A study on association of thyroid function and frailty in elderly

(1)

A STUDY ON ASSOCIATION OF THYROID

FUNCTION AND FRAILTY IN ELDERLY

submitted in partial fulfillment of the regulations

M.D., IN GERIATRIC MEDICINE

THE TAMILNADU DR.M.G.R. MEDICAL UNIVERSITY

DEPARTMENT OF GERIATRIC MEDICINE

MADRAS MEDICAL COLLEGE

DISSERTATION ON

A STUDY ON ASSOCIATION OF THYROID

FUNCTION AND FRAILTY IN ELDERLY

for the award of the degree of

M.D., IN GERIATRIC MEDICINE

BRANCH – XVI

THE TAMILNADU DR.M.G.R. MEDICAL UNIVERSITY

CHENNAI

DEPARTMENT OF GERIATRIC MEDICINE

MADRAS MEDICAL COLLEGE

CHENNAI – 600003

MAY 2018

A STUDY ON ASSOCIATION OF THYROID

FUNCTION AND FRAILTY IN ELDERLY

M.D., IN GERIATRIC MEDICINE

THE TAMILNADU DR.M.G.R. MEDICAL UNIVERSITY

(2)

CERTIFICATE

This is to certify that the dissertation titled “A STUDY ON

ASSOCIATION OF THYROID FUNCTION AND FRAILTY

IN ELDERLY” is the bonafide work done by

Dr. ARULMOZHISELVAN.V, Post Graduate Student, Department of

Geriatric Medicine, Madras Medical College, Chennai – 600003, in

partial fulfilment of the University rules and regulations for the award of

MD DEGREE in GERIATRIC MEDICINE BRANCH – XVI, under

our guidance and supervision, for the examination to be held on

May 2018.

Prof. Dr.G.S.SHANTHI, M.D.(Geriatrics), Professor and Head,

Department of Geriatric Medicine,

Madras medical college,

Rajiv Gandhi Govt. General Hospital

Chennai – 600003

Prof. Dr. R.NARAYANABABU, M.D., D.C.H., Dean

Madras medical college,

(3)

DECLARATION

I solemnly declare that this dissertation titled “A STUDY ON

ASSOCIATION OF THYROID FUNCTION AND FRAILTY IN

ELDERLY” was done by me at Madras Medical College, Chennai –

600003,during the period February 2017 to July 2017 under the guidance

and supervision of Prof. Dr.G.S.SHANTHI, M.D.(Geriatrics), to be

submitted to the The TamilnaduDr.M.G.R. Medical University, towards

the partial fulfilment of requirements for the award of MD DEGREE IN

GERIATRIC MEDICINE BRANCH – XVI.

Place : Chennai Dr. ARULMOZHISELVAN.V,

Date : MD GERIATRIC MEDICINE,

Post Graduate Student,

Department of Geriatric Medicine,

Madras Medical College,

(4)

ACKNOWLEDGEMENT

I thank Prof. Dr.R.NARAYANABABU, M.D., D.C.H., Dean, Madras

Medical College, for permitting me to conduct the study and use the hospital

resources in the study.

I express my heartfelt gratitude to Prof. Dr.G.S.SHANTHI,

M.D.(Geriatrics), Professor and Head, Department of Geriatric Medicine, for her inspiration, advice and guidance in making this work complete.

I also extend my sincere thanks to Prof. Dr.S.DEEPA, M.D., Associate

Professor, Department of Geriatric Medicine for guiding me duringthe study

period.

I am extremely thankful to Dr.K.UMA KALYANI, M.D., D.Diab.,

Assistant Professor, Dr.M.SENTHIL KUMAR, M.D., AssistantProfessor,

Dr.D.THANGAM, M.D., Assistant Professor and Dr.C.PRIYA MALINI, M.D., D.Diab., Assistant Professor, Department of GeriatricMedicine, for guiding me during the study period.

I thank my friend Dr.PADMANABAN, M.D., Biochemistry who has

helped me throughtout the study.

I thank our physiotherapists who has helped me in data collection.

I also thank all the postgraduate students, my colleagues and

paramedical staffs for their cooperation which enormously helped me in this

study. I am also indebted to thank all the patients and their caring relatives,

without whom this study would not have been possible.

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LIST OF ABBREVIATIONS AND SYMBOLS

TSH Thyroid Stimulating Hormone

fT4 Free Thyroxine

fT3 Free Triiodothyronine

UN United Nations

US United States

SRS Sample Registration System

WHO World Health Organisation

ATP Adenosine TriPhospate

MVO2 Max Maximal Oxygen Consumption

RMR Resting Metabolic Rate

ADL Activities of Daily Living

SHARE Survey of Health, Ageing and Retirement in Europe

↑ Increase

↓ Decrease

→ Leads to

↔ No change / equivocal

ROS Reactive Oxygen Species

TNF-α Tumor Necrosis Factor-α

PUFA Poly Unsaturated Fatty Acids

CP-II CarnitinPalmitoylTransferaseII

ALT Alanine Transaminase

HDL High density Lipoprotein

BNP Brain Natriuretic Peptide

S.D. Standard Deviation

(6)

DHEA DeHydroEpiAndrosterone sulphate

Vit D Vitamin D

GH Growth Hormone

IGF-1 Insulin like Growth Factor

CNS Central nervous System

CNTF CiliaryNeuroTrophic Factor

DM Diabetes Mellitus

CCF Congestive Cardiac Failure

LH Lutenising Hormone

FSH Follicle Stimulating Hormone

T Testosterone

E Estrogen

WBC White Blood Corpuscles

CD Cluster Differentiation

CCR5 C-C Chemokine Receptor 5

Il-6 Interleukin -6

CHS Cardiovascular Health Study

TUG Timed Up and Go test

SPPB Short Physical Perfomance Battery

SOF Study of Osteoporotic Fracture

BGS British Geriatric Society

GEM Geriatric Evaluation & Management

CGA Comprehensive Geriatric Assessment

PACE Program for All Inclusive Care for the Elderly

RAA Renin Angiotensin Aldosterone System

Vit-C Vitamin C

Ab Antibody

(7)

MIT MonoIodoThyronine

DIT DiIodoThyronine

TRH Thyrotrophin Releasing Hormone

TBG Thyroxine Binding Globulin

TTR Transthyretin

TRE Thyroid hormone Receptor Response Element

DNA Deoxyribo Nucleic Acid

RXR Retinoid X receptor

TR Thyroid hormone Receptor

CoA Co-Activator

Co-R Co-Repressor

mRNA Messenger Ribo Nucleic Acid

Na+ Sodium

K+ Potassium

Na+K+ ATPase Sodium Potassium Adenosine TriPhosphatase

FFA Free Fatty Acids

TGL Triglycerides

LDL Low Density Lipoprotein

BP Blood Pressure

MAP Mean Arterial Pressure

O2 Oxygen

CO2 Carbon di oxide

NHANES II National Health and Nutrition Examination Survey

Ca-ATPase Calcium ATPase

Na-K pump Sodium Potassium Pump

N Number of Samples

CKD Chronic Kidney disease

(8)

BA Bronchial Asthma

CAD Coronary Artery Disease

CVA Cerebro Vascular Accident

CLIA ChemiLuminescentImmuno Assay

CES Center for Epidemiologic Studies

PASE Physical Activity Scale for Elderly

BMI Body Mass Index

SPSS Statistical Package for the Social Sciences

Std. Standard

Ft. Feet

Kg Kilogram

MrOS study Osteoporotic Fractures in Men Study

WHAS study Women’s Health and Aging Study

inCHIANTI

(9)

LIST OF FIGURES

Figure 1 Percentage distribution of population aged 65 and over by region:

2015 and 2050

Figure 2 Hypothesized levels of the syndrome of frailty(

Figure 3 Vicious Cycle of Energetic Frailty(1)

Figure 4 Phenotypic and index method

Figure 5 Mechanisms of sarcopenia

Figure 6 Hormones and frailty

Figure 7 Inflammatory and immunologic changes and frailty

Figure 8 Metabolic Causes of Frailty

Figure 9 Other risk factors for fraility

Figure10 Frailty trajectory

Figure 11 Thyroid hormones formation & secretion

Figure 12 Thyroid hormones structure

Figure 13 Regulation of thyroid hormone secretion

Figure 14 Thyroid hormone action

(10)

LIST OF CHARTS

Chart 1 Decadal growth in elderly population in relation to that of general

population

Chart 2 Vulnerability of frail elderly people to a sudden, change in health

status after a minor illness

Chart 3 Pathway towards frailty, disability and death.

Chart 4 Age distribution in total

Chart 5 Sex distribution in total

Chart 6 Frequency distribution of frailty phenotype categories

Chart 7 Prevalence of individual components of frailty phenotype criteria

Chart 8 Frequency distribution of individual components of frailty phenotype

Chart 9 Frequency distribution no. Of components of frailty phenotype

Chart 10 Median age of study groups

Chart 11 Age distribution among the study groups

Chart 12 Sex distribution among the study groups

Chart 13 Median bmi of study groups

Chart 14 Bmi distribution among the study groups

Chart 15 Median hand grip of study groups

Chart 16 Median 15 ft walking time of study groups

(11)

[image:11.595.102.530.70.766.2]

LIST OF TABLES

Table 1 Percentage share of elderly population aged 60 and above

to total population

Table 2a Life expectancy at birth

Table 2b Life expectancy at birth and at old age in India

Table 3a Phenotypic and index method

Table 3b Phenotypic and index method

Table 4 Risk factors of Sarcopenia

Table 5 Thyroid hormones action on metabolism

Table 6 Aging Changes of Thyroid Gland

Table 7 Hormonal changes in thyroid dysfunction

Table 8 Summary of studies on thyroid abnormalities and frailty.

Table 9 Criteria Used to define Frailty

Table 10 PASE Scoring

Table 11 Age distribution in total

Table 12 Sex distribution in total

Table 13 Frequency distribution of Frailty Phenotype Categories

Table 14 Prevalence of individual components of frailty phenotype

criteria

Table 15 Frequency distribution of individual components of frailty

phenotype

Table 16 Frequency distribution of no. Of components of frailty

phenotype

Table 17 Total Descriptives of other characteristics of the study

sample

Table 18 Median age of study groups

(12)

[image:12.595.100.533.67.441.2]

Table 20 SEX DISTRIBUTION AMONG THE STUDY GROUPS

Table 21 Descriptives of baseline characteristics & their significance

Table 22 Median BMI of study groups

Table 23 Median hand grip of study groups

Table 24 Median 15 ft walking time of study groups

Table 25 Median PASE score of study groups

Table 26 Correlation between BMI and ft3,ft4 & TSH

Table 27 BMI category vs ft3,ft4 , TSH

Table 28 Frailty categories vs ft3 , ft4 , TSH

Table 29 THYROID FUNCTION CATEGORY * FRAILTY

AIMS AND OBJECTIVES

AIM:

To investigate into the relationship between Thyroid Function and

Frailty in elderly.

OBJECTIVES:

By simple random sampling, selecting 200 patients and categorize

them as frail, intermediate/pre-frail, non-frail/robust by applying Fried's

Frailty Phenotype criteria.

1) To find the prevalence of Frailty in OP and IP patients attending a

tertiary care centre.

2) To do Thyroid Function Test to find association between fT4,

fT3,TSH levels and Frail, Pre-frail, Robust/Non-frail Category.

3) To find correlation between fT4, fT3, TSH and individual

(21)

(22)

6

REVIEW OF LITERATURE

DEFINITION OF ELDERLY

Definition of elderly is arbitrary. There is no standard United

Nations numerical criterion. However “the cut-off of 60 years and above

is agreed by UN for defining elderly.” >65 years of age is considered by

most developed countries to define the older population

(23).Conventionally, “the chronological age of 65 years and above is

depicted as the Cut-off for elderly(24).” National policy on Older persons

defines “Elderly as the citizens who have crossed the age of 60 years and

above in India(25).”

DEMOGRAPHICS OF ELDERLY

Global Scenario

At a faster rate, the global population is growing old, owing to

decreased fertility, improving health and longevity. Remarkably, there is

great rise in elderly population at never before seen rate. 562 million

people (8%) constituted the elderly population >65 years, when world

population reaches 7 billion in 2012. 3 years after the elderly population

rose by 0.5% i.e., 617 million, 8.5% of total population. This rising trend

(23)

7

generations post world war and also due to a novel increase of elderly

population in Latin America and Asia(26).

Japan remains as the World’s oldest country because 26.6% of

Japan’s population are above the age of 65.The Graying nations

succeeding Japan are Germany, Italy, Greek and many other European

countries. By 2050, the older population aged 65 and above is estimated

to be 39% of the total population in Japan and the world will continue to

view Japan as the oldest country. The other Graying nations estimated to

be the successors of Japan in order are South Korea (35.9%), Hong Kong

(35%), Taiwan (34.9%) and other European countries(26).

Variations exist between different countries and countries with

respect to onset and duration of the stages of demographic transition. The

transition was started in the more developed countries like Western and

Northern countries of Europe and Japan in the last century itself and this

transition took decades to complete in many countries. This process of

demographic transition has found its inception in less developed countries

in Latin America and Asia in recent decades. However the transition

(24)

8

Figure 1 percentage distribution of population aged 65

and over by region: 2015 and 2050

DEMOGRAPHIC TRANSITION

8.5% of population aged over 65 is expected to increase by 12.1%

in 2030 and 18.8% in 2015 in Asia. From 2015-2050, the oldest

population in 23 Asian countries is estimated to be quadrupled(26). Due

to increasing life expectancy at older ages, Elderly population aged or

over 80, about 126.5 million globally in 2015 is going to be tripled

around 446.6 million(28).

The oldest old (80 and above) are different from rest of the older

population and are likely to have problems which needs long-term care.

More public resources will be consumed by them and there will be a

(25)

9

By 2020, elderly population is going to be more than children

under age 5 populations historically for the first time. In 2050, the

proportion of world’s population aged 65 and above is estimated by UN

to be doubled from 7.6% presently to 16.2% (28).

China and India, the two population giants are in different path of

aging mainly because of varied fertility trends and methods of family

planning. China’s share of older population aged 65 and above is 10.1%

whereas India shares only 6 percent and the share by China is expected to

double by 2030 to 238.8 million (17.2%) of Total Population.

Indian Scenario

As per census 2011, India’s total population was 1210.9 million

with elderly above 60 years contributes 8.6% to total population i.e.

around 103.9 million with 51.1 million are elderly males (8.2%) and 52.8

million are elderly females (9%) with respect to residence, the proportion

of rural elderly population was 8.8%. In urban areas it was 8.1

(26)

10

Table 1 Percentage share of elderly population aged 60 and above to total population(30)

Census Person Male Female Rural Urban

1961 5.6 5.5 5.8 5.8 4.7

1971 6.0 5.9 6.0 6.2 5.0

1981 6.5 6.4 6.6 6.8 5.4

1991 6.8 6.7 6.8 7.1 5.7

2001 7.4 7.1 7.8 7.7 6.7

2011 8.6 8.2 9.0 8.8 8.1

The percentage share of elderly to total population of India since

1961 rose by 3 percent in 2011 and this proportion of elderly is projected

(27)

11

Chart 1 Decadal growth in elderly population in relation to that of

general population (28)

Till 2001, there is a decreasing trend in the decadal growth in

elderly population like that of general population. In the last one decade

(2001-2011), the growth in elderly population rose to 36 percent from 25

percent in the earlier decade.

According to population census 1991, the elderly males exceeded

in number than that of elderly females. Interestingly reversal of trend has

been observed. The female elders outnumbered the male. Comparing to

elderly male, elderly females are more vulnerable which policy makers

(28)

12

State Wise Scenario

According to census 2011, South Indian State Kerala has the

highest proportion of elderly aged 60 and above (12.6%).Following

Kerala, Goa has 11.2% and Tamilnadu has 10.4%.The increased

proportion in these states is because of the declining fertility increasing

longevity and better medical facilities available. North East States like

Meghalaya, Arunachal Pradesh have less than 5% of elderly

population(31)

[image:28.595.117.511.402.712.2]

Life Expectancy at Birth

Table 2alife expectancy at birth(32)

2015 Expected at 2050

World General Population 68.6 76.2

Female 70.7 78.8

Male 66.6 73.7

Asia General 71.0 78.5

Female 73.0 81.1

Male 69.1 76.0

(29)

13

As of 2015, life expectancy at birth is >80 years for 24 countries

with Japan, Singapore, Hong Kong in the leading list.

In United States life expectancy at older ages in 2009 has increased

to 19.1 years from 11.9 years in 1900. Amidst the same period, the life

expectancy at age 80 has increased to 9.1 years from 5.3 years(33). Even

countries, like Afghanistan with lowest life expectancy at older ages are

also projected to see improvement with 11 years to 13 years for male by

2050, 12.1 year to 15 years for female during the same period for Afghan

elderly aged 65 years above(26).

In Indian rural areas, life expectancy at birth has increased to 66.3

years in 2009-2013 from 48 years in 1970-75.Whereas in urban areas the

increase is from 58.9 years to 71.2 years.

LIFE EXPECTANCY

Table 2b life expectancy at birth and at old age in india(34)

India

At Birth At old age

1970-75 2009-2013 1970-75 2009-2013

Rural 48 66.3 13.5 17.5

Urban 58.9 71.2 15.7 19.1

(30)

14

In India

Kerala has the highest life expectancy at birth, 71.8 years for men

and 77.8 years for women, followed by Maharashtra and Punjab. Punjab

has the highest life expectancy at the age of 60 years (19.3 years) for

males followed by Himachal Pradesh (18.3 Years) and Kerala (18 years)

and it is lowest for Assam and Madhya Pradesh (15.4 years).For women,

Kerala has the highest life expectancy at the age of 60 years (21.6 years)

and Bihar has the lowest (17.5 years)(30).

The increase in life expectancy is due to falling tobacco use among

male population and decreasing cardiovascular mortality in both male and

female population. Other contributing factors are improvements in

housing, sanitation, nutrition, the control of infectious diseases and

maternal mortality and the advent of antibiotics and vaccination(14).

However, disability free life expectancy is not increasing as fast as

life expectancy in many countries. Hence measures to achieve better

living in addition to longevity have to gain the momentum.

To live with dignity and with optimum health are fundamental

rights of an individual and elderly are no exception. The supreme aim in

elderly care is to maintain their functional status. For this the best strategy

(31)

15

there is already established disability) to avoiding the decline of

functional status shortly prevention from disability(35).

There are some questions to answer: Whether disability is

avoidable? Is disability an unavoidable consequence of the aging

process? The available data support the answer that disability can be

avoided (36),(37).

In short, the challenge for the future is to prevent or delay

disability? To face this challenge, the focus should be on the people at

risk. In the past, the people at risk were thought to have chronic diseases

as they are the most common factor in adverse outcomes of health. But

chronic diseases do not seen to be an appropriate predictor in older

people.

By 1980, the concept of frailty found its origin and it’s gaining

acceptance as a predictor of morbidity and mortality. There is no

universally accepted definition of frailty. As per Fretwell statement in

1990, “Frailty in an individual is defined as an inherent vulnerability to

challenge from the environment”. In 1993, according to W.Bortz, “active

life expectancy is threatened by the development of frailty.”

In the mid-to-late 1990s Rockwood and colleagues proposed that

(32)

16

performing function of daily living. Later this group developed a Frailty

Index, a longer Clinical Frailty Scale and a brief screening tool known as

frail(10).

DEFINITION OF FRAILTY

Frailty is theoretically defined as a clinically recognizable state of

increased vulnerability resulting from aging- associated decline in reserve

and function across many physiological systems such that the ability to

cope with everyday or acute stressors is compromised(38).

Fried and colleagues defined it “as a biologic syndrome of

decreased reserve and resistance to stressors, resulting from cumulative

decline across multiple physiologic system and causing vulnerability to

adverse outcomes(12).”

As per world report on aging and health, by WHO(39) , “the

definition of frailty remains contested , but it can be considered as a

progressive age-related decline in physiological systems that results in

decreased reserves of intrinsic capacity , which confers extreme

vulnerability to stressors and increases the risk of a range of adverse

(33)

17

FRAILTY IS AT THE CORE OF GERIATRIC MEDICINE

Frailty forms the central core of geriatric medicine(38) for the

following reasons

Frail elders are at risk for adverse outcomes of health like

disability, dependency, institutionalization, injuries, falls, poor

tolerance to hospitalization and invasive procedures, acute illness,

prolonged recovery from illness or hospitalization and the

mortality rate is being high in these individuals. And there is high

risk of iatrogenicity.

They are in high need of health care resources.

Caring those at risk people needs increased costs and it consumes

time and the caring requires special expertise skills.

The prevalence of frailty increases with increase in age.

Severity of Frailty spans from subclinical to a clinical stage to

impending death and it underlies the heterogeneity of health status

in elderly.

With increasing age, there is increased vulnerability to multiple

(34)

18

vulnerability is not explained by changes in recognizable risk

factors and can be attributed to poor homeostatic equilibrium.

Diseases alone or in combination are not enough to explain

functional outcomes in elderly.

Disease independent age related alterations in the reserve and

associated physiologic vulnerabilities is associated with variable

effects to treatments.

Frailty is a condition of impending deterioration in health and

functional status and it requires attention to prevent disability and

other associated outcomes and it needs expert skills to diagnose

intervene frail elders.

In most countries, health care cost, reimbursement is based on

specific diagnostic categorization and treatment and the

reimbursement is not based on presence or absence of frailty or

frailty even in the absence of disease.

But specialized geriatric care (expert care) needs a greater real cost

of caring. Redesign of care and reimbursement will match the needs,

(35)

19

THEORIES OF FRAILTY(1)

1) Rockwood posits deficit accumulation theory

According to this, frailty results from accumulation of potentially

unrelated diseases, subclinical dysfunctions and disability across organs,

parts and system of the body. A simple count of all deficits (symptoms,

signs, disease, geriatric conditions, laboratory abnormalities, disabilities)

leads to a close response relationship with mortality.

2) Unique pathophysiologic process

Frailty is due to a primary defect in basic biologic system (energy

production, distribution and utilization) which in turn affects key

physiologic systems (neuroendocrine, inflammatory and immunologic

processes) leading to a short circuit in the homeostatic regulatory network

in which each system have mutual effect on each other and compensate to

a degree when any one is impaired. Compromised homeostasis results in

increased vulnerability to adverse outcomes triggered by minor

(36)

[image:36.595.120.510.126.491.2]

20

Figure 2 hypothesized levels of the syndrome of frailty(1)

3) Energetic Pathway of Frailty

Every living cell needs energy for its life and this energy is

acquired in the form of phosphate release from ATP. ATP is stored only

for 6 sec. Neverthless ATP is constantly resynthesized to maintain the

harmony. ATP can be synthesized both by aerobic and anaerobic

pathways. Most energy generated in our body is through aerobic

(37)

21

generated in a time unit). Large amount of energy produced is spent in

resting metabolic rate - to maintain homeostatic equilibrium.

Normally, an extra amount of energy is needed for compensatory

mechanisms to balance the unstable homeostasis caused by pathologies

(Homeostatic effort). The remaining energy is spent for cognitive and

physical activities. Elderly who are unhealthy and with chronic disease

have a higher RMR than people of same age and sex. Homeostatic effort

is increased rapidly with health status deterioration and with increasing

work load, the individual starts experiencing fatigue within the range of

energy used for physical activity as most energy is usually spent in

performing basic ADLS and they feel exhausted and ultimately land up in

sedentary existence (decreased physical activity) and in long term the

total amount of energy produced is reduced thereby triggering a vicious

cycle, leading to progressive, accelerated decline in physical

(38)

[image:38.595.120.522.132.413.2]

22

Figure 3 Vicious Cycle of Energetic Frailty(1)

OPERATIONAL DEFINITIONS

To provide frail elderly patients the care they used, it is foremost

important to identify Frailty with a proper diagnostic criterion. However

there is no gold standard criterion to define frailty. In an attempt to

standardize the definition of Frailty, Fried et al (2001) proposed the

“phenotypic method(12).” Later Rockwood and colleagues proposed the

(39)

[image:39.595.113.528.387.777.2]

23

Figure 4 phenotypic and index method

Table 3a phenotypic and index method

Frailty Phenotype Frailty Index

Qualitative Quantitative

Rules based method Index Based method

Several specific signs and

symptoms are defined which

together from a geriatric

syndrome

Based on counting of number of

health deficits.

Excluded the presence of

disease and disability

Includes disease and disabilities along

with symptoms, signs and lab values

Clinically recognizable. Helps

in recognizing the biological

nature of frailty not interfered

with disease or disability .

Attractive mathematical model that

support the idea of reduced

homeostatic reserve. “The more

(40)

24

Frailty Phenotype Frailty Index

accumulated the more likely they are

to be frail”.

categorically defines the

presence/ absence of a

condition of risk for

subsequent adverse events

Allows frailty to be graded rather than

present or absent

Cognitive impairment which

has been associated with

functional decline and

disability is not taken into

account.

More sensitive predictor of adverse

outcomes like worsening health status,

rate of institutionalization and death

[image:40.595.115.532.71.417.2]

because of its finer graded risk scale.

Table 3b phenotypic and index method

Phenotypic Method Index method

Frailty status is identified by

the occurrence of atleast 3 of

the following 5 phenotypes

1. Unintentional weight loss

2. Poor hand grip strength

3. Self reported

exhaustion(s/o poor

endurance & low energy)

4. Slow gait speed

5. Low physical activity

Frailty status has been marked as a

state at risk caused by accumulation of

deficits, which has been counted and

an index is derived from the

information gathered from

Comprehensive Geriatric Assessment.

Frailty Index =

No. of Deficits in an individual

---

(41)

25

Phenotypic Method Index method

Frailty phenotypic method

takes approximately only

10-20 min to ascertain the frailty

status and it might serve as a

basis for detection of frailty

in routine care to predict and

prevent the adverse outcomes.

Biologically rooted and

affords a pathophysiological

understanding of frailty.

Despite it’s a sensitive indicator in

predicting adverse outcomes

individually large no. of information

around 70 items collected and they

make the approach less attractive in

clinical practice and primary care (time

consuming).

Also the inclusion of co-morbidity and

disability in this method impairs the

use of frailty index in prevention.

The diffuse set of impairments

amalgamated by the FI is not amenable

to targeted therapeutic interventions.

Both the above methods have considerable overlap in identifying

frailty and demonstrate a convergence in predicting adverse outcomes.

Those two different models should be considered complimentary in the

evaluation of the older person.

Regardless of the definition, literature shows that frail elderly

persons have changes in the 4 main domains of the aging phenotype

namely body composition, homeostatic dysregulation, energetic failure,

(42)

26

EPIDEMIOLOGY

Global epidemiology

There are many epidemiologic studies of frailty and there are

discrepancies in data on frailty prevalence which can be attributed to

different operational definitions of frailty inclusion or exclusion criteria,

study population and the study setting. Fried’s Frailty phenotypic criteria

or their modifications were used in most studies.

In US, several recent and older community based studies in elderly

population >65 years of age in men and women, depict the prevalence of

frailty to range from 4 to 26% and the prevalence increases with increase

in age i.e., 3 to 7% aged 65-75 years, 20 to 26% >80 years and 1/3 of 90

years are frail(42)(2).

In the SHARE study(43) (the largest survey performed in Europe

and Israel, covering 10 European countries and Israel) the overall

prevalence of Frailty was determined to be 17% ranging from 5.8% in

Switzerland to 27.3% in Spain. The prevalence of Pre-frailty was higher

in Germany (34.6%) and Spain (50.9%).

Prevalence varies according to sex (more in women as women’s

life expectancy is more than men and tends to live longer than men and so

(43)

27

Hispanic and African Americans), socioeconomic status (poor education

and poverty are closely associated with frailty)(44).

INDIAN EPIDEMIOLOGY

Only few studies are available to show the prevalence of frailty in

India. The level of frailty was higher in the higher income countries than

the lower income countries which were evident in a study done across 14

countries of higher income status and 6 countries of lower income status

including India. The variability in prevalence between developed and

lower income countries was due to increased life expectancy in wealthier

countries where advanced health care system, social support increase the

longevity of life(86).

A hospital based study of 250 individuals showed the prevalence of

frailty to be 33%(88). Based on frailty Index, cumulative deficit model

comprising about 40 variables, a large population study conducted across

6 countries including India, the prevalence of frailty was found to be

55.5% in India(87).

FRAILTY AND AGING

The definition of Frailty (i.e., a state in which, Dysregulated

multiple system results in decline in functional reserves and increases the

(44)

28

which loss of molecular/ cellular functional properties results in

diminished adaptability responses to internal/external stress thereby an

augmented vulnerability to disease and mortality).

Failing homeostasis forms the basis of both. The failure in

homeodynamics in aging process is global whereas the failure of

homeodynamics circles around energy metabolism and neuromuscular

changes(45).

This is evident from the following schematic illustration and it

shows that chronological and biological ages are not synonymous.

Chart 2 Vulnerability of Frail elderly people to a sudden, change in

health status after a minor illness(12)

The blue line represents a fit elderly individual who, after a minor

stressor event such as an infection, has a small deterioration in function

(45)

29

individual who, after a similar stressor event, undergoes a larger

deterioration, which may manifest as functional dependency, and who

does not return to baseline homoeostasis. The two horizontal dashed lines

represent the homoeostasis level of functional abilities before the stressor

event.

Frailty is a synergistic, multifactorial, complex phenomenon in

which sarcopenia (or) melting of muscle mass is the central component

and initiator of a circle of frailty. Frailty is self perpetuating.The

development of Frailty results in a negative spiral which further leads to

greater frailty and risk of adverse outcomes like disability, etc.

chart3 pathway towards frailty, disability and death.(2)

Excessive loss of energy and reserves bends ‘‘successful’’ ageing

toward prefrail and frail status, which also can happen due to disease

alone. Green dotted lines depict potential reversibility, which

is more feasible in prefrailty, but is possible even in the disability stage.

(46)

30

due to constellation of decrease in energy reserves. Frailty may also be

reversible to a point (green dotted lines) if appropriate steps of prevention

(Primary/ Secondary) are taken. If not intervened, a point of no return is

reached and irreversible disabilities will develop. This idea of continum

of frailty should be taken into account while planning for prevention and

treatment in later and end stage frailty.

Frailty is considered a biological syndrome of decreased

physiological reserve. To understand its casuality, the basic principles of

(47)

31

BASIC FRAMEWORK OF FRAILTY(14)figure4

Genetic Factors Environmental Factors

Molecular (or) biological level damage more than as expected in

aging

Physiological system affected and dysregulated

Other factors

1. Poor nutrition 2. Sedentary life style

3. Sarcopenia and its risk factors 4. Neuroendocrine changes with

aging

5. Oxidative stress ↑ed free radicals, ROS, ↓ed Antioxidants.

6. ↑Inﬂammatory Phenomena 7. ↓Immune mechanism

Compromised network of Homeostasis

Manifestation as Frailty

To be identified at this level and therapeutic interventions to be

planned to prevent adverse outcomes

Failure of compensatory mechanisms even in response to

minor stressful events

Clinically evident as ↓ed functional capacity frail status

Will develop adverse outcomes. Hospitalization → institutionalisation → Disability → can progress upto death

Falls, fear of falling → Hip Fracture

(48)

32

A large number of direct, indirect and interacting risk factors are

involved in its causation. Many factors thought to be influential, have yet

to be thoroughly studied and their pathways to be elucidated. The main

links in this process are discussed here.

CELLULAR RESPONSES TO STRESSORS(45)

The cellular responses to stressors involves

1) Apoptosis (by controlled cell death, removes damaged/ aberrant

cells).

2) Senescence (alters the phenotype and blocks further proliferation)

Repair (removes damaged proteins, lipids and organelles and recycles

constitutent parts). Dysregulation of these responses, can contribute to the

failure in homeodynamics seen in frailty.

1) Increased apoptosis → Tissue/ organ atrophy → Weakness

2) Expression of senescent cellular phenotype → Increased

proinflammatory cytokine release →Dysregulated inflammatory

state.

3) Deficits in repair in specific tissue (muscle, nervous, bone) →

Oxidative stress and further damage due to other products of

(49)

33

Oxidative Stress

Imbalance among reactive oxygen species, free radicals and

antioxidants lead to oxidative stress and this imbalance stimulate

apoptotic effects of TNF-α and they are thought to be associated with

aging and sarcopenia.

POOR NUTRITION

Poor appetite regulation in elderly and the deficient intake of

multiple nutrients like Vitamin B6, Vitamin B12, Vitamin C, Beta-

Carotene, Selenium, Vitamin E, and PUFA are all independent correlate

with frailty in several studies(46)(47).

Low levels of certain proteins like carnitine, mitochondrial CP-II,

ALT, nutritional markers like HDL Cholesterol, BNP correlate with

frailty(35).

Body composition:

1) Advancing age is linked with profound changes in body

composition and the most remarkable of which is sarcopenia, a

major cause of physical function decay, disability and mortality.

2) Frailty and sarcopenia resembles the problem of the egg and the

(50)

34

3) It is unfortunate that a clear defining architecture to accommodate

and study the two conditions, sarcopenia and Frailty has yet to

come.

4) However the two would converge in near future because both

conditions deal with the common subclincal and clinical

manifestations of aging. From a practical view point sarcopenia

may be considered a chief component in the pathway of Road to

Frailty(48).

5) The term “Sarcopenia” is delineated as loss of muscle mass and

decline in muscle function which occurs with aging.

6) Operationally it is described as an appendicular lean body mass <2

S.D. below that of a young healthy population corrected for height

in meters squared(49)

The following are the changes occurring in muscular system with aging

Lean body mass (composed of Muscle & Visceral organs)

decreases steadily from thirties and the % represented by muscle

decline rapidly in late life.

Decrease in muscle mass due to atrophy of muscle fibres (Fast

twitch fibers>Slow twitch fibres) is probably because of

progressive loss of motor neurons.

Fat and fibro connective tissue accumulates inside muscle and it

(51)

35

Both decrease in muscle mass and decrease in muscle quality and

function leads to decrements in muscle strength and it contributes to

weakness and decreased functional capacity and loss of independence.

Diminished muscular strength is also a predictor of mortality

independently.

Many candidate mechanisms may lead to sarcopenia, some of

which are portrayed in figure No.5 and Table 4.

(52)

[image:52.595.90.545.108.643.2]

36

Table 4 Risk factors of sarcopenia

Risk factors of sarcopenia

Factors Aging process Chronic health

conditions constitutional

female sex

LBW

genetic

susceptibility

lifestyle

malnutrition

low protein

intake

smoking

physical

inactivity

living conditions immobility

starvation

deconditioning

increased muscle turn over

↑protein degradation(catabolism)

↓protein synthesis(anabolism)

reduced number of muscle cells

↑myostatin

↑apoptosis

endocrine deregulation

↓testosterone,DHEA

↓oestrogen, ↓vit.D3

↑thyroid function

↓GH,IGF-1

↑Insulin resistance

Changes in neuromuscular system

↓ CNS input (loss of a-motor

neurons)

Neuromuscular disjunction

↓CNTF, ↓motor unit firing

rate

Mitochondrial dysfunction

↓Peripheral vascular flow

cognitive

impairment

mood disturbances

osteoarthritis

chronic pain

DM

CCF

Renal failure

Liver failure

Respiratory failure

obesity

catabolic effects of

drugs

cancer?

chronic

inflammatory

state?

Most sarcopenic individual have lost fat as well. However a subset

of individuals remain fat whicle losing muscle mass. These individuals

(53)

37

“Myosteatosis”- the infiltration of fat into muscle appears to be a separate

condition related to insulin resistance. Longitudinally, those sarcopenic

obese individuals have been found to be the most likely to develop future

disability and mortality.

Other changes in Body composition(40)

Though the fat mass increases in middle age and declining in late

life, the visceral fat continues to accumulate and it increases the waist

circumference across life span.

Fibroconnective tissue also increases in multiple organ systems. In

bony tissue, bone strength is decreased due to progressive

demineralization and modification of bony architecture and so the

fracture risk is augmented. Due to influence of gonadal hormones and

peak bone mass, there are sex differences in bony strength.

HORMONAL CHANGES(50)

Via the hypothalamus- Pituitary axis, the neural system and the

endocrine system are linked and through the signaling action of a series

of homeostatic hormones they control the metabolism and energy

utilization.

The 3 main endocrine changes occurring with aging which are

(54)

38

1) ↓in GH levels →↓ in IGF-1 production by liver.

2) ↓in Estrogen and Testosterone →↑ release of LH & FSH 3) ↑ in Cortisol Secretion + ↓ in DHEA production

Other proposed hormonal changes implicated in the genesis of

[image:54.595.120.514.264.642.2]

Frailty are all in its infancy level.

Figure 6Hormones and frailty

T _ testosterone; E _ estrogen; GH _ growth hormone; IGF-1 _

insulin growth factor 1; DHEA _ dehydroepiandrosterone; Vit D _

(55)

39

[image:55.595.121.498.163.594.2]

Inflammaging and immune system alterations in frailty(51).

(56)

40

[image:56.595.116.539.145.594.2]

Metabolic Causes of Frailty(49)

(57)

41

[image:57.595.112.527.148.532.2]

Other risk factors for fraility(49)

Figure 9 Other risk factors for fraility

FRAILITY AND DISABILITY

The terms disability, co-morbidity were considered synonymous

previously. Now they should be regarded as separate clinical entity

although interrelated.

Disability is considered as difficulty or dependency in carrying out

(58)

42

or several disease in combination. The two key factors which differential

frailty from disability are

1) Disabilty can result from dysfunction of single or multiple systems.

Whereas frailty is always due to multisystem contributions.

2) Disability is not necessarily associated with instability whereas for

frailty, instability is intrinsic.

Frailty is not the stage prior to disability, rather it predisposes to

stage of disability. Disability can follow from a previous stage of

robustness or from the stage of frailty or from the previous state of

dependency which is deteriorating(35).

Similarly frailty can head away to disability or recover to previous

level of functional status or be maintained.

FRAILTY AND COMORBIDITIES

Not all older adults with co-morbid diseases are frail. Also not all

frail elderly people have multiple co-morbid diseases. This is evident

from CHS in which 67.7% frail elderly had multimorbidity among the 9

diseases considered. However only 9.7% of older adults with

multimorbidity were frail. It suggests that frailty may be caused either

(59)

43

involved in chronic diseases which have reached a severe or advanced

state(52).

[image:59.595.126.508.235.546.2]

Frailty Trajectory(53)

Figure 10 frailty trajectory

IDENTIFICATION OF FRAILTY STATUS

To avoid the development of disability, frailty status has to be

identified in its earlier course to implement strategies for prevention and

(60)

44

USE OF BIOMARKERS(2)

A biomarker is defined as “A characteristic that is objectively

measured and evaluated as an indicator of normal biological process,

pathogenic process or pharmacologic responses to a therapeutic

intervention”.

Functional, biological (laboratory variables), imaging, related

parameters may be considered as biomarkers.

Some of the currently proposed biomarkers are

1) Physical performance and muscle strength measures (Gait speed

and Grip strength).

2) Body composition measures (Appendicular mass and

anthropometry values).

3) Inflammatory markers (IL-6 and CRP).

4) Antioxidants and oxidative markers.

5) Nutritional parameters (Albumin, Hb, urinary creatinine)

6) Hormonal Levels (GH, IGF-1, Testosterone, DHEA) and much

more.

However none are good biomarkers for detecting frailty. Their use

(61)

45

SCREENING TOOLS FOR FRAILTY

There are several instrumental tools to screen for frailty. Most of

the screening tools assess physical functioning gait speed and cognition.

The most commonly cited, screening is Fried’s Frailty phenotype.

It was developed on the basis of observation of progressive weakness and

declines in activity in older adults most vulnerable to adverse outcomes

and has been validated in the cardiovascular health study (CHS)

involving over 5000 men and women age >65 years.

Other tools which are used to screen frailty are

1) Single item surrogate assessments of frailty include TUG and Hand

grip strength.

2) SPPB(54)(It includes balance test , chair stand test and 5 m gait

speed test).

3) FRAIL Scale(55)

Fatigue (“are you fatigued?”)

Resistance (“can you climb one flight of stairs”)

Ambulation (“can you walk one block?”)

Illness (greater than five)

(62)

46

“Yes” to three or more questions indicates frailty. “Yes” to

one or two questions indicates pre-frailty.

4) SOF Frailty Tool(56) (Annexure d))

Frailty is defined as the presence of atleast two of three

components:

• Weight loss of 5 percent in last year

• Inability to rise from a chair five times without use of arms • A “No” response to the questions “ do you feel full of

energy”

5) PRISMA questionnaire(57) (Annexure e))

6) Clinical Fraility Scale(58) (Annexure f))

It is a rapid frailty screening tool that is scored between 1(very fit)

and 7(severely frail) based on self report of co-morbidities and the

need for help with activities of daily living(ADLs)

7) BGS Guidelines(59)

• It recommends assessment of the elderly for presence of frailty at all encounters with health care workers. It includes

Gait speed , the Timed-Up and- Go test and the PRISMA

questionnaire.

• Edmonton frail scale is recommended for elective surgery.

8) Rockwood Frailty Index

The deficit accumulation or index approach to measue frailty is

based on the accumulation of illnesses, functional and cognitive

(63)

47

frailty. It requires 20 or more medical and functional –related

questions. The higher the number of deficits , the higher the frailty

score.

9) Edmonton Frail Scale(60) (Annexure g))

PREVENTION AND MANAGEMENT

Frailty is often identified at the end stage when there is clinically

evident history of recurrent falls and injuries, disability, recurrent hospital

visits due to acute illness, poor recovery from acute stress. Due to risk of

high morbidity & mortality secondary to frailty, it is imperative to

recognise them at an earlier stage & strategies for intervention to be

implemented even at the prefrail stage to give healthy quality of life to

older individuals who are at risk of adverse outcomes. To date, curative

treatments for frailty are unavailable.

However the currently available evidences suggest that the

modalities available can improve clinical outcomes in this patient

population and thereby it’s possible to prevent disability and frail status

can even be reverted back to the stage of prefrailty due to its dynamic

nature. Though there is no universal consensus definition & assessment

tools for frailty, the ultimate aim is to prevent the at risk individuals from

adverse outcomes. Most management strategies concern to improve the

(64)

48

for elderly(61) are 1) GEM (geriatric evaluation and management) in

which direct care & follow up care is given by the interdisciplinary team,

2) CGA (comprehensive geriatric interdisciplinary assessment and

treatment) in which the consultative interdisciplinary team makes specific

recommendations to the patient’s primary care provider, 3) PACE

(Program for All inclusive Care for the Elderly) and 4) acute care for

elderly(35).

Following are the approaches which can be incorporated in clinical

practice for prevention & management of frailty.

1) To find at risk individuals in routine practice & for effective

clinical care an extensive CGA /an interdisciplinary assessment &

management is needed.

2) Identify secondary frailty from latent undertreated or end stage

disease, other catabolic states

3) Screen for factors which exacerbate vulnerability to stressors-

polypharmacy, hospitalisation, surgery or other stressors.

4) Establish patient centered goals and advise regular follow up

with geriatric interdisciplinary management team.

5) To institute preventive measures for primary frailty once

(65)

49

PRIMARY PREVENTION(2):

It is vital to prevent the triggers. Primary prevention with probable

potential to prevent or postpone frailty focus mainly on lifestyle issues

and they are regular physical activity, vascular healthy diet , avoiding

smoking, weight control, proper nutrition, moderation with alcohol.

Recent evidences suggest drugs targeting RAA system affect body

composition & prevent sarcopenia. Drugs with potential side effects like

statins causing myopathy which probably limits the physical activity can

be avoided.

SECONDARY PREVENTION:

Aims to improve the prognosis and prevent or postpone the

development of disability and other adverse outcomes from frail status.

The therapeutic targets for frailty which are under investigation(35) are

1) Antioxidants (vit C, allopurinol)

2) Hormonal supplements (testosterone, DHEA, GH, vit D)

3) Behavioural interventions (calorie restriction & ↑ physical activity)

4) Drugs like acetaminophen, anti myostatinAb, ACEIs

5) Genetic manipulation

(66)

50

Good numbers of evidence are there which show Resistance

training Exercise with proper nutrition can increase the strength in a frail

as well as non-frail group(62). Earliest the patient can start, better will be

the response. Though there are areas which need investigation, it is highly

recommended for elderly frail individuals to have regular physical

activity and exercise, especially Resistance training exercise rather than

aerobic exercise to modify frailty & its adverse outcomes.

THYROID GLAND –ANATOMIC CONSIDERATIONS

Thyroid gland one among the largest endocrine glands weighs

about 15-20 grams. It is situated in the anterior portion of neck, below

and lateral to the thyroid cartilages. It consists of 2 lateral lobes with an

isthmus which connects the two lateral lobes, and sometimes a pyramidal

lobe. Embryologically, it arises from a small tissue at the base of tongue,

which later descends down as the thyroglossal duct and occupies the

anterior portion of neck between larynx and trachea. Multiple spherical

follicles (acini) lined by polarised epithelial cells, that surround secreted

(67)

51

THYROID HORMONES FORMATION & SECRETION(64)

Figure 11 THYROID HORMONES FORMATION & SECRETION

THYROID HORMONES STRUCTURE(63)

(68)

52

[image:68.595.167.490.151.436.2]

REGULATION OF THYROID HORMONE SECRETION(65)

Figure 13 REGULATION OF THYROID HORMONE SECRETION

Hypothalamus secretes TRH which stimulates anterior pituitary to

produce TSH which in turn stimulates thyroid gland to synthesize T4 &

T3 from dietary iodides and follicular thyroglobulin, and are released in

to circulation. Both T3 & T4 in turn has both direct & indirect negative

feedback effect on secretion of TSH by action on anterior pituitary &

hypothalamus separately.

TRANSPORT OF THYROID HORMONES

Both T3 & T4 will bind with plasma proteins mainly with TBG

(Thyroxine – binding globulin), less withTransthyretin (TTR) and

(69)

53

peripherally (Liver, Muscle, kidney & other tissues) by Deiodinase

enzymes (Type I, II, III) to T3 .About 85% of T3 is derived from T4 to

T3 conversion. The direct production from thyroid constitutes only 15%.

More over T3 is less protein bound than T4 and has quick onset of action.

Also T3 has high affinity to Thyroid hormone receptors. Reverse T3, a

biologically inactive form is also derived from deiodination of T4 inner

tyrosyl ring rather than at outer phenolic ring.

MECHANISM OF ACTION OF THYROID HORMONES(66)

There are specific thyroid hormone response elements (TRE) on

the DNA at which the thyroid hormone receptor forms a heterodimer with

RXR (Retinoid X receptor) TR-RXR. T4 exerts its action by converting

into T3. In the absence of T3 binding to TR, TR-RXR heterodimer

bounded with TRE, recruits COR – Co-repressor & results in gene

silencing. When T3 binds with TR, it disrupts CoR binding with the

heterodimer & it promotes binding of CoA (Co-activator) & increase

(70)

54

Figure 14 thyroid hormone action

PHYSIOLOGIC ACTIONS OF THYROID HORMONE(67):

At Cellular level

Thyroid hormones act at cellular level to increase size and number

of mitochondria and the total membrane surface area of mitochondria

increases directly proportional to the increased metabolic rate of the

whole individual. They also increase Na+ K+ ATPase activity, which in

turn causes increase in transport of Na+ & K+ ions across cell

membranes. This process uses energy and it increases the heat production

in the body. Also they activate the sodium pump & further increases heat

production. However the increase in number and activity of mitochondria

could be the result of increased activity of the cells. Also uncoupling of

oxidative phosphorylation is stimulated(64).

On Growth: the effect of thyroid hormone on growth is evident by

A study on association of thyroid function and frailty in elderly

A STUDY ON ASSOCIATION OF THYROID

FUNCTION AND FRAILTY IN ELDERLY

M.D., IN GERIATRIC MEDICINE

THE TAMILNADU DR.M.G.R. MEDICAL UNIVERSITY

DEPARTMENT OF GERIATRIC MEDICINE

MADRAS MEDICAL COLLEGE

DISSERTATION ON

A STUDY ON ASSOCIATION OF THYROID

FUNCTION AND FRAILTY IN ELDERLY

M.D., IN GERIATRIC MEDICINE

BRANCH – XVI

THE TAMILNADU DR.M.G.R. MEDICAL UNIVERSITY

CHENNAI

DEPARTMENT OF GERIATRIC MEDICINE

MADRAS MEDICAL COLLEGE

CHENNAI – 600003

MAY 2018

A STUDY ON ASSOCIATION OF THYROID

FUNCTION AND FRAILTY IN ELDERLY

M.D., IN GERIATRIC MEDICINE

THE TAMILNADU DR.M.G.R. MEDICAL UNIVERSITY

CERTIFICATE

DECLARATION

LIST OF FIGURES

LIST OF CHARTS

TABLE OF CONTENTS

AIMS AND OBJECTIVES

REVIEW OF LITERATURE