Higher Mortality Among Lean Patients With Non-alcoholic Fatty Liver Disease Despite Fewer Metabolic comorbidities

Karn Wijarnpreecha; Fang Li; Sori K. Lundin; Deepika Suresh; Michael W. Song; Cui Tao; Vincent L. Chen; Anna S. F. Lok

Aliment Pharmacol Ther. 2023;57(9):1014-1027.

Abstract and Introduction

Abstract

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) can develop in individuals who are not overweight. Whether lean persons with NAFLD have lower mortality and lower incidence of cirrhosis, cardiovascular diseases (CVD), diabetes mellitus (DM) and cancer than overweight/obese persons with NAFLD remains inconclusive. We compared mortality and incidence of cirrhosis, CVD, DM and cancer between lean versus non-lean persons with NAFLD.

Methods: This is a retrospective study of adults with NAFLD in a single centre from 2012 to 2021. Primary outcomes were mortality and new diagnosis of cirrhosis, CVD, DM and cancer. Outcomes were modelled using competing risk analysis and Cox proportional hazards regression analysis.

Results: A total of 18,594 and 13,420 patients were identified for cross-sectional and longitudinal analysis respectively: approximately 11% lean, 25% overweight, 28% class 1 obesity and 35% class 2–3 obesity. The median age was 51.0 years, 54.6% were women. The median follow-up was 49.3 months. Lean patients had lower prevalence of metabolic diseases at baseline and lower incidence of cirrhosis and DM than non-lean patients and no difference in CVD, any cancer or obesity-related cancer during follow-up. However, lean patients had significantly higher mortality with incidence per 1000 person-years of 16.67, 10.11, 7.37 and 8.99, respectively, in lean, overweight, obesity class 1 and obesity class 2–3 groups respectively.

Conclusions: Lean patients with NAFLD had higher mortality despite lower incidence of cirrhosis and DM, and similar incidence of CVD and cancer and merit similar if not more attention as non-lean patients with NAFLD.

Introduction

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, affecting 25% of the population worldwide, and its clinical burden is expected to rise.^[1] NAFLD is strongly associated with obesity and its comorbidities but can also develop in individuals who are not overweight ('lean NAFLD').^[2] The prevalence of NAFLD among lean individuals in the general population is 10%–20% with most studies reported from Asian countries, and the highest prevalence reported in Mexico (37%).^[3–6]

NAFLD is associated with a wide spectrum of extrahepatic diseases, such as cardiovascular diseases (CVD), metabolic diseases (diabetes mellitus [DM], hypertension, dyslipidaemia), chronic kidney diseases (CKD) or cancers.^[7,8] Several cross-sectional studies have evaluated prevalence of hepatic and extra-hepatic diseases among lean versus obese individuals with NAFLD. A cross-sectional analysis of the TARGET-NASH study cohort with 3386 NAFLD patients in the United States found a lower prevalence of cirrhosis, DM and CVD in lean individuals compared to overweight/obese individuals.^[2] Another study from Austria with 4091 NAFLD participants had similar findings with lower prevalence of metabolic diseases (DM, metabolic syndrome, hypertension, dyslipidaemia) and lower Framingham risk score for CVD but no significant difference in prevalence of coronary artery disease in lean patients compared with overweight/obese patients.^[9] By contrast, a recent Korean study with 4786 NAFLD patients found higher atherosclerotic CVD scores among lean persons.^[10] However, cross-sectional studies can only show an association but not a cause–effect relationship.

Data on the impact of baseline body mass index (BMI) on the incidence of outcomes such as cirrhosis, CVD, cancers and mortality among patients with NAFLD are limited. One longitudinal study on the natural history of NAFLD in lean subjects included 1090 U.S. participants with biopsy-proven NAFLD followed for a mean of 133 ± 81.3 months demonstrated an increased overall mortality in lean patients compared to non-lean patients despite lower prevalence of metabolic diseases and advanced fibrosis.^[11] A retrospective cohort study from the Olmsted county database with 4834 NAFLD patients with the median follow-up of 6.4 years showed similar findings with higher overall mortality in the lean persons and no significant differences in risk of cirrhosis, hepatic decompensation, CVD events or malignancy between lean and obese persons.^[12] Finally, a recent multi-centre study from Western countries with 1339 participants with biopsy-proven NAFLD with the median follow-up of 94 months, demonstrated a lower prevalence of non-alcoholic steatohepatitis (NASH), advanced fibrosis and DM among lean versus obese individuals but no significant differences in overall mortality or incidence of liver-related events between lean versus non-lean participants.^[5] Notably, the criteria for inclusion and the definition of outcomes in these published studies were not uniform. Given these inconsistencies, we conducted a comprehensive evaluation of multiple outcomes in a large cohort of patients with NAFLD with the aim to compare the mortality and incidence of cirrhosis, CVD, DM and cancers between lean versus overweight and obese individuals with NAFLD.

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Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Baseline characteristics, laboratory values and prevalence of diseases among 18,594 patients with NAFLD ^a.
Characteristics	Lean (n = 2137)	Non-lean (n = 16,457)			p value (lean vs. non-lean)
Characteristics	Lean (n = 2137)	Overweight (n = 4692)	Obesity class 1 (n = 5234)	Obesity class 2–3 (n = 6531)	p value (lean vs. non-lean)
Age, years	51.0 (36, 63)	52.5 (41, 63)	52.0 (40, 61)	48.0 (37, 58)	0.70
Sex (male, %)	881 (41.2%)	2574 (54.9%)	2761 (52.8%)	2551 (39.1%)	<0.0001
Race, %					0.89
Asian	106 (5.0%)	375 (8.0%)	270 (5.2%)	161 (2.5%)
African American	178 (8.3%)	323 (6.9%)	410 (7.8%)	664 (10.2%)
Caucasian	1724 (80.7%)	3661 (78.0%)	4227 (80.8%)	5305 (81.2%)
Other/Unknown	129 (6.0%)	333 (7.1%)	327 (6.3%)	401 (6.1%)
Smoking, %					<0.0001
Never	1475 (69.0%)	3283 (70.0%)	3580 (68.4%)	4508 (69.0%)
Former	376 (17.6%)	1016 (21.7%)	1181 (22.6%)	1420 (21.7%)
Current	286 (13.4%)	393 (8.4%)	473 (9.0%)	603 (9.2%)
ALT (U/L)	27 (18, 49)	36 (24, 59)	39 (26, 62)	38 (25, 61)	<0.0001
AST (U/L)	28 (22, 44)	30 (23, 42)	31 (24, 43)	30 (23, 44)	<0.0001
Platelet (K/μL)	239 (192, 291)	236 (195, 283)	239 (197, 286) &	251 (206, 299)	0.01
HbA1c (%)	5.8 (5.4, 6.7)	5.8 (5.5, 6.5)	5.9 (5.5, 6.7)	6.1 (5.6, 7.2)	<0.0001
Total cholesterol (mg/dL)	173 (143, 210)	184 (155, 213)	180 (150, 212)	176 (148, 206)	0.003
HDL (mg/dL)	51 (38, 66)	45 (38, 55)	43 (36, 52)	42 (36, 50)	<0.0001
LDL (mg/dL)	91 (66, 116)	101 (76, 125)	99 (75, 123)	95 (72, 119)	<0.0001
Triglyceride (mg/dL)	125 (88, 189)	153 (107, 226)	163 (115, 240)	164 (119, 240)	<0.0001
Cirrhosis	27 (1.3%)	61 (1.3%)	77 (1.5%)	165 (2.5%)	0.07
Cardiovascular diseases
Coronary artery disease	206 (9.6%)	562 (12.0%)	607 (11.6%)	660 (10.1%)	0.04
Congestive heart failure	73 (3.4%)	158 (3.4%)	195 (3.7%)	268 (4.1%)	0.45
Cerebrovascular accident	135 (6.3%)	243 (5.2%)	266 (5.1%)	279 (4.3%)	0.003
Peripheral arterial disease	124 (5.8%)	249 (5.3%)	283 (5.4%)	267 (4.1%)	0.07
Any cardiovascular disease	370 (17.3%)	855 (18.2%)	965 (18.4%)	1099 (16.8%)	0.65
Metabolic diseases
Diabetes mellitus	288 (13.5%)	828 (17.7%)	1138 (21.7%)	1972 (30.2%)	<0.0001
Hypertension	608 (28.5%)	1689 (36.0%)	2187 (41.8%)	3042 (46.6%)	<0.0001
Dyslipidaemia	473 (22.1%)	1626 (34.7%)	1928 (36.8%)	2195 (33.6%)	<0.0001
Any metabolic disease	845 (39.5%)	2467 (52.6%)	2995 (57.2%)	3933 (60.2%)	<0.0001
CKD (stage 3–5)	261 (12.3%)	754 (16.3%)	867 (16.7%)	953 (14.7%)	<0.0001

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CKD, chronic kidney disease; HbA1c, haemoglobin A1c; HDL, high-density lipoprotein; IQR, interquartile range; LDL, low-density lipoprotein.
^aData are expressed as median (interquartile range) for continuous variables or number (percentage) for categorical variables.

Table 2. Logistic regression analysis of factors associated with the prevalence of cardiovascular disease, cirrhosis and chronic kidney disease.
BMI category	Any cardiovascular disease		Coronary artery disease		Peripheral artery disease		Cerebrovascular accident		Congestive heart failure		Cirrhosis		Chronic kidney disease stage ≥3
BMI category	OR (95% CI)^a	p value	OR (95% CI)	p value	OR (95% CI)	p value	OR (95% CI)	p value	OR (95% CI)	p value	OR (95% CI)	p value	OR (95% CI)	p value
Lean	Referent		Referent		Referent		Referent		Referent		Referent		Referent
Overweight	0.88 (0.75–1.02)	0.08	0.91 (0.75–1.12)	0.38	0.73 (0.58–0.93)	0.01	0.68 (0.54–0.86)	0.001	0.76 (0.56–1.02)	0.07	0.96 (0.61–1.55)	0.87	1.09 (0.92–1.28)	0.34
Obesity class 1	0.75 (0.65–0.88)	<0.001	0.77 (0.63–0.94)	0.009	0.70 (0.56–0.89)	0.003	0.61 (0.48–0.77)	<0.001	0.76 (0.57–1.02)	0.06	1.04 (0.67–1.66)	0.86	1.13 (0.96–1.34)	0.14
Obesity class 2–3	0.77 (0.66–0.89)	<0.001	0.72 (0.59–0.87)	<0.001	0.58 (0.46–0.74)	<0.001	0.51 (0.40–0.64)	<0.001	0.88 (0.66–1.17)	0.36	1.66 (1.11–2.58)	0.02	1.22 (1.03–1.44)	0.02

Abbreviations: CI, confidence interval; OR, odds ratio.
^aOR was adjusted for age, sex, race, smoking status, type 2 diabetes, alcohol consumption, hypertension, dyslipidaemia and use of aspirin and statin.

Table 3. Competing risk analysis for death and incidence of diseases by BMI category ^a.
Weight category	Death^b		Any cardiovascular diseases		Cirrhosis		Liver-related events		Type 2 diabetes Mellitus^c		Obesity-related cancer		Any cancer
Weight category	HR (95% CI)	p value	HR (95% CI)	p value	HR (95% CI)	p value	HR (95% CI)	p value	HR (95% CI)	p value	HR (95% CI)	p value	HR (95% CI)	p value
Lean	Referent		Referent		Referent		Referent		Referent		Referent		Referent
Overweight	0.54 (0.42–0.69)	<0.001	1.40 (1.00–1.95)	0.051	1.53 (0.81–2.88)	0.19	1.08 (0.42–2.78)	0.88	1.22 (0.87–1.71)	0.25	0.87 (0.53–1.42)	0.58	0.76 (0.56–1.02)	0.07
Obesity class 1	0.40 (0.31–0.52)	<0.001	1.08 (0.77–1.50)	0.66	1.50 (0.80–2.81)	0.20	0.77 (0.30–2.01)	0.60	1.78 (1.29–2.45)	<0.001	0.97 (0.60–1.56)	0.90	0.75 (0.56–1.00)	0.049
Obesity class 2–3	0.52 (0.41–0.66)	<0.001	1.27 (0.91–1.76)	0.15	2.19 (1.20–4.01)	0.011	1.15 (0.48–2.76)	0.76	2.85 (2.08–3.91)	<0.001	1.02 (0.64–1.62)	0.93	0.78 (0.59–1.04)	0.09

Abbreviations: CI, confidence interval; HR, hazard ratio.
^aHR was adjusted for age, sex, race, smoking status, alcohol consumption, type 2 diabetes mellitus, hypertension, dyslipidaemia and use of aspirin and statin.
^bCox proportional hazards model was performed for death analysis.
^cFor type 2 diabetes mellitus, HR was adjusted with the same confounders^a excluding type 2 diabetes mellitus.

Table 4. Causes of death of all deceased patients in each BMI group.
Causes of death	Total (n = 616)	Lean (n = 111)	Non-lean (n = 505)			p value (lean vs. non-lean)
Causes of death	Total (n = 616)	Lean (n = 111)	Overweight (n = 162)	Obesity 1 (n = 136)	Obesity 2–3 (n = 207)	p value (lean vs. non-lean)
Overall death	616/13,420 (4.6%)	111/1454 (7.6%)	162/3373 (4.8%)	136/3830 (3.6%)	207/4763 (4.3%)	<0.0001
Cardiovascular diseases	190 (30.8%)	29 (26.1%)	46 (28.4%)	45 (33.1%)	70 (33.8%)	0.24
Neoplasms	103 (16.7%)	14 (12.6%)	31 (19.1%)	21 (15.4%)	37 (17.9%)	0.20
Digestive and liver cancers	33 (5.4%)	3 (2.7%)	7 (4.3%)	12 (8.8%)	11 (5.3%)	0.17
Other neoplasms^a	70 (11.3%)	11 (9.9%)	24 (14.8%)	9 (6.6%)	26 (12.6%)	0.59
Respiratory diseases	75 (12.2%)	17 (15.3%)	15 (9.3%)	18 (13.2%)	25 (12.1%)	0.26
Digestive diseases	48 (7.8%)	11 (9.9%)	13 (8.0%)	8 (5.9%)	16 (7.7%)	0.36
Liver diseases	33 (5.4%)	8 (7.2%)	8 (4.9%)	6 (4.4%)	11 (5.3%)	0.34
Digestive diseases other than liver diseases	15 (2.4%)	3 (2.7%)	5 (3.1%)	2 (1.5%)	5 (2.4%)	0.84
External cause^b	45 (7.3%)	6 (5.4%)	19 (11.7%)	12 (8.8%)	8 (3.9%)	0.40
Mental-neurological diseases	40 (6.5%)	9 (8.1%)	13 (8.0%)	8 (5.9%)	10 (4.8%)	0.45
Metabolic diseases^c	36 (5.8%)	9 (8.1%)	6 (3.7%)	6 (4.4%)	15 (7.3%)	0.26
Diabetes mellitus	7 (1.1%)	0 (0.0%)	2 (1.2%)	1 (0.7%)	4 (1.9%)	0.22
Infectious diseases	27 (4.4%)	6 (5.4%)	8 (4.9%)	3 (2.2%)	10 (4.8%)	0.56
Genitourinary diseases	25 (4.1%)	1 (0.9%)	4 (2.5%)	9 (6.62%)	11 (5.3%)	0.06
Musculoskeletal and connective tissue diseases	9 (1.5%)	3 (2.7%)	2 (1.2%)	3 (2.2%)	1 (1.5%)	0.23
Other^d	18 (2.9%)	6 (5.4%)	5 (3.1%)	3 (2.2%)	4 (1.9%)	0.09

Note: The cause of death was categorised based on the ICD-10-CM codes.
^aOther neoplasms refer to neoplasms that are other than digestive cancers, mainly including (1) C15-C26 Malignant neoplasms of digestive organs; (2) C30-C39 Malignant neoplasms of respiratory and intrathoracic organs; (3) C50-C50 Malignant neoplasms of breast; (4) C69-C72 Malignant neoplasms of eye, brain and other parts of central nervous system; (5) C81-C96 Malignant neoplasms of lymphoid, haematopoietic and related tissue; (6) D10-D36 Benign neoplasms, except benign neuroendocrine tumours and (7) D37-D48 Neoplasms of uncertain behaviour, polycythaemia vera and myelodysplastic syndromes.
^bExternal cause comprises (1) S00-T88 Injury, poisoning and certain other consequences of external causes and (2) V00-Y99 External causes of morbidity.
^cMetabolic diseases refer to E00-E89 Endocrine, nutritional and metabolic diseases.
^dOther includes (1) D50-D89 Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism; (2) Q00-Q99 Congenital malformations, deformations and chromosomal abnormalities and (3) R263 unknown.

Authors and Disclosures

Karn Wijarnpreecha^1,2, Fang Li³, Sori K. Lundin⁴, Deepika Suresh⁵, Michael W. Song⁵, Cui Tao³, Vincent L. Chen¹ and Anna S. F. Lok¹

¹Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA
²Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine, Phoenix, Arizona, USA
³School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas, USA
⁴School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA
⁵Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA

Correspondence
Vincent L. Chen and Anna S. F. Lok, Division of Gastroenterology and Hepatology, University of Michigan, 3912 Taubman Center, 1500 E. Medical Center Dr., SPC 5362, Ann Arbor, MI 48109-5362, USA. Email: vichen@med.umich.edu and aslok@med.umich.edu

Author Contributions
Karn Wijarnpreecha: Conceptualization (lead); data curation (lead); formal analysis (lead); investigation (lead); methodology (lead); software (lead); validation (lead); writing – original draft (lead); writing – review and editing (lead). Fang Li: Data curation (lead); formal analysis (lead); methodology (supporting); software (lead); validation (lead); writing – original draft (supporting); writing – review and editing (supporting). Sori K. Lundin: Data curation (supporting); formal analysis (lead); software (supporting); validation (supporting). Deepika Suresh: Data curation (supporting); investigation (supporting); resources (supporting); validation (lead). Michael W. Song: Data curation (supporting); investigation (supporting); resources (supporting); validation (lead). Cui Tao: Data curation (supporting); formal analysis (supporting); methodology (supporting); project administration (supporting); software (supporting); validation (supporting). Vincent Lingzhi Chen: Conceptualization (lead); data curation (lead); formal analysis (equal); funding acquisition (lead); investigation (lead); methodology (lead); software (supporting); supervision (lead); validation (lead); visualization (lead); writing – review and editing (lead). Anna S. Lok: Conceptualization (lead); investigation (lead); methodology (lead); project administration (lead); resources (lead); supervision (lead); validation (lead); visualization (lead); writing – review and editing (lead). All authors approved the final version of the article, including the authorship list.

Conflict of Interest Statement
Vincent Chen receives research grant funding from KOWA and Astra Zeneca. Anna Lok receives research grant funding from KOWA, Astra Zeneca and TARGET, and serves on Data and Safety Monitoring Board for Novo Nordisk.