Long-term albumin improves the outcomes of patients with decompensated cirrhosis and diabetes mellitus: Post hoc analysis of the ANSWER trial.

Type-2 diabetes mellitus is a frequent comorbidity of cirrhosis independently associated with cirrhosis-related complications and mortality. This post hoc analysis of the ANSWER trial database assessed the effects of long-term human albumin (HA) administration on top of the standard medical treatment (SMT) on the clinical outcomes of a subgroup of 85 outpatients with liver cirrhosis, uncomplicated ascites and insulin-treated diabetes mellitus type 2 (ITDM). Compared to patients in the SMT arm, the SMT + HA group showed a better overall survival (86% vs. 57%, p = .016) and lower incidence rates of paracenteses, overt hepatic encephalopathy, bacterial infections, renal dysfunction and electrolyte disorders. Hospital admissions did not differ between the two arms, but the number of days spent in hospital was lower in the SMT + HA group. In conclusion, in a subgroup of ITDM outpatients with decompensated cirrhosis and ascites, long-term HA administration was associated with better survival and a lower incidence of cirrhosis-related complications.

The Role of Transjugular Intrahepatic Portosystemic Shunt for the Management of Ascites in Patients with Decompensated Cirrhosis.

The development and progression of ascites represent a crucial event in the natural history of patients with cirrhosis, predisposing them to other complications and carrying a heavy impact on prognosis. The current standard of care for the management of ascites relies on various combinations of diuretics and large-volume paracenteses. Periodic long-term albumin infusions on top of diuretics have been recently shown to greatly facilitate the management of ascites. The insertion of a transjugular intrahepatic portosystemic shunt (TIPS), an artificial connection between the portal and caval systems, is indicated to treat patients with refractory ascites. TIPS acts to decrease portal hypertension, thus targeting an upstream event in the pathophysiological cascade of cirrhosis decompensation. Available evidence shows a significant benefit on ascites control/resolution, with less clear results on patient survival. Patient selection plays a crucial role in obtaining better clinical responses and avoiding TIPS-related adverse events, the most important of which are hepatic encephalopathy, cardiac overload and failure, and liver failure. At the same time, some recent technical evolutions of available stents appear promising but deserve further investigations. Future challenges and perspectives include (i) identifying the features for selecting the ideal candidate to TIPS; (ii) recognizing the better timing for TIPS placement; and (iii) understanding the most appropriate role of TIPS within the framework of all other available treatments for the management of patients with decompensated cirrhosis.

Predictors of clinical trajectories of patients with acutely decompensated cirrhosis. An external validation of the PREDICT study.

BACKGROUND AND AIMS: The PREDICT study recently showed that acutely decompensated (AD) patients with cirrhosis can present three different clinical phenotypes in the 90 days after admission: (1) pre-ACLF, developing acute-on-chronic liver failure (ACLF); (2) unstable decompensated cirrhosis (UDC), being re-admitted for AD without ACLF and (3) stable decompensated cirrhosis (SDC), not presenting readmission or ACLF. This study aimed to externally validate the existence of these three distinct trajectories and to identify predictors for the occurrence of each trajectory. METHODS: Baseline data, 3-month ACLF and readmission incidence and 1-year survival were analysed in a prospective cohort of patients admitted for AD. A multinomial multivariable model was used to evaluate the association between baseline features and clinical trajectories. RESULTS: Of the 311 patients enrolled, 55% met the criteria for SDC, 18% for UDC and 27% for pre-ACLF, presenting a significantly different 1-year mortality: pre-ACLF 65%, UDC 46%, SDC 21% (p < .001). The presence of hepatic encephalopathy (HE) was associated with UDC (p = .043), while the absence of ascites to SDC (p = .017). Among laboratory parameters, an increase in MELD-Na (p = .001) and C-reactive protein (p = .009) and a decrease in haemoglobin (p = .004) and albumin (p = .008) levels were associated with pre-ACLF. CONCLUSION: The present study confirms that AD patients have three different clinical trajectories with different mortality rates. Besides the severity of cirrhosis, the association with C-reactive protein supports the predominant role of systemic inflammation in ACLF pathophysiology. Finally, HE is associated with the UDC phenotype highlighting the need for better management of this complication after discharge.

Albumin administration in internal medicine: A journey between effectiveness and futility.

Albumin is the most abundant circulating protein and provides about 70% of the plasma oncotic power. The molecule also carries many other biological functions (binding, transport and detoxification of endogenous and exogenous compounds, antioxidation, and modulation of inflammatory and immune responses). Hypoalbuminemia is a frequent finding in many diseases, representing usually only a biomarker of poor prognosis rather than a primary pathophysiological event. Despite that, albumin is prescribed in many conditions based on the assumption that correction of hypoalbuminemia would lead to clinical benefits for the patients. Unfortunately, many of these indications are not supported by scientific evidence (or have been even disproved), so that a large part of albumin use is nowadays still inappropriate. Decompensated cirrhosis is the clinical area where albumin administration has been extensively studied and solid recommendations can be made. Besides prevention and treatment of acute complications, long-term albumin administration in patients with ascites has emerged in the last decade has a potential new disease-modifying treatment. In non-hepatological settings, albumin is widely used for fluid resuscitation in sepsis and critical illnesses, with no clear superiority over crystalloids. In many other conditions, scientific evidence supporting albumin prescription is weak or even absent. Thus, given its high cost and limited availability, action is needed to avoid the use of albumin for inappropriate and futile indications to ensure its availability in those conditions for which albumin has been demonstrated to have a real effectiveness and an advantage for the patient.

Low haemoglobin level predicts early hospital readmission in patients with cirrhosis and acute decompensation.

Background & Aims: Patients with decompensated cirrhosis present frequent hospitalisations with a relevant clinical and socio-economic impact. This study aims to characterise unscheduled readmissions up to 1-year follow-up and identify predictors of 30-day readmission after an index hospitalisation for acute decompensation (AD). Methods: We performed a secondary analysis of a prospectively collected cohort of patients admitted for AD. Laboratory and clinical data at admission and at discharge were collected. Timing and causes of unscheduled readmissions and mortality were recorded up to 1 year. Results: A total of 329 patients with AD were included in the analysis. Acute-on-chronic liver failure was diagnosed in 19% of patients at admission or developed in an additional 9% of patients during the index hospitalisation. During the 1-year follow-up, 182 patients (55%) were rehospitalised and 98 (30%) more than once. The most frequent causes of readmission were hepatic encephalopathy (36%), ascites (22%), and infection (21%). Cumulative incidence of readmission was 20% at 30 days, 39% at 90 days, and 63% at 1 year. Fifty-four patients were readmitted for emergent liver-related causes within 30 days. Early readmission was associated with a higher 1-year mortality (47 vs. 32%, p = 0.037). Multivariable Cox regression analysis showed that haemoglobin (Hb) ≤8.7 g/dl (hazard ratio 2.63 [95% CI 1.38-5.02], p = 0.003) and model for end-stage liver disease-sodium score (MELD-Na) >16 at discharge (hazard ratio 2.23 [95% CI 1.27-3.93], p = 0.005), were independent predictors of early readmission. In patients with MELD-Na >16 at discharge, the presence of Hb ≤8.7 g/dl doubles the risk of early rehospitalisation (44% vs. 22%, p = 0.02). Conclusion: Besides MELD-Na, a low Hb level (Hb ≤8.7 g/dl) at discharge emerged as a new risk factor for early readmission, contributing to identification of patients who require closer surveillance after discharge. Impact and Implications: Patients with decompensated cirrhosis face frequent hospitalisations. In the present study, type and causes of readmissions were analysed during 1-year follow-up in patients discharged after the index hospitalisation for an acute decompensation of the disease. Early (30-day) liver-related readmission was associated with higher 1-year mortality. The model for end-stage liver disease-sodium score and low haemoglobin at discharge were identified as independent risk factors for early readmissions. Haemoglobin emerged as a new easy-to-use parameter associated with early readmission warranting further investigation.

A case of peri­stomal ectopic variceal bleeding in a patient with decompensated cirrhosis treated with TIPS placement.

Peri-stomal variceal bleeding is an underestimated complication in patients with colostomy and portal hypertension. Due to the small number of reported cases, there is currently no unified consensus on the best treatment and several options may be available. We report a case in which TIPS placement was effective.

The Role of New Technological Opportunities and the Need to Evaluate the Activities Performed in the Prevention of Diabetic Foot with Exercise Therapy.

The diabetic foot (DF) is one of the most feared conditions among chronic complications of diabetes, which affects a growing number of patients. Although exercise therapy (ET) has always been considered a pillar in the treatment of patients at risk of DF it is not usually used. Several causes can contribute to hindering both the organization of ET protocols for Diabetes Units and the participation in ET programs for patients at different levels of risk of foot ulceration. The risk of favoring the occurrence of ulcers and the absence of clear evidence on the role played by ET in the prevention of ulcers could be considered among the most important causes leading to the low application of ET. The increased availability of new technologies and in particular of systems and devices equipped with sensors can enable the remote monitoring and management of physical activity performed by patients. Consequently, they can become an opportunity for introducing the systematic use of ET for the treatment of patients at risk. Considering the complexity of the clinical conditions that patients at risk or with diabetic foot ulcer can show, the evaluation of how patients perform the ET proposed can consequently be very important. All this can contribute to improving the treatment of patients and avoiding possible adverse effects. The aim of this brief review was to describe that the use of new technologies and the assessment of the execution of the ET proposed allows an important step forward in the management of patients at risk.

Management of Ascites in Patients with Cirrhosis: An Update.

Ascites represents a critical event in the natural history of liver cirrhosis. From a prognostic perspective, its occurrence marks the transition from the compensated to the decompensated stage of the disease, leading to an abrupt worsening of patients' life expectancy. Moreover, ascites heralds a turbulent clinical course, characterized by acute events and further complications, frequent hospitalizations, and eventually death. The pathophysiology of ascites classically relies on hemodynamic mechanisms, with effective hypovolemia as the pivotal event. Recent discoveries, however, integrated this hypothesis, proposing systemic inflammation and immune system dysregulation as key mechanisms. The mainstays of ascites treatment are represented by anti-mineralocorticoids and loop diuretics, and large volume paracentesis. When ascites reaches the stage of refractoriness, however, diuretics administration should be cautious due to the high risk of adverse events, and patients should be treated with periodic execution of paracentesis or with the placement of a trans-jugular intra-hepatic portosystemic shunt (TIPS). TIPS reduces portal hypertension, eases ascites control, and potentially modify the clinical course of the disease. Further studies are required to expand its indications and improve the management of complications. Long-term human albumin administration has been studied in two RCTs, with contradictory results, and remains a debated issue worldwide, despite a potential effectiveness both in ascites control and long-term survival. Other treatments (vaptans, vasoconstrictors, or implantable drainage systems) present some promising aspects but cannot be currently recommended outside clinical protocols or a case-by-case evaluation.

Continuous Movement Monitoring of Daily Living Activities for Prevention of Diabetic Foot Ulcer: A Review of Literature.

Lower extremity ulcers represent the most ominous, feared, and costly complications of diabetes mellitus. The aim of this review is to highlight the role of daily life physical activities (PAs) and continuous movement monitoring (CMM) in the prevention of foot ulcers. Peripheral neuropathy and peripheral vascular disease are the main causes of foot ulceration and contribute, in turn, to the development of additional risk factors such as foot deformities and/or joint and muscular alterations. Moreover, a deficit of balance, posture abnormalities, followed by gait alterations, increases the risk of ulceration. PA can play a key role in the management of patients with diabetes and in the prevention of ulcers; however, even if it has been reported that some of these risk factors significantly improve after a few weeks of exercise therapy (ET), the real preventive role of ET has not yet been demonstrated. These uncertain results can occur due to some limitations in the management of the same relationship between PA and diabetic foot prevention. Technological advances during the last years enable timely management of overall daily PA. The use of these modern technologies and devices allows CMM assessment and description of daily PA even in the long term. The data collected from these devices can be used to properly manage patients' PA and thus contribute to the prevention of foot ulcers.

Prediction of nosocomial acute-on-chronic liver failure in patients with cirrhosis admitted to hospital with acute decompensation.

Nosocomial acute-on-chronic liver failure (nACLF) develops in at least 10% of patients with cirrhosis hospitalized for acute decompensation (AD), greatly worsening their prognosis. In this prospective observational study, we aimed to identify rapidly obtainable predictors at admission, which allow for the early recognition and stratification of patients at risk of nACLF. METHODS: A total of 516 consecutive patients hospitalized for AD of cirrhosis were screened: those who did not present ACLF at admission (410) were enrolled and surveilled for the development of nACLF. RESULTS: Fifty-nine (14%) patients developed nALCF after a median of 7 (IQR 4-18) days. At admission, they presented a more severe disease and higher degrees of systemic inflammation and anemia than those (351; 86%) who remained free from nACLF. Competing risk multivariable regression analysis showed that baseline MELD score (sub-distribution hazard ratio [sHR] 1.15; 95% CI 1.10-1.21; p ≪0.001), hemoglobin level (sHR 0.81; 95% CI 0.68-0.96; p = 0.018), and leukocyte count (sHR 1.11; 95% CI 1.06-1.16; p ≪0.001) independently predicted nACLF. Their optimal cut-off points, determined by receiver-operating characteristic curve analysis, were: 13 points for MELD score, 9.8 g/dl for hemoglobin, and 5.6x109/L for leukocyte count. These thresholds were used to stratify patients according to the cumulative incidence of nACLF, being 0, 6, 21 and 59% in the presence of 0, 1, 2 or 3 risk factors (p ≪0.001). Nosocomial bacterial infections only increased the probability of developing nACLF in patients with at least 1 risk factor, rising from 3% to 29%, 16% to 50% and 52% to 83% in patients with 1, 2 or 3 risk factors, respectively. CONCLUSIONS: Easily available laboratory parameters, related to disease severity, systemic inflammation, and anemia, can be used to identify, at admission, hospitalized patients with AD at increased risk of developing nACLF. LAY SUMMARY: More than 10% of patients with cirrhosis hospitalized because of an acute decompensation develop acute-on-chronic liver failure, which is associated with high short-term mortality, during their hospital stay. We found that the combination of 3 easily obtainable variables (model for end-stage liver disease score, leukocyte count and hemoglobin level) help to identify and stratify patients according to their risk of developing nosocomial acute-on-chronic liver failure, from nil to 59%. Moreover, if a nosocomial bacterial infection occurs, such an incidence proportionally increases from nil to 83%. This simple approach helps to identify patients at risk of developing nosocomial acute-on-chronic liver failure at admission to hospital, enabling clinicians to put in place preventive measures.

Glycemic Control Maintained over Time and Joint Stiffness in Young Type 1 Patients: What Is the Mathematical Relationship?

BACKGROUND: It is widely known that diabetes can induce stiffness and adversely affect joint mobility even in young patients with type 1 diabetes mellitus (T1D). The aim of this study was to identify a mathematical model of diabetes mellitus long-term effects on young T1D patients. METHODS: Ankle joint mobility (AJM) was evaluated using an inclinometer in 48 patients and 146 healthy, sex- BMI-, and age-matched controls. Assuming time invariance and linear superposition of the effects of hyperglycemia, the influence of T1D on AJM was formalized as an impulse response putting into relationship past supernormal HbA1c concentrations with the ankle total range of motion. The proposed model was identified by means of a nonlinear evolutionary optimization algorithm. RESULTS: AJM was significantly reduced in young T1D patients (P < .001). AJM in both plantar and dorsiflexion was significantly lower in subjects with diabetes than in controls (P < .001). The identified impulse response indicates that impaired metabolic control requires 3 months to bring out its maximum effect on the reduction of AJM, while the following long-lasting decay phase with the expected AJM recovery times, normally depends on the slow turnover of collagen. HbA1c concentration levels above 7.2% are sufficient to produce a reduction of ankle ROM. CONCLUSIONS: In young patients with T1D the lack of glycemic control over time affects AJM. HbA1c levels can serve as a relevant prognostic factor for assessing the progression of LJM in subjects with diabetes.

Type 1 diabetes, sport practiced, and ankle joint mobility in young patients: What is the relationship?

BACKGROUND/OBJECTIVE: It is known that patients with diabetes can develop limited joint mobility (LJM) and that this can depend on the metabolic control maintained and the duration of the disease. The aims of this study were to verify the presence of ankle joint mobility (AJM) deficits in both plantar and dorsiflexion in young type 1 diabetic patients (T1D) considering also the possible role of sport practiced as a further factor, able to modify AJM. METHODS: AJM was evaluated by an inclinometer in 82 T1D patients (M/F: 48/34), mean age 12.9 ± 2.6 years, body mass index (BMI) 19.7 ± 3.6 kg/m2 , duration of diabetes 5.6 ± 3.3 years, mean HbA1c 7.5 ± 1.0% and in 226 healthy controls (M/F: 146/80), age-, gender-, and BMI-matched practicing different sports (soccer, volleyball, basketball, and dance). RESULTS: The patients' ankle range of motion was significantly lower than that in controls (132.7 ± 22.3° vs 126.1 ± 17.9°; P < .017). In particular, ankle plantar flexion was significantly lower in the patients group (31.6° ± 7.9° vs 28.5° ± 6.6°; P < .002). Soccer players showed lower AJM in both groups: patients (120.1 ± 15.9° vs 127.3 ± 18.1) and controls (119.4 ± 21.1° vs 142.0 ± 18.1; P < .0001) than subjects practicing other sports or who were sedentary. In both groups, patients and controls, age, sex, duration of disease, hemoglobin 1Ac, and BMI have not been shown to be correlated to the mobility assessed. CONCLUSIONS: The results of this study, in addition to confirming the negative effect of diabetes on AJM of young T1D patients, suggest that during these evaluations the sport-related effect should be considered because it can induce significant changes of AJM.