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Capinha F, Carvalhana S, Cortez-Pinto H. Role of Alcohol in Steatotic Liver Disease: Impact on Patients with Cardiometabolic Risk Factors. Dig Dis Sci 2025:10.1007/s10620-025-08912-4. [PMID: 40025309 DOI: 10.1007/s10620-025-08912-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 02/03/2025] [Indexed: 03/04/2025]
Abstract
The new definition of steatotic liver disease (SLD), as a broader concept, was a step forward in the increasing recognition of the substantial overlap between alcohol and cardiometabolic risk factors (CMRFs), in a continuum way. The spectrum of pathophysiological aspects, ranging from liver steatosis to fibrosis, has similarities in MASLD and ALD. Also, there is now considerable evidence that the association of metabolic dysfunction with increased alcohol consumption impacts on the risk of severe liver disease and prognosis. The new MetALD class, as recently proposed, shows clear differences in prognosis when comparing with MASLD and ALD groups. However, there is room for improvement, such as considering the role of previous alcohol intake, fluctuations of consumption over time, including binge drinking, refinement of alcohol assessment, and better understanding of the role of biomarkers. In summary, SLD is no doubt a significant improvement, but the new classification needs to be dynamic and adapting to patients needing frequent reassessment. Furthermore, it brings opportunities for research on the interaction between alcohol consumption and CMRFs.
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Affiliation(s)
- Francisco Capinha
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal
| | - Sofia Carvalhana
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal
| | - Helena Cortez-Pinto
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal.
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Lee HJ, Choi MS, Song BG, Kang WS, Gwak GY, Goh MJ, Paik YH, Lee JH, Sinn DH. Glycemic Burden and Clinical Outcomes of Early Stage Hepatocellular Carcinoma after Curative Treatment. Cancers (Basel) 2024; 16:2652. [PMID: 39123380 PMCID: PMC11311804 DOI: 10.3390/cancers16152652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024] Open
Abstract
Early-stage hepatocellular carcinoma (HCC) is still difficult to cure for its high recurrence rate. This study aimed to examine whether glycemic burden management could be one way to improve outcomes of early-stage HCC. A total of 137 very early or early-stage HCC patients who underwent resection or ablation at Samsung Medical Center and had glycemic burden assessment were analyzed. Glycemic burden was assessed using hemoglobin A1c (HbA1c) level. Outcomes were recurrence and overall survival. Risks of recurrence and overall survival were compared according to glycemic burden using a cut-off point of 6.5% or two cut-off points of 6.0% and 7.5%. Overall, 51 (37.2%) patients experienced HCC recurrence. The adjusted hazard ratio (aHR) for recurrence comparing patients with HbA1c > 6.5% to those with HbA1c ≤ 6.5% was 2.66 (95% CI: 1.26-5.78). The risk of recurrence increased in a dose-dependent manner by glycemic burden; aHR for 6.0 < HbA1c ≤ 7.5%: 2.00 (95% CI: 0.78-5.55); aHR for HbA1c > 7.5%: 6.05 (95% CI: 2.31-17.5). Mortality was observed in 16 (11.7%) patients. The risk of mortality was higher for HbA1c > 6.5% than for HbA1c ≤ 6.5% (aHR: 2.33; 95% CI: 1.10-5.08). There was also a dose-response relationship between overall survival and glycemic burden. Glycemic burden assessed using HbA1c level was significantly associated with outcomes of early-stage HCC patients. Good glycemic control could be a therapeutic goal to improve clinical outcomes in these populations.
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Affiliation(s)
| | | | - Byeong Geun Song
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea; (H.J.L.)
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Pham YTH, Jin A, Wang R, Behari J, Koh WP, Yuan JM, Luu HN. Low-Carbohydrate Diet Score and Risk of Hepatocellular Carcinoma: Findings from a Prospective Cohort Study. Cancer Prev Res (Phila) 2024; 17:265-274. [PMID: 38530112 PMCID: PMC11150087 DOI: 10.1158/1940-6207.capr-23-0517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 02/01/2024] [Accepted: 03/22/2024] [Indexed: 03/27/2024]
Abstract
Limited data are reported on the association between low-carbohydrate diet (LCD) score, a comprehensive measure of dietary pattern according to sources of carbohydrate, fat, and protein, and risk of hepatocellular carcinoma (HCC). We evaluated this score with HCC risk in the Singapore Chinese Health Study, a prospective cohort of 63,275 middle-aged and elderly Chinese living in Singapore and recruited during 1993-1998 period. LCD scores were derived from the semi-quantitative food frequency questionnaire at baseline. A nested case-control study involved 197 HCC cases and 465 controls was also constructed among 28,346 participants who provided blood samples. Cox proportional hazard regression method was used to calculate HRs and 95% confidence intervals (CI) for HCC with different levels of LCD scores. Conditional logistic regression was performed for the case-control study analysis. After 17.6 years of follow-up with 819,573 person-years, 561 participants developed primary HCC. Although there was a null association between total LCD score and HCC risk (HRper-SD increment = 1.07; 95% CI, 0.98-1.16; Ptrend = 0.06), there was a positive association between animal-based LCD and the risk of HCC (HRper-SD increment = 1.11; 95% CI, 1.02-1.21; Ptrend = 0.01). Furthermore, this association was present in both HBsAg-negative and HBsAg-positive individuals in the case-control study. In stratified analysis for the entire cohort, this positive association was only present in those who consumed alcoholic beverages monthly or less frequent but not in weekly or daily drinker (Pinteraction = 0.79). In summary, a diet with lower carbohydrate, higher animal fat and protein was significantly associated with higher risk of HCC among Chinese Singaporeans. PREVENTION RELEVANCE In a large cohort study of more than 63,000 Chinese Singaporeans, we found that a diet with lower carbohydrate and higher animal fat and protein was associated with increased risk of HCC, suggesting that dietary modification could be an effective strategy in primary prevention to reduce the HCC burden.
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Affiliation(s)
- Yen Thi-Hai Pham
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Aizhen Jin
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Renwei Wang
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
| | - Jaideep Behari
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Woon-Puay Koh
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore
| | - Jian-Min Yuan
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Hung N. Luu
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
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Wang M, Liu J, Yan L, Wang J, Jin Y, Zheng ZJ. Burden of liver cancer attributable to high fasting plasma glucose: a global analysis based on the global burden of disease study 2019. J Nutr Health Aging 2024; 28:100261. [PMID: 38810511 DOI: 10.1016/j.jnha.2024.100261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 04/28/2024] [Accepted: 05/02/2024] [Indexed: 05/31/2024]
Abstract
OBJECTIVE Liver cancer is the world's sixth most prevalent cancer and the third most frequent cause of cancer-related mortality. Glucose metabolic disorders, indicated by a high fasting plasma glucose (HFPG) concentration, is a contributor to the etiology of liver cancer. With the rising prevalence of glucose metabolic disorders, an assessment of the global burden of liver cancer attributable to HFPG is warranted to inform global liver cancer prevention and control strategies. METHODS AND ANALYSIS We evaluated the global death and disability-adjusted life years (DALYs) of liver cancer and its subtypes attributable to HFPG at global, regional, and country level. The temporal trend and disparity across geographic regions, social development level, age groups and sex were assessed. RESULTS In 2019, HFPG-attributable liver cancer was estimated to have caused 4,729.49 deaths and to be responsible for 99,302.25 DALYs. The age-standardized mortality and DALY rate were 0.06 and 1.20 per 100,000 population, and displayed a significantly increasing temporal trend from 1990 to 2019. The age-standardized mortality rate of patients with liver cancer that was attributable to HFPG was higher in men than women. Sex-based disparity narrowed after the women reached menopause, but increased between 1990 and 2019. CONCLUSION The burden of liver cancer that are attributable to HFPG has been influenced by longitudinal changes in lifestyle, the etiology of liver disease, age demographics, and hormonal status in women. These findings suggest that comprehensive strategies could be implemented, especially for patients with NASH and hyperglycemia, to prevent liver cancer.
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Affiliation(s)
- Minmin Wang
- Department of Global Health, School of Public Health, Peking University, Beijing, China; Institute for Global Health and Development, Peking University, Beijing, China
| | - Jingyi Liu
- School of Nursing, Peking University, Beijing, China
| | - Liang Yan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital and Institute, Beijing, China
| | - Jia Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Yinzi Jin
- Department of Global Health, School of Public Health, Peking University, Beijing, China; Institute for Global Health and Development, Peking University, Beijing, China.
| | - Zhi-Jie Zheng
- Department of Global Health, School of Public Health, Peking University, Beijing, China; Institute for Global Health and Development, Peking University, Beijing, China
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Mai Y, Liao C, Wang S, Zhou X, Meng L, Chen C, Qin Y, Deng G. High glucose-induced NCAPD2 upregulation promotes malignant phenotypes and regulates EMT via the Wnt/β-catenin signaling pathway in HCC. Am J Cancer Res 2024; 14:1685-1711. [PMID: 38726276 PMCID: PMC11076239 DOI: 10.62347/hynz9211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 03/29/2024] [Indexed: 05/12/2024] Open
Abstract
Diabetes mellitus (DM) is recognized as a risk factor for hepatocellular carcinoma (HCC). High glucose levels have been implicated in inducing epithelial-mesenchymal transition (EMT), contributing to the progression of various cancers. However, the molecular crosstalk remains unclear. This study aimed to elucidate the molecular mechanisms linking DM to HCC. Initially, the expression of NCAPD2 in HCC cells and patients was measured. A series of functional in vitro assays to examine the effects of NCAPD2 on the malignant behaviors and EMT of HCC under high glucose conditions were then conducted. Furthermore, the impacts of NCAPD2 knockdown on HCC proliferation and the β-catenin pathway were investigated in vivo. In addition, bioinformatics methods were performed to analyze the mechanisms and pathways involving NCAPD2, as well as its association with immune infiltration and drug sensitivity. The findings indicated that NCAPD2 was overexpressed in HCC, particularly in patients with DM, and its aberrant upregulation was linked to poor prognosis. In vitro experiments demonstrated that high glucose upregulated NCAPD2 expression, enhancing proliferation, invasion, and EMT, while knockdown of NCAPD2 reversed these effects. In vivo studies suggested that NCAPD2 knockdown might suppress HCC growth via the β-catenin pathway. Functional enrichment analysis revealed that NCAPD2 was involved in cell cycle regulation and primarily interacted with NCAPG, SMC4, and NCAPH. Additionally, NCAPD2 was positively correlated with EMT and the Wnt/β-catenin pathway, whereas knockdown of NCAPD2 inhibited the Wnt/β-catenin pathway. Moreover, NCAPD2 expression was significantly associated with immune cell infiltration, immune checkpoints, and drugs sensitivity. In conclusion, our study identified NCAPD2 as a novel oncogene in HCC and as a potential therapeutic target for HCC patients with DM.
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Affiliation(s)
- Yuhua Mai
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
| | - Chuanjie Liao
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of EducationNanning 530021, Guangxi, China
| | - Shengyu Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
| | - Liheng Meng
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
| | - Cuihong Chen
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
| | - Yingfen Qin
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
| | - Ganlu Deng
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of EducationNanning 530021, Guangxi, China
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Matono T, Tada T, Nishimura T, Takashima T, Aizawa N, Ikeda N, Shiomi H, Enomoto H, Iijima H. VFMAP predicted hepatocellular carcinoma development in patients with chronic hepatitis C who were treated with direct-acting antiviral and achieved sustained virologic response. J Med Ultrason (2001) 2024; 51:293-300. [PMID: 38147196 PMCID: PMC11972991 DOI: 10.1007/s10396-023-01398-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 10/16/2023] [Indexed: 12/27/2023]
Abstract
PURPOSE Risk factors for the development of hepatocellular carcinoma (HCC) remain unclear in patients with hepatitis C virus (HCV) who achieve sustained virological response (SVR) after direct-acting antiviral (DAA) therapy. This study investigated the usefulness of the VFMAP scoring system for predicting the development of HCC in these patients. METHODS This study included 358 patients with HCV who achieved SVR after DAA treatment. The VFMAP system defines and scores cutoff values for virtual touch quantification (VTQ), fasting plasma glucose, sex, age, and alpha-fetoprotein values. All patients were grouped according to their VFMAP scores as follows: 0 or 1 point, low-score group; 2 or 3 points, intermediate-score group; and 4 or 5 points, high-score group. RESULTS Nineteen patients developed HCC. The median follow-up duration was 3.2 (1.5-4.0) years. The respective cumulative incidence rates of HCC at 12, 24, and 36 months were as follows in different subgroups: all study patients, 3.0%, 4.8%, and 6.6%; low-score group, 0.96%, 0.96%, and 0.96%; intermediate-score group, 2.6%, 4.5%, and 6.8%; and high-score group, 10.0%, 15.3%, and 18.5%. The cumulative incidence rates of HCC in the high-score group were significantly higher than those in the low- and intermediate-score groups (p < 0.001 and < 0.05, respectively). CONCLUSION VFMAP accurately predicted the development of HCC in HCV patients who achieved SVR following treatment with DAAs.
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Affiliation(s)
- Tomomitsu Matono
- Department of Gastroenterology, Division of Hepatobiliary and Pancreatic Disease, Hyogo Medical University, 1-1 Mukogawacho, Nishinomiyashi, Hyogo, 663-8501, Japan.
- Department of Internal Medicine, Himeji St. Mary's Hospital, Himeji, Hyogo, Japan.
- Department of Gastroenterology, Hyogo Prefectural Harima-Himeji General Medical Center, Himeji, Hyogo, Japan.
| | - Toshifumi Tada
- Department of Gastroenterology, Division of Hepatobiliary and Pancreatic Disease, Hyogo Medical University, 1-1 Mukogawacho, Nishinomiyashi, Hyogo, 663-8501, Japan
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Hyogo, Japan
| | - Takashi Nishimura
- Department of Gastroenterology, Division of Hepatobiliary and Pancreatic Disease, Hyogo Medical University, 1-1 Mukogawacho, Nishinomiyashi, Hyogo, 663-8501, Japan
- Ultrasound Imaging Center, Hyogo Medical University, Hyogo, Japan
| | - Tomoyuki Takashima
- Department of Gastroenterology, Division of Hepatobiliary and Pancreatic Disease, Hyogo Medical University, 1-1 Mukogawacho, Nishinomiyashi, Hyogo, 663-8501, Japan
| | - Nobuhiro Aizawa
- Department of Gastroenterology, Division of Hepatobiliary and Pancreatic Disease, Hyogo Medical University, 1-1 Mukogawacho, Nishinomiyashi, Hyogo, 663-8501, Japan
| | - Naoto Ikeda
- Department of Gastroenterology, Division of Hepatobiliary and Pancreatic Disease, Hyogo Medical University, 1-1 Mukogawacho, Nishinomiyashi, Hyogo, 663-8501, Japan
| | - Hideyuki Shiomi
- Department of Gastroenterology, Division of Hepatobiliary and Pancreatic Disease, Hyogo Medical University, 1-1 Mukogawacho, Nishinomiyashi, Hyogo, 663-8501, Japan
| | - Hirayuki Enomoto
- Department of Gastroenterology, Division of Hepatobiliary and Pancreatic Disease, Hyogo Medical University, 1-1 Mukogawacho, Nishinomiyashi, Hyogo, 663-8501, Japan
| | - Hiroko Iijima
- Department of Gastroenterology, Division of Hepatobiliary and Pancreatic Disease, Hyogo Medical University, 1-1 Mukogawacho, Nishinomiyashi, Hyogo, 663-8501, Japan
- Ultrasound Imaging Center, Hyogo Medical University, Hyogo, Japan
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Otero Sanchez L, Chen Y, Lassailly G, Qi X. Exploring the links between types 2 diabetes and liver-related complications: A comprehensive review. United European Gastroenterol J 2024; 12:240-251. [PMID: 38103189 PMCID: PMC10954434 DOI: 10.1002/ueg2.12508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 10/24/2023] [Indexed: 12/18/2023] Open
Abstract
In recent decades, the prevalence of type 2 diabetes has been steadily increasing, presenting a significant global public health challenge. These epidemiological trends can be attributed to significant lifestyle changes in modern societies, characterized by sedentary behavior and the consumption of hypercaloric, highly processed foods, along with the aging of the human population. As a result, it has become crucial for both public healthcare systems and healthcare providers to prioritize the management of diabetes and identify its systemic consequences. Emerging research has shed light on the links and risks between diabetes and liver events. This comprehensive review aims to explore the complex interplay between type 2 diabetes mellitus and liver-related outcomes, especially hepatocellular carcinoma and cirrhosis, offering insights into effective methods for detecting liver risk in individuals with diabetes. Additionally, the review will assess the various treatments that could hold the potential for positive outcomes in managing both diabetes and metabolic dysfunction-associated steatotic liver disease and liver fibrosis.
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Affiliation(s)
- Lukas Otero Sanchez
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Yuping Chen
- Center of Portal Hypertension, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Guillaume Lassailly
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
- Service des maladies de l'appareil digestif, hôpital Huriez, CHU de Lille, Université de Lille, Lille, France
| | - Xiaolong Qi
- Center of Portal Hypertension, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
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Mai Y, Meng L, Deng G, Qin Y. The Role of Type 2 Diabetes Mellitus-Related Risk Factors and Drugs in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2024; 11:159-171. [PMID: 38268569 PMCID: PMC10806369 DOI: 10.2147/jhc.s441672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 01/04/2024] [Indexed: 01/26/2024] Open
Abstract
With changes in modern lifestyles, type 2 diabetes mellitus (T2DM) has become a global epidemic metabolic disease, and hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. T2DM is a complex metabolic disorder and has been considered an independent risk factor for HCC. Growing evidence supports that T2DM-related risk factors facilitate hepatocarcinogenesis via abundant mechanisms. With the wide implementation of microbiomics, transcriptomics, and immunotherapy, the understanding of the complex mechanisms of intestinal flora and immune cell subsets have advanced tremendously in T2DM-related HCC, uncovering new findings in T2DM-related HCC patients. In addition, reports have indicated the different effects of anti-DM drugs on the progression of HCC. In this review, we summarize the effects of major T2DM-related risk factors (including hyperglycemia, hyperinsulinemia, insulin, chronic inflammation, obesity, nonalcoholic fatty liver disease, gut microbiota and immunomodulation), and anti-DM drugs on the carcinogensis and progression of HCC, as well as their potential molecular mechanisms. In addition, other factors (miRNAs, genes, and lifestyle) related to T2DM-related HCC are discussed. We propose a refined concept by which T2DM-related risk factors and anti-DM drugs contribute to HCC and discuss research directions prompted by such evidence worth pursuing in the coming years. Finally, we put forward novel therapeutic approaches to improve the prognosis of T2DM-related HCC, including exploiting novel diagnostic biomarkers, combination therapy with immunocheckpoint inhibitors, and enhancement of the standardized management of T2DM patients.
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Affiliation(s)
- Yuhua Mai
- Department of Endocrinology, The First Affiliated Hospital of GuangXi Medical University, Nanning, Guangxi, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, 530021, People’s Republic of China
| | - Liheng Meng
- Department of Endocrinology, The First Affiliated Hospital of GuangXi Medical University, Nanning, Guangxi, 530021, People’s Republic of China
| | - Ganlu Deng
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, 530021, People’s Republic of China
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China
| | - Yingfen Qin
- Department of Endocrinology, The First Affiliated Hospital of GuangXi Medical University, Nanning, Guangxi, 530021, People’s Republic of China
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Mezzacappa C, Mahmud N, Serper M, John BV, Taddei TH, Kaplan DE. HCC is associated with diabetes and longitudinal blood glucose control in a national cohort with cirrhosis. Hepatol Commun 2023; 7:e0344. [PMID: 38055642 PMCID: PMC10984661 DOI: 10.1097/hc9.0000000000000344] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 11/05/2023] [Indexed: 12/08/2023] Open
Abstract
BACKGROUND Diabetes is associated with HCC; however, the impact of longitudinal blood glucose (BG) control on HCC risk in cirrhosis is not well known. We investigated this knowledge gap in a cohort of United States Veterans with cirrhosis from 2015 to 2021. METHODS We used repeated hemoglobin A1c measurements to categorize follow-up time according to BG control (defined as hemoglobin A1c < 7%) state over time: uncontrolled, nonsustained control (≤2 y), or sustained control (>2 y). We performed a sensitivity analysis using hemoglobin A1c < 8% to define BG control. We used Fine and Gray Cox proportional hazards regression with death and transplant as competing events to compare rates of incident HCC. RESULTS Our study included 81,907 individuals, 56.2% of whom had diabetes at baseline. There were 8,002 incident HCCs. The rate of HCC was 18% higher in diabetes (95% CI: 13% - 24%), and the relative increase in the rate of HCC varied by etiology of cirrhosis from nonsignificant (HCV) to an increase of 120% (HBV). Uncontrolled and nonsustained BG control was associated with 1.80 (95% CI: 1.70-1.91) and 2.34 (95% CI: 2.21-2.48) times the rate of HCC compared to sustained BG control, respectively. Using Hgb A1c < 8% to define BG control, HCC rates in uncontrolled and nonsustained BG control were 2.43 (2.28-2.58) and 2.23 (2.11-2.36) times that observed in sustained BG control. CONCLUSIONS Associations between diabetes and HCC in cirrhosis vary according to the longitudinal BG control state. Inadequate BG control is consistently associated with a higher risk of HCC, and long-term BG control should be considered in comprehensive cirrhosis care.
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Affiliation(s)
- Catherine Mezzacappa
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
- VA Connecticut Healthcare System, Department of Internal Medicine West Haven, Connecticut, USA
| | - Nadim Mahmud
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Marina Serper
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Binu V. John
- University of Miami School of Medicine, Miami, Florida, USA
- Bruce W Carter VA Medical Center, Miami, Florida, USA
| | - Tamar H. Taddei
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
- VA Connecticut Healthcare System, Department of Internal Medicine West Haven, Connecticut, USA
| | - David E. Kaplan
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
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10
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Abdalla MMI. Serum resistin and the risk for hepatocellular carcinoma in diabetic patients. World J Gastroenterol 2023; 29:4271-4288. [PMID: 37545641 PMCID: PMC10401662 DOI: 10.3748/wjg.v29.i27.4271] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/11/2023] [Accepted: 06/27/2023] [Indexed: 07/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the predominant type of liver cancer, is a major contributor to cancer-related fatalities across the globe. Diabetes has been identified as a significant risk factor for HCC, with recent research indicating that the hormone resistin could be involved in the onset and advancement of HCC in diabetic individuals. Resistin is a hormone that is known to be involved in inflammation and insulin resistance. Patients with HCC have been observed to exhibit increased resistin levels, which could be correlated with more severe disease stages and unfavourable prognoses. Nevertheless, the exact processes through which resistin influences the development and progression of HCC in diabetic patients remain unclear. This article aims to examine the existing literature on the possible use of resistin levels as a biomarker for HCC development and monitoring. Furthermore, it reviews the possible pathways of HCC initiation due to elevated resistin and offers new perspectives on comprehending the fundamental mechanisms of HCC in diabetic patients. Gaining a better understanding of these processes may yield valuable insights into HCC’s development and progression, as well as identify possible avenues for prevention and therapy.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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11
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Yue Z, Pei L, Meng G, Zhang A, Li M, Jia M, Wang H, Cao L. Simultaneous Quantification of Serum Lipids and Their Association with Type 2 Diabetes Mellitus-Positive Hepatocellular Cancer. Metabolites 2023; 13:metabo13010090. [PMID: 36677015 PMCID: PMC9865394 DOI: 10.3390/metabo13010090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/16/2022] [Accepted: 12/21/2022] [Indexed: 01/07/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) has been recognized as one of the most important and independent risk factors for hepatocellular cancer (HCC). However, there is still a lack of ideal tumor markers for HCC detection in the T2DM population. Serum lipids have been revealed as potential tumor markers for HCC. In this study, our objective was to develop a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to detect several lipids including 8,15-dihydroxy-5,9,11,13-eicosatetraenoic acid (8,15-DiHETE), hexadecanedioic acid (HDA), 15-keto-13,14-dihydroprostaglandin A2 (DHK-PGA2), ricinoleic acid (RCL), octadecanedioic acid (OA) and 16-hydroxy hexadecanoic acid (16OHHA) in serum and explore their diagnostic potential for T2DM-positive [T2DM(+)] HCC. A robust LC-MS/MS method was established for the measurement of 8,15-DiHETE, HDA, DHK-PGA2, RCL, OA, and 16OHHA. The methodology validation was conducted, and the results suggested the reliability of this LC-MS/MS method for targeted lipids. Several serum lipids, including 8,15-DiHETE, HDA, DHK-PGA2, and OA were increased in T2DM(+) HCC patients. A biomarker signature that incorporated HDA, DHK-PGA2, and AFP was established and showed good diagnostic potential for T2DM(+) HCC, and the area under the ROC curve (AUC) was 0.87 for diagnosing T2DM(+) HCC from T2DM individuals. Additionally, the biomarker signature diagnosed small-size (AUC = 0.88) and early-stage (AUC = 0.79) tumors with high efficacy. Moreover, the biomarker signature could differentiate T2DM(+) HCC from other T2DM(+) tumors, including pancreatic, gastric and colorectal cancer (AUC = 0.88) as well. In conclusion, our study develops a novel tool for early diagnosis of T2DM(+) HCC in T2DM patients.
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Affiliation(s)
- Zhihong Yue
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing 100044, China
| | - Lin Pei
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing 100044, China
| | - Guangyan Meng
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing 100044, China
| | - Aimin Zhang
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing 100044, China
| | - Meng Li
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing 100044, China
| | - Mei Jia
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing 100044, China
| | - Hui Wang
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing 100044, China
| | - Linlin Cao
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing 100044, China
- Correspondence:
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Nakatsuka T, Tateishi R. Development and prognosis of hepatocellular carcinoma in patients with diabetes. Clin Mol Hepatol 2023; 29:51-64. [PMID: 35903020 PMCID: PMC9845683 DOI: 10.3350/cmh.2022.0095] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/03/2022] [Indexed: 02/02/2023] Open
Abstract
The incidence of diabetes mellitus and hepatocellular carcinoma (HCC) has been increasing worldwide during the last few decades, in the context of an increasing prevalence of obesity and non-alcoholic fatty liver disease (NAFLD). Epidemiologic studies have revealed that patients with diabetes have a 2- to 3-fold increased risk of developing HCC, independent of the severity and cause of the underlying liver disease. A bidirectional relationship exists between diabetes and liver disease: advanced liver disease promotes the onset of diabetes, and HCC is an important cause of death in patients with diabetes; conversely, diabetes is a risk factor for liver fibrosis progression and HCC development, and may worsen the long-term prognosis of patients with HCC. The existence of close interconnections among diabetes, obesity, and NAFLD causes insulin resistance-related hyperinsulinemia, increased oxidative stress, and chronic inflammation, which are assumed to be the underlying causes of hepatocarcinogenesis in patients with diabetes. No appropriate surveillance methods for HCC development in patients with diabetes have been established, and liver diseases, including HCC, are often overlooked as complications of diabetes. Although some antidiabetic drugs are expected to prevent HCC development, further research on the optimal use of antidiabetic drugs aimed at hepatoprotection is warranted. Given the increasing medical and socioeconomic impact of diabetes on HCC development, diabetologists and hepatologists need to work together to develop strategies to address this emerging health issue. This article reviews the current knowledge on the impact of diabetes on the development and progression of HCC.
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Affiliation(s)
- Takuma Nakatsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan,Corresponding author : Ryosuke Tateishi Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Tel: +81-3-3815-5411, Fax: +81-3-3814-0021, E-mail:
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13
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Tsurudome Y, Morita N, Horiguchi M, Ushijima K. Decreased ZO1 expression causes loss of time-dependent tight junction function in the liver of ob/ob mice. Mol Biol Rep 2022; 49:11881-11890. [PMID: 36224445 DOI: 10.1007/s11033-022-07940-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 08/18/2022] [Accepted: 09/08/2022] [Indexed: 11/30/2022]
Abstract
Diabetes patients are at a high risk of developing complications related to angiopathy and disruption of the signal transduction system. The liver is one of the multiple organs damaged during diabetes. Few studies have evaluated the morphological effects of adhesion factors in diabetic liver. The influence of diurnal variation has been observed in the expression and functioning of adhesion molecules to maintain tissue homeostasis associated with nutrient uptake. The present study demonstrated that the rhythm-influenced functioning of tight junction was impaired in the liver of ob/ob mice. The tight junctions of hepatocytes were loosened during the dark period in control mice compared to those in ob/ob mice, where the hepatocyte gaps remained open throughout the day. The time-dependent expression of zonula occludens 1 (ZO1, encoded by Tjp1 gene) in the liver plays a vital role in the functioning of the tight junction. The time-dependent expression of ZO1 was nullified and its expression was attenuated in the liver of ob/ob mice. ZO1 expression was inhibited at the mRNA and protein levels. The expression rhythm of ZO1 was found to be regulated by heat shock factor (HSF)1/2, the expression of which was reduced in the liver of ob/ob mice. The DNA-binding ability of HSF1/2 was decreased in the liver of ob/ob mice compared to that in control mice. These findings suggest the involvement of impaired expression and functioning of adhesion factors in diabetic liver complications.
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Affiliation(s)
- Yuya Tsurudome
- Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 756-0884, Yamaguchi, Japan
| | - Nao Morita
- Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 756-0884, Yamaguchi, Japan
| | - Michiko Horiguchi
- Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 756-0884, Yamaguchi, Japan
| | - Kentaro Ushijima
- Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 756-0884, Yamaguchi, Japan. .,Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Tochigi, Japan.
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Кузнецов КО, Сафина ЭР, Гаймакова ДВ, Фролова ЯС, Оганесян ИЮ, Садертдинова АГ, Назмиева КА, Исламгулов АХ, Каримова АР, Галимова АМ, Ризванова ЭВ. [Metformin and malignant neoplasms: a possible mechanism of antitumor action and prospects for use in practice]. PROBLEMY ENDOKRINOLOGII 2022; 68:45-55. [PMID: 36337018 PMCID: PMC9762452 DOI: 10.14341/probl13097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 06/16/2023]
Abstract
Metformin is a first-line antidiabetic drug for the treatment of type 2 diabetes mellitus (DM2); its molecular target is AMP-activated protein kinase (AMPK), which is involved in many metabolic processes. Metformin not only reduces blood glucose levels and improves insulin sensitivity, but also inhibits lipolysis and reduces cardiovascular risk in patients with DM2. In recent years, it has been proven that metformin slows down the aging process, stimulates hair growth, eliminates cognitive impairment, and also has an antitumor effect. Most basic studies have shown that metformin inhibits the growth of tumor cells and promotes cellular apoptosis, while clinical studies show contradictory results. This discrepancy can be explained by the difference in the concentration of metformin between basic and clinical studies. The maximum daily dose of metformin for patients with DM2 is 2500 mg / day, and the dose used in basic research was much higher. Metformin directly activates the AMPK signaling pathway, inhibits the production of reactive oxygen species, induces the activation of mTORC1, inhibits cyclin D1, which leads to a reduction in the risk of the occurrence and development of malignant neoplasms. In addition, metformin indirectly inhibits tumor growth, proliferation, invasion and metastasis by reducing the concentration of glucose in the blood, insulin resistance, as well as by reducing inflammation and affecting the tumor microenvironment. Glycolysis plays an important role in the energy metabolism of tumors, and metformin is able to have an inhibitory effect on it. Currently, studies of the mechanism of antitumor effects of metformin are becoming more extensive and in-depth, but there are still some contradictions.
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Affiliation(s)
- К. О. Кузнецов
- Российский национальный исследовательский медицинский университет им. Н.И. Пирогова
| | - Э. Р. Сафина
- Башкирский государственный медицинский университет
| | | | - Я. С. Фролова
- Первый Московский государственный медицинский университет им. И.М. Сеченова
| | - И. Ю. Оганесян
- Первый Московский государственный медицинский университет им. И.М. Сеченова
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15
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Cao LL, Han Y, Pei L, Yue ZH, Liu BY, Cui JW, Jia M, Wang H. A Serum Metabolite Classifier for the Early Detection of Type 2 Diabetes Mellitus-Positive Hepatocellular Cancer. Metabolites 2022; 12:metabo12070610. [PMID: 35888734 PMCID: PMC9315765 DOI: 10.3390/metabo12070610] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/19/2022] [Accepted: 06/22/2022] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) has been identified as an independent risk factor for hepatocellular cancer (HCC). However, there are no ideal biomarkers for the surveillance and early detection of HCC in the T2DM population at present. In this study, we aimed to explore novel metabolite biomarkers for T2DM-positive [T2DM(+)] HCC by metabolomic analysis. At first, many serum metabolites were found dysregulated in T2DM(+) HCC patients in untargeted metabolomic analyses. Targeted metabolite analyses confirmed that serum benzoic acid and citrulline were increased, and creatine was decreased in T2DM(+) HCC compared to the T2DM group. A metabolite classifier including benzoic acid, creatine, and citrulline was identified as a novel biomarker for the diagnosis of T2DM(+) HCC, with an area under the ROC curve (AUC) of 0.93 for discriminating T2DM(+) HCC patients from T2DM patients. In addition, the metabolite classifier detected small-size (AUC = 0.94), early-stage (AUC = 0.94), and AFP-negative (AUC = 0.96) tumors with high sensitivity and specificity. The combination of this metabolite classifier and AFP might be useful in the surveillance and early detection of HCC in the T2DM population. In conclusion, this study establishes a novel diagnostic tool for T2DM(+) HCC.
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Affiliation(s)
- Lin-Lin Cao
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing 100044, China; (L.-L.C.); (Y.H.); (L.P.); (Z.-H.Y.); (M.J.)
| | - Yi Han
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing 100044, China; (L.-L.C.); (Y.H.); (L.P.); (Z.-H.Y.); (M.J.)
| | - Lin Pei
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing 100044, China; (L.-L.C.); (Y.H.); (L.P.); (Z.-H.Y.); (M.J.)
| | - Zhi-Hong Yue
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing 100044, China; (L.-L.C.); (Y.H.); (L.P.); (Z.-H.Y.); (M.J.)
| | - Bo-Yu Liu
- Department of Pharmacy, Peking University People’s Hospital, Beijing 100044, China;
| | - Jing-Wen Cui
- SCIEX Analytical Instrument Trading Co., Shanghai 200335, China;
| | - Mei Jia
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing 100044, China; (L.-L.C.); (Y.H.); (L.P.); (Z.-H.Y.); (M.J.)
| | - Hui Wang
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing 100044, China; (L.-L.C.); (Y.H.); (L.P.); (Z.-H.Y.); (M.J.)
- Correspondence: ; Tel.: +86-10-88326300
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Cao JZ, Wang ZG, Yu J, Tao YP, Yang Y, Liu H, Zhou WP, Lu J, Huang Q. Antidiabetic treatment improves prognosis after radical resection in hepatocellular carcinoma patients with diabetes mellitus: a retrospective cohort study from 2000 to 2013. J Gastrointest Oncol 2022; 13:1330-1339. [PMID: 35837203 PMCID: PMC9274028 DOI: 10.21037/jgo-22-478] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/14/2022] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND It remains unclear whether diabetic medications, such as metformin and insulin, affect the post-liver resection prognosis of hepatocellular carcinoma (HCC) patients complicated with diabetes mellitus (DM). This study try to find out the prognostic factors in HCC patients with DM and provide a better antidiabetic therapy after liver resection. METHODS Patients presenting with HCC complicated with DM undergoing liver resection were enrolled in this study. They were examined and followed up every 3-6 months after surgery. Patients were divided into the antidiabetic treatment group and no antidiabetic treatment group according to whether they received medications for diabetes or not. Then patients in the antidiabetic treatment group were further divided into insulin group, metformin group, insulin plus metformin group and others group, according to the medications they received. Overall survival (OS) and recurrence-free survival (RFS) were compared among two groups and four subgoups. Comparative and multivariate analyses were performed to investigate the effects of DM medication on the prognosis of these HCC patients, using Cox proportional hazards model. RESULTS The 1-, 3-, 5-, and 7-year OS rates for the antidiabetic treatment group were 87.5%, 75.5%, 48.7%, and 29.1%, respectively, and for the no antidiabetic treatment group, the OS rates were 85.4%, 57.7%, 33.6%, and 19.1%, respectively (P=0.007). The 1-, 3-, 5-, 7-year RFS rates for the antidiabetic treatment group were 76.4%, 53.5%, 28.5%, and 17.5%, respectively, and for the no antidiabetic treatment group, the RFS rates were 69.5%, 32.5%, 16.5%, and 10.7%, respectively (P=0.001). In subgroup analysis, There was no significant difference in either RFS (P=0.934) nor OS (P=0.412) among the different types of antidiabetic treatment regimens. Cox proportional hazard regression analysis revealed that tumor size (HR: 1.048), tumor number (HR: 1.626), vascular invasion (HR: 2.074, P=0.003), satellite tumor (HR: 1.592), Edmondson classification (HR: 1.468) and antidiabetic treatment (HR: 0.722) were independent prognostic factors of DFS, while tumor size (HR: 1.048), tumor number (HR: 1.779), vascular invasion (HR: 2.545), Edmondson classification (HR: 1.596) and antidiabetic treatment (HR: 0.713) were independent prognostic factors of OS. CONCLUSIONS For HCC patients with DM, antidiabetic treatment should be recommended aggressively in order to improve the surgical outcome, regardless of which antidiabetic drugs are used.
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Affiliation(s)
- Jing-Zhu Cao
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhen-Guang Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jian Yu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yuan-Ping Tao
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yuan Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hui Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Wei-Ping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jin Lu
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Qin Huang
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China
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17
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Hydes TJ, Cuthbertson DJ, Graef S, Berhane S, Teng M, Skowronska A, Singh P, Dhanaraj S, Tahrani A, Johnson PJ. The Impact of Diabetes and Glucose-Lowering Therapies on Hepatocellular Carcinoma Incidence and Overall Survival. Clin Ther 2022; 44:257-268. [DOI: 10.1016/j.clinthera.2021.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/08/2021] [Accepted: 12/31/2021] [Indexed: 12/15/2022]
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18
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Peng CW, Teng W, Lui KW, Hung CF, Jeng WJ, Huang CH, Chen WT, Lin CC, Lin CY, Lin SM, Sheen IS. Complete response at first transarterial chemoembolization predicts favorable outcome in hepatocellular carcinoma. Am J Cancer Res 2021; 11:4956-4965. [PMID: 34765303 PMCID: PMC8569367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 07/19/2021] [Indexed: 06/13/2023] Open
Abstract
Transarterial chemoembolization (TACE) is the mainstay of treatment for patients with intermediate/advanced stage or unresectable hepatocellular carcinoma (HCC). Despite the palliative nature of TACE treatment, embolizing the tumor feeding vessels and leading to progressive tumor necrosis, complete response (CR) after TACE could still be observed in a certain population. Thus, this study aimed to investigate both the predictors for CR and the long-term prognosis of the patients with CR after TACE. The study recruited new diagnosed HCC patients initially treated with TACE from 2010 to 2013. Post TACE response was assessed by scheduled image studies according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Then, pre-TACE factors were compared between patients with and without CR. After the first session of TACE, 22.3% of the 669 TACE treated patients achieved CR. During a median of 26.6 months follow-up, patients with CR had better overall survival than those without (median: 35.8 vs. 24.0 months, P<0.001). By multivariate logistic regression analysis, Child-Turcotte-Pugh class B (OR: 0.419, P=0.005), tumor burden beyond up-to-7 criteria (OR: 0.118, P<0.001), bilobar tumor extent (OR: 0.236, P<0.001), higher alpha-fetoprotein (AFP) level (≥20 ng/ml, OR: 0.614, P=0.039) and higher platelet counts (>150 k/μl, OR: 0.482, P=0.002) were unfavorable predictors for CR after first TACE. In addition, macrovascular invasion (HR: 3.113, P=0.001) and higher AFP levels (≥15 ng/ml, HR: 2.601, P=0.007) were predictors for early HCC recurrence whereas diabetes mellitus (DM) (HR: 2.166, P=0.006) was the only significant predictor for late HCC recurrence in CR patients. In conclusion, more than one-fifth of HCC patients achieved CR after first TACE and these patients had favorable prognosis. Furthermore, tailored post-TACE follow-up strategies shall be considered in patients with different risk factors of early or late recurrence after CR.
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Affiliation(s)
- Chien-Wei Peng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial HospitalLinkou Branch, Taiwan
- College of Medicine, Chang Gung UniversityTaiwan
| | - Wei Teng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial HospitalLinkou Branch, Taiwan
- College of Medicine, Chang Gung UniversityTaiwan
| | - Kar-Wai Lui
- Department of Medical Imaging & Intervention, Chang Gung Memorial Hospital at LinkouTaoyuan, Taiwan
- College of Medicine, Chang Gung UniversityTaiwan
| | - Chien-Fu Hung
- Department of Radiology, Tucheng Composite Municipal HospitalTaiwan
- College of Medicine, Chang Gung UniversityTaiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial HospitalLinkou Branch, Taiwan
- College of Medicine, Chang Gung UniversityTaiwan
| | - Chien-Hao Huang
- Department of Gastroenterology and Hepatology, Chang Gung Memorial HospitalLinkou Branch, Taiwan
- College of Medicine, Chang Gung UniversityTaiwan
| | - Wei-Ting Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial HospitalLinkou Branch, Taiwan
- College of Medicine, Chang Gung UniversityTaiwan
| | - Chen-Chun Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial HospitalLinkou Branch, Taiwan
- College of Medicine, Chang Gung UniversityTaiwan
| | - Chun-Yen Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial HospitalLinkou Branch, Taiwan
- College of Medicine, Chang Gung UniversityTaiwan
| | - Shi-Ming Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial HospitalLinkou Branch, Taiwan
- College of Medicine, Chang Gung UniversityTaiwan
| | - I-Shyan Sheen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial HospitalLinkou Branch, Taiwan
- College of Medicine, Chang Gung UniversityTaiwan
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Rodríguez-Escaja C, Á Navascués C, González-Diéguez L, Cadahía V, Varela M, de Jorge MÁ, Castaño-García A, Rodríguez M. Diabetes is not associated with an increased risk of hepatocellular carcinoma in patients with alcoholic or hepatitis C virus cirrhosis. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2021; 113:505-511. [PMID: 33244982 DOI: 10.17235/reed.2020.6953/2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND AIMS diabetes has been reported as a risk factor for hepatocellular carcinoma (HCC) in population-based studies but there are controversial data in patients with cirrhosis. Metformin could have a protective role in HCC development. The aim of this study was to determine the influence of diabetes on the risk of developing HCC in patients with alcohol- and hepatitis C virus (HCV)-related cirrhosis. METHODS a cohort of 982 Caucasian patients were analyzed with alcoholic or HCV cirrhosis, included from 1992 to 2014 in a HCC surveillance program and prospectively followed. The influence of diabetes on the development of HCC was analyzed by Kaplan Meier analysis and adjusted with a Cox regression for relevant co-factors. RESULTS after a median follow-up of 49.5 (24.0-96.0) months, 156 patients (15.8 %) developed HCC. There were no differences in the cumulative incidences of HCC after 20 years between diabetic and non-diabetic patients in the global (53.5 % vs 45.4 %; p = 0.26), alcoholic (50.4 % vs 45.4 %; p = 0.21) or HCV (60 % vs 43.1 %; p = 0.57) cirrhosis series. Diabetes did not constitute a risk factor after adjusting for other potential co-factors, neither in the whole series (hazard ratio [HR]: 1.12, 95 % CI: 0.78-1.51; p = 0.26), alcoholic (HR: 1.160, 95 % CI: 0.74-1.82; p = 0.50) or HCV cirrhosis cohort (HR: 1.17, 95 % CI: 0.63-2.19; p = 0.60). These figures did not change after excluding patients treated with metformin. CONCLUSIONS in Caucasian patients with alcoholic or HCV cirrhosis, diabetes is not a risk factor for developing HCC. This lack of an association does not seem to be a consequence of the protective effect of metformin.
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Affiliation(s)
- Carlos Rodríguez-Escaja
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
| | - Carmen Á Navascués
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
| | - Luisa González-Diéguez
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
| | - Valle Cadahía
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
| | - María Varela
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
| | - Miguel Ángel de Jorge
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
| | - Andrés Castaño-García
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
| | - Manuel Rodríguez
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
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20
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Conway RBN, Sudenga S, McClain D, Blot WJ. Diabetes and liver cancer risk: A stronger effect in Whites than Blacks? J Diabetes Complications 2021; 35:107816. [PMID: 33323327 PMCID: PMC8045414 DOI: 10.1016/j.jdiacomp.2020.107816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 11/10/2020] [Accepted: 11/11/2020] [Indexed: 10/22/2022]
Abstract
BACKGROUND Both diabetes and liver cancer are overrepresented among African Americans, but limited information is available on the interrelationship of these two diseases among African Americans. We examined the association of diabetes with the incidence of liver cancer and whether this varied by participant self-reported race/ethnicity. METHODS Using the Southern Community Cohort Study, we conducted a cancer follow up (2002-2016) of a cohort of mostly low-income participants aged 40-79 with diabetes (n = 15,879) and without diabetes (n = 59,077) at study baseline. Cox regression was used to compute Hazard Ratios (HR) and 95% CIs for the risk of incident liver cancer. RESULTS With 790,132 person years of follow up, 320 incident cases of liver cancer were identified. In analyses controlling for age, sex, race, BMI, current and former smoking, total alcohol consumption, family history of liver cancer, any hepatitis infection, hyperlipidemia and socioeconomic factors, the association between diabetes and risk of liver cancer differed significantly (pinteraction = 0.0001) between participants identifying as Black/African American (AA) or White/European American (EA). Diabetes was associated with 5.3-fold increased cancer risk among EAs (HR 5.4, 95% CI 3.2-9.3) vs an 80% increase (HR 1.8, 95% CI 1.3-2.5) among AAs. Furthermore, controlling for diabetes greatly attenuated the higher risk of liver cancer among AAs; indeed, while the cancer risk among those without diabetes was twice as high among AAs than EAs (HR = 2.0, 95% CI = 1.4-2.9), no excess in AAs was observed among those with diabetes (HR = 0.7, 95% CI = 0.4-1.1). CONCLUSION While liver cancer risk in general is greater in AAs than EAs and diabetes increases this risk in both racial/ethnic groups, diabetes appears to impact liver cancer to a much greater extent among EAs. The findings raise the possibility of racially different mechanisms and impacts of diabetes on this often fatal cancer among AAs and EAs.
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Affiliation(s)
- Rebecca Baqiyyah N Conway
- School of Community and Rural Health, University of Texas Health Science Center at Tyler, Tyler, TX, United States of America.
| | - Staci Sudenga
- Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, United States of America
| | - Donald McClain
- Section of Endocrinology and Metabolism, Wake Forest School of Medicine, Winston-Salem, NC, United States of America
| | - William J Blot
- Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, United States of America
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21
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Metformin Improves Biochemical and Pathophysiological Changes in Hepatocellular Carcinoma with Pre-Existed Diabetes Mellitus Rats. Pathogens 2021; 10:pathogens10010059. [PMID: 33440701 PMCID: PMC7830090 DOI: 10.3390/pathogens10010059] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/24/2020] [Accepted: 12/28/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the world’s most widely recognized malignant tumors that accounts for 90% of all the primary liver cancers and is a major cause of death from cancer, representing half a million deaths per year. Obesity and associated metabolic irregularities, particularly diabetes mellitus (DM) and insulin resistance, are important risk factors for the advancement of HCC. Recently, retrospective studies showed that metformin (MET) could protect the hepatic tissues in pre-existing diabetes mellitus from HCC. The purpose of this study was to assess the role of MET treatment in the pre-existing diabetic rats before and after HCC induction by diethylnitrosamine (DEN). Thirty-five male Sprague Dawley albino rats were partitioned into the following groups: Group 1 (Gp1) was the control. Gp2 was injected intraperitoneally (i.p) with streptozotocin (STZ) (80 mg/kg) and DEN (50 mg/kg/7 weeks). Gp3, Gp4, and Gp5 were injected as in Gp2 and treated with MET (150 mg/kg) before and/or after HCC induction. Biochemical parameters including liver functions, lipid profile, and oxidative stress biomarkers were determined. Furthermore, histological and immunohistochemical changes were assessed in all groups. Our results illustrated that the group of rats that were treated with STZ and DEN had significant changes in both liver functions and were associated with alterations in the liver histopathological architectures. Treatment with MET before or after HCC induction ameliorated the cellular changes in the liver tissues; however, the utmost protection was found in a group of rats, which were treated with MET before and after HCC induction.
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22
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Leng W, Jiang J, Chen B, Wu Q. Metformin and Malignant Tumors: Not Over the Hill. Diabetes Metab Syndr Obes 2021; 14:3673-3689. [PMID: 34429626 PMCID: PMC8380287 DOI: 10.2147/dmso.s326378] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/06/2021] [Indexed: 12/11/2022] Open
Abstract
Malignant tumors are a major cause of death, and their incidence is increasing worldwide. Although the survival rate for some cancers has improved, treatments for other malignant tumors are limited, and their mortality rate continues to increase. People with type 2 diabetes have a higher risk of malignant tumors and a higher mortality rate than those without diabetes. Metformin is a commonly used hypoglycemic drug. In recent years, a growing number of studies have indicated that metformin has antitumor effects and increases the sensitivity of malignant tumors to chemotherapy. However, the effect of metformin on different tumors is currently controversial, and the mechanism of metformin's antitumor action is not fully understood. Insights into the effect of metformin on malignant tumors and the possible mechanism may contribute to the development of antitumor drugs.
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Affiliation(s)
- Weiling Leng
- Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Juan Jiang
- Endocrinology and Nephrology Department, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, People’s Republic of China
| | - Bing Chen
- Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
- Bing Chen Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China Email
| | - Qinan Wu
- Endocrinology Department, Dazu Hospital of Chongqing Medical University, The People’s Hospital of Dazu, Chongqing, People’s Republic of China
- Correspondence: Qinan Wu Endocrinology Department, Dazu Hospital of Chongqing Medical University, The People’s Hospital of Dazu, Chongqing, People’s Republic of China Email
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23
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Yuan JM, Wang Y, Wang R, Luu HN, Adams-Haduch J, Koh WP, Gao YT, Behari J, Lotze MT. Serum IL27 in Relation to Risk of Hepatocellular Carcinoma in Two Nested Case-Control Studies. Cancer Epidemiol Biomarkers Prev 2020; 30:388-395. [PMID: 33203693 DOI: 10.1158/1055-9965.epi-20-1081] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/24/2020] [Accepted: 11/12/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND IL27 mRNA is highly enriched in the tissue of hepatocellular carcinoma. Overexpression of IL27 gene has been found to increase T-cell expression of inhibitory receptors, an immunosuppressive feature in tumor microenvironment, that promotes the development of hepatocellular carcinoma. METHODS Two parallel case-control studies of hepatocellular carcinoma, each with 100 case-control pairs were conducted in the Singapore Chinese Health Study and the Shanghai Cohort Study to examine the association between serum IL27 levels and risk of developing hepatocellular carcinoma. RESULTS The IL27 concentrations were significantly elevated in sera collected from study participants 4 to 5 years prior to the diagnosis of hepatocellular carcinoma in both cohort studies. Compared with the lowest tertile of IL27, odds ratios (OR) of hepatocellular carcinoma for the highest tertile of IL27 was 46.08 [95% confidence interval (CI), 4.68-453.86] in the Singapore Chinese Health Study and 19.09 (95% CI, 3.81-95.57) in the Shanghai Cohort Study (both P trend <0.001). The corresponding ORs in both cohort studies were 42.47 (95% CI, 8.30-217.40) among individuals negative for hepatitis B surface antigen (HBsAg) and 242.46 (95% CI, 38.42-1,529.01) among those positive for HBsAg compared with the lowest tertile of interleukin-27 and negative HBsAg. CONCLUSIONS Levels of IL27 in prediagnostic sera were significantly associated with increased risk of hepatocellular carcinoma development. IMPACT IL27, through its immunosuppressive property, may play a significant role in the development of hepatocellular carcinoma. Serum levels of IL27 may be used as a biomarker for prediction of hepatocellular carcinoma development.
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Affiliation(s)
- Jian-Min Yuan
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania. .,Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - Yue Wang
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Renwei Wang
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Hung N Luu
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.,Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | | | - Woon-Puay Koh
- Health Service and Systems Research, Duke-NUS Medical School, Singapore.,Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Yu-Tang Gao
- Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jaideep Behari
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michael T Lotze
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.,Departments of Surgery, Immunology and Bioengineering, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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24
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Liu G, Xia F, Fan G, Yu J, Bao L, Zhang C, Chi R, Zhang T, Wang L, Shen F, Wang D. Type 2 diabetes mellitus worsens the prognosis of intermediate-stage hepatocellular carcinoma after transarterial chemoembolization. Diabetes Res Clin Pract 2020; 169:108375. [PMID: 32827592 DOI: 10.1016/j.diabres.2020.108375] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 08/01/2020] [Accepted: 08/14/2020] [Indexed: 12/16/2022]
Abstract
AIMS The aim of this study was to investigate the impact of type 2 diabetes mellitus (T2DM) on the prognosis of hepatocellular carcinoma (HCC) patients following transarterial chemoembolization (TACE). METHODS Time to progression (TTP) and cancer-specific mortality (CSM) in competing risk model were compared in patients with (n = 289) or without (n = 763) T2DM. Propensity score matching (PSM) was used to reduce bias between the two groups. Multivariate competing risk regression was used to evaluate independent risk factors for TTP and CSM. RESULTS The T2DM group showed significantly worse 5-year TTP and CSM rates than the non-T2DM group both in the whole cohort (n = 1052) and the PSM cohort (n = 514) (81.3% vs. 70.9%, P < 0.001, and 61.5% vs. 49.3%, P = 0.006; 81.4% vs. 68.6%, P = 0.003, and 61.7% vs. 43.2%, P = 0.014, respectively). Multivariate competing risk regression identified T2DM as an independent risk factor for TTP and CSM before and after PSM (hazard ratio: 1.37 [95% confidence interval: 1.07-1.77] and 1.36 [1.05-1.75]; 1.29 [1.04-1.60] and 1.24 [1.02-1.52], respectively). T2DM worsened the long-term outcomes of patients in the cirrhosis subgroup but not those in the noncirrhosis subgroup. CONCLUSIONS T2DM worsened the long-term survival of intermediate-stage HCC patients who underwent TACE, especially in patients with cirrhosis.
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Affiliation(s)
- Guanghua Liu
- Department of Interventional Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China; Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| | - Fang Xia
- Department of Cardiology, Dahua Hospital, Xuhui District, Shanghai, China.
| | - Guoping Fan
- Department of Interventional Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China; Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Juming Yu
- Department of Interventional Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China; Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Lei Bao
- Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Caiyuan Zhang
- Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Runmin Chi
- Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Tingting Zhang
- Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Lijun Wang
- Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Feng Shen
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| | - Dengbin Wang
- Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
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25
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Fifield BA, Talia J, Stoyanovich C, Elliott MJ, Bakht MK, Basilious A, Samsoondar JP, Curtis M, Stringer KF, Porter LA. Cyclin-like proteins tip regenerative balance in the liver to favour cancer formation. Carcinogenesis 2020; 41:850-862. [PMID: 31574533 DOI: 10.1093/carcin/bgz164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 08/30/2019] [Accepted: 09/30/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. A variety of factors can contribute to the onset of this disease, including viral infection, obesity, alcohol abuse and non-alcoholic fatty liver disease (NAFLD). These stressors predominantly introduce chronic inflammation leading to liver cirrhosis and finally the onset of HCC; however, approximately 20% of HCC cases arise in the absence of cirrhosis via a poorly defined mechanism. The atypical cyclin-like protein Spy1 is capable of overriding cell cycle checkpoints, promoting proliferation and has been implicated in HCC. We hypothesize that Spy1 promotes sustained proliferation making the liver more susceptible to accumulation of deleterious mutations, leading to the development of non-cirrhotic HCC. We report for the first time that elevation of Spy1 within the liver of a transgenic mouse model leads to enhanced spontaneous liver tumourigenesis. We show that the abundance of Spy1 enhanced fat deposition within the liver and decreased the inflammatory response. Interestingly, Spy1 transgenic mice have a significant reduction in fibrosis and sustained rates of hepatocyte proliferation, and endogenous levels of Spy1 are downregulated during the normal fibrotic response. Our results provide support that abnormal regulation of Spy1 protein drives liver tumorigenesis in the absence of elevated fibrosis and, hence, may represent a potential mechanism behind non-cirrhotic HCC. This work may implicate Spy1 as a prognostic indicator and/or potential target in the treatment of diseases of the liver, such as HCC. The cyclin-like protein Spy1 enhances lipid deposition and reduces fibrosis in the liver. Spy1 also promotes increased hepatocyte proliferation and onset of non-cirrhotic hepatocellular carcinoma (HCC). Thus, Spy1 may be used as a potential target in the treatment of HCC.
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Affiliation(s)
- Bre-Anne Fifield
- Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
| | - John Talia
- Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
| | - Carlee Stoyanovich
- Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
| | - Mitchell J Elliott
- Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
| | - Martin K Bakht
- Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
| | - Amy Basilious
- Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
| | - Joshua P Samsoondar
- Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
| | - Madison Curtis
- Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
| | - Keith F Stringer
- Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada.,Department of Pathology, Cincinnati Children's Hospital Medical Center Cincinnati, Cincinnati, OH, USA
| | - Lisa A Porter
- Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
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26
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Sumida Y, Shima T, Mitsumoto Y, Katayama T, Umemura A, Yamaguchi K, Itoh Y, Yoneda M, Okanoue T. Epidemiology: Pathogenesis, and Diagnostic Strategy of Diabetic Liver Disease in Japan. Int J Mol Sci 2020; 21:E4337. [PMID: 32570776 PMCID: PMC7352222 DOI: 10.3390/ijms21124337] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/08/2020] [Accepted: 06/16/2020] [Indexed: 12/14/2022] Open
Abstract
Type 2 diabetes (T2D) is closely associated with nonalcoholic fatty liver disease (NAFLD). Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to cirrhosis, hepatocellular carcinoma (HCC), and hepatic decompensation. Patients with T2D have twice the risk of HCC incidence compared with those without T2D. Because the hepatic fibrosis grade is the main determinant of mortality in patients with NAFLD, identifying patients with advanced fibrosis using non-invasive tests (NITs) or imaging modalities is crucial. Globally, the fibrosis-4 index (FIB-4 index), NAFLD fibrosis score, and enhanced liver fibrosis test have been established to evaluate hepatic fibrosis. Two-step algorithms using FIB-4 index as first triaging tool are globally accepted. It remains unknown which kinds of NITs or elastography are best as the second step tool. In Japan, type IV collagen 7s or the CA-fibrosis index (comprising type IV collagen 7s and aspartate aminotransferase (AST)) is believed to precisely predict advanced fibrosis in NAFLD. Patients with NAFLD who have high non-invasive test results should be screened for HCC or esophageal varices. Risk factors of rapid fibrosis progression in NAFLD includes age, severe obesity, presence of T2D, menopause in women, and a patatin-like phospholipase domain containing the 3 GG genotype. Patients with NAFLD who have these risk factors should be intensively treated with lifestyle modification or pharmacotherapies for preventing liver-related mortality.
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Affiliation(s)
- Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan;
| | - Toshihide Shima
- Center of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka 564-0013, Japan; (T.S.); (Y.M.); (T.K.); (T.O.)
| | - Yasuhide Mitsumoto
- Center of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka 564-0013, Japan; (T.S.); (Y.M.); (T.K.); (T.O.)
| | - Takafumi Katayama
- Center of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka 564-0013, Japan; (T.S.); (Y.M.); (T.K.); (T.O.)
| | - Atsushi Umemura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (A.U.); (K.Y.); (Y.I.)
| | - Kanji Yamaguchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (A.U.); (K.Y.); (Y.I.)
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (A.U.); (K.Y.); (Y.I.)
| | - Masashi Yoneda
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan;
| | - Takeshi Okanoue
- Center of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka 564-0013, Japan; (T.S.); (Y.M.); (T.K.); (T.O.)
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27
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Lim CT, Goh GBB, Li H, Lim TKH, Leow WQ, Wan WK, Azhar R, Chow WC, Kumar R. Presence of Hepatic Steatosis Does Not Increase the Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Over Long Follow-Up. Microbiol Insights 2020; 13:1178636120918878. [PMID: 32435130 PMCID: PMC7223198 DOI: 10.1177/1178636120918878] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 03/16/2020] [Indexed: 12/11/2022] Open
Abstract
Background Chronic hepatitis B (CHB) infection and nonalcoholic fatty liver disease (NAFLD) are liver diseases which may lead to hepatocellular carcinoma (HCC) formation. Both disease entities have been attributed independently to increase risk of HCC development. While concomitant hepatic steatosis in patients with CHB are becoming more frequent in view of increasing NAFLD prevalence, there is no conclusive evidence linking presence of hepatic steatosis and increased HCC risk in patients with CHB infection. This study explores the association of hepatic steatosis among CHB-infected individuals in HCC development. Methods This is a retrospective study on a cohort of patients with CHB who underwent liver biopsy between January 2000 and December 2014. They were stratified according to presence and severity of histologically proven hepatic steatosis and subsequently followed up to evaluate the association between hepatic steatosis and HCC development. Results Among 289 patients with a median follow-up of 111.1 months, hepatic steatosis was present in 185 patients (64.0%). In all, 27 patients developed HCC on follow-up and 21 of them had hepatic steatosis. Univariate Cox analysis showed that age (hazard ratio [HR] = 1.08, 95% CI = 1.042-1.12), type 2 diabetes mellitus (T2DM) (HR = 4.00, 95% CI = 1.622-9.863), and Ishak score (HR = 1.221, 95% CI = 1.014-1.472) were associated with HCC development, whereas multivariate Cox analysis demonstrated that age and T2DM (HR = 2.69, 95% CI = 1.072-6.759) were significant risk factors for development of HCC. Conclusions Concurrent hepatic steatosis in patients with CHB infection is not a risk factor for hepatocellular carcinoma formation.
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Affiliation(s)
- Chong Teik Lim
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
| | - George Boon Bee Goh
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.,Duke-NUS Graduate Medical School, Singapore
| | - Huihua Li
- Department of Health Services Research Unit, Singapore General Hospital, Singapore.,Centre of Quantitative Medicine, Duke-NUS Medical School, Singapore
| | - Tony Kiat-Hon Lim
- Duke-NUS Graduate Medical School, Singapore.,Department of Pathology, Singapore General Hospital, Singapore
| | - Wei Qiang Leow
- Duke-NUS Graduate Medical School, Singapore.,Department of Pathology, Singapore General Hospital, Singapore
| | - Wei Keat Wan
- Duke-NUS Graduate Medical School, Singapore.,Department of Pathology, Singapore General Hospital, Singapore
| | - Rafay Azhar
- Duke-NUS Graduate Medical School, Singapore.,Department of Pathology, Singapore General Hospital, Singapore
| | - Wan Cheng Chow
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.,Duke-NUS Graduate Medical School, Singapore
| | - Rajneesh Kumar
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.,Duke-NUS Graduate Medical School, Singapore
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28
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Johnston MP, Patel J, Byrne CD. Diabetes is associated with increased risk of hepatocellular carcinoma in non-alcoholic steatohepatitis with cirrhosis-implications for surveillance and future pharmacotherapy. Hepatobiliary Surg Nutr 2020; 9:230-234. [PMID: 32355688 DOI: 10.21037/hbsn.2019.10.09] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Michael P Johnston
- Department of Hepatology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Janisha Patel
- Department of Hepatology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Christopher D Byrne
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.,National Institute for Health Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK
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29
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Sarin SK, Kumar M, Eslam M, George J, Al Mahtab M, Akbar SMF, Jia J, Tian Q, Aggarwal R, Muljono DH, Omata M, Ooka Y, Han KH, Lee HW, Jafri W, Butt AS, Chong CH, Lim SG, Pwu RF, Chen DS. Liver diseases in the Asia-Pacific region: a Lancet Gastroenterology & Hepatology Commission. Lancet Gastroenterol Hepatol 2020; 5:167-228. [PMID: 31852635 PMCID: PMC7164809 DOI: 10.1016/s2468-1253(19)30342-5] [Citation(s) in RCA: 339] [Impact Index Per Article: 67.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 07/20/2019] [Accepted: 08/02/2019] [Indexed: 02/06/2023]
Abstract
The Asia-Pacific region is home to more than half of the global population and accounted for 62·6% of global deaths due to liver diseases in 2015. 54·3% of global deaths due to cirrhosis, 72·7% of global deaths due to hepatocellular carcinoma, and more than two-thirds of the global burden of acute viral hepatitis occurred in this region in 2015. Chronic hepatitis B virus (HBV) infection caused more than half of the deaths due to cirrhosis in the region, followed by alcohol consumption (20·8%), non-alcoholic fatty liver disease (NAFLD; 12·1%), and chronic infection with hepatitis C virus (HCV; 15·7%). In 2015, HBV accounted for about half the cases of hepatocellular carcinoma in the region. Preventive strategies for viral hepatitis-related liver disease include increasing access to clean drinking water and sanitation. HBV vaccination programmes for neonates have been implemented by all countries, although birth-dose coverage is extremely suboptimal in some. Availability of screening tests for blood and tissue, donor recall policies, and harm reduction strategies are in their initial stages in most countries. Many governments have put HBV and HCV drugs on their essential medicines lists and the availability of generic versions of these drugs has reduced costs. Efforts to eliminate viral hepatitis as a public health threat, together with the rapid increase in per-capita alcohol consumption in countries and the epidemic of obesity, are expected to change the spectrum of liver diseases in the Asia-Pacific region in the near future. The increasing burden of alcohol-related liver diseases can be contained through government policies to limit consumption and promote less harmful patterns of alcohol use, which are in place in some countries but need to be enforced more strictly. Steps are needed to control obesity and NAFLD, including policies to promote healthy lifestyles and regulate the food industry. Inadequate infrastructure and insufficient health-care personnel trained in liver diseases are issues that also need to be addressed in the Asia-Pacific region. The policy response of most governments to liver diseases has thus far been inadequate and poorly funded. There must be a renewed focus on prevention, early detection, timely referral, and research into the best means to introduce and improve health interventions to reduce the burden of liver diseases in the Asia-Pacific region.
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Affiliation(s)
- Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India.
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Mohammed Eslam
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, Australia
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Sheikh M Fazle Akbar
- Department of Pathology, Ehime University Proteo-Science Center, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medial University, Beijing, China
| | - Qiuju Tian
- Liver Research Center, Beijing Friendship Hospital, Capital Medial University, Beijing, China
| | - Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | | | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan; University of Tokyo, Tokyo, Japan
| | - Yoshihiko Ooka
- Department of Gastroenterology, Chiba University Hospital, Chiba, Japan
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Wasim Jafri
- Department of Medicine, Section of Gastroenterology, The Aga Khan University, Karachi, Pakistan
| | - Amna S Butt
- Department of Medicine, Section of Gastroenterology, The Aga Khan University, Karachi, Pakistan
| | - Chern H Chong
- Division of Gastroenterology & Hepatology, National University Health System, Singapore; Division of General Medicine, Woodlands Health Campus, Singapore
| | - Seng G Lim
- Division of Gastroenterology & Hepatology, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Raoh-Fang Pwu
- National Hepatitis C Program Office, Ministry of Health and Welfare, Taipei, Taiwan
| | - Ding-Shinn Chen
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Taipei, Taiwan
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Marsella M, Ricchi P. Thalassemia and hepatocellular carcinoma: links and risks. J Blood Med 2019; 10:323-334. [PMID: 31572038 PMCID: PMC6756274 DOI: 10.2147/jbm.s186362] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 08/22/2019] [Indexed: 01/19/2023] Open
Abstract
The increased survival and lifespan of thalassemia patients, in the setting of better iron overload monitoring and chelation, have also however increased the incidence of diseases and complications, which were less likely to develop. Among these, one of the most worrying in recent years is hepatocellular carcinoma (HCC). Due to blood transfusions, many patients with thalassemia are or have been infected with hepatitis C virus (HCV) or hepatitis B virus (HBV), especially those born before the 1990s or in countries in which universal HBV vaccination and safe blood programs are still not completely implemented. However, HCC has also been described in nontransfused patients and in those who are HCV- and HBV-negative. Therefore, other risk factors are involved in hepatocarcinogenesis in thalassemia. The following review analyzes recent literature on the role of different risk factors in the progression of liver disease in thalassemia as well as the importance of surveillance. Treatment of HCC in thalassemia is still highly debated and requires further studies.
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Affiliation(s)
- Maria Marsella
- Department of Woman and Child, Pediatric Unit, San Giuseppe Moscati Hospital, Avellino, Italy
| | - Paolo Ricchi
- Unità Operativa Semplice Dipartimentale (UOSD) Malattie Rare Del Globulo Rosso, Dipartimento di oncoematologia, Azienda Ospedaliera Di Rilievo Nazionale “A. Cardarelli”, Napoli, Italy
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31
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Wang CP, Kuhn J, Shah DP, Schmidt S, Lam YWF, MacCarthy D, Tenner L, Ramirez AG. Metformin modifies disparity in hepatocellular carcinoma incidence in men with type 2 diabetes but without chronic liver diseases. Cancer Med 2019; 8:3206-3215. [PMID: 30993905 PMCID: PMC6558591 DOI: 10.1002/cam4.2142] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 03/06/2019] [Accepted: 03/15/2019] [Indexed: 12/18/2022] Open
Abstract
Background We assessed racial/ethnic disparity in hepatocellular carcinoma (HCC) incidence among men with type 2 diabetes (T2D) but without chronic liver diseases (CLD), and whether metformin use modified the disparity. Methods Study cohort: the nationwide Veterans Administration Health Care System electronic medical records among 40‐89 years old men with T2D; without CLD, cancer, cardiovascular or renal diseases previously; insulin and thiazolidinedione naive. Logistic regression analyses compared HCC incidence between race/ethnicity groups under no metformin use adjusted for covariates and inverse propensity score weights (IPSW) for race/ethnicity. The generalizability technique integrated with IPSW was incorporated to compare covariates adjusted odds ratios (aOR) of HCC associated with metformin use among race/ethnicity groups. Results Study cohort: N = 84 433; 79.47% non‐Hispanic white (NHW), 15.5% non‐Hispanic African American (NHAA), 5.03% Hispanics; 36.76% metformin users; follow‐up 6.10 ± 2.87 years; age 67.8 ± 9.8 years, HbA1c 6.57 ± 0.98%; 0.14% HCC cases. Under no metformin use, HCC incidence was lower for NHAA vs NHW (aOR = 0.60 [0.40‐0.92]), similar between NHW and Hispanics. Metformin was associated with reduced HCC risk: aOR = 0.57 (0.40‐0.81) for NHW; aOR = 0.35 (0.25‐0.47) for NHAA; aOR = 0.31 (0.22‐0.43) for Hispanics. Metformin dose >1000 mg/d was neutral for NHW; less effective for NHAA (P = 0.02); more effective for Hispanics (P = 0.002). Conclusions In men with T2D but without CLD nor metformin use, HCC incidence was lower for NHAA compared to NHW or Hispanics; similar between NHW and Hispanics. Metformin use reduced HCC risk and modified the race/ethnicity disparity. Impact Metformin's heterogeneous HCC prevention effect elucidates potential interventions to modify HCC disparity in patients with T2D.
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Affiliation(s)
- Chen-Pin Wang
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas
| | - John Kuhn
- Department of Pharmacology, UTHSCSA, San Antonio, Texas
| | - Dimpy P Shah
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas.,Institute for Health Promotion Research, UTHSCS, San Antonio, Texas
| | - Susanne Schmidt
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas
| | | | - Daniel MacCarthy
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas
| | | | - Amelie G Ramirez
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas.,Institute for Health Promotion Research, UTHSCS, San Antonio, Texas
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Shima T, Uto H, Ueki K, Kohgo Y, Yasui K, Nakamura N, Nakatou T, Takamura T, Kawata S, Notsumata K, Sakai K, Tateishi R, Okanoue T. Hepatocellular carcinoma as a leading cause of cancer-related deaths in Japanese type 2 diabetes mellitus patients. J Gastroenterol 2019; 54:64-77. [PMID: 30006904 DOI: 10.1007/s00535-018-1494-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Accepted: 06/30/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND We reported a cross-sectional study on causes of liver injury in Japanese type 2 diabetes mellitus (T2D) patients (JG 2013). We assessed overall and cause-specific mortality risk during follow-up of patients enrolled in JG 2013. METHODS This was a longitudinal, multicenter cohort study. Of the 5642 Japanese T2D patients who visited T2D clinics of nine hospitals in the original study, 3,999 patients were followed up for an average of 4.5 years. Expected deaths in T2D patients were estimated using age-specific mortality rates in the general population (GP) of Japan. Standardized mortality ratios (SMRs) were calculated to compare mortality between T2D patients and GP. RESULTS All-cancer mortality was significantly higher in T2D patients than in the GP [SMR 1.58, 95% confidence interval (CI) 1.33-1.87]. Among malignancies, hepatocellular carcinoma (HCC) conferred the highest mortality risk in T2D patients (SMR 3.57, 95% CI 2.41-5.10). HCC-associated mortality risk in T2D patients remained significantly high (SMR 2.56, 95% CI 1.64-3.97) after adjusting for high positivity rates of hepatitis B surface antigen (1.7%) and anti-hepatitis C virus (5.3%). In T2D patients with platelet counts < 200 × 103/μl, SMR of HCC increased from 3.57 to 6.58 (95% CI 4.34-9.58). T2D patients with platelet count > 200 × 103/μl showed no increase in mortality risk (SMR 0.68) of HCC. CONCLUSIONS HCC-associated mortality risk was the highest among all cancers in Japanese T2D patients. Regular follow-up may be important for T2D patients with platelet counts < 200 × 103/μl for early detection of HCC.
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Affiliation(s)
- Toshihide Shima
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita, Japan
| | - Hirofumi Uto
- Department of Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kohjiro Ueki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yutaka Kohgo
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical College, Asahikawa, Japan
| | - Kohichiroh Yasui
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Naoto Nakamura
- Department of Endocrinology Diabetes and Metabolism, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tatsuaki Nakatou
- Diabetes Center, Okayama Saiseikai General Hospital, Okayama, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Sumio Kawata
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Kazuo Notsumata
- Department of Gastroenterology, Fukui-ken Saiseikai Hospital, Fukui, Japan
| | - Kyoko Sakai
- Department of Clinical Laboratory, Saiseikai Suita Hospital, Suita, Japan.,Department of Health Informatics, Kyoto University School of Public Health, Kyoto, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takeshi Okanoue
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita, Japan.
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Hurley DL. Neoplasia in Patients with Excess Fat Mass. BARIATRIC ENDOCRINOLOGY 2019:293-323. [DOI: 10.1007/978-3-319-95655-8_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Hamed AE, Elsahar M, Elwan NM, El-Nakeep S, Naguib M, Soliman HH, Ahmed Aboubakr A, AbdelMaqsod A, Sedrak H, Assaad SN, Elwakil R, Esmat G, Salh S, Mostafa T, Mogawer S, Sadek SE, Saber MM, Ezelarab H, Mahmoud AA, Sultan S, El Kassas M, Kamal E, ElSayed NM, Moussa S. Managing diabetes and liver disease association. Arab J Gastroenterol 2018; 19:166-179. [PMID: 30420265 DOI: 10.1016/j.ajg.2018.08.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 08/26/2018] [Indexed: 02/05/2023]
Abstract
There is strong association between liver diseases and diabetes (DM) which is higher than expected by a chance association of two very common disorders. It can be classified into three categories: Liver disease related to diabetes, hepatogenous diabetes (HD), and liver disease occurring coincidentally with DM. The criteria for the diagnosis of diabetes associating liver disease are the same for primary diabetes. Two hours post glucose load is a better screening test for HD. HbA1c may not be suitable for diagnosis or monitoring of diabetes associating advanced liver disease. Apart from the increased cardiovascular risk in patients with type 2 DM (T2 DM) and NAFLD, the cardiovascular and retinopathy risk is low in HD. Patients with metabolic derangement should be screened for NAFLD which in turn may predict T2 DM development. Similarly, patients with established T2 DM should also be screened for NAFLD which further contributes to diabetes worsening. Diabetes is a significant risk factor for progression of the chronic liver disease. It is associated with poor patient survival. Treatment of diabetes associating liver disease appears beneficial. Metformin, if tolerated and not contraindicated, is recommended as a first-line therapy for patients with diabetes and chronic liver disease (CLD). If the hepatic disease is severe, insulin secretagogues should be avoided because of the increased risk of hypoglycaemia. Pioglitazone may be useful in patients with fatty liver disease. DPP-4 inhibitors showed effectiveness and safety for the treatment of T2 DM in CLD patients up to those with child B stage. GLP-1 receptor agonists and SGLT-2 inhibitors exhibit positive effects on weight and are associated with minimal risk of hypoglycaemia. Insulin must be used with caution, as hypoglycaemia may be a problem. Insulin analogues are preferred in the context of hypoglycaemia Statins can be used to treat dyslipidaemia in NAFLD, also the use of angiotensin II receptor antagonist for hypertension is safe and beneficial Given the clear association between diabetes mellitus and hepatocellular carcinoma, the strict control of glycaemia with insulin sensitizers can be essential in its prevention. The addition of DM to the currently used scores (Child-Pugh and MELD scores) may enhance the sensitivity and the specificity for prediction of morbidity and mortality rates in cirrhotic patients. In the new era of directly acting antiviral agents (DAAs) for HCV treatment, it is recommended to follow up lipid profile and blood sugar levels following SVR in order to adjust doses of medications used in diabetic (SVR is associated with reduction in insulin requirements) and dyslipidaemic patients (rebound increase in the lipid profile after clearing the virus may increase risk of cardiovascular disease (CVD)). The issues of post liver transplant diabetes and relation between DM and chronic HBV are highlighted. This narrative review and Consensus-based practice guidance (under revision and criticism) are based on a formal review and analysis of the recently published world literature on the topic (Medline search up to September 2017); and the experience of the authors and independent reviewers.
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Affiliation(s)
- Abd Elkhalek Hamed
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt.
| | - Medhat Elsahar
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Police Medical Academy, Egypt
| | | | | | | | | | - Ashraf Ahmed Aboubakr
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | | | | | | | - Reda Elwakil
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Ain Shams University, Egypt
| | - Gamal Esmat
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Kasr Al Aini, Egypt
| | - Samira Salh
- Department of Pharmacy, Cairo University, Egypt
| | | | | | - Sameh Emil Sadek
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | - Maha M Saber
- Department of Clinical Nutrition National Research Centre, Egypt
| | - Hanan Ezelarab
- Department of Clinical Nutrition National Research Centre, Egypt
| | - Asem Ashraf Mahmoud
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | | | | | - Ehab Kamal
- Medical Department, National Research Centre, Egypt
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Ohkuma T, Peters SAE, Woodward M. Sex differences in the association between diabetes and cancer: a systematic review and meta-analysis of 121 cohorts including 20 million individuals and one million events. Diabetologia 2018; 61:2140-2154. [PMID: 30027404 PMCID: PMC6133170 DOI: 10.1007/s00125-018-4664-5] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 05/02/2018] [Indexed: 12/14/2022]
Abstract
AIMS/HYPOTHESIS Diabetes has been shown to be a risk factor for some cancers. Whether diabetes confers the same excess risk of cancer, overall and by site, in women and men is unknown. METHODS A systematic search was performed in PubMed for cohort studies published up to December 2016. Selected studies reported sex-specific relative risk (RR) estimates for the association between diabetes and cancer adjusted at least for age in both sexes. Random-effects meta-analyses with inverse-variance weighting were used to obtain pooled sex-specific RRs and women-to-men ratios of RRs (RRRs) for all-site and site-specific cancers. RESULTS Data on all-site cancer events (incident or fatal only) were available from 121 cohorts (19,239,302 individuals; 1,082,592 events). The pooled adjusted RR for all-site cancer associated with diabetes was 1.27 (95% CI 1.21, 1.32) in women and 1.19 (1.13, 1.25) in men. Women with diabetes had ~6% greater risk compared with men with diabetes (the pooled RRR was 1.06, 95% CI 1.03, 1.09). Corresponding pooled RRRs were 1.10 (1.07, 1.13) for all-site cancer incidence and 1.03 (0.99, 1.06) for all-site cancer mortality. Diabetes also conferred a significantly greater RR in women than men for oral, stomach and kidney cancer, and for leukaemia, but a lower RR for liver cancer. CONCLUSIONS/INTERPRETATION Diabetes is a risk factor for all-site cancer for both women and men, but the excess risk of cancer associated with diabetes is slightly greater for women than men. The direction and magnitude of sex differences varies by location of the cancer.
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Affiliation(s)
- Toshiaki Ohkuma
- The George Institute for Global Health, University of New South Wales, Level 10, King George V Building, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW, 2050, Australia.
| | - Sanne A E Peters
- The George Institute for Global Health, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, OX1 3QX, UK
| | - Mark Woodward
- The George Institute for Global Health, University of New South Wales, Level 10, King George V Building, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW, 2050, Australia.
- The George Institute for Global Health, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, OX1 3QX, UK.
- Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
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Update in global trends and aetiology of hepatocellular carcinoma. Contemp Oncol (Pozn) 2018; 22:141-150. [PMID: 30455585 PMCID: PMC6238087 DOI: 10.5114/wo.2018.78941] [Citation(s) in RCA: 148] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 08/25/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver responsible for an increasing number of cancer-related deaths, especially in developing economies of Asia and Africa. A plethora of risk factors have been described in the literature. Some of the important ones include chronic viral hepatitis, liver cirrhosis, environmental toxins such as aflatoxin, non-alcoholic fatty liver disease, lifestyle factors like alcohol consumption, smoking, and dietary factors, metabolic diseases like diabetes mellitus and obesity, and genetic and hereditary disorders. The development of HCC is complex involving sustained inflammatory damage leading to hepatocyte necrosis, regeneration, and fibrotic deposition. It also poses multiple challenges in diagnosis and treatment despite advances in diagnostic, surgical, and other therapeutic advancements. This is a narrative review of findings of multiple studies that were retrieved from electronic databases like PubMed, MEDLINE, Embase, Google Scholar, Scopus, and Cochrane. We summarise the current knowledge regarding the epidemiology and various risk factors for the development of HCC with a brief note on various prevention strategies.
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Yang S, Liu L, Luo Y, Chen M, Li N, Xu L, Wang Y, Lin Z, Li H, Qu S. Lower alpha fetoprotein and higher risk of hepatocellular carcinoma, study from the type 2 diabetes mellitus patients. Diabetes Res Clin Pract 2018; 143:239-244. [PMID: 30009939 DOI: 10.1016/j.diabres.2018.07.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 06/15/2018] [Accepted: 07/09/2018] [Indexed: 10/28/2022]
Abstract
AIMS To explore the association of type 2 diabetes mellitus (T2DM) with hepatocellular carcinoma (HCC) and alpha fetoprotein (AFP). METHODS 750 patients with T2DM (T2DM group), 800 healthy people (control group) and 501 patients newly diagnosed with HCC were recruited from 2010 to 2016. The HCC patients were further divided into a HCC with T2DM (HCC+DM) group and a HCC without diabetes mellitus (HCC+NDM) group. RESULTS The T2DM group had a 12.61% lower geometric mean AFP level than the healthy control group (2.08 vs. 2.38 μg/L, P < 0.001). Of 501 HCC patients, 230 (45.91%) had T2DM. When compared to the HCC+NDM group, the HCC+DM group had a higher negative rate of AFP (55.22% vs. 37.26%, P < 0.001), worse liver function (P = 0.011) and a 64.87% lower geometric mean AFP level (25.71 vs. 73.18 μg/L, P < 0.001). T2DM was significantly associated with the risk of high-grade (grade 3 and 4) HCC (OR = 2.02, 95% CI 1.18-3.44, P = 0.010). CONCLUSIONS T2DM was associated with lower AFP level, worse liver function and higher risk of high-grade HCC. We speculated that low AFP levels in diabetics might delay and interfere with HCC diagnosis, leading to higher degree of malignant HCC.
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Affiliation(s)
- Shaoling Yang
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Lu Liu
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yili Luo
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Ming Chen
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Nan Li
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Lu Xu
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yanru Wang
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Ziwei Lin
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Hong Li
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
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Sacerdote C, Ricceri F. Epidemiological dimensions of the association between type 2 diabetes and cancer: A review of observational studies. Diabetes Res Clin Pract 2018; 143:369-377. [PMID: 29596949 DOI: 10.1016/j.diabres.2018.03.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 02/27/2018] [Accepted: 03/01/2018] [Indexed: 12/15/2022]
Abstract
Type 2 diabetes (T2D) is a major cause of complications and death in many countries. The possible causal relation between T2D and cancer has been the aim of many research investigations. In view of the importance of the topic we carried out a narrative review of observational studies to summarize the available evidence of the association between T2D and cancer. To deal with the problem of abundance of published studies, we reviewed up to December 2017, the literature of meta-analyses of observational studies first, then we reviewed cohort studies not reported in meta-analyses because of more recent publication. We found that the association of T2D with risk of colorectal cancer was robust, whereas the evidence of the associations with other cancer sites was lower. Some of the observed associations could be overestimated, due to publication bias, unmeasured confounders (such as obesity) and surveillance bias. In conclusion a probable causal association of T2D with risk of colorectal cancer was confirmed. A possible causal association with pancreatic, endometrial, hepatocellular and gallbladder carcinoma was also found. Substantial uncertainty exists for other cancer sites.
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Affiliation(s)
- Carlotta Sacerdote
- Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy.
| | - Fulvio Ricceri
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy; Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco, Turin, Italy
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Simon TG, King LY, Chong DQ, Nguyen L, Ma Y, VoPham T, Giovannucci EL, Fuchs CS, Meyerhardt JA, Corey KE, Khalili H, Chung RT, Zhang X, Chan AT. Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: Results from two prospective cohort studies. Hepatology 2018; 67:1797-1806. [PMID: 29152763 PMCID: PMC5906170 DOI: 10.1002/hep.29660] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 11/04/2017] [Accepted: 11/13/2017] [Indexed: 12/31/2022]
Abstract
UNLABELLED Type 2 diabetes (T2D) is a risk factor for hepatocellular carcinoma (HCC). However, it is unknown whether T2D duration or additional metabolic comorbidities further contribute to HCC risk. From the Nurses' Health Study (NHS), 120,826 women were enrolled in 1980, and from the Health Professionals Follow-up Study (HPFS), 50,284 men were enrolled in 1986 and followed through 2012. Physician-diagnosed T2D was ascertained at baseline and updated biennially. Cox proportional hazards regression models were used to calculate age- and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident HCC. Over 32 years of follow-up (4,488,410 person-years), we documented 112 cases of HCC (69 women, 43 men). T2D was associated with an increased HCC risk (multivariable HR, 4.59; 95% CI, 2.98-7.07), as was an increasing T2D duration (Ptrend < 0.001). Compared to nondiabetics, the multivariable HRs for HCC were 2.96 (95% CI, 1.57-5.60) for 0-<2 years; 6.08 (95% CI, 2.96-12.50) for 2-<10 years; and 7.52 (95% CI, 3.88-14.58) for ≥10 years. Increasing number of metabolic comorbidities (T2D, obesity, hypertension, and dyslipidemia) was associated with increased HCC risk (Ptrend < 0.001); compared to individuals without metabolic comorbidity, those with four metabolic comorbidities had an 8.1-fold increased HCC risk (95% CI, 2.48-26.7). In T2D, neither insulin use nor oral hypoglycemic use was significantly associated with HCC risk (HR, 2.04 [95% CI, 0.69-6.09] and HR, 1.45 [95% CI, 0.69-3.07], respectively). CONCLUSION T2D is independently associated with increased risk for HCC in two prospective cohorts of U.S. men and women. This risk is enhanced with prolonged diabetes duration and with comorbid metabolic conditions, suggesting the importance of insulin resistance in the pathogenesis of HCC. (Hepatology 2018;67:1797-1806).
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Affiliation(s)
- Tracey G. Simon
- Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital,Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital,Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital
| | - Lindsay Y. King
- Division of Gastroenterology and Hepatology, Duke University, Durham NC
| | | | - Long Nguyen
- Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital,Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital,Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital
| | - Yanan Ma
- Harvard Medical School, Boston, MA,Department of Biostatistics and Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning, PR China,Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston MA
| | - Trang VoPham
- Harvard Medical School, Boston, MA,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA,Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston MA
| | - Edward L. Giovannucci
- Harvard Medical School, Boston, MA,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston MA,Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston MA
| | | | | | - Kathleen E. Corey
- Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital,Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital,Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital
| | - Hamed Khalili
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital,Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital
| | - Raymond T. Chung
- Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital,Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital,Harvard Medical School, Boston, MA
| | - Xuehong Zhang
- Harvard Medical School, Boston, MA,Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston MA
| | - Andrew T. Chan
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital,Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital,Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston MA
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40
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Fang HJ, Shan SB, Zhou YH, Zhong LY. Diabetes mellitus and the risk of gastrointestinal cancer in women compared with men: a meta-analysis of cohort studies. BMC Cancer 2018; 18:422. [PMID: 29661174 PMCID: PMC5902961 DOI: 10.1186/s12885-018-4351-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 04/08/2018] [Indexed: 02/06/2023] Open
Abstract
Background The increasing epidemic proportions of diabetes mellitus (DM) are a major cause of premature illness and death. However, whether DM confers the same excess risk of gastrointestinal cancer for women as it does for men remains controversial. The purpose of this study was to estimate the relation between DM and gastrointestinal cancer in women compared with men after accounting for other major risk factors based on cohort studies. Methods We performed a meta-analysis of cohort studies published through May 2017 from PubMed, Embase, and the Cochrane Library. Studies with cohort designs were stratified by sex and reported the relation between DM and esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), colon cancer (CC), rectal cancer (RC), hepatocellular carcinoma (HCC), or pancreatic cancer (PC) risk. The ratio of relative risk (RRR) between men and women was employed to measure the sex differences in the relation between DM and gastrointestinal cancer with a random effects model with inverse variance weighting. Results We included 38 cohort studies reporting data on 18,060,698 individuals. The pooled RRR indicated DM women was associated with an increased risk of GC (RRR: 1.14; 95%CI: 1.06–1.22; p < 0.001), while the risk of HCC was lower (RRR: 0.88; 95%CI: 0.79–0.99; p = 0.031) as compared with DM men. Further, there was no evidence of sex differences in the RRR between participants who had DM compared with those without DM for EC (p = 0.068), CRC (p = 0.618), and PC (p = 0.976). In addition, the pooled RRR showed a statistically significant association between DM and the risk of CC in women compared with men (RRR: 0.93; 95%CI: 0.86–1.00; p = 0.050), and there was no evidence of sex differences for RC among participants with DM compared to those without DM (p = 0.648). Finally, the sex differences of the comparison between DM and non-DM for gastrointestinal cancer risk at different sites were variable after stratification for different effect estimates. Conclusions The findings of this study suggested female-to-male RRR of DM was increased for GC, while reduced for HCC and CC. However, there were no sex differences for the relation between DM and the risk of EC, CRC, PC, and RC. Electronic supplementary material The online version of this article (10.1186/s12885-018-4351-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hong-Juan Fang
- Department of Endocrinology, Beijing Tiantan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China
| | - Shao-Bo Shan
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China
| | - Yu-Hao Zhou
- Department of Rehabilitation Institute, Seventh People's Hospital of Shanghai University of TCM, Datong road 358, Pudong District, Shanghai, 200137, China.
| | - Li-Yong Zhong
- Department of Endocrinology, Beijing Tiantan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China.
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41
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Chon YE, Jung KS, Kim MJ, Choi JY, An C, Park JY, Ahn SH, Kim BK, Kim SU, Park H, Hwang SK, Rim KS, Han KH, Kim DY. Predictors of failure to detect early hepatocellular carcinoma in patients with chronic hepatitis B who received regular surveillance. Aliment Pharmacol Ther 2018; 47:1201-1212. [PMID: 29492988 DOI: 10.1111/apt.14578] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 09/28/2017] [Accepted: 01/30/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND A proportion of chronic hepatitis B (CHB) patients are diagnosed with advanced hepatocellular carcinoma (HCC) despite regular surveillance. AIMS To determine predictors for HCC detection failure in CHB patients who underwent regular surveillance. METHODS CHB patients with well-preserved liver function, who underwent ultrasonography and alpha-foetoprotein (AFP) analysis every 6 months, were enrolled. Cox regression analysis was used to identify predictors for detection failure, defined as HCC initially diagnosed at Barcelona Clinic Liver Cancer (BCLC) stage B or C. RESULTS Of the 4590 CHB patients (mean age, 52.1 years; men, 61.6%), 169 patients were diagnosed with HCC (3.68%) and 35 (20.7%) HCC patients were initially diagnosed with HCC BCLC stage B or C. The cumulative incidence of HCC detection failure was 0.2% at year 1 and 1.3% at year 5. Multivariate analyses indicated that cirrhosis (hazard ratio [HR], 3.078; 95% CI, 1.389-6.821; P = 0.006), AFP levels ≥9 ng/mL (HR, 5.235; 95% CI, 2.307-11.957; P = 0.010), and diabetes mellitus (HR, 3.336; 95% CI, 1.341-8.296; P = 0.010) were independent predictors of HCC detection failure. Another model that incorporated liver stiffness (LS) values identified LS values ≥11.7 kPa (HR, 11.045; 95% CI, 2.066-59.037; P = 0.005) and AFP levels ≥9 ng/mL (HR, 4.802; 95% CI, 1.613-14.297; P = 0.005) as predictors of detection failure. CONCLUSIONS In CHB patients undergoing regular surveillance with ultrasonography and alpha-foetoprotein (AFP) analysis every 6 months, the HCC detection failure rate was not high (0.8% per person; 0.1% per test). However, careful attention should be paid in patients with advanced liver fibrosis (clinical cirrhosis or LS value >11.7 kPa), high AFP levels, or diabetes mellitus, who are prone to surveillance failure.
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Affiliation(s)
- Y E Chon
- Department of Internal Medicine, CHA Bundang Medical Center, Institute of Gastroenterology, CHA University, Seongnam, Korea.,CHA Bundang Liver Center, CHA Bundang Medical Center, Seongnam, Korea
| | - K S Jung
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - M-J Kim
- Department of Radiology, Yonsei University College of Medicine, Seoul, Korea
| | - J-Y Choi
- Department of Radiology, Yonsei University College of Medicine, Seoul, Korea
| | - C An
- Department of Radiology, Yonsei University College of Medicine, Seoul, Korea
| | - J Y Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - S H Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - B K Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - S U Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - H Park
- Department of Internal Medicine, CHA Bundang Medical Center, Institute of Gastroenterology, CHA University, Seongnam, Korea.,CHA Bundang Liver Center, CHA Bundang Medical Center, Seongnam, Korea
| | - S K Hwang
- Department of Internal Medicine, CHA Bundang Medical Center, Institute of Gastroenterology, CHA University, Seongnam, Korea.,CHA Bundang Liver Center, CHA Bundang Medical Center, Seongnam, Korea
| | - K S Rim
- Department of Internal Medicine, CHA Bundang Medical Center, Institute of Gastroenterology, CHA University, Seongnam, Korea.,CHA Bundang Liver Center, CHA Bundang Medical Center, Seongnam, Korea
| | - K-H Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - D Y Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
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42
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Should we undertake surveillance for HCC in patients with NAFLD? J Hepatol 2018; 68:326-334. [PMID: 29122695 DOI: 10.1016/j.jhep.2017.10.006] [Citation(s) in RCA: 127] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 10/07/2017] [Accepted: 10/10/2017] [Indexed: 02/07/2023]
Abstract
The pandemic of obesity and its related complications is rapidly changing the epidemiology of many types of cancer, including hepatocellular carcinoma (HCC). Non-alcoholic fatty liver disease (NAFLD) is becoming a major cause of HCC, with a steadily rising trend compared to viral or alcohol-induced chronic hepatitis. The much greater prevalence of the underlying liver disease in the general population and the chance of HCC occurrence in non-cirrhotic liver are the most worrisome aspects of HCC in NAFLD. Effective screening programmes are currently hampered by limited knowledge of the pathways of carcinogenesis and a lack of tools able to stratify the risk of HCC in the NAFLD population. Hence, poor surveillance has prevented the development of an adequate treatment for NAFLD-related HCC. Systemic and hepatic molecular mechanisms involved in hepatocarcinogenesis, as well as potential early markers of HCC are being extensively investigated. This review describes the current clinical impact of HCC in NAFLD and discusses the most important unmet needs for its effective management.
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43
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Metformin mediates resensitivity to 5-fluorouracil in hepatocellular carcinoma via the suppression of YAP. Oncotarget 2018; 7:46230-46241. [PMID: 27323827 PMCID: PMC5216793 DOI: 10.18632/oncotarget.10079] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 05/29/2016] [Indexed: 11/25/2022] Open
Abstract
Metformin plays an anti-proliferative role in tumor cells in many types of cancer. However, the correlation between metformin and sensitivity to chemotherapeutic agents in hepatocellular carcinoma (HCC) and the relevant mechanism are unclear. The present study showed that HCC patients with type 2 diabetes mellitus benefited from metformin administration, with a longer overall survival. Metformin resensitized Bel-7402/5-fluorouracil (Bel/Fu) cells to 5-fluorouracil (5-Fu) in vitro and in vivo, and the combination of metformin and 5-Fu inhibited cell proliferation, promoted cell apoptosis and induced G0/G1 cell cycle arrest in the Bel/Fu cells. Moreover, metformin repressed YAP by both decreasing the total protein expression and accelerating the phosphorylation of YAP. The inhibition of YAP subsequently promoted the expression of PTEN, and suppressed the Akt pathway. Therefore, the expression of P-gp and MRP1 was downregulated. Taken together, our findings suggested that metformin may increase sensitivity to chemotherapeutic agents by suppressing YAP in hepatocellular carcinoma.
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44
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Teng W, Hsieh YC, Lui KW, Chen WT, Hung CF, Huang CH, Chen YC, Jeng WJ, Lin CC, Lin CY, Lin SM, Sheen IS. Eradication of hepatitis C virus profoundly prolongs survival in hepatocellular carcinoma patients receiving transarterial chemoembolization. J Viral Hepat 2017. [PMID: 28643457 DOI: 10.1111/jvh.12745] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Adjuvant pegylated interferon plus ribavirin treatment (PegIFN/RBV) reduces recurrence and prolongs survival in early stage hepatocellular carcinoma (HCC) patients with chronic hepatitis C (CHC) infection receiving resection or ablation. However, the impact of antiviral therapy in intermediate and advanced stage of CHC-HCC patients is uncertain. This study aimed to investigate the impact PegIFN/RBV treatment on recurrence-free interval and survival in patients with HCC receiving transarterial chemoembolization (TACE). From 2010 to 2013, 274 CHC patients from a 1073 patient-based cohort composed of freshly diagnosed HCC and receiving TACE treatment the Chang Gung Memorial Hospital, Linkou Medical Center were recruited. Propensity score matching (PSM) (age, gender, AST to Platelet Ratio Index (APRI), tumour size, tumour number and Child-Turcotte-Pugh score) with the ratio 1:2 for patients with and without PegIFN/RBV treatment was performed. Statistics were performed with SPSS V.20 (IBM, USA). After matching, 153 patients were analysed and 27 patients (17.6%) achieved sustained virologic response (SVR). The 2-year cumulative overall survival rate and recurrence-free survival rate among patients with SVR, non-SVR, and untreated were 85.2% vs 58.3% vs 69.6% (P=.001) and 73.3% vs 53.8% vs 58.5% (P=.013). By Cox regression analysis, non-SVR, untreated, increase CTP score and nonresponder to TACE were independent factors related to mortality. The SVR achieved by PegIFN/RBV treatment markedly improves survival and reduces tumour recurrence in CHC-HCC patients receiving TACE treatment after complete response.
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Affiliation(s)
- W Teng
- Department of Gastroenterology & Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,College of Medicine, Chang Gung University, Gueishan, Taiwan
| | - Y-C Hsieh
- Department of Gastroenterology & Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan.,College of Medicine, Chang Gung University, Gueishan, Taiwan
| | - K-W Lui
- Department of Radiology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan.,College of Medicine, Chang Gung University, Gueishan, Taiwan
| | - W-T Chen
- Department of Gastroenterology & Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan.,College of Medicine, Chang Gung University, Gueishan, Taiwan
| | - C-F Hung
- Department of Radiology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan.,College of Medicine, Chang Gung University, Gueishan, Taiwan
| | - C-H Huang
- Department of Gastroenterology & Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan.,College of Medicine, Chang Gung University, Gueishan, Taiwan
| | - Y-C Chen
- Department of Gastroenterology & Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan.,College of Medicine, Chang Gung University, Gueishan, Taiwan
| | - W-J Jeng
- Department of Gastroenterology & Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,College of Medicine, Chang Gung University, Gueishan, Taiwan.,School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Gueishan, Taiwan
| | - C-C Lin
- Department of Gastroenterology & Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan.,College of Medicine, Chang Gung University, Gueishan, Taiwan
| | - C-Y Lin
- Department of Gastroenterology & Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan.,College of Medicine, Chang Gung University, Gueishan, Taiwan
| | - S-M Lin
- Department of Gastroenterology & Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan.,College of Medicine, Chang Gung University, Gueishan, Taiwan.,School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Gueishan, Taiwan
| | - I-S Sheen
- Department of Gastroenterology & Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan.,College of Medicine, Chang Gung University, Gueishan, Taiwan
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45
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Klein S, Dufour JF. Nonalcoholic fatty liver disease and hepatocellular carcinoma. Hepat Oncol 2017; 4:83-98. [PMID: 30191057 DOI: 10.2217/hep-2017-0013] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 08/22/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease is becoming more common globally. The incidence of HCC due to nonalcoholic steatohepatitis in comparison to other etiologies is increasing. This is due to the pandemic of obesity and diabetes mellitus, two important risk factors for HCC. HCC arising in this context occurs in about 40% of the cases in a liver which is not yet cirrhotic. This has implications regarding the population which should be enrolled in an HCC surveillance program and regarding the treatment options. Surgery is more frequently contemplated in patients with HCC and no cirrhosis. However, patients with nonalcoholic steatohepatitis-induced HCC have frequent co-morbidities which have to be taken into account when developing a management strategy. Interestingly, these patients are frequently on medications which have been suggested to decrease the risk to develop HCC.
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Affiliation(s)
- Stephanie Klein
- Department of Clinical Research, Hepatology, University of Bern, Bern, Switzerland.,University Clinic for Visceral Surgery & Medicine, Inselspital Bern, Bern, Switzerland.,Department of Clinical Research, Hepatology, University of Bern, Bern, Switzerland.,University Clinic for Visceral Surgery & Medicine, Inselspital Bern, Bern, Switzerland
| | - Jean-François Dufour
- Department of Clinical Research, Hepatology, University of Bern, Bern, Switzerland.,University Clinic for Visceral Surgery & Medicine, Inselspital Bern, Bern, Switzerland.,Department of Clinical Research, Hepatology, University of Bern, Bern, Switzerland.,University Clinic for Visceral Surgery & Medicine, Inselspital Bern, Bern, Switzerland
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46
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Shouhed D, Steggerda J, Burch M, Noureddin M. The role of bariatric surgery in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 2017; 11:797-811. [PMID: 28712339 DOI: 10.1080/17474124.2017.1355731] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects between 25% and 33% of the population, is more common in obese individuals, and is the most common cause of chronic liver disease in the United States. However, despite rising prevalence, effective treatments remain limited. Areas covered: We performed a literature search across multiple databases (Pubmed, Medline, etc.) to identify significant original research and review articles to provide an up-to-date and concise overview of disease pathogenesis and diagnostic evaluation and to expand on available treatment options with a specific focus on the potential role of bariatric surgery. Here we provide the most comprehensive review of bariatric surgery for the management of NAFLD, noting benefits from different procedures and multiple reports showing improvements in steatosis, inflammation and fibrosis over the duration of follow-up. Expert commentary: The morbidity of NAFLD is significant as it may become the most common indication for liver transplantation within the next 5 years. In addition to known benefits of weight loss and diabetes resolution, bariatric surgery has the potential to halt and reverse disease progression and future controlled trials should be performed to further define its benefit in the treatment of NAFLD in morbidly obese patients.
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Affiliation(s)
- Daniel Shouhed
- a Department of Surgery , Cedars-Sinai Medical Center , Los Angeles , CA , USA.,b Division of Bariatric Surgery , Cedars-Sinai Medical Center , Los Angeles , CA , USA
| | - Justin Steggerda
- a Department of Surgery , Cedars-Sinai Medical Center , Los Angeles , CA , USA
| | - Miguel Burch
- a Department of Surgery , Cedars-Sinai Medical Center , Los Angeles , CA , USA.,b Division of Bariatric Surgery , Cedars-Sinai Medical Center , Los Angeles , CA , USA
| | - Mazen Noureddin
- c Fatty Liver Disease Program, Division of Digestive and Liver Diseases, Department of Medicine , Comprehensive Transplant Center, Cedars-Sinai Medical Center , Los Angeles , CA , USA
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47
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Ye J, Zhang Z, Zhu L, Lu M, Li Y, Zhou J, Lu X, Du Q. Polaprezinc inhibits liver fibrosis and proliferation in hepatocellular carcinoma. Mol Med Rep 2017; 16:5523-5528. [PMID: 28849143 DOI: 10.3892/mmr.2017.7262] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 06/02/2017] [Indexed: 11/06/2022] Open
Abstract
Hepatic fibrosis is defined as a pathological process, and activation of hepatic stellate cells (HSCs) is believed to be the key event of liver fibrosis. Additionally, activated HSCs may participate in the formation of the tumor microenvironment. Polaprezinc, a protector of the gastric mucosa, has been recently demonstrated to be an inhibitor of liver fibrosis in a mouse model. Proliferation and colony formation assays were performed to determine the inhibitory effects of polaprezinc on the growth of LX‑2 and hepG2 cells. A migration assay was used to evaluate the change in mobility of LX‑2 cells and quantitative polymerase chain reaction was performed to detect the expression levels of key markers of fibrosis. Finally, a gene chip assay for polaprezinc‑treated hepG2 cells was performed to evaluate the effect of polaprezinc on the hepG2 gene expression profile. The proliferation assay indicated that polaprezinc may inhibit the LX‑2 cell proliferation and the migration assays confirmed the inhibition of mobility. The expression levels of fibrotic markers such as collagen I, fibronectin and α‑smooth muscle actin were downregulated following polaprezinc treatment. The proliferation activity of polaprezinc‑treated hepG2 cells was reduced and the gene chip assay indicated that series of gene expression changes associated with cancer migration, cell skeletal organization and proliferation had occurred. In conclusion, polaprezinc treatment mayinhibit the proliferation of hepatocellular carcinoma cells and reverse liver fibrosis by deactivating HSCs. The present findings suggest that polaprezinc provides a novel treatment for patients with gastritis complicated with cirrhosis.
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Affiliation(s)
- Jun Ye
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Zhengsen Zhang
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Liang Zhu
- Department of Laboratory Construction and Management, Hangzhou Normal University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Minfang Lu
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Yan Li
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Jingjing Zhou
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Xinliang Lu
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Qin Du
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
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Mantovani A, Targher G. Type 2 diabetes mellitus and risk of hepatocellular carcinoma: spotlight on nonalcoholic fatty liver disease. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:270. [PMID: 28758096 DOI: 10.21037/atm.2017.04.41] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The incidence of both type 2 diabetes mellitus (T2DM) and multiple cancer types are rapidly increasing worldwide. Several studies documented that T2DM is closely associated with an increased incidence of cancer. However, while some methodological considerations preclude a definitive association between T2DM and the risk of certain cancers, the relationship between T2DM and increased risk of incident hepatocellular carcinoma (HCC) remains significant even after adjustment for detection bias and reverse causation, indicating that such association is clinically reliable and robust. In addition, a number of observational studies also showed that T2DM is associated with higher mortality among persons with HCC. Some recent meta-analyses suggested that treatment with metformin may be associated with a lower risk of HCC, and may also beneficially influence HCC prognosis, whereas treatment with sulphonylureas or insulin seems to be related to a higher HCC risk. The underlying biological mechanisms linking T2DM and HCC are complex and difficult to elucidate, but the existence of close inter-connections among T2DM, obesity and nonalcoholic fatty liver disease (NAFLD) induces hepatic/systemic insulin resistance and causes the release of multiple pro-inflammatory cytokines, vasoactive factors and pro-oxidant molecules, which are all potentially implicated in the development and progression of HCC. In this clinical review, we discuss the epidemiological evidence linking T2DM to the risk of HCC. Moreover, we also briefly discuss the putative underlying mechanisms linking T2DM, NAFLD and HCC, and the potential effect of certain hypoglycemic agents on the risk of developing HCC.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism Disease, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism Disease, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
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49
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Cao Y, Wang RH. Associations among Metabolism, Circadian Rhythm and Age-Associated Diseases. Aging Dis 2017; 8:314-333. [PMID: 28580187 PMCID: PMC5440111 DOI: 10.14336/ad.2016.1101] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 11/01/2016] [Indexed: 12/12/2022] Open
Abstract
Accumulating epidemiological studies have implicated a strong link between age associated metabolic diseases and cancer, though direct and irrefutable evidence is missing. In this review, we discuss the connection between Warburg effects and tumorigenesis, as well as adaptive responses to environment such as circadian rhythms on molecular pathways involved in metabolism. We also review the central role of the sirtuin family of proteins in physiological modulation of cellular processes and age-associated metabolic diseases. We also provide a macroscopic view of how the circadian rhythm affects metabolism and may be involved in cell metabolism reprogramming and cancer pathogenesis. The aberrations in metabolism and the circadian system may lead to age-associated diseases directly or through intermediates. These intermediates may be either mutated or reprogrammed, thus becoming responsible for chromatin modification and oncogene transcription. Integration of circadian rhythm and metabolic reprogramming in the holistic understanding of metabolic diseases and cancer may provide additional insights into human diseases.
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Affiliation(s)
- Yiwei Cao
- Faculty of Health Science, University of Macau, Macau, China
| | - Rui-Hong Wang
- Faculty of Health Science, University of Macau, Macau, China
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50
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Abstract
PURPOSE OF REVIEW This review aims to assess the epidemiological evidence for a link between type 2 diabetes and hepatocellular carcinoma and to investigate possible pathophysiological mechanisms. RECENT FINDINGS The presence of type 2 diabetes significantly increases the risk of developing hepatocellular carcinoma, and treatment with metformin may be associated with a lower risk. Treatment with insulin and sulphonylureas may be associated with increased risk. The pathophysiology underlying development of hepatocellular carcinoma in this context is complex and is likely to involve increased proinflammatory mediators, oxidative stress, JNK-1 activation, increased IGF-1 activity, altered gut microbiota and immunomodulation. Hepatocellular carcinoma incidence is increasing and this is likely to be linked to the increasing incidence of type 2 diabetes, obesity and the metabolic syndrome. These conditions increase the risk of developing hepatocellular carcinoma, and a greater understanding of the underlying pathophysiology may help with the development of novel treatments.
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Affiliation(s)
- P Wainwright
- Clinical Biochemistry, University Hospital Southampton, Southampton, UK.
- Chemical Pathology and Metabolic Medicine, Department of Laboratory Medicine, D-Level Pathology Block, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD, UK.
| | - E Scorletti
- Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK
- National Institute for Health Research Southampton Biomedical Research Center (in Nutrition) and Respiratory Biomedical Research Unit, University of Southampton and University Hospital Southampton National Health Service (NHS) Foundation Trust, Southampton, UK
| | - C D Byrne
- Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK
- National Institute for Health Research Southampton Biomedical Research Center (in Nutrition) and Respiratory Biomedical Research Unit, University of Southampton and University Hospital Southampton National Health Service (NHS) Foundation Trust, Southampton, UK
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