ABSTRACT

Tea is an aromatic beverage commonly prepared bypouring hot or boiling water over cured leaves of thetea plant. All tea is produced from a plant calledCamellia sinensis. The thousands of different varieties ofteas available in the world only vary by the regionit was grown, the time of year picked, and theprocessing method. There are three main varieties oftea : green, black, and oolong.

Tea contains a large number of potentially bioactivechemicals, including flavinoids, amino acids,vitamins, caffeine and several polysaccharides, and avariety of health effects have been proposed andinvestigated. It has been suggested that green andblack tea may protect against cancer, though thecatechins found in green tea are thought to be moreeffective in preventing certain obesity-relatedcancers such as liver and colorectal while both greenand black tea may protect against cardiovasculardisease.Numerous recent epidemiological studies have beenconducted to investigate the effects of green teaconsumption on the incidence of human cancers. Thesestudies suggest significant protective effects ofgreen tea against oral, pharyngeal, esophageal,prostate, digestive, urinary tract, pancreatic,bladder, skin, lung, colon, breast, and livercancers, and lower risk for cancer metastasis andrecurrence.[34]

Keywords: tea, cardiovascular disease, cancer, prostat

1

CHAPTER I

INTRODUCTION

Asthma affects 5-10% of the population or an estimated

23.4 million persons, including 7 million children. The

overall prevalence rate of exercise-induced bronchospasm is 3-

10% of the general population if persons who do not have

asthma or allergy are excluded, but the rate increases to 12-

15% of the general population if patients with underlying

asthma are included. Asthma affects an estimated 300 million

individuals worldwide. Annually, the World Health Organization

(WHO) has estimated that 15 million disability-adjusted life-

years are lost and 250,000 asthma deaths are reported

worldwide. (1)

2

The management of asthma differs according to the

classification of severity. Corticosteroids may be used from

mild to severe – persistent asthma, ranging from low dose with

alternative medicines to high dose and its combinations.

Although use of systemic corticosteroids is recommended early

in the course of acute exacerbations in patients with an

incomplete response to beta agonists, oral administration is

equivalent in efficacy to intravenous administration.

Corticosteroids speed the resolution of airway obstruction and

prevent a late-phase response. (1,2)

Diabetes is a chronic disease, which occurs when the

pancreas does not produce enough insulin, or when the body

cannot effectively use the insulin it produces. This leads to

an increased concentration of glucose in the blood

(hyperglycaemia). Type 1 diabetes (previously known as

insulin-dependent or childhood-onset diabetes) is

characterized by a lack of insulin production. Type 2 diabetes

(formerly called non-insulin-dependent or adult-onset

diabetes) is caused by the body’s ineffective use of insulin.

It often results from excess body weight and physical

inactivity. (3)

3

Rates of diabetes are increasing worldwide. The

International Diabetes Federation predicts that the number of

people living with diabetes will to rise from 366 million in

2011 to 552 million by 2030. The top 10 countries in number of

people with diabetes are currently India, China, the United

States, Indonesia, Japan, Pakistan, Russia, Brazil, Italy, and

Bangladesh. (4)

Patient with diabetes has impaired immunity which leads

to high risk from infections. In the following chapter we will

be talking about the necessity of using corticosteroids for

asthma in diabetes.

4

CHAPTER II

LITERATURE REVIEW

I. Asthma

Asthma is best described as a chronic disease that

involves inflammation of the pulmonary airways and bronchial

hyperresponsiveness that results in the clinical expression of

a lower airway obstruction that usually is reversible. Asthma

is characterised by a specific pattern of inflammation that is

largely driven via immunoglobulin (Ig)E-dependent mechanisms.

Genetic factors have an important influence on whether atopy

develops and several genes have now been identified. Most of

the genetic linkages reported for asthma are common to all

5

allergic diseases. However, environmental factors appear to be

more important in determining whether an atopic individual

develops asthma, although genetic factors may exert an

influence on how severely the disease is expressed and the

amplification of the inflammatory response. (5,6)

I. A. Etiology

Genetics

Genome-wide linkage studies and case–control studies

have identified 18 genomic regions and more than 100 genes

associated with allergy and asthma in 11 different

populations. In particular, there are consistently replicated

regions on the long arms of chromosomes 2, 5, 6, 12 and 13.

Association studies of unrelated individuals have also

identified more than 100 genes associated with allergy and

asthma, 79 of which have been replicated in at least one

further study. A recent genome-wide association

study identified a new gene, ORMDL3, that exhibited a highly

significantly association with asthma (p < 10−12) (for single

nucleotide polymorphism rs8067378, odds ratio 1.84, 95%

confidence interval 1.43–2.42) a finding that has now been

replicated in several populations. (7,8,9,10)

6

Stress

A number of animal models have suggested that prenatal

maternal stress acts through regulation of the offspring’s

hypothalamic–pituitary–adrenal axis to decrease cortisol

levels, which may affect the development of an allergic

phenotype. Although there is a correlation between caregiver

stress early in the infant’s life and higher levels of

immunoglobulin E in the infant  and early wheezing, no studies

to date have shown an association with asthma. (11.12)

Obesity

A study by Cottrell et al explored the relationship

between asthma, obesity, and abnormal lipid and glucose

metabolism. The study found that community-based data linked

asthma, body mass, and metabolic variables in children.

Specifically, these findings described a statistically

significant association between asthma and abnormal lipid and

glucose metabolism beyond body mass association. Accelerated

weight gain in early infancy is associated with increased

risks of asthma symptoms according to one study of preschool

children. (1)

7

Other etiologies include environmental allergens, viral

respiratory tract infections, exercise, hyperventilation,

gastroesophageal reflux disease, chronic sinusitis or

rhinitis, aspirin or nonsteroideal anti-inflammatory drug

(NSAID) hypersensitivity, sulfite sensitivity, use of beta-

adrenergic receptor blockers, environmental pollutants,

tobacco smoke, occupational exposure, irritants and perinatal

factors. (1)

I. B. Pathophysiology

The pathophysiology of asthma can be divided into four

events: bronchoconstriction, airway edema, airway

hyperresponsiveness and airway remodeling. (13)

Bronchoconstriction

In asthma, the dominant physiological event leading to

clinical symptoms is airway narrowing and a subsequent

interference with airflow. In acute exacerbations of asthma,

bronchial smooth muscle contraction (bronchoconstriction)

occurs quickly to narrow the airways in response to exposure

to a variety of stimuli including allergens or irritants.

Allergen-induced acute bronchoconstriction results from an

IgE-dependent release of mediators from mast cells that

8

includes histamine, tryptase, leukotrienes, and prostaglandins

that directly contract airway smooth muscle. (13)

Airway edema

As the disease becomes more persistent and inflammation

more progressive, other factors further limit airflow. These

include edema, inflammation, mucus hypersecretion and the

formation of inspissated mucus plugs, as well as structural

changes including hypertrophy and hyperplasia of the airway

smooth muscle. (13)

Airway hyperresponsiveness

Airway hyperresponsiveness—an exaggerated

bronchoconstrictor response to a wide variety of stimuli—is a

major, but not necessarily unique, feature of asthma. The

degree to which airway hyperresponsiveness can be defined by

contractile responses to challenges with methacholine

correlates with the clinical severity of asthma. The

mechanisms influencing airway hyperresponsiveness are multiple

and include inflammation, dysfunctional neuroregulation, and

structural changes; inflammation appears to be a major factor

in determining the degree of airway hyperresponsiveness.

9

Treatment directed toward reducing inflammation can reduce

airway hyperresponsiveness and improve asthma control. (13)

Airway remodeling

In some persons who have asthma, airflow limitation may

be only partially reversible. Permanent structural changes can

occur in the airway; these are associated with a progressive

loss of lung function that is not prevented by or fully

reversible by current therapy. Airway remodeling involves an

activation of many of the structural cells, with consequent

permanent changes in the airway that increase airflow

obstruction and airway responsiveness and render the patient

less responsive to therapy. These structural changes can

include thickening of the sub-basement membrane, subepithelial

fibrosis, airway smooth muscle hypertrophy and hyperplasia,

blood vessel proliferation and dilation, and mucous gland

hyperplasia and hypersecretion. (13)

10

I. C. Treatment

The goal of asthma treatment is to achieve and maintain

clinical control. Medications to treat asthma can be

classified as controllers or relievers. The following will

discussed only about the role of glucocorticosteroids in

treating asthma. (14)

I. C. 1. Controllers

Inhaled glucocorticosteroids

Inhaled glucocorticosteroids are currently the most

effective anti-inflammatory medications for the treatment of

persistent asthma. Studies have demonstrated their efficacy in

reducing asthma symptoms, improving quality of life, improving11

lung function, decreasing airway hyperresponsiveness,

controlling airway inflammation, reducing frequency and

severity of exacerbations, and reducing asthma mortality.

However, they do not cure asthma, and when they are

discontinued deterioration of clinical control follows within

weeks to months in a proportion of patients. (14)

Systemic glucocorticosteroids

Long-term oral glucocorticosteroid therapy (that is, for

periods longer than two weeks as a glucocorticosteroid

“burst”) may be required for severely uncontrolled asthma, but

its use is limited by the risk of significant adverse effects.

The therapeutic index (effect/side effect) of long-term

inhaled glucocorticosteroids is always more favorable than

long-term systemic glucocorticosteroids in asthma. If oral

glucocorticosteroids have to be administered on a long-term

basis, attention must be paid to measures that minimize the

systemic side effects. Oral preparations are preferred over

parenteral (intramuscular or intravenous) for long-term

therapy because of their lower mineralocorticoid effect,

relatively short half-life, and lesser effects on striated

muscle, as well as the greater flexibility of dosing that

12

permits titration to the lowest acceptable dose that maintains

control. (14)

Other controllers are leukotriene modifiers,

theophylline, long-acting inhaled and oral β2 agonists, anti

Ig-E, allergen-specific immunotherapy and oral anti-allergic

compounds.

I. C. 2. Relievers

Systemic glucocorticosteroid

Although systemic glucocorticosteroids are not usually

thought of as reliever medications, they are important in the

treatment of severe acute exacerbations because they prevent

progression of the asthma exacerbation, reduce the need for

referral to emergency departments and hospitalization, prevent

early relapse after emergency treatment, and reduce the

morbidity of the illness. The main effects of systemic

glucocorticosteroids in acute asthma are only evident after 4

to 6 hours. Oral therapy is preferred and is as effective as

intravenous hydrocortisone. A typical short course of oral

glucocorticosterods for an exacerbation is 40-50 mg

prednisolone given daily for 5 to 10 days depending on the

severity of the exacerbation. When symptoms have subsided and

13

lung function has approached the patientʼs personal best

value, the oral glucocorticosteroids can be stopped or

tapered, provided that treatment with inhaled

glucocorticosteroids continues. Intramuscular injection of

glucocorticosteroids has no advantage over a short course of

oral glucocorticosteroids in preventing relapse. (14)

II. Diabetes

Diabetes is a chronic disease, which occurs when the

pancreas does not produce enough insulin, or when the body

cannot effectively use the insulin it produces. This leads to

an increased concentration of glucose in the blood

(hyperglycaemia). (3)

II. A. Type 1 Diabetes Mellitus

Type 1 diabetes mellitus (DM) is a multisystem disease

with both biochemical and anatomic/structural consequences. It

is a chronic disease of carbohydrate, fat, and protein

metabolism caused by the lack of insulin, which results from

the marked and progressive inability of the pancreas to

secrete insulin because of autoimmune destruction of the beta

cells. (3)

Pathophysiology

14

Type 1 diabetes usually develops as a result of

autoimmune pancreatic beta-cell destruction in genetically

susceptible individuals. Up to 90% of patients will have

autoantibodies to at least one of 3 antigens: glutamic acid

decarboxylase (GAD); insulin; and a tyrosine-phosphatase-like

molecule, islet auto-antigen-2 (IA-2). Beta-cell destruction

proceeds sub-clinically for months to years as insulitis

(inflammation of the beta cell). When 80% to 90% of beta cells

have been destroyed, hyperglycaemia develops. Insulin

resistance has no role in the pathophysiology of type 1

diabetes. However, with increasing prevalence of obesity, some

type 1 diabetic patients may be insulin resistant in addition

to being insulin deficient. (15)

II. B. Type 2 Diabetes Mellitus

Type 2 diabetes mellitus is a progressive disorder defined

by deficits in insulin secretion and action that lead to

abnormal glucose metabolism and related metabolic

derangements. Although the aetiologies of type 1 and type 2

diabetes differ dramatically, both lead to hyperglycaemic

states, and both share common macrovascular (coronary heart,

cerebrovascular, and peripheral vascular disease) and

15

microvascular (retinopathy, nephropathy, and neuropathy)

complications. Type 2 diabetes is usually diagnosed based on

screening. It is preceded by a state of pre-diabetes, which

may be clinically detected by a fasting plasma glucose of 5.6

mmol/L to 6.9 mmol/L (100 to 125 mg/dL). Diabetes diagnosis is

based on 2 confirmed values of: fasting plasma glucose >6.9

mmol/L (125 mg/dL); HbA1c of 48 mmol/mol (6.5%) or greater; or

(less commonly) abnormal glucose tolerance test results, or a

random plasma glucose of ≥200 mg/dL plus symptoms of

hyperglycaemia. (16)

Pathophysiology

The precise mechanism by which the diabetic metabolic

state leads to microvascular and macrovascular complications

is only partly understood but likely involves both

uncontrolled BP and uncontrolled glucose, increasing the risk

of microvascular complications such as retinopathy and

nephropathy. Mechanisms may involve defects in aldose

reductase and other metabolic pathways, damage to tissues from

accumulation of glycated end products, and other mechanisms.

With respect to macrovascular complications, high BP and

glucose raise risk, but so do lipid abnormalities and tobacco

16

use. One unifying theory postulates the existence of a

metabolic syndrome that includes diabetes mellitus,

hypertension, dyslipidaemias, and obesity, and predisposes to

coronary heart disease, stroke, and peripheral artery

disease. However, this theory is not universally accepted as

more clinically useful than assessing individual

cardiovascular risk factors. (16)

\

17

Source: Taylor SI, Olefsky JM. Diabetes mellitus: a fundamental and clinical text.3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2004.

Source: http://www.caninsulin.com/Pathophysiology-algorithm.htm

18

CHAPTER III

DISCUSSION

As seen in previous chapter, asthma can be determined in

any of the following ways: the underlying cause of asthma

symptoms, severity of symptoms, and the way it’s controlled.

19

20

Source: . New York State Department of Health. Clinical guideline for the

diagnosis, evaluation and management of adults and children with asthma. Available

at: http://www.nyhealth.gov. accessed on : December 1st 2012.

21

Type 1 diabetes mellitus (T1DM) is an autoimmune disease

that involves the progressive destruction of the

insulin-producing beta cells in the islets of langerhans. It

is a complex process that results from the loss of tolerance

to insulin and other beta-cell-specific antigens. Various

genetic and environmental factors have been studied so far,

but precise causation has yet to be established. Numerous

studies in rodents and human subjects have been performed in

order to elucidate the role of B and T cells, which determine

the risk of development and progression of diabetes. These

studies have demonstrated that while T1DM is fundamentally a

T-cell-mediated autoimmune response, the development of this

disease results from complex interactions between the adaptive

and innate immune systems, with numerous cell types thought to

contribute to pathogenesis. Like any complex disease, the

variation in severity and incidence of T1DM can be attributed

to a combination of genetic and environmental factors. (17)

22

Source: Ting C, Bansal V, Batal I, Mounayar M, et al. Impairment of immune

systems in diabetes. In: Diabetes: an old disease, a new insight. Ahmad

SI, editor. Texas: LANDES Bioscience; 2012.

Infectious diseases are common and serious complication

of diabetes mellitus (DM) and hyperglycemia. The increase of

infections in patients with DM is known to depend upon an

immunosuppressive condition which is brought about by impaired

innate immunity and acquired immunity. For instance, functions

of neutrophils such as phagocyte, chemotaxis and cytokine-

production are decreased in DM model mouse and hyperglycemia

and a Th2-axis shift which reduces Th1-dependent immunity are

observed in DM patients. However, the majority of results

23

concerning interaction of hyperglycemia and immune function

are controversial and relevance of hyperglycemia and/or

hyperinsulinemia to immunosuppressive mechanisms remains

unclear. (18)

High glucose levels lead to shunting through the polyol

pathway, an increase in diacylglycerol which activates protein

kinase C, an increase in the release of electrons that react

with oxygen molecules to form superoxides, and the non-

enzymatic glycosylation of proteins that result in greater

formation of advanced glycation end products. Each of these

can lead to aberrant cell signalling that affects innate

immunity for example, by activating the MAP kinase pathway or

inducing activation of transcription factors such as NF-

kappaB. This may be a common feature of several complications

including periodontal disease, atherosclerosis, nephropathy,

impaired healing and retinopathy. These complications are

frequently associated with increased expression of

inflammatory cytokines such as TNF-alpha, IL-1beta and IL-6

and enhanced generation of reactive oxygen species. (19)

24

Source: Graves DT, Kayal RA. Diabetic complications and dysregulated innate

immunity. Front Biosci 2008;13:1227-1239.

In the management of asthma, inhaled corticosteroids

(ICS) can be prescribed in low dose in mild persistent to high

dose ICS in severe persistent asthma. Whilst oral

corticosteroid is used to maintain control in severe

persistent after the initiating treatment is done. Most of the

benefit from ICS is achieved in adults at low doses,

25

equivalent to 400 ug of budenoside per day. Increasing to

higher doses provides little further benefit in terms of

asthma control but increases the risk of side effects. Current

evidence suggest that in adults, systemic effects of ICS are

not a problem at doses of 400 ug or less budesonide or

equivalent daily. In long-term high doses however, side

effects can occur such as cataract and osteoporosis. It does

not mention the correlation between ICS and blood glucose

serum. (14)

In a study by Slatore CG, et all in side effect of

inhaled corticosteroid in diabetic subjects however; there is

evidence in increasing blood glucose concentration by 1.82

mg/dL in every additional 100 ug of ICS dose. On the other

hand, oral corticosteroid has greater impact in increasing

blood glucose serum. (20)

Other study shows that moderately high dose ICS for

treatment of asthma and COPD is associated with small

disturbances in glucose control after a relatively brief

period of therapy in diabetic subjects relative to oral

montelukast therapy. The changes are detectable but smaller

than those that would be considered clinically significant,

26

therefore changing or stopping therapy is not necessary.

Careful monitoring of blood glucose is required when ICS

therapy is initiated. In diabetics use of steroids may warrant

adjusting or increasing dose of anti-diabetic therapy. (21)

The systemic side effects of long-term oral or

parenteral corticosteroid treatment include osteoporosis,

arterial hypertension, diabetes, hypothalamicpituitary-

adrenal axis suppression, obesity, cataracts, glaucoma, skin

thinning leading to cutaneous striae and easy bruising, and

muscle weakness. Patients with asthma who are on long-term

systemic glucocorticosteroids in any form should receive

preventive treatment for osteoporosis. Caution and close

medical supervision are recommended when considering the use

of systemic glucocorticosteroids in patients with asthma who

also have tuberculosis, parasitic infections, osteoporosis,

glaucoma, diabetes, severe depression, or peptic ulcers. (14)

CHAPTER IV

27

CONCLUSION

The pathophysiology of asthma involves four events:

bronchoconstriction, airway edema, airway hyperresponsiveness

and airway remodeling. Management of asthma includes

prescription of inhaled corticosteroid or oral corticosteroid,

ranging from low doses to high doses depends on the severity

of asthma. These medicines have effects in endocrine,

metabolic and immune system. Diabetes is characterized in

increased blood glucose concentration (hyperglycemia).

Diabetic patient with asthma should be monitored carefully

because the side effects of corticosteroids medicine.

In conclusion, there are some important points:

Careful monitoring of blood glucose is required

when ICS therapy is initiated.

In diabetics use of steroids may warrant adjusting

or increasing dose of anti-diabetic therapy.

Caution and close medical supervision are

recommended when considering the use of systemic

glucocorticosteroids in patients with asthma who

also have diabetes.

28

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