Osteosarcopenia in autoimmune cholestatic liver diseases:Causes,management,and challenges

Primary biliary cholangitis and primary sclerosing cholangitis(PSC)are the most common cholestatic liver diseases(CLD)in adults and are both characterized by an immune pathogenesis.While primary biliary cholangitis is a model autoimmune disease,with over 90%of patients presenting very specific autoantibodies against mitochondrial antigens,PSC is considered an immune mediated disease.Osteoporosis is the most common bone disease in CLD,resulting in frequent fractures and leading to significant morbidity.Further,sarcopenia is emerging as a frequent complication of chronic liver diseases with a significant prognostic impact and severe implications on the quality of life of patients.The mechanisms underlying osteoporosis and sarcopenia in CLD are still largely unknown and the association between these clinical conditions remains to be dissected.Although timely diagnosis,prevention,and management of osteosarcopenia are crucial to limit the consequences,there are no specific guidelines for management of osteoporosis and sarcopenia in patients with CLD.International guidelines recommend screening for bone disease at the time of diagnosis of CLD.However,the optimal monitoring strategies and treatments have not been defined yet and vary among centers.We herein aim to comprehensively outline the pathogenic mechanisms and clinical implications of osteosarcopenia in CLD,and to summarize expert recommendations for appropriate diagnostic and therapeutic approaches.

Guidelines for the Management of Cholestatic Liver Diseases (2021)

In 2015, the Chinese Society of Hepatology and the Chinese Society of Gastroenterology issued a consensus statement on the diagnosis and management of cholestatic liver diseases. More clinical data on this topic have appeared during recent years. The Autoimmune Liver Disease Group of the Chinese Society of Hepatology organized an expert group to review recent evidence and provide an update to these previous guidelines. Herein, we provide 22 recommendations as a working reference for the management of cholestatic liver diseases by clinical practitioners.

Chinese Expert Consensus for the Diagnosis and Treatmentof Cholestatic Liver Disease

Cholestatic liver disease (CLD) is a common problem in clinical practice with the main manifestation being cholestasis.Recently,there has been a steady increase in knowledge associated with the diagnosis and treatment of CLD.Therefore,the experts in China were organized by the editorial board of Chinese Journal of Experimental and Clinical Infectious Diseases (Electronic Edition),Chinese Journal of Liver Diseases (Electronic Edition) and Infection International (Electronic Edition) to collect and analyze relevant research,ultimately resulting in the development of this work (Chinese Expert consensus for the diagnosis and treatment of CLDs,also abbreviated as consensus).

Bile acid signaling through farnesoid X and TGR5 receptors in hepatobiliary and intestinal diseases

BACKGROUND： The well-known functions of bile acids（BAs） are the emulsification and absorption of lipophilic xenobiotics. However, the emerging evidences in the past decade showed that BAs act as signaling molecules that not only autoregulate their own metabolism and enterohepatic recirculation, but also as important regulators of integrative metabolism by activating nuclear and membrane-bound G protein-coupled receptors. The present review was to get insight into the role of maintenance of BA homeostasis and BA signaling pathways in development and management of hepatobiliary and intestinal diseases.DATA SOURCES： Detailed and comprehensive search of PubM ed and Scopus databases was carried out for original and review articles.RESULTS： Disturbances in BA homeostasis contribute to the development of several hepatobiliary and intestinal disorders, such as non-alcoholic fatty liver disease, liver cirrhosis, cholesterol gallstone disease, intestinal diseases and both hepatocellular and colorectal carcinoma.CONCLUSION： Further efforts made in order to advance the understanding of sophisticated BA signaling network may be promising in developing novel therapeutic strategies related not only to hepatobiliary and gastrointestinal but also systemic diseases.

Primary sclerosing cholangitis in Turkish patients:characteristic features and prognosis

BACKGROUND:Primary sclerosing cholangitis(PSC)is a chronic cholestatic liver disease characterized by destruction and fibrosis of the bile ducts.This study aimed to demonstrate the hepatic and extrahepatic characteristic findings and prognostic outcomes of Turkish patients with PSC. METHODS:The medical records of 35 consecutive patients with PSC from January 1988 to June 2007 were recorded prospectively.From the time of diagnosis,clinical features and laboratory data were collected. RESULTS:The mean age of the 35 patients was 41.69 years (range 15-80 years)at the time of diagnosis;14(40%)were female,and 21(60%)were male.The mean duration of follow-up was 58.86 months(1-180 months).Twenty(57.1%) of the patients with PSC were asymptomatic and 22(62.9%) had inflammatory bowel disease.At the time of diagnosis, 20(57.1%)of the patients had both intra-and extra-hepatic PSC.Twenty-one(60%)of the patients,who had undergone ERCP for stent placement,had dominant bile duct stenosis. Cholangiocarcinoma was found in 2(5.7%)of the patients and cirrhosis was detected in 7(20%);5(14.3%)underwent liver transplantation.The median follow-up time after liver transplantation was 23 months and all are still alive.Six (17.1%)patients died. CONCLUSIONS:PSC has a clinical course varied from advanced liver disease requiring liver transplantation within a short time to being asymptomatic for decades. The prognosis of Turkish patients with PSC is also disappointing as described in other studies.

Gut microbiome in liver pathophysiology and cholestatic liver disease

An increasing amount of evidence has shown critical roles of gut microbiome in host pathophysiology.The gut and the liver are anatomically and physiologically connected.Given the critical role of gut-liver axis in the homeostasis of the liver,gut microbiome interplays with a diverse spectrum of hepatic changes,including steatosis,inflammation,fibrosis,cholestasis,and tumorigenesis.In clinic,cholestasis manifests with fatigue,pruritus,and jaundice,caused by the impairment in bile formation or flow.Studies have shown that the gut microbiome is altered in cholestatic liver disease.In this review,we will explore the interaction between the gut microbiome and the liver with a focus on the alteration and the role of gut microbiome in cholestatic liver disease.We will also discuss the prospect of exploiting the gut microbiome in the development of novel therapies for cholestatic liver disease.

Primary biliary cirrhosis in India

BACKGROUND: Primary biliary cirrhosis (PBC) is a rare cause of chronic liver disease in India. We analyzed the clinical, biochemical, serological and histological features of patients with PBC for over a 10-year period. METHODS: PBC was diagnosed by the presence of raised level of serum alkaline phosphatase (ALP), anti-mitochondrial antibody (AMA) positivity (1:40 dilution), and/or diagnostic liver histology. RESULTS:Fifteen female patients with mean age of 46.5±11 years were studied. Pruritis (80%) followed by jaundice (67%), skin changes (pigmentation, coarsening, xanthelesma and vitiligo) (67%) and fatigue (60%) were common symptoms. The mean duration of the symptoms was 3.5± 5.4 years (3 months to 20 years). Dryness of eyes was observed in only 2 patients. Hepatomegaly was noted in 87% of the patients and ascites at presentation in 40%. Mean levels of bilirubin and albumin at the time of diagnosis were 3.4±3.3 mg/dl and 3.5±0.8 g/dl, respectively. The level of serum ALP ranged from 54 to 2400 IU/L, with a median being 552 IU/L (2×ULN). In all the 15 patients with AMA positive, 8(53%) were also positive for either anti-nuclear or anti-smooth muscle antibodies. Two patients presented with persistently elevated SAP after an acute hepatitic illness. Liver biopsy was available in 13 patients, diagnostic of PBC Ⅱ & Ⅲ(8) and with evidence of cirrhosis (5). Associated autoimmune disorders were observed in 5 patients (33%). The mean time for follow-up was 26±21 months (1 to 87 months). In 4 deaths, 3 were due to liver related causes. CONCLUSION: PBC is a rare cause of chronic liver disease in India. PBC in India, unlike in the West, presents late, often with features of cirrhosis and decompensation.

Bile acid metabolism and signaling in liver disease and therapy

Bile acids play a critical role in the regulation of glucose,lipid,and energy metabolism through activation of the nuclear bile acid receptor farnesoid X receptor(FXR)and membrane G protein-coupled bile acid receptor-1(Gpbar-1,aka TGR5).Agonist activation of FXR and TGR5 improves insulin and glucose sensitivity and stimulates energy metabolism to prevent diabetes,obesity,and non-alcoholic fatty liver disease(NAFLD).Bile acids have both pro-and anti-inflammatory actions through FXR and TGR5 in the intestine and liver.In the intestine,bile acids activate FXR and TGR5 to stimulate fibroblast growth factor 15 and glucagon-like peptide-1 secretion.FXR and TGR5 agonists may have therapeutic potential for treating liver-related metabolic diseases,such as diabetes and NAFLD.

Long non-coding RNA in liver metabolism and disease:Current status

Long non-coding RNAs(lncRNAs)are comprised of RNA transcripts exceeding 200 nucleotides in length but lacking identifiable open reading frames(with rare exceptions).Herein,we highlight emerging evidence demonstrating that lncRNAs are critical regulators of liver metabolic function and diseases.We summarize current knowledges about dysregulated lncRNAs and outline the underlying molecular mechanisms by which lncRNAs control hepatic lipid ad glucose metabolism,as well as cholestatic liver disease.Liver-specific triglyceride regulator(lncLSTR),Lnc18q22.2,steroid RNA activator(SRA),highly upregulated in liver cancer(HULC),metastasis associated in lung adenocarcinoma transcript 1(MALAT1),liver glucokinase repressor(lncLGR),maternally expressed gene 3(MEG3),and H19,lncHR1,lnc-HC,apolipoprotein A1 antisense transcript(APOA1-AS),DYNLRB2-2,and LXR-induced sequence(LeXis)are included in the discussion.

Emerging Therapeutic Strategies in The Fight Against Primary Biliary Cholangitis

The liver has a vital role in many metabolic and regulatory processes in the body.Primary biliary cholangitis(PBC),previously known as primary biliary cirrhosis,is a chronic cholestatic autoimmune disease of the intrahepatic bile ducts associated with loss of tolerance to mitochondrial antigens.At this time there is no definitive cure for PBC;however,ursodeoxycholic acid(UDCA)has been shown to reduce injury when administered as the first line of treatment.Additional therapeutics can be given concurrently or as an alternative to UDCA to manage the symptoms and further curb disease progression.Currently,a liver transplant is the only potentially curative option when the patient has developed end-stage liver disease or intractable pruritus.This review aims to delineate the pathogenesis of primary biliary cholangitis and shed light on current therapeutic strategies in the treatment of PBC.

Antihepatic Fibrosis Drugs in Clinical Trials

Liver fibrosis is not an independent disease.It refers to the abnormal proliferation of connective tissues in the liver caused by various pathogenic factors.Thus far,liver fibrosis has been considered to be associated with a set of factors,such as viral infection,alcohol abuse,non-alcoholic fatty liver disease,and autoimmune hepatitis,as well as genetic diseases.To date,clinical therapeutics for liver fibrosis still face challenges,as elimination of potential causes and conventional antifibrotic drugs cannot alleviate fibrosis in most patients.Recently,potential therapeutic targets of liver fibrosis,such as metabolism,inflammation,cell death and the extracellular matrix,have been explored through basic and clinical research.Therefore,it is extremely urgent to review the antihepatic fibrosis therapeutics for treatment of liver fibrosis in current clinical trials.

Severe Alcoholic Hepatitis:Atypical Presentation with Markedly Elevated Alkaline Phosphatase

Alcoholic hepatitis(AH)is an acute inflammatory liver disease with poor prognosis.Infections in AH are difficult to detect and contribute to short-term mortality.Intrahepatic cholestasis and elevated alkaline phosphatase levels are also associated with worse outcomes.This report describes an uncommon presentation of severe AH.