Abu Zubair meriwayatkan dari Jabir bin Abdullah bahwa Nabi Muhammad SAW bersabda:

"Setiap penyakit ada obatnya. Jika obat yang tepat diberikan dengan izin Allah, penyakit itu akan sembuh".

(HR. Muslim, Ahmad dan Hakim).

Kamis, 21 Januari 2010

Vitamin A Deficiency


The word vitamin was originally derived from Funk's term "vital amine." In 1912, he was referring to Christian Eijkman's discovery of an amine extracted from rice polishings that could prevent beriberi. Funk's recognition of the antiberiberi factor as vital for life was indeed accurate. Researchers have since found that vitamins are essential organic compounds that the human body cannot synthesize. Vitamins A, D, K, and E are classified as fat-soluble vitamins, whereas others are classified as water-soluble vitamins.1,2

Vitamin A was the first fat-soluble vitamin to be discovered. Early observations by ancient Egyptians recognized that night blindness could be treated with consumption of liver. Two independent research teams, Osborne and Mendel at Yale University and McCollum and Davis at the University of Wisconsin, simultaneously discovered vitamin A in 1913. Vitamin A is made up of a family of compounds called the retinoids. The retinoid designation resulted from finding that vitamin A had the biologic activity of retinol, which was originally isolated from the retina.

There are essentially 3 forms of vitamin A: retinols, beta carotenes, and carotenoids. Retinol, also known as preformed vitamin A, is the most active form and is mostly found in animal sources of food. Beta carotene, also known as provitamin A, is the plant source of retinol from which mammals make two-thirds of their vitamin A. Carotenoids, the largest group of the 3, contain multiple conjugated double bonds and exist in a free alcohol or in a fatty acyl-ester form.

In the human body, retinol is the predominant form, and 11-cis -retinol is the active form. Retinol-binding protein (RBP) binds vitamin A and regulates its absorption and metabolism. Vitamin A is essential for vision (especially dark adaptation), immune response, bone growth, reproduction, the maintenance of the surface linings of the eyes, epithelial cell growth and repair, and the epithelial integrity of the respiratory, urinary, and intestinal tracts. Vitamin A is also important for embryonic development and the regulation of adult genes. It functions as an activator of gene expression by retinoid alpha-receptor transcription factor and ligand-dependent transcription factor.

Deficiency of vitamin A is found among malnourished, elderly, and chronically sick populations in the United States, but it is more prevalent in developing countries. Abnormal visual adaptation to darkness, dry skin, dry hair, broken fingernails, and decreased resistance to infections are among the first signs of vitamin A deficiency (VAD).3

Once ingested, provitamins A are released from proteins in the stomach. These retinyl esters are then hydrolyzed to retinol in the small intestine, because retinol is more efficiently absorbed. Carotenoids are cleaved in the intestinal mucosa into molecules of retinaldehyde, which is subsequently reduced to retinol and then esterified to retinyl esters. The retinyl esters of retinoid and carotenoid origin are transported via micelles in the lymphatic drainage of the intestine to the blood and then to the liver as components of chylomicrons. In the body, 50-80% of vitamin A is stored in the liver, where it is bound to the cellular RBP. The remaining vitamin A is deposited into adipose tissue, the lungs, and the kidneys as retinyl esters, most commonly as retinyl palmitate.

Vitamin A can be mobilized from the liver to peripheral tissue by a process of deesterification of the retinyl esters. In blood, vitamin A is bound to RBP, which transports it as a complex with transthyretin. The hepatic synthesis of RBP is dependent on the presence of zinc and amino acids to maintain its narrow serum range of 40-50 mcg/dL. Through a receptor-mediated process, the retinol is taken up by the peripheral tissues from the RBP-transthyretin complex.

VAD may be secondary to decreased ingestion, defective absorption and altered metabolism, or increased requirements. An adult liver can store up to a year's reserve of vitamin A, whereas a child's liver may have enough stores to last only several weeks. Serum retinol concentration reflects an individual's vitamin A status. Because serum retinol is homeostatically controlled, its levels do not drop until the body's stores are significantly limited. The serum concentration of retinol is affected by several factors, including RBP synthesis in the liver, infection, nutritional status, and the existing level of other nutrients, such as zinc and iron.4

In zinc deficiency, impaired synthesis of proteins occurs with rapid turnover (eg, RBP). In turn, this impairment affects retinol transport by RBP from the liver to the circulation and to other tissues. The mechanism by which iron affects vitamin A metabolism has not been identified, but randomized, double-blind studies have shown that vitamin A supplementation alone is not sufficient to improve VAD in the presence of coexisting iron deficiency.

The bioavailability of the carotenoids varies; this availability depends on absorption and on their yield of retinol. Only 40-60% of ingested beta carotene from plant sources is absorbed by the human body, whereas 80-90% of retinyl esters from animal proteins are absorbed. Carotenoid absorption is affected by dietary factors, including zinc deficiency, abetalipoproteinemia, and protein deficiency.

Because vitamin A is a fat-soluble vitamin, any GI diseases affecting the absorption of fats also affect vitamin A absorption. Patients with cystic fibrosis, sprue, pancreatic insufficiency, inflammatory bowel disorder (IBD), or cholestasis, as well as persons who have undergone small-bowel bypass surgery, are at increased risk for VAD. These patients should be advised to consume vitamin A.

One factor affecting the metabolism of vitamin A is alcoholism. Alcohol dehydrogenase catalyzes the conversion of retinol to retinaldehyde, which is then oxidized to retinoic acid. The affinity of alcohol dehydrogenase to ethanol impedes the conversion of retinol to retinoic acid.

Increased requirements of vitamin A most commonly occur among sick children. The American Academy of Pediatrics has recommended vitamin A supplementation for infants aged 6-24 months who are hospitalized with measles and for all hospitalized children older than 6 months. In the 1960s, the World Health Organization (WHO) undertook the first global survey of VAD with associated xerophthalmia and complicated measles.5 In 1973, an international vitamin A board was set up to alleviate global malnutrition.

The WHO and the United Nations International Children's Emergency Fund (UNICEF) have issued joint statements recommending that vitamin A be administered to all children, especially those younger than 2 years, who are diagnosed with measles. Coexistent VAD in young children increases the risk of death. The Cochrane Database Systemic Review concluded that daily treatment with 200,000 IU of vitamin A for at least 2 days reduces mortality rates.6,7

Pregnant women do not require increased vitamin A supplementation. In fact, the Teratology Society advocates that women be informed of the possible risk of cranial neural crest defects and other malformations resulting from excessive use of vitamin A shortly before or during pregnancy.8 The recommended daily allowance (RDA) of 800 mcg for all adult females is also appropriate for pregnant women, because their stores of vitamin A meet the fetal accretion rate. The requirements for lactating women have been debated, but the current RDA is 1300 mcg in the first 6 months and 1200 mcg in the second 6 months.

The RDAs of vitamin A for various age groups are as follows:

* Infants aged 1 year or younger - 375 mcg
* Children aged 1-3 years - 400 mcg
* Children aged 4-6 years - 500 mcg
* Children aged 7-10 years - 700 mcg
* All males older than 10 years - 1000 mcg
* All females older than 10 years - 800 mcg

United States

Statistics from the US Centers for Disease Control and Prevention, based on a 1988-1991 survey, showed that age-specific intakes of carotenes were higher among males than females during that period and were higher among adults than children.9 Significant differences in intake existed among different ethnic groups.

Clinical and subclinical VAD are problems in at least 75 countries.10 In 1994, the WHO classified countries as having clinical or subclinical, severe, moderate, or mild VAD. Clinical VAD (in which children demonstrate ophthalmic signs and symptoms, including blindness) occurs mainly in countries in Southeast Asia and sub-Saharan Africa.5 Severe VAD is also found in persons in refugee settlements and in displaced populations.

* United States - VAD is uncommon in the general population, but subgroups of patients suffering from fat malabsorption, cholestasis, or IBD or who have undergone small-bowel bypass may have subclinical deficiency with dark-adaptation abnormalities in the range of 60%. Vegans, persons with alcoholism, toddlers and preschool children living below the poverty line, and recent immigrants or refugees from developing countries all have increased risk of VAD secondary to decreased ingestion.
* Developing countries - An estimated 250 million children are at risk for vitamin deficiency syndromes. The most widely affected group includes up to 10 million malnourished children, who develop xerophthalmia and have an increased risk of complications and death from measles. Each year, 250,000-500,000 children become blind because of VAD. Improving the vitamin A status of children with deficiencies (aged 6-59 mo) can reduce measles and diarrhea mortality rates by 50% and 33%, respectively, and can decrease risk rates from all causes of mortality by 23%.


Subclinical forms of VAD may not cause any symptoms, but the risk of developing respiratory and diarrheal infections is increased, the growth rate is decreased, and bone development is slowed. Patients may have a recent history of increased infections, infertility secondary to impaired spermatogenesis, or recent spontaneous abortion secondary to impaired embryonic development. The patient may also report increased fatigue, as a manifestation of VAD anemia.

Signs and symptoms of vitamin A deficiency include the following:

* Bitot spots - Areas of abnormal squamous cell proliferation and keratinization of the conjunctiva can be seen in young children with VAD.
* Blindness due to retinal injury - Vitamin A has a major role in phototransduction. The cone cells are responsible for the absorption of light and for color vision in bright light. The rod cells detect motion and are responsible for night vision. In the rod cells of the retina, all-trans-retinol is converted into 11-cis -retinol, which then combines with a membrane-bound protein called opsin to yield rhodopsin.11 A similar type of reaction occurs in the cone cells of the retina to produce iodopsin. The visual pigments absorb light at different wavelengths, according to the type of cone cell they occupy. VAD leads to a lack of visual pigments; this reduces the absorption of various wavelengths of light, resulting in blindness.
* Poor adaptation to darkness (nyctalopia)
* Dry skin
* Dry hair
* Pruritus
* Broken fingernails
* Keratomalacia
* Xerophthalmia
* Corneal perforation
* Follicular hyperkeratosis (phrynoderma) secondary to blockage of hair follicles with plugs of keratin.
* Other signs of VAD include excessive deposition of periosteal bone secondary to reduced osteoclastic activity, anemia, keratinization of mucous membranes, and impairment of the humoral and cell-mediated immune system.


The risk of VAD is increased in patients suffering from fat malabsorption, cystic fibrosis, sprue, pancreatic insufficiency, IBD, or cholestasis, as well as in persons who have undergone small-bowel bypass surgery. The risk is also increased in vegans, refugees, recent immigrants, persons with alcoholism, and toddlers and preschool children living below the poverty line. These patients should be advised to consume vitamin A.


Head Trauma


Traumatic brain injury (TBI) continues to be an enormous public health problem, even with modern medicine in the 21st century. Most patients with TBI (75-80%) have mild head injuries; the remaining injuries are divided equally between moderate and severe categories.

The cost to society of TBI is staggering, from both an economic and an emotional standpoint. Almost 100% of persons with severe head injury and as many as two thirds of those with moderate head injury will be permanently disabled in some fashion and will not return to their premorbid level of function. In the United States, the direct cost of care for patients with TBI, excluding inpatient care, is estimated at more than $25 billion annually. The impact is even greater when one considers that most severe head injuries occur in adolescents and young adults.

For excellent patient education resources, visit eMedicine's Back, Ribs, Neck, and Head Center, Back, Neck, and Head Injury Center, and Eye and Vision Center. Also, see eMedicine's patient education articles Concussion, Bicycle and Motorcycle Helmets, and Black Eye.

The annual incidence of TBI in the United States has been estimated to be 180-220 cases per 100,000 population. In the United States, with a population of almost 300 million, approximately 600,000 new TBIs occur per year. As many as 10% of these injuries are fatal, resulting in almost 550,000 persons hospitalized annually in the United States with head injuries.

While various mechanisms may cause TBI, the most common causes include motor vehicle accidents (eg, collisions between vehicles, pedestrians struck by motor vehicles, bicycle accidents), falls, assaults, sports-related injuries, and penetrating trauma.

Motor vehicle accidents account for almost half of the TBIs in the United States, and in suburban/rural settings, they account for most TBIs. In cities with populations greater than 100,000, assaults, falls, and penetrating trauma are more common etiologies of head injury.

The male-to-female ratio for TBI is nearly 2:1, and TBI is much more common in persons younger than 35 years.

Motorcycle-related head injury

Motorcycle-related head injuries deserve special mention. Motorcycle rights organizations dedicated to promoting safety and to preserving individual freedom suggest that safety should be a choice rather than a requirement; safety is a good choice, but individual motorcyclists should have the right to make a bad choice that ends in disaster if they so choose. A hallmark of the antihelmet movement is the argument that motorcyclists who do not wear helmets can perceive (ie, see and hear) their environment more effectively and, thus, can avoid impending accidents by anticipating them earlier. This argument is fallacious.

Most accidents involving adult, otherwise responsible, motorcyclists are caused by moving objects hitting motorcyclists or by motorcyclists hitting a stationary object after being forced into an unusual position in an attempt to avoid something in their path. A full-face helmet restricts a relatively small portion of inconsequential downward and lateral peripheral vision. Similarly, it is highly improbable that a motorcyclist will hear an impending accident. A marginal increase in the ability to hear road noise and to see downward and laterally is not an improvement in the ability to avoid most accidents.

The medical literature regarding motorcyclists’ head injury is clear. Head trauma is a devastating injury for motorcyclists and their families, and rehabilitation for survivors is prolonged and expensive. Injury expenses for motorcyclists who do not wear helmets far exceed that of motorcyclists who wear helmets. More importantly, the burden of caring for a motorcyclist with a head injury is frequently borne by the taxpayers, regardless of the insurance status of the injured motorcyclist.

Appropriate management of TBI requires an understanding of the pathophysiology of head injury. In addition to the obvious functional differences, the brain has several features that distinguish it from other organ systems. The most important of these differences is that the brain is contained within the skull, a rigid and inelastic container. Because the brain is housed within this inelastic container, only small increases in volume within the intracranial compartment can be tolerated before pressure within the compartment rises dramatically. This concept is defined by the Monro-Kellie doctrine, which states that the total intracranial volume is fixed because of the inelastic nature of the skull. The intracranial volume (V i/c) is equal to the sum of its components, as follows:

V i/c = V (brain) + V (cerebrospinal fluid) + V (blood)

In the typical adult, the intracranial volume is approximately 1500 mL, of which the brain accounts for 85-90%, intravascular cerebral blood volume accounts for 10%, and cerebrospinal fluid (CSF) accounts for the remainder (<3%). When a significant head injury occurs, cerebral edema often develops, which increases the relative volume of the brain. Because the intracranial volume is fixed, the pressure within this compartment rises unless some compensatory action occurs, such as a decrease in the volume of one of the other intracranial components. This is intimately related to the concept of intracranial compliance, which is defined as the change in pressure due to changes in volume.

Compliance = Change in volume / change in pressure

Compliance is based on the pressure volume index (PVI) within the intracranial compartment. The PVI describes the change in intracranial pressure (ICP) that occurs when a small amount of fluid is added to or withdrawn from the intracranial compartment. Simply stated, the brain has very limited compliance and cannot tolerate significant increases in volume that can result from diffuse cerebral edema or from significant mass lesions, such as a hematoma. The rationale for each treatment of head injury is based on the concept of the Monro-Kellie doctrine and how a particular intervention affects the intracranial compliance. When the volume of any of the components of the total intracranial volume is decreased, the ICP may be decreased.

A second crucial concept in TBI pathophysiology is the concept of cerebral perfusion pressure (CPP). CPP is defined as the difference between the mean arterial pressure (MAP) and the ICP.


In practical terms, CPP is the net pressure of blood delivery to the brain. In the noninjured brain in individuals without long-standing hypertension, cerebral blood flow (CBF) is constant in the range of MAPs of 50-150 mm Hg. This is due to autoregulation by the arterioles, which will constrict or dilate within a specific range of blood pressure to maintain a constant amount of blood flow to the brain.

When the MAP is less than 50 mm Hg or greater than 150 mm Hg, the arterioles are unable to autoregulate and blood flow becomes entirely dependent on the blood pressure, a situation defined as pressure-passive flow. The CBF is no longer constant but is dependent on and proportional to the CPP. Thus, when the MAP falls below 50 mm Hg, the brain is at risk of ischemia due to insufficient blood flow, while a MAP greater than 160 mm Hg causes excess CBF that may result in increased ICP. While autoregulation works well in the noninjured brain, it is impaired in the injured brain. As a result, pressure-passive flow occurs within and around injured areas and, perhaps, globally in the injured brain.

TBI may be divided into 2 categories, primary brain injury and secondary brain injury. Primary brain injury is defined as the initial injury to the brain as a direct result of the trauma. This is the initial structural injury caused by the impact on the brain, and, like other forms of neural injury, patients recover poorly. Secondary brain injury is defined as any subsequent injury to the brain after the initial insult. Secondary brain injury can result from systemic hypotension, hypoxia, elevated ICP, or as the biochemical result of a series of physiologic changes initiated by the original trauma. The treatment of head injury is directed at either preventing or minimizing secondary brain injury.

Elevated ICP may result from the initial brain trauma or from secondary injury to the brain. In adults, normal ICP is considered 0-15 mm Hg. In young children, the upper limit of normal ICP is lower, and this limit may be considered 10 mm Hg. Elevations in ICP are deleterious because they can result in decreased CPP and decreased CBF, which, if severe enough, may result in cerebral ischemia. Severe elevations of ICP are dangerous because, in addition to creating a significant risk for ischemia, uncontrolled ICP may cause herniation. Herniation involves the movement of the brain across fixed dural structures, resulting in irreversible and often fatal cerebral injury.

Maloney-Wilensky et al found that in patients with TBI, brain hypoxia as measured by brain tissue oxygen levels is associated with worse outcome.1 Their review showed that, in 150 patients with severe TBI, those with brain tissue oxygen levels below 10 mm Hg had worse outcomes (odds ratio [OR], 4.0) and higher mortality (OR, 4.6). However, use of direct brain tissue oxygen probes proved to be safe, with only 2 adverse events in 292 patients.1 The researchers suggest that treatment to increase brain tissue oxygen levels deserves investigation as a possible means of improving outcome in severe TBI.

TBI may be divided into 2 broad categories, closed head injury and penetrating head injury. This is not purely a mechanistic division because some aspects of the treatment of these 2 types of TBIs differ. The clinical presentation of the patient with TBI varies significantly, from an ambulatory patient complaining of a sports-related head injury to the moribund patient arriving via helicopter following a high-speed motor vehicle accident.

The Glasgow Coma Scale (GCS) developed by Jennett and Teasdale is used to describe the general level of consciousness of patients with TBI and to define broad categories of head injury.2 The GCS is divided into 3 categories, eye opening (E), motor response (M), and verbal response (V). The score is determined by the sum of the score in each of the 3 categories, with a maximum score of 15 and a minimum score of 3, as follows:

GCS score = E + M + V

Glasgow Coma Scale

Open table in new window
Eye Opening
Score 1 Year or Older 0-1 Year
4 Spontaneously Spontaneously
3 To verbal command To shout
2 To pain To pain
1 No response No response
Best Motor Response
Score 1 Year or Older 0-1 Year
6 Obeys command

5 Localizes pain Localizes pain
4 Flexion withdrawal Flexion withdrawal
3 Flexion abnormal (decorticate) Flexion abnormal (decorticate)
2 Extension (decerebrate) Extension (decerebrate)
1 No response No response
Best Verbal Response
Score >5 Years 2-5 Years 0-2 Years
5 Oriented and converses Appropriate words Cries appropriately
4 Disoriented and converses Inappropriate words Cries
3 Inappropriate words; cries Screams Inappropriate crying/screaming
2 Incomprehensible sounds Grunts Grunts
1 No response No response No response
Eye Opening
Score 1 Year or Older 0-1 Year
4 Spontaneously Spontaneously
3 To verbal command To shout
2 To pain To pain
1 No response No response
Best Motor Response
Score 1 Year or Older 0-1 Year
6 Obeys command

5 Localizes pain Localizes pain
4 Flexion withdrawal Flexion withdrawal
3 Flexion abnormal (decorticate) Flexion abnormal (decorticate)
2 Extension (decerebrate) Extension (decerebrate)
1 No response No response
Best Verbal Response
Score >5 Years 2-5 Years 0-2 Years
5 Oriented and converses Appropriate words Cries appropriately
4 Disoriented and converses Inappropriate words Cries
3 Inappropriate words; cries Screams Inappropriate crying/screaming
2 Incomprehensible sounds Grunts Grunts
1 No response No response No response

Patients who are intubated are unable to speak, and their verbal score cannot be assessed. They are evaluated only with eye opening and motor scores, and the suffix T is added to their score to indicate intubation. In intubated patients, the maximal GCS score is 10T and the minimum score is 2T. The GCS is often used to help define the severity of TBI. Mild head injuries are generally defined as those associated with a GCS score of 13-15, and moderate head injuries are those associated with a GCS score of 9-12. A GCS score of 8 or less defines a severe head injury. These definitions are not rigid and should be considered as a general guide to the level of injury.

Traumatic injury and brain failure

As a type of organ system failure, brain failure invariably affects consciousness. Consciousness is structurally produced in the cerebral hemispheres, including the pons and the medulla. These structures are all interconnected by the reticular formation, which begins in the medulla and extends to the midbrain, where it forms the reticular activating system. This pathway modulates the perception of events and controls integrated responses.

Clinical evaluation of consciousness states is heavily dependent on the findings from the physical examination. When the physical examination yields visual and palpable clues to the integrity of consciousness, impairment thereof may be classified into one of the following categories:

* Cloudy consciousness: This state is defined as a mild deficit in the speed of information processing by the brain. This results from macrotearing and histological-level disruption of cell-to-cell connectivity occurring throughout the brain disrupting physical connectivity between brain regions, exacerbated by vascular compromise of a mechanical and/or biochemical nature causing islands of nonfunctional or impaired tissue in the brain parenchyma. Cloudy consciousness may be noted after mild-to-moderate head trauma and may persist for several months. Memory of recent events is often diminished, but long-term memory typically remains intact.
* Lethargy: This state is defined as a decrease in alertness, resulting in impaired ability to perform tasks that are normally accomplished without effort. Patients rouse briefly in response to stimuli and then settle back into inactivity when left alone. They retain awareness of their immediate environment.
* Obtundation: This state is defined as a decrease in awareness and alertness, in which patients rouse briefly in response to stimuli and follow simple commands but are unaware of their immediate surroundings. When stimulation ceases, they settle back into inactivity.
* Stupor: In this state, patients cannot communicate clearly but can be aroused by continued painful stimulation. Arousal may be manifested only as withdrawal from painful stimuli. As soon as stimuli are removed, the patient settles back into inactivity.
* Coma: In this state, patients do not respond to even the most vigorous stimuli.
* Brain death: This state is equivalent to functional decapitation and is characterized by irreversible cessation of whole-brain function and hemisphere and brainstem function.

The efficacy of the physical examination in the evaluation of consciousness diminishes when visual clues disappear (eg, during heavy sedation, therapeutic musculoskeletal paralysis). In such situations, monitoring of cerebral function by compressed spectral array is helpful in assessing the effect of therapy on neuronal function.
Processed electroencephalogram (compressed spectral array) in consciousness assessment

The processed electroencephalogram (EEG) does not require as many head electrodes to generate a satisfactory signal that can be used for clinical data in the intensive care unit (ICU). Brain wave monitoring by portable, noninvasive computer processed monitors allow quick recognition of some brain functions under titrated suspended animation in real time. These parameters are not effectively evaluated by raw signal EEG monitors, but some progress has been made using computerized processed signal EEGs. Advantages of the processed EEG during neuromuscular blockade are that data are more easily interpreted by clinicians not specifically trained in electroencephalography.

The continuum from wakefulness to sleep involves a progressive decrease in the alpha band followed by increased activity in the beta, theta, and delta bands. The alpha rhythm contains waves of 8-12 Hz and is very responsive to volitional mental activity, increasing with excitement and decreasing with tranquility. These rhythms occur mainly in the posterior head and are the predominant brain activity in the normal brain.

A technique has been developed to simplify pattern recognition and interpretation of the brain electrical activity using the key word SAFE:

* S - SYMMETRY - Compare the pattern of asymmetrical patterns. Can indicate diminished perfusion to one hemisphere, cerebral embolism, or thrombosis.
* A - AMPLITUDE - Compare the altitude of the vectors. Asymmetric hemispherical amplitude suggests agitation under paralysis. Low amplitude suggests sedation and quiescence.
* F - FREQUENCY - Compare the distribution of vectors throughout all frequency bands. Absent or attenuated activity in the “conscious” side suggests sedation or anesthesia.
* E - EDGE - Observe the activity edge. Significant dips in one hemisphere compared to the other suggest focal brain ischemia.

Agitation is represented by linear activity depicting intensity of brain activity and position of this activity within the brain topography. Sedation can be effectively titrated until this activity is reduced to normalcy using continuous infusion of sedative agents, while ensuring patient comfort under paralysis as the search for underlying pathology follows. Different classifications and combinations of sedatives, analgesics, or antipsychotics can be tried until the combination that brings about the most appropriately calm cerebral function tracing is discovered. Attention can then be turned to protecting other organs from damage.
Relevant Anatomy

Several aspects of neuroanatomy and neurophysiology require review in a discussion of TBI. Although a comprehensive review of neuroanatomy is beyond the scope of this discussion, a few key concepts are reviewed.

The brain essentially floats within the CSF; as a result, the brain can undergo significant translation and deformation when the head is subjected to significant forces. In a deceleration injury, in which the head impacts a stationary object, such as the windshield of a car, the skull stops moving almost instantly. However, the brain continues to move within the skull toward the direction of the impact for a very brief period after the head has stopped moving. This results in significant forces acting on the brain as it undergoes both translation and deformation.

In an acceleration injury, as in a direct blow to the head, the force applied to the skull causes the skull to move away from the applied force. The brain does not move with the skull, and the skull impacts the brain, causing translation and deformation of the brain. The forces that result from either deceleration or acceleration of the brain can cause injury by direct mechanical effects on the various cellular components of the brain or by shear-type forces on axons. In addition to the translational forces, the brain can experience significant rotational forces, which can also lead to shear injuries.

The intracranial compartment is divided into 3 compartments by 2 major dural structures, the falx cerebri and the tentorium cerebelli. The tentorium cerebelli divides the posterior fossa or infratentorial compartment (the cerebellum and the brainstem) from the supratentorial compartment (cerebral hemispheres). The falx cerebri divides the supratentorial compartment into 2 halves and separates the left and right hemispheres of the brain. Both the falx and the tentorium have central openings and prominent edges at the borders of each of these openings. When a significant increase in ICP occurs, caused by either a large mass lesion or significant cerebral edema, the brain can slide through these openings within the falx or the tentorium, a phenomenon known as herniation. As the brain slides over the free dural edges of the tentorium or the falx, it is frequently injured by the dural edge.

Several types of herniation exist, as follows: (1) transtentorial herniation, (2) subfalcine herniation, (3) central herniation, (4) upward herniation, and (5) tonsillar herniation.

Transtentorial herniation occurs when the medial aspect of the temporal lobe (uncus) migrates across the free edge of the tentorium. This causes pressure on the third cranial nerve, interrupting parasympathetic input to the eye and resulting in a dilated pupil. This unilateral dilated pupil is the classic sign of transtentorial herniation and usually (80%) occurs ipsilateral to the side of the transtentorial herniation. In addition to pressure on the third cranial nerve, transtentorial herniation compresses the brainstem.

Subfalcine herniation occurs when the cingulate gyrus on the medial aspect of the frontal lobe is displaced across the midline under the free edge of the falx. This may compromise the blood flow through the anterior cerebral artery complexes, which are located on the medial side of each frontal lobe. Subfalcine herniation does not cause the same brainstem effects as those caused by transtentorial herniation.

Central herniation occurs when a diffuse increase in ICP occurs and each of the cerebral hemispheres is displaced through the tentorium, resulting in significant pressure on the upper brainstem.

Upward, or cerebellar, herniation occurs when either a large mass or an increased pressure in the posterior fossa is present and the cerebellum is displaced in an upward direction through the tentorial opening. This also causes significant upper brainstem compression.

Tonsillar herniation occurs when increased pressure develops in the posterior fossa. In this form of herniation, the cerebellar tonsils are displaced in a downward direction through the foramen magnum, causing compression on the lower brainstem and upper cervical spinal cord as they pass through the foramen magnum.

Another aspect of the intracranial anatomy that has a significant role in TBI is the irregular surface of the skull underlying the frontal and temporal lobes. These surfaces contain numerous ridges that can cause injury to the inferior aspect of the frontal lobes and the temporal lobes as the brain glides over these irregular ridges following impact. Typically, these ridges cause cerebral contusions. The roof of the orbit has many ridges, and, as a result, the inferior frontal lobe is one of the most common sites of traumatic cerebral contusions.


Burns, Thermal


Burn injuries account for an estimated 700,000 annual ED visits per year. Of these, 45,000 require hospitalization. Approximately half of these patients are hospitalized at one of the 125 specialized burn treatment centers in the United States.

Most burns are not life threatening, but each burn causes a significant amount of pain for the patient and often some degree of psychological trauma. At temperatures greater than 120 º F, a child's skin is burned severely enough to require surgery in 3 seconds. Rapid evaluation by the emergency physician (EP) is essential to address pain management, provide initial wound care, evaluate appropriate disposition, mitigate the psychological impact of the burn, and identify intentional burns. Follow-up for even superficial thickness burns is imperative, particularly when involving the hands, feet, face, genital area, or other particularly sensitive areas.

To effectively evaluate, treat, and prevent potential future burns, understanding the different methods of categorizing burns is helpful. The general categories include life-threatening versus non–life-threatening, accidental versus intentional, recreational versus occupational, and domestic (home or residence) versus industrial.

Identifying the type of burn is essential because interventions must be appropriately tailored to the underlying cause. Type of burns include thermal burns, chemical burns, and radiation burns. Thermal burns can be further classified according to skin depth and percentage of total body area burned. Additional descriptions for thermal burns include contact, flame, heat, and scalding. Accurate documentation of the burn location (such as ophthalmic, hand, face, inhalation, soles, or perineum) and measurement of involved surface area are essential for follow-up and specialist referral/consultation.

The skin is the largest organ of the body. Although not very active metabolically, the skin serves multiple functions essential to the survival of the organism, which may be compromised by the presence of a burn, including the following:

* Thermal regulation and prevention of fluid loss by evaporation
* Hermetic barrier against infection
* Sensory receptors that provide information about environment

The skin is divided into 3 layers, as follows:

* Epidermis: This is the outermost layer of skin composed of cornified epithelial cells. Outer surface cells die and are sloughed off as newer cells divide at the stratum germinativum.
* Dermis: This is the middle layer of skin composed of primarily connective tissue. It contains capillaries that nourish the skin, nerve endings, and hair follicles.
* Hypodermis: This is a layer of adipose and connective tissue between the skin and underlying tissues.

The most common type of burns are thermal burns. Soft tissue is burned when it is exposed to temperatures above 115ºF (46°C). The extent of damage depends on surface temperature and contact duration. A thermal burn causes coagulation of soft tissue. As the marginally perfused areas become reperfused, it is thought that there is a release of vasoactive substances causing formation of reactive oxygen species, which leads to increases in capillary permeability. This causes fluid loss as well as increasing plasma viscosity with resultant microthrombi formation.1

This third spacing of fluid "seals" at 18-24 hours, which is why the guidelines for fluid resuscitation are based on a 24-hour time scale. After the initial 24 hours, the fluid requirements abruptly drop as the capillary permeability returns to normal. Underresuscitation in this initial 24-hour time period leads to significant morbidity from hypovolemia and shock.

Burns may cause a hypermetabolic state manifested by fever, increased metabolic rate, increased minute ventilation, increased cardiac output, decreased afterload, increased gluconeogenesis resistant to glucose infusion, and increased skeletal and visceral muscle catabolism. Patients need support in this state, which continues until wound closure is complete.1 To a large degree, how the individual responds to the increased energy demands determine recovery.
United States

Nearly one million Americans seek ED treatment of burns each year. According to data provided by the American Burn Association, the incidence of burn injuries in the United States has declined from 2 million annual injuries estimated from 1957-1961.

According to 2007 data from the US Fire Administration, in 2006, 3,245 Americans lost their lives, and another 16,400 were injured as the result of fire. Notably, although the number of fires and deaths due to fires has decreased from 1997 to 2006, the direct dollar loss in millions has significantly increased from $8,525 to $11,307. Not included in these data are the deaths or the monetary value attributed to fires caused by the terrorist attacks of September 11, 2001. In 2002-2004, the United States had one of the highest fire death rates reported in the industrialized world at 12.4 deaths per million population, a slight decrease from 12.9 deaths per million population last reported in 2003.2 Most of these fatalities (79.5%) occurred in the home.

Slightly different findings were released by the World Fire Statistics in 2007.3 They reported that the fire-related death rate in the United States was 1.39 deaths per 100,000 (18.6 per million) in the years 2002-2004. For comparison, fire-related death rates per 100,000 were higher in Finland and Hungary at 2.08 and 2.10, respectively.

States with the highest death rates in 2004 were the District of Columbia (36.1 per million), Mississippi (32.1 per million), and Alabama (25.6 per million). The states with the lowest rates were Colorado (4.3 per million), Vermont (3.2 per million), and Wyoming (2 per million).2 Interestingly, in 2006, fire killed more Americans than all natural disasters combined.2

From 1990-2006, an estimated 2,054,563 patients aged 20 years or younger were treated in US EDs for burn-related injuries, with an average of 120,856 cases per year.4

The incidence of burn injuries varies from country to country, typically peaking during the country's holiday period.

In 2007, the World Fire Statistics Centre released fire-related death data by country (from lowest to highest number of deaths per 100,000 person) from 2002-2004.3 The countries with the lowest incidences include Singapore (0.08) and Switzerland (0.51). Those with the highest include Finland (2.08) and Hungary (2.10).3

In the United Kingdom, more than 47 fire-related injuries occur every day.

In Greece, the estimated annual incidence of childhood firework injuries treated in EDs is 7 injuries per 100,000 children per year. Seventy percent of injuries occur in children aged 10-14 years. Boys sustain self-inflicted accidental injuries; girls are typically injured as bystanders. A sharp peak of firework injuries occurs in the spring when the Greek Orthodox Easter is celebrated.5

Interesting data from Northern Ireland allows a comparison of burn incidence before and after the enactment of firework legislation. In the prelegislation series, the mean number of patients admitted annually was 0.38 per 100,000, whereas in the postlegislation series, the mean was 0.43 per 100,000. The authors concluded that legislation did not significantly affect the incidence of burns. Also in Northern Ireland, blast injuries to the hand account for more than 50% of injuries in this series.6

Although fire-related deaths still rank fifth in the leading causes of unintentional injury-related deaths,7 the number of deaths from fires and burns has declined since the 1960s. Improvements in burn care (ie, quality burn centers, recognition, and effective management of burn shock) have reduced the number of deaths in the early postburn period. Improved wound management and antibiotics have decreased deaths from burn wound infection as well. The legislature has passed acts aimed at the prevention of injury due to fires. In 1971, the Flammable Fabrics Act was passed in an attempt to regulate the sale of flammable children’s clothing, especially that of sleepwear in infants, as it was noted to be a major cause of morbidity and mortality. Over time, this decreased the number of fire-related deaths and injuries in children.8

However, the greatest factors in the reduction of burn-related deaths is the use of smoke detectors and regulations on hot water heater temperature. In the United States, most people killed in house fires die from smoke inhalation rather than from burns (see Smoke Inhalation and Toxicity, Carbon Monoxide).


Native American and black children are more than 2 times and 3 times as likely to die in a fire than white children, respectively.7 Black children and adolescents had the highest rates of burn and fire-related deaths. This is attributed to the decreased likelihood of minorities to engage in safe practices (fireplace guards, smoke alarm use, and adjusting water heater temperature).7

Minor burns are more common in younger adults, often as a result of cooking or occupational exposures. Teenaged males are at increased risk of injury from fireworks; scald injuries are more common in young children. Most scald injuries in young children result from improper setting of domestic hot water heaters and spillage of cooking pots or beverages. Both types of injuries are easily prevented.

Most children aged 4 years and younger who are hospitalized for burn-related injuries suffer from scald burns (65%) or contact burns (20%). Most scald burns to children, especially small children aged 6 months to 2 years, are caused by hot foods or liquids spilled in the kitchen or other areas where food is prepared and served.

Water heater temperature must be set lower than 120°F. Within 3 seconds, a child's skin can be burned severely enough to require surgery when they are scalded with water temperature greater than 120°F.

The EP must consider intentional injury when burn patterns, such as absence of splash marks, stocking glove distribution, sharply defined wound margins, soles, palms, and pinpoint "cigarette ash" burns, are identified. Children aged 4 years and younger and children with disabilities are at the greatest risk of burn-related death and injury, especially scald and contact burns.

The leading cause of residential fire-related death and injury among children aged 9 years and younger is due to carelessness. Fires kill more than 600 children aged 14 years and younger each year and injure approximately 47,000 other children. Approximately 88,000 children aged 14 years and younger were treated at hospital EDs for burn-related injuries; 62,500 were thermal burns and 25,500 were scald burns. The most common causes of product-related thermal burn injuries among children aged 14 years and younger are hair curlers, curling irons, room heaters, ovens and ranges, irons, gasoline, and fireworks.

Elderly persons are also at increased risk not only for having a burn-related injury but for having increased morbidity due to their thinner skin and decreased healing abilities.

The EP must consider the type of burn (thermal, chemical, radiation) and the location during early burn management. Once it has been determined that the burn is a thermal burn, the EP can add to the description: contact (with source name), scald (with fluid or gas type), heat, and flame. Systemic injury, duration, intentional versus accidental, and location of the burn must all be considered during the critical early burn period.

Other important points to determine include the patient's tetanus immunization status as well as the components of the history including past medical history, medications, and allergies.

Ascertain the history early because often the paramedics may be the only source of information about the event.

History should also include the following:

* Medical personnel must consider abuse as a cause of burns in all children. As many as 10% of abuse cases involve burns (see Pediatrics, Child Abuse).
* Components of the history that should raise suspicion of abuse include the
o Multiple/conflicting stories of how injury was sustained
o Injury attributed to a sibling
o Injury claimed to be unwitnessed
o Injury incompatible with developmental level of the child
o Presence of adult male who is not child's father (such as mother's boyfriend) living in household
* Characteristics of the burn that should raise suspicion of abuse include the following:
o Pattern burns that suggest contact with an object
o Cigarette burns
o Stocking, glove, or circumferential burns
o Burns to genitalia or perineum
* All health care personnel are obligated to contact appropriate law enforcement and protective services if they suspect the burn was intentional.
* Medical personnel must be aware that burns resulting from abuse or neglect may also be seen in the geriatric population.


* Burn depth is described as superficial, partial thickness, or full thickness (corresponding to first, second, or third degree). (See Causes for more information.)
* Superficial (first-degree) burns involve only the epidermis.
o Tissue blanches with pressure.
o Tissue is erythematous.
o Tissue damage is minimal.
o Edema may be present; generally blisters do not form.
o Sunburn is a classic example of this type of burn (see Sunburn for more details and management).
o These wounds are red, dry, painful, and generally heal in 3-6 days without scarring.9
* Partial-thickness burns (second-degree) are often further delineated into superficial and deep types.;
o Epidermis and portions of the dermis are involved.
o Blisters usually form either very quickly or within 24 hours.
o Superficial and deep partial-thickness can be difficult to differentiate at the bedside. The difference lies in the depth of penetrance into the dermis with the transition occurring at about half of dermal depth. Superficial partial-thickness burns usually blanch and do not result in scarring. Deep partial-thickness burns often do not blanch and do scar. The deeper the injury, the longer the healing time, which may vary from 7-21 days in the more superficial dermis burns to greater than 21 days in the deep dermis burns.
o Adnexal structures (eg, sweat glands, hair follicles) are often involved, but enough of these structures are preserved for function, and the epithelium lining them can proliferate and allow for regrowth of skin.
o If deep second-degree burns are not cared for properly, edema, which accompanies the injury, and decreased blood flow in the tissue can result in conversion to full-thickness burn.
o These wounds are red, wet, and painful (with decreasing pain, color, and moisture with increasing depth into the dermis).9
* Full-thickness (third-degree) burns extend completely through the skin to subcutaneous tissue. They may involve underlying structures including tendon, nerves, muscle, or bone (sometimes previously referred to as fourth-degree burn). Full-thickness and partial thickness burns are shown in the image below.

Partial- and full-thickness burns from a structur...
Partial- and full-thickness burns from a structure fire. Note facial involvement.


Partial- and full-thickness burns from a structur...

Partial- and full-thickness burns from a structure fire. Note facial involvement.

o These burns are characterized by charring of skin or a translucent white color, with coagulated vessels visible below.
o The area is insensate, but the patient complains of pain, which is usually a result of surrounding second-degree burn.
o As all of the skin tissue and structures are destroyed, healing is very slow. Full-thickness burns are often associated with extensive scarring because epithelial cells from the skin appendages are not present to repopulate the area.
o These wounds vary from waxy white, to charred and black often with a leathery texture, they are dry and usually painless to touch. These wounds generally do not heal on their own.9
* Burn extent
o The more body surface area (BSA) involved in a burn, the greater the morbidity and mortality rates and the difficulty in management. Emergency medical services (EMS) personnel tend to overestimate the extent of the burn, whereas ED personnel tend to underestimate it.
o An individual's palmar surface classically represents 1% of the BSA, but, in actuality, it represents about 0.4%, whereas the entire hand represents about 0.8%.10,11 A simple method to estimate burn extent is to use the patient's palmar surface including fingers to measure the burned area. Burn extent is calculated only on individuals with partial-thickness or full-thickness burn.
o Another quick method is to use the Rule of Nines to estimate the extent of burn injury (as is shown in the image below).

Rule of nines for calculating burn area.
Rule of nines for calculating burn area.


Rule of nines for calculating burn area.

Rule of nines for calculating burn area.
o The head represents a greater portion of body mass in children than it does in adults. Lund and Browder first described a method for compensating for the differences, and the Lund and Browder Chart is used to calculate BSA in children (as is shown in the image below).

Lund and Browder chart illustrating the method fo...
Lund and Browder chart illustrating the method for calculating the percentage of body surface area affected by burns in children.


Lund and Browder chart illustrating the method fo...

Lund and Browder chart illustrating the method for calculating the percentage of body surface area affected by burns in children.
o If the chart is unavailable, estimate BSA by the Rule of Nines and adjust for age as follows:
+ In children younger than 1 year, the head and neck are 18% of BSA and each leg is 15% of BSA. The torso and arms represent the same percentages as in adults (10% and 16%, respectively).
+ For each year older than 1 year, add 0.5% to each leg and decrease percentage for the head by 1% until adult values are reached.
* On the basis of burn extent and depth, EPs can determine the severity of burn injury and whether the patient requires transfer to a burn center. The American Burn Association has developed criteria for burn center admission, as follows:
o Full-thickness (third-degree) burns over 5% BSA
o Partial-thickness (second-degree) burns over 10% BSA
o Any full-thickness or partial-thickness burn involving critical areas (eg, face, hands, feet, genitals, perineum, skin over any major joint), as these have significant risk for functional and cosmetic problems
o Circumferential burns of the thorax or extremities
o Significant chemical injury, electrical burns, lightning injury, coexisting major trauma, or presence of significant preexisting medical conditions
o Presence of inhalation injury
o Greater than 15% BSA in adults
o Greater than 10% BSA in children
o Hand and foot burns can lead to significant morbidity if not properly treated; therefore, most are treated with aggressive therapy. However, with careful follow-up, the patient may be monitored on an outpatient basis.


* Flame burns
o Contact with open flame causes direct injury to tissue.
o Flame may ignite clothing. Although natural fibers tend to burn, synthetic fibers may melt or ignite, adding a contact burn component to the injury.
o If the burn occurs in an enclosed area, the patient is also at risk for CO poisoning and cyanide poisoning as well as inhalational injury from the smoke and heat.
* Contact burns
o Contact burns result from direct contact with a hot object.
o Burn injury is confined to the point of contact.
o Examples are burns from cigarettes and tools (eg, soldering irons, cooking appliances, curling irons).
* Scalds
o Scalds result from contact with hot liquids (as is shown in the image below).

Child with burns from a scald. Hot soup was spill...
Child with burns from a scald. Hot soup was spilled when the child grabbed the handle of a pot. Note the full-thickness burn to left upper part of the chest. Edema of the lips and blisters on the face and nose indicate second-degree burns of the face.


Child with burns from a scald. Hot soup was spill...

Child with burns from a scald. Hot soup was spilled when the child grabbed the handle of a pot. Note the full-thickness burn to left upper part of the chest. Edema of the lips and blisters on the face and nose indicate second-degree burns of the face.
o The more viscous the liquid and the longer the contact with the skin, the greater the damage.
o Accidental scalds often show a pattern of splashing, with burns separated by patches of uninjured skin.
o In contrast, intentional scalds often involve the entire extremity, appearing in a circumferential pattern with a line that marks the liquid surface.
* Steam burns
o Steam burns most often occur in industrial accidents or result from automobile radiator accidents.
o These burns produce extensive injury from the high heat-carrying capacity of steam and the dispersion of pressurized steam and liquid.
o Steam inhalation can actually cause thermal injury to the distal airways of the lung.
* Gas burns
o Inhalation of hot gas normally does not injure distal airways, as the heat-exchange capacity of the upper airway is excellent.
o In this situation, the upper airway is at risk for thermal injury and subsequent occlusion due to edema.
o Distal airway injury is more likely to be due to the direct effects of the products of combustion on the mucosa and alveoli.
* Electrical burns, including lightning12
o Electrical burns produce heat injury by passing through tissue.
o Most problems from these burns present in patients exposed to more than 1000V.
o Children can have significant injury after exposure to 200-1000V.
o Ignition of clothing may produce some flame burn, but most of the injury is deep in the skin (see Electrical Injuries).
o Cardiac injury is prominent, and patients must be monitored for 4-72 hours depending on the strength of the voltage and the age of the patient.
o The EP must consider visceral injuries, long bone and spine fractures, myoglobinuria, and compartment syndromes.
* Flash burns
o Flash burns are a subset of flame burns and are a result of rapid ignition of a flammable gas or liquid.
o The body parts involved are those exposed to the agent when it ignites.
o Areas covered by clothing are usually spared.
o The face may be involved, but if this type of injury takes place outside, then the risk for inhalation injury is low. A careful examination of the airway is indicated.
o A classic example of this type of injury occurs when a person pours gasoline on a trash or leaf fire to increase the flame and is burned by the subsequent fireball.
* Tar burns (see Emergency Department Care)
* Chemical burns12
o Alkaline substances and acid substances can burn the skin and can be associated with systemic toxicity.
o Alkaline burns produce liquefactive necrosis and are considered higher risk burns due to their likelihood to penetrate deeper.
o Acid burns are the result of coagulation necrosis, limiting the depth and penetration of the burn.
o The upper GI tract and oropharynx may also be at risk if the chemicals were ingested; therefore, the EP should be aware that the airway may occlude due to edema.
o Circumoral burns may be present if the agent was ingested.



Acute Lymphoblastic Leukemia


Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children, representing nearly one third of all pediatric cancers. The annual incidence rate for acute lymphoblastic leukemia is 30.9 cases per million population. The peak incidence occurs in children aged 2-5 years.

Although a few cases are associated with inherited genetic syndromes (ie, Down syndrome, Bloom syndrome, Fanconi anemia), the cause remains largely unknown. Many environmental factors (ie, exposure to ionizing radiation and electromagnetic fields, parental use of alcohol and tobacco) have been investigated as potential risk factors, but none has been definitively shown to cause acute lymphoblastic leukemia. Various viruses may be linked to the development of leukemia, particularly when prenatal viral exposure occurs in mothers recently infected with influenza or varicella. However, no direct link has been established between viral exposure and the development of leukemia.

Acute lymphoblastic leukemia may also occur in children with various congenital immunodeficiencies (ie, Wiskott-Aldrich syndrome, congenital hypogammaglobulinemia, ataxia-telangiectasia) that have an increased predisposition to develop lymphoid malignancies.

With improvements in diagnosis and treatment, overall cure rates for children with acute lymphoblastic leukemia now approach 80%. Further refinements in therapy, including the use of risk-adapted treatment protocols, may improve cure rates for patients at high risk while limiting the toxicity of therapy for patients with a low risk of relapse. This article summarizes advances in the diagnosis and treatment of childhood acute lymphoblastic leukemia.

In acute lymphoblastic leukemia, a lymphoid progenitor cell becomes genetically altered and subsequently undergoes dysregulated proliferation, survival, and clonal expansion. In most cases, the pathophysiology of transformed lymphoid cells reflects the altered expression of genes whose products contribute to the normal development of B cells and T cells. Several studies indicate that leukemic stem cells are present in certain types of acute lymphoblastic leukemia.1,2
United States

Annually, 2500-3500 children are diagnosed with acute lymphoblastic leukemia.

Throughout the world, the incidence rate is thought to be similar to that in the United States.

Overall cure rates for children with acute lymphoblastic leukemia now approach 80%. The 4-year event-free survival (EFS) rate for high-risk patients is approximately 65%.

The overall incidence of acute lymphoblastic leukemia varies among different racial groups within the United States. White children are more frequently affected than black children.

Acute lymphoblastic leukemia occurs slightly more frequently in boys than in girls. This difference is most pronounced for T-cell acute lymphoblastic leukemia.

The incidence of acute lymphoblastic leukemia peaks in children aged 2-5 years.

Children with acute lymphoblastic leukemia (ALL) generally present with signs and symptoms that reflect bone marrow infiltration and extramedullary disease. Because leukemic blasts replace the bone marrow, patients present with signs of bone marrow failure, including anemia, thrombocytopenia, and neutropenia. Clinical manifestations include fatigue and pallor, petechiae and bleeding, and fever. In addition, leukemic spread may manifest as lymphadenopathy and hepatosplenomegaly. Other signs and symptoms of leukemia include weight loss, bone pain, and dyspnea.

Signs or symptoms of CNS involvement, even when it occurs, are rarely observed at the time of the initial diagnosis. The signs and symptoms include headache, nausea and vomiting, lethargy, irritability, nuchal rigidity, and papilledema. Cranial nerve involvement, which most frequently involves the seventh, third, fourth, and sixth cranial nerves, may occur. Also, leukemia can present as an intracranial or spinal mass, which causes numerous neurologic symptoms, most of which are due to nerve compression.

Testicular involvement at diagnosis is rare. However, if present, it appears as painless testicular enlargement and is most often unilateral.

Physical findings in children with acute lymphoblastic leukemia reflect bone marrow infiltration and extramedullary disease. Patients present with pallor caused by anemia and petechiae and bruising secondary to thrombocytopenia. They also have signs of infection because of neutropenia. In addition, leukemic spread may be seen as lymphadenopathy and hepatosplenomegaly.

Careful neurologic examination to look for CNS involvement is important because the treatment for leukemia with CNS involvement is different.

In male patients, testicular examination is necessary to look for testicular involvement of leukemia.

Although a small percentage of cases are associated with inherited genetic syndromes, the cause of acute lymphoblastic leukemia remains largely unknown.


Acute Myelogenous Leukemia


Acute myelogenous leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education articles Leukemia and Bruises.

The underlying pathophysiology in acute myelogenous leukemia (AML) consists of a maturational arrest of bone marrow cells in the earliest stages of development. The mechanism of this arrest is under study, but in many cases, it involves the activation of abnormal genes through chromosomal translocations and other genetic abnormalities.1,2

This developmental arrest results in 2 disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. Second, the rapid proliferation of these cells, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, blood, and, frequently, the spleen and liver.
United States

Estimates of new cases of acute myelogenous leukemia (AML) in the United States in 2007 were 13,410 (7060 men; 6350 women).

Acute myelogenous leukemia (AML) is more commonly diagnosed in developed countries.

* In 2007, an estimated 8990 deaths from acute myelogenous leukemia (AML) occurred in the United States. Of these, 5020 occurred in men and 3970 occurred in women.
* In adults, treatment results are generally analyzed separately for younger (18-60 y) and older (>60 y) patients with acute myelogenous leukemia (AML).
o With current standard chemotherapy regimens, approximately 30-35% of adults younger than 60 years survive longer than 5 years and are considered cured.
o Results in older patients are more disappointing, with fewer than 10% of surviving over the long term.


* Acute myelogenous leukemia (AML) is more common in whites than in other populations.


* Acute myelogenous leukemia (AML) is more common in men than in women. The difference is even more apparent in older patients. This is likely because myelodysplastic syndromes (MDSs) are more common in men, and advanced MDS frequently evolves into AML. Some have proposed that the increased prevalence of acute myelogenous leukemia (AML) in men may be related to occupational exposures.


* The prevalence of acute myelogenous leukemia (AML) increases with age. The median age of onset is approximately 70 years. However, acute myelogenous leukemia (AML) affects all age groups.


* Patients with acute myelogenous leukemia (AML) present with symptoms resulting from bone marrow failure, organ infiltration with leukemic cells, or both. The time course is variable.
o Some patients, particularly younger ones, present with acute symptoms over a few days to 1-2 weeks.
o Others have a longer course, with fatigue or other symptoms lasting from weeks to months. A longer course may suggest an antecedent hematologic disorder (AHD) such as MDS.
* Symptoms of bone marrow failure are related to anemia, neutropenia, and thrombocytopenia.
o The most common symptom of anemia is fatigue. Patients often retrospectively note a decreased energy level over past weeks.
o Other symptoms of anemia include dyspnea upon exertion, dizziness, and, in patients with coronary artery disease, anginal chest pain. In fact, myocardial infarction may be the first presenting symptom of acute leukemia in an older patient.
o Patients often have decreased neutrophil levels despite an increased total white blood cell (WBC) count.
o Patients with acute myelogenous leukemia (AML) present with fever, which may occur with or without specific documentation of an infection. Patients with the lowest absolute neutrophil counts (ANCs) (ie, <500 cells/µL, especially <100 cells/µL) have the highest risk of infection.
o Patients often have a history of upper respiratory infection symptoms that have not improved despite empiric treatment with oral antibiotics.
o Patients present with bleeding gums and multiple ecchymoses. Bleeding may be caused by thrombocytopenia, coagulopathy that results from disseminated intravascular coagulation (DIC), or both.
o Potentially life-threatening sites of bleeding include the lungs, gastrointestinal tract, and the central nervous system.
* Alternatively, symptoms may be the result of organ infiltration with leukemic cells.
o The most common sites of infiltration include the spleen, liver, gums, and skin.
o Infiltration occurs most commonly in patients with the monocytic subtypes of acute myelogenous leukemia (AML).
o Patients with splenomegaly note fullness in the left upper quadrant and early satiety.
o Patients with gum infiltration often present to their dentist first. Gingivitis due to neutropenia can cause swollen gums, and thrombocytopenia can cause the gums to bleed.
o Patients with markedly elevated WBC counts (>100,000 cells/µL) can present with symptoms of leukostasis (ie, respiratory distress and altered mental status). Leukostasis is a medical emergency that requires immediate intervention.
o Patients with a high leukemic cell burden may present with bone pain caused by increased pressure in the bone marrow.


* Physical signs of anemia, including pallor and a cardiac flow murmur, are frequently present in those with acute myelogenous leukemia (AML).
* Fever and other signs of infection can occur, including lung findings of pneumonia.
* Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities. The petechiae are small, often punctate, hemorrhagic rashes that are not palpable. Areas of dermal bleeding or bruises (ie, ecchymoses) that are large or present in several areas may indicate a coexistent coagulation disorder such as DIC. Purpura is characterized by flat bruises that are larger than petechiae but smaller than ecchymoses.
* Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and, to a lesser degree, lymphadenopathy. Occasionally, patients have skin rashes due to infiltration of the skin with leukemic cells (leukemia cutis). Chloromata are extramedullary deposits of leukemia. Rarely, a bony or soft-tissue chloroma may precede the development of marrow infiltration by acute myelogenous leukemia (AML) (granulocytic sarcoma).
* Signs relating to leukostasis include respiratory distress and altered mental status.


* Although several factors have been implicated in the causation of acute myelogenous leukemia (AML), most patients who present with de novo AML have no identifiable risk factor.
* Antecedent hematologic disorders
o The most common risk factor for acute myelogenous leukemia (AML) is the presence of an antecedent hematologic disorder, the most common of which is MDS. MDS is a disease of the bone marrow of unknown etiology that occurs most often in older patients and manifests as progressive cytopenias that occur over months to years.
o Patients with low-risk MDS (eg, refractory anemia with normal cytogenetics findings) generally do not develop acute myelogenous leukemia (AML), whereas patients with high-risk MDS (eg, refractory anemia with excess blasts-type 2) frequently do develop AML.
o Other antecedent hematologic disorders that predispose patients to acute myelogenous leukemia (AML) include aplastic anemia, myelofibrosis, paroxysmal nocturnal hemoglobinuria, and polycythemia vera.
* Congenital disorders
o Some congenital disorders that predispose patients to acute myelogenous leukemia (AML) include Bloom syndrome, Down syndrome, congenital neutropenia, Fanconi anemia, and neurofibromatosis.
o Usually, these patients develop acute myelogenous leukemia (AML) during childhood; rarely, some may present in young adulthood.
o More subtle genetic disorders, including polymorphisms of enzymes that metabolize carcinogens, also predispose patients to acute myelogenous leukemia (AML). For example, polymorphisms of NAD(P)H:quinone oxidoreductase (NQO1), an enzyme that metabolizes benzene derivatives, are associated with an increased risk of AML.3 Particularly increased risk exists for AML that occurs after chemotherapy for another disease or for de novo AML with an abnormality of chromosomes 5, 7, or both. Likewise, polymorphisms in glutathione S -transferase are associated with secondary acute myelogenous leukemia (AML) following chemotherapy for other malignancies.4
* Familial syndromes
o Germ-line mutations in the gene AML1 (RUNX1, CBFA2) occur in the familial platelet disorder with predisposition for myelogenous leukemia (AML), an autosomal-dominant disorder characterized by moderate thrombocytopenia, a defect in platelet function, and propensity to develop AML.
o Mutation of CEBPA (the gene encoding CCAAT/enhancer binding protein, alpha; a granulocytic differentiation factor and member of the bZIP family) was described in a family with 3 members affected by myelogenous leukemia (AML).5
o Some hereditary cancer syndromes, such as Li-Fraumeni syndrome, can manifest as leukemia. However, cases of leukemia are less common than the solid tumors that generally characterize these syndromes.
* Environmental exposures
o Several studies demonstrate a relationship between radiation exposure and leukemia.
o Early radiologists (before the use of appropriate shielding) were found to have an increased likelihood of developing leukemia.
o Patients receiving therapeutic irradiation for ankylosing spondylitis were at increased risk of leukemia.
o Survivors of the atomic bomb explosions in Japan were at a markedly increased risk for the development of leukemia.
o Persons who smoke have a small but statistically significant (odds ratio, 1.5) increased risk of developing myelogenous leukemia (AML). In several studies, the risk of AML was slightly increased in people who smoked compared with those who did not smoke.
o Exposure to benzene is associated with aplastic anemia and pancytopenia. These patients often develop AML. Many of these patients demonstrate M6 morphology.
* Previous exposure to chemotherapeutic agents for another malignancy
o As more patients with cancer survive their primary malignancy and more patients receive intensive chemotherapy (including bone marrow transplantation [BMT]), the number of patients with myelogenous leukemia (AML) increases because of exposure to chemotherapeutic agents. For example, the cumulative incidence of acute leukemia in patients with breast cancer who were treated with doxorubicin and cyclophosphamide as adjuvant therapy was 0.2-1.0% at 5 years.6
o Patients with previous exposure to chemotherapeutic agents can be divided into 2 groups: (1) those with previous exposure to alkylating agents and (2) those with exposure to topoisomerase-II inhibitors.
o Patients with a previous exposure to alkylating agents, with or without radiation, often have a myelodysplastic phase before the development of myelogenous leukemia (AML). Cytogenetics testing frequently reveals -5 and/or -7 (5q- or monosomy 7).
o Patients with a previous exposure to topoisomerase-II inhibitors do not have a myelodysplastic phase. Cytogenetics testing reveals a translocation that involves chromosome band 11q23. Less commonly, patients developed leukemia with other balanced translocations, such as inversion 16 or t(15;17).7
o The typical latency period between drug exposure and acute leukemia is approximately 3-5 years for alkylating agents/radiation exposure, but it is only 9-12 months for topoisomerase inhibitors.


Chronic Myelogenous Leukemia


Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Leukemia.

Chronic myelogenous leukemia (CML) is an acquired abnormality that involves the hematopoietic stem cell. It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9; t(9;22). The translocation results in a shortened chromosome 22, an observation first described by Nowell and Hungerford and subsequently termed the Philadelphia (Ph) chromosome after the city of discovery.

This translocation relocates an oncogene called abl from the long arm of chromosome 9 to the long arm of chromosome 22 in the BCR region. The resulting BCR/ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. The expression of this protein leads to the development of the chronic myelogenous leukemia (CML) phenotype through processes that are not yet fully understood.1,2,3,4,5,6,7,8

The presence of BCR/ABL rearrangement is the hallmark of chronic myelogenous leukemia (CML), although this rearrangement has also been described in other diseases. It is considered diagnostic when present in a patient with clinical manifestations of CML.
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Chronic myelogenous leukemia (CML) accounts for 20% of all leukemias affecting adults. It typically affects middle-aged individuals. Although uncommon, the disease also occurs in younger individuals.

Increased incidence of chronic myelogenous leukemia (CML) was reported among individuals exposed to radiation in Nagasaki and Hiroshima after the dropping of the atomic bomb.

Generally, 3 phases of chronic myelogenous leukemia (CML) are recognized. The general course of the disease is characterized by an eventual evolution to a refractory form of acute myelogenous or, occasionally, lymphoblastic leukemia. The median survival of patients using older forms of therapy is 3-5 years.

* Most patients with chronic myelogenous leukemia (CML) present in the chronic phase, characterized by splenomegaly and leukocytosis (see image below) with generally few symptoms.

Blood film at 400X magnification demonstrates leu...
Blood film at 400X magnification demonstrates leukocytosis with the presence of precursor cells of the myeloid lineage. In addition, basophilia, eosinophilia, and thrombocytosis can be seen. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.


Blood film at 400X magnification demonstrates leu...

Blood film at 400X magnification demonstrates leukocytosis with the presence of precursor cells of the myeloid lineage. In addition, basophilia, eosinophilia, and thrombocytosis can be seen. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
* This phase is easily controlled by medication. The major goal of treatment during this phase is to control symptoms and complications resulting from anemia, thrombocytopenia, leukocytosis, and splenomegaly. Newer forms of therapy aim at delaying the onset of the accelerated or blastic phase.
* After an average of 3-5 years, chronic myelogenous leukemia (CML) usually evolves into the blast crisis, which is marked by an increase in the bone marrow or peripheral blood blast count or by the development of soft-tissue or skin leukemic infiltrates. Typical symptoms are due to increasing anemia, thrombocytopenia, basophilia, a rapidly enlarging spleen, and failure of the usual medications to control leukocytosis and splenomegaly. The manifestations of blast crisis are similar to those of acute leukemia. Treatment results are unsatisfactory, and most patients succumb to the disease once this phase develops.
* In approximately two thirds of cases, the blasts are myeloid. However, in the remaining one third of patients, the blasts exhibit a lymphoid phenotype, further evidence of the stem cell nature of the original disease. Additional chromosomal abnormalities are usually found at the time of blast crisis, including additional Ph chromosomes or other translocations.
* In many patients, an accelerated phase occurs 3-6 months before the diagnosis of blast crisis. Clinical features in this phase are intermediate between the chronic phase and blast crisis.


* In general, chronic myelogenous leukemia (CML) occurs in the fourth and fifth decades of life.
* Younger patients aged 20-29 years may be affected and may present with a more aggressive form, such as in accelerated phase or blast crisis.
* Uncommonly, chronic myelogenous leukemia (CML) may appear as a disease of new onset in elderly individuals.


* The clinical manifestations of chronic myelogenous leukemia (CML) are insidious and are often discovered incidentally when an elevated white blood cell (WBC) count is revealed by a routine blood count or when an enlarged spleen is revealed during a general physical examination.
* Nonspecific symptoms of tiredness, fatigue, and weight loss may occur long after the onset of the disease. Loss of energy and decreased exercise tolerance may occur during the chronic phase after several months.
* Patients often have symptoms related to enlargement of the spleen, liver, or both.
o The large spleen may encroach on the stomach and cause early satiety and decreased food intake. Left upper quadrant abdominal pain described as "gripping" may occur from spleen infarction. The enlarged spleen may also be associated with a hypermetabolic state, fever, weight loss, and chronic fatigue.
o The enlarged liver may contribute to the patient's weight loss.
* Some patients with chronic myelogenous leukemia (CML) may have low-grade fever and excessive sweating related to hypermetabolism.
* The disease has 3 clinical phases, and chronic myelogenous leukemia (CML) follows a typical course of an initial chronic phase, during which the disease process is easily controlled; followed by a transitional and unstable course (accelerated phase); and, finally, a more aggressive course (blast crisis), which is usually fatal.
o Most patients are diagnosed while still in the chronic phase. The WBC count is usually controlled with medication (hematologic remission). This phase varies in duration depending on the maintenance therapy used. It usually lasts 2-3 years with hydroxyurea (Hydrea) or busulfan therapy, but the chronic phase has lasted for longer than 9.5 years in patients who respond well to interferon alfa therapy. Furthermore, the addition of imatinib mesylate in recent years has dramatically improved the duration of hematologic and, indeed, cytogenetic remissions.
o Some patients with chronic myelogenous leukemia (CML) progress to a transitional or accelerated phase, which may last for several months. The survival of patients diagnosed in this phase is 1-1.5 years. This phase is characterized by poor control of the blood counts with myelosuppressive medication and the appearance of peripheral blast cells (>15%), promyelocytes (>30%), basophils (>20%), and platelet counts less than 100,000 cells/μL unrelated to therapy. Promyelocytes and basophils are shown in the image below.

Blood film at 1000X magnification shows a promyel...
Blood film at 1000X magnification shows a promyelocyte, an eosinophil, and 3 basophils. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.


Blood film at 1000X magnification shows a promyel...

Blood film at 1000X magnification shows a promyelocyte, an eosinophil, and 3 basophils. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
o Usually, the doses of the medications need to be increased. Splenomegaly may not be controllable by medications, and anemia can worsen. Bone pain and fever, as well as an increase in bone marrow fibrosis, are harbingers of the last phase. Thus, signs of transformation or accelerated phase in patients with chronic myelogenous leukemia are poor control of blood counts with myelosuppression or interferon, increasing blast cells in peripheral blood with basophilia and thrombocytopenia not related to therapy, new cytogenetic abnormalities, and increasing splenomegaly and myelofibrosis.
o Acute phase, or blast crisis, is similar to acute leukemia, and survival is 3-6 months at this stage. Bone marrow and peripheral blood blasts of 30% or more are characteristic. Skin or tissue infiltration also defines blast crisis. Cytogenetic evidence of another Ph-positive clone (double) or clonal evolution (other cytogenetic abnormalities such as trisomy 8, 9, 19, or 21, isochromosome 17, or deletion of Y chromosome) is usually present.
* In some patients who present in the accelerated, or acute, leukemia phase of the disease (skipping the chronic phase), bleeding, petechiae, and ecchymoses may be the prominent symptoms. In these situations, fever is usually associated with infections.


* Splenomegaly is the most common physical finding in patients with chronic myelogenous leukemia (CML).
o In more than 50% of the patients with CML, the spleen extends more than 5 cm below the left costal margin at time of discovery.
o The size of the spleen correlates with the peripheral blood granulocyte counts (see image below), with the largest spleens being observed in patients with high WBC counts.

Blood film at 1000X magnification demonstrates th...
Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.


Blood film at 1000X magnification demonstrates th...

Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
o A very large spleen is usually a harbinger of the transformation into an acute blast crisis form of the disease.
* Hepatomegaly also occurs, although less commonly than splenomegaly. Hepatomegaly is usually part of the extramedullary hematopoiesis occurring in the spleen.
* Physical findings of leukostasis and hyperviscosity can occur in some patients, with extraordinary elevation of their WBC counts, exceeding 300,000-600,000 cells/μL. Upon funduscopy, the retina may show papilledema, venous obstruction, and hemorrhages.


* The initiating factor of CML is still unknown, but exposure to irradiation has been implicated, as observed in the increased prevalence among survivors of the atomic bombing of Hiroshima and Nagasaki.
* Other agents, such as benzene, are possible causes.


Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes. It is the most common form of leukemia found in adults in Western countries.1 See histologic sample in the image below.

Peripheral smear from a patient with chronic lymp...
Peripheral smear from a patient with chronic lymphocytic leukemia, small lymphocytic variety.


Peripheral smear from a patient with chronic lymp...

Peripheral smear from a patient with chronic lymphocytic leukemia, small lymphocytic variety.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Leukemia and Lymphoma.

The cells of origin in the majority of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) are clonal B cells arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells. Morphologically in the peripheral blood, these cells resemble mature lymphocytes.

B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) lymphocytes typically show B-cell surface antigens, as demonstrated by CD19, CD20, CD21, and CD23 monoclonal antibodies. In addition, they express CD5, which is more typically found on T cells. Because normal CD5+ B cells are present in the mantle zone (MZ) of lymphoid follicles, B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is most likely a malignancy of an MZ-based subpopulation of anergic self-reactive cells devoted to the production of polyreactive natural autoantibodies.

B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) cells express extremely low levels of surface membrane immunoglobulin, most often immunoglobulin M (IgM) or IgM/IgD and IgD. Additionally, they also express extremely low levels of a single immunoglobulin light chain (kappa or lambda).

An abnormal karyotype is observed in the majority of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). The most common abnormality is deletion of 13q, which occurs in more than 50% of patients. Individuals showing 13q14 abnormalities have a relatively benign disease that usually manifests as stable or slowly progressive isolated lymphocytosis.

The presence of trisomy 12, which is observed in 15% of patients, is associated with atypical morphology and progressive disease. Deletion in the short arm of chromosome 17 has been associated with rapid progression, short remission, and decreased overall survival in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). 17p13 deletions are associated with loss of function of the tumor suppressor gene p53. Deletions of bands 11q22-q23, observed in 19% of patients, are associated with extensive lymph node involvement, aggressive disease, and shorter survival.

More sensitive techniques have demonstrated abnormalities of chromosome 12. Forty to 50% of patients demonstrate no chromosomal abnormalities on conventional cytogenetic studies. However, 80% of patients will have abnormalities detectable by fluorescence in situ hybridization (FISH). Approximately 2-5% of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) exhibit a T-cell phenotype.

Studies have demonstrated that the protooncogene bcl2 is overexpressed in B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).2 The protooncogene bcl2 is a known suppressor of apoptosis (programmed cell death), resulting in a long life for the involved cells. Despite the frequent overexpression of bcl-2 protein, genetic translocations that are known to result in the overexpression of bcl2, such as t(14;18), are not found in patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).

Studies have shown that this upregulation in bcl2 is related to deletions of band 13q14. Two genes, named miRNA15a and miRNA16-1, are located at 13q14 and have been shown to encode not for proteins, but rather for a regulatory RNA called microRNA (miRNA).3,4 These miRNA genes belong to a family of highly conserved noncoding genes throughout the genome whose transcripts inhibit gene expression by causing degradation of mRNA or by blocking transcription of mRNA. Deletions of miRNA15a and miRNA16-1 lead to overexpression of bcl2 through loss of downregulating miRNAs. Genetic analyses have demonstrated deletion or downregulation of these miRNA genes in 70% of cases of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).

Investigations have also identified a number of high-risk genetic features and markers that include germline immunoglobulin variable heavy chain (IgVH), IgVH V3-21 gene usage, increased CD38 expression, increased Zap70 expression, elevated serum beta-2-microglobulin levels, increased serum thymidine kinase activity, short lymphocyte doubling time (<6 mo), and increased serum levels of soluble CD23. These features have been associated with rapid progression, short remission, resistance to treatment, and shortened overall survival in patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).

Germline IgVH has been shown to indicate a poor prognosis. Studies have shown that these patients also have earlier progression of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) after treatment with chemotherapy. The use of certain IgV H genes, V3-21, have also been associated with poor prognosis regardless of IgV H mutational status.

Zeta-associated peptide of 70 kilodaltons (Zap70) is a cytoplasmic tyrosine kinase whose expression has been associated with a poor prognosis. Cells with germline IgV H often have an increased expression of Zap70; however, studies have shown discordance rates of 10-20% between IgV H mutational status and Zap70 expression levels. Elevated levels of Zap70 are believed to decrease the threshold for signaling through bcl2, thereby facilitating the antiapoptotic effects of bcl2. Zap70 function also appears to be dependent on heat shock protein 90 (hsp90), whose inhibition may provide a future therapeutic option.

Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) should also be distinguished from prolymphocytic leukemia, in which more than 65% of the cells are morphologically less mature prolymphocytes.
United States

More than 17,000 new cases of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) are reported every year. The true incidence in the US is unknown and is likely higher, as estimates of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) incidence come from tumor registries, and many cases are not reported. One case series had the actual incidence at 38% higher than estimated from tumor registries.

Unlike the incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) in Western countries, which is similar to that of the United States, chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is extremely rare in Asian countries (ie, China, Japan), where it is estimated to comprise only 10% of all leukemias. However, underreporting and incomplete registry may significantly underestimate the true incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) in these countries.

* The natural history of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is heterogeneous.
* Some patients die rapidly, within 2-3 years of diagnosis, because of complications from chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).
* The majority of patients live 5-10 years, with an initial course that is relatively benign but followed by a terminal, progressive, and resistant phase lasting 1-2 years. During the later phase, morbidity is considerable, both from the disease and from complications of therapy.5,6


The incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is higher among whites compared with blacks.

The incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is higher in males than in females, with a male-to-female ratio of 1.7:1.

* Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is a disease that primarily affects elderly individuals, with the majority of cases reported in individuals older than 55 years. The incidence continues to rise in those older than 55 years.
* However, there are reports that individuals aged 35 years or younger are being diagnosed with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) more frequently.


Patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) present with a wide range of symptoms and signs at presentation. Onset is insidious, and it is not unusual for chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) to be discovered incidentally after a blood cell count is performed for another reason; 25-50% of patients will be asymptomatic at time of presentation.

Symptoms and signs of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) may include the following:

* A predisposition to repeated infections such as pneumonia, herpes simplex labialis, and herpes zoster may be noted.
* Enlarged lymph nodes are the most common presenting symptom, seen in 87% of patients symptomatic at time of diagnosis.
* Early satiety and/or abdominal discomfort may be related to an enlarged spleen.
* Mucocutaneous bleeding and/or petechiae may be due to thrombocytopenia.
* Tiredness and fatigue may be present secondary to anemia.
* Fevers, chills, and night sweats and weight loss constitute B symptoms seen in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).
* Ten percent of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) will present with an autoimmune hemolytic anemia.


* Localized or generalized lymphadenopathy (80-90% of cases)
o Splenomegaly (30-54% of cases)
o Hepatomegaly (10-20% of cases)
o Petechiae
o Pallor


* As in the case of most malignancies, the exact cause of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is uncertain.
* The protooncogene bcl2 is known to be overexpressed, which leads to suppression of apoptosis (programmed cell death) in the affected lymphoid cells. In the majority of cases, this appears to be secondary to alterations in the expression of the miRNAs MIRN15a and MIRN16-1.
* Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is an acquired disorder, and reports of truly familial cases are exceedingly rare.7


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