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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