Elisa Pose

Characterization of inflammatory response in acute-on-chronic liver failure and relationship with prognosis

ACLF is characterized by a systemic inflammatory response, but the cytokines involved in this process have not been well studied. The aim of this study was to characterize the systemic inflammatory response in patients with cirrhosis and ACLF and its relationship with prognosis. Fifty-five patients with cirrhosis, 26 with ACLF, were studied prospectively. Systemic inflammatory response was analyzed by measuring a large array of plasma cytokines by using a multiplex kit. A principal component analysis show noticeable differences between ACLF and decompensated cirrhosis without ACLF. Patients with ACLF had significant abnormal levels of 12 cytokines compared to those without ACLF, including: VCAM-1, VEGF-A, Fractalkine, MIP-1α, Eotaxin, IP-10, RANTES, GM-CSF, IL-1β, IL-2, ICAM-1, and MCP-1. Cytokines showing the most marked relationship with ACLF were VCAM-1 and VEGF-A (AUCROC 0.77; p = 0.001). There was a significant relationship between some of inflammatory mediators and 3-month mortality, particularly VCAM-1, ICAM-1, and GM-CSF (AUCROC>0.7; p < 0.05). Functional Enrichment Analysis showed that inflammatory markers differentially expressed in ACLF patients were enriched in leukocyte migration, particularly monocytes and macrophages, and chemotaxis pathways. In conclusion, ACLF is characterized by a marked inflammatory reaction with activation of mediators of adhesion and migration of leukocytes. The intensity of the inflammatory reaction correlates with prognosis.

Treatment of type 2 hepatorenal syndrome in patients awaiting transplantation: Effects on kidney function and transplantation outcomes

There is little information on the effects of treatment with vasoconstrictors plus albumin in patients with type 2 hepatorenal syndrome (HRS), particularly those awaiting liver transplantation (LT). This study reports the effects of treatment of type 2 HRS in patients on the waiting list for LT. We included 56 patients with type 2 HRS who were awaiting LT. Out of these 56 patients, 31 were treated with terlipressin and albumin. Nineteen (61%) of these 31 patients had response to therapy, and 11 of them relapsed after treatment withdrawal. There were no differences in mortality on the waiting list between responders and nonresponders. Among the 46 (82%) patients who underwent transplantation, 15 underwent transplantation with reversal of type 2 HRS, whereas the remaining 31 underwent transplantation with type 2 HRS. There were no significant differences in serum creatinine or estimated glomerular filtration rate between the 2 cohorts of patients at 3, 6, and 12 months after transplantation. There were no significant differences regarding development of acute kidney injury, need for renal replacement therapy, frequency of chronic kidney disease 1 year after transplant, length of hospitalization, and survival. In conclusion, treatment of patients with type 2 HRS with terlipressin and albumin does not appear to have beneficial effects either in pretransplantation or in posttransplantation outcomes. Liver Transpl 21:1347‐1354, 2015.

Severe acute kidney injury associated with non-steroidal anti-inflammatory drugs in cirrhosis: A case-control study

BACKGROUND & AIMS Non-steroidal anti-inflammatory drugs (NSAIDs) may cause impairment of kidney function in patients with cirrhosis. Investigational studies demonstrated reversibility of kidney dysfunction after drug withdrawal, but information based on clinical practice is lacking. The aim of the study was to investigate the characteristics and outcome of Acute Kidney Injury (AKI) developing in patients with cirrhosis treated with NSAIDs. METHODS Prospective cohort study in a tertiary referral center of all patients with NSAIDs-associated AKI seen from 2002 to 2014. For comparison, three control groups of patients with hypovolemic-induced AKI, type-1 HRS and ATN, respectively, were also evaluated. Urinary excretion of neutrophil gelatinase-associated lipocalin (uNGAL) was measured in a subset of patients. RESULTS Thirty patients with cirrhosis and NSAIDs-associated AKI were identified. In 19 patients (63%) AKI was transient and kidney function rapidly recovered (4±3 days) after NSAIDs withdrawal. In the remaining 11 patients (37%) AKI was more severe and persisted during hospitalization despite drug withdrawal. Patients with persistent AKI had remarkably higher uNGAL levels compared with those of patients with transient AKI (953±1,198 vs. 83±79 μg/g of creatinine, respectively, p=0.008). Moreover, seven of the 11 patients with persistent AKI (64%) died within three months compared with only one of the 19 (5%) patients with transient AKI (p=0.001). Mortality of persistent AKI was similar in NSAIDs patients compared to control groups. The only independent predictive factor of three-month mortality was persistent AKI. CONCLUSIONS Patients with cirrhosis treated with NSAIDs may develop severe AKI which may be irreversible and associated with poor short-term outcome.

Validation of a Staging System for Acute Kidney Injury in Patients With Cirrhosis and Association With Acute-on-Chronic Liver Failure

BACKGROUND & AIMS In patients with cirrhosis of the liver, acute kidney injury (AKI) is classified into 3 stages. Recent studies indicate that there are 2 subgroups of stage 1 disease, associated with different outcomes and serum levels of creatinine (SCr): stage 1A (SCr <1.5 mg/dL) and stage 1B (SCr ≥1.5 mg/dL). We performed a prospective study to validate, in a large series of patients with cirrhosis, the association between this new description and patient outcomes, and assess the relationship between AKI stage and the presence of acute‐on‐chronic liver failure. METHODS We collected data from 547 consecutive patients admitted for cirrhosis with acute decompensation to 2 tertiary hospitals (Italy and Spain), from February 2011 through June 2015. A total of 290 patients had AKI (53%; 197 had stage 1 disease); AKI stages were determined based on levels of SCr at diagnosis. Patients were followed up until death, liver transplantation, or for 90 days. The primary outcome was 90‐day survival; secondary outcomes were progression and resolution of AKI and association with acute‐on‐chronic liver failure. RESULTS Based on level of sCr at diagnosis, 58 patients had stage 1A disease and 139 had stage 1B disease. Of patients with stage 1A disease, 82% survived for 90 days; of patients with stage 1B disease, 55% survived for 90 days (P = .001). Hepatorenal syndrome and acute tubular necrosis were the most common causes of stage 1B AKI, and hypovolemia was the most common cause of stage 1A AKI. AKI progressed in a higher proportion of patients with 1B than 1A AKI (31% vs 15%; P = .017) and resolved in a higher proportion of patients with 1A disease (90% vs 52% of patients with stage 1B; P < .001). Stage 1B disease, but not 1A, was an independent predictor of AKI progression and mortality. ACLF developed in a significantly greater proportion of patients with stage 1B disease (76%) than stage 1A disease (22%; P < .001), which could account for the poor outcomes of patients with stage 1B disease. CONCLUSIONS In a large group of patients with decompensated cirrhosis, we validated the association between AKI stages IA and IB (based on level of sCR) with survival times and AKI progression. We also associated these subgroups of AKI with development of acute‐on‐chronic liver failure. These findings are important for management of patients with decompensated cirrhosis.

Limited Efficacy of Tolvaptan in Patients with Cirrhosis and Severe Hyponatremia: Real-Life Experience

BACKGROUND Vaptans, vasopressin selective V2-receptor antagonists, represent the first pharmacologic approach to the treatment of hypervolemic hyponatremia in cirrhosis. However, information on the use of vaptans for patients with cirrhosis and hyponatremia in a real-life scenario is limited. Therefore, this study evaluated the effect of tolvaptan on serum sodium in patients with cirrhosis and severe hypervolemic hyponatremia. METHODS Nine patients with cirrhosis and serum sodium ≤125 mEq/L were included. RESULTS Only 2 of the 9 patients (22%) gained an increase in serum sodium >130 mEq/L that persisted throughout treatment. In the remaining patients, serum sodium did not change or increased during the first days but decreased thereafter despite continuation of treatment. Only 1 patient developed hyperkalemia as a side effect. CONCLUSIONS The efficacy of tolvaptan in patients with cirrhosis and severe hypervolemic hyponatremia seems to be limited.

Adipocyte fatty-acid binding protein is overexpressed in cirrhosis and correlates with clinical outcomes

Fatty-acid-binding proteins (FABPs) are small intracellular proteins that coordinate lipid-mediated processes by targeting metabolic and immune response pathways. The aim of the study was to investigate plasma FABPs levels and their relationship with clinical outcomes in cirrhosis. Plasma levels of L-FABP1(liver and kidney), I-FABP2(intestine), and A-FABP4(adipocyte and macrophages) were measured in 274 patients with decompensated cirrhosis. Hepatic gene expression of FABPs was assessed in liver biopsies from patients with decompensated cirrhosis and in liver cell types from mice with cirrhosis. Immunohistochemistry of A-FABP4 in human liver biopsy was also performed. Plasma levels of FABPs were increased in patients with decompensated cirrhosis compared to those of healthy subjects (L-FABP1: 25 (17–39) vs 10 (9–17) ng/mL p = 0.001, I-FABP2: 1.1 (0.5–2.1) vs 0.6 (0.4–1) ng/mL p = 0.04 and A-FABP4: 37 (20–68) vs 16 (11–33) ng/mL p = 0.002), respectively. Increased A-FABP4 levels were associated with complications of cirrhosis, acute-on-chronic liver failure and poor survival. Hepatic A-FABP4 gene expression was upregulated in decompensated cirrhosis. Macrophages were the main liver cell that over-expressed A-FABP4 in experimental cirrhosis and increased A-FABP4 was found in macrophages of human biopsies by immunohistochemistry. A-FABP4 levels are increased in decompensated cirrhosis and correlate with poor outcomes. Liver macrophages appear to be the main source of A-FABP4 in decompensated cirrhosis.

Plasma copeptin as biomarker of disease progression and prognosis in cirrhosis

BACKGROUND & AIMS Research on vasopressin (AVP) in cirrhosis and its role in the assessment of prognosis has been hindered by the difficulty of measuring AVP levels accurately. Copeptin, a 39-aminoacid glycopeptide, is released from the neurohypophysis together with AVP. Copeptin could have a role as biomarker of prognosis in cirrhosis as it may reflect circulatory dysfunction. The aim of this study is to investigate the role of copeptin as biomarker of disease progression and prognosis in cirrhosis. METHODS This prospective study is divided in 2 study protocols including 321 consecutive patients. Plasma copeptin levels were measured in all patients at study inclusion. Protocol 1: to investigate the relationship of copeptin with kidney and circulatory function (56 patients). Protocol 2: to investigate the relationship between copeptin and prognosis, as assessed by the development of complications of cirrhosis or mortality at 3months (265 patients admitted to hospital for complications of cirrhosis). RESULTS Patients with decompensated cirrhosis showed significantly higher plasma copeptin levels compared to those of patients with compensated cirrhosis. Copeptin levels had a significant positive correlation with model for end-satge liver disease (MELD) score, AVP, endogenous vasoconstrictor systems, and kidney function parameters. Patients developing complications of cirrhosis or mortality had significantly higher plasma copeptin levels compared to those of the remaining patients. Plasma copeptin levels were an independent predictive factor of both the development of complications and mortality at 3months. This was confirmed in a validation series of 120 patients. CONCLUSIONS Copeptin is a novel biomarker of disease progression and prognosis in cirrhosis. LAY SUMMARY Copeptin is a fragment of the vasopressin precursor, a hormone that is known to be increased in patients with cirrhosis and that plays a role in the development of complications of the disease. Vasopressin is difficult to measure, but copeptin is a more stable molecule and is easier to measure in blood. Solà and Kerbert and colleagues have shown in a series of 361 patients that copeptin is markedly increased in patients with cirrhosis who develop complications during the following 3months, compared to those patients who do not develop complications. Moreover, copeptin correlates with prognosis.

Effects of alfapump™ system on kidney and circulatory function in patients with cirrhosis and refractory ascites

The alfapump system has been proposed as a new treatment for the management of refractory ascites. The system removes ascites from the peritoneal cavity to urinary bladder, producing a continuous low‐volume paracentesis. The aim of the study is to investigate the effects of treatment with the alfapump™ system on kidney and circulatory function in patients with cirrhosis and refractory ascites. This was a prospective study including 10 patients with cirrhosis and refractory ascites. Primary outcomes were changes in glomerular filtration rate (GFR), as assessed by isotopic techniques, and changes in circulatory function assessed by arterial pressure, cardiac output, and activity of vasoconstrictor systems. Secondary outcomes were the need for large‐volume paracentesis and adverse events. Follow‐up was 1 year. GFR decreased significantly from 67 mL/minute/1.73 m2 (41‐90 mL/minute/1.73 m2) at baseline to 45 mL/minute/1.73 m2 (36‐74 mL/minute/1.73 m2) at month 6 (P = 0.04). Mean arterial pressure and cardiac output did not change significantly; however, there was a marked increase in plasma renin activity and norepinephrine concentration (median percent increase with respect to baseline +191% and 59%, respectively). There were 68 episodes of complications of cirrhosis in 8 patients during follow‐up, the most frequent being acute kidney injury. In conclusion, treatment with alfapump™ system was associated with marked activation of endogenous vasoconstrictor systems and impairment of kidney function. The chronological relationship observed between kidney impairment and vasoconstrictor systems activation after device insertion suggests a cause‐effect relationship, raising the possibility that treatment with alfapump impairs effective arterial blood volume mimicking a postparacentesis circulatory dysfunction syndrome. In this context, the potential role of albumin in counteracting these effects should be investigated in future studies. Liver Transplantation 23 583–593 2017 AASLD.

Translating Our Current Understanding of Ascites Management into New Therapies for Patients with Cirrhosis and Fluid Retention

Ascites is the most common complication associated with cirrhosis resulting in poor quality of life, high risk of development of other complications of cirrhosis, increased morbidity and mortality associated with surgical interventions, and poor long-term outcome. Patients with cirrhosis and a first onset of ascites, have a probability of survival of 85% during the first year and 56% at 5 years without liver transplantation. Ascites is caused due to increased renal sodium retention as a result of increased activity of the renin-angiotensin-aldosterone system in response to marked vasodilation of the splanchnic circulation. The practical management of ascites involves the proper evaluation of a patient with a thorough history and physical exam. In addition, complete laboratory, ascitic fluid, and radiological tests should be performed. One of the most important steps in the initial assessment of patients with ascites is to refer the appropriate candidates for liver transplantation, as it offers a definitive cure for cirrhosis and its complications. While the initial management of uncomplicated ascites with low sodium diet and diuretic treatment is straightforward in a majority of patients, approximately 10% of patients fail to respond to diuretics and become a real therapeutic challenge. The initial treatment of choice in patients with refractory ascites is large-volume paracentesis (LVP) associated with intravenous albumin; some patients also benefit from transjugular intrahepatic portosystemic shunts (TIPS). When repeated LVP or TIPS cannot be performed, other approaches using vasoconstrictors such as midodrine can be considered although data are scarce. A newly designed automated low flow pump system (Alfapump), which is designed to move ascites from the peritoneal cavity to the urinary bladder where it is eliminated spontaneously through diuresis is promising, but the data are also limited and safety is still a matter of concern. This article focuses on the practical aspects of the evaluation and treatment of patients with ascites and cirrhosis and also discusses how to translate our current understanding of ascites pathophysiology into new treatment methods for patients with fluid retention.

Urine Monocyte Chemoattractant Protein-1 Is an Independent Predictive Factor of Hospital Readmission and Survival in Cirrhosis

MCP-1 (monocyte chemoattractant protein-1) is a proinflammatory cytokine involved in chemotaxis of monocytes. In several diseases, such as acute coronary syndromes and heart failure, elevated MCP-1 levels have been associated with poor outcomes. Little is known about MCP-1 in cirrhosis. AIM: To investigate the relationship between MCP-1 and outcome in decompensated cirrhosis. METHODS: Prospective study of 218 patients discharged from hospital after an admission for complications of cirrhosis. Urine and plasma levels of MCP-1 and other urine proinflammatroy biomarkers: osteopontin(OPN), trefoil-factor3 and liver-fatty-acid-binding protein were measured at admission. Urine non-inflammatory mediators cystatin-C, β2microglobulin and albumin were measured as control biomarkers. The relationship between these biomarkers and the 3-month hospital readmission, complications of cirrhosis, and mortality were assessed. RESULTS: 69 patients(32%) had at least one readmission during the 3-month period of follow-up and 30 patients died(14%). Urine MCP-1 and OPN levels, were associated with 3-month probability of readmission (0.85 (0.27–2.1) and 2003 (705–4586) ug/g creat vs 0.47 (0.2–1.1) and 1188 (512–2958) ug/g creat, in patients with and without readmission, respectively; p<0.05; median (IQR)). Furthermore, urine levels of MCP-1 were significantly associated with mortality (1.01 (1–3.6) vs 0.5 (0.2–1.1) μg/g creat, in dead and alive patients at 3 months; p<0.05). Patients with higher levels of urine MCP-1 (above percentile 75th) had higher probability of development of hepatic encephalopathy, bacterial infections or AKI. Urine MCP-1 was an independent predictive factor of hospital readmission and combined end-point of readmission or dead at 3 months. Plasma levels of MCP-1 did not correlated with outcomes. CONCLUSION: Urine, but not plasma, MCP-1 levels are associated with hospital readmission, development of complications of cirrhosis, and mortality. These results suggest that in cirrhosis there is an inflammatory response that is associated with poor outcomes.