1. Controversial issues In
medicine...
Dr. Muhammad Sayedul Arefin
Resident ,Gastroenterology ,BSMMU

2. List of controversial issues
Use of Steroids in Tuberculosis
Pioglitazone in Diabetes
Steroid in stroke
Protein restriction in CKD
Embryonic Stem Cell Transplantation

3. Use of STEROID in Tuberculosis

4. Background
Corticosteroids:
 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. Steroid in Tubercular Meningitis
Corticosteroids 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

12. 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

13. Adrenal TB
Clinically 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

14. Steroid in other extrapulmonary TB
Evidence is inconclusive for use of
corticosteroids in
Genitourinary TB
Laryngeal TB
Peritoneal TB
Miliary TB
Mediastinal TB lymphadenitis

15. Steroid in pulmonary TB
The 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

17. Endobronchial TB

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. Pioglitazone in diabetes

25. 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

26. 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

27. 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

28. 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.

29. 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

30. 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

31. 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

32. • Dietary Protein Restriction in CKD

33. 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

34. 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 Decreased muscle mass
control
Better H⁺control
Improved insulin
sensitivity
Improved proteinuria*
Controversial Extending time to ESRD Posible weight gain
Increase mortality

35. The role of dietary protein restriction in
slowing progression of CKD is more
controversial, although several meta-
analyses indicate a beneficial effect, albeit
small

36.  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

37. 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

38. 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

39. • These result emphasize the importance of
follow-up when evaluating the impact of
Interventions designed to slow the chronic
disease

40. Steroid in Stroke

41. Steroid in Stroke
Theoretically, steroids are
immunosuppressive agents that
 Lessen Cerebral edema
Decrease intracranial pressure
 Strengthen the blood-brain barrier

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. 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

50. 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

51. Summary
• 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.

52. 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

53. • THE STEM CELL DEBATE: IS IT OVER

54. 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

55. 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

56. • 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

57. 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

58. 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

59. 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.

60. 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

61. 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?

62. 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

63. 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

64. 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

66. 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.