Journal of Crohn's and Colitis, 2022, 16, 852–862

https://doi.org/10.1093/ecco-jcc/jjab212
Advance access publication 22 November 2021
Review Article

Inflammatory Bowel Disease-associated Fatty Liver

Disease: the Potential Effect of Biologic Agents
Apostolis Papaefthymiou,a,b, Spyros Potamianos,a Antonis Goulas,b Michael Doulberis,b,c
Jannis Kountouras,d, Stergios A. Polyzosb,

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a
Department of Gastroenterology, University Hospital of Larisa, Larisa, Thessaly, Greece
b
First Laboratory of Pharmacology, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
c
Division of Gastroenterology and Hepatology, Medical University Department, Kantonsspital Aarau, Aarau, Switzerland
d
Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
Corresponding author: Apostolis Papaefthymiou, MD, PhD Candidate, First Laboratory of Pharmacology, Aristotle University of Thessaloniki, Campus of
Aristotle University of Thessaloniki, 54124 Thessaloniki, Macedonia, Greece. Tel.: +302310999316, +306973853042; email: apostokp@auth.gr

Abstract
Inflammatory bowel diseases [IBD] exhibit intestinal and systemic manifestations. Nonalcoholic fatty liver disease [NAFLD] is a common
co-existing condition, possibly contributing to the cardio-metabolic burden and overall morbidity. Εmerging therapeutic choices of biologic agents
have modified the clinical course of IBD; however, their impact on IBD-associated NAFLD has not been extensively evaluated. The prevalence
of NAFLD varies among IBD patients, but it appears higher than in the general population in the majority of quality studies. In terms of patho-
genetic and risk factors of NAFLD, they may vary with IBD activity. Dysbiosis, mucosal damage, and cytokine release have been implicated in
the pathogenesis during the relapses, whereas metabolic risk factors seem to play a dominant role during the remissions of IBD. Considering
biologics, although quality data are scarce, agents suppressing tumour necrosis factor may offer potential benefits in IBD-associated NAFLD,
whereas anti-integrins do not appear to confer any therapeutic advantage.
In conclusion, IBD-associated NAFLD possibly follows two different patterns, one manifested during the relapses and one during the remissions
of IBD. Some, but not all, biologics may benefit NAFLD in patients with IBD. Further mechanistic and prospective cohort studies are warranted
to illuminate the effects of various biologics on NAFLD.
Key Words: Biologics; inflammatory bowel diseases; nonalcoholic fatty liver disease

1. Introduction IBD-associated parameters, including disease activity and dur-

Inflammatory bowel diseases [IBD], i.e., Crohn’s disease [CD] and
ulcerative colitis [UC], represent multifactorial disorders of the
gastrointestinal [GI] tract with a broad spectrum of clinical mani-
festations. The introduction of biological treatments [or biologics]
has modified the natural history of CD and UC and expanded the
periods of remission.1 Despite their GI origin, IBD have been as-
sociated with a plethora of extra-intestinal manifestations.2 In this
regard, nonalcoholic fatty liver disease [NAFLD] has been linked
to IBD, representing a common diagnosis during the workup for
elevated liver function tests [LFTs] among patients with IBD.3,4
NAFLD has a global prevalence of 25% in the general
population, being much higher in specific subgroups, e.g., pa-
tients with obesity and/or type 2 diabetes mellitus [T2DM].5
NAFLD refers to a phenotypic spectrum, starting from sim-
ple steatosis or nonalcoholic fatty liver [NAFL] which may
progress to nonalcoholic steatohepatitis [NASH], hepatic
fibrosis, cirrhosis, and hepatocellular carcinoma in a mi-
nority of patients.6 Of note, the additive burden of NAFLD
in patients with IBD has been associated with a 2-fold risk
of cardiovascular events and a 5-fold risk of chronic kidney
disease [CKD], thus increasing overall mortality.7,8 NAFLD is
a multifactorial disease that may affect, but also be affected
by, the components of metabolic syndrome [MetS] including
obesity, T2DM, dyslipidaemia, and arterial hypertension.9
ation and prior surgical intervention, may also impact on the de-
velopment of NAFLD.10 Non-metabolic factors, such as chronic
uncontrolled inflammation, use of glucocorticosteroids, pro-
longed starvation, rapid weight loss or uncontrolled refeeding,
and sarcopenia have also been proposed to contribute to the
pathogenesis of NAFLD in patients with IBD.11–14
Despite its high prevalence, there is to date no approved
medication for NAFLD.15 On the other hand, the treatment
choices for IBD have been expanded after the introduction of
biologics16 which seem to optimise the therapeutic schemes,
thus improving the control of disease activity in the long term
as well as its systemic manifestations. Nonetheless, the potential
serious adverse effects of biologics on patients with IBD should
be carefully weighed before and during their clinical use.17
The above considering, this narrative review aims to sum-
marise evidence on the association between IBD and NAFLD,
as well as on the potential effects of biologics having been
introduced in the treatment of IBD, on NAFLD.
2. Evidence Linking IBD with NAFLD
2.1. Prevalence of NAFLD in IBD
A broad range of NAFLD prevalence has been reported in
various studies, probably due to the different populations

Received: September 8, 2021. Revised: November 2, 2021. Accepted: November 19, 2021
© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions,
please email: journals.permissions@oup.com
NAFLD in IBD; Focus on Biologics 853

and differing pharmacotherapy, the variability of diagnostic nosis and staging of NAFLD] and the retrospective design of
methods for NAFLD documentation [different imaging mo- some studies [Table 1].18–24 In this regard, Gizard et al.3 re-
dalities, non-invasive markers in the absence of histological viewed NAFLD prevalence between 1.5% and 55% among
confirmation, being currently the ‘gold-standard’ for the diag- IBD cases, which should be cautiously interpreted. The lower

Table 1. Prevalence of NAFLD among IBD patients and relative risk factors.

First author [year of Country Study design IBD Diagnostic method NAFLD Main risk factors
publication]a cases of NAFLD [%] of NAFLD

Adams et al [2018] Germany Retrospective cross-sectional 130 MRI 54.6 Underweight [BMI <18.5 kg/

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m2]
Balaban et al [2017] Romania Prospective case series 36 CAP-TE 30.5 CD, history of bowel resec-
tion, steroid use, and longer
disease duration
Bargiggia et al [2003] Italy Prospective case-control 511 US 38.0 None
Bessissow et al [2016] Canada Retrospective case series 321 Non-invasive serum 33.6 IBD activity, duration, and
biomarkers, Hepatic history of surgery
Steatosis Index [HIS] and
FIB-4
Bosch et al [2017] USA Retrospective cross-sectional 123 Histology 26.9 Increased BMI and hyper-
tension
Fousekis et al [2019] Greece Retrospective case series 220 Imagingb 20.0 N/A
Glassner et al [2017] USA Retrospective case-control 421 Imagingb 13.3 Older age, prolonged disease
duration, T2DM, increased
BMI, MetS
Hoffmann et al [2020] Germany Retrospective with two parts: 694 US 46.5 Older age, BMI, disease activ-
a cross-sectional and a lon- ity, bowel resection, endo-
gitudinal scopic activity, azathioprine
use
Kang et al [2020] Korea Retrospective case-control 443 CT 11.1 MetS, sarcopenia,
hyperuricaemia, small bowel
resection
Li et al [2017] China Retrospective case-control 206 Imagingb 10.6 For CD: age, female sex, low-
normal BMI, TGF or UC: low
albumin
Likhitsup et al [2019] USA Retrospective cross-sectional 80 US 54.0 CD activity
Magrì et al [2019] Italy Prospective case-control 178 US, TE 40.4 Male sex, older age, obesity,
high caloric consumption
Mancina et al [2016] Italy Prospective case series 158 US, CAP-TE 70.0 PNPLA3-I148M
McHenry et al [2019] USA Prospective case-control 311 MR-PDFF 38.0 BMI <25 kg/m2
Morsy et al [2012] Egypt Prospective case series 33 US 45.5 N/A
Palumbo et al [2018] Canada Prospective case-control 384 CAP elastography 32.8 Age, increased BMI, TG
Principi et al [2018] Italy Prospective case-control 465 US 28.0 T2DM, MetS, abdominal
circumference >102 cm for
males and >88 cm for females.
Ritaccio et al [2020] USA Retrospective cross-sectional 1672 US 12.4 Increased BMI, CD
Sagami et al [2017] Japan Retrospective case-control 303 US 21.8 Age, prolonged disease dur-
ation, low BMI, ileitis
Schroder et al [2015] Germany Retrospective cross-sectional 259 US 28.2 N/A
Simon et al [2018] USA Prospective case series 462 CT 52.0 Age, T2DM, PNPLA3 geno-
type
Sourianarayanane et al USA Retrospective cross-sectional 928 Imaging╪ 8.2 History of surgery, hyperten-
[2013] sion, obesity, steroid use at
imaging
Whorwell et al [1984] UK Case-control 38 US 11.0 N/A
Yamamoto-Furusho [2010] Mexico Prospective case series 200 US 11.2 N/A
Yen et al [2021] Taiwan Retrospective case series 81 US and CAP-TE 29.6 BMI, age at diagnosis

BMI, body mass index; CAP, controlled attenuation parameter; CD, Crohn’s disease; CT, computerised tomography; IBD, inflammatory bowel disease;
MetS, metabolic syndrome; MRI-PDFF, magnetic resonance imaging-proton density fat fraction; NAFLD, non-alcoholic fatty liver disease; N/A, not
applicable; PSC, primary sclerosing cholangitis; T2DM, type 2 diabetes mellitus; TE, transient elastography; TG, triglycerides; TNF, tumour necrosis factor;
UC, ulcerative colitis; US, ultrasound.
a
Studies are sorted according to the last name of the first author.
b
Various imaging modalities included.
854 A. Papaefthymiou et al.

prevalence of NAFLD was mainly reported in older studies,
using serological, imaging or histological methods of ques-
tionable validity. A meta-analysis of 19 relevant studies with
5620 cases reported that 27.2% of IBD patients had NAFLD,25
which is very close to the global prevalence of NAFLD in the
general population [25%].5 However, NAFLD prevalence in
IBD may be underestimated in this meta-analysis that dis-
played marked heterogeneity [I2 = 98%]. In another relevant
meta-analysis of 27 studies, the prevalence of NAFLD among
IBD patients was 32%, i.e., somewhat higher than the general
population.26
When considering studies where NAFLD diagnosis was
metabolic and genetic risk factors [Figure 1]. Regarding body
weight, in one study NAFLD was detected, via magnetic res-
onance imaging, in 87.6% of underweight patients with IBD,
who were also more prone to advanced steatosis [>33% of
hepatocytes] compared with normal-weight individuals; no fi-
brosis was presumed, using non-invasive indices,30 thus prob-
ably implying the necessity of further insults [pathogenetic
‘hits’] to promote liver damage. This rate is much higher than
the rate reviewed for lean individuals with NAFLD, being
10–20% in the USA and Europe.31 The presence of active in-
testinal inflammation, assessed by C-reactive protein [CRP]
and platelet count, was a significant contributor to NAFLD

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based on methods of high accuracy, such as controlled at-
tenuation parameter elastography [CAP-E] and magnetic res-
onance proton density fat fraction, the prevalence of NAFLD
was higher than in general population [Table 1].8,21,27–29
Further well and specifically designed, large epidemiological
studies of NAFLD,with cutting edge diagnostic methods, are
required to clarify the prevalence of NAFLD in IBD.
2.2. Risk factors of NAFLD in IBD
Observational studies have evaluated potential risk factors of
NAFLD in IBD, which may be subdivided into those related
with IBD and those not specifically related with IBD, e.g.,
in patients with low body mass index [BMI].30,32 Notably, pa-
tients with NAFLD and IBD in remission had higher BMI.32
Obesity and aging represent distinct risk factors of NAFLD in
IBD, similarly to the general population in which the propor-
tion of NAFLD among obese patients ranges between 30%
and 80%.8,14,19,31,33–36 Upon evaluating the disease activity,
BMI and increasing age are risk factors of NAFLD among
patients with IBD in remission in all studies8,34,36–38 but one.33
Furthermore, sarcopenia has been proposed as an additional
independent predisposing factor for NAFLD in IBD patients,
after adjustment for other potential cofounders including
BMI, T2DM, and MetS.39 The above considered, it seems that

IBD non-specific IBD specific

Overweight Aging
Active Sarcopenia
inflammation

Lack of physical Diet

activity

Bowel IBD
resection duration
T2DM Hypertriglyceridemia

PNPLA3 Anti-integrins Corticosteroids

Hypertension variants

Figure 1. Risk factors associated with NAFLD in patients with IBD. Risk factors are subdivided into those specific and not specific for IBD. Regarding
IBD-specific ones: active and long-term disease, especially CD, small bowel resection, sarcopenia, and some medications have accounted for NAFLD.
IBD non-specific risk factors are common in the general population, including dietary habits, lack of physical activity, obesity, T2DM, dyslipidaemia,
arterial hypertension, aging, and genetic predisposition. Clip arts were obtained by Servier Medical Art [https://smart.servier.com]; no permission is
required. IBD, inflammatory bowel disease; NAFLD, nonalcoholic fatty liver disease; CD, Crohn’s disease; PNPLA, patatin-like phospholipase domain-
containing protein; T2DM, type 2 diabetes mellitus.
NAFLD in IBD; Focus on Biologics
sarcopenic obesity may emerge as a predisposing factor for
NAFLD in the IBD setting,40 as it constitutes a contributor
towards NAFLD in non-IBD populations.41
Malfunctioning intestinal mucosal barrier has been trad-
itionally associated with NAFLD.42 In this regard, active
IBD-related gut permeability has been incriminated for
NAFLD prevalence of 50–60%.10,20,43 Among patients with
active CD, NAFLD rates rise in parallel with CRP44 or with
glucocorticosteroid treatment at the time of NAFLD diagno-
sis.19,28 Further IBD-associated variables regarded as NAFLD
risk factors include disease duration and prior relevant sur-
gery.10,14,19,28,33,36,39 More specifically, a mean disease duration
of 9–20 years and small bowel resections in patients with
CD were independently associated with NAFLD, thus pos-
sibly implying an impact of chronic alterations of intestinal
pathophysiology, such as small bowel bacterial overgrowth
[SIBO], in NAFLD.10,14,19,28,33,36,39,45 A case-control study has
demonstrated that severe forms of IBD with history of ileal
or ileo-colonic resection or total procto-colectomy, frequent
relapses [more than one per year] necessitating courses of
glucocorticosteroids, and extended intestinal involvement
[more than 100 cm for CD or at least left-sided UC] were as-
sociated with advanced steatosis.46
Moreover, some studies have reported that MetS,14,37,39,47,48 or
its components such as T2DM,14,37,49 high triglycerides,8,32 arter-
ial hypertentsion19,50 or great waist circumference,37 were asso-
ciated with NAFLD. Moreover, a recent meta-analysis showed
that disease duration [16.5–20.0 years], history of IBD-related
surgery, and methotrexate treatment were IBD-specific risk
factors of NAFLD, along with non-specific risk factors such
as older age, MetS, its relevant components (T2DM, insulin
resistance [IR], obesity, arterial hypertension) and CKD.25 The
described variability of risk factors strengthens the rationale
of different pathogenetic pillars in IBD-associated NAFLD.40 It
seems that in patients with more severe IBD or in those with ac-
tive disease, IBD-specific risk factors may contribute more than
non-specific ones in the pathogenesis of NAFLD, whereas in
patients with milder IBD or in those in remission, non-specific
risk factors may contribute more than the IBD-specific ones.
In line, IBD patients in remission were shown to be prone
to hypercaloric diets which favour NAFLD.34 However, this
speculation remains to be definitely demonstrated.
2.3. The role of inflammation
The inflammatory load, its fluctuations and chronicity, deter-
mine the natural history and manifestations of IBD, including
NAFLD. The associated chronic over-expression and system-
atic release of cytokines triggers IR, a key underlying mechan-
ism of MetS and NAFLD.51 Cytokines activate an intrahepatic
cascade, which facilitates NAFLD development and progres-
sion.52 In this respect, colonic inflammation has been found to
aggravate NASH and fibrosis, thus implying a potential gut-
liver axis.53,54 A well-studied cytokine in IBD is tumour necro-
sis factor [TNF], which is also associated with the severity of
NAFLD.55 By acting on its receptor, TNF receptor [TNFR]-I,
TNF impairs insulin signalling, thus inducing inflammation
and IR.56 TNF may also participate in the progression of
NAFL to NASH and possibly liver fibrosis, by perpetuating
the inflammatory process and inducing the local proliferation
and activation of the hepatic stellate cells [HSCs].51,55,57–61
Therefore it has been proposed that active inflammation, pos-
sibly orchestrated by TNF, may be a key driver of NAFLD
development even in lean IBD patients.62
855
Beyond the classic cytokines, adipokines seem to partici-
pate in the pathogenesis of chronic inflammatory diseases.63
The most extensively studied adipokines are adiponectin and
leptin. Adiponectin acts as an anti-inflammatory, insulin-
sensitising and anti-steatotic mediator; 64 it antagonises TNF
and IL-6 and, vice versa, it is downregulated by TNF.64,65 In
IBD, adiponectin was shown to be negatively correlated with
the severity of the disease, although both preclinical and clin-
ical studies showed controversial results regarding its serum
and adipose tissue concentrations.66 Leptin, the prototype
adipokine, shown to be implicated in the pathogenesis of
NAFLD,67 seems to increase in the serum and the mesenteric
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adipose tissue of IBD patients, thus contributing to inflam-
mation, IR, and possibly the NAFLD and cardiovascular
burden of these patients.44 Additionally apelin, a peptide as-
sociated with hepatic fibrosis, has been isolated in the intes-
tinal mucosa of IBD patients and in the mesenteric adipose
tissue of those with CD, thus comprising another potential
linkage between gut inflammation and NAFLD progression.68
Apelin may promote liver fibrosis via the extracellular signal-
regulated kinase signalling pathway.68
Integrins, transmembrane proteins involved in cell-cell and
cell-extracellular matrix interactions, have also been recog-
nised as key molecules in chronic inflammatory and fibrotic
conditions, thus constituting rational pharmaceutical targets.
The most representative example is β7-integrin, which binds to
the mucosal addressin cell adhesion molecule [MAdCAM]-1
of intestinal epithelium to facilitate leukocyte migration in
cases of IBD.69 Although MAdCAM-1 has been considered
as a bowel-specific molecule, it is additionally over-expressed
in chronic liver diseases and may promote fibrosis through
inducing remodelling of the extracellular matrix.70–72
2.4. The role of gut microbiota
The symbiosis of host and gut microbiota is disrupted in
chronic inflammatory conditions, such as IBD, thus further
burdening the inflammatory load locally and systemically.73–75
Additionally, patients with CD are vulnerable to SIBO, which
has also been documented as a distinct risk factor of IR, MetS,
and NAFLD.76–78 Specifically, the disruption of the integrity of
intestinal epithelium is supposed to be an early event in IBD
pathogenesis, permitting bacteria and their products to pene-
trate via a barrier leak, resulting in aberrant immune response
and inflammation.79 The imbalance between Bacteroidetes
and Firmicutes, to the side of Firmicutes, facilitates the over-
growth of abnormal colonies which express mediators of IR
[lipopolysaccharides] that contribute to local inflammation
and possibly to hepatic inflammation through the gut-liver
axis.77,78 The intestinal inflammation and the subsequent oxi-
dative stress disrupt the mucosal tight junctions, thereby al-
lowing bacterial translocation to the liver through the portal
circulation, accompanied by pathogen-associated molecu-
lar patterns, danger-associated molecular patterns, reactive
oxygen species, and Toll-like receptor [TLR]4 and TLR9
agonists.74,77,80 As a consequence, an endogenous immune re-
sponse is induced in the hepatic parenchyma, predisposing to
NAFLD development.74,81
In line, preclinical studies investigated potential implica-
tions of regulatory molecules, inflammasomes, to dysbiosis-
related IBD and NAFLD. Common inflammasomes, such
as nucleotide-binding oligomerisation domain-like receptor
protein [NLRP]3 and NLRP6, regulate immune response via
the expression of IL-1b and IL-18 and serve as modulators
856 A. Papaefthymiou et al.

of normal microbiota, whereas stereotactic abnormalities in
inflammasomes advocate IBD development through bacter-
ial overgrowth.82–84 Other studies revealed that NLRP3 and
NLRP6 activation improved NAFLD and MetS parameters in
rodent models, whereas knockdown of inflammasomes made
mice prone to obesity and NAFLD.85,86 Nevertheless, the exact
pathophysiological pathways implicated in the inflammasome-
microbiota–NAFLD interaction have not been elucidated. The
dynamic relationships of gut microbiota and the dysbiosis ob-
served in patients with IBD warrant further evaluation to elu-
cidate whether changes in the composition of the symbiotic
microbiome contribute to the pathogenesis of IBD and its re-
activity could be proposed to support their beneficial role.
However, disease remission predisposes to increased nutri-
tional intake and improvement in the absorption of nutrients,
leading to obesity, MetS, and NAFLD. The main relevant pre-
clinical and clinical data are presented below. Clinical data
are also summarised in Table 2, in which it is apparent that
there are only observational studies; importantly, the effect
of biologics on NAFLD was a secondary aim in most cases
and should carefully interpreted. There are also two ongoing
studies for NAFLD in patients with IBD, which are presented
in Table 3. Moreover there are some reports on biologic-
induced liver injury, which should be taken into account

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lated NAFLD, which may have therapeutic perspectives. A syn-
opsis of all the above considerations is illustrated in Figure 2.
3. Biologics: Their Potential Effect on NAFLD
Τhere are currently conflicting data on the effect of biologics
on IBD-associated NAFLD. A relative meta-analysis of seven
studies, with high heterogeneity [I2 >55%], revealed no asso-
ciation between IBD pharmaceutical choices and NAFLD.87
Nonetheless, based on the aforementioned rationale and the
proposed mechanisms, decrease in inflammation and disease
when evaluating NAFLD.88,89 More specifically, anti-TNF–in-
duced liver injury has been rarely diagnosed during the in-
duction period, associated with autoimmunity and significant
increase of anti-nuclear antibodies and IgG.89 In such cases,
elevated LFTs are usually normalised after biologic cessation
and/or after occasional glucocorticosteroid administration.89
Vedolizumab, when compared with placebo, was not found
to trigger liver injury, albeit isolated cases have been also de-
scribed.88,90 Awareness of biologic-induced liver injury is im-
portant to avoid misdiagnosing NAFLD in rare patients with
IBD and high LFTs on biologics.

MAdCAM NAFLD
expression
IR

Downregulation of insulin
HSC signaling pathways
stimulation

Autophagy

TNFα
Gut-liver axis

Adiponectin
ROS LPS
Leptin
TNFα Dysbiosis
Apelin NLRP3/6
Resistin

TNFα

Tight junctions
disruption

PAMPs LPS

ROS
Portal
IBD circulation

Figure 2. The main pathophysiological pathways of IBD related NAFLD. The increased inflammatory load in intestinal mucosa disrupts intracellular tight
junctions, thus allowing the translocation of mediators of inflammation and other molecules in the portal circulation, through which they may affect the
liver. Pro-inflammatory cytokines, products of bacterial dysbiosis, and reactive oxygen species migrate to the hepatic parenchyma, thus triggering IR,
inflammation, and possibly fibrogenesis. Clip arts were obtained by Servier Medical Art [https://smart.servier.com]; no permission is required. HSC,
hepatic stellate cells; IBD, inflammatory bowel disease; IR, insulin resistance; LPS, lipopolysaccharides; MAd-CAM, mucosal addressin cell adhesion
molecule; NAFLD, nonalcoholic fatty liver disease; NLRP, nucleotide-binding oligo-merisation domain-like receptor protein; PAMPs, pathogen-associated
molecular patterns; ROS, reactive oxygen species; TNF, tumour necrosis factor.
NAFLD in IBD; Focus on Biologics 857

Table 2. Clinical studies evaluating the potential effect of biologic agents on NAFLD in patients with IBD

First author [year of Study design Βiologic agent[s] OR or RR 95% CI p-value

publication]a

Bessissow et al [2016] Retrospective case series Anti-TNF 1.69 0.99-2.90 0.056

Glassner et al [2017] Retrospective case-control Anti-TNF, anti-integrin, 0.50 0.20-0.90 0.100
anti-interleukin 12/23
Hoffmann et al [2020] Retrospective with two parts: a cross-sectional and Overall 1.01 0.85-1.17 0.959
a longitudinal
Adalimumab 1.09 0.93-1.25 0.709
Infliximab 1.64 1.48-1.79 0.135

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Golimumab 1.34 1.19-1.50 0.874
Vedolzumab 1.40 1.24-1.56 0.523
Ustekinumab 1.13 0.01-2.25 0.833
Kang et al [2020] Retrospective case-control Not specifically defined 1.07 0.50-2.12 0.856
Magrì et al [2019] Prospective case-control Not specifically defined 0.78 0.42-1.43 0.410
Palumbo et al [2018] Prospective case-control Anti-TNF 0.78 0.50-1.22 0.279
Sagami et al [2017] Retrospective case-control Anti-TNF 1.26 0.71-2.23 0.789
Sourianarayanane et al [2013] Retrospective cross-sectional Anti-TNF 0.63 0.31-1.27 0.194
Yen et al [2021] Retrospective case series Anti-TNF 1.43 0.54-3.81 0.476
Anti-integrin 0.45 0.05–4.09 0.480

IBD, inflammatory bowel disease; NAFLD, non-alcoholic fatty liver disease; OR, odds ratio; RR, relative risk; TNF, tumour necrosis factor; CI, confidence
interval.
a
Studies are sorted according to the last name of the first author.

Table 3. Registered ongoing trials on NAFLD in patients with IBD.

ID, registration date [DD/MM/ Title Design Patients Duration Primary outcome[s]
YYYY]

NCT03760172, 30/11/2018
NCT04328259, 31/03/2021
Immunomediated Non-alcoholic Observational cohort 7300 3 Years Prevalence of NAFLD
SteaTohepatitis; Prevalence and in patients with
Characterization. INSTInCT Study immune-mediated
inflammatory disease
including IBD
Prevalance of Non-Alcoholic Fatty Observational cohort 30 2 years Prevalance of
Liver Diseases in Patient With In- non-alcoholic fatty liver
flammatory Bowel Diseases Attend- in inflammatory bowel
ing Assiut University Hospitals disease participants

IBD, inflammatory bowel disease; NAFLD, non-alcoholic fatty liver disease.

3.1. Anti-TNF agents inflammation, through reduction of intrahepatic expression

The initially introduced biologics in IBD were anti-TNF
agents and to date they represent a rational choice for the
management of moderate to severe disease.91,92 Infliximab, a
chimeric monoclonic antibody, was the prototype anti-TNF
agent used in IBD, followed by adalimumab, golimumab, and
certolizumab pegol.93–96 The amelioration of disease activ-
ity generated the hypothesis that these agents could improve
NAFLD at least, through their effect on the inflammation of
both the bowel and the liver and possibly through the de-
crease in glucocorticosteroid need.66 Sarcopenia, which is also
related to NAFLD, may be also diminished, since TNF has
a catabolic role in the skeletal muscle.20 Nevertheless, any
beneficial effect of anti-TNF on the intestinal mucosa may
be accompanied by a ‘rebound’ of weight gain with increased
visceral adiposity.20
Experimental studies, mainly from obese rodents treated
with anti-TNF agents, have documented improvement
in LFTs and, most importantly, in hepatic steatosis and
of TNF and subsequently decreased activation of the Jun
N-terminal kinase [JNK] pathway, resulting in downregulation
of stearoyl-CoA desaturase, a key enzyme for hepatic trigly-
ceride accumulation.97–99 Furthermore, the hepatic expression
of TNF was shown to impede the mitochondrial respiratory
chain and to trigger steatosis, which were resolved after anti-
TNF infusion.100 Other authors also investigated the impact
of anti-TNF on intrahepatic insulin activity by intervening in
the Janus kinase [JAK]2/signal transducer and activator of
transcription protein [STAT]3 pathway, which interconnects
IR with inflammation;98,101 short-term intraperitoneal treat-
ment with infliximab decreased the hepatic inflammatory
load and NAFLD.98 Furthermore it was shown that a 12-week
blockage of TNF, in a TNF-knockdown mouse line, decreased
IR and improved hepatic histology via improving lipid me-
tabolism, inflammatory cytokine expression, and fibrogenic
factors.102 Moreover by treating high-fat diet models with
infliximab, visceral fat composition was reduced103 and resistin
858
expression was downregulated, thus preventing the develop-
ment of obesity, T2DM, and NAFLD.104 Notably, the inflam-
mation of NASH seems to be improved more effectively than
steatosis after TNF blockage, probably because TNF acts
primarily as an early pro-inflammatory cytokine.99,105 Finally,
an orally administered anti-TNF fusion protein, PRX-106,
showed promising results by improving serum and hepatic
triglycerides, LFTs, and IR.106 These preclinical data provided
a promising background for IBD-associated NAFLD manage-
ment which, however, necessitates clinical confirmation.
Initial clinical data were based on the metabolic effects
of anti-TNF agents in patients with chronic inflammatory
diseases, such as rheumatoid or psoriatic arthritis.107 In this
regard, a study of 48 psoriatic patients receiving anti-TNF
agents showed that the progression of hepatic steatosis was
halted 12 months later, even if the disease activity was min-
imally reduced.108 Liver stiffness was also lower in psoriatic
patients treated with ant-TNF agent, implying an antifibrotic
effect.109 Infliximab or adalimumab exerted beneficial effects
on IR and central obesity, leading to a subsequent improve-
ment in MetS-related components such as NAFLD, and in
cardiovascular risk.110–112 Importantly, studies investigating
the impact of anti-TNF agents on dyslipidaemia showed an
increase in serum high-density lipoprotein-cholesterol with-
out affecting other lipoproteins, whereas a potentially adverse
effect was recorded on triglyceride concentrations.113–116
Limited retrospective clinical studies investigated the effect
of anti-TNF agents on NAFLD in patients with IBD, albeit as
a confounder. Infliximab, 14 weeks after the first dose, did not
restore IR and led to higher BMI in IBD patients with clinical
response.117 In longer-term studies, anti-TNF achieving remis-
sion was also associated with higher probability of weight
gain, especially in patients with CD.20 These results warrant
further research, since the subsequent weight gain may at-
tenuate any beneficial effect of anti-TNF agents on NAFLD.
Most studies in IBD patients do not show an association be-
tween the treatment with biologics and NAFLD rates and/or
severity.8,10,14,21,33,34,36,38,39
In one retrospective study,19 patients with IBD not on anti-
TNF had double the rate of NAFLD compared with those
on anti-TNF, albeit without being statistically significant.19 In
another study, anti-TNF treatment was the only factor that
was inversely associated with NAFLD severity in patients
with IBD, as implied from LFTs.46 On the contrary, other au-
thors43 reported a high rate of NAFLD in patients on anti-
TNF [54%]; however, in this study there was not a control
group.43 Of note, in the same study, NAFLD patients had in-
dependently higher CD activity than those without NAFLD.43
These findings warrant the need of further prospective studies
in carefully selected patients with IBD and a primary endpoint
of the effect of anti-TNF on NAFLD parameters, especially
those related to hepatic inflammation and fibrosis; in this re-
gard, studies with paired liver biopsies may be considered to
be the optimal design, but due to their invasive nature, studies
with parameters of elastography and/or non-invasive indices
of hepatic fibrosis may be acceptable alternatives.
3.2. Anti-integrin agents
In 2014, an anti-α4β7 integrin monoclonal antibody,
vedolizumab, was introduced into clinical practice for pa-
tients with IBD, based on the GEMINI study which targeted
remission and its maintenance for both naïve and non-naïve
patients.118,119 Despite the initial notion of its absolute select-
A. Papaefthymiou et al.
ivity in the intestinal mucosa, α4β7 integrin was shown to af-
fect other tissues, thus possibly resulting in the progression of
NASH and hepatic fibrosis, probably via facilitating the mi-
gration of inflammatory cells through the gut-liver axis.120,121
The first liver disease shown to be implicated by
α4β7/MAdCAM-1 treatment was primary scleros-
ing cholangitis, showing α4β7-positive T lymphocytes in
immunohistochemical analysis.122 Two years later, other au-
thors documented that, after inhibiting the expression or
functionality of α4β7/MAdCAM in IBD, the hepatic adhe-
sion of α4β7 positive T lymphocytes was also impaired, thus
implying a possible role of anti-integrins to manage liver dis-
Downloaded from https://academic.oup.com/ecco-jcc/article/16/5/852/6433262 by ECCO Member Access user on 24 June 2022
eases.121 In this regard, data from mouse models indicated a
potentially protective effect of α4β7/MAdCAM-1 activation
in T2DM and liver injury.123–125 Nevertheless, a more de-
tailed study on NAFLD showed potentially opposing roles
for MAdCAM-1 and β7-integrin in NASH.70 More specific-
ally, the absence of MAdCAM-1 expression seems to play a
protective role against hepatic steatosis.70 In this regard, the
role of the α4β7 complex, which activates MAdCAM-1 in
the liver, remains conflicting since β7 integrin knockdown
mice were, unexpectedly, prone to NASH development.70
These complicated and largely unresolved interactions have
triggered an ongoing debate on the potential role of α4β7
complex and MAdCAM-1 in the gut-liver axis, which war-
rant further research.
Despite the scarcity of relevant clinical data, a recent
retrospective cohort study, using CAP-E, documented that
NAFLD patients with IBD had higher rates of treatment
with vedolizumab [16.7%] compared with those without
NAFLD [1.8%]; however, vedolizumab treatment was neither
the primary aim of the study nor independently associated
with NAFLD after adjustment for potential confounders.38
Moreover, a study reviewing the safety of vedolizumab con-
cluded that, in patients with IBD experiencing hepatic adverse
events, NAFLD was the most common diagnosis.90 Thus,
until further studies elucidate this topic, anti-integrin treat-
ment is not recommended in patients with IBD and NAFLD.
3.3. Anti-IL-12/23 agents
IL-23 participates in autoimmunity pathways by triggering
the differentiation of T helper-17 lymphocytes. In this re-
gard ustekinumab, an anti-IL12/23 monoclonal antibody
directed against the p40 protein subunit of IL-23 and IL-12,
had been initially introduced in the treatment of psoriasis.126
Subsequently, ustekinumab was approved for CD in 2016
and then for UC.127,128 However, due to its short-term clinical
use, limited data exist on its effect on NAFLD in patients with
IBD.14,33
In one retrospective study, ustekinumab treatment, used as
a potential confounder, was not associated with NAFLD.33
Nevertheless, data from its administration in extra-intestinal
diseases indicated that treatment with anti-interleukin 12/23
seems to positively affect lipid metabolism, through its effect
on leptin expression. More specifically ustekinumab induces
leptin, suggesting a potential benefit for MetS and visceral
adiposity.129 Other authors also showed that patients receiv-
ing anti-IL12/23 do not gain weight, in contrast to those
treated with anti-TNF agents.130
However, induction of leptin may have a dual role in
NAFLD: leptin was shown to be beneficial in the early
stages of NAFLD through its anti-steatotic effect, but may
favour NAFLD progression in the later stages through its
NAFLD in IBD; Focus on Biologics
inflammatory and fibrogenic action.67,101 Therefore, until more
data specifically clarify the role of anti-IL12/23 in NAFLD, its
use in patients with IBD and NAFLD should be carefully con-
sidered, especially in cases of NASH and hepatic fibrosis.
4. Closing Remarks
NAFLD seems to co-exist in a high proportion of patients
with IBD and to follow two distinct forms, most likely reflect-
ing different predominant pathophysiological mechanisms
during IBD relapses and remissions. Intestinal inflammation
facilitates the dysbiosis of microbiota, mucosal disruption,
release of pro-inflammatory cytokines, and translocation of
inflammatory cells through the gut-liver axis, thus represent-
ing the predominant type of NAFLD during disease relapses.
During remissions, high-calorie nutrition and the restored
mucosal absorption may contribute to weight gain, thus
predisposing to dysmetabolism and thus to NAFLD. Due to
this special and distinct association between IBD and NAFLD,
which includes the classic predisposing factors [dysmetabolic
ones] and also the disease-specific ones, we may consider the
introduction of a specific NAFLD type which could be named
IBD-associated fatty liver disease [IBDAFLD]. This may be
a subtype of the metabolic dysfunction-associated fatty liver
disease [MAFLD],131 representing an emerging nomenclature,
but also a different definition of the disease despite fruitful
criticism by us and other authors.132
There is current necessity of a holistic management of pa-
tients with IBD. In this regard the effect of biologics, which
have been largely introduced in the treatment of IBD, on
NAFLD should be scrutinised. The relevant scientific lit-
erature is inconsistent, probably reflecting the diversity of
action of different biologics as well as the lack of studies
specifically designed for NAFLD endpoints. The more exten-
sively studied anti-TNF agents, having been included mostly
as confounders in relevant studies, showed a neutral or a po-
tentially beneficial association with NAFLD. On the contrary
the anti-integrin antibody, vedolizumab, may lead to the
progression of NAFLD, based on limited data from not spe-
cifically designed studies. Anti-IL12/23 are even less studied
in NAFLD, but should be cautiously considered in patients
with NASH and advanced fibrosis, because they upregulate
leptin which may have adverse effect in NASH and hepatic
fibrosis. Current data warrant further mechanistic studies
to enlighten the mechanisms of action of biologics, as well
as prospective cohort studies and possibly, clinical trials in
patients with IBD and concomitant NAFLD. In this way, we
will be able to select the best biologic agent for each patient
with IBD, achieving together a potentially beneficial or at
least neutral effect on NAFLD [or IBDAFLD]. If a beneficial
effect of some biologics is shown in patients with IBD, this
may open a new window for clinical trials of biologics in
NAFLD patients without IBD, as no approved treatment for
NAFLD exists.133
Funding
There was no grant or financial support for this review.
Conflict of Interest
No author has any conflict of interest.
859
Author Contributions
AP designed the study, performed the research, collected and
analysed the data, and wrote the paper; SP, AG, MD, and JK
further analysed the collected data, drafted and critically re-
vised the manuscript; SAP designed the study, drafted and
critically revised the manuscript. All the authors approved the
final version of this article.
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