Laboratory Tests for Diagnosing Anemia and Organomegaly

OBJECTIVES
General Instructional Objectives

After completing this module, students are expected to choose and
interpret laboratory test especially at hematology, clinic-chemist, and
immunoassay which is needed to help standing the diagnosis, observing, and
definiting the prognosis of diseases.
Laboratory Based Diagnosis Module,
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group, Medical $aculty of Airlangga %niversity
CHAPTER 1
BRAIN STORING
1!1! SCENARIO
A woman, Ms. &, "' years old, a student candidate in a university,
came up with complain( rather pale, wea), and felt enlargement of
abdomen in recent years. !he was afraid if she suffered a chronic disease.
1!"! AIN PROB#E
Ms. &, "' years old, complaining of rather pale, wea), and feels
enlargement of abdomen in recent years.
1!$! %E&'OR(S
*oman, "' years old
+ather pale
*ea)
$eels enlargement of abdomen
,n recent years
1!)! H&POTHESIS
Ms. & suffered a myeloproliferatif disease.
Ms. & suffered a chronic diseases, such as( anemia, lac) of
nutrition, or obstruction of -, tract
1!*! A((ITIONA# IN+ORATION
,dentity( Ms. &, "' y.o, a candidate of a college student
!he comes from .ulungagung
!he lives in a dormitory at /ali)epiting , !urabaya
.he main complain( rather pale, wea), feels enlargement of abdomen0
she forgot since when.
.here are no pain, no fever, easy masu) angin, nggliyeng, seems li)e
seeing bright stars
!he have not been treated
.here is no same complain at her family
.heres is no nausea,
!he had normal menstruation
1hysical examination(
.B2BB( "# cm234 )g
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.ension( ""5265 mm&g
.emperature of body( 7#,8 9
++( "#x2minute
1ulse rate( 6#x2minute, normal
,cterus :-;
Anemic :<;
!ianosis :-;
+etraction of costae while breathing :-;
!immetrical thorax
Liver is on finger under the arcus costae
!pleen is on !chuffner 3
=ormal bowel sounds
Laboratory test(
&b( '.4 mg2dL
*B9( '.'x"5
7
per microlitre
1latelet( 45.555 per microlitre
M9&( "' pg
M9>( 8' fl
M9&9( 4'2dl
1!,! EAR#& IN( AP
1!-! #EARNING ISS.ES 1
". ?xplain all about anemia, include its prosses and its tests@
. ?xplain about organomegaly, hepatomegaly, and spleenomegaly@
7. *hat are the differential diagnosis of myeloproliferatif diseasesA
3. ?xplain about the laboratory tests for myeloproliferatif diseases@
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CHAPTER "
#EARNING ISS.ES
"!1 ANS'ER O+ #EARNING ISS.ES 1
"!1!1 E/0lain all about ane1ia2 inclu3e its 0rosses an3 its tests4
Anemia is present in adults if the hematocrit is less than 3"B
:hemoglobin C "7.8 g2dl; in males or less than 76B :hemoglobin C "
g2dl; in females. 1hysical examination includes attention to signs of
primary hematologic diseases, there are( lymphadenopathy,
hepatosplenomegaly, or bone tenderness.516
1ossible symptoms include chest pain, diDDiness or light-
headedness :especially when standing up or with activity;, $atigue or
lac) of energy, &eadaches, 1roblems concentrating, !hortness of
breath :especially during exercise;. Blood tests used to diagnose
some common types of anemia may include( Blood levels of
vitamin B", folic acid, and other vitamins and minerals, +ed
blood count and hemoglobin level, +eticulocyte count, $erritin
level, ,ron level. Anemia are classified according to their
pathophysiologic basis, which related to diminished production or
accelerated loss of red blood cell, or according to cell siDe.
9lassification of anemias by pathophsiology
(ecrease3 0ro3ution
&emoglobin synthesis( iron deficiency, thalassemia, anemia of chronic
disesase
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D=A synthesis( megaloblastic anemia
!tem cell( aplastic anemia, myeloproliferative leu)emia
Bone marrow infiltration( carcinoma, lymphoma
1ure red aplasia
Increase3 3estruction
Blood loss
&emolysis :intrinsic;
Membrane( hereditary spherocytosis, ellyptocytosis
&emoglobin( sic)le cell, unstable hemoglobin
-lycolisis( piruvat )inase deficiency, etc
Exidation( glucose # phosphate dehidrogenase deficiency
&emolysis :extrinsic;
immune warm antibody, cold antibody
microanyopathic( thrombotic thrombopenic purpura, hemolytic-
uremic syndrome, mechanical cardiac valve, paravalvular lea)
,nfection( clostridial
&ypersplenism
9lassification of anemias by Mean 9ell >olume
icroc7tic 8CV9 -: ;l<
,ron deficiency
.halassemia
Anemia of chronic disease
!ideroblastic anemia
acroc7tic 8CV = 1"* ;l<
Megaloblastic
>itamin B" deficiency
$olate deficiency
=onmegaloblastic
Myelodysplasia, chemotherapy
Liver disease
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,ncreased reticulocytosis
Myxedema
=ormocytic
Many causes F"G
,n our cases, in additional information, we )now that the M9>
and M9&9 are low. .herefore, we discuss the anemia more focusing
on microcytic.
IRON (E+ICIENC&
,ron deficiency is the most common cause of anemia worldwide.
,ron is necessary for the formation of heme and other enDymes. .otal
body iron ranges between and 3 g( approximately 85 mg2)g in men
and 78 mg2)g in women. Most :65-'8B; of the iron is present in
hemoglobin in circulating red blood cells. ,ron absorption occurs in
the stomach, duodenum, and upper HeHunum.
Menstrual blood loss in women plays a maHor role in iron
metabolism. .he average monthly menstrual blood loss is
approximately 85 mL, or about 5.6 mg2d.
,ron loss can be due to bleeding. 9ommon causes of bleeding
are(
&eavy, long, or freIuent menstrual periods
9ancer in the esophagus, stomach, or colon
?sophageal varices
.he use of aspirin, ibuprofen, or arthritis medicines for a long
time
1eptic ulcer diseaseFG
!ymptoms and !igns
As a rule, the only symptomps of iron deficiency anemia are
those of anemia itelf :easy fatigability, tachycardia, palpitations and
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tachypnea on exertion;. !evere deficiency causes s)in and mucosal
changes, including a smooth tongue, brittle nails, and cheilosis.
Dysphagia because of the formation of eosophageal webs :plummer-
vinson syndrome; also occurs.
An upper eso0>a?eal @eb :arrow; in a patient with Plu11er-
Vinson s7n3ro1e
Laboratory findings
,ron deficiency develops in stages. .he first is depletion of iron
stores. At this point, there is anemia and no changes in +B9 siDe. .he
M9> remains normal. .he serum ferritin will become abnormally
low. $erritin value less than 75 Jg2L is highly reliable indicator of iron
deficiency. .he serum total iron binding capacity :.,B9; rises.
After the depletion of iron stores, red blood cell formation will
continue with deficient supplies of iron. !erum iron values decline to
less than 75 Jg2dL and transferrin saturation less than "8B. $or the
M9>, it subseIuently falls and the blood smear shows hypochromic
microcytic cells. *ith further progression, anisocytosis and
poi)ilocytosis develop. !evere iron deficiency will produce a biDarre
pheripheral blood smear, with severely hypochromic cells, target cells,
hypochromic pencil-shaped cells, and occasionally small numbers of
nucleated red blood cells. .he platelet count is commonly increased.
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F"G
ANEIA O+ CHRONIC (ISEASE
Anemia of chronic disease is a blood disorder that refers to
anemia that is found in people with certain long-term :chronic;
medical conditions. FG Many chronic systemic diseases are associated
with mild and moderate anemia. 9ommon causes include
Autoimmune disorders0 such as crohnKs disease, systemic lupus
erythematosus, rheumatoid arthritis, ulcerative colitis, chronic
infection or inflammation0 such as bacterial endocarditis,
osteomyelitis :bone infection;, &,>2A,D!, hepatitis B or hepatitis 9,
cancer :particularly lymphoma and &odg)inKs disease; FG, chronic
renal disease and liver disease. +ed blood cell survival is modestly
reduced, and the bone marrow fails to compensate adeIuately by
increasing red blood cell production. $ailure to increase +B9 is
largely due to seIuestration of iron within the reticuloendothelial
system. Decrease in erythropoietin is rarely important cause of
underproduction of +B9 except in renal failure. F"G
!ymptoms and signs
.he clinical features are those of the causative condition.
Laboratory findings
.he diagnosis should be suspected in patients with )nown
chronic diseases which is confirmed by the findings of low serum
iron, low .,B9, and normal or increased serum ferritin. ,f the serum
ferritin value of less than 75 Jg2dL, should suggest coexistent iron
deficiency. .he transferrin saturation may be extremely low, leading to
an erroneous diagnosis of iron deficiency. .he hematocrit rarely falls
below #5B of baseline :except in renal failure;. .he M9> is usually
normal or slightly reduced. +ed blood cell morphology is non-
diagnostic, and the reticulocyte count is neither stri)ingly reduced nor
increased.
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THA#ASSEIAS
ESSENTIALS OF DIAGNOSIS
Microcytosis out of proportion to the degree of anemia.
1ositive family history of lifelong personal history of
microcytic anemia.
Abnormal red blood cell morphology with microcytes,
acanthocytes, and target cells
,n L-thalassemia, elevated level of hemaglobin A
or $
General Consi3erations
.he thalassemia are hereditary disorders characteriDed by
reduction in the synthesis of globin chains :M or L;. +educed golobin
chain synthesis causes reduced hemoglobin synthesis and eventually
produces a hypochromic microcytic anemia because of defective
hemoglobiniDation of red blood cells. .halassemias can be considered
among the hypoproliferative anemias, the hemolytic anemias, and the
anemias related to abnormal hemoglobin, since all of these factors
play a role in pathogenesis.
=ormal adult hemoglobin is primarily hemoglobin A, which
represents approximately '4B of circulating hemoglobin.
&emoglobin A is formed from a tetramer N two M chains and two L
chains- and can be designate M
. .wo copies of the M-globin gene

are located on chromosome "#, and there is no substitute for M-globin
in the formation of hemoglobin. .he L-globin gene resides on
chromosome "" adHacent to genes encoding the L-li)e chains, O and P.
.he tetramer of M
forms hemoglobin A
, which normally comprises

"-B of adult hemoglobin., the terramer M

P
forms hemoglobin $,
which is the maHor hemoglobin of fetal life but which comprises less
than "B of normal adult hemoglobin.
M-thalassemia is due primarily to gene deletion causing reduced
M-globin chain synthesis :.able "7-3;. !ince all adult hemoglobins are
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M containing, M-thalassemia produces no change in the percentage
distribution of hemoglobins A, A
, and $. in severe forms of M-

thalassemia, excess L chains may form a L
3
tetramer called
hemoglobin &.
L- .halassemias are usually caused by point mutations rather
than deletions : .able "7-8;. .hese mutations result in premature
chain termination or in problems with transcription of +=A and
ultimately result in reduced or absent L-globin chain synthesis. .he
molecular defects leading to L-thalassemia are numerous and
heterogeneous. Defects that result in absent globin chain expression
are termed L
5
, whereas those causing reduced synthesis are termed L
<
.
.he reduced L-globin chain synthesis in L-thalassemia results in a
relative increase in the percentages of hemoglobins A

and $ compared
to hemoglobin A, as the L-li)e globin :P and M; substitute for the
missing L chains. ,n the presence of reduced L chains, the excess M
chains are unstable and precipitate, leading to damage of red blood
cell membranes. .his leads to intra medullary and peripheral
hemolysis . the bone marrow becomes hyperplastic under the drive of
anemia.
Table 13-4. M-.halassemia syndromes.
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AGlobin
Genes
S7n3ro1e He1atocrit CVB
3
7
"
5
=ormal
!ilent carrier
.halassemia minor
&emoglobin & disease
&ydrops fetalis
=ormal
=ormal
4-35B
-7B
#5-68 fl
#5-65 fl
CV C 1ean cell volu1e
Table 13-4. L-.halassemia syndromes.
DEGlobin Genes Hb
1
A Hb A
"
Hb +
=ormal
.halassemia maHor
.halassemia maHor
.halassemia intermedia
.halassemia minor
&omoDygous L
&omoDygous L
5
&omoDygous L
<
&omoDygous L
<
:mild;
&eteroDygous L
5
&eteroDygous L
<
'6-''B
5B
5-"5B
5-75B
45-'8B
45-'8B
"-7B
3-"5B
3-"5B
5-"5B
3-4B
3-4B
C"B
'5-'#B
'5-'#B
#-"55B
"-8B
"-8B
and ineffective erythropoiesis resulting from the intramedullary
destruction of the developing erythroid cells. ,n cases of severe
thalassemia, the mar)ed expansion of the erythroid element in the
bone marrow may cause severe bony deformities, osteopenia, and
phatologic fractures.
Clinical +in3in?s
S&PTOS AN( SIGNS
.he M-thalassemia syndromes are seen primarily in person from
southeast Asia and 9hina, and, less commonly, in blac)s. =ormally,
adults have four copies of the M-globin chain.. when three M-globin
genes are present, the patient is a hematologically normal : silent
carrier;. *hen two M-globin genes are present, the patient is said to
have M-thalassemia trait, one form of thalassemia minor. .hese
patients are clinically normal and have normal life expectancy and
performance status, with a mild microcytic anemia. *hen only one M-
globin chain is present, the patient has hemoglobin & disease. .his is
a chronic hemolytic anemia of variable severity :thalassemia minor of
intermedia;. 1hysical examination will reveal pallor and
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splenomegaly. Although affected individuals do not usually reIuire
transfusions, they may do so during periods of hemolytic exacerbation
caused by infection or other stresses. *hen all four M-globin genes
are deleted, the affected fetus is stillborn as a result of hydrops fetalis.
L-.halassemia primarily affects persons of Mediterranean origin
:,talian, -ree); and to a lesser extent 9hinese, other Asians, and
blac)s. 1atients homoDygous for L-thalassemia have thalassemia
maHor. Affected children are normal at birth but after # months, when
hemoglobin synthesis switches from hemoglobin $ to hemoglobin A,
develop severe anemia reIuiring transfusion. =umerous clinical
problems ensue, including growth failure, bony deformities :abnormal
facial structure, pathologic fractures;, hepatosplenomealy, and
Haundice. .he clinical course is modified significantly by transfusion
therapy, but the transfusional iron overload :hemosiderosis; results in
a clinical picture similar to hemochromation, with heart failure,
cirrhosis, and endocrinopathies, usually after more than "55 units of
red blood cells. .hese problems develop because of the bodyQs
inability to excrete the iron :see above; from transfused red cells.
Before the application of allogeneic stem cell transplantation and the
development of more effective forms of iron chelation, death from
cardiac failure usually occurred between the ages of 5 and 75 years.
1atients homoDygous for a milder form of L-thalassemia
:allowing a higher rate of globin gene synthesis; have thalassemia
intermedia. .hese patients have chronic hemolytic anemia but do not
reIuire transfusions except under periods of stress. .hey also may
develop iron overload because of periodic transfusion. .hey survive
into adult life but with hepatosplenomegaly and bony deformities.
1atients heteroDygous for L-thalassemia have thalassemia minor and a
clinically insignificant microcytic anemia.
1renatal diagnosis is available, and genetic counseling should be
offered and the opportunity for prenatal diagnosis discussed.
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#ABORATIOR& +IN(INGS
FET>alasse1ia trait-1atients with two M-globin genes
have mild anemia, with hematocrits between 4B and 35B. .he
M9> is stri)ingly low :#5-65fL; despite the modest anemia, and the
red blood count is normal or increased. .he peripheral blood smear
shows microcytes, hypochromia, occasional target cells, and
acanthocytes :cells with irregualarly spaced bulbous proHections;. .he
reticulocyte count and iron parameters are normal. &emoglobin
electrophoresis will show no increase in the percentage of
hemoglobins A
or $ and no hemoglobin &. M-.halassemia trait is

thus usually diagnosed by exclusion. -enetic testing to demonstrate
M-globin gene delection is available in research laboratories.
He1o?lobin H 3iseaseE.hese patients have a more mar)ed
hemolytic anemia, with hematocrits between B and 7B. .he
M9> is remar)ably low :#5-65 fL; and the peripheral blood smear is
mar)edly abnormal, with hypochromia, microcytosis, target cells, and
poi)ilocytosis. .he reticulocyte count is elevate. &emoglobin
electrophoresis will show the presence of a fast mingrating
hemoglobin :hemoglobin &;, which comprises "5-35B of the
hemoglobin. A peripheral blood smear can be stained with supravital
dyes to demonstrate the presence of hemoglobin &.
GET>alasse1ia 1inor-As in M-.halassemia trait, these
patients have a modest anemia with hemotocrit between 4B and
35B. .he M99 ranges from 88 to 68 fL, and the red blood cell count
is normal of increased. .he peripheral blood smear is mildly
abnormal, with hyochromia, microcytosis, and target cells. ,n contrast
to M-thalassemia, basophilic stippling may be present. .he
reticulocyte count is normal or slightly elevated. &emoglobin
electrophoresis : using Iuantitative techniIues; may show an elevation
of hemoglobin A

to 3-4B and occasional elevations of hemoglobin $
to "-8B.
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GET>alasse1ia 1ajorEGE.halassemia maHor produces
severe anemia, and without transfusion the hematocrit may fall to less
than "5B. .he peripheral blood smear is biDarre, showing severe
poi)ilocytosis, hypochromia, microcytosis, target cells, basophilie
stippling, and nucleated red blood cells. Little or no hemoglobin A is
present. >ariable amounts of hemoglobin A
are seen, and the maHor

hemoglobin present is hemoglobin $.
SI(EROB#ASTIC ANEIA
!ideroblastic anemias are a heterogeneous group of disorders in
which hemoglobin synthesis is reduced because of failure to
incorporate heme into protoporphyrin to form hemoglobin. .his
disorder is usually acIuired.
1atients have no specific clinical features other than those
related to anemia. .he anemia is usually moderate, hematocrits 5-
75B, but transfusions may occasionally be reIuired. Although M9> is
usually normal or slightly increased, it may occasionally be low,
leading to confusion with iron deficiency, the pheripheral blood smear
characteristically shows a dimorphic population of +B9, one normal
one hypochromic.
Diagnosis
$rom examination of the bone marrow, there is mar)ed erythroid
hyperplasia, a sign of ineffective erythropoiesis. .he iron stain of bone
marrow shows a generaliDed increase in iron stores and the presence
of ringed sideroblasts. Ether laboratory features include a high serum
iron and a high transferrin saturation. Eccasionally, the anemia is so
severe that support with transfussion is reIuired. .he patient usually
do not respond to erithropoietin therapy.
"!1!" E/0lain about or?ano1e?al72 >e0ato1e?al72 an3 s0leeno1e?al74
He0ato1e?al7
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&epatomegaly is a condition in which liver enlarges.
&epatomegaly can easily be mimic)ed under palpation by
phrenoptosis in lung emphysema, ptosis of the liver, asthenic habitus
and also by an enlarged +iedelQs lobe. ,t is very difficult to state the
extent of liver enlargement exactly in terms of Rfinger breadthsS
below the costal arch( when "5 Rfinger breadthsS were compared,
they were found to range from ".7 to .3 cm :/untD, 55#;.
&epatomegaly is present if :".; palpation locates the lower
border of the right lobe of liver to be more than cm :" finger
breadths; below the left costal arch :M9L lateral to rectus abdominis;
:caution( phrenoptosis;, :.; the absolute liver dullness on percussion
is more than "3 cm, or :7.; the longitudinal diameter of the liver in the
M9L is greater than approximately "8 cm in the sonogram.
&epatomegaly is a cardinal symptom in a number of liver
diseases or a concomitant reaction of the liver in various extrahepatic
or systemic diseases. *hen detected, differential diagnostic
clarification is always necessary.
Pat>o?enesis
". +eplication of cells
A diffuse enlargement of the liver can be caused by cell
replication.
a; +eplication of hepatocytes in the form of excessive
hyperplasia can occur occasionally after extensive parenchymal
necrosis or partial liver resection. &owever, this does not generally
cause a clinical discernible form of hepatomegaly.
b; ,n systemic haematological diseases, the liver is usually
involved in extramedullary haematopoiesis. .his can result in
hepatomegaly.
c; Diffuse enlargement of the liver can also be brought about
by lymphohistiocytic cell infiltrations. .his generally involves
inflammatory reactions to viral or bacterial diseases.
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d; Diffuse hepatomegaly is also expected to occur as a result
of malignant cell growth.
. ?nlargement of cellular structures
An increase in the volume of sinusoidal cells and hepatocytes
due to an enlargement of their cellular structures can be caused
actively by proliferation or passively by storage processes.
a; ?ndothelia and /upffer cells can be stimulated to
considerable proliferation, so that in clinical terms hepatomegaly
occasionally results.
b; 1roliferation of the smooth endoplasmic reticulum due to
the prolonged induction of the biotransformatory system localiDed at
this site as a result of toxins, noxae or chemicals can bring about
clinically and sonographically detectable hepatomegaly.
c; &epatocellular storage of abnormal Iuantities of
cholesterol, fat, glycogen, proteins, mucopolysaccharides, copper,
iron, etc. occasionally leads to pronounced hepatomegaly. &ydropic
swelling of the hepatocytes is also included in this category.
7. Augmentation of the extracellular space
Diffuse enlargement of the liver can also arise from
augmentation of the extracellular space.
a; An increase in blood both in the sinusoids and in DisseQs
spaces culminates in hepatomegaly. .his can be witnessed particularly
in cases of right heart failure, constrictive pericarditis, veno-occlusive
disease and the Budd-9hiari syndrome. ,nflammation-related
hyperaemia also occurs in acute viral hepatitis.
b; An enhanced formation of lymph or reduced lymph
drainage can cause enlargement of the liver. &ere fluidfilled cysts can
also be regarded as a cause of hepatomegaly.
c; A disorder of the bile flow, particularly in infants, leads to
extensive hepatomegaly.
d; An increase in the extracellular matrix due to collagens,
elastin, proteoglycans, glycoproteins, etc. Also produces various
degrees of hepatomegaly.
3. Local processes
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9ircumscribed enlargement of the liver is precipitated by local
lesions such as cysts, abscesses, parasites :e. g. echinococcus; and
benign or malignant tumours0 this also results in diffuse enlargement
of the liver in some cases.
&epatomegaly, could be caused by various reasons. $or example
by a fatty liver, displays a rounded liver edge with little or no
sensitivity to pressure, whereas in congestive liver, the blunt liver edge
proves to be very painful on palpation. .he conditions below are some
conditions that could cause a hepatomegaly.
1! In;la11ator7 #iver (iseases
Acute >iral &epatitis
Acute Autoimmune &epatitis
Alcoholic &epatitis
9oncomitant &epatitis with ,nfections
Bacterial !epsis
Miliary .uberculosis
1arasitoses :?. -. ?chinococcus, .oxocariasis, 9apillaria
&epatica, !chistosomiasis;
&,> ,nfection
Liver Abscess
Bacterial 9holangitis, ?tc.
"! C>ronic #iver (iseases
9hronic &epatitis
Liver 9irrhosis
&epatic -ranulomatosis, ?tc.
$! etabolic H To/ic (iseases
$atty Liver
&epatic 1orphyrias
Amyloidosis of .he Liver, ?tc.
)! Biliar7 (iseases
Biliary Ebstruction
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1rimary Biliary 9holangitis
9holestasis
BylerQs !yndrome, ?tc.
*! Vascular #iver (iseases
9ongestive Liver,
1eliosis &epatis
9onstrictive 1ericarditis
Budd-9hiari !yndrome
>eno-Ecclusive Disease
Arterial Diseases, ?tc.
,! Tu1ours
Benign Liver .umours
Malignant Liver .umours
Metastatic Liver
-! C7stic #iver
I! Con?enital (iseases
&ereditary Liver !torage Diseases :&aemochromatosis,*ilsonQs
Disease, Amyloidosis, -lycogenoses, Lipopathies, .yrosinaemia,
TellwegerQs 9erebrohepatorenal !yndrome, $ructose ,ntolerance, U"-
Antitrypsin Deficiency, Bur)aQs !yndrome, -alactosaemia, Mauriac
!yndrome, ?tc.;
Malformations of .he Liver Er .he Bile Ducts
J! S7ste1ic Hae1atolo?ical (iseases
1:! S7ste1ic I11unolo?ical (iseases
,ntrahepatic portal hypertension is caused by lesions which are
easy to distinguish morphologically as well aspathogenetically and
which occur in the following regions( :".; presinusoidal veins of the
intrahepatic periportal triangles, :.; liver sinusoids, and :7.; draining
postsinusoidal veins. 1athogenic overlapping is possible, since some
lesions affect both the presinusoidal and sinusoidal vascular sections
simultaneously. $reIuency is estimated at 65-45B.
Ene of the reasons why intrahepatic portal could be portal
hypertension is presinusoidal bloc). .he presinusoidal bloc) can be
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classified under nonparenchymatous portal hypertension. .he *&>1
is normal. .here is no impairment of liver function until a later stage
of the underlying disease has been reached. .his type of bloc) is
caused by a congenital or acIuired constriction of the lumen or by a
reduction in portal venous branches within the periportal triangles.
And this bloc) might be caused by myeloproliferative syndromes.
Because we tal) about haematological, we are about to explain
why could hepatomegaly could happen in systemic haematological
diseases.
E/tra1e3ullar7 Hae1o0oiesis
,ntrahepatic haemopoiesis is a physiological process in foetuses
and neonates. $rom #th to 3th wee) of pregnancy, haemopoiesis
ta)es place in the liver :and spleen; in a diffuse manner within the
sinusoids. .hereafter, focal haemopoiesis may still continue in the
liver up to about the second wee) of life.
Myeloid metaplasia beyond this physiological endpoint of
intrahepatic haemopoiesis is regarded as a pathological event.
&aemopoietic foci are seen in the sinusoids, in DisseQs spaces and
sometimes to a minor degree in the portal fields0 they consist of
erythropoietic and myeloproliferative precursors as well as
polynuclear giant cells of the mega)aryocyte type. .his variety of
cells provides important evidence in histological differential diagnosis
for excluding leu)aemic infiltrates and mononuclear hepatitis.
Myeloid metaplasia accompanies displacement of the bone marrow, e.
g. in osteomyelofibrosis, bonemarrow carcinomatosis and
myeloproliferative diseases.
Eccasionally, mega)aryocytes are also present in the liver.
=aphtol-A!-D chloracetate esterase-positive cells of granulopoiesis
are a stri)ing feature in this context. &epatomegaly is generally found.
Ascites can develop due to portal hypertension.
Acute #euKae1ia
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,n acute myeloid leu)aemia or lymphatic leu)aemia as well as in
acute leu)aemic episodes in non-&odg)in lymphoma, involvement of
the liver may only be detectable clinically by the presence of
hepatomegaly and subicterus. Laboratory parameters usually show
slightly elevated transaminase as well as bilirubin values, and distinct
cholestasis is occasionally observed. Acute hepatic failure can occur
during the course of acute leu)aemia. &istologically, there are
massive, yet uniform blast-cell infiltrates0 these are found mainly
within the portal fields in acute lymphatic leu)aemia :about '8B; and
within the sinusoids in acute myeloid leu)aemia :about 68B;.
,nvolvement of the liver is of no conseIuence with regard to the
underlying disease and its therapy. !econdary infections reIuire
systemic treatment with antibiotics and2or antimycotics.
7elo0roli;erative S7n3ro1e
.he term myeloproliferative syndrome encompasses the
following( :".; chronic myeloid leu)aemia, :.; idiopathic
osteomyelofibrosis and sclerosis, :7.; polycythaemia vera, and :3.;
essential thrombocytosis. ,ntermediate forms of these manifestations
are possible. .he pathogenesis is based on the transformation of a
stem cell and its clonal proliferation. 9hronic lymphatic leu)aemia is
classified as malignant non-&odg)in lymphoma. Everlaps between
the different forms of disease are freIuent. .here is a tendency for
fibrosis to develop in all types of the myeloproliferative syndrome
with subseIuent sclerosis of bone marrow in later stages. 9ertain
forms may progress to acute leu)aemia, which is termed blast crisis.
9hronic Myeloid Leu)aemia
,n 9ML, granulopoiesis is mar)edly accelerated, with increased
formation of immature precursors. .his occurs predominantly in the
bone marrow. Accordingly, there is only a rare and slight involvement
of the liver in 9ML, with the exception of a terminal myeloblast crisis.
&epatomegaly may be very pronounced in some cases. Massive
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splenomegaly is generally evident0 it often presents as a sugar-icing
spleen :perisplenitis cartilaginea;. :s. fig. 74.7; ,nfiltrations of
immature granulocytes and erythrocytes as well as of mega)aryocytes
are identifiable above all in the :generally dilated; sinusoids.
Biochemically, there is an elevation of al)aline phosphatase and LD&.
9omplications include portal hypertension following obstruction of
the sinusoids and as a result of increased hepatic blood flow. Acute
liver failure has been observed. ,n the final stage, metastasis-li)e
structures can appear in the liver :so-called chloroma;. ,maging
procedures reveal no abnormalities in the area of the liver
parenchyma. .herapy with imatinib was recently reported as being
successful.
Esteomyelofibrosis
Esteomyelofibrosis is a chronic, progressive, fibrous
obliteration of the bone marrow. -reyish-white discolouration appears
with an increase in collagenous fibrils and later also in reticular fibrils.
9linically, there is hepatomegaly :and generally also splenomegaly;
correlating with the stage of disease. Arthralgia also occurs
occasionally. Laboratory parameters may show a slight elevation of P-
-., A1, transaminases and bilirubin. Leucocyte al)aline phosphatase
is enhanced. &istologically, extramedullary haemopoiesis, comprising
erythrocyte and granulocyte precursors as well as dysplastic
mega)aryocytes, is found in the liver in V'5B of cases. ,nfiltrates
appear in the sinusoids, which are partly dilated and display fibrosis
and deposits of haemosiderin. .his results in portal hypertension 0
ascites and oesophageal varices are rare :about 6B of cases;. $urther
potential complications include cholelithiasis :its relationship has not
been clarified so far;, Budd-9hiari syndrome and portal vein
thrombosis. .he diagnosis is established by liver histology. ,maging
procedures are of no significance here.
1olycythaemia >era
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Liver involvement in Esler->aIueD disease is rare or not
detectable at all. .here is, however, evidence of hepatosplenomegaly
due to extramedullary haemopoiesis. Ef importance here is the
association with Budd-9hiari syndrome and veno-occlusive disease.
1olycythaemia vera should be considered in cases of aetiologically
unclarified portal vein thrombosis.
?ssential thrombocytosis
*ith the exception of occasional hepatosplenomegaly, liver
involvement is rare. .here is again an association with Budd-9hiari
syndrome and veno-occlusive disease.
Hae1ol7tic S7n3ro1e
=umerous congenital or acIuired diseases lead to haemolysis.
.hey are subsumed under the term haemolytic syndrome. 1articularly,
sic)le-cell anaemia, thalassaemia and paroxysmal nocturnal
haemoglobinuria are worthy of mention in this context.
!ic)le-9ell Anaemia
.his form of genetic haemoglobinopathy is characteriDed by
chronic haemolysis and haemolytic crises. Acute haemolysis is
associated with acute right upper Iuadrant pain, leucocytosis, Haundice
and elevated transaminases, A1 and LD&. .his hepatic crisis can
mimic acute cholecystitis. ,t lasts 7 wee)s. .he condition is caused
by a slowing down of the sinusoidal blood flow, which contains sic)le
cells, and, in addition, by a multiplication of the /upffer cells. .he
liver is enlarged, rich in blood and violet-red. .he sinusoids are dilated
and contain agglutinates of sic)le cells. .he /upffer cells contain
ceroid and siderin as well as phagocytosed erythrocytes. :s. fig.a;
!ingle-cell necroses of hepatocytes with 9ouncilman bodies are
detectable. Acute liver failure, usually with cholestasis and deep
Haundice, is a rare event. 9hronic haemolysis can lead to mostly
asymptomatic gallstones :approx. 8B in children, 8565B in adults;.
$urthermore, portal hypertension and portal fibrosis may develop.
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.herapy( ?xchange transfusion is indicated. !urgery must be avoided
in cases where acute cholecystitis is only mimic)ed. !uccessful liver
transplantation has been reported.
$ig A. ?rythrophagocytosis in /upffer cells :arrows; in
haemolytic anaemia
.halassaemia
As a result of the crises entailing destruction of the red blood
cells and the freIuently reIuired blood transfusions, liver siderosis
develops. .his may subseIuently lead to fibrosis in some cases.
?pisodic cholestasis can be witnessed. ,n progressive siderosis,
treatment with deferoxamine is indicated. 1igment gallstones can
appear in the course of chronic haemolysis.
1aroxysmal &aemoglobinuria
1aroxysmal nocturnal haemoglobinuria may also give rise to
chronic haemolysis. .his membrane defect of the erythrocytes is due
to mutation of the 1,--A gene on chromosome W resulting in deficient
biosynthesis of the glycosylphosphatidlinositol anchor. .he
erythrocytes are sensitive to lysis when the p& of the blood becomes
more acidic during sleep. .his clinical picture can lead to
hepatomegaly, a rise in transaminases, iron deficiency and siderosis as
well as centriDonal necrosis. .hrombosis of the portal and splenic
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veins as well as Budd-9hiari syndrome are possible complications.
!clerosing cholangitis is li)ely to develop due to ischaemia.
S0leeno1e?al7
A normal spleen is "" :"5"3; cm in length, 6 :#4; cm in width
and 3 :73; cm in depth. .he weight of the spleen varies considerably
:C "55 g to V85 g;0 a mean value of "85"65 :"45; g can be accepted.
.he normal diameter of the splenic artery is 38 mm, while that of the
splenic vein is 4"3 mm with a normal mean value of about "5 mm.
*ith a flow rate of 855655 ml per minute, the blood flow through the
spleen exceeds the arterial blood supply of the liver by a factor of
almost 7. .he longitudinal axis of the spleen runs parallel to ribs '""
from the upper dorsal to the lower ventral :/untD, 55#;.
.he symptom of splenomegaly is defined as an enlargement of
the spleen in which the normal values :3 6 "" cm; are clearly
exceeded by V7 cm in at least two dimensions with a corresponding
rise in the normal 9. index :"#5335;. !onographic reliability depends
largely on spleen thic)ness( V8cm #6B, V# cm 48B, and V6 cm
"55B. .he thic)ness of the spleen is therefore regarded as the
parameter which correlates best with clinical findings. An increase in
the longitudinal diameter to well over "" cm is also considered to be
RsplenomegalyS. A diameter of the splenic vein of V"5 mm is deemed
pathological.
?nlargement of the spleen can have numerous causes. ,t is
important to rule out any possibility that the method of investigation
itself could lead to splenomegaly being simulated, such as Rupside-
downS spleen, accessory spleen:s; or wandering spleen. .he
involvement of the spleen in disorders of the lymphatic and
reticuloendothelial system as well as of the portal and systemic
circulation explains why splenomegaly is freIuently found in
connection with widely differing diseases.
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!plenomegaly is very closely related to a number of liver
diseases and, in particular, to the clinically recogniDable involvement
of the liver in a variety of pathological processes. ,nclusion of the
differential diagnosis of splenomegaly can, therefore, provide valuable
information for the clarification of hepatological findings.
(raina?e (isor3ers In T>e Portal an3 S7ste1ic Circulation
Liver 9irrhosis, Liver .umours, Liver ?chinococcosis, 1ortal
>ein .hrombosis, .hrombosis of .he !plenic >ein, +ight &eart
$ailure, Budd-9hiari !yndrome, 1eliosis &epatis, etc.
He0atolienal Stora?e (iseases
Amyloidosis, $atty Liver, -lycogenoses, *olmanQs !yndrome,
&yperchylomicronaemia, *ilsonQs Disease, TellwegerQs
9erebrohepatorenal !yndrome, =iemann-1ic) Disease,
Mucopolysaccharidoses, etc.
In;ectious (iseases
Acute >iral &epatitis, Acute !almonellosis, Measles, Bacterial
!epsis, &istoplasmosis, Leptospirosis, Malaria, Mononucleosis,
BangQs Disease, >isceral Leishmaniasis :;, +ic)ettsioses,
.oxoplasmosis, .ularaemia, !chistosomiasis, etc.
C>ronic In;ections
9holangitis, ?ndocarditis Lenta, Malaria, ?osinophilic
-ranuloma, .uberculosis, 9hronic &epatitis, etc.
Colla?enoses an3 R>eu1atic (iseases
$eltyQs !yndrome, Lupus ?rythematosus, +eiterQs Disease,
!tillQs Disease, *egenerQs Disease, &istiocytosis, etc.
(iseases o; T>e Hae1ato0oietic S7ste1
Acute Leucosis, 9hronic Lymphadenosis, 9hronic Myelosis,
?rythroblastosis, &aemolytic Anaemias, *erlhofQs Disease,
Esteomyelosclerosis, 1olycythaemia >era, .halassaemia, !hunt
&yperbilirubinaemia, etc.
(iseases o; T>e #710>oreticulo>istioc7tic S7ste1
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Lipogranulomatosis, Lymphosarcoma, &odg)inQs Disease :7#;,
Brill-!ymmers Disease, *aldenstrXmQs Disease, etc.
C>ronic E/0osure To Arsenic
Isolate3 8Pri1ar7< S0leno1e?al7
?chinococcus, !plenic Abscess, !plenic .umours, !plenic
9ysts, etc.
NonETro0ical I3io0at>ic S0leno1e?al7
DacieQs syndrome
Tro0ical I3io0at>ic S0leno1e?al7 S7n3ro1e
Massive spleen is a condition in which spleen may extend into
one or both lower Iuadrants of the abdomen. ,t could be caused by
9hronic Myeloid Leu)emia, -aucher disease, &airy 9ell Leu)emia,
,diopathic and !econdary Myelofibrosis, Leishmaniasis :)ala aDar;,
Lymphoma, Malaria, and .halassemia maHor.
!plenectomy for hypersplenism in patients with a massive
spleen siDe :V"855 g;, especially in idiopathic myelofibrosis, is
accompanied by higher morbidity and mortality than is removal of
spleens for immune cytopenias. 1ossible postoperative complications
include extensive adhesions with collateral blood vessels, concomitant
hemostatic disturbances, a tendency to hepatic or portal vein
thrombosis, inHury to the tail of the pancreas, operative site infections,
and subdiaphragmatic abscesses :/untD, 55#;.
.he differential diagnostic possibilities are much fewer when the
spleen is Ymassively enlarged,Y palpable more than 4 cm below the left
costal margin or its drained weight is "555 g. .he vast maHority of
such patients will have non-&odg)inKs lymphoma, chronic
lymphocytic leu)emia, hairy cell leu)emia, chronic myelogenous
leu)emia, Autoimmune hemolytic anemia, myelofibrosis with myeloid
metaplasia, or polycythemia vera :$auci, 554;.
"!1!$ '>at are t>e 3i;;erential 3ia?nosis o; 17elo0roli;erati; 3iseasesL
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Myeloproliferative disorders is the name for a group of conditions
that cause blood cells -- platelets, white blood cells, and red blood cells
-- to grow abnormally in the bone marrow. .hough myeloproliferative
disorders are serious, and may pose certain health ris)s, people with
these conditions often live for many years after diagnosis. .he
prognosis largely depends on the type of disorder.

Myeloproliferative disorders include(
Z1olycythemia vera -- occurs when the bone marrow produces too
many blood cells, especially red blood cells. More than '8B of people
with polycythemia vera carry the blood mutation [A/>#"6$.
Z?ssential thrombocytosis -- occurs when the body produces too
many platelet cells, which help blood to clot. 9lots can bloc) blood vessels
leading to heart attac) or stro)e.
Z1rimary or idiopathic myelofibrosis, also )nown as
myelosclerosis -- occurs when the bone marrow produces too much
collagen or fibrous tissue in the bone marrow. .his reduces bone marrowKs
ability to produce blood cells.
Z9hronic myelogenous leu)emia :9ML; -- cancer of the bone
marrow that produces abnormal granulocytes, a type of white blood cell,
in the bone marrow.

!igns and !ymptoms(
Many people with myeloproliferative disorders have no symptoms
when their doctors first ma)e the diagnosis. Ene symptom shared by all
myeloproliferative disorders, with the exception of essential
thrombocytosis, is an enlarged spleen. An enlarged spleen can cause
abdominal pain and a feeling of fullness.
!ome signs and symptoms of the different types of
myeloproliferative disorders include(

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1olycythemia vera
Z$atigue, general malaise
Z.rouble breathing
Z,ntense itching after bathing in warm water
Z!tomachaches
Z1urple spots or patches on the s)in
Z=osebleeds, gum or stomach bleeding, or blood in the urine
Z.hrobbing and burning pain in the s)in, often with dar)ened, blotchy
areas
Z&eadache and problems with vision
Z&igh blood pressure
ZBloc)age of blood vessels. .his may cause heart disease, stro)e, or
gangrene :tissue death; of the arms and legs.

Z&eart attac) or sto)e
Z&eadache
ZBurning or throbbing pain, redness, and swelling of the hands and feet
ZBruising
Z-astrointestinal bleeding or blood in the urine

1rimary myelofibrosis
Z.rouble breathing
ZAnemia
Z*eight loss
Z$ever and night sweats
ZAbnormal bleeding

9hronic myelogenous leu)emia :9ML;
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Z*eight loss or loss of appetite
Z$ever and night sweats
ZBone or Hoint pain
Z&eart attac) or stro)e
Z.rouble breathing
Z-astrointestinal bleeding
Z,nfection

9auses(

All myeloproliferative disorders are caused by overproduction of one or
more types of cells. =o one )nows what triggers the overproduction of
cells, but theories include(
Z-enetics -- !ome people with 9ML have an abnormally shortened
chromosome )nown as the 1hiladelphia chromosome.
Z?nvironment -- !ome studies suggest that myeloproliferative disorders
may result from an overexposure to radiation, electrical wiring, or
chemicals.

+is) $actors(

.hese factors may increase your ris) for developing a myeloproliferative
disorder(

1olycythemia vera
Z-ender -- Men are times more li)ely than women to develop the
condition.
ZAge -- 1eople older than #5 are most li)ely to develop the condition,
though it may happen at any age.
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Z?nvironment -- ?xposure to intense radiation may increase the ris) for
the condition.

Z-ender -- *omen are ".8 times more li)ely than men to develop the
condition.
ZAge -- 1eople older than #5 are most li)ely to develop the condition,
though 5B of those with this condition are under 35.
Z?nvironment -- !ome researchers suggest that exposure to chemicals or
to electrical wiring may increase a personKs ris) for the condition.

Z-ender -- Men are slightly more li)ely than women to develop the
condition.
ZAge -- 1eople ages #5 - 65 are most li)ely to develop the condition.
Z?nvironment -- ?xposure to petrochemicals, such as benDene and
toluene, and intense radiation may increase the ris) of developing the
condition.

Z-ender -- Men are more li)ely than women to develop the condition.
ZAge -- 1eople ages 38 - 85 are the most li)ely to develop the condition.
Z?nvironment -- ?xposure to intense radiation may increase the ris) of
developing the condition.

Diagnosis(

A sign shared by all myeloproliferative disorders, with the exception of
essential thrombocytosis, is an enlarged spleen. \our doctor may detect an
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enlarged spleen during a routine physical examination. ,n addition to doing
a physical exam, the doctor may also conduct the following tests(
ZBlood tests -- to find abnormal types or numbers of red or white blood
cells. .hey can also detect anemia and leu)emia.
ZBone marrow biopsy -- sample of bone marrow may be ta)en after blood
tests. ,t can show the presence of abnormal types or numbers of red or
white blood cells and may detect certain types of anemia and cancer in the
marrow.
Z9ytogenetic analysis -- views blood or bone marrow are viewed under a
microscope to loo) for changes in the chromosomes.

.reatment(

.here is no cure for most myeloproliferative disorders. .here are,
however, several treatments that help improve symptoms and prevent
complications associated with the conditions.

.he treatment for each type of myeloproliferative disorder is slightly
different(
Z1olycythemia vera -- lower red blood cell count by removing blood,
called phlebotomy. .reatment with medication, called myelosuppressive
therapy, is also available.
Z?ssential thrombocytosis -- treat symptoms, when present, with
medications
Z1rimary myelofibrosis -- treat symptoms, when present, with medications
and blood transfusion
Z9ML -- .reatment options for 9ML have expanded greatly and may
include( targeted therapy, chemotherapy, biologic therapy, high-dose
chemotherapy with stem cell transplant, donor lymphocyte infusion :DL,;,
surgery.
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Medications

A personKs diagnosis and symptoms will determine the type of medication
prescribed. !ome possible medications include(

1olycythemia vera
Z&ydroxyurea :Droxia, &ydrea; or anagrelide :Agrylin; -- reduces number
of blood cells.
ZLow-dose aspirin -- reduces s)in redness and burning, and lowers
increased temperature that may occur with the condition.
ZAntihistamines -- decreases itching.
ZAllopurinol -- reduces symptoms of gout, a potential complication of
polycythemia vera.

?ssential .hrombocytosis
ZLow-dose aspirin -- may treat headache and burning pain in the s)in.
Z&ydroxyurea :Droxia, &ydrea; or anagrelide :Agrylin; -- reduces number
of blood cells.
ZAminocaproic acid -- reduces bleeding. .his treatment may be used
before surgery to prevent bleeding as well.

Z&ydroxyurea -- may control complications, such as enlargement of the
liver and spleen, reduce the number of white cells and platelets in the
blood, and improve anemia.
Z.halidomide and lenalidomide -- to reduce symptoms and treat anemia.

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Z.argeted drugs -- affect a specific protein that lets cancer cells multiply.
.hese drugs include Dasatinib :!prycel;, ,matinib :-leevec;, and =ilotinib
:.asigna;.
Z,nterferon -- helps the immune system combat cancer cells. %sed only if
bone marrow transplant is not an option.
Z9hemotherapy -- drugs such as cyclophosamide and cytarabine are often
combined with other treatments to )ill cancer cells.

!urgery and Ether 1rocedures

*ith primary myelofibrosis, 9ML, and late stage polycythemia vera,
blood cells are produced in sites other than the bone marrow, such as the
liver and spleen. .hat causes these organs to get bigger. *hen enlargement
of the spleen becomes painful, the person may have surgery to remove it.

,n very serious cases of primary myelofibrosis, the person may undergo a
stem cell transplant. ,n this procedure, abnormal stem cells :cells that
manufacture blood cells; in the bone marrow are replaced with healthy
stem cells. A stem cell transplant has life-threatening ris)s, however. ,n
one study, 8-year survival was #B in patients younger than 38 years and
"3B in those that were older.

$or people with 9ML, a bone marrow transplant may be an option. After
either a stem cell or bone marrow transplant, the healthy bone marrow
cells begin to grow and produce healthy blood cells.

1hlebotomy -- removing some blood from the body -- may lower the ris)
of stro)e in people with polycythemia vera. ,t is the primary therapy in
polycythemia vera, and itKs the only treatment that has improved survival.
1eople with anemia may need blood transfusions. ,n one study, researchers
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suggest that low dose aspirin :4"-78 mg2day; may lower the ris) of blood
clots in people with polycythemia vera.

=utrition and Dietary !upplements

A treatment plan for myeloproliferative disorders may include a range of
complementary and alternative therapies. As) your team of health care
providers about the best ways to incorporate these therapies into your
overall treatment plan. Always tell your doctor about the herbs and
supplements you are using or considering using, as some supplements may
interfere with conventional cancer treatments.

Myeloproliferative disorders need conventional medical treatment. .here
arenKt any supplements that can specifically help with these conditions.
&owever, following a healthy diet and getting regular exercise may help to
)eep your body strong while coping with a myeloproliferative disorder.
.ry these tips(
Z?at antioxidant foods, including fruits :such as blueberries, cherries, and
tomatoes;, and vegetables :such as sIuash and bell peppers;.
ZAvoid refined foods, such as white breads, pastas, and especially sugar.
Z?at fewer red meats and more lean meats, cold-water fish, tofu :soy, if no
allergy;, or beans for protein.
Z%se healthy oils, such as olive oil or vegetable oil.
Z+educe or eliminate trans-fatty acids, found in commercially ba)ed
goods such as coo)ies, crac)ers, ca)es, $rench fries, onion rings, donuts,
processed foods, and margarine.
ZAvoid caffeine, alcohol, and tobacco.
ZDrin) # - 4 glasses of filtered water daily.
Z?xercise at least 75 minutes daily, 8 days a wee).

As) your doctor if you would benefit from the following supplements(
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ZA daily multivitamin, containing the antioxidant vitamins A, 9, ?, the B-
complex vitamins, and trace minerals such as magnesium, calcium, Dinc,
and selenium.
ZEmega-7 fatty acids, such as fish oil, " - capsules or " - 7
tablespoonfuls oil, " - 7 times daily, to help decrease inflammation and
help with immunity. 9old-water fish, such as salmon or halibut, are good
sources, but you may need to ta)e supplements to get enough omega-7
fatty acids. ,f you are ta)ing aspirin or other blood thinners such as
warfarin :9oumadin; or clopidogrel :1lavix;, tal) to your doctor. Emega-7
fatty acids may increase bleeding.
Z1robiotic supplement :containing Lactobacillus acidophilus;, 8 - "5
billion 9$%s :colony forming units; a day, when needed for maintenance
of gastrointestinal and immune health. \ou should refrigerate your
probiotic supplements for best results. 1eople with wea)ened immune
systems or those who ta)e drugs to suppress the immune system should
as) their doctor before ta)ing probiotics.

&erbs

&erbs are generally a safe way to strengthen and tone the bodyKs systems.
As with any therapy, you should wor) with your health care provider to
diagnose your problem before starting any treatment. \ou may use herbs
as dried extracts :capsules, powders, teas;, glycerites :glycerine extracts;,
or tinctures :alcohol extracts;. %nless otherwise indicated, ma)e teas with
" tsp. herb per cup of hot water. !teep covered 8 - "5 minutes for leaf or
flowers, and "5 - 5 minutes for roots. Drin) - 3 cups per day. \ou may
use tinctures alone or in combination as noted.

,f you are undergoing treatment for cancer, you should always as) your
doctor before ta)ing any herbs or supplements. =o herbs have been
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studied specifically for myeloproliferative disorders, but the following
herbs may help your general health(
Z-reen tea :9amellia sinensis; standardiDed extract, 85 - 855 mg daily,
for inflammation, and for antioxidant and immune effects. %se caffeine-
free products. \ou may also prepare teas from the leaf of this herb.
Z,ndirubin :,ndigofera tinctoria; -- ,n case reports, indirubin showed
positive results in treating 9ML long-term. &owever, no scientific studies
have been done on using indirubin for 9ML. ,ndirubin is from the indigo
plant and is included in a traditional 9hinese herb formula that has been
used historically to treat 9ML. =ot much is )nown about the safety of
indirubin. As) your doctor before ta)ing it and only use under the
guidance of a )nowledgeable prescriber.
ZElive leaf :Elea europaea; -- for anticancer and immune effects. 1eople
with diabetes and high blood pressure should as) their doctor before
ta)ing olive leaf.
Z.urmeric :9urcuma longa; -- for pain and inflammation. Do not use
turmeric if you have gallbladder problems. .urmeric may increase the ris)
of bleeding, especially if you ta)e blood-thinners such as warfarin
:9oumadin;, clopidogrel :1lavix;, or aspirin.

Ether 9onsiderations(

1regnancy

1regnant women should avoid the drug hydroxyurea because it may pose a
ris) to the baby.

1rognosis and 9omplications

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Myeloproliferative disorders are slow acting, and donKt always cause life-
threatening symptoms. .he complications of these conditions, however,
may be serious. !ome complications include(
Z?nlargement of the spleen and liver
Z-out
ZAnemia
ZBleeding
Z/idney or liver failure
Z&eart attac)s or stro)e
Z,nfection
Z9ML can transform into acute leu)emia, a more dangerous condition.

.he survival rate for myeloproliferative disorders varies, depending on
both the type of disorder and the )ind of symptoms each person
experiences.
?hrlich, !. D., 5"", Myeloproliferative disorders, available at
http(22www.umm.edu2altmed2articles2myeloproliferative-disorders-
555""3.htm accessed at [une 8 5"
"!1!) E/0lain about t>e laborator7 tests ;or 17elo0roli;erati; 3iseases4
A. 1olycythemia vera
!igns and symptoms are usually caused by an increase in
hematocrit :plethora symptoms;, hyperviscosity :causing
symptoms of headache, diDDiness, vertigo, tinnitus, visual
disturbances, stro)e, angina pectoris, myocardial infarction, and
claudication;, splenomegaly, hepatomegaly, pruritus, urticaria and
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gout. Manifestations of thrombotic and bleeding into the cause of
death which is common in patients with this disease.
1> diagnosis is confirmed by the following criteria(
Z 9riteria for 9ategory A(
A" ,ncreased hematocritV 8B
A .here were no causes of secondary polycythemia
A7 .here is splenomegalyA 1alpableA
9lonality A3 mar)er
Z 9riteria for category B
B" .hrombocytosis( platelet numbersV 355.5552ul
B -ranulositosis( neutrophilsV "5.5552ul
B7 !plenomegaly s)ening obtained through examination of the
isotope 2 %ltrason
B3 eritropoitin reduction and increased levels of B$%-?
.o note the use of these criteria is that(
- Levels of hematocrit chec)ed by inspection using the 8"9r
erythrocyte labeling, unless the levels of hematocritV #5B
- =o examination of clonal applicable clinically for evidence of 1>
- ,tem B3 can not be applied widely and is not specific for 1>
Definitive diagnosis is made when the 1> obtained(
- 9ategory A" and A and either A7 or A3 or
- 9ategory A" and A and one of the criteria B
. .rombositemia essential
9riteria for the diagnosis of .? include(
A. 1latelet countV " million 2 ?%+ which are persistent.
. =o other causes of thrombocytosis :eg( a history of splenectomy,
the signs of $e deficiency, malignancy, gastrointestinal bleeding;.
nd
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7. Bone marrow examination showed an increase in the number
mega)aryosit hiperselularitas and the results of the cytogenetic examination
showed 1hiladelphia chromosome gene rearrangement without B9+ 2 ABL
and signs of myelodysplasia
7. 9hronic idiopathic myelofibrosis with myeloid metaplasia :MMM;
9riteria for the diagnosis of this disease include(
- !plenomegaly.
- .he leu)oeritroblasti) :erythrocyte nucleus and granulositosis;,
anisositosis and poi)ilositosis on examination of peripheral blood smear.
- .he number of normal hematocrit :by examination of 8"9r;
- ?xamination of bone marrow aspiration( fibrosis inV "27 cross
sectional area. $ibrosis is not secondary due to other causes.
- =o 1&" chromosomes and no diseritropoisis
MMM patients with laboratory test results usually show(
A. Anemia was :on 27 of cases; is probably caused by an ineffective
eritropoisis,
autoimmune hemolysis, hemoglobin & disease or paroxysmal
hemoglobinuria li)e syndrome. ?xamination of peripheral blood smear
shows erythrocyte shape da)rosit 2 teardrop cells, ovalosit, anisositosis,
poli)romasia and erythrocyte nucleus is patognomonis to MMM
. .he number of granulocytes ranged between "5 thousand - 75
thousand 2 MM/ by the blast and promielosit C"5B. $ifteen percent of
patients experienced granulositopeni.
7. 1latelet counts vary :depending on the stage of disease; with an
abnormal morphology.
3. ?xamination of bone marrow aspiration showed decreased fat
content description, granulositi) hyperplasia, increased number of dysplastic
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th
mega)aryosit, fibrosis that isAA 1atchyA and spread as well as decrease the
amount of reticuline.
8. ,mmunological examination showed abnormalities in the form of a
monoclonal antibody :"5B of cases;, circulating immune complexes :V
85B of cases;, polyclonal hiperglobulinemia, rheumatoid factor and
antinuclear antibody, and provide the results of :<; on direct examination
9oombAA ! test :5B of cases ;
!igns and symptoms that occur is the manifestation of anemia and
splenomegaly
Ether signs and symptoms that can be found include fever, weight loss
and bone pain. !ome of the syndrome, which can be found in this disease is
acute myelofibrosis :)nown as the LMA type M6;, portal hypertension,
tumors and dermatoses netrofili) hematopoiti) e)strameduler
3. &ipereosinofili) syndrome :!&?;
.he criteria used for diagnosis of this disease are(
A. 1ersistent increase in absolute eosinophil count :V "8552mm); forV
# months.
. .here were no parasites, allergies or other causes of eosinophilic.
7. .here are signs of organ system involvement.
3. .here were no chromosomal abnormalities
8. 9hronic Leu)emia netrofili)
.he disease is similar to the 9ML and is one of the differential
diagnosis of 9ML. LM/ is a difference with a normal cytogenetic
examination results in these patients.
.his diagnosis should be considered when patients with suspicion of
9ML found that showed non-clonal mature picture netrofilia and found no
other cause of netrofilianya. ,f the disease is found in patients with other
nd
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malignancies :eg myeloma;, the diagnosis should be confirmed by
cytogenetic examination results illustrating myeloid malignancies
#. Mielogenous chronic leu)emia 2 9ML
Approximately 75B of patients are asymptomatic at the time was
diagnosed while the rest showed the symptoms are not specific such as
feeling tired, fatigue, malaise, anorexia, weight loss, abdominal discomfort
and a sense of early satiety due to hepatosplenomegaly. !mall fraction of
patients experience mild symptoms such as fever and hypermetabolic
hyperhidrosis.
En physical examination found anemia, splenomegaly and sternal
tenderness.
!ymptoms and signs of hyperviscosity le)ostasis and disruption of the
microcirculation in the lungs, brain, eyes, ears or penis may occur in "8B of
patients by the number of leu)ocytesV 755 ribu2mm7 where the symptoms
can be ta)ipneu, dyspnoea, cyanosis, diDDiness, speech pelo, impairment of
consciousness, visual disturbances :blurred vision and double, v distension.
retinalis, retinal hemorrhages and edema papil; and hearing :tinnitus or
deafness;
a3e Putra Se3ana2 T! Ivone 'ulansari2
>tt0MHHejournal!unu3!ac!i3HabstraKH,N "I"N "J!03;
"!" A((ITIONA# IN+ORATION
!he drin)s no alcohol, no smo)ing, rather of doing some sports
!he slept normally
+eview of !ystem(
=ormal defecation
1hysical examination(
Ascites :-;
Laboratory test(
19>( hitung@
!erum iron( "54 microgram2dL
nd
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th
&bA( 6#,#B
&bA( .8B
&b$( 5.'B
&bL3( 5B
"!$ #EARNING ISS.ES "
". *hat is .halassemiaA
. ?xplain about chronic diseases@
7. Mention )ind of &bs@
CHAPTER $
ANA#&SIS AN( CONC#.SION
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$!1 ANS'ER O+ #EARNING ISS.ES "
$!1!1 '>at is T>alasse1iaL
(isor3ers o; Globin S7nt>esisM T>e T>alasse1ias
.he thalassemias are the most common monogenic diseases in
man. .hey are seen commonly in countries to which these high-
freIuency populations immigrate.
.halassemia consists of two main classes, M and L, in which
the M- and L-globin genes are involved. +arer forms of thalassemia
result from abnormalities of other globin genes. .he conditions have
in common an imbalanced rate of production of the globin chains of
adult hemoglobin( excessive M chains in L-thalassemia and L chains
in M-thalassemia. !everal hundred different mutations at the M- and
L-globin loci have been defined as the cause of the reduced or absent
output of M or L chains. .he high freIuency and genetic diversity of
the thalassemias are related to past or present heteroDygote resistance
to malaria.
.he pathophysiology of the thalassemias can be traced to the
deleterious effects of the excessively produced globin-chain subunits.
,n L-thalassemia, excess M chains damage the red cell precursors and
red cells, leading to profound anemia. .he result is extensive
expansion of erythropoietic marrow, which is ineffective in producing
mature red cells but impinges on developing bones, severely affecting
development, bone formation, and growth. .he maHor cause of
morbidity and mortality is the effect of iron deposition on the
endocrine organs, liver, and heart, which results from increased
intestinal absorption and the effects of blood transfusion. .he
pathophysiology of the M-thalassemias is different because the excess
L chains resulting from defective M-chain production form L
3
molecules, or hemoglobin &, which is soluble. &owever, hemoglobin
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& is unstable and precipitates in older red cells. &ence, the anemia of
M-thalassemia is hemolytic rather than dyserythropoietic.
(e;initions
9ooley and Lee first described a form of severe anemia that
occurred early in life and was associated with splenomegaly and
bone changes. -eorge &. *hipple and *illiam L. Bradford
published a comprehensive account of the pathologic findings in this
disease. *hipple coined the phrase thalassic anemia and condensed
it to thalassemia. .he disease described by 9ooley and Lee is the
homoDygous state of an autosomal gene for which the heteroDygous
state is associated with much milder hematologic changes. .he
severe homoDygous condition became )nown as thalassemia major.
.he heteroDygous states, thalassemia trait, were designated
according to their severity as thalassemia minor or minima. Later,
the term thalassemia intermedia was used to describe disorders that
were milder than the maHor form but more severe than the traits.
.halassemia is not a single disease but a group of disorders,
each resulting from an inherited abnormality of globin production.
.he conditions form part of the spectrum of diseases )nown
collectively as the hemoglobinopathies, which can be classified
broadly into two types. .he first subdivision consists of conditions,
such as sic)le cell anemia, that result from an inherited structural
alteration in one of the globin chains. Although such abnormal
hemoglobins may be synthesiDed less efficiently or bro)en down
more rapidly than normal adult hemoglobin, the associated clinical
abnormalities result from the physical properties of the abnormal
hemoglobin. .he second maHor subdivision of the
hemoglobinopathies, the thalassemias, consists of inherited defects
in the rate of synthesis of one or more of the globin chains. .he
nd
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result is imbalanced globin chain production, ineffective
erythropoiesis, hemolysis, and a variable degree of anemia
(i;;erent +or1s o; T>alasse1ia
.halassemia can be defined as a condition in which a reduced
rate of synthesis of one or more of the globin chains leads to
imbalanced globin-chain synthesis, defective hemoglobin
production, and damage to the red cells or their precursors from
the efects of the globin subunits that are produced in
relative excess.
.he L-thalassemias are divided into two main varieties. ,n one
form, L
5
-thalassemia, there is no L-chain production. ,n the other
form, L
<
-thalassemia, there is a partial deficiency of L-chain
production. .he hallmar) of the common forms of L-thalassemia is
an elevated level of hemoglobin A
in heteroDygotes. ,n a less
common class of G-thalassemias, heteroDygotes have normal
hemoglobin A
levels. Ether rare forms include varieties of

-thalassemia intermedia that are inherited in a dominant fashion, that
is, heteroDygotes are severely affected, and there is a variety in
which the genetic determinants are not lin)ed to the G-globin gene
cluster.
.he A-thalassemias are characteriDed by reduced output A
chains and hence reduced hemoglobin A
levels in heteroDygotes and

an absence of hemoglobin A
in homoDygotes. .hey are of no

clinical significance except that, when inherited with G-thalassemia
trait, the level of hemoglobin A
is reduced to the normal range.

nd
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Because A chains are present in both fetal and adult
hemoglobins, a deficiency of A-chain production affects hemoglobin
synthesis in fetal and in adult life. A reduced rate of A-chain
synthesis in fetal life results in an excess of O chains, which form O
3
tetramers, or hemoglobin BartKs. ,n adult life, a deficiency of A
chains results in an excess of G chains, which form G
3
tetramers, or
hemoglobin &. Because there are two A-globin genes per haploid
genome, the genetics of A-thalassemia is more complicated than that
of G-thalassemia. .here are two main groups of A-thalassemia
determinants. $irst, in the A
5
-thalassemias :formerly called A-
thalassemia ";, no A chains are produced from an affected
chromosome, that is, both lin)ed A-globin genes are inactivated.
!econd, in the A
<
-thalassemias :formerly called A-thalassemia ;, the
output of one of the lin)ed pair of A-globin genes is defective. .he
A
<
-thalassemias are subdivided into deletion and nondeletion types.
Both the A
5
-thalassemias and deletion and nondeletion forms of A
<
-
thalassemia are extremely heterogeneous at the molecular level.
.here are two maHor clinical phenotypes of A-thalassemia( the
hemoglobin BartKs hydrops syndrome, which usually reflects the
homoDygous state for A
5
-thalassemia, and hemoglobin & disease,
which usually results from the compound heteroDygous state for A
5
-
and A
<
-thalassemia.
Because the structural hemoglobin variants and the
thalassemias occur at a high freIuency in some populations, the two
types of genetic defect can be found in the same individual. .he
different genetic varieties of thalassemia and their combinations
with the genes for abnormal hemoglobins produce a series of
disorders )nown collectively as the thalassemia syndromes.
Pat>o0>7siolo?7
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Almost all the pathophysiologic features of the thalassemias can
be related to a primary imbalance of globin-chain synthesis. .his
phenomenon ma)es the thalassemias fundamentally different from all
the other genetic and acIuired disorders of hemoglobin production
and, to a large extent, explains their extreme severity in the
homoDygous and compound heteroDygous states.
ec>anis1s o; Er7t>roi3 Precursor an3 Re3 Cell (a1a?e
Damage to the red cell membrane by the globin-chain
precipitation process occurs by two maHor routes( generation of
hemichromes from excess alpha chains with subseIuent structural
damage to the red cell membrane, and similar damage mediated
through the degradation products of excess alpha chains. .he
degradation products of free alphachains]globin, heme, hemin
:oxidiDed heme;, and free iron]also play a role in damaging red cell
membranes. ?xcess globin chains bind to different membrane proteins
and alter their structure and function. ?xcess iron, by generating
oxygen free radicals, damages several red cell membrane components
:including lipids and protein; and intracellular organelles. &eme and
its products can catalyDe the formation of a variety of reactive oxygen
species that can damage the red cell membrane. .hese changes are
reflected in an increased rate of apoptosis of red cell precursors. .he
red cells are rigid and underhydrated, lea) potassium, and have
increased levels of calcium and low, unstable levels of A.1. Damage
to the red cells can be mediated by the presence of rigid inclusion
bodies during passage of the red cells through the spleen.
.he anemia of beta-thalassemia has three maHor components.
$irst and most important is ineffective erythropoiesis with
intramedullary destruction of a variable proportion of the developing
red cell precursors. !econd is hemolysis resulting from destruction of
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mature red cells containing alpha-chain inclusions. .hird are
hypochromic and microcytic red cells resulting from the overall
reduction in hemoglobin synthesis.
Because the primary defect in beta-thalassemia involves beta-
chain production, synthesis of hemoglobins $ and A
should be
unaffected. $etal hemoglobin production in utero is normal. .he
clinical manifestations of thalassemia appear only when the neonatal
switch from gama- to beta-chain production occurs. &owever, fetal
hemoglobin synthesis persists beyond the neonatal period in nearly all
forms of beta-thalassemia. beta-.halassemia heteroDygotes have an
elevated level of hemoglobin A
. .he elevated level appears to reflect

not only a relative decrease in hemoglobin A as a result of defective
beta-chain synthesis but also an absolute increase in the output of
deltachains both cis and trans to the mutant beta-globin gene.
.he conseIuences of excess nonNalpha-chain production in the
alpha-thalassemias are Iuite different. Because alphachains are shared
by both fetal and adult hemoglobin, defective alpha-chain production
is manifest in both fetal and adult life. ,n the fetus, it leads to excess
gama-chain production0 in the adult, to an excess of betachains.
?xcess gamachains form gama
3
homotetramers or hemoglobin BartKs0
excess betachains form beta
3
homotetramers or hemoglobin &. .he
fact that betaand gamachains form homotetramers is the reason for the
fundamental difference in the pathophysiology of alpha- and beta-
thalassemia. Because gama
3
and beta
3
tetramers are soluble, they do
not precipitate to any significant degree in the marrow, and therefore
the alpha-thalassemias are not characteriDed by severe ineffective
erythropoiesis. &owever, beta
3
tetramers precipitate as red cells age,
with the formation of inclusion bodies. .hus, the anemia of the more
severe forms of alpha-thalassemia in the adult results from a shortened
survival of red cells conseIuent to their damage in the
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microvasculature of the spleen as a result of the presence of the
inclusions. ,n addition, because of the defect in hemoglobin synthesis,
the cells are hypochromic and microcytic. &emoglobin BartKs is more
stable than hemoglobin & and does not form large inclusions.
Another factor exacerbates the tissue hypoxia of the anemia of
the alpha-thalassemias. Both hemoglobin BartKs and hemoglobin &
show no hemeNheme interaction and have almost hyperbolic oxygen
dissociation curves with very high oxygen affinities. .hus, they are
not able to liberate oxygen at physiologic tissue tensions0 in effect,
they are useless as oxygen carriers.
ConsePuences o; Co10ensator7 ec>anis1s ;or t>e Ane1ia o;
T>alasse1ia
.he profound anemia of homoDygous beta-thalassemia and the
high oxygen affinity of the blood produced combine to cause severe
tissue hypoxia. Because of the high oxygen affinity of hemoglobins
BartKs and &, a similar defect in tissue oxygenation occurs in the more
severe forms of alpha-thalassemia. .he maHor response is
erythropoietin production and expansion of the dyserythropoietic
marrow. .he results are deformities of the s)ull and face and porosity
of the long bones. ?xtramedullary hematopoietic tumors may develop
in extreme cases. Apart from the production of severe s)eletal
deformities, marrow expansion may cause pathologic fractures and
sinus and middle ear infection as a result of ineffective drainage.
Another important effect of the enormous expansion of the
marrow mass is the diversion of calories reIuired for normal
development to the ineffective red cell precursors. .hus, patients
severely affected by thalassemia show poor development and wasting.
nd
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.he massive turnover of erythroid precursors may result in secondary
hyperuricemia and gout and severe folate deficiency.
.he effects of gross intrauterine hypoxia in homoDygous alpha
5
-
thalassemia have been described. ,n the symptomatic forms of alpha-
thalassemia :e.g., hemoglobin & disease; that are compatible with
survival into adult life, bone changes and other conseIuences of
erythroid expansion are seen, although less commonly than in beta-
thalassemia.
S0leno1e?al7M (ilutional Ane1ia
9onstant exposure of the spleen to red cells with inclusions
consisting of precipitated globin chains gives rise to the phenomenon
of Ywor) hypertrophy.Y 1rogressive splenomegaly occurs in both
alpha- and beta-thalassemia and may worsen the anemia. A large
spleen acts as a sump for red cells, seIuestering a considerable
proportion of the red cell mass. $urthermore, splenomegaly may cause
plasma volume expansion, a complication that can be exacerbated by
massive expansion of the erythroid marrow. .he combination of
pooling of the red cells in the spleen and plasma volume expansion
can exacerbate the anemia in both alpha- and beta-thalassemia. .he
same process can occur in an enlarged liver, particularly after
splenectomy.
GET>alasse1ia ajor
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&emoglobin levels at presentation may range from to 7 g2dl or
even lower. .he red cells show mar)ed anisopoi)ilocytosis, with
hypochromia, target cell formation, and a variable degree of
basophilic stippling. .he appearance of the blood film varies,
depending on whether the spleen is intact. ,n nonsplenectomiDed
patients, large poi)ilocytes are common. After splenectomy, large, flat
macrocytes and small, deformed microcytes are freIuently seen. .he
reticulocyte count is moderately elevated, and nucleated red cells
nearly always are present in the blood. .hese red cell forms may reach
very high levels after splenectomy. .he white cell and platelet counts
are slightly elevated unless secondary hypersplenism occurs. !taining
of the blood with methyl violet, particularly in splenectomiDed
subHects, reveals stippling or ragged inclusion bodies in the red cells.
.hese inclusions can nearly always be found in the red cell precursors
in the marrow. .he marrow usually shows erythroid hyperplasia with
nd
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morphologic abnormalities of the erythroblasts, such as stri)ing
basophilic stippling and increased iron deposition. ,ron )inetic studies
indicate mar)edly ineffective erythropoiesis, and red cell survival
usually is shortened. 1opulations of cells with very short survival and
longer-lived populations of cells are seen. .he latter contain relatively
more fetal hemoglobin. An increased level of fetal hemoglobin,
ranging from less than "5 percent to greater than '5 percent, is
characteristic of homoDygous L-thalassemia. =o hemoglobin A is
produced in L
5
-thalassemia. .he acid elution test shows that fetal
hemoglobin is heterogeneously distributed among the red cells.
&emoglobin A
levels in homoDygous L-thalassemia may be low,

normal, or high. &owever, expressed as a proportion of hemoglobin A,
the hemoglobin A
level almost invariably is elevated. Differential

centrifugation studies indicate some heterogeneity of hemoglobin $
and A
distribution among thalassemic red cells, but their level in

whole blood gives little indication of their total rates of synthesis.
GET>alasse1ia inor
&emoglobin values of patients with L-thalassemia minor usually
range from ' to "" g2dl. .he most consistent finding is small, poorly
hemoglobiniDed red cells, resulting in M9& values of 5 to pg and
M9> values of 85 to 65 fl. .he red cell indices are particularly useful
in screening for heteroDygous carriers of thalassemia in population
surveys. .he marrow in heteroDygous L-thalassemia shows slight
erythroid hyperplasia with rare red cell inclusions. Megaloblastic
transformation as a result of folic acid deficiency occurs occasionally,
particularly during pregnancy. A mild degree of ineffective
erythropoiesis is noted, but red cell survival is normal or nearly
normal. .he hemoglobin A
level is increased to 7.8 to 6 percent. .he

level of fetal hemoglobin is elevated in approximately 85 percent of
cases, usually to " to 7 percent and rarely to greater than 8 percent.
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AET>alasse1ias
He1o?lobin BartQs H73ro0s +etalis S7n3ro1e
,n infants with the hydrops fetalis syndrome, the blood film
shows severe thalassemic changes with many nucleated red cells. .he
hemoglobin consists mainly of hemoglobin BartKs, with approximately
"5 to 5 percent hemoglobin 1ortland. %sually no hemoglobin A or $
is present, although rare cases that seem to result from interaction of
M
5
-thalassemia with a severe nondeletion form of M
<
-thalassemia show
small amounts of hemoglobin A.
He1o?lobin H (isease
.he blood film shows hypochromia and anisopoi)ilocytosis. .he
reticulocyte count usually is approximately 8 percent. ,ncubation of
the red cells with brilliant cresyl blue results in ragged inclusion
bodies in almost all cells. .hese bodies form because of precipitation
of hemoglobin & in vitro as a result of redox action of the dye. After
splenectomy, large, single &einD bodies are observed in some cells.
.hese bodies are formed by in vitro precipitation of the unstable
hemoglobin & molecule and are seen only after splenectomy.
&emoglobin & constitutes between 8 and 35 percent of the total
hemoglobin. .races of hemoglobin BartKs may be present, and the
hemoglobin A
level usually is slightly subnormal.

A
:
ET>alasse1ia an3 A
R
ET>alasse1ia Traits
.he M
5
-thalassemia trait is characteriDed by the presence of 8 to
"8 percent hemoglobin BartKs at birth.
6
.his hemoglobin disappears
during maturation and is not replaced by a similar amount of
hemoglobin &. An occasional cell with hemoglobin & inclusion
bodies may appear after incubation with brilliant cresyl blue. .his
nd
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phenomenon is often used as a diagnostic test for the M-thalassemia
trait. &owever, the test is difficult to standardiDe and reIuires much
experience to be useful. ,n adult life, the red cells of heteroDygotes
have morphologic changes of heteroDygous thalassemia with low
M9& and M9> values. .he electrophoretic pattern is normal. -lobin-
synthesis studies show a deficit of M-chain production, with an M-2L-
chain production ratio of approximately 5.6.
.he M
<
-thalassemia trait : M M2 MN; is characteriDed by no or
minimal hematologic changes, " to percent of hemoglobin BartKs at
birth in some but not all cases, and a slightly reduced M-2L-chain
production ratio of approximately 5.40 thus, this genotype often is
referred to as silent carrier. Approximately 75 percent of African
Americans carry one or two chromosomes with N M
7.6
deletion, so
hematologists should be aware of the range of hematologic values
associated with this genotype. %nfortunately, few firm data are
available. &owever, in one study of African-American neonates, a
large number of newborns with the N M
7.6
deletion had nondetectable
hemoglobin BartKs. -lobin-gene synthetic ratios can be distinguished
from normal only by studying relatively large numbers of samples and
comparing the mean M2L ratio with that of normal control subHects.
.his approach is not reliable for diagnosing individual cases of the M
<
-
thalassemia trait, and unfortunately no truly reliable method of
diagnosis in adults is available except for D=A analysis.
!tudies using D=A analysis indicate a mar)ed overlap between
the different M-thalassemia carrier states with regard to the
hematologic and globin-synthesis findings. ,n addition, the studies
show that many M
<
-thalassemia carriers do not have elevated levels of
hemoglobin BartKs at birth. .hese studies confirm that, short of gene-
mapping analysis, no method identifies specific M-thalassemia carrier
states with certainty.
nd
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$!1!" E/0lain about c>ronic 3iseases4
a! '>at is c>ronic in;ectionL
A chronic infection is an infection that develops slowly and
lasts a long time. :!tephen .. 55';
http(22www.mansfield.ohio-
state.edu2^sabedon2biol535.htm_chronic`infection
!tephen .. Abedon. 55'. 1rinciples of disease.
b! '>at is t>e linK bet@een ane1ia an3 c>ronic in;ectionL
Ane1ia o; C>ronic (isease
Anemia of chronic disease :A9D; is also referred to as anemia of
inflammatory response. Although A9D can accompany life-threatening illness,
anemia of inflammatory response is in fact a protective and natural mechanism
that the human body uses to limit the amount of iron available when potentially
harmful things get into our body. All living things, including bacteria and cancer
cells, which are living things, depend upon iron to sustain life Hust li)e humans
and plants do. .his system was described by ?ugene *einberg, 1h.D., ,ndiana
%niversity in the early "'45Qs.
*hen the body senses a potential threat, iron gets shuttled to ferritin to be
contained so that the harmful invader cannot get to the iron. [ust enough iron is
made available to ma)e red blood cells but no surplus is left to nourish harmful
pathogens. Depending on the underlying cause of disease, a person with A9D will
experience a modest decline in hemoglobin. .his will ta)e place over time
following the onset of inflammation due to the presence of the infection or
disease. &emoglobin values will generally reach a low normal range of '.8N"5.8
g2dL and remain there within this moderately low range until the underlying
condition is cured. ,f disease that results in blood loss is present, the person will
develop iron deficiency anemia :,DA;. A9D and ,DA can be distinguished with a
serum ferritin test. .a)ing iron pills for anemia of chronic disease could be
nd
!cenario
"#
th
harmful, even fatal.
.he exact mechanism of A9D is not fully understood. Dr. ?ugene
*einberg, 1rofessor of Microbiology ,ndiana %niversity and ,ron Disorders
,nstitute Medical a !cientific Advisory Board Member, is an expert in anemia of
chronic disease. !ince the mid "'85s *einberg has been aware of the bodyQs
alteration of iron metabolism during disease. &e first defined the ,ron
*ithholding Defense !ystem in the early "'45Qs where he described how the
human body recogniDes iron as a potential haDard to health. ,ron is one metal that
cannot be excreted by the body effeciently0 so, extra precautions are ta)en by
humans to avoid absorbing too much iron. *hen a harmful germ invades the
body, the immune system team of white blood cells charge to the site to destroy
the pathogen before it has time to multiply. ,nflammation results as a part of this
natural immune response. ,nflammation triggers the release of chemicals that
signal the iron regulation mechanism to adopt a defense mode.
*hat physicians see when the iron withholding defense system is activated is a
mild drop in hemoglobin. &owever, what many physicians miss is that less iron is
being absorbed and extra free iron is being collected by macrophages and stored
in liver cells :hepatocytes;. As a result serum ferritin rises. Anemia of chronic
disease is not progressive. &emoglobin values may remain in a slightly low range,
but the levels can drop to as low as 6.5 g2dL depending on the severity of the
inflammation and the length of time present. Ether tests such as serum ferritin or
9-reactive protein :9+1; can be performed to help differentiate between iron-
deficiency anemia, where oral iron can be beneficial and anemia of chronic
disease, where oral iron should not be given.
,n adults, anemia of chronic disease is li)ely due to some common ailment
such as urinary tract infection, a head or chest cold, mononucleosis, tonsillitis or
strep, stomach or intestinal flu, and bacterial infections such as &. pylori. A9D
can also occur when an autoimmune disease is present. Most of these conditions
are treatable and when the patient is cured, the anemia will be corrected. ,f the
nd
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th
anemia persists once an illness is cured, the doctor will want to investigate further
for a secondary underlying cause of anemia that may be more serious such as
)idney disease, tumor, or cancer.
Anemia of chronic disease can be an indicator that a serious life-threatening
condition is in the initial stages of development. &owever, when disease advances
beyond this mild form of anemia, where treatment of the underlying condition
cannot affect a cure, levels such as serum ferritin and transferrin iron saturation
percentage change. $or this reason, persons who have experienced anemia of
chronic disease, where suspected underlying conditions have been addressed but
the anemia persists, further investigation is needed. Blood loss, )idney function,
bone marrow function, cancer, abnormal absorption or chronic hemolysis could
be pursued as causes.
Anemia of chronic disease can also be present even when tissues have excessive
levels of iron. .issue iron is different from functional iron in hemoglobin. 1ersons
with hereditary hemochromatosis can have excessively high tissue iron but
develop anemia because of iron damage to the )idney, anterior pituitary, or bone
marrow. .he damaged )idney produces less erythropoietin, a hormone vital to red
blood cell production :erythropoiesis;. An inflamed or damaged anterior pituitary
can result in hypothyroidism, which causes diminished erythropoiesis and mild
anemia. .he bone marrow is the site of red blood cell formation.
Differentiating between anemia of chronic disease and iron-deficiency
anemia. 1atients with anemia of chronic disease do not generally have
hemoglobin values below '.8 g2dL, although levels can go much lower. ,ron-
deficiency anemia is often suspected in patients with anemia of chronic disease
because the two conditions have many similarities. ,n both conditions, the serum
iron level is low. !mall or microcytic cells can be present in either disorder,
though this type of cell is more indicative of true iron deficiency. .ransferrin, a
protein that transports iron, is elevated in iron-deficiency anemia, indicating that
the body needs more iron. .he total iron-binding capacity :.,B9;, an indirect
nd
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th
measurement of transferrin, is low in anemia of chronic disease because there is
ample iron, but it is not easily available. .,B9 tends to be increased when iron
stores are diminished and decreased when they are elevated. ,n iron-deficiency
anemia, the .,B9 is higher than 355N385 mcg2dL because stores are low. ,n
anemia of chronic disease, the .,B9 is usually below normal because the iron
stores are elevated.
,n nearly two-thirds of the patients, the serum ferritin is one test that can be used
to distinguish between anemia of chronic disease and iron-deficiency anemia.
$erritin is an acute-phase reactant, which means that it can be elevated in the
presence of inflammation and this factor must be ta)en into consideration when
examining the findings. !erum ferritin can be raised to normal levels even in the
presence of iron deficiency. $or this reason, difficulties arise in distinguishing
iron deficiency in a patient with inflammation or infection from the anemia of
chronic disease. .ests for inflammation li)e 9+1 are not helpful in this case. $or
some cases in which both iron deficiency and anemia of chronic disease are
possible, bone marrow aspiration with iron staining is the traditional means of
determining that a person is iron deficient. &owever the serum transferrin
receptor test can be used to help differentiate between iron-deficiency anemia and
anemia of chronic disease. .he serum transferrin receptor is much less affected by
inflammation than serum ferritin0 results will be high in iron-deficiency anemia
and usually low to low-normal in anemia of chronic disease. .he ratio of the
serum transferrin receptor to the logarithim of the serum ferritin concentration is
better able to distinguish anemia of chronic disease from iron deficiency than is
either test alone.
.he greatest ris) for harm is mista)ing anemia of chronic disease for iron-
deficiency anemia and allowing the patient to ta)e iron pills. .his ris) can be
reduced or eliminated by differenetiating between to the two iron disorders with
serum ferrtin test and by informing the patient about the differences in these two
iron disorders.
nd
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th
Treat1ent
.here is no treatment for anemia of chronic disease except to address the
underlying condition. ,ron supplementation is inappropriate in these patients
because the added iron can become free to nourish bacteria and cancer cells. :,D,.
5";
http(22www.irondisorders.org2anemia-of-chronic-disease
,ron Disorders ,nstitute. 5". Anemia of 9hronic Disease.
c! Ho@ is t>e 0at>o0>7siolo?7 an3 t>e 3ia?nosis o> ane1ia o;
c>ronic 3iseaseL
Pat>o0>7siolo?7
,n response to inflammatory cyto)ines, increasingly ,L-#
:=emeth ?. 553;, the liver produces increased amounts of
hepcidin. &epcidin in turn stops ferroportin from releasing iron
stores. ,nflammatory cyto)ines also appear to affect other
important elements of iron metabolism, including decreasing
ferroportin expression, and probably directly blunting
erythropoiesis by decreasing the ability of the bone marrow to
respond to erythropoietin.
Before the recent discovery of hepcidin and its function in
iron metabolism, anemia of chronic disease was seen as the result
of a complex web of inflammatory changes. Ever the last few
years, however, many investigators have come to feel that hepcidin
is the central actor in producing anemia of chronic inflammation.
&epcidin offers an attractive EccamKs +aDor :parsimonious;
explanation for the condition, and more recent descriptions of
nd
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th
human iron metabolism and hepcidin function reflect this view.
:=ermeth ?.55#;
=onetheless, in addition to effects of iron seIuestration,
inflammatory cyto)ines promote the production of white blood
cells. Bone marrow produces both white blood cells and red blood
cells from the same precursor stem cells. .herefore, the
upregulation of white blood cells causes fewer stem cells to
differentiate into red blood cells. .his effect may be an important
additional cause for the decreased erythropoiesis and red blood cell
production seen in anemia of inflammation, even when
erythropoietin levels are normal, and even aside from the effects of
hepcidin. =onetheless, there are other mechanisms that also
contribute to the lowering of hemoglobin levels during
inflammation( :i; ,nflammatory cyto)ines suppress the
proliferation of erythroid precursors in the bone marrow0 :ii;
inflammatory cyto)ines inhibit the release of erythropoietin :?1E;
from the )idney0 and :iii; the survival of circulating red cells is
shortened.
,n the short term, the overall effect of these changes is li)ely
positive( it allows the body to )eep more iron away from bacterial
pathogens in the body, while producing more immune cells to fight
off infection. Bacteria, li)e most life forms, depend on iron to live
and multiply. &owever, if inflammation continues, the effect of
loc)ing up iron stores is to reduce the ability of the bone marrow
to produce red blood cells. .hese cells reIuire iron for their
massive amounts of hemoglobin which allow them to transport
oxygen.
Because anemia of chronic disease can be the result of non-
bacterial causes of inflammation, future research is li)ely to
nd
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th
investigate whether hepcidin antagonists might be able to treat this
problem.
Anemia of chronic disease may also be due to the neoplastic
disorder and non infectious inflammmatory diseases. :*eng, 9&,
et al. 5""; =eoplastic disorder include &odg)inQs disease lung
and breast carcinoma and non infectious inflammmatory diseases
include +heumatoid arthritis and systemic lupus erythematosus.
Anemia of chronic disease as it is now understood is to at
least some degree separate from the anemia seen in renal failure in
which anemia results from poor production of erythropoietin, or
the anemia caused by some drugs :li)e AT., used to treat &,>
infection; that have the side effect of inhibiting erythropoiesis. ,n
other words, not all anemia seen in people with chronic disease
should be diagnosed as anemia of chronic disease. En the other
hand, both of these examples show the complexity of this
diagnosis( &,> infection itself can produce anemia of chronic
disease, and renal failure can lead to inflammatory changes that
also can produce anemia of chronic disease.
(ia?nosis
Anemia of chronic disease is often a mild normalcy anemia,
but can sometimes be more severe, and can sometimes be a
microcytic anemia0 :*eng, 9&, et al. 5"";. thus, it often closely
resembles iron-deficiency anemia. ,ndeed, many people with
chronic disease can also be genuinely iron deficient, and the
combination of the two causes of anemia can produce a more
severe anemia. As with iron deficiency, anemia of chronic disease
is a problem of red cell production. .herefore, both conditions
show a low reticulocyte production index, suggesting that
nd
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th
reticulocyte production is impaired and not enough to compensate
for the decreased red blood cell count.
*hile no single test is always reliable to distinguish the two
causes of disease, there are sometimes some suggestive data(
,n anemia of chronic disease without iron deficiency,
ferritin levels should be normal or high, reflecting the fact that iron
is stored within cells, and ferritin is being produced as an acute
phase reactant but the cells are not releasing their iron. ,n iron
deficiency anemia ferritin should be low. :*eng, 9&, et al. 5"";
.,B9 should be high in genuine iron deficiency,
reflecting efforts by the body to produce more transferrin and bind
up as much iron as possible0 .,B9 should be low or normal in
anemia of chronic disease.
,f the importance of pethidine in this condition is borne out,
tests to measure heparin or cellular expression of proportionate
may one day be useful, but neither are available as validated
clinical assays.
?xamination of the bone marrow to loo) for the absence or
presence of iron, or a trial of iron supplementation :pure iron
deficiency anemia should improve mar)edly in response to iron,
while anemia of chronic disease will not; can provide more
definitive diagnoses.
". =emeth ?, +ivera !, -abayan >, /eller 9, .audorf !,
1edersen B/, -anD .. :553;. Y,L-# mediates hypoferremia of
inflammation by inducing the synthesis of the iron regulatory
hormone hepcidin.Y. J Clinical Invest. 11$ :';( "8"N7.
DE,("5.""62[9,5'38. 1M9 7'437. 1M,D "8"35"4.
nd
!cenario
"#
th
. =emeth ?, -anD .. :55#;. Y+egulation of iron
metabolism by hepcidin.Y. Annu. Rev. Nutr. ", :";( 77N3.
DE,("5.""3#2annurev.nutr.#.5#"858."""757. 1M,D "#4346"5.
7. *eng, 9&0 9hen [B, *ang [, *u 99, \u \, Lin .&
:5"";. Y!urgically 9urable =on-,ron Deficiency Microcytic
Anemia( 9astlemanKs Disease.Y. Onkologie $) :4-';( 38#N4.
DE,("5.""8'255577"47. 1M,D "'73736.
3! '>at is t>e association bet@een 1alnutrition an3 ane1iaL
anemia was high in children, particularly those aged #--""
months. Anemia is a common clinical manifestation of
micronutrient deficiency, particularly iron deficiency. .he
prevalence of anemia was much higher in the children than in their
mothers, despite access to similar foods. 1otential reasons for this
include "; inadeIuate numbers of iron-rich foods, ; poor feeding
practices, and 7; freIuent episodes of common diseases, such as
those causing diarrhea and respiratory infections, which can
increase loss of micronutrients.
9D9. 554. Malnutrition and Micronutrient Deficiencies
Among Bhutanese +efugee 9hildren --- =epal, 556.
>tt0MHH@@@!c3c!?ovH11@rH0revie@H11@r>t1lH11*-1)a$!>t
1. access on ( May 75,5"
$!1!$ ention Kin3 o; Hbs4
&emoglobin :abbreviated &b or &gb; is the iron-containing
oxygen-transport metalloprotein in the red blood cells of all vertebrates
:with the exception of the fish family 9hannichthyidae
;
as well as the
tissues of some invertebrates. &emoglobin in the blood carries oxygen
nd
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from the respiratory organs :lungs or gills; to the rest of the body :i.e.
the tissues; where it releases the oxygen to burn nutrients to provide
energy to power the functions of the organism, and collects the resultant
carbon dioxide to bring it bac) to the respiratory organs to be dispensed
from the organism. :"- di daftar pusta)a;
&emoglobin has an oxygen binding capacity of ".73 ml E
per
gram of hemoglobin,which increases the total blood oxygen capacity
seventy-fold compared to dissolved oxygen in blood. .he mammalian
hemoglobin molecule can bind :carry; up to four oxygen molecules. :7-
3 di daftar pusta)a;
&emoglobin is involved in the transport of other gases( it carries
some of the bodyKs respiratory carbon dioxide :about "5B of the total;
as carbaminohemoglobin, in which 9E
is bound to the globin protein.

.he molecule also carries the important regulatory molecule nitric
oxide bound to a globin protein thiol group, releasing it at the same
time as oxygen. &emoglobin is also found outside red blood cells and
their progenitor lines. Ether cells that contain hemoglobin include the
A' dopaminergic neurons in the substantia nigra, macrophages, alveolar
cells, and mesangial cells in the )idney. ,n these tissues, hemoglobin
has a non-oxygen-carrying function as an antioxidant and a regulator of
iron metabolism.&emoglobin and hemoglobin-li)e molecules are also
found in many invertebrates, fungi, and plants. ,n these organisms,
hemoglobins may carry oxygen, or they may act to transport and
regulate other things such as carbon dioxide, nitric oxide, hydrogen
sulfide and sulfide. :8 N # di daftar pusta)a;
He1e Bios7nt>esis
&emoglobin :&b; is synthesiDed in a complex series of steps. .he
heme part is synthesiDed in a series of steps in the mitochondria and the
cytosol of immature red blood cells, while the globin protein parts are
synthesiDed by ribosomes in the cytosol..he first step in heme synthesis
ta)es place in the mitochondrion, with the condensation of succinyl
nd
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9oA and glycine by ALA synthase to form 8-aminolevulic acid :ALA;.
.his molecule is transported to the cytosol where a series of reactions
produce a ring structure called coproporphyrinogen ,,,. .his molecule
returns to the mitochondrion where an addition reaction produces
protoporhyrin ,W
.he enDyme ferrochelatase inserts iron into the ring structure of
protoporphyrin ,W to produce heme. Deranged production of heme
produces a variety of anemias. ,ron deficiency, the worldKs most
common cause of anemia, impairs heme synthesis thereby producing
anemia. A number of drugs and toxins directly inhibit heme production
by interfering with enDymes involved in heme biosynthesis. Lead
commonly produces substantial anemia by inhibiting heme synthesis,
particularly in children.
1roduction of &b continues in the cell throughout its early
development from the proerythroblast to the reticulocyte in the bone
marrow. At this point, the nucleus is lost in mammalian red blood cells,
but not in birds and many other species. ?ven after the loss of the
nucleus in mammals, residual ribosomal +=A allows further synthesis
of &b until the reticulocyte loses its +=A soon after entering the
vasculature :this hemoglobin-synthetic
+=A in fact gives the reticulocyte its
reticulated appearance and name;.
+i?ure 1 &eme Biosynthesis.
.he sythesis of heme is a complex process
that involves multiple enDymatic steps.
.he process begins in the mitochondrion
with the condensation of succinyl-9oA
and glycine to form 8-aminolevulinic
acid. A series of steps in the cytoplasm
nd
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th
produce coproporphrynogen ,,,, which re-enters the mitochondrion.
.he final enDymatic steps produce heme.
Globin S7nt>esis
.wo distinct globin chains :each with its individual heme
molecule; combine to form hemoglobin. Ene of the chains is designated
alpha. .he second chain is called Ynon-alphaY. *ith the exception of the
very first wee)s of embryogenesis, one of the globin chains is always
alpha. A number of variables influence the nature of the non-alpha chain
in the hemoglobin molecule. .he fetus has a distinct non-alpha chain
called gamma. After birth, a different non-alpha globin chain, called
beta, pairs with the alpha chain. .he combination of two alpha chains
and two non-alpha chains produces a complete hemoglobin molecule :a
total of four chains per molecule;.
.he combination of two alpha chains and two gamma chains
form YfetalY hemoglobin, termed Yhemoglobin $Y. *ith the exception of
the first "5 to " wee)s after conception, fetal hemoglobin is the
primary hemoglobin in the developing fetus. .he combination of two
alpha chains and two beta chains form YadultY hemoglobin, also called
Yhemoglobin AY. Although hemoglobin A is called YadultY, it becomes
the predominate hemoglobin within about "4 to 3 wee)s of birth.
.he pairing of one alpha chain and one non-alpha chain
produces a hemoglobin dimer :two chains;. .he hemoglobin dimer does
not efficiently deliver oxygen, however. .wo dimers combine to form a
hemoglobin tetramer, which is the functional form of hemoglobin.
9omplex biophysical characteristics of the hemoglobin tetramer permit
the exIuisite control of oxygen upta)e in the lungs and release in the
tissues that is necessary to sustain life.
.he genes that encode the alpha globin chains are on
chromosome "# :$igure ;. .hose that encode the non-alpha globin
nd
!cenario
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th
chains are on chromosome "". Multiple individual genes are expressed
at each site. 1seudogenes are also present at each location. .he alpha
complex is called the Yalpha globin locusY, while the non-alpha
complex is called the Ybeta globin locusY. .he expression of the alpha
and non-alpha genes is closely balanced by an un)nown mechanism.
Balanced gene expression is reIuired for normal red cell function.
Disruption of the balance produces a disorder called thalassemia .
Alpha Globin Locus
?ach chromosome "# has two alpha globin genes that are aligned
one after the other on the chromosome. $or practical purposes, the two
alph globin genes :termed alpha" and alpha; are identical. !ince each
cell has two chromosomes "#, a total of four alpha globin genes exist in
each cell. ?ach of the four genes produces about one-Iuarter of the
alpha globin chains needed for hemoglobin synthesis. .he mechanism
of this coordination is un)nown. 1romoter elements exist 8K to each
alpha globin gene. ,n addition, a powerful enhancer region called the
locus control region :L9+; is reIuired for optimal gene expression. .he
L9+ is many )ilobases upstream of the alpha globin locus. .he
mechanism by which D=A elements so distant from the genes control
their expression is the source of intense investigation. .he transiently
expressed embryonic genes that substitute for alpha very early in
development, designated Deta, are also in the alpha globin locus.
Beta Globin Locus
.he genes in the beta globin locus are arranged seIuentially from
8K to 7K beginning with the gene expressed in embryonic development
:the first " wee)s after conception0 called episolon;. .he beta globin
locus ends with the adult beta globin gene. .he seIuence of the genes
is( epsilon, gamma, delta, and beta. .here are two copies of the gamma
gene on each chromosome "". .he others are present in single copies.
.herefore, each cell has two beta globin genes, one on each of the two
chromosomes "" in the cell. .hese two beta globin genes express their
nd
!cenario
"#
th
globin protein in a Iuantity that precisely matches that of the four alpha
globin genes. .he mechanism of this balanced expression is un)nown.
.he globin genes are activated in seIuence during development,
moving from 8K to 7K on the chromosome. .he Deta gene of the alpha
globin gene cluster is expressed only during the first few wee)s of
embryogensis. .hereafter, the alpha globin genes ta)e over. $or the beta
globin gene cluster, the epsilon gene is expressed initially during
embryogensis. .he gamma gene is expressed during fetal development.
.he combination of two alpha genes and two gamma genes forms fetal
hemoglobin, or hemoglobin $. Around the time of birth, the production of
gamma globin declines in concert with a rise in beta globin synthesis. A
significant amount of fetal hemoglobin persists for seven or eight months
after birth. Most people have only trace amounts, if any, of fetal
hemoglobin after infancy. .he combination of two alpha genes and two
beta genes comprises the normal adult hemoglobin, hemoglobin A. .he
delta gene, which is located between the gamma and beta genes on
chromosome "" produces a small amount of delta globin in children and
adults. .he product of the delta globin gene is called hemoglobin A, and
normally comprises less than 7B of hemoglobin in adults, is composed of
two alpha chains and two delta chains.
+i?ure "! !chematic representation
of the globin gene loci. .he lower
panel shows the alpha globin locus
that resides on chromosome "#. ?ach
of the four alpha globin genes
contribute to the synthesis of the
alpha globin protein. .he upper panel
shows the beta globin locus. .he two
gamma globin genes are active
nd
!cenario
"#
th
during fetal growth and produce hemoglobin $. .he YadultY gene,
beta, ta)es over after birth.
:no ' di daftar pusta)a dari heme synthesis sampe beta globin locus;
Hu1an He1o?lobins
&emoglobin variants are a part of the normal embryonic and fetal
development, but may also be pathologic mutant forms of hemoglobin in a
population, caused by variations in genetics. !ome well-)nown
hemoglobin variants such as sic)le-cell anemia are responsible for
diseases, and are considered hemoglobinopathies. Ether variants cause no
detectable pathology, and are thus considered non-pathological variants.
,n the embryo(
-ower " :b
;
-ower :M
;
&emoglobin 1ortland :b
;
,n the fetus(
&emoglobin $ :M
;
,n adults(
&emoglobin A :M
; :1DB "BT5; - .he

most common with a normal amount over
'8B
&emoglobin A
:M
; - O chain synthesis
begins late in the third trimester and in
adults, it has a normal range of ".8-7.8B
&emoglobin $ :M
; - ,n adults
&emoglobin $ is restricted to a limited
population of red cells called $-cells.
&owever, the level of &b $ can be
elevated in persons with sic)le-cell
disease and beta-thalassemia.
>ariant forms that cause disease(
nd
!cenario
"#
th
&emoglobin & :L
3
; - A variant form of hemoglobin, formed by a tetramer
of L chains, which may be present in variants of M thalassemia.
&emoglobin Barts :P
3
; - A variant form of hemoglobin, formed by a
tetramer of P chains, which may be present in variants of M thalassemia.
&emoglobin ! :M
L
!
; - A variant form of hemoglobin found in people with

sic)le cell disease. .here is a variation in the L-chain gene, causing a
change in the properties of hemoglobin, which results in sic)ling of red
blood cells.
&emoglobin 9 :M
L
9
; - Another variant due to a variation in the L-chain

gene. .his variant causes a mild chronic hemolytic anemia.
&emoglobin ? :M
L
?
; - Another variant due to a variation in the L-chain

gene. .his variant causes a mild chronic hemolytic anemia.
&emoglobin A! - A heteroDygous form causing !ic)le cell trait with one
adult gene and one sic)le cell disease gene
&emoglobin !9 disease - Another heteroDygous form with one sic)le gene
and another encoding &emoglobin 9.
:6 N 4 nih di daftar pusta)a;
Daftar 1usta)a
". Maton, Anthea0 [ean &op)ins, 9harles *illiam McLaughlin, !usan
[ohnson, Maryanna duon *arner, David La&art, [ill D. *right :"''7;.
uman !iology and ealth. ?nglewood 9liffs, =ew [ersey, %!A( 1rentice
&all.
. !idell, Bruce0 /ristin EKBrien :55#;. Y*hen bad things happen to good
fish( the loss of hemoglobin and myglobin expression in Antarctic
icefishesY. "he Journal of #$perimental !iology 5' :1t "5;( "6'"N"45
7. DomingueD de >illota ?D, +uiD 9armona M., +ubio [[, de Andres !
:December "'4";. Y?Iuality of the in vivo and in vitro oxygen-binding
capacity of haemoglobin in patients with severe respiratory diseaseY.
3. 9ostanDo, Linda !. :556;. %hysiology. &agerstwon, MD( Lippincott
*illiams a *il)ins.
nd
!cenario
"#
th
8. +espiratory $unction of &emoglobin. 9onnie 9.*. &sia, M.D. = ?ngl [
Med "''40 774(7'-34 [anuary , "''4
#. Biagioli M,et al. %nexpected expression of falphag- and fbetag-globin in
mesencephalic dopaminergic neurons and glial cells.
6. Y&emoglobin >ariantsY. &ab "ests Online. American Association for
9linical 9hemistry. 556-""-"5.
http(22www.labtestsonline.org2understanding2analytes2hemoglobin`var2gla
nce-7.html. +etrieved 554-"5-".
4. &uisman .&[ :"''#;. YA !yllabus of &uman &emoglobin >ariantsY.
'lobin 'ene (erver. 1ennsylvania !tate %niversity.
http(22globin.cse.psu.edu2html2huisman2variants2. +etrieved 554-"5-".
'. Y&emoglobin( molecular, genetic, and clinical aspectsY, Bunn and $orget,
!aunders, "'4#
$!" A((ITIONA# IN+ORATION
=ormal urin
=o symptoms of DM
.arget cell <
+eticulocyte <
&b& inclusion body <
$!$ ANA#&SIS
$!) +INA# IN( AP
$!* CONC#.SION
nd
!cenario
"#
th

Laboratory Tests for Diagnosing Anemia and Organomegaly

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OBJECTIVES

General Instructional Objectives

. .wo copies of the M-globin gene

, which normally comprises

, and $. in severe forms of M-

or $ and no hemoglobin &. M-.halassemia trait is

are seen, and the maHor

levels. Ether rare forms include varieties of

levels in heteroDygotes and

in homoDygotes. .hey are of no

is reduced to the normal range.

. .he elevated level appears to reflect

levels in homoDygous L-thalassemia may be low,

level almost invariably is elevated. Differential

distribution among thalassemic red cells, but their level in

level is increased to 7.8 to 6 percent. .he

level usually is slightly subnormal.

is bound to the globin protein.

; :1DB "BT5; - .he

; - A variant form of hemoglobin found in people with

; - Another variant due to a variation in the L-chain

; - Another variant due to a variation in the L-chain

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