Enzyme Abnormalities Research Articles

COVID-19 liver and gastroenterology findings: An in silico analysis of SARS-CoV-2 interactions with liver molecules.

BACKGROUNDCoronavirus disease 19 (COVID-19) has not only been shown to affect the respiratory system, but has also demonstrated variable clinical presentations including gastrointestinal tract disorders. In addition, abnormalities in liver enzymes have been reported indicating hepatic injury. It is known that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) might infect cells via the viral receptor angiotensin-converting enzyme 2 (ACE2) which is expressed in several organs including the liver. The viral Spike glycoprotein binds to ACE2 and must be cleaved by Furin and Type 2 Serine Protease to enter the cells. After that, the Akt/mTOR signaling pathway is activated and several COVID-19 changes are triggered.AIMTo analyze liver and gastrointestinal symptoms and cell signaling pathways triggered by SARS-CoV-2 infection due to virus-liver interactions in silico.METHODSIn this in silico study, the three-dimensional structures of the Akt, mTORC1 and Furin (receptors) were selected from the Protein Data Bank (PDB) and the structures of inhibitors (ligands) MK-2206, CC-223 and Naphthofluorescein were selected from PubChem and ZINC databases. Ligand files were downloaded as 2D structures and converted to optimized 3D structures using ViewerLite 4.2 software. Marvin Sketch® software was used to calculate prediction of the protonated form of inhibitors in a physiological environment (pH 7.4). AutoDock Tools (ADT) software was used to calculate and delimit the Grid box used in the molecular docking of each structure selected in the PDB. In addition, protonated ligands were prepared for molecular docking using ADT software. Molecular docking was performed using ADT software tools connected to Vina software. Analysis of the amino acid residues involved in ligand interactions, as well as ligand twists, the atoms involved in interactions, bond type and strength of interactions were performed using PyMol® and Discovery Studio® (BIOVIA) software.RESULTSMolecular docking analysis showed that the mTORC1/CC-223 complex had affinity energy between the receptor and ligand of -7.7 kcal/moL with interactions ranging from 2.7 to 4.99 Å. There were four significant chemical bonds which involved two of five polypeptide chains that formed the FKBP12–Rapamycin-Binding (FRB) domain. The strongest was a hydrogen bond, the only polar interaction, and Van der Waals interactions shown to be present in 12 residues of mTORC1’s FRB domain. With regard to the Akt/MK-2206 complex there were three Van der Waals interactions and 12 chemical bonds in which seven residues of Akt were involved with all five rings of the MK-2206 structure. In this way, both ASP 388 and GLN 391 bind to the same MK-2206 ring, the smaller one. However, LYS 386 had four chemical bonds with the inhibitor, one with each structure ring, while LYS 387 binds two distinct rings. One of the MK-2206 inhibitor's rings which binds to LYS 387 also binds simultaneously to ILE 367 and LEU 385 residues, and the fifth ring of the structure was involved in a bond with the ALA 382 residue. The hydrogen bonds were the shortest bonds in the complex (2.61 and 3.08 Å) and all interactions had an affinity energy of -8.8 kcal/moL. The affinity energy in the Furin/Naphhofluorescein complex was -9.8 kcal/moL and involved six interactions ranging from 2.57 to 4.98 Å. Among them, two were polar and the others were non-polar, in addition to twelve more Van der Waals interactions. Two distinct hydrogen bonds were formed between Furin and its inhibitor involving GLN 388 and ALA 532 residues. ALA 532 also binds to two distinct rings of Naphthofluorescein, while TRP 531 residue has two simultaneous bonds with the inhibitor.CONCLUSIONLiver infection and signaling pathways altered by SARS-CoV-2 can be modulated by inhibitors that demonstrate significant interaction affinity with human proteins, which could prevent the development of infection and symptoms.

Pancreatic Dysfunction and Duodenal Inflammatory Responses Coordinate with Refractory Epigastric Pain Including Functional Dyspepsia: A Narrative Review.

Some patients with functional dyspepsia (FD) have abnormalities in pancreatic enzymes and chronic pancreatitis. Since 2009, when the idea of early chronic pancreatitis (ECP) first emerged, the utility of endoscopic ultrasonography gained attention, as it can help identify early chronic pancreatitis in patients with dyspepsia. Although the symptoms associated with pancreatic enzyme abnormalities and pancreatic dysfunction overlap with those of dyspepsia, no available data explain the direct relationships and linkages between pancreatic dysfunction and dyspeptic symptoms. Disturbance of exocrine pancreatic enzyme function and reduction in pancreatic endocrine levels, such as insulin, may be associated with dyspeptic symptoms through impaired gastric emptying and duodenal inflammation. Some recent studies have examined the role of duodenal pathophysiology in gastric motility, bicarbonate secretion, and digestion. Because reduced bicarbonate secretion, which is caused by pancreatic dysfunction, leads to a failure to neutralize gastric acid in the proximal duodenum, impaired bicarbonate secretion in turn fails to protect the duodenal mucosa against gastric acid influx, thereby inducing duodenal inflammation. In addition, elevated trypsin levels might be associated in part with duodenal inflammatory responses through PAR2-related immunomodulatory cells. This review describes how duodenal inflammation might affect the pathogenesis of FD and examines whether pancreatic dysfunction is associated with FD through intestinal inflammation.

Polystyrene microplastics-induced cardiotoxicity in chickens via the ROS-driven NF-κB-NLRP3-GSDMD and AMPK-PGC-1α axes

Microplastics (MPs) pollution is getting increasingly prominent, and its dangers have attracted widespread attention. The heart is the central hub of the organism's survival, and the mechanism of MPs-induced heart injury in chickens is unknown. Here, we investigated the effects of 5 μm polystyrene microplastics (PS-MPs) on the heart and primary cardiomyocytes of chickens at varied concentrations. We observed that PS-MPs caused severe pathological damage and ultrastructural changes in heart, induced myocardial pyroptosis, inflammatory cell infiltration and mitochondrial lesions. PS-MPs evoked abnormal antioxidant enzyme content and ROS overproduction. Detailed mechanistic investigation indicated that PS-MPs triggered pyroptosis via NF-κB-NLRP3-GSDMD axis and exacerbated myocardial inflammation (NLRP3, Caspase-1, IL-1β, IL-18, ASC, GSDMD, NF-κB, COX-2, iNOS and IL-6 overexpression). Additionally, PS-MPs induced mitochondrial damage (TFAM, OPA1, MFN1 and MFN2 down-expression, DRP1 and Fis1 overexpression) and energy metabolism disorders (HK2, PKM2, PDHX and LDH up-regulation) by inhibiting AMPK-PGC-1α pathway. Interestingly, NAC alleviated these aberrant manifestations in vitro. We suggested that PS-MPs driven alterations in NF-κB-NLRP3-GSDMD and AMPK-PGC-1α pathways via ROS overload, which in turn triggered oxidative stress, myocardial pyroptosis, inflammation, mitochondrial and energy metabolism dysfunction. This provided theoretical bases for protecting chickens from toxic injury by MPs.

Assessment of Liver Enzyme Abnormality among Antiretroviral Therapy Experienced HIV- Seropositive Patients in Asmara, Eritrea

Liver disease are predominant in HIV/AIDS patients and a wide range of the population have been affected. However, studies that have assessed the burden and risks of liver enzyme alterations among antiretroviral therapy experienced patients are hardly available in Eritrea. Thus, the present study targets to determine the prevalence and the risks related with abnormal liver enzymes among HIVinfected individuals.

Comparison of clinical characteristics, eating behaviors, and clinical symptoms following fat intake in functional dyspepsia with functional dyspepsia with pancreatic enzyme abnormalities between Singapore and Japan.

To clarify whether there were any significant differences in clinical symptoms and eating patterns between functional dyspepsia (FD) patients and FD with pancreatic enzyme abnormalities (FD-P) patients as refractory FD, we compared these factors in multicenter studies in Singapore and Japan. One hundred ninety-eight consecutive patients presenting with FD (n=88), FD-P patients (n=81) based on Rome III classification and controlled group (n=39) recruited from six institutions in Singapore and Japan. Clinical characteristics, clinical symptoms for dietary fat intake, and eating behaviors were estimated using questionnaires. Anxiety and health-related quality of life were determined by STAI-state/-trait and SF-8, respectively. There were no significant differences in age, sex, BMI, smoking, alcohol intake, past medical history, and history of allergy in FD and FD-P patients between Singapore and Japan. There were no significant differences in FD subtypes, gastrointestinal symptom rating scale score, severity of FD symptoms, and eating pattern in Singapore and Japan. Moreover, there were significant differences in certain eating behaviors between FD and FD-P patients in Singapore and Japan. Interestingly, epigastric pain and early satiety following fat meals in FD-P patients were significantly (P=0.003 and P=0.008, respectively) higher compared with those in FD patients in Japan. Physical component score in FD-P patients was significantly (P=0.019) disturbed compared with those in FD patients in Japan. Epigastric pain and early satiety following fat meals in FD-P patients may be useful tools to differentiate FD-P patients from FD patients in Japan.

SARS-CoV-2 Infection and Liver Involvement

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped, single-stranded RNA virus that can also be transmitted from person to person via the droplet (secretions shed when speaking, sneezing, or coughing) route, suspended droplet nuclei, and the mucous membranes of the eyes, nose, and mouth after touching a contaminated surface. It enters the cells through the angiotensin converting enzyme 2 (ACE- 2) receptor. Although non-specific respiratory symptoms such as fever, loss of smell/taste, runny nose, and cough are most common, SARS-CoV-2 can lead to a systemic and multiorgan involvement, including the gastrointestinal tract. The liver is the second most frequently involved organ after the lung. Gastrointestinal symptoms such as diarrhea, anorexia, nausea, vomiting, loss of appetite and abdominal pain are also common. Abnormal liver function enzyme levels may also be observed. The liver is affected by direct infection of hepatocytes, medical therapy of the management, or by indirect means if there is an underlying co-morbid disease. However, there are significant differences between studies in the reporting of gastrointestinal and liver symptoms. The most frequently reported gastrointestinal symptom in COVID-19 disease is diarrhea, reported in 1-36% of patients. In this review, it is aimed to review the current data on the effects of COVID-19 on the liver.

Review of Liver Enzymes Abnormalities in Patients with SARS-CoV-2 Infection

Background: Liver function derangements have been reported in COVID-19, but reported rates are variable. Treatment in intensive care units (ICU) has become a major challenge; therefore, early recognition of severe and critical cases is absolutely essential for timely triaging of patients. Objectives: to review incidence of acute liver injury in patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Patients and methods: obtaining clinical records and laboratory results prospectively from one hundred patients with PCR-confirmed or radiography-confirmed COVID-19, who are admitted to the isolation wards and emergency departments of three different hospitals in Baghdad from 1st of December 2020 to 31st of March 2021. Results: The mean age group of study sample was (61.2±12.36) years, males formed 59%. GI manifestations were recorded in 47% of total cases, and were statistically correlated with disease severity (P value 0.001). Wide range of LFT abnormalities are found in patients with COVID-19, but none of which showed statistical significance in relation to disease severity. When LFT results were reviewed in relation to previous comorbidities, GGT was found to be statistically correlated with the underlying CLD (P value 0.001), and ALP with both underlying CLD and DM (P values <0.001 and 0.029, respectively) and even in the absence of underlying comorbidity (P value 0.006). Conclusion: Liver enzyme derangements are increasingly reported in patients with COVID-19, but are not necessarily correlate with disease severity. Cholestatic picture of liver enzyme derangement is a more commonly recorded manifestation.

Gastrointestinal manifestations in hospitalized patients with chronic liver disease and COVID-19.

Gastrointestinal manifestations in COVID-19 have been frequently acknowledged by clinicians and scientists. However, their clinical significance and potential influence on the disease outcome is not entirely elucidated. In this study we aim to evaluate gastrointestinal involvement, both digestive symptoms and liver-related changes in hospitalized COVID-19 patients in correlation to the presence or absence of underlying liver disease and rate of mortality. We performed a retrospective cohort study of COVID-19 patients, consecutively admitted in a hospital from Chisinau, between September 3, 2020 and May 31, 2021. Data on clinical symptoms and laboratory findings were collected from electronic clinical records. The cohort was divided into two groups, with and without pre-existing liver disease. The Fisher exact, Pearson Chi-square tests were used to compare groups. A total of 1835 patients were included, 108 (5.9%) with pre-existing liver disease and 1727 (94.1%) without this comorbidity. Digestive symptoms were reported by 331(18%) of the patients, diarrhea being the most common symptom 11.8% (217) and being encountered more in patients with underlying chronic liver disease. No statistical difference was identified between the groups in regard to other symptoms, comorbidities and rate of mortality. But patients with chronic liver disease had significant (P < 0.001) lower ferritin, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in comparison with the other group. At admission, 341 (19.2%) had increased aspartate aminotransferase level (AST) and 317 (17.8%) alanine aminotransferase. The enzyme abnormalities were predominantly mild and transitory. Abnormal AST level at admission and during follow up, higher ESR, CRP, ferritin, lactate dehydrogenase (LDH) was found to correlate with higher rates of mortality. Digestive implications, especially diarrhea in COVID-19 patients is frequent, but do not appear to be associated with mortality. Elevated liver enzymes during hospitalization, age, high ferritin, CRP, LDH might be interpreted as risk factors for mortality in COVID-19 but further studies are needed to address this topic.

A case of alveolar echinococcosis in the liver that ruptured into the pericardium treated by a combination of hepatectomy and albendazole

BackgroundAlveolar echinococcosis (AE) is a rare parasitic disease caused by the larva of Echinococcus multilocularis. It nearly always occurs in the liver, and cardiac involvement is extremely rare. Liver resection is the most effective intervention for AE because the only potentially curative treatment is removal of the lesion. Even when complete resection is not performed, long-term survival can be expected after surgical removal of most of the lesion with lifelong administration of albendazole (ABZ).Case presentationA 64-year-old man who lived in Hokkaido was referred to our hospital due to abnormalities in biliary enzymes. According to the findings from enhanced computed tomography and magnetic resource imaging of the abdomen, transthoracic echocardiography and serologic tests, he was diagnosed with hepatic AE with rupture into the pericardium. He underwent extended left hemi-hepatectomy with reconstruction of the inferior vena cava and opening of the pericardium with drainage as reduction surgery. Pathological examination revealed echinococcal infection in the pericardium as well as the liver. He started chemotherapy with 400 mg ABZ per Day 67 days after surgery. Although the surgical margin was positive in the pathological findings, he was alive 19 months later with no regrowth of the echinococcal lesion.ConclusionAE with cardiac involvement is extremely rare. Even if the complete removal of cardiac-involved AE is not possible, surgical debulking with lifelong ABZ treatment can successfully manage the disease.

Hepatic Enzyme Profile in Horses.

Simple SummaryThis review aims to highlight the importance of using enzyme profiles for the diagnosis of common liver disorders in the horse. This review also highlights the limitations and alternative explanations for isolated or collective abnormalities of the different liver enzymes. This review also provides information on the screening test(s) of choice, their interpretation, and the results to confirm the diagnosis. Similarly, documented liver cases in the equine clinic are reviewed, with emphasis on abnormal enzyme activity.For diagnostic purposes, liver enzymes are usually classified into hepatocellular and cholestatic. These two groups of equine liver-specific enzymes include sorbitol dehydrogenase (SDH), glutamate dehydrogenase (GLDH), γ-glutamyl transferase (GGT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP). SDH and GLDH mostly reflect hepatocellular injury and cholestasis, while GGT expresses high values in biliary necrosis or hyperplasia. Likewise, AST, LDH, and ALP also reflect hepatocellular and biliary disease, but these enzymes are not liver specific. From the clinical point of view of the course of liver or biliary disease, AST and ALP are indicative of chronic disease, whereas SDH, GGT, and GLDH indicate an acute course. The patterns of enzymatic changes at the blood level are associated with different types of liver pathologies (infectious, inflammatory, metabolic, toxic, etc.). Increases in hepatocellular versus biliary enzyme activities are indicative of a particular process. There are different ways to diagnose alterations at the hepatic level. These include the evaluation of abnormalities in the predominant pattern of hepatocellular versus cholestatic enzyme abnormalities, the mild, moderate, or marked (5–10-fold or >10-fold) increase in enzyme abnormality concerning the upper limit of the reference range, the evolution over time (increase or decrease) and the course of the abnormality (acute or chronic).

Modulation effects of danshen-honghua herb pair on gut microbiota of acute myocardial ischemia model rat.

In the recent years, a growing number of studies have shown that the occurrence of myocardial ischemia (MI) is closely related to the gut microbiota (GM). The Danshen-Honghua herb pair (DHHP), a classic combination in traditional Chinese herbal formulas, has been widely applied throughout history to cure cardiovascular disease, exhibiting remarkable clinical efficacy to treat ischemic heart disease (IHD). However, the intrinsic regulation mechanism of DHHP in treating MI remains unclear. This study aims to investigate the possible protective mechanism of DHHP in rats with acute myocardial ischemia (AMI) induced by isoproterenol (ISO) through 16S rRNA gene sequencing technique. Pharmacodynamic results showed that DHHP significantly ameliorated the pathological changes and improved the abnormal cardiac enzymes levels in the AMI rats. In addition, GM analysis demonstrated that DHHP effectively ameliorated the ISO-induced dysbiosis of the GM community, mainly by enhancing the GM diversity and increasing the relative abundance of Bacteroides, Roseburia, unclassified_f__Lachnospiraceae, and Lachnospiraceae_NK4A136_group, the abundance ratio of Bacteroidetes to Firmicutes, and decreasing the relative abundance of Escherichia-Shigella and Enterococcus. In summary, this study revealed that DHHP could improve ischemic myocardial injury in rats, and that its regulation mechanism is associated with significantly ameliorating the composition of GM, thus contributing to further our understanding of the anti-MI mechanisms of DHHP.

The prevalence of hepatitis C virus infection in patients with lichen planus: Case- Control Study

Background: Lichen planus (LP) is an idiopathic inflammatory disease of the skin and mucous membranes. It has been reported to be associated with diseases such as hepatitis C virus infection. However, this association vary from one geographic area to another. Objective: The aim of this study is to assess the prevalence of hepatitis C virus infection and liver enzymes abnormalities among patients with lichen planus compared to controls. Materials and Methods: This case- control study included 204 participants (102 with L.P. and 102 controls) from the dermatology clinic at Tishreen University Hospital, Lattakia, Syria, during the period (2020- 2021). The diagnosis was made clinically and confirmed histologically whenever the clinical features were not inclusive. Sera were analyzed for anti- HCV antibodies and liver enzymes; aspartate aminotransferase (AST), alanine aminotransferase (ALT). Results: Out of 102 cases and 102 controls, none was tested positive for Anti- HCV antibodies. There were no statistically significant differences neither in serum levels of liver enzymes; alanine aminotransferase (ALT) (P.value= 0.4), aspartate aminotransferase (AST) (P.value= 0.08) nor in frequencies of its abnormalities; alanine aminotransferase (ALT) (P.value= 0.2), aspartate aminotransferase (AST) (P.value= 0.1) in any of the studied groups. Conclusion: This study did not reveal association between lichen planus and HCV infection, neither revealed any statistically significant elevation in serum levels of liver enzymes among patients with lichen planus compared to controls.

Evaluating the impact of a Risk Evaluation and Mitigation Strategy with tolvaptan to monitor liver safety in patients with autosomal dominant polycystic kidney disease.

On approval of JYNARQUE (tolvaptan) for use in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk for rapid progression, the US Food and Drug Administration required a Risk Evaluation and Mitigation Strategy (REMS) from the sponsor, which includes collection of post marketing liver safety data. This is a retrospective interim analysis of the ongoing REMS. The period evaluated was from REMS implementation (14 May 2018) at tolvaptan commercialization to the analysis cutoff date (23 February 2021). Patients were previously tolvaptan-naïve and initiated tolvaptan in the post marketing setting. Reports of possible severe drug-induced liver injury (DILI) were evaluated for severity based on the evidence obtained (e.g. liver enzyme levels, symptoms, diagnostic tests and event outcomes). The incidence of DILI was compared between the REMS and tolvaptan clinical trials in ADPKD. Among 6711 REMS patients, 60 (0.9%) cases of possible severe DILI were reported, 4 of which were confirmed as serious and potentially fatal by the sponsor. One of these four patients met Hy's law criteria. In all four patients, liver enzymes normalized after tolvaptan discontinuation. The duration of tolvaptan exposure in the REMS is currently shorter than in completed clinical trials, but within this limitation, the incidence of possible severe DILI was lower in the REMS than in clinical trials (incidence rate ratio 0.587; P = .000411). In interim data on >6000 tolvaptan REMS patients, <1% experienced possible severe DILI. Monthly monitoring, as described in the tolvaptan prescribing information, enables the prompt detection of liver enzyme abnormalities and appropriate drug discontinuation.

Delineating the epilepsy phenotype of NGLY1 deficiency.

We delineated the phenotypic spectrum of epilepsy in individuals with NGLY1 deficiency from an international cohort. We collected detailed clinical and electroencephalographic data from 29 individuals with bi-allelic (likely) pathogenic variants in NGLY1 as part of an ongoing prospective natural history study. Participants were evaluated in-person at a single center and/or remotely. Historical medical records were reviewed. Published cases were included for comprehensive phenotyping. Of 29 individuals (mean 11.4 years, range 3-27 years), 17 (58.6%) participants had a history of epilepsy. Seizure onset was in early childhood (mean 43 months, range 2 months to 19 years). The most common seizure types were myoclonic and atonic. Epilepsy course was variable, but 35.2% (6/17) of participants with epilepsy achieved seizure freedom. The most common medications included levetiracetam, valproate, lamotrigine, and clobazam. Electroencephalogram (EEGs) were abnormal in 80% (12/15) of participants with or without epilepsy, although encephalopathy was uncommon. There was a trend in neurodevelopmental outcomes that participants with epilepsy had more developmental delays. In summary, epilepsy is common in NGLY1 deficiency. Over half of the participants had a history of epilepsy and nearly all had EEG abnormalities indicating an increased risk of epilepsy. This work expands the electroclinical phenotype of NGLY1 deficiency and supports a high clinical suspicion for seizures. Some of the more common seizure types (epileptic spasms, myoclonic, and atonic seizures) can be subtle and require counseling to ensure early recognition and treatment to ensure the best possible outcomes. Despite transient liver enzyme abnormalities in this disorder, hepatically metabolized medications were well tolerated.

The association between elevated lipid profile and liver enzymes: a study on Bangladeshi adults

Dyslipidemia, a major contributor to cardiovascular diseases, is rapidly increasing in Asian countries including Bangladesh. In addition to the cardiovascular system, abnormal lipid levels are also known to cause complications in renal and hepatic systems. The data regarding dyslipidemia and its relationship with liver enzymes are scarce for the Bangladeshi population. Therefore, this study was conducted to estimate the prevalence of dyslipidemia and determine the relationship between lipid profile and liver enzymes in Bangladeshi adults. A total of 405 participants (318 males and 87 females) were enrolled in the study. Serum levels of TG, TC, LDL, HDL and liver enzymes including ALT, AST, GGT and ALP were analyzed using standard methods. Dyslipidemia and liver function tests abnormalities were defined according to the international standard guidelines. The association between elevated lipid profile markers and liver enzyme abnormalities was assessed by logistic regression analysis. Overall, the prevalence of elevated TG, TC, LDL and low HDL were 30.9%, 23.7%, 26.2% and 78.8%, respectively. On the other hand, the prevalence of elevated liver enzymes ALT, AST, GGT and ALP were 18.8%, 21.6%, 12.9% and 21.9%, respectively. Dyslipidemia and liver enzyme abnormalities were higher in diabetic and hypertensive participants than in the healthy participants. About 61% of participants with dyslipidemia had at least one or more elevated liver enzymes. In regression analysis, an independent association was observed between serum GGT and all lipid components. In conclusion, a high prevalence of dyslipidemia and liver enzyme abnormalities were observed among the study participants. Of the four liver enzymes, the serum levels of GGT showed an independent association with all lipid components. Moreover, this study indicates that subjects with dyslipidemia often have a higher chance of having liver diseases than subjects with no dyslipidemia. However, large-scale prospective studies are needed to understand the underlying mechanisms of lipid-induced hepatic dysfunction in the Bangladeshi population.

Exclusive Enteral Nutrition Remission Induction Treatment Influence on Transient Hypertransaminasemia in Children with Newly Onset Crohn's Disease.

Pediatric Crohn's disease (CD) is commonly associated with hepatobiliary complications, including transient liver enzymes elevation (LEE). Exclusive enteral nutrition (EEN) is recommended as primary treatment in mild-to-moderate pediatric CD. Data concerning EEN and liver enzymes (LE) abnormalities are limited. The aim of this study was to assess the LEE occurrence in newly diagnosed CD pediatric patients during EEN. Retrospective analysis of 73 patients, with no previous signs of liver disease, qualified to EEN. LE were assessed at diagnosis, during EEN, after completion of the nutritional treatment, and reintroduction of free diet. Thirty-one (42%) children presented with LEE and 28 (38%) with transient LEE. The LEE cohort presented with higher percentage of protein energy (24.0% ± 29.4 IQR [interquartile range] vs. 18.6% ± 23.6 IQR, P < .05) versus nonprotein energy (fat and carbohydrates) in total energy intake (75.9% ± 29.4 IQR vs. 81.4% ± 23.6 IQR, P < .05). Also, the protein/energy ratio was higher in the LEE group compared with the group with normal LE (0.026 vs. 0.024, P = .028). At the fourth week of EEN, aspartate aminotransferase elevation correlated with higher daily protein intake (P < .018). The LEE during EEN is typically a low-grade and transient condition that may be connected to applied treatment. We hypothesize that higher protein/energy ratio during EEN may be associated with mild, temporary LEE. Careful observation with repeated measurement of LE activity may be sufficient proceeding in patients without any other symptoms of CD-associated liver disease.

Prevalence and Correlates of Physical Comorbidities in Alcohol Use Disorder (AUD): a Pilot Study in Treatment-Seeking Population

This study aimed to understand the prevalence of physical comorbidities, undiagnosed and inadequately controlled chronic physical conditions and correlates of high cholesterol, hypertension and liver enzyme abnormalities in those with alcohol use disorder (AUD). Participants (n = 101) with AUD were recruited from a tertiary care centre through convenient sampling. The prevalence of physical and psychiatric comorbidities in the sample was 83.17% and 51.49%, respectively. Around 53.47% had two or more chronic physical conditions (multimorbidity). Hypertension (44.55%), asthma (23.76%), high cholesterol (22.77%) and liver enzyme abnormalities (21.78%) were the top four physical comorbidities. The prevalence of undiagnosed and inadequately controlled chronic physical conditions was 61.4% and 32.7%, respectively. Gender, education and body mass index (BMI) were associated with hyperlipidaemia while age and education were associated with hypertension. Higher waist-hip ratio was associated with liver enzyme abnormalities. Routine clinical care must include regular screening and follow-up of the risk groups to monitor their physical and mental health.

Safety and activity of pembrolizumab in combination with rituximab in relapsed or refractory follicular lymphoma

PD-1 blockade enhances the function of antitumor T cells and antibody-dependent, cell-mediated cytotoxicity (ADCC) of NK cells. In a single-center, open-label, phase 2 trial, we tested the combination of pembrolizumab, an anti-PD-1 monoclonal antibody, and rituximab, an anti-CD20 monoclonal antibody that induces ADCC, in 30 patients with follicular lymphoma (FL) with rituximab-sensitive disease who had relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 16 cycles, and rituximab was given at 375 mg/m2 IV weekly for 4 weeks in cycle 1 only. The most common grade 3/4 adverse events (AEs) were liver enzyme abnormalities (3%), diarrhea (3%), nausea (3%), aseptic meningitis (3%), and pancreatitis (3%). Low-grade immune-related AEs were reported in 80% of patients, including diarrhea (43%), liver enzyme abnormalities (33%), thyroid dysfunction (27%), and rash (23%). Grade 3 or 4 immune-related AEs occurred in 13% of the patients. Treatment-related AEs led to discontinuation in 6 (20%) patients. The overall response rate (primary end point) was 67%, and the complete response (CR) rate was 50%. Median progression-free survival (PFS) was 12.6 months (95% confidence interval, 8.2-27.6), the 3-year overall survival rate was 97%, and 23% of patients were in remission at a median follow-up of 35 months. The presence of a high CD8+ T-effector score at baseline in the tumor was associated with induction of a CR and improved PFS. In this single-arm, phase 2 study, the combination of pembrolizumab and rituximab demonstrates favorable efficacy and safety profile in relapsed FL. This trial is registered at www.clinicaltrials.gov as #NCT02446457.

Activity-Based Diagnostics: Recent Advances in the Development of Probes for Use with Diverse Detection Modalities.

Abnormal enzyme expression and activity is a hallmark of many diseases. Activity-based diagnostics are a class of chemical probes that aim to leverage this dysregulated metabolic signature to produce a detectable signal specific to diseased tissue. In this Review, we highlight recent methodologies employed in activity-based diagnostics that provide exquisite signal sensitivity and specificity in complex biological systems for multiple disease states. We divide these examples based upon their unique signal readout modalities and highlight those that have advanced into clinical trials.

Diffuse plate-like sheets of desquamation

Diffuse plate-like sheets of desquamation