Primary liver injury and delayed resolution of liver stiffness after alcohol detoxification in heavy drinkers with the PNPLA3 variant I148M

doi:10.4254/wjh.v8.i35.1547

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World Journal of Hepatology

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World J Hepatol. Dec 18, 2016; 8(35): 1547-1556
Published online Dec 18, 2016. doi: 10.4254/wjh.v8.i35.1547

Table 1 Patient characteristics before and after alcohol withdrawal

Parameters	Before withdrawal(n = 521)	After withdrawal(n = 370)
Demographic characteristics
Male (%)	72.1
Age (yr)	50.2 ± 11.3
Risk factors
BMI (kg/m²)	25.2 ± 4.6
H/W ratio	1.0 ± 0.1
Alcohol consumption (g/d)	192.1 ± 139.7
Duration (yr)	19.9 ± 13.3
Smoker (%)	70.9
Diabetes (%)	10.0
Coronary heart disease (%)	5.1
RR (%)	34.5
Ascites (%)	9.0
F0 (%)	47.4
F1-2 (%)	17.1
F3 (%)	10.8
F4 (%)	24.7
Noninvasive parameters
Hepatic steatosis (0-3, US)	1.9 ± 0.9
Liver stiffness (kPa)	15.8 ± 21.1	12.6 ± 18.1
Laboratory parameters
AST (U/L)	101 ± 108	54 ± 48
ALT (U/L)	70 ± 79	52 ± 46
GGT (U/L)	398 ± 577	268 ± 360
AP (U/L)	109 ± 76	88 ± 55
Bilirubin (mg/dL)	1.3 ± 2.8	0.9 ± 2.3
Albumin (g/dL)	5.0 ± 6.0
INR	1.2 ± 3.4	1.2 ± 5.1
Urea (mg/dL)	22.6 ± 16.6	23.7 ± 12.5
Creatinine (mg/dL)	0.7 ± 0.3	0.8 ± 0.2
Hemoglobin (g/dL)	14.2 ± 2.2	13.8 ± 1.8
Platelets (/nL)	209 ± 87	215 ± 82
Glucose (mg/dL)	109.1 ± 36.4
HbA1C (%)	5.6 ± 1.0
Triglycerides (mg/dL)	195.7 ± 206.6
Cholesterol (mg/dL)	215.9 ± 58.2
HDL cholesterol (mg/dL)	72.3 ± 36.9
LDL cholesterol (mg/dL)	112.6 ± 45.6
Lipase (U/L)	63.6 ± 164.8	60.7 ± 56.3
Ferritin (ng/mL)	580.6 ± 650.5
CRP (mg/dL)	6.1 ± 15.9	7.1 ± 12.5

Data are presented as mean ± SD or in %. BMI: Body mass index; H/W ratio: Hip to waist ratio; RR: Hypertension; F: Fibrosis stage; AST: Aspartate transaminase; ALT: Alanine transaminase; GGT: Gamma-glutamyl-transpeptidase; AP: Alkaline phosphatase; INR: International normalized ratio (Prothrombin); HDL: High-density lipoprotein; LDL: Low-density lipoprotein; CRP: C-reactive protein; US: Ultrasound.

Table 2 Characteristics of alcoholic liver disease sub-cohorts (n = 521) based on genotype distribution of rs738409 polymorphism

Parameters	PNPLA3 CC (n = 204)	PNPLA3 CG (n = 274)	PNPLA3 GG (n = 43)	PNPLA3 CG + GG (n = 317)
Demographic characteristics
Patients (%)	39.2	52.6	8.2	60.8
Age (yr)	49.5 ± 11.0	50.7 ± 11.8	50.1 ± 9.7	50.7 ± 11.5
Risk factors
BMI (kg/m²)	25.4 ± 4.9	25.1 ± 4.5	25.6 ± 3.9	25.2 ± 4.4
H/W ratio	1.0 ± 0.1	1.0 ± 0.1	1.0 ± 0.1	1.0 ± 0.1
Alcohol consumption (g/d)	194.0 ± 136.1	190.8 ± 146.2	181.2 ± 116.1	189.4 ± 142.0
Duration (yr)	18.3 ± 13.3	20.9 ± 13.1	17.2 ± 14.2	20.4 ± 13.3
Smoker (1 = yes)	0.7 ± 0.4	0.7 ± 0.5	0.6 ± 0.5	0.7 ± 0.5
Diabetes (1 = yes)	0.1 ± 0.3	0.1 ± 0.3	0.0 ± 0.2	0.1 ± 0.3
Coronary heart disease (1 = yes)	0.1 ± 0.2	0.1 ± 0.3	0.0 ± 0.0	0.1 ± 0.3
Noninvasive parameters
Hepatic steatosis (0-3, US)	1.8 ± 0.9	2.0 ± 0.8	1.9 ± 0.8	2.0 ± 0.8
Liver stiffness (kPa)	13.1 ± 17.7	17.6 ± 23.0^a	17.2 ± 22.2	17.5 ± 22.9^a
Laboratory parameter
AST (U/L) before detox	95.2 ± 100.8	102.8 ± 111.4	113.1 ± 116.8	104.0 ± 111.9
AST (U/L) after detox	47.8 ± 32.9	52.6 ± 46.0	82.8 ± 89.5^a	56.2 ± 53.5
ALT (U/L) before detox	66.0 ± 59.4	71.9 ± 93.0	76.4 ± 60.4	72.5 ± 89.2
ALT (U/L) after detox	47.5 ± 35.9	52.4 ± 50.9	67.7 ± 55.0^a	54.2 ± 51.5
GGT (U/L) before detox	406.3 ± 572.2	365.9 ± 516.1	537.7 ± 869.6	389.6 ± 578.9
GGT (U/L) after detox	254.8 ± 290.9	261.7 ± 347.3	389.7 ± 671.6	276.9 ± 399.6
AP (U/L) before detox	105.5 ± 76.2	111.6 ± 75.8	112.7 ± 72.6	111.8 ± 75.3
AP (U/L) after detox	83.3 ± 45.1	90.5 ± 59.2	97.5 ± 68.4	91.3 ± 60.2
Bilirubin (mg/dL)	1.2 ± 2.8	1.4 ± 3.0	0.9 ± 1.1	1.3 ± 2.8
Albumin (g/dL)	4.7 ± 4.7	5.3 ± 7.2	4.5 ± 0.5	5.2 ± 6.7
INR	1.4 ± 5.4	1.0 ± 0.4	0.9 ± 0.2	1.0 ± 0.4
Urea	20.6 ± 10.8	24.6 ± 20.2^a	20.1 ± 9.9	24.0 ± 19.2^a
Creatinine	0.7 ± 0.2	0.7 ± 0.3	0.7 ± 0.2	0.7 ± 0.3
Hemoglobin (g/dL)	14.2 ± 1.8	14.2 ± 2.5	14.6 ± 2.0	14.2 ± 2.4
Platelets (/nL)	216.7 ± 92.7	201.1 ± 80.0^a	224.2 ± 91.4	204.5 ± 82.0
Glucose (mg/dL)	112.0 ± 46.2	107.7 ± 28.5	110.7 ± 34.6	108.1 ± 29.3
HbA1C (%)	5.6 ± 1.1	5.6 ± 0.8	5.8 ± 1.3	5.6 ± 0.9
Triglycerides (mg/dL)	190.6 ± 202.2	192.0 ± 205.8	240.9 ± 230.4	198.7 ± 209.6
Cholesterol (mg/dL)	219.9 ± 55.0	213.1 ± 61.1	222.9 ± 53.4	214.4 ± 60.1
HDL cholesterol (mg/dL)	73.2 ± 35.9	71.4 ± 37.6	75.6 ± 37.3	71.9 ± 37.5
LDL cholesterol (mg/dL)	113.5 ± 46.3	112.4 ± 45.5	118.0 ± 44.7	113.0 ± 45.3
Lipase (U/L)	48.5 ± 45.9	75.9 ± 216.5	45.3 ± 26.0	72.0 ± 202.7
Ferritin (ng/mL)	546.1 ± 611.6	599.6 ± 668.3	685.2 ± 708.2	610.8 ± 673.1
CRP (mg/dL)	4.7 ± 11.1	7.1 ± 18.9	6.0 ± 12.0	7.0 ± 18.1

Data are presented as mean ± SD or in %; significant paired T tests (^aP < 0.05) with CC. BMI: Body mass index; H/W ratio: Hip to waist ratio; AST: Aspartate transaminase; ALT: Alanine transaminase; GGT: Gamma-glutamyl-transpeptidase; AP: Alkaline phosphatase; INR: International normalized ratio (Prothrombin); HDL: High-density lipoprotein; LDL: Low-density lipoprotein; CRP: C-reactive protein; US: Ultrasound; PNPLA3: Adiponutrin.

Table 3 Risk factors associated with F4 cirrhosis

Factor	OR	95%CI	P value
PNPLA3 G (CG + GG)	1.295	0.787-2.131	> 0.05
Gender	0.855	0.496-1.475	> 0.05
Age	1.040	1.017-1.064	< 0.001
BMI	1.037	0.983-1.093	> 0.05

BMI: Body mass index; OR: Odds ratio; PNPLA3: Adiponutrin.

Table 4 Spearman rank correlation of PNPLA3 carrier status and liver stiffness with histological parameters

Parameter (n = 80)	PNPLA3 CC (n = 43)	PNPLA3 CG (n = 29)	PNPLA3 GG (n = 8)	Liver stiffness (kPa)
Steatohepatitis (score 0-2)	-0.163	-0.099	0.404^b	0.391^b
Microgranulomas (score 0-1)	-0.095	-0.139	0.357^b	0.387^b
Ballooning (score 0-2)	-0.221^a	0.020	0.319^b	0.516^b
Glycogenated nuclei (score 0-1)	-0.124	-0.080	0.316^b	0.335^b
Steatosis (score 0-3)	-0.125	-0.045	0.264^a	0.096
Lobular inflammation (score 0-3)	-0.142	-0.003	0.227^a	0.420^b
Megamitochondria (score 0-1)	-0.121	-0.005	0.198	0.278^b
Large lipogranulomas (score 0-1)	0.134	-0.238^a	0.145	0.144
Acidophil bodies (score 0-1)	-0.016	-0.072	0.133	0.285^b
Pericellular fibrosis (score 0-3)	-0.224	0.141	0.131	0.567^b
Chevallier fibrosis score (SSS)	-0.189	0.112	0.131	0.828^b
Ballooning k8/18 stain (score 0-2)	-0.537^b	0.490^b	0.089	0.692^b
Kleiner fibrosis score (score 0-4)	-0.163	0.148	0.035	0.745^b
Mallory Denk Bodies (score 0-1)	-0.121	0.110	0.026	0.530^b
Apoptosis M30 stain (score 0-3)	-0.039	0.031	0.014	0.490^b
Pigmented macrophages (score 0-1)	0.003	0.012	-0.022	-0.009
Portal inflammation (score 0-1)	-0.027	0.099	-0.106	0.427^b
Liver stiffness (kPa)	-0.045	0.017	0.037	1.000

Liver stiffness primarily correlates with fibrosis and liver damage but not significant with steatosis. In contrast, GG carrier status is tightly associated with liver injury and weakly with steatosis.

^aP < 0.05 vs

^bP < 0.01. PNPLA3: Adiponutrin.

Citation: Rausch V, Peccerella T, Lackner C, Yagmur E, Seitz HK, Longerich T, Mueller S. Primary liver injury and delayed resolution of liver stiffness after alcohol detoxification in heavy drinkers with the PNPLA3 variant I148M. World J Hepatol 2016; 8(35): 1547-1556
URL: https://www.wjgnet.com/1948-5182/full/v8/i35/1547.htm
DOI: https://dx.doi.org/10.4254/wjh.v8.i35.1547