Increased Risk of Nonalcoholic Fatty Liver Disease in Patients With Coeliac Disease on a Gluten-free Diet

Beyond Traditional Metabolic Factors

F. Tovoli; G. Negrini; R. Farì; E. Guidetti; C. Faggiano; L. Napoli; L. Bolondi; A. Granito

Aliment Pharmacol Ther. 2018;48(5):538-546.

Abstract and Introduction

Abstract

Background: A gluten-free diet (GFD) is known to be associated with altered macronutrient intake and metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) is the hepatic hallmark of metabolic syndrome. The risk of NAFLD in patients with coeliac disease (CD) adhering to a GFD remains to be fully investigated; in particular, data from real-life clinical settings are lacking.

Aim: To assess the prevalence and relative risk of NAFLD in CD patients treated with a GFD.

Methods: Case-control study, with prospective enrolment of CD outpatients following a GFD and controls. Patients were matched for demographic characteristics (age and gender) and metabolic risk factors (overweight, diabetes mellitus, total cholesterol, and triglycerides) using a 1:1 ratio. NAFLD was diagnosed according to the European Association for the Study of the Liver criteria.

Results: 202 CD patients and 202 controls were compared. The raw prevalence of NAFLD was 34.7% and 21.8% in the CD and control group, respectively (P = 0.006). Binary logistic regression confirmed an increased risk of NAFLD in the CD group (adjusted odds ratio = 2.90, 95% confidence interval: 1.64–5.15, P < 0.001). Additionally, the relative risk for NAFLD was notably higher in non-overweight CD patients (adjusted odds ratio = 5.71, 95% confidence interval: 2.30–14.19, P < 0.001).

Conclusions: More than one-third of CD patients adhering to a GFD had concurrent NAFLD, accounting for a three-fold increased risk compared to the general population. Dietary advice provided using a patient-tailored approach should assist CD patients with NAFLD in achieving an appropriate nutritional intake whilst reducing the risk of long-term liver-related events.

Introduction

Patients with coeliac disease (CD) have to follow a lifelong gluten-free diet (GFD). This diet is safe and can reduce the long-term risk of serious complications, both neoplastic and non-neoplastic.^[1] A GFD is related to increased lipid^[2–6] and carbohydrate^[2,7–9] intake. Moreover, many adults and children with CD become overweight after treatment.^[10–13] Recent evidence also shows that a GFD can worsen glucose tolerance and induce metabolic syndrome in a proportion of CD patients,^[14] potentially increasing their cardiovascular risk.^[15,16]

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and is related to an increased risk of liver cirrhosis and primary liver cancer.^[17] Historically, liver steatosis has been reported to be a possible manifestation of CD in patients still on a gluten-containing diet.^[18] Additionally, about 3% of patients diagnosed with NAFLD actually have an underlying CD.^[19,20]

Data on the development of a fatty liver whilst following a GFD are still emerging. In a Swedish registry study, Reilly et al^[21] described an increased risk of NAFLD in CD patients treated with a GFD, with a hazard ratio of 2.8 (95% CI: 2.0–3.8). Cohort studies and evaluations in geographically different populations are missing, leaving uncertainties about the actual prevalence of NAFLD in the CD population, and the potential influence of local nutritional factors in determining the relative risk.

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Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Clinical, demographic and laboratory characteristics of coeliac patients and controls. Continuous variables are expressed as median (interquartile range). Categorical variables are reported as frequencies (%)
	CD	Controls	P
Age (y)	45 (32–57)	46 (33–62)	0.251
Female gender	147 (72.8)	132 (65.3)	0.132
BMI (kg/m²)	22.9 (20.9–25.5)	23.5 (21.1–25.8)	0.494
BMI categorisation
Underweight (<18.5)	5 (2.5)	6 (3.0)	0.972
Normal-weight (18.5–25)	135 (66.8)	131 (64.9)
Overweight (25–30)	51 (25.2)	53 (26.2)
Obesity (>30)	11 (5.4)	12 (5.9)
Total cholesterol (mg/dL)	194.9 (170.0–215.0)	190.9 (171.5–210.0)	0.153
Total cholesterol >200 mg/dL	85 (42.1)	77 (38.1)	0.477
HDL cholesterol (mg/dL)	56.0 (48.0–65.3)	54.0 (47.9–60.7)	0.140
HDL cholesterol low^a	50 (24.8)	47 (23.3)	0.816
Triglycerides (mg/dL)	76.4 (62.9–101.0)	88.1 (73.0–101.6)	0.213
Triglycerides >150 mg/dL	16 (7.9)	14 (6.9)	0.850
Diabetes	14 (6.9)	14 (6.9)^b	1.000
AST (UI/L)	20.0 (17.0–26.0)	20.0 (16.0–25.1)	0.989
AST high^c	12 (5.9)	6 (3.0)	0.227
ALT (UI/L)	18.0 (14.0–27.0)	18.6 (15.0–25.8)	0.530
ALT high^c	22 (10.9)	9 (4.5)	0.021

CD, coeliac disease; BMI, body mass index; HDL, high-density lipoproteins; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
^a<50 mg/dL in women and <40 mg/dL in men.
^bIncluding three cases of type 1 diabetes mellitus.
^c>35 U/L in women and >50 U/L in men.

Table 2. Univariate and multivariate binary logistic regression analysis to nonalcoholic fatty liver disease (NAFLD) in the whole study population
Univariate analysis		Variable	Multivariate analysis
Exp(B) (95% CI)	P	Variable	Exp(B) (95% CI)	P
1.904 (1.224–2.963)	0.004	Group (CD = 1)	2.904 (1.639–5.146)	<0.001
1.019 (1.006–1.032)	0.004	Age	1.008 (0.991–1.026)	0.348
0.797 (0.502–1.266)	0.337	Gender (F = 1)
1.473 (1.348–1.609)	<0.001	BMI	1.467 (1.330–1.619)	<0.001
1.017 (1.010–1.025)	<0.001	Total cholesterol (mg/dL)	1.016 (1.007–1.026)	<0.001
0.979 (0.960–0.999)	0.041	HDL cholesterol (mg/dL)	0.996 (0.986–1.005)	0.375
1.013 (1.007–1.019)	<0.001	Triglycerides (mg/dL)	1.004 (0.998–1.009)	0.232
7.050 (2.898–16.630)	<0.001	Diabetes (No = 1, Yes = 2)	2.681 (0.947–7.584)	0.063
1.042 (1.017–1.067)	0.001	AST (UI/L)^a
1.033 (1.015–1.072)	<0.001	ALT (UI/L)	1.022 (1.006–1.039)	0.007

CI, confidence interval; CD, coeliac disease; BMI, body mass index; HDL, high-density lipoproteins; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
^aNot included in the multivariable analysis due to colinearity.

Table 3. Clinical, demographic and laboratory characteristics of the 70 CD patient and 44 reference subjects with evidence of nonalcoholic fatty liver disease (NAFLD). Continuous variables are expressed as median (interquartile range). Continuous variables are reported as frequencies (%)
	CD (n = 70)	Controls (n = 44)	P
BMI	25.3 (23.6–27.9)	27.2 (25.7–29.9)	0.002
BMI categorisation
Underweight (<18.5)	0	0	0.033
Normal weight (18.5–25)	28 (40)	8 (18.1)
Overweight (25–30)	34 (48.6)	26 (59.1)
Obesity (>30)	8 (11.4)	10 (22.8)
Total cholesterol (mg/dL)	206.0 (188.3–235.5)	206.0 (178.8–224.3)	0.218
HDL cholesterol (mg/dL)	53.9 (45.9–61.3)	53.1 (45.4–56.1)	0.297
Triglycerides (mg/dL)	87.5 (67.4–126.0)	98.6 (76.5–137.5)	0.044
Diabetes	11 (15.7)	8 (18.1)
AST (UI/L)	23.5 (19.0–32.0)	22.9 (17.3–29.0)	0.322
ALT (UI/L)	22.5 (17.0–36.5)	19 (15.4–31.4)	0.341
Grade (ultrasound)
Mild	50 (71.4)	30 (68.1)	0.592
Moderate	19 (27.1)	12 (27.2)
Severe	1 (1.5)	2 (4.5)
FIB4 score
No fibrosis	69 (98.6)	42 (95.5)
Undetermined	1 (1.4)	2 (4.5)	0.311
Fibrosis	0	0
NAFLD fibrosis score^a
No fibrosis	39 (86.7)	26 (86.7)
Undetermined	6 (13.3)	4 (13.3)	1.000
Fibrosis	0	0

CD, coeliac disease; BMI, body mass index; HDL, high-density lipoproteins; AST, aspartate aminotransferase; ALT, alanine aminotransferase; FIB4, fibrosis4.
^aCalculated in 45 CD and 30 control subjects for whom all of the required parameters (which included also albumin and platelets) were available.

Table 4. Univariate and multivariate binary logistic regression analysis to nonalcoholic fatty liver disease (NAFLD) in the coeliac population
Univariate analysis		Variable	Multivariate analysis
Exp(B) (95% CI)	P		Exp(B) (95% CI)	P
0.797 (0.502–1.266)	0.337	Female gender
1.019 (1.006–1.032)	0.004	Age	1.003 (0.987–1.019)	0.715
1.811 (0.770–4.259)	0.174	Diagnosis in childhood^a
1.510 (0.703–3.243)	0.290	GFD duration >2 y
10.656 (6.462–17.575)	<0.001	BMI >25	9.892 (5.739–17.051)	<0.001
2.508 (1.611–3.905)	<0.001	Total cholesterol >200 mg/dL	2.725 (1.590–4.670)	<0.001
1.351 (0.825–2.212)	0.232	Low HDL cholesterol^b
5.957 (2.692–13.182)	<0.001	Triglycerides >150 mg/dL	1.705 (0.611–4.759)	0.308
7.050 (2.989–16.630)	<0.001	Diabetes	3.846 (1.374–10.766)	0.010
8.909 (3.852–20.606)	<0.001	Elevated ALT^c	9.167 (3.361–25.001)	<0.001

CI, confidence interval; GFD, gluten free diet; BMI, body mass index; HDL, high-density lipoproteins; ALT, alanine aminotransferase.
^aBefore the 15th year of age.
^b<50 mg/dL in women and <40 mg/dL in men.
^c>35 U/L in women and >50 U/L in men.