THALASSEMIAS بحراألبيض المتوسط

دم كهم فقرخوینى دهرياى سپى

ناوهراست

ProfessorAnwar SheikhaAnwar Sheikha

MD, FRCP, FRCPath., FCAP, FRCPA, FRCPI, FACP

Senior Consultant Clinical & Lab. Hematologist

Clinical Professor of HematologyUniversity of Mississippi Medical Center, Jackson,

Mississippi

Professor of Hematology, University of Salahaddin, Erbil, Kurdistan,

IRAQ

IT IS VERY COMMON IN KURDISTAN

IT IS A VERY EXPENISIVE DISEASE

IT IS PREVENTABLE

IT HAS BECOME AN ADULT PROPBLEM

AS WELL

RESEARCH POTENTIAL

THALASSEMIAS

AMONG THE COMMONEST GENETIC DISORDERS WORLDWIDE

5%Globin Variants

~ 2% α and β heterozygotes

WORLDWIDE BIRTHRATE OF HOMOZYGOUS OR DOUBLE

HETEROZYGOUS GLOBIN DISORDERS2.4/ 1000 BIRTH

2/1000HbSS

0.44/1000THALASSEMIAS

SULY OR HAWLER SHOULD HAVE440 PATIENTS/ MILLION

THALASSEMIAS

AMONG THE COMMONEST GENETIC DISORDERS WORLDWIDE

5%Globin Variants

~ 2% α and β heterozygotes

WORLDWIDE BIRTHRATE OF HOMOZYGOUS OR DOUBLE

HETEROZYGOUS GLOBIN DISORDERS2.4/ 1000 BIRTH

0.44/1000THALASSEMIAS

SULY OR HAWLER SHOULD HAVE440 PATIENTS/ MILLION

Thalassemia

Minor

%

Hawler 7%

Mosul 6%

Suly 4%

Basra 4.6%

Baghdad 3.2%

Duhok 3.7%

ANEMIA

BLOODLOSS

MARROWCAUSES

HEMOLYSIS

ACD28%

IRON DEFICIENCY29%

HEMOLYSIS18%

ACUTEBLEEDING

18%

MAIN CAUSESOF

ANEMIA

OTHERS

ANEMIA

BLOODLOSS

MARROWCAUSES

HEMOLYSISHb

Hemoglobin

Hemoglobin Synthesis in the Red cell

Globin Chains

α 141 amino acids

β 146 amino acidsγ 146 amino acidsδ 146 amino acids

HbA

α2β2

HbF

α2γ2

HbA2

α2δ2

Globin Chains

α 141 amino acids کویخا

β 146 amino acids ژنγ 146 amino acids ژنδ 146 amino acids ژن

HbA

α2β2

HbF

α2γ2

HbA2

α2δ2

GlobinChains Synthesis

The thalassemia syndromes are a group of hereditary disorders in which a defect in the synthesis of one or more of the globin chains of Hb is present.

Definition

↓Hb

Hypochromic Red cells

Microcytic Red cells

The continued normal synthesis of the unaffected globin chain leads to the accumulation of unstable aggregates of these unmatched globin chains.

Definition

Precipitatedunstable

aggregates

OXIDATIVEMEMEBRANE

DAMAGE

MarrowDestruction

SplenicDestruction

β-Thalassemia

β-thalassemia

minor

β-thalassemia

major

Problem for thePatient

Problem for theCommunity

Southern Italian,

Sicilian, and 10% Greek populations

In certain Greek islands & some villages of Sardinia 20% to 30%.

In Southeast Asian populations 5%

In African and

American blacks 1.5%.

Incidence of Heterozygous β Thalassemia

Marriage Counseling

Heterozygousβ

ThalassemiaFemale

Heterozygousβ

ThalassemiaMale

A T A T

AT AT TTAA

β Thalassemia

βα- chains

EXCESSChain

Precipitates

γ Chains

α2 γ2

HbF↑↑

β Thalassemia

βα- chains

EXCESSChain

Precipitates

MarrowDestruction

IneffectiveErythrpoiesis

HEMOLYSIS

SplenicDestruction

Hypersplenism

ANEMIA

An α- Hb-stabilizing protein

blocks reactive oxygen production &

reduces oxidative RBC damage

βα- chains

EXCESSChain

Precipitates

MarrowDestruction

IneffectiveErythrpoiesis

HEMOLYSIS

SplenicDestruction

Hypersplenism

ANEMIA

γ Chains

α2 γ2

HbF↑↑

↑ O2

Affinity

↑ EPO

Proliferation of IneffectiveErythroid Marrow

Skeletal ChangesHyper metabolism

Hyperuricemia

β- Thal.

β Thalassemiaβ

α- chains

EXCESSChain

Precipitates

MarrowDestruction

IneffectiveErythrpoiesis

HEMOLYSIS

SplenicDestruction

Hypersplenism

ANEMIABLOOD

TRANSFUSION

IRONOVER-LOAD

CARDIACDEATH

βα- chains

EXCESSChain

Precipitates

MarrowDestruction

IneffectiveErythrpoiesis

HEMOLYSIS

SplenicDestruction

Hypersplenism

ANEMIABLOOD

TRANSFUSION

IRONOVER-LOAD

CARDIACDEATH

γ Chains

α2 γ2

HbF↑↑

↑ O2

Affinity

↑ EPO

Proliferation of IneffectiveErythroid Marrow

↑ IRON Absorption

Skeletal ChangesHyper metabolism

Hyperuricemia

β- Thal.

Hepcidin Down Regulation

β

BLOODTRANSFUSION

IRONOVER-LOAD

CARDIACCARDIACDEATHDEATH

↑ IRON Absorption

β- Thal.

Pancreatic β cells

Diabetes

EndocrineGrowth Failure

Hypothalamic PituitaryAdrenal Axis

Secondary Sex Features

Liver Cirrhosis

SkinDusky Coloration

Severe hypochromic & microcytic anemia Severe hypochromic & microcytic anemia

Marked anisocytosis, poikilocytosis, misshapen microcytes, occasional macrocytes,

target cells, and erythroblasts.

Before and after splenectomy, ragged inclusion bodies in the cytoplasm of nucleated red cells and

reticulocytes consisting of precipitated α -chains are evident after incubation with methyl violet.

In well transfused patients, the blood picture may appear virtually normal, reflecting almost total

suppression of endogenous erythropoiesis

Blood Picture in Homozygous Thalassemia

Hemoglobin Electrophoresis

أفسا>

α- Thalassemias

α αα α

Father Mother

αα/αααα/αα

αα/αα

αα/αα

αα/αα

-α/αα

--/αα --/-α

--/--

αα/αα-α/αα

--/αα --/-α

--/--

HbH (β4)

Hb Barts (γ 4)

αα/αα

-α/αα

--/αα --/-α

--/--Silent

α- thal minor HbH

Hydrops

Thalassemia Intermedia

Thal.major

Thal.intermedia

Hb

6 gm/dL

9 gm/dL

12 gm/dL

Thal.minor

MANAGEMENTOF

THALASSEMIAS

VERY

COSTLYESPECIALLY

IN EMERGING COUNTRIES

UNDISCOUNTED LIFETIME COST OF ONE PATIENT IN UK IS > ₤800,000

DO NOT ALLOWANOTHER THALASSEMIA

CHILD TO BE BORN IN

KURDISTAN

This is the cheapest way to manage this disease

βα- chains

EXCESSChain

Precipitates

MarrowDestruction

IneffectiveErythrpoiesis

HEMOLYSIS

SplenicDestruction

Hypersplenism

ANEMIABLOOD

TRANSFUSION

IRONOVER-LOAD

CARDIACDEATH

γ Chains

α2 γ2

HbF↑↑

↑ O2

Affinity

↑ EPO

Proliferation of IneffectiveErythroid Marrow

↑ IRON Absorption

Skeletal ChangesHyper metabolism

Hyperuricemia

β- Thal.

β

BLOODTRANSFUSION

IRONOVER-LOAD

CARDIACCARDIACDEATHDEATH

↑ IRON Absorption

β- Thal.

Pancreatic β cells

Diabetes

EndocrineGrowth Failure

Hypothalamic PituitaryAdrenal Axis

Secondary Sex Features

Liver Cirrhosis

SkinDusky Coloration

MANAGEMENT OF THALASSEMIAS

BLOODTRANSFUSION

IRON CHELATION

GENETHERAPY

SPLENECTOMY

BMT

EVALUATION

? HEPCIDIN? α - STABILIZING AGENTS

HEPCIDIN NORMALLYCONTROLS IRON ABSORPTION; IT ISDOWNREGULATED IN THALASSEMIA

Evaluation of the Patient with ThalassemiaInitial

Clinical assessmentHematologic evaluation (CBC, Hb electrophoresis)α:non-α globin chain synthesis ratioRed cell phenotypeSerum iron, total iron-binding capacitySerum Ferritin concentrationRed blood cells and serum folateTotal and direct BilirubinSerum ALT, albumin, PT, APTTHepatitis screenInitiation of hepatitis B vaccine seriesParental counseling and education

Evaluation of the Patient with ThalassemiaMonthly

History and physical examination

CBC

Parental counseling

If receiving iron chelation therapy, compliance review

Evaluation of the Patient with Thalassemia6

monthly

Serum ALT

Ferritin

Evaluation of the Patient with ThalassemiaYearly<10

LIVER BIOPSY (Histology & HIC)Hepatitis screen

Serum ALT, Albumin, PT

Serum Ca2 , PO4, Mg2, Zn2 , PTH, TSHENDOCRINE

Monitoring of deferoxamine toxicity

Evaluation of the Patient with Thalassemia>10 Years

BIOPSY (Histology & HIC)

Hepatitis screenSerum ALT, Albumin, PT

LIVER

HEARTCardiology consultationRadionuclide angiography?48-h Holter monitoring

ENDOCRINE

Endocrinology consultationFasting blood glucoseSerum Ca2, PO4, Mg2, Zn2 Serum PTH, TSHGnRH stimulation test

Monitoring of deferoxamine

toxicity

Blood Transfusion

When & How?

,

Presence & severity of S&S of anemia Failure of

growth &

development

Deterioration in appetite or activity level

Presence of disfiguring

skeletal changes

Assess patient for few months after Dx before making this decision

Many patients with thal. intermedia embark on a life of unnecessary B.T. if they present with an unusually low Hb during an intercurrent illness

+

+

+

TRANSFUSION REGIMENS

GOALS

DO NOT AVOID B.T. BECAUSE OF IRON OVERLOADIRON ABSORPTION IS ALREADY INCREASED

Correct AnemiaSuppress Erythropoiesis

Inhibit increased GIT absorption of iron

HYPERTRANSFUSIONPre B.T. Level

> 10 gm/dL

SUPERTRANSFUSIONPre B.T. Level

> 12 gm/dL

HYPERTRANSFUSIONPre B.T. Level

> 10 gm/dL

SUPERTRANSFUSIONPre B.T. Level

> 12 gm/dL

IRON

OVERLOAD

Moderate TransfusionMaintain Pre-Transfusion Hb at ~ 9.5 gm/dL

This regimen reduces transfusion requirements, adequately suppresses marrow activity & is associated with a

lower incidence of endocrine and cardiac complications

Ideally Transfuse

15 mL Packed Red Cells/Kg B.Wt.

every 28 to 35 days

AVAILABILITY OF VOLUNTARY BLOOD DONORS

Steady-State Hb exceeding

9 g/dL

Reduces

the incidence

of bone

Malformations &

causes regression

of bone changes

NO direct

evidence of

improved impact of super-

transfusion on

bone metabolism

NOevidence

that super-

transfusion is

associated with linear

growth superior to that of

other regimens

EFFECTIVENESS OF DIFFERENT TRANSFUSION PROGRAMS

splenectomy has decreased after hypertransfusion programs

Leukocyte-reduced RBC preparations

The most convenient and cost-effective procedure depends on

the financial resources

Type of Red Cell Concentrates

FILTERSPRACTICAL EXPENSIVE

Effective in reducing WBC & Frequency of FTR

NEOCYTES

Complications of Blood Transfusion

ALLOIMMUNIZATION

Mediterranean Patients3% and 10%

Asian ~ 21%

↑ ~ LATE TRANSFUSION (> 1 to 2 years) ↑~ Highest # of B.T

<

Anti- KellAnti-Rh

LOWER RATESin ABO, Rh, and Kell Ag-matched BT from 1st transfusion

AIHA is more common in splenectomized patients

DISEASES TRANSMITTED THROUGH BLOOD TRANSFUSION

HEPATITISB

HEPATITIS

C

HIVCMV

MalariaSyphilis

Yersiniaetc.

SPLENECTOMY

PAST PRESENT

~ 10 YEARS OF AGE~ Annual Transfusion

Requirement

>200 to 250 ml Packed cells/kg B. Wt.

With improved transfusion,

hypersplenism is reduced &

many patients do not require splenectomy

PARTIAL SPLENECTOMY

SPLENECTOMY

OPSIStreptococcuspneumoniae

Hib

Neisseriameningitides

PneumovaxDaily OralPenicillin

PartialSplenectomy

DELAY SPLENECTOMY UNTIL AFTER AGE 5

IronChelationDOUBLES LIFE EXPECTANCY

IronChelation

Deferoxamine

DesferrioxamineDesferal

Thalassemia Survival without (Group 1) &

with (Group 2) Effective Chelation

Survival Beyond 12 Years

EFFECTIVENESS OF DFO

Deferoxamine

EXPENSIVE

PARENTERALONLY

COMPLIANCEPROBLEMS

BUT

INCONVENIENT

UNTIL YESTERYEAR

IT WAS THE ONLY TREATMENT AVAILABLE

IRON OVERLOAD & HEART in THALASSEMIA

IT IS THE LEADINGCAUSE

OFDEATHIN

THALASSEMIA

Serum FERRITIN maintained < 2500 µg/L ~ Cardiac DFS

of 91% after 15 years

HIC< 15 mg iron/g liver, dry weight, is protected from

cardiac disease

DFO from an early age ~ prevalence of heart disease

by age 15 years

2%

Assessment of Body Iron Burden in Thalassemia

Test Comments

Indirect

Serum/plasma Ferritin concentration

Noninvasive

Lacks sensitivity and specificity

Poorly correlated with hepatic iron concentration in individual patients===============

Serum transferrin saturation

Poorly correlated with hepatic iron concentration in individual patients===============

Tests of 24-h deferoxamine-induced urinary iron excretion

Less than half of outpatient aliquots collected correctly; Ratio of stool:urine iron variable; poorly correlated with hepatic iron concentration

Test Comments

Imaging of tissue iron

CT: Liver Variable correlation with hepatic iron

MRI: Liver

Heart &

Anterior Pituitary

Variable correlations with hepatic iron; cannot distinguish acceptable and dangerous ranges; imprecise if hepatic iron >20 mg/g, or if fibrosis present

Only modality available to image cardiac or pituitary iron stores; correlations with tissue iron not demonstrated

Evaluation of organ function

Direct Hepatic Biopsy

Iron Quantitation

Most tests lack sensitivity and specificity; Limited information ~ functional status

Reference Method. Precise assessment of body iron burden. Safe under US guidance.

SQUID “Superconducting susceptometry”

Noninvasive; excellent correlation with biopsy-determined hepatic iron

MANAGEMENT OF IRON CHELATION IN THALASSEMIAS

HICHEAPTIC IRON CONCENTRATION

mg iron/gm LiverDry Weight

NORMAL

0.2-1.6

To achieve thislevel, DFO

toxicity will be very high

3.2 to 7(As in

HeterozygousHemochroma-tosis Patients)

No MorbidityNormal Life Expectancy

7 to 15(As in

HomozygousHemochrom-

atosis)

Hepatic Fibrosis

>15

Cardiac Disease

Early Death

Hepatic Iron Burden

NormalHIC =0.2 – 1.6

HeterozygousHemochromatosisHIC = 3.2 – 7.0

HomozygousHemochromatosisHIC = 7.0 – 15.0

ONE YEARAFTER BLOODTRANSFUSON

*LIVER BIOPSY BY US GUIDE*QUANTITATIVE LIVER IRON*LIVER HISTOLOGY*PCR FOR HEPATITIS C RNA

HIC <3.2 mg/g

Dry Wt.

DEFER CHELATION

ReassessHIC in 6/12

BASELINE

Radiographs of cartilage in wrists, knees, thoraco-lumbosacral spine; bone age; standing & sitting Ht.

Ped. Radiologist & Endocrinologist with experience in DFO toxicity

HIC >3.2 mg/g

Dry Wt.

Initiate DFO 25

mg/kg/night X5 nights/wk

MANAGEMENT OF IRON CHELATION IN THALASSEMIAS

MANAGEMENT OF IRON CHELATION IN THALASSEMIAS II

YEARLYBEFORE

AGE

5

Liver Biopsy

assessAs

Before

+All

OtherTests

& Exams

(Fe/TIBC/Ferritin, etc)

As Before

HIC <3.2 mg/g

Dry Weight

Discontinue DFOReassess HIC

in 6 mo

HIC3.2 to 7

mg/g Dry Weight

Continue DFO 25 mg/kg/night

x 5 nights/wk

HIC> 7

mg/g Dry Weight

Increase DFO to 35 mg/kg/night

x 6 nights/wk

Severe spinal or

metaphyseal changes

↓DFO 25 mg/kg/night x 4 nights/wk even if HIC >7 mg/g Dry Wt.;

Reassess HIC in 12 mo

Q18

monthly from age

5-10 yr

Liver Biopsy

assessAs

Before+All

OtherTests

& Exams

(Fe/TIBC/Ferritin, etc)

As Before

HIC <3.2 mg/g

Dry Weight

Discontinue DFO

Reassess HIC in 6/12

HIC3.2 to 7

mg/g Dry Weight

Continue DFO at 40 mg/kg/night

x 5 nights/wk

HIC 7 to 15

mg/g Dry Weight

Increase DFO to 50 mg/kg/night

x 6 nights/wk

HIC >15 mg/g

Dry Weight

Increase DFO to 50 mg/kg/night

x 7 nights/wk

Severe spinal or metaphyseal changes ↓ DFO to 25 mg/kg/night x 4 nights/wk even if HIC >7; Reassess HIC in 12 months

Q18

monthly >10

Years

Liver Biopsy

assessAs

Before+All

OtherTests

& Exams

(Fe/TIBC/Ferritin, etc)

As Before

HIC <3.2 mg/g

Dry Weight

Discontinue DFO

Reassess HIC in 6/12

HIC3.2 to 7

mg/g Dry Weight

Continue DFO at 40 mg/kg/night

x 5 nights/wk

HIC 7 to 15

mg/g Dry Weight

Increase DFO to 50 mg/kg/night

x 6 nights/wk

HIC >15 to 18 mg/g

Dry Weight

Increase DFO to 50 mg/kg/night

x 7 nights/wk

Severe spinal or metaphyseal changes ↓ DFO to 25 mg/kg/night x 4 nights/wk even if HIC >7; Reassess HIC in 12 months

HIC >18 mg/g Consider continuous IV DFO 50 mg/kg/24 h by implantable port

Ascorbate Supplementation

Vitamin C supplementation may result in a marked improvement in deferoxamine-induced iron excretion through expansion of the chelatable iron pool to which deferoxamine has access.

In parallel, ascorbate-induced expansion of this pool may aggravate the toxicity of iron in vivo.

100 mg ascorbic acid should be administered approximately 30 to 60 minutes after initiation of an infusion of deferoxamine, only on days during which deferoxamine is administered

Vitamin C is given PO 100 mg/night

during DFO infusion

Initiation of Iron Chelation

WHEN?

Early IntensiveDFO before

3 years

Abnormal linear growth &

metaphyseal dysplasia

Early Chelation

Reduces risk of hepatic fibrosis from early iron overload,

prior to ↑Ferritn.

Prevents Growth failure &

Helps sexual maturation

DO LIVER BIOPSY ONE YEAR AFTER

Regular Blood Transfusion

MEASURE

HIC

Start DFO if

>6 mg/gm Liver Dry Wt.

IF BIPOSY CANNOT BE DONE START S.C. DFO AT 25 to 35 mg/kg B.Wt. /24 hrs

one year after Regular Blood Transfusion

Usually, patients and parents administer DFO by an overnight S.C. infusion over 8 to 12 hrs through a needle inserted into

the abdomen, thigh, or upper arm.

Net negative iron balance is usually maintained with 50 mg/kg

body weight/night,5 nights each week.

Monitoring of DFO-Related Toxicity

Toxicity Investigations Frequency Alteration in Therapy

High Frequency Sensorineural Hearing Loss

Audiogram Yearly; if patient symptomatic, immediate reassessment

Interrupt DFO immediatelyAssess body iron burden D/C DFO x 6 mo if HIC <3 mg/g Repeat audiogram at 3-mo intervals until normal or stableAdjust DFO to HIC

Retinal abnormalities

Retinal Exam Yearly; if patient symptomatic, immediate reassessment

Interrupt DFO immediately; Assess body iron burden D/C DFO x 6 mo if HIC <3 mg/g Review at 3-mo intervals until normal or stableAdjust DFO to HIC

Metaphyseal & spinal abnormalities

X-rays of wrists, knees, thoraco-lumbar-sacral spine; bone age of wrist

Yearly Reduce DFO to 25 mg/kg/dAssess body iron burden discontinue DFO x 6 mo if HIC <3 Reassess HIC and radiographs after 6 mo; Adjust DFO to HIC

Decline in height velocity, sitting height, or both

Determination of sitting and standing heights

Twice yearly Reduce DFO to 25 mg/kg/dAssess body iron burden; discontinue DFO x 6 mo if HIC <3 Reassess HIC and radiographs after 6 mo. Adjust DFO to HIC; Regular (6-mo) assessment

DEFERIPRONE

“L1”Serum Ferritin noticed to rise during therapy ??

L1 has been acknowledged to be inadequately effective in a substantial proportion of patients in all peer-reviewed

articles to have quantitated body storage iron

In all of these studies, HIC have exceeded the threshold for cardiac disease and premature death in between 18% and 65%

of patients after extended therapy

Apotex2005

Before L1 can be considered for clinical use, evaluation of its long-term toxicity in controlled clinical trials in which hepatic iron and histology

are evaluated prospectively is mandatory. This step is particularly important in view of the grave prognostic implications of the progression

of liver and cardiac disease in iron-loaded patients.

The decision in 1999 to permit licensing of deferiprone in Europe was under legal challenge

Rodents: Adrenal hypertrophy / gonadal & thymic atrophy, marrow atrophy and pancytopenia, growth retardation, & embryotoxicity

Humans: Embryotoxicity, teratogenicity, neutropenia, and agranulocytosis

DEFERIPRONE TOXICITY

DEFERIPRONE

“L1”CUMULATIVE WORLDWIDE EXPERIENCE INDICATES THAT IT IS SAFE & EFFECTIVE

ADVANTAGES OVER DESFERALCAN PENETRATE CELL MEMBRANE & CHELATE TOXIC

INTRACELLULAR IRON

?MORE EFFECTIVE IN REMOVING MYOCARDIAL IRON

2006

DEFERIPRONE

“L1”SEQUENTIAL COMBINED DESFERAL DEFERIPRONE CHELATION

SHUTTLE HYPOTHESISDEFERIPRONE CHELATES IC IRON & TRANSPORTSIT EXTRACULLARLY TO THE MORE POWERFUL DF

BETTER COMPLIANCE

New Oral Chelator

DEFERASIROX“EXJADE”

A VERY PROMISING IRON CHELATORGIVEN CONVENIENTLY ONCE DAILYINSHALLA WILL REPLACE ALL OTHER CHELATORS

NOVARTIS

DEFERASIROX

“EXJADE”

Start with 20 ug/kg/day

Dissolve in a big glass of water or apple juice using a non-metallic stirrerGiven one daily preferably before meal

Half-life is around 10 hours, so once daily dose gives 24-houriron chelation from labile iron pool. Iron is excreted almost entirely through feces

BMTSUCCESS

OFBMT

HEPATOMEGALY>2 cm BCM

PORTAL FIBROSIS

H/O EFFECTIVECHELATION

CLASS Pre-BMT Criteria

OS in <16 Years

(3 Year Post-BMT)

DFS <16 Year

(3 Year Post-BMT)

I 0 90% 83%

II 1-2 86% 82%

III 3 62% 51%>16 Yr = III i.e. 62% i.e. 51%

Post-BMT

GvHDACUTE CHRONIC

Moderate 8%

Severe 2%

Mixed Chimerism25% ? Graft Failure

Original Iron OverloadR/ Phlebotomy

R/ DFO

CORD BLOOD TRANSPLANTATION IN UTERO TRANSPLANTATION

Thalassemia Intermedia

Thal.major

Thal.intermedia

Hb

6 gm/dL

9 gm/dL

12 gm/dL

Thal.minor

FEATURESOF

THALASSEMIA INTERMEDIA

ANEMIA

HYPER-SPLENISM

IRONOVERLOAD

LEG ULCERSGALL STONES

PREGNANCYCOMPLICATIONS

FOLATEDEFICIENCY

URATENEPHROPATHY

ECTOPICMARROW

Temporal BoneParaspinal

MANAGEMENT OF THALASSEMIA INTERMEDIA

AGGRESSIVE===========

SplenectomyHypertransfusion

Chelation

FolateSplenectomy

Blood Transfusion

W&W?

Gene Therapy

BMT

Malaria & Thalassemia

The high frequency of the α- thalassemias and almost

certainly of the β- thalassemias is a

reflection of heterozygote advantage against

Plasmodium falciparum malaria.

Malaria & Thalassemia

α- thalassemia appears to enhance the susceptibility of children to infection with Plasmodium vivax at a time when maternal immunity may confer some protection against these infections. Thus, early

increased exposure to P. vivax may act as a natural vaccine, inducing cross-species protection later in life against the more dangerous P.

falciparum.

In severe untreated β- thalassemia, erythropoiesis

may be increased up to tenfold, of which

5% or less may be effective

OSTEOPENIAOSTEOPOROSIS

↓DISABLING PAIN & #

CAUSES: I.E. ENDOCRINE DESFERAL

CAREFULCHELATION

LIFESTYLE ADJUSTMENTS↑ Ca ↑ ACTIVITY NO SMOKING

HORMONETHERAPY

VITAMIND

BISPHOSPHONATEPAMIDRONATE & ZOLEDRONATE

R/

HEPCIDINA SMALL PEPTIDE THAT INHIBITS IRON ABSORPTION IN SMALL BOWEL

NORMALLY HEPCIDIN ↑ IN IRON OVERLOAD

IN THALASSEMIA MAJOR HEPCIDIN IS INAPPROPRIATELY REDUCED

HEPCIDIN IS FOUND TO BE HUMORALLY DOWNREGULATED

HEPCIDIN MAY BE USED THERAPEUTICALLY

MAGNETICSUSCEPTOMETRY

GIVES RESULTS EVEN BETTER THAN HIC FOR

IRON OVERLOAD MEASUREMENT

AS OF LATE 2005 ONLY 4 CENTERS IN THE WORLD

HAVE THIS CAPACITY