Efficacy and safety of mycophenolate mofetil and tacrolimus as second-line therapy for patients with autoimmune hepatitis

Background: Predniso(lo)ne, alone or in combination with azathioprine, is the standard of care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH. Patients and methods: We performed a retrospective study of data (from 19 centres in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6–190 months). Patients were categorized according to their response to SOC. Patients in group 1 (n=108) had a complete response to the SOC, but were switched to second line therapy due to side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n=93) had not responded to SOC. Results: There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P=.639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P=.682). Significantly more group 2 patients given tacrolimus compared to MMF had a complete response (56.5 % vs. 34%, P=.029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P=.472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. Conclusions: Long-term therapy with MMF or tacrolimus was generally well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous non-responder patients compared to MMF

Review Article: Pregnancy and CVD Risk Factors

Elevated concentrations of total cholesterol, particular lipoproteins (e.g., LDL) and homocysteine are risk factors for cardiovascular disease and vascular dysfunction that can adversely affect the health of a pregnant woman and her fetus. Although it has been documented in many populations worldwide that the serum total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglyceride levels increase substantially by the third trimester, there are few reports of the levels of these risk factors in pregnant women in sub-Saharan Africa. We therefore compared the levels of these lipids and homocysteine in the serum of third-trimester pregnant women (n=18) and healthy, age-matched non-pregnant controls (n=38) in Abuja, Nigeria. Relative to the controls, the following substances were significantly elevated in the pregnant women: total cholesterol, 212 vs. 191 mg/dL (p=0.02); triglycerides, 153 vs. 89.5 mg/dL (p=0.004); and HDL, 67.0 vs. 56.6 mg/dL (p=0.004). The mean LDL-cholesterol levels of the pregnant (116 mg/dL) and non-pregnant controls (110 mg/dL) were not significantly different. However, the mean homocysteine concentration of the pregnant women was about 30% lower compared with the control group (7.1 vs. 10.1 mol/L,

Serum Lipid Profiles, Homocysteine Levels And Cardiovascular Disease Risk In Pregnant Nigerian Women

Objectives: To compare the levels of lipids and homocysteine in the serum of third- trimester pregnant women and health , age –matched non pregnant controls. Methods: We compared the levels of these lipids {total cholesterol, particularly lipoproteins such as LDL} and homocysteine in the serum of third- trimester pregnant women healthy, age –matched non –pregnant controls. Blood samples were obtained by venipuncture and the samples were allowed to clot at room temperature for 45 minutes before centrifugation to separate the serum. Result: Compared to the controls, the following substances were significantly elevated in the pregnant women: total cholesterol, 212vs.191mg/dL{p=0.02}; triglycerides, 153vs. 89.5 mg/dL{p=0.004};and hdL,67.0vs.56.6 mg/dL{p=.004}.the mean LDL-cholesterol levels of the pregnant {116mg/dL}and non pregnant controls{110mg/dLwere not significantly different. However, the mean homocysteine concentration of the pregnant women was about 30% lower compared with the controls group {7.1vs.10.1m01/L,

Limited performance of subjective global assessment compared to computed tomography-determined sarcopenia in predicting adverse clinical outcomes in patients with cirrhosis.

BACKGROUND & AIMS The subjective global assessment (SGA) is commonly used to assess nutritional status in patients with cirrhosis. Sarcopenia, a major component of malnutrition, is associated with survival in cirrhosis, and can be objectively diagnosed by computing the skeletal muscle index (SMI) using cross-sectional imaging. The aim of this study was to assess the prevalence of sarcopenia between SGA categories in patients with cirrhosis, and to determine their association with decompensation/mortality. METHODS We included 315 patients (66% males) who were assessed for liver transplantation. All patients had SGA and SMI, and were evaluated for the presence of hepatic encephalopathy (HE) and ascites. RESULTS Mean age was 54 ± 8 years. SGA categories were 126 SGA A (40%), 155 SGA B (49%), 34 SGA C (11%). Sarcopenia was present in 121 (38%) patients; of these, 82% were SGA A/B. Of SGA A patients, 25 (20%) had sarcopenia. There was a significant but only weak concordance between sarcopenia and SGA B/C (κ = 0.28, p < 0.001), and SGA C (κ = 0.13, p < 0.001). The latter was lost in overweight/obese patients. SGA B/C was associated with HE (OR 2.8, p = 0.01) and ascites (OR 2.3, p = 0.002). Median survival was shorter in patients with sarcopenia (20 [IQR 15.9-24.5] vs. 42 [IQR: 25.8-58.9] months, p < 0.001) and in SGA C patients (9.4 [IQR: 0-26.2] vs. 33 [IQR 20.2-45.7] months, p = 0.01). In univariate analysis both sarcopenia and SGA C were associated with mortality, but sarcopenia was the only factor that remained significant on multivariate analysis. CONCLUSIONS There was only a weak concordance between SGA and sarcopenia. This concordance was non-significant in patients who were overweight/obese. Sarcopenia was associated with mortality, whereas SGA was not. Sarcopenia by the SMI is a more efficient method to predict adverse outcomes in a timely fashion and has prognostic implications

Sarcopenia Severity Based on Computed Tomography Image Analysis in Patients with Cirrhosis

Standardized sex-specific cut-offs for sarcopenia in cirrhosis are needed to identify the risk of clinical complications and to discriminate the severity of sarcopenia. We aimed to compare clinical characteristics between patients with cirrhosis categorized according to the severity of sarcopenia. Computed tomography images were taken at the 3rd lumbar vertebra from 603 patients with cirrhosis and 129 adult donors for living liver transplantation. Patients with skeletal muscle index (SMI) two standard deviations (SD) below the sex-specific mean value of young donors (18&ndash;40 years old) were categorized as having severe sarcopenia whereas patients with SMI between &minus;1 and &minus;2 SD of the sex-specific young adult mean values were categorized as having sarcopenia. In the cirrhosis group, 408 patients (68%) were male with the mean age of 57 &plusmn; 0.4 years, and MELD score of 14 &plusmn; 0.4. Patients were divided into three groups: severe-sarcopenic (SMI &lt; 30 cm2/m2 in females and &lt;42 cm2/m2 in males), sarcopenic (30 &le; SMI &lt; 37 cm2/m2 in females and 42 &le; SMI &lt; 50 cm2/m2 in males) and non-sarcopenic (SMI &ge; 37 cm2/m2 in females and &ge;50 cm2/m2 in males). Patients with cirrhosis and severe sarcopenia had lower muscle radiodensity and higher plasma neutrophil as well as neutrophil to lymphocyte ratio levels than both non- and sarcopenic groups. The frequency of alcohol-induced cirrhosis, refractory ascites, hepatic encephalopathy, CRP &gt; 20 mg/mL, and severe malnutrition was also higher in severe-sarcopenic patients. The interval between sarcopenia and severe sarcopenia may reflect a window of opportunity in which to intervene and mitigate muscle wasting to improve patient outcomes

Association between gut colonization of vancomycin-resistant enterococci and liver transplant outcomes

Background: Vancomycin-resistant enterococci (VRE) colonization is common in liver transplant recipients and has been associated with worse post-transplant outcomes. Methods: We conducted a retrospective cohort study at the University of Alberta Hospital including patients who underwent a liver transplant between September 2014 and December 2017. Results: Of 343 patients, 68 (19.8%) had pre-transplant VRE colonization and 27 (27/275, 9.8%) acquired VRE post-transplant, 67% were males and the median age was 56.5 years. VRE colonized patients at baseline had higher MELD scores and required longer post-transplant hospitalization. VRE colonization was associated with increased risk of early acute kidney injury (AKI) (64% vs 52%, p = 0. 044), clinically significant bacterial/fungal infection (29% vs 17%, p = 0. 012) and invasive VRE infection (5% vs 1%, p = 0. 017). Mortality at 2-years was 13% in VRE-colonized versus 7% in non-colonized (p = 0.085). On multivariate analysis, VRE colonization increased the risk of post-transplant AKI (HR 1.504, 95% CI: 1.077-2.100, p = 0.017) and clinically significant bacterial or fungal infection at 6 months (HR 2.038, 95%CI: 1.222-3.399, p = 0.006), and was associated with non-significant trend towards increased risk of mortality at 2-years post-transplant (HR 1.974 95% CI 0.890-4.378; p = 0.094). Conclusions: VRE colonization in liver transplant patients is associated with increased risk of early AKI, clinically significant infections, and a trend towards increased mortality at 2-years

Skeletal Muscle Pathological Fat Infiltration (Myosteatosis) Is Associated with Higher Mortality in Patients with Cirrhosis

Myosteatosis (pathological fat accumulation in muscle) is defined by lower mean skeletal muscle radiodensity in CT. We aimed to determine the optimal cut-offs for myosteatosis in a cohort of 855 patients with cirrhosis. CT images were used to determine the skeletal muscle radiodensity expressed as Hounsfield Unit (HU). Patients with muscle radiodensity values below the lowest tertile were considered to have myosteatosis. Competing-risk analysis was performed to determine associations between muscle radiodensity and pre-transplant mortality. Muscle radiodensity less than 33 and 28 HU in males and females, respectively, were used as cut-offs to identify myosteatosis. In the univariate analysis, cirrhosis etiology, MELD score, refractory ascites, variceal bleeding, hepatic encephalopathy, sarcopenia and myosteatosis were predictors of mortality. Myosteatosis association with mortality remained significant after adjusting for confounding factors (sHR 1.47, 95% CI 1.17&ndash;1.84, p = 0.001). Patients with concurrent presence of myosteatosis and sarcopenia constituted 17% of the patient population. The cumulative incidence of mortality was the highest in patients with concomitant sarcopenia and myosteatosis (sHR 2.22, 95% CI 1.64&ndash;3.00, p &lt; 0.001). In conclusion, myosteatosis is common in patients with cirrhosis and is associated with increased mortality. The concomitant presence of myosteatosis and sarcopenia is associated with worse outcomes

Myosteatosis in Cirrhosis: A Review of Diagnosis, Pathophysiological Mechanisms and Potential Interventions

Myosteatosis, or pathological excess fat accumulation in muscle, has been widely defined as a lower mean skeletal muscle radiodensity on computed tomography (CT). It is reported in more than half of patients with cirrhosis, and preliminary studies have shown a possible association with reduced survival and increased risk of portal hypertension complications. Despite the clinical implications in cirrhosis, a standardized definition for myosteatosis has not yet been established. Currently, little data exist on the mechanisms by which excess lipid accumulates within the muscle in individuals with cirrhosis. Hyperammonemia may play an important role in the pathophysiology of myosteatosis in this setting. Insulin resistance, impaired mitochondrial oxidative phosphorylation, diminished lipid oxidation in muscle and age-related differentiation of muscle stem cells into adipocytes have been also been suggested as potential mechanisms contributing to myosteatosis. The metabolic consequence of ammonia-lowering treatments and omega-3 polyunsaturated fatty acids in reversing myosteatosis in cirrhosis remains uncertain. Factors including the population of interest, design and sample size, single/combined treatment, dosing and duration of treatment are important considerations for future trials aiming to prevent or treat myosteatosis in individuals with cirrhosis

Skeletal Muscle Pathological Fat Infiltration (Myosteatosis) Is Associated with Higher Mortality in Patients with Cirrhosis

Myosteatosis (pathological fat accumulation in muscle) is defined by lower mean skeletal muscle radiodensity in CT. We aimed to determine the optimal cut-offs for myosteatosis in a cohort of 855 patients with cirrhosis. CT images were used to determine the skeletal muscle radiodensity expressed as Hounsfield Unit (HU). Patients with muscle radiodensity values below the lowest tertile were considered to have myosteatosis. Competing-risk analysis was performed to determine associations between muscle radiodensity and pre-transplant mortality. Muscle radiodensity less than 33 and 28 HU in males and females, respectively, were used as cut-offs to identify myosteatosis. In the univariate analysis, cirrhosis etiology, MELD score, refractory ascites, variceal bleeding, hepatic encephalopathy, sarcopenia and myosteatosis were predictors of mortality. Myosteatosis association with mortality remained significant after adjusting for confounding factors (sHR 1.47, 95% CI 1.17&ndash;1.84, p = 0.001). Patients with concurrent presence of myosteatosis and sarcopenia constituted 17% of the patient population. The cumulative incidence of mortality was the highest in patients with concomitant sarcopenia and myosteatosis (sHR 2.22, 95% CI 1.64&ndash;3.00, p &lt; 0.001). In conclusion, myosteatosis is common in patients with cirrhosis and is associated with increased mortality. The concomitant presence of myosteatosis and sarcopenia is associated with worse outcomes

Tacrolimus and Mycophenolate Mofetil as Second-Line Therapies for Pediatric Patients with Autoimmune Hepatitis

Background: We studied the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy in pediatric patients with autoimmune hepatitis (AIH) who were intolerant or non-responders to standard therapy (corticosteroid and azathioprine). Patients and Methods: We performed a retrospective study of data from 13 centers in Europe, USA, and Canada. Thirty-eight patients (< 18\ua0years old) who received second-line therapy (18 MMF and 20 tacrolimus), for a median of 72\ua0months (range 8\u2013182) were evaluated. Patients were categorized into two groups: Group 1 (n = 17) were intolerant to corticosteroid or azathioprine, and group 2 (n = 21) were non-responders to standard therapy. Results: Overall complete response rates were similar in patients treated with MMF and tacrolimus (55.6 vs. 65%, p = 0.552). In group 1, MMF and tacrolimus maintained a biochemical remission in 88.9 and 87.5% of patients, respectively (p = 0.929). More patients in group 2 given tacrolimus compared to MMF had a complete response, but the difference was not statistically significant (50.0 vs. 22.2%, p = 0.195). Biochemical remission was achieved in 71.1% (27/38) of patients by tacrolimus and/or MMF. Decompensated cirrhosis was more commonly seen in MMF and/or tacrolimus non-responders than in responders (45.5 vs. 7.4%, p = 0.006). Five patients who received second-line therapy (2 MMF and 3 tacrolimus) developed side effects that led to therapy withdrawal. Conclusions: Long-term therapy with MMF or tacrolimus was generally well tolerated by pediatric patients with AIH. Both MMF and tacrolimus had excellent efficacy in patients intolerant to corticosteroid or azathioprine. Tacrolimus might be more effective than MMF in patients failing previous therapy