The effects of hyperthermia on human hepatocellular carcinoma stem and mature cancer cells.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) can recur following radiofrequency ablation and other hyperthermic treatment modalities. Cancer stem cells (CSCs) are a subpopulation of HCC cells that are difficult to eradicate and largely responsible for tumor recurrences. Thus, the principal objective of this study was to determine whether human HCC CSCs are relatively thermal-resistant compared to non-stem or mature cancer cells (MCCs). MATERIALS AND METHODS: Epithelial cell adhesion molecule (EpCAM) positive enriched CSCs and EpCAM- MCCs were derived from a human HCC cell line using fluorescence activated cell sorting. Each cell population was exposed to 65°C heat for 0-16min and survival documented at various time points. RESULTS: Cell survival curves were similar in CSC and MCCs throughout the 16min heat exposure period. Maximum killing was obtained after 12-14min of heat exposure. Cytoprotective, heat shock proteins-70 (HSP70) and -90 (HSP90) mRNA expression were not disproportionately increased in CSCs. CONCLUSIONS: These results suggest that human HCC CSCs are not more thermal resistant than MCCs and therefore, do not support the hypothesis that HCC recurrences following hyperthermic treatment reflect CSC thermal-resistance.

Exploring autoantibodies as predictors of severe fibrosis or cirrhosis in metabolic dysfunction associated with steatotic liver disease.

Background: Metabolic dysfunction associated steatotic liver disease (MASLD) and metabolic dysfunction associated steatohepatitis (MASH) are rapidly growing public health concerns. Identifying predictive markers for advanced liver disease in MASLD patients is crucial for early intervention. This study investigates the association between autoantibody positivity and risk for severe fibrosis or cirrhosis across various subgroups. Methods: We conducted a retrospective study of adult patients diagnosed with MASLD between 1994 and 2019. Autoantibody status (anti-nuclear and anti-smooth muscle antibodies) was assessed using laboratory studies. Hepatic fibrosis or cirrhosis was determined histologically or through accepted non-invasive measures. Logistic regression analyses were employed to evaluate the association between autoantibody positivity and severe fibrosis or cirrhosis. Patients with comorbid viral and alcohol liver disease were assessed separately. Results: Among 2,749 MASLD patients, 1,425 (51.8%) were male and 1,324 (48.2%) were female, with a mean age of 58.7 years. A total of 541 (19.7%) patients tested positive for autoantibodies. Autoantibody positivity was associated with a higher risk of severe fibrosis or cirrhosis in MASLD patients (odds ratio 1.28, 95% CI [1.0-1.6]). This association persisted across various subgroups, including those with concurrent hepatitis B and C virus infections. In contrast, in alcohol liver disease, autoantibody-positive patients exhibited a lower risk. Conclusion: Autoantibody positivity emerges as a potential predictive marker for advanced liver disease in MASLD patients, facilitating risk stratification and tailored interventions. This study highlights the clinical relevance of autoantibodies in MASLD and underscores the need for prospective validation and mechanistic investigations to refine risk assessment and management strategies.

Comparison of different definitions of metabolic syndrome and their associations with non-alcoholic fatty liver disease: a retrospective study.

Background: Metabolic syndrome (MetS) is considered an important risk factor for non-alcoholic fatty liver disease (NAFLD). The aim of this study was to measure the prevalence of MetS based on six different MetS definitions and compare the performance of various definitions for identifying diabetes, hypertension, and dyslipidemia among NAFLD patients. Methods: The definitions compared were those developed by the World Health Organization (WHO), National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III), International Diabetes Federation (IDF), American Association of Clinical Endocrinologists (AACE), American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI), and Interim Joint Statement "harmonized" criteria. Receiver operator characteristic (ROC) curves were plotted for the six MetS definitions with NAFLD diagnosis. The diagnosis for NAFLD was established based on liver imaging or biopsy compatible with fatty liver disease. Results: A total of 500 NAFLD patients were analyzed. The mean age was 61.2 (SD 13.2) years, and BMI was 32.7 (SD 8.0) kg/m2. The most prevalent MetS component was dyslipidemia (83%), followed by hypertension (60%), obesity (61%), and diabetes (57%). The prevalence of MetS according to the WHO, NCEP/ATP-III, IDF, AACE, AHA/NHLBI, and harmonized criteria was 69%, 59%, 54%, 64%, 78%, and 79%, respectively. The highest area under the ROC curve for diabetes and hypertension was with the WHO definition (0.7405) and (0.8120), respectively. Conclusions: The prevalence of MetS in NAFLD patients varies according to the definitions of MetS employed. The modified WHO definition appeared to be most useful for the screening of MetS in NAFLD patients.

The impact of primary biliary cholangitis on non-alcoholic fatty liver disease.

BACKGROUND: The impact of chronic cholestatic liver diseases such as primary biliary cholangitis (PBC) on non-alcoholic fatty liver disease (NAFLD) has yet to be described. OBJECTIVES: To document and compare the severity and course of liver disease in patients with NAFLD/PBC versus NAFLD alone. METHODS: In this retrospective, case-control study 68 adult NAFLD/PBC patients were matched 1:2 for age and sex with 136 NAFLD alone patients. Disease activity and severity were documented by serum aminotransferases, albumin, bilirubin and international normalized ratio (INR) values and hepatic fibrosis by Fib-4 and aspartate aminotransferase/platelet ratio indices (APRI). RESULTS: On presentation (baseline), NAFLD/PBC patients had similar serum aminotransferase, albumin and bilirubin levels but lower INR values than NAFLD alone patients. Fib-4 and APRI levels were similar. Despite longer follow-up (favouring more advanced disease) in NAFLD/PBC patients, serum aminotransferases and bilirubin values were similar but albumin and INR levels significantly lower in NAFLD/PBC versus NAFLD alone patients at the end of follow-up. NAFLD/PBC patients also had significantly lower and less worsening of Fib-4 values at the end of follow-up. Transition from intermediate Fib-4 levels to those compatible with no or limited fibrosis was higher in NAFLD/PBC patients. CONCLUSION: These findings suggest PBC does not adversely affect the severity or course of NAFLD.

Low serum alkaline phosphatase levels in patients with chronic liver diseases: Possible contributions to disease pathogenesis.

OBJECTIVES: A low serum alkaline phosphatase (ALP) level is an uncommon finding in patients with chronic liver disease (CLD). The prevalence of this finding and whether low ALP expression influences CLD remain to be determined. The objectives of this study were: (1) to document the prevalence of low serum ALP levels in adult CLD patients and (2) compare features of CLD in patients with low versus normal or elevated serum ALP levels. METHODS: An adult, outpatient liver disease database was searched for patients with low serum ALP levels (<40 IU/L). Hepatic inflammation, function, fibrosis and disease severity were determined by serum aminotransferases, albumin, bilirubin and INR levels, Fib-4 calculations and MELD scores respectively. RESULTS: Of 19,037 patients entered into the database, 47 (0.25%) had consistently low serum ALP levels, 51 (0.27%) low levels on the majority and 469 (2.44%) on the minority of determinations. Patients with consistently low levels were matched (1:2) by age, gender and nature of the underlying liver disease to patients with normal or elevated serum ALP levels. Matched patients with consistently low ALP levels had significantly lower serum aminotransferase and bilirubin levels at their initial visit and throughout the follow-up period (p < 0.05 respectively) while Fib-4 levels and MELD scores were similar at the initial and last follow-up visit. CONCLUSIONS: These results establish the prevalence of low serum ALP levels in adult CLD patients and describe a hitherto unreported association between low serum ALP levels and less biochemical evidence of active disease.

Liver disease referrals to an urban, hospital-based hepatology outpatient clinic over the past 25 years.

BACKGROUND: Additional hepatologists are required to manage the rapidly increasing number of patients with liver disease. One disincentive to trainees considering a career in hepatology is the longstanding perception that outpatient hepatology consists largely of managing patients with alcohol-induced liver disease (ALD). OBJECTIVES: To document the types of liver diseases and changes in liver disease referrals to an urban outpatient liver disease clinic over the past 25 years. METHODS: The nature of the liver disorder, age, gender, and socioeconomic status of patients referred to an urban, hospital-based, liver diseases outpatient program were documented from 1992 to 2017. Joinpoint analysis was performed to identify significant trends in referral prevalence rates of various disorders. RESULTS: In 1992/1993, hepatitis C virus (HCV), followed by hepatitis B virus (HBV), "other", non-alcoholic fatty liver disease (NAFLD), and primary biliary cholangitis (PBC) were the most common underlying liver diseases in referred patients (39, 36, 12, 4.5, and 3.5% respectively), whereas in 2016/2017, NAFLD, HBV, HCV, "other," and ALD were most common (60, 15, 12, 8.7, and 3.3%, respectively). Aside from NAFLD referrals, which consistently increased over the 25-year period, the prevalence of all other liver disease referrals fluctuated but generally declined. Recently referred patients were significantly older (38 ± 13 years in 1992/1993 and 49 ± 15 years in 2016/2017, P < 0.0001), while gender and socioeconomic status have not changed. CONCLUSIONS: Hepatology is a diverse, dynamic subspecialty where ALD continues to constitute less than 5% of all patient referrals.

The Psychological and Financial Impact of Long-distance Travel for Liver Transplantation.

BACKGROUND: Patients who travel long distances to undergo liver transplantation have limited opportunities to develop confidence in their new healthcare providers and experience fewer support visits from family and friends at the transplant site. The objectives of this study were to document the psychological and financial impact of having to travel long distances for liver transplantation in adult liver disease patients. METHODS: This was a single-center, prospective study that used a 7-question survey, including Likert scales, patient recall, and administrative databases. RESULTS: Ninety-six adult outpatient liver transplant recipients (59% males; mean age, 43.1 ± 2.1 y) participated in the survey. Approximately 70% (more so among males and higher educated patients) felt that they had sufficient time to develop confidence in their new healthcare providers and 87% felt that confidence in their local healthcare providers had not been diminished by undergoing the procedure elsewhere. Forty-four percent of patients felt that their overall liver transplant experience had been compromised by more limited opportunities for support visits, a perception that was twice as common in females. Median out-of-pocket expenses were under $5000, and inflation corrected costs to third-party payers have been stable for the past 20 y. CONCLUSIONS: The principal psychological impact of travelling long distances for liver transplantation relates to the consequences of fewer support visits. Confidence in the new and local healthcare teams is not compromised by such travel in most patients. Out-of-pocket expenses are under $5000, and transplant costs to third-party payers have remained stable over the past 20 y.