Background and Aims NAFLD and its more‐advanced form, steatohepatitis (NASH), is associated with obesity and is an independent risk factor for cardiovascular, liver‐related, and all‐cause mortality. Available human data examining hepatic mitochondrial fatty acid oxidation (FAO) and hepatic mitochondrial turnover in NAFLD and NASH are scant. Approach and Results To investigate this relationship, liver biopsies were obtained from patients with obesity undergoing bariatric surgery and data clustered into four groups based on hepatic histopathological classification: Control (CTRL; no disease); NAFL (steatosis only); Borderline‐NASH (steatosis with lobular inflammation or hepatocellular ballooning); and Definite‐NASH (D‐NASH; steatosis, lobular inflammation, and hepatocellular ballooning). Hepatic mitochondrial complete FAO to CO2 and the rate‐limiting enzyme in β‐oxidation (β‐hydroxyacyl‐CoA dehydrogenase activity) were reduced by ~40%–50% with D‐NASH compared with CTRL. This corresponded with increased hepatic mitochondrial reactive oxygen species production, as well as dramatic reductions in markers of mitochondrial biogenesis, autophagy, mitophagy, fission, and fusion in NAFL and NASH. Conclusions These findings suggest that compromised hepatic FAO and mitochondrial turnover are intimately linked to increasing NAFLD severity in patients with obesity.

Background and Aim: Although constitutional and respiratory symptoms such as cough and fever are the most common symptoms in patients infected with COVID-19, gastrointestinal (GI) tract involvement has been observed by endoscopic biopsies. Multiple GI symptoms, including diarrhea, nausea or vomiting and abdominal pain, have also been reported. This review aims to present the currently available data regarding the GI symptoms of COVID-19 patients, and to compare the frequency of GI symptoms in early stage (Eastern) mostly Chinese data to the current stage (Western) non-Chinese data. Methods: We performed a systematic literature search to identify both published studies by using PubMed, Google Scholar, and CNKI (Chinese medical search engine), and yet unpublished studies through medRxiv and bioRxiv. We also reviewed the cross references of the detected articles. We conducted a Medical Subject Headings (MeSH) search up until 20 September 2020. We pooled the prevalence of symptoms of diarrhea, anorexia, nausea, vomiting, and abdominal pain by using the Freeman–Tukey’s transforming random effect model. Results: A total of 118 studies were included in the systematic review and 44 of them were included in the meta-analysis. There was a significant heterogeneity between the studies; therefore, the random effects model was used. The pooled prevalence estimate of any GI symptoms reported was found to be 0.21 (95%CI, 0.16–0.27). Anorexia was the most commonly reported GI symptom at 18% (95%CI, 0.10–0.27) followed by diarrhea at 15% (95%CI, 0.12–0.19). Diarrhea, abdominal pain, nausea/vomiting, and respiratory symptoms were more common in non-Chinese studies. The prevalence of abdominal pain was lower in the “inpatient-only” studies when compared with studies that included outpatients only and those including both inpatients and outpatients. Conclusions: In this comprehensive systematic review and meta-analysis study, we observed higher rates of diarrhea, nausea/vomiting, and abdominal pain in COVID-19 infected patients among non-Chinese studies compared to Chinese studies. We also observed a higher prevalence of GI symptoms in Chinese studies than was reported previously. Non-respiratory symptoms, including GI tract symptoms, should be more thoroughly and carefully evaluated and reported in future studies.

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Considerable ambiguity exists in the literature regarding the role of hepatic mitochondrial dysfunction in the pathological progression of nonalcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH) and fibrosis. To investigate this relationship, liver biopsies were obtained from patients with morbid obesity undergoing bariatric surgery [n=110, age 44.7±11.7 y, weight 136.3±25.5 kg, BMI 48.7±7.4 kg/m2, AST 35.6±32.1 U/L, ALT 41.0±35.6 U/L, NAFLD activity score 3±2 (NAS; liver injury score: steatosis, ballooning, and inflammation; range: 0-8), fibrosis score 0.5±1.0 (range: 0-4), glucose 104±33 mg/dL] and assessments of mitochondrial function and turnover performed. Data were clustered into four groups based on NAS (No Disease, NAS=0, n=13; Mild NAS=1-2, n=28; Moderate NAS=3-4, n=41; and Severe NAS≥5, n=28). Complete hepatic mitochondrial oxidation of palmitate to CO2 was reduced by ∼50% with Moderate and Severe NAS vs. no disease (p<0.05). This was accompanied by a 50% decrease in hepatic β-HAD activity in all groups with NAFLD (p<0.01), without any differences in citrate synthase activity (p>0.05). In addition to reduced hepatic mitochondrial function, elevated NAS was associated with reduced hepatic mitochondrial biogenesis (PGC1α, SIRT1, PPARα, and AMPKα1 mRNA; p<0.05) and mitochondrial turnover (BNIP3, PARKIN mRNA; p<0.05) markers. Furthermore, hepatic mitochondrial H2O2 emission was elevated in Severe NAS (p<0.01) and positively related to lobular inflammation (r=0.336, p<0.01) and hepatocellular ballooning (r=0.379, p<0.001). Here, we provide novel insight into the relationship between NAFLD severity and hepatic mitochondrial dysfunction. Our findings suggest that compromised hepatic mitochondrial fatty acid metabolism and reduced hepatic mitochondrial biogenesis/turnover may be linked to NAFLD progression in patients with morbid obesity. Disclosure M.P. Moore: None. R. Cunningham: None. G.M. Meers: None. S.A. Johnson: None. A.A. Wheeler: None. R. Ganga: None. J. Pitt: None. N. Spencer: None. A.A. Diaz-Arias: None. A. Swi: None. J.A. Ibdah: None. E.J. Parks: None. R.S. Rector: None. Funding National Institutes of Health (R01DK113701); U.S. Department of Veterans Affairs (I01BX003271)

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