Ped Lapkas

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CASE REPORT

Presenter : Sasikala S Balakrishnan

Yeoh Shu TIng

Day/Date : Wednesday, 28th of August 2013

Supervisor : dr. Tina Christina. L. Tobing , Sp.A(K)

CHAPTER I

INTRODUCTION

1.1. BACKGROUND

The term thalassemia is derived from the Greek words Thalassa (sea)

and Haema (blood) and refers to disorders associated with defective synthesis of

alpha- or beta-globin subunits of hemoglobin (Hb)A(alpha2; beta2), inherited as

pathologic alleles of one or more of the globin genes located on chromosomes 11

(beta) and 16 (alpha). More than 200 deletions or point mutations that impair

transcription, processing, or translation of alpha- or beta-globin mRNA have been

identified. The clinical manifestations are diverse, ranging from absence of

symptoms to profound fatal anemias in utero, or, if untreated, in early childhood.

Thalassemias are genetic disorders in globin chain production, inherited

autosomal recessive blood disease. In thalassemia, the genetic defect results in

reduced rate of synthesis of one of the globin chains that make up hemoglobin.

Reduced synthesis of one of the globin chains causes the formation of abnormal

hemoglobin molecules, and this in turn causes the anemia which is the

characteristic presenting symptom of the thalassemias.1,2Thalassemia was first defined in 1925 when Dr. Thomas B. Cooley

described five young children with severe anemia, splenomegaly, and unusual

bone abnormalities and called the disorder erythroblastic or Mediterranean anemia

because of circulating nucleated red blood cells and because all of his patients

were of Italian or Greek ethnicity. In 1932 Whipple and Bradford coined the term

thalassemia from the Greek word thalassa, which means the sea (Mediterranean)

to describe this entity. Somewhat later, a mild microcytic anemia was described in

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families of Cooley anemia patients, and it was soon realized that this disorder was

caused by heterozygous inheritance of abnormal genes that, when homozygous,

produced severe Cooley anemia.2,3

In Europe, Riette described Italian children with unexplained mild

hypochromic and microcytic anemia in the same year Cooley reported the severe

form of anemia later named after him. In addition, Wintrobe and coworkers in the

United States reported a mild anemia in both parents of a child with Cooley

anemia. This anemia was similar to the one that Riette described in Italy. Only

then was Cooley's severe anemia recognized as the homozygous form of the mild

hypochromic and microcytic anemia that Riette and Wintrobe described. This

severe form was then labeled as thalassemia major and the mild form as

thalassemia minor. These initial patients are now recognized to have been

afflicted with thalassemia. In the following few years, different types of

thalassemia that involved polypeptide chains other than chains were recognized

and described in detail. In recent years, the molecular biology and genetics of the

thalassemia syndromes have been described in detail, revealing the wide range of

mutations encountered in each type of thalassemia.2,4

Pericardial effusion is a common finding in everyday clinical practice. The

first challenge to the clinician is to try to establish an etiologic diagnosis.

Sometimes, the pericardial effusion can be easily related to a known underlying

disease, such as acute myocardial infarction, cardiac surgery, end-stage renal

disease or widespread metastatic neoplasm. When no obvious cause is apparent,

some clinical findings can be useful to establish a diagnosis of probability.

The presence of acute inflammatory signs (chest pain, fever, pericardial

friction rub) is predictive for acute idiopathic pericarditis irrespective of the size

of the effusion or the presence or absence of tamponade. Severe effusion with

absence of inflammatory signs and absence of tamponade is predictive for chronic

idiopathic pericardial effusion, and tamponade without inflammatory signs for

neoplastic pericardial effusion. Epidemiologic considerations are very important,

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as in developed countries acute idiopathic pericarditis and idiopathic pericardial

effusion are the most common etiologies, but in some underdeveloped geographic

areas tuberculous pericarditis is the leading cause of pericardial effusion. The

second point is the evaluation of the hemodynamic compromise caused by

pericardial fluid. Cardiac tamponade is not an all or none phenomenon, but a

syndrome with a continuum of severity ranging from an asymptomatic elevation

of intrapericardial pressure detectable only through hemodynamic methods to a

clinical tamponade recognized by the presence of dyspnea, tachycardia, jugular

venous distension, pulsus paradoxus and in the more severe cases arterial

hypotension and shock. In the middle, echocardiographic tamponade is

recognized by the presence of cardiac chamber collapses and characteristic

alterations in respiratory variations of mitral and tricuspid flow. Medical treatment

of pericardial effusion is mainly dictated by the presence of inflammatory signs

and by the underlying disease if present. Pericardial drainage is mandatory when

clinical tamponade is present. In the absence of clinical tamponade, examination

of the pericardial fluid is indicated when there is a clinical suspicion of purulent

pericarditis and in patients with underlying neoplasia. Patients with chronic

massive idiopathic pericardial effusion should also be submitted to pericardial

drainage because of the risk of developing unexpected tamponade. The selection

of the pericardial drainage procedure depends on the etiology of the effusion.

Simple pericardiocentesis is usually sufficient in patients with acute idiopathic or

viral pericarditis. Purulent pericarditis should be drained surgically, usually

through subxiphoid pericardiotomy. Neoplastic pericardial effusion constitutes a

more difficult challenge because reaccumulation of pericardial fluid is a concern.

The therapeutic possibilities include extended indwelling pericardial catheter,

percutaneous pericardiostomy and intrapericardial instillation of antineoplastic

and sclerosing agents. Massive chronic idiopathic pericardial effusions do not

respond to medical treatment and tend to recur after pericardiocentesis, so wide

anterior pericardiectomy is finally necessary in many cases. 5

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CHAPTER II

LITERATURE REVIEW

2.1. THALASSEMIA

2.1.1. DEFINITION

Thalassemia syndromes are inherited genetic diseases caused by mutation

of alpha or beta globin genes, which result in abnormal hemoglobin synthesis. The

patho-physiologic mechanisms can be divided into decreased production of par-

ticular types of hemoglobin (Thalassemias) and production of abnormal structure

of hemoglobin types (Hemoglobinopathies). These lead to not only abnormal

morphologic of erythrocytes (red blood cells), but also shorten life span of

erythrocytes due to increased in vivo fragility and extra-vascular red cell

destruction (hemolysis) along with ineffective erythropoiesis (bizarre, dys-

functional marrow production). Thalassemia gene is an autosomal inheritance,

which implies that both parents of the affected child must have a silent carrier

state, so called thalassemia trait or hetero- zygote, while they are both

asymptomatic.

2.1.2. EPIDEMIOLOGY

Certain types of thalassemia are more common in specific parts of the

world. thalassemia is much more common in Mediterranean countries such as

Greece, Italy, and Spain. Many Mediterranean islands, including Cyprus,

Sardinia, and Malta, have a significantly high incidence of severe thalassemia,

constituting a major public health problem. For instance, in Cyprus, 1 in 7

individuals carries the gene, which translates into 1 in 49 marriages between

carriers and 1 in 158 newborns expected to have b thalassemia major. As a result,

preventive measures established and enforced by public health authorities have

been very effective in decreasing the incidence among their populations. B

thalassemia is also common in North Africa, the Middle East, India, and Eastern

Europe.

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Conversely, thalassemia is more common in Southeast Asia, India, the

Middle East, and Africa. Worldwide, 15 million people have clinically apparent

thalassemic disorders. Reportedly, disorders worldwide, and people who carry

thalassemia in India alone number approximately 30 million. These facts confirm

that thalassemias are among the most common genetic disorders in humans; they

are encountered among all ethnic groups and in almost every country around the

world.2,4,5

Although -thalassemia has >200 mutations, most are rare. Approximately

20 common alleles constitute 80% of the known thalassemias worldwide; 3% of

the world's population carries genes for -thalassemia, and in Southeast Asia, 5

10% of the population carries genes for -thalassemia. In a particular area there

are fewer common alleles. In the U.S., an estimated 2,000 individuals have -

thalassemia.1

2.1.3. AETIOLOGY

Thalassemia syndromes are characterized by varying degrees of ineffective

hematopoiesis and increased hemolysis. Clinical syndromes are divided into -

and -thalassemias, each with varying numbers of their respective globin genes

mutated. There is a wide array of genetic defects and a corresponding diversity of

clinical syndromes. Most -thalassemias are due to point mutations in one or both

of the two -globin genes (chromosome 11), which can affect every step in the

pathway of -globin expression from initiation of transcription to messenger RNA

synthesis to translation and post translation modification. Picture below shows the

organization of the genes (i.e., and , which are active in embryonic and fetal

life, respectively) and activation of the genes in the locus control region (LCR),

which promote transcription of the -globin gene. There are four genes for -

globin synthesis (two on each chromosome 16). Most -thalassemia syndromes

are due to deletion of one or more of the -globin genes rather than to point

mutations. Mutations of -globin genes occur predominantly in children of

Mediterranean, Southern, and Southeast Asian ancestry. Those of -globin are

most common in those of Southeast Asian and African ancestry.6

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(source:Manual of Pediatric Hematology and Oncology)

Major deletions in thalassemia are unusual (in contrast to thalassemia),

and most of the encountered mutations are single base changes, small deletions, or

insertions of 1-2 bases at a critical site along the gene, as in the image below.

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(source: Thalassemia, Emedicine Multimedia)

2.1.4. CLASSIFICATION

The thalassemias can be defined as a heterogeneous group of genetic

disorders of hemoglobin synthesis, all of which result from a reduced rate of

production of one or more of the globin chains of hemoglobin. This basic defect

results in imbalanced globin chain synthesis, which is the hallmark of all forms of

thalassemia. The thalassemias can be classified at different levels. Clinically, it is

useful to divide them into three groups: the severe transfusion-dependent (major)

varieties; the symptomless carrier states (minor) varieties; and a group of

conditions of intermediate severity that fall under the loose heading thalassemia

intermedia. This classification is retained because it has implications for both

diagnosis and management.4

-THALASSEMIA2,8

The -thalassemia syndromes are caused by abnormalities of the b-gene

complex on chromosome 11. More than 150 different mutations have been

described, and most of these are small nucleotide substitutions within the b gene

complex. Deletions and mutations that result in abnormal cleavage or splicing of

-globin RNA may also result in thalassemia characterized by absent (0) or

reduced (+) production of -globin chains.2,7

THALASSEMIA MINOR (THALASSEMIA TRAIT)

Heterozygosity for a b-thalassemia gene results in a mild reduction of b-

chain synthesis and, therefore, a reduction in HbA and mild anemia. Hemoglobin

levels are 10 to 20 g/L lower than that of normal persons of the same age and

gender, but the anemia may worsen during pregnancy. This mild anemia usually

produces no symptoms, and longevity is normal. Thalassemia trait is almost

always accompanied by familial microcytosis and hypochromia of the red blood

cells. Target cells, elliptocytes, and basophilic stippling are seen on the peripheral

blood smear. Almost all individuals with b-thalassemia trait have MCVs less than

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75 fL, and mean MCV is 68 fL. In thalassemia trait the MCV is disproportionately

low for the degree of anemia because of a red blood cell count that is normal or

increased. The RDW is normal in thalassemia trait. The ratio of MCV/RBC

(Mentzer index) is 12 in iron deficiency. Iron studies

are normal. In an individual with microcytic red blood cells, a diagnosis of b-

thalassemia trait is confirmed by an elevated HbA2 (22) level. The normal level

of HbA2 is 1.5 to 3.4%, and HbA2 >3.5% is diagnostic of the most common form

of -thalassemia trait. Levels of HbF (22) are normal (


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ineffective erythropoiesis that are a consequence of unbalanced globin chain

synthesis. In homozygous -thalassemia, -globin chains are produced in normal

amounts and accumulate, denature, and precipitate in the RBC precursors in the

bone marrow and circulating RBC. These precipitated -globin chains damage the

RBC membrane, resulting in destruction within the bone marrow (ineffective

erythropoiesis) and in the peripheral blood.

The fetus and the newborn infant with homozygous -thalassemia are

clinically and hematologically normal. In vitro measurements demonstrate

reduced or absent -chain synthesis. Increasingly, homozygous -thalassemia is

being diagnosed in the United States by neonatal electrophoretic hemoglobin

screening that shows only HbF and no HbA Symptoms of -thalassemia major

develop gradually in the first 6 to 12 months after birth, when the normal

postnatal switchover from -chains to -chains results in a decreased level of

HbF). By the age of 6 to 12 months, most affected infants show pallor, irritability,

growth retardation, jaundice, and hepatosplenomegaly as a result of

extramedullary hematopoiesis. By 2 years of age, 90% of infants are symptomatic,

and progressive changes in the facial and cranial bones develop. The hemoglobin

level may be as low as 30 to 50 g/L at the time of diagnosis.

Other varian of -thalassemia are:6

Silent carrier thalassemia: Similar to patients who silently carry

thalassemia, these patients have no symptoms, except for possible low

RBC indices. The mutation that causes the thalassemia is very mild and

represents a + thalassemia.

Thalassemia intermedia: This condition is usually due to a compound

heterozygous state, resulting in anemia of intermediate severity, which

typically does not require regular blood transfusions.

thalassemia associated with chain structural variants: The most

significant condition in this group of thalassemic syndromes is the Hb E/

thalassemia, which may vary in its clinical severity from as mild as

thalassemia intermedia to as severe as thalassemia major.

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-THALASSEMIA2,9

The a-thalassemia syndromes are prevalent in people from Southeast Asia

and usually result from deletion of one or more of the four -globin genes on

chromosome 16. In general, the severity is proportional to the number of -globin

genes deleted which can be quantitated by DNA analysis.1,6

SILENT CARRIER (2-THALASSEMIA TRAIT, - /)

Individuals with a single -globin gene deletion are clinically and

hematologically normal, but they may be identified at birth by the presence of

small amounts (1-3%) of the fast-migrating Barts hemoglobin (4) by neonatal

hemoglobin electrophoresis. In later life, the diagnosis can be established only by

determining the number of a-globin genes by DNA analysis.

1-THALASSEMIA TRAIT (-/- OR --/)

Individuals in whom two of four -globin genes are deleted have mild

microcytic anemia. At birth, relative microcytosis with 5 to 8% of HbBarts is

present. Barts hemoglobin disappears by 3 to 6 months of age, and the

hemoglobin electrophoresis becomes normal. After the newborn period, a

definitive diagnosis may be impractical in this mild disorder, and the diagnosis is

usually suspected when other causes of microcytic anemia, such as -thalassemia

trait or iron deficiency, are ruled out.

1-Thalassemia trait can occur in two ways: a cis-deletion in which the two

deleted a genes are on the same chromosome 16, and a trans-deletion in which

one a-gene is deleted from each of the 16 chromosomes. The cis-deletion is usual

in Southeast Asian populations, whereas the trans-deletions are usual in people of

African ethnicity. Thus, although -thalassemia commonly occurs in African

people, a maximum of only two genes can be deleted in any individual because of

the trans-configuration. Consequently, the more severe -thalassemia syndromes

associated with three and four -deletions are not seen.

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HEMOGLOBIN H DISEASE (--/-)

Three -globin gene deletions result in hemoglobin H disease, which is

associated with a marked imbalance between a- and -globin chain synthesis.

Excess free chains accumulate and combine to form an abnormal hemoglobin, a

tetramer of chains (4) called HbH. HbH is unstable and precipitates within red

blood cells, leading to chronic microcytic, hemolytic anemia. Laboratory findings

include a moderately severe microcytosic anemia (Hb 60-100 g/L with evidence

of hemolysis). Precipitated HbH can be demonstrated in the red blood cells with

supravital stains. On hemoglobin electrophoresis, HbH has a fast mobility and

accounts for 10 to 15% of the total hemoglobin.

FETAL HYDROPS SYNDROME (--/--)

Deletion of all four a-globin genes results in a syndrome of hydrops fetalis

with stillbirth or immediate postnatal death. In the absence of -chain synthesis,

such fetuses are incapable of synthesizing embryonic hemoglobins. At birth,

hemoglobin electrophoresis shows predominantly Barts hemoglobin (4) and small

amounts hemoglobin H (4) as well as embryonic hemoglobins. The high oxygen

affinity of Barts hemoglobin makes it oxygen transport ineffective, leading to the

intrauterine manifestations of severe hypoxia, out of proportion to the degree of

anemia. A number of infants with this syndrome who have been identified

prenatally and treated with intrauterine and postnatal transfusions have survived.

These infants are transfusion dependent, but some are developing normally. As in

thalassemia major, the only curative therapy is bone marrow transplantation.

Termination of the pregnancy is often recommended because of a high frequency

of severe maternal toxemia associated with a hydropic fetus.

Thalassemias can also be classified at the genetic level into the , , or

thalassemias, according to which globin chain is produced in reduced

amounts. In some thalassemias, no globin chain is synthesized at all, and hence

they are called 0 or 0 thalassemias, whereas in others some globin chain is

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produced but at a reduced rate; these are designated + or + thalassemias. The

thalassemias, in which there is defective and chain synthesis, can be

subdivided in the same way, i.e., into ()+ and ()0 varieties.4

(source:Pediatric Hematology)

2.1.5. PATHOGENESIS

The basic defect in all types of thalassemia is imbalanced globin chain

synthesis. However, the consequences of accumulation of the excessive globin

chains in the various types of thalassemia are different. In thalassemia,

excessive chains, unable to form Hb tetramers, precipitate in the RBC

precursors and, in one way or another, produce most of the manifestations

encountered in all of the thalassemia syndromes; this is not the situation in

thalassemia.

The excessive chains in thalassemia are chains earlier in life and chains

later in life. Because such chains are relatively soluble, they are able to form

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homotetramers that, although relatively unstable, nevertheless remain viable and

able to produce soluble Hb molecules such as Hb Bart (4 chains) and Hb H (4

chains). These basic differences in the 2 main types of thalassemia are responsible

for the major differences in their clinical manifestations and severity.

chains that accumulate in the RBC precursors are insoluble, precipitate in

the cell, interact with the membrane (causing significant damage), and interfere

with cell division. This leads to excessive intramedullary destruction of the RBC

precursors. In addition, the surviving cells that arrive in the peripheral blood with

intracellular inclusion bodies (excess chains) are subject to hemolysis; this means

that both hemolysis and ineffective erythropoiesis cause anemia in the person with

thalassemia.

The ability of some RBCs to maintain the production of chains, which are

capable of pairing with some of the excessive chains to produce Hb F, is

advantageous. Binding some of the excess a chains undoubtedly reduces the

symptoms of the disease and provides additional Hb with oxygen-carrying ability.

Furthermore, increased production of Hb F, in response to severe anemia,

adds another mechanism to protect the RBCs in persons with thalassemia. The

elevated Hb F level increases oxygen affinity, leading to hypoxia, which, together

with the profound anemia, stimulates the production of erythropoietin. As a result,

severe expansion of the ineffective erythroid mass leads to severe bone expansion

and deformities. Both iron absorption and metabolic rate increase, adding more

symptoms to the clinical and laboratory manifestations of the disease. The large

numbers of abnormal RBCs processed by the spleen, together with its

hematopoietic response to the anemia if untreated, results in massive

splenomegaly, leading to manifestations of hypersplenism.

If the chronic anemia in these patients is corrected with regular blood

transfusions, the severe expansion of the ineffective marrow is reversed. Adding a

second source of iron would theoretically result in more harm to the patient.

However, this is not the case because iron absorption is regulated by 2 major

factors: ineffective erythropoiesis and iron status in the patient.

Ineffective erythropoiesis results in increased absorption of iron because of

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downregulation of the HAMP gene, which produces a liver hormone called

hepcidin. Hepcidin regulates dietary iron absorption, plasma iron concentration,

and tissue iron distribution and is the major regulator of iron. It acts by causing

degradation of its receptor, the cellular iron exporter ferroportin. When ferroportin

is degraded, it decreases iron flow into the plasma from the gut, from

macrophages, and from hepatocytes, leading to a low plasma iron concentration.

In severe hepcidin deficiency, iron absorption is increased and macrophages are

usually iron depleted, such as is observed in patients with thalassemia intermedia.

Malfunctions of the hepcidin-ferroportin axis contribute to the etiology of

different anemias, such as is seen in thalassemia, anemia of inflammation, and

chronic renal diseases. Improvement and availability of hepcidin assays facilitates

diagnosis of such conditions. The development of hepcidin agonists and

antagonists may enhance the treatment of such anemias.

By administering blood transfusions, the ineffective erythropoiesis is

reversed, and the hepcidin level is increased; thus, iron absorption is decreased

and macrophages retain iron.

Iron status is another important factor that influences iron absorption. In

patients with iron overload (eg, hemochromatosis), the iron absorption decreases

because of an increased hepcidin level. However, this is not the case in patients

with severe thalassemia because a putative plasma factor overrides such

mechanisms and prevents the production of hepcidin. Thus, iron absorption

continues despite the iron overload status.

As mentioned above, the effect of hepcidin on iron recycling is carried

through its receptor "ferroportin," which exports iron from enterocytes and

macrophages to the plasma and exports iron from the placenta to the fetus.

Ferroportin is upregulated by iron stores and downregulated by hepcidin. This

relationship may also explain why patients with thalassemia who have similar

iron loads have different ferritin levels based on whether or not they receive

regular blood transfusions.

For example, patients with thalassemia intermedia who are not receiving

blood transfusions have lower ferritin levels than those with thalassemia major

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who are receiving regular transfusion regimens, despite a similar iron overload. In

the latter group, hepcidin allows recycling of the iron from the macrophages,

releasing high amounts of ferritin. In patients with thalassemia intermedia, in

whom the macrophages are depleted despite iron overload, lower amounts of

ferritin are released, resulting in a lower ferritin level.

Most nonheme iron in healthy individuals is bound tightly to its carrier

protein, transferrin. In iron overload conditions, such as severe thalassemia, the

transferrin becomes saturated, and free iron is found in the plasma. This iron is

harmful since it provides the material for the production of hydroxyl radicals and

additionally accumulates in various organs, such as the heart, endocrine glands,

and liver, resulting in significant damage to these organs.

2.1.6. CLINICAL MANIFESTATIONS

History

Thalassemia minor usually presents as an asymptomatic mild microcytic

anemia and is detected through routine blood tests. Thalassemia major is a severe

anemia that presents during the first few months after birth. Thalassemia minor

(beta thalassemia trait) usually is asymptomatic, and it typically is identified

during routine blood count evaluation. Thalassemia major (homozygous beta

thalassemia) is detected during the first few months of life, when the patient's

level of fetal Hb decreases.

Physical Examination

Patients with the beta thalassemia trait generally have no unusual physical

findings. The physical findings are related to severe anemia, ineffective

erythropoiesis, extramedullary hematopoiesis, and iron overload resulting from

transfusion and increased iron absorption. Skin may show pallor from anemia and

jaundice from hyperbilirubinemia. The skull and other bones may be deformed

secondary to erythroid hyperplasia with intramedullary expansion and cortical

bone thinning. Heart examination may reveal findings of cardiac failure and

arrhythmia, related to either severe anemia or iron overload. Abdominal

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examination may reveal changes in the liver, gall bladder, and spleen.1,2,5

Hepatomegaly related to significant extramedullary hematopoiesis typically

is observed. Patients who have received blood transfusions may have

hepatomegaly or chronic hepatitis due to iron overload; transfusion-associated

viral hepatitis resulting in cirrhosis or portal hypertension also may be seen. The

gall bladder may contain bilirubin stones formed as a result of the patient's life-

long hemolytic state. Splenomegaly typically is observed as part of the

extramedullary hematopoiesis or as a hypertrophic response related to the

extravascular hemolysis. Extremities may demonstrate skin ulceration. Iron

overload also may cause endocrine dysfunction, especially affecting the pancreas,

testes, and thyroid.11

2.1.7. DIAGNOSIS

1.History

The history in patients with thalassemia widely varies, depending on the severity

of the condition and the age at the time of diagnosis.

In most patients with thalassemia traits, no unusual signs or symptoms are

encountered.

Some patients, especially those with somewhat more severe forms of the

disease, manifest some pallor and slight icteric discoloration of the sclerae with

splenomegaly, leading to slight enlargement of the abdomen. An affected child's

parents or caregivers may report these symptoms. However, some rare types of

thalassemia trait are caused by a unique mutation, resulting in truncated or

elongated chains, which combine abnormally with chains, producing

insoluble dimers or tetramers. The outcome of such insoluble products is a

severe hemolytic process that needs to be managed like thalassemia intermedia

or, in some cases, thalassemia major.

The diagnosis is usually suspected in children with an unexplained

hypochromic and microcytic picture, especially those who belong to one of the

ethnic groups at risk. For this reason, physicians should always inquire about the

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patient's ethnic background, family history of hematologic disorders, and dietary

history.

Thalassemia should be considered in any child with hypochromic

microcytic anemia that does not respond to iron supplementation.

In more severe forms, such as thalassemia major, the symptoms vary

from extremely debilitating in patients who are not receiving transfusions to

mild and almost asymptomatic in those receiving regular transfusion regimens

and closely monitored chelation therapy.

Children with thalassemia major usually demonstrate none of the initial

symptoms until the later part of the first year of life (when chains are needed

to pair with chains to form hemoglobin (Hb) A, after chains production is

turned off). However, in occasional children younger than 3-5 years, the

condition may not be recognized because of the delay in cessation of Hb F

production.

Patients with Hb E/ thalassemia may present with severe symptoms and a

clinical course identical to that of patients with thalassemia major.

Alternatively, patients with Hb E/ thalassemia may run a mild course similar to

that of patients with thalassemia intermedia or minor. This difference in severity

has been described among siblings from the same parents. Some of the variation

in severity can be explained based on the different genotypes, such as the type of

thalassemia gene present (ie, + or -0), the co-inheritance of an thalassemia

gene, the high level of Hb F, or the presence of a modifying gene These changes

are caused by massive expansion of the bone due to the ineffective erythroid

production.

The ineffective erythropoiesis also creates a state of hypermetabolism

associated with fever and failure to thrive.

Occasionally, gout due to hyperuricemia, as well as kidney stones, are

seen more frequently as patients with thalassemia major are living longer.

Chronic anemia and exposure to chelating agents were thought to be blamed for

this complication.

Iron overload is one of the major causes of morbidity in all patients with

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severe forms of thalassemia, regardless of whether they are regularly transfused.

o In transfused patients, heavy iron turnover from transfused blood is

usually the cause; in nontransfused patients, this complication is usually

deferred until puberty (if the patient survives to that age).

o Increased iron absorption is the cause in nontransfused patients, but

the reason behind this phenomenon is not clear. Many believe that, despite the

iron overload state in these patients and the increased iron deposits in the bone

marrow, the requirement for iron to supply the overwhelming production of

ineffective erythrocytes is tremendous, causing significant increases in GI

absorption of iron.

o Bleeding tendency, increased susceptibility to infection, and organ

dysfunction are all associated with iron overload.

Poor growth in patients with thalassemia is due to multiple factors and

affects patients with well-controlled disease as well as those with uncontrolled

disease.

Patients may develop symptoms that suggest diabetes, thyroid disorder, or

other endocrinopathy; these are rarely the presenting reports.Patients with

thalassemia minor rarely demonstrate any physical abnormalities. Because the

anemia is never severe and, in most instances, the Hb level is not less than 9-10

g/dL, pallor and splenomegaly are rarely observed.

In patients with severe forms of thalassemia, the findings upon physical

examination widely vary, depending on how well the disease is controlled.

Findings include the following:

Children who are not receiving transfusions have a physical appearance so

characteristic that an expert examiner can often make a spot diagnosis.

In Cooley's original 4 patients, the stigmata of severe untreated

thalassemia major included the following:

o Severe anemia, with an Hb level of 3-7g/dL

o Massive hepatosplenomegaly

o Severe growth retardation

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o Bony deformities

These stigmata are typically not observed; instead, patients look healthy.

Any complication they develop is usually due to adverse effects of the treatment

(transfusion or chelation).

Bony abnormalities, such as frontal bossing, prominent facial bones, and

dental malocclusion, are usually striking.

Severe pallor, slight to moderately severe jaundice, and marked

hepatosplenomegaly are almost always present.Complications of severe anemia

are manifested as intolerance to exercise, heart murmur, or even signs of heart

failure. Growth retardation is a common finding, even in patients whose disease

is well controlled by chelation therapy. Patients with signs of iron overload may

also demonstrate signs of endocrinopathy caused by iron deposits. Diabetes and

thyroid or adrenal disorders have been described in these patients. In patients

with severe anemia who are not receiving transfusion therapy, neuropathy or

paralysis may result from compression of the spine or peripheral nerves by large

extramedullary hematopoietic masses.

2. Laboratory studies in thalassemia include the following:

The CBC count and peripheral blood film examination results are usually

sufficient to suspect the diagnosis. Hemoglobin (Hb) evaluation confirms the

diagnosis in thalassemia, Hb H disease, and Hb E/ thalassemia.

o In the severe forms of thalassemia, the Hb level ranges from 2-8

g/dL.

o Mean corpuscular volume (MCV) and mean corpuscular Hb

(MCH) are significantly low, but, unlike thalassemia trait, thalassemia major is

associated with a markedly elevated RDW, reflecting the extreme anisocytosis.

o The WBC count is usually elevated in thalassemia major; this is

due, in part, to miscounting the many nucleated RBCs as leukocytes.

Leukocytosis is usually present, even after excluding the nucleated RBCs. A

shift to the left is also encountered, reflecting the hemolytic process.

o Platelet count is usually normal, unless the spleen is markedly

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enlarged.

o Peripheral blood film examination reveals marked hypochromasia

and microcytosis, hypochromic macrocytes that represent the

polychromatophilic cells, nucleated RBCs, basophilic stippling, and occasional

immature leukocytes, as shown below.

o

Peripheral blood film in Cooley anemia.

o Contrast this with the abnormalities associated with Hb H, an

thalassemia, shownbelow.

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Supra vital stain in hemoglobin H disease that reveals Heinz bodies (golf ball

appearance).

o Hb electrophoresis usually reveals an elevated Hb F fraction,

which is distributed heterogeneously in the RBCs of patients with

thalassemia, Hb H in patients with Hb H disease, and Hb Bart in newborns

with thalassemia trait. In -0 thalassemia, no Hb A is usually present; only

Hb A2 and Hb F are found.

Iron studies are as follows:

o Serum iron level is elevated, with saturation reaching as high as

80%.

o The serum ferritin level, which is frequently used to monitor the

status of iron overload, is also elevated. However, an assessment using serum

ferritin levels may underestimate the iron concentration in the liver of a

transfusion-independent patient with thalassemia.

Complete RBC phenotype, hepatitis screen, folic acid level, and human

leukocyte antigen (HLA) typing are recommended before initiation of blood

transfusion therapy.9

3.Imaging Studies

Skeletal survey and other imaging studies reveal classic changes of the bones that

are usually encountered in patients who are not regularly transfused.

The striking expansion of the erythroid marrow widens the marrow spaces,

thinning the cortex and causing osteoporosis. These changes, which result from

the expanding marrow spaces, usually disappear when marrow activity is halted

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by regular transfusions. Osteoporosis and osteopenia may cause fractures, even in

patients whose conditions are well-controlled.

In addition to the classic "hair on end" appearance of the skull, shown

below, which results from widening of the diploic spaces and observed on plain

radiographs, the maxilla may overgrow, which results in maxillary overbite,

prominence of the upper incisors, and separation of the orbit. These changes

contribute to the classic "chipmunk facies observed in patients with thalassemia

major

The classic "hair on end" appearance on plain skull radiographs of a patient with

Cooley anemia.

Other bony structures, such as ribs, long bones, and flat bones, may also

be sites of major deformities. Plain radiographs of the long bones may reveal a

lacy trabecular pattern. Changes in the pelvis, skull, and spine become more

evident during the second decade of life, when the marrow in the peripheral bones

becomes inactive while more activity occurs in the central bones.

Compression fractures and paravertebral expansion of extramedullary

masses, which could behave clinically like tumors, more frequently occur during

the second decade of life. In a recent study from Thailand, investigating

unrecognized vertebral fractures in adolescents and young adults with thalassemia

syndrome, 13% of the patients studied were found to have fractures and 30% of

them had multiple vertebral fractures. Those who were thought to be older had

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more severe disease, were splenectomized, and had been on chelation therapy for

a longer time.

MRI and CT scanning are usually used in diagnosing such complications.

Chest radiography is used to evaluate cardiac size and shape. MRI and CT

scanning can be used as noninvasive means to evaluate the amount of iron in the

liver in patients receiving chelation therapy.

A newer non invasive procedure involves measuring the cardiac T2* with

cardiac magnetic resonance (CMR). This procedure has shown decreased values

in cardiac T2* due to iron deposit in the heart. Unlike liver MRI, which usually

correlates very well with the iron concentration in the liver measured using

percutaneous liver biopsy samples and the serum ferritin level, CMR does not

correlate well with the ferritin level, the liver iron level, or echocardiography

findings. This suggests that cardiac iron overload cannot be estimated with these

surrogate measurements. This is also true in measuring the response to chelation

therapy in patients with iron overload. The liver is clear of iron loading much

earlier than the heart, which also suggests that deciding when to stop or reduce

treatment based on liver iron levels is misleading.

The relationship between hepatic and myocardial iron concentration was

assessed by T2-MRI in patients receiving chronic transfusion. A poor correlation

was noted, and approximately 14% of patients with cardiac iron overload were

identified who had no matched degree of hepatic hemosiderosis. Left ventricular

ejection fraction (LVEF) was insensitive for detecting high myocardial iron. For

this reason, cardiac evaluation should be addressed separately.

T2* MRI technique (T2* is the time needed for the organ to lose two

thirds of its signal, and it is measured in milliseconds (ms); when iron concentrate

increases, T2* shortens). R2* is the reciprocal of T2* and equals 1000/T2* and is

measured in a unit of inverse seconds. This technique has been recently validated

and is used for evaluation of cardiac and liver iron load. A shortening of

myocardial T2* to shorter than 20 ms is associated with an increased likelihood of

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decreased LVEF, whereas patients with T2 value of longer than 20 ms have a very

low likelihood of decreased LVEF; values from 10-20 ms indicate a 10% chance

of decreased LVEF, 8-10 ms an 18% chance, 6 ms a 38% chance, and 4 ms a 70%

chance of decreased LVEF.[2]

This T2* MRI technique. is not readily available in many parts of the

world. For this reason, the need for simpler and more available procedure was

addressed in a study conducted recently in Italy, where serial echocardiographic

LVEF measurements were proved to be very accurate and reproducible. The study

suggested that a reduction in of LVEF greater than 7% , over time, as determined

by 2-dimensional echocardiography, may be considered a strong predictive tool

for the detection of thalassemia major patients with increased risk of cardiac

death.

Hepatic iron content (HIC) obtained by liver biopsy, cardiac function tests

obtained by echocardiography measurements, and multiple-gated acquisition scan

(MUGA) findings were compared with the results of iron measurements on R2-

MRI in the liver and heart.

Various iron overload patients were involved in the study, which revealed

that R2-MRI was strongly associated with HIC (weakly but significantly with

ferritin level) and represents an excellent noninvasive method to evaluate iron

overload in the liver and heart and to monitor response to chelation therapy. T2*

and R2* MRI are preferred by many, however, because they allow measurements

of both liver and cardiac iron at the same time.

HIC should be measured annually if possible in all patients on long-term

blood transfusion therapy. Normal HIC values are up to 1.8 mg Fe/g dry weight

levels, while a level of up to 7 mg/g/dry weight seen in carriers of

hemochromatosis was shown to be asymptomatic and without any adverse effects.

High levels of greater than 15 mg/g/dry weight is consistent with significant iron

deposition and is associated with progression to liver fibrosis. Nontransferrin-

bound iron (NTBI) is usually elevated in the plasma at this level.

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4. The following tests may be indicated:

ECG and echocardiography are performed to monitor cardiac function.

HLA typing is performed for patients for whom bone marrow

transplantation is considered.

Eye examinations, hearing tests, renal function tests, and frequent blood

counts are required to monitor the effects of deferoxamine (DFO) therapy and

the administration of other chelating agents

5.Procedures

Bone marrow aspiration is needed in certain patients at the time of the

initial diagnosis to exclude other conditions that may manifest as thalassemia

major.

Liver biopsy is used to assess iron deposition and the degree of

hemochromatosis. However, using liver iron content as a surrogate for evaluation

of cardiac iron is misleading. Many studies have shown very poor correlation

between the two; hence, cardiac evaluation for the presence of iron overload needs

to be addressed separately.

Measurement of urinary excretion of iron after a challenge test of DFO is

used to evaluate the need to initiate chelation therapy and reflects the amount of

iron overload

6.Histologic Findings

All severe forms of thalassemia exhibit hyperactive marrow with erythroid

hyperplasia and increased iron stores in marrow, liver, and other organs. In the

untreated person with severe disease, extramedullary hematopoiesis in unusual

anatomic sites is one of the known complications.

Erythroid hyperplasia is observed in bone marrow specimens. Increased

iron deposition is usually present in marrow, as depicted in the image below, liver,

heart, and other tissues.

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Excessive iron in a bone marrow preparation.

7.Staging

Some use a relevant staging system based on the cumulative numbers of

blood transfusions given to the patient to grade cardiac-related symptoms and

determine when to start chelation therapy in patients with thalassemia major or

intermedia. In this system, patients are divided into 3 groups.

The first group contains those who have received fewer than 100 units of

packed RBCs (PRBCs) and are considered to have stage I disease. These patients

are usually asymptomatic; their echocardiograms reveal only slight left ventricular

wall thickening, and both the radionuclide cineangiogram and the 24-hour ECG

findings are normal.

Patients in the second group (stage II patients) have received 100-400 units of

blood and may report slight fatigue. Their echocardiograms may demonstrate left

ventricular wall thickening and dilatation but normal ejection fraction. The

radionuclide cineangiogram findings are normal at rest but show no increase or

fall in ejection fraction during exercise. Atrial and ventricular beats are usually

noticed on the 24-hour ECG.

Finally, in stage III patients, symptoms range from palpitation to

congestive heart failure, decreased ejection fraction on echocardiogram, and

normal cineangiogram results or decreased ejection fraction at rest, which falls

during exercise. The 24-hour ECG reveals atrial and ventricular premature beats,

often in pairs or in runs.

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A second classification, introduced by Lucarelli, is used for patients with

severe disease who are candidates forhematopoietic stem cell transplantation

(HSCT).This classification is used to assess risk factors that predict outcome and

prognosis and addresses 3 elements: (1) degree of hepatomegaly, (2) presence of

portal fibrosis in liver biopsy sample, and (3) effectiveness of chelation therapy

prior to transplantation.

If one of these elements is unfavorable prior to HSCT, the chance of event-free

survival is significantly poorer than in patients who have neither hepatomegaly

nor fibrosis and whose condition responds well to chelation (class 1 patients). The

event-free survival rate after allogeneic HSCT for class 1 patients is 90%,

compared with 56% for those with hepatomegaly and fibrosis and whose

condition responds poorly to chelation (class 3).10

2.1.8. DIFFERENTIAL DIAGNOSIS

Iron-deficiency anaemia also produces a hypochromic, microcytic anaemia

but Fe and ferritin are low whilst iron-binding capacity is high. Acute leukaemia may require bone marrow aspiration to differentiate.

Rhesus incompatibility is rare now and postmortem Hb electrophoresis

should differentiate in cases of hydrops fetalis.

Diamond-Blackfan syndrome is a rare congenital cause of erythroid

aplasia. It causes a severe normochromic, macrocytic anaemia usually in

infancy and is often associated with craniofacial or upper limb anomalies. 11

2.1.9. TREATMENT

Person with thalassemia trait require no treatment or long term monitoring.

They usually do not have iron deficiency, so iron supplements will not improve

their anemia. Accordingly, iron therapy should only be administered if iron

deficiency occurs.

Blood transfusions

Person with beta thalassemia major require periodic and lifelong blood

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transfusions to maintain a haemoglobin level higher than 9.5g per dl (95g per L)

and sustain normal growth. The need for blood transfusions may begin as early as

six months age. For persons with beta thalassemia intermedia, the decision to

transfuse is a more subjective clinical assessment. Transfusion requirements are

episodic and become necessary when the persons haemoglobin is inadequate for

a normal life or when the anemia impairs growth and development.

Chelation

Transfusion- dependent patients develop iron overload because they have

no physiologic process to remove excess iron from multiple transfusions.

Therefore they require treatment with an iron chelator starting between five and

eight years of age. Deferoxamine, subcutaneously or intravenously, has been the

treatment of choice. Although this therapy is relatively nontoxic, it is cumbersome

and expensive. The U.S Food and Drug Administration recently approved oral

deferasirox(Exjade) as an alternative treatment. Adverse effects of deferasirox

were transient and gastrointestinal in nature,, and no cases of agranulocytosis were

reported.

Bone Marrow Transplant

Bone marrow transplantation in childhood is the only curative therapy for

beta thalassemia major. Hematopoietic stem cell transplantation generally results

in an excellent outcome in low-risk persons, defined as those with no

hepatomegaly, no portal fibrosis on liver biopsy, and regular chelation therapy, or

at most, two of these abnormalities.

Management of Specific Conditions

Hypersplenism

If hypersplenism causes a marked increase in transfusion requirements,

splenectomy may be needed. Surgery is usually delayed until at least four years of

age because of the spleens role in clearing bacteria and preventing sepsis. At least

one month before surgery, patient should receive the pneumococcal

polysaccharide vaccine. Children should also receive the pneumococcal conjugate

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vaccine series. Antibiotic prophylaxis with penicillin, 250mg orally twice a day, is

recommended for all persons during the first two years after surgery and for

children younger than 16 years.

Cardiac

Serum ferritin has been used as a marker of iron storage to predict cardiac

complications. Ferritin levels less than 2500ng per ml are associated with

improved survival. However, ferritin levels are unrealiable when liver disease is

present.9

2.1.10. COMPLICATIONS

Iron overload is one of the major causes of morbidity in severe forms of

thalassaemia. Iron overload can occur even without transfusions as

absorption is increased by 2-5 g per year and this increases with regular

transfusions to an excess of over 10 g of iron per year. Excess iron is

deposited in body organs, especially the pancreas, liver, pituitary and heart,

causing fibrosis and eventual organ failure. Bleeding tendency and

susceptibility to infection are also related to iron overload. Endocrine

dysfunction secondary to iron overload is common in multiply transfused

patients, manifesting ashypogonadotrophic hypogonadism, short stature,

acquired hypothyroidism, hypoparathyroidism and diabetes mellitus.

Repeated transfusions increase the risk of blood-borne diseases,

including hepatitis Band C, although all blood is screened for known blood-

borne infections. Infection with rare opportunistic organisms may causepyrexia and enteritis in patients with iron overload. Yersinia

enterocolitica thrives with the abundant iron. Unexplained fever, especially

with diarrhoea, should be treated with gentamicin and co-trimoxazole, even

when cultures are negative.

Severe anaemia may cause high-output cardiac failure.

Osteoporosis is common and apparently multifactorial in aetiology but

alendronate or pamidronate is an effective treatment.

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The long-term increased red-cell turnover causes hyperbilirubinaemia

and gallstones.

Hyperuricaemia may lead to gout.

With increasing length of survival, hepatocellular carcinoma is becoming

an increasing problem.

Desferrioxamine can cause toxicity:

Local reaction at the site of injection can be severe.

High-frequency hearing loss has been reported in 30-40% of patients.

Colour andnight blindness can occur. These complications may be reversible.

Eye and hearing examinations should be performed every 6-12 months in

patients on chelation therapy.7

2.1.11. PROGNOSIS

The prognosis depends on the severity of the disease and adherence to

treatment.

thalassaemia:

The prognosis is excellent for asymptomatic carriers.

The overall survival for HbH disease is good overall but

variable. Many patients survive into adulthood, but some patients

have a more complicated course.

Hydrops fetalis is incompatible with life.

thalassaemia:

Thalassaemia minor (thalassaemia trait) usually causes

mild, asymptomatic microcytic anaemia, with no effect on

mortality or significant morbidity.

Severe thalassaemia major (also called Cooley's anaemia)

has traditionally had a poor prognosis with 80% dying from

complications of the disease in the first five years of life.

Until recently, patients who received transfusions only did

not survive beyond adolescence because of cardiac complications

caused by iron toxicity. The introduction of chelating agents to

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remove excessive iron has increased life expectancy dramatically.

The overall survival following stem cell transplantation has

been shown to be 90% with a disease-free survival of 86% over a

mean follow-up period of 15 years.13

2.2. PERICARDIAL EFFUSION

2.2.1. DEFINITION

The normal pericardium is a fibro elastic sac surrounding the heart that

contains a thin layer of fluid. Pericardial effusion is the presence of an abnormal

amount of fluid and/or an abnormal character to fluid in the pericardial space. It

can be caused by a variety of local and systemic disorders, or it may be

idiopathic.6

2.2.2. AETIOLOGY

Inflammation of the pericardium (pericarditis) is a response to disease,

injury or an inflammatory disorder that affects the pericardium. Pericardial

effusion is often a sign of this inflammatory response.

Pericardial effusion may also occur when the flow of pericardial fluids is

blocked or when blood accumulates within the pericardium. It's not clear how

some diseases contribute to pericardial effusion, and sometimes the cause can't be

determined.

Specific causes of pericardial effusion may include:

Viral, bacterial, fungal or parasitic infections

Inflammation of the pericardium due to unknown cause (idiopathic

pericarditis)

Inflammation of the pericardium following heart surgery or a heart attack

(Dressler's syndrome)

Autoimmune disorders, such as rheumatoid arthritis or lupus

Waste products in the blood due to kidney failure (uremia)

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Underactive thyroid (hypothyroidism))

Spread of cancer (metastasis), particularly lung cancer, breast cancer,melanoma, leukemia, non-Hodgkin's lymphoma or Hodgkin's disease

Cancer of the pericardium or heart

Radiation therapy for cancer if the heart was within the field of radiation

Chemotherapy treatment for cancer, such as doxorubicin (Doxil) and

cyclophosphamide (Cytoxan)

Trauma or puncture wound near the heart

Certain prescription drugs, including hydralazine, a medication for high

blood pressure; isoniazid, a tuberculosis drug; and phenytoin (Dilantin,

Phenytek, others), a medication for epileptic seizures 7

2.2.3. CLINICAL MANIFESTATION

The 1st symptom of pericardial disease is often precordial pain. The major

complaint is a sharp, stabbing sensation over the precordium and often the left

shoulder and back; the pain may be exaggerated by lying supine and relieved by

sitting, especially leaning forward. Because of the absence of sensory innervation

of the pericardium, the pain is probably referred pain from diaphragmatic and

pleural irritation. Cough, dyspnea, abdominal pain, vomiting, and fever may also

occur. The presence of symptoms or signs associated with other organs depends

on the cause of the pericarditis.

Many of the findings on physical examination are related to the degree of

fluid accumulation in the pericardial sac. The presence of a friction rub is helpful

but is a variable sign in acute pericarditis; it usually becomes apparent when the

effusion is small. When the effusion is larger, muffled heart sounds may be the

only auscultatory finding. Narrow pulses, tachycardia, neck vein distention, and

increased pulsus paradoxus suggest significant fluid accumulation.

Pulsus paradoxus is caused by the normal slight decrease in systolic

arterial pressure during inspiration. With cardiac tamponade, this normal

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phenomenon is exaggerated, probably because of decreased filling of the left side

of the heart with the inspiratory phase of respiration. The degree of pulsus

paradoxus is determined with a mercury manometer. The patient is told to breathe

normally without exaggeration. By allowing the manometer to fall slowly, the 1st

Korotkoff sound will initially be heard intermittently (varying with respirations).

This 1st point is noted, and the manometer is then allowed to fall until the 1st

Korotkoff sound is heard continuously. The difference between these two systolic

pressures is the pulsus paradoxus. A pulsus paradoxus greater than 20 mm Hg in a

child with pericarditis is an indicator of the presence of cardiac tamponade; a 10

20 mm Hg change is equivocal. Increased pulsus paradoxus may also be seen in

patients with severe dyspnea of any cause, in patients with pulmonary disease

(emphysema or asthma), in obese individuals, or in patients being ventilated with

a positive pressure respirator. In these patients, the paradoxical pulse is due to a

marked increase in intrathoracic pressure. The cause of a paradoxical pulse in a

child maintained on a ventilator after heart surgery may therefore be difficult to

assess.8

2.2.4.PATHOPHYSIOLOGY

The pericardium consists of 2 layers, the visceral pericardium

(epicardium) and the parietal pericardium, which enclose a potential space (ie, the

pericardial cavity) between them. This cavity is normally lubricated by a very

small amount of serous fluid (< 30 mL in adults). Inflammation of the pericardium

or obstruction of lymphatic drainage from the pericardium of any etiology causes

an increase in fluid volume, referred to as a pericardial effusion.

Pericardial inflammation results in an accumulation of fluid in the

pericardial space. The fluid varies according to the cause of the pericarditis and

may be serous, fibrinous, purulent, or hemorrhagic. Cardiac tamponade occurs

when the amount of pericardial fluid reaches a level that compromises cardiac

function. In a healthy child, 1015 mL of fluid is normally found in the pericardial

space, whereas in an adolescent with pericarditis, fluid in excess of 1,000 mL may

accumulate. For every small increment of fluid, pericardial pressure rises slowly;

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once a critical level is reached, pressure rises rapidly and culminates in severe

cardiac compression. Inhibition of ventricular filling during diastole, elevated

systemic and pulmonary venous pressure, and if untreated, eventual compromised

cardiac output and shock occur.

Malignant involvement of the pericardium may be primary (less common)

or secondary (spreading from a nearby or distant focus of malignancy). Secondary

neoplasms can involve the pericardium by contiguous extension from a

mediastinal mass, nodular tumor deposits from hematogenous or lymphatic

spread, and diffuse pericardial thickening from tumor infiltration (with or without

effusion). In diffuse pericardial thickening, the heart may be encased by

an effusive-constrictive pericarditis.

Other rare mechanisms include chronic myelomonocytic leukemia and

intrapericardial extramedullary hematopoiesis with preleukemic conditions or

during blast crisis in chronic myeloid leukemia. Obstruction of lymphatic

drainage by mediastinal tumors, either benign or malignant, can also give rise to

pericardial effusion, which can be chylous. These mechanisms may act

independently or jointly in any particular child with malignancy. The underlying

myocardium is not involved in most patients.6

2.2.5. DIAGNOSIS AND LABORATORY STUDIES

The extent to which pericardial effusions should be evaluated with fluid

analysis remains an area of some debate. Initially, in a patient with a new

pericardial effusion, the likelihood of myocarditis or pericarditis should beassessed, and the initial diagnostic evaluation should be directed toward these

conditions. In general, all patients with pericardial tamponade, suspected purulent

effusion, or poor prognostic indicators in the setting of pericarditis should

undergodiagnosticpericardiocentesis.

The following lab studies may be performed in patients with suspected pericardial

effusion.

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Electrolytes - Metabolic abnormalities (eg, renal failure)

CBC count with differential - Leukocytosis for evidence of infection, as

well as cytopenias, as signs of underlying chronic disease (eg, cancer,

HIV)

Cardiac enzymes: Troponin level is frequently minimally elevated in acute

pericarditis, usually in the absence of an elevated total creatine kinase

level. Presumably, this is due to some involvement of the epicardium by

the inflammatory process. Although the elevated troponin may lead to the

misdiagnosis of acute pericarditis as a myocardial infarction, most patients

with an elevated troponin and acute pericarditis have normal coronary

angiograms. An elevated troponin level in acute pericarditis typically

returns to normal within 1-2 weeks and is not associated with a worse

prognosis.

Thyroid-stimulating hormone - Thyroid-stimulating hormone screen for

hypothyroidism

Rickettsial antibodies - If high index of suspicion of tick-borne disease

Rheumatoid factor, immunoglobulin complexes, antinuclear antibody test

(ANA), and complement levels (which would be diminished) - In

suspected rheumatologic causes

PPD and controls

Pericardial fluid analysis - Routine tests (these should be considered part

of the standard pericardial fluid analysis)

o Lactic (acid) dehydrogenase (LDH), total protein - The Light

criteria (for exudative pleural effusion) found to be as reliable in

distinguishing between exudative and transudative effusions

Total protein fluid-to-serum ratio >0.5

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LDH fluid-to-serum ratio >0.6

LDH fluid level exceeds two thirds of upper-limit of

normal serum level

o Other indicators suggestive of exudate - Specific gravity >1.015,

total protein >3.0 mg/dL, LDH >300 U/dL, glucose fluid-to-serum

ratio 10,000) with neutrophil

predominance suggests bacterial or rheumatic cause, although

unreliable

o Gram stain - Specific but insensitive indicator of bacterial infection

o Cultures - Signals and identifies infectious etiology

o Fluid hematocrit for bloody aspirates - Hemorrhagic fluid

hematocrits usually significantly less than simultaneous peripheral

blood hematocrits

Pericardial fluid - Special tests (these should be considered individually

based on the pretest probability of the coexisting condition under concern)

o Viral cultures

o Adenosine deaminase; polymerase chain reaction (PCR); culture

for tuberculosis; smear for acid-fast bacilli in suspected

tuberculosis infection, especially in patients with HIV

o A definite diagnosis of tuberculous pericarditis is based on the

demonstration of tubercle bacilli in pericardial fluid or on a

histological section of the pericardium. Probable tuberculous

pericarditis is based on the proof of tuberculosis elsewhere in a

patient with otherwise unexplained pericarditis, a lymphocytic

pericardial exudate with elevated adenosine deaminase levels,

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and/or appropriate response to a trial of antituberculosis

chemotherapy.

Tumor markers: Elevated carcinoembryonic antigen (CEA) levels in

pericardial fluid have a high specificity for malignant effusions.

Imaging Studies

Chest radiography

Findings include enlarged cardiac silhouette (so-called water-bottle heart)

and pericardial fat stripe.

Image is from a patient with malignant pericardial effusion. Note the

"water-bottle" appearance of the cardiac silhouette in the

anteroposterior (AP) chest film.

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A third of patients have a coexisting pleural effusion.

Radiography is unreliable in establishing or refuting diagnosis of

pericardial effusion.

Echocardiography

Echocardiography is the imaging modality of choice for the diagnosis of

pericardial effusion, as the test can be performed rapidly and in unstable patients.

Most importantly, the contribution of pericardial effusion to overall cardiac

enlargement and the relative roles of tamponade and myocardial dysfunction to

altered hemodynamics can be evaluated with echocardiography.9

Echocardiogram (parasternal, long axis) of a patient with a moderate

pericardial effusion.

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Subcostal view of an echocardiogram that shows a moderate-to-large amount

of pericardial effusion.

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This echocardiogram shows a large amount of pericardial effusion (identified

by the white arrows).

2-D echocardiography

o Pericardial effusion appears as an echo-free space between the

visceral and parietal pericardium. Early effusions tend to

accumulate posteriorly owing to expandable posterior/lateral

pericardium. Large effusions are characterized by excessive motion

within the pericardial sac. Small effusions have an echo-free space

of less than 10 mm, and are generally seen posteriorly. Moderate-

sized effusions range from 10-20 mm and are circumferential, and

greater than 20 mm indicates a large effusion. Fluid adjacent to the

right atrium is an early sign of pericardial effusion. [10 ]

o Severe cases may be accompanied by diastolic collapse of the right

atrium and right ventricle (and in hypovolemic patients, the left

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atrium and left ventricle), signaling the onset of pericardial

tamponade (see Cardiac Tamponade).

o

This image is from a patient with malignant pericardial

effusion. The effusion is seen as an echo-free region to the right

of the left ventricle (LV).

M-mode echocardiography

o

M-mode is adjunctive to 2D imaging for the detection ofpericardial effusion. Effusions can be classified using M-mode

according to a system proposed by Horowitz, et al.[11 ]

Type A: No effusion

Type B: Separation of epicardium and pericardium

Type C1: Systolic and diastolic separation of pericardium

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Type C2: Systolic and diastolic separation of pericardium,

attenuated pericardial motion

Type D: Pronounced separation of pericardium and

epicardium with large echo-free space

o In the parasternal long-axis view, discordant changes in right and

left ventricular cavity size can suggest pronounced interventricular

dependence.

Doppler echocardiography

o Transmitral and transtricuspid inflow velocities should be

interrogated to assess for respiratory variation. Decreases in flow

during inspiration (transmitral) or expiration (transtricuspid) should

raise the suspicion of clinically significant interventricular

dependence and tamponade physiology.

o

Pulmonic vein inflow may show a decrease in early diastolic flowwith hemodynamically significant effusions. Hepatic vein diastolic

flow reversal may also be seen.

False-positive echocardiograms can occur in pleural effusions, pericardial

thickening, increased epicardial fat tissue, atelectasis, and mediastinal lesions.

Epicardial fat tissue is more prominent anteriorly but may appear

circumferentially, thus mimicking effusion. Fat is slightly echogenic and tends tomove in concert with the heart, 2 characteristics that help distinguish it from an

effusion, which is generally echolucent and motionless.

In addition to its mimicry, pericardial fat accumulation is a source of

bioactive molecules, is significantly associated with obesity-related insulin

resistance, and may be a coronary risk factor.12

In patients with pericardial effusion, imaging from low to midposterior

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thorax can provide additional diagnostic echocardiographic images and should be

used in patients in whom conventional images are technically difficult or require

additional information.

Transesophageal echocardiography (TEE)

TEE maintains all of the advantages of transthoracic echocardiography

and is useful in characterizing loculated effusions. However, this may be difficult

to perform in patients with symptomatic effusions due to hemodynamic

instability, making the required sedation more difficult.

Intracardiac echocardiography (ICE)

ICE is generally reserved for the assessment of pericardial effusion in the

setting of percutaneous interventional or electrophysiology procedure. Phased

array ICE systems can perform both 2-D and Doppler interrogations.

Computed tomography

CT can potentially determine composition of fluid and may detect as little

as 50 mL of fluid.

CT can detect pericardial calcifications, which can be indicative of

constrictive pericarditis.

CT results in fewer false-positive results than echocardiography.

CT can be problematic in patients who are unstable given the time

required to transport to and from the scanner and perform the test.

Magnetic resonance imaging

MRI can detect as little as 30 mL of pericardial fluid.

May be able to distinguish hemorrhagic and no hemorrhagic fluids, as

hemorrhagic fluids have a high signal intensity on T-1 weighted images,

whereas no hemorrhagic fluids have a low signal intensity.

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Nodularity or irregularity of the pericardium seen on MRI may be

indicative of a malignant effusion.

MRI is more difficult to perform than CT scan acutely, given the length of

time the patient must remain in the scanner.

Both MRI and CT scan may be superior to echocardiography in detecting

loculated pericardial effusions, especially when located anteriorly. Also, these

modalities allow for greater visualization of the thoracic cavity and adjacent

structures, and therefore may identify other abnormalities relating to the cause of

the effusion.12

Other Tests

Electrocardiography

Early in the course of acute pericarditis, the ECG typically displays diffuse

ST elevation in association with PR depression. The ST elevation is

usually present in all leads except for aVR, but postmyocardial infarction

pericarditis, the changes may be more localized. Classically, the ECG

changes of acute pericarditis evolve through 4 progressive stages:

o Stage I - Diffuse ST-segment elevation and PR-segment depression

o Stage II - Normalization of the ST and PR segments

o Stage III - Widespread T-wave inversions

o

Stage IV - Normalization of the T waves

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This electrocardiogram (ECG) is from a patient with malignant

pericardial effusion. The ECG shows diffuse low voltage, with a

suggestion of electrical alternans in the precordial leads.

Patients with uremic pericarditis frequently do not have the typical ECG

abnormalities.

2.2.6. DIFFERENTIAL DIAGNOSIS

Cardiac Tamponade Pericarditis, Constrictive-Effusive

Cardiomyopathy, Dilated Pericarditis, Uremic

Myocardial Infarction Pulmonary Edema, Cardiogenic

Pericarditis, Acute Pulmonary Embolism

Pericarditis, Constrictive

2.2.7. TREATMENT

Medical Care

Initially, medical care of pericardial effusion is focused on determination

of the underlying etiology.

Aspirin/nonsteroidal anti-inflammatory agents (NSAIDs)

o Most acute idiopathic or viral pericarditis occurrences are self-

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limited and respond to treatment with aspirin (650 mg q6h) or

another NSAID.

o Aspirin may be the preferred nonsteroidal agent to treat pericarditis

after myocardial infarction because other NSAIDs may interfere

with myocardial healing.

o Indomethacin should be avoided in patients who may have

coronary artery disease.

o Meurin et al performed a multicenter, randomized, double-blind

trial on the effect of the NSAID diclofenac in reducing

postoperative pericardial effusion volume. Diclofenac, 50 mg, or

placebo twice daily for 14 days was given to 196 patients at high

risk for tamponade because of pericardial effusion more than 7

days after cardiac surgery. The authors found that diclofenac was

not effective at reducing the size of the effusion or preventing late

cardiac tamponade.[15 ]

Colchicine: The routine use of colchicine is supported by results from the

COlchicine for acute PEricarditis (COPE) trial. In this trial, 120 patients

with a first episode of acute pericarditis (idiopathic, acute,

postpericardiotomy syndrome, and connective tissue disease) entered a

randomized, open-label trial comparing aspirin treatment alone with

aspirin plus colchicine (1-2 mg for the first day followed by 0.5-1 mg/d for

3 mo). Colchicine reduced symptoms at 72 hours (11.7% vs

36.7%;P=0.03) and reduced recurrence at 18 months (10.7% vs

36.7%;P=0.004; 5 needed treatment). Colchicine was discontinued in 5

patients because of diarrhea. No other adverse events were noted.

Importantly, none of the 120 patients developed cardiac tamponade or

progressed to pericardial constriction.12

Steroids

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o Steroid administration early in the course of acute pericarditis

appears to be associated with an increased incidence of relapse

after tapering the steroids.

o In the COPE trial, steroid use was an independent risk factor for

recurrence (odds ratio=4.3). Also, an observational study strongly

suggests that the use of steroids increases the probability of relapse

in patients treated with colchicine.[16 ]

o Systemic steroids should be considered only in patients with

recurrent pericarditis unresponsive to NSAIDs and colchicine or as

needed for treatment of an underlying inflammatory disease. If

steroids are to be used, an effective dose (1-1.5 mg/kg of

prednisone) should be given, and it should be continued for at least

1 month before slow tapering.

o The intrapericardial administration of steroids has been reported to

be effective in acute pericarditis without producing the frequentreoccurrence of pericarditis that complicates the use of systemic

steroids, but the invasive nature of this procedure limits its use.

Hemodynamic support

o Patients who have effusions with actual or threatened tamponade

should be considered to have a true or potential emergency. Most

patients require pericardiocentesis to treat or prevent tamponade.

However, treatment should be carefully individualized.

o Hemodynamic monitoring with a balloon flotation pulmonary

artery catheter is useful, especially in those with threatened or mild

tamponade in whom a decision is made to defer pericardiocentesis.

Hemodynamic monitoring is also helpful after pericardiocentesis to

assess both reaccumulation and the presence of underlying

constrictive disease. However, insertion of a pulmonary artery

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catheter should not be allowed to delay definitive therapy in

critically ill patients.

o Intravenous fluid resuscitation may be helpful in cases of

hemodynamic compromise.

o In patients with tamponade who are critically ill, intravenous

positive inotropes (dobutamine, dopamine) can be used but are of

limited use and should not be allowed to substitute for or delay

pericardiocentesis.

Antibiotics

o In patients with purulent pericarditis, urgent pericardial drainage

combined with intravenous antibacterial therapy (eg, vancomycin 1

g bid, ceftriaxone 1-2 g bid, and ciprofloxacin 400 mg/d) is

mandatory. Irrigation with urokinase or streptokinase, using large

catheters, may liquify the purulent exudate, but open surgical

drainage is preferable.

o The initial treatment of tuberculous pericarditis should include

isoniazid 300 mg/day, rifampin 600 mg/day, pyrazinamide 15-30

mg/kg/day, and ethambutol 15-25 mg/kg/day. Prednisone 1-2

mg/kg/day is given for 5-7 days and progressively reduced to

discontinuation in 6-8 weeks. Drug sensitivity testing is essential.

Uncertainty remains whether adjunctive corticosteroids are

effective in reducing mortality or progression to constriction.

Surgical resection of the pericardium remains the appropriate

treatment for constrictive pericarditis. The timing of surgical

intervention is controversial, but many experts recommend a trial

of medical therapy for noncalcific pericardial constriction and

pericardiectomy in nonresponders after 4-8 weeks of

antituberculosis chemotherapy.

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Antineoplastic therapy (eg, systemic chemotherapy, radiation) in

conjunction with pericardiocentesis has been shown to be effective in

reducing recurrences of malignant effusions.

Corticosteroids and NSAIDs are helpful in patients with autoimmune

conditions.12

Surgical Care

Surgical care of pericardial effusion includes the following:

Subxiphoid pericardial window with pericardiostomy

o This procedure is associated with low morbidity, mortality, and

recurrence rates, and can be considered as a reasonable alternative

diagnostic or treatment modality to pericardiocentesis in selected

patients.

o It can be performed under local anesthesia. This is advantageous

because general anesthesia often leads to decreased sympathetic

tone, resulting in hemodynamic collapse in patients with

pericardial tamponade and shock.

o It may be less effective when effusion is loculated.

o One study indicated it may be safer and more effective at reducing

recurrence rates than pericardiocentesis. However, only patients

who were hemodynamically unstable underwentpericardiocentesis, and no change in overall survival rate was

observed.

Thoracotomy

o This should be reserved for patients in whom conservative

approaches have failed.

o Thoracotomy allows for creation of a pleuropericardial window,

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which provides greater visualization of pericardium.

o Thoracotomy requires general anesthesia and thus has higher

morbidity and mortality rates than the subxiphoid approach.

Video-assisted thoracic surgery

o Video-assisted thoracic surgery (VATS) enables resection of a

wider area of pericardium than the subxiphoid approach without

the morbidity of thoracotomy.

o The surgeon is able to create a pleuropericardial window and

address concomitant pleural pathology, which is especially

common in patients with malignant effusions.

o One disadvantage of VATS is that it requires general anesthesia

with single lung ventilation, which may be difficult in otherwise

seriously ill patients.

Median sternotomy

o This procedure is reserved for patients with constrictive

pericarditis.

o Operative mortality rate is high (5-15%).

Consultations

A cardiologist should be involved in the care of patients with pericardial

effusion.

Cardiothoracic surgery may be required for recurrent or complicated cases

(see Surgical Care).

2.2.8. COMPLICATIONS

Pericardial tamponade

o Can lead to severe hemodynamic compromise and death.

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o Heralded by equalization of diastolic filling pressures.

o Treat with expansion of intravascular volume (small amounts of

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