Cancer Risk in Patients With Biopsy‐Confirmed Nonalcoholic Fatty Liver Disease: A Population‐Based Cohort Study
Open accessAbstract
Background and Aims: Recent studies link NAFLD to an increased incidence of HCC and extrahepatic cancers. However, earlier studies were small or lacked liver histology, which remains the gold standard for staging NAFLD severity. Approach and Results: We conducted a population‐based cohort study of all adults with histologically defined NAFLD in Sweden from 1966 to 2016 (N = 8,892). NAFLD was defined from prospectively recorded liver histopathology submitted to all 28 Swedish pathology departments and categorized as simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis. NAFLD patients were individually matched to ≤5 general population controls without NAFLD by age, sex, calendar year, and county (N = 39,907). Using Cox proportional hazards modeling, we calculated multivariable adjusted HRs (aHRs) and 95% CIs. Over a median of 13.8 years, we documented 1,691 incident cancers among NAFLD patients and 6,733 among controls. Compared with controls, NAFLD patients had significantly increased overall cancer incidence (10.9 vs. 13.8 per 1,000 person‐years [PYs]; difference = 2.9 per 1,000 PYs; aHR, 1.27 [95% CI, 1.18‐1.36]), driven primarily by HCC (difference = 1.1 per 1,000 PYs; aHR, 17.08 [95% CI, 11.56‐25.25]). HCC incidence rates increased monotonically across categories of simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis (0.8 per 1,000 PYs, 1.2 per 1,000 PYs, 2.3 per 1,000 PYs, and 6.2 per 1,000 PYs, respectively; P trend < 0.01) and were further amplified by diabetes (1.2 per 1,000 PYs, 2.9 per 1,000 PYs, 7.2 per 1,000 PYs, and 15.7 per 1,000 PYs, respectively). In contrast, NAFLD was associated with modestly increased rates of pancreatic cancer, kidney/bladder cancer, and melanoma (differences = 0.2 per 1,000 PYs, 0.1 per 1,000 PYs, and 0.2 per 1,000 PYs, respectively), but no other cancers. Conclusions: Compared with controls, patients with biopsy‐proven NAFLD had significantly increased cancer incidence, attributable primarily to HCC, whereas the contribution of extrahepatic cancers was modest. Although HCC risk was highest with cirrhosis, substantial excess risk was also found with noncirrhotic fibrosis and comorbid diabetes.
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Cancer-related mortality is among the leading causes of mortality in NAFLD patients, mainly driven by extrahepatic malignancies followed by hepatocellular carcinoma.
“cancer‐related mortality is among the leading causes of mortality in NAFLD patients, mainly driven by extrahepatic malignancies followed by hepatocellular carcinoma [23, 24].”
From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [23]
The introductory passage (indexed under Abstract; page unavailable) says mortality from both extrahepatic cancers and HCC has increased among patients with NAFLD. It does not establish that cancer is a leading cause of death or that extrahepatic malignancies account for more cancer deaths than HCC. The Discussion addresses cancer incidence, not that mortality ranking. (LLM, conf=0.82)
Experimental — accuracy not yet measuredT2D is associated with poor outcomes in individuals with biopsy-proven MASH and compensated cirrhosis, including a 4-fold increased risk of death and an approximately 2-fold increased risk of liver-related outcomes including HCC over a median follow-up of 5 years.
“T2D is also associated with poor outcomes in individuals with biopsy-proven MASH and compensated cirrhosis, including a 4-fold increased risk of death and an approximately 2-fold increased risk of liver-related outcomes, including HCC, over a median follow-up of 5 years.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [54]
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Experimental — accuracy not yet measuredIn a study of histologically confirmed MASLD in Sweden, the overall HCC rate varied with advancing stage of MASLD: 0.8 in simple steatosis, 1.2 in MASH without fibrosis, 2.3 in fibrosis F1-F3 without cirrhosis, and 6.2 in cirrhosis per 1,000 person-years.
“In a study of histologically con fi rmed MASLD in Sweden, the overall HCC rate varied with the advancing stage of MASLD (per 1,000 PY): 0.8 in simple steatosis, 1.2 in MASH without fi brosis, 2.3 in fi brosis (F1-F3) without cirrhosis, and 6.2 in cirrhosis. 54”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [54]
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- Authors
- Simon, T. G., Roelstraete, B., Sharma, R., Khalili, H., Hagström, H., & Ludvigsson, J. F.
- Affiliations
- Harvard University (US)
- Department of Medical Epidemiology and Biostatistics,Karolinska Institute,Stockholm,Sweden
- Columbia University Irving Medical Center (US)
- Karolinska University Hospital (SE)
- University of Nottingham (GB)
- Corresponding author
- Ludvigsson, Jonas F.
- Venue
- Hepatology
- Published
- 2021-08-25
- Volume
- 74
- Issue
- 5
- Pages
- 2410-2423
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC10367111
- OpenAlex
- W3149682645
- Cited by
- 176
- References
- 51
- Citations by year
- 2026: 24 · 2025: 24 · 2024: 38 · 2023: 44 · 2022: 29 · 2021: 16
- FWCI
- 23.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Crohn's and Colitis Foundation of America
- Harvard University
- Harvard University Center for AIDS Research
- Dana-Farber/Harvard Cancer Center
- Crohn's and Colitis Foundation
- Karolinska Institutet
- National Institutes of Health
- Center for AIDS Research, University of Washington
- National Institute of Diabetes and Digestive and Kidney Diseases (K23DK122104)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- non-alcoholic fatty liver disease, cancer risk, hepatocellular carcinoma, extrahepatic cancer, liver histopathology, NAFLD severity, liver cirrhosis, simple steatosis, diabetes mellitus, cancer incidence, liver cancer screening
- MeSH terms
- Adult, Aged, Aged, 80 and over, Biopsy, Female, Follow-Up Studies, Carcinoma, Hepatocellular, Humans, Liver, Liver Cirrhosis, Liver Neoplasms, Male, Middle Aged, Prospective Studies, Risk Factors, Sweden, Incidence, Diabetes Complications, Non-alcoholic Fatty Liver Disease
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