Table 1.

Human studies on per- and polyfluorinated chemicals and biomarkers or outcomes of liver injury included for systematic review.

Reference	Populationa	Year of exposure assessment	Exposure assessmentb	Year of outcome assessment	Outcomec	Confounding	Results
								Attanasio67,169	NHANES adolescents (USA) $n=$ 353 (M), 305 (F)	2013–2016	Geometric mean (SE) PFOAd $1.50\left(0.06\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (M), $1.22\left(0.06\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (F); PFOSd $3.68\left(0.12\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (M), $2.76\left(0.14\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (F); PFNAd $0.58\left(0.03\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (M), $0.49\left(0.03\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (F); PFHxSd $1.31\left(0.09\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (M), $0.88\left(0.06\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (F)	Same as exposure	ALT (U/L),d GGT (U/L),d AST (U/L)d	Adjusted for age, race/ethnicity, weight category, poverty–income ratio, tobacco exposure, and education.	Males: PFOA and PFNA were associated with lower ALT. PFNA was associated with lower AST. There was no association between any PFAS and GGT. Females: PFOA and PFNA were associated with higher ALT. PFOA, PFOS, and PFNA were associated with higher AST. PFOA and PFOS were associated with higher GGT.
Bassler et al.68	C8 Health Study adults (USA) $n=$200	2006	Mean (SE) PFOAd $94.6\left(183.6\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFOSd $26.9\left(16.7\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFNAd $1.6\left(0.7\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFHxSd $4.2\left(3.9\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$	Same as exposure	CK18 (U/mL)d	Adjusted for e-GFR, alcohol consumption category, BMI, age, and sex.	CK18-M30 and CK18-M65 were positively associated with PFOA, PFNA, and PFHxS, and there was a positive trend with PFOS.
Darrow et al.39	C8 Health Study adults (USA) $n=$28,047	1951–2006 (cumulative); 2005–2006 (cross-sectional)	PFOA (modeled cumulative exposure) Median PFOAd $16.5\text{\hspace{0.17em}ng}/\mathrm{mL}$	2005–2006 (enzymes); 2008–2011 (liver disease)	Liver disease (enlarged liver, fatty liver, or cirrhosis), ALT (U/L),d GGT (U/L)d	Adjusted for age, sex, BMI, alcohol consumption, regular exercise, smoking status, education, insulin resistance, fasting status, history of working at DuPont plant, and race.	Cross-sectional PFOA and longitudinal (estimated) PFOA were positively associated with ALT. There was no relationship between PFOA and liver disease.
Emmett et al.69	Residents (adults and children) of Little Hocking (USA) $n=$371	Not Specified	Median (IQR) PFOA $354\left(181–571\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$	Same as exposure	Liver disease, ALT (U/L), GGT (U/L), AST (U/L)	No adjustment for covariates.	No linear association between PFOA and ALT, GGT, or AST. Having abnormal AST levels was associated with lower PFOA. There was no relationship between liver disease and PFOA.
Gilliland et al.165	Male employees of PFOA plant Adults (USA) $n=$115	1985–1989	Mean (range) Total fluorine 3.3 (0– $26\text{\hspace{0.17em}ppm}$) (surrogate for PFOA)	Same as exposure	ALT (IU/dL), AST (IU/dL), GGT (IU/dL)	Age, cigarette use, alcohol use, and BMI	Total serum fluorine was not associated with ALT, AST, or GGT. ALT, AST, and GGT levels did not differ by level of fluorine exposure. There was a significant interaction between serum fluorine and BMI: There was a positive association between serum fluorine and both ALT and AST in people with obesity.
Gallo et al.70	C8 Health Study adults (USA) $n=$46,452	2005–2006	Median (IQR) PFOAd $28.0\left(13.5–70.8\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFOSd $20.3\left(13.7–29.4\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$	Same as exposure	ALT (U/L),d GGT (U/L)d	Adjusted for alcohol consumption, socioeconomic status, fasting status, race, month of blood sample collection, age, sex, smoking, BMI, physical activity, and insulin resistance.	PFOA and PFOS were positively associated with ALT.
Gleason et al.40	NHANES adults and adolescents (USA) $n=$4,333	2007–2010	Median (IQR) PFOAd $3.7\left(2.5–5.2\right)\mathrm{\mu }\mathrm{g}/\mathrm{L}$; PFOSd $11.3\left(7.0–18.0\right)\mathrm{\mu }\mathrm{g}/\mathrm{L}$; PFNAd $1.4\left(1.0–2.1\right)\mathrm{\mu }\mathrm{g}/\mathrm{L}$; PFHxSd $1.8\left(1.0–3.1\right)\mathrm{\mu }\mathrm{g}/\mathrm{L}$	Same as exposure	ALT (U/L),d GGT (U/L),d AST (U/L)d	Adjusted for age, sex, race/ethnicity, BMI, poverty, smoking, and alcohol consumption.	PFHxS, PFOA, and PFNA were positively associated with ALT. PFOA and PFNA were positively associated with GGT. PFHxS was positively associated with AST.
Jain71	NHANES adults (USA) $n=$9,523	2003–2014	PFOA (ng/mL)e; PFOS (ng/mL)e	Same as exposure	ALT (U/L),e GGT (U/L),e AST (U/L)e	Adjusted for sex, race/ethnicity, smoking status, age, BMI, diabetes status, hypertension status, fasting time, poverty–income ratio, survey year, and alcohol consumption.	PFOA and PFOS were inconsistently associated with ALT, GGT, and AST when stratified by glomerular function stage and obesity status.
Jain and Ducatman72	NHANES adults (USA) $n=$2,883	2011–2014	Geometric mean (95% CI) PFOAe $2.2\left(2.0–2.3\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (non-obese); $2.0\left(1.8–2.1\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (obese); PFOSe $6.3\left(5.8–6.8\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (non-obese); $5.5\left(5.0–6.0\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (obese); PFNAe $0.83\left(0.76–0.89\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (non-obese); $0.73\left(0.68–0.79\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (obese); PFHxSe $1.41\left(1.29–1.54\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (non-obese); $1.24\left(1.13–1.37\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$ (obese)	Same as exposure	ALT (U/L),e GGT (U/L),e AST (U/L)e	Adjusted for sex, race/ethnicity, age, age-squared, poverty–income ratio, physical activity, BMI, and serum cotinine.	Positive associations between PFOA, PFHxS, and PFNA and ALT were observed in participants with obesity. In those with obesity, PFOA and PFNA were also positively associated with GGT. Additional PFAS: PFDA was not found to be associated with liver enzymes.
Jin et al.73	Children with NAFLD (USA) $n=$74	2007–2015	Median (IQR) PFOA $3.42\left(1.65\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFOS $3.59\left(4.46\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFHxS $1.53\left(3.17\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$	Same as exposure	Histological severity of NAFLD	—	Higher PFOS, PFOA, and PFHxS concentrations were associated with more severe NAFLD (NASH, fibrosis, lobular/portal inflammation, NAFLD activity score).
Khalil et al.74	Dayton Obese Cohort children (USA) $n=$48	2016	Median (IQR) PFOA $0.99\left(0.45\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFOS $2.79\left(2.10\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFNA $0.24\left(0.15\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFHxS $1.09\left(1.41\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$	Same as exposure	ALT (U/L), AST (U/L)	Adjusted for age, sex, race, and multiple testing.	There were no significant relationships between PFAS and ALT or AST.
Lin et al.75	NHANES adults (USA) $n=$2,216	1999–2003	Mean (SE) PFOAe $4.51\left(1.04\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFOSe $24.60\left(1.04\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFNAe $0.79\left(1.07\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFHxSe $1.98\left(1.04\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$	Same as exposure	ALT (U/L), GGT (U/L)e	Adjusted for age, sex, race/ethnicity, smoking, alcohol consumption, education level, BMI, HOMR-IR, metabolic syndrome, iron saturation status.	PFOA was positively associated with ALT and GGT, with a stronger effect in those with obesity.
Mora et al.76	Project Viva children (USA) $n=$508 (longitudinal); 630 (cross-sectional)	1999–2002 (longitudinal); 2007–2010 (cross-sectional)	Median (IQR) Longitudinal: PFOA (maternal) $5.4\left(3.9–7.6\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFOS (maternal) $24.6\left(17.9–34\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFNA (maternal) $0.6\left(0.5–0.9\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFHxS (maternal) $2.4\left(1.6–3.8\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; Cross-sectional: PFOA (child) $4.3\left(3.0–7.0\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFOS (child) $6.2\left(4.2–9.7\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFNA (child) $1.5\left(1.1–2.3\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFHxS (child) $1.9\left(1.2–3.4\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$	2007–2010 (longitudinal, cross-sectional)	ALT (U/L)	Longitudinal: Adjusted for maternal education, prenatal smoking, gestational age at blood draw, sex, race/ethnicity, and age at ALT measurements. Cross-Sectional: Adjusted for maternal education, prenatal smoking, sex, race/ethnicity, and age.	There was an inverse but not statistically significant inverse relationship between maternal PFOS, PFOA, and PFHxS exposure and ALT in girls. Higher childhood PFOA and PFOS concentrations were associated with lower ALT. Additional PFAS: Maternal EtFOSAA and MeFOSAA were not associated with liver enzymes.
Mundt et al.35	Employees at a chemical manufacturer (USA) $n=$592	1976–2003	High, low, no exposure PFNA	1989–2003	ALT (U/L), GGT (U/L), AST (U/L)	Adjusted for age and BMI.	PFNA exposure was not associated with mean ALT, GGT, or AST.
Nian et al.41	Adult residents of Shenyang, China $n=$1,605	2015–2016	Median (IQR) PFOA $6.19\left(4.08–9.31\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFOS $24.22\left(14.62–37.19\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFNA $1.96\left(1.11–3.07\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFHxS $0.73\left(0.01–2.68\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$	Same as exposure	ALT (U/L),d GGT (U/L),d AST (U/L)d	Adjusted for age, sex, career, income, education, alcohol consumption, smoking, giblet/seafood consumption, physical activity, and BMI.	PFOA, PFOS, and PFNA were positively associated with ALT. There were also positive associations between PFOA and AST and GGT. Additional PFAS: PFDA was positively associated with ALT.
Olsen et al.36	Male employees at two fluorochemical manufacturers (Antwerp, Belgium, and Decatur, Alabama) $n=$178 (1995); 149 (1997)	1995, 1997	Mean PFOS $1.93\text{\hspace{0.17em}ppm}$ (Antwerp, 1995); $2.44\text{\hspace{0.17em}ppm}$ (Decatur, 1995); $1.48\text{\hspace{0.17em}ppm}$ (Antwerp, 1997); $1.96\text{\hspace{0.17em}ppm}$ (Decatur, 1997)	Same as exposure	ALT (U/L), GGT (U/L), AST (U/L)	Adjusted for age, BMI, alcohol use, and smoking.	PFOS exposure was not associated with ALT, GGT, or AST.
Olsen et al.37	Employees at two fluorochemical manufacturers (Antwerp, Belgium, and Decatur, Alabama) $n=$263 (Decatur), 255 (Antwerp), 174 (longitudinal)	1994–2000 (longitudinal); 2000 (cross-sectional)	Geometric mean (95% CI): PFOA $0.33\left(0.27–0.40\right)\text{\hspace{0.17em}ppm}$ (Antwerp); $1.13\left(0.99–1.30\right)\text{\hspace{0.17em}ppm}$ (Decatur); PFOS $0.44\left(0.38–0.51\right)\text{\hspace{0.17em}ppm}$ (Antwerp); $0.91\left(0.82–1.02\right)\text{\hspace{0.17em}ppm}$ (Decatur)	2000	ALT (U/L), GGT (U/L), AST (U/L)	Adjusted for age, BMI, alcohol use, smoking, and location.	Those in the highest quartile of PFOS exposure had higher mean ALT. PFOS was not associated with increased odds of elevated ALT or GGT. There were no associations between PFOS or PFOA and liver enzymes in the longitudinal analysis.
Olsen and Zobel38	Male employees at three fluorochemical manufacturers (Antwerp, Belgium; Decatur, Alabama; Cottage Grove, Minnesota) $n=$196 (Antwerp), 188 (Decatur), 122 (Cottage Grove)	2000	Mean (SD) PFOAd $1.02\left(1.06\right)\mathrm{\mu }\mathrm{g}/\mathrm{mL}$ (Antwerp); $1.89\left(1.61\right)\mathrm{\mu }\mathrm{g}/\mathrm{mL}$ (Decatur); $4.63\left(12.53\right)\mathrm{\mu }\mathrm{g}/\mathrm{mL}$ (Cottage Grove)	Same as exposure	ALT (U/L),d GGT (U/L),d AST (U/L)d	Adjusted for age, BMI, and alcohol use.	There were no significant linear associations between PFOA and ALT, GGT, or AST, or between PFOA and elevated liver enzymes.
Rantakokko et al.77	Kupio Obesity Surgery Study adult participants (Finland) $n=$ 161	2005–2010	Median (5th, 95th percentile) PFOAe $2.56\left(1.04,4.66\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFOSe $3.2\left(0.89,10.3\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFNAe $0.83\left(0.30,2.19\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFHxSe $1.18\left(0.54,2.90\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$	Same as exposure 12 months post (ALT)	ALT (U/L),e steatosis, NASH, lobular inflammation, liver cell ballooning	Adjusted for age, fasting insulin, and weight change.	There were no significant associations between PFOA, PFOS, PFNA, or PFHxS and ALT at either baseline or 12 months later. PFOA, PFNA, and PFHxS were inversely associated with lobular inflammation at baseline. Additional PFAS: PFHxA was associated with ALT at 12 months. PFDA and sum of PFCA were associated with lobular inflammation at baseline.
Sakr et al.44	Employees at the Washington Works polymer manufacturing site (USA) $n=$ 205	1979–2007	Mean (SD) PFOA $1.13\left(2.1\right)\text{\hspace{0.17em}ppm}$	1980–2007	ALT (U/L), GGT (U/L), AST (U/L)	Adjusted for age, sex, BMI, and decade of hire.	There was a positive association between PFOA and AST.
Sakr et al.43	Employees at Washington Works polymer manufacturing site (USA) $n=$ 1,018	2004	Mean (SD) PFOA $0.428\left(0.86\right)\text{\hspace{0.17em}ppm}$	Same as exposure	ALT (U/L),d GGT (U/L),d AST (U/L)d	Adjusted for age, sex, BMI, alcohol consumption, family history of heart attack, and use of lipid-lowering medications.	There was a positive association between PFOA and GGT.
Salihovic et al.42	Older adults (Sweden) $n=$ 1,002	2001–2014	Median (IQR) PFOAd $3.31\left(2.52–4.39\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFOSd $13.2\left(9.95–17.8\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFNAd $0.70\left(0.52–0.97\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFHxSd $2.08\left(1.6–3.42\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$	2006–2014	ALT (ukat/L), GGT (ukat/L)	Adjusted for sex, LDL and HDL cholesterol, serum triglycerides, BMI, fasting glucose levels, statin use, and smoking.	There were positive associations between PFOA, PFOS, PFNA, and PFHxS and ALT. There was also a positive association between PFOA and GGT. Additional PFAS: PFHpA was positively associated with ALT, and PFUnDA was positively associated with GGT.
Sen et al.79	Adults undergoing laparoscopic bariatric surgery without other risk factors for NAFLD (Sweden) $n=$ 105	Not Specified	Median (min–max) PFOA $1.89\left(0.49–6.36\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; Br-PFOS $2.13\left(0.63–9.71\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; L-PFOS $2.50\left(0.74–11.79\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFNA $0.37\left(0.09–1.08\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFHxS $0.60\left(0.16–10.58\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$	Same as exposure	NAFLD), NASH), macrosteatosis), necroinflammatory activity), fibrosis	None	Positive associations were observed between PFAS (PFOA, PFOS, PFNA, and PFHxS) and macrosteatosis. PFOA and PFOS were positively associated with necroinflammation and NASH. PFNA was negatively associated with NASH. PFOS was positively associated with fibrosis.
Stratakis et al.78	Children in the HELIX cohort (UK, France, Spain, Lithuania, Norway, Greece) $n=$ 1,105	2005–2009 (prenatal)	PFAS mixture Median (IQR) PFOA $2.38\left(1.45–3.45\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFOS $6.74\left(4.43–10.35\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFNA $0.72\left(0.47–1.11\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFHxS $0.59\left(0.34–0.93\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$	2014–2015	Liver injury risk (ALT, AST, or GGT $\text{levels\hspace{0.17em}}\ge 90\text{th}$ percentile)	Adjusted for cohort, maternal age, maternal education, maternal prepregnancy BMI, child ethnicity, child age, and child sex.	Higher prenatal PFAS exposure was associated with increased ALT, AST, and GGT, and with being at increased risk of liver injury. Additional PFAS: PFUnDA was included in the mixture analysis.
Yamaguchi et al.80	Japanese residents with no occupational PFAS exposure $n=$ 608	2008–2010	Median (IQR) PFOAe $2.1\left(1.5–3.3\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$; PFOSe $5.8\left(3.7–8.8\right)\text{\hspace{0.17em}ng}/\mathrm{mL}$	Same as exposure	ALT (IU/L), AST (IU/L), GGT (IU/L)	Adjusted for age, sex, BMI, regional block, and smoking, and alcohol intake.	PFOA and PFOS were significantly positively correlated with ALT and AST. There was also a significant positive correlation with GGT, but not after adjustment for alcohol intake.

Note: —, not available; ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; CI, confidence interval; CK18, cytokeratin 18; eGFR, estimated glomerular filtration rate; EtFOSAA, $N$-ethyl perfluorooctane sulfonamidoacetic acid; F, female; GGT, gamma-glutamyl transferase; HDL, high-density lipoprotein; HELIX, Human Early Life Exposome; HOMR-IR, Homeostatic Model Assessment of Insulin Resistance; IQR, interquartile range; LDL, low-density lipoprotein; M, male; max, maximum; MeFOSAA, $N$-methylperfluorooctane sulfonamidoacetic acid; min, minimum; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NHANES, National Health and Nutrition Examination Survey; PFAS, per- and polyfluorinated substances; PFDA, perfluorodecanoic acid; PFHpA, perfluoroheptanoic acid; PFHxA, perfluorohexanoic acid; PFHxS, perfluorohexanesulfonic acid; PFNA, perfluorononanoic acid; PFOA, perfluorooctanoic acid; PFOS, perfluorooctanesulfonic acid; PFUnDA, perfluoroundecanoic acid; SD, standard deviation; SE, standard error.

^aSample sizes given here represent the maximum number of subjects available for at least one of the analyses of interest. Specific analyses may have slightly different sample sizes.

^bBlood concentration of PFOA, PFOS, PFNA, PFHxS only. Exposure concentrations are reported where available.

^cOutcomes listed here are limited to liver enzymes (ALT, AST, GGT), NAFLD, NASH, and liver histopathology. Studies may have reported additional outcomes.

^dNatural log (ln) transformed.

^e${\text{Log}}_{10}$ transformed.