Cause-specific mortality among adults with histologically-confirmed NAFLD* and matched population comparators
| Cause of death, N. | Population comparators | Nafld* | P for trend† | ||||
| All NAFLD | Simple steatosis | NASH without fibrosis | Non-cirrhotic fibrosis | Cirrhosis | |||
| Cancer‡ | 3776 | 1343 | 992 | 131 | 158 | 62 | -- |
| Incidence rate§, per 1000 PY (95% CI) | 4.8 (4.6 to 5.0) | 9.3 (8.8 to 9.8) | 9.2 (8.7 to 9.8) | 8.7 (7.3 to 10.3) | 9.3 (7.9 to 10.8) | 11.3 (8.8 to 14.3) | -- |
| Incidence rate difference§ (95% CI) | 0 (ref.) | 4.5 (3.9 to 5.0) | 4.4 (3.8 to 5.0) | 3.9 (2.4 to 5.4) | 4.5 (3.0 to 5.9) | 6.5 (3.7 to 9.3) | -- |
| 20-Year absolute risk difference§ (95% CI) | 1 (ref.) | 7.1 (6.0 to 8.2) | 7.1 (5.9 to 8.4) | 6.3 (3.0 to 9.6) | 7.9 (4.3 to 11.5) | 10.4 (3.5 to 17.2) | -- |
| Multivariable-adjusted HR¶ (95% CI) | 1 (ref.) | 2.16 (2.03 to 2.30) | 2.17 (2.01 to 2.34) | 2.08 (1.70 to 2.55) | 2.26 (1.87 to 2.73) | 2.12 (1.58 to 2.84) | 0.09 |
| Cardiovascular disease | 5439 | 1199 | 823 | 145 | 148 | 83 | -- |
| Incidence rate§, per 1000 PY (95% CI) | 6.9 (6.7 to 7.1) | 8.3 (7.8 to 8.7) | 7.6 (7.1 to 8.2) | 9.6 (8.2 to 11.3) | 8.7 (7.4 to 10.1) | 15.1 (12.2 to 18.5) | -- |
| Incidence rate difference§ (95% CI) | 0 (ref.) | 1.4 (0.9 to 1.9) | 0.7 (0.2 to 1.3) | 2.7 (1.2 to 4.3) | 1.8 (0.4 to 3.2) | 8.2 (5.0 to 11.5) | -- |
| 20-Year absolute risk difference§ (95% CI) | 1 (ref.) | 2.4 (1.2 to 3.5) | 0.8 (−0.4 to 2.1) | 5.2 (1.4 to 9.1) | 5.7 (1.7 to 9.8) | 16.9 (7.6 to 26.1) | -- |
| Multivariable-adjusted HR¶ (95% CI) | 1 (ref.) | 1.35 (1.26 to 1.44) | 1.25 (1.16 to 1.35) | 1.66 (1.38 to 2.01) | 1.40 (1.17 to 1.69) | 2.11 (1.63 to 2.73) | <0.01 |
| Cirrhosis‡ | 121 | 413 | 147 | 47 | 96 | 123 | -- |
| Incidence rate§, per 1000 PY (95% CI) | 0.2 (0.1 to 0.2) | 2.8 (2.6 to 3.1) | 1.4 (1.2 to 1.6) | 3.1 (2.4 to 4.1) | 5.6 (4.6 to 6.8) | 22.4 (18.8 to 26.5) | -- |
| Incidence rate difference§ (95% CI) | 0 (ref.) | 2.7 (2.4 to 2.8) | 1.2 (1.0 to 1.4) | 3.0 (2.1 to 3.9) | 5.5 (4.4 to 6.6) | 22.3 (18.3 to 26.2) | -- |
| 20-Year absolute risk difference§ (95% CI) | 1 (ref.) | 5.1 (4.5 to 5.7) | 2.4 (1.9 to 2.9) | 5.7 (3.7 to 7.7) | 9.2 (6.9 to 11.5) | 32.8 (24.6 to 41.1) | -- |
| Multivariable-adjusted HR¶ (95% CI) | 1 (ref.) | 18.15 (14.78 to 22.30) | 9.29 (7.09 to 12.18) | 28.29 (13.77 to 58.12) | 26.03 (16.08 to 42.12) | 166.25 (67.45 to 409.77) | <0.01 |
| Hepatocellular carcinoma‡ | 96 | 186 | 88 | 22 | 45 | 31 | -- |
| Incidence rate§, per 1000 PY (95% CI) | 0.1 (0.1 to 0.2) | 1.3 (1.1 to 1.5) | 0.8 (0.7 to 1.0) | 1.5 (1.0 to 2.1) | 2.6 (2.0 to 3.5) | 5.7 (4.0 to 7.8) | -- |
| Incidence rate difference§ (95% CI) | 0 (ref.) | 1.2 (1.0 to 1.3) | 0.7 (0.5 to 0.9) | 1.3 (0.7 to to 2.0) | 2.5 (1.8 to 3.3) | 5.5 (3.5 to 7.5) | -- |
| 20-Year absolute risk difference§ (95% CI) | 1 (ref.) | 2.2 (1.8 to 2.6) | 1.2 (0.9 to 1.6) | 3.0 (1.2 to 4.7) | 5.3 (3.2 to 7.3) | 12.3 (6.4 to 18.2) | -- |
| Multivariable-adjusted HR¶ (95% CI) | 1 (ref.) | 11.12 (8.65 to 14.30) | 7.13 (5.18 to 9.83) | 18.16 (7.9 to 41.6) | 32.67 (15.15 to 70.45) | 30.92 (14.30 to 66.87) | <0.01 |
| Other causes | 3685 | 1008 | 650 | 116 | 157 | 85 | -- |
| Incidence rate§, per 1000 PY (95% CI) | 4.7 (4.5 to 4.8) | 6.9 (6.5 to 7.4) | 6.0 (5.6 to 6.5) | 7.7 (6.4 to 9.2) | 9.2 (7.9 to 10.7) | 15.5 (12.5 to 18.9) | -- |
| Incidence rate difference§ (95% CI) | 0 (ref.) | 2.3 (1.8 to 2.7) | 1.4 (0.9 to 1.9) | 3.0 (1.6 to 4.4) | 4.5 (3.1 to 6.0) | 10.8 (7.5 to 14.1) | -- |
| 20-Year absolute risk difference§ (95% CI) | 1 (ref.) | 4.8 (3.8 to 5.9) | 2.8 (1.7 to 4.0) | 6.9 (3.3 to 10.5) | 11.1 (6.9 to 15.2) | 20.0 (11.1 to 29.0) | -- |
| Multivariable-adjusted HR¶ (95% CI) | 1 (ref.) | 1.75 (1.63 to 1.87) | 1.55 (1.42 to 1.69) | 2.06 (1.67 to 2.55) | 2.28 (1.89 to 2.76) | 2.91 (2.25 to 3.78) | <0.01 |
20-Year absolute risks and risk differences (percentage points) were calculated based on Kaplan-Meier estimates.
*NAFLD was defined from liver histology, as outlined in the Methods and supplemental methods. The analyses of cause-specific mortality contain fewer subjects than the analyses of all-cause mortality, because the end of follow-up for the Cause of Death Register was 31 December 2016.
†P for linear trend was estimated across NAFLD histology categories (modelled continuously), compared with population comparators; for details, see Methods.
‡Because HCC-specific mortality was assessed separately, cancer-specific mortality included deaths from all cancers except HCC; similarly, cirrhosis-specific mortality encompassed deaths from all non-HCC related complications of chronic liver disease (online supplemental eMethods).
§Incidence rate differences per 1000 PY. CIs for incidence rates and absolute rate differences were approximated by the normal distribution.
¶The multivariable model accounted for the covariates outlined in the footnotes to table 2.
HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; ; PY, person years.