Abstract Ferroptosis is a form of cell death characterized by a pro‐oxidative cellular milieu and iron‐dependent lipid peroxidation. Ferroptosis has been implicated in various forms of liver injury, in keeping with the major role of the liver in iron metabolism. Limited research has addressed potential differences in ferroptosis mediators with age and sex, especially in an in vivo model. The goal of this investigation was to evaluate hepatic labile iron and mediators of ferroptosis with ageing in both sexes. Because female animals generally display greater antioxidant defences than males, we hypothesized that females would display a phenotype resistant to ferroptosis. Here, we determined iron contents, protein expression of ferroptosis mediators and measures of oxidative injury in liver samples from 12‐ and 24‐month‐old male and female Fischer 344 rats. In comparison to males, the livers of female rats at both ages contained more non‐haem iron, which was associated with greater ferritin heavy chain expression and attenuated expression of transferrin receptor‐1. In female rats, the 24‐month‐old group had higher contents of thiobarbituric acid reactive substances compared with their 12‐month‐old counterparts, yet similar contents of labile iron. These results suggest a disconnect between labile iron contents and oxidative injury with age. Female animals also displayed greater expression of acyl‐CoA synthetase long‐chain family member 4 (ACSL4), a modulator of ferroptosis, and greater abundance of high molecular weight 4‐hydroxnonenal‐modified proteins. These results demonstrate clear differences in iron and ferroptosis mediators between sexes and suggest that female rats of this strain might be more susceptible to ferroptosis.

ABSTRACTBackgroundNationwide US data on readmission rates for patients with cirrhosis admitted with hepatorenal syndrome (HRS) is lacking. We reviewed 30‐day readmission rates after HRS‐related hospitalizations, the associated predictors of readmissions, and their impact on resource utilization and mortality in the United States.MethodsWe identified all adults admitted with HRS between 2016 and 2019 using the Nationwide Readmission database of the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project. The primary outcome was all‐cause 30‐day readmission rate. Secondary outcomes were inpatient mortality rate, predictors of readmission, and resource utilization.ResultsWe identified 245 850 hospitalizations of patients admitted for HRS in the United States from 2016 to 2019. Of these, 214 890 met the inclusion criteria. Mean age was 59.16 years, and 61.31% were males. Medicare was the most common primary payer (44.82%) followed by Medicaid (25.58%). The readmission rate was 24.6% within 30 days of discharge from index hospitalization. The most common cause of readmission was alcoholic cirrhosis with ascites (14.87%), followed by sepsis (9.32%) and unspecified hepatic failure (9%). The in‐hospital mortality rate for index hospitalization was 29.52% and 14.35% among those readmitted within 30 days. The mean length of stay (12.33 days vs. 7.15 days, p < 0.01) and hospitalization costs ($44 903 vs. $22 353, p < 0.01) were higher for index hospitalizations than readmissions.ConclusionsOur study demonstrated that all‐cause 30‐day readmission and in‐hospital mortality rates after the development of HRS were strikingly high. This warrants health policies and interventions at the institutional level, including close post‐hospital discharge follow‐up, to decrease readmission rates, improve patient outcomes, and reduce cost burden.

Spur cell anemia (SCA) is an acquired form of non-autoimmune hemolytic anemia that occurs in advanced liver disease. It is characterized by the presence of acanthocytes or spur cells, spiculated erythrocytes whose shortened life span causes anemia that is unresponsive to transfusion. SCA has been regarded as a rare condition with an ominous prognosis for which the only known cure is liver transplantation, but recent prospective studies have demonstrated the existence of a milder form of SCA in which there are smaller numbers of acanthocytes, but which is nevertheless associated with hemolysis and poor outcomes. This form of SCA appears to be considerably more common than the severe classical variant. The conventional understanding of the pathogenesis of SCA is that abnormalities of lipid metabolism are the primary event driving the formation of spur cells. However, the studies that underpin this theory are based on small numbers of patients with heterogeneous clinical features and inconsistent use of nomenclature for dysmorphic red blood cells. In this review, we discuss the evolution of the current understanding of SCA and therapeutic strategies that have been employed based on this understanding. Our goal is to raise awareness of this understudied condition that has significant implications for patient outcomes. Furthermore, we highlight the need for rigorous, contemporary research into the underlying cause or causes of SCA in order to develop an effective therapy for this disorder.

Abstract Background and Aim Previous studies conducted at single centers have suggested that patients with cirrhosis are at a greater risk for worse outcomes with COVID‐19. However, there is limited data on a national level in the United States. We aimed to study hospital‐related outcomes and identify the predictors of poor outcomes in patients with cirrhosis and concurrent COVID‐19. Methods We queried 2020 National Inpatient and Readmission databases to identify all hospitalizations due to cirrhosis in adults with a diagnosis of COVID‐19. Primary outcomes included inpatient mortality, mechanical ventilation (MV), and intensive care unit (ICU) utilization. Secondary outcomes included mean length of stay (LOS) and mean hospitalization costs. We classified cirrhosis into compensated (CC) and decompensated (DC) groups. Results We identified 25194 hospitalizations of adult patients due to cirrhosis with a concurrent diagnosis of COVID‐19. These patients had higher mortality (19.50% vs 6.19%, P ≤ 0.01), MV (11.7% vs 2.8%, P ≤ 0.01), ICU utilization (17.3% vs 8.1%, P ≤ 0.01), LOS (8.89 days vs 6.16 days, P ≤ 0.01), and total hospitalization costs ($24 817 vs $18 505, P ≤ 0.01) than those without COVID‐19. On subgroup analysis, patients in the DC group had higher mortality, LOS, and hospitalization costs compared to those in the CC group. On multivariate analysis, we also found that COVID‐19 infection, age, Charlson Comorbidity Index ≥3, acute kidney injury, end‐stage renal disease, septic shock, acute respiratory failure, MV, and ICU status were independent predictors for mortality. Conclusion Our study suggests that COVID‐19 infection is an independent predictor of mortality in patients with cirrhosis, with threefold higher mortality and increased resource utilization. Early intervention through immunizations and advanced COVID‐19 therapies can help improve these outcomes.

OBJECTIVES:Dysregulation of hepcidin-iron axis is presumed to account for abnormal iron status in patients with chronic liver disease (CLD). Our aim is to determine the effect of specific etiologies of CLD and of cirrhosis on serum hepcidin levels. METHODS:PubMed, Embase, Web of Science were searched for studies comparing serum hepcidin levels in patients with CLD to that in controls using enzyme-linked immunosorbent assay. The study was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Guidelines. Statistical analysis was carried out with STATA using random effects model to calculate the mean difference (MD) between two groups. RESULTS:Hepcidin levels were significantly lower in subjects with hepatitis C virus (16 studies) [MD -1.6 (95 % CI: -2.66 to -0.54), p<0.01] and alcoholic liver disease (3 studies) [MD -0.84 (95 % CI: -1.6 to -0.07), p=0.03] than controls. Serum hepcidin was significantly higher in subjects with non-alcoholic fatty liver disease (12 studies) [MD 0.62 (95 % CI: 0.21 to 1.03), p<0.01], but did not differ in subjects with hepatitis B and controls (eight studies) [MD -0.65 (95 % CI: -1.47 to 0.16), p=0.12]. Hepcidin levels were significantly lower in patients with cirrhosis of any etiology (four studies) [MD -1.02 (CI: -1.59 to -0.45), p<0.01] vs. controls (CI: confidence interval). CONCLUSIONS:Serum hepcidin levels are altered in common forms of CLD albeit not in a consistent direction. Additional study is needed to determine how changes in hepcidin levels are related to dysregulation of iron metabolism in CLD.

Her medical history included gastroesophageal reflux disease and Sjögren syndrome. She had recently returned from travel to Malaysia.

Introduction: Acute liver failure (ALF) affects ∼2000 individuals annually in the United States. ALF due to malignancy accounts for 1.4% of cases and 0.16% are due to T-cell lymphomas. ALF due to malignant infiltration is associated with a mortality of 85% within 3 weeks. Case Description/Methods: A 60-year-old man with a history of peripheral T-cell lymphoma (PTCL) presented to an emergency department (ED) with fatigue, lethargy, nausea, and diarrhea for 7 days. He had completed 6 cycles of chemotherapy 2 weeks prior to presentation (PTP) and was reported to be in remission. He had taken antibiotics for perianal abscess 5 days PTP. Labs at ED showed ALT 261 U/L, AST 202 U/L, ALP 909 U/L, GGT 1215 U/L, total bilirubin 3 mg/dL, LDH 251 U/L, INR 1.2. Liver panel 1 week prior was normal. Hepatitis A, B, C were negative. No significant alcohol history. MRCP showed no obstruction and normal liver parenchyma. On day 2, he developed erythematous, non-blanching papules all over the body (Figure 1). He was transferred to our tertiary care facility on day 5. Liver biopsy was deferred since biopsy of the rash showed lymphoma cutis. WBC differential showed atypical lymphoid cells with irregular nuclear features. Flow cytometry confirmed the atypical cells were consistent with PTCL. The number of PTCL cells doubled daily and the patient’s condition deteriorated, precluding further treatment of his PTCL. On day 8, he developed encephalopathy and labs were ALT 859, AST 2691, ALP 1113, total bilirubin 16.7, INR 2.8, and LDH 1851. Lactate rose to >20 mmol/L. He was transferred to the ICU on day 9 and died the same day due to multiorgan failure secondary to infiltrative PTCL. Discussion: ALF due to malignant infiltration can be difficult to diagnose. We initially considered drug induced liver injury since he completed 6 cycles of chemotherapy and was reported to be in remission 2 weeks PTP. Skin biopsy showing lymphoma cutis and atypical lymphoid cells on flow cytometry strongly suggested malignant infiltration of the liver. Early tissue diagnosis may improve outcomes, given how rapidly patients can deteriorate. A case series by Rich et al with 27 cases of ALF due to malignancy, initially found that 10 cases were indeterminant until liver biopsy showed malignancy, emphasizing the utility of obtaining a liver biopsy when the cause of ALF is uncertain. Reference Rich NE, Sanders C, Hughes RS, et al. Malignant infiltration of the liver presenting as acute liver failure. Clin Gastroenterol Hepatol. 2015;13(5):1025-1028.Figure 1.: A) taken on day 6 showing erythematous, non-blanching papules. H&E x20X (B) and CD7 (pan-T cell immunohistochemical stain) x20X (C). Sections of a punch of skin show an unremarkable epidermis with perivascular and periadnexal collections of markedly atypical T cells.

Portal hypertension contributes to splenomegaly in cirrhotic patients. Reduction in spleen size may represent improvement in portal hypertension. The goal was to determine whether reduction in spleen size following sustained virologic response (SVR) in patients with hepatitis C virus (HCV) cirrhosis is associated with lower risk of liver-related adverse outcomes. A retrospective cohort study was performed regarding HCV-infected patients treated with direct-acting antiviral agents at the Iowa City Veterans Administration Medical Center between 2014 and 2019. Patients with cirrhosis and splenomegaly on baseline ultrasound were included. Spleen size, platelet counts, decompensations, hepatocellular carcinoma (HCC) status, and mortality were recorded through July 31, 2021. Decrease in spleen size ≥1.5 cm was regarded as significant. Intergroup comparisons were performed on SPSS 28. Eighty patients with cirrhosis and splenomegaly before SVR were identified. Spleen sizes decreased significantly after SVR in 31 patients over a median of 1 year (Group A), whereas 49 patients did not meet this endpoint (Group B). Lack of spleen size reduction was associated with the presence of varices before SVR (odds ratio (OR): 5.3, p < 0.01). Group A had significantly greater increases in platelet count after SVR than did Group B. Patients in Group B had greater risk of HCC (OR: 9.7, CI: 1.2–79; p = 0.03) and death (OR: 3.6, CI: 1.1–12; p = 0.04). Reduced spleen size in patients with HCV cirrhosis after SVR is associated with greater increment in platelet count, decreased risk of HCC, and reduced mortality compared to patients whose spleen size does not decrease.

Introduction: Colonoscopy is widely used to diagnose colon cancers (CRC) and remove premalignant lesions. Per literature review, CRC continues to be diagnosed after an adequate colonoscopy and prior to the recommended time for repeat exam in between 3.7% to 8.2% of cases. The goal of our study was to determine the frequency of interval colorectal cancers (iCRCs) at our center, to assess factors associated with diagnoses of iCRC, and to evaluate the effects of iCRC on patient outcomes. Methods: We identified all patients with a histopathological diagnosis of CRC at the Iowa City VAMC for the past 10 years by searching specific SNOMED codes within the Pathology database. Interval CRC was defined as CRC diagnosed in the interval after a colonoscopy disclosed no cancer and before the recommended interval for repeat exam. Primary variables include demographics, comorbidities, stage & location of cancer, and quality of bowel preparation. Secondary variables were the length of survival after diagnosis, morbidity and mortality of iCRC patients. Kaplan Meier analysis was used to assess survival. Binomial logistic regression analysis was used to assess risk factors and poor prognosis. Chi square analysis was used to assess comorbidities and type of CRC. P-value < 0.05 was considered statistically significant. Results: One hundred and thirty-six patients were diagnosed with CRC over a 10-year interval. Type of CRC, mean age, and statistical significance of comorbidities are listed in Table 1. Right-sided CRCs were significantly more common in the group with iCRC (P=0.01). Tumor location and iCRC versus non-iCRC were not associated with prognosis (p >0.05), but older age at diagnosis (OR = 1.07 [1.02-1.12]; P=0.005) and advanced stage of cancer (OR=2.60 [1.02-6.63]; P=0.045) were significantly associated with poor prognosis. Of the 27 iCRC patients, 13 died with iCRC cited as the reason for hospice in 7. Median survival time (yrs) of iCRC and non-iCRC patients were 3.20 (95% CI 1.47-4.92) and 6.20 (95% CI 3.29-9.10), respectively (NS) (Figure 1). Conclusion: iCRCs comprised nearly 20% of total CRC cases in this series . The iCRC group tended to be older but there were no other clinical factors that differed between the iCRC and non-iCRC groups. The quality of bowel preparation documented on the prior colonoscopies of the iCRC group was adequate in most cases, making it unlikely that inadequate visualization was a major factor. The higher frequency of right-sided CRCs in iCRCs suggests that flat polyps that were missed may contribute to iCRCs.Figure 1.: Kaplan Meier Analysis of Survival Time Between iCRC and Non-iCRC Patients. Table 1. - Chi Square Analysis of Patient Comorbidities Between iCRC and Non-iCRC Patient Comorbidities iCRC (n=27) non-iCRC (n=109) P-value Mean (SD) age, years 73.9 (7.5) 64.9 (4.5) Alcohol Use (%) 8 (29.6) 27 (24.8) 0.605 Diabetes (%) 14 (51.9) 42 (38.5) 0.208 Diverticulosis (%) 16 (59.3) 42 (38.5) 0.051 Obesity (%) 13 (48.1) 48 (44) 0.701 Tobacco Use (%) 11 (40.7) 58 (53.2) 0.246

Introduction: Serum Hepcidin levels in chronic liver disease (CLD) are proposed biomarkers for hepatic iron load, inflammation, and fibrosis. Studies correlating serum hepcidin with these factors have yielded variable results. We carried out a meta-analysis to understand the effect on serum hepcidin levels on various aspects of CLD including systemic and hepatic iron levels, inflammation and liver synthetic capacity. Methods: We searched Pubmed, Embase and Web of Science for studies which measured serum hepcidin levels in patients with CLD from inception till 2020. We included studies where correlation of serum hepcidin levels with serum iron indices, inflammatory markers, grade of inflammation/fibrosis or iron score on liver biopsy was examined. Meta-analysis was done using STATA software applying the random effects model. Results: We found 1840 studies out of which 33 studies met inclusion criteria. Our meta-analysis showed that overall in patients with CLD, serum hepcidin levels (i) Correlated positively with iron indices, including serum ferritin (r50.41, p5, 0.0001), hemoglobin (r50.21, p5 0.011), transferrin saturation (r50.15, p50.01) and negatively with total iron binding capacity (r5-0.17, p50.048). There was no correlation with serum iron levels (r 5 0.07, p 50.333) (ii) Correlated positively with serum albumin levels (r50.19, p 50.007) (iii) Correlated positively with histological iron stores (r 5 0.46, p 5 0.001) (iv) Correlated positively with liver hepcidin mRNA levels (r50.51, p50.001) (v) Did not correlate with grade of inflammation or fibrosis on liver biopsy. On subgroup analysis chronic viral hepatitis differed significantly in that serum hepcidin levels had no correlation with iron indices such as hemoglobin (r50.14, p50.534), transferrin saturation (r50.13, p50.36) or total iron binding capacity (r5-0.01, p50.18). There continued to be a positive correlation with ferritin, albumin, hepcidin mRNA and histological iron score. (Figure) Conclusion: (i) Correlation with hepatic iron levels indicates that hepcidin iron axis is intact in CLD including viral hepatitis (ii) Lack of correlation with iron indices indicates that overall hepcidin production is suppressed in viral hepatitis (iii) Serum hepcidin levels likely depend on hepatic synthetic capacity as indicated by a positive correlation with serum albumin.