Mycophenolate mofetil use is associated with reduced incidence of food allergy in liver transplanted children.

OBJECTIVES: The incidence of food allergy in children following liver transplantation is high and the pathogenesis is still not known. We aimed to identify risk factors for development of food allergies in liver transplant children. METHODS: 107 children and adolescents who underwent liver transplantation from 1999 to 2019 were included. Data were retrospectively collected from medical records included total and specific IgE, eosinophil cationic protein and eosinophil count 12 months after transplantation and at yearly follow up (median follow-up). RESULTS: 24/107 (22%) patients reported clinical food reactions. Median time from transplantation to debut of food allergy was 1.6 (IQR 0.6-3.3) years. Mycophenolate mofetil (MMF) was discontinued in 24/78 patients (31%) due to side effects. Children treated with MMF in addition to tacrolimus one year after transplantation reported less food allergy (12.5% vs. 37.8%, p=0.003) and sensitization to food allergens one year after transplantation (8.9% vs. 17.8%, p=0.02) than those not receiving MMF. Tacrolimus trough levels did not differ between the patients treated with MMF and those who were not. Treatment with MMF two years after transplantation was associated with less food allergy (p=0.001) and food sensitization (p=0.002), also when adjusted for age at transplantation (p=0.006 and p=0.03, respectively) or for use of basilixmab (p=0.015 and p=0.018, respectively). Basiliximab was also associated with less food allergy. CONCLUSIONS: Use of MMF one and two years after transplantation was associated with less food allergy and sensitization against food allergens. The effect of MMF was not due to reduced trough levels of of tacrolimus. An infographic is available for this article at: https://links.lww.com/MPG/C821.

Cytokine profile in children with food allergy following liver transplantation.

BACKGROUND: LTX in children is associated with increased risk of food allergy, and the mechanisms underlying this are unknown. We wanted to study whether plasma cytokine profile differed in liver transplanted children, with and without food allergy, and whether it differed from untransplanted children with CLD. METHODS: Plasma cytokines, total and specific IgE in nine patients with food allergy were compared with 13 patients without food allergy following LTX, and also with seven untransplanted patients with CLD. RESULTS: No difference was found in the cytokine profile between liver transplanted patients with and without food allergy. Transplanted patients with food allergy having received a prescription of epinephrine had a significantly higher total IgE (2033 [234-2831] vs 10 [5-41] IU/L, P = .002) and MIP-1b (52 [37-96] vs 36 [32-39], P = .035) compared with transplanted patients without food allergy. Two patients with severe food allergy responded favorably to conversion from tacrolimus-based immunosuppression to MMF and corticosteroids with reduction in clinical symptoms, total IgE, specific IgE, IL-1ra, IL-4, RANTES, PDGF, MIP-1a, and TNFα. The transplantation group had higher levels of IL-1b, IL-5, IL-7, IL-13, GCSF, IFNγ, and MIP-1a compared with the CLD group. CONCLUSIONS: No overall difference was found in plasma cytokine profile between patients with and without food allergy. Patients with severe food allergy had significant elevation of MIP-1b. Discontinuation of tacrolimus reduced total and specific IgE and changed plasma cytokine profile. The plasma cytokine profile in liver transplanted children was different compared with children with CLD.

Asthma, Eczema, and Food Allergy in Children Following Liver Transplantation.

OBJECTIVES: To describe the prevalence and the relationship between asthma, eczema, food allergy, and rhinitis in children after liver transplantation. STUDY DESIGN: Children who were liver transplant recipients were investigated to assess whether the high prevalence of food allergies was accompanied by eczema, rhinitis, and asthma. Furthermore, we included 56 children with chronic liver disease to explore the risk of allergy, eczema, and asthma in this group. RESULTS: After liver transplantation, children had higher prevalence of allergic reactions to food as compared with children with chronic liver disease (P < .001). Current asthma (P = .04) and eczema (P < .02) were observed more frequently in transplanted children as compared with children with chronic liver disease. For transplanted children who had ever received tacrolimus the relative risk (RR) of asthma was 1.7 (95% CI, 1.2-2.4; P = .02) as compared with children with chronic liver disease. Transplanted children with asthma had higher rates of sensitization to food allergens than those without asthma (RR, 3.6; 95% CI, 1.3-10.3; P = .01). The most frequent food allergens associated with asthma in transplanted children were milk (RR for asthma, 3.9; 95% CI, 1.6-9.4; P < .01), eggs (RR, 2.9; 95% CI, 1.2-7.0; P = .03), and peanuts (RR, 3.7; 95% CI, 1.6-8.3; P < .01). Food allergies occurred earlier than asthma, at 1.5 years after transplantation (IQR, 0.5-3.0 years) vs 2.5 years after transplantation (IQR, 1.0-4.5 years; P < .05). Food allergies were also associated with eczema, but not with sensitization to aero-allergens or rhinitis. CONCLUSIONS: The high risk of food allergies in children who were liver transplant recipients was associated with eczema and asthma, but not rhinitis. The most frequent food allergens associated with asthma were milk, eggs, and peanuts.

Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Histologic analysis of liver biopsy specimens allows for grading and staging of nonalcoholic fatty liver disease (NAFLD). We performed a longitudinal study to investigate the long-term prognostic relevance of histologic features for patients with NAFLD. METHODS: We performed a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand. Patients underwent laboratory and biopsy analyses, and were examined every 3-12 months after their diagnosis. Outcomes analyzed were overall mortality, liver transplantation, and liver-related events. Cumulative outcomes were compared by log-rank analysis. Cox proportional-hazards regression was used to estimate adjusted hazard ratios (HRs). Time at risk was determined from the date of liver biopsy to the date of outcome or last follow-up examination. RESULTS: Over a median follow-up period of 12.6 years (range, 0.3-35.1 y), 193 of the patients (33.2%) died or underwent liver transplantation. Features of liver biopsies significantly associated with death or liver transplantation included fibrosis stage 1 (HR, 1.88; 95% confidence interval [CI], 1.28-2.77), stage 2 (HR, 2.89; 95% CI, 1.93-4.33), stage 3 (HR, 3.76; 95% CI, 2.40-5.89), and stage 4 (HR, 10.9; 95% CI, 6.06-19.62) compared with stage 0, as well as age (HR, 1.07; 95% CI, 1.05-1.08), diabetes (HR, 1.61; 95% CI, 1.13-2.30), current smoking (HR, 2.62; 95% CI, 1.67-4.10), and statin use (HR, 0.32; 95% CI, 0.14-0.70). Twenty-six patients (4.2%) developed liver-related events; fibrosis stage 3 (HR, 14.2; 95% CI, 3.38-59.68) and stage 4 (HR, 51.5; 95% CI, 9.87-269.2) compared with stage 0, were associated significantly with the events. Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis. CONCLUSIONS: In a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events.

Long-term follow-up and liver-related death rate in patients with non-alcoholic and alcoholic related fatty liver disease.

BACKGROUND: Few studies have compared the prognosis and liver-related mortality in patients with NAFLD (nonalcoholic fatty liver disease) and AFLD (alcoholic fatty liver disease). We aimed to investigate the etiology and liver-related mortality of patients with liver biopsy verified fatty liver disease in a population based setting. METHODS: In this retrospective study, all patients who underwent a liver biopsy 1984-2009 at the National University Hospital of Iceland were identified through a computerized pathological database with the code for fatty liver. Only patients with NAFLD and AFLD were included and medical records reviewed. The patients were linked to the Hospital Discharge Register, the Causes of Death Registry and Centre for Addiction Medicine. RESULTS: A total of 151 had NAFLD and 94 AFLD with median survival of 24 years and 20 years, respectively (p = NS). A total of 10/151 (7%) patients developed cirrhosis in the NAFLD group and 19/94 (20%) in AFLD group (p = 0.03). The most common cause of death in the NAFLD group was cardiovascular disease (48%). Liver disease was the most common cause of death in the AFLD group (36%), whereas liver-related death occurred in 7% of the NAFLD group. The mean liver-related death rate among the general population during the study period was 0.1% of all deaths. There was a significantly worse survival for patients in the AFLD group compared to the NAFLD group after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.16, p = 0.009). The survival for patients with moderate to severe fibrosis was significantly worse than for patients with mild fibrosis after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.09, p = 0.01). CONCLUSIONS: Patients with fatty liver disease showed a markedly higher risk of developing liver-related death compared to the general population. The AFLD group had higher liver-related mortality and had a worse survival than the NAFLD group. Patients with more severe fibrosis at baseline showed a worse survival than patients with none or mild fibrosis at baseline.

Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND: Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD. METHODS AND FINDINGS: English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69-2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65-1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58-4.05) and incidence (HR 2.12, 95% CI 1.42-3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14-8.61) and incidence (HR 3.29, 95% CI 2.30-4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies. CONCLUSION: The presence and severity of NAFLD are associated with an increased risk and severity of CKD. Please see later in the article for the Editors' Summary.

Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Some patients with nonalcoholic fatty liver disease (NAFLD) develop liver-related complications and have higher mortality than other patients with NAFLD. We determined the accuracy of simple, noninvasive scoring systems in identification of patients at increased risk for liver-related complications or death. METHODS: We performed a retrospective, international, multicenter cohort study of 320 patients diagnosed with NAFLD, based on liver biopsy analysis through 2002 and followed through 2011. Patients were assigned to mild-, intermediate-, or high-risk groups based on cutoff values for 2 of the following: NAFLD fibrosis score, aspartate aminotransferase/platelet ratio index, FIB-4 score, and BARD score. Outcomes included liver-related complications and death or liver transplantation. We used multivariate Cox proportional hazard regression analysis to adjust for relevant variables and calculate adjusted hazard ratios (aHRs). RESULTS: During a median follow-up period of 104.8 months (range, 3-317 months), 14% of patients developed liver-related events and 13% died or underwent liver transplantation. The aHRs for liver-related events in the intermediate-risk and high-risk groups, compared with the low-risk group, were 7.7 (95% confidence interval [CI]: 1.4-42.7) and 34.2 (95% CI: 6.5-180.1), respectively, based on NAFLD fibrosis score; 8.8 (95% CI: 1.1-67.3) and 20.9 (95% CI: 2.6-165.3) based on the aspartate aminotransferase/platelet ratio index; and 6.2 (95% CI: 1.4-27.2) and 6.6 (95% CI: 1.4-31.1) based on the BARD score. The aHRs for death or liver transplantation in the intermediate-risk and high-risk groups compared with the low-risk group were 4.2 (95% CI: 1.3-13.8) and 9.8 (95% CI: 2.7-35.3), respectively, based on the NAFLD fibrosis scores. Based on aspartate aminotransferase/platelet ratio index and FIB-4 score, only the high-risk group had a greater risk of death or liver transplantation (aHR = 3.1; 95% CI: 1.1-8.4 and aHR = 6.6; 95% CI: 2.3-20.4, respectively). CONCLUSIONS: Simple noninvasive scoring systems help identify patients with NAFLD who are at increased risk for liver-related complications or death. NAFLD fibrosis score appears to be the best indicator of patients at risk, based on HRs. The results of this study require external validation.