Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure.

BACKGROUND AND AIMS: In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of hepatocyte nuclear factor 4α (HNF4α), its regulators, and targets in LPCs determines clinical outcome of patients with ALF. APPROACH AND RESULTS: Clinicopathological associations were scrutinized in 19 patients with ALF (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4α, and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure. Recovered patients with ALF robustly express HNF4α in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α expression in LPCs requires the forkhead box protein H1-Sma and Mad homolog 2/3/4 transcription factor complex, which is promoted by the TGF-ß superfamily member activin. Activin signaling in LPCs is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated Sma and Mad homolog 2 and HNF4α in LPCs, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of acute-on-chronic liver failure. CONCLUSIONS: These results highlight a crucial role of the follistatin-controlled activin-HNF4α-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggest a key role of the systemic metabolic state in ALF.

Novel therapeutic avenues for the study of chronic liver disease and regeneration: The foundation of the Iberoamerican Consortium for the study of liver Cirrhosis.

Unfortunately, there is a gap of understanding in the pathophysiology of chronic liver disease due to the lack of experimental models that exactly mimic the human disease. Additionally, the diagnosis of patients is very poor due to the lack of biomarkers than can detect the disease in early stages. Thus, it is of utmost interest the generation of a multidisciplinary consortium from different countries with a direct translation. The present reports the meeting of the 2021 Iberoamerican Consortium for the study of liver Cirrhosis, held online, in October 2021. The meeting, was focused on the recent advancements in the field of chronic liver disease and cirrhosis with a specific focus on cell pathobiology and liver regeneration, molecular and cellular targets involved in non-alcoholic hepatic steatohepatitis, alcoholic liver disease (ALD), both ALD and western diet, and end-stage liver cirrhosis and hepatocellular carcinoma. In addition, the meeting highlighted recent advances in targeted novel technology (-omics) and opening therapeutic avenues in this field of research.

Phase Angle From Bioelectrical Impedance for the Assessment of Sarcopenia in Cirrhosis With or Without Ascites.

BACKGROUND AND AIMS: Skeletal muscle index (SMI) from computed tomography (CT) reliably assesses sarcopenia, however, it is expensive and involves serial radiation exposure. Phase angle (PhA) from bioimpedance analysis (BIA) is a noninvasive, low cost, bedside nutritional tool used to monitor changes to nutritional interventions. We aimed to compare the performance of PhA with SMI to assess sarcopenia in cirrhosis. METHODS: Ambispective cohort study. Consecutive patients with cirrhosis and available images from abdominal CT scan were included. Monofrequency BIA was performed within 2 weeks CT. Spearman's correlation, ROC curve, and survival analysis with Kaplan-Meier, Cox and competing-risk regression were performed. RESULTS: 136 patients were included with a mean age of 54.5 years (60% female). Most had decompensated disease (66%) with ascites in 47%, and a mean MELD of 14 ± 6. We found positive correlations between SMI and PhA (r = 0.58 , P < .001), irrespective of the presence of ascites. The AUROC of PhA-sarcopenia in all patients was 0.702; (0.748 in males,0.677 in females). The best cutoffs of PhA for diagnosing sarcopenia were ≤5.6° in males and ≤5.4° in females. SMI and PhA were significantly associated with survival in Kaplan-Meier curves. In multivariable analyses, SMI was outperformed by age and MELD, whereas PhA remained independently associated with mortality. Considering transplantation as a competing risk, regression analysis showed both SMI and PhA to be independent predictors of mortality (sHR:0.95 [0.90-0.99] and sHR:0.61 [0.42-0.88]). CONCLUSION: PhA moderately correlates with SMI for the identification of sarcopenia in patients with cirrhosis. However, its prognostic accuracy is comparable to that of SMI, and it is not influenced by ascites.

Hepatic manifestations in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multi-organic autoimmune disease with a wide variety of clinical manifestations. However, hepatic dysfunction is not included in the diagnostic criteria for the disease and has not been recognized properly. The spectrum of hepatic involvement described in these patients ranges from abnormalities in liver function tests (LFTs) to fulminant hepatic failure. Usually, abnormalities in LFTs are only mild and transient, have a hepatocellular pattern and are not related to SLE but rather are mostly drug related. The most frequent finding on liver biopsy is steatosis (non-alcoholic fatty liver disease). Patients do not frequently progress to advanced chronic liver disease, and their outcome is favourable. Those who develop cirrhosis have traditional risk factors, such as other non-SLE-related conditions. In this work, we aim to review hepatic manifestations in patients with SLE, as well as the diagnostic and therapeutic approaches used for different liver diseases in these patients.

Reclassifying Hepatic Cell Death during Liver Damage: Ferroptosis-A Novel Form of Non-Apoptotic Cell Death?

Ferroptosis has emerged as a new type of cell death in different pathological conditions, including neurological and kidney diseases and, especially, in different types of cancer. The hallmark of this regulated cell death is the presence of iron-driven lipid peroxidation; the activation of key genes related to this process such as glutathione peroxidase-4 (gpx4), acyl-CoA synthetase long-chain family member-4 (acsl4), carbonyl reductase [NADPH] 3 (cbr3), and prostaglandin peroxidase synthase-2 (ptgs2); and morphological changes including shrunken and electron-dense mitochondria. Iron overload in the liver has long been recognized as both a major trigger of liver damage in different diseases, and it is also associated with liver fibrosis. New evidence suggests that ferroptosis might be a novel type of non-apoptotic cell death in several liver diseases including non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), drug-induced liver injury (DILI), viral hepatitis, and hemochromatosis. The interaction between iron-related lipid peroxidation, cellular stress signals, and antioxidant systems plays a pivotal role in the development of this novel type of cell death. In addition, integrated responses from lipidic mediators together with free iron from iron-containing enzymes are essential to understanding this process. The presence of ferroptosis and the exact mechanisms leading to this non-apoptotic type of cell death in the liver remain scarcely elucidated. Recognizing ferroptosis as a novel type of cell death in the liver could lead to the understanding of the complex interaction between different types of cell death, their role in progression of liver fibrosis, the development of new biomarkers, as well as the use of modulators of ferroptosis, allowing improved theranostic approaches in the clinic.

Inactivation of caspase 8 in liver parenchymal cells confers protection against murine obstructive cholestasis.

BACKGROUND & AIMS: Caspase 8 (CASP8) is the apical initiator caspase in death receptor-mediated apoptosis. Strong evidence for a link between death receptor signaling pathways and cholestasis has recently emerged. Herein, we investigated the role of CASP8-dependent and independent pathways during experimental cholestasis. METHODS: Liver injury was characterized in a cohort of human sera (n = 28) and biopsies from patients with stage IV primary biliary cholangitis. In parallel, mice with either specific deletion of Casp8 in liver parenchymal cells (Casp8Δhepa) or hepatocytes (Casp8Δhep), and mice with constitutive Ripk3 (Ripk3-/-) deletion, were subjected to surgical ligation of the common bile duct (BDL) from 2 to 28 days. Floxed (Casp8fl/fl) and Ripk3+/+ mice were used as controls. Moreover, the pan-caspase inhibitor IDN-7314 was used, and cell death mechanisms were studied in primary isolated hepatocytes. RESULTS: Overexpression of activated caspase 3, CASP8 and RIPK3 was characteristic of liver explants from patients with primary biliary cholangitis. Twenty-eight days after BDL, Casp8Δhepamice showed decreased necrotic foci, serum aminotransferase levels and apoptosis along with diminished compensatory proliferation and ductular reaction. These results correlated with a decreased inflammatory profile and ameliorated liver fibrogenesis. A similar phenotype was observed in Ripk3-/- mice. IDN-7314 treatment decreased CASP8 levels but failed to prevent BDL-induced cholestasis, independently of CASP8 in hepatocytes. CONCLUSION: These findings show that intervention against CASP8 in liver parenchymal cells - specifically in cholangiocytes - might be a beneficial option for treating obstructive cholestasis, while broad pan-caspase inhibition might trigger undesirable side effects. LAY SUMMARY: Loss of caspase 8 - a protein involved in programmed cell death - in liver parenchymal cells protects against experimental cholestasis. Therefore, specific pharmacological intervention against caspase 8 might be a valid alternative for the treatment of obstructive cholestasis in the clinic, whereas broad pan-caspase inhibiting drugs might trigger undesirable side effects.

Exercise and physical activity for patients with end-stage liver disease: Improving functional status and sarcopenia while on the transplant waiting list.

Sarcopenia and physical deconditioning are frequent complications in patients with cirrhosis and end-stage liver disease (ESLD). They are the end result of impaired dietary intake, chronic inflammation, altered macronutrient and micronutrient metabolism, and low physical activity. Frailty is the end result of prolonged sarcopenia and physical deconditioning. It severely affects a patient's functional status and presents in approximately 1 in 5 patients on the liver transplantation waiting list. Sarcopenia, poor physical fitness/cardiopulmonary endurance (CPE), and frailty are all associated with increased mortality in ESLD. Clinical trials addressing the usefulness of exercise in patients with cirrhosis have shown that it improves the metabolic syndrome, sarcopenia, CPE, health-related quality of life, and hepatic venous pressure gradient. Although evidence on the benefits of exercise on clinical outcomes derived from large clinical trials is still missing, based on existing literature from multiple medical subspecialties, we believe that an exercise program coupled to a tailored nutritional intervention benefits both cardiopulmonary and musculoskeletal functions, ultimately translating into improved functional status, sense of well-being, and possibly less complications from portal hypertension. In conclusion, although supervised exercise training is the prevailing approach to manage ESLD patients, such intervention is not sustainable or feasible for most patients. Innovative home-based physical activity interventions may be able to effectively reach a larger number of patients. Liver Transplantation 24 122-139 2018 AASLD.

Changes in Cerebral Hemodynamics in Patients With Cirrhosis After Liver Transplantation.

Improvement in cognitive function after orthotopic liver transplantation (LT) has been demonstrated in the acute setting immediately after LT and in acute liver failure. However, the longterm changes in cerebral hemodynamics after LT remain unexplored. Therefore, we aimed to evaluate the longterm changes in cerebral hemodynamics of patients with cirrhosis after LT. In this prospective cohort study, we performed transcranial Doppler ultrasonography (TCD) measuring the pulsatility index (PI), resistance index (RI), and breath-holding index (BHI) to evaluate cerebrovascular structural integrity and reactivity, respectively, in both middle cerebral arteries before and after LT. Neuropsychometric tests and West-Haven criteria were used for hepatic encephalopathy (HE) characterization. Interleukin 6 and tumor necrosis factor α plasma levels were measured. Descriptive statistics and Wilcoxon's test were used. There were 27 patients who were included. Median follow-up after LT was 6 months, mean age before LT was 46.3 ± 10.3 years, the main etiology was hepatitis C virus (59%), and most of the patients were Child-Pugh B (15/27). Model for End-Stage Liver Disease (MELD) score was 16 ± 7.5, MELD-Na was 19.3 ± 7.1, Psychometric Hepatic Encephalopathy Score was -3.48 ± 3.66, and critical flicker fusion (CFF) was 40.28 ± 5.70 Hz. Before LT, 17/27 patients had HE and 11/27 ascites. A decrease of 20.8% and 13.5% in PI and RI was observed after LT (P < 0.001, both), together with an increase in BHI (32.4%, P = 0.122). These changes in cerebral hemodynamics paralleled those in systemic inflammation. Clinical improvement in cognition was observed in all patients with overt HE after LT. In conclusion, these results show a significant improvement in cerebral hemodynamics after LT, obtained through TCD, indicating less arterial cerebral vasoconstriction together with a decrease in systemic inflammation. Changes in cerebral vasoconstriction can be the basis for the improvement in cognitive function after LT in the long term.

Fibroblast growth factor 21 is an early predictor of acute-on-chronic liver failure in critically ill patients with cirrhosis.

Acute-on-chronic liver failure (ACLF) develops in acute decompensation (AD) of cirrhosis and shows high mortality. In critically ill patients, early diagnosis of ACLF could be important for therapeutic decisions (eg, renal replacement, artificial liver support, liver transplantation). This study evaluated fibroblast growth factor 21 (FGF21) as a marker of mitochondrial dysfunction in the context of ACLF. The study included 154 individuals (112 critically patients and 42 healthy controls) divided into a training and a validation cohort. In the training cohort of 42 healthy controls and 34 critically ill patients (of whom 24 were patients with cirrhosis), levels of FGF21, interleukin (IL) 6, and IL8 were measured. In the validation cohort of 78 patients with cirrhosis, 17 patients were admitted with or developed ACLF during follow-up and underwent daily clinical and nutritional assessment. Levels of FGF21 were higher in critically ill patients, especially in patients with cirrhosis admitted to the intensive care unit (ICU). Moreover, FGF21 as well as IL6 and IL8 levels were higher in patients with ACLF, but they did not increase with the severity of ACLF. Interestingly, in the validation cohort, FGF21 was also elevated in the patients who developed ACLF in the next 7 days. In these patients, FGF21 levels were an independent predictor of ACLF presence and development in multivariate analysis together with Child-Pugh score. FGF21 levels had no impact on the survival of critically ill patients with cirrhosis. In conclusion, this study demonstrates that FGF21 levels are of specific diagnostic value regarding the presence and development of ACLF in patients admitted to ICU for AD of liver cirrhosis. Further studies are warranted to address pathophysiological and possible therapeutic implications. Liver Transplantation 24 595-605 2018 AASLD.

Cerebral haemodynamics in cirrhotic patients with hepatic encephalopathy.

BACKGROUND & AIMS: Factors other than elevated levels of ammonia may be implicated in hepatic encephalopathy (HE) pathophysiology, including abnormal cerebral haemodynamics. Transcranial Doppler ultrasonography (TCD) evaluates cerebrovascular structural integrity and reactivity, through pulsatility index (PI) and breath-holding index (BHI) respectively. The aim of this study was to evaluate cerebral haemodynamics by TCD in patients with compensated and decompensated cirrhosis, and patients with and without HE. METHODS: We studied 90 subjects by TCD measuring PI and BHI in the middle cerebral artery: 30 with cirrhosis and no HE, 30 with cirrhosis and low-grade HE and 30 healthy subjects. Critical flicker frequency, psychometric hepatic encephalopathy score and West-Haven criteria were performed to assess MHE and HE respectively. RESULTS: Pulsatility index increased in decompensated cirrhotics (Child ≥ 7) when compared with compensated cirrhotics and healthy subjects [median (IQR) 1.07 (0.95-1.21) vs 0.90 (0.83-1.05) vs 0.87 (0.78-0.96); P < 0.001]. A reverse relationship was observed for BHI among the three groups [0.82 (0.45-1.11) vs 1.20 (0.82-1.52) vs 1.28 (1.06-1.68); P < 0.001]. Similar findings were observed in decompensation [model for end-stage liver disease (MELD) score ≥14]. Patients with HE showed higher PI and lower BHI [1.05 (1.00-1.16) and 0.89 (0.59-1.15)], when compared with patients without HE [0.96 (0.83-1.13) and 1.00 (0.60-1.53)] or controls [0.87 (0.78-0.96) and 1.28 (1.06-1.68)] (P < 0.001 for PI, and P = 0.007 for BHI). In multivariate regression models, only PI predicted HE, but it was outperformed by MELD-sodium and tumour necrosis factor-alpha. CONCLUSIONS: These results indicate that cerebral haemodynamics are altered in patients with cirrhosis, in relation to severity of disease and HE. Findings on impaired PI and BHI suggest that structural vascular damage and loss of vascular autoregulation are implicated in the pathophysiology of HE.

Assessing nutrition status, sarcopenia, and frailty in adult transplant recipients.

The assessment of nutrition status, sarcopenia, and frailty holds significant relevance in the context of adult transplantation, as these factors are associated with an unfavorable prognosis; thus, transplant candidates must undergo a full nutrition assessment. Screening tools may be used to prioritize patients, this can be done using the Nutrition Risk Screening 2002 or Royal Free Hospital-Nutritional Prioritizing Tool. Subsequently, a thorough nutrition-focused physical examination should be conducted to evaluate clinical signs of nutrition deficiencies, fat and muscle loss, and fluid overload; dietary history and current intake must also be assessed. Apart from physical examination, specific testing for sarcopenia and frailty are recommended. For sarcopenia assessment, specifically for muscle quantification, the gold standard is the cross-sectional measurement of the muscle at L3 obtained from a computed tomography scan or magnetic resonance imaging; dual-energy x-ray absorptiometry is also a good tool especially when appendicular skeletal muscle index is calculated. Other more readily available options include phase angle from bioelectrical impedance or bioimpedance spectroscopy. In the sarcopenia assessment, muscle function evaluation is required, handgrip strength stands as the primary test for this purpose; this test is also part of the subjective global assessment and is included in some frailty scores. Finally, for frailty assessment, the Short Physical Performance Battery is useful for evaluating physical frailty, and for a multidimensional evaluation, the Fried frailty phenotype can be used. Specifically for liver transplant candidates, the use of Liver Frailty Index is recommended.

Effect of a monitored exercise protocol in cerebral and hepatic hemodynamics in patients with cirrhosis and portal hypertension.

BACKGROUND: Physical exercise (PE) has been proven to be beneficial in patients with cirrhosis; effects in cognitive function and cerebral hemodynamics, are yet to be explored. AIM: To evaluate the effects of a PE program (LFN-exercise protocol) in hepatic/cerebral hemodynamics. METHODS: Randomized open clinical trial in patients with cirrhosis; Control: Diet(n = 13),Intervention: Diet + exercise(n = 14) for 12 weeks. Patients received an educational session, mental exercises (printed book and sudoku), and high-protein diet. Exercise intervention consisted of walking 4 times/week with an intensity rated between 12 and 14 on the Borg scale, monitored through bracelet accelerometers. Patients received weekly text messages to encourage adherence and had monthly in-person visits. RESULTS: Patients were mainly Child-Pugh A(88.9 %), median MELD 8(8-10), mean age 53±8 years. In the exercise group the number of steps increased from 9667±3008 to 11,931±4463 (p = 0.002), vs 8004±3224 to 8903±3504 (p = 0.053) in controls. Exercise decreased HVPG from 11(8-14) to 8(6-11)mmHg (p = 0.032) vs no change in the control group from 14(12-16) to 15(11-17)mmHg (p = 0.959). Intervention group showed better cerebral hemodynamics, cognitive function, nutritional status and quality of life after the intervention. Adherence was >90 %, with no adverse events. CONCLUSION: The LFN-exercise protocol improves portal hypertension, cerebral hemodynamics and cognitive function, as well as nutritional status and quality of life. GOV NUMBER: NCT03932552.

Myostatin is associated with the presence and development of acute-on-chronic liver failure.

Background & Aims: Acute-on-chronic liver failure (ACLF) has been linked to different pathophysiological mechanisms, including systemic inflammation and mitochondrial dysfunction. Sarcopenia has also been proposed as a potential mechanism; myostatin is a key factor inducing sarcopenia. Therefore, this study aimed to evaluate the association of myostatin levels with the development of ACLF and mortality in patients with cirrhosis. Methods: We performed a prospective cohort study, including both outpatient and hospitalized patients with cirrhosis. Clinical, biochemical, and nutritional parameters were evaluated, and the development of acute decompensation (AD) or ACLF during follow-up was recorded. ACLF was defined according to the EASL-CLIF criteria. Receiver-operating characteristic, Kaplan-Meier and Cox regression analyses were performed. Results: A total of 186 patients with the whole spectrum of cirrhosis were included; mean age was 53.4 ± 14 years, mean Child-Pugh score was 8 ± 2.5 and mean MELD score was 15 ± 8. There was a stepwise decrease in myostatin levels from a compensated stage to AD and ACLF. Myostatin correlated positively with nutritional markers and negatively with severity scores. The prevalence of sarcopenia was 73.6%. During follow-up, 27.9% of patients developed AD and 25.8% developed ACLF. Most episodes were grade 2-3, mainly (62.5%) precipitated by infections. The most common organ failures observed were in the liver (63.3%) and the kidney (64.6%). Receiver-operating characteristic analysis yielded <1,280 pg/ml as the best serum myostatin cut-off for the prediction of ACLF. In Kaplan-Meier curves and multivariate analysis, myostatin levels remained independently associated with the incidence of ACLF and survival. Conclusions: There is a progressive decrease in myostatin levels as cirrhosis progresses, demonstrating an association of sarcopenia with the development of ACLF and increased mortality. Impact and implications: Myostatin is a muscle hormone, it is decreased in patients with muscle loss and is a marker of impaired muscle function. In this study we show that myostatin levels are decreased in patients with cirrhosis, with lower levels in patients with acute decompensation and acute-on chronic liver failure (ACLF). Low myostatin levels in cirrhosis predict the development of ACLF and mortality independently of liver disease severity and sex.

Changes in peripheral blood mononuclear cells glutamine synthetase mRNA after exercise in healthy volunteers: exploring an alternative proposal for non hepatic ammonia metabolism.

BACKGROUND: Glutamine synthetase (GS) plays a central role in the inter-organ metabolism of ammonia and hepatic encephalopathy. The main objective of the present work was to disclose the possible effect of exercise on GS mRNA expression in peripheral blood mononuclear cells (PBMC) within a group of healthy volunteers. MATERIAL AND METHODS: PBMC were studied instead of skeletal muscle because of ethical concerns. Characterization of GS in lymphocytes was carried out by indirect immunofluorescence and Western blot. After a pilot trial, expression of GS mRNA in PBMC was assayed by serial measurements in healthy volunteers who had exercised on a treadmill, and on a control group who had not. Muscle mass was estimated by bioimpedance. RESULTS: Cytoplasmic GS had a molecular weight of 44 kDa. Serial measurements of its mRNA demonstrated an increase in the treadmill (n = 29), but not in the control group (n = 13) (p < 0.05). Peak expression occurred at 1 h in males and at 6 h in females. There was a positive correlation between muscle mass and the increase of the enzyme mRNA after exercise. CONCLUSION: Exercise can increase the expression of GS mRNA in PBMC in healthy volunteers. Based on these preliminary results and on well-established physiological concepts, a hypothesis for non-hepatic ammonia metabolism is conceived. In the future could become part of the treatment of low-grade hepatic encephalopathy.

Secondary sclerosing cholangitis after critical COVID-19: Three case reports.

BACKGROUND: The global coronavirus disease 2019 (COVID-19) pandemic has caused more than 5 million deaths. Multiorganic involvement is well described, including liver disease. In patients with critical COVID-19, a new entity called "post-COVID-19 cholangiopathy" has been described. CASE SUMMARY: Here, we present three patients with severe COVID-19 that subsequently developed persistent cholestasis and chronic liver disease. All three patients required intensive care unit admission, mechanical ventilation, vasopressor support, and broad spectrum antibiotics due to secondary infections. Liver transplant protocol was started for two of the three patients. CONCLUSION: Severe COVID-19 infection should be considered a potential risk factor for chronic liver disease and liver transplantation.

Clinicopathologic characteristics of severe COVID-19 patients in Mexico City: A post-mortem analysis using a minimally invasive autopsy approach.

OBJECTIVE: Describe the histological findings of minimally ultrasound-guided invasive autopsies in deceased patients with severe SARS-CoV-2 and compare the diagnostic yield with open autopsies. DESIGN: Observational post-mortem cohort study. Minimally invasive ultrasound-guided autopsies were performed in fourteen deceased patients with a confirmed diagnosis of SARS-CoV-2 pneumonia. Histological and clinical findings of lung, kidney, and liver tissue are described and contrasted with those previously reported in the literature. SETTING: Single-center COVID-19 reference center in Mexico City. RESULTS: Fourteen minimally invasive autopsies revealed a gross correlation with open autopsies reports: 1) Lung histology was characterized mainly by early diffuse alveolar damage (12/13). Despite low lung compliances and prolonged mechanical ventilation, the fibrotic phase was rarely observed (2/13). 2) Kidney histopathology demonstrated acute tubular injury (12/13), interstitial nephritis (11/13), and glomerulitis (11/13) as the predominant features 3) Liver histology was characterized by neutrophilic inflammation in all of the cases, as well as hepatic necrosis (8/14) despite minimal alterations in liver function testing. Hepatic steatosis was observed in most cases (12/14). SARS-CoV-2 positivity was widely observed throughout the immunohistochemical analysis. However, endothelitis and micro thrombosis, two of the hallmark features of the disease, were not observed. CONCLUSION: Our data represents the largest minimally invasive, ultrasound-guided autopsy report. We demonstrate a gross histological correlation with large open autopsy cohorts. However, this approach might overlook major histologic features of the disease, such as endothelitis and micro-thrombosis. Whether this represents sampling bias is unclear.

Prognostic performance of an index based on lactic dehydrogenase and transaminases for patients with liver steatosis and COVID-19.

BACKGROUND: Metabolic associated fatty liver disease (MAFLD) is associated with complications and mortality in patients with coronavirus disease 2019 (COVID-19). However, there are no prognostic scores aimed to evaluate the risk of severe disease specifically in patients with MAFLD, despite its high prevalence. Lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase have been used as markers of liver damage. Therefore, we propose an index based on lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase for the prediction of complications and mortality in patients with MAFLD and COVID-19. AIM: To evaluate the prognostic performance of an index based on lactate dehydrogenase and transaminases (aspartate aminotransferase/alanine aminotransferase) in patients with COVID-19 and MAFLD [liver fibrosis and nutrition (LNF)-COVID-19 index]. METHODS: In this retrospective cohort study, two cohorts from two different tertiary centers were included. The first was the derivation cohort to obtain the score cutoffs, and the second was the validation cohort. We included hospitalized patients with severe COVID-19 and MAFLD. Liver steatosis was evaluated by computed tomography scan. Area under the receiver operating characteristic (ROC) curve analysis and survival analysis were used. RESULTS: In the derivation cohort, 44.6% had MAFLD; ROC curve analysis yielded a LFN-COVID-19 index > 1.67 as the best cutoff, with a sensitivity of 78%, specificity of 63%, negative predictive value of 91% and an area under the ROC curve of 0.77. In the multivariate analysis, the LFN-COVID-19 index > 1.67 was independently associated with the development of acute kidney injury (odds ratio: 1.8, 95% confidence interval: 1.3-2.5, P < 0.001), orotracheal intubation (odds ratio: 1.9, 95% confidence interval: 1.4-2.4, P < 0.001), and death (odds ratio: 2.86, 95% confidence interval: 1.6-4.5, P < 0.001) in both cohorts. CONCLUSION: LFN-COVID-19 index has a good performance to predict prognosis in patients with MAFLD and COVID-19, which could be useful for the MAFLD population.

Clinical perspectives, assessment, and mechanisms of metabolic-associated fatty liver disease in patients with COVID-19.

Metabolic diseases are highly prevalent worldwide and have been associated with adverse clinical outcomes, including mortality, in patients developing coronavirus disease (COVID-19). Because of the close relationship between metabolic diseases such as type 2 diabetes mellitus and obesity and the presence of metabolic-associated fatty liver disease (MAFLD), a high number of cases of patients affected by both MAFLD and COVID-19 would be expected, especially in high-risk populations. Some studies have shown an increased risk of adverse clinical outcomes, viral shedding, and deep vein thrombosis, especially in patients with MAFLD- related liver fibrosis. The predisposition to poor outcomes and severe acute respiratory syndrome coronavirus 2 infection in patients with MAFLD could be secondary to mechanisms common to both, including preexisting systemic chronic inflammation, endothelial dysfunction, and involvement of the renin-angiotensin system. Because of the increased risk of adverse outcomes, MAFLD should be screened in all patients admitted for COVID-19. Available computed tomography scans could be of help, assessment of liver fibrosis is also recommended, favoring noninvasive methods to limit the exposure of healthcare workers. Liver involvement in this population ranges from abnormalities in liver chemistry to hepatic steatosis in postmortem biopsies. Finally, preventive measures should be strongly advocated in patients already known to have MAFLD, including the use of telemedicine and vaccination in addition to general measures.

Nutritional therapy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and presents together with cirrhosis in most cases. In addition to commonly recognized risk factors for HCC development, such as hepatitis B virus/hepatitis C virus infection, age and alcohol/tobacco consumption, there are nutritional risk factors also related to HCC development including high intake of saturated fats derived from red meat, type of cooking (generation of heterocyclic amines) and contamination of foods with aflatoxins. On the contrary, protective nutritional factors include diets rich in fiber, fruits and vegetables, n-3 polyunsaturated fatty acids and coffee. While the patient is being evaluated for staging and treatment of HCC, special attention should be paid to nutritional support, including proper nutritional assessment and therapy by a multidisciplinary team. It must be considered that these patients usually develop HCC on top of long-lasting cirrhosis, and therefore they could present with severe malnutrition. Cirrhosis-related complications should be properly addressed and considered for nutritional care. In addition to traditional methods, functional testing, phase angle and computed tomography scan derived skeletal muscle index-L3 are among the most useful tools for nutritional assessment. Nutritional therapy should be centered on providing enough energy and protein to manage the increased requirements of both cirrhosis and cancer. Supplementation with branched-chain amino acids is also recommended as it improves response to treatment, nutritional status and survival, and finally physical exercise must be encouraged and adapted to individual needs.

Abnormal Liver Function Test in Patients Infected with Coronavirus (SARS-CoV-2): A Retrospective Single-Center Study from Spain.

The outbreak of the novel coronavirus SARS-CoV-2 epidemic has rapidly spread and still poses a serious threat to healthcare systems worldwide. In the present study, electronic medical records containing clinical indicators related to liver injury in 799 COVID-19-confirmed patients admitted to a hospital in Madrid (Spain) were extracted and analyzed. Correlation between liver injury and disease outcome was also evaluated. Serum levels of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma-glutamyltransferase (GGT), Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH) and AST/ALT ratio were elevated above the Upper Limit of Normal (ULN) in 25.73%, 49.17%, 34.62%, 24.21%, 55.84% and 75% of patients, respectively. Interestingly, significant positive correlation between LDH levels and the AST/ALT ratio with disease outcome was found. Our data showed that SARS-CoV-2 virus infection leads to mild, but significant changes in serum markers of liver injury. The upregulated LDH levels as well as AST/ALT ratios upon admission may be used as additional diagnostic characteristic for COVID-19 patients.