The Association Between Diabetes and Hepatocellular Carcinoma: A Systematic Review of Epidemiologic Evidence

doi:10.1016/j.cgh.2005.12.007

Clinical Gastroenterology and Hepatology

Volume 4, Issue 3, March 2006, Pages 369-380

https://doi.org/10.1016/j.cgh.2005.12.007 Get rights and content

Background & Aims: We conducted a systematic review and a meta-analysis to estimate the magnitude and determinants of association between diabetes and hepatocellular carcinoma (HCC). Methods: MEDLINE searches were conducted for published full studies (between January 1966 and February 2005) that provided risk estimates and met criteria concerning the definition of exposure and outcomes. Two investigators independently performed standardized search and data abstraction. Unadjusted and adjusted odds ratios for individual outcomes were obtained or calculated for each study and were synthesized using a random-effects model. Results: A total of 26 studies met our inclusion and exclusion criteria. Among 13 case-control studies, diabetes was associated significantly with HCC in 9 studies (pooled odds ratio, 2.5; 95% confidence interval, 1.8–3.5). Among 13 cohort studies, diabetes was associated significantly with HCC in 7 studies (pooled risk ratio, 2.5; 95% confidence interval, 1.9–3.2). The results were relatively consistent in different populations, different geographic locations, and a variety of control groups. The significant association between HCC and diabetes was independent of alcohol use or viral hepatitis in the 10 studies that examined these factors. Few studies adjusted for diet and obesity. Conclusions: Diabetes is associated with an increased risk for HCC. However, more research is required to examine issues related to the duration and treatment of diabetes, and confounding by diet and obesity.

Section snippets

Literature Search

We searched MEDLINE for studies published in English from January 1966 through February 2005. The search strategy included “diabetes AND (hepatocellular carcinoma OR HCC OR liver cancer) AND (risk OR odds OR incidence).” A hand search of cited bibliographies also was performed. Only fully published articles were considered.

Study Selection Criteria

We searched for analytic epidemiologic studies (cross-sectional, case-control, or cohort study design) that examined the association between diabetes and HCC. We excluded

Case-Control Studies

Thirteen case-control studies met the inclusion and exclusion criteria of the review.13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 The characteristics of these studies are shown in Table 1. Five studies were from the United States, 2 from Greece, 2 from Italy, 1 from the United Kingdom, and 3 studies were from the same single-district hospital in Japan. Diabetes was defined based on in-person or mailed questionnaires in 10 studies and based on chart review or diagnostic codes in 3 studies.

Discussion

This systematic review of published epidemiologic studies indicates that type 2 diabetes is associated with an approximately 2.5-fold increase in the risk for HCC. The risk estimate from 13 case-control studies indicates a statistically significant 2.5-fold increased odds of diabetes among patients with HCC compared with controls without diabetes. Similarly, the pooled estimates from 13 cohort studies indicate a statistically significant 2.5-fold increase in HCC incidence among patients with

References (41)

L.A. Adams et al.
The natural history of nonalcoholic fatty liver diseasea population-based cohort study
Gastroenterology
(2005)
L.A. Adams et al.
The histological course of nonalcoholic fatty liver diseasea longitudinal study of 103 patients with sequential liver biopsies
J Hepatol
(2005)
Z.M. Younossi et al.
Nonalcoholic fatty liver disease in patients with type 2 diabetes
Clin Gastroenterol Hepatol
(2004)
H.P. Cotrim et al.
Nonalcoholic steatohepatitis and hepatocellular carcinomanatural history?
Am J Gastroenterol
(2000)
E. Bugianesi et al.
Expanding the natural history of nonalcoholic steatohepatitisfrom cryptogenic cirrhosis to hepatocellular carcinoma
Gastroenterology
(2002)
C. Braga et al.
Attributable risks for hepatocellular carcinoma in northern Italy
Eur J Cancer
(1997)
H.B. El-Serag et al.
The role of diabetes in hepatocellular carcinomaa case-control study among United States Veterans
Am J Gastroenterol
(2001)
M.M. Hassan et al.
Risk factors for hepatocellular carcinomasynergism of alcohol with viral hepatitis and diabetes mellitus
Hepatology
(2002)
H.B. El-Serag et al.
Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma
Gastroenterology
(2004)
M. Ragozzino et al.
Subsequent cancer risk in the incidence cohort of Rochester, Minnesota, residents with diabetes mellitus
J Chronic Dis
(1982)

G. Marchesini et al.

Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome

Hepatology

(2003)

H.B. El-Serag et al.

Rising incidence of hepatocellular carcinoma in the United States

N Engl J Med

(1999)

H.B. El-Serag et al.

Risk factors for the rising rates of primary liver cancer in the United States

Arch Intern Med

(2000)

A.M. Di Bisceglie

Hepatitis C and hepatocellular carcinoma

Semin Liver Dis

(1995)

P. Angulo et al.

Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis

Hepatology

(1999)

I.R. Wanless et al.

Fatty liver hepatitis (steatohepatitis) and obesityan autopsy study with analysis of risk factors

Hepatology

(1990)

Y. Zen et al.

Hepatocellular carcinoma arising in non-alcoholic steatohepatitis

Pathol Int

(2001)

J.M. Regimbeau et al.

Obesity and diabetes as a risk factor for hepatocellular carcinoma

Liver Transpl

(2004)

J. Davila et al.

Diabetes and the risk of hepatocellular carcinomaa population-based case-control study

Gut

(2005)

K. Fukuda et al.

A hospital-based case-control study on hepatocellular carcinoma in Fukuoka and Saga Prefectures, northern Kyushu, Japan

Jpn J Cancer Res

(1993)

Cited by (718)

Nonalcoholic steatohepatitis: A comprehensive updated review of risk factors, symptoms, and treatment
2024, Heliyon
Non-alcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease and a progressive and chronic liver disorder with a significant risk for the development of liver-related morbidity and mortality. The complex and multifaceted pathophysiology of NASH makes its management challenging. Early identification of symptoms and management of patients through lifestyle modification is essential to prevent the development of advanced liver disease. Despite the increasing prevalence of NASH, there is no FDA-approved treatment for this disease. Currently, medications targeting metabolic disease risk factors and some antifibrotic medications are used for NASH patients but are not sufficiently effective. The beneficial effects of different drugs and phytochemicals represent new avenues for the development of safer and more effective treatments for NASH. In this review, different risk factors, clinical symptoms, diagnostic methods of NASH, and current treatment strategies for the management of patients with NASH are reviewed.
AKR1B1 drives hyperglycemia-induced metabolic reprogramming in MASLD-associated hepatocellular carcinoma
2024, JHEP Reports
The mechanism behind the progressive pathological alteration in metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH)-associated hepatocellular carcinoma (HCC) is poorly understood. In the present study, we investigated the role of the polyol pathway enzyme AKR1B1 in metabolic switching associated with MASLD/MASH and in the progression of HCC.
AKR1B1 expression was estimated in the tissue and plasma of patients with MASLD/MASH, HCC, and HCC with diabetes mellitus. The role of AKR1B1 in metabolic switching in vitro was assessed through media conditioning, lentiviral transfection, and pharmacological probes. A proteomic and metabolomic approach was applied for the in-depth investigation of metabolic pathways. Preclinically, mice were subjected to a high-fructose diet and diethylnitrosamine to investigate the role of AKR1B1 in the hyperglycemia-mediated metabolic switching characteristic of MASLD-HCC.
A significant increase in the expression of AKR1B1 was observed in tissue and plasma samples from patients with MASLD/MASH, HCC, and HCC with diabetes mellitus compared to normal samples. Mechanistically, in vitro assays revealed that AKR1B1 modulates the Warburg effect, mitochondrial dynamics, the tricarboxylic acid cycle, and lipogenesis to promote hyperglycemia-mediated MASLD and cancer progression. A pathological increase in the expression of AKR1B1 was observed in experimental MASLD-HCC, and expression was positively correlated with high blood glucose levels. High-fructose diet + diethylnitrosamine-treated animals also exhibited statistically significant elevation of metabolic markers and carcinogenesis markers. AKR1B1 inhibition with epalrestat or NARI-29 inhibited cellular metabolism in in vitro and in vivo models.
Pathological AKR1B1 modulates hepatic metabolism to promote MASLD-associated hepatocarcinogenesis. Aldose reductase inhibition modulates the glycolytic pathway to prevent precancerous hepatocyte formation.
This research work highlights AKR1B1 as a druggable target in metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC), which could provide the basis for the development of new chemotherapeutic agents. Moreover, our results indicate the potential of plasma AKR1B1 levels as a prognostic marker and diagnostic test for MASLD and associated HCC. Additionally, a major observation in this study was that AKR1B1 is associated with the promotion of the Warburg effect in HCC.
Altered expression of activated induced hepatocellular carcinoma markers (HCCmk) in murine model treated with Portulaca oleraceae L.
2023, South African Journal of Botany
Hepatocellular carcinoma (HCC) is a wan prognosis and is highly resistant to cancer therapy, pushing the search for safe drugs as an essential issue. Plant-based bioproducts may reduce the negative side effects of cancer treatment. By the present study, we evaluated the ability of a defatted methanol and hexane extracts from Portulaca oleracea to regulate HCC in an animal model. The anticancer activity of Portulaca oleraceae L. (PO) extract was evaluated against HepG2 cell line where IC₅₀ was 241.79 µg/ml for PO MeOH extract and 122.19 µg/ml for PO Hex extract. Overall, treatment with DEN+ PO Hex 200 mg/kg shows 100% survival rate. Furthermore, it improved the preservation of hepatocyte architecture in animals with small hepatocyte alterations but interspersed with foci of hepatocyte apoptosis as well as liver enzymes ALP (11.77±4.02 IU/L), AST (114.15±11.79 IU/L), ALT (22.11±2.66 IU/L) and TBILR (0.4±0.20 IU/L). The relative expression of serum TNF-α was significantly up-regulated in DEN induced HCC mice to reach (322.44±11.2) compared to normal mice (0.07±0.02). Besides the TNF-α in DEN/ PO groups were significantly down-regulated to be (73.98±2.7), so the relative expression level of tumor markers BCl-2 and AFP. In addition, apoptotic markers BAX and Cas-8 were significantly increased in DEN/ P. oleracea treated mice. Chemical profiling of methanol and hexan extracts using GC–MS and HPLC analysis revealed that 9,12,15 octadecatrienoic acid, (2-phenyl-1,3-dioxolan-4-yl) methyl ester, mesitylene, 2-Hydroxy-3-[(9E)-9-octadec-enoylox] propyl(9E) octadecenoate, and 2-(phenymethylene) octanal are the major compounds that were identified by GC_MS analysis of PO Hex extract. While, HPLC clarified the presence of pyrogallol, Syringenic acid, Caffeic acid, P-coumaric acid and Cinnamic acid as major phenolic compounds besides Catechin, Luteolin, and rutin as major flavonoid compounds in PO MeOH extract. Taken together, these results provide the first visualization of the action effects of several compounds in PO and represent potential anti HCC therapy.
The impact of diabetes status on total and site-specific cancer risk in the elderly population: A nationwide cohort study
2023, Diabetes Research and Clinical Practice
We aimed to evaluate the association of prediabetes, diabetes, and diabetes duration with risk of total and site-specific cancer in the Korean population aged 65 years and above.
This study included 1,232,173 subjects aged ≥ 65 years who underwent a general health screening program. Diabetes status was categorized as normal glucose tolerance, impaired fasting glucose, new-onset diabetes, diabetes duration of < 5 years, and diabetes duration of ≥ 5 years. Cox proportional hazards models were used to investigate the association of diabetes status with cancer risk.
The risk of total cancer increased as diabetes status worsened, as did the risks of liver, biliary, and pancreatic cancer. Risks of liver, biliary, and pancreatic cancer were significantly higher in subjects aged 65–74 years than in those aged ≥ 75 years. The relationship of diabetes status with overall cancer incidence was found to significantly interact with sex. Among subjects with diabetes, the risks of liver and lung cancer were significantly higher in men than in women regardless of diabetes duration.
Diabetes status is associated with increased risk of cancer in the elderly. There are age and sex differences in the risk of total and site-specific cancers, including liver, biliary, and pancreatic cancer. This study highlights the importance of cancer screening for elderly subjects with diabetes.
EASL Clinical Practice Guidelines on hepatitis delta virus
2023, Journal of Hepatology
Hepatitis D virus (HDV) is a defective virus that requires the hepatitis B virus to complete its life cycle and cause liver damage in humans. HDV is responsible for rare acute and chronic liver diseases and is considered the most aggressive hepatitis virus. Acute infection can cause acute liver failure, while persistent infection typically causes a severe form of chronic hepatitis which is associated with rapid and frequent progression to cirrhosis and its end-stage complications, hepatic decompensation and hepatocellular carcinoma. Major diagnostic and therapeutic innovations prompted the EASL Governing Board to commission specific Clinical Practice Guidelines on the identification, virologic and clinical characterisation, prognostic assessment, and appropriate clinical and therapeutic management of HDV-infected individuals.
Tumours and Tumour-Like Lesions
2023, MacSween's Pathology of the Liver, Eighth Edition
This chapter presents a comprehensive approach to primary liver tumours as per the World Health Organization Classification of Liver Tumours 2019. The discussions include clinical features, aetiology and treatment summaries, as well as detailed gross pathology, histopathology and the use of up-to-date immunohistochemistry and molecular pathology in the diagnosis. Cytopathologic features, emphasizing fine-needle aspiration diagnosis, are also included. Numerous detailed tables and photographs of liver lesions highlight important diagnostic features. The immunohistochemical approach to aid in the identification of metastatic versus primary liver tumours is also discussed.

View all citing articles on Scopus

View full text

Original articleThe Association Between Diabetes and Hepatocellular Carcinoma: A Systematic Review of Epidemiologic Evidence

Section snippets

Literature Search

Study Selection Criteria

Case-Control Studies

Discussion

Gastroenterology

J Hepatol

Clin Gastroenterol Hepatol

Am J Gastroenterol

Gastroenterology

Eur J Cancer

Am J Gastroenterol

Hepatology

Gastroenterology

J Chronic Dis

Hepatology

Rising incidence of hepatocellular carcinoma in the United States

N Engl J Med

Risk factors for the rising rates of primary liver cancer in the United States

Arch Intern Med

Hepatitis C and hepatocellular carcinoma

Semin Liver Dis

Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis

Hepatology

Fatty liver hepatitis (steatohepatitis) and obesityan autopsy study with analysis of risk factors

Hepatology

Hepatocellular carcinoma arising in non-alcoholic steatohepatitis

Pathol Int

Obesity and diabetes as a risk factor for hepatocellular carcinoma

Liver Transpl

Diabetes and the risk of hepatocellular carcinomaa population-based case-control study

Gut

A hospital-based case-control study on hepatocellular carcinoma in Fukuoka and Saga Prefectures, northern Kyushu, Japan

Jpn J Cancer Res

Original article
The Association Between Diabetes and Hepatocellular Carcinoma: A Systematic Review of Epidemiologic Evidence