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Patients with chronic liver disease (CLD) and cirrhosis present a rebalanced hemostatic system in the three phases of haemostasis. This balance is however unstable and can easily tip towards bleeding or thrombosis. Management of both spontaneous bleeding and bleeding during invasive procedures remains a challenge in this patient population. Transfusion of blood products can result in circulatory overload and thereby worsen portal hypertension. As an alternative to fresh frozen plasma (FFP), prothrombin complex concentrates (PCC) may have merit in patients with liver disease because of their low volume. The impact of PCC in in-vitro spiking experiments of cirrhotic plasma is promising, but also warrants cautious use in light of thromboembolic risk. The majority of existing studies carried-out in CLD patients are retrospective or do not have an adequate control arm. A prospective study (the PROTON trial) was set up in 2013 to investigate the utility of PCC in patients undergoing liver transplantation. However, the study has never recruited the planned number of patients. Robust data on PCC safety in CLD is also required. The limited existing evidence does not seem to indicate an excessive thromboembolic risk. Currently, the utilisation of PCC in CLD cannot be routinely recommended but can provide an option for carefully selected cases in which other measures were not sufficient to control bleeding and after delicately weighing risks and benefits.

Background Male osteoporosis is under-diagnosed and poorly studied. With the ageing population, osteoporotic fracture in men is an emerging health problem. The aim of this study was to study the prevalence of osteoporosis and its association with serum testosterone and serum vitamin D in elderly men (>60 years old) attending the outpatient department (OPD). Methods An observational cross-sectional study was performed in elderly men (>60 years old) attending OPD of a tertiary care hospital of Western Maharashtra between April 2017 and June 2019. Patients with rheumatological disorders, history of vertebral/femoral fractures, chronic kidney disease, chronic liver disease, thyroid disorders and alcohol dependence were excluded. Data were analysed using the chi-square test and descriptive statistics. Results In total, 408 male patients were included. The mean age was 68.33 years. Osteoporosis was seen in 39.5% of patients (161/408) with a T score of ≤2.5. Osteopenia was noted in 48.3% of patients (197/408). T and Z scores had significant correlation (p = Conclusion Osteoporosis was noted in 39.5% of the elderly men. In addition, decreased testosterone, COPD and BPH were significantly associated with male osteoporosis. It is important to screen elderly men to diagnose osteoporosis early and prevent osteoporotic fractures.

Since the first identification in December of 2019 and the fast spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, it has represented a dramatic global public health concern. Though affecting mainly the respiratory system, SARS-CoV-2 disease, defined as coronavirus disease 2019 (COVID-19), may have a systemic involvement leading to multiple organ dysfunction. Experimental evidence about the SARS-CoV-2 tropism for the liver and the increasing of hepatic cytolysis enzymes during infection support the presence of a pathophysiological relationship between liver and SARS-CoV-2. On the other side, patients with chronic liver disease have been demonstrated to have a poor prognosis with COVID-19. In particular, patients with liver cirrhosis appear extremely vulnerable to infection. Moreover, the etiology of liver disease and the vaccination status could affect the COVID-19 outcomes. This review analyzes the impact of the disease stage and the related causes on morbidity and mortality, clinical outcomes during SARS-CoV-2 infection, as well as the efficacy of vaccination in patients with chronic liver disease.

Hepatopulmonary syndrome (HPS) is a serious complication of chronic liver disease, characterised by portal hypertension and arterial hypoxaemia due to intrapulmonary vascular dilatation. We report an unusual case in which a 27-year-old man had a first presentation of portal hypertension and cirrhosis complicated by HPS. This patient presented with progressive dyspnoea on exertion and deterioration in mobility, with a type 1 respiratory failure and increased oxygen demand. A bubble echocardiogram showed a possible right-to-left shunt, CT aortogram displayed evidence of portal hypertension and cirrhosis, and liver biopsy findings were consistent with alpha-1 antitrypsin deficiency. The patient’s increased oxygen demand was subsequently treated with continuous positive airway pressure before he was discharged with 8 L home oxygen. With no current established medical therapy for HPS, the patient was assessed for liver transplantation and a decision was made in favour of this.

Aim Dyslipidemia and altered iron metabolism are typical features of non-alcoholic fatty liver disease (NAFLD). Proprotein convertase subtilisin/kexin type 7 (PCSK7), a transmembrane-anchored endonuclease, is associated with triglycerides level and processing of transferrin receptor 1. However, the significance of circulating PCSK7 has not been fully addressed, though prosegment PCSK7 is secreted from cells. We investigated the associations of plasma PCSK7 level with several parameters. Methods Plasma PCSK7 concentration was measured in 282 subjects (male/female: 126/156) without medication of the Tanno-Sobetsu Study, a population-based cohort study. Results There was no significant sex difference in PCSK7 level. Current smoking habit, but not alcohol drinking habit, was associated with increased PCSK7 level. PCSK7 concentration was negatively correlated with age and blood urea nitrogen and was positively correlated with body mass index (BMI) and levels of γ-glutamyl transpeptidase (γGTP), triglycerides and fatty liver index (FLI), which is calculated by BMI, waist circumference and levels of γGTP and triglycerides, as a noninvasive and simple predictor of NAFLD. There were no significant correlations of PCSK7 level with levels of iron and plasma PCSK9, a secreted PCSK family member and a regulator of low-density lipoprotein cholesterol level. Multivariable regression analyses after adjustment of age, sex and current smoking habit showed that PCSK7 concentration was independently associated with BMI (β=0.130, P=0.035), triglycerides (β=0.141, P=0.027) or FLI (β=0.139, P=0.030). Conclusions Plasma PCSK7 concentration is independently associated with chronic liver disease including obesity and elevated triglycerides level in a general population of individuals who had not regularly taken any medications.

Sarcopenia, defined as progressive and generalized loss of muscle mass and strength, is common in chronic liver disease. It significantly impacts the quality of life and increases the risk of liver-related complications and mortality in cirrhotic patients. Moreover, recent studies showed a negative impact of sarcopenia on patients awaiting liver transplantation (LT), on post-LT outcomes, and on response to hepatocellular carcinoma therapies. Data about the influence of sex on the incidence, prevalence, diagnosis and treatment of sarcopenia in chronic liver diseases are poor and conflicting. The aims of this review of the literature are to define sex differences in sarcopenic cirrhotic patients and to highlight the necessity of a sex stratified analysis in future studies. This analysis of the literature showed that most of the studies are retrospective, with a higher prevalence of sarcopenia in males, probably due to anatomical differences between the sexes. Moreover, diagnostic criteria for sarcopenia are different between studies, as there is not a defined cut-off and, as a consequence, no comparable results. In conclusion, sex seems to have an impact on sarcopenia, and future studies must accurately investigate its role in identifying and treating high-risk patients, reducing the negative impact of sarcopenia on the survival and quality of life of cirrhotic patients.

Background Patients with cirrhosis suffer from many complications, including malnutrition, which must be managed promptly and effectively by the healthcare team. Educating patients about their medical condition, the risk of malnutrition and other complications of cirrhosis, could contribute to optimal nutritional status, quality of life and general health. Objective This review provides an overview of the literature on a variety of nutritional education strategies used with patients suffering from cirrhosis. This review also identifies barriers and facilitators which impact the adherence in using these strategies. Patient involvement A patient-partner contributed to this review by providing insights on different issues and concerns that patients with cirrhosis might ask themselves regarding nutritional education strategies. The patient-partner was also involved in the overall revision of the review. Methods Articles published between the years 2000–2023 focusing on nutritional education strategies in patients living with cirrhosis were identified using Google Scholar and PubMed and were screened for inclusion in the study. All selected studies were intervention studies. A quality assessment of the included studies was conducted using the Mixed Methods Appraisal Tool (MMAT). Results Only a few nutritional education strategies in patients with cirrhosis were documented in the literature. The strategies ranged from using traditional printed materials to advanced technologies. These strategies may prove beneficial in complementing routine interventions provided by health professionals, such as registered dietitians, in their clinical practice. Discussion This narrative review clearly highlights the need for further research to elaborate and evaluate nutritional education strategies for people living with cirrhosis. Practical value Elaborating and evaluating educational strategies in nutrition for patients living with cirrhosis will be an adjuvant to health professionals and dietitians in their clinical practice by providing them, and the patients, with targeted education resources.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) continues to have a devastating impact across the globe. However, little is known about the disease course in patients with autoimmune hepatitis (AIH). Methods Data for patients with AIH and SARS-CoV-2 infection were combined from three international reporting registries and outcomes were compared to those with chronic liver disease of other aetiology (non-AIH CLD) and to patients without liver disease (non-CLD). Results Between 25th March and 24th October 2020, data were collected for 932 patients with CLD and SARS-CoV-2 infection including 70 with autoimmune hepatitis (AIH). Fifty-eight (83%) of AIH patients were taking one or more immunosuppressive drug. There were no differences in rates of major outcomes between AIH and non-AIH CLD including hospitalization (76% vs 85%; p= 0.06), ICU admission (29% vs. 23%; p=0.240), and death (23% vs. 20%; p=0.643). Factors associated with death within the AIH cohort included age (OR 2.16/10 years; 1.07–3.81), Child-Turcotte-Pugh (CTP) class B (OR 42.48; 4.40–409.53), and CTP-C cirrhosis (OR 69.30; 2.83–1694.50), but not use of immunosuppression. Propensity score matched (PSM) analysis comparing AIH with non-AIH CLD demonstrated no increased risk adverse outcomes including death (+3.2%; -9.2%–15.7%). PSM analysis of AIH versus non-CLD patients (n=769) demonstrated increased risk of hospitalization with AIH (+18.4%; 5.6–31.2%), but equivalent risk of all other outcomes including death (+3.2%; -9.1%–15.6%). Conclusion AIH patients were not at increased risk of adverse outcomes despite immunosuppressive treatment compared to other causes of CLD and to matched cases without liver disease., Graphical abstract, Highlights • This is the largest cohort of patients with autoimmune hepatitis and laboratory proven SARS-COV-2 infection reported to date. • There were no differences in rates of major adverse COVID-19 outcomes including hospitalization, intensive care unit (ICU) admission, and death between AIH patients and those with other aetiologies of liver disease. • When compared to patients without liver disease in propensity score matched analysis, patients with AIH had higher rates of hospitalization but no increased risk of ICU admission or death despite potential reporting of AIH cases with more severe baseline liver disease. • Independent risk factors for death in AIH patients were age and baseline liver disease severity, but not the use of immunosuppression., Lay summary: Little is known about the outcomes of COVID-19 in patients with autoimmune hepatitis (AIH), a rare chronic inflammatory liver disease. This study combines data from three large registries to describe the course of COVID-19 in this patient group. We show that AIH patients do not appear to have an increased risk of death from COVID-19 compared to patients with other forms of liver disease and compared to patients without liver disease, despite the use of medications which suppress the immune system.

Hepatic encephalopathy (HE) is a frequent complication of chronic liver disease (CLD) and has a complex pathogenesis. Several preclinical and clinical studies have reported the presence of both peripheral and brain inflammation in CLD and their potential impact in the development of HE. Altered brain vascular density and tone, as well as compromised cerebral and systemic blood flow contributing to the development of brain hypoxia, have also been reported in animal models of HE, while a decrease in cerebral metabolic rate of oxygen and cerebral blood flow has consistently been observed in patients with HE. Whilst significant strides in our understanding have been made over the years, evaluating all these mechanistic elements in vivo and showing causal association with development of HE, have been limited through the practical constraints of experimentation. Nonetheless, improvements in non-invasive assessments of different neurophysiological parameters, coupled with techniques to assess changes in inflammatory and metabolic pathways, will help provide more granular insights on these mechanisms. In this special issue we discuss some of the emerging evidence supporting the hypothesis that brain inflammation and abnormal oxygen homeostasis occur interdependently during CLD and comprise important contributors to the development of HE. This review aims at furnishing evidence for further research in brain inflammation and oxygen homeostasis as additional therapeutic targets and potentially diagnostic markers for HE.

Brain manganese (Mn) accumulation is a key feature in patients with acquired hepatocerebral degeneration (AHD). The role of trace elements other than Mn in AHD needs to be clarified. In this study, using inductively coupled plasma mass spectrometry, we aimed to evaluate blood levels of trace elements in patients with AHD before and after liver transplantation (LT). Trace element levels in the AHD group were also compared with those of healthy controls (blood donors, n = 51). Fifty-one AHD patients were included in the study (mean age: 59.2 ± 10.6 years; men: 72.5%). AHD patients had higher levels of Mn, Li, B, Ni, As, Sr, Mo, Cd, Sb, Tl and Pb and a higher Cu/Se ratio, and lower levels of Se and Rb. Six patients (two women; mean age 55 ± 8.7 years) underwent LT, and there was an improvement in neurological symptoms, a significant increase in the Zn, Se and Sr levels, and a decrease in the Cu/Zn and Cu/Se ratios. In summary, several trace element imbalances were identified in AHD patients. Liver transplantation resulted in the improvement of neurological manifestations and the oxidant/inflammatory status. It is possible that observed changes in trace element levels may play a role in the pathophysiology and symptomatology of AHD.

Decreased circulating branched chain amino acids (BCAA) represent a prominent change in amino acid profiles in patients with end-stage liver disease (ESLD). These alterations are considered to contribute to sarcopenia and hepatic encephalopathy and may relate to poor prognosis. Here, we cross-sectionally analyzed the association between plasma BCAA levels and the severity of ESLD and muscle function in participants of the liver transplant subgroup of TransplantLines, enrolled between January 2017 and January 2020. Plasma BCAA levels were measured by nuclear magnetic resonance spectroscopy. Physical performance was analyzed with a hand grip strength test, 4 m walking test, sit-to-stand test, timed up and go test, standing balance test and clinical frailty scale. We included 92 patients (65% men). The Child Pugh Turcotte classification was significantly higher in the lowest sex-stratified BCAA tertile compared to the highest tertile (p = 0.015). The times for the sit-to-stand (r = −0.352, p < 0.05) and timed up and go tests (r = −0.472, p < 0.01) were inversely correlated with total BCAA levels. In conclusion, lower circulating BCAA are associated with the severity of liver disease and impaired muscle function. This suggests that BCAA may represent a useful prognostic marker in the staging of liver disease severity.

Evaluation of hepatic fibrosis is essential to prevent liver-related morbidity and mortality. Although various types of ultrasound shear wave elastography (SWE) have been used and validated, there are limited studies on the relatively newer technique, two-dimensional SWE (2D-SWE). Therefore, this study aimed to compare the diagnostic performances of 2D-SWE and point SWE (p-SWE) for evaluating liver fibrosis using histology as the reference standard. To measure liver stiffness (LS) values, 87 patients underwent 2D-SWE and p-SWE using the same machine. Technical failures and unreliable measurements were also evaluated. The diagnostic performances of 2D-SWE and p-SWE were compared using area under the receiver operating characteristic (AUROC) curve analysis. No technical failures were observed in either method; however, unreliable measurements were less frequent in 2D-SWE (1/87 [1.1%]) than in p-SWE (8/87 [9.2%]) (p < 0.001). The AUROC of the LS values of 2D-SWE were significantly higher than those of p-SWE for diagnosing significant fibrosis (0.965 vs. 0.872, p = 0.022) and cirrhosis (0.994 vs. 0.886, p = 0.042). In conclusion, 2D-SWE is more reliable and accurate than p-SWE for diagnosing hepatic fibrosis.

Chronic liver disease (CLD) is a serious condition where various toxins present in the blood affect the brain leading to type C hepatic encephalopathy (HE). Both adults and children are impacted, while children may display unique vulnerabilities depending on the affected window of brain development.We aimed to use the advantages of high field proton Magnetic Resonance Spectroscopy (1H MRS) to study longitudinally the neurometabolic and behavioural effects of Bile Duct Ligation (animal model of CLD-induced type C HE) on rats at post-natal day 15 (p15) to get closer to neonatal onset liver disease. Furthermore, we compared two sets of animals (p15 and p21-previously published) to evaluate whether the brain responds differently to CLD according to age onset.We showed for the first time that when CLD was acquired at p15, the rats presented the typical signs of CLD, i.e. rise in plasma bilirubin and ammonium, and developed the characteristic brain metabolic changes associated with type C HE (e.g. glutamine increase and osmolytes decrease). When compared to rats that acquired CLD at p21, p15 rats did not show any significant difference in plasma biochemistry, but displayed a delayed increase in brain glutamine and decrease in total-choline. The changes in neurotransmitters were milder than in p21 rats. Moreover, p15 rats showed an earlier increase in brain lactate and a different antioxidant response. These findings offer tentative pointers as to which neurodevelopmental processes may be impacted and raise the question of whether similar changes might exist in humans but are missed owing to 1H MRS methodological limitations in field strength of clinical magnet.

BACKGROUND AND AIMS: Noninvasive tools (NITs) reliably categorise patients with compensated advanced chronic liver disease (cACLD) into high-risk and low-risk group for harbouring varices needing treatment. Here, we assess the ability of these NITs to predict the need for nonselective beta-blockers at baseline based on risk of variceal bleeding (VB) on follow-up. METHODS: This was a retrospective multicentre analysis of patients with cACLD categorised at baseline into different risk groups by NITs (Baveno-VI, expanded Baveno-VI, platelet-albumin, platelet-model for end-stage liver disease (MELD) and anticipate study platelet criteria) and by endoscopy (high risk vs low risk/no varices). VB event rates on follow-up were estimated in different risk strata. Decision curve analysis (DCA) was used to estimate the benefit of administering nonselective beta-blockers (NSBB) using NITs over endoscopic classification at different threshold probabilities of VB event rates and estimating the number needed to treat (NNT) to identify one additional bleeder over endoscopy. RESULTS: A total of 1284 patients (mean age: 44.7 ± 13.5 years, 72.4% males) of hepatitis B (29.2%), nonalcoholic fatty liver disease (24.9%), hepatitis C (20.1%), and alcohol (17.5%)-related cACLD were included with 323 (25.2%) having high-risk varices. Ninety-eight (7.6%) patients developed VB over a median follow-up of 20 (9–35) months. The 1-year and 3-year rate of VB with all NITs was 5.7–7.4% and 13.2–16.4% among high-risk and 0–2.3% and 0–5% among low-risk subgroups, respectively (P

Patients with chronic liver disease (CLD) with or without cirrhosis remain at risk of developing hepatic decompensation when infected with viral or bacterial pathogens. The Advisory Committee on Immunization Practices (ACIP) currently recommends vaccination in CLD against hepatitis A virus (HAV), hepatitis B virus (HBV), influenza, pneumococcus, herpes zoster, tetanus, diphtheria, pertussis, and SARS-CoV-2. Inactivated vaccines are preferred over live attenuated ones, especially in transplant recipients where live vaccines are contraindicated. As the severity of the liver disease progresses, vaccine efficacy declines, and therefore, vaccines should be ideally administered early in the disease course for optimal immune response. Despite the strong recommendations, overall vaccination coverage in CLD remains poor; however, it is encouraging to note that in recent years coverage against influenza and pneumococcus has shown some improvement. Inadequate access to healthcare, lack of information on vaccine safety, poor financial reimbursement for healthcare providers, and vaccine misinformation are often responsible for low immunization rates. This review summarizes the impact of vaccine-preventable illness in those with CLD, updated vaccine guidelines, seroconversion rates in the vaccinated, and barriers faced by healthcare professionals in immunizing those with liver disease.

Background Patients with cirrhosis and coronavirus disease-2019 (COVID-19) have high in-hospital mortality. The information on outcome of cirrhosis patients in post-hospitalization period are limited. Aims We aimed to study the outcome of cirrhosis patients with COVID-19 after hospital discharge. Methods The records of the cirrhosis patients discharged after COVID-19 were reviewed. Their data were compared with a similar number of cirrhosis patients without COVID-19 after propensity score matching for age, sex, etiology of cirrhosis, and model for end-stage liver disease (MELD) score. Results Cirrhosis patients with (n=92) or without (n=92) COVID-19 were included in 1:1 ratio. The mortality among COVID-19 (22; 23.9%) and non-COVID-19 (19; 20.7%) were comparable (HR 1.224; 95% CI 0.663-2.263, P=0.520), over a similar duration of follow-up [186 (86-271) vs 183 (103-274)]. Among COVID-19 patients, 45; 48.9% developed a new acute decompensation-increased ascites (40; 43.5%), hepatic encephalopathy (20; 21.7%), or variceal bleeding (8; 8.7%) whereas 25 (27.2%) patients needed re-hospitalization. A proportion of participants continued to have either fatigue/weakness (24/80; 30.0%), sleep disturbances (11/80; 13.7%), or joint pains (16/80; 20.0%). The most common causes of death in patients of both groups were end-stage liver disease: 16 (72.7%) vs 9 (47.4%), followed by multiorgan dysfunction: 4 (18.2%) vs 6 (31.6%), GI bleeding: 2 (9.1%) vs. 4 (21.0%), P=0.484. A lower albumin level, higher international normalized ratio, bilirubin, Child-Turcotte-Pugh, and MELD scores at discharge predicted mortality in the COVID-19 group. Conclusion Short-term outcomes of patients with cirrhosis who survive the initial insult of COVID-19 are not different from patients without COVID-19, and survival is determined by the severity of liver disease at discharge.

Background/Aims: Sarcopenia is an independent prognostic factor of liver cirrhosis (LC). However, the association between LC-related systemic inflammation and sarcopenia is unclear.Methods: Sprague-Dawley rats were treated with thioacetamide (TAA) or saline as a control. Rifaximin was administered to TAA-induced LC rats. Enzyme-linked immunosorbent assay was performed to measure inflammatory mediators in rat serum. RT-PCR was performed to measure the molecular expression in tissues. Hematoxylin and eosin (H&E) staining and immunohistochemistry were performed to investigate tissue pathology. Serum tumor necrosis factor-α levels, liver stiffness (LS), and the L3 skeletal muscle index (L3SMI) were measured in 60 patients with chronic liver disease.Results: LC and sarcopenia were successfully induced by TAA. Serum TNF-α levels were increased in LC rats and correlated with myostatin expression, muscle weight, and myofiber diameter. The expression of intestinal occludin and zona occludens-1 was reduced in LC rats and associated with serum TNF-α levels and sarcopenia. In patients with LS ≥7 kPa or sarcopenia, serum TNF-α levels were significantly increased, which was also confirmed when we raised the LS cutoff to 10 kPa. The L3SMI was inversely correlated with serum TNF-α levels in patients with LS ≥7 kPa. TNF-α was reduced by rifaximin, which might have resulted in reduced expression of muscular MuRF1 and myostatin and improvements in myofiber diameters within muscle tissues.Conclusions: These results suggest that serum TNF-α is associated with LC-related sarcopenia. Rifaximin might be effective in reducing serum TNF-α levels and improving sarcopenia in LC, but these results need to be validated in future studies.

We appreciate the interest in our study by Majumdar and Tsochatzis1 and welcome the opportunity to provide some clarifications. The literature to date has examined non-invasive test (NIT) algorithms to rule-in and rule-out advanced fibrosis (AF). The main use of such algorithms is to identify those at low risk of AF who can be managed in primary care. We propose an algorithm2 where the rule-out cut-offs remain optimised for AF, whereas the rule-in cut-offs are optimised for cirrhosis. The false-negative (FN) rate of 10% in our proposed algorithm refers to the FN rate for AF and not cirrhosis as Majumdar and Tsochatzis state in their letter.1 Only 18/570 (3%) of patients with cirrhosis are missed using our proposed algorithm (table 1). View this table: Table 1 Number of patients with fibrosis stage F0–2, F3 and F4 according to LSM cut-offs recommended by the Baveno 6 consensus (10 and 15 kPa) and our previous paper (8 and 20, and 8 and 28 kPa) We also argue2 that patients with NITs above the rule-in cut-off for AF should undergo liver biopsy to identify those with cirrhosis who should undergo …

Patients with chronic liver disease (CLD) and cirrhosis present a rebalanced hemostatic system in the three phases of haemostasis. This balance is however unstable and can easily tip towards bleeding or thrombosis. Management of both spontaneous bleeding and bleeding during invasive procedures remains a challenge in this patient population. Transfusion of blood products can result in circulatory overload and thereby worsen portal hypertension. As an alternative to fresh frozen plasma (FFP), prothrombin complex concentrates (PCC) may have merit in patients with liver disease because of their low volume. The impact of PCC in in-vitro spiking experiments of cirrhotic plasma is promising, but also warrants cautious use in light of thromboembolic risk. The majority of existing studies carried-out in CLD patients are retrospective or do not have an adequate control arm. A prospective study (the PROTON trial) was set up in 2013 to investigate the utility of PCC in patients undergoing liver transplantation. However, the study has never recruited the planned number of patients. Robust data on PCC safety in CLD is also required. The limited existing evidence does not seem to indicate an excessive thromboembolic risk. Currently, the utilisation of PCC in CLD cannot be routinely recommended but can provide an option for carefully selected cases in which other measures were not sufficient to control bleeding and after delicately weighing risks and benefits.

To investigate the relationship between chronic liver disease and tendon disorder, a retrospective cohort study was conducted using the Kaohsiung Veterans General Hospital database. Patients >18 years with newly diagnosed liver disease and with at least a two-year follow-up in the hospital were included. An equal number of 20,479 cases were enrolled in both the liver-disease and non-liver-disease groups using a propensity score matching method. Disease was defined using ICD-9 or ICD-10 codes. The primary outcome was the development of tendon disorder. Demographic characteristics, comorbidities, use of tendon-toxic drugs, and status of HBV/HCV infection were included for analysis. The results showed 348 (1.7%) and 219 (1.1%) individuals developed tendon disorder in the chronic liver disease group and non-liver-disease group. Concomitant use of glucocorticoids and statins may have further raised the risk of tendon disorder in the liver disease group. The co-existence of HBV/HCV infection did not increase the risk of tendon disorder in the patients with liver disease. Considering these findings, physicians should be more aware of tendon issues in advance, and a prophylactic strategy should be adopted in patients with chronic liver disease.

Background:Factor V plays a crucial role in the coagulation process. Factor V Leiden (FVL) is considered a mutant form of factor V, which may contribute to blood vessel thrombosis. Also, Hepatitis C Virus (HCV) infection may exert some coagulation changes leading to Portal Vein Thrombosis (PVT). Thrombocytopenia in patients with chronic HCV infection constitutes a major challenge. Objective: This study aimed to investigate the incidence of FVL (factor V gene G1691A mutation) and its influence on coagulation among HCV chronically infected patients suffering from thrombocytopenia. Besides, it was designed to demonstrate the association of chronic HCV infection with coagulation disturbances in such patients. Methods: This study was conducted on blood samples of a total of 54 subjects (33 HCV chronically infected patients and 21 healthy controls). HCV chronically infected patients with thrombocytopenia (Platelet Count [PLC] below 150 thousand/microliter) were selected. Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPPT) were previously determined as coagulation parameters. Protein C and protein S antigens were determined by ELISA as coagulation-regulating (anticoagulants) parameters. All samples were investigated for the presence of FVL by real-time PCR. Results: PLC, PT, and protein C antigen showed highly significant differences (p < 0.001) between controls (group 1) and HCV chronically infected patients (group 2). Likewise, a highly significant change (p = 0.006) was achieved for the protein S antigen. A non-significant change was detected for the incidence of FVL with a heterozygous pattern between controls (group 1) and HCV chronically infected patients (group 2). Additionally, non-significant changes were detected for all of the investigated coagulation and coagulation-regulating (anticoagulants) parameters between control subjects with negative FVL (subgroup 1) and others with positive FVL (subgroup 2). Similarly, non-significant changes for such parameters were recoded for HCV chronically infected patients with negative FVL (subgroup 3) and others with positive FVL (subgroup 4). Conclusion: Chronic HCV infection in the presence of thrombocytopenia is associated with coagulation disturbances. The incidence of FVL with its heterozygous pattern is unaffected by chronic HCV infection, and no association is shown with worsening of coagulation in chronic hepatitis C patients suffering from thrombocytopenia.

Patients with chronic liver disease (CLD), including cirrhosis, are at increased risk of intractable viral infections and are hyporesponsive to vaccination. Hallmarks of CLD and cirrhosis include microbial translocation and elevated levels of type I interferon (IFN-I). We aimed to investigate the relevance of microbiota-induced IFN-I in the impaired adaptive immune responses observed in CLD.We combined bile duct ligation (BDL) and carbon tetrachloride (CCl4) models of liver injury with vaccination or lymphocytic choriomeningitis virus infection in transgenic mice lacking IFN-I in myeloid cells (LysM-Cre IFNARflox/flox), IFNAR-induced IL-10 (MX1-Cre IL10flox/flox) or IL-10R in T cells (CD4-DN IL-10R). Key pathways were blocked in vivo with specific antibodies (anti-IFNAR and anti-IL10R). We assessed T-cell responses and antibody titers after HBV and SARS-CoV-2 vaccinations in patients with CLD and healthy individuals in a proof-of-concept clinical study.We demonstrate that BDL- and CCL4-induced prolonged liver injury leads to impaired T-cell responses to vaccination and viral infection in mice, subsequently leading to persistent infection. We observed a similarly defective T-cell response to vaccination in patients with cirrhosis. Innate sensing of translocated gut microbiota induced IFN-I signaling in hepatic myeloid cells that triggered excessive IL-10 production upon viral infection. IL-10R signaling in antigen-specific T cells rendered them dysfunctional. Antibiotic treatment and inhibition of IFNAR or IL-10Ra restored antiviral immunity without detectable immune pathology in mice. Notably, IL-10Ra blockade restored the functional phenotype of T cells from vaccinated patients with cirrhosis.Innate sensing of translocated microbiota induces IFN-/IL-10 expression, which drives the loss of systemic T-cell immunity during prolonged liver injury.Chronic liver injury and cirrhosis are associated with enhanced susceptibility to viral infections and vaccine hyporesponsiveness. Using different preclinical animal models and patient samples, we identified that impaired T-cell immunity in BDL- and CCL4-induced prolonged liver injury is driven by sequential events involving microbial translocation, IFN signaling leading to myeloid cell-induced IL-10 expression, and IL-10 signaling in antigen-specific T cells. Given the absence of immune pathology after interference with IL-10R, our study highlights a potential novel target to reconstitute T-cell immunity in patients with CLD that can be explored in future clinical studies.

Background and Objectives: Many quantitative imaging modalities are available that quantify chronic liver disease, although only a few of them are included in clinical guidelines. Many more imaging options are still competing to find their place in the area of diagnosing chronic liver disease. We report our first prospective single-center study evaluating different imaging modalities that stratify viral hepatitis-associated liver fibrosis in a treatment-naïve patient group. Materials and Methods: The aim of our study is to compare and to combine already employed 2D shear wave elastography (2D-SWE) with dynamic liver scintigraphy with 99mTc-mebrofenin in chronic viral hepatitis patients for the staging of liver fibrosis. Results: Seventy-two patients were enrolled in the study. We found that both 2D-SWE ultrasound imaging, with dynamic liver scintigraphy with 99mTc-mebrofenin are able to stratify CLD patients into different liver fibrosis categories based on histological examination findings. We did not find any statistically significant difference between these imaging options, which means that dynamic liver scintigraphy with 99mTc-mebrofenin is not an inferior imaging technique. A combination of these imaging modalities showed increased accuracy in the non-invasive staging of liver cirrhosis. Conclusions: Our study presents that 2D-SWE and dynamic liver scintigraphy with 99mTc-mebrofenin could be used for staging liver fibrosis, both in singular application and in a combined way, adding a potential supplementary value that represents different aspects of liver fibrosis in CLD.

Red blood cell (RBC) alloimmunization is an important complication of blood transfusion. Variations in the frequency of alloimmunization have been noted among different patient populations. We aimed to determine the prevalence of RBC alloimmunization and associated factors among chronic liver disease (CLD) patients in our center. This is a case-control study involving 441 patients with CLD who were being treated at Hospital Universiti Sains Malaysia and subjected to pre-transfusion testing from April 2012 until April 2022. Clinical and laboratory data were retrieved and statistically analyzed. A total of 441 CLD patients were included in our study, with the majority being elderly, with the mean age of patients 57.9 (SD ± 12.1) years old, male (65.1%) and Malays (92.1%). The most common causes of CLD in our center are viral hepatitis (62.1%) and metabolic liver disease (25.4%). Twenty-four patients were reported to have RBC alloimmunization, resulting in an overall prevalence of 5.4%. Higher rates of alloimmunization were seen in females (7.1%) and patients with autoimmune hepatitis (11.1%). Most patients developed a single alloantibody (83.3%). The most common alloantibody identified belonged to the Rh blood group, anti-E (35.7%) and anti-c (14.3%), followed by the MNS blood group, anti-Mia (17.9%). There was no significant factor association of RBC alloimmunization among CLD patients identified. Our center has a low prevalence of RBC alloimmunization among CLD patients. However, the majority of them developed clinically significant RBC alloantibodies, mostly from the Rh blood group. Therefore, phenotype matching for Rh blood groups should be provided for CLD patients requiring blood transfusions in our center to prevent RBC alloimmunization.

Background and Aim: Physical activity confers health benefits in many diseases but remains almost unstudied for cirrhosis. We investigated whether a period of resistance training affects the subsequent long-term risk of hospitalization or mortality among patients with cirrhosis. Methods: The study includes 39 participants with cirrhosis Child–Pugh class A/B who participated in a prior clinical trial randomized to either resistance training three times per week for 12 weeks or a control group. We gathered data through medical records from trial entry and the following 3 years. The outcomes were time to first hospitalization and all-cause mortality. We used regression models to examine the associations between trial groups and outcomes, adjusting for Child–Pugh class, age, gender, and comorbidity. Results: Nine patients who trained and 15 controls were hospitalized, resulting in a lower risk of first hospitalization in the training group (adjusted subdistribution hazard ratio of 0.40, 95% confidence interval [CI] [0.17, 0.92]; P = 0.03). One patient who trained and six controls died, resulting in a lower all-cause mortality in the training group (adjusted hazard ratio of 0.06, 95% CI [0.01, 0.66]; P = 0.02). Conclusion: Twelve weeks of resistance training was associated with a reduced risk of first hospitalization and mortality among patients with cirrhosis Child–Pugh class A/B 3 years after trial entry. The mechanisms of this effect are not identified, and larger studies are warranted.

The incidence of chronic liver disease is on the rise. One of the primary causes of hospital admissions for patients with cirrhosis is hepatic encephalopathy (HE), a debilitating neurological complication. HE is defined as a reversible syndrome, yet there is growing evidence stating that, under certain conditions, HE is associated with permanent neuronal injury and irreversibility. The pathophysiology of HE primarily implicates a strong role for hyperammonemia, but it is believed other pathogenic factors are involved. The fibrotic scarring of the liver during the progression of chronic liver disease (cirrhosis) consequently leads to increased hepatic resistance and circulatory anomalies characterized by portal hypertension, hyperdynamic circulatory state and systemic hypotension. The possible repercussions of these circulatory anomalies on brain perfusion, including impaired cerebral blood flow (CBF) autoregulation, could be implicated in the development of HE and/or permanent brain injury. Furthermore, hypotensive insults incurring during gastrointestinal bleed, infection, or liver transplantation may also trigger or exacerbate brain dysfunction and cell damage. This review will focus on the role of hypotension in the onset of HE as well as in the occurrence of neuronal cell loss in cirrhosis.

Bolest COVID-19 je u rekordnom vremenu iz respiratorne viroze prerasla u globalnu pandemiju koja je u svega nekoliko mjeseci paralizirala gotovo svaki aspekt modernoga života. Uzročnik bolesti, SARS-CoV-2, ulazi u ljudske stanice putem ACE2 receptora koji su prisutni na stanicama organa kao što su pluća, tanko i debelo crijevo, srce, štitnjača, ali i jetra. Suprotno očekivanjima, pokazalo se da je ACE2 receptor više prisutan na kolangiocitima nego na hepatocitima. Štoviše, na životinjskim modelima utvrđena je povećana ekspresija ACE2 receptora na kolangiocitima nakon parcijalne hepatektomije što se može izravno povezati s povećanom incidencijom COVID-19 kod pacijenata s presadkom jetre. Oštećenje jetre može nastati izravnim učinkom virusa, pretjeranim imunološkim odgovorom na infekciju, hepatotoksičnošću lijekova, hipoksijskom ozljedom i/ili egzacerbacijom kronične bolesti jetre. Akutna jetrena lezija kod oboljelih od COVID-19 najčešće se očituje kao asimptomatski porast jetrenih enzima. Pacijenti s kroničnom bolesti jetre i pacijenti s transplantiranom jetrom pod povećanim su rizikom od oboljenja od COVID-19 i od razvoja teške kliničke slike, a osobe s dekompenziranom cirozom jetre, alkoholnom bolesti jetre te hepatocelularnim karcinomom imaju povećan rizik smrtnosti od COVID-19. Pokazalo se da imunosupresivni lijekovi stupaju u interakciju s virusnim mehanizmom na različite načine koji mogu biti ili štetni ili protektivni ovisno o vrsti lijeka koji se koristi. Shodno navedenome, opravdano je promijeniti vrstu imunosupresivne terapije u svrhu poboljšanja kliničkog ishoda kod pacijenata s transplantiranom jetrom oboljelih od COVID-19. Nadalje, pokazalo se da smanjenje doze imunosupresivne terapije nema pozitivnog učinka na klinički ishod, te zbog toga nije preporučeno, osim u specifičnim slučajevima. Kvalitetna i pravovremena zdravstvena skrb najznačajniji je čimbenik preživljenja zbog čega su svjetska društva za bolesti jetre izdala preporuke za provođenje programa probira i kontrolnih pregleda u uvjetima pandemije. Također, dostupno je i cijepljenje protiv COVID-19 koje se preporuča svim pacijentima s kroničnom bolesti jetre i pacijentima s transplantiranom jetrom., COVID-19 has gone from a respiratory disease to a global pandemic that has paralyzed nearly every facet of the modern world in mere months. SARS-CoV-2 infiltrates human cells via the ACE2 receptor which is expressed in many different organs such as the lungs, the intestines, the heart, the thyroid and the liver. Contrary to expectations, it has been observed that ACE2 receptors are several times more commonly found on cholangiocytes as opposed to hepatocytes. Moreover, tests done on animal models have shown increased ACE2 receptor expression in cholangiocytes following a partial hepatectomy which could be directly associated with the increased incidence of COVID-19 in liver transplant patients. Liver damage may arise as a consequence of direct viral infection, excessive immune response, drug hepatotoxicity, hypoxic tissue injury and/or exacerbation of chronic liver disease. Acute liver damage in COVID-19 patients most commonly manifests as an asymptomatic elevation in liver enzymes. Patients with chronic liver disease and liver transplant patients are at an increased risk of contracting COVID-19 and developing severe COVID while increased mortality risk of COVID-19 has been found in patients with cirrhosis, alcoholic liver disease and hepatocellular carcinoma. It has been observed that immunosuppressants interact with viral replication mechanisms in ways that can be either beneficial or damaging depending on the type of drug used. Therefore, it is justified to change the type of immunosuppressant therapy in order to achieve a more favourable clinical outcome in liver transplant patients. In addition, immunosuppressant dosage reduction does not appear to have a positive clinical effect and is thus not recommended, except under specific circumstances. Timely medical care of high quality is the most impactful factor of survival in these patients which is why the world liver societies have issued recommendations for carrying out screening programmes and check-ups under the restraints of the pandemic. On top of that, anti-COVID vaccines are readily available and vaccination is recommended for all patients with chronic liver disease and liver transplant patients.

A scoping review to identify core components in effective symptom self-management interventions among adults with chronic illness.

L’épidémie d’obésité représente un enjeu de santé majeur. Les femmes en âge de procréer sont particulièrement touchées. L’objectif de cette thèse est de comprendre l’impact de l’obésité maternelle sur le risque de développer une maladie hépatique. Nous avons démontré que l’obésité maternelle entraînait de profonds changements de l’expression des gènes hépatiques. Nous avons constaté une association entre l’obésité maternelle et des taux plus élevés de stéatose, fibrose et d’inflammation. La descendance des mères obèses présente également un risque plus élevé de développer des tumeurs hépatiques. Les modifications du microbiome intestinal de la progéniture des souris obèses sont conservées à l’âge adulte. En restaurant un microbiome normal, nous avons pu réduire le risque de développer un cancer du foie. Ces observations mettent en évidence le rôle clé du microbiome intestinal dans la transmission des maladies du foie de la mère à l’enfant, et ouvrent la voie vers le développement de thérapies., The obesity epidemic represents a major challenge to our health systems. Women of childbearing age are particularly affected. Overweight and obesity have a multitude of adverse health effects and can lead to chronic liver disease and liver cancer. In addition, maternal obesity is associated with metabolic disorders in children, and an increased rate of childhood cancers. Obesity alters the composition of the gut microbiome, which contributes to the progression of chronic liver disease and is passed on to the next generation. The objective of this thesis is to understand the impact of maternal obesity on the risk of developing chronic liver disease and liver cancer in children, and the role of the microbiome in this context. We have demonstrated, in a mouse model, that maternal obesity leads to profound changes in gene expression in their offspring. We observed that signaling pathways of the innate immune system and the cell cycle are altered, and that genes important for the development of chronic liver diseases are dysregulated. In addition, we found that maternal obesity leads to higher rates of steatosis, fibrosis and inflammation in adult offspring of obese mothers. The offspring of obese mothers also have a significantly higher risk of developing liver tumors. The gut microbiome of offspring of obese mouse mothers is altered and these alterations are retained into adulthood. By restoring a normal microbiome, we were able to normalize the next generation's risk of developing liver cancer. This highlights the key role of the gut microbiome and its alterations in the transmission of liver disease from mother to child, and paves the way for the development of a future therapy.

Adult hepatocyte identity is constructed throughout embryonic development and fine-tuned after birth. A multinodular network of transcription factors, along with pre-mRNA splicing regulators, define the transcriptome, which encodes the proteins needed to perform the complex metabolic and secretory functions of the mature liver. Transient hepatocellular dedifferentiation can occur as part of the regenerative mechanisms triggered in response to acute liver injury. However, persistent downregulation of key identity genes is now accepted as a strong determinant of organ dysfunction in chronic liver disease, a major global health burden. Therefore, the identification of core transcription factors and splicing regulators that preserve hepatocellular phenotype, and a thorough understanding of how these networks become disrupted in diseased hepatocytes, is of high clinical relevance. In this context, we review the key players in liver differentiation and discuss in detail critical factors, such as HNF4α, whose impairment mediates the breakdown of liver function. Moreover, we present compelling experimental evidence demonstrating that restoration of core transcription factor expression in a chronically injured liver can reset hepatocellular identity, improve function and ameliorate structural abnormalities. The possibility of correcting the phenotype of severely damaged and malfunctional livers may reveal new therapeutic opportunities for individuals with cirrhosis and advanced liver disease.

© 2023 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)., Background & aims: The response of patients with chronic liver disease (CLD) to COVID-19 vaccines remains unclear. Our aim was to assess the humoral immune response and efficacy of two-dose COVID-19 vaccines among patients with CLD of different aetiologies and disease stages. Methods: A total of 357 patients were recruited in clinical centres from six European countries, and 132 healthy volunteers served as controls. Serum IgG (nM), IgM (nM), and neutralising antibodies (%) against the Wuhan-Hu-1, B.1.617, and B.1.1.529 SARS-CoV-2 spike proteins were determined before vaccination (T0) and 14 days (T2) and 6 months (T3) after the second-dose vaccination. Patients fulfilling inclusion criteria at T2 (n = 212) were stratified into 'low' or 'high' responders according to IgG levels. Infection rates and severity were collected throughout the study. Results: Wuhan-Hu-1 IgG, IgM, and neutralisation levels significantly increased from T0 to T2 in patients vaccinated with BNT162b2 (70.3%), mRNA-1273 (18.9%), or ChAdOx1 (10.8%). In multivariate analysis, age, cirrhosis, and type of vaccine (ChAdOx1 > BNT162b2 > mRNA-1273) predicted 'low' humoral response, whereas viral hepatitis and antiviral therapy predicted 'high' humoral response. Compared with Wuhan-Hu-1, B.1.617 and, further, B.1.1.529 IgG levels were significantly lower at both T2 and T3. Compared with healthy individuals, patients with CLD presented with lower B.1.1.529 IgGs at T2 with no additional key differences. No major clinical or immune IgG parameters associated with SARS-CoV-2 infection rates or vaccine efficacy. Conclusions: Patients with CLD and cirrhosis exhibit lower immune responses to COVID-19 vaccination, irrespective of disease aetiology. The type of vaccine leads to different antibody responses that appear not to associate with distinct efficacy, although this needs validation in larger cohorts with a more balanced representation of all vaccines. Impact and implications: In patients with CLD vaccinated with two-dose vaccines, age, cirrhosis, and type of vaccine (Vaxzevria > Pfizer BioNTech > Moderna) predict a 'lower' humoral response, whereas viral hepatitis aetiology and prior antiviral therapy predict a 'higher' humoral response. This differential response appears not to associate with SARS-CoV-2 infection incidence or vaccine efficacy. However, compared with Wuhan-Hu-1, humoral immunity was lower for the Delta and Omicron variants, and all decreased after 6 months. As such, patients with CLD, particularly those older and with cirrhosis, should be prioritised for receiving booster doses and/or recently approved adapted vaccines., Partial funds were provided through Fundação para a Ciência e a Tecnologia (grants PTDC/MED-PAT/31882/2017 and EXPL/MED-OUT/1317/2021) and through La Caixa Scientific Foundation (grant HR17-00601).

Background & aims There is no “gold standard” tool for the assessment of frailty in cirrhosis. This study compares Liver Frailty Index (LFI), Short Physical Performance Battery (SPPB), Fried Frailty Criteria (FFC), and Clinical Frailty Scale (CFS) for frailty assessment and ascertains its impact on predicting mortality and hospitalizations in a cohort of outpatients with cirrhosis. Methods 116 patients were enrolled in this prospective observational cohort study. Frailty assessment was done using LFI, SPPB, FFC, and CFS. All patients were followed up for 6 months. The primary outcome was the first of either all-cause unplanned hospitalization or all-cause mortality occurring within 6 months of the study period. Results 100 (86.2%) males and 16 (13.8%) females with a mean age of 50.2 (48.4–51.9, 95% CI) years were included. The most common cause of cirrhosis was alcoholic liver disease (47.4%) followed by hepatitis C (12.9%) and Nonalcoholic steatohepatitis (NASH) (10.3%). There was no significant difference in prevalence of frailty based on LFI (43.1%), FFC (36.2%), CFS (44%), and SPPB (47.4%) (P > 0.05). Frail patients had worse outcomes compared to the Not frail group. At 6 months, the mortality rate in Frail patients was 42% versus 1.5% for the Not frail; hospitalization in Frail patients occurred in 92% versus 6% in the Not frail. On multivariable analysis, independent predictors of mortality were Frailty [OR 14 (1.4–54.2)], alcohol-related cirrhosis [OR 4.2 (1.1–16.3)], Child-Turcotte-Pugh (CTP) [OR 2.1 (1.4–2.9)] and Chronic liver disease questionnaire (CLDQ) [OR 0.1 (0.1–0.4)] scores. Conclusions LFI, SPPB, FFC, and CFS are comparable in frailty assessment in patients with cirrhosis. Importantly, comparability of the commonly used scores for frailty assessment and prediction of hospitalization and mortality allows flexibility for clinical application.

Depression and chronic liver disease (CLD) are important causes of disability, morbidity and mortality worldwide and their prevalence continues to rise. The rate of depression in CLD is high compared to that of the general population and is comparable to the increased rates observed in other medical comorbidities and chronic inflammatory conditions. Notably, a comorbid diagnosis of depression has a detrimental effect on outcomes in cirrhosis. Systemic inflammation is pivotal in cirrhosis-associated immune dysfunction - a phenomenon present in advanced CLD (cirrhosis) and implicated in the development of complications, organ failure, disease progression, increased infection rates and poor outcome. The presence of systemic inflammation is also well-documented in a cohort of patients with depression; peripheral cytokine signals can result in neuroinflammation, behavioural change and depressive symptoms via neural mechanisms, cerebral endothelial cell and circumventricular organ signalling, and peripheral immune cell-to-brain signalling. Gut dysbiosis has been observed in both patients with cirrhosis and depression. It leads to intestinal barrier dysfunction resulting in increased bacterial translocation, in turn activating circulating immune cells, leading to cytokine production and systemic inflammation. A perturbed gut-liver-brain axis may therefore explain the high rates of depression in patients with cirrhosis. The underlying mechanisms explaining the critical relationship between depression and cirrhosis remain to be fully elucidated. Several other psychosocial and biological factors are likely to be involved, and therefore the cause is probably multifactorial. However, the role of the dysfunctional gut-liver-brain axis as a driver of gut-derived systemic inflammation requires further exploration and consideration as a target for the treatment of depression in patients with cirrhosis.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. Despite the high prevalence, no screening recommendations yet exist. We designed a prospective observational study to estimate the prevalence of NAFLD in the family of patients with NAFLD and develop a predictive model for identifying it. METHODOLOGY: The prevalence of NAFLD in patients’ family members was estimated using ultrasonography, and univariate and multivariate odds were calculated for its predictors. A model was created using the significant parameters on multivariate odds, and its performance was tested using the area under the receiver operating characteristic (AUROC). RESULTS: Among 447 family members of 191 patients with NAFLD, the prevalence of NAFLD was 55.9%. Family members with NAFLD were younger and had lower serum levels of aspartate aminotransferase, alanine aminotransferase (ALT), triglycerides. The liver stiffness measurement and controlled attenuation parameter values were also lesser in family members compared to the index cases. Age, body mass index (BMI), and ALT were independent predictors of NAFLD in the family members. A model combining age and BMI had an AUROC of 0.838 [95% confidence interval (CI) 0.800–0.876, P < 0.001]. Age ≥30 years and BMI ≥25 kg/m(2) had an odds ratio of 33.5 (95% CI 17.0–66.0, P < 0.001) for prediction of NAFLD, in comparison to BMI

BACKGROUND/OBJECTIVES: Cirrhosis of liver is associated with loss of liver function, portal hypertension, and pancreatic β-cell dysfunction leading to hepatogenous diabetes (HD). Often HD is an underestimated and understudied problem, particularly in the Indian subcontinent, where the prevalence of both Chronic liver disease (CLD) and diabetes is high. Hence this study was planned to highlight the prevalence of HD and its association with the severity of cirrhosis. METHODS: A total of 121 cirrhotic patients without a history of diabetes were included in this prospective cross-sectional study. Seventy five g oral glucose tolerance test (OGTT) was done in all patients. Fasting serum insulin levels were done to calculate insulin resistance (IR) using homeostatic model assessment-insulin resistance (HOMA-IR). Upper gastrointestinal endoscopy was done to detect varices. Patients were divided into HD group and non-HD group for comparison of results. RESULTS: HD was seen in 52 (42.98%) patients; among them, 63.4% did not show evidence of HD by fasting plasma glucose (FPG) levels. Impaired glucose tolerance (IGT) was seen in 58 (47.93%) patients. Compared with the non-HD group, the HD group had significantly higher model for end-stage liver disease (MELD) score (P = 0.038), HOMA-IR (P 15), CTP score (>10), higher bilirubin levels, large varices, bleeding varices, and HCC. FPG levels and glycated hemoglobin (HbA1c) cannot be relied upon, and OGTT aids in the unmasking of HD in these patients.

Chronic liver diseases, resulting from chronic injuries of various causes, lead to cirrhosis with life-threatening complications including liver failure, portal hypertension, hepatocellular carcinoma. A key unmet medical need is robust non-invasive biomarkers to predict patient outcome, stratify patients for risk of disease progression and monitor response to emerging therapies. Quantitative imaging biomarkers have already been developed, for instance, liver elastography for staging fibrosis or proton density fat fraction on magnetic resonance imaging for liver steatosis. Yet, major improvements, in the field of image acquisition and analysis, are still required to be able to accurately characterize the liver parenchyma, monitor its changes and predict any pejorative evolution across disease progression. Artificial intelligence has the potential to augment the exploitation of massive multi-parametric data to extract valuable information and achieve precision medicine. Machine learning algorithms have been developed to assess non-invasively certain histological characteristics of chronic liver diseases, including fibrosis and steatosis. Although still at an early stage of development, artificial intelligence-based imaging biomarkers provide novel opportunities to predict the risk of progression from early-stage chronic liver diseases toward cirrhosis-related complications, with the ultimate perspective of precision medicine. This review provides an overview of emerging quantitative imaging techniques and the application of artificial intelligence for biomarker discovery in chronic liver disease. journal article review 2022 Jun 2022 02 09 imported

Dual-energy computed tomography (DECT) is an advancement in the field of CT, where images are acquired at two energies. Materials are identified and quantified based on their attenuation pattern at two different energy beams using various material decomposition algorithms. With its ability to identify and quantify materials such as fat, calcium, iron, and iodine, DECT adds great value to conventional CT and has innumerable applications in body imaging. Continuous technological advances in CT scanner hardware, material decomposition algorithms, and image reconstruction software have led to considerable growth of these applications. Among all organs, the liver is the most widely investigated by DECT, and DECT has shown promising results in most liver applications. In this article, we aim to provide an overview of the role of DECT in the assessment of diffuse liver diseases, mainly the deposition of fat, fibrosis, and iron and review the most relevant literature.

BACKGROUND: Sickle cell disease (SCD) is a rare hemoglobinopathy which can result in chronic liver disease and cirrhosis. Patients with SCD have an increased risk of hematologic malignancy, but the prevalence of hepatocellular carcinoma (HCC) in this population is unknown. Herein, the association of SCD with HCC was examined using registry data. METHODS: The SEER-Medicare database was queried to identify patients diagnosed with HCC between 2000 and 2015, and further stratified by SCD status. Propensity matching was performed to examine cancer-related survival and treatment outcomes. RESULTS: Overall 56,934 patients with HCC were identified, including 81 patients with SCD. Patients with SCD more frequently had cirrhosis [48.1% (39/81) vs 23.5% (13,377/56,853), p

Obesity and its associated comorbidities are rapidly increasing in the US population. Therefore, metabolic associated fatty liver disease (MAFLD), previously known as nonalcoholic fatty liver disease (NAFLD), has become a leading indication for liver transplantation. Lifestyle modifications as a sole therapy have been insufficient to reduce the burden of chronic liver disease secondary to MAFLD. Endoscopic bariatric interventions (EBI) appear to be safe and effective therapies for obesity and chronic liver disease secondary to MAFLD. Gastric EBI include endoscopic sleeve gastroplasty (ESG) and intragastric balloons (IGB). Small bowel EBI are also evolving in the field of bariatric endoscopy.

Hepatocellular adenomas (HCA) are rare hepatocellular neoplasms which usually arise in non-cirrhotic liver, although rarely can arise in the background of chronic liver disease. While the majority of hepatocellular adenoma (HCA) are benign and may be managed conservatively, complications like hemorrhage and transformation to hepatocellular carcinoma (HCC) can occur. Risk stratification based on a combination of clinical, radiologic, histologic, and molecular features is necessary for appropriate management. This review focuses on diagnostic challenges in the diagnosis of HCA and its distinction from other hepatocellular proliferations such as focal nodular hyperplasia (FNH), hepatocellular carcinoma (HCC) and hepatocellular nodules in other clinical setting.

Management of coagulopathy in patients with advanced liver disease undergoing therapeutic endoscopic procedures is complex. Improvements in the understanding of hemostasis at a physiologic level have highlighted the inaccuracy of currently available clinical tests, like platelet count and prothrombin time, in estimating hemostasis in patients with cirrhosis. With identification of novel factors that contribute to bleeding risk in patients with cirrhosis, there is a dearth of clinical trial data that account for all potentially relevant factors and that examine interventions to reduce bleeding risk. Precise recommendations regarding transfusion strategies based on hemostatic test results in patients with cirrhosis are impractical.

Physiologic aging leads to attrition of telomeres and replicative senescence. An acceleration of this process has been hypothesized in the progression of chronic liver disease. We sought to examine the association of telomere length (TL) with liver disease and its impact on mortality risk. A cohort of 7,072 adults with leukocyte TL measurements from the National Health and Nutrition Examination Survey 1999‐2002 with mortality follow‐up through 2015 was analyzed. Liver disease was defined by aminotransferase levels and classified into etiology‐based and advanced fibrosis categories. Multivariable‐adjusted linear regression models estimated effect sizes, with 95% confidence intervals (CIs), of the presence of liver disease on TL. Cox regression models evaluated associations between TL and all‐cause mortality risk using adjusted hazard ratios (HRs). The cohort was representative of the US population with mean age 46.1 years and mean TL 5.79 kilobase pairs. No overall association between TL and liver disease was found; however, there was a significant negative association of TL and advanced liver fibrosis in individuals aged 65 and above. The liver disease cohort (HR 1.22, 95% CI 0.99‐1.51) and those with metabolic syndrome (HR 1.26, 95% CI 0.96‐1.67) had increased mortality risk with shorter TL. The relationship between TL and all‐cause mortality was stronger in women (HR 1.51, 95% CI 1.02‐2.23) and in non‐Hispanic Whites (HR 1.37, 95% CI 1.02‐1.84). Conclusion: Shortened leukocyte TL is independently associated with advanced liver disease at older ages, and with a higher risk of all‐cause mortality in those with liver disease. These associations reaffirm the need to better understand the role of telomeres in the progression of liver disease., We examined the association of peripheral telomere length with liver disease and assessed its impact on mortality using data from the National Health and Nutrition Examination Survey (NHANES). We discovered that shortened leukocyte telomere length is independently associated with advanced liver disease at older ages, and also with a higher risk of all‐cause mortality in those with liver disease.

Background : The purpose of the study was to assess the epidemiology, risk factors and outcomes of native vertebral osteomyelitis (NVO) in patients with Staphylococcus aureus bacteremia (SAB). Methods : A retrospective institutional review was conducted at Mayo Clinic, Minnesota. Patients aged ≥ 18 years with SAB who developed NVO from January 1, 2006 to December 31, 2020 were included and 3-month follow-up data were abstracted. Data pertaining to patient demographics, risk factors and outcomes were recorded using REDCap. A 1:2 nested case-control analysis was performed, and controls were matched according to age, sex and year of SAB diagnosis. Results : A total of 103 patients had NVO. A majority (60.2%) of patients was male, with a median age of 62.0 years. Thirty-one (30.1%) cases were caused by methicillin-resistant S. aureus (MRSA). The lumbar spine was most commonly (57.6%) and the most commonly reported comorbid conditions included diabetes mellitus (36.9%) and coronary artery disease (27.2%). Mortality at three-month follow-up was 18.6%. Nested case-control analysis revealed that injection drug use (IDU) and tobacco consumption were significant risk factors associated with NVO, while chronic hemodialysis and chronic liver disease (CLD) were associated with a decreased risk of NVO. Conclusions : Atherosclerotic vascular disease was prominent in our contemporary cohort with NVO in the setting of SAB. Diabetes mellitus, tobacco consumption, older age and male sex likely contributed to this profile. Because IDU was associated with NVO, an increased number of cases should be anticipated among patients with IDU given the ongoing opioid epidemic in the United States.

Objectives: To identify association of underlying pre-morbidities with disease severity and mortality in hospitalized patients with Corona virus disease 2019. Methods: Total 884 COVID RT-PCR positive patients admitted to KRL Hospital Islamabad from April 2020 to August 2020 were included in this cross-sectional study. Pre-morbidities recorded were hypertension, diabetes mellitus, ischemic heart disease, chronic respiratory disease, chronic kidney disease, chronic liver disease, chronic neuro-psychiatric conditions (stroke and depression) and malignancy. Oxygen requirement, requirement of invasive ventilation, and outcome (recovered versus died) was documented. WHO categories for disease severity were used. Demographic profile and symptoms were also noted. SPSS 22 was used for data analysis. Pearson’s Chi square test was used to see association between pre-morbidities and disease severity categories, oxygen requirement, invasive ventilation and outcome. Pearson’s correlation was applied to analyze the correlation between individual pre-morbidities and disease severity categories. P-value < 0.05 was considered statistically significant. Results: The mean age was 40 ± 12.21 years with 98.5% being males. Majority patients (74.8%) were asymptomatic. Fever was the most common symptom. Diabetes mellitus and hypertension were the most commonly recorded co-morbidity. Significant correlation (p-value < 0.05) was found between the presence of underlying pre-morbidities and disease severity as well as oxygen requirement, requirement of invasive ventilation and mortality. Conclusion: Results are compatible with worldwide studies and underlying pre-morbidities are convincing risk factors for disease severity and mortality. doi: https://doi.org/10.12669/pjms.38.1.4235 How to cite this:Toori KU, Qureshi MA, Chaudhry A. Pre-morbidity and COVID-19 disease outcomes in Pakistani population: A cross-sectional study. Pak J Med Sci. 2022;38(1):287-292. doi: https://doi.org/10.12669/pjms.38.1.4235 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background Although acute hepatitis E is not fatal in healthy individuals, it is unclear whether hepatitis E superinfection increases the mortality in patients with pre-existing liver disease. Thus, we investigated the prognosis of patients with acute hepatitis E according to their cirrhosis diagnosis, and the prognosis according to the development of acute-on-chronic liver failure (ACLF) in patients with cirrhosis and chronic liver disease (CLD). Methods This study included 74 consecutive patients who were diagnosed with acute viral hepatitis E between January 2007 and December 2019. Of them, 39 patients without CLD, 13 patients with non-cirrhotic CLD, and 22 patients with cirrhotic CLD were analyzed. Results Among the 74 patients with HEV infection, 7 (9.5%) died within 180 days: 5 with underlying cirrhosis (71.4%) and 2 without cirrhosis (28.6%). The 180-day mortality was significant higher for patients with cirrhosis than for patients without cirrhosis (22.7% vs. 3.8%, P = 0.013). The age- and sex-adjusted proportional-hazard model revealed an approximately eightfold increase in the 180-day mortality risk in patients with cirrhosis compared to patients without cirrhosis. In addition, development of hepatitis E virus-related ACLF due to acute liver function deterioration in patients with pre-existing CLD or cirrhosis worsened the 180-day mortality rate. Conclusions Our findings suggest that the acute hepatitis E mortality rate was low in healthy individuals but higher in patients with cirrhosis, and especially high in those with ACLF.

Objectives: To determine the frequency of Non-Alcoholic Fatty Liver Disease (NAFLD) and its associated risk factors among Type-2 Diabetic patients. Methods: This cross-sectional study was conducted in Diabetic Clinic of Shaikh Zayed Postgraduate Medical Institute Lahore from September 2019-February 2020. Type-2 diabetics regardless of age were divided into two groups, one with fatty liver disease and the other without this, evaluated by Abdominal Ultrasonography and were further evaluated by measurement of BMI, obesity, HbA1c and lipid profile. Exclusion criteria were patients having history of or currently taking alcohol, chronic Liver Disease of any cause and intake of hepatotoxic drugs. Qualitative measures were compared between groups by using Chi-square test. Binary logistic regression was used to see the association of factors with fatty liver disease. P-value ≤ 0.05 was considered significant. Results: A total of 185 subjects were included in the study with the mean age of 53.0±9.0 years. About 54.6% patients were diagnosed to have fatty liver disease. When compared the cases with and without fatty liver disease, age and HDL cholesterol had no significant difference between groups while other measures like BMI, TGs & cholesterol levels, ALT and AST were significantly higher among cases with NAFLD. BMI >24.5, HbA1c >7.0 and ALT >40.0 can predict NAFLD among Type-2 diabetic patients with 96.8% accuracy. Conclusion: There is high prevalence of NAFLD among Type-2 diabetic patients and strong association between Type-2 diabetics with NAFLD and risk factors like; obesity, high HbA1c, hyperlipidemia and high ALT. Therefore, early recognition by ultrasonography in high risk patients and intervention like life style modification, maintenance of healthy weight, obesity prevention, treatment of dyslipidemia and good glycemic control should be achieved in such subjects and can prevent NAFLD. doi: https://doi.org/10.12669/pjms.38.1.4968 How to cite this:Ali A, Amin MJ, Ahmed MU, Taj A, Aasim M, Tabrez E. Frequency of non-alcoholic fatty liver disease (NAFLD) and its associated risk factors among Type-2 diabetics. Pak J Med Sci. 2022;38(1):28-33. doi: https://doi.org/10.12669/pjms.38.1.4968 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.