Vargas, Hugo E.

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, with potential causes stemming from obesity, metabolic syndrome, genetic disorders, and drug toxicity. We report a 42-year-old woman with lipodystrophy and NAFLD due to a pathogenic variant in the LMNA (D300N) gene. This case report attempts to encourage clinicians to consider genetic diseases, specifically lipodystrophies, when working up uncommon causes of NAFLD.

Objectives: To report long-term outcomes of nonmelanoma skin cancer (NMSC) in immunosuppressed cardiac and liver transplant recipients (CLTR). Materials and Methods: The authors reviewed CLTR at the Mayo Clinic in Arizona from 1986 to 2013. Patient and tumor characteristics were recorded. Survival rates were calculated using the Kaplan-Meier method. Patient-specific and lesion-specific analyses were performed. Univariate and multivariate cox regressions were performed for comparisons. Results: Seven-hundred and forty-seven patients underwent cardiac (138) or liver (609) transplantation and of these, 97 patients (13%) developed 382 invasive NMSC. The median follow-up was 11 (range, 3 to 27) years for surviving patients. Primary treatment was mainly surgery alone. At 10 years, the local recurrence (LR) rate was 20% (95% confidence interval, 15%-28%), and 14% of patients had multiple LRs. At 10 years, LR rates were higher for T3/T4 tumors when compared with T1/T2 tumors (32.5% vs. 20%, P=0.05). At 10 years, overall survival was 79% (95% confidence interval, 64%-88%). On multivariate analysis, age 61 years and more demonstrated inferior overall survival (P<0.01). Conclusions: This is the first study describing the AJCC 8th edition stage-based patterns of recurrence and long-term outcomes of surgically managed NMSC in a large cohort of immunosuppressed CLTRs. T3 and T4 tumors recur more often than early stage tumors. Further study is required to identify factors related to recurrence and guide upfront treatment intensification in this high-risk population.

Spontaneous portosystemic shunts (SPSSs) have been associated with worse clinical outcomes in the pre–liver transplantation (LT) setting, but little is known about their post‐LT impacts. Our aim was to compare LT candidates with and without SPSSs and assess the impact of SPSSs on patient mortality and graft survival in the post‐LT setting. Patients 18 years or older with abdominal imaging done prior to LT were included. Exclusion criteria were the presence of pre‐LT surgical shunts, LT indications other than cirrhosis, and combined solid organ transplantations. SPSSs were classified as absent, small, or large according to their maximum diameter (8 mm). Multiple variables that could influence the post‐LT course were extracted for analysis. Patient and graft survival were estimated using the Kaplan‐Meier method and were compared between groups using a log‐rank test. The project received institutional review board approval. We extracted data from 326 patients. After comparing patients without SPSS or with small or large SPSSs, no statistical difference was found for overall patient survival: no SPSS (n = 8/63), reference; small SPSS (n = 18/150), hazard ratio (HR), 1.05 (95% confidence interval [CI], 0.45‐2.46); and large SPSS (n = 6/113), HR, 0.60 (95% CI, 0.20‐1.78); P = 0.20. Also, no difference was found for graft survival: no SPSS (n = 11/63), reference; small SPSS (n = 21/150), HR, 0.80 (95% CI, 0.38‐1.70); large SPSS (n = 11/113), HR, 0.59 (95% CI, 0.25‐1.40); P = 0.48. Similarly, no statistical significance was found for these variables when comparing if the graft used was procured from a donation after circulatory death donor versus a donation after brain death donor. In conclusion, the previously described association between SPSSs and worse clinical outcomes in pre‐LT patients seems not to persist once patients undergo LT. This study suggests that no steps to correct SPSS intraoperatively are necessary.

Background and Aims Interleukin‐22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol‐associated hepatitis (AH). F‐652 is a recombinant fusion protein of human interleukin‐22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F‐652 in patients with moderate and severe AH. Approach and Results A phase‐2 dose‐escalating study was carried out. F‐652 (10 μg/kg, 30 μg/kg, or 45 μg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End‐Stage Liver Disease [MELD] scores: 11‐20) and severe AH (MELD scores: 21‐28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity‐matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half‐life of F‐652 following the first dose was 61‐85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day‐7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down‐regulated, and regeneration markers were up‐regulated at days 28 and 42. Conclusions F‐652 is safe in doses up to 45 μg/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo‐controlled trials to test the efficacy of F‐652 in AH.

BACKGROUND: Patients with cirrhosis are growing older and the overlap between hepatic encephalopathy (HE) & pre-dementia mild cognitive impairment (MCI) is unclear. HE affects visuospatial/psychomotor speed while MCI affects memory. Aim: Determine the performance of elderly cirrhotics on tests for HE and dementia and their impact on quality of life (QOL). METHODS: Outpatient cirrhotics and controls ages 65–95 years were recruited at 4 centers. Subjects had to have MMSE > 25, no current HE or dementia to be eligible. All subjects got tests for HE (psychometric hepatic encephalopathy score, PHES: 5 tests & low score = poor, EncephalApp, OffTime + OnTime, high score = poor) and QOL: Sickness Impact profile (SIP, high score = poor QOL). Cirrhotics also got tests for MCI; RBANS (tests immediate memory, delayed memory, language, visuo-spatial & attention). A neuro-psychologist evaluated results and divided cirrhotics into (A) unimpaired (B) MCI only (C) HE only & (D) (MCI/HE overlap). Demographics, MELD, alcohol etiology, and SIP were compared. Finally, age, gender and education-adjusted norms were created for PHES and EncephalApp based on the controls. Presence of MHE and sensitivity of EncephalApp for MHE diagnosis were evaluated. RESULTS: 109 cirrhotics and 100 non-cirrhotic subjects were included. Demographics/education levels were statistically similar between centers. Controls were older than cirrhotics (74.9 ± 6.6 vs 70.5 ± 4.4, P < 0.05) and had similar education/gender distribution. Despite this, controls performed better than cirrhotics on all tests (PHES 2.9 ± 12.4 vs −4.5 ± +4.5, P < 0.001, EncephalApp Off+On 181.4 ± +71.9 vs 218.2 ± +80.0, P = 0.03) and had a better QOL (SIP total 3.8 ± +7.1 vs 7.9 ± +9.5, Psych 3.3 ± +8.4 vs 7.2 ± +11.1, Phys 3.0 ± +6.2 vs 6.7 ± +9.5, all P < 0.001). Within cirrhosis subgroups (Table 1), demographics, MELD/alc & MMSE were similar. Pts with both MCI/HE had worse cognition on all tests, which translated into a worse QOL compared to other groups. Presence of HE, with/without MCI, contributed towards poor QOL. Norms for PHES/EncephalApp: Adjusting for age, gender & education, 17% (n = 17) patients were positive for MHE on PHES compared to controls. On EncephalApp, 49% (n = 47) patients were positive. AUC for EncephalApp using PHES as the gold standard was 0.86 (0.78-0.95 CI). CONCLUSIONS: In this multi-center study, adjusted norms defining the high sensitivity of EncephalApp to diagnose HE in older individuals were created. Presence of HE regardless of MCI contributed towards poor cognition and QOL in patients >65 years.