HLTH 643 LU Nutrition and Chronic Disease Discussion assign.pdf

Review classmates' threads carefully noting anything of which you had a

different understanding. Add any point(s) you feel are important that might be

missing.

After reading your classmates' opinions, state if and why you agree or

disagree. Support your assertions with evidence from the Bible, text, and

articles, using AMA citations. Integrate findings from articles that may add a

different perspective than your classmates' perspectives.

1. DISCUSSION POST

2. For me personally, this topic is where God and science collide. Many

scientists would argue that genes represent the most immutable

determinates of ourselves, they set limits to what we are capable of

being and doing and provide us with our potential in life.1 I understand

that science does support this but as a Christian, I find this statement

untrue because with God there are no limits to what we are capable of.

In addition, in the Bible, God constantly speaks about promises,

blessings, and curses which are passed on from generation to

generation. For example, the lineage of Abraham, Isaac, Ishmael, and

David. Lineage in the Bible is basically genetics; blessings and curses

translate into genetics as health and diseases. This is why we see

diseases passed from generation to generation and scientists would

say they are genetically predisposed to something. However, God sent

Jesus for our sins and to heal us from sickness and disease. In 2

Corinthians 5:17 it says, “If anyone is in Christ, he is a new creation.

The old has passed away; behold, the new has come”2. Jesus

changes everything, for those who believe in Jesus they are a new

creation, sickness, disease, and generational curses are wiped away

and we are new creations. People are not doomed to the fate of their

genetics.

As nutrition and dietetics professionals the first thing we need to do is pray.

We understand the science behind our bodies, health, and nutrition but

ultimately, we need to put our trust in God and not science. We can recognize

these generational curses such as diabetes, obesity, and cancer and help

guide our patients on a path of nutritional health and break these generational

curses, in the name of Jesus.

The role of a nutrition professional is to determine the problem or health goal

and advise a diet that will support the desired outcome the patient or health

professional is seeking. The nutrition professional needs to be prepared with

the necessary knowledge and skills to treat the patient with solid evidence-

based dietetics and nutrition practices and take into consideration nutritional

genomics to make a more tailored approach to diet.3 Nutrigenomics is the

scientific study of the way particular genes and bioactive food components

interact. This helps provide professionals with a basis for understanding the

health consequences of eating behaviors which may be different for each

person. Nutrition professionals understand that dietary components can

influence or change the risk of disease development by modulating the

processes involved with onset, incidence, progression, and severity. The food

prescribed can act on the human genome directly or indirectly altering the

expression of genes and gene products. Nutrition professionals can create a

diet for an individual to potentially compensate for genetic polymorphisms.

The outcome of the diet is dependent on the balance of health and disease

states and on an individual’s genetic background1.

Based on up-to-date knowledge of the relationship between diet and disease

the guidelines do not take into consideration the account of genetics and

epigenetic variations and how the variations can play a role in an individual

response to dietary factors such as health and disease. Genomics offers more

insight into a patient’s genetic disposition, and I think modifications can be

made to prevent diabetes, obesity, and cancer. There is not a blanket solution

for dietary and nutritional health. Each patient will need a personalized

nutrition plan taking into consideration current health status, food preferences,

environmental factors, and if available, genotype.3 God created our bodies so

unique, it is important that a professional remember that each person has a

different genetic background so a different dietary intervention will be needed

for each person. 4 Yes, gene-environment interactions are relevant to public

health nutrition because people may be presumed genetically more

susceptible to a disease so a diet prescription can be tapered to meet those

needs. However, environmental interactions can alter the onset of a disease

or increase the onset of disease. 1

Reference

Trujillo E, Davis C, Milner J. Nutrigenomics, proteomics, metabolomics, and

the practice of dietetics. Journal of the American Dietetic Association.

2006;106(3):403-413. doi:https://doi.org/10.1016/j.jada.2005.12.002

English Standard Version Bible. Crossway Bibles, Good News Publishers;

2016. https://esv.literalword.com

Nelms, MN, Sucher, KP. Nutrition Therapy and Pathophysiology. 4th ed.

Cengage; 2019.

Gene–environment interactions and public health nutrition. Public Health

Nutrition. 2006;9(7):821-822. doi:https://doi.org/10.1017/phn20062001

Editorial

Gene–environment interactions and public health nutrition

A non-scientific survey of the scientific literature reveals

that the number of articles dealing with gene–environ-

ment interactions has exploded over the past decade. A

Medline search on the terms ‘gene’, ‘environment’ and

‘interaction’ shows 120 articles published in 1995, 309 in

2000 and 1211 in 2005. In this issue of Public Health

Nutrition, two articles join that surge, in some sense

marking a shift in the articles we are seeing and publishing

in our journal.

Using data from the Swedish Young Male Twins Register,

Karnehed et al.

found that low physical activity and low

fibre intake were significantly associated with greater waist

circumference in their sample. Moreover, they discovered

an interaction between genetic susceptibility and physical

activity: among twins with higher genetic susceptibility to

greater waist circumference, low physical activity appeared

to have a greater effect on attained waist circumference

than it did among twins at low genetic risk.

In the second of the two articles, Salminen et al.

examined data from a 2- to 3-year family-based health

education and counselling intervention. They saw no

significant differences in serum lipids between risk

(children with 13/4 or 14/4 genotype) and non-risk

(children with 12/3 or 13/3 genotype) groups, with the

exception of the total cholesterol/high-density lipoprotein

cholesterol ratio among boys. Their findings indicate that

the effects of the intervention were similar in children

regardless of their apolipoprotein E genotype.

The two articles raise two methodological issues of

concern in gene–environment (G £E) studies: the

measurement of genetic factors and the measurement of

environmental (or more broadly, non-genetic) factors.

Error in the measurement of non-genetic factors is a

longstanding problem in epidemiology and is no less a

concern in epidemiological studies on G £E interactions.

Karnehed et al. discuss the possible implications of error

in measuring dietary intake and physical activity in their

observational study of male twins. But even in an

intervention study, in which we have the greatest control

over the ‘exposure’ of interest, we can raise questions

about the exposure that was measured. Would a more

intensive intervention have had a more visible effect?

Might we have seen different results if the intervention had

targeted a more specific age group (e.g. 6–9-year-olds)? In

any case, the interpretation of findings for non-genetic

factors merits close scrutiny, as it always does.

The measurement of genetic characteristics, likewise,

merits close scrutiny. A twin study allows for a clever and

efficient analysis, but classifying twins as being at high or

low genetic risk based on their concordance in falling

above or below the residual median for waist circumfer-

ence leaves some room for interpretation. To what extent

does their concordance reflect similar early-life environ-

ment rather than true genetic risk? That the G £E analysis

findings for dizygotic twins resembled those for mono-

zygotic twins, in fact, gives some support to the possibility

that shared environment contributed to their concordant

risk status. Salminen et al. use a different approach to

represent the ‘gene’ in their G £E study by selecting a

polymorphism hypothesised a priori to affect cholesterol

absorption and plasma lipids. The question that it leaves

unanswered, though certainly not by any shortcoming of

the study’s design, is whether we might expect to find any

genes by which responders to such an intervention can be

distinguished from non-responders.

A final question that we might ask as readers of Public

Health Nutrition is this: are articles on G £E interactions

relevant to public health nutrition? A purist might argue

that the greatest value of G £E studies is in their potential

to elucidate aetiology and to suggest more targeted

recommendations and interventions – but public health

nutritionists are more concerned with practical impli-

cations than with aetiology, with broad population

measures rather than with specific, targeted advice.

I would argue that G £E articles are relevant to the field

of public health nutrition, and hence to our journal, in

three ways. First, the studies generally reaffirm the

importance of the environment in G £E studies. Less

physical activity, for example, predicted greater waist

circumference among male twins regardless of their

presumed genetic susceptibility

. By itself, confirming the

importance of non-genetic factors is of course not reason

enough for an article to be published in Public Health

Nutrition. But a corollary is that G £E articles in Public

Health Nutrition must have a relevant E component and

so, in that sense, they retain their broader relevance.

A second reason that G £E articles are relevant is that

they provide some sense as to the limits of public health

measures. Besides pointing out how unfair genetic

inheritance can be – in the study by Karnehed et al., for

example, ‘45 minutes of moderate PA may be enough to

prevent weight gain in some, whereas 60 minutes might be

too little in others’ – G £E studies also reveal whether

variability in genetic characteristics contributes to varia-

bility in the success or failure of public health measures

and recommendations.

qThe Author 2006

Public Health Nutrition: 9(7), 821–822 DOI: 10.1017/PHN20062001

https://doi.org/10.1017/PHN20062001 Published online by Cambridge University Press

Finally, besides the academic reasons generally given

for interest in G £E studies – aetiological knowledge,

targeted prevention, etc. – there is the desire for

knowledge of self. Gene therapy notwithstanding,

genes represent the most immutable determinants of

ourselves. They set limits on what we are capable of

being and doing, and they provide us with our

potential in life. G £E studies often and necessarily

appear to dwell in the minutiae of biology, in response

to which we might wonder if we are being reduced to

a single gene or protein. But each study is part of an

endeavour to determine the extent to which we are

able to maintain our own health and, in the bigger

picture, to control our own destinies. Studies at the

interface of nutrition and genetics can be worrisome

when they appear too far-flung from the realm of

public health. Still, such studies inform us about our

potential and our limits as public health practitioners

(and as ourselves). For that reason they have a place in

our journal – a place that will likely grow in coming

years.

Marilyn Tseng

Editor

References

1 Karnehed N, Tynelius P, Heitmann BL, Rasmussen F. Physical

activity, diet and gene–environment interactions in relation to

body mass index and waist circumference: The Swedish

Young Male Twins Study. Public Health Nutrition 2006; 9(7):

851–858.

2 Salminen M, Lehtima

¨ki T, Fan Y-M, Vahlberg T, Kivela

¨SL.

Apolipoprotein E polymorphism and changes in serum lipids

during a family-based counselling intervention. Public Health

Nutrition 2006; 9(7): 859–865.

M Tseng822

https://doi.org/10.1017/PHN20062001 Published online by Cambridge University Press

10.1

INTRODUCTION

2003,

the

International

Human

Genome

Sequencing

Con-

sortium

published

the

finished

version

the

human

genome

sequence,

thereby

marking

historic

milestone

science

with

great

implications

for

the

future

health

care

(see

Figure

10.1).!

The

human

genome

the

blueprint

for

over

20,000

different

proteins.”

many

respects,

the

human

body

system

proteins.

Proteins serve

structural

compo-

nents,

hormones,

neurotransmitters,

and

cell-signaling

agents

that

ensure

the

body

operating smoothly.

Production

and

degradation

each

these

proteins

tightly

regulated

but

also

influenced

environmental

factors

such

as nutri-

tion.

This

interaction

between

nutrients

and

other

bioactive

dietary

components

and

the

genome

known

nutritional

genomics.’

The

promise

nutritional

genomics,

ultimately,

translation

knowledge

such

interactions

into

health

care

applications

that

improve

health

for

both

individuals

and

populations.*

Nutritional

genomics

further

subdivided

into

the

areas

nutrigenetics,

nutrigenomics,

and

nutritional

epigenomics.’

Nutrigenetics

studies

the

role

interactions

between

individual

gene

sequence

variations

(genotype)

and

dietary

components

determining

health.’

Interventions

that

consider

genotype

conjunction

with

other

factors

such

current

health

status,

food

preferences,

and

other

environ-

mental

factors,

may

referred

to as

personalized

nutrition

precision

nutrition,

component

personalized

medi-

cine.‘

The

field

nutrigenomics

focuses

the

influence

dietary

components

gene

expression

(whether

genes

are

Figure

10.1

Timeline

Genetics

and

Genomics

from

Discovery

by Mendel

the

Laws

Genetics

1865

Completion

the

Human

Genome

Project

2003

‘chibald

Garrod

formusates

‘the

concept

(Gregor

Mende

human

sce

‘rbom

errs

(ws

genetics

wor,

1992

Source:

Courtesy

National

Human

Genome

Research

Insitute/NIH

210

Part

3 Introduction to

Pathophysiology

‘Reeanscovery

Mendes

‘of

metabolism

heredtary

material

pee

1993

”

‘red

Henry

Oswald

Avery,

Colin

Maci.tod

James

Watson

and

‘Sturtevant

‘and

Mactyn

McCarty

Francis

Crick

makes

‘demonstrate

that

OMA

describe

the

‘he

frst

near

ste

‘map

genes,

}

ne)

prada

any

2020

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Leaming.

All

Rights

Reserved.

May

not

copied,

scanned,

duplicated,

whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

learning

experience.

Cengage

Learning

reserves

the

right

toremove

additional

content

any

time

subsequent

rights

restrictions

requice

it,

Tees

turned

off)

and,

ultimately,

production

proteins

and

metabolites.

The

term

nutritional

epigenomics

described

precisely

diet-informed

changes

DNA

(i.e.,

meth-

ylation,

modifications

histones,

microRNAs

that

alter

control

gene

expression).?

Other

terms

including

transcriptomics,

proteomics,

metabolomics,

lipidomics,

and

foodomics

have

also

been

introduced

describe

the

anal-

ysis

RNA

transcripts,

proteins,

metabolites,

lipids,

and

food,

respectively,

and

how

they

relate

metabolism

and

health

organism.*°

The

genomic

contribution

the

gut

microbi-

ome

has

also

been

proposed

as a

component

nutrigenomics

and

comprehensive

approach

personalized

nutri-

tion

and

health.®

These

components,

the

genome

itself,

are

responsive

dietary

components

and

all

are

integrated

to establish

the

role

diet

determining

phenotype.’

Thus,

genotyping

only

tells

part

of the

story

and

realizing

personal-

ized

precision

nutrition

will

much

complex.

10.2

NUTRITIONAL

GENOMICS:

NUTRIGENETICS,

NUTRIGENOMICS,

AND

NUTRITIONAL

EPIGENOMICS

Over

the

past

few

decades,

various

dietary

guidelines

have

been

developed

for

the

purpose

optimizing

overall

health,

preventing

treating

cardiovascular

disease

(CVD),

prevent-

ing

cancer,

treating

hypertension,

and

treating

diabetes.°!!

While

based

the

best

available

knowledge

of the

relation-

ship

between

diet

and

disease,

these

guidelines

not

take

1998 1999

2000

nature

Executive order

bans

genetic

discrimination

federal

workplace

P10)

Suet)

VSO

sequence

Coane)

rere

Hature

nature

Chapter

Nutritional

Genomics.

211

2020

Cengage

Leaming.

All

Rights

Reserved.

May

not

copied,

scanned,

duplicated,

whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

learning

experience.

Cengage

Learning

reserves

the

right

toremove

additional

content

any

time

subsequent

rights

restrictions

requice

it,

into

account

the

genetic

and

epigenetic

variation

within

the

population

and

how

that

variation

can

play

role

individual

response

dietary

factors

and,

hence,

health

and

disease.

Such

information

has

heretofore

been

unavailable,

but

completion

the

Human

Genome

Project

and

heavy

research

emphasis

on.

identifying

the

specific

and

complex

interactions

between

diet

and

the

genome

are

beginning

yield

results

while

also

reveal-

ing

the

complexity

implementing

precision

nutrition.>

Attention

nutritional

genomics

and

pharmacog-

enomics

has

been

escalating,

and

this

trend

likely

con-

tinue

the

coming

years.

For

example,

the

Academy

Nutrition

and

Dietetics

(AND)

2014

issued

the

first

posi-

tion

paper

nutritional

genomics,

and

Nutrition

Genom-

ics

Project

currently

underway

within

the

AND

Evidence

Analysis

Library.°"?

In the

Academy’s

position,

stated

that

“...

registered

dietitians

need

basic

competency

genetics

foundation

for

understanding

nutritional

genomics;

profi-

ciency

requires

advanced

knowledge

and

skills.’

further

goes

onto

state

that

“the

practical

application

nutritional

genomics

for

complex

chronic

disease

emerging

science

and

the

use

nutrigenetic

testing

provide

dietary

advice

not

ready

for

routine

dietetics

practice.”

In 2017,

group

leading

researchers

nutrigenetics

issued

proposed

guide-

lines

for

evaluation

the

scientific

validity

and

current

evi-

dence

for

diet

intervention

based

genotype,

noting

the

prevalence

unsupported

claims

based

genetic

testing

and

the

propensity

commercial

purveyors

personalized

nutrition

oversimplify

information

that

is,

reality,

quite

complex.!?

Thus,

while

genomics

holds

great

potential

for

revolutionizing

health

care

and

registered

dietitian

nutrition-

ists

(RDNs) must

prepared

with

the

requisite

knowledge

and

skills,

the

solid

evidence

base

that

underlies

other

areas

dietetics

practice

must

also

established

nutritional

genomics.°

Furthermore,

the

advent

genomics—including

nutritional

genomics—is

not

without

its

ethical

challenges

(see

Box

10.1).

BOX

10.

RESEARCH

PRACTICE

Ethics

and

the

ELSI

Research

Program

The

National

Human

Genome

Research

Institute

(NHGRI)

estab-

lished

the

Ethical,

Legal

and

Social

Implications

(ELSI)

Research

Program

1990

part

the

Human

Genome

Project.'

Its

purpose

support

research

the

ethical,

legal,

and

social

implications

genetics

and

genomics

research.

Although

there

great

public

interest

the

application

personal

genetic

knowledge

improved

health,

there

also

concern

regarding

misuse

personal

genetic

information.”

May

2008,

the

Genetic

Information

Nondiscrimination

Act

(GINA)

was

signed

into

federal

law

President

George

Bush.?

This

legislation

prohibits

insurers

from

requesting

requiring

genetic

testing

individual

family,

and

from

using

genetic

information

establish

eligibility

premiums.

Furthermore,

prohibits

employers

from

requesting

requiring

genetic

testing

and

from

using

genetic

testing

for

hiring

promotional

decisions.?

2013,

anew

rule

adopted

the

U.S.

Department

Health

and

Human

Services

filled

some

the

gaps by

extending

pro-

tections

Medicare,

Medicaid,

the

Indian

Health

Service,

and

other

programs.*

While

the

passage

GINA

step

the

right

direction,

does

not

cover

life,

long-term

nursing

home

care,

disability

insurance

and

the

application

genomics

itself

can

still

be an

ethical

minefield.

For

example,

examining

the

complex

relation-

ship

genomics

with

race,

ethnicity,

and

behavioral

character-

istics

goes

beyond

studying

the

relationship

the

genome

disease

propensity.

Linking

specific

genotypes

intelligence

sexual

orientation,

for

example,

has

the

potential

overstate

the

role

genetics

and

confer

stigmatization

suggesting

alleles

associated

with

perceived

negative

traits

are

com-

mon

some

populations

than

others.

Thus,

the

implications

for

individuals

and

society

uncovering

the

genomic

contri-

bution to

specific

behaviors

traits

are

immense.

These

impli-

cations

must be

considered,

along

with

input

from

diverse

group

individuals

and

organizations,

before

such

research

undertaken.”

2011,

the

NHGRI

published

their

most

recent

strategic

plan,

which

includes

section

“Genomics

and

Society,”

delineating

number

psychosocial,

ethical,

legal

and

public

policy,

and

broad

societal

issues

genomics.'?

2018,

they

announced

the

launch

the

latest

strategic

planning

process

with

expected

issue

the

new

stra-

tegic

plan

October

2020.

part

this

new

plan,

NHGRI

expects

ongoing

emphasis

several

areas,

including

ethical,

legal,

and

social

implications

genomics.°

The

ELS!

Research

Program

funds

and

manages

research

and

also

supports

work-

shops,

research

consortia,

and

policy

conferences

these

NHGRI

priority

areas:

Genetic

and

genomic

research.

This

area

includes

issues

to protection of

human

research

participants

(i.e.,

privacy

and

identifiability

genetic

information),

recruit-

ment

diverse

participants

genomics

research,

commu-

nity

engagement,

and

other

areas.

Genetic

and

genomic

health

care.

This

area

includes

util-

ity

genomic

health

information

personal

and

clinical

levels,

fair

access,

economic

considerations

such

cost

effectiveness

and

reimbursement,

public health

applica-

tions, rights

patients

and

their

families,

laboratories,

and

health

care

providers,

various

ethical

issues

including

impact

results

and

patient

health

behaviors

and

outcomes,

and

attending

issues

associated

with

genetic

diagnoses

pre-implantation,

prenatally,

and

postnatally,

and

other

areas.

Broader

legal,

policy,

and

societal

implications.

This

area

includes

number

issues

the

role

the

Citizen

Science

movement

including

patient-driven

medicine,

regulation

emerging

genomic

technologies,

potential

harmful

effects

genetic

determinism

pub-

lic

attitudes

and

policies,

and

how

increasing

genomic

knowledge

will

change

understanding

race,

ethnicity,

and

identity

and

relationships

both

within

and

among

human

populations,

human

relationships

with

nonhumans,

and

human

origins.

further

addresses

nonmedical

uses

genomic

information

including

areas

such

ancestry

testing,

insurance

eiigibility,

and

criminal

responsibility.

212

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3 Introduction to

Pathophysiology

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Rights

Reserved.

May

not

copied,

scanned,

duplicated,

whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

leaming

experience.

Cengage

Learning

reserves

the

right

remove

additional

content

any

time

subsequent

rights

restrictions

requive

it.

One

the

hottest

areas

debate

regarding

the

interplay

between

ethics

and

genetics

has

with

direct-to-consumer

(DTC)

marketing

genetic

tests.®

After

completion

the

Human

Genome

Project,

direct

marketing

companies

began

offering

genetic

testing

directly

consumers

over

the

Internet,

thereby

bypassing

health

care

providers.

Health

care

practice,

particularly

clinical

genetics,

very

focused

informed

con-

sent,

confidentiality,

and

appropriate

counseling

and

guidance

regarding

test

results.’

These

elements

are

often

missing

the

DTC

environment,

potentially

misleading

consumers

and

result-

ing

inappropriate

health care

choices.

Consumers

may

also

subject

dubious

interpretation

scant

research

regard-

ing

the

strength

relationships

between

specific

genes

and

disease.

Twenty companies

were

offering

DTC

genetic

testing

2011,

with

additional

seven

offering

DTC

genetic

testing

through

physician.

However,

the

intervening

years,

the

DTC

genetic

testing

landscape

has

experienced

upheaval.

late

November

2013,

the

FDA

issued

letter

requiring

high

profile

DTC

company

23andMe

discontinue

marketing

their

Personal

Genome

Service,

calling

violation

the

Federal

Food,

Drug,

and Cosmetic

Act

due

its

being

mar-

keted

medical

device.

The

company

was

forced

take

all

health-related

testing

off

the

market

for

time,

but

has

since

gone

through

FDA

approval

and

began

offering

limited

genetic

health

risk

testing

the

DTC

market

2017.°

The

diseases

and

conditions

addressed

through

these

tests

include

Parkinson's

Disease,

late-onset

Alzheimer’s

Disease,

celiac

disease,

and

few

blood

conditions

among

others.

2018

23andMe

gained

approval to

add

health

risk

test

for

variants

BRCA1/BRCA2,

genes

linked

breast

cancer

risk.'°

key

distinction

that

the

testing

offered

can

used

predict

risk,

but

cannot be

used

for

diagnostic

purposes.?

Despite

DTC

changes,

myriad

concerns remain

regarding

the

need

for

regulation

privacy

use

genetic

information.

For

example,

possible

for

someone

other

than

the

sample

source

submit

genetic

sample

without

consent

first

being

obtained.

For

further

exploration

ethics

specifically

relating

10.3

OVERVIEW

THE

STRUCTURE

AND

FUNCTION

GENETIC

MATERIAL

Deoxyribonucleic

Acid

and

Genome

Structure

While

Mendel,

the

father

modern-day

genetics,

discovered

the

laws

of genetics

1865,

deoxyribonucleic

acid

(DNA)

was

not

itself

identified as

the

blueprint

life

until

1944,

and

its

double-helical

structure

was

not

discovered

until

1953.!*

DNA

makes

the

genome,

which

does

not

itself

build

organism,

but

provides

the

instructions

that

tell

how

build

organism.

From

human

perspective,

the

genes

contained

each

person’s

DNA

encode

essentially

the

same

proteins,

but

this

code

varies

from

person

person,

thus

yielding

inherited

differences

physical

characteristics,

intellect,

and

behavioral

characteristics

well

the

propensity

for

devel-

oping

disease.!*

Ethics

and

the

ELSI

Research

Program

(continued)

nutritional

genomics,

see

the

section

“Nutritional

Genomics

and

the

Practice

Dietetics”

near

the

end

this

chapter.

References

National

Human

Genome

Research

Institute

(NHGRI),

ELSI

Research

Program.

The

Ethical,

Legal

and

Social Implications

(ELSI)

Research

Program.

Bethesda,

MD:

NHGRI;

2018.

https://(www.genome

-gov/10001618/the-elsi-research-program/.

Green

ED,

Guyer

MS,

National

Human

Genome

Research

Institute.

Charting

course

for

genomic

medicine

from

base

pairs

bedside.

Nature.

2011;

470:204-13.

National

Human

Genome

Research

Institute

(NHGRI).

Genetic

Discrimination.

Bethesda,

MD:

NHGRI;

2017.

https:/Avww.genome

-gov/10002077/genetic-discrimination/.

Department

of Health

and

Human

Services.

Modifications

the

HIPAA

Privacy,

Security,

Enforcement,

and

Breach

Notification

Rules

Under

the

Health

Information

Technology

for

Economic

and

Clinical

Health

Act

and

the

Genetic

Information

Nondiscrimina-

tion

Act;

Other

Modifications

the

HIPAA

Rules.

Fed.

Reg.

Jan.

25,

2013;

78:5565-702.

http:/Awww.gpo.gov/fdsys/pkg/FR-2013-

01-25/pdf/2013-01073.pdf.

National

Human

Genome

Research

Institute

(NHGRI).

Strategic

Plan-

ning:

Overview.

Bethesda,

MD:

NHGRI;

2018.

https://www.genome

.gov/27570607/strategic-planning-overview/.

Hogarth

Javitt

Melzer

The

current

landscape

for

direct-to-

consumer

genetic

testing:

Legal,

ethical,

and

policy

issues.

Ann

Rev

Genomics

Hum

Genet.

2008;

9:16

1-82.

ACMG

Board

Directors.

Direct-to-consumer

genetic

testing:

revised

position

statement

the

American

College

Medical

Genetics

and

Genomics.

Genet

Med.

2016;

18(2):207-8.

U.S.

Food

and Drug

Administration.

Inspections,

Compliance,

Enforcement,

and

Criminal

Investigations.

23andMe,

Inc.

11/22/13.

Silver

Spring,

MD:

U.S.

Food and Drug

Administration;

2013.

http://

www.

fda.goviC

/EnforcementActions/WarningLetters/2013/

ucm376296.htm.

U.S.

Food and Drug

Administration.

FDA

Allows

Marketing

First

Direct-to-Consumer

Tests

that

Provide

Genetic

Risk

Information

for

Certain

Conditions.

4/6/2017.

Silver

Spring,

MD:

U.S.

Food and

Drug

Administration;

2018.

https://www.fda.gov/NewsEvents/

Newsroom/PressAnnouncements/ucm551185.htm.

10.

U.S.

Food and Drug

Administration.

FDA

Authorizes,

with

Special

Controls,

Direct-To-Consumer

Test

that

Reports

Three

Mutations

the

BRCA

Breast

Cancer

Genes.

3/6/2018.

Silver

Spring,

MD:

U.S.

Food and Drug

Administration;

2018.

https://www.fda.gow/NewsEv-

ents/Newsroom/PressAnnouncements/ucm599560.htm.

11.

May

Sociogenetic

risks—ancestry

DNA

testing,

third-party

iden-

tity,

and

protection

privacy.

Eng!

Med.

2018.

doi:

10.1056/

NEJMp1805870.

The

genetic

material

genome

lies

within

each

nucleus

each

cell

the

body

(except

mature

red

blood

cells,

which

not

contain

nuclei).!*

humans,

the

genome

comprises

pairs

chromosomes.

During

mitosis

(cell

division)

within

individual,

all

pairs

chromosomes

are

copied

during

the

creation

new

daughter

cell.

During

meiosis

(reproduction),

only

one

member

each

pair

chromo-

somes

passed

each

ovum

sperm

cell;

the

result

offspring

that

contain

chromosomal

pairs

created

the

donation

one

copy

each

chromosome

from

each

parent.

the

pairs,

are

autosomes

and

one

pair

comprises

the

sex

chromosomes.

Males

have

one

and one

chromo-

some,

while

females

have

two

chromosomes,

so the

gender

offspring

determined

the

sex

chromosome

passed

the

male

parent.

Each

chromosome

consists

DNA

con-

taining

linear

sequence

of genes,

each

encoding

specific

Chapter

Nutritional

Genomics.

213

2020

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Leaming.

All

Rights

Reserved.

May

not

copied,

scanned,

duplicated,

whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

leaming

experience.

Cengage

Learning

reserves

the

right

remove

additional

content

any

time

subsequent

rights

restrictions

require

it.

protein.

The

copy

each

gene

inherited

from

the

father

the

paternal

allele,

and

the

one

inherited

from

the

mother

the

maternal

allele.

Each

gene

inhabits

particular

location

ona

particular

chromosome

called

its

“locus.”

For

example,

Figure

10.2

shows

map

chromosome

that

identifies

the

location

defects

this

chromosome

associated

with

spe-

cific

disease

states.

Each

gene

itself

linear

sequence

nucleotides

that

are

actually

responsible

for

encoding

proteins

(see

Figure

10.2

Chromosome

Figure

10.3).

Nucleotides

have

three

primary

components:

purine

pyrimidine

nitrogenous

base,

ribose

pen-

tose

sugar),

and

phosphate

group.

The

backbone

the

chain

alternating

strand

the

ribose

and

phosphate

residues.

The

nitrogenous

bases

project

from

this

backbone

and

include

adenine

(A)

and

guanine

(G)

(both

purines)

well

thymine

(T)

and

cytosine

(C),

which

are

both

pyrim-

idines.

As DNA,

this

chain

paired

with

complementary

strand

which

always

pair

with

and

always

pair

Sequencing

and

analysis

human

chromosomes

have

enabled

researchers

characterize

detail

number

genes

associated

with

diseases.

Identifying

the

genes

all

human

chromosomes

offers

scientists

worldwide

invaluable

resource

for

improving

human

health

and

combating

disease.

Knowledge

about

genes

will

increase

understanding

how

genetics

influences

the

development

disease,

help

researchers

find

genes

associated

with

particular

diseases,

and

aid

the

identification

appropriate

dietary

interventions

and

development

new

pharmaceuticals.

Chromosome

(pictured

here)

includes

700-800

genes

and

has

been

linked

various

disease

states

with

nutritional

implications

including

several

cancers,

type

diabetes,

and

Crohn's

disease.

disease,

adult

renal

dysplasia

facial

syndrome

Leukemia

rombocytopenia

thyroid

oncogene

Ewing

Sarcoma

Obesity,

susceptibility

Multiple

endocrine

neoplasia

Medullary

thyroid

carcinoma

Hirschsprung

disease

Thyroid

papillary

carcinoma

Deafness,

autosomal

recessive

Serotonin

receptor

Moebius

syndrome

Hemolytic

anemia

Hyperphenylalaninemia

Metachromatic

leukodystrophy

Gaucher

disease,

variant

form

SEMD,

Pakistani

type

Hermansky-Pudlak

syndrome

Breast

cancer

Multiple

advanced

cancers

Cowden

disease

Lhermitte-Duclos

syndrome

Bannayan-Zonana

syndrome

Endometrial

carcinoma

Polyposis,

juvenile

intestinal

Prostate

cancer

Progressive

external

ophthalmoplegia

Corneal

dystrophy,

Thiel-Behnke

type

Leukemia,

T-cell

acute

lymphocytic

Spinocerebellar

ataxia,

infantile-onset

Split

hand/foot

malformation,

type 3

Polycystic

kidney

disease

Meningioma-expressed

antigen

Adrenal

hyperplasia,

congenital

Diabetes

mellitus,

insulin-dependent

segment

mesenchymal

dysgenesis

Cataract,

congenital

Malignant

brain

tumors

Glioblastoma

multiforme

Medulloblastoma

Crouzon

syndrome

Jackson-Weiss

syndrome

Beare-Stevenson

cutis

gyrata

syndrome

214

Part

3 Introduction to

Pathophysiology

135

million

base

pairs

Suppression

tumorigenicity,

prostate

Prostate

adenocarcinoma

Interleukin

receptor,

alpha

chain,

deficiency

Arrhythmogenic

right

ventricular

dysplasia

Myasthenic

antigen

Lambert-Eaton

syndrome

Megaloblastic

anemia

Diabetes

mellitus,

insulin-dependent

Severe

combined

immunodeficiency

disease,

Athabascan

Cockayne

syndrome,

type

Cerebrooculofacioskeletal

syndrome

Opsonic

defect

Chronic

infections

Retinal

nonattachment,

nonsyndromic

congenital

Cardiomyopathy,

dilated,

autosomal

dominant

Neuropathy,

congenital

hypomyelinating

Graves

disease

autoantigen

Hypermethioninemia,

persistent,

autosomal

dominant

Hemophagocytic

lymphohistiocytosis,

familial

Retinitis

pigmentosa,

autosomal

recessive

and

dominant

Urofacial

syndrome

(Ochoa

syndrome)

Hypoglobulinemia

and

absent

cells

Hyperinsulinism-hyperammonemia

syndrome

Spastic

paraplegia

Dubin-Johnson

syndrome

Warfarin

sensitivity

Wolman

disease

Cholesteryl

ester

storage

disease

Tumor

necrosis

factor

receptor

superfamily,

member

Autoimmune

lymphoproliferative

syndrome

Epidermolysis

bullosa,

generalized

atrophic

benign

Optic

nerve

coloboma

with

renal

disease

Prostate

cancer

Neurofibrosarcoma

Porphyria,

congenital

erythropoietic

Endometrial

carcinoma

Gyrate

atrophy

choroid

and

retina

Pancreatic

lipase

deficiency

Glaucoma

Pfeiffer

syndrome

Apert

syndrome

Saethre-Chotzen

syndrome

Schizencephaly

Polykaryocytosis

inducer

(promoter)

Usher

syndrome,

autosomal

recessive,

severe

2020

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Leaming.

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Rights

Reserved. May

not

copied,

scanned,

duplicated,

whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

leaming

experience.

Cengage

Learning

reserves

the

right

remove

additional

content

any

time

subsequent

rights

restrictions

requice

it.

Figure

10.3

Nucleotides

within

the

DNA

Molecule

The

four

nitrogenous

bases

DNA

are

arranged

along

the

sugar-phosphate

backbone

particular

order,

encoding

all

genetic

instructions

for

organism.

Adenine

(A)

pairs

with

thymine

(T),

while

cytosine

(C)

pairs

with

guanine

(G).

The

two

DNA

strands

are

held

together

codon,

encodes

specific

amino

acid.

Thus,

specific

sequence

nucleotides

(the

genetic

code)

translates

into

specific

chain

weak

bonds

between

the

bases.

Deoxyribonucleic

Acid

(DNA)

Base

Pairs

Hydrogen

bonds

Cytosine

Guanine

j—H—-—----

Phosphate

O=P-O—CHy

Weecceue

H-N

Thymine

CHs

Gare

Hydroxyl

with

form

double-stranded

molecule.

The

DNA

tightly

twisted

into

double-helical

form,

which

makes

each

chromosome

extremely

compact.!>

Translating

the

Message

from

DNA

Protein

The

Genetic

Code

The

code

responsible

for

translation

DNA

into

proteins

was

identified

triplet

code

1961.

other

words,

a series

three

nucleotide

bases,

called

amino

acids.

This

specific

chain

amino

acids

protein.

Proteins

have

various

functions,

including

serving

hormones,

enzymes,

receptors,

transporters,

cell-signaling

agents

(transcrip-

tion

factors,

etc.),

and

antibod-

ies.

Table

10.1

shows

how

each

the

codons

translates

into

its

respective

amino

acid.

Note

that

place

the

“T”

base

there

“U”

for

uracil,

which

takes

the

place

thymine

RNA

during

the

process

creating

protein!

DNA

also

contains

noncod-

ing

regulatory

sequences

called

promoter

regions

which

mol-

ecules

can

bind

order

signal

unwinding

specific

region

DNA

for

creation

needed

protein.

Furthermore,

over

95%

DNA

humans

made

noncoding

DNA,

which

lies

within

between

expressed

genes.

Due

the

apparent

lack

purpose,

noncoding

DNA

was

initially

classified

“junk

DNA?’!*15

This

view

has

been

challenged

recent

years

researchers

continue

identify

functions

these

noncoding

regions.

For

example,

numerous

sections

noncoding

DNA

have

been

found

transcribed

into

RNA,

but

this

does

not

result

production

proteins.

These

noncoding

RNA

sequences

microRNAs

(miRNAs)

bind

mRNA

block

translation

the

mRNA

into

protein,

thus

con-

trolling cellular

processes

such

the

cell

cycle,

cell

death,

and

tumor

development.'¢

short,

noncoding

DNA

appears

play

fhioaptale

largely

regulatory

role.

2017

review

identifies

that

60%

protein-coding

genes

are

regulated

miRNAs

and

nearly

2000

miRNAs

are

encoded

the

human

genome.”

Expres-

sion

these

miRNAs

may

affected

diet,

and,

addition-

ally,

both

endogenous

and

diet-derived

microRNAs

may

have

biological

effects,”

Research

suggests

miRNAs

play

role in

the

metabolic

response

chronic

inflammatory

conditions.!”

rather

than

much

the

genome

being

classified

“junk

DNA,’

the

Encyclopedia

DNA

Elements

(ENCODE)

Proj-

ect

found

that

most

the

human

genome

(80.4%)—much

Chapter

Nutritional

Genomics.

215

2020

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Leaming.

All

Rights

Reserved.

May

not

copied,

scanned,

duplicated,

whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

leaming

experience.

Cengage

Learning

reserves

the

right

remove

additional

content

any

time

subsequent

rights

restrictions

requive

it.

Table

10.1

The

Triplet

Code

UUU

Phe

UCU

Ser

UAU

Tyr

UGU

Cys

UUC

Phe

UCC

Ser

UAC

Tyr

UGC

Cys

UUA

Leu

UCA

Ser

UAA

STOP

UGA

STOP.

UUG

Leu

UCG

Ser

UAG

STOP

UGG

Try

CUU

Leu

CCU

Pro

CAU_

His

CGU

Arg

CUC

Leu

CCC

Pro

CAC

His

CGC

Arg

CUA

Leu

CCA

Pro

CAA

Gin

CGA

Arg

CUG

Leu

CCG

Pro

CAG

Gin

CGG

Arg

AUU

ile

ACU

Thr

AAU

Asn

AGU

Ser

AUC

lle

ACC

Thr

AAC

Asn

AGC

Ser

AUA

lle

ACA

Thr

AAA

Lys

AGA

Arg

AUG

Met

ACG

Thr

AAG

Lys

AGG

Arg

GUU_

Val

GCU

Ala

GAU_

Asp

GGU_

Gly

GUC

Val

Gcc

Ala

GAC

Asp

GGC

Gly

GUA

Val

GCA

Ala

GAA

Glu

GGA

Gly

GUG

Val

GCG

Ala

GAG

Glu

GGG

Gly

Note:

The

left-hand

column

represents

the

first

nucleotide

base

for

each

codon

the

row,

while

the

row

across

the

top

the

table

represents

the

second

nucleotide

base

each

codon.

All

triplet

codons

have

meaning,

with

them

encoding

amino

acids

and

three

serving

STOP

codons

signal

the

end

coding

sequence.

Methionine

(Met)

always

the

first

amino

acid

protein,

and

its

codon,

therefore,

serves

as a

START

codon.

Standard

amino

acid

abbreviations

are

follows:

Ala,

alanine

Gly,

glycine

His,

histidine

lle,

isoleucine

Pro,

proline

Asn,

asparagine

Ser,

serine

Asp,

aspartic

acid

Arg,

arginine

Thr,

threonine

Leu,

leucine

Try,

tryptophan

Cys,

cysteine

Lys,

lysine

Tyr,

tyrosine

Gin,

glutamine

Glu,

glutamic

acid

Met,

methionine

Phe,

phenylalanine

Val,

valine

than

previously

thought—is

likely

have

some

func-

tional

purpose.!®

Ongoing

exploration

this

area

will

con-

tribute

better

understanding

the

role

of the

genome

human

health

and

disease

well

beyond

gene sequence

alone.

Transcription

and

Translation

Progression

from

the

trip-

let

code

protein-coding

regions

production

protein

involves

two

major

steps:

transcription

and

translation.

transcription,

DNA

unwinds

the area

encoding

the

gene

interest.

The

code

then

transcribed

(copied)

means

complementary

base

pairing

(see

Figure

10.4)

into

mes-

senger

RNA

(mRNA),

single-stranded

molecule

consisting

the

bases

U, C,

and

mRNA

the

medium

which

the

code

for

needed

protein

carried

from

the

DNA

the

cytosol,

where

the

new

protein

created.

Transcription

accomplished

the

enzyme

RNA

poly-

merase,

which

first

complexes

with

transcription

factors

in a

gene's

promoter

region

before

facilitating

production

mRNA.

Binding

transcription

factors

can

either

prevent

RNA

poly-

merase

from

binding,

thus

repressing

transcription

specific

gene,

enhance

RNA

polymerase

binding,

thereby

increas-

ing

transcription

that

specific

gene.

Transcription

very

tightly

regulated

and

dependent

part

upon

environmental

216

Part

Introduction

Pathophysiology

variables

such

dietary

factors.

For

example,

intracellular

cholesterol

levels

(derived

from

diet

well

endogenous

synthesis)

regulate

the

expression

genes

that

regulate

choles-

terol

synthesis

and

uptake

from

the

circulation,

example

nutrigenomics.!?

The

DNA

strand

that

serves

the

template

for

mRNA

synthesis

known

the

sense

strand,

whereas

the

noncoding

strand

the

antisense

strand.

Once

transcription

complete,

mRNA

undergoes

post-transcriptional

processing.

Enzymes

the

nucleus

excise

segments

the

mRNA

known

introns

(intervening

sequences),

while

leaving

the

segments

known

exons

(expressed

sequences).

Thus,

only

exons

are

ultimately

translated

into

the

final

protein

product.

While

DNA

remains

the

nucleus,

the

mRNA

carries

the

code

out

the

nucleus

into

the

cytosol,

where

ribosomes

the

rough

endo-

plasmic

reticulum

(RER)

are

prepared

for

protein

assembly.!>

The

complement

RNA

transcripts

produced

when

genes

are

“expressed”

referred

to as

the

transcriptome.

During

translation,

the

triplet

codons

come

into

play.

shown

Table

10.1,

most amino

acids

have

multiple

codons,

but

each

codon

only

encodes

one

specific

amino

acid.!°

Small

molecules

another

form

RNA,

transfer

RNA

(tRNA),

serve

anticodons.

The

tRNA

molecules

each

consist

three-

base

sequence

that

complementary

the

codons

found

mRNA.

After

the

corresponding

amino

acids

are

transferred

the

appropriate

URNA,

the

(RNAs

carry

each

amino

acid

the

ribosomes,

which

serve

the

protein-making

machinery

the

cell,

and

attach

the

mRNA

via

complementary

base

pair-

ing

with

and

with

(see

Figure

10.4).

After

the

amino

acids

are

positioned

sequence,

peptide

bonds

are

formed

between

adjacent

amino

acids

and

the

new

protein

elongates

until

stop

(nonsense)

codon

reached

and

the

newly

cre-

ated

protein

released.

Additional

processing

new

proteins

called

post-translational

modification.!>

For

example,

the

insulin

polypeptide

folds

and

forms

two

disulfide

bonds,

after

which

cut

twice

the

middle

remove

center

section.

‘What

remains

are

two

polypeptide

chains

connected

two

disulfide

bonds—the

active

form

insulin.

Genetic

Variation

Polymorphisms

(variations)

exist

within

genes

throughout

the

population.'*

Most

these

variations

are

not

cause

for

concern.

The

outcome

given

variation

depends

its

nature

and

location

within

given

gene.

other

words,

specific

variation

may

have

appreciable

effect

the

pro-

duction

and

function

of the

protein

product.

However,

also

possible

that

a single

nucleotide

change

com-

plex

alteration in a

single

gene

can

have

profound

effects.

Inheritance

specific

genes

can

classified

autosomal

dominant,

autosomal

recessive,

X-linked

dominant,

X-linked

recessive, or

Y-linked.!°

Because

indi-

viduals

inherit

one

copy

each

gene

from

each

their

par-

ents,

the

actual

expression

inherited

gene

can

vary

and

gene

expression

what

determines

phenotype.

For

exam-

ple,

brown

eyes

are

autosomal

dominant,

whereas

blue eyes

are

autosomal

recessive.

individual

inherits

the

gene

for

brown

eyes

from

one

parent

and

the

gene

for

blue eyes

from

the

other,

his

her

eyes

will

brown

because

that

the

dominant

gene.

While

the

genotype

includes

genes

for

both

blue

and

brown

eyes,

the

eye

color

phenotype

brown.

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Rights

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scanned,

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whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

leaming

experience,

Cengage

Learning

reserves

the

right

remove

additional

content

any

time

subsequent

rights

restrictions

requice

Figure

10.4

Transcription

and

Translation

When

genes

are

expressed,

the

genetic

information

(base

sequence)

DNA

first

transcribed

(copied)

molecule

messenger

RNA

(mRNA)

process

similar

DNA

replication.

The

mRNA

molecules

then

leave

the

cell

nucleus

and

enter

the

cytoplasm,

where

triplets

mRNA

bases

(codons)

forming

tne

genetic

code

specify

the

particular

amino

acids

that

make

upan

individual

protein.

This

process,

called

translation,

accomplished

ribosomes

(cellular

components

composed

proteins

and

another

class

RNA)

that

read

the

genetic

code

from

the

mRNA,

and

transfer

RNAs

(tRNAs)

that

transport

the

corresponding

amino

acids

the

ribosomes

for

attachment

the

growing

protein.

Cell

Thus,

whether

trait

recessive

dominant

determines

whether

thattrait

phenotypically

expressed.

When

the

alleles

from

each

parent

differ

from

each

other,

this

case,

individual

heterozygous

for

that

gene

(/etero

differ-

ent).

the

alleles

from

both

parents

are

match,

then

that

individual

homozygous

for

that

gene

(homo

= same).

Autosomal

recessive

dominant

traits

can

inher-

ited

both males

and

females.

One

common

example

autosomal

recessive

trait

with

nutritional

implications

phe-

nylketonuria,

which

affected

individuals

must

inherit

one

mutated

copy

the

phenylalanine

hydroxylase

gene

from

each

parent

(homozygous).

The

resulting

inability

con-

vert

phenylalanine

tyrosine requires

lifelong

phenylalanine

restriction

prevent

mental

retardation

(see

Chapter

26).

Cystic

fibrosis

another

common

autosomal

recessive

dis-

ease

(see

Chapters

and

21).

Familial

hypercholesterolemia

autosomal

dominant

disorder

characterized

absence

mutation

low-density

lipoprotein

(LDL)

receptors

leading

severely

elevated

LDL

cholesterol

levels

and

risk

early

myocardial

infarction

and

death

(see

Chapter

13).

Cell

Familial

hypercholesterolemia

homozygotes

are rare

and

have

much

severe

manifestation

the disorder

than

heterozygotes.

The

sex

chromosomes

also

contain

genes

that

can

result

recessive

dominant

disorders.!°

Two

examples

X-linked

recessive

disorders

are

red-green

colorblind-

ness

and

hemophilia.

red-green

colorblindness,

individu-

als

are

unable

distinguish

shades

red

and

green

the

color

spectrum,

whereas

hemophilia,

individuals

most

commonly

lack

clotting

factor

VIII,

their

blood

does

not

clot

normally.

Hemophilia

requires

transfusions

supply

the

clotting

factor

and

replace

blood

losses

(see

Chapter

19).

Because

these

X-linked

disorders

are recessive disorders,

individuals

require

only

one

normal

copy

the

gene

for

nor-

mal

function.

However,

because

males

have

only

one

chro-

mosome

and,

thus,

only

one

copy

this

gene,

they

are

much

susceptible

inheriting

these

disorders.

Occurrence

females

rare

because

they

would

need

inherit

defec-

tive

copy

the

gene

from

both

the

mother

and

father,

who

would

himself

have

the

disorder.

Male

offspring

affected

Chapter

Nutritional

Genomics.

217

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not

copied,

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whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

learning

experience.

Cengage

Learning

reserves

the

right

toremove

additional

content

any

time

subsequent

rights

restrictions

requize

it,

fathers

will

not

inherit

the

disorder

because

only

chro-

mosome

inherited

from

the

father.

However,

female

off-

spring

affected

fathers

are

carriers

(heterozygotes),

and

male

children

born

them

have

50%

chance

having

the

disorder,

depending

wholly

which

copy

the

maternal

chromosome

passed

on.

X-linked

dominant

traits

are

rel-

atively

rare.

Y-linked

disorders

are

extremely

rare,

occurring

only

males

result

the

inheritance

mutations

the

chromosome

from

the

father.

Y-linked

disorders

are

not

considered

dominant

recessive

because

only

one

copy

the

affected

chromosome

can

exist

individual.

Single-Nucleotide

Polymorphisms

Understand-

ing

monogenic

disorders

such

those

described

earlier

helps

lay

the

groundwork

for

comprehending

the

complex-

ities

polygenic

diseases

such

obesity,

diabetes,

cancer,

and

CVD.

The

study

gene—nutrient

interactions

that

are

dependent

upon

gene

variance

(nutrigenetics)

focused

pri-

marily

single-nucleotide

polymorphisms

(SNPs;

pro-

nounced

“snips”).?

SNPs

are

defined

those

genetic

variants

polymorphisms

which

single

nucleotide

present

place

another.

For

example,

place

of the

common

codon

UGU,

the

codon

UGC

found.

Because

both

encode

the

amino

acid

cytosine,

this

particular

SNP

does

not

result

any

difference

function.

However,

UGA

present

place

UGU,

that

potential

problem,

because

UGA

nonsense

orstop

codon

(see

example

SNP

Figure

10.5).

Depending

the

location

of the

polymorphism

within

gene,

there

could

deleterious

effects.

the

affected

codon

near

the

end

coding

sequence,

possible

that

the

Figure

10.5

DNA

Sequence

Variation

Gene

Specific

codons

direct

the

cell's

protein-synthesizing

machinery

add

specific

amino

acids.

For

example,

the

base

sequence

ATG

codes

for

the

amino

acid

methionine.

Since three

bases

code

for

one

amino

acid,

the

protein

coded

by an

average-sized

gene

(3000

bp)

will

contain

1000

amino

acids.

The

DNA

code

thus

series

codons

that

specify

which

amino

acids

are

required

make

specific

proteins.

Some

variations

person’s

genetic

code

will

have

effect

the

protein

that

produced;

others

can

lead

disease

increased

susceptibility

disease.

DNA

Sequence

Variation

Gene

Can

Change

the

Protein

Produced

the

Genetic

Code

GCA AGA

GAT

AAT

TCT...

final

protein

product

will

not

functionally

altered.

How-

ever,

UGG

present

rather

than

UGU,

then

altering

that

one

amino

acid

from

cytosine

tryptophan

has

the

potential

for

altering

the

shape

and

function

the

protein

product.

SNP

nomenclature

standardization

has

been

evolving,

but

various

examples

appear

throughout

the

research

litera-

ture.

SNPs

may

include

SNP

and

are

generally

identified

also

the

gene

name,

the

location

the

affected

nucleotide

within

the

gene

sequence,

the

common

nucleotide

that

position,

and

arrow

indicating

that

less

common

nucle-

otide

present.

For

example,

MTHFR

677C>T

indicates

that

there

SNP

nucleotide

number

677

one

allele

the

methylenetetrahydrofolate

(MTHFR)

reductase

gene

charac-

terized

thymine

place

the

common

cytosine.

Since

each

individual

inherits

one

copy

the

gene

from

each

parent,

genotype

can

further

identify

them

MTHFR

677CC,

677

CT,

677TT

indicate

the

nucleotides

place

posi-

tion

677

both

copies

the

gene.

The

MTHFR

677C>T

SNP

results

amino

acid

change

that

position

from

the

typical

alanine

the

less

typical

valine.

This

particular

SNP

has

implications

for

folate

metabolism

and

cancer

risk,

as dis-

cussed

later

this

chapter.

SNPs

may

also

defined

the

amino

acid

change;

for

instance,

PPARA-Leul62Val

indicates

the

162nd

amino

acid

the

protein

sequence

for

peroxisome

proliferator

activated

receptor-a

valine

(Val)

when

the

typical

amino

acid

this

position

leucine

(Leu).

Other

similar

variations

may

seen

the

literature

well.

Note

that

symbols

for

genes

are

commonly

italicized,

whereas

ref-

erences

their

protein

products

are

not,

although

alternative

nomenclature

for

genes

prevalent

the

literature.

Identification

SNPs

has

been

primary

focus

genomics

research

since

completion

the

Human

Genome

Project

2003.

The

human

genome

has

approximately

million

polymorphisms,

meaning

that

any

two

unrelated

humans

have

millions

genetic

differences.”

These

poly-

morphisms

are

not

all

independent

each

other.

Rather,

when

specific

gene

variant

present

chromo-

some,

associated

with

other

par-

ticular

gene

variants

that

same

chromosome.

This

group

gene

variants

that

associate

together

referred

as a

haplotype,

and

these

Protein

Products

variants

may

work

concert

pro-

Gene

from

Person

1 on

2 3

Gene

from

GCG

AGA

GAT AAT

TCT...

Person2

Codon

change

made

difference

amino

acid

sequence

GCA

AAA

Codon

change

resulted

[re]

difference

amino

acid

position

GAT

AAT

TCT

...

Gene

from

Person

Source:

U.S.

Department

Energy

Human

Genome

Program,

http://genomics.energy.gov.

218

Part

Introduction

Pathophysiology

duce

specific

phenotype.

One

focus

genomics

research

now

deter-

mine

which

these

millions of

poly-

morphisms

likely

functionally

important,

and

continue

identify

how

each

might

relate

each

other

and

environment

and

health.”!

Other

Polymorphisms

Other

types

polymorphisms

include

insertion

deletion

polymor-

phisms,

which

number

nucle-

otide

base

pairs

are

either

added

or deleted

from

gene.

For

example,

2020

Cengage

Leaming.

All

Rights

Reserved.

May

not

copied,

scanned,

duplicated,

whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

leaming

experience.

Cengage

Learning

reserves

the

right

remove

additional

content

any

time

subsequent

rights

restrictions

requice

the

angiotensin-converting

enzyme

(ACE)

gene

has

inser-

tion/deletion

polymorphism

characterized

the

presence

absence

287—base

pair

fragment

one

its

introns,

which

linked

alterations

circulating

levels

ACE

and

risk

renal

complications

type

diabetes.””

Frameshift

mutations

can occur

when

the

reading

frame

a gene

altered

inserting

deleting

single

nucleotide

series

nucleotides.

These

tend

have

less

impact

the

insertion

the

form

triplet

but

can

devastating

when

only

one

two

nucleotides

are

inserted.

For

example,

see

what

happens

when

the

reading

frame

for

the

following

sequence

shifted

insertion

single

nucleotide

(ade-

nine,

shown

red):

CUU

AUG UUA

CGU

AAG...

Leu

Met

Leu

Arg Lys

CUU AAU

GUU

ACG

UAA

4G...

Leu

Asn

Val

Thr

STOP

Other

syndromes

can

occur

result

inheriting

extra

copies of

chromosomes,

as in

Down

syndrome,

deletions

of sections of

chromosomes,

which

one

cause

the

neuro-

logical

disorder

Angelman

syndrome.

Epigenetic Regulation

Epigenetics

relates

not

the

genome

sequence

itself

but

the inherited

pattern

gene

expression

regulated

modifi-

cations

DNA.°

Gene

expression

regulated

many

ways,

including

DNA

methylation;

histone

methylation,

acetyla-

tion,

phosphorylation;

and

transcription

factors.!®

recently,

noncoding

RNAs,

such

the

miRNAs

described

earlier

the

chapter,

have

been

identified

playing

reg-

ulatory

role

well.!””>

All

these regulatory

mechanisms

can

influenced

early

programming

response

nutrition

and

other

environmental

factors

fetal

life

or infancy

well

throughout

the

life

span.

For

example,

monozygotic

(iden-

tical)

twins

have

identical

genotype

but

have

been

found

have

differing

epigenetic

patterns

they

got

older.2*”>

This

was

especially

true of

those

who

spent

their

lifetime

apart

and

had

the

greatest

lifestyle

differences.

This

could

explain

differences

disease

risk

twin

pairs

and

indicates

that

modifying

the

epigenome

activate

suppress

genes

through

diet

has

potential

modify

risk

chronic

disease

and

cancer.

Epigenetic

patterns

may

also

passed

from

one

generation

the

next;”°

thus,

individual

patterns

may

reflect

environmental

exposures

generations.

DNA

Methylation

Although

humans

have

the

full

comple-

ment

genetic

material

all

nucleated

cells, not

all

genes

are

expressed

all

cells,

and

the

actual

level

expression

var-

ies

based

DNA

methylation

patterns.

Each

tissue

type

the

body

has

distinctive

methylation

pattern

that

results

the

tissue-specific

gene

expression,’

such

the

expression

of the

gene

for

insulin

only

the

beta

cells

of the pancreas.

Approximately

2%-5%

cytosines

mammalian

DNA

are

methylated,

primarily

CpG

dinucleotides

present

the

promoter

regions

genes,

and

the pattern

methylation

inherited,

though

also

changes

with

aging

and

influenced

environmental

factors.!°

This

methylation

CH;

group

donated

S-adenosylmethionine

SAM)

provides

tight

con-

trol

over

genes

keeping

chromatin

(DNA

plus

the

histone

proteins

with

which

associated)

condensed

and

thereby

suppressing

gene

expression,

keeping

the

genes

“silenced?!

For

most

genes,

both

maternal

and

paternal

alleles

con-

tribute

production

of the

protein

product,

but

for

others,

genomic

imprinting

takes

place.

other

words,

for

specific

genes,

only

the

maternal

paternal

allele

expressed.

For

example,

the

gene

encoding

insulin-like

growth

factor

(IGF2)

expressed

only

from

the

paternal

allele,

while

the

maternal

allele

mammals

silenced.2”

humans,

predicted

that

there

are

few

hundred

imprinted

genes.”*

Imprinting

errors

can

result

devastating

outcomes

offspring,

including

the

neurological disorders

Angelman

syndrome

and

Prader—Willi

syndrome.”

proposed

that

imprinted

genes

(as

opposed

gene

sequence)

hold

the

most

promise

for

rapid evolution-

ary

adaptation

changes

the

nutritional

environment

and

may

therefore

implicated

the

current

epidemic

obe-

sity,

metabolic

syndrome,

and

type

diabetes mellitus.”

Methyl

groups

are

derived

from

dietary

sources

including

folate,

choline,

methionine,

and

vitamin

By.”

shown

Figure

10.6,

MTHER

catalyzes

conversion

5,10-methylenetetrahydrofolate

5-methyl-tetrahydrofolate,

which

then

donates

ils

methyl

group

vitamin

Bj).

Vitamin

By,

thus

activated,

then

methylates

homocysteine

order

form

methionine.

Alternatively,

choline

can

converted

to betaine,

which

can

also

methylate

homocysteine

form

methionine.

Methionine

adenosyl

transferase

then

unites

methionine

with

adenosine

form

SAM,

which

methylates

DNA

via

the

action of

DNA

methyltransferases.°°

Thus,

dietary

adequacy

plays

role in

maintaining

appropriate

DNA

methylation.”

deficiency

methyl

groups

to lack

of the

previously

listed

nutrients

means

that

cells

divide,

methylation

may

reduced,

and

some

that

tran-

scriptional

regulation

lost.

Impaired

methylation

DNA

strongly

impaired

fetal

development

and

can-

cer?!

For

example,

hypomethylation

DNA

chromosomal

instability,

including

gain

loss

entire

chro-

mosomes

increased

gene

mutation

rates

during

mitosis,

both

which

can

contribute

cancer.*”

Research

also

sug-

gests

that

hypomethylation

DNA

coupled

with

genetic

risk

factors

contributes

greater

susceptibility

autoimmune

diseases

such

type

diabetes

mellitus.*”

Histone

Modification

DNA

methylation,

histone

modification

form

epigenetic

regulation.**

Histones

are

small

proteins

around

which

DNA

wrapped.

The

histone

tail

can be

modified

methylation,

acetylation,

phosphoryla-

tion,

ubiquitination,

biotinylation,

and

forth,

which

helps

regulate

transcription,

DNA

repair,

apoptosis

(programmed

cell

death),

mitosis,

and

meiosis.

This

pattern

often

referred

the

histone

code.

Histone

modifications

work

concert

with

DNA

methylation

determine

shape

and

accessibility

chromatin

for

transcription

(see

Figure

10.7).

For

example,

enzymes

called

histone

acetyltransferases

attach

acetyl

groups

histones,

and

this

acetylation

associated

with

unfolding

and

accessibility

chromatin

for

transcription,

whereas

his-

tone

deacetylases,

which

remove

acetyl

groups,

promote

fold-

ing

chromatin

and

block

gene

transcription.

Several

dietary

factors—including

sulforaphane

cruciferous

vegetables,

Chapter

Nutritional

Genomics.

219

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Leaming.

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Rights

Reserved.

May

not

copied,

scanned,

duplicated,

whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

leaming

experience.

Cengage

Learning

reserves

the

right

remove

additional

content

any

time

subsequent

rights

restrictions

requice

The

unit

for

measuring

relative

acidity

alkalinity

fluid

called

pH.

Simply

stated,

the

ratio

acids

bases.

Hydrogen

ion

concentration

(H*)

the

negative

logarithm

hydrogen

ions

solution:

log

1/[H*]

—log[H*]

Because

the

scale

logarithmic,

order

for

the

change

one

unit

(e.g.,

changing

from

4),

there

must

10-fold

change

H*.

The

substance

measured

range

from

14.

the

scale

indicates

the

most

acidic,

anda

indi-

cates

the

most

alkaline.

Water

considered

neutral

7.0.

For

humans,

normal

serum

within

the

range

7.35—7.45.

Note

that

reported

normal

values

for

arterial

vary

among

the

numerous

references

available;

for

this

chapter,

the

range

7.35—7.45

used.!~?

shown

Figure

8.1,

the

other

body

fluids

varies,

with

gastric

juice

being

the

most

acidic.

Terms

Describing

Acidosis

the

process

(or

processes)

that

leads

accumu-

lation

of acid or

loss

base.

Acidemia

the

actual

decrease

within

the

body

to <7.35.

Likewise,

alkalosis

the

process

(or

processes)

that

leads

accumulation

base

loss

acid,

whereas

alkalemia

the

condition

where

actual

increase

>7.45

observed.

clinical

practice,

this

distinction

generally

not

made

and

the

terms

acidosis

and

alkalosis

are

used

refer

abnormal

pH.

8.3

REGULATION

ACID-BASE

BALANCE

illustrated

Figure

8.2,

the

body

has

several

physiological

means

accommodating

all

the

hydrogen

ions

constantly

produces.

These

include

(1)

chemical

buffers,

(2)

the

respi-

ratory

regulation

pH,

and

(3)

the

kidney

regulation

pH.

Chemical

Buffering

buffer

reacts

with

free

order

maintain

acid-base

equilibrium.

Effectiveness

the

power

the

particular

buf-

fer

determined

its

association

with

cellular

salt

(pK)

and

its

overall

concentration

the

fluid

compartment.

Buffers

are

present

all

body

fluids—both

extracellular

and

intracellular.

Table

8.1

summarizes

the

chemical

buffers.

The

Bicarbonate-Carbonic

Acid

Buffer

System

The

primary

buffer

extracellular

fluid

(ECF)

the

bicarbonate—

carbonic

acid

buffer

system.

This

buffer

system

accommo-

dates

than

80%

the

required

buffering

the

ECF.

It is

outlined

follows:

HCO,

H,CO,

CO,

H,O

the

buffer

system

reacts

with

fixed

acids,

HCO;

produced.

discussed

previously,

HyCO3

readily

dissolves

CO,

and

H,O.

Therefore,

the

lungs

will

accommodate

the

increased

load

acids

increasing

rate

and

depth

breath-

ing

and by

expiring

the

CO,

(see

Figure

8.2).

The

kidney

Figure

8.1

Body

Fluids

and

Other

Common

Solutions

Hydrochloric

acid

(HCl)

Gastric

fluid

(1.0-3.0)

Lemon

juice,

cola

drinks,

some

acid

rain

Vinegar,

wine,

beer,

oranges

Acidic

Tomatoes

Bananas

Black

coffee

Bread

Typical

rainwater

Urine

(5.0-70)

Milk

(6.6)

Pure

water

[H*]

[OH7]

Blood

(735-745)

Egg

white

(8.0)

Seawater

(7.8-8.3)

Baking

soda

Phosphate

detergents,

bleach,

antacids

Soapy

solutions,

milk

magnesia

Basic

ses

Household

ammonia

(10.5—-11.9)

Hair

remover

Oven

cleaner

Sodium

hydroxide

(NaOH)

helps

with

this

buffer

system

either

reabsorbing

HCO3"

regenerating

additional

HCO;

from

CO,

and

H,0.!”

Historically,

the

Henderson—Hasselbalch

equation

has

been

used

explain

the

interrelationships

between

HCO,

and

pH.

humans,

the

pH,

ratio

acids

to bases,

part

HyCO3

parts

HCO;

order

for

remain

within

the

normal

range,

this

ratio

has

maintained.

Any

change

HyCO3

must

accompanied

proportional

change

HCO,g

one

part of the

equation

changes

without

the

other

and

the

ratio

not

maintained,

will

move

out

the

normal

range.

Other

Chemical

Buffer

Systems

The

body

has

additional

buffer

systems

place

compensate

for

changes

that

could

occur

from

other

sources

acid.

important

buffer

system

within

red

blood

cells

and

tubules

the

kidney

the

diso-

dium/monosodium

phosphate

(NayHPO,)

buffer.

Excretion

could

potentially

make

urine

acidic

that

excretion

would

physically

damaging

the

kidney.

Fortunately,

phosphate

Chapter

Acid-Base

Balance

161

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Leaming.

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Rights

Reserved. May

not

copied,

scanned,

duplicated,

whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

leaming

experience.

Cengage

Learning

reserves

the

right

remove

additional

content

any

time

subsequent

rights

restrictions

require

Figure

8.2

Overall

Schema

for

Maintenance

Acid-Base

Balance

the

usual

mixed

diet,

threatened

production

strong

acids

(e.g.,

sulfuric,

hydrochloric,

and

phosphoric),

which

result

mainly

from

protein

metabolism.

These

strong

acids

are

buffered

chemical

buffers

the

body.

Removal

extra

H*s

and

the

accompanying

anions

from

the

body

accomplished

renal

excretion.

When

the

kidneys

excrete

H*s,

they

add

new

bicarbonate

the

blood,

thereby

restoring

depleted

body

buffer

bases.

The

respiratory

system

eliminates

CO,

produced

metab-

olism.

CO,

not

threat

acid-base

balance,

provided

its

par-

tial

pressure

arterial

blood

kept

at a

normal

value.

}

Food

intake

s/f

Digestion,

absorption

Cell

metabolism

foodstuffs

»)

Sulfate,

chloride,

phosphate

anions

co,

Depleted

HCO3~

replaced

CO,

blown

kidneys

off

lungs

Sulfate,

chloride,

phosphate

soaked

excreted

chemical

kidneys

buffer

bases

(2.9,

HCOs)

combined

with

urinary

buffers

excreted

by kidneys

Source:

Lauralee

Sherwood,

Human

Physiology:

From

Cells

Systems.

5th

ed.

2004,

793.

helps

with

this

buffer

system

either

reabsorbing

HCO;

regenerating

additional

HCO;”

from

CO,

and

H,0.!?

Historically,

the

Henderson—Hasselbalch

equation

has

been

used

explain

the

interrelationships

between

HyCOs,

162

Part

3 Introduction to

Pathophysiology

Table

8.1

Chemical

Buffers

and

Their

Primary

Roles

Bicarbonate-carbonic

acid

buffer

Primary

ECF

buffer against

system

non-carbonic-acid

changes

Protein

buffer

system

Primary

ICF

buffer;

also

buffers

ECF

Primary

buffer against

carbonic

acid

changes

Hemoglobin

buffer

system

Phosphate

buffer

system

Important

urinary

buffer;

also

buffers

ICF

Note:

ECF,

extracellular

fluid;

ICF,

intracellular

fluid.

Source:

Reprinted

from

Sherwood

Human

Physiology:

From

Cells

Systems.

9th

ed.

Boston

MA:

Cengage;

2016,

Table

15-6,

552.

accepts

the

and

weaker

acid

that

less

harmful

the

kidney

formed.

This

buffer

system

outlined

as follows:

NayHPO,+

NaH,PO,+

Nat

Proteins

present

the

plasma

can

act

as buffers; their

contribution

most

important

intracellularly.

The

protein

buffer

system

acts in

the

same

fashion

the

bicarbonate—

carbonic

acid

buffer

system

that

protein accepts

the

H*.

Many

proteins

can

also

release

the

alkalinity

increases.

The

proteins’

ability

act

both

situations

increases the

effectiveness

this

buffer

system.

Hemoglobin

within

the red

blood

cell

acts

the

most

important

buffer

blood.

Carbon

dioxide

diffuses

into

the

blood

asit

produced

throughout

the

body.

Most

the

CO)

will

combine

with

water,

forming

carbonic

acid. As

stated

earlier,

carbonic

acid

will

dissociate

bicarbonate

and

free

Ht.

Hemo-

globin

then

binds

the

H*.

The

reaction

reversed

blood

passes

through

the

lungs

and

becomes

oxygenated.

Oxygenated

hemoglobin

gives

the

HCO3~

and

thus

carbonic

acid

(HCOs)

generated.

stated

earlier,

HCO,

dissolves

CO)

and

H,O.

CO,

then

expired

via

the

lungs

(see

Figure

8.3).

Respiratory

Regulatory

Control

The

line

defense

maintaining

acid—base

balance

respiratory

control.

The

lungs

have

the

ability

change

respi-

ratory

rate

and

depth

breathing

control

either

release

retention

CO)

and

hence

assist

management

acid—

base

balance.

This

control

system

very

sensitive

and

able

respond

spontaneously.

The

level

CO,

the

blood

controls

the

cerebrospinal

fluid,

since

and

HCO;°

not

cross

the

blood-brain

barrier.

Changes

pH—specifically

the

level

CO,—are

detected

cerebrospinal

fluid

respiratory

cen-

ter

the

brain.

response,

respiratory

rate

changes

move

the

toward

normal

range.

For

example,

when

acidosis

occurs

and

the

buffer

system

not

adequate

control

the

acidosis,

respiratory

rate

and

depth

will

increase

(hyperventilation).

This

allows

larger

amounts

CO,

expired.

situation

where

PaCO,

(see

chapter

endnote

has

decreased

(alkalosis),

respirations

will

slow,

CO)

concentrations

will

increase,

and

will

normalize.

Any

change

anatomy

physiology

of the

respiratory

system,

nervous

2020

Cengage

Leaming.

All

Rights

Reserved.

May

not

copied,

scanned,

duplicated,

whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

leaming

experience.

Cengage

Learning

reserves

the

right

remove

additional

content

any

time

subsequent

rights

restrictions

require

it.

Figure

8.3

Transport

and

Exchange

Carbon

Dioxide

and

Oxygen

Carbon

dioxide

(CO2)

picked

the

tissue

level

transported

the

blood

three

ways:

(1)

physically dissolved,

(2)

bound

hemoglobin

(Hb),

and

(3)

bicarbonate

ion

(HCO3

Hemoglobin

present

only

the

red

blood

cells,

carbonic

anhydrase,

the

enzyme

that

catalyzes

the

production

HCO;.

The

generated

during

the

production

HCO;

also

binds

Hb.

Bicarbonate

moves

facilitated

diffusion

down

its

concentration

gradient

out

the

red

blood

cell

into

the

plasma,

and

chloride

(CI)

moves

means

the

same

passive

carrier

into

the

red

blood

cell

down

the

electrical

gradient

created

the

outward

diffusion

HCO;

Alveoli

Tissue

cells

From

systemic

circulation

ca,

carbonic

anhydrase

Source:

Sherwood,

Human

Physiology:

From

Cells

Systems.

9th

ed.

Figure

13-27,

476.

system

control

respiration,

mus-

Figure

8.4

Control

the

Rate

Tubular

Secretion

and

HCO3”

Reabsorption

cles

that

assist

breathing

will

affect

the

ability

the

respiratory

system

Alleviates

Buffers

respond

changes

pH.

The

line

defense

secondary

response

(often

referred

to as

com-

pensation)

coordinated

the

kid-

neys,

described

the

section.

dealing

with

the

large

amount

nonvolatile

(fixed)

acids

since

these

cannot

expired

gases.

maintain

pH,

healthy,

nor-

and

H,0,

which

then

forms

HCO;

and

free

H*.

This

allows

Renal

Regulatory

Control

Hydrogen

and

Bicarbonate

lons

The

kidney’s

role

controlling

both

and

HCO;

critical

component

for

the

maintenance

homeosta-

sis.

Respiratory

control

ineffectual

mally

functioning

kidney

will

reabsorb

the

majority

all

for

constant

regeneration

bicarbonate,

which

needed

HCO,"

that

needed

(see

Figure

8.4).

This

function

requires

buffer

the

fixed acids

being

continuously

released.

the

kidney

secrete

(see

Figure

8.5),

which

combines

In the

situation

where

alkalosis

occurs,

the

kidney

will

with

HCO,

forming

H,CO3.

H,CO3

dissolves

form

CO,

respond

reducing

the

amount

HCO;

reabsorbed.

the

Chapter

Acid-Base

Balance

163

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Cengage

Leaming.

All

Rights

Reserved.

May

not

copied,

scanned,

duplicated,

whole

part,

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

learning

experience.

Cengage

Learning

reserves

the right

toremove

additional

content

any

time

subsequent

rights

restrictions

requize

it,

Figure

8.5

Hydrogen

lon

Secretion

Coupled

with

Bicarbonate

Reabsorption

Kidney

Tubular

Cell

Because

the

disappearance

filtered

HCO3°

from

the

tubular

fluid

coupled

with

the

appearance

another

HCO37

the

plasma,

HCO3

considered

have

been

“reabsorbed.”

Tubular

lumen

Peritubular

capillary

plasma

Type

intercalated

tubular

cell

KEY

Carbonic

anhydrase

Active

transport

Secondary

active

transport

—

Passive

diffusion

———>

Chemical

reaction

Catalyzed

membrane-bound

other

hand,

acidosis

occurs,

the

kidney

will

increase

secretion

and

increase

the

amount

HCO"

reabsorbed.

Renal

reg-

ulatory

control

much

slower

than

respiratory

regulation

and

may

take

several

days

fully

respond

imbalances.*

Secretion

isa

vital

component

the

renal

regulation

acid—base

balance.

The

minimum

urine

humans

4.5.

drops

below

4.5,

the

urine’s

acidity

becomes

harmful.

The

kidney

cannot

use

bicarbonate

buffer

since

cannot

excreted

the

same

time

the

hydrogen

ions.

Thus,

the

kidney

uses

two

other

buffers

(dibasic

phosphate

and

ammo-

nium)

prevent

damage

from

acidic urine,

described

the

section.

Other

Renal

Regulatory

Controls

The

base

NH;

(ammonia)

formed

renal

tubular

cells

from

the

amino

acid

glutamine.

Free

combines

with

NH;

form

ammo-

nium

(NH,*).

Ammonium

cannot

cross

back

across

the

cell

membrane,

H™

trapped

and

thus

excreted

the

urine.

Table

8.2

Summary

Renal

Responses

Acidosis

and

Alkalosis

Alkalinization

toward

normal

Acidosis

SSE

Dibasic

phosphate

and

sulfur

both

function

to accept

order

control

acid—base

balance.

situation

where

large

load

fixed

acids

produced,

the

kidney

will

respond

increasing

formation

acids

within

this

buffer

system.*°

This

may

occur,

for

example,

during

protein

catabolism.

Approximately

one-third

the

free

excreted

phos-

phoric

acid

(HjPO,)

and

sulfuric

acid

(H)SO,).

Table

8.2

sum-

marizes

renal

responses

changes

acid—base

balance.

Effect

Acid

and

Base

Shifts

Electrolyte

Balance

Hydrogen

ions

and

bicarbonate

are

both

electrolytes.

Acid—base

changes

will

therefore

affect

concentrations

other

electrolytes

both

ECF

and

intracellular

fluid

(ICF).

For

example,

movement

HCO;

the

plasma

requires

the

exchange

another

negatively

charged

ion

that

electroneutrality

maintained.

Chloride

(CI)

the

ion

that

Normal

(zero;

all

Acidic

filtered

reabsorbed)

Source:

Reprinted

from

Sherwood

Human

Physiology:

Fram

Cells

Systems.

9th

ed.

Boston

MA:

Cengage;

2016,

Table

15-8,

557.

164

Part

Introduction to

Pathophysiology

2020

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Leaming.

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Rights

Reserved.

May

not

copied,

scanned,

duplicated,

whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

learning

experience.

Cengage

Learning

reserves

the

right

toremove

additional

content

any

time

subsequent

rights

restrictions

requice

it,

moves

the

opposite

direction

HCO;

(as

shown

Figure

8.5).

Changes

potassium

(K*),

chloride

(CI-),

and

sodium

(Na*)

may

accompany

acid—base

disorders.”3*

Assessment

Acid-Base

Balance

It is

understatement

say

that

assessment

acid—base

disturbances

may

difficult.

This

difficulty

arises

because

the body’s

attempt

self-correct

changes

pH.

These

compensatory

secondary

responses

confuse

the

clinical

situation,

making

origin

the

disturbance

difficult

assess.

Assessment

acid—base

balance

requires

than

simply

examining

laboratory

values—it

needs

placed

into

the

context

the

patient's

current

medical

condition.

Examining

laboratory

values

elicits

only

the

current

state

blood

pH.

Furthermore,

because

the

body

can

actually

tolerate

changes

acid—base

balance

asymptomatically,

assessment

based

the

two-dimensional

model

that

generally

taught

not always

accurate.’

This,

course,

difficult

for

novice

clinicians,

but

with time

and

experience,

one

begins

able

piece

together the

puzzle

acid—base

disturbances.

Common

laboratory

measurements

arterial

blood

gases

(ABGs)

(see

Table

8.3)

and

serum

chemistries

will

provide

values

needed

initially

assess

acid—base

balance.®

These

include

arterial

measures

both

CO,

and

(PaCO,

and

PaO,).

Additionally,

pH,

CO,

HCO;",

base

excess,

and

anion

gap

are

also

measured.

Even

though

both

base

excess

and

HCO;

are

measured,

they

directly

correlate,

Table

8.3

Normal

Arterial

Blood

Gas

(ABG)

Values

for

Assessment

Acid-Base

Balance

7.35-7.45

pO2,

mmHg

280

pCO,

mmHg

35-45

HCO3,,

mEq/L

24-28

Base

excess,

mEq/L

Anion

gap,

mmol/L

10-20

Anion

gap,

mEq/L 8-16

saturation,

295

not

necessary

evaluate

both

values.

See

Table

8.3

for

outline

normal

values of

ABG

parameters

and

analysis

ABGs.

When

evaluating

pH,

remember

that

humans

this

measures

the

ratio

acids

bases.

both

acid

and

base

increase

(or

decrease)

within

the

same

proportion,

will

remain

steady.

only

when

one

changes

out

proportion

the

other

that

change

will

measurable.

other

words,

just

because

pII

within

normal

range,

does

not

exclude

the

possibility

acid-base

disturbance.”

<7.35

>7.45

indicates

acidosis

alkalosis,

respectively.

The

represents

the

difference

between

unmeasured

anions

and

cations.

This

calculation

important

further

evaluate

situations

metabolic

acidosis.

calculated

using

the

following equation:

Nat—(Cl-

HCO3;,).

The

reference

range

for

calculated

8-16

mEq/L.””

Most

clinicians

not

use

the

calculation

due

its

vari-

ability

acid—base

imbalances

but

this

assumption

con-

troversial.”*

When

assessing

acid—base

balance,

the

primary

response

determined

first

but

investigation

of the

sec-

ondary

response

compensation

well

allows

for a

com-

plete

assessment.

Application

these

values

discussed

throughout

the

following

sections.

Acid-Base

Disorders

There

are

four

major

types

simple

acid—base

disorders:

respiratory

acidosis,

respiratory

alkalosis,

metabolic

acido-

sis,

and

metabolic

alkalosis

(see

Table

8.4).

Combinations

each

these—indicating

mixed

disorder—can

and

often

occur.

The

only

combination

imbalances

that

not

pos-

sibility

simultaneous

respiratory

acidosis

and

respiratory

alkalosis,

since

obviously

hypoventilation

and

hyperventila-

tion

cannot

happen

together.

Respiratory

Acidosis

Respiratory

acidosis

occurs

when

there

excess

acid

relationship

base

caused

retention

carbon

dioxide.

This

generally

occurs

when

there

inability

the

lungs

expire

COQ).

the

level

CO)

rises,

hypercapnia

occurs,

carbonic

acid

(HyCO3)

formed,

and

shifted

toward

acidosis.1”°

Table

8.4

Summary

CO,,

HCO;,,

and

Uncompensated

and

Compensated

Acid-Base

Abnormalities

Normal Normal

Uncompensated

respiratory

acidosis

Decreased

Compensated

respiratory

acidosis

Normal

Uncompensated

respiratory

alkalosis

Increased

Compensated

respiratory

alkalosis

Normal

Uncompensated

metabolic

acidosis

Decreased

Compensated

metabolic

acidosis

Normal

Uncompensated

metabolic

alkalosis

Increased

Compensated

metabolic

alkalosis

Normal

Source:

Reprinted

from

Sherwood

Human

Physiology:

From

Cells

Systems.

9th

ed.

Boston MA;

2016,

Table

15-9,

562.

Normal Normal

20/1

Increased

Normal

20/2

(10/1)

Increased Increased

40/2

(20/1)

Decreased

Normal

20/0.5

(40/1)

Decreased

10/0.5

(20/1)

Normal

Decreased

10/1

Decreased Decreased

15/0.75

(20/1)

Normal

Increased

40/1

Increased Increased

25/1.25

(20/1)

Chapter

Acid-Base

Balance

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Rights

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not

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party

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the

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suppressed

content

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materially

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experience.

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Learning

reserves

the

right

remove

additional

content

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time

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rights

restrictions

requice

165

Etiology

Any

factor

that

inhibits

the

medullary

respiratory

center

can

affect

ventilation

and

thus

the

ability

release

CO.

Medications

such

opiates

sedatives

can

inhibit

respira-

tion.

Chronic

conditions

such

sleep

apnea

acute

events

such

cardiac

arrest

can

also

affect

normal

ventilation.

Diseases

that

affect

musculature

the

respiratory

system

and

chest

wall

can

result

in poor

ventilation.

These

may

include

neurological

conditions

such

myasthenia

gravis

extreme

obesity

such

seen

Pickwickian

syndrome.

Additionally,

any

injury

or trauma

the

chest

wall

can

potentially

result

inability

expire

adequate

amounts

carbon

dioxide.

Respiratory

diseases,

such

chronic

obstructive

pulmo-

nary

disease,

result

inability

maintain

adequate

oxygenation

release

carbon

dioxide.

Other

conditions

such

pneumo-

nia,

acute

pulmonary

edema,

pneumothorax

can

result

respiratory

acidosis.'”

Common

causes

are

outlined

Table

8.5.

Pathophysiology

respiratory

acidosis,

the

major

cellular

buffering

defense

available

expiration

CO,

the

lungs.

But

since

the

major

cause

respiratory

acidosis

respiratory

dysfunction,

this

buffering

system

typically

inefficient.

Body

stores

HCO;

are

released

order

maintain

the

appropri-

ate

ratio

CO)

HCO",

keeping

within

normal

range.

During

acute

respiratory

acidosis,

the

kidney

regulatory

sys-

tems

not

have time

compensate,

since

these

only

begin

react

within

—

hours.

Chronic

respiratory

acidosis

less

critical

because

the

kidneys

have

time

provide

for

ongoing

compensation.

Renal

compensation,

which

works

over

longer

period,

includes

increased

excretion

and

resorp-

tion of

HCO;

Other

renal

buffer

systems

such

the

use

ammonium

(NH,)

will

also

provide

secondary

response.

Clinical

Manifestations

Laboratory

values

acute

respiratory

failure

will

indicate

decreased

and

ele-

vated

pCO.

Bicarbonate

levels

will

slightly

elevated

renal

compensation

has begun.

Compensatory

mechanisms

secondary

responses

allow

the

remain

normal

but

serum

bicarbonate

and

arterial

pCO)

are

elevated.

Serum

Table

8.5

Common

Causes

Respiratory

Acidosis

Hypoventilation

Chronic

obstructive

pulmonary

disease

Severe

pneumonia

asthma

Acute

pulmonary

edema

Pneumothorax

Drugs:

opiate,

sedative,

anesthetic

overdose

(acute)

Excessive

oxygen

treating

chronic

hypercapnia

Sleep

apnea

Neuromuscular

disease

such

amyotrophic

lateral

sclerosis

(ALS),

Guillain-Barré

syndrome,

spinal

cord

injury

Morbid

obesity,

Pickwickian

syndrome

Chest

wall

injury

skeletal

deformity

Aspiration

foreign

body

vomitus

Laryngospasm,

laryngeal

edema,

severe

bronchospasm

Excessive

production

COz

Overfeeding,

especially

with

high-carbohydrate

components

nutrition

support

166

Part

Introduction

Pathophysiology

electrolytes

will

show

increase

serum

Ca*,

K*,

and

pos-

sibly

CI’

due

changes

renal

controls."*?

both

acute

and

chronic

respiratory

acidosis,

hypox-

emia

present.

This

reduced

level

oxygen

responsible

for

most

symptoms

associated

with

the

acidosis.

general,

acute

onset

will

result

increased

severity

symp-

toms.

Alterations

respiration

will

include

increased

respi-

ratory

rate

(hyperventilation)

and an

increase

depth

respirations,

Other

symptoms

are

result

of the

change

oxygenation

the

brain

and/or

decrease

neurotransmis-

sion.

These

include

restlessness,

apprehension,

lethargy,

mus-

cle

twitching,

tremors,

convulsions,

and

finally,

coma.2*

Treatment

will

focus

correcting

the

under-

lying

condition causing

respiratory

changes.

Presence

hypoxemia

would

focus

treatment

increasing

oxygenation

through

administration

oxygen

provision

mechani-

cal

ventilation.

those

patients

with

chronic

hypoxemia,

crucial

realize

that

the

hypoxemia

may

providing

the

stimulus

for

ventilation.

oxygen

therapy reduces

hypox-

emia,

ventilation

may

acutely

decline

without

this

stimulus.

Respiratory

Alkalosis

Respiratory

alkalosis

(see

Table

8.6)

characterized

relative

excess

amount

base

(HCO;

)

result

reduc-

tion

CO).

This

acid—base

disturbance

generally

a result

conditions

causing

hyperventilation.

Rapid

breathing

results

decreased

PaCO).

Etiology

Hyperventilation

commonly

result

reduc-

tion

serum

oxygen

levels

(hypoxemia).

Hypoxemia

can

a result

respiratory

diseases

such

pneumonia,

asthma,

pulmonary

embolism,

pulmonary

edema,

exposure

high

altitudes.

Direct

stimulation

the

respiratory

center

the

brain

can

also

cause

hyperventilation

and

resulting

loss

CO).

For

exam-

ple,

disorders

the

CNS

such

as a

malignancy

stroke

can

affect

respiratory

centers

and

result

hyperventilation.

Hyper-

metabolic

states

such

fever

and

sepsis

can

directly

stimu-

late

hyperventilation.

Drugs—including

theophylline,

salicylates,

progesterone,

doxapram,

and

catecholamines—and

even

anxiety

other

types

emotional

distress

can

result

hyperventila-

tion.

Hyperventilation

can

also

occur

adaptive

response

high

oxygen

demands

during

strenuous

physical

activity.

Pathophysiology

The

acute

response

respiratory

alka-

losis

(within

the

first

hours)

shift

acid

from

the

ICF

the

ECF

with

accompanying

movement

bicarbonate

Table

8.6

Common

Causes

Respiratory

Alkalosis

Hyperventilation

Respiratory

infection;

pneumonia

Asthma

Change

altitude

environment

(i.e.,

high

altitude)

Drugs

that

stimulate

respirations

(e.g.,

theophylline,

catecholamines)

Anxiety

Cerebrovascular

accident

Fever

and

sepsis

2020

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Leaming.

All

Rights

Reserved.

May

not

copied,

scanned,

duplicated,

whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

leaming

experience.

Cengage

Learning

reserves

the

right

remove

additional

content

any

time

subsequent

rights

restrictions

requice

into

cells

exchange

for

chloride.

Additional

syn-

thesized

increase

lactic

acid

derived

from

pyruvate

within

cells.

Shifts in

are

generally

not

adequate

han-

dle

continued

decrease

PaCOy.

For

chronic

respiratory

alkalosis

(lasting

longer

than 24

hours),

secondary

renal

response

(compensation)

occurs.

The

kidneys

reduce

their

secretion

(which

also

reduces

regeneration

HCO;

)

and

increase

their

excretion

bicarbonate

(HCO;

Clinical

Manifestations

acute

respiratory

alkalosis,

>7.45

and

PaCOy

decreased. In

chronic

respiratory

alka-

losis,

>7.45

and

plasma

HCO,

low.

both

situations,

alkalosis

may

accompanied

electrolyte

imbalances.

Labs

may

reveal

low

serum

levels

and

Ca*

well

high

levels

Cl.

Other

symptoms

respiratory

alkalosis

are

seen

the

cardiovascular,

central

nervous,

and

respiratory

systems.

Car-

diac

arrhythmias

may

noted.

Symptoms

the

respiratory

system

vary

but

may

include

frequent

yawning

and

deeper

breaths.

Symptoms

the

central

nervous

system

are

most

obvious

and

may

include

“lightheadedness,”

mental

confu-

sion,

anxiety,

and

seizures.

Patients

also

relate

paresthesias

with

cold

and

clammy

extremities.

Treatment

Correction

of the

underlying cause

respira-

tory

alkalosis

the

only

significant

treatment.

Correction

hypoxia

providing

oxygen

therapy

would

com-

mon

first

step.

the

cause

psychological

hyperventilation,

rebreathing

(see

chapter

endnote

CO)

can

correct

the

symptoms.

Metabolic

Acidosis

Metabolic

acidosis

refers

all

types

acidosis

that

are

not

caused

excessive

CO).

can

result

from

either

excessive

loss

base

(HCO;

)

excessive

gain

fixed

(nonvolatile)

acids

(see

Table

8.7).

Metabolic

acidosis

can

develop

both

acute

and

chronic

conditions,

but

due

respiratory

compen-

sation,

most

often

chronic

condition

(see

Table

8.8).

Metabolic

acidosis

further

characterized

using

the

calculation

determine

the

origin

the

disorder.*°°

Etiology

Conditions

that

result in

excessive

loss

bicarbon-

ate

from

the

gastrointestinal

system

from

renal

excretion

bicarbonate

can

result

metabolic

acidosis.

Diarrhea

the

most

common

cause.

Additionally,

HCO;

may

lost

from

ileostomy

from

pancreatic,

biliary,

intestinal

fistulas.”“

Table

8.7

Common

Causes

Metabolic

Acidosis

Kidney

loss

HCO3"

Chronic

kidney

disease

Systemic

loss

HCO3~

Diarrhea

Fistula

drainage

Excessive

production

of acid

Ketoacidosis

secondary

conditions

such

as diabetes

mellitus,

alcoholism,

starvation

Lactic

acidosis

secondary

conditions

such

diabetes

mellitus,

salicylate

overdose

Table

8.8

Respiratory

Adjustments

Acidosis

and

Alkalosis

Induced by

Nonrespiratory

Causes

Respiratory

rate

Tidal

volume*

Ventilation

Rate

CO,

removal

it Ay

Rate

carbonic

acid

formation

Rate

generation

ity

from

*Volume

oxygen

inhaled

and

exhaled

during

normal

breath.

Source:

Adapted

from

Sherwood

Human

Physiology:

From

Cells

Sys-

tems.

9th

ed.

Boston

MA:

Cengage;

2016,

Table

15-7,

5553.

Carbonic

anhydrase

inhibitors

such

the

drug

acet-

azolamide/Diamoz™

(used

antiseizure

medication

and

diuretic)

can

result in

excessive

loss

base

while

inhibiting

production

carbonic

acid

the

kidney.

the

condition

renal

tubular

acidosis,

ability

reabsorb

bicarbonate

decreased.

chronic

kidney

disease,

the

ability

restore

bicarbonate

may

fail

well.

Other

mechanisms

correct

acid—base

disturbances,

such

production

NH,*,

may

also

fail

renal

function

declines.

Metabolic

acidosis

may

also

result

from

situations

that

increase

the

amount

acid,

such

administration

ammo-

nium

chloride

(used

for

treatment

metabolic

alkalosis)

and

rapid

administration

saline.

Accidental

poisoning

with

substances

such

salicylate

(aspirin),

ethylene

glycol

(anti-

freeze),

formaldehyde

can

result

metabolic

acidosis.

Lactic

acidosis

(see

Figure

8.6)

occurs

as a

result

increased

production

lactate

ketoacids.

High

levels

lactate

may

result

when

the

kidney

liver

fails

convert

lactate

pyruvate.

Diabetic

ketoacidosis,

one

the

most

common

causes,

results

metabolic

acidosis

due

both

increased

production

and

inability

metabolize

ketones

(see

Box

8.1).

both

starvation

and

chronic

alcoholism,

synthesis

ketoacids

increased.

Starvation,

with

its

reliance

fat

stores,

can

also

increase

synthesis

ketoacids

and

result

acidosis."

Figure

8.6

Lactic

Acid

Production

When

NAD

concentration

decreased

compared

NADH

H*,

the

scale

leans

the

direction

lactic

acid

production

and

not

pyruvic

acid

production.

Conditions

that

result

decreased

con-

centrations

NAD

include

decreased

oxygenation

the

tissues,

excessive

ketone

body

production

(as

diabetes),

and

metabo-

lism

ethanol.

NAD

Lactic

Acid

NADH

Pyruvic

Acid

Chapter

Acid-Base

Balance

167

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restrictions

requice

BOX

CLINICAL

APPLICATIONS

Diabetic

Ketoacidosis

One

out

every

four

emergency

room

visits

for

patients

with type

diabetes

mellitus

for

diabetic

ketoacidosis

(DKA).

has

been

estimated

that

over

billion

spent

each

year

treating

this

condition

and

its

complications.

What

DKA,

and

how

this

condi-

tion related

the

acid-base

imbalances

you

have

learned

about

this

chapter?

Diabetes

mellitus

the

disease

caused

either

the

absence

inefficient

use

the

hormone

insulin

(see

Chapter

17).

Ketoacidosis

one

the

most

serious

acute

complications

type

diabetes

mel-

litus.

Diabetic

ketoacidosis

typically

develops

as a

result

infections

because

the

patient

does

not

take

adequate

amounts

insulin.

Without

adequate

insulin,

there

increased

dependence

lipids

the

primary

fuel

source.

The

increased

rate

lipolysis

results

the

production

ketones:

aceto-acetic

acid

and

hydroxybutyric

acid.

These

ketone

bodies

are

acids

that

lower

serum

pH.

The

kidney

reacts

excreting

the

ketone

bodies

the

urine

(ketonuria).

The

increased

levels

hydrogen

ions

are

buffered

plasma

bicarbonate.

This

combination

events

results

metabolic

acidosis.

High

levels

ketoacids

lead

increase

the

plasma

anion

gap.”

explained

this

chapter,

both

the

respiratory

and

renal

systems

serve

compensatory

secondary

mechanisms

acid-base

imbalance.

DKA,

lowers,

respiratory

ventilation

changes

accommodate

the

need

reduce

pCO).

Respirations are

deep

and

labored—

referred

Kussmaul's

respirations.

Second,

the

renal

system

compensates

conserving

bicarbonate

(HCO;

Furthermore,

urinary

excretion

positively

charged

cations

(Na*,

K*,

NH4*)

increases.

DKA

must

treated

quickly

and

accu-

rately

prevent

coma

and

death.

Providing

adequate

insulin,

fluids,

and

electrolytes

allows

the

correction of

the

metabolic

aci-

dosis

and

prevents

these

complications.

References

Kitabchi

AE,

Umpierrez

GE,

Fisher

JN,

Murphy

MB,

Stentz

FB.

Thirty

years

personal

experience

hyperglycemic

crises:

diabetic

ketoacidosis

and

hyperglycemic

hyperosmolar

state.

Clin

Endocrinol

Metab.

2008;

93:

1541-52.

Mendez

Surani

Varon

Diabetic

keto-

acidosis:

Treatment

the

intensive

care

unit

general

medical/surgical

ward?

World

Diabetes.

2017;

40-4.

Beer

Michael

Thacker

al.

Diabetic

ketoacidosis

and

hyperglycemic

hyperosmolar

syndrome—clinical

guidelines.

Nurs

Crit

Care.

2008;

13:

5-11.

Pathophysiology

WhenH*

levels

increase,

the

bicarbonate—

carbonic

acid

buffer

system

stimulated.

This

shift

into

ECF

reduces

serum

the

same

time

order

maintain

equilibrium

between

the

ECF

and

ICE.

High

levels

the

blood

stimulate

respiratory

cen-

ters

the

brain.

The

lungs

respond

increasing

rate

and

depth

breathing.

Finally,

the

kidneys

begin

their

com-

pensatory

response

increasing

their

excretion

and

retention

HCO;~.

Renal

compensation

much

slower

than

respiratory,

and

kidney

disease

present,

effectiveness

the compensation

decreased.

Clinical

Manifestations

Symptoms

metabolic

acido-

sis

are

not

clear

those

other

acid—base

disturbances.

Changes

respiration

include

deep

labored

breaths

which

are

referred

Kussmaul

breathing.

The

cardiovascular

system

affected

decreased

contractility

and

response

catecholamines.

Vasodilation

may

cause

hypotension

and

dysrhythmias.

Neurologically,

lethargy

and

stupor

with

even-

tual

coma

are

observed

the

falls

cerebrospinal

fluid.

chronic

renal

disease,

ongoing

metabolic

acidosis

relies

carbonate

from

bone

buffer

the

acid

load.

This

results

growth

failure

children

and

renal

osteodystrophy

adults.)

Treatment

focused

the

underlying

cause

the

acidosis.

Correcting

too quickly

can

cause

additional

complications.

The

goal

raise

systemic

safe

level.

Metabolic

Alkalosis

Presence

excessive

amount

base

(HCO3,)

results

metabolic

alkalosis

(see

Table

8.9).

Generally,

this

acid—base

disturbance

caused

a loss

nonvolatile

acids

the

excessive

administration

bicarbonate

transfusion

within

whole

blood.

168

Part

Introduction

Pathophysiology

Table

8.9

Common

Causes

Metabolic

Alkalosis

Loss

acid

Vomiting

Nasogastric

suctioning

Hypokalemia

Excessive

base

Intravenous

therapy

Blood

transfusion

Excessive

chronic

use

antacids

Etiology

Clinical

situations

resulting

alkalosis

can

catego-

rized

either

those

conditions

involving

fluid

imbalance

(alka-

losis

with

volume

decrease)

those

without

fluid

imbalances

(alkalosis

without

volume

contraction).

Conditions

that

involve

fluid

imbalance

include

prolonged

vomiting,

nasogastric

(NG)

suction,

use

diuretics.

suction

may

seen

post-

operative

patients

who

are

experiencing

ileus.

The

suction

removes

gastric

secretions

prevention

vomiting

aspi-

ration.

Conditions

leading

alkalosis

that

not

involve

fluid

imbalance

would

include

hyperaldosteronism,

excessive

use

corticosteroids,

blood

transfusions,

chronic use

antacids,

and

excessive

administration

sodium

bicarbonate.“

Pathophysiology

Initiation

metabolic

alkalosis

begins

with

the

underlying

event

that

causes

either

excessive

loss

acid

accumulation

base.

This

could

be,

for

example,

prolonged

vomiting

that

results

decreased

concentration

HCI.

Normally,

the

kidney

will

compensate

for

the

decrease

nonvolatile

acid

generating

and

decreasing

reab-

sorption

bicarbonate.

order

for

metabolic

alkalosis

progress,

other

events

need

occur

that

prevent

adequate

compensation

the

kidney.

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Leaming.

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Rights

Reserved.

May

not

copied,

scanned,

duplicated,

whole

part.

Due

electronic

rights,

some

third

party

content

may

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from

the

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and/or

eChapter(s).

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review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

leaming

experience.

Cengage

Learning

reserves

the

right

remove

additional

content

any

time

subsequent

rights

restrictions

requice

situations

where

there

also

volume

depletion,

such

use

diuretics,

there

both

fluid

loss

and

subsequent

decrease

levels.

maintain

serum

levels

within

safe

range,

the

kidney

will

excrete

exchange

for

K*.

Even

though

may

increase,

the

loss

results

generation

bicarbonate.

This

further

contributes

alkalosis.

Stored

blood

contains

citrate

as a

preservative.

individual

receives

large

amount

transfused

blood,

possible

the

body

will

convert

the

citrate

bicarbonate.

This

potentially

could

lead

metabolic

alkalosis.

Another

example

non-volume-related

alkalosis

the

condition

primary

secondary

hyperaldostero-

nism.

Increased

secretion

aldosterone

causes

the

kidney

increase

reabsorption

sodium.

This

accompanied

secretion

H*,

which

increases

regeneration

HCO;

Clinical

Manifestations

ABGs

metabolic

alkalosis

will

indicate

>7.45

and

elevated

levels

HCO,

(>26

mEq/L).

Accompanying

electrolyte

imbalances

may

indicate

<3.5

mEq/L

and

Cl"

<98

mEq/L.

compensation

the

respiratory

system

place

(see

Table

8.8),

PaCO,

will

remain

within

normal

range

slightly

elevated.

There

are

specific

signs

and

symptoms

for

metabolic

alkalosis.

Signs

and

symptoms

are

determined

accompanying

Table

8.10

Common

Mixed

Acid-Base

Disorders

Metabolic

acidosis

Cardiopulmonary

arrest

tespiratory

acidosis

Patient

with

COPD

goes

into

shock

PaCO,

too

high

Chronic

kidney

disease

with

fluid

HCO;

too

low

volume

excess

and pulmonary

edema

very

low

Patient

with

DKA

receives

potent

opiate

barbiturate

Metabolic

alkalosis

respiratory

alkalosis

Patient

with

previously

compensated

respiratory

acidosis

caused

COPD

overventilated

mechanical

respirator

Hyperventilating

patient

with

CHF

hepatic

cirrhosis

who

vomiting

treated

with

potent

diuretics

nasogas-

tric

suction

PaCO;

too

low

HCO;

too

high

very

high

Head

trauma

patient

with

hyperventila-

tion

treated

with

diuretics

Metabolic

acidosis

Lactic

acidosis

complicating

septic

shock

respiratory

alkalosis

Hepatorenal

syndrome

PaCO>

too

low

HCO3°

too

low

Salicylate

intoxication

near

normal

Patient

with

COPD

who

vomiting

who

treated

with

suction

potent

diuretics

* Adult

respiratory

distress

syndrome

Metabolic

alkalosis

respiratory

acidosis

PaCO;

too

high

HCO;

too

high

near

normal

Note:

CHF,

congestive

heart

failure;

COPD,

chronic

obstructive

pulmonary

disease;

DKA,

diabetic

ketoacidosis;

NG,

nasogastric.

Source:

Reprinted

from

Price

SA,

Wilson

LM,

eds.

Pathophysiology:

Clinical

Concepts

Disease

Processes.

6th

ed.

St.

Louis,

MO:

Mosby;

2003,

Table

22-5,

306.

2003,

with

permission

from

Elsevier.

conditions

volume

deficit

electrolyte

abnormalities.

For

example,

the

situation

where

there

hypokalemia

and

decrease

ECF,

the

patient

may

experience

muscle

cramping,

weakness,

and

cardiac

arrhythmias.

Treatment

chloride-responsive

metabolic

alkalosis,

cor-

recting

volume

imbalance

with

isotonic

saline

with

added

KCL

will

correct

alkalosis.

Metabolic

alkalosis

that

does

not

involve

fluid

deficit

requires

treatment

underlying

causes

before

alkalosis

can

corrected.

severe

conditions,

use

carbonic

anhydrase

inhibitor

will

enhance

HCO,"

excretion.”

Mixed

Acid-Base

Disorders

Several

acid—base

disturbances

(see

Table

8.10)

can

coexist

complex

medical

problems.

For

instance,

this

may

occur

in a

patient

who

respiratory-compromised

and

unable

respond

situation

producing

metabolic

disorder.

This

could

also

occur

situations of

drug

overdose

where

different

medications

cause

both

respiratory

and

metabolic

responses.”

When

examining

ABGs,

mixed

disorder

should

suspected

when

PaCO,

and

HCO;

are

not

consistent

with

the

measured

pH.

mixed

disorder

may

also

present

when

the

compensatory/secondary

response

exaggerated.

For

example,

metabolic

alkalosis

and

respiratory

acidosis

may

occur

when

patient

with

chronic

obstructive

pulmonary

disease

receives

diuretics.

Assessment

Acid-Base

Disorders

place

all

this

into

perspective,

Table

8.4

summarizes

major

components

needed

assess

all

acid—base

disorders.

was

discussed

earlier

this

chapter,

ABG

measure-

ments

will

provide

data

needed

evaluate

acid—base

status

and

begin

steps

toward

intervention.

8.4

CONCLUSION

Remembering

basic

concepts

acid—base

balance

will

keep

you

track

evaluating

these

complex

clinical

situations.

The

scale

for

measuring

acidity

alkalinity

fluid

the

measurement

pH.

Simply

stated,

the

ratio

bases

acids.

Normal

humans

7.35—7.45.

The

maintained

ratio

20:1

base

acid

within

body

fluids.

There

will

change

the

ratio

remains

stable,

but

changes

either

portion

the

ratio

will

result

changes

pH.

The

largest

source

of acid

within

the

body

carbonic

acid.

‘We

measure

concentration

CO)

indirect

measure

acidity,

Concentration

CO)

expressed

PaCO).

The

lungs

are

the

primary

regulators of

CO)

levels.

The

largest

source

base

HCO;

which

regulated

primarily

the

kidneys.

Respiratory

acidosis

result

retention

CO»,

whereas

respiratory

alkalosis

result

hyperventila-

tion

and

subsequent

decrease

CO)

levels.

Metabolic

acidosis

occurs

when

there

retention

fixed

acids

excessive

loss

bases.

Metabolic

alkalosis

result

excessive

loss

fixed acids

retention

bases.

Chapter

Acid-Base

Balance

169

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Cengage

Leaming.

All

Rights

Reserved.

May

not

copied,

scanned,

duplicated,

whole

part.

Due

electronic

rights,

some

third

party

content

may

suppressed

from

the

eBook

and/or

eChapter(s).

Editorial

review

has

deemed

that

any

suppressed

content

does

not

materially

affect

the

overall

leaming

experience.

Cengage

Learning

reserves

the

right

remove

additional

content

any

time

subsequent

rights

restrictions

requice

APPLICATION

THE

NUTRITION

CARE

PROCES

ACI

BASE

IMBALANCE

INTRODUCTION

Mr.

visits

his

physician

with

complaints

the

following:

pain,

dizziness,

and

difficulty

breathing.

Mr.

N's

daughter

also

indi-

cates

has

become

and

confused

over

the

hours.

the

physician

proceeds

his

physical

exam,

notes

that

blood

pressure

out

the

normal

range

and

respi-

ratory

rate

and

heart

rate

are

high.

Further

tests

indicate Mr.

N’s

hemoglobin

low

while

his

white

blood

cell

count

elevated.

chronic

obstructive

pulmonary

disease,

and

a history

coronary

heart

disease.

Which

these

might

interfere

with

his

ability

maintain

normal

acid-base

balance?

NUTRITION

ASSESSMENT:

BIOCHEMICAL

DATA

The

physician

has

ordered

arterial

blood

gases.

Values

you

note

abnormal

are

follows:

7.47;

pCO

mmHg;

pO,

mmHg;

HCO;

mEd/L.

Classify

the

pH.

Outline

items

from

Mr.

N's

case

that

fall

into

each

the

Assess

pCO>.

following

categories:

Assess

HCO;.

Signs

you

see

any

indication

compensation?

Why

Symptoms

why

not?

Laboratory

abnormalities

Upon

examination

his

medical

record,

you

find

that

Mr.

has

the

following

diagnoses:

renal

insufficiency,

Identify

the

primary

acid-base

disorder.

How

his

medical

diagnoses

relate

this

acid-base

imbalance?

CHAPTER

REVIEW

QUESTIONS

Define

the following

terms:

pH,

volatile

acid,

nonvolatile

(fixed)

acid,

and

buffer.

What

organ

controls

the

level

pCO,

the

blood?

What

organ

controls

HCO;

the

blood?

What

the

essential

problem

respi-

ratory

acidosis?

Respiratory

alkalosis?

What

the

most

important

differ-

ence

between

metabolic

acid—base

disorders

and

those

respiratory

origin?

Name

some

conditions

that

might

result

respiratory

acidosis.

Name

some

conditions

that

might

result

metabolic

acidosis.

What

anion

gap?

How

can

respiratory

mechanisms

compensate

for

metabolic

alkalosis?

Are

there

any

major

limitations

this

compensation?

ENDNOTES

Reported

blood

gas

abbreviations.

The

letter

“P”

before

CO,

the

partial

pressure

the

gas,

but

could

arterial,

venous,

mixed

blood.

When

the

letters

“Pa”

are

front

the

gas,

the

partial

pressure

the

gas

the

arterial

blood.

Rebreathing

into

paper

bag:

Have

you

heard

doing

this

for

someone

when

she

nervous

and

breathing

too

fast

(e.g,,

for

hyperventilation)?

The

rationale

that

rebreathing

into a

paper

bag

will

allow

the

person

replace

the

carbon

dioxide

“blown

off”

while

hyperventilating.

REFERENCES

Sherwood

Fluid and

acid-base

balance.

In:

Human

Physiology:

From

Cells

Systems.

ed.

Boston

MA:

Cengage;

2016:

535-64.

DuBose

TD,

Jr.

Acidosis

and

alkalosis.

In:

Kasper

Fauci

Hauser

Longo

Jameson

Loscalzo

eds.

Harrison's

Principles

Internal

Medicine.

19"

ed.

New

York,

NY:

McGraw-Hill;

2014.

http://accessmedicine.mhmedical.com/con-

tent.aspx?bookid=1130&

sectionid=79726883,

accessed

August

2018.

Berend

Acid-base

pathophysiology

after

130

years:

confusing,

irrational

and

controversial.

Nephrol.

2013;

26:

254-65.

American

Society

for

Parenteral

and

Enteral

Nutrition

(A.S.PE.N).

Fluids,

Electrolytes

and

Acid-Base

Disorders

Handbook.

Canada

170

Part

Introduction to

Pathophysiology

Tajchman

SK,

Tucker

AM,

Ybarra

JV,

eds.

Silver

Spring

MD:

ASPEN;

2015.

Morris

CG,

Low

Metabolic

acidosis

the

critically

ill:

part

Classification

and

pathophysi-

ology.

Anaesthesia.

2008;

63:

294-301.

Morris

CG,

Low

Metabolic

acidosis

the

critically

ill: part

Causes

and

treatment.

Anaes-

thesia.

2008;

63:

396-411.

Kraut

JA,

Nagami

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Response

Student’s Name

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Date

Response

As you argue, I agree with you that science and God collide. In my understanding, I think

that nutrition genomics is an unethical practice because it contradicts God's work. As a Christian,

I believe that it is inhumane to use humans as research subjects and use their genes to perform

experiments. God created humans with perfection, and no science should be used to modify

human health. On the other hand, nutrition genomics has improved the general well-being of

individuals, even if I don't support it for moral reasons.1 The science behind nutrition genomics

has significantly helped create medicines that treat complications such as cardiovascular disease,

diabetes, cancers, and hypertension.1 As you argue, I agree that nutrition professionals aim to

advise individuals on specific nutrition to optimize their health. On top of this, I would like to

support your assertion by stating that nutrition genomics knowledge guides nutrition

professionals in knowing the best diets for specific individuals. Concerning gene-environment

interaction, analyzing the relationship between environmental and genetic factors helps scientists

develop solutions to various diseases, like nutrition and physical and social surrounding.2 For

example, nutrition professionals advise individuals on specific foods that they should take to

prevent the development of specific diseases. This applies when scientists establish that an

individual's genes are susceptible to a specific disease. The dietary prescription that reacts well

with the gene may help delay or prevent the development of a disease the person is at high risk

of getting.

References

1. Introduction to pathophysiology, (n.d).Introduction: Introduction to pathophysiology.

2. Public health nutrition, (n.d). Gene-environment interactions and public health nutrition.

HLTH 643 LU Nutrition and Chronic Disease Discussion assign.pdf

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