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Received: 10 December 2018    Revised: 19 January 2019    Accepted: 20 February 2019
DOI: 10.1111/hel.12588
EDITORIAL
Helicobacter pylori infection and nonalcoholic fatty liver
disease: Time for large clinical trials evaluating eradication
therapy
1 |  I NTRO D U C TI O N
Nonalcoholic fatty liver disease (NAFLD) has become one of the main
causes of chronic liver diseases, with an estimated global prevalence
of 25%‐30%, rising up to 90% in morbidly obese patients.1 NAFLD in‐
cludes simple steatosis (SS) and nonalcoholic steatohepatitis (NASH),
which may advance to cirrhosis and hepatocellular carcinoma (HCC).2
NAFLD‐related mortality, attributing to hepatic diseases (ie, cirrhosis,
its complications, and HCC) and extra‐hepatic diseases (ie, chronic
kidney disease, cardiovascular diseases [CVD], cerebrovascular disor‐
ders, and malignancies), 2 continues to increase in contrast to decreas‐
3
ing trends in viral hepatitis‐related mortality. Nonetheless, the need
for noninvasive diagnosis 4 and treatment of NAFLD remain unmet.5
The pathogenesis of NAFLD is not fully elucidated. It is a mul‐
tifactorial disease, with multiple genetic and environmental factors
(“hits”) interplaying, thus contributing to a “multiple parallel‐hit”
model.6 Specific genetic polymorphisms (eg, of patatin‐like phospho‐
lipase domain‐containing protein 3 gene, transmembrane 6 super‐
family member 2), epigenetic mechanisms, diet (eg, excessive fat and
fructose), lack of physical activity, insulin resistance (IR), and dysreg‐
ulation of adipokines are regarded as key contributors,7 but other
factors, including endocrine disruptors8 and dysbiosis of the gut mi‐
crobiota9 have been recognized as emerging pathogenetic “hits.”
In this regard, though controversy still exists, there is growing evi‐
dence for an association between Helicobacter pylori and NAFLD, sim‐
ilarly to other manifestations of IR syndrome or metabolic syndrome,
including obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, and
CVD.10,11 As for NAFLD,1 H pylori infection (H pylori‐I) is also highly
12
prevalent worldwide and both are increasing with age. The association
of H pylori‐I and NAFLD is appealing and has a potential clinical implica‐
tion: if an association is established, H pylori eradication might inhibit
NAFLD development and/or progression toward advanced disease.
2 |  C LI N I C A L S T U D I E S O N TH E
A S S O C I ATI O N B E T W E E N H ELI CO BAC TER
PY LO R I I N FEC TI O N A N D N A FLD
The first case report linking H pylori‐I with NAFLD showed the pres‐
ence of 16S recombinant RNA of H pylori spp. on liver samples of a
13
NASH patient. This finding was then validated by a case series, in
Helicobacter. 2019;e12588. wileyonlinelibrary.com/journal/hel © 2019 John Wiley & Sons Ltd  |  1 of 7
https://doi.org/10.1111/hel.12588
which the 16S recombinant RNA of H pylori was detected in five of
11 liver samples of NAFLD patients compared with two of 13 con‐
trols.14 We showed, for the first time, higher rates of H pylori IgG se‐
ropositivity in NAFLD patients than controls, as well as higher rates of
previous H pylori eradication treatment in NASH than SS patients.15
Moreover, in accordance with our previous systematic review sup‐
porting a positive association between H pylori‐I and homeostasis
model assessment IR (HOMA‐IR), as index of IR,16 the individuals
with H pylori‐I had higher glucose, insulin, and HOMA‐IR compared
to those without previous or current H pylori‐I. Noteworthy, the
former had also higher liver function tests (alanine transaminase
[ALT] and aspartate transaminase [AST]) and tumor necrosis fac‐
tor (TNF)‐α 15; TNF‐α is considered a key pathogenetic cytokine for
NAFLD, and experimental data appear to confirm that anti‐TNF‐α
agents may be significant for NASH treatment.17 Of note, one study
published previous to ours reported that H pylori‐I was one of the
independent risk factors for the development of NAFLD18; however,
due to language restriction, this study cannot be presented in detail.
Following the aforementioned initial reports, there have been
amounting data from observational studies (mostly cross‐sectional)
having evaluated the potential association between H pylori‐I and
NAFLD.19-32 The main characteristics and results of these studies
are summarized in Table 1. The majority of them (n = 12) have been
carried out in Asia (China, South Korea, Japan, and Turkey), two in
Europe (Greece and Spain), and one in the USA. The diagnosis of
NAFLD was based on abdominal ultrasonography in most studies,
whereas on histology only in few studies.15,20,25 Noninvasive indices
of steatosis or fibrosis were also used in some studies. 22,27,31 Briefly,
most studies reported higher rates of H pylori‐I in NAFLD patients
and, inversely, higher rates of NAFLD in H pylori‐infected individuals
(Table 1). However, a minority of studies reported no association be‐
tween H pylori‐I and NAFLD. 22,28,30 Only one study reported inverse
association, that is, lower rates of NASH in H pylori‐infected than
noninfected individuals25; in the same study, H pylori‐infected indi‐
viduals had higher rates of steatosis than noninfected ones, which is
a seeming paradox. 25 In some studies, H pylori‐I was independently
associated with NAFLD, though in other studies their relationship
did not remain robust after adjustment for potential cofounders
(Table 1). It should be underlined that 95 genes were associated
with both H pylori‐I and NAFLD in one study, 26 possibly implying
common genetic predisposition. In line, a recent meta‐analysis of
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2 of 7       EDITORIAL
six observational studies (one case‐control and five cross‐sectional)
also showed higher risk of NAFLD in patients with H pylori‐I (odds
ratios 1.21; 95% confidence interval 1.07‐1.37).33
Limited studies have to‐date evaluated the effect of H pylori
eradication regimen on NAFLD. Improved liver function tests (ALT
and gamma‐glutamyl transferase [GGT]), hepatic steatosis (assessed
with liver ultrasonography and the noninvasive fatty liver index [FLI]),
and IR (assessed with HOMA‐IR) were reported in a man 2 months
after successful eradication of H pylori‐I.34 Likewise, we performed
a pilot, 12‐month open‐label study evaluating the effect of H pylori
eradication treatment on hepatic fat fraction (evaluated by magnetic
resonance imaging) and noninvasive indices of fibrosis and NASH
(NAFLD fibrosis score and homocysteine, serum AST, erythrocyte
sedimentation rate, nonalcoholic steatohepatitis index [HSENSI], re‐
spectively) in biopsy‐proven NAFLD patient with H pylori‐I, whereas
noninfected NAFLD patients served as controls.35 We showed no
effect of H pylori eradication on hepatic steatosis, but a trend to‐
ward improvement in noninvasive indices of fibrosis and NASH.
Moreover, a 6‐month randomized controlled trial (RCT) comparing
lifestyle modification alone or in combination with H pylori eradica‐
tion in patients with H pylori‐I and NAFLD (diagnosed with persistent
elevated serum aminotransferases and abdominal ultrasonography)
showed no effect of H pylori eradication on liver function tests (AST,
ALT, and GGT), liver fat content (a noninvasive index of hepatic ste‐
atosis), and HOMA‐IR.36 Since all the above markers were improved
in the sum of patients, this study supported that H pylori eradication
had no additive effect on lifestyle modifications. It is underlined that
paired liver biopsies were not performed, and placebo was not used
in none of the aforementioned interventional studies.
3 |  W H AT I S N E W I N “ H E LI CO BAC TE R ”
“Helicobacter” has recently published a study that further estab‐
lishes the association between H pylori‐I and NAFLD, and provides
evidence for a therapeutic potential of H pylori eradication treat‐
ment on NAFLD.37 Specifically, this was a multicentre cohort study
with 369 adults without NAFLD at baseline (evaluated by abdomi‐
nal ultrasonography) followed up for 2 years. The effect of H pylori‐I
on NAFLD was prospectively evaluated between H pylori‐positive
and negative individuals (evaluated by fecal antigen test). To avoid
weight changes after eradication treatment that could distort the
effect of H pylori‐I on NAFLD, dietary counseling was provided, tar‐
geting to maintain weight. During follow‐up, higher rates of NAFLD
were observed in H pylori‐positive individuals (7.0% and 13.5%, at
month 12 and 24, respectively) than H pylori negative ones (none
developed NAFLD). 37 These results were further supported by re‐
spective changes in two noninvasive indices of steatosis (hepatic
steatosis index [HIS] and NAFLD liver fat score). Importantly, H py-
lori‐I was shown to be an independent predictor for the subsequent
development of NAFLD together with other more established in‐
dices, including age, C‐reactive protein, and leptin‐to‐adiponectin
ratio.37
After a 2‐year follow‐up, H pylori eradication treatment was ad‐
ministered in H pylori‐positive individuals. Successful H pylori eradi‐
cation was achieved in 127 (74.3%), which were followed up for extra
3 months. Importantly, eradication treatment decreased both HIS
and NAFLD liver fat score. NAFLD remained in only five of 23 pa‐
tients (21.7%) who had developed NAFLD during the 2‐year follow‐
up and resolved in the rest 18 (78.3%).37 Triglycerides (−8.3%), GGT
(−12.3%), HOMA‐IR (−14.8%), leptin (−16.3%), leptin‐to‐adiponectin
ratio (−16.7%), TNF‐α (−26.4%), IL‐6 (−13.9%), and CRP (−17.9%) were
also reduced after successful eradication treatment.37
This study has certain strengths. Its design (prospective cohort)
allow the establishment of a more robust association between H py-
lori‐I and NAFLD compared with the majority of previous studies
that were case‐control or cross‐sectional (Table 1). More impor‐
tantly, H pylori eradication decreased rates of NAFLD, together with
HOMA‐IR, adipokines, and low‐grade inflammation, regarded as key
contributors to the pathogenesis of NAFLD.38,39 Despite its limita‐
tion, mainly being the lack of paired liver biopsies and the lack of
control group during the 3‐month extension of H pylori eradication
regimen, this study provides probably the best to‐date evidence
supporting the association between H pylori‐I and NAFLD.
4 | C LOS I N G R E M A R K S
Most existing studies favor an association between H pylori‐I and
NAFLD and are in accordance with the axiom that H pylori‐I is not
and never was protective against anything.40 In line, animal data
also support that H pylori‐I aggravates diet‐induced NAFLD.41
Following oral inoculation, H pylori approaches the liver and causes
inflammation,42 thereby playing an additive role on the pathogenesis
of the disease, together with other established risk factors. The mo‐
lecular links between H pylori‐I and NAFLD are not fully elucidated,
as extensively summarized.43 H pylori invasion into gastric and in‐
testinal mucosa increases their permeability; thus, they are becom‐
ing more penetrable to endotoxins, which then pass via the portal
vein to the liver44; endotoxins and translocated bacteria owing to
augmented intestinal permeability are involved in NAFLD develop‐
ment and its progression to NASH. H pylori‐I also contributes to a
low‐grade systematic inflammation, by releasing proinflammatory
and vasoactive mediators, including cytokines and interleukins, and
downregulating adiponectin.43 Moreover, H pylori‐I increases oxida‐
tive stress and apoptosis, processes both contributing to NAFLD
pathogenesis.43 Furthermore, H pylori‐I is positively associated with
IR,16 being a key pathogenetic factor for NAFLD.
Based on current evidence, the initiation of large RCTs eval‐
uating the effect of H pylori eradication treatment on patients
with NAFLD is warranted. Paired liver biopsies are required to
provide core evidence on histological endpoints, that is, hepatic
steatosis, inflammation, and mainly fibrosis, regarded as the main
histological endpoint for advanced disease.45 Importantly, total
adiponectin and all its isoforms were increased after successful
H pylori eradication treatment in humans, 46 a finding that further
TA B L E 1   Main characteristics and results of observational studies having evaluated the association between Helicobacter pylori infection and NAFLD

First author,
EDITORIAL

origin, year
[reference]a  Study design NAFLD diagnosis Hp diagnosis Participants (N) Age (y) Main results

Polyzos, Case‐control (NAFLD vs Liver biopsy Combination of NAFLD: 28 54 ± 2 1) Higher rates of Hp IgG seropositivity in NAFLD patients than
Greece, controls) history of Hp Controls: 25 55 ± 2 controls.
201215 eradication 2) Higher rates of previous Hp eradication treatment in NASH than
treatment, Hp IgG SS patients.
seropositivity and
13
C urea breath
test
Dogan, Cross‐sectional (patients Ultrasonography Gastric biopsy Hp(+): 95 40 ± 13 1) Higher rates of NAFLD, liver size and spleen size in Hp(+) than
Turkey, with functional dyspepsia) Hp(−): 79 43 ± 13 Hp(−) individuals.
201319 2) Lower liver‐to‐spleen ratio in Hp(+) than Hp(−) individuals.
Sumida, Case‐control (SS vs NASH) Liver biopsy Hp IgG NASH: 87 55 ± 15 1) Higher rates of Hp IgG seropositivity in NASH than SS patients.
Japan, seropositivity SS: 43 (overall) 2) Hp IgG seropositivity was independently positively associated
201520 with NASH.
3) Hp IgG seropositivity was positively associated with NAS and
hepatocyte ballooning.
Okushin, Cross‐sectional (adults Ultrasonography Hp IgG NAFLD: 1802 Females: 1) Higher rates of Hp IgG seropositivity in NAFLD than controls in
Japan, receiving medical check‐up) seropositivity Controls: 3487 51 ± 8 females, but not in males
201521 48 ± 9 2) Hp IgG seropositivity was not independently associated with
Males: NAFLD in either sex.
48 ± 9
47 ± 10
13
Baeg, South Cross‐sectional, retrospec‐ Noninvasive C urea breath test Hp(+): 1636 46‐61 Hp infection was not independently associated with either HSI or
Korea, tive (adults receiving indices of Hp(−): 2027 43‐60 NAFLD‐LFS.
201522 medical check‐up) steatosis (HSI
and NAFLD‐LFS)
14
Zhang, Case‐control (NAFLD vs NA C urea breath test NAFLD: 600 NA Higher rates of Hp infection in NAFLD patients than controls.
China, controls) Controls: 600
201623
Kim, South Cross‐sectional (adults Liver function Hp IgG Hp(+): 21 985 50 ± 10 Higher ALT and AST in Hp(+) than Hp(−) individuals.
Korea, receiving medical check‐up) tests seropositivity Hp(−): 15 278 48 ± 11
201624
Lecube, Cross‐sectional (morbidly Liver biopsy Gastric biopsy 93 (overall) NA 1) Similar rates of NAFLD in Hp(+) and Hp(−) individuals.
Spain, obese adults waiting for 2) Higher rates of steatosis in Hp(+) than Hp(−) individuals.
201625 bariatric surgery) 3) Lower rates of NASH in Hp(+) than Hp(−) individuals.
13
Chen, China, Case‐control (NAFLD vs Ultrasonography C urea breath test NAFLD: 603 69 ± 7 1) Higher rates of Hp infection in NAFLD patients than controls.
201626 controls) Controls: 1660 (overall) 2) Hp infection was independently positively associated with
NAFLD.
|

3) 95 genes were associated with both Hp infection and NAFLD

      3 of 7

(Continues)
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4 of 7      

TA B L E 1 (Continued)

First author,
origin, year
[reference]a  Study design NAFLD diagnosis Hp diagnosis Participants (N) Age (y) Main results

Kim, South Cohort study (adults without Ultrasonography; Hp IgG Hp(+): 9918 50 ± 9 1) Independently higher hazard ratio of NAFLD in Hp(+) than Hp(−)
Korea, NAFLD at baseline noninvasive seropositivity Hp(−): 7110 48 ± 10 individuals.
201727 participating in repeat index of steatosis 2) Similar results were retrieved when FLI replaced ultrasonogra‐
medical check‐up followed (FLI) phy for the diagnosis of NAFLD.
up for a median of 5.1 y)
13
Cai, China, Cross‐sectional (adults Ultrasonography C urea breath test NAFLD: 433 41 ± 10 Similar rates of Hp infection in NAFLD patients and controls.
201828 receiving medical check‐up) Controls: 1618 37 ± 10
14
Fan, China, Cross‐sectional (adults Ultrasonography C urea breath test Hp(+): 10 848 48 ± 15 1) Higher rates of NAFLD in Hp(+) than Hp(−) individuals.
201829 receiving medical check‐up) Hp(−): 17 323 48 ± 15 2) Difference between groups did not remain robust after
adjustment for BMI and blood pressure.
3) In subgroup analysis, higher rates of NAFLD in Hp(+) than Hp(−)
women, but not men.
13
Lu, China, Cross‐sectional (adults Ultrasonography C urea breath test Hp(+): 589 54 ± 10 1) Similar rates of NAFLD in Hp(+) and Hp(−) individuals.
201830 receiving medical check‐up) Hp(−): 1278 (overall) 2) Within NAFLD patients, higher ALT in Hp(+) than Hp(−)
individuals.
Kang, USA, Cross‐sectional (National Ultrasonography Hp IgG NAFLD: 1723 46 ± 1 1) Higher rates of Hp IgG seropositivity in NAFLD patients than
201831 Health and Nutrition and noninvasive seropositivity Controls: 3681 42 ± 1 controls.
Examination Survey III) indices of fibrosis 2) Higher rates of NAFLD in Hp(+) than Hp(−) individuals.
(NAFLD fibrosis 3) Higher rates of NAFLD in Hp cag(−) than Hp cag(+) individuals.
score, FIB‐4 and 4) Similar rates of fibrosis in Hp(+) and Hp(−), and in Hp cag(−) and
APRI) Hp cag(+) individuals.
Abdel‐Razik, Cohort study (adults without Ultrasonography Hp fecal antigen Hp(+): 171 50 ± 8 1) Higher rates of NAFLD in Hp(+) than Hp(−) individuals.
Egypt, NAFLD at baseline followed and noninvasive test Hp(−): 198 49 ± 9 2) Hp infection was independently positively associated with
201837 up for 2 y) indices of NAFLD.
steatosis (HSI 3) Eradication treatment decreased both HIS and NAFLD‐LFS.
and NAFLD‐LFS)
13
Yu, China, Cross‐sectional (adults Ultrasonography C urea breath test NAFLD: 7592 50 ± 12 1) Higher rates of Hp infection in NAFLD patients than controls.
201832 receiving medical check‐up) Controls: 46 ± 14 2) The combination of Hp infection and WBC were independently
12 797 positively associated with NAFLD.

ALT, alanine aminotransferase; APRI, aspartate aminotransferase to platelet ratio index; AST, aspartate aminotransferase; BMI, body mass index; FIB‐4, fibrosis score‐4; FLI, fatty liver index; HSI, hepatic
steatosis index; Hp, Helicobacter pylori; IgG, immunoglobulins G; NA, not available; NAFLD, nonalcoholic fatty liver disease; NAFLD‐LFS, NAFLD liver fat score; NAS, nonalcoholic fatty liver disease activity
score; NASH, nonalcoholic steatohepatitis; SS, simple steatosis; WBC, white blood cells.
a
References are presented in publication date order (e‐publication date were used, when available).
EDITORIAL
EDITORIAL |
      5 of 7

supports the beginning of clinical trials, since adiponectin upreg‐ the prevalent model is that of “parallel multiple‐hit,” in which H py-
ulation exhibits anti‐steatotic, anti‐inflammatory, anti‐fibrotic, lori‐I may be a pathogenetic “hit”.15 Therefore, since we previously
47
and anti‐apoptotic effect in NAFLD. In this regard, thiazoli‐ recommended a multiple‐target management, thereby concurrently
dinediones (pioglitazone and rosiglitazone), which have shown targeting more than one of its pathogenetic hits,52 H pylori eradica‐
beneficial effect on NAFLD histology, act at least partly through tion may contribute to a more integrated management of the dis‐
48
adiponectin upregulation. However, there are some consider‐ ease. In this regard, H pylori eradication may not “eradicate” NAFLD,
ations regarding RCTs in NAFLD patients with concurrent H py- but may provide certain therapeutic benefits, given that H pylori‐I is
lori‐I. First, since the current practice is to "test‐and‐treat" all still a major global burden.53
individuals with H pylori‐I, the duration of RCTs may not be long,
due to ethical considerations on untreated patients of placebo
D I S C LO S U R E S O F I N T E R E S T S
arms. Based on Abdel‐Razik et al study, 37 a 3‐month period may
be sufficient to show a histological difference in NAFLD after a The authors have no competing interests.
successful H pylori eradication, especially in hepatic steatosis and
inflammation; this short duration seems to be ethically accept‐
ORCID
able. Second, antibiotics may per se affect NAFLD, which may
distort the effect of RCTs, a potential “artifact” needing careful Stergios A. Polyzos  https://orcid.org/0000-0001-9232-4042
consideration since the design of the RCTs. Animal data have Jannis Kountouras  https://orcid.org/0000-0001-6459-5136
shown either beneficial 49 or adverse 50 effects antibiotics on
NAFLD, which may probably largely differ among different antibi‐
Keywords
otics. The actions of antibiotics mainly target the intestinal micro‐
Helicobacter pylori, homeostasis model assessment, insulin
biota; to the most, the effects of antibiotics are indirect through
resistance, metabolic syndrome, nonalcoholic fatty liver disease,
affecting the relevant populations of different types of microbi‐
nonalcoholic steatohepatitis
ota and gut permeability, whose association with NAFLD is highly
51
emerging. Furthermore, when calculating sample size, the rate
Stergios A. Polyzos1
of nonresponders to H pylori eradication treatment should be
Jannis Kountouras2
considered a priori, so as the sample to be of adequate power.
1
First Department of Pharmacology, Faculty of Medicine, Aristotle
Considering the above‐mentioned claims, an RCT would be
University of Thessaloniki, Thessaloniki, Greece
performed in biopsy‐proven NAFLD patients, initially divided into
2
Second Medical Clinic, Faculty of Medicine, Aristotle University of
active antibiotic and placebo arms. Patients should be ideally sub‐
Thessaloniki, Ippokration Hospital, Thessaloniki, Greece
jected to a repeat liver biopsy at 3 months post‐treatment to eval‐
Correspondence
uate the main endpoint, being the effect of H pylori eradication on
Stergios A. Polyzos, First Department of Pharmacology, Faculty of
hepatic steatosis and inflammation, as well as the NAFLD activity
Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
score (NAS), being a composite index. The study could be extended
Email: spolyzos@auth.gr
by providing H pylori eradication treatment in patients on the pla‐
cebo arm and evaluating its effect after another 3‐month treat‐
ment, ideally with a third liver biopsy. A secondary endpoint would
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