LN°1 – 10.03.

2022
HUMAN NUTRITION – PROF. CENA
SANTALUCIA, ALBERTINI

INTRODUCTION TO THE COURSE

Professor Cena is the head of the laboratory of dietetics & clinical nutrition in Pavia. It consists in a group of
medical doctors that devote 40% of their time to clinical assistance and 60% to research. They do both clinical
research and epidemiological research.

The course will focus on the basis of dietetics and nutrition such as physiological diet, energy requirement and
nutritional status assessment (which is crucial). Nutrition is a cross-sectional topic, all pathological conditions
have something to do with nutrition and every medical doctor needs to have a basis in nutrition because it
may lead to a better outcome if applied to disease treatment. Thus, at the end of the course students will
acquire some basis of dietetics and will be able to deal with some crucial common pathologies such as:

• Obesity and metabolic syndrome: very prevalent not only in industrialized countries but also in
developing ones
• Inflammatory bowel diseases and GI diseases: increasing prevalence
• Nutrition and brain: nutrition is strongly involved in cognition, especially during the fetal, newborn
and adolescent life. Plus, nutrition has to do with neurodegenerative diseases which are another
common cause of non-communicable diseases nowadays.
• Eating disorders: first cause of mortality between psychiatric disorders
• Oncology and nutrition

There is no specific textbook, just listen to the lectures and write to professor for any doubts or to ask to treat
a specific topic.
Two helpful books may be “Food & The Nutrition Care Process” by Kraus and Mahan’s or “Nutrition in Lifestyle
Medicine” by James M.Ripper, extremely interesting and “fashionable” topic, as we live in a world that needs
to reach sustainability. To be sustainable even Big Pharma has to lower CO2 emission and produce less
medications, so it is important to propose a different approach for therapy and this is the reason why lifestyle
medicine is gaining interest in the medical field.

The exam will probably be both open questions and multiple choice questions, but it may also be an oral
examination, it depends on how things go further.

For those interested, there are additional lectures from a Master Course that we can attend (for a maximum
of 2 lectures each). You can email the professor to have the lecture calendar, they start on March 21.
Plus there is the Sustainable Development Goals Course for European Alliance Lifestyle and Nutrition and it is
coordinated by other professors which work for research that will be invited to hold the lessons.

HEALTH AND NUTRITION

This lecture will be an overview on the importance of nutrition both in health and disease.
Starting from our genotype we know that we have a DNA which is similar to the one of our ancestors, in fact
what has changed a lot in these centuries are environmental conditions. Environment is able to change not
the genotype itself but what the genotype dictates. We see its influence throughout the impact on the
phenotype, so by the interaction between genotype and environment we have different phenotypes, also in
the same disease. For example in the case of PCOS among young women different signs and symptoms can be
shown. When talking about nutrition usually people refer to it as an external factor that is able to interact with
the phenotype and genotype of every individual, thus affecting the course of diseases. In particular, nutrition
is one of the main environmental factors able to shape our phenotype.
The definition of Health according to the WHO is “a state of complete physical, mental and social well-being
and not merely the absence of the disease or infirmity”.
We may encounter during life different risk factors
which lead us to the disease.
The disease starts before we feel the symptoms, when
we develop risk factors which are also connected to
nutrition. Nutrition can impact positively or negatively
the disease. For example a healthy eating can be a
protective factor while poor nutrition (not just
undernutrition but for example an unbalanced diet
which leads to a deficiency of macronutrients) can
increase the risk for disease.

Note: educating children to a healthy diet is very important as it is able to prevent or postpone some diseases,
even the familiar ones (not the genetic ones). Indeed, chronic degenerative diseases or non-communicable
diseases have been shown to be preventable in 95% of the cases. The remaining 5% are genetic disorders.

MEDICAL NUTRITION THERAPY

Nutrition is mostly considered a first grade prevention: it consists in maintaining people considered healthy in
health. In fact, nutrients can be used by a specific diet, for example in celiac disease the gluten-free diet is
necessary for survival. On other situation we may not have a complete or useful GI-tract so we need enteral
or parental nutrition.

By using nutrition to deal with subjects who are already ill (they already developed the disease) instead of
dietetics the term medical nutrition therapy is used. It consists of nutrition assessment and treatment of a
condition, illness or injury that places an individual at risk for nutritional problems, management of symptoms,
amelioration of quality of life, recovery or decrease risk of progression, nutritional stores maintenance.
It refers to the action of understanding how different nutrients taken by diet can affect the progression of a
specific disease, e.g. renal diseases. It is now well-known that patients with these pathologies should have a
low-protein diet, which might help in postponing dialysis and ESRF. So when many of the risk factors manifest
together they are already a disease, although the single patient does not have the perception of not being
health. In fact diabetes (or glucose intolerance) may be present in subject who has no symptoms and be a
silent killer. Due to the latency the patients are not evaluated in the right way to verify which are the first risk
factors which should be counteracted to not develop the disease.

CAUSES OF DEATH IN 2017

In this century the causes of death have changed: once the
main causes were infectious diseases while nowadays
although they are still present but there is a growing
prevalence of other diseases which manifest later in life,
This chapter highlights why every medical doctor should
care about nutrition: in 2017 the WHO showed that 60%
of population died because of non-communicable
diseases which develop because of lifestyle, food,
smoking, physical inactivity, endocrine disruptors and
other factors. They are linked to long life expectancy and
they are mainly chronic degenerative disease
(cardiovascular, metabolic and cancer which is mostly associated with environment rather than with genetics).
In 2010 for the first time in history cardiovascular diseases were bypassed by cancer which started growing in
prevalence. One of the reason of this increase is the general increase in overweight and obesity prevalence in
the general population.
We are not only aware that these diseases are usually associated with elderly age but WHO is concerned about
the high prevalence of premature deaths because of these diseases. People between 35-60 years (50M) get
the disease and die prematurely. Interestingly, nowadays the incidence of cardiovascular deaths is slightly
decreasing because of food policies and campaigns aimed at alarming the target population (mainly adults)
about the risk factors of these conditions.

When thinking about the relationship between food and non-communicable diseases, it is important to
consider a life-course approach because these illnesses arise as a result of an accumulated risk which starts
even before conception (mothers are responsible for the fetal development). Dietary habits add up to an
intrinsic genetic susceptibility, which is different for every individual.

The graph on the side shows the risks associated to

global death. These risks factors are associated with
lifestyle, indirectly also the first and third ones. The
following are the most relevant one:

• Blood Pressure
• Smoking
• Cholesterol
• Low fruits and vegetable intake: please note
that it weights more than High BMI. It is
fundamental to note that if the fruits and
vegetables intake does not reach the minimum
amount recommended (three portions/day, the ideal would be five portions/day), it leads to the death
of almost 153.000 people in Europe per year. For an adult one portion is for example an apple and it
is recommended 1 fruit and 2 sides of vegetable per day or vice versa. It is really important to educate
the patients on the importance of nutrition1.
• Physical Inactivity
• High BMI
• Alcohol intake
• Iron deficiency: from the graph it does not seem to have a big impact, but it is still one of the biggest
deficiencies in the world. In Europe > 25% of females in the childbearing age have iron deficiency
anemia.
• Vitamin A deficiency: crucial, found mainly in underdeveloped countries. It might be so severe that
vaccines cannot exert their effect because of this.

N.B. Iron and vitamin A deficiencies arise mainly because the absence of these nutrients does not cause an
overt clinical picture i.e. a patient might have an inadequate intake of one of these nutrients and develop a
deficiency without having symptoms. However, this situation is still not optimal because micro-nutrients
deficiency builds up to create an accumulated risk.

NON-COMMUNICABLE DISEASES (NCD): A LIFE COURSE APPROACH

When thinking about the relationship between food and non-communicable diseases, it is important to
consider a life-course approach because these illnesses arise as a result of an accumulated risk which starts
even before conception (mothers are responsible for the fetal development). Dietary habits add up to an
intrinsic genetic susceptibility, which is different for every individual. The factors influencing anyone’s risk are
different according to the stage of life the subjects are into:

1
Prof. Cena noted that in her personal professional experience in outpatient clinics at Harvard University doctors were
better at communicating to patients, they took their time to explain (also visually, through slides) the aim of therapeutic
treatment, discussing possible outcomes and so on.
Fetal life: SES, Mother’s nutrition, Growth, Birth weight.
Infancy and childhood: SES, Infection, PEM,
Micronutrients, Growth rate, Stature, Physical Activity,
Food behavior.
Adolescence: Obesity, Sedentarism, Inactivity, Smoking
Adult life & elderly: Established adult risky behavior,
Diet, Physical activity, Tobacco, Alcohol, Biological risk,
Socioeconomic status, Environmental conditions.

This accumulated risk which is at the base of the NCD

pathophysiology is the reason why usually non-
communicable diseases appear later in life. However,
nowadays it is more frequent to see them during earlier
part of life. Italy is the first country in Europe for the prevalence of childhood obesity. This means that Italian
children are exposed to a higher risk of non-communicable diseases development. This can be seen also in the
clinic, as in the pediatric department it is possible to diagnose 5 years-old children with metabolic syndrome
(a condition usually seen in grown-ups). This usually occurs in case the subject already has a genetic
susceptibility for the disease.

The researches started asking why risk factors can impact positively or negatively even before preconception.
They kept imprinting during fetal development and programming in the very initial period. The results have
been translated into epigenetic modifications and into microbiota (less or more diversity which impacts health)
and have been demonstrated to be reversable.

The real problem is that these modifications are transgenerational. A study has been conducted regarding this
topic, called “The Dutch famine study” started in the 1950s. A bunch of pregnant women who were starving
because of the post-world war period, were studied. The main food of their diet was probably potatoes and
carrots, therefore no proteins, no macronutrients and no sufficient energy. Most of the women had
miscarriage, but the ones who delivered were followed-up during the years and it was showed that their
babies, despite having born under-weight, developed a higher prevalence of obesity. Why? Because of the
switching on of the so-called Thrifty genes, which are activated to keep all the energy in order to increase the
storages in case of a future absence of food, even in the next generations and even if food is sufficient. So the
development of obesity was also present in the following generation when the patients had the possibility to
eat normally.

So there are two important influences and impacts of nutrition:

1. Nutrigenetics: it is a branch of science that aims to discover how people respond to nutrients
depending on their genetic variation. Due to differences in people’s DNA, the absorption, the
transportation and metabolization of nutrients vary from one person to the next. Think about insulin
receptor inactivity which leads to glucose intolerance and diabetes type 2. The metabolites which are
produced might interfere with cellular processes and confer different phenotypes.

2. Nutrigenomics: it is the study of how different foods are metabolized and may interact with specific
genes to increase the risk of common chronic disease such as type 2 diabetes, obesity, heart disease,
stroke and certain cancers. It has been demonstrated that different patients by eating the same food,
produce different metabolites. These are marker of our diversity, also related to the environment
where we live.
Vitamin D might be deficient in winter and the same person may be not deficient in summer. The
vitamin is not only related to bone density, but is speculated to have anti-oxidant effect because it can
interfere with fluidity of cell membrane and it is capable of increasing insulin sensitivity.

Thus, nutrigenetic and nutrigenomic can interfere with DNA, RNA, protein synthesis and metabolites handling,
interacting with all the cellular processes which define the phenotype of a certain individual.
It is important to keep in mind that other factors should be taken into account when evaluating an individual’s
nutritional status (not only the diet and physical activity, which determine the energy balance):

- The microbiome. Indeed, the latter is shaped by the dietary habits and behaviors, and it is able to cross- talk
with brain. Thus, if it is shaped in a positive way when the subject is very young, that subject will preserve that
microbiome forever, while if it is shaped when the subject is 20-25 years old, then it is conserved that way
only until a certain is maintained e.g. a dietary change or a pro-biotic intake.

- Metabolomics. It is the way genetics interferes with the diet.

- Epigenetics. It is the way food can shape the transcriptomics of the DNA i.e. the information contained in the
DNA does not change but what varies is which information is being transmitted. The latter in turn depends
also on what and how the subject eats. This characteristic is not only transferred from the mother to the kid
but it is trans-generational, meaning that what a mother eats affect both the epigenetic of her children and of
her nephews.

BIOACTIVE FOOD COMPONENTS

We think of food as energy, as macronutrients
(proteins, lipids, sugar, etc.), but we do not always think
that food has many bioactive compounds, which are
not even considered nutrients. Anti-oxidants,
phytoextracts that can be found in vegetables,
polyphenols in olive oil. During the COVID pandemic
lactoferrin was talked about, it is a bioactive compound
extracted from milk, which has been demonstrated to
prevent severity of infection. All these compounds
together with food have a synergic effect, different
from a multivitamin pills intake, because there are
more and more compounds interacting together (we
do not even know all of them).

It is difficult to perform research in nutrition on human beings because of the influence of many factors.
Most of the studies have been done on enteral and parenteral nutrition on hospitalized patients. Nowadays
there are other tools called -omic sciences like metabolomic, proteonomic, metagenomic. They all allow
studies on people who live outside the hospital.

RISK FACTORS FOR DIABETES

There is strong evidence about diabetes type 2 risk factors,
which are obesity and abdominal obesity, even in patients
with normal weight. If we could erase these two risk factors
we would erase 80% of cases of diabetes type 2. Once
diabetes was shown just in adults while now is diagnosed in
adolescence. At this point it is important to remember that
there are different kinds of adiposities and between them
the visceral one is the most harmful. Indeed, this tissue
releases a large number of cytokines which have a pro-
inflammatory action. This is also the reason why obese
subjects with diabetes undergo bariatric surgery: a
reduction in the abdominal obesity will allow the patient to
fully recover from the disease, even if he/she is already on insulin therapy.
Evidence shows that increased intake of saturated fats, contained mostly in food of animal origin, is associated
to diabetes as well. They have not double boundaries and are stiff and break the cellular membrane.
Other risk factors are total fat intake and trans fatty acids, typical of Western and industrialized diet (fried
food).

RISK FACTORS FOR CARDIOVASCULAR DISEASES

For cardiovascular disease one of the main risk
factor is high sodium intake, which is linked to
hypertension. We shouldn’t get more than 1-2
g/day of salt even if the average in the population is
of 8-13 g/day. Instead, the risk decreases with (i) the
assumption of fruits, berries & vegetables. This is
because of two reasons: they contain a lot of fibers,
which slow down the absorption of sugars and fat,
and they contain a lot of anti-oxidants. The latter are
molecules able to counteract the oxidative stress
which is at the base of any insulin resistance. Thus,
they protect from diabetes and cardiovascular
diseases.
Moreover, also (ii) omega 3 have been show to have a protective effect. The latter are poly-unsaturated fatty
acids which are mainly contained in the fatty part of fish and some nuts (for those who are vegans). Finally,
(iii) potassium is another important protective factor.
In the paper it has been explained how salt is also
related to neurovascular and cognitive
dysfunction.
Thus, these considerations reveal that the western
diet itself (a high-salt, low-potassium diet)
predisposes to the development of non-
communicable disease. This is very different from
what happened in the past: the diet was a low-salt
(as salt was very expensive and impossible to be
extracted from sea water and thus used only to
preserve meat), high-potassium one (people used
to eat more fruits and vegetables, which contain
various minerals between which potassium). Thus,
for instance in the Paleolithic Era, subjects had a
very low blood pressure and, in order to have more energy they
had to eat meat, which could slightly increase the blood pressure.

NEURODEGENERATIVE DISEASES
Results make us think that all these factors are linked
and are important mostly in neurogenerative
disease, which are increasing in prevalence.
These diseases have a strong social impact that
affects both families and the whole society for
everything that involves assistance and the caregiver
system. This occurs first of all because there are no
effective medications: companies are not willing to
invest money in this field2, making prevention the
only possible way to control the problem. Treatment

2
Why are pharmaceutical companies not willing to invest in research for neurodegenerative disease medications? The
costs of research development would exceed the monetary gain in selling new medications. The strategies attempted
so far are “one size fits all” but have resulted to be inefficient, meaning that a more individual-specific approach is
necessary, which requires a greater deal of investment.
must start from lifestyle, socialization and specific vitamins and macronutrients. Luckily, the latest discoveries
showed that diet plays a fundamental role in the development of these diseases, thus lifestyle changes could
relevantly benefit the subjects affected.

THE MIND DIET

It was demonstrated that a particular diet, referred to as “the mind diet” is able to slow down the progression
of an initial cognitive impairment. This alimentary regiment is rich of some molecules such as: (i) anti- oxidants,
in particular polyphenols, (ii) Vitamin D and (iii) Vitamin B, mainly B9 (folic acid) and B12.These factors are
crucial because they are mediators of the homocysteine methionine circle. Methionine is an essential amino-
acid which can be found almost everywhere in food (it is very hard to be deficient of methionine) and it is used
in case of DNA damage. Indeed, it plays a major role in conditions characterized by extensive cellular
proliferation e.g. childhood, reparation processes, pregnancy etc. In these settings, in order to repair the DNA,
methionine donates an CH3 and it is transformed into homocysteine. The latter is not stable and can create
damage to the brain and other organs. Thus, thanks to folate and Vitamin B12, homocysteine is transformed
back to methionine.

THE VITACOG STUDY

The Vitacog study is a 2-years long double-blind clinical trial in which the patients were divided into two groups:
the first group received a placebo, while the second group had a cocktail of vitamin B, mainly B6, B12 and
folate. The results of the study had a statistical significance: as it can be seen from the picture below, there
was a greater loss of grey matter in the placebo group than in the Vitamin B group. Thus, overall, it is possible
to state that even though non-communicable diseases do need medications, they can be efficiently prevented
with life-style procedures. A lot of other studies investigated lifestyle medicine application in these diseases,
and have shown incredible results, even higher than metformin for diabetes or statins for cardiovascular
diseases. However, two main problems might be identified in this approach:
1. It is very expensive because it requires the presence of a multidisciplinary team, which is not convenient
for the hospital in terms of costs and resources.
2. It takes a long time (especially compared to medications).

DIETARY PATTERNS
Is there one or more than one nutrient which is responsible for all the diseases? There a lot of different factors
that can help to get sick but finding one single element is successful in lab and in animal models but not in
humans.
It is not possible to go to the drugstore and “buy” health. All different nutrients are linked in a dietary pattern.
If we have a deficiency we can use supplements, which cannot do anything without a healthy dietary pattern.
There are different healthy dietary patterns, one of the most common is the Mediterranean diet. All the
studies conducted on the Mediterranean diet showed a reduction of the risk of diabetes, cardiovascular
diseases, neurodegenerative diseases and overall mortality. Concerning CVD, suggestive evidence supports
the greater effectiveness in lowering total cholesterol levels, increasing HDL-cholesterol levels and reducing
weight, BMI and waist circumference. Conversely, no association was reported for LDL-cholesterol levels.
Studies try to show the important role of Mediterranean diet in treatments. Clinical trials showed a decrease
in diabetes/obesity in those who were affected. So with nutrition we reach both prevention and treatment.
The Mediterranean diet has
shown to work not only on
overweight and obesity but
also on more serious diseases
such as diabetes and, in some
instances, cancer. This is
especially relevant since,
starting from 2010, the
prevalence of cancer has
dramatically increased. The latter phenomenon is probably related also to the important increase in
overweight and obesity i.e. in subjects with increased BMI there is a strong evidence of increased risk for
certain cancers such as: esophageal adenocarcinoma, multiple myeloma, cancers of gastric cardias, colon,
rectum, biliary tract, pancreas, breast, endometrium, ovary and kidney.

Note: this does not mean that there is a strong and permanent association between adiposity and all the kinds
of cancer; indeed, first of all 5% of them are genetic, and in the remaining 95% only around 15 of them have
been shown to be strongly promoted by obesity. However, this link does exist and it is the reason for which
overweight patients should be screened more.

In general, a good alimentation consists in a diet which is rich in protective factors such as omega 3 and
bioavailable minerals, while low in risk factors such as simple sugars and trans-saturated fatty acids.

Harvard university showed that there are two dietary patters which are considered the best ones (also because
it is easy to be compliant to): the Mediterranean and the DASH. The DASH is for Americans the Western
analogue of Mediterranean diet. This dietary allowed to stop hypertension and cardiovascular diseases which
were very common in America. The only difference compared to Mediterranean diet is the absence of olive
oil and more cheese and dairy products.

The professor analyzed the eating dietary pattern all over the word and it was demonstrated that more than
one dietary pattern can be healthy. For example the Asian diet, mostly vegetarian and vegan, works very well
in Asian country while the Nordic diet which works in Japan and North, it is rich in fish. To be healthy it is
necessary to consider the cultural context where you live.

CONCLUSIONS
Good health and wellbeing have to be prioritize, both for ourselves and our patients. When we talk about
nutrition, we should acknowledge that obesity and central adiposity and cancer (over 13 types) are linked, and
that they could therefore be prevented.
Nutrition is an important component of cancer care and management. It should be done in patients that are
newly diagnosed, undergoing therapy, recovering from treatment, in remission and trying to prevent cancer
recurrence.
Thus, in cancer treatment nutrition has to be addressed at all the stages of the disease, as oncologic patients
generally have a rapid decrease of their nutritional status, a factor which can negatively influence the response
to chemotherapy and radiotherapy. Indeed, the nutritional status can be considered as an index of health and
ability to heal. Moreover, the treatment for cancer itself increases the nutritional needs. This once again
underlines the need of an individualized nutrition intervention.
Notably, the American Institute of Cancer Research published a list of food which might be considered
protective, or, on the contrary, risky, for this category of patients.

Goals (especially important for fragile patients): prevent/reverse nutrition deficiencies, preserve lean body
mass (this is an important point since cancer is related to a state of hyper-metabolism which can result in
cachexia - the last stage of a bad nutritional status), minimize nutrition related side effects and monitor the
possible interferences between nutrients and drugs (in this case it is possible to change the method of
administration e.g. from an oral to a parenteral one), maximize the quality of life.

Two years ago the professor conducted a study with the 4-5-6th year of medical school in Pavia and with other
7 countries, trying to follow Dr. Ancel Keys, the father of Mediterranean diet3. It was demonstrated that all
over Europe students who will be healthcare workers have a low awareness of what is an healthy diet and
healthy lifestyle. Except from the basics of clinical nutrition and diets, we should be able to transfer to the
patients what we know as well as learning for ourselves.

3
In the 1950s, a research conducted by Dr. Ancel Keys (the Seven Countries Study) found that individuals living in the
Mediterranean region of the world had lower rates of coronary heart disease (CHD) compared to other parts of the
world. Starting from that period, a lot of studies started (clinical trials, observational studies or cohort studies, either
longitudinal or cross-sectional) and many positive effects on NCDs have been demonstrated since then.