Dipeptidyl peptidase-4: A key player in chronic liver disease

Dipeptidyl peptidase-4 (DPP-4) is a membrane-associated peptidase, also known as CD26. DPP-4 has widespread organ distribution throughout the body and exerts pleiotropic effects via its peptidase activity. A representative target peptide is glucagon-like peptide-1, and inactivation of glucagon-like peptide-1 results in the development of glucose intolerance/diabetes mellitus and hepatic steatosis. In addition to its peptidase activity, DPP-4 is known to be associated with immune stimulation, binding to and degradation of extracellular matrix, resistance to anti-cancer agents, and lipid accumulation. The liver expresses DPP-4 to a high degree, and recent accumulating data suggest that DPP-4 is involved in the development of various chronic liver diseases such as hepatitis C virus infection, non-alcoholic fatty liver disease, and hepatocellular carcinoma. Furthermore, DPP-4 occurs in hepatic stem cells and plays a crucial role in hepatic regeneration. In this review, we described the tissue distribution and various biological effects of DPP-4. Then, we discussed the impact of DPP-4 in chronic liver disease and the possible therapeutic effects of a DPP-4 inhibitor.

Insulin resistance and chronic liver disease

Increased insulin resistance is frequently associated with chronic liver disease and is a pathophysiological feature of hepatogenous diabetes.Distinctive factors including hepatic parenchymal cell damage,portalsystemic shunting and hepatitis C virus are responsible for the development of hepatogenous insulin resistance/diabetes.Although it remains unclear whether insulin secretion from pancreatic beta cells is impaired as it is in type 2 diabetes,retinopathic and cardiovascular risk is low and major causes of death in cirrhotic patients with diabetes are liver failure,hepatocellular carcinoma and gastrointestinal hemorrhage.Hemoglobin A1c is an inaccurate marker for the assessment and management of hepatogenous diabetes.Moreover,exogenous insulin or sulfonylureas may be harmful because these agents may promote hepatocarcinogenesis.Thus,pathogenesis,cause of death,assessment and therapeutic strategy for hepatogenous insulin resistance/diabetes differ from those for lifestyle-related type 2 diabetes.In this article,we review features of insulin resistance in relationship to chronic liver disease.We also discuss the impact of anti-diabetic agents on interferon treatment and hepatocarcinogenesis.

Importance of hepatitis C virus-associated insulin resistance:Therapeutic strategies for insulin sensitization

Insulin resistance is one of the pathological features in patients with hepatitis C virus(HCV) infection.Generally,persistence of insulin resistance leads to an increase in the risk of life-threatening complications such as cardiovascular diseases.However,these complications are not major causes of death in patients with HCV-associated insulin resistance.Indeed,insulin resistance plays a crucial role in the development of various complications and events associated with HCV infection.Mounting evidence indicates that HCV-associated insulin resistance may cause(1) hepatic steatosis;(2) resistance to anti-viral treatment;(3) hepatic f ibrosis and esophageal varices;(4) hepatocarcinogenesis and proliferation of hepatocellular carcinoma;and(5) extrahepatic manifestations.Thus,HCV-associated insulin resistance is a therapeutic target at any stage of HCV infection.Although the risk of insulin resistance in HCV-infected patients has been documented,therapeutic guidelines for preventing the distinctive complications of HCV-associated insulin resistance have not yet been established.In addition,mechanisms for the development of HCV-associated insulin resistance differ from lifestyle-associated insulin resistance.In order to ameliorate HCV-associated insulin resistance and its complications,the eff icacy of the following interventions is discussed:a late evening snack,coffee consumption,dietary iron restriction,phlebotomy,and zinc supplements.Little is known regarding the effect of anti-diabetic agents on HCV infection,however,a possible association between use of exogenous insulin or a sulfonylurea agent and the development of HCC has recently been reported.On the other hand,insulin-sensitizing agents are reported to improve sustained virologic response rates.In this review,we summarize distinctive complications of,and therapeutic strategies for,HCVassociated insulin resistance.Furthermore,we discuss supplementation with branched-chain amino acids as a unique insulin-sensitizing strategy for patients with HCVassociated insulin resistance.

Simple scoring system for predicting cirrhosis in nonalcoholic fatty liver disease

AIM:To investigate a simple noninvasive scoring system for predicting liver cirrhosis in nonalcoholic fatty liver disease(NAFLD)patients.METHODS:A total of 1048 patients with liver-biopsyconfirmed NAFLD were enrolled from nine hepatology centers in Japan(stage 0,216;stage 1,334;stage 2,270;stage 3,190;stage 4,38).The weight and height of the patients were measured using a calibrated scale after requesting the patients to remove their shoes and any heavy clothing.Venous blood samples were obtained in the morning after the patients had fasted overnight for 12 h.Laboratory evaluation was performed in all patients.Statistical analysis was conducted using SPSS version 12.0.Continuous variables were expressed as mean±SD.RESULTS:The optimal cutoff value of platelet count,serum albumin,and aminotransferase/alanine aminotransferase ratio(AAR)was set at<15.3 104/μL,<4.0g/dL,and>0.9,respectively,by the receiver operating characteristic curve.These three variables were combined in an unweighted sum(platelet count=1 point,serum albumin=1 point,AAR=1 point)to form an easily calculated composite score for predicting cirrhosis in NAFLD patients,called the PLALA(platelet,albumin,AAR)score.The diagnosis of PLALA≥2 had sufficient accuracy for detecting liver cirrhosis in NAFLD patients.CONCLUSION:The PLALA score may be an ideal scoring system for detecting cirrhosis in NAFLD patients with sufficient accuracy and simplicity to be considered for clinical use.

Motor vehicle accidents: How should cirrhotic patients be managed?

Motor vehicle accidents (MVAs) are serious social issues worldwide and driver illness is an important cause of MVAs. Minimal hepatic encephalopathy (MHE) is a com- plex cognitive dysfunction with attention deficit, which frequently occurs in cirrhotic patients independent of severity of liver disease. Although MHE is known as a risk factor for MVAs, the impact of diagnosis and treatment of MHE on MVA-related societal costs is largely unknown. Recently, Bajaj et al demonstrated valuable findings that the diagnosis of MHE by rapid screening using the inhibitory control test (ICT), and subsequent treatment with lactulose could substantially reduce the societal costs by preventing MVAs. Besides the ICT and lactulose, there are various diagnostic tools and therapeutic strategies for MHE. In this commentary, we discussed a current issue of diagnostic tools for MHE, including neuropsychological tests. We also discussed the advantages of the other therapeutic strategies for MHE, such as intake of a regular breakfast and coffee, and supplementation with zinc and branched chain amino acids, on the MVA-related societal costs.

An ever-increasing metabolic dysfunction-associated fatty liver disease-related hepatocellular carcinoma:what are problems and countermeasures?

Hepatocellular carcinoma(HCC)is the third leading cause of cancer deaths worldwide(1).HCC has been classified into viral or non-viral HCC according to the etiology and the incidence of viral HCC is decreasing.In contrast,the incidence of non-viral HCC is increasing and fatty liver is becoming a major etiology for the HCC.In 2020,a new concept of fatty liver disease,metabolic dysfunction-associated fatty liver disease(MAFLD).

Challenges and prospects in prediction and treatment for hepatocellular carcinoma with microvascular invasion

Microvascular invasion(MVI)is an independent risk factor for early recurrence of hepatocellular carcinoma(HCC)after local treatment as well as poor prognosis in patients with HCC(1-3).MVI is an important factor for management of patients with HCC;however,MVI is based on a histopathological diagnosis using resected surgical specimens and is thus difficult to determine preoperatively.Recently,Lee et al.developed a new MVI risk score using the following 4 non-histological parameters:(I)alpha-fetoprotein(AFP);(II)protein induced by vitamin K absence-II(PIVKA-II);(III)arterial peritumoral enhancement on hepatobiliary phase of magnetic resonance imaging(MRI);(IV)peritumoral hypointensity on hepatobiliary phase of MRI(4).They also reported that,in HCC patients with MVI,the HCC recurrence rate was lower in patients treated with hepatic resection than with radiofrequency ablation(RFA)and proposed that patients with HCC who were at high risk of MVI should be treated with hepatic resection rather than RFA(4).This editorial summarizes the recent progress of the prediction method for MVI and discusses the therapeutic strategy for small HCC with MVI.