Dr. Muhammad Sayedul Arefin

Resident ,Gastroenterology ,BSMMU

Controversial issues In

medicine...

List of controversial issues

Use of Steroids in Tuberculosis

Pioglitazone in Diabetes

Steroid in stroke

Protein restriction in CKD

Embryonic Stem Cell Transplantation

Use of STEROID in Tuberculosis

BackgroundCorticosteroids:

Decrease inflammation, especially in the subarachnoid space

Reduce cerebral and spinal cord oedema

Reduce inflammation of small blood vessels and therefore

Reduce damage from decreased blood flow to the underlying brain tissue

Corticosteroids:

It may Suppress the immune response to mycobacteria, making the systemic effects worse

May reduce inflammation of the meninges, reducing drug penetration into the subarachnoid space

Cause gastrointestinal haemorrhage, electrolyte imbalance, hyperglycaemia, infections from fungi or bacteria, and psychosis

Steroids in TB

Although much of the morbidity in

tuberculosis results from an excessive

cellular host response to the bacillus, the

use of steroids in TB management remains

controversial

Steroids in TB Corticosteroids are often used as an adjunct

in the treatment of various forms of TB and

for the prevention of complications, such as

Constrictive pericarditis

Hydrocephalus

Focal neurological deficits

Pleural adhesions

Intestinal stricture

Steroids in TB

But they have been proven in clinical trials to

improve the following outcomes only — death

or disability in HIV-seronegative patients with:

Tubercular meningitis and

Tubercular pericarditis

Despite a lack of specific evidence for

efficacy in HIV co-infected patients with

tubercular meningitis or pericarditis,

corticosteroids are generally recommended

in them as well

Steroid in Tubercular Meningitis

Tubercular meningitis (TBM) is uniformly

fatal if not treated

An earlier Cochrane systematic review

concluded that corticosteroids significantly

improved the mortality among children with

TBM

But the effect on mortality in adults was

inconclusive

Steroid in Tubercular Meningitis

But largest-ever RCT done in Vietnam

revealed corticosteroids to significantly

decrease the risk of death and improve the

disability-free survival in TBM

Central nervous system TB may at times

present as focal space-occupying lesions of

the brain parenchyma or the spinal cord

(TUBERCULOMA) with or without evidence

of meningitis

Steroid in Tubercular MeningitisCorticosteroids may hasten symptomatic

improvement when tuberculoma results in

mass effect or refractory seizures

But eficacy of corticosteroids in this clinical

setting has not been formally evaluated in

clinical trials

Paradoxically,tuberculoma may develop in

patients being treated for TBM despite the

use of adjunctive corticosteroids

Steroid in Tubercular Pericarditis

Patients with tubercular pericarditis may

develop

Cardiac tamponade

Constrictive pericarditis

Meta-analysis of different RCTs reveal

corticosteroids decreased the risk of all-cause

mortality by in tubercular pericarditis

• But this reduction failed to achieve statistical

significance

Corticosteroids did not significantly reduce

the need for pericardiectomy also

Adrenal TBClinically manifest adrenal insufficiency as a

result of TB is an absolute indication for

corticosteroids

Subclinical adrenal insufficiency which is

common among patients with pulmonary as

well as extrapulmonary TB

Adrenal function recovers in most of these

patients with ATT alone

Steroid in other extrapulmonary TB

Evidence is inconclusive for use of

corticosteroids in

Genitourinary TB

Laryngeal TB

Peritoneal TB

Miliary TB

Mediastinal TB lymphadenitis

Steroid in pulmonary TBThe role of corticosteroids in pulmonary TB

modern-day rifampicin-based regimens is

questionable

Anecdotal reports suggest that

corticosteroids might be beneficial in patients

with endobronchial TB

But in one trial of 34 patients with

endobronchial TB, corticosteroids had no

appreciable effect on bronchoscopic healing

rate, radiological findings, and pulmonary

functions

Endobronchial TB

Steroid in Tubercular pleural Effusuion

Most tubercular pleural effusions resolve

spontaneously even without specific ATT.

The resolution is often incomplete leaving

behind loculated collections and considerable

pleural thickening

It is believed that corticosteroids might

reduce these fibrotic sequelae and hasten

the resolution of pleural effusion as well as

clinical symptoms

Steroid in Tubercular pleural Effusuion

Different studies revealed both positive &

negative results regarding improvement of

pleural effusion & prevention of pleural

adhesion by steroid

But no study revealed significant improvement

in pulmonary function (evidenced by forced

vital capacity at the end of treatment)

Thus, the clinical significance of the reduction

in pleural thickening by corticosteroids is

QUESTIONABLE

Corticosteroids in HIV-related TB

Paradoxical reactions in TB is defined by a

clinical or radiological worsening of pre-

existing tuberculous lesions or the

development of new lesions, in patients

receiving anti-tuberculous medication who

initially improved on treatment

This phenomenon is also known as Immune

Reconstitution Inflammatory syndrome (IRIS)

This is well-recognised phenomenon,

particularly in HIV-infected individuals where

they are associated with HAART

Corticosteroids in HIV-related TB

This phenomenon is also noticed in few

cases of HIV-negative TB

Most cases of paradoxical reactions are

self-limited and respond to NSAID

corticosteroids may be used to treat severe

paradoxical reactions and those

unresponsive to NSAIDs

Final Words

The only clinical indication for which

corticosteroids have been demonstrated to be

beneficial beyond reasonable doubt is TBM

Corticosteroids seem to have a potential

benefit in patients with tubercular pericarditis,

But more robust evidence is required

Though corticosteroids reduced the risk of

pleural thickening,clinical significance of this

benefit is unclear

Hence,the use of corticosteroids is not

recommended in tubercular pleural effusion

Patients with diabetes were understandably

worried, and their physicians were faced, as

often is the case with such media events,

with the dilemma of determining what should

be the correct advice at a time of limited data

availability

Pioglitazone in diabetes

Pioglitazone in diabetes

• The type-2 diabetes drug pioglitazone, is at

the center of a great deal of controversy

lately

• Studies have shown that it may carry a

substantial risk of side effects

• Yet experts say it remains one of the most

effective treatments for poorly managed

blood sugar

Pioglitazone in diabetes

The European Medicines Agency recently

affirmed that the medication should not be

taken off the market, despite fears that it

may increase the risk of bladder cancer

The agency stated that the studies

indicating increases in bladder cancer risk

only showed a modest correlation, and

pioglitazone is an invaluable medicine for

managing blood sugar

Pioglitazone in diabetes

• Piglitazones are usually given when other

medications have proven ineffective

• This may mean that concerns about a

slight increase in bladder cancer risk are

the least of these patients' worries

• They should be primarily concerned about

poorly managed blood sugar

Pioglitazone in diabetes

• For these reasons, the agency only

recommended putting warning labels on

the medication and letting medical

professionals determine whether the risk is

worth it

• The U.S. Food and Drug Administration

issued a similar warning about the

medication but declined to pull

pioglitazone.

Pioglitazone in diabetes

• Still, some groups are concerned about the

increased risks associated with Actos

• The law firm Williams Kherkher recently

initiated a suit against Takeda

Pharmaceuticals, the company that makes

the medication

• Lawyers said the organization may be

responsible for the pain, suffering and

medical expenses of individuals who have

developed bladder cancer while taking Actos

Pioglitazone in diabetes

• Much of the concern over the potential side

effects associated with Actos stems from a

review of the safety and efficacy of the drug

conducted by Takeda five years after it was

approved by the FDA

• The results initially showed little overall

correlation between pioglitazone use and

bladder cancer

Pioglitazone in diabetes

• However, when investigators dug deeper

into the numbers, they found that those who

had been taking the drug for extended

periods of time appeared to have slightly

higher rates of cancer

• The FDA now warns physicians to be aware

of this risk and weigh them against potential

benefits

• Dietary Protein Restriction in CKD

Dietary Protein Restriction in CKD: The Debate

Continues

Dietary protein restriction has been one of

the mainstays of nutritional intervention in CKD

patients

The apparent benefits of such dietary

manipulation include :

Diminishing the accumulation of nitrogenous

wastes

Limiting the metabolic disturbances,characteristic

of advanced CKD

Proven and Controversial Advantages and Disadvantages of

Dietary Protein Restriction in CKD Patient

Advantage Disadvantage

Proven Dereased toxin load Predisposition to PEM

Slowing progression Complex diet

Better BP control Needs close supervision

Better phosphorus

control

Decreased muscle mass

Better H⁺control

Improved insulin

sensitivity

Improved proteinuria*

Controversial Extending time to ESRD Posible weight gain

Increase mortality

The role of dietary protein restriction in

slowing progression of CKD is more

controversial, although several meta-

analyses indicate a beneficial effect, albeit

small

Concern has been raised by several investigators

that low-protein diets(LPDs) especially very low

quantities of dietary protein (VLPDs), can lead to

Deterioration in the nutritional status

predispose to adverse clinical outcomes,

especially after the initiation long-term of

dialysis

These concerns have been mostly defied by

a number of studies showing

well-designed diets planned by skilled

dietitians & followed by motivated & adherent

patients are :

a)Effective

b) and do not have harmful effects on

nutritional condition

An article published in American Journal of

Kidney Diseases in 2009 by Menon et el.

ignite the controversy by providing evidence

that

Compared with an LPD, ssignment to a very

low-protein diet increased the risk of death

in long-term follow-up of the MDRD study

• But had no impact on delaying the

progression to kidney failure & no

relatioship with a composite outcome of

kidney failure & death

• These result emphasize the importance of

follow-up when evaluating the impact of

Interventions designed to slow the chronic

disease

Steroid in Stroke

Steroid in Stroke

Theoretically, steroids are

immunosuppressive agents that

Lessen Cerebral edema

Decrease intracranial pressure

Strengthen the blood-brain barrier

Steroid in Stroke

These possible benefits have to be weighed

against potentially serious steroid-related

side effects, such as

Immunosuppression and infection

Diabetic exacerbation

Gastrointestinal hemorrhage

Compromised wound healing

The place of steroids in the management of

stroke is still controversial

Steroid in Stroke

Perhaps the only general agreement on the

use of steroids in stroke is where vasculitis

is suspected or proven

As a cause of stroke, vasculitis is very rare

(<1% of all strokes), but treatment with

steroids should be started whenever it is

suspected

Steroid in Stroke

The effectiveness of steroids as one of the

options for the treatment of acute stroke,

either hemorrhagic or infarction, has never

been shown

So far only 2 randomized, controlled trials

concerning the use of dexamethasone in

primary supratentorial intracerebral

hemorrhage have been reported

Steroid in Stroke

In 2001, Ogun and Odusote performed a

prospective double-blind, placebo-controlled,

randomized clinical trial to determine

The effectiveness of a short course of high-

dose dexamethasone on mortality and

neurological recovery in acute stroke patient

Forty patients were eligible for the study

27 were presumed to have hemorrhagic

stroke and 13 patients had cerebral infarction

Steroid in Stroke

• Of the 27 hemorrhagic stroke patients, 15

were treated with 100 mg dexamethasone

immediately and 16 mg every 6 hours for 2

days, and 12 patients were given placebo

• Of the 13 patients with cerebral infarction, 5

were in the steroid group and 8 in the

placebo group

• At 1 month, 16 patients (80%) in the

dexamethasone group and 17 (85%) in the

placebo group had died

Steroid in Stroke

• This study failed to demonstrate any

benefit of a short-term course of high-dose

steroids in improving the mortality of acute

stroke patients, and the use of these

steroids should be discouraged

SAH• Subarachnoid hemorrhage (SAH) accounts

for 7% to 8% of all strokes and leads to early

death (1 month) in about 30% to 35%

• Important contributing factors to the

development of delayed cerebral ischemia

after aneurysmal SAH

Decreasing plasma volume

Hyponatremia

Impaired autoregulation of cerebral blood

flow

Reactive inflammation

Steroid in Stroke

Mineralocorticoid treatment with

fludrocortisone acetate prevents plasma

volume depletion

Glucocorticoid treatment

anti-inflammatory effect

cerebral vasodilation and

Improvement of cerebral blood flow after SAH

Steroid in Stroke

• However, a beneficial effect of steroids on

the clinical outcome in patients with SAH

has not been proven by any well-conducted

clinical trial

• Steroids have a very limited role in stroke

therapy

• The only definite proven indication of steroids

in stroke is in patients with vasculitis

• Steroid use in acute stroke (either cerebral

infarction or hemorrhage) has been

confirmed by several well-controlled clinical

trials to be of no benefit

• With regard to SAH, it is still debatable whether

steroids are beneficial and further studies are

necessary to document their benefit.

Summary

Controversies in Stroke

Steroids Have No Role in Stroke Therapy

Niphon Poungvarin, MD, FRCP, FRCP(E), FRCP(Glasg)

+ Author Affiliations

From the Division of Medicine, Department of Neurology,

Siriraj Hospital Medical School, Mahidol University,

Bangkok, Thailand.

Correspondence to Prof Niphon Poungvarin, Mahidol

University - Thailand, Siriraj Hospital Medical School,

Dept of Medicine/Division of Neurology, Bangkok, 1070

Thailand. E-mail sinpg@mucc.mahidol.ac.th

• THE STEM CELL DEBATE: IS IT OVER

Definition of Stem cell

• A stem cell is a generic cell that can make

exact copies of itself indefinitely

• stem cell has the ability to produce

specialized cells for various tissues in the

body, such as heart muscle, brain tissue, and

liver tissue

Types of stem cells• Embryonic stem cells : these are taken

from aborted fetuses or fertilized eggs that

are left over from from in vitro fertilization

(IVF)

• They are useful for medical and research

purposes because they can produce cells for

almost every tissue in the body

• Adult stem cells - these are not as

versatile for research purposes because

they are specific to certain cell types, such

as blood, intestines, skin, and muscle

• The term "adult stem cell" may be

misleading because both children and

adults have them

Excitement and Controversy

• Doctors have been performing bone

marrow stem cell transplants for decades

• But when scientists learned how to

remove stem cells from human embryos in

1998, both excitement and controversy

ensued

• The excitement was due to the huge

potential these cells have in curing human

disease

Excitement and Controversy

• The controversy centered on the moral

implications of destroying human embryos

• Political leaders began to debate over how

to regulate and fund research involving

human embryonic stem (hES) cells

New Possibilities

• But Scientists have learned how to

stimulate a patient's own cells to behave

like embryonic stem cells

• These so-called induced pluripotent stem

(iPS) cells are reducing the need for

human embryos in research and opening

up exciting new possibilities for stem cell

therapies.

The Ethical Questions• Until recently, the only way to get pluripotent

stem cells for research was to remove the

inner cell mass of an embryo and put it in a

dish

• The thought of destroying a human embryo

can be unsettling, even if it is only five days

old

The Ethical Questions

• Stem cell research thus raised difficult

questions:

Does life begin at fertilization, in the womb,

or at birth?

Is a human embryo equivalent to a human

child?

Does a human embryo have any rights?

Is it justified to destroy a single embryo to

cure a countless number of patients?

IPS Cells: Problem Solved?

With iPS cells now available as an

alternative to hES cells, the debate over

stem cell research is becoming

increasingly irrelevant

But ethical questions regarding hES cells

may not entirely go away

Inevitably, some human embryos will still

be needed for research

iPS cells are not exactly the same as hES

cells, and hES cells still provide important

controls

IPS Cells: Problem Solved?

• hES cells are a gold standard against

which the "stemness" of iPS cells is

measured

• Some experts believe it's wise to continue

the study of all stem cell types, since we're

not sure yet which one will be the most

useful for cell replacement therapies

IPS Cells: Problem Solved?

• An additional ethical consideration is that

iPS cells have the potential to develop into

a human embryo, in effect producing a

clone of the donor

• Many nations are already prepared for

this, having legislation in place that bans

human cloning

Stem Cell Research Legislation• The U.S. government released new stem

cell guidelines in 2009

• The new guidelines cover issues such as

informed consent of donors and the

wording of consent, as well as the issue of

financial gain

• The National Institutes of Health (NIH)

maintains a register of stem cells,

including human embryonic lines, that are

eligible for government funding.