Clinical evolution of antisynthetase syndrome-associated interstitial lung disease after COVID-19 in a man with Klinefelter syndrome:A case report

BACKGROUND This study presents a case of rapidly developing respiratory failure due to antisynthetase syndrome(AS)following coronavirus disease 2019(COVID-19)in a 33-year-old man diagnosed with Klinefelter syndrome(KS).CASE SUMMARY A 33-year-old man with a diagnosis of KS was admitted to the Department of Pulmonary and Critical Care Medicine of a tertiary hospital in China for fever and shortness of breath 2 wk after the onset of COVID-19.Computed tomography of both lungs revealed diffuse multiple patchy heightened shadows in both lungs,accompanied by signs of partial bronchial inflation.Metagenomic next-generation sequencing of the bronchoalveolar lavage fluid suggested absence of pathogen.A biopsy specimen revealed organizing pneumonia with alveolar septal thickening.Additionally,extensive auto-antibody tests showed strong positivity for anti-SSA,anti-SSB,anti-Jo-1,and anti-Ro-52.Following multidisciplinary discussions,the patient received a final diagnosis of AS,leading to rapidly progressing respiratory failure.CONCLUSION This study underscores the clinical progression of AS-associated interstitial lung disease subsequent to viral infections such as COVID-19 in patients diagnosed with KS.

Autoimmune hepatitis-primary biliary cholangitis overlap syndrome complicated by various autoimmune diseases:A case report

BACKGROUND Autoimmune hepatitis(AIH)and primary biliary cholangitis(PBC)are two common clinical autoimmune liver diseases,and some patients have both diseases;this feature is called AIH-PBC overlap syndrome.Autoimmune thyroid disease(AITD)is the most frequently overlapping extrahepatic autoimmune disease.Immunoglobulin(IgG)4-related disease is an autoimmune disease recognized in recent years,characterized by elevated serum IgG4 levels and infiltration of IgG4-positive plasma cells in tissues.CASE SUMMARY A 68-year-old female patient was admitted with a history of right upper quadrant pain,anorexia,and jaundice on physical examination.Laboratory examination revealed elevated liver enzymes,multiple positive autoantibodies associated with liver and thyroid disease,and imaging and biopsy suggestive of pancreatitis,hepatitis,and PBC.A diagnosis was made of a rare and complex overlap syndrome of AIH,PBC,AITD,and IgG4-related disease.Laboratory features improved on treatment with ursodeoxycholic acid,methylprednisolone,and azathioprine.CONCLUSION This case highlights the importance of screening patients with autoimmune diseases for related conditions.

Correlation of neutrophil to lymphocyte ratio to severity of coronary artery disease and in-hospital clinical outcomes in patients with acute coronary syndrome: A prospective observational study

Objective:To explore correlation of neutrophil-to-lymphocyte ratio(NLR)to severity of coronary artery disease(CAD)and in-hospital clinical outcomes in patients with acute coronary syndrome(ACS).Methods:In this prospective and observational study,we recruited 500 patients with ACS.For all the eligible patients,demographic details were collected,and laboratory parameters were evaluated.The CAD severity was evaluated in terms of the number of involved vessels.The NLR was calculated based on neutrophils and lymphocytes and the correlation of various risk factors and severity and outcome of CAD was performed.Results:77.2%of Patients was male,and 52%of the patients aged between 55-70 years.Based on the type of ACS,396 out of 500 patients had ST-elevation myocardial infarction.An ascending trend in the white blood cell levels and NLR value was noted as the severity of the ACS increased and the highest white blood cell levels and NLR was noted among classⅣpatients.The mean NLR value among the non-survivors were higher compared to the survivors(9.52±5.72 vs.4.76±2.36;P<0.01).Receiver operating curve showed that the cut-off NLR value was 5.76 with a sensitivity of 75.0%and a specificity of 77.3%.Conclusions:The NLR can be used as an independent prognostic marker in ACS.An elevated NLR value serves as a reliable predictor for short-term complications,notably in-hospital mortality.

Predictors of survival in autoimmune liver disease overlap syndromes

BACKGROUND Survival in patients with autoimmune liver disease overlap syndromes(AILDOS)compared to those with single autoimmune liver disease is unclear.AIM To investigate the survival of patients with AILDOS and assess the accuracy of non-invasive serum models for predicting liver-related death.METHODS Patients with AILDOS were defined as either autoimmune hepatitis and primary biliary cholangitis overlap(AIH-PBC)or autoimmune hepatitis and primary sclerosing cholangitis overlap(AIH-PSC)and were identified from three tertiary centres for this cohort study.Liver-related death or transplantation(liver-related mortality)was determined using a population-based data linkage system.Prognostic scores for liver-related death were compared for accuracy[including liver outcome score(LOS),Hepascore,Mayo Score,model for end-stage liver disease(MELD)score and MELD incorporated with serum sodium(MELD-Na)score].RESULTS Twenty-two AILDOS patients were followed for a median of 3.1 years(range,0.35-7.7).Fourteen were female,the median age was 46.7 years(range,17.8 to 82.1)and median Hepascore was 1(range,0.07-1).At five years post enrolment,57%of patients remained free from liver-related mortality(74%AIH-PBC,27%AIH-PSC).There was no significant difference in survival between AIH-PBC and AIH-PSC.LOS was a significant predictor of liver-related mortality(P<0.05)in patients with AIH-PBC(n=14)but not AIH-PSC(n=8).A LOS cut-point of 6 discriminated liver-related mortality in AIH-PBC patients(P=0.012,log-rank test,100%sensitivity,77.8%specificity)(Harrell's C-statistic 0.867).The MELD score,MELD-Na score and Mayo Score were not predictive of liver-related mortality in any group.CONCLUSION Survival in the rare,AILDOS is unclear.The current study supports the LOS as a predictor of liver-related mortality in AIH-PBC patients.Further trials investigating predictors of survival in AILDOS are required.

Clinical Observation of the Therapeutic Effects of Wenzhong Hewei Formula in Treating Spleen and Stomach Qi Deficiency Syndrome in Internal Medicine Diseases

Objective:To observe the clinical efficacy and safety of Wenzhong Hewei Formula in treating spleen and stomach qi deficiency syndrome in internal medicine diseases.Methods:Sixty patients with spleen and stomach qi deficiency syndrome admitted to the hospital from April 2022 to June 2023 were randomly divided into observation and control groups,with 30 patients in each group.The control group received conventional internal medicine treatment,while the observation group was additionally treated with Wenzhong Hewei Formula on the basis of conventional treatment.Both groups were treated for 4 weeks.Results:The total effective rate of treatment in the observation group was higher than that of the control group(P<0.05).After treatment,the traditional Chinese medicine syndrome scores of both groups were significantly lower than before treatment,with the observation group showing a more pronounced reduction(P<0.05).There was no statistically significant difference in the incidence of adverse reactions between the two groups(P>0.05).Conclusion:Wenzhong Hewei Formula can effectively improve clinical symptoms in patients with spleen and stomach qi deficiency syndrome,enhance clinical efficacy,and have a high level of safety,making it worthy of clinical promotion.

Associations between irritable bowel syndrome and non-alcoholic fatty liver disease:A systematic review

BACKGROUND Irritable bowel syndrome(IBS)is associated with obesity and metabolic syndrome.IBS and non-alcoholic fatty liver disease(NAFLD)are highly prevalent entities worldwide and may share similar mechanisms including gut dysbiosis,impaired intestinal mucosal barrier and immune system activation.AIM To systematically review their association according to the Preferred Reporting Items for Systemic Review and Meta-analyses guidelines.METHODS PubMed,EMBASE and Cochrane Database of Systematic Reviews were searched for relevant papers.Manual searches were also performed.RESULTS Six studies were included.Both IBS and NAFLD subjects had significantly more metabolic risk factors like hypertension,obesity,dyslipidaemia and diabetes.Our review showed that 23.2%to 29.4%of NAFLD patients had IBS.IBS was significantly higher in NAFLD patients compared with patients without NAFLD(23.2%vs 12.5%,P<0.01).A higher proportion of IBS patients had NAFLD(65.8%to 74.0%).IBS patients were three times more likely to have NAFLD compared with non-IBS patients(P<0.001).Two studies showed a significant correlation between the severity of IBS and NAFLD.The proportion of NAFLD subjects with IBS increased with NAFLD severity.CONCLUSION Further prospective studies are warranted to evaluate the relationship and shared pathways between IBS and NAFLD,potentially leading to the development of future therapeutics.

Persistent Xerophthalmia in a Patient with Rheumatological Disease and Priiviary Sjogren’s Syndrome: Case Report from Northern Brazil

This case study aims to contribute to the literature in order to highlight the importance of this collaboration between medical specialties. A female patient R.N.N. F, age 66, from the city of Manaus, with a previous diagnosis of Sjogren’s syndrome in regular follow-up by the Rheumatology team at the Araujo Lima outpatient clinic and referred to the Ophthalmology sector for complementary evaluation related to visual discomfort. The fundoscopy performed in the patient was within normal limits, but the symptoms experienced by her proved to be an important clinical finding, which has ratified the need for regular and multidisciplinary follow-up. This report unequivocally demonstrates that even in the face of tests considered within the expected limits for a given population, the clinical presentation can be specific and particular for each analyzed individual. Early screening exams should contemplate the patient in a holistic and individualized way whenever possible.

Prevalence of non-alcoholic fatty liver disease in patients with nephrotic syndrome:A population-based study

BACKGROUND Non-alcoholic fatty liver disease(NAFLD) is a global health concern with a prevalence of about 25% amongst United States adults. Its increased prevalence is attributed to increase in patients with obesity and metabolic syndrome, partly due to similar mechanisms of injury. Nephrotic syndrome(NS) is a clinical entity resulting from extensive proteinuria leading to hypoalbuminemia, hyperlipidemia, edema, and other complications. Given its association with hyperlipidemia, there is concern that patients with NS may be at increased risk of NAFLD.AIM To perform a cross-sectional population-based study to investigate the prevalence and risk factors of NAFLD in patients with NS.METHODS A large multicenter database(Explorys Inc., Cleveland, OH, United States) was utilized for this retrospective cohort study. A cohort of 49700 patients with a diagnosis of “Non-Alcoholic fatty liver disease” using the Systematized Nomenclature of Medicine-Clinical Terms(SNOMED-CT) between 1999-2022 was identified. Inclusion criteria were age ≥ 18 years, presence of NAFLD, presence of NS. There were no specific exclusion criteria. Univariate and multivariate analysis were performed to adjust for multiple risk factors including age, gender, Caucasian race, NS, type Ⅱ diabetes mellitus, hypothyroidism, dyslipidemia, obesity, metabolic syndrome and chronic kidney disease. Statistical analysis was conducted using R, and for all analyses, a 2-sided P value of < 0.05 was considered statistically significant.RESULTS Among the 78734750 individuals screened in this database, there were a total of 49700 subjects with NAFLD. In univariate analysis, the odds of having NAFLD in patients with NS, type 2 diabetes mellitus, hypothyroidism, dyslipidemia, obesity, metabolic syndrome and chronic kidney disease were 14.84 [95% confidence interval(95%CI) 13.67-16.10], 17.05(95%CI 16.78-17.32), 6.99(95%CI 6.87-7.11), 13.61(95%CI 13.38-13.84), 19.19(95%CI 18.89-19.50), 29.09(95%CI 28.26--29.95), and 9.05(95%CI 8.88-9.22), respectively. In multivariate analysis, the odds of having NAFLD amongst patients with NS were increased to 1.85(95%Cl 1.70-2.02), while the odds were also remained high in patients that have type 2 diabetes mellitus [odds ratio(OR) 3.84], hypothyroidism(OR 1.57), obesity(OR 5.10), hyperlipidemia(OR 3.09), metabolic syndrome(OR 3.42) and chronic kidney disease(OR 1.33).CONCLUSION Patients with NS are frequently found to have NAFLD, even when adjusting for common risk factors. Hence, clinicians should maintain a high index of suspicion regarding presence of NAFLD in patients with NS.

Creutzfeldt-Jakob disease presenting as Korsakoff syndrome caused by E196A mutation in PRNP gene:A case report

BACKGROUND Prion diseases are a group of degenerative nerve diseases that are caused by infectious prion proteins or gene mutations.In humans,prion diseases result from mutations in the prion protein gene(PRNP).Only a limited number of cases involving a specific PRNP mutation at codon 196(E196A)have been reported.The coexistence of Korsakoff syndrome in patients with Creutzfeldt-Jakob disease(CJD)caused by E196A mutation has not been documented in the existing literature.CASE SUMMARY A 61-year-old Chinese man initially presented with Korsakoff syndrome,followed by rapid-onset dementia,visual hallucinations,akinetic mutism,myoclonus,and hyperthermia.The patient had no significant personal or familial medical history.Magnetic resonance imaging of the brain revealed extensive hyperintense signals in the cortex,while positron emission tomography/computed tomography showed a diffuse reduction in cerebral cortex metabolism.Routine biochemical and microorganism testing of the cerebrospinal fluid(CSF)yielded normal results.Tests for thyroid function,human immunodeficiency virus,syphilis,vitamin B1 and B12 levels,and autoimmune rheumatic disorders were normal.Blood and CSF tests for autoimmune encephalitis and autoantibody-associated paraneoplastic syndrome yielded negative results.A test for 14-3-3 protein in the CSF yielded negative results.Whole-genome sequencing revealed a diseasecausing mutation in PRNP.The patient succumbed to the illness 11 months after the initial symptom onset.CONCLUSION Korsakoff syndrome,typically associated with alcohol intoxication,also manifests in CJD patients.Individuals with CJD along with PRNP E196A mutation may present with Korsakoff syndrome.

Immune checkpoint inhibitor therapy-induced autoimmune polyendocrine syndrome typeⅡand Crohn's disease:A case report

BACKGROUND The development of immune checkpoint inhibitors(ICIs)has heralded a new era in cancer treatment,enabling the possibility of long-term survival in patients with metastatic disease.Unfortunately,ICIs are increasingly implicated in the development of autoimmune diseases.CASE SUMMARY We present a man with squamous cell carcinoma of the oropharynx on a combination of teriprizumab,docetaxel,and cisplatin therapy who developed autoimmune polyendocrine syndrome typeⅡ(APS-2)including thyroiditis and type 1 diabetes mellitus and Crohn’s disease(CD).He developed thirst,abdominal pain,and fatigue after two-week treatment with the protein 1 ligand inhibitor teriprizumab.Biochemistry confirmed APS-2 and thyrotoxicosis.He was commenced on an insulin infusion.However,his abdominal pain persisted.Follow-up surgery confirmed CD and his abdominal pain was relieved by mesalazine.He was continued on insulin and mesalazine therapy.CONCLUSION Immunotherapy can affect all kinds of organs.When clinical symptoms cannot be explained by a single disease,clinicians should consider the possibility of multisystem damage.

A review of the neurotransmitter system associated with cognitive function of the cerebellum in Parkinson's disease

The dichotomized brain system is a concept that was generalized from the‘dual syndrome hypothesis’to explain the heterogeneity of cognitive impairment,in which anterior and posterior brain systems are independent but partially overlap.The dopaminergic system acts on the anterior brain and is responsible for executive function,working memory,and planning.In contrast,the cholinergic system acts on the posterior brain and is responsible for semantic fluency and visuospatial function.Evidence from dopaminergic/cholinergic imaging or functional neuroimaging has shed significant insight relating to the involvement of the cerebellum in the cognitive process of patients with Parkinson’s disease.Previous research has reported evidence that the cerebellum receives both dopaminergic and cholinergic projections.However,whether these two neurotransmitter systems are associated with cognitive function has yet to be fully elucidated.Furthermore,the precise role of the cerebellum in patients with Parkinson’s disease and cognitive impairment remains unclear.Therefore,in this review,we summarize the cerebellar dopaminergic and cholinergic projections and their relationships with cognition,as reported by previous studies,and investigated the role of the cerebellum in patients with Parkinson’s disease and cognitive impairment,as determined by functional neuroimaging.Our findings will help us to understand the role of the cerebellum in the mechanisms underlying cognitive impairment in Parkinson’s disease.

Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease(MAFLD)is a hepatic manifestation of the metabolic syndrome.It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries.MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma.Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis.The mechanisms involved in maintaining gut-liver axis homeostasis are complex.One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gutliver axis functionality.An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis.Moreover,alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis.Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are a class of drugs developed for the treatment of type 2 diabetes mellitus.They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis.The mechanisms reported to be involved in this effect include an improved regulation of glycemia,reduced lipid synthesis,β-oxidation of free fatty acids,and induction of autophagy in hepatic cells.Recently,multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment.A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD.This review presents the current understanding of the role of the gutliver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.

Insulin resistance as the molecular link between diabetes and Alzheimer's disease

Diabetes mellitus(DM)and Alzheimer's disease(AD)are two major health concerns that have seen a rising prevalence worldwide.Recent studies have indicated a possible link between DM and an increased risk of developing AD.Insulin,while primarily known for its role in regulating blood sugar,also plays a vital role in protecting brain functions.Insulin resistance(IR),especially prevalent in type 2 diabetes,is believed to play a significant role in AD's development.When insulin signalling becomes dysfunctional,it can negatively affect various brain functions,making individuals more susceptible to AD's defining features,such as the buildup of beta-amyloid plaques and tau protein tangles.Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD.This review aims to explore the relationship between DM and AD,with a focus on the role of IR.It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR.Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.

Metabolic syndrome’s new therapy:Supplement the gut microbiome

This letter to the editor discusses the publication on gut microbiome supple-mentation as therapy for metabolic syndrome.Gut microbiome dysbiosis disrupts intestinal bacterial homeostasis and is related to chronic inflammation,insulin resistance,cardiovascular diseases,type 2 diabetes mellitus,and obesity.Previous research has found that increasing the abundance of beneficial microbiota in the gut modulates metabolic syndrome by reducing chronic inflammation and insulin resistance.Prebiotics,probiotics,synbiotics,and postbiotics are often used as supplements to increase the number of beneficial microbes and thus the produc-tion of short-chain fatty acids,which have positive effects on the gut microbiome and metabolic syndrome.In this review article,the author summarizes the available supplements to increase the abundance of beneficial gut microbiota and reduce the abundance of harmful microbiota in patients with metabolic disorders.Our group is also researching the role of the gut microbiota in chronic liver disease.This article will be of great help to our research.At the end of the letter,the mechanism of the gut microbiota in chronic liver disease is discussed.

Glucagon-like peptide-1 receptor agonists:Exploring the mechanisms from glycemic control to treatment of multisystemic diseases

This editorial takes a deeper look at the insights provided by Soresi and Giannitrapani,which examined the therapeutic potential of glucagon-like peptide-1 receptor agonists(GLP-1RAs)for metabolic dysfunction-associated fatty liver disease.We provide supplementary insights to their research,highlighting the broader systemic implications of GLP-1RAs,synthesizing the current understanding of their mechanisms and the trajectory of research in this field.GLP-1RAs are revolutionizing the treatment of type 2 diabetes mellitus and beyond.Beyond glycemic control,GLP-1RAs demonstrate cardiovascular and renal protective effects,offering potential in managing diabetic kidney disease alongside renin–angiotensin–aldosterone system inhibitors.Their role in bone metabolism hints at benefits for diabetic osteoporosis,while the neuroprotective properties of GLP-1RAs show promise in Alzheimer's disease treatment by modulating neuronal insulin signaling.Additionally,they improve hormonal and metabolic profiles in polycystic ovary syndrome.This editorial highlights the multifaceted mechanisms of GLP-1RAs,emphasizing the need for ongoing research to fully realize their therapeutic potential across a range of multisystemic diseases.

Effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease:Clinical implications

In this editorial,we comment on the article by Chen et al recently published in 2024.We focus the debate on whether reducing the upper limit of normal of alanine aminotransferase(ALT)would effectively identify cases of fibrosis in metabolic-dysfunction associated fatty liver disease(MAFLD).This is important given the increasing prevalence of MAFLD and obesity globally.Currently,a suitable screening test to identify patients in the general population does not exist and most patients are screened after the finding of an abnormal ALT.The authors of this paper challenge the idea of what a normal ALT is and whether that threshold should be lowered,particularly as their study found that 83.12%of their study population with a diagnosis of MAFLD had a normal ALT.The main advantages of screening would be to identify patients and provide intervention early,the mainstay of this being changing modifiable risk factors and monitoring for liver fibrosis.However,there is not enough suitable therapeutic options available as of yet although this is likely to change in the coming years with more targets for therapy being discovered.Semaglutide is one example of this which has demonstrated benefit with an acceptable side effect profile for those patients with MAFLD and obesity,although studies have not yet shown a significant improvement in fibrosis regression.It would also require a huge amount of resource if a reduced ALT level alone was used as criteria;it is more likely that current scoring systems such as fibrosis-4 may be amended to represent this additional risk.Currently,there is not a good argument to recommend wide-spread screening with a reduced ALT level as this is unlikely to be cost-effective.This is compounded by the fact that there is a significant heterogeneity in what is considered a normal ALT between laboratories.Although studies previously have suggested a more pragmatic approach in screening those over the age of 60,this is likely to change with the increasing incidence of obesity within the younger age groups.The main message from this study is that those who have hypercholesterolemia and high body metabolic index should have these risk factors modified to maintain a lower level of ALT to reduce the risk of progression to fibrosis and cirrhosis.

Investigating causal links between gastroesophageal reflux disease and essential hypertension

Gastroesophageal reflux disease(GERD)is a prevalent global health concern with a rising incidence.Various risk factors,including obesity,hiatal hernia,and smo-king,contribute to its development.Recent research suggests associations bet-ween GERD and metabolic syndrome,cardiac diseases,and hypertension(HTN).Mechanisms linking GERD to HTN involve autonomic dysfunction,inflammatory states,and endothelial dysfunction.Furthermore,GERD medications such as pro-ton-pump inhibitors may impact blood pressure regulation.Conversely,antihy-pertensive medications like beta-blockers and calcium channel blockers can exacerbate GERD symptoms.While bidirectional causality exists between GERD and HTN,longitudinal studies are warranted to elucidate the precise relationship.Treatment of GERD,including anti-reflux surgery,may positively influence HTN control.However,the interplay of lifestyle factors,comorbidities,and medications necessitates further investigation to comprehensively understand this relation-ship.In this editorial,we comment on the article published by Wei et al in the recent issue of the World Journal of Clinical Cases.We evaluate their claims on the causal association between GERD and HTN.

Prevalence and risk factors for impaired renal function among Asian patients with nonalcoholic fatty liver disease

Background:Nonalcoholic fatty liver disease(NAFLD)is associated with impaired renal function,and both diseases often occur alongside other metabolic disorders.However,the prevalence and risk factors for impaired renal function in patients with NAFLD remain unclear.The objective of this study was to identify the prevalence and risk factors for renal impairment in NAFLD patients.Methods:All adults aged 18-70 years with ultrasound-diagnosed NAFLD and transient elastography examination from eight Asian centers were enrolled in this prospective study.Liver fibrosis and cirrhosis were assessed by FibroScan-aspartate aminotransferase(FAST),Agile 3+and Agile 4 scores.Impaired renal function and chronic kidney disease(CKD)were defined by an estimated glomerular filtration rate(eGFR)with value of<90 mL/min/1.73 m^(2) and<60 mL/min/1.73 m^(2),respectively,as estimated by the CKD-Epidemiology Collaboration(CKD-EPI)equation.Results:Among 529 included NAFLD patients,the prevalence rates of impaired renal function and CKD were 37.4%and 4.9%,respectively.In multivariate analysis,a moderate-high risk of advanced liver fibrosis and cirrhosis according to Agile 3+and Agile 4 scores were independent risk factors for CKD(P<0.05).Furthermore,increased fasting plasma glucose(FPG)and blood pressure were significantly associated with impaired renal function after controlling for the other components of metabolic syndrome(P<0.05).Compared with patients with normoglycemia,those with prediabetes[FPG≥5.6 mmol/L or hemoglobin A1c(HbA1c)≥5.7%]were more likely to have impaired renal function(P<0.05).Conclusions:Agile 3+and Agile 4 are reliable for identifying NAFLD patients with high risk of CKD.Early glycemic control in the prediabetic stage might have a potential renoprotective role in these patients.

Two missense STK11 gene variations impaired LKB1/adenosine monophosphate-activated protein kinase signaling in Peutz-Jeghers syndrome

BACKGROUND Peutz-Jeghers syndrome(PJS)is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11(STK11/LKB1)gene mutations.Preimplantation genetic testing can protect a patient’s offspring from mutated genes;however,some variations in this gene have been interpreted as variants of uncertain significance(VUS),which complicate reproductive decision-making in genetic counseling.AIM To identify the pathogenicity of two missense variants and provide clinical guidance.METHODS Whole exome gene sequencing and Sanger sequencing were performed on the peripheral blood of patients with PJS treated at the Reproductive and Genetic Hospital of Citic-Xiangya.Software was employed to predict the protein structure,conservation,and pathogenicity of the two missense variation sites in patients with PJS.Additionally,plasmids were constructed and transfected into HeLa cells to observe cell growth.The differences in signal pathway expression between the variant group and the wild-type group were compared using western blot and immunohistochemistry.Statistical analysis was performed using one-way analysis of variance.P<0.05 was considered statistically significant.RESULTS We identified two missense STK11 gene VUS[c.889A>G(p.Arg297Gly)and c.733C>T(p.Leu245Phe)]in 9 unrelated PJS families who were seeking reproductive assistance.The two missense VUS were located in the catalytic domain of serine/threonine kinase,which is a key structure of the liver kinase B1(LKB1)protein.In vitro experiments showed that the phosphorylation levels of adenosine monophosphate-activated protein kinase(AMPK)at Thr172 and LKB1 at Ser428 were significantly higher in transfected variation-type cells than in wild-type cells.In addition,the two missense STK11 variants promoted the proliferation of HeLa cells.Subsequent immunohistochemical analysis showed that phosphorylated-AMPK(Thr172)expression was significantly lower in gastric,colonic,and uterine polyps from PJS patients with missense variations than in non-PJS patients.Our findings indicate that these two missense STK11 variants are likely pathogenic and inactivate the STK11 gene,causing it to lose its function of regulating downstream phosphorylated-AMPK(Thr172),which may lead to the development of PJS.The identification of the pathogenic mutations in these two clinically characterized PJS patients has been helpful in guiding them toward the most appropriate mode of pregnancy assistance.CONCLUSION These two missense variants can be interpreted as likely pathogenic variants that mediated the onset of PJS in the two patients.These findings not only offer insights for clinical decision-making,but also serve as a foundation for further research and reanalysis of missense VUS in rare diseases.

Managing end-stage carcinoid heart disease:A case report and literature review

BACKGROUND Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)are rare tumors,often diagnosed in an advanced stage when curative treatment is impossible and grueling symptoms related to vasoactive substance release by tumor cells affect patients’quality of life.Cardiovascular complications of GEP-NENs,primarily tricuspid and pulmonary valve disease,and right-sided heart failure,are the leading cause of death,even compared to metastatic disease.CASE SUMMARY We present a case of a 35-year-old patient with progressive dyspnea,back pain,polyneuropathic leg pain,and nocturnal diarrhea lasting for a decade before the diagnosis of neuroendocrine carcinoma of unknown primary with extensive liver metastases.During the initial presentation,serum biomarkers were not evaluated,and the patient received five cycles of doxorubicin,which he did not tolerate well,so he refused further therapy and was lost to follow-up.After 10 years,he presented to the emergency room with signs and symptoms of right-sided heart failure.Panneuroendocrine markers,serum chromogranin A,and urinary 5-hydroxyindoleacetic acid were extremely elevated(900 ng/mL and 2178µmol/L),and transabdominal ultrasound confirmed hepatic metastases.Computed tomo-graphy(CT)showed liver metastases up to 6 cm in diameter and metastases in mesenteric lymph nodes and pelvis.Furthermore,an Octreoscan showed lesions in the heart,thoracic spine,duodenum,and ascendent colon.A standard trans-thoracic echocardiogram confirmed findings of carcinoid heart disease.The patient was not a candidate for valve replacement.He started octreotide acetate treatment,and the dose escalated to 80 mg IM monthly.Although biochemical CONCLUSION Carcinoid heart disease occurs with carcinoid syndrome related to advanced neuroendocrine tumors,usually with liver metastases,which manifests as right-sided heart valve dysfunction leading to right-sided heart failure.Carcinoid heart disease and tumor burden are major prognostic factors of poor survival.Therefore,they must be actively sought by available biochemical markers and imaging techniques.Moreover,imaging techniques aiding tumor detection and staging,somatostatin receptor positron emission tomography/CT,and CT or magnetic resonance imaging,should be performed at the time of diagnosis and in 3-to 6-mo intervals to determine tumor growth rate and assess the possibility of locoregional therapy and/or palliative surgery.Valve replacement at the onset of symptoms or right ventricular dysfunction may be considered,while any delay can worsen right-sided ventricular failure.