October 1, 2005
Dear Doctor:
Nearly 2000 years ago the Greek physician Aretaeus wrote that diabetes is “a
melting down of the flesh and limbs into urine . . .. the patients never stop
making water, but the flow is incessant, as if from the opening of aqueducts.” Today the trickle of diabetes has become a torrential flood. Almost
all physicians have to deal with some issues related to diabetes and its complications. The Medical Newsletter is also very keen to draw attention to the
burden of this disease. Therefore to coincide with World Diabetes Day 2005
on November 14, an article in this issue spans on Diabetes regarding its natural history and on the availability of new oral antidiabetic agents.
World Psoriasis Day 2005 is going to be marked on October 29. The day's
primary purpose is to act as a focus for people - patients, doctors, nurses and
the general public - to raise awareness about psoriasis and psoriatic arthritis
and to give people with psoriasis and/or psoriatic arthritis the attention and
consideration they deserve. World Psoriasis Day is also useful as a channel
to encourage health authorities to offer better access to the most appropriate treatments. In support of the day this time we have chalked out an article on Psoriasis.
Over the past two decades there has been an explosion of diagnosis, treatment and research regarding Attention Deficit Hyperactivity Disorder
(ADHD). As clinicians and researchers have gained more experience working with ADHD, it has become clearer that its impact on life is far greater
than we had ever anticipated. ADHD not only can interfere with learning
and behavior control in childhood, but, as a critical neurobehavioral condition, it can profoundly lead to significant educational, occupational, and family dysfunction throughout the life span. In this issue we have concisely
reviewed an article on this subject.
We are very much optimistic that this time you will be immensely rewarded
getting the “Ongoing Views”.
Ramadan, the holy month for the Muslims is a period of worship, self-discipline, austerity and charity. Our pray to the Almighty that our souls be
divine with the spirit of this blessing month. Also our best wishes to the
Hindu community on their greatest festival.
Prof. Farida Huq
Dr. Selina Akhtar
MBBS, M.Phil, FCPS, Ph.D.(London)
Medical Director
Beximco Pharmaceuticals Ltd.
Manager
Medical Department
Beximco Pharmaceuticals Ltd.
DERMATOLOGY
Psoriasis
soriasis is a chronic, hyperproliferative papulosquamous skin disorder with an immunologic
pathogenesis. It is a noncontagious condition
often marked by inflamed, edematous skin lesions
covered with a silvery white scale. 1,2
P
Epidemiologic and Genetic Features
More than 4.5 million adults in the United States have
been diagnosed with psoriasis and approximately
150,000 new cases are diagnosed each year. An estimated 20% have moderate to severe psoriasis.
Psoriasis occurs about equally in males and females.
Recent studies show that there may be an ethnic link.
It seems that psoriasis is most common in Caucasians
and slightly less common in African Americans.
Worldwide, psoriasis is most common in Scandinavia
and other parts of northern Europe. It appears to be far
less common among Asians and is rare in native
Americans. About 75% psoriasis develop before age
40. However, it is possible to develop at any age. After
age 40, a peak onset period occurs between 50 and 60
years of age. About 1 in 10 people develop psoriasis
during childhood, and it can begin in infancy. The earlier the psoriasis appears, the more likely it is to be
widespread and recurrent.
Psoriatic arthritis develops in roughly one million
people across the United States, and 5% to 10% experience some disability. Psoriatic arthritis usually first
appears between 30 and 50 years of age - often months
to years after skin lesions first occur. However, about
30% of people who get psoriatic arthritis never develop the skin condition.3
Numerous family studies have provided compelling
evidence of a genetic predisposition to the disease,
although the inheritance pattern is still unclear. The
illness develops in as many as half of the siblings of
persons with psoriasis when both parents are affected,
it falls to 16% when one parent is affected and to 8%
when neither parent is affected. The concordance rate
for monozygotic twins is about 70%, as compared
with some 20% for dizygotic twins. As many as 71%
of patients with childhood psoriasis have a positive
family history. 4
Etiological Factors
Psoriasis may be one of the oldest recorded skin conditions. Yet, until recently, little was known about psoriasis. While scientists still do not fully know what
causes psoriasis, research has significantly advanced
the understanding about the disease. One important
break- through began when kidney-transplant patients
with psoriasis experienced clearing while taking
cyclosporine, a potent immunosuppressive medication. This obviously indicates involvement of immune
system with the disease. This means the conditIon is
caused by faulty signals in the body's immune system.
Normally, skin cells mature and are shed from the skin
surface every 28 to 30 days. When psoriasis develops,
the skin cells mature in 3 to 6 days and move to the
skin surface. Instead of being shed, the skin cells pile
up, causing the visible lesions. 3
Researchers have indentified genes that cause psoriasis. These genes determine how a person's immune
system reacts. These genes can cause psoriasis or
other immune mediated condition, such as rheumatoid
arthritis or type I diabetes. Within the past decade,
several putative loci for genetic susceptibility to the
disease has been reported on the basis of genome-wide
linkage studies. However, one locus in the major his tocompatibility complex ( MHC) region on chromosome 6 has been replicated in several populations.
This locus, termed psoriasis susceptibility 1 (PSORS
1), is considered the most important susceptibility
locus.
For many patients, the symptoms of psoriasis
improve in the summer and worsen in the winter,
reflecting the well established notion that the course of
the disease is influenced by various environmental
factors. Physical trauma may trigger psoriatic lesions
at sites of injury (Koebner's phenomenon), possibly
through the release of proinflammatory cytokines, the
unmasking of autoantigens, or both. In fact, some
treatments for psoriasis that have proinflammatory
potential ( e.g., anthralin and phototherapy ) appear to
trigger the disease if applied too aggressively - for
example, in high initial doses. Molecular mechanisms
underlying drug-induced flares of psoriasis are incompletely understood. Medications that can trigger psoriasis include anti-malarial drugs, β - blockers and lithium. 3,4
Infections, particularly streptococcal infections of the
upper respiratory tract, have long been recognized as
triggers of psoriasis. In addition, exacerbation or even
initial manifestation of the disease has been observed
3
DERMATOLOGY
Fig. 2 : Putative T-Cell Responses in the Pathogenesis of a Psoriatic Lesion
To generate a cutaneous T-cell response, antigen-presenting cells (Langerhans' cells in the epidermis) take up and process autoantigens and migrate to the regional lymph nodes. There, they come in contact with naïve T lymphocytes (CD45RA+). Within an
immunologic synapse (inset), molecular interactions result in T-Cell activation. According to the putative theory, antigen-presenting cells present processed antigen bound to major-histocompatibility-complex (MHC) molecules to the T-cell receptor (TCR).
MHC class II molecules present antigen to CD4+ T cells, whereas MHC class I molecules present antigen to CD8+ T cells,
Additional signals are transmitted through interactions of costimulatory molecules with their ligands such as CD2 with CD58,
CD28 with either CD80 or CD86, or both. In addition, adhesive interactions (e.g., by integrins and their immunoglobulin superfamily ligands) also stabilize the immunologic synapse and transmit additional signals. Following the activating signals, T cells differentiate into CD45RO+ memory T cells and express skin-homing receptor cutaneous lymphocyte-associated antigen (CLA).
Once activated, T cells (CD45RO+ and CLA+) reenter the circulation and preferentially extravasate at sites of cutaneous inflammation. In the skin, on encountering the respective antigen, T cells exert their effector functions, which include the secretion of
proinflammatory cytokines. Psoriasis is characterized by a chronically persisting response in effector T cells. ICAM-1 denotes
intercellular adhesion molecule 1.
4
D ERMATOLOGY
Fig. 3 : The Cytokine and Chemokine Network
The transition from normal skin to the full-fledged psoriatic lesion is orchestrated by complex interactions of various cytokines and
chemokines. Proinflammatory cytokines are thought to account for many of the histopathological changes seen in psoriatic skin. For
example, interferon-γ and tumor necrosis factors α (TNF-α) can stimulate the expression of major-histocompatibility-complex
(MHC) class II molecules and intercellular adhesion molecule 1 (ICAM-1). Vascular endothelial growth factor (VEGF) and TNF-α
stimulate angiogenesis. At the same time, interleukin-1 activates mast cells, granulocyte-macrophage colony-stimulating factor (GMCSF) activates neutrophils, nerve growth factor (NGF) stimulates the growth of cutaneous nerves, and interleukin-6 and transforming growth factor α (TGF-α) promote keratinocyte proliferation. TNF-α, in particular, appears to affect the functions of many different cell types in psoriatic skin. Thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC)
are expressed by the cutaneous vasculature and contribute to the recruitment of CCR4+T cells. Cutaneous T-cell-attracting
chemokine (CTACK) contributes to epidermal recruitment of T cells expressing its receptor, CCR10. In addition, macrophage
inflammatory protein 3α (MIP-3α) colocalizes in psoriatic epidermis with epidermal T cells expressing its receptor, CCR6, and can
be induced on keratinocytes by proinflammatory cytokines, such as TNF-α. Another T-cell-attracting chemokine, monokine induced
by interferon-γ (MIG), is expressed by endothelial cells and macrophages directly underneath the hyperplastic psoriatic epidermis.
Since MIG can be induced by T-cell-derived interferon-γ, there is a microenvironmental T-cell-associated inflammation-boosting
loop. This process may be augmented by RANTES (regulated on activation, normal T-cell expressed and secreted) and monocyte
chemotactic protein 1 (MCP-1), both of which also attract mast cells to psoriatic skin. Within psoriatic scales, there is a high content of interleukin-8 and growth-related cytokine α (GRO-α), both of which are neutrophil-attracting chemokines that contribute to
the formation of Munro microabscesses, a hallmark of psoriatic epidermis. Keratinocyte hyperproliferation in psoriatic skin also
appears to be induced, at least in part, by interleukin-8 and GRO-α.
5
DERMATOLOGY
A
B
C
D
F
I
E
G
H
J
K
Fig. 1 : Clinical Features of Psoriasis
Panel A: The typical psoriatic lesion (a sharply demarcated erythematous plaque covered by silvery white scales, often appearing on
the elbow) . Panel B: Initial eruptions of psoriasis (a guttate distribution pattern). Panel C: In a dark-skinned patient, erythrodermic
psoriasis, Panel D: Scalp involvement in psoriasis, (the lesions typically extend a short distance beyond the region covered by terminal hair). Panel E: Inverse psoriasis (located at intertriginous areas and usually shows only scant scaling). Panel F: In patients with
psoriasis vulgaris, small sterile pustules may develop (which is a magnification of the periumbilical region from Panel B). Panel G:
Generalized pustular psoriasis. Panel H: Localized forms of psoriasis include acrodermatitis continua suppurativa, or Hallopeau's disease, which shows the fingers of a patient with severe onychodystrophy. Panel I: Psoriatic arthritis. Panel J: Nail involvement in psoriasis, (mild cases are characterized by small pits and yellowish discoloration of the nail plate). Panel K: Psoriatic nail pits were recreated in a wax-model moulage manufactured approximately 100 years ago (which is item 1766 from the collection of the Johann
Wolfgang Goethe University, Frankfurt, Germany).
6
DERMATOLOGY
and lumbar area. Peeling away the scale causes pin points of bleeding (Auspitz sign). Psoriatic plaques can
also form at sites of skin trauma (Koebner’s phenomenon). Interestingly, psoriatic plaques may result from
excess sun exposure, a treatment that may improve pso riasis if used appropriately. This so-called light induced
psoriasis is also a form of Koebner’s phenomenon.4
The scalp is often the only site involved. Scalp psoriatic
lesions look similar to lesions that occur at other sites,
but they may have significantly more scale and may
adhere to the hair shaft. Itching may be significant, but
permanent, hair loss is not usually seen. 1,3
Inverse psoriatic lesions develop in intertriginous
areas. The lesions do not have as much scale as typical psoriatic plaques. They are usually smooth and
erythematous and are often macerated.
Psoriatic arthritis is an extracutaneous manifestation
that affects at least 5% and perhaps as many as 20% of
patients with psoriasis.
Majority of patients (upto 80%) with psoriatic arthritis exhibit nail changes (nail psoriasis), but nail
changes can be seen in all types of psoriasis (25-50%).
The nature of the changes depends on which part of
the nail matrix is affected. Disease of the proximal
matrix produces pitting and may lead to onycholysis.
Midmatrix disease can produce leukonychia. Because
some of these changes may mimic those of onychomycosis, potassium hydroxide testing should be
considered. Distal matrix disease can cause red spotting in the lunula.
in patients infected with the human immunodeficiency virus (HIV). Stress and sunburn are also known as
potential triggers.3,4
Clinical Manifestations
Psoriasis comes in various forms:
When psoriasis produces plaques, it is referred to as
plaque psoriasis, psoriasis vulgaris, or chronic plaque
psoriasis. The most common form of the disease, plaque
psoriasis is a chronic condition that may remain for
months or years. It presents as symmetrical, well-circumscribed, erythematous plaques with silvery scale.
The extensor surfaces are most commonly affected. It
appears mostly on the elbows, knees, scalp, umbilicus,
Guttate psoriasis is also called acute eruptive psoriasis. The term guttate is derived from the Latin word
gutta, meaning "drop". Guttate psoriasis presents as
drop-shaped lesions that most often occur on the
trunk, buttocks, and proximal limbs. The lesions,
which are smaller than those of plaque psoriasis, are
erythematous, scaly, and mostly nonpruritic. They
may develop rapidly about 2 to 3 weeks after the onset
of pharyngitis (commonly streptococcal pharyngitis or
another upper respiratory tract infection) and may
indicate a propensity for future psoriatic disease.
Guttate psoriasis occurs most often in children and
young adults. It is often self-limited.
Psoriatic diaper rash appears to be the most common
type of psoriasis in children under two years of age. 4
7
DERMATOLOGY
Erythrodermic psoriasis is a severe variant of the disease
that may occur after withdrawal of systemic therapy for
chronic psoriasis. It may appear on its own, but it is more
likely to occur in conjunction with chronic psoriasis.
Persons with erythrodermic psoriasis experience generalized erythema, often over 80% to 90% of their body.
Desquamation and exfoliation can occur.
Pustular psoriasis (Also called von Zumbusch's psoriasis ) is severe, uncommon, and potentially fatal.
Affected persons may have a history of a nonpustular
form of psoriasis. Large, erythematous patches form,
and small, discrete pustules coalesce to form lakes.
Although this pus is generally sterile, consideration
must be given to possible bacterial superinfection,
often with Staphylococcus aureus. This condition typically has a rapid onset, often as a result of too rapid
withdrawal from topical or systemic corticosteroids,
coal tar, or anthralin. However, pustular psoriasis may
have no obvious cause. Patients with pustular psoriasis may present with sepsis and may require hospitalization.
Genital psoriasis is not uncommon and can cause significant distress to patients. These lesions typically do
not itch and may not scale, particularly on an uncircumcised penis. Koebner’s phenomenon may cause a
flare of genital lesions after sexual intercourse.
Some drug-induced dermatologic eruptions ( druginduced psoriasis) may resemble early psoriatic lesions.
In-addition, there are some classes of drugs that are
known to exacerbate preexisting psoriasis. 1,3,4
Therapy
The severity of the disease usually determines the
therapeutic approach. Approximately 70 to 80 percent
of all patients with psoriasis can be treated adequately
with use of topical therapy. Mainly for practical reasons, the vitamin D3 analogues (calcipotriol and tacalcitol) and the topical retinoid tazarotene - all of which
affect keratinocyte functions and the immune response
- are in wider use than is either anthralin or coal tar.
Since most of the compounds that have been mentioned may irritate delicate areas of skin, topical corticosteroids are used in combination with those compounds, particularly in intertriginous areas.
In cases of moderate-to-severe psoriasis (e.g., affecting
large surface areas), the use of phototherapy, systemic
drugs, or both must be considered. Among the estab lished regimens, various therapeutic methods may
8
Fig. 4 : New Pathogenesis - Oriented
Therapeutic Principles
Five general therapeutic principles target the key pathogenic
mechanisms of psoriasis. The first involves inhibition of T-cell
activation through inhibition of molecules involved in the formation of the immunologic synapse (Panel A). The second
principle is depletion of pathogenic T cells (Panel B). This has
been achieved by targeting molecules expressed specifically
by activated T cells, such as the high-affinity interleukin-2
receptor or CD4. The third approach involves inhibition of
leukocyte recruitment to the inflamed skin - for example, by
inhibiting key adhesion molecules such as selectins or certain
integrins (Panel C). A prominent example is the use of efalizumab, a monoclonal antibody that interferes with adhesion
mediated by leukocyte-function-associated antigen 1 (LFA-1).
The fourth principle is functional inhibition of key inflammatory cytokines (Panel D). Perhaps the most important example
is tumor necrosis factor α (TNF-α), the functions of which are
targeted by several biologic agents, the monoclonal antibodies
infliximab and adalimumab, and the fusion proteins etanercept
and onercept. Finally, it is possible to induce an immune deviation to shift the cytokine milieu dominated by type 1 helper T
(Th1) calls to a milieu weighted with type 2 helper T (Th2)
cells, thus alleviating psoriasis. This has been demonstrated in
principle for interleukin-10 and interleukin-4 (Panel E).
DERMATOLOGY
A
have distinct modes of action. For example, fumarates
and cyclosporine are primarily immunosuppressive
agents, whereas retinoids and methotrexate also target
keratinocyte functions. Rational combination treatments
target inflammation as well as epidermal alterations, and
may provide improved efficacy and safety. Thus, combinations of topical vitamin D3 analogues with photother apy or systemic retinoids ( acitrecin) plus psoralen (a
drug extracted from plants) and ultraviolet A phototherapy ( RePUVA) are well-established treatment regimens
for psoriasis.
B
C
D
E
F
G
Fig. 5 : Complex Pathological Tissue Alterations in
Psoriatic Skin
As compared with normal skin (Panel A), the epidermis in psoriatic skin (Panel B) is characterized by dramatic histopathological alterations, including profound acanthosis (thickening
of the viable cell layers) with elongation of epidermal rete
ridges (arrowheads), marked hyperkeratosis (thickening of the
cornified layer), loss of the granular layer, and parakeratosis
(nuclei in the stratum corneum). In addition, dermal blood vessels are increased in number and size (by both angiogenesis and
dilatation); they are contorted and reach up to locations directly underneath the epidermis (arrows). Finally, a mixed leukocytic infiltrate is seen in both dermis and epidermis. As a
histopathological hallmark of psoriatic lesions, neutrophilic
granulocytes transmigrate through the epidermis (Panel C,
arrow) and form the telltale Munro microabscesses underneath
the stratum corneum (Panel C, arrowhead). As the lesions
progress, these microabscesses are transported to the upper layers of the stratum corneum, where they slough off (Panel D,
arrow). (Panels A through D show staining with hematoxylin
and eosin.) Focal expression of intercellular adhesion molecule
1 (ICAM-1) in psoriatic epidermis (Panel E) indicates the activation of keratinocytes. Immunostaining of CD3, a T-cell receptor-associated antigen, shows that abundant T lymphocytes are
present in psoriatic skin within both the dermis and the epidermis (Panel F). The integrin E(CD103) 7, an adhesion receptor
that binds to epidermal E-cadherin, is expressed almost exclusively by intraepidermal T cells (Panel G). (Panels E through G
are highlighted with an immunoperoxidase stain) It is thought
that ICAM-1, the E(CD103) 7 integrin, and other adhesion
receptors contribute to the recruitment of pathogenic lymphocytes to psoriatic skin.
Psoriasis in children, in pregnant women, or in patients
with the acquired immunodeficiency syndrome may provide considerable therapeutic challenges, arguably best
handled by consultation with a specialist. Likewise,
severe nail involvement or pustular psoriasis should be
the province of the specialist.
Although most established treatment regimens are
reasonably effective as short-term therapy for psoriasis, extended disease control is difficult to achieve
because the safety profile of most therapeutic agents
limits their long-term use. Another unmet medical
need is for agents that can be applied easily, since
application of various currently available agents is difficult and thus compliance may be problematic. More
convenient preparations improve adherence to recommended regimens.
Recent advances in psoriasis research have provided a
sound platform for the rational design of new biologic agents and biologic immune-response modifiers
that specifically target key mechanisms of the pathogenesis of psoriasis. Three of these agents - alefacept,
efalizumab, and etanercept - are currently approved by
the Food and Drug Administration (FDA) for the treatment of psoriasis; several others (e.g., infliximab) are
in the final phase of clinical development. The most
promising compounds are monoclonal antibodies,
cytokines, and fusion proteins. Three fundamental
modes of action are being explored: decreasing the
number of pathogenic T cell, blocking T-cell migration and adhesion, and antagonizing effector
cytokines.
References
1. Shenenberger DW. Curbing the psoriasis cascade:
Therapies to minimize flares and frustration.
Postgraduate Medicine 2005; 117(5): 9-16
2. Park R. Psoriasis. eMidicine.com
3. www.skincarephysicians.com/psoriasisnet
4. Schon MP. Psoriasis. New England Journal of
Medicine 2005; 352: 1899-912
9
CHILD P SYCHIATRY
Attention Deficit Hyperactivity Disorder
ttention Deficit Hyperactivity Disorder
(ADHD) is an American concept: a syndrome
encompassing severe restlessness, poor concentration and markedly impulsive, impatient,
excitable behavior. The concept has become popular
in the UK, partly because it offers an alternative explanation for antisocial behavior (other than imperfect
parenting), and partly because it shows a remarkable
response to stimulant medication. The World Health
Organization has named ADHD one of its priority
mental disorders of children and adolescents on the
basis of its prevalence, the degree of associated
impairment, and its treatability.
A
Prevalence
In the US the incidence of ADHD in school-age children
is estimated to be 3-7%. In Great Britain, incidence is
reported to be less than 1%. The differences between the
US and British reported frequencies may be cultural
("environmental expectations") and due to the heterogeneity of ADHD. In children, ADHD is 3 to 5 times
more common in boys than in girls. Some studies report
an incidence ratio of as high as 5:1. However, the pre dominantly inattentive type of ADHD is found more
commonly in girls than in boys. In adults, the sex ratio is
closer to even.
Causes
The exact etiology of ADHD is unknown, although
neurotransmitter deficits, genetics, and perinatal complications have been implicated. Concordance of
ADHD in monozygotic twins is greater than in dizygotic twins, suggesting some contribution of genetics.
Adoption studies also support the genetic cause for
ADHD. The involved genes or chromosomes are not
known. Hypotheses exist that include in-utero exposures to toxic substances, food additives or colorings,
or allergic causes. However, diet, especially sugar, is
not a cause of ADHD. How much of a role family
environment has in the pathogenesis of ADHD is
unclear, but it certainly may exacerbate symptoms.
The pathology of ADHD is not clear. Findings indi10
cating that psychostimulants (which facilitate
dopamine release) and noradrenergic tricyclics treat
this condition have led to speculation that certain brain
areas related to attention are deficient in neural transmission. The neurotransmitters dopamine and norepinephrine have been associated with ADHD. The
underlying brain regions predominantly thought to be
involved are frontal and prefrontal. In one functional
MRI study, children with ADHD who performed
response-inhibition tasks were reported to have differing activation in frontal-striatal areas compared to
healthy controls. Adults with ADHD also have been
reported to have deficits in anterior cingulate activation while performing similar tasks.
Clinical Features
The types of ADHD are (1) predominantly hyperactive (2) predominantly inattentive and (3) combined.
The DSM-IV (Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition) criteria are given in
Table 1.
The symptoms of hyperactivity may be apparent in
very young pre-schoolers and are nearly always present before the age of 7. Children suffering from
ADHD may perform poorly at school, they may be
unpopular with their peers. Their behavior can present
significant challenges for parents, leading some to be
overly harsh.
Table 1: DSM-IV criteria for Attention Deficit
Hyperactivity Disorder
w
w
w
w
w
w
w
w
w
Inattention
Hyperactivity/impulsivity
Careless with detail
Fails to sustain attention
Appears not to listen
Does not finish instructed
tasks
Poor self-organization
Avoids tasks requiring
sustained mental effort
Loses things
Easily distracted
Seems forgetful
w Fidgets
w Leaves seat when should be
seated
w Runs/climbs excessively and
inappropriately
w Noisy in play
w Persistent motor activity
unmodified by social context
w Blurts out answers before
question completed
w Fails to wait turn or queue
w Interrupts others'
conversations or games
w Talks excessively for social
context
*The minimum is six criteria from either of the above lists for 'ADHD',
or six from both lists for 'ADHD combined type'. These must be:
w Pervasive (present in more than one type of situation)
w Present from an early age (below six years)
w Severe enough to significantly impair a child's normal social or academic functioning
w Not be better explained by another condition
CHILD PSYCHIATRY
Fig. 1 : Psychiatric comorbidity
in children with ADHD
This diagram shows the enormous degree of psychiatric problems
in children who have ADHD combined type (that is, who are both
inattentive and hypereactive/impulsive). CD = conduct disorder,
ODD = oppositional defiant disorder, Tics = tic disorders,
Anxiety = anxiety disorders, Mood = mood disorders (mainly
depression). Note that children with ADHD usually have other
problems as well.
Many of the symptoms occur from time to time in normal
children. However, in children with ADHD they occur
very frequently and in several settings. After childhood,
symptoms may persist into adolescence and adulthood, or
they may ameliorate or disappear. The percentages in
each group are not well established, but at least an estimated 15-20% of children with ADHD maintain the full
diagnosis into adulthood. As many as 65% of these children will have ADHD or some residual symptoms of
ADHD as adults. The prevalence rate in adults has been
estimated at 2 to 7%.
Differential Diagnosis
Below are a number of conditions commonly associated with ADHD which should be ruled out before a
definitive diagnosis of ADHD can be made. However,
‘normality’ is the most important differential diagnosis.
w Medical conditions: impairment of hearing and/or
vision, adverse drug event, asthma, allergic rhinitis
(or reaction to antihistamine), incontinence of urine
or feces, malnutrition (vitamin or metabolic deficiency), thyroid disorder, and lead toxicity.
w Neurological and psychiatric conditions: learning
disorder, tic disorder, seizure disorder (or effect of
antiepileptic), mental retardation, developmental
delay, brain damage or injury, sleep disorders
(including sleep apnea and insomnia), oppositional
defiance and conduct disorders, substance abuse,
anxiety, depression (or bipolar disorder), obsessivecompulsive disorder, and post-traumatic stress disorder.
w Environmental conditions: improper or poor learning environment, mismatched curriculum and child
(gifted, learning disabled, language issues), dysfunctional family or stressful home, poor parenting
(inconsistent, punitive), neglect or abuse, and
parental psychopathology.
Investigations
The diagnosis of ADHD is based on clinical evaluation. No laboratory-based medical tests are available
to confirm the diagnosis. Basic laboratory
Fig. 2 : Overview of Management of ADHD
Consider diagnosis in every child with behavioral problems
Obtain school report including rating scale
Behavioral
management at home
Education of parent and child
Reduce condemnation and
criticism
Reward increased persistence
Medication
See figure 3
Managing associated
problems
Low self-esteem
Depression in parents
Behavioral management at
school
Other interventions
See table 2
Consider dietary intervention
Education
Inappropiate housing
(e.g., no garden, busy
road)
Immediate rewards
Drug abuse
Reduce emphasis on punishments
Do as many as practicable of the interventions shows. The order of importance varies with the child, but most common order is shown from left to right
11
CHILD P SYCHIATRY
Fig. 3 : Medication in ADHD
Contraindication to stimulants?
No
Yes
Consider clodine,
atomoxetine
Parents willing to medicate?
No
Yes
Assess their ideas, concerns,
expectations
Baseline BP, HR, height,
weight.
Start with low dose,
review after 1-2 weeks
Educate
Clinical response
Negligible
or negative
Reconsider
diagnosis
Ensure
assessment
is objective
Partial
Increase
dose if needed
Adequate
Review after 3
months (reducing to 6-monthly)
Too quiet
(‘zombie effect’)
Reduce dose
Assess compliance
(↑pulse from
baseline and
↓appetite)
2nd-line medication
Yearly review of progress, BP, HR, height, weight
studies that may help confirm diagnosis and aid in
treatment are as follows: i) Serum CBC count with
differential, ii) Electrolytes, iii) Liver function tests
(before beginning stimulant therapy) and iv) Thyroid
function tests. Brain imaging, such as functional MRI
or single photon emission computed tomography
(SPECT) scans have been useful for research, but no
clinical indication exists for these procedures because
the diagnosis is clinical.
Other tests : I. Psychological testing such as- a. The
Conners Parent-Teacher Rating Scale, b. Barkley
Home Situations Questionnaire, c. The Wender Utah
Rating Scale (may be helpful in diagnosing ADHD in
adults) and d. The Continuous Performance Tests
(CPTs). II. Vision and hearing tests.
12
Management
ADHD management involves a team approach that
includes the patient, the family, the teachers, and the
physician. The American Academy of Pediatrics
(AAP) practice guidelines recommend that the clinician should offer stimulant medication and/or behavior therapy as appropriate to improve target symptoms
in children with ADHD.
Pharmacotherapy
Psychostimulants: Pharmacological treatment with psychostimulants is the most widely studied treatment for
ADHD. Stimulant treatment has been used for childhood
behavioral disorders since the 1930s. These are highly
effective for 75 to 90 percent of children with ADHD. At
least four separate psychostimulant medications consistently reduce the core features of ADHD in literally hundreds of randomized controlled trials: methylphenidate,
dextroamphetamine, pemoline, and a mixture of amphetamine salts. Methylphenidate and dextroamphetamine
are first-line therapy and probably the most effective
treatment.
All stimulants have similar efficacy but differ by dosing,
duration of action, and adverse effect profiles in individual patients. Care should be made to start at the lowest
possible dose and titrate up keeping in mind the clinical
efficacy and the level of tolerance. Targeted symptoms
include impulsivity, distractibility, poor task adherence,
hyperactivity, and lack of attention. Some stimulants
come in sustained-release preparations, which may
decrease the number of total daily doses. Otherwise, dosing should be spaced every 4-6 hours. Care should be
taken not to give any dose too close to bedtime because
stimulants may cause significant insomnia. Other com mon adverse effects include appetite suppression and
weight loss, headaches, and mood effects (depression,
irritability). Stimulants may exacerbate tics in children
with underlying tic disorders. Whether growth might be
affected while a child is taking stimulants remains
unclear. Drug holidays (during summer or on weekends)
may or may not be recommended to allow periods of normal growth. The decision is based on the child's growth
rate chart and behavior and cognition off medication.
Magnesium pemoline may be used, but concerns of
rare but potentially fatal hepatotoxicity have made it a
second-line or third-line medication.
Other Medications: Recent data suggest the use of
bupropion or venlafaxine. Dosages are similar to those
for depression.
CHILD P SYCHIATRY
Table 2 : Tips for Parents
w Learn about ADHD
w Praise your child when he or she does well. Build your child's abilities. Talk about and encourage his or her strengths and talents
w Be clear, be consistent, and be positive. Set clear rules for your
child. Tell your child what he or she should do, not just what he
shouldn't do. Be clear about what will happen if your child does
not follow the rules. Have a reward program for good behavior.
Praise your child when he or she shows the behaviors you like
w Learn about strategies for managing your child's behavior. These
include valuable techniques such as: charting, having a reward
program, ignoring behaviors, natural consequences, logical consequences, and time-out. Using these strategies will lead to more
positive behaviors and cut down on problem behaviors
Tricyclic antidepressants (imipramine, desipramine,
nortriptyline) have been used in children with ADHD.
If these agents are used, obtain a baseline ECG
because these agents can affect cardiac conduction. A
few reports have described sudden death in boys taking desipramine, although the exact cause of death
was unclear and may have been unrelated to
desipramine use.
Clonidine and guanfacine have been used with mixed
reports of efficacy. Sudden deaths have been reported
in children taking clonidine with methylphenidate at
bedtime. Again, the etiology of these deaths is unclear,
and this remains as a controversial topic.
w Talk with your doctor about whether medication will help your child
w Pay attention to your child's mental health (and your own!). Be
open to counselling. It can help you deal with the challenges of
raising a child with ADHD. It can help your child deal with frustration, feel better about him or herself, and learn more about social
skills
w Talk to other parents whose children have ADHD. Parents can
share practical advice and emotional support
w Meet with the school and develop an educational plan to address
your child's needs. Both you and your child's teachers should get
a written copy of this plan
w Keep in touch with your child's teacher. Tell the teacher how your
child is doing at home. Ask how your child is doing in school. Offer
support
Table 3 : Tips for Teachers
w Learn more about ADHD
w Figure out what specific things are hard for the student. For
example, one student with ADHD may have trouble starting a
task, while another may have trouble ending one task and starting the next. Each student needs different help
w Post rules, schedules, and assignments. Clear rules and routines will help a student with ADHD. Have set times for specific
tasks. Call attention to changes in the schedule
w Show the student how to use an assignment book and a daily
schedule. Also teach study skills and learning strategies, and
reinforce these regularly
w Help the student channel his or her physical activity (e.g., let the
student do some work standing up or at the board). Provide regularly scheduled breaks
w Make sure directions are given step by step, and that the student
is following the directions. Give directions both verbally and in
writing. Many students with ADHD are also benefited from doing
the steps as separate tasks
w Let the student do work on a computer
w Work together with the student's parents to create and implement an educational plan tailored to meet the student's needs.
Regularly share information about how the student is doing at
home and at school
Atomoxetine was introduced nearly a year ago in UK
and it differs from the stimulants in three ways: it
blocks brain synaptic reuptake of noradrenaline; it is
not a controlled drug and seems to have no addictive
potential; and it promotes sleep rather than causing
onset insomnia. A single daily dose is sufficient for
most children.
Behavioral Psychotherapy
It is often effective when used in combination with an
effective medication regimen. Working with parents
and teachers to ensure environments conducive to
focus and attention is necessary. Behavioral therapy or
modification programs can help diminish uncertain
expectations and increase organization.
For adults with ADHD, working to establish ways of
decreasing distractions and improving organizational
skills may be helpful.
Diet
For decades, speculation and folklore have suggested
that foods containing preservatives or food coloring or
foods high in simple sugars may exacerbate ADHD.
Many controlled studies have examined this question.
But to date, no adequate data has confirmed the speculation
References
1. Kiki D Chang, Kiki D Chang, et al. AttentionDeficit/Hyperactivity Disorder. eMedicine June 20,
2005.
2. Williams J and Hill PP. Practitioner 2005; 249: 516-526
3.www.surgeongeneral.gov/library/mentalhealth/chapter3/sec4.html
4. www.nichcy.org/pubs/factshe/fs19txt.htm
5. http://pediatrics.uchicago.edu
6. www.merckmedicus.com
13
ONGOING VIEWS
Risk for Schizophrenia and
Schizophrenia-Like Psychosis Among
Patients with Epilepsy
he association between epilepsy and psychosis
has been researched since the nineteenth century. Several studies but not all have found a
higher prevalence of schizophrenia-like psychosis in
patients with epilepsy compared with the general population. Yet many questions remain unanswered and
large scale studies using empirical data are scant.
T
In a cohort comprising 2.27 million people it was
investigated whether age at onset of epilepsy, type of
epilepsy, family history of psychosis, or family history of epilepsy affect the risk of schizophrenia or schizophrenia-like psychosis among patients with epilepsy.
Danish longitudinal registers were used in this setting.
An increased risk of schizophrenia (relative risk 2.48,
95% confidence interval 2.20 to 2.80) and schizophrenia-like psychosis (2.93, 2.69 to 3.20) were found in
people with a history of epilepsy. The effect of epilepsy was the same in men and in women and increased
with age. Family history of psychosis and a family
history of epilepsy were significant risk factors for
schizophrenia and schizophrenia-like psychosis; and
the effect of epilepsy, both in cases and families, was
greater among people with no family history of psychosis. In addition, the increased risk for schizophrenia or schizophrenia-like psychosis did not differ by
type of epilepsy but increased with increasing number
of admissions to hospital and, particularly, was significantly greater for people first admitted for epilepsy at
later ages.
From this study it may be concluded that there is a
strong association between epilepsy and schizophrenia or schizophrenia-like psychosis. The two conditions may share common genetic or environmental
causes.
Source: BMJ June 17, 2005
Screening with Magnetic Resonance
Imaging Vs. Mammography : A
Prospective Multicentre Cohort Study
omen genetically predisposed to breast cancer often develop the disease at a young age
when dense breast tissue reduces the sensitivity of X-ray mammography. A prospective multicentre cohort study was conducted in 649 women aged
W
14
35-49 years with a strong family history of breast cancer or a high probability of a BRCA1, BRCA2, or
TP53 mutation. Participants were recruited from 22
centers in the UK, and offered the women annual
screening with contrast enhanced magnetic resonance
imaging (CE MRI) and mammography for 2-7 years.
The aim of the study was to compare CE MRI with
mammography for screening.
Thirty-five cancers cases were diagnosed in the 649
women screened with both mammography and CE
MRI (1881 screens): 19 by CE MRI only, 6 by mammography only, and 8 by both, with 2 intervals cases.
Sensitivity was significantly higher for CE MRI (77%,
95% CI 60-90) than for mammography (40%, 24-58;
p=0.01), and was 94% (81-99) when both methods
were used. Specificity was 93% (92-95) for mammography, 81% (80-83) for CE MRI (p<0.0001), and 77%
(75-79) with both methods. The difference between
CE MRI and mammography sensitivities was particularly pronounced in BRCA1 carriers (13 cancers; 92%
vs. 23%, p=0.004).
The findings indicate that CE MRI is more sensitive
than mamography for breast cancer detection.
Specificity for both procedures was acceptable.
Despite a high proportion of grade 3 cancers, tumors
were small and few women were node positive. This
study implies that annual screening, combining CE
MRI and mammography, would detect most tumors in
this risk group.
Source: Lancet 2005; 365:1769-78
Filmmaker Focuses on Female Infanticide
world without women might sound absurd,
but in parts of rural India, where female infanticide is on the increase, it might not seem
such a distant scenario. The feature film
Matrubhoomi, subtitled A Nation Without Women,
explores the hypothetical consequences of widespread
female infanticide and, unsurprisingly, finds them
devastating. Matrubhoomi is a horrifying tale of gender discrimination and violence against women in
India.
A
In one scene a man waits outside the family home
while his wife is in labor. He gets excited by the birth
of the child, but the mood changes with the announcement that it’s a girl. The newborn is brutally killed,
dipped into a large vat of milk. “Next year, a boy,” a
gruff voice commands. In the near womanless
ONGOING VIEWS
world of Matruboomi, men seek to release their sexual desire through rape, pornography, homosexuality,
and bestiality. Against this backdrop, a desperate family hunts down a pretty teenager, who is sold by her
father at a good price. She is forced to marry five
brothers, who, along with their father, repeatedly rape
her. Only the youngest brother begins to grow emotionally close to her, but then he is murdered by the
eldest brother. When the girl plans to escape with a
servant from a lower caste the pair are caught. This
triggers a caste war, and the teenager is chained up in
a cowshed and gang raped by men from both the
castes. When she becomes pregnant everyone claims
paternity.
Much more brutal than Bandit Queen, Matrubhoomi
could be seen as providing the false sense of comfort
that the film is a mere exaggeration. But it could also
be regarded as a worrying reminder of the systematic
infanticide that has plagued India for years. The
killing of girl children has increased in the past couple
of decades, thanks in part to illegal sex selection
using ultrasonography, and it is thought that some
doctors have promoted sex selective abortions.
Despite legal prohibitions, India’s girl to boy ratio
(aged 0-6 years) has declined from 945 to 1000 in
1991, to 927 to 1000 in 2001. And in the North Indian
state of Punjab, the ratio has declined from 875 to
1000 in 1991, to 793 to 1000 in 2001. While
Matrubhoomi is clearly a cinematic exaggeration, the
country’s shortage of women has led to a rise in the
abduction and kidnapping of girls, forced polyandry,
gang rape, and child prostitution in various Indian
provinces.
Source: BMJ 2005; 331: 36
Prophylactic Antibiotics Improve
Survival After Chemotherapy
rophylactic antibiotics can prevent infections
and save lives in patients who develop neutropenia after chemotherapy for cancer, say
researchers from Israel. Their meta-analysis of 95 randomized trials showed a clear survival advantages for
patients given prophylaxis (relative risk of death from
all causes 0.67; 95% confidence interval 0.55 to 0.81),
a finding that could overturn current guidelines.
Quinolone such as ciprofloxacin looked particularly
effective, reducing mortality from all causes by about
half compared with placebo (relative risk 0.52; 0.35 to
0.77). Most of the 9283 patients in these trials had
P
hematological cancers such as acute leukemia, lymphomas, or multiple myeloma, and in most trials
patients were given antibiotics with their chemotherapy.
This is not the first meta-analysis to look at this issue,
but it is the first to report a clear result for mortality in
favor of antibiotic prophylaxis, possibly because this
meta-analysis is at least four times bigger than previous attempts.
Source: BMJ 2005; 331: 14
Antibiotics for Patients with Cough
ost primary care doctors now think twice
before prescribing antibiotics to patients
with a simple cough, but the debate rumbles
on because of limited evidence from decent randomized trials. In search of a definitive answer,
researchers from the United Kingdom spent five years
recruiting and studying 800 primary care patients with
cough but no signs of pneumonia. Patients were given
immediate antibiotics, no antibiotics, or a prescription
they could pick up from the practice receptionist if
they weren’t better within two weeks.
M
Immediate antibiotics (10 days of amoxicillin or
erythromycin) did not reduce the duration or severity
of patients’ coughs, although other symptoms such as
wheeze and disturbed sleep got better about one day
earlier than with no antibiotics. Since patients in this
trial coughed for a mean of nine days before going to
their doctor and for a mean of nearly 12 days afterwards, one day less of other symptoms is arguably a
poor trade off against the well known risks of antibiotic resistance caused by liberal prescribing. Results
for vulnerable subgroups such as elderly people and
those with green sputum were no more convincing. If
anything, older people did worse after immediate
treatment with antibiotics.
Source: JAMA 2005; 293: 3029-35
Poorer Countries will Not Meet Health
Targets, Warns WHO
any of the world’s poorer countries will not
meet the health millennium development goals
without concerted effort. This was the warning
of the report, Health and the Millennium Development
Goals, published by the World Health Organization, just
ahead of the G8 summit (a meeting of the leaders of the
world’s most industrialized nations). The goals,
M
15
ONGOING VIEWS
a 3% reduction, for example. The report predicted that
if current trends continued, death rates among children
younger than 5 would fall by only 25% by 2015 far
short of the goal.
But the proportion of women with a skilled medical
person in attendance during labor had increased rapidly in some regions, particularly in Asia. Overall, this
figure had risen from 42% in 1990 to 53% in 2000.
But in sub-Saharan Africa, the figure had remained
static at about 40% over the decade.
Use of effective tuberculosis treatment and case finding had expanded, but too slowly to meet the target of
70% case detection.
agreed in the 1990s by 189 countries, include reducing
child mortality, improving maternal health and combating infectious diseases.
No region of the developing world was currently on
track to meet the child mortality target of cutting death
rates in children younger than 5 years by two thirds by
2015. The data showed that countries with high child
mortality had not improved and death rates had even
worsened in some. Sub-Saharan Africa achieved only
The establishment of fully functioning and equitable
health systems is a prerequisite for reaching the health
goals, the report found, but “in too many countries, the
health systems either do not exist or are on the point
of collapse,” it says. Andrew Cassels, Director of
health and development policy at WHO, said, “The
real priority is to encourage countries to develop better health systems, with the right skill mix, staff numbers and in service training-particularly in... southern
Arfica.” Countries needed to put political muscle
behind health improvement measures, he added.
Source: World Health Organization
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16
ENDOCRINOLOGY
World Diabetes Day : Footing The Bill
World Diabetes Day, organized by the International Diabetes Federation (IDF)
and supported by the World Health Organization (WHO), is the primary global
awareness campaign of the diabetes world. It was first introduced in 1991 in
response to concern over the escalating incidence of diabetes around the world.
Since then, it has grown in popularity and now unites more than 350 million people worldwide including opinion leaders, health-care professionals, people with
diabetes, and the general public.
The aim of World Diabetes Day 2005 on November 14 is not only to draw attention to the impact of the disease on health and the economy, but also to emphasize how this burden can be reduced. The spotlight of World Diabetes Day in
2005 falls on the foot. Disease of the foot ranks among the most feared complications of diabetes, and yet is one of the most neglected. Probably more than a
million people lose a leg because of diabetes each year, which means that one
major amputation is done somewhere in the world about every 30 seconds. The
patient often becomes permanently dependent on the support of others and
both the patient and their family may be deprived of their livelihood. Amputation
is also associated with a high mortality, even in developed countries. Because
there is good evidence that the incidence of major amputation can be reduced by
the provision of accessible expert integrated care, the problem of the diabetic
foot is one which should receive far greater attention - from the public, from professionals, and from health-care planners.
The Natural History of Type
2 Diabetes: New Perspectives,
New Drugs
ype 2 diabetes, previously referred to as adultonset or non-insulin-dependent diabetes, progresses from an early asymptomatic stage with
insulin resistance to mild postprandial hyperglycemia
to frank diabetes requiring pharmacological intervention. Understanding this natural history of type 2 diabetes will guide primary care providers in formulating
effective treatment regimens that reflect the pathological differences between these stages of the disease.
The optimal medication regimen, when used in conjunction with dietary changes and exercise, will
require modifications for each patient as the disease
progresses.
T
Pathogenesis
Type 2 diabetes is a heterogeneous disorder. Three
basic metabolic defects characterize the disease:
insulin resistance, an insulin secretory defect that is
not autoimmune-mediated, and an increase in glucose
Blood Glucose Monitor for Diabetic Patients
production by the liver.
The cause of these metabolic defects, and therefore
the cause of type 2 diabetes, is largely unknown.
Clearly, type 2 diabetes has a strong genetic component and is found more frequently in certain families
and ethnic minority groups. Many acquired factors
also play a role in the pathogenesis of the disease like
obesity, aging, and a sedentary lifestyle. Other
acquired factors that may contribute to the insulin
secretory defect include chronic glucotoxicity and elevated free fatty acid levels.
17
ENDOCRINOLOGY
2 diabetes precede the development of hyperglycemia
by years or even decades. Insulin resistance, that is,
resistance to insulin's role in promoting glucose
uptake by skeletal muscle and fat cells, is the initial
metabolic defect. At first, the pancreatic β cell is able
to compensate by increasing insulin levels, leading to
hyperinsulinemia. This compensation is able to keep
glucose levels normalized for a period of time (up to
several years), but IGT develops with mild postprandial hyperglycemia.
Three test strips for blood glucose measuring
Some controversy still exists as to whether insulin
resistance or inadequate insulin secretion occurs first
in the pathogenesis of diabetes. However, a general
consensus has emerged that insulin resistance is the
primary defect in type 2 diabetes. Insulin resistance is
characterized by a subnormal response to a given concentration of insulin and can be measured indirectly
by a fasting insulin level: higher levels of insulin correspond to higher degrees of insulin resistance.
The cause of pancreatic β cell dysfunction, the second
metabolic defect that appears in type 2 diabetes, is still
a focus of intense research and debate. Changes in the
β cell do occur early in the pathogenesis of type 2 diabetes. However, it is later defects in glucose-stimulated insulin release that clearly play a role in the progression to diabetes and then continue to affect the
course of diabetes itself. For example, the decline in
insulin levels, and thus a decrease in insulin's inhibitory effects, allows for increased hepatic glucose production. β Cell exhaustion may be genetically mediated or result from hypothesized damage to the β cell
from chronic exposure to hyperglycemia, or it may
result from adverse effects of increased free fatty
acids. Whatever the underlying causes and mechanisms, it is clear that the full phenotypic expression of
type 2 diabetes requires both insulin resistance and β
cell dysfunction.
Progression of Impaired Glucose Tolerance to Mild
Type 2 Diabetes
The term impaired glucose tolerance (IGT) or pre-diabetes was first coined in 1979 by the World Health
Organization and the National Diabetes Data Group to
replace the terms borderline, chemical, and asymptomatic diabetes mellitus.
The metabolic sequences that eventually lead to type
18
As insulin resistance worsens, more global defects in
insulin secretion occur that result in increased hepatic
glucose production. Together these defects lead to further elevations in fasting blood glucose. The American
Diabetes Association has encouraged the use of the
term impaired fasting glucose (IFG) to denote this
stage. IFG is defined as having a fasting plasma glucose level >110 mg/dl but <126 mg/dl. Both IGT and
IFG serve as markers for those who are at greatest risk
for developing type 2 diabetes. Depending on the
duration of follow-up and the ethnic group studied,
prospective clinical trials have shown that approximately one-third of individuals with IGT will progress
to type 2 diabetes.
The progression from IGT to early type 2 diabetes is
marked by a decrease in β cell function and thus a
decline in insulin secretion. It is the failure over time of
the β cell to compensate for insulin resistance with
hyperinsulinemia that marks the beginning of type 2
diabetes. As long as the pancreatic β cell is able to
compensate for insulin resistance by increasing insulin
production and secretion, glucose levels remain normal
or near normal. However, eventually the β cell begins
to fail, and insulin secretion falls, resulting in hyperglycemia. Eventual failure of the pancreatic β cell has
been a predictable abnormality leading to changes in a
patient's response to various therapies.
Two additional pathophysiological changes become
manifest during the transition from IGT to type 2 diabetes. Insulin resistance becomes more severe, a progression that may not be due to only full expression of
genetic defects, but also to acquired factors such as
obesity, decreased physical activity, and aging. The
second change is an increase in basal hepatic glucose
production. Although early type 2 diabetes may be as
asymptomatic as IGT, the degree of hyperglycemia is
now severe enough to start the clock for the development of microvascular complications.
E NDOCRINOLOGY
Progression of Mild Type 2 Diabetes to InsulinRequiring Type 2 Diabetes
Insulin resistance is the primary pathogenic insult
underlying type 2 diabetes and remains a factor
throughout the natural history of the disease. Yet, it is
changes in β cell function that determine both the
onset of frank diabetes and the progression of the disease.
Over time, however, the β cell becomes refractory to
glucose, and although it continues to secrete supraphysiological amounts of insulin, a relative insulin
deficiency develops, and hyperglycemia worsens to
the point of frank diabetes. Later, the β cell's secretory capacity further declines. An absolute insulin deficiency develops, and eventually the β cell becomes
unresponsive to interventions aimed at improving β
cell function (such as insulin secretagogues including
sulfonylureas). By this point in the disease process,
patients with type 2 diabetes will most likely require
exogenous insulin or multiple oral agents used in combination to achieve adequate glucose control. These
stages in the natural history of type 2 diabetes are
important to consider in choosing and modifying a
treatment regimen. Different classes of antidiabetic
agents appear to be effective at different stages.
Role of Obesity in the Pathogenesis and
Treatment of Type 2 Diabetes
Obesity has a profound impact on the progression of
the diabetic state and on patients' responses to any
particular form of treatment. Central obesity often
precedes the development of many metabolic disorders characterized by insulin resistance including
type 2 diabetes, hypertension, and cardiovascular
disease. Central obesity is defined as an increase in
primarily abdominal visceral fat. Lean type 2 diabetic patients characteristically have less severe insulin
resistance and a more profound insulin secretory
defect. These individuals typically respond better to
exogenous insulin and medications that stimulate
insulin secretion (insulin secretagogues). In contrast,
centrally obese diabetic patients have a more profound degree of insulin resistance and compensatory
hyperinsulinemia and tend to achieve better control
with agents that improve insulin sensitivity such as
biguanides and thiazolidinediones.
Diabetic glomerulosclerosis, a complication of diabetes mellitus.
The image shows the thickening of the mesangia and capillary
loops caused by increased quantities of basement membrane.
Few clinicians would doubt that type 2 diabetic patients
have a three-fold increased risk of coronary artery dis ease, but too few clinicians realize that IGT is associated
with at least a two-fold increased risk. IGT and insulin
resistance are associated with low levels of HDL cholesterol, increases in triglycerides, and hypertension. These
metabolic problems, in combination with changes in factors involved in the coagulation cascade, may result in
accelerated atherosclerosis and early macrovascular
complications.
Prospective studies have shown that cardiovascular risk
factors are associated with a subsequent diagnosis of
IGT, suggesting that there is overlap between the pathogenic mechanisms for macrovascular disease and IGT.
So early intervention in patients with IGT has the potential not only to delay progression to type 2 diabetes, but
also to treat early macrovascular disease.
Management of Type 2 Diabetes
Diet and Exercise
Sedentary lifestyle and poor physical fitness are both
risk factors for the progression of IGT to type 2 diabetes. Although these factors are interrelated, they are
both reversible and are potential targets for preventive
intervention. The same comments also apply to obesity, a risk factor that has been identified unequivocally
in all clinical trials addressing the issue.
Several clinical trials have demonstrated the utility of
diet or exercise, with or without specific weight loss
goals, in the prevention of type 2 diabetes in high-risk
individuals. Studies have also demonstrated that even
modest amounts of weight loss have beneficial effects
on glucose control.
Macrovascular Disease and IGT
19
ENDOCRINOLOGY
Figure 1: Multiple metabolic defects coexist in type 2 diabetes (A), including insulin resistance in skeletal muscle, adipose tissue,
and liver, as well as impaired insulin secretion. Involvement of many tissues presents a variety of targets for therapeutic intervention. Sulfonylureas and meglitinides (B) stimulate pancreatic b cells to secret more insulin. Biguanides-i.e., metformin (C) chiefly suppress hepatic glucose production. Thiazolidinediones (D) promote peripheral glucose utilization. (Both biguanides and
thiazolidinediones improve insulin action without increasing insulin secretion.) The putative molecular target of thiazolidinediones
occurs at highest levels in adipose tissue, making it unclear whether the effect of the drugs on muscle and other tissues is direct or
indirect. Thiazolidinediones are known to promote differentiation of smaller, more insulin-sensitive adipocytes, perhaps accompanied by "suicide" of the preexisting adipocytes.
20
ENDOCRINOLOGY
with a decrease in fasting plasma glucose concentration of about 60 to 70 mg/dl (3.3 to 3.9 mmol/l) and a
drop in HbA1c levels of about 1.5% to 2% compared
with placebo when maximal doses are used.
Unfortunately, as evidenced by the UKPDS, most
patients treated with sulfonylurea monotherapy show
a progressive decline in blood glucose control. It has
been postulated that this failure is due to sulfonylureainduced "exhaustion" of β cells; however, a similar
decline in glucose control was seen in the subgroup of
patients taking metformin hydrochloride, which does
not stimulate pancreatic insulin secretion.
Cross section of a coronary artery from a 53 year old male diabetic. Arteriosclerosis, the hardening and thickening of artery walls,
is a late complication of diabetes mellitus.
Pharmacotherapy
Today, physicians can choose from among a variety of
medications targeting numerous facets of the disease
(Figure 1); the drugs augment pancreatic insulin
secretion, improve peripheral glucose disposal,
decrease glucose release from the liver, or limit
absorption of carbohydrate and fat from the gut. The
prevalence of pancreatic β cell exhaustion or failure
often necessiates the need for introduction of insulin.
However, this article has given emphasis on the orally
available antidiabetic agents. Currently, there are five
general classes of oral agents available and several
more on the horizon.
Sulfonylureas
In the early 1950s, sulfonylureas debuted as the first
class of oral antidiabetic agents. Sulfonylureas pro mote increased pancreatic insulin secretion through
interaction with the sulfonylurea receptor on islet
cells. They target pancreatic secretory dysfunction
and raise serum insulin levels high enough to overcome insulin resistance in peripheral tissues.
Increased insulin levels flow directly into the portal
vein, decreasing hepatic glucose production.
It is clear that sulfonylureas can lead to hypoglycemia
and weight gain, but suggestions that their use encourages the atherogenic process have not been proved.
The more recent United Kingdom Prospective
Diabetes Study (UKPDS) showed no evidence of an
increased cardiovascular mortality rate in patients
receiving sulfonylurea monotherapy. Indeed,
microvascular (but not macrovascular) complications
were decreased with tighter glycemic control.
All drugs of this class appear to be equally efficacious,
Meglitinides
The recently introduced class of meglitinides consists
of nateglinide, which binds to the same site of sulphonylurea receptor 1 as do the sulphonylurea derivatives,
and repaglinide, which binds to a nearby site of the
receptor, both leading to insulin release. These agents
cannot further stimulate insulin release in patients on
maximal doses of sulphonylurea derivatives. Both
agents have a shorter action than sulphonylurea derivatives, are therefore associated with lower risk of
hypoglycemia, and can also be used in patients with
decreased renal function.
Biguanides
Little is known about the exact molecular mechanism
of these agents. As an insulin sensitizer, metformin
acts predominantly on the liver, where it suppresses
glucose release. The drug is the successor to phenformin, which was withdrawn from the market when a
potential for fatal lactic acidosis was identified (the
risk of lactic acidosis with metformin is only 0.03 per
1,000 patient-years of use).
Major clinical limitation of metformin is that it is
cleared through the kidneys. Accordingly, metformin
should not be prescribed if a patient has an elevated
serum creatinine concentration or low creatinine
clearance. Caution should be exercised if significant
heart failure or other cardiovascular disease raises the
possibility of acute renal insufficiency. On the same
basis, the drug should be withheld in the settings of
possible renal insult. Some patients taking metformin
initially experience gastrointestinal discomfort. In
most instances, the problem can be forestalled by
titrating up from a low initial dose. A small number of
patients experience severe nausea, abdominal cramps,
or diarrhea, limiting the use of the agent.
21
ENDOCRINOLOGY
Table: Oral Agents Used in the Treatment of Type 2 Diabetes
Class
Oral Agent
Target
Organ
Blood Glucose
Reduction;
Percentage A1C
Reduction
Adverse
Reactions
Precautions
Sulfonylurea
Glyburide; Glipizide;
Glimepiride;
Chlorpropamide;
Tobutamide
Pancreas
↓ FBG 50-60 mg/dl;
↓ A1C 1.5-2
Hypoglycemia;
weight gain;
hyperinsulinemia
Use with caution in elderly
patients, renal or hepatic impairment
Biguanide
Metformin
Liver
↓ FBG 50-60 mg/dl;
↓ A1C 1.5-2
Diarrhea; metallic
taste
Contraindicated if SrCr > 1.5
mg/dl in men; > 1.4 mg/dl in
women; or if CrCl < 60-75
ml/min; use with caution in
patients with CHF, renal or
hepatic disease
Thiazolidinedione
Rosiglitazone;
Pioglitazone
Peripheral
tissue
↓ FBG 30-60 g/dl;
↓ A1C 0.8-1.5
Weight gain;
edema
Contraindicated if ALT > 2.5
upper limit of normal; use with
caution in patients with CHF
or hepatic disease
Nonsulfonylurea
secretagogue
Repaglinide;
Nataglinide
Pancreas
↓ PPG 40-50 mg/dl;
↓ A1C 0.4-1.7
Hypoglycemia;
weight gain;
hyperinsulinemia
Use with caution in renal or
hepatic Impairment
Alpha-glucosidase
inhibitor
Acarbose; Miglitol
Intestine
↓ PPG 50 mg/dl;
↓ A1C 1.5-2
Flatulence; diarrhea
Avoid if SrCr > 2.0 mg/dl;
avoid in patients with GI
disorders
Note: FBG= fasting blood glucose; SrCr = serum creatinine; CrCl = creatinine clearance; CHF= congestive heart failure; ALT= alanine
transaminase; PPG= postprandial glucose; GI = gastrointestinal
If precautions are taken in selecting its recipients, metformin has some advantages over sulfonylureas. In
improving the action of insulin, metformin addresses
the insulin resistance of type 2 diabetes more directly
than an insulin secretagogue does. As it does not
heighten insulin secretion, metformin confers nearly
no risk of hypoglycemia. Additionally, metformin is
associated with less weight gain than that seen for sulfonylureas and insulin, and may even promote a small
weight loss.
Thiazolidinediones
Current treatment strategies support the use of thiazolidinediones (TZDs) as first-line agents for type 2 diabetes, to reduce blood glucose levels, increase insulin
sensitivity, improve lipid abnormalities associated
with dyslipidemia, and reduce the decline in β cell
function. These agents have been used since 1997
with the introduction of troglitazone, which was withdrawn from the US market in 2000 after it was found
to cause idiosyncratic hepatocellular injury in some
patients. The currently available thiazolidinediones,
22
rosiglitazone maleate and pioglitazone hydrochloride,
are not known to contribute to idiosyncratic hepatocellular injury.
Thiazolidinediones exert their action by binding with
peroxisome proliferator-activated receptor-gamma
(PPAR-γ), a second messenger molecule within the
nucleus of the peripheral tissue cells. PPAR-γ stimulation
then signals transcription for glucose transport 4 (GLUT4) molecule production. The more GLUT-4 transporters
available, the more glucose molecules are allowed to
enter into the cell from the bloodstream, resulting in
improved glucose uptake and improved insulin sensitivity. PPAR-γ receptors are most plentiful in muscle, adi pose tissue and vascular tissue; of which muscle is the
principal site for insulin resistance.
Another benefit of TZDs is the positive effect on
lipoproteins associated with dyslipidemia. Although
patients with diabetes may have similar LDL levels
as those without diabetes, it is the size and density of
the LDL particle that differ. Due to the elevated
ENDOCRINOLOGY
triglyceride levels, often patients with diabetes present
with a larger quantity of small, dense LDLs that are
more atherosclerotic. TZDs convert these small, dense
LDLs to larger, more buoyant particles, thereby stabilizing them and reducing their atherogenicity. TZDs
increase HDL levels.
TZDs have also been shown to improve and preserve
β cell function. The β cell function is believed to be
lost due to prolonged exposure to elevated concentrations of free fatty acids. Because TZDs display
improvement on the lipoprotein components, there is
a reduction in circulating free fatty acids, decreasing
stress to the β cell. As TZDs' target organ is peripheral tissue opposed to the pancreas, there is no risk of
hypoglycemia when used as monotherapy. TZDs
reduce fasting and postprandial glucose levels, as well
as HbA1C levels.
Alpha-glucosidase inhibitors
First approved in 1996, the α glucosidase inhibitors
retard the rate of absorption of carbohydrates through
the intestine. The use of acarbose and miglitol, the
only available agents, is limited by both their relatively mild efficacy and the high frequency of gastrointestinal distress associated with their use. Alpha glucosidase inhibitors act as competitive inhibitors of the
enzyme in the brush border of enterocytes that cleave
oligosaccharides to monosaccharides. These drugs
may be suitable for patients with mild diabetes or
those taking other oral agents who continue to have
large postprandial blood glucose excursions. They
must be taken with each meal to reduce the rise of
postprandial plasma glucose levels. Alpha glucosidase
inhibitors do not cause hypoglycemia when used as
monotherapy, and their use does not lead to weight
gain.
nosed with type 2 diabetes were older than the age of
40 and commonly had a positive family history.
Today, however, older age is not a major risk factor. A
76% increase in type 2 diabetes has been observed in
the 30- to 39- year-old age group over the past 10
years, and more and more children are being diagnosed with this disease that is accompanied by multiple microvascular and macrovascular complications.
The reasons behind this increase is unclear, and both
genetic and environmental explanations, including
environmental influences on genetic predispositions,
are being sought.
Over the past few years, the choice of a first-line
agent for type 2 diabetes has been shifting from
insulin secretagogues to insulin sensitizers, with their
more direct mechanisms, their ability to lower insulin
as well as glucose levels, their smaller risk of triggering hypoglycemia, and the potential for cardiovascular benefit. So far, the shift has been primarily
to metformin as a first-line agent. As experience with
thiazolidinediones mounts, and especially if large trials identify benefits beyond glycemic control, these
newest antidiabetic drugs are likely to gain favor.
However, the treatment strategies that minimize the
number of medications and at the same time target
the multiple dysfunctions associated with diabetes
are obviously preferred.
References
1.
Barbara A. The Natural History of Type 2
Diabetes: Practical Points to Consider in
Developing Prevention and Treatment Strategies.
Clinical Diabetes Vol. 18 No. 2; Spring 2000
2.
Allison B. Type 2 Diabetes: New Drugs, New
Perspectives. Hospital Practice
Most studies have shown that α glucosidase inhibitors
decrease postprandial plasma glucose levels by 40 to
60 mg/dl (2.2 to 3.3 mmol/l), fasting plasma glucose
levels by 20 to 30 mg/dl (1.1 to 1.7 mmol/l), and
HbA1c levels by 0.5% to 1.0% when compared with
placebo. Many patients experience abdominal bloating, cramping, and flatulence during initial therapy.
These adverse effects typically subside with continued
use and can be minimized with gradual increases in
dosage.
3.
Cornell S. Newer Treatment Strategies for the
Management of Type 2 Diabetes Mellitus.
Journal of Pharmacy Practice 2004; 17(1): 49-54
4.
Mayerson AB, Inzucchi SE. Type 2 diabetes therapy: a pathophysiologically based approach.
Postgraduate Medicine 2002; 111(3): 83-95
5.
Jeffcoate W. World Diabetes Day: footing the bill.
Lancet 2005; 365:1527
6.
World Diabetes Day 2005. California Diabetes
Program
Today's Clinical Climate
7.
Stumvoll M. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 2005; 365:1333-1346
Type 2 diabetes mellitus is growing at an alarming
epidemic rate. Historically, people who were diag-
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