IFI. The 90-day cumulative incidence of death in patients infected with sAH and patients infected with DAC was 46% and 41.5%, respectively (P = 0.43). CONCLUSIONS: Patients with sAH are more susceptible to develop infection than those with DAC. In life-threatening forms of ALD, patients who were infected share a similar mortality rate. Corticosteroid treatment, not sAH, seems to be the main risk factor triggering IFI.

IL-33/ST2 pathway regulates neutrophil migration and predicts outcome in patients with severe alcoholic hepatitis.

BACKGROUND & AIMS: Severe alcoholic hepatitis (SAH) is associated with a high risk of infection. The IL-33/ST2 pathway is involved in sepsis control but data regarding its role in alcohol-related liver disease (ALD) are lacking. We aimed to characterize the role of IL-33/ST2 in the polymorphonuclear neutrophils (PMNs) of patients with ALD and SAH. METHODS: Serum and circulating neutrophils were collected from patients with SAH, alcoholic cirrhosis and healthy controls. We quantified IL-33/ST2 pathway activity and CXCR2 at baseline and after exposure to IL-33. We also determined the migration capacity of PMNs. RESULTS: The decoy receptor of IL-33 (soluble ST2 [sST2]) was increased in SAH vs. cirrhosis and controls, demonstrating the defect in this pathway during ALD. The sST2 level was associated with response to treatment, 2-month survival, infection-free survival and probability of infection in SAH. Endotoxemia was weakly correlated with sST2. GRK2, a negative regulator of CXCR2, was overexpressed in PMNs of patients with SAH and cirrhosis and was decreased by IL-33. CXCR2 levels on PMNs were lower in SAH vs. cirrhosis and controls. Treatment with IL-33 partially restored CXCR2 expression in SAH and cirrhosis. PMN migration upon IL-8 was lower in patients with SAH and cirrhosis vs. controls. Treatment with IL-33 partially restored migration in those with SAH and cirrhosis. Interestingly, the migration capacity of PMNs and the response to IL-33 were enhanced in responders to corticosteroids (Lille <0.45) compared to non-responders. CONCLUSION: The IL33/ST2 pathway is defective in SAH and predicts outcome. This defect is associated with decreased CXCR2 expression on the surface of PMNs and lower migration capacity, which can be corrected by IL-33, especially in patients responding to steroids. These results suggest that IL-33 has therapeutic potential for SAH and its infectious complications. LAY SUMMARY: The neutrophils of patients with severe alcoholic hepatitis are associated with a defect in the IL-33/ST2 pathway. This defect is associated with lower migration capacities in neutrophils and a higher probability of getting infected. Administration of IL-33 to the neutrophils at least partly restores this defect and may be effective at reducing the risk of infection in patients with severe alcoholic hepatitis.

Methyl helicterilate ameliorates alcohol-induced hepatic fibrosis by modulating TGF-ß1/Smads pathway and mitochondria-dependent pathway.

This study aimed to investigate the effect and underlying mechanism of Methyl helicterilate from Helicteres angustifolia (MHHA) on alcohol-induced hepatic fibrosis. The results showed that MHHA treatment markedly alleviated alcohol-induced liver injury and notably reduced collagen deposition in liver tissue. It significantly enhanced the activity of alcohol dehydrogenase and aldehyde dehydrogenase. Moreover, MHHA treatment markedly decreased the content of inflammatory cytokines, alleviated collagen accumulation, and inhibited the expression of TGF-ß1 and Smad2/3 in liver tissue. The experiments in cells showed that MHHA significantly inhibited HSC activation by blocking TGF-ß1/Smads signaling pathway. Additionally, it notably induced HSC apoptosis by modulating the mitochondria-dependent pathway. The present study demonstrates that MHHA treatment significantly ameliorates alcoholic hepatic fibrosis and the underlying mechanism may be ascribed to the inhibition of the TGF-ß1/Smads pathway and regulation of the mitochondria-mediated apoptotic pathway.

Yokenella regensburgei necrotizing fasciitis in an immunocompromised host.

We report a case of necrotizing skin infection caused by Yokenella regensburgei in an immunosuppressed patient with orthotopic liver transplantation. Initial bacterial culture identification was suggestive of Hafnia alvei. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) confirmed identification of Y. regensburgei. Necrotizing fasciitis is potentially fatal and requires aggressive management, including early diagnosis, appropriate antibiotic selection, and operative debridement.

Liver fibrosis and accelerated immune dysfunction (immunosenescence) among HIV-infected Russians with heavy alcohol consumption - an observational cross-sectional study.

BACKGROUND: The multifactorial mechanisms driving negative health outcomes among risky drinkers with HIV may include immunosenescence. Immunosenescence, aging of the immune system, may be accentuated in HIV and leads to poor outcomes. The liver regulates innate immunity and adaptive immune tolerance. HIV-infected people have high prevalence of liver-related comorbidities. We hypothesize that advanced liver fibrosis/cirrhosis is associated with alterations in T-cell subsets consistent with immunosenescence. METHODS: ART-naïve people with HIV with a recent history of heavy drinking were recruited into a clinical trial of zinc supplementation. Flow cytometry was used to characterize T-cell subsets. The two primary dependent variables were CD8+ and CD4+ T-cells expressing CD28-CD57+ (senescent cell phenotype). Secondary dependent variables were CD8+ and CD4+ T-cells expressing CD45RO + CD45RA- (memory phenotype), CD45RO-CD45RA+ (naïve phenotype), and the naïve phenotype to memory phenotype T-cell ratio (lower ratios associated with immunosenescence). Advanced liver fibrosis/cirrhosis was defined as FIB-4 > 3.25, APRI≥1.5, or Fibroscan measurement ≥10.5 kPa. Analyses were conducted using multiple linear regression adjusted for potential confounders. RESULTS: Mean age was 34 years; 25% female; 88% hepatitis C. Those with advanced liver fibrosis/cirrhosis (N = 25) had higher HIV-1 RNA and more hepatitis C. Advanced liver fibrosis/cirrhosis was not significantly associated with primary or secondary outcomes in adjusted analyses. CONCLUSIONS: Advanced liver fibrosis/cirrhosis was not significantly associated with these senescent T-cell phenotypes in this exploratory study of recent drinkers with HIV. Future studies should assess whether liver fibrosis among those with HIV viral suppression and more advanced, longstanding liver disease is associated with changes in these and other potentially senescent T-cell subsets.

RIPK3-Mediated Necroptosis and Neutrophil Infiltration Are Associated with Poor Prognosis in Patients with Alcoholic Cirrhosis.

Alcoholic cirrhosis is an end-stage liver disease with impaired survival and often requires liver transplantation. Recent data suggests that receptor-interacting protein kinase-3- (RIPK3-) mediated necroptosis plays an important role in alcoholic cirrhosis. Additionally, neutrophil infiltration is the most characteristic pathologic hallmark of alcoholic hepatitis. Whether RIPK3 level is correlated with neutrophil infiltration or poor prognosis in alcoholic cirrhotic patients is still unknown. We aimed to determine the correlation of RIPK3 and neutrophil infiltration with the prognosis in the end-stage alcoholic cirrhotic patients. A total of 20 alcoholic cirrhotic patients subjected to liver transplantation and 5 normal liver samples from control patients were retrospectively enrolled in this study. Neutrophil infiltration and necroptosis were assessed by immunohistochemical staining for myeloperoxidase (MPO) and RIPK3, respectively. The noninvasive score system (model for end-stage liver disease (MELD)) and histological score systems (Ishak, Knodell, and ALD grading and ALD stage) were used to evaluate the prognosis. Neutrophil infiltration was aggravated in patients with a high MELD score (≥32) in the liver. The MPO and RIPK3 levels in the liver were positively related to the Ishak score. The RIPK3 was also significantly and positively related to the Knodell score. In conclusion, RIPK3-mediated necroptosis and neutrophil-mediated alcoholic liver inflammatory response are highly correlated with poor prognosis in patients with end-stage alcoholic cirrhosis. RIPK3 and MPO might serve as potential predictors for poor prognosis in alcoholic cirrhotic patients.

False-positive Troponin I Assay elevation due to occult Mixed Cryoglobulinemic Vasculitis.

A 53-year-old man with active hepatitis C and cirrhosis presented with a vasculitic rash, myalgias, and fatigue, and was found to have an elevated cardiac troponin I up to 15.7 ng/mL with normal electrocardiogram, echocardiogram, and coronary angiogram prior to being discharged. Subsequently, during a similar presentation to another academically affiliated hospital, the patient had a normal cardiac troponin T (< 0.01 ng/mL). Upon his third presentation with significantly elevated troponin I to 15.98 ng/mL, the patient was found to have cryoglobulinemic vasculitis and elevated rheumatoid factor due to active hepatitis C, causing interference with the troponin I immunoassay. In conclusion, troponin I assays may have high false-positive values due to interference by rheumatoid factor and/or a polyclonal antibody found in cryoglobulinemia.

IgA nephropathy featuring massive wire loop-like deposits in two patients with alcoholic cirrhosis.

BACKGROUND: Various renal manifestations are known to develop in patients with liver disease, including chronic hepatitis and cirrhosis. CASE PRESENTATION: We evaluated renal disease in two 47-year-old Japanese men with liver cirrhosis and chronic alcoholism for 34 years and 27 years, respectively. Renal biopsy demonstrated massive wire loop-like deposits in the subendothelial space of the glomerular basement membrane and in the mesangium. However, immunofluorescence was only positive for IgA and C3, and electron microscopy did not reveal any organized structures in the electron-dense deposits. IgA nephropathy was diagnosed, although the features were different from primary IgA nephropathy. Both patients had portosystemic shunts associated with liver cirrhosis. Their renal deposits and proteinuria resolved completely after 1 year of steroid therapy. CONCLUSION: Alcohol abuse may have contributed to development of secondary IgA nephropathy in these two patients, probably via their portosystemic shunts.

Type I interferon signaling in systemic immune cells from patients with alcoholic cirrhosis and its association with outcome.

BACKGROUND & AIMS: In immune cells, constitutively and acutely produced type I interferons (IFNs) engage autocrine/paracrine signaling pathways to induce IFN-stimulated genes (ISGs). Enhanced activity of IFN signaling pathways can cause excessive inflammation and tissue damage. We aimed to investigate ISG expression in systemic immune cells from patients with decompensated alcoholic cirrhosis, and its association with outcome. METHODS: Peripheral blood mononuclear cells (PBMCs) from patients and heathy subjects were stimulated or not with lipopolysaccharide (LPS, an IFN inducer) or increasing concentrations of IFN-ß. The expression of 48 ISGs and ten "non-ISG" inflammatory cytokines were analyzed using RT-qPCR. RESULTS: We developed an 8-ISG signature (IFN score) assessing ISG expression. LPS-stimulated ISG induction was significantly lower in PBMCs from patients with cirrhosis compared to healthy controls. Non-ISGs, however, showed higher induction. Lower induction of ISGs by LPS was not due to decreased IFN production by cirrhotic PBMCs or neutralization of secreted IFN, but a defective PBMC response to IFN. This defect was at least in part due to decreased constitutive ISG expression. Patients with the higher baseline IFN scores and ISG levels had the higher risk of death. At baseline, "non-ISG" cytokines did not correlate with outcome. CONCLUSIONS: PBMCs from patients with decompensated alcoholic cirrhosis exhibit downregulated ISG expression, both constitutively and after an acute stimulus. Our finding that higher baseline PBMC ISG expression was associated with higher risk of death, suggests that constitutive ISG expression in systemic immune cells contributes to the prognosis of alcoholic cirrhosis. LAY SUMMARY: Enhanced activity of IFN signaling pathways can cause excessive inflammation and tissue damage. Here we show that peripheral blood mononuclear cells (PBMCs) from patients with alcoholic cirrhosis exhibit a defect in interferon-stimulated genes (ISGs). We found that higher baseline ISG expression in PBMCs was associated with higher risk of death, revealing a probable contribution of ISG expression in immune cells to the outcome of alcoholic cirrhosis.

Circulating granulocyte lifespan in compensated alcohol-related cirrhosis: a pilot study.

Although granulocyte dysfunction is known to occur in cirrhosis, in vivo studies of granulocyte lifespan have not previously been performed. The normal circulating granulocyte survival half-time (G - t½), determined using indium-111 ((111)In)-radiolabeled granulocytes, is ~7 h. In this pilot study, we aimed to measure the in vivo G - t½ in compensated alcohol-related cirrhosis. Sequential venous blood samples were obtained in abstinent subjects with alcohol-related cirrhosis over 24 h post injection (PI) of minimally manipulated (111)In-radiolabeled autologous mixed leukocytes. Purified granulocytes were isolated from each sample using a magnetic microbead-antibody technique positively selecting for the marker CD15. Granulocyte-associated radioactivity was expressed relative to peak activity, plotted over time, and G - t½ estimated from data up to 12 h PI This was compared with normal neutrophil half-time (N - t½), determined using a similar method specifically selecting neutrophils in healthy controls at a collaborating center. Seven patients with cirrhosis (six male, aged 57.8 ± 9.4 years, all Child-Pugh class A) and seven normal controls (three male, 64.4 ± 5.6 years) were studied. Peripheral blood neutrophil counts were similar in both groups (4.6 (3.5 - 5.5) × 10(9)/L vs. 2.8 (2.7 - 4.4) × 10(9)/L, respectively, P = 0.277). G - t½ in cirrhosis was significantly lower than N - t½ in controls (2.7 ± 0.5 h vs. 4.4 ± 1.0 h, P = 0.007). Transient rises in granulocyte and neutrophil-associated activities occurred in four patients from each group, typically earlier in cirrhosis (4-6 h PI) than in controls (8-10 h), suggesting recirculation of radiolabeled cells released from an unidentified focus. Reduced in vivo granulocyte survival in compensated alcohol-related cirrhosis is a novel finding and potentially another mechanism for immune dysfunction in chronic liver disease. Larger studies are needed to corroborate these pilot data and assess intravascular neutrophil residency in other disease etiologies.

New approaches for fibrosis regression in alcoholic cirrhosis.

Liver fibrosis is a dynamic process of fibrinogenesis and fibrinolysis. It is sequelae of recurrent injury and inflammation to the liver. Only recently has there been significant progress in understanding the pathophysiology behind liver fibrosis. This has allowed for the development of identifiable targets for potential therapies. In this article we will discuss the underlying general cellular mechanisms that play a key role in the pathway of fibrinogenesis and fibrinolysis and then focus on the mechanisms that are key in alcohol-induced liver fibrosis. Challenges in formulating potential fibrosis therapies as well as current potential targets for liver fibrosis will be reviewed as well.

Betaine treatment decreased oxidative stress, inflammation, and stellate cell activation in rats with alcoholic liver fibrosis.

The aim of this study was to investigate the effect of betaine (BET) on alcoholic liver fibrosis in rats. Fibrosis was experimentally generated with ethanol plus carbon tetrachloride (ETH+CCl4) treatment. Rats were treated with ETH (5% v/v in drinking water) for 14 weeks. CCl4 was administered intraperitoneally (i.p.) 0.2mL/kg twice a week to rats in the last 6 weeks with/without commercial food containing BET (2% w/w). Serum hepatic damage markers, tumor necrosis factor-α, hepatic triglyceride (TG) and hydroxyproline (HYP) levels, and oxidative stress parameters were measured together with histopathologic observations. In addition, α-smooth muscle-actin (α-SMA), transforming growth factor-ß1 (TGF-ß1) and type I collagen (COL1A1) protein expressions were assayed immunohistochemically to evaluate stellate cell (HSC) activation. mRNA expressions of matrix metalloproteinase-2 (MMP-2) and its inhibitors (TIMP-1 and TIMP-2) were also determined. BET treatment diminished TG and HYP levels; prooxidant status and fibrotic changes; α-SMA, COL1A1 and TGF-ß protein expressions; MMP-2, TIMP-1 and TIMP-2 mRNA expressions in the liver of fibrotic rats. In conclusion, these results indicate that the antifibrotic effect of BET may be related to its suppressive effects on oxidant and inflammatory processes together with HSC activation in alcoholic liver fibrosis.

Dysfunction of Circulating Polymorphonuclear Leukocytes and Monocytes in Ambulatory Cirrhotics Predicts Patient Outcome.

BACKGROUND: Cirrhosis represents a state of functional immune paresis with increased infection risk. AIMS: To investigate polymorphonuclear (PMN) leukocyte and monocyte function in ambulatory cirrhotics, and their potential relation with cirrhosis etiology or patient outcome. METHODS: Consecutive ambulatory cirrhotics without current or recent (<1 month) infection or acute decompensation were prospectively enrolled in 2013 and followed for a median time of 20 months until death, transplant or end of 2014. Oxidative burst and phagocytosis of circulating PMNs and monocytes were investigated at baseline and after in vitro Escherichia coli stimulation. Seventeen healthy blood donors served as controls. Baseline clinical and laboratory data as well as follow-up data on the development of cirrhosis complications, including acute-on-chronic liver failure (ACLF), and bacterial infections were collected. RESULTS: Sixty patients were included (70 % male, median age 63 years, 52 % with alcoholic cirrhosis). Compared to controls, cirrhotics showed increased resting and stimulated burst as well as reduced phagocytosis of PMNs, and increased stimulated monocyte burst (p < 0.05 for all). Alcoholic etiology was not related to PMN or monocyte dysfunction (p > 0.05 for all). In Cox regression analysis, increased stimulated monocyte and PMN burst were independent predictors of sepsis, severe sepsis and ACLF occurrence. Also, increased stimulated monocyte burst was associated with worse transplant-free survival (p < 0.05 for all). CONCLUSIONS: Stimulated PMN and monocyte oxidative burst are increased in ambulatory cirrhotics without acute decompensation. In turn, these changes are associated to sepsis and ACLF occurrence.

Chemokine Receptor Ccr6 Deficiency Alters Hepatic Inflammatory Cell Recruitment and Promotes Liver Inflammation and Fibrosis.

Chronic liver diseases are characterized by a sustained inflammatory response in which chemokines and chemokine-receptors orchestrate inflammatory cell recruitment. In this study we investigated the role of the chemokine receptor CCR6 in acute and chronic liver injury. In the absence of liver injury Ccr6-/- mice presented a higher number of hepatic macrophages and increased expression of pro-inflammatory cytokines and M1 markers Tnf-α, Il6 and Mcp1. Inflammation and cell recruitment were increased after carbon tetrachloride-induced acute liver injury in Ccr6-/- mice. Moreover, chronic liver injury by carbon tetrachloride in Ccr6-/- mice was associated with enhanced inflammation and fibrosis, altered macrophage recruitment, enhanced CD4+ cells and a reduction in Th17 (CD4+IL17+) and mature dendritic (MHCII+CD11c+) cells recruitment. Clodronate depletion of macrophages in Ccr6-/- mice resulted in a reduction of hepatic pro-inflammatory and pro-fibrogenic markers in the absence and after liver injury. Finally, increased CCR6 hepatic expression in patients with alcoholic hepatitis was found to correlate with liver expression of CCL20 and severity of liver disease. In conclusion, CCR6 deficiency affects hepatic inflammatory cell recruitment resulting in the promotion of hepatic inflammation and fibrosis.

Inflammatory status in human hepatic cirrhosis.

This review focuses on new findings about the inflammatory status involved in the development of human liver cirrhosis induced by the two main causes, hepatitis C virus (HCV) infection and chronic alcohol abuse, avoiding results obtained from animal models. When liver is faced to a persistent and/or intense local damage the maintained inflammatory response gives rise to a progressive replacement of normal hepatic tissue by non-functional fibrotic scar. The imbalance between tissue regeneration and fibrosis will determine the outcome toward health recovery or hepatic cirrhosis. In all cases progression toward liver cirrhosis is caused by a dysregulation of mechanisms that govern the balance between activation/homeostasis of the immune system. Detecting differences between the inflammatory status in HCV-induced vs alcohol-induced cirrhosis could be useful to identify specific targets for preventive and therapeutic intervention in each case. Thus, although survival of patients with alcoholic cirrhosis seems to be similar to that of patients with HCV-related cirrhosis (HCV-C), there are important differences in the altered cellular and molecular mechanisms implicated in the progression toward human liver cirrhosis. The predominant features of HCV-C are more related with those that allow viral evasion of the immune defenses, especially although not exclusively, inhibition of interferons secretion, natural killer cells activation and T cell-mediated cytotoxicity. On the contrary, the inflammatory status of alcohol-induced cirrhosis is determined by the combined effect of direct hepatotoxicity of ethanol metabolites and increases of the intestinal permeability, allowing bacteria and bacterial products translocation, into the portal circulation, mesenteric lymph nodes and peritoneal cavity. This phenomenon generates a stronger pro-inflammatory response compared with HCV-related cirrhosis. Hence, therapeutic intervention in HCV-related cirrhosis must be mainly focused to counteract HCV-immune system evasion, while in the case of alcohol-induced cirrhosis it must try to break the inflammatory loop established at the gut-mesenteric lymph nodes-peritoneal-systemic axis.

Liver-related deaths in HIV-infected patients between 1995 and 2010 in France: the Mortavic 2010 study in collaboration with the Agence Nationale de Recherche sur le SIDA (ANRS) EN 20 Mortalité 2010 survey.

OBJECTIVES: The aim of this study was to describe the proportion of liver-related diseases (LRDs) as a cause of death in HIV-infected patients in France and to compare the results with data from our five previous surveys. METHODS: In 2010, 24 clinical wards prospectively recorded all deaths occurring in around 26 000 HIV-infected patients who were regularly followed up. Results were compared with those of previous cross-sectional surveys conducted since 1995 using the same design. RESULTS: Among 230 reported deaths, 46 (20%) were related to AIDS and 30 (13%) to chronic liver diseases. Eighty per cent of patients who died from LRDs had chronic hepatitis C, 16.7% of them being coinfected with hepatitis B virus (HBV). Among patients who died from an LRD, excessive alcohol consumption was reported in 41%. At death, 80% of patients had undetectable HIV viral load and the median CD4 cell count was 349 cells/µL. The proportion of deaths and the mortality rate attributable to LRDs significantly increased between 1995 and 2005 from 1.5% to 16.7% and from 1.2‰ to 2.0‰, respectively, whereas they tended to decrease in 2010 to 13% and 1.1‰, respectively. Among liver-related causes of death, the proportion represented by hepatocellular carcinoma (HCC) dramatically increased from 5% in 1995 to 40% in 2010 (p = 0.019). CONCLUSIONS: The proportion of LRDs among causes of death in HIV-infected patients seems recently to have reached a plateau after a rapid increase during the decade 1995-2005. LRDs remain a leading cause of death in this population, mainly as a result of hepatitis C virus (HCV) coinfection, HCC representing almost half of liver-related causes of death.

Vasculitis of anti-neutrophil cytoplasmic antibody after liver transplantation.

OBJECTIVE: We reported a case of vasculitis of anti-neutrophil cytoplasmic antibody after liver transplantation. A 56-year-old male patient underwent orthotopic liver transplantation of the classic style on February 25, 2010 because of alcoholic cirrhosis. METHODS: Pathology analysis showed it was nodular cirrhosis. The patient was given conventional treatment programs of FK (tacrolimus) + mycophenolate mofetil + hormone; hormone was suspended at the third month. He began to cough and spit, and there was blood in the sputum in September. Lung CT scanning images showed that there was a visible multiple low-density patchy shadow in both lungs; however, a number of other detecting results were negative. RESULTS: Considering the patient with contact suspected mold, we improved the inspection and switched to experimental treatment (itraconazole), and the patient improved and was then discharged. Two months later, he complained about appearing hemoptysis. Final diagnostic results showed it was anti-neutrophil cytoplasmic antibody-associated vasculitis after liver transplantation. Then we stopped medication with itraconazole. Treatment with methylprednisolone was continued, and the patient gradually stopped coughing and had no expectoration and hemoptysis. CONCLUSIONS: Reviewing CT respectively showed significant improvement at the 7th and 24th days of hormone therapy; thus, we confirmed it was anti-neutrophil cytoplasmic antibody-associated vasculitis after liver transplantation.

Correction of all-trans retinoic acid deficiency in alcoholic cirrhosis lessens the excessive inflammatory monocyte response: a translational study.

BACKGROUND & AIMS: Patients with alcoholic liver disease (ALD) have vitamin A (VA) deficiency and an enhanced immune response associated with disease severity. All-trans retinoic acid (ATRA), a VA-active metabolite, has anti-inflammatory effects and its deficiency could contribute to the exacerbated proinflammatory reaction. The aim of this study was to investigate the effects of ATRA/VA deficiency and supplementation on the monocyte response in ALD. METHODS: Vitamin A and ATRA plasma levels were quantified in ALD patients and healthy subjects (HS). The in vitro effect of ATRA on lipopolysaccharide (LPS)-induced TNF-α production by human peripheral blood mononuclear cells (PBMC) was assessed by ELISA and RT-PCR. The activation pattern of peritoneal macrophages (PerMΦ) and circulating monocytes isolated from VA-deficient mice and ALD patients, respectively, was evaluated by flow cytometry, quantification of TNF-α and NO2 production. RESULTS: Alcoholic liver disease patients (n = 85) showed plasmatic VA deficiency that was correlated with scores of severity and with the hepatic venous pressure gradient. ATRA levels correlated significantly with VA levels. In vitro, ATRA pretreatment decreased the overproduction of TNF-α by LPS-stimulated PBMC of ALD patients. In vivo, VA deficiency in mice was associated with increased activation of PerMΦ, while oral ATRA supplementation normalized it. CONCLUSION: For the first time, we show that VA/ATRA deficiencies in ALD patients are associated with disease severity. Furthermore, our data strongly suggest that the VA deficiency observed in ALD patients might participate in the pathophysiology of the disease by priming immune cells, and that ATRA supplementation could downregulate the deleterious proinflammatory state in cirrhosis and might thus be of therapeutic use.

Alcohol consumption promotes the intestinal translocation of Streptococcus suis infections.

Streptococcus suis is an emerging zoonotic agent. This study aimed to investigate whether S. suis is likely to translocate across the intestines of human hosts who have liver disease and/or consume alcohol. Both the alcoholism and cirrhosis models exhibited high mRNA expression of TGF and collagen1, but only the cirrhosis model had fibrosis in the liver. After both models were infected with S. suis, significantly different concentrations of S. suis were detected in the blood and brains of the alcoholism model (Blood: 36.4%; Brain: 31.8%) and the cirrhosis model (Blood: 62.5%; Brain: 62.5%) compared to the concentrations in the healthy mice (Blood: 15.4%; Brain: 0%). Trans-epithelial electrical resistance (TER) was used to examine the Caco-2 cells in the in vitro that had an S. suis infection combined with 1% ethanol. Although the ethanol did not influence the Caco-2 cells' barriers, it did rapidly decrease the barriers' TER value and then their E-cadherin compared to the infected Caco-2 cells without the ethanol treatment. Immunofluorescence also indicated that the barriers of the Caco-2 cells treated with ethanol were disrupted and that S. suis translocated from the apical to the basolateral side. This study demonstrated that alcohol consumption helped S. suis to translocate.