CLINICAL MEDICAL EDUCATION

“Is Increased Intake of Whole Grains Tied to Lower Liver

Cancer Risk ?”

Disusun Oleh :
Rachmah Khoerunnisa 1820221151

Pembimbing :
dr. Wahyu Djatmiko, Sp.PD-KHOM

SMF ILMU PENYAKIT DALAM

RSUD PROF. DR. MARGONO SOEKARJO PURWOKERTO

2019
 LEMBAR PENGESAHAN

CLINICAL MEDICAL EDUCATION

“Is Increased Intake of Whole Grains Tied to Lower Liver Cancer Risk ?”

Disusun Oleh :

Rachmah Khoerunnisa 1820221151

Diajukan untuk memenuhi syarat mengikuti Kepaniteraan Klinik di Bagian Ilmu

Penyakit Dalam RSUD Prof. DR. Margono Soekarjo Purwokerto

Telah disetujui dan dipresentasikan

Pada Tanggal : Agustus 2019

Purwokerto, Agustus 2019

Pembimbing,

dr. Wahyu Djatmiko, Sp.PD (KHOM)

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CLINICAL CONTEXT
Increased dietary consumption of whole grains and fiber has been linked
to lower risk for insulin resistance, hyperinsulinemia, and systemic inflammation,
which are known to be associated with greater risk for hepatocellular carcinoma
(HCC). Furthermore, intake of whole grains and dietary fiber may benefit gut
integrity and microbiota composition, increasing production of microbiota-related
metabolites, including butyrate and other short-chain fatty acids that may affect
risk for development of HCC and other liver diseases.
In the United States, a large proportion of HCC cases cannot be explained
by currently known risk factors, including hepatitis B and C virus (HBV and
HCV) infections, metabolic disorders, and smoking. The hypothesis tested by this
cohort study was that greater long-term consumption of whole grains and dietary
fiber would be linked to lower risk for HCC in 2 cohorts from the Nurses' Health
Study and the Health Professionals Follow-up Study.

STUDY SYNOPSIS AND PERSPECTIVE

Higher intake of whole grains and possibly cereal fiber and bran may be
associated with reduced risk for HCC among adults in the United States,
according to a large observational study of 2 health professional cohorts with long
follow-up.
Diet is suspected as a possible important risk factor for HCC, but only
heavy alcohol use and certain fungus-contaminated foods (eg, affected nuts and
spices) have been established as such, say study authors led by Xuehong Zhang,
MD, ScD, from Brigham and Women's Hospital and Harvard Medical School,
Boston, Massachusetts.
So the investigators turned their attention to other foods.
They focused on whole grains and dietary fiber, especially cereal fiber,
because these have been associated with lower risk for obesity, type 2 diabetes,
and nonalcoholic fatty liver disease, all of which are "known predisposing factors
for HCC."
The team performed a cohort study among 125,455 participants from the
Nurses' Health Study and the Health Professionals Follow-up Study and looked at

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the intake of whole grains, their subcomponents (bran and germ), and dietary fiber
(cereal, fruit, and vegetable).
Study participants from both cohorts were scheduled to fill out food
questionnaires every 2 years. Investigators divided study subjects into tertiles
based on their levels of consumption of the study foods.
After an average follow-up of 24 years among the participants, there were
141 patients identified with HCC, which is a very low incidence cancer type.
The team reports that increased whole-grain intake was significantly associated
with lower risk for HCC (the highest vs lowest tertile intake: hazard ratio [HR],
0.63; P=.04 for trend).
The findings were published online February 21, 2019, in JAMA
Oncology.
An inverse HCC association was also observed for total bran (HR,
0.70; P=.11 for trend), but it was nonsignificant.
In addition, increased intake of cereal fiber (HR, 0.68; P = .07 for trend),
but not fruit or vegetable fiber, was associated with a reduced risk for HCC (but it
was also nonsignificant).
"If our findings [are] confirmed, increasing whole-grain or possibly cereal
fiber consumption may serve as a possible strategy for HCC primary prevention,"
said Dr Zhang in an email to Medscape Medical News.
Medscape Medical News also asked another researcher who has studied
diet and liver cancer to evaluate the new results.
Lemonica Koumbi, PhD, research fellow, Hepatology and
Gastroenterology, Imperial College London, England, said the results showed that
increased consumption of whole grains and bran and cereal fiber is associated
with lower HCC, risk but not fruit or vegetable fiber.
"It is a powerful study with excellent statistical methods. Nevertheless the
associations shown are not very strong, so I would say promising evidence with
potential," she told Medscape Medical News in an email.

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Some Examples of These Foods
Asked for comment, Nicola McKeown, PhD, a nutrition epidemiologist at
Tufts University, Boston, listed some examples of specific, easily purchased foods
the investigators highlighted as possibly protective.
Whole grains, said Dr McKeown, who was not involved in the study,
include whole-grain breads and rolls, ready-to-eat breakfast cereals, cooked
oatmeal, and cooked grains such as quinoa, brown rice, and millet.
Cereal fiber also includes ready-to-eat breakfast cereals (but not highly
processed cereals that do not contain a lot of dietary fiber) and whole-wheat
crackers.
And bran includes wheat bran, which is the main source of bran for most
Americans.
"Eating more whole grains as part of an overall healthy diet is a good
dietary strategy for overall health, but more research is needed to ascertain how
whole grains [and] cereal fiber impact liver cancer," Dr McKeown said in an
email to Medscape Medical News.
She also pointed out that the new study is observational, "so causality
cannot be inferred."
Other lifestyle factors were accounted for in the statistical models, said Dr
McKeown, but residual confounding is possible.
Dr Koumbi offered an opinion about the possible mechanisms at work in
the new findings. "Diets with a high fiber content, like cereals, may lower HCC
occurrence by decreasing subjective appetite and energy intake...hence
contributing to the maintenance of normal body weight, as well as exerting
beneficial effects on postprandial glucose level and blood lipid profile," she said.
The study authors hope that more research is performed in this area. They
believe "future studies that carefully consider hepatitis B and C virus infections
are needed to replicate our findings," and should examine these associations "in
other racial/ethnic or high-risk populations."

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 Dr Zhang commented that the participants in the 2 cohorts used in the new
study were mostly white, and that hepatitis infections are the most important risk
factors for HCC, but were not prevalent in the current study population.
"Although our results showed no evidence of the differential association of
whole grain and dietary fiber with the risk of viral and nonviral [HCC], or with
the risk of cirrhotic and noncirrhotic HCC, [the] small number of HCC cases may
limit the statistical power and restrict further interaction analyses in these high-
risk populations," he explained.
The study was funded by National Institutes of Health grants. One study
author reports financial ties to Bayer, Janssen, and Pfizer.

STUDY HIGHLIGTHS
 The cohort for this study consisted of 125,455 participants (mean age,
63.4±10.7 years; 77,241 women) from 2 cohorts from the Nurses' Health Study
and the Health Professionals Follow-up Study.
 Approximately every 4 years, participants completed validated food
frequency questionnaires regarding intake of whole grains, their subcomponents
(bran and germ), and dietary fiber from cereals, fruits, and vegetables.
 Cox proportional hazards regression models adjusted for most known
HCC risk factors, including alcohol intake, body mass index, and type 2 diabetes,
allowed estimation of multivariable HRs.
 However, lack of data on chronic HBV/HCV infection status in all
participants precluded analyses adjusting for or stratifying by HBV/HCV
infection status.
 Among 183 participants for whom such data were available (105 with
HCC and 78 controls), HBV/HCV infection status was not correlated with
consumption of whole grains or dietary fiber.
 During follow-up (average, 24.2 years), 141 patients developed HCC.
 The National Death Index was also used to identify unreported HCC.
 For the highest vs the lowest tertile of whole-grain intake, risk for HCC
was significantly lower (HR, 0.63; 95% CI, 0.41-0.96; P=.04 for trend).

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 For total bran, the inverse association with HCC did not reach statistical
significance (HR, 0.70; 95% CI, 0.46-1.07; P=.11), and there was no apparent
association for germ.
 Risk for HCC was nonsignificantly reduced with increased consumption
of cereal fiber (HR, 0.68; 95% CI, 0.45-1.03; P=.07 for trend), but not of fruit or
vegetable fiber.
 Excluding the patients with HCC and known chronic HBV/HCV
infections led to similar findings.
 On the basis of their findings, the investigators concluded that increased
intake of whole grains and possibly cereal fiber and bran could be linked to lower
risk for HCC among US adults.
 However, the results should be interpreted cautiously in light of limitations
including the lack of data on HBV/HCV infection in the full cohort and the small
number of HCC cases resulting in limited statistical power.
 Other limitations include observational design with potential
misclassifications in dietary data, possible selection bias because of loss to follow-
up, and limited generalizability to racial/ethnic populations or geographic regions
other than white patients of European origin living in the United States.
 The investigators recommend future research to confirm or rule out their
findings while accounting for hepatitis B and C virus infections, to evaluate these
associations in other racial/ethnic or high-risk populations, and to determine the
underlying mechanisms.
 It may be necessary to pool analyses across cohorts with many participants
with HCC, because incidence is low in the United States.
 If the study results are confirmed, increasing dietary intake of whole
grains, bran, and cereal fiber may be a potential strategy to help prevent primary
HCC; meanwhile, eating more whole grains as part of an overall healthy diet is a
good dietary strategy to benefit overall health.
 Foods containing these components include whole-grain breads and rolls,
breakfast cereals that are not highly processed; cooked oatmeal, quinoa, brown
rice, and millet; whole-wheat crackers; and wheat bran.

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 These dietary components may protect against HCC by mitigating the
carcinogenic effect of hyperinsulinemia and inflammation or by improving gut
integrity and microbiota composition.
 The stronger beneficial association for the whole grain subcomponent of
bran than for germ regarding HCC risk is consistent with findings of previous
studies of the Nurses' Health Study and the Health Professionals Follow-up Study
cohorts, suggesting that bran, but not germ, was significantly associated with
lower risk for total and cardiovascular disease-specific mortality, type 2 diabetes,
hypertension, and coronary heart disease in persons with diabetes.
 These results might be explained by low consumption of germ in this
cohort (median, 4.2 g/d for total bran vs 0.74 g/d for total germ), or by the
presence of beneficial bioactive compounds, such as cereal fiber, vitamins,
minerals, and phytonutrients, mainly in the bran component.
 Cereal fiber, but not fruit or vegetable fiber, was associated with lower risk
for HCC in this study and in the European Prospective Investigation into Cancer
and Nutrition cohort.
 Compared with fruit or vegetable fiber, cereal fiber has also been shown to
be more consistently associated with lower risk for total mortality, cardiovascular
disease, type 2 diabetes, and colorectal cancer.
 Fruits and vegetables, particularly fruit juice, may contain sugar or added
sugar, leading to liver damage and nonalcoholic fatty liver disease, which could
outweigh the potential benefit of fruit or vegetable fiber intake.
 However, the explanations underlying this difference are still unclear and
merit further study.

CLINICAL IMPLICATION
 Increased intake of whole grains was associated with a significantly
reduced risk for HCC, and bran and cereal fiber with a nonsignificantly reduced
risk for HCC, in a large US cohort study.
 These dietary components may protect against HCC by mitigating the
carcinogenic effect of hyperinsulinemia and inflammation, or by improving gut
integrity and microbiota composition.

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 Implications for the Healthcare Team: If the study results are confirmed,
increasing dietary intake of whole grains, bran, and cereal fiber may be a potential
strategy to help prevent primary HCC; meanwhile, eating more whole grains as
part of an overall healthy diet is a good dietary strategy to benefit overall health.

CME TEST
Question 1 of 1
You are a member of the healthcare team for a 67-year-old diabetic, overweight
man with a history of alcoholism who is interested in possible lifestyle strategies
to lower his risk for hepatocellular carcinoma (HCC). On the basis of the cohort
study from the Nurses' Health Study and the Health Professionals Follow-up
Study by Yang and colleagues, which one of the following statements about the
association between long-term consumption of whole grains and dietary fiber with
HCC risk is correct?

For the highest vs the lowest tertile of whole grain intake, risk for HCC was
37% lower
The inverse association of whole grain intake with HCC did not reach
statistical significance

Risk for HCC was significantly decreased with increased consumption of

wheat germ

Fiber from vegetables was more strongly associated with reduced HCC risk
than fiber from cereals or fruits

Question 2 of 2

According to the cohort study from the Nurses' Health Study and the Health
Professionals Follow-up Study by Yang and colleagues, which one of the
following statements about clinical implications of the association between long-
term consumption of whole grains and dietary fiber with HCC risk is correct?

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 The study proves that eating more whole grains prevents HCC

The potential benefit from eating more whole grains to prevent HCC risk is
canceled by the risk for weight gain

Whole grains may protect against HCC by mitigating the carcinogenic effect
of hyperinsulinemia and inflammation or by improving gut integrity and
microbiota composition

Compared with fruit fiber or cereal fiber, vegetable fiber has been more
consistently associated with lower risk for total mortality, cardiovascular disease,
type 2 diabetes, and colorectal cancer

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CERTIFICATE

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