Nonalcoholic fatty liver disease (NAFLD), together with metabolic syndrome and obesity, has shown a rapid increase in prevalence worldwide and is emerging as a major cause of chronic liver disease and liver transplantation. Among the various phenotypes of NAFLD, nonalcoholic steatohepatitis (NASH) is highly likely to progress to development of end-stage liver disease and cardiometabolic disease, resulting in liver-related and non-liver–related mortality. Nonetheless, there is no standardized pharmacotherapy against NASH and many drugs are under development in ongoing clinical trials. To develop a successful anti-NASH drug, it is necessary to select an appropriate target population and treatment outcomes depending on whether the mode of action is anti-metabolic, anti-inflammatory or anti-fibrotic. Recently, innovative surrogate markers have been investigated to replace hard outcomes such as liver histology and mortality and reduce the clinical trial duration. Currently, several drugs with fast track designation are being tested in phase III clinical trials, and many other drugs have moved into phase II clinical trials. Both lean NAFLD and typical obese NAFLD have been extensively studied and genetic variants such as PNPLA3 and TM6SF2 have been identified as significant risk factors for lean NAFLD. In the near future, noninvasive biomarkers and effective targeted therapies for NASH and associated fibrosis are required to develop precision medicine and tailored therapy according to various phenotypes of NAFLD.
Biomarkers ; Drug Therapy ; Fibrosis ; Health Services Needs and Demand ; Liver ; Liver Diseases ; Liver Transplantation ; Mortality ; Non-alcoholic Fatty Liver Disease ; Obesity ; Phenotype ; Precision Medicine ; Prevalence ; Risk Factors

BACKGROUND/AIMS: Cellulitis is a common infection in patients with liver cirrhosis. We aimed to compare risk factors, microbial aspects, and outcomes of cellulitis in compensated and decompensated hepatitis C virus (HCV)-related cirrhosis. METHODS: Six hundred twenty consecutive HCV-related cirrhotic patients were evaluated for cellulitis. Demographic and clinical data were evaluated, along with blood and skin cultures. Severity of cirrhosis was assessed using Child-Pugh score. In-hospital mortality was assessed. RESULTS: Seventy-seven (12.4%) cirrhotic patients had cellulitis (25 with compensated and 52 with decompensated disease). Smoking and venous insufficiency were risk factors of cellulitis in compensated cirrhosis. Leg edema, ascites, hyperbilrubinemia and hypoalbuminemia were risk factors in decompensated cirrhosis. Gram-positive bacteria (Staphylococcus spp. and Streptococcus pyogenes) were the infective organisms in compensated patients, while gram negative bacteria (Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) were the predominant organisms in decompensated cirrhosis. Fungi (Candida albicans and Aspergillus niger) were detected in 3 decompensated cases. In-hospital mortality in patients with cellulitis was 27.3%, approaching 100% in decompensated patients with gram-negative cellulitis. Prolonged hospitalization, higher model for end-stage liver disease (MELD)-Na score, septic shock, local complication, and recurrent cellulitis were predictors of mortality. CONCLUSIONS: Cellulitis in compensated cirrhosis is different from that of decompensated patients regarding microorganisms, pathogenesis, and prognosis. Cellulitis has a poor prognosis, with mortality rates approaching 100% in decompensated patients with gram-negative cellulitis. Stratifying patients according to severity of cirrhosis is important to identify the proper empirical antibiotic and to decide the proper means of care.
Ascites ; Aspergillus ; Cellulitis ; Edema ; Fibrosis ; Fungi ; Gram-Negative Bacteria ; Gram-Positive Bacteria ; Hepacivirus ; Hepatitis C ; Hepatitis ; Hospital Mortality ; Hospitalization ; Humans ; Hypoalbuminemia ; Klebsiella pneumoniae ; Leg ; Liver Cirrhosis ; Liver Diseases ; Mortality ; Prognosis ; Pseudomonas ; Risk Factors ; Shock, Septic ; Skin ; Smoke ; Smoking ; Streptococcus ; Venous Insufficiency

Cholangiopathies are rare diseases of the bile duct with high mortality rates. The current treatment for cholangiopathies is liver transplantation, but there are significant obstacles including a shortage of donors and a high risk of complications. Currently, there is only one available medicine on the market targeting cholangiopathies, and the results have been inadequate in clinical therapy. To overcome these obstacles, many researchers have used human induced pluripotent stem cells (hPSC) as a source for cholangiocyte-like cell generation and have incorporated advances in bioprinting to create artificial bile ducts for implantation and transplantation. This has allowed the field to move dramatically forward in studies of biliary regenerative medicine. In this review, the authors provide an overview of cholangiocytes, the organogenesis of the bile duct, cholangiopathies, and the current treatment and advances that have been made that are opening new doors to the study of cholangiopathies.
Bile Ducts ; Bile ; Bioprinting ; Humans ; Induced Pluripotent Stem Cells ; Liver Transplantation ; Mortality ; Organogenesis ; Rare Diseases ; Regenerative Medicine ; Tissue Donors

BACKGROUND: This study aimed to determine the prognostic role of the categorized hemodynamic stage (HS) based on the hepatic venous pressure gradient (HVPG) in patients with portal hypertension. METHODS: Of 1,025 cirrhotic patients who underwent HVPG measurement, data on 572 non-critically-ill patients were collected retrospectively between 2008 and 2013. The following two HS categorizations were used: HS-1 (6–9, 10–12, 13–16, 17–20, and > 20 mmHg; designated as groups 1–5, respectively) and HS-2 (6–12, 13–20, and > 20 mmHg). Clinical characteristics, mortality rates, and prognostic predictors were analyzed according to the categorized HS. RESULTS: During the mean follow-up period of 25 months, 86 (15.0%) patients died. The numbers of deaths in HS-1 groups were 7 (6.3%), 7 (6.9%), 30 (18.0%), 20 (15.6%), and 22 (34.4%), respectively (P < 0.001). However, the traditional HVPG cutoffs of 10 and 16 mmHg did not improve the discrimination of mortality. In contrast, the mortality rates did differ significantly between the three HS-2 groups (P < 0.05). In the multivariate analysis, all models revealed that HS-2 was a common prognostic factor in predicting mortality. The mortality rates increased significantly according to HS-2 in patients with hypoalbuminemia (HVPG, 13–20 mmHg; hazard ratio [HR], 2.54 and HVPG > 20 mmHg; HR, 5.45) and intermediate model for end-stage liver disease (MELD) score (HVPG, 13–20 mmHg; HR, 3.86 and HVPG > 20 mmHg; HR, 8.77; P < 0.05). CONCLUSION: Categorizing HVPG values according to HS-2 is a useful prognostic modality in patients with portal hypertension and can play an independent role in predicting the prognosis in patients with hypoalbuminemia and an intermediate MELD score.
Discrimination (Psychology) ; Fibrosis ; Follow-Up Studies ; Hemodynamics ; Humans ; Hypertension, Portal ; Hypoalbuminemia ; Liver Diseases ; Mortality ; Multivariate Analysis ; Prognosis ; Retrospective Studies ; Venous Pressure

The HEV is a known cause of water-borne outbreaks of acute non-A non-B hepatitis in developing countries, which affects young people and may result in high mortality in pregnant women. In recent decades, however, HEV genotypes 3 and 4 have been known as a cause of sporadic zoonotic infections in older males from swine HEV worldwide. Most acute HEV infections are self-limited. On the other hand, in immunosuppressed patients, including solid organ transplant recipients, chronic HEV infections may exist and progress to liver cirrhosis or decompensation. Therefore, physicians need to recognize HEV as a major pathogen for acute and chronic hepatitis of unknown causes and investigate this disease.
Developing Countries ; Diagnosis ; Disease Outbreaks ; Female ; Genotype ; Hand ; Hepatitis E virus ; Hepatitis E ; Hepatitis ; Hepatitis, Chronic ; Humans ; Liver Cirrhosis ; Male ; Mortality ; Pregnant Women ; Swine ; Transplants ; Waterborne Diseases ; Zoonoses

BACKGROUND/AIMS: A diagnosis of hepatorenal syndrome (HRS) is based on a differential evaluation of acute kidney injury (AKI), which may aggravate the clinical course. This study assessed the clinical significance of the urinary neutrophil gelatinase-associated lipocalin (u-NGAL) levels in a differential diagnosis of AKI in patients with liver cirrhosis (LC). METHODS: Patients with LC who developed AKI were enrolled prospectively. Clinically, patients with AKI were classified into prerenal azotemia (PRA), HRS, and acute tubular necrosis (ATN) groups. RESULTS: Fifty-five patients (male, 74.5%) with LC who exhibited AKI upon admission were enrolled; 28, 9, and 18 patients were included in the PRA, HRS, and ATN groups, respectively. The baseline model for end-stage liver disease (MELD) scores was similar in the subgroups. The median event creatinine level, measured at the time of the AKI diagnosis, was similar in the HRS and ATN subgroups. On the other hand, the median event u-NGAL level differed significantly between the three subgroups (PRA, HRS, and ATN: 37 vs. 134 vs. 2,625 ng/mL, p=0.003). In particular, the median u-NGAL level of the HRS group was clearly different from those of the PRA (p<0.001) and ATN (p<0.001) groups. Multivariable analysis revealed the natural logarithm of the u-NGAL level (hazard ratio [HR] 1.77, p=0.031) and the MELD score (HR 1.17, p=0.027) to be independent prognostic factors for in-hospital mortality in patients with LC and AKI. CONCLUSIONS: The median u-NGAL level differentiated HRS from ATN and served as a clinical indicator of in-hospital mortality for patients with LC and AKI.
Acute Kidney Injury ; Azotemia ; Creatinine ; Diagnosis ; Diagnosis, Differential ; Hand ; Hepatorenal Syndrome ; Hospital Mortality ; Humans ; Kidney Tubular Necrosis, Acute ; Lipocalins ; Liver Cirrhosis ; Liver Diseases ; Liver ; Necrosis ; Neutrophils ; Prospective Studies

HBV is the most common etiology of both liver cirrhosis and hepatocellular carcinoma in Korea. Despite much progress made, the currently available antiviral therapies cannot eradicate or eliminate this virus. Hence, the benefits and risks of antiviral therapy should be carefully evaluated on an individual basis and within the context of the clinical situation. The ultimate goals of treatment are to decrease the mortality from liver disease. The benefits of antiviral therapy come from prevention of progression of liver disease. Understanding the natural history of chronic HBV infection is a key step in the decision making process to treat patients with chronic HBV infection. Generally, chronic hepatitis B patients in the immune tolerant phase and immune inactive phase are not recommended to undergo antiviral treatment, except for those patients in special conditions (e.g., immunosuppression or anticancer chemotherapy). Chronic hepatitis B patients in the immune active phase are recommended for antiviral therapy. For patients with liver cirrhosis, treatment should be considered when serum HBV DNA is detectable regardless of the serum level of ALT.
Carcinoma, Hepatocellular ; Decision Making ; DNA ; Hepatitis B virus ; Hepatitis B, Chronic ; Hepatitis, Chronic ; Humans ; Immunosuppression ; Korea ; Liver Cirrhosis ; Liver Diseases ; Mortality ; Natural History ; Risk Assessment

BACKGROUND: Liver disease is one of the top causes of death globally. Although liver transplantation is a very effective treatment strategy, the shortage of available donor organs, waiting list mortality, and high costs of surgery remain huge problems. Stem cells are undifferentiated cells that can differentiate into a variety of cell types. Scientists are exploring the possibilities of generating hepatocytes from stem cells as an alternative for the treatment of liver diseases. METHODS: In this review, we summarized the updated researches in the field of stem cell-based therapies for liver diseases as well as the current challenges and future expectations for a successful cell-based liver therapy. RESULTS: Several cell types have been investigated for liver regeneration, such as embryonic stem cells, induced pluripotent stem cells, liver stem cells, mesenchymal stem cells, and hematopoietic stem cells. In vitro and in vivo studies have demonstrated that stem cells are promising cell sources for the liver regeneration. CONCLUSION: Stem cell-based therapy could be a promising therapeutic method for patients with end-stage liver disease, which may alleviate the need for liver transplantation in the future.
Cause of Death ; Embryonic Stem Cells ; Hematopoietic Stem Cells ; Hepatocytes ; Humans ; In Vitro Techniques ; Induced Pluripotent Stem Cells ; Liver Diseases ; Liver Regeneration ; Liver Transplantation ; Liver ; Mesenchymal Stromal Cells ; Methods ; Mortality ; Stem Cells ; Tissue Donors ; Waiting Lists

PURPOSE: Hepatic hydrothorax is a complication of decompensated liver cirrhosis that is difficult and complex to manage. Data concerning the optimal treatment method, other than liver transplantation, are limited. This study aimed to compare the clinical features and outcomes of patients treated with various modalities, while focusing on surgical management and pigtail drainage. MATERIALS AND METHODS: Forty-one patients diagnosed with refractory hepatic hydrothorax between January 2013 and December 2017 were enrolled. RESULTS: The mean Child-Turcotte-Pugh and model for end stage liver disease scores of the enrolled patients were 10.1 and 19.7, respectively. The patients underwent four modalities: serial thoracentesis (n=11, 26.8%), pigtail drainage (n=16, 39.0%), surgery (n=10, 24.4%), and liver transplantation (n=4, 9.8%); 12-month mortality rate/median survival duration was 18.2%/868 days, 87.5%/79 days, 70%/179 days, and 0%/601.5 days, respectively. Regarding the management of refractory hepatic hydrothorax, surgery group required less frequent needle puncture (23.5 times in pigtail group vs. 9.3 times in surgery group), had a lower occurrence of hepatorenal syndrome (50% vs. 30%), and had a non-inferior cumulative overall survival (402.1 days vs. 221.7 days) compared to pigtail group. On multivariate analysis for poor survival, body mass index <19 kg/m², refractory hepatic hydrothorax not managed with liver transplantation, Child-Turcotte-Pugh score >10, and history of severe encephalopathy (grade >2) were associated with poor survival. CONCLUSION: Serial thoracentesis may be recommended for management of hepatic hydrothorax and surgical management can be a useful option in patients with refractory hepatic hydrothorax, alternative to pigtail drainage.
Body Mass Index ; Brain Diseases ; Drainage ; End Stage Liver Disease ; Fibrosis ; Hepatorenal Syndrome ; Humans ; Hydrothorax ; Liver Cirrhosis ; Liver Transplantation ; Methods ; Mortality ; Multivariate Analysis ; Needles ; Punctures ; Thoracentesis

Little is known about the benefits of statin use on liver cancer mortality among patients with chronic hepatitis B (CHB) considering hypercholesterolemia and obesity. A nationwide retrospective cohort study was conducted using data from a Health Examination Cohort of the National Health Insurance Service of Korea. Data on CHB patients with no other concurrent liver disease were acquired, and statin use was defined as a cumulative daily dose ≥28. A 3-year landmark analysis was performed to avoid immortal time bias. Patients who started statin therapy within the landmark date were considered statin users. A Cox regression analysis was applied to assess associations between statin use and liver cancer mortality considering hypercholesterolemia and obesity. Among 13063 patients, 193 (1.5%) died of liver cancer during the mean follow-up period of 10.6 years. After adjusting for demographic and metabolic factors, statin use [hazard ratio (HR), 0.17; 95% confidence interval (CI), 0.04–0.70] and hypercholesterolemia (HR, 0.46; 95% CI, 0.24–0.88 for total cholesterol ≥240 mg/dL) were associated with a decreased risk of liver cancer mortality, whereas body mass index (BMI) ≥30 kg/m² was associated with an increased risk of liver cancer mortality (HR, 2.46; 95% CI, 1.20–5.06). This study showed that statin use was associated with decreased liver cancer mortality when adjusting for cholesterol levels and BMI. This study found that hypercholesterolemia was independently associated with decreased liver cancer mortality regardless of statin use.
Bias (Epidemiology) ; Body Mass Index ; Carcinoma, Hepatocellular ; Cholesterol ; Cohort Studies ; Follow-Up Studies ; Hepatitis B, Chronic ; Hepatitis, Chronic ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Hypercholesterolemia ; Korea ; Liver Diseases ; Liver Neoplasms ; Liver ; Mortality ; National Health Programs ; Obesity ; Retrospective Studies