osteosarcoma

OsteosarcomaOsteogenic sarcoma

Last reviewed: November 5, 2009.

Osteosarcoma is a cancerous (malignant) bone tumor that usually develops during the period of rapid growth that occurs in adolescence, as a teenager matures into an adult.

Causes, incidence, and risk factors

Osteosarcoma is the most common cancerous (malignant) bone tumor in youth. The average age at diagnosis is 15. Boys and girls have a similar incidence of this tumor until late adolescence, at which time boys are more commonly affected.

The cause is not known. In some cases, osteosarcoma runs in families, and at least one gene has been linked to increased risk. This gene is also associated with familial retinoblastoma, a cancer of the eye that occurs in children.

Osteosarcoma tends to occur in the bones of the:

Shin (near the knee) Thigh (near the knee) Upper arm (near the shoulder)

This cancer occurs most commonly in larger bones and in the area of bone with the fastest growth rate. Osteosarcoma can occur in any bone, however.

Although it is rare, osteosarcoma can occur in adults.

Symptoms

Bone fracture (may occur after what seems like a routine movement) Bone pain Limitation of motion Limping (if the tumor is in the leg) Pain when lifting (if the tumor is in the arm) Tenderness, swelling, or redness at the site of the tumor

Signs and tests

Blood tests Bone scan to see if the cancer has spread to other bones CT scan of the chest to see if the cancer has spread to the lungs CT scan of the affected area Open biopsy (at time of surgery for diagnosis) X-ray of the affected area

Treatment

Treatment usually starts after a biopsy of the tumor.

Before major surgery to remove the tumor, chemotherapy is usually given. Chemotherapy is also used to kill or shrink any cancer cells that may have spread to other parts of the body.

Common chemotherapy medicines include:

Cisplatin Carboplatin (Paraplatin) Cyclophosphamide (Cytoxan) Doxorubicin (Adriamycin) High-dose methotrexate with leucovorin Ifosfamide (Ifex)

Surgery is used after chemotherapy to remove any remaining tumor. In most cases, surgery can remove the tumor while saving the affected limb (this is called limb-salvage surgery). Rarely, more radical surgery (such as amputation) may be necessary.

Support Groups

Association of Cancer Online Resources -- www.acor.org

Cure Search (formerly the National Childhood Cancer Foundation) --www.curesearch.org

Expectations (prognosis)

If the tumor has not spread to the lungs (pulmonary metastasis), long-term survival rates are very high. If the cancer has spread to other parts of the body, there is still a good chance of cure with effective treatment.

Complications

Limb removal Spread of cancer to the lungs Side effects of chemotherapy

Calling your health care provider

Call your health care provider if you have persistent bone pain, tenderness, or swelling.

References

1.Skubitz KM, D'Adamo D. Sarcoma. Mayo Clin Proc. 2007;82:1409-1432. [PubMed]2.Baker MH. Bone tumors: primary and metastatic bone lesions. In: Goldman L, Ausiello D, eds.

Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier; 2007:chap 212.

Review Date: 11/5/2009.

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Osteosarcoma is an aggressive cancerous neoplasm arising from primitive transformed cells of mesenchymal origin that exhibit osteoblastic differentiation and produce malignant osteoid. It is the most common histological form of primary bone cancer.[1]

Contents[hide]

1 Incidence 2 Prevalence 3 Treatment 4 Mortality and Survival 5 Pathology 6 Causes 7 Symptoms 8 Diagnosis 9 Treatment 10 Prognosis 11 Canine osteosarcoma

o 11.1 Risk factors o 11.2 Clinical presentation o 11.3 Treatment and prognosis o 11.4 Experimental laser procedure

12 Osteosarcoma in cats 13 People diagnosed with osteosarcoma 14 References 15 Further reading 16 External links

Incidence

Osteosarcoma is the eighth most common form of childhood cancer, comprising 2.4% of all malignancies in pediatric patients, and approximately 20% of all bone cancers.[1]

Incidence rates for osteosarcoma in U.S. patients under 20 years of age are estimated at 5.0 per million per year in the general population, with a slight variation between individuals of black, Hispanic, and white ethnicities (6.8, 6.5, and 4.6 per million per year, respectively). It is slightly more common in males (5.4 per million per year) than in females (4.0 per million per year).[1]

There is a preference for origination in the metaphyseal region of tubular long bones, with 42% occurring in the femur, 19% in the tibia, and 10% in the humerus. About 8% of all cases occur in the skull and jaw, and another 8% in the pelvis.[1]

Prevalence

Osteogenic sarcoma is the sixth leading cancer in children under age 15. Osteogenic sarcoma affects 400 children under age 20 and 500 adults (most between the ages of 15-30) every year in the USA. Approximately 1/3 of the 900 will die each year, or about 300 a year. A second peak in incidence occurs in the elderly, usually associated with an underlying bone pathology such as Paget's disease, medullary infarct, or prior irradiation.

Treatment

Complete radical surgical en bloc resection is the treatment of choice in osteosarcoma.[1]

Although about 90% of patients are able to have limb-salvage surgery, complications, such as infection, prosthetic loosening and non-union, or local tumor recurrence may cause the need for further surgery or amputation.

Mortality and Survival

Deaths due to malignant neoplasms of the bones and joints account for an unknown amount of childhood cancer deaths.[1]

Mortality rates due to osteosarcoma have recently been declining at approximately 1.3% per year.[1] Current long-term survival probabilities for osteosarcoma have improved dramatically in recent decades and now approximate 68%.[1]

Pathology

Predilections of osteosarcoma

The tumor may be localized at the end of the long bone. Most often it affects the upper end of tibia or humerus, or lower end of femur. Osteosarcoma tends to affect regions around the knee in 60% of cases, 15% around the hip, 10% at the shoulder, and 8% in the jaw. The tumor is solid, hard, irregular ("fir-tree," "moth-eaten" or "sun-burst" appearance on X-ray examination) due to

the tumor spicules of calcified bone radiating in right angles. These right angles form what is known as Codman's triangle. Surrounding tissues are infiltrated.

High magnification micrograph showing osteoid formation in an osteosarcoma, H&E stain

Microscopically: The characteristic feature of osteosarcoma is presence of osteoid (bone formation) within the tumor. Tumor cells are very pleomorphic (anaplastic), some are giant, numerous atypical mitoses. These cells produce osteoid describing irregular trabeculae (amorphous, eosinophilic/pink) with or without central calcification (hematoxylinophilic/blue, granular) - tumor bone. Tumor cells are included in the osteoid matrix. Depending on the features of the tumor cells present (whether they resemble bone cells, cartilage cells or fibroblast cells), the tumor can be subclassified. Osteosarcomas may exhibit multinucleated osteoclast-like giant cells.[2]

Causes

The causes of osteosarcoma are not known.

Several research groups are investigating cancer stem cells and their potential to cause tumors.[3] The connection between osteosarcoma and fluoride has been investigated; there is no clear association between water fluoridation and deaths due to osteosarcoma.[4] Radiotherapy for unrelated conditions may be a rare cause.[5]

Symptoms

Many patients first complain of pain that may be worse at night, and may have been occurring for some time. If the tumor is large, it can appear as a swelling. The affected bone is not as strong as normal bones and may fracture with minor trauma (a pathological fracture).

Diagnosis

Family physicians and orthopedists rarely see a malignant bone tumor (most bone tumors are benign). Thus, many patients are initially misdiagnosed with cysts or muscle problems, and some are sent straight to physical therapy without an x-ray.

The route to osteosarcoma diagnosis usually begins with an x-ray, continues with a combination of scans (CT scan, PET scan, bone scan, MRI) and ends with a surgical biopsy. The diagnostic image seen in an X-ray is the 'Codman's Triangle' which is basically a subperiosteal lesion formed when the periosteum is raised due to the tumor. Films are suggestive, but bone biopsy is the only definitive method to determine whether a tumor is malignant or benign.

The biopsy of suspected osteosarcoma should be performed by a qualified orthopedic oncologist. The American Cancer Society states: "Probably in no other cancer is it as important to perform this procedure properly. An improperly performed biopsy may make it difficult to save the affected limb from amputation."

Treatment

Patients with osteosarcoma are best managed by a medical oncologist and an orthopedic oncologist experienced in managing sarcomas. Current standard treatment is to use neoadjuvant chemotherapy (chemotherapy given before surgery) followed by surgical resection. The percentage of tumor cell necrosis (cell death) seen in the tumor after surgery gives an idea of the prognosis and also lets the oncologist know if the chemotherapy regime should be altered after surgery.

Standard therapy is a combination of limb-salvage orthopedic surgery when possible (or amputation in some cases) and a combination of high dose methotrexate with leucovorin rescue, intra-arterial cisplatin, adriamycin, ifosfamide with mesna, BCD, etoposide, muramyl tri-peptite (MTP). Rotationplasty is also another surgical technique that may be used. Ifosfamide can be used as an adjuvant treatment if the necrosis rate is low.

Despite the success of chemotherapy for osteosarcoma, it has one of the lowest survival rates for pediatric cancer. The best reported 10-year survival rate is 92%; the protocol used is an aggressive intra-arterial regimen that individualizes therapy based on arteriographic response.[6] Three-year event-free survival ranges from 50% to 75%, and five-year survival ranges from 60% to 85+% in some studies. Overall, 65-70% patients treated five years ago will be alive today .[7] These survival rates are overall averages and vary greatly depending on the individual necrosis rate.

Fluids are given for hydration, while drugs like Kytril and Zofran help with nausea and vomiting. Neupogen and Neulasta help with white blood cell counts and neutrophil counts. Blood transfusions and epogen help with anemia.

Prognosis

Prognosis is separated into three groups.

Stage I osteosarcoma is rare and includes parosteal osteosarcoma or low-grade central osteosarcoma. It has an excellent prognosis (>90%) with wide resection.

Stage II prognosis depends on the site of the tumor (proximal tibia, femur, pelvis, etc.), size of the tumor mass (in cm.), and the degree of necrosis from neoadjuvant chemotherapy

(chemotherapy prior to surgery). Other pathological factors such as the degree of p-glycoprotein, whether the tumor is cxcr4-positive,[8] or Her2-positive are also important, as these are associated with distant metastases to the lung. The prognosis for patients with metastatic osteosarcoma improves with longer times to metastases, (more than 12 months-24 months), a smaller number of metastases, and their resectability. It is better to have fewer metastases than longer time to metastases. Those with a longer length of time(>24months) and few nodules (two or fewer) have the best prognosis with a 2-year survival after the metastases of 50%, 5-year of 40% and 10 year of 20%. If metastases are both local and regional, the prognosis is worse.

Initial presentation of stage III osteosarcoma with lung metastases depends on the resectability of the primary tumor and lung nodules, degree of necrosis of the primary tumor, and maybe the number of metastases. Overall survival prognosis is about 30%.[9]

Canine osteosarcoma

X-ray of osteosarcoma of the distal femur in a dog

Risk factors

Osteosarcoma is the most common bone tumor in dogs and typically afflicts middle-age large and giant breed dogs such as Irish Wolfhounds, Greyhounds, German Shepherds, Rottweilers, Doberman Pinschers and Great Danes. It has a ten times greater incidence in dogs than humans.[10] A hereditary base has been shown in St. Bernard dogs.[11] Spayed/neutered dogs have twice the risk of intact ones to develop osteosarcoma.[12] Infestation with the parasite Spirocerca lupi can cause osteosarcoma of the esophagus.[13]

Clinical presentation

The most commonly affected bones are the proximal humerus, the distal radius, the distal femur, and the tibia,[14] following the basic premise "far from the elbow, close to the knee". Other sites include the ribs, the mandible, the spine, and the pelvis. Rarely, osteosarcoma may arise from soft-tissues (extraskeletal osteosarcoma). Metastasis of tumors involving the limb bones is very common, usually to the lungs. The tumor causes a great deal of pain, and can even lead to fracture of the affected bone. As with human osteosarcoma, bone biopsy is the definitive method to reach a final diagnosis. Osteosarcoma should be differentiated from other bone tumours and a

range of other lesions, such as osteomyelitis. Differential diagnosis of the osteosarcoma of the skull in particular includes, among others, chondrosarcoma and the multilobular tumour of bone.[15][16]

Treatment and prognosis

Amputation of the leg is the initial treatment, although this alone will not prevent metastasis. Chemotherapy combined with amputation improves the survival time, but most dogs still die within a year.[14] There are surgical techniques designed to save the leg (limb-sparing procedures), but they do not improve the prognosis. One key difference between osteosarcoma in dogs and humans is that the cancer is far more likely to spread to the lungs in dogs.

Some current studies indicate that osteoclast inhibitors such as alendronate and pamidronate may have beneficial effects on the quality of life by reducing osteolysis, thus reducing the degree of pain as well as the risk of pathological fractures.[17]

Experimental laser procedure

Autologous patient specific tumor antigen response (apSTAR Veterinary Cancer Laser System: The use of a laser combined with a polymer has been shown to enhance tumor immunity and improve the rate of primary and metastatic tumor regression in laboratory models of tumors. IMULAN BioTherapeutics, LLC has recently started examining the use of this laser device, termed apSTAR, for dogs with osteosarcoma and other tumor types.[18]

Osteosarcoma in cats

Osteosarcoma is also the most common bone tumor in the cat, although not as frequently encountered, and most typically affects the rear legs. The cancer is less aggressive in cats than in dogs, and therefore amputation alone can lead to a significant survival time.[14]

People diagnosed with osteosarcoma

Terry Fox (1958–1981) began a run across Canada to raise money for cancer research. He developed osteogenic sarcoma as a teenager and had a leg amputated.

Antonietta Meo Terry Fox Edward M. Kennedy, Jr. Chiara Badano Samual Gordon Bish Bruce Feiler

References

1. ^ a b c d e f g h Ottaviani G., Jaffe N. (2009). The epidemiology of osteosarcoma. In: Jaffe N. et al. “Pediatric and Adolescent Osteosarcoma”. New York: Springer. doi:10.1007/978-1-4419-0284-9_1. ISBN 978 1 4419 0283 2.

2. ̂ Papalas JA, Balmer NN, Wallace C, Sangüeza OP (June 2009). "Ossifying dermatofibroma with osteoclast-like giant cells: report of a case and literature review". Am J Dermatopathol 31 (4): 379–83. doi:10.1097/DAD.0b013e3181966747. PMID 19461244.

3. ̂ Osuna D, de Alava E (2009). "Molecular pathology of sarcomas". Rev Recent Clin Trials 4 (1): 12–26. doi:10.2174/157488709787047585. PMID 19149759.

4. ̂ National Health and Medical Research Council (Australia) (2007). "A systematic review of the efficacy and safety of fluoridation" (PDF). http://www.nhmrc.gov.au/PUBLICATIONS/synopses/_files/eh41.pdf. Retrieved 2009-02-24.[dead link] Summary: Yeung CA (2008). "A systematic review of the efficacy and safety of fluoridation". Evid Based Dent 9 (2): 39–43. doi:10.1038/sj.ebd.6400578. PMID 18584000. Lay summary – NHMRC (2007).

5. ̂ Dhaliwal J, Sumathi VP and Grimer RJ. Radiation-induced periosteal osteosarcoma. Grand Rounds 10: 13-18 [1]

6. ̂ Wilkins RM, Cullen JW, Odom L, Jamroz BA, Cullen PM, Fink K, Peck SD, Stevens SL, Kelly CM, Camozzi AB: Superior survival in treatment of primary non-metastatic pediatric osteosarcoma of the extremity. Ann Surg Oncol 10:498-507, 2003.

7. ̂ Buecker, PJ, Gebhardt, M and Weber, K (2005). "Osteosarcoma". ESUN. http://sarcomahelp.org/osteosarcoma.html. Retrieved 2009-04-15.

8. ̂ http://www.osteosarcomasupport.org/cxcr4_metastases.pdf9. ̂ Koshkina, NV and Corey, S (2008). "Novel Targets to Treat Osteosarcoma Lung Metastases". ESUN.

http://sarcomahelp.org/research_center/osteosarcoma_lung_metastases.html. Retrieved 2009-04-14.10. ̂ Withrow, S.J. (2003). "Limb Sparing Trials and Canine Osteosarcoma". Genes, Dogs and Cancer: 3rd

Annual Canine Cancer Conference, 2003. http://www.ivis.org/proceedings/Keystone/2003/withrow/chapter_frm.asp?LA=1. Retrieved 2006-06-16.

11. ̂ Bech-Nielsen, S., Haskins, M. E. et al. (1978). "Frequency of osteosarcoma among first-degree relatives of St. Bernard dogs". J Natl Cancer Inst 60(2):349-53.

12. ̂ Ru, B., Terracini, G. et al. (1998). "Host related risk factors for canine osteosarcoma". Vet J 156(1):31-9 156 (1): 31–9. doi:10.1016/S1090-0233(98)80059-2. PMID 9691849.

13. ̂ Ranen E, Lavy E et al. (2004). "Spirocercosis-associated esophageal sarcomas in dogs. A retrospective study of 17 cases (1997-2003)". Vet Parasitol 119(2-3):209-21 119: 209. doi:10.1016/j.vetpar.2003.10.023.

14. ^ a b c Morrison, Wallace B. (1998). Cancer in Dogs and Cats (1st ed.). Williams and Wilkins. ISBN 0-683-06105-4.

15. ̂ Loukopoulos P, Thornton JR , Robinson WF. Clinical and pathologic relevance of p53 index in canine osseous tumors. Veterinary Pathology 2003; 40:237-248

16. ̂ Psychas V, Loukopoulos P, Polizopoulou ZS , Sofianidis G. Multilobular tumour of the caudal cranium causing severe cerebral and cerebellar compression in a dog. Journal of Veterinary Science 2009; 10:81-83.

17. ̂ Tomlin, J. L., Sturgeon, C. et al. (2000). "Use of the bisphosphonate drug alendronate for palliative management of osteosarcoma in two dogs". Vet Rec 147(5):129-32.

18. ̂ [2]

Further reading

James, H. (1979). Promises in the Dark. New York: Bantam Books. ISBN 0-553-13453-1. Story of a young girl's osteosarcoma fight and its effect on her relationship with her boyfriend

Belshaw, Sheila M. (2001). Fly With a Miracle. Denor Press. ISBN 0 9526056 7 8. The story of a family's journey through teenage osteosarcoma and its aftermath.

Trottier, Maxine (2005). Terry Fox: A Story of Hope. Markham, Ont: Scholastic Canada. ISBN 0-439-94888-6. About Terry Fox and his quest to raise $25 million for cancer research by running across Canada on his prosthetic leg. Also The Terry Fox Story, a 1983 movie.

Jaffe, N. et al. (2009). Pediatric and Adolescent Osteosarcoma. New York: Springer. ISBN 978 1 4419 0283 2. Osteosarcoma research: past, present and future.

External links

Osteosarcoma at the Open Directory Project EURAMOS - The European and American Osteosarcoma Study Group National Cancer Institute - patient information on osteosarcoma University of Minnesota - Genetics of Osteosarcoma research study

[hide]v · d · e Connective tissue neoplasm : Osseous and Chondromatous tumors (ICD-O 9180–9269) (C40–C41/D16, 170/213)

Diaphysis

MyeloidMultiple myeloma

EpithelialAdamantinoma

PNET/Ewing family

Ewing's sarcoma

Metaphysis

OsteoblastOsteoid osteoma · Osteoblastoma

Osteoma/osteosarcoma

Chondroblast

Chondroma/ecchondroma/enchondroma (Enchondromatosis, Extraskeletal chondroma) · Chondrosarcoma (Mesenchymal chondrosarcoma, Myxoid chondrosarcoma)

Osteochondroma (Osteochondromatosis)

Chondromyxoid fibroma

FibrousOssifying fibroma · Fibrosarcoma

Epiphysis

ChondroblastChondroblastoma

MyeloidGiant cell tumor of bone

Other/ungrouped

Notochord

Chordoma

M: BON/CAR anat(c/f/k/f, u, t/p, l)/phys/devp/cell

noco/cong/tumr, sysi/epon, injr

proc, drug(M5)

Retrieved from "http://en.wikipedia.org/wiki/Osteosarcoma"Categories: Cat diseases | Dog diseases | Skeletal disorders | Types of cancer | Sarcoma

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Osteosarcoma (also called osteogenic sarcoma) Back to top

Around 30 children in the UK develop osteosarcomas each year. These tumours occur more commonly in older children and teenagers, and are very rarely seen in children under five. They are more common in boys than girls.

Osteosarcoma is a cancer that starts in the bone. It often starts at the ends of the bones, where new bone tissue forms as a young person grows. Any bone in the body can be affected, but the most common sites are the arms or legs, particularly around the knee joint.

There are several different types of osteosarcoma. Most occur in the centre of the bone. There are also rare subtypes, such as parosteal, periosteal telangiectatic, and small cell osteosarcoma.

Causes of osteosarcoma Back to top

As with most cancers, the cause of osteosarcoma is unknown. Children who have hereditary retinoblastoma (a rare tumour of the eye) have an increased risk of developing osteosarcoma. Children who have had previous radiotherapy and chemotherapy also have an increased risk of developing osteosarcoma.

It is not caused by injuries or damage to the bone, although an injury may draw attention to a bone tumour.

Signs and symptoms Back to top

Pain in the affected bone is the most common symptom. This pain may initially come and go, and then gradually become more severe and constant. There may also be swelling around the affected bone. Primary bone cancer is sometimes discovered when a bone that has been weakened by cancer breaks after the person has had a minor fall or accident.

The symptoms described above can be caused by many things other than cancer. However, any persistent bone pain, particularly at night, should be checked by your child's doctor.

How it is diagnosed Back to top

Usually you begin by seeing your family doctor (GP), who will examine your child and may arrange tests or x-rays. If a bone tumour is suspected, they will refer your child directly to a specialist hospital or bone tumour centre for further tests. Many of the specific tests for diagnosing bone tumours, such as biopsies, require experience and specialist techniques.

The doctor at the hospital will take a full medical history. They  will then do a physical examination. This will include an examination of the painful bone to check for any swelling or tenderness. Your child will probably have a blood test done to check their general health.

A variety of tests and investigations may be needed to diagnose an osteosarcoma. An x-ray of the painful part of the bone will usually identify a tumour, although sometimes they can be difficult to see. A small piece of the tumour will be removed and looked at under a microscope. This is called a biopsy. It is a small operation performed under general anaesthetic.

Other tests are taken to check whether the cancer has spread elsewhere in the body. These include a chest x-ray, blood tests, a bone scan, a bone marrow aspirate and an MRI or CT scan.

Any tests and investigations that your child needs will be explained to you. The Macmillan/CCLG booklet A parent’s guide to children’s cancer gives details of what the tests and scans involve.

Grading Back to top

Grading refers to the appearance of the cancer cells under the microscope, and gives an idea of how quickly the cancer may develop. Low-grade cancer cells look very much like normal cells, and are usually slow growing and less likely to spread.

In high-grade tumours, the cells look very abnormal, are likely to grow quickly, and are more likely to spread.

Most osteosarcomas are high grade, but a type known as parosteal osteosarcoma is usually low grade. A further subtype (periosteal osteosarcoma) is usually treated as though it was high grade.

Staging Back to top

The stage of a cancer is a term used to describe its size and whether it has spread beyond its original site. Knowing the particular type, and stage, of the cancer helps the doctors to decide on the most appropriate treatment.

Most patients are grouped depending on whether cancer is found in only one part of the body (localised disease), or whether the cancer has spread from one part of the body to another (metastatic disease).

A commonly used staging system for osteosarcomas is described below:

Stage 1A The cancer is low grade and is found only within the hard coating of the bone. Stage 1B The cancer is low grade, extending outside the bone and into the soft tissue spaces

that contain nerves and blood vessels. Stage 2A The cancer is high grade and is completely contained within the hard coating of the

bone. Stage 2B The cancer is high grade and has spread outside the bone and into surrounding soft

tissue spaces that contain nerves and blood vessels. Most osteosarcomas are stage 2B. Stage 3 The cancer can be low or high grade and is found either within the bone or extends

outside the bone. The cancer has spread to other parts of the body, or to other bones not directly connected to the bone where the tumour started.

If the cancer comes back after initial treatment, this is known as recurrent or relapsed cancer.

Treatment Back to top

Treatment will depend on a number of factors including the size, position and stage of the tumour.

Surgery is a very important part of treatment for osteosarcoma. Chemotherapy uses anti-cancer (cytotoxic) drugs to destroy cancer cells, and is usually given to shrink the main tumour before surgery. It is also given after the tumour has been removed by surgery, to help reduce the risk of the cancer coming back (recurring). It is common for a combination of drugs to be used.

Radiotherapy may occasionally be given. This treats cancer by using high-energy rays to destroy the cancer cells, while doing as little harm as possible to normal cells.

Surgery Back to top

The type and extent of surgery depends on the position and size of the tumour in the body. This surgery will need to be carried out at a specialist orthopaedic centre, and your child should be referred to one. 

Surgery may include removing the whole limb (amputation) or part of the affected bone, which is then replaced by some form of false limb (prosthesis). If only part of the affected bone is removed, this is known as limb-sparing surgery.

Amputation of the limb is sometimes unavoidable if the cancer is affecting the surrounding blood vessels and nerves. After amputation, a false limb will be fitted and will be regularly adjusted as your child grows. False limbs can work very well. It should be possible for your child to join in with normal activities and even sport.

Limb-sparing surgery preserves the limb. There are two ways in which this may be done:

replacing the bone with a prosthesis (a specially designed artificial part) replacing the affected bone with bone taken from another part of the body.

After this type of surgery, children will usually be able to use their limbs almost normally. However, they are advised not to participate in any contact sports, because any damage to the bone graft or prosthesis might require another major operation to repair or replace it.

If your child is still growing, the limb prosthesis will need to be lengthened as the bone grows. This will mean further short stays in hospital.

Side effects of treatment Back to top

Treatment often causes side effects, and your child’s doctor will discuss these with you before the treatment starts. Any possible side effects will depend upon the treatment being given and the part of the body that is being treated.

For example, side effects of chemotherapy can include feeling sick (nausea) and being sick (vomiting), hair loss, an increased risk of infection, bruising and bleeding. Radiotherapy can

cause irritation or soreness of the skin in the area being treated and tiredness. If your child is having surgery, the surgeon will explain about any possible complications of surgery.

We have booklets that describe these side effects in more detail.

Late side effects Back to top

A small number of children may develop late side effects, sometimes many years later. These include a reduction in bone growth, infertility, a change in the way the heart and lungs work, and a slight increase in the risk of developing another cancer in later life.

Your child’s doctor or nurse will talk to you about any possible late side effects. There is more detailed information about these long-term side effects in the Macmillan/CCLG booklet A parent’s guide to children’s cancer.

Clinical trials Back to top

Many children have their treatment as part of a clinical research trial. Trials aim to improve our understanding of the best way to treat an illness, usually by comparing the standard treatment with a new or modified version.

Specialist doctors carry out trials for children's cancer. If appropriate, your child's medical team will talk to you about taking part in a clinical trial and will answer any questions you have. Written information is provided to help explain things.

Taking part in a research trial is completely voluntary, and you'll be given plenty of time to decide if it's right for your child. Your child's doctor can tell you what trials are available that might be suitable for your child.

Before any trial is allowed to take place it must be approved by an ethics committee, which protects the interests of the patients taking part.

If you decide to let your child take part in a trial, your doctor or a research nurse must discuss the treatment with you, so that you have full understanding of the trial and what it means for your child to take part. You may decide not to take part or you can withdraw from a trial at any stage, and your child will then receive the best standard treatment available.

Follow-up Back to top

Many children with osteosarcoma are cured. However, the child may need to have surgery to lengthen the affected limb from time to time. Your child will have regular check-ups and x-rays in the paediatric or adolescent oncology clinic and at the orthopaedic centre.

If you have specific concerns about your child’s condition and treatment, it is best to discuss them with your child’s doctor, who knows the situation in detail.

Your feelings Back to top

As a parent, the fact that your child has cancer is one of the worst situations you can be faced with. You may have many different emotions, such as fear, guilt, sadness, anger and uncertainty. These are all normal reactions, and are part of the process that many parents go through at such a difficult time. 

It's not possible to address all of the feelings you may have on this factsheet. However, the Macmillan/CCLG booklet A parent’s guide to children’s cancer talks about the emotional impact of caring for a child with cancer, and suggests sources of help and support.

Your child may have a variety of powerful emotions throughout their experience of cancer. The parent's guide discusses these further and talks about how you can support your child.

Our booklet Peppermint Ward is a storybook for younger children with cancer. It looks at the issues that they and their family may face and helps them to explore their feelings. Our booklet Katie's Garden is a storybook for primary school-age children about a girl's experience of cancer.

Our website click4tic.org.uk has information developed especially for teenagers with cancer.

Useful organisations Back to topCLIC SargentGriffin House, 161 Hammersmith Road, London W6 8SGTel 0800 197 0068Email [email protected]

Offers practical support to children and young people aged 21 and under with cancer or leukaemia, and to their families.

Children's Cancer and Leukaemia Group (CCLG)University of Leicester, 3rd Floor, Hearts of Oak House,9 Princess Road West, Leicester LE1 6THTel 0116 249 4460Email [email protected]

Coordinates research and care for children and their parents. There are 21 CCLG specialist centres for the treatment of childhood cancer and leukaemia, covering all areas of the UK and Ireland (there's a map of the centres on the website). Has information about the CCLG, childhood cancer and leukaemia.

References Back to top

This section has been compiled using information from a number of reliable sources, including:

Voute PA, et al. Cancer in Children: Clinical Management. 5th edition. 2005. Oxford University Press.

Pinkerton R, et al. Evidence-based paediatric oncology. 2nd edition. 2007. Blackwell Publishing. Wang L, et al. Osteosarcoma: Epidemiology, pathogenesis, clinical presentation, diagnosis, and

histology. (accessed September 2010).

For further references, please see the general bibliography.

Content last reviewed: 1 December 2010

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Disease InformationSolid Tumor: OsteosarcomaAlternate Names: NoneDefinition

Osteosarcoma is the most common type of bone cancer in children and adolescents. It occurs most often in the bones on either side of the knee and in the upper arm. It most commonly arises from

the metaphysis (the wider part) of the bone.

Incidence

Each year in the United States, osteosarcoma is diagnosed in approximately 400 children and adolescents younger than 20 years. 

The peak incidence of osteosarcoma is in the second decade of life, during the adolescent growth spurt. It is extremely rare in children before the age of 5 years. 

Osteosarcoma is somewhat more likely to affect males than females.  The incidence in black children is higher than that in whites.

Influencing Factors

The cause of osteosarcoma is unknown; however, irradiation and genetic influences have been implicated in its development.

Osteosarcoma occurs in long-term survivors of cancer who were treated with radiation therapy. The interval between irradiation and the appearance of osteosarcoma ranges from four to more than 40 years

(median, 12-16 years). It is apparent that two suppressor genes, p53 and Rb, have major roles in tumorigenesis in

osteosarcoma. Approximately 3-4 percent of children with osteosarcoma carry constitutional germline mutations in p53. The majority of these cases with germline p53 mutations occur in patients with a strong family history of cancer or with family histories suggestive of the Li-Fraumeni syndrome (a familial cancer syndrome) or in patients with multiple cancers. 

By far the strongest genetic predisposition to osteosarcoma is found in patients with hereditary retinoblastoma. In hereditary retinoblastoma, germline mutations of the Rb gene are common.

Clinical Features and Symptoms

Patients usually present with pain, swelling, and sometimes decreased joint motion. Occasionally, a patient may present with a fracture at the tumor site. Symptoms are usually present for several months before the diagnosis is made.  About 15-20 percent of the patients have metastatic disease at the time of diagnosis – usually in the lung and

the bones. The work up of a patient with suspected osteosarcoma typically includes blood tests, plain x-rays and

magnetic resonance imaging (MRI) of the affected bone, computerized tomography (CT) scan of the chest and a radionuclide bone scan.

A biopsy is always required to make the diagnosis. It is preferable to have the biopsy done by the surgeon who will ultimately perform the definitive surgical treatment. Fine-needle aspiration and core-needle biopsy have been recommended at a number of centers, but most patients require open biopsy to obtain a generous sample of adequate and representative tissue.

Survival Rates

Currently, the estimated 5-year survival for patients with osteosarcoma is 65 percent compared with 15 percent in the early 1960s.

The presence of metastasis at diagnosis has a major impact on patient survival. The estimated survival rate for patients with localized osteosarcoma is about 75 percent compared to 30 percent for patients with metastatic disease.

Treatment Strategies

Treatment of osteosarcoma includes surgery and chemotherapy. Surgical removal of all gross and microscopic tumor is required to prevent local tumor recurrence. Before the

1970s, amputation was the only surgical approach. Currently, 95 percent of patients with localized osteosarcoma of the extremity can be considered for limb-salvage surgery.

When osteosarcoma is treated by surgery alone, the natural history is recurrence and more than 80 percent of patients will develop metastatic disease.

The use of multi-agent chemotherapy has markedly improved the outcome of patients with osteosarcoma. Active agents against osteosarcoma include cisplatin, doxorubicin, high-dose methotrexate and ifosfamide used alone or in combination with carboplatin or etoposide.  Studies done at St. Jude since 1968 have shown the importance of chemotherapy in the treatment of osteosarcoma. In 1986, we initiated a trial (OS86) of ifosfamide, cisplatin, doxorubicin, and high-dose methotrexate. The subsequent trial (OS91), which was completed in 1997, substituted carboplatin for cisplatin. The five-year survival estimates for patients with localized osteosarcoma were 69.2 percent ± 7.4 percent for those treated on OS86 and 74.5 percent ± 6.3 percent for those treated on OS91. The results of OS91 demonstrated that the carboplatin and ifosfamide combination has substantial antitumor activity. When used with doxorubicin and high-dose methotrexate to treat patients with localized osteosarcoma, this combination yielded outcomes comparable to those of trials using cisplatin-based therapy, with less long-term toxicity. The OS91 study also showed that dynamic contrast-enhanced MR imaging (DEMRI) may be useful in predicting tumor response to chemotherapy. Our most recently completed trial (OS99) used ifosfamide, carboplatin, and doxorubicin for treatment of patients with localized and resectable osteosarcoma. High-dose methotrexate, which may interfere with the dose-intensive delivery of other agents, was eliminated from the protocol. OS99 is the first St. Jude trial conducted as an international collaboration (with Chile) through our International Outreach Program and serves as a model for international collaborations particularly with developing countries. Twenty-two of the 72 eligible patients were treated in Chile and patients treated in Chile had similar treatment tolerance and outcome compared to patients treated at St. Jude. 

Current Research

Results of studies suggest that the outcome of patients with localized osteosarcoma has reached a plateau with no added benefit from intensifying or adding new cytotoxic chemotherapy, and the outcome of patients with metastatic or unresectable disease remains poor. We are currently conducting a trial (OS2008) which adopts a novel strategy for first-line treatment of osteosarcoma by combining chemotherapy with anti-angiogenic therapy using bevacizumab (Avastin®), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF). Bevacizumab stops tumor growth by inhibiting the function of VEGF, a natural protein that stimulates new blood vessel formation. Bevacizumab has improved the efficacy of chemotherapy in adult patients with various types of cancer by increasing tumor response and increasing the chances of survival. The primary objectives of OS2008 are: 1) to study the feasibility of combining bevacizumab with standard chemotherapy in patients with osteosarcoma, and 2) to study the effect of adding bevacizumab to chemotherapy on the event-free survival in patients with localized resectable osteosarcoma compared to historical controls treated with the same chemotherapy without bevacizumab. The importance of this study goes beyond the potential to improve treatment efficacy since it includes multiple secondary objectives related to:o Reproductive functiono Angiogenic markerso Bevacizumab pharmacokinetics and pharmacogenomic studieso Imaging studies (dynamic-enhanced MRI and PET CT ) o Tumor biology o Surgical resection and reconstructive techniqueso Quality of lifeo Functional outcome of the limbo Neuropathic pain management

In addition, laboratory investigations are ongoing to better understand the biology of the disease and identify prognostic factors and new effective agents. Such investigations are essential to improve the treatment and outcome of osteosarcoma.  

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Pediatric Osteosarcoma

Author: Timothy P Cripe, MD, PhD, Professor of Pediatrics, Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center; Clinical Director, Musculoskeletal Tumor Program, Co-Medical Director, Office for Clinical and Translational Research, Cincinnati Children's Hospital Medical Center; Director of Pilot and Collaborative Clinical and Translational Studies Core, Center for Clinical and Translational Science and Training, University of Cincinnati College of MedicineContributor Information and Disclosures

Updated: Dec 8, 2010

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Introduction

Background

Osteosarcoma is the third most common cancer in adolescence, occurring less frequently than only

lymphomas and brain tumors. It is thought to arise from a primitive mesenchymal bone-forming cell and is

characterized by production of osteoid. The mainstay of therapy is removal of the lesion. Limb-sparing

procedures can often be used to preserve function. Chemotherapy is also required to treat micrometastatic

disease, which is present but not detectable in most patients at diagnosis.

See the following image below.

Lateral plain radiograph of the knee reveals an osteosarcoma of the distal femur. The

lesion is mainly posterior, with disruption and elevation of the periosteum (Codman

triangle), and extends beyond the bone into the soft tissue.

Pathophysiology

Osteosarcoma is a bone tumor that can occur in any bone. It most commonly occurs in the long bones of the

extremities near metaphyseal growth plates. The most common sites include the femur (42%), with 75% of

tumors in the distal femur; tibia (19%), with 80% of tumors in the proximal tibia; and humerus (10%), with 90%

of tumors in the proximal humerus.1 Other locations of note include the skull or jaw (8%) and pelvis (8%).

Any sarcoma that arises from bone is technically called an osteogenic sarcoma. Therefore, this term includes

fibrosarcoma, chondrosarcoma, and osteosarcoma, all named for their morphologic characteristics. The focus

of this article is osteosarcoma. Numerous variants of osteosarcoma are known and include conventional types

(ie, osteoblastic, chondroblastic, fibroblastic types) and telangiectatic, multifocal, parosteal, and periosteal

types.

Frequency

United States

The incidence is 400 cases per year (4.8 cases per million persons <20 y).

Mortality/Morbidity

The overall 5-year survival rate for patients whose condition was diagnosed between 1974 and 1994 was 63%

(59% for male patients, 70% for female patients).

Race

The incidence is slightly higher in African Americans than in Caucasians (data from the National Cancer

Institute [NCI] Surveillance, Epidemiology, and End Results [SEER] Study Pediatric Monograph, 1975-1995).1

In African Americans, the annual incidence is 5.2 cases per million population younger than 20 years.

In Caucasians, the annual incidence is 4.6 cases per million population younger than 20 years.

Sex

The incidence is slightly higher in male individuals than in female individuals.

In male individuals, the incidence is 5.2 cases per million population per year.

In female individuals, the incidence is 4.5 cases per million population per year.

Age

The incidence of osteosarcoma increases steadily with age; a relatively dramatic increase in adolescence

corresponds with the growth spurt.

Osteosarcoma is rarely diagnosed in patients younger than 5 years (about 1% of cases).2

In children aged 5-9 years, the annual incidence is 2.6 cases for African Americans and 2.1 cases for

Caucasians per million population.

In children aged 10-14 years, the annual incidence is 8.3 cases for African Americans and 7 cases for

Caucasians per million population.

In adolescents aged 15-19 years, the annual incidence is 8.9 cases for African Americans and 8.2

cases for Caucasians per million population.

Patients whose disease is diagnosed during their growth spurt are taller than average, although

patients identified in adulthood have average height.

Clinical

History

Symptoms may be present for weeks, months, or occasionally longer before osteosarcoma is diagnosed. The

most common presenting symptom of osteosarcoma is pain, particularly with activity. Patients may complain of

a sprain, arthritis, or so-called growing pains. The patient often has a history of trauma, although pathologic

fractures are not particularly common. The exception is the telangiectatic type of osteosarcoma, which is

commonly associated with pathologic fractures. If pain affects a lower extremity, it may result in a limp.

The patient may have a history of swelling, depending on the size of the lesion and its location. Systemic

symptoms, such as fever and night sweats, are rare. Tumoral spread to the lungs rarely results in respiratory

symptoms, and such symptoms usually indicate extensive lung involvement. Metastases to other sites are

extremely rare; therefore, other symptoms are unusual. Only 15-20% of patients present with metastases,

which primarily affect the lungs but can also affect other bones. Manifestations at several bone sites at

diagnosis may indicate multifocal sclerosing osteosarcoma.

Osteosarcoma most commonly involves the distal femur and proximal tibia, followed by the proximal humerus

and mid and proximal femur. As many as 20% of patients present with tumors of the flat bones of the body

including the skull and pelvis. Tumors of the jaw are relatively uncommon.

Physical

Physical findings are usually limited to those of the primary tumor site.

Mass: A palpable mass may be present. The mass may be tender and warm, although these signs are

indistinguishable from those of osteomyelitis. Increased skin vascularity over the mass may be

discernible. Pulsations or a bruit may be detectable.

Decreased range of motion: Joint involvement should be obvious on physical examination.

Lymphadenopathy : Involvement of local or regional lymph nodes is unusual.

Respiratory findings: Auscultation is usually uninformative unless extensive pulmonary disease is

present.

Causes

The exact cause of osteosarcoma is unknown. However, numerous risk factors are known.

Rapid bone growth appears to predispose patients to osteosarcoma, as suggested by the increased

incidence during the adolescent growth spurt,3 the high incidence among large dogs (eg, Great Danes,

St Bernards, German shepherds), and the typical location of osteosarcomas near the metaphyseal

growth plate of long bones.

Exposure to radiation is the only known environmental risk factor.

There appears to be a cluster of tumor suppressor genes on chromosome 3.4

A genetic predisposition may be present.  o Retinoblastoma, especially the combination of a constitutional mutation of the RB gene

(germline retinoblastoma) with radiation therapy, is associated with a particularly high risk of

osteosarcoma development. Of note, the genetic locus retinoblastoma at band 13q14 has

also been implicated in the pathogenesis of sporadic osteosarcoma.o Bone dysplasias, including Paget disease, fibrous dysplasia, enchondromatosis, and

hereditary multiple exostoses, increase the risk for osteosarcoma.o Li-Fraumeni syndrome (germline TP53 mutation) is a predisposing factor for osteosarcoma.

o Rothmund-Thomson syndrome (ie, autosomal recessive association of congenital bone

defects, hair and skin dysplasias, hypogonadism, cataracts) is associated with an increased

risk of osteosarcoma.

thalasemia

Definition of ThalassemiaThalassemia, also known as Mediterranean Anemia, Cooley's Anemia or Homozygous Beta Thalassemia, is a group of inherited disorders in which there is a fault in the production of hemoglobin (oxygen-carrying pigment found in red blood cells).

Description of ThalassemiaBlood is red because the red blood cells contain an oxygen-carrying substance called hemoglobin. The principal function of hemoglobin is to combine with and transport oxygen from the lungs and deliver it to all body tissues, where it is required to provide energy for the chemical reaction of all living cells.

Hemoglobin contains a large amount of iron. When red blood cells are broken down, most of the iron from the hemoglobin is used again to make new hemoglobin.

In the case of thalassemia the hemoglobin is fragile and breaks down sooner than normal, thus leaving the person with not enough hemoglobin in their body. This lack of hemoglobin causes anemia.

There are different types of anemia. The most common is iron-deficiency anemia. This happens when people do not have enough hemoglobin because they're not eating enough of the foods that contain iron (See Health Profile on Anemia).

Thalassemia is a different type of anemia. This happens when people do not have enough hemoglobin and is caused by the inheritance of a defective gene.

There are two forms of thalassemia:

Thalassemia trait

People with thalassemia trait carry thalassemia, but they are not ill. They are healthy and normal, however, some may have slight anemia.

People with thalassemia trait also have slightly more hemoglobin called hemoglobin A2 in their blood.

Thalassemia trait is present at birth, it remains the same for life, and it can be handed down from parents to children.

Thalassemia major

This a very serious blood disease that begins in early childhood.

Children with thalassemia major are normal at birth but become anemic between the age of three months and eighteen months. They become pale, do not sleep well, do not want to eat, and may vomit frequently after feedings.

If thalassemia major goes untreated, children usually die between one and eight years of age.

Text Continues Below

Causes and Risk Factors of ThalassemiaThalassemia is a genetically determined disease. It tends to be found in individuals whose families come from the Mediterranean region, Africa, and sometimes Asia.

Symptoms of ThalassemiaPeople with thalassemia major may experience the following:

Paleness Headaches Fatigue Shortness of breath Jaundice Spleen enlargement

Diagnosis of ThalassemiaThe diagnosis of thalassemia trait and thalassemia major is made from microscopic examination of the blood, which shows many small, pale red blood cells, and from other blood tests that show reduced levels of adult hemoglobin in the blood.

Treatment of ThalassemiaThalassemia trait

Normally, there are no treatments recommended. However, the doctor may suggest taking iron medication if they feel it is necessary.

Thalassemia major

The primary treatment is regular blood transfusions, usually every four weeks. In addition to the blood transfusions, doctors recommend injections of Desferal to help the body flush out the extra iron created by the new blood. The injections are given under the skin from a small pump 5 to 7 nights a week.

Additionally, splenectomy (removal of the spleen), bone marrow transplants and chelation therapy are being researched as possible treatments for thalassemia.

Questions To Ask Your Doctor About ThalassemiaHow can having the thalassemia trait affect a person's life?

Children's lives?

Do you recommend genetic counseling if a couple is planning on having children?

Is a thalassemia carrier more likely to get other diseases?

Is a thalassemia carrier physically or mentally weak?

Can thalassemia trait turn into thalassemia major?

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Introduction

Background

The thalassemias are inherited disorders of hemoglobin (Hb) synthesis. Their clinical severity widely varies,

ranging from asymptomatic forms to severe or even fatal entities. The name Mediterranean anemia, which

Whipple introduced, is misleading because the condition can be found in any part of the world. As described

below, different types of thalassemia are more endemic to certain geographic regions.

In 1925, Thomas Cooley, a Detroit pediatrician, described a severe type of anemia in children of Italian origin.

He noted abundant nucleated red blood cells (RBCs) in the peripheral blood, which he initially thought was

erythroblastic anemia, an entity that von Jaksh described earlier. Before long, Cooley realized that

erythroblastemia is neither specific nor essential in this disorder and that the term erythroblastic anemia was

nothing but a diagnostic catchall. Although Cooley was aware of the genetic nature of the disorder, he failed to

investigate the apparently healthy parents of the affected children.

In Europe, Riette described Italian children with unexplained mild hypochromic and microcytic anemia in the

same year Cooley reported the severe form of anemia later named after him. In addition, Wintrobe and

coworkers in the United States reported a mild anemia in both parents of a child with Cooley anemia. This

anemia was similar to the one that Riette described in Italy. Only then was Cooley's severe anemia recognized

as the homozygous form of the mild hypochromic and microcytic anemia that Riette and Wintrobe described.

This severe form was then labeled as thalassemia major and the mild form as thalassemia minor. The word

thalassemia is a Greek term derived from thalassa, which means "the sea" (referring to the Mediterranean),

and emia, which means "related to blood."

These initial patients are now recognized to have been afflicted with β thalassemia. In the following few years,

different types of thalassemia that involved polypeptide chains other than β chains were recognized and

described in detail.

In recent years, the molecular biology and genetics of the thalassemia syndromes have been described in

detail, revealing the wide range of mutations encountered in each type of thalassemia, depicted in the image

below.

Various mutations in the beta gene that result in beta thalassemia.

β thalassemia alone can arise from any of more than 150 mutations.

Pathophysiology

The thalassemias are inherited disorders of Hb synthesis that result from an alteration in the rate of globin

chain production. A decrease in the rate of production of a certain globin chain or chains (α, β, γ, δ) impedes

Hb synthesis and creates an imbalance with the other, normally produced globin chains.

Because 2 types of chains (α and non-α) pair with each other at a ratio close to 1:1 to form normal Hbs, an

excess of the normally produced type is present and accumulates in the cell as an unstable product, leading to

the destruction of the cell. This imbalance is the hallmark of all forms of thalassemia. For this reason, most

thalassemias are not considered hemoglobinopathies because the globin chains are normal in structure and

because the defect is limited to a decreased rate of production of these normal chains. However, thalassemic

hemoglobinopathies are recognized, as discussed below.

The type of thalassemia usually carries the name of the underproduced chain or chains. The reduction varies

from a slight decrease to a complete absence of production. For example, when β chains are produced at a

lower rate, the thalassemia is termed β+, whereas β-0 thalassemia indicates a complete absence of production

of β chains from the involved allele.

The consequences of impaired production of globin chains ultimately result in the deposition of less Hb into

each RBC, leading to hypochromasia. The Hb deficiency causes RBCs to be smaller, leading to the classic

hypochromic and microcytic picture of thalassemia. This is true in almost all anemias caused by impairment in

production of either of the 2 main components of Hb: heme or globin. However, this does not occur in the silent

carrier state, since both Hb level and RBC indices remain normal.

In the most common type of β thalassemia trait, the level of Hb A2 (δ2/α2) is usually elevated. This is due to the

increased use of δ chains by the excessive free α chains, which results from a lack of adequate β chains with

which to pair. The δ gene, unlike β and α genes, is known to have a physiologic limitation in its ability to

produce adequate δ chains; by pairing with the α chains, δ chains produce Hb A2 (approximately 2.5-3% of the

total Hb).

Some, but not all, of the excessive α chains are used to form Hb A2 with the δ chains, whereas the remaining α

chains precipitate in the cells, reacting with cell membranes, intervening with normal cell division, and acting as

foreign bodies, leading to destruction of RBCs. The degree of toxicity caused by the excessive chains varies

according to the type of such chains (eg, the toxicity of α chains in β thalassemia is more prominent than the

toxicity of β chains in α thalassemia).

β thalassemia is mostly related to a point mutation in the β globin gene. However, large deletions that may

involve the entire β gene, or even extend to delete the neighboring δ gene, have been previously reported.

Four new such mutations were identified in French patients. In 3 of these mutations, the deletion has extended

to involve the δ gene, resulting in failure to produce any Hb A2. In such cases, the β/δ thalassemia is to be

differentiated from the phenotypically similar condition known as hereditary persistence of fetal hemoglobin

(HPFH). The importance of differentiating the conditions is reflected in prenatal and newborn screening for

hemoglobinopathy.1

In the severe forms, such as β thalassemia major or Cooley anemia, the same pathophysiology applies with

substantial exaggeration. The significant excess of free α chains caused by the deficiency of β chains causes

destruction of the RBC precursors in the bone marrow (ie, ineffective erythropoiesis).

Globin chain production

To understand the genetic changes that result in thalassemia, one should be familiar with the physiologic

process of globin chain production in the healthy individual. The globin chain as a unit is a major building block

for Hb: together with heme, it produces the Hb molecule (heme plus globin equals Hb). Two different pairs of

globin chains form a tetrameric structure with a heme moiety in the center. All normal Hbs are formed from 2 α-

like chains and 2 non-α chains. Various types of Hb are formed, depending on the types of chains pairing

together. Such Hbs exhibit different oxygen-binding characteristics, normally related to the oxygen delivery

requirement at different developmental stages in human life.

In embryonic life, ζ chains (α-like chains) combine with γ chains to produce Hb Portland (ζ2/γ2) and with ε

chains to produce Hb Gower-1 (ζ2/ε2).

Subsequently, when α chains are produced, they form Hb Gower-2, pairing with ε chains (α2/ε2). Fetal Hb is

composed of α2/γ2 and the primary adult Hb (Hb A) of α2/β2. A third physiologic Hb, known as Hb A2, is

formed by α2/δ2 chains, as in the image below.

Alpha chain genes in duplication on chromosome 16 pairing with non-alpha chains to

produce various normal hemoglobins.

Genetic changes

All the genes that control the production of globin chains lie within 1 of 2 clusters located on 2 different

chromosomes. Chromosome 11 is the site of 5 functional b-like globin genes arranged in a link cluster over 60

kilobases (kb). From left to right (5'-3'), they are ε/γ-G/γ-A/δ/β. γ-G and γ-A differ by only one amino acid

(alanine vs glycine).

A critical control region of the d-globin gene (promoter) is known to be defective; it inhibits messenger RNA

(mRNA) processing, resulting in only a small amount of Hb A2 (α2/δ2) production, which thus accounts for less

than 3% of total Hb in adult RBCs.

The α-like globin gene cluster is located on chromosome 16 and consists of 3 functional genes. From left to

right (5'-3'), the genes are α/α2/α1.

Understanding the structure of the globin genes, how they are regulated to produce globin chains, and how the

chains pair together to produce the various Hbs is critical for appreciating the different pathologic changes of

this process that result in thalassemia.

Molecular biology

Each globin gene consists of a string of nucleotide bases divided into 3 coding sequences, termed exons, and

2 noncoding regions, known as introns or intervening sequences (IVS). See the image below.

Alpha and beta globin genes (chromosomes 16 and 11, respectively).

Three other regions, known as regulatory regions, are also present in the 5' noncoding or flanking region of

each globin gene.

The first is the promoter, which plays a major role in the transcription of the structural genes. The second

region is the enhancer, which has an important role in promoting erythroid-specific gene expression, as well as

in coordinating the changes in globin gene activity at different stages of development (embryonal, fetal, adult).

Enhancers can influence gene expression, despite being located some distance away from the gene itself, and,

unlike the promoter, they can stimulate transcription irrespective of their orientation relative to the transcription

start site. Finally, master regulatory sequences, known as locus control regions (in the β-globin gene family)

and HS40 (in the α gene complex), are responsible for activating the genes in erythroid cells.

Each of these regulatory sequences has a modular structure that consists of short nucleotide motifs that act as

binding sites for transcriptional activator or suppressor molecules. Such molecules activate or suppress gene

expression in different cell types at different stages of development. A certain gene is transcribed by an

initiation complex formed of certain proteins and a number of transcription factors, which interact with binding

sites on the promoters and other regulatory sequences of the relevant genes.

When a gene is transcribed, mRNA is synthesized from one of the gene's DNA strands by the action of RNA

polymerase. The initial product is a large mRNA precursor. Both exons and introns are initially present on this

mRNA precursor; the introns are ultimately subsequently eliminated, and the exons are spliced together in the

nucleus. At this stage, the mRNA, which has also been modified at both 5' and 3' ends, moves to the cytoplasm

to act as a template for the production of globin chains.

Carrier molecules (transfer RNA [tRNA]) transport amino acids to the mRNA template. Each amino acid has a

specific tRNA, which also contains 3 bases (anticodon), complimentary to the mRNA codons for that amino

acid. The position of each amino acid in the globin chain is thus established by its corresponding triplet code

(codon) in the globin gene. The cytidine, uridine, and guanosine (CUG) codon, for example, encodes the amino

acid leucine, while the adenosine, adenosine, and adenosine (AAA) codon encodes lysine. When a tRNA

molecule carries the initial amino acid to the template, directed by codon-anticodon base pairing, globin chain

synthesis begins.

Once the first tRNA is in place, a complex is formed between several protein initiation factors and the subunit of

the ribosome that is to hold the growing peptide chains together on the mRNA as it is translated. A second

tRNA moves in alongside, and a new amino acid is bound to the first with a peptide bond, resulting in a peptide

chain 2 amino acids long. This process continues from left to right until a specific codon for termination is

reached. At this point, the completed peptide chain drops off the ribosome-mRNA complex and the ribosomal

subunits are recycled. The globin chain is now ready to join a heme molecule and 3 other globin chains to form

an Hb molecule.

The developmental switches from embryonic to fetal and then to adult Hb production are synchronized

throughout the different organs of hematopoiesis (yolk sack, liver, bone marrow), which function at various

stages of development. Even though the mechanism of such switches is not clearly understood, the globin

gene promoter is known to contain information that specifies developmental stages of transcription.

Molecular pathology

To date, more than 1000 inherited mutations that affect either the structure or synthesis of the α- and β-globin

chains are known. Mutations that result in β or α thalassemia are similar in principle but different in their

patterns. Presently, more than 200 molecular defects known to downregulate the expression of β globin have

been characterized. Such defects result in various types of β thalassemia.

Major deletions in β thalassemia are unusual (in contrast to α thalassemia), and most of the encountered

mutations are single base changes, small deletions, or insertions of 1-2 bases at a critical site along the gene,

as in the image below.

Various mutations in the beta gene that result in beta thalassemia.

These mutations occur in both exons and introns. For example, in a nonsense mutation, a single base change

in the exon generates a stop codon in the coding region of the mRNA, resulting in premature termination of

globin chain synthesis. This termination leads to the production of short, nonviable β chains.

Conversely, in the frame shift mutation, one or more bases on the exon are lost or inserted, resulting in a

change in the reading frame of the genetic code or the production of a new stop codon.

RNA-splicing mutations are fairly common and represent a large portion of all mutations that result in β

thalassemia. These mutations corrupt the splicing process. The importance of precise splicing in the

quantitative production of stable functional mRNA cannot be overemphasized.

Slippage by even one nucleotide changes the reading frame of the mRNA. Both ends of the RNA introns (at the

junction with the exons) have specific consensus sequences; these motifs include GT in the 5' (left end or

donor site) consensus sequence and AG in the 3' (right end or acceptor site) consensus sequence. Such

sequences are obligatory for correct splicing, and a single substitution at the invariant GT or AG sequence

prevents splicing altogether and results in β-0 or α-0 thalassemia. Mutations in the other members of the

consensus sequences, although still highly conserved, result in variable degrees of ineffective β-globin

production, causing milder types of β thalassemia.

Mutations in exon sequences may activate a cryptic splice site. For example, in exon 1 of the β-globin gene, a

consensus sequence that resembles a sequence in IVS-1 has been identified as the site for several distinct

mutations, resulting in a gene that carries the features of both thalassemia and hemoglobinopathy

simultaneously (quantitatively and qualitatively abnormal Hb production). This type of mutation represents a

clear link between the thalassemias and the hemoglobinopathies, and, accordingly, these are labeled

thalassemic hemoglobinopathies.

Thus, mutations at codon 19 (A to G), 26 (G to A), and 27 (G to T)—all in exon 1—result in reduced production

of mRNA (thalassemia) because of inefficient splicing and an amino acid substitution encoded by the mRNA

that is spliced and translated (albeit inefficiently) into protein. The resulting abnormal Hbs are Malay, E, and

Knossos, respectively.

The flanking regions of the β-globin gene are also sites for various mutations. A single base substitution that

involves the promoter element, for example, can downregulate β-globin gene transcription, resulting in a mild

form of β thalassemia. Conversely, a mutation that affects the 3' end of the β-globin mRNA can interfere with its

processing, resulting in a severe form of β thalassemia.

Clearly, many different β thalassemia mutations exist, and compound heterozygosity is frequently encountered.

The resulting laboratory findings may lead to confusion. An example is the patient who manifests symptoms

of β thalassemia major without an elevated Hb A2 level. The explanation for such a situation is often co-

inheritance of β and δ thalassemia. δ/β thalassemia further is divided into δ/β+ or δ/β-0.

In the first type, a misalignment in the δ/β genes during meiosis results in the production of fused δ/β genes, a

process responsible for the production of an Hb variant termed Hb Lepore.

The fused δ/β gene is under the control of a δ-globin gene promoter region (the β gene promoter is deleted in

the process). Because the δ gene promoter carries mutations that lead to ineffective transcription, the fused δ/β

chains are produced in limited amounts, resulting in thalassemia. This is in addition to the hemoglobinopathy.

Conversely, in d/β-0 thalassemia, a large deletion occurs in the β-globin gene cluster, removing both the δ and

the β genes, which can also extend to involve all globin genes on chromosome 11, thus producing ε, γ, δ, and

β-0 thalassemia.

Cellular pathophysiology

The basic defect in all types of thalassemia is imbalanced globin chain synthesis. However, the consequences

of accumulation of the excessive globin chains in the various types of thalassemia are different. In β

thalassemia, excessive α chains, unable to form Hb tetramers, precipitate in the RBC precursors and, in one

way or another, produce most of the manifestations encountered in all of the β thalassemia syndromes; this is

not the situation in α thalassemia.

The excessive chains in α thalassemia are γ chains earlier in life and β chains later in life. Because such chains

are relatively soluble, they are able to form homotetramers that, although relatively unstable, nevertheless

remain viable and able to produce soluble Hb molecules such as Hb Bart (4 γ chains) and Hb H (4 β chains).

These basic differences in the 2 main types of thalassemia are responsible for the major differences in their

clinical manifestations and severity.

α chains that accumulate in the RBC precursors are insoluble, precipitate in the cell, interact with the

membrane (causing significant damage), and interfere with cell division. This leads to excessive intramedullary

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

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

ineffective erythropoiesis cause anemia in the person with β thalassemia.

The ability of some RBCs to maintain the production of γ chains, which are capable of pairing with some of the

excessive α chains to produce Hb F, is advantageous. Binding some of the excess a chains undoubtedly

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

Furthermore, increased production of Hb F, in response to severe anemia, adds another mechanism to protect

the RBCs in persons with β thalassemia. The elevated Hb F level increases oxygen affinity, leading to hypoxia,

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

expansion of the ineffective erythroid mass leads to severe bone expansion and deformities. Both iron

absorption and metabolic rate increase, adding more symptoms to the clinical and laboratory manifestations of

the disease. The large numbers of abnormal RBCs processed by the spleen, together with its hematopoietic

response to the anemia if untreated, results in massive splenomegaly, leading to manifestations of

hypersplenism.

If the chronic anemia in these patients is corrected with regular blood transfusions, the severe expansion of the

ineffective marrow is reversed. Adding a second source of iron would theoretically result in more harm to the

patient. However, this is not the case because iron absorption is regulated by 2 major factors: ineffective

erythropoiesis and iron status in the patient.

Ineffective erythropoiesis results in increased absorption of iron because of downregulation of the HAMP gene,

which produces a liver hormone called hepcidin. Hepcidin regulates dietary iron absorption, plasma iron

concentration, and tissue iron distribution and is the major regulator of iron. It acts by causing degradation of its

receptor, the cellular iron exporter ferroportin. When ferroportin is degraded, it decreases iron flow into the

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

severe hepcidin deficiency, iron absorption is increased and macrophages are usually iron depleted, such as is

observed in patients with thalassemia intermedia.

Malfunctions of the hepcidin-ferroportin axis contribute to the etiology of different anemias, such as is seen in

thalassemia, anemia of inflammation, and chronic renal diseases. Improvement and availability of hepcidin

assays facilitates diagnosis of such conditions. The development of hepcidin agonists and antagonists may

enhance the treatment of such anemias.2

By administering blood transfusions, the ineffective erythropoiesis is reversed, and the hepcidin level is

increased; thus, iron absorption is decreased and macrophages retain iron.

Iron status is another important factor that influences iron absorption. In patients with iron overload (eg,

hemochromatosis), the iron absorption decreases because of an increased hepcidin level. However, this is not

the case in patients with severe β thalassemia because a putative plasma factor overrides such mechanisms

and prevents the production of hepcidin. Thus, iron absorption continues despite the iron overload status.

As mentioned above, the effect of hepcidin on iron recycling is carried through its receptor "ferroportin," which

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

Ferroportin is upregulated by iron stores and downregulated by hepcidin. This relationship may also explain

why patients with β thalassemia who have similar iron loads have different ferritin levels based on whether or

not they receive regular blood transfusions.

For example, patients with β thalassemia intermedia who are not receiving blood transfusions have lower

ferritin levels than those with β thalassemia major who are receiving regular transfusion regimens, despite a

similar iron overload. In the latter group, hepcidin allows recycling of the iron from the macrophages, releasing

high amounts of ferritin. In patients with β thalassemia intermedia, in whom the macrophages are depleted

despite iron overload, lower amounts of ferritin are released, resulting in a lower ferritin level.

Most nonheme iron in healthy individuals is bound tightly to its carrier protein, transferrin. In iron overload

conditions, such as severe thalassemia, the transferrin becomes saturated, and free iron is found in the

plasma. This iron is harmful since it provides the material for the production of hydroxyl radicals and

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

significant damage to these organs.

By understanding the etiology of the symptoms in thalassemia, one can appreciate that certain modifiers may

result in the development of milder types of thalassemia. Factors that may reduce the degree of globin chain

imbalance are expected to modify the severity of the symptoms; co-inheritance of α thalassemia, the presence

of higher Hb F level, or the presence of a milder thalassemia mutation all typically ameliorate the symptoms of

thalassemia.

Malaria hypothesis

In 1949, Haldane suggested a selective advantage for survival in individuals with the thalassemia trait in

regions where malaria is endemic. He argued that lethal RBC disorders such as thalassemia, sickle cell

disease, and G-6-PD deficiency are present almost exclusively in tropical and subtropical regions of the world.

The incidence of these genetic mutations in a certain population thus reflects the balance between the

premature death of homozygotes and the increased fitness of heterozygotes.

For instance, in β thalassemia, the frequency of the gene is greater than 1% in the Mediterranean Basin, India,

Southeast Asia, North Africa, and Indonesia; it is very uncommon in other parts of the world. α thalassemia

may be the most common single gene disorder in the world (5-10% in the Mediterranean, 20-30% in West

Africa, approximately 68% in the South Pacific); however, the gene prevalence in Northern Europe and Japan

is less than 1%.

The mechanism of protection against malaria is not clear. Hb F in cells has been demonstrated to retard the

growth of the malaria parasite, and, by virtue of its high level in infants with β thalassemia trait, the fatal

cerebral malaria known to kill infants in these areas may be prevented. The RBCs of patients with Hb H

disease have also shown a suppressive effect on the growth of the parasites. This effect is not observed in α

thalassemia trait.

Classification of thalassemia

A large number of thalassemic syndromes are currently known; each involves decreased production of one

globin chain or more, which form the different Hbs normally found in RBCs. The most important types in clinical

practice are those that affect either α or β chain synthesis.

α thalassemia

Several forms of α thalassemia are known in clinical practice. The most common forms are as follows:

Silent carrier α thalassemia o This is a fairly common type of subclinical thalassemia, usually found by chance among

various ethnic populations, particularly African American, while the child is being evaluated for

some other condition. As pointed out above, 2 α genes are located on each chromosome 16,

giving α thalassemia the unique feature of gene duplication, see the image below. This

duplication is in contrast to only one β-globin gene on chromosome 11.o

Alpha and beta globin genes (chromosomes 16 and 11, respectively).

In the silent

carrier state, one of the α genes is usually absent, leaving only 3 of 4 genes (aa/ao). Patients

are hematologically healthy, except for occasional low RBC indices.

o In this form, the diagnosis cannot be confirmed based on Hb electrophoresis results, which

are usually normal in all α thalassemia traits. More sophisticated tests are necessary to

confirm the diagnosis. One may look for hematologic abnormalities in family members (eg,

parents) to support the diagnosis. A CBC count in one parent that demonstrates hypochromia

and microcytosis in the absence of any explanation is frequently adequate evidence for the

presence of thalassemia.

α thalassemia trait: This trait is characterized by mild anemia and low RBC indices. This condition is

typically caused by the deletion of 2 α (a) genes on one chromosome 16 (aa/oo) or one from each

chromosome (ao/ao). This condition is encountered mainly in Southeast Asia, the Indian subcontinent,

and some parts of the Middle East. The ao/ao form is much more common in black populations

because the doubly deleted (oo) form of chromosome 16 is rare in this ethnic group.

Hb H disease: This condition, which results from the deletion or inactivation of 3 α globin genes

(oo/ao), represents α thalassemia intermedia, with mildly to moderately severe anemia, splenomegaly,

icterus, and abnormal RBC indices. When peripheral blood films stained with supravital stain or

reticulocyte preparations are examined, unique inclusions in the RBCs are usually observed. These

inclusions represent b chain tetramers (Hb H), which are unstable and precipitate in the RBC, giving it

the appearance of a golf ball. These inclusions are termed Heinz bodies, depicted below.

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

appearance).

α thalassemia major:

This condition is the result of complete deletion of the a gene cluster on both copies of chromosome

16 (oo/oo), leading to the severe form of homozygous α thalassemia, which is usually incompatible

with life and results in hydrops fetalis unless intrauterine blood transfusion is given.

β thalassemia

Similar to α thalassemia, several clinical forms of β thalassemia are recognized; some of the more common

forms are as follows:

Silent carrier β thalassemia: Similar to patients who silently carry α thalassemia, these patients have

no symptoms, except for possible low RBC indices. The mutation that causes the thalassemia is very

mild and represents a β+ thalassemia.

β thalassemia trait: Patients have mild anemia, abnormal RBC indices, and abnormal Hb

electrophoresis results with elevated levels of Hb A2, Hb F, or both. Peripheral blood film examination

usually reveals marked hypochromia and microcytosis (without the anisocytosis usually encountered in

iron deficiency anemia), target cells, and faint basophilic stippling, as depicted below. The production

of β chains from the abnormal allele varies from complete absence to variable degrees of deficiency.

Peripheral blood film in thalassemia minor.

Thalassemia intermedia:

This condition is usually due to a compound heterozygous state, resulting in anemia of intermediate

severity, which typically does not require regular blood transfusions.

β thalassemia associated with β chain structural variants: The most significant condition in this group

of thalassemic syndromes is the Hb E/β thalassemia, which may vary in its clinical severity from as

mild as thalassemia intermedia to as severe as β thalassemia major.

Thalassemia major (Cooley anemia): This condition is characterized by transfusion-dependent anemia,

massive splenomegaly, bone deformities, growth retardation, and peculiar facies in untreated

individuals, 80% of whom die within the first 5 years of life from complications of anemia. Examination

of a peripheral blood preparation in such patients reveals severe hypochromia and microcytosis,

marked anisocytosis, fragmented RBCs, hypochromic macrocytes, polychromasia, nucleated RBCs,

and, on occasion, immature leukocytes, as shown below.

Peripheral blood film in Cooley anemia.

Frequency

United States

Because of immigration to the United States from all parts of the world and the intermarriages that have taken

place over the years, all types of thalassemia occur in any given part of the country. However, until recently, the

number of patients with severe forms of both β and α thalassemia has been very limited. For this reason,

finding more than 2-5 patients with the very severe forms in any pediatric hematology center is unusual (except

for in the few referral centers in the United States).

However, this situation is changing rapidly in certain parts of the country. In the last 10 years, Asian

immigration has been steadily increasing. According to the Federal Census Bureau, in 1990, 6.9 million Asians

were in the United States, twice that reported in the 1980 Census count. The prevalence of various thalassemia

syndromes in this population is very high. β and α thalassemia, as well as Hb E/β thalassemia, are currently on

the rise in the state of California as a result of the large concentration of Asian immigrants in that part of the

country.

The interaction between Hb E (a β chain variant) and β thalassemia (both very common among Southeast

Asians) has created the Hb E/β thalassemia entity, which is now believed to be the most common thalassemia

disorder in many regions of the world, including coastal North America, thus replacing β thalassemia major in

frequency. For this reason, the cord-blood screening program for detection of hemoglobinopathy in California

has been modified to include the detection of Hb H disease. In California alone, 10-14 new cases of β

thalassemia major and Hb E/β thalassemia and 40 cases of neonatal Hb H disease are detected annually.

International

Worldwide, 15 million people have clinically apparent thalassemic disorders. Reportedly, disorders worldwide,

and people who carry thalassemia in India alone number approximately 30 million. These facts confirm that

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

ethnic groups and in almost every country around the world.

Certain types of thalassemia are more common in specific parts of the world. β thalassemia is much more

common in Mediterranean countries such as Greece, Italy, and Spain. Many Mediterranean islands, including

Cyprus, Sardinia, and Malta, have a significantly high incidence of severe β thalassemia, constituting a major

public health problem. For instance, in Cyprus, 1 in 7 individuals carries the gene, which translates into 1 in 49

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

preventive measures established and enforced by public health authorities have been very effective in

decreasing the incidence among their populations. β thalassemia is also common in North Africa, the Middle

East, India, and Eastern Europe. Conversely, α thalassemia is more common in Southeast Asia, India, the

Middle East, and Africa.

Mortality/Morbidity

α thalassemia major is a mortal disease, and virtually all affected fetuses are born with hydrops fetalis as a

result of severe anemia. Several reports describe newborns with α thalassemia major who survived after

receiving intrauterine blood transfusions. Such patients require extensive medical care thereafter, including

regular blood transfusions and chelation therapy, similar to patients with β thalassemia major. Morbidity and

mortality remain high among such patients. In the rare reports of newborns with α thalassemia major born

without hydrops fetalis who survived without intrauterine transfusion, high level of Hb Portland, which is a

normally functioning embryonic Hb, is thought to be the cause for the unusual clinical course.

Patients with Hb H disease also require close monitoring. They may require frequent or only occasional blood

transfusions, depending on the severity of the condition. Some patients may require splenectomy. Morbidity is

usually related to the anemia, complications of blood transfusions, massive splenomegaly in some patients, or

the complications of splenectomy in others.

In patients with various types of β thalassemia, mortality and morbidity vary according to the severity of the

disease and the quality of care provided. Severe cases of β thalassemia major are fatal if not treated. Heart

failure due to severe anemia or iron overload is a common cause of death in affected persons. Liver disease,

fulminating infection, or other complications precipitated by the disease or by its treatment are some of the

causes of morbidity and mortality in the severe forms of thalassemia.

Morbidity and mortality are not limited to untreated persons; those receiving well-designed treatment regimens

also may be susceptible to the various complications of the disease. Organ damage due to iron overload,

chronic serious infections precipitated by blood transfusions, or complications of chelation therapy, such as

cataracts, deafness, or infections with unusual microorganisms (eg, Yersinia enterocolitica), are all considered

potential complications.

Race

Although thalassemia occurs in all races and ethnic groups, certain types of thalassemia are more common in

some ethnic groups than in others (see Frequency). β thalassemia is common in southern Europe, the Middle

East, India, and Africa. α thalassemia is more common in Southeast Asia; nevertheless, it is also seen in other

parts of the world. Furthermore, specific mutations of the same type of thalassemia are more common among

certain ethnic groups than others; this facilitates the screening and diagnostic processes because certain

probes for the more common mutations in a particular region are usually readily available.

The α thalassemia trait in Africa is usually not of the cis deletion on chromosome 16, unlike the condition in

Southeast Asia, which is associated with complete absence of the α gene on one chromosome. When both

parents have the cis deletion, the fetus may develop hydrops fetalis. For this reason, hydrops fetalis is not a

risk in the African population, although it remains a risk for Southeast Asian population.

Sex

Both sexes are equally affected with thalassemia.

Age

Despite thalassemia's inherited nature, age at onset of symptoms varies significantly. In α thalassemia, clinical

abnormalities in patients with severe cases and hematologic findings in carriers are evident at birth.

Unexplained hypochromia and microcytosis in a neonate, depicted below, are highly suggestive of the

diagnosis.

Peripheral blood film in hemoglobin H disease in a newborn.

However, in the severe forms of β thalassemia, symptoms may not be evident until the second half of the first

year of life; until that time, the production of γ -globin chains and their incorporation into fetal Hb can mask the

condition.

Milder forms of thalassemia are frequently discovered by chance and at various ages. Many patients with an

apparent homozygous β thalassemia condition (ie, hypochromasia, microcytosis, electrophoresis negative for

Hb A, evidence that both parents are affected) may show no significant symptoms or anemia for several years.

Almost all such patients' conditions are categorized as β thalassemia intermedia during the course of their

disease. This situation usually results when the patient has a milder form of the mutation, is a compound

heterozygote for β + and β -0 thalassemia, or has other compound heterozygosity.

Clinical

History

The history in patients with thalassemia widely varies, depending on the severity of the condition and the age at

the time of diagnosis.

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

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

pallor and slight icteric discoloration of the sclerae with splenomegaly, leading to slight enlargement of

the abdomen. An affected child's parents or caregivers may report these symptoms. However, some

rare types of β thalassemia trait are caused by a unique mutation, resulting in truncated or elongated β

chains, which combine abnormally with α chains, producing insoluble dimers or tetramers. The

outcome of such insoluble products is a severe hemolytic process that needs to be managed like

thalassemia intermedia or, in some cases, thalassemia major.

The diagnosis is usually suspected in children with an unexplained hypochromic and microcytic

picture, especially those who belong to one of the ethnic groups at risk. For this reason, physicians

should always inquire about the patient's ethnic background, family history of hematologic disorders,

and dietary history.

Thalassemia should be considered in any child with hypochromic microcytic anemia that does not

respond to iron supplementation.

In more severe forms, such as β thalassemia major, the symptoms vary from extremely debilitating in

patients who are not receiving transfusions to mild and almost asymptomatic in those receiving regular

transfusion regimens and closely monitored chelation therapy.

Children with β thalassemia major usually demonstrate none of the initial symptoms until the later part

of the first year of life (when β chains are needed to pair with α chains to form hemoglobin (Hb) A, after

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

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

Patients with Hb E/β thalassemia may present with severe symptoms and a clinical course identical to

that of patients with β thalassemia major. Alternatively, patients with Hb E/β thalassemia may run a

mild course similar to that of patients with thalassemia intermedia or minor. This difference in severity

has been described among siblings from the same parents. Some of the variation in severity can be

explained based on the different genotypes, such as the type of β thalassemia gene present (ie, β + or

β -0), the co-inheritance of an α thalassemia gene, the high level of Hb F, or the presence of a

modifying gene.

Patients with heterozygous or homozygous Hb E are usually slightly anemic, with hypochromasia and

microcytosis, and are usually asymptomatic.

If further studies are not performed, benign homozygous Hb E is usually misdiagnosed as Hb E/β

thalassemia, a condition that is frequently severe.

In α thalassemia, the hematologic abnormalities are clearly evident in newborns with mild or moderate

forms of the disease. Lethal clinical consequences and physical deformities encountered at the time of

birth are the rule in severe homozygous α thalassemia.

In β thalassemia, symptoms of anemia start when the γ chain production is switched off and the β

chains fail to form in adequate numbers.

Manifestations of anemia include extreme pallor and enlarged abdomen due to hepatosplenomegaly. o Patients' typical reports may lead a physician who is not familiar with the condition to a first

impression of acute leukemia.o This impression is supported by the large spleen, which leads to thrombocytopenia, and by

the high WBC count and immature WBCs seen on the peripheral blood film due to the

extreme activity of the marrow.

o To support the impression of acute leukemia further, the elevated level of reticulocytes

expected in all hemolytic anemias does not occur, despite the severe hemolysis; this anomaly

is due to the massive splenomegaly and the ineffective erythropoiesis that prevents the

release of the cells from the bone marrow. Evidence of hemolysis is usually present, with

elevated indirect bilirubin level, high lactate dehydrogenase (LDH) level, and low level of

haptoglobin.

Bony changes may be severe, resulting in a characteristic radiologic picture (see Imaging Studies and

the image below). These changes are caused by massive expansion of the bone due to the ineffective

erythroid production.

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

Cooley anemia.

The ineffective erythropoiesis

also creates a state of hypermetabolism associated with fever and failure to thrive.

Occasionally, gout due to hyperuricemia may be encountered.

Iron overload is one of the major causes of morbidity in all patients with severe forms of thalassemia,

regardless of whether they are regularly transfused. o In transfused patients, heavy iron turnover from transfused blood is usually the cause; in

nontransfused patients, this complication is usually deferred until puberty (if the patient

survives to that age).o Increased iron absorption is the cause in nontransfused patients, but the reason behind this

phenomenon is not clear. Many believe that, despite the iron overload state in these patients

and the increased iron deposits in the bone marrow, the requirement for iron to supply the

overwhelming production of ineffective erythrocytes is tremendous, causing significant

increases in GI absorption of iron.o Bleeding tendency, increased susceptibility to infection, and organ dysfunction are all

associated with iron overload.

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

controlled disease as well as those with uncontrolled disease.

Patients may develop symptoms that suggest diabetes, thyroid disorder, or other endocrinopathy;

these are rarely the presenting reports.

Physical

Patients with thalassemia minor rarely demonstrate any physical abnormalities. Because the anemia is never

severe and, in most instances, the Hb level is not less than 9-10 g/dL, pallor and splenomegaly are rarely

observed.

In patients with severe forms of thalassemia, the findings upon physical examination widely vary, depending on

how well the disease is controlled. Findings include the following:

Children who are not receiving transfusions have a physical appearance so characteristic that an

expert examiner can often make a spot diagnosis.

In Cooley's original 4 patients, the stigmata of severe untreated β thalassemia major included the

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

o Massive hepatosplenomegaly

o Severe growth retardation

o Bony deformities

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

develop is usually due to adverse effects of the treatment (transfusion or chelation).

Bony abnormalities, such as frontal bossing, prominent facial bones, and dental malocclusion, are

usually striking.

Severe pallor, slight to moderately severe jaundice, and marked hepatosplenomegaly are almost

always present.

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

heart failure. Growth retardation is a common finding, even in patients whose disease is well controlled by

chelation therapy. Patients with signs of iron overload may also demonstrate signs of endocrinopathy caused

by iron deposits. Diabetes and thyroid or adrenal disorders have been described in these patients. In patients

with severe anemia who are not receiving transfusion therapy, neuropathy or paralysis may result from

compression of the spine or peripheral nerves by large extramedullary hematopoietic masses.

Causes

Thalassemias are inherited disorders caused by various gene mutations. The clinical expression and severity

are subject to numerous factors that may either mask the condition or exaggerate the symptoms, leading to a

more severe disease.

Treatment

Medical Care

Patients with thalassemia traits do not require medical or follow-up care after the initial diagnosis is made. Iron

therapy should not be used unless a definite deficiency is confirmed and should be discontinued as soon as the

potential hemoglobin (Hb) level for that individual is reached. Counseling is indicated in all persons with genetic

disorders, especially when the family is at risk of a severe form of disease that may be prevented.

Patients with severe thalassemia require medical treatment, and a blood transfusion regimen was the first

measure effective in prolonging life. In the process of experimenting with blood transfusion, it was found to

provide patients with many benefits, including reversal of the complications of anemia, elimination of ineffective

erythropoiesis and its complications, allowance of normal or near-normal growth and development, and

extension of patients' life spans. Blood transfusion should be initiated at an early age when the child is

symptomatic and after an initial period of observation to assess whether the child can maintain an acceptable

level of Hb without transfusion.

After many years of monitoring transfused patients, the inadequacy of transfusion alone as a therapy became

clear. Accumulation of transfused iron and its consequences also needed to be addressed. Chelation therapy

was considered after extensive research and many clinical trials. Today, regular blood transfusion combined

with well-monitored chelation therapy has become the standard therapy and has drastically changed the

outlook for this population of patients.

Blood transfusions o Several blood transfusion regimens have been introduced. Of these, one seems practical,

less demanding, and more cost-effective than any of the others. This regimen attempts to

maintain a pretransfusion Hb level of 9-9.5 g/dL at all times.o Like all patients who require long-term regular blood transfusions, patients with thalassemia

require a pretransfusion workup. This workup should include RBC phenotype, hepatitis B

vaccination (if needed), and hepatitis workup. Iron and folate levels should also be measured.o Transfused blood should always be leukocyte poor; 10-15 mL/kg packed RBCs (PRBCs) at

the rate of 5 mL/kg/h every 3-5 weeks is usually adequate to maintain the pretransfusion Hb

level needed.o Consider administration of acetaminophen and diphenhydramine hydrochloride before each

transfusion to minimize febrile or allergic reactions.o Patients with documented transfusion reactions may benefit from having RBCs washed with

saline or from receiving deglycerolized RBCs.

Complications of blood transfusion: The major complications of blood transfusions are those related to

transmission of infectious agents or the development of iron overload. Patients with thalassemia major

are somewhat prone to develop infection more than normal children, regardless of the transfusion

status. Reports of suppressed cell- mediated immunity in such patients, as well as abnormal neutrophil

function, are available in the literature. A study showed that accelerated aging of T lymphocytes in

patients with β thalassemia could play a role in the suppressed cell-mediated immunity that may be

translated into increased incidence of infections.6 A second study has suggested an abnormality in the

results of the nitroblue tetrazolium (NBT) test conducted on the neutrophils from patients with

thalassemia compared with controls.7

Infectious agents o As recently as a few years ago, 25% of transfused patients were exposed to hepatitis B virus.

At present, both immunization and strict screening of potential donors have significantly

decreased the incidence. Hepatitis C virus (HCV) is the most common cause of hepatitis in

adolescents older than 15 years with thalassemia (risk of exposure was 6%). Because both

liver failure and hepatocellular carcinoma occur in 20% of adults with HCV, aggressive

combined treatment with pegylated interferon alfa (IFN-alfa) and ribavirin is warranted in

patients who contract HCV.8

o The incidence of transfusion-transmitted HCV is expected to drop significantly because of

stricter blood screening now mandated. Data from the Registry of the Thalassemia Clinical

Research Network (TCRN) demonstrated how successful the screening for HCV was in

reducing the incidence of HCV infection in such patients. The incidence was shown to be only

5% in children younger than 15 years compared to 75% in adults older than 25 years;

unfortunately, this is not true in developing countries.

o Infection with rare organisms that are not considered pathogenic in healthy hosts may cause

febrile illness and symptoms of enteritis in patients with iron overload, especially those

receiving chelation therapy with deferoxamine (DFO). The pathogen Y enterocolitica uses the

abundant iron scavenger molecules, known as siderophores, which the microorganism needs

but cannot synthesize. Fever without any apparent cause, especially when associated with

diarrhea, should be treated with gentamicin and trimethoprim-sulfamethoxazole, even when

culture results are negative.

Iron overload o Even though blood transfusion is supposed to decrease the excessive iron absorption in the

GI tracts of patients with thalassemia, patients nevertheless receive large amounts of iron with

each blood transfusion. Why patients with excessive iron absorb large amounts of iron from

the GI tract is not clear.o Many believe that the highly active marrow in these patients is iron deficient and needs large

amounts of iron to produce the massive numbers of RBCs usual in this disease. The iron

absorbed from the gut by the enterocyte, which coordinates iron uptake and transport into the

body with its release from the reticuloendothelial system, is bound to transferrin in the plasma.

The erythron claims most of the iron, while other tissues and cells that express transferrin

receptors pick most of the rest. Both iron and transferrin enter the cells by endocytosis,

forming the labile iron pool that provides iron to the cells and the iron-containing enzymes.o The major regulator of iron absorption and use is a protein produced in the liver called

hepcidin. It has a negative effect on iron absorption. Hepcidin production is stimulated in

several situations such as iron overload and inflammation. As a result, iron is not absorbed in

such conditions. On the other hand, when a patient has iron deficiency anemia, hepcidin level

is downregulated, so iron is absorbed.o In patients with thalassemia who experience iron overload, a high level of hepcidin is

expected to prevent iron absorption. However, this is not the case because such patients

absorb a significant amount of iron despite their known iron overload status. This action is

mediated by a marrow derived factor called growth differentiation factor 15 (GDF15), which

abrogates hepcidin-mediated protection against iron absorption in patients with iron

overloaded who have increased erythropoiesis, such as those with chronic hemolytic

anemias.9

o As iron accumulates and exceeds body needs, production of apoferritin is accelerated to

provide means for storing iron in nontoxic forms as ferritin or hemosiderin. Measuring the

ferritin level in the first few years after the diagnosis of thalassemia is usually helpful in

detecting iron overload status because ferritin correlates well with total body iron burden at

this time. Later on, the correlation becomes poor, since ferritin is produced by hepatocellular

damage and it acts as an acute-phase reactant. The ferritin level rises in individuals with

hepatitis, infections, and heart failure. When ferritin molecules accumulate further, the protein

moiety disintegrates, leaving small iron-concentrated hemosiderin particles; this alone is not

harmful, but it may cause release from lysosomes of hydrolytic enzymes that are toxic to the

cells.o In patients with iron overload, a unique situation develops as a result of the very high

saturation of the carrier protein transferrin, approximately 90% or more (reference range for

children and adults, 23-34%). A new iron pool, which is not present in healthy individuals, is

formed (the nontransferrin-bound or the free serum iron pool), which is probably an expansion

of the labile pool.

Tissue toxicity in iron overload

o Peroxidation of cell membrane components by iron in the free pool is probably the major

cause of organ damage from excessive iron. This effect was noted to worsen when ascorbic

acid was added and was corrected partially by either vitamin E or deferoxamine. Patients with

thalassemia with iron overload are typically deficient in vitamin E.o The route of iron access to the body and its relation to the development of hemosiderosis

have been controversial issues for some time. Many believe that absorption of iron from the

bowel is the major factor in the etiology of this condition. The parenchymal tissue damage in

the livers of patients with hereditary hemochromatosis and those with thalassemia intermedia

who are not receiving transfusions and the lower incidence of liver cirrhosis in heavily

transfused patients with aplastic anemia support their claims.o This interpretation should not create the wrong impression that transfusional iron is not

involved in the etiology of iron overload; on the contrary, every effort should be made to

minimize all iron intake from any source in patients at risk whenever possible.

Chelation therapy o Until recently, patients with thalassemia major who received only transfusion therapy could

not survive beyond adolescence, largely because of cardiac complications caused by iron

toxicity. The introduction of chelating agents capable of removing excessive iron from the

body has dramatically increased life expectancy.o When administered in conjunction with blood transfusion regimens, chelation can delay the

onset of cardiac disease and, in some patients, even prevent its occurrence.o Several chelating agents have been tested, and, although many failed, one particular agent

was proven effective and safe. DFO is a complex hydroxylamine with high affinity for iron; it

targets the labile pool, the nontransferrin-bound iron (free pool), and the ferritin generated

from reticuloendothelial iron.o Route of administration is critical in achieving the goal of therapy, which is reaching a negative

iron balance (ie, excreting more iron than acquired from both intestinal absorption and

transfusion). In the adult, reaching this goal involves removing 35 mg of iron per day.o Because the agent is not absorbed in the gut, it must be administered parenterally, whether

intramuscularly, intravenously, or subcutaneously. Because of its short half-life, subcutaneous

infusion must be prolonged if it is to achieve the stated goal.o A total dose of 30-40 mg/kg/d is infused over 8-12 hours during the child's sleep for 5 d/wk by

a mechanical pump.o If doses larger than those tolerated by the subcutaneous route are needed, the intravenous

route may be safely used, especially when a vascular access device is in place.o Doses as high as 6-10 g were administered intravenously in selected patients and proved

effective in reversing serious iron overload complications.o The optimal time to initiate chelation therapy is dictated by the amount of accumulated iron

and its accessibility for chelation. This usually occurs after 1-2 years of transfusions. Severe

toxicity may develop if chelation is started prematurely. A DFO challenge test is usually helpful

in deciding whether a patient is a candidate for chelation.o DFO toxicity concerns are as follows:

Local reaction at the site of injection is reported in many patients and can

occasionally be severe.

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

neurosensory complications of chelation therapy include color and night blindness

and visual field loss. These complications are frequently reversible and more

commonly occur when not enough iron is available for chelation, when aggressive

chelation therapy is administered, or when the chelation agent is administered in

continuous intravenous infusions in a dose greater than 50 mg/kg/d. For this reason,

eye and hearing examinations are to be scheduled every 6-12 months in patients

receiving chelation therapy.

Pulmonary infiltrates as a complication have been reported in only a few patients.

For several reasons and despite all the advantages of DFO, chelation with this agent

has been inadequate. In countries where it is needed the most, the high cost of the

drug and the supplies needed for its administration make it unavailable for most

patients. DFO has been prescribed for only 25,000 of 72,000 patients with

thalassemia major receiving blood transfusion worldwide. In the Western world, on

the other hand, despite the wide availability of the agent, some patients do not

comply because of the unpleasant and cumbersome nature of the regimen. Others

who cannot tolerate the drug have to modify the dose or the route or stop use all

together.

One report showed that 105 of 328 patients in North America had to modify their

regimen, and 20 patients had to stop taking the agent. For such reasons, the search

for more practical chelators (especially the targeted chelators that can more

effectively remove iron from specific organs [eg, heart, liver]) has continued to be a

major task for the last few decades.o Oral chelating agents have been in use in other countries for some time, and newer ones are

showing efficacy and some specificity for removing iron more efficiently from certain organs

than DFO.o Deferasirox (Exjade) is a relatively new oral chelating agent with a long half-life, for this

reason it is administered orally once daily. Several studies in the last few years have shown

that this agent is as effective as its predecessor, deferoxamine, in reducing ferritin level and

tissue iron accumulation. One study with 3.5 years median follow-up has confirmed the

efficacy and safety of this agent. A dose of 30 mg/kg/d has resulted in negative iron balance in

most patients on chronic blood transfusion.10 Furthermore, several studies have proved the

safety and efficacy of this agent as a chelator in patients with thalassemia, sickle cell disease,

and myelodysplastic anemia.11 Oral medication taken only once a day may significantly

improve compliance.o Deferasirox toxicity concerns include the following:

Skin rash

Hepatic dysfunction

Postmarketing surveillance reports of acute renal failure

Cytopenia (eg, agranulocytosis, neutropenia, thrombocytopenia)

Auditory disturbances

Ocular disturbances

Hypersensitivity reactions

Gastric ulceration (rare)12

o The previously known oral chelating agent deferiprone (Ferriprox, DFP), which failed when

administered alone, is now showing superiority in reducing cardiac iron concentration. DFP is

co-administered with DFO or is administered sequentially with DFO. The additive and

synergistic effects contribute to significant removal of iron from different organs at risk for

siderosis, such as the liver and heart. DFP is currently designated as an orphan drug in the

United States.o Initially, DFP provided some promising results. However, after a few years of observation and

monitoring, the agent was found to be less effective than DFO in preventing organ damage. In

addition, some adverse effects such as neutropenia or even agranulocytosis were reported in

as many as 8% of patients.o More recently, DFP was demonstrated to have efficacy comparable to that of DFO, with

minimal adverse effects and better compliance, leading some investigators to reconsider the

use of DFP. The drug is now in use in more than 50 countries. Significant improvement based

on cardiac MRI findings, indicating a reduction in cardiac iron overload and improved cardiac

function, was reported in some studies as a result of DFP therapy. This observation suggests

a cardioprotective role of DFP. This observation was recently confirmed by more than one

study.o Finally, combinations of 2 iron chelators (parenteral DFO plus the oral chelator) have been

demonstrated to produce additive and synergistic effects. Such an approach would enable a

flexible schedule and improve compliance and overall quality of life.o Patients receiving chelation therapy have been demonstrated to have some degree of vitamin

C deficiency. This deficiency has been attributed, in part, to increased catabolism.

Administration of vitamin C increases the urinary excretion of iron and raises both serum iron

and ferritin levels; this is probably related to the fact that vitamin C slows down the conversion

of ferritin to hemosiderin, leading to the availability of more chelatable iron. Conversely,

vitamin C enhances iron-mediated peroxidation of membrane lipids, leading to significant

toxicity, mostly cardiac dysfunction in patients who are receiving large doses of vitamin C

supplementation in addition to chelation therapy. For this reason, only small doses should be

administered to enhance chelation (3 mg/kg/d at the start of infusion of the chelator). Large

doses should be avoided.

Vitamin E deficiency: Vitamin E deficiency has been reported in patients with severe thalassemia.

Some of the hemolysis in this population was attributed to peroxidation of the RBC membrane lipids by

an iron-mediated free radical effect. As an antioxidant, vitamin E is expected to decrease cell toxicity.

Folic acid deficiency: This deficiency is a common complication in patients with thalassemia, mainly

because of the extreme demand associated with the severe expansion of the marrow. Other causes,

such as poor absorption and intake, can also contribute to folate deficiency. For this reason, folic acid

(1 mg/d) has been recommended as a supplement for this patient population.

Hematopoietic stem cell transplantation (HSCT) o HSCT is recommended only for selected patients; it is the only known curative treatment for

thalassemia. Poor outcome after HSCT correlates with the presence of hepatomegaly and

portal fibrosis and with ineffective chelation prior to transplant. The event-free survival rate for

patients who have all 3 features is 59%, compared to 90% for those who lack all 3.o Platelet transfusion refractoriness has been an issue in patients undergoing HSCT, mainly

due to frequent blood transfusions. Human leukocyte antigen (HLA)-matched platelets were

reported to be effective in 74% of cases compared with only 26% with random donor

platelets.13

o When cyclosporine is used as immunosuppresive agent for graft versus host disease (GVHD)

in children with hemoglobinopathies, a high incidence of neurotoxicity preceded by prodromal

symptoms was reported.14

o Even though blood transfusion is not required after a successful transplant, certain individuals

need continued chelation therapy to remove excessive iron. The optimal time to start such

treatment is a year after the successful HSCT.o Parents and caregivers of patients with severe thalassemia are frequently confronted with a

choice between standard therapy and HSCT. The 15-year cardiac disease-free survival rate

for patients receiving standard therapy exceeds 90% and is similar for those without risk

factors who have undergone HSCT.

o Long-term outcome for transplant patients, including fertility, is not known. The cost of long-

term standard therapy is known to be higher than the cost of transplant. The possibility of

developing cancer after HSCT should also be considered. In many centers, the donor has to

be a matched sibling with or without a thalassemia trait.

Investigational agents known to increase Hb F level: This therapeutic strategy is investigational at this

time. Several agents administered to raise the Hb F level have been investigated in patients with

severe thalassemia. Unfortunately, the initial results of these studies are not promising. However, in

one study, hydroxyurea was given to 11 patients with transfusion-dependent Hg E/β thalassemia.15

Treatment was effective in 4 patients who became transfusion independent; 4 other patients required

less transfusions, and 3 patients did not respond.

Gene therapy: This therapy is an attractive therapeutic modality, the efficacy of which remains to be

demonstrated.

Surgical Care

Splenectomy is the principal surgical procedure used for many patients with thalassemia. The spleen is known

to contain a large amount of the labile nontoxic iron (ie, storage function) derived from sequestration of the

released iron. The spleen also increases RBC destruction and iron distribution (ie, scavenger function). These

facts should always be considered before the decision is made to proceed with splenectomy. In addition, with

recent reports of venous thromboembolic events (VTEs) after splenectomy, one should carefully consider the

benefits and the risks before splenectomy is advocated. The spleen acts as a store for nontoxic iron, thereby

protecting the rest of the body from this iron. Early removal of the spleen may be harmful (liver cirrhosis has

occurred in such individuals).

Conversely, splenectomy is justified when the spleen becomes hyperactive, leading to excessive destruction of

RBCs and thus increasing the need for frequent blood transfusions, resulting in more iron accumulation.

Furthermore, if the labile iron pool in the spleen becomes the target for the action of the DFO (ie, removing the

nonharmful pool and leaving the toxic one), splenectomy is further justified. The goal in this confusing dilemma

should always be to achieve a negative iron balance, which, in many patients, has been possible by continuous

administration of subcutaneous DFO.

Several criteria are used to aid in the decision for splenectomy; a practical one suggests that splenectomy may

be beneficial in patients who require more than 200-250 mL/kg of PRBC per year to maintain an Hb level of 10

g/dL.

The risks associated with splenectomy are minimal, and many of the procedures are now performed by

laparoscopy. Postsplenectomy risk of infections with encapsulated organisms and malaria in endemic areas is

always a concern. The problem is minimal at the present time, since presplenectomy immunizations and

postsurgical prophylactic antibiotics have significantly decreased the rates of such complications. Traditionally,

the procedure is delayed whenever possible until the child is aged 4-5 years or older. Aggressive treatment

with antibiotics should always be administered for any febrile illness while awaiting the results of cultures. Low-

dose daily aspirin is also beneficial when the platelet count rises to more than 600,000/µL postsplenectomy.

Another surgical procedure in patients with severe thalassemia on transfusion therapy is the placement of a

central line for the ease and convenience of administering blood transfusions, chelation therapy, or both.

Consultations

The following consultations may be indicated:

Pediatric surgeon

Pediatric endocrinologist

Pediatric ophthalmologist

Pediatric otolaryngologist

Pediatric gastroenterologist

Pediatric HSCT specialist

Diet

A normal diet is recommended, with emphasis on the following supplements: folic acid, small doses of ascorbic

acid (vitamin C), and alpha-tocopherol (vitamin E). Iron should not be given, and foods rich in iron should be

avoided. Drinking coffee or tea has been shown to help decrease absorption of iron in the gut.

In an animal study, green tea as antioxidant was shown to inhibit or delay the deposition of hepatic iron in

thalassemic mice.16 This prevented iron-induced free radical generation, which has been implicated in liver

damage and fibrosis.

Activity

Patients with well-controlled disease are usually fully active. Patients with anemia, heart failure, or massive

hepatosplenomegaly are usually restricted according to their tolerances.

Medication

Medications needed for the treatment of various types of thalassemias are nonspecific and only supportive. A

list of such medications is provided in this article.

Antipyretics, analgesics

Administration before blood transfusion prevents or decreases febrile reactions.

Acetaminophen (Tylenol, Tempra, Panadol)

Antipyretic effect through action on hypothalamic heat-regulating center. Action equal to that of aspirin but

preferred because does not have adverse effects of aspirin.

Dosing

Interactions

Contraindications

Precautions

Adult

325-650 mg/dose PO prior to blood transfusion

Pediatric

10-15 mg/kg/dose PO prior to blood transfusion

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Administration prior to blood transfusion may decrease or prevent allergic reactions.

Diphenhydramine hydrochloride (Benadryl)

Antihistamine with anticholinergic and sedative effects.

Dosing

Interactions

Contraindications

Precautions

Adult

25-50 mg PO/IV q6-8h prn; not to exceed 400 mg/d

Pediatric

1 mg/kg/dose PO/IV or 5 mg/kg/d PO/IV divided q6h

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These agents are used to chelate excessive iron from the body in patients with iron overload.

Deferoxamine mesylate (Desferal)

Chelates iron from ferritin or hemosiderin but not from transferrin, cytochrome, or Hb.

Dosing

Interactions

Contraindications

Precautions

Adult

20-40 mg/kg/d SC infusions through infusion pump over 8-12 h

After blood transfusion: 1-2 g IV at slow rate of 15 mg/kg/h

Pediatric

Administer as in adults

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Deferasirox (Exjade)

Tab for PO susp. PO iron chelation agent demonstrated to reduce liver iron concentration in adults and children

who receive repeated RBC transfusions. Binds iron with high affinity in a 2:1 ratio. Approved to treat chronic

iron overload due to multiple blood transfusions. Treatment initiation recommended with evidence of chronic

iron overload (ie, transfusion of about 100 mL/kg packed RBCs [about 20 U for patient weighing 40 kg] and

serum ferritin level consistently >1000 mcg/L).

Dosing

Interactions

Contraindications

Precautions

Adult

Initial: 20 mg/kg PO qd on empty stomach 30 min ac; calculate dose to nearest whole tablet

Maintenance: Adjust dose by 5- to 10-mg/kg/d increments q3-6mo according to serum ferritin level trends; not

to exceed 30 mg/kg/d

Note: Dissolve tab completely in water, orange juice, or apple juice, then immediately drink susp; resuspend

any remaining residue in small volume of liquid and swallow

Pediatric

<2 years: Not established

≥ 2 years: Administer as in adults

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Some patients may develop local reaction at the site of DFO injection. Hydrocortisone in the DFO solution may

help to reduce the reaction.

Hydrocortisone (Solu-Cortef, Cortef, Hydrocortone)

Anti-inflammatory action. Both Na succinate (Solu-Cortef) and Na phosphate (Cortef) forms used for IV

infusion, but not Na acetate form (Hydrocortone).

Dosing

Interactions

Contraindications

Precautions

Adult

10-20 mg IV/SC added to chelating solution

Pediatric

Administer as in adults

Dosin

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Certain antibacterial agents are known to be effective against organisms that often cause infection in patients

with iron overload who also are receiving DFO therapy. Although rare in healthy patients, Y enterocolitica

requires siderophores; thus, infections with this pathogen occur with relative frequency in patients with

thalassemia. Appropriate therapy is a combination of trimethoprim-sulfamethoxazole (TMP/SMX) and

gentamicin. Patients who require splenectomy need to receive prophylactic penicillin to prevent fulminating

sepsis, especially those younger than 5 years. Many recommend that older patients receive prophylactic

antibiotics for at least 3 years after splenectomy.

Trimethoprim-sulfamethoxazole (TMP/SMX, Bactrim, Septra)

In combination with gentamicin, DOC for infections by Y enterocolitica.

Dosing

Interactions

Contraindications

Precautions

Adult

160 mg TMP/800 mg SMZ PO q12h for 10-14 d

Pediatric

<2 months: Contraindicated

≥ 2 months: 8-10 mg/kg/d PO/IV divided q12h; dose usually based on TMP component

Dosin

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Gentamicin (Garamycin)

Aminoglycoside known to be effective against gram-negative microorganisms. Dosing regimens are numerous;

adjust dose based on CrCl and changes in volume of distribution.

Dosing

Interactions

Contraindications

Precautions

Adult

3-6 mg/kg/d IV divided q8h

Pediatric

6-7.5 mg/kg/d IV divided q8h

Dosin

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Penicillin V (Pen-Vee, Veetids, V-Cillin K)

DOC for postsplenectomy prophylaxis; erythromycin used in patients allergic to penicillin. Active against most

microorganisms considered to be major offenders in splenectomized patients, namely, streptococcal,

pneumococcal, and some staphylococcal microorganisms, but not penicillinase-producing species.

Dosing

Interactions

Contraindications

Precautions

Adult

250 mg PO bid

Pediatric

<5 years: 125 mg PO bid

≥ 5 years: Administer as in adults

Dosin

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Several vitamins are required, as either supplements or enhancers of the chelating agent.

Serum level of vitamin C is low in patients with thalassemia major, likely due to increased consumption in the

face of iron overload.

Ascorbic acid (Vitamin C, Cebid, Vita-C, Ce-Vi-Sol, Cecon, Dull-C)

Delays conversion of transferrin to hemosiderin, thus making iron more accessible to chelation.

Dosing

Interactions

Contraindications

Precautions

Adult

3 mg/kg/d PO administered with SC deferoxamine infusion

Pediatric

Administer as in adults

Dosin

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Alpha-tocopherol (Vitamin E, Aquasol E, Vita-Plus E Softgels, Vitec, E-Vitamin)

An antioxidant. Prevents iron-mediated toxicity caused by peroxidation of cell membrane lipids, reducing extent

of accompanying hemolysis. Protects polyunsaturated fatty acids in membranes from attack by free radicals

and protects RBCs against hemolysis. Demonstrated to be deficient in patients with iron overload receiving

chelation therapy.

Dosing

Interactions

Contraindications

Precautions

Adult

200-400 IU/d PO

Pediatric

1 IU/kg/d PO

Dosin

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Folic acid (Folvite)

Required for DNA synthesis; therefore in great demand in these patients because of increased cellular

turnover. Deficient in most patients with chronic hemolysis.

Dosing

Interactions

Contraindications

Precautions

Adult

0.4-1 mg/d PO

Pediatric

1 mg/d PO

Dosin

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Splenectomized patients are usually prone to developing infections with the encapsulated organisms such as

pneumococci, Haemophilus influenzae, and meningococcal organisms. For this reason, such patients now are

immunized against these organisms 1-2 wk prior to the procedure to prevent infections.

Pneumococcal vaccine polyvalent (Pneumovax)

Polyvalent polysaccharide vaccine (PS23) contains 23 serotypes that cause 70% of invasive infections. This

vaccine should not be given to children <2 y. In rare cases in which splenectomy is required in children <2 y

and no previous vaccination has been given, conjugate type (PCV7), which contains only 7 serotypes, is

required.

Dosing

Interactions

Contraindications

Precautions

Adult

0.5 mL IM/SC once

Pediatric

<2 years: Immunity may not be conferred; antibody response poor in this age group

≥ 2 years: 0.5 mL IM/SC as single dose 1-2 wk before splenectomy; repeat dose after 5 y for high-risk children

(eg, functional or anatomic asplenia, conditions associated with rapid antibody decline after initial vaccination)

Dosin

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Haemophilus b conjugate vaccine (ActHIB, HibTITER, PedvaxHIB)

Used for routine immunization of children against invasive diseases caused by H influenzae type b. Decreases

nasopharyngeal colonization. The CDC's Advisory Committee on Immunization Practices (ACIP) recommends

that all children receive one of the conjugate vaccines licensed for infant use beginning routinely at age 2 mo.

Conjugate form usually given in series of 3 doses at ages 2, 4, and 6 mo. Patients who have already received

primary vaccine and booster dose at age 12 mo or older are usually protected and do not require further

vaccination prior to splenectomy.

Dosing

Interactions

Contraindications

Precautions

Adult

Not indicated

Pediatric

Regimens vary depending on product; the use of HibTITER is the example that follows:

2-6 months: 0.5 mL IM q2mo for 3 doses

7-11 months: 0.5 mL IM q2mo for 2 doses if previously unvaccinated

12-14 months: 0.5 mL IM once if previously unvaccinated

Booster dose: All children receive 0.5 mL at age 15 mo or at least 2 mo after last dose of immunization series;

for children aged 15-71 mo and previously unvaccinated, 0.5 mL IM is given only once

Dosin

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Meningitis group A C Y and W-135 vaccine (Menomune-A/C/Y/W-135)

Used only in children >2 y. Serogroup specific against groups A, C, Y, and W-135 Neisseria meningitidis.

Dosing

Interactions

Contraindications

Precautions

Adult

Pediatric

<2 years: Contraindicated

≥ 2 years: 0.5 mL SC; consider revaccination after 2-3 y

Dosin

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Pneumococcal 7-valent conjugate vaccine (Prevnar)

Sterile solution of saccharides of capsular antigens of S pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and

23F individually conjugated to diphtheria CRM197 protein. These 7 serotypes have been responsible for >80%

of invasive pneumococcal disease in children <6 y in the United States. Also accounted for 74% of penicillin-

nonsusceptible S pneumoniae (PNSP) and 100% of pneumococci with high-level penicillin resistance.

Customary age for first dose is 2 mo but can be given to infants as young as 6 wk. Preferred sites of IM

injection are anterolateral aspect of the thigh in infants or deltoid muscle of upper arm in toddlers and young

children. Do not inject vaccine in gluteal area or areas that may contain a major nerve trunk or blood vessel. A

3-dose series, 0.5 mL each, is initiated in infants aged 7-11 mo (4 wk apart; third dose after first birthday).

Children aged 12-23 mo are given 2 doses (2 mo apart). Children >24 mo through 9 y are given 1 dose. Minor

illnesses, such as a mild upper respiratory tract infection, with or without low-grade fever, are not generally

considered contraindications.

Dosing

Interactions

Contraindications

Precautions

Adult

Not indicated

Pediatric

Series initiated at age 2 months: 0.5 mL IM x 3 doses at 4-8 wk intervals, followed by a fourth dose of 0.5 mL at

age 12-15 mo; administer fourth dose 2 mo or later following the third dose

Series initiated at age 7-11 months: 0.5 mL IM x 2 doses at 4 wk intervals, followed by third dose after 1-year

birthday, separate second and third dose by at least 2 mo

Series initiated at age 12-23 months: 0.5 mL IM x 2 doses administered 2 mo apart

Administration of pneumococcal polysaccharide-23 (PPV-23) and pneumoccal-7 (PCV-7) vaccines should

follow the schedule below for patients undergoing splenectomy at a young age.

Age 24-59 months and 4 PCV-7 doses were previously given:

PPV-23: 1 dose at 24 mo, 6-8 wk after last PCV-7; repeat 3-5 y later

Age 24-59 months and 1-3 PCV-7 doses were previously given:

Initiated at age 2-9 years: 0.5 mL IM once

PCV-7: 1 dose

PPV-23: 1 dose 6-8 wk after PCV-7; repeat 3-5 y later

Age 24-59 months and 1 PPV-23 was previously given:

PCV-7: 2 doses given 6-8 w apart

PPV-23: Repeat 3-5 y later

Age 24-59 months and no PPV-23 or PCV-7 previously given:

PCV-7: 2 doses given 6-8 w apart

PPV-23: 1 dose 6-8 wk after PCV-7; repeat 3-5 y later

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Some patients may respond to hydroxyurea and subsequently decrease or eliminate transfusion requirements.

Patients with homozygous or heterozygous XmnI polymorphism were found to respond favorably in one study.17

Improvement of pulmonary hypertension following hydroxyurea has also been observed.18

Hydroxyurea (Droxia, Hydrea)

Inhibitor of deoxynucleotide synthesis.

Dosing

Interactions

Contraindications

Precautions

Adult

15 mg/kg/d PO (range 10-20 mg/kg/d) initially; may increase by increments of 5 mg//kg/d q12wk; not to exceed

35 mg/kg/d

Pediatric

Administer as in adults

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3333333333333333

ThalassemiaFrom Wikipedia, the free encyclopedia

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Thalassemia

Classification and external resources

ICD-10 D 56.

ICD-9 282.4

MedlinePlus 000587

eMedicine ped/2229 radio/686

MeSH D013789

Thalassemia (also spelled thalassaemia) is an inherited autosomal recessive blood disease. In thalassemia the genetic defect, which could be either mutation or deletion, results in reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin. This can cause the formation of abnormal hemoglobin molecules, thus causing anemia, the characteristic presenting symptom of the thalassemias.

Thalassemia is a quantitative problem of too few globins synthesized, whereas sickle-cell anemia (a hemoglobinopathy) is a qualitative problem of synthesis of an incorrectly functioning globin. Thalassemias usually result in underproduction of normal globin proteins, often through mutations in regulatory genes. Hemoglobinopathies imply structural abnormalities in the globin proteins themselves.[1] The two conditions may overlap, however, since some conditions which cause abnormalities in globin proteins (hemoglobinopathy) also affect their production (thalassemia). Thus, some thalassemias are hemoglobinopathies, but most are not. Either or both of these conditions may cause anemia.

The two major forms of the disease, alpha- and beta- (see below), are prevalent in discrete geographical clusters around the world - probably associated with malarial endemicity in ancient times. Alpha is prevalent in peoples of Western African descent, and is nowadays found in populations living in Africa and in the Americas. Beta is particularly prevalent among Mediterranean peoples, and this geographical association was responsible for its naming: Thalassa (θάλασσα) is Greek for the sea, Haema (αἷμα) is Greek for blood. In Europe, the highest concentrations of the disease are found in Greece, coastal regions in Turkey, in particular, Aegean Region such as Izmir, Balikesir, Aydin, Mugla and Mediterranean Region such as Antalya, Adana, Mersin, in parts of Italy, in particular, Southern Italy and the lower Po valley. The major Mediterranean islands (except the Balearics) such as Sicily, Sardinia, Malta, Corsica, Cyprus and Crete are heavily affected in particular. Other Mediterranean people, as well as those in the vicinity of the Mediterranean, also have high rates of thalassemia, including people from the West Asia and North Africa. Far from the Mediterranean, South Asians are also affected, with the world's highest concentration of carriers (16% of the population) being in the Maldives.

The thalassemia trait may confer a degree of protection against malaria, which is or was prevalent in the regions where the trait is common, thus conferring a selective survival advantage on carriers (known as heterozygous advantage), and perpetuating the mutation. In that respect the

various thalassemias resemble another genetic disorder affecting hemoglobin, sickle-cell disease.[2]

Contents[hide]

1 Pathophysiology o 1.1 Alpha (α) thalassemias o 1.2 Beta (β) thalassemias o 1.3 Delta (δ) thalassemia o 1.4 In combination with other hemoglobinopathies

2 Cause 3 Treatment

o 3.1 Medication o 3.2 Carrier detection

4 Epidemiology 5 Benefits 6 References 7 External Links

Pathophysiology

Normal hemoglobin is composed of two chains each of α and β globin. Thalassemia patients produce a deficiency of either α or β globin, unlike sickle-cell disease which produces a specific mutant form of β globin.

The thalassemias are classified according to which chain of the hemoglobin molecule is affected. In α thalassemias, production of the α globin chain is affected, while in β thalassemia production of the β globin chain is affected.

β globin chains are encoded by a single gene on chromosome 11; α globin chains are encoded by two closely linked genes on chromosome 16. Thus in a normal person with two copies of each chromosome, there are two loci encoding the β chain, and four loci encoding the α chain. Deletion of one of the α loci has a high prevalence in people of African or Asian descent, making them more likely to develop α thalassemias. β thalassemias are common in Africans, but also in Greeks and Italians.

Alpha ( ) thalassemiasαMain article: Alpha-thalassemia

The α thalassemias involve the genes HBA1[3] and HBA2,[4] inherited in a Mendelian recessive fashion. There are two gene loci and so four alleles. It is also connected to the deletion of the 16p chromosome. α thalassemias result in decreased alpha-globin production, therefore fewer alpha-

globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. The excess β chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves.

Beta ( ) thalassemiasβMain article: Beta-thalassemia

Beta thalassemias are due to mutations in the HBB gene on chromosome 11 ,[5] also inherited in an autosomal-recessive fashion. The severity of the disease depends on the nature of the mutation. Mutations are characterized as (βo or β thalassemia major) if they prevent any formation of β chains (which is the most severe form of β thalassemia); they are characterized as (β+ or β thalassemia intermedia) if they allow some β chain formation to occur. In either case there is a relative excess of α chains, but these do not form tetramers: rather, they bind to the red blood cell membranes, producing membrane damage, and at high concentrations they form toxic aggregates.

Delta ( ) thalassemiaδMain article: Delta-thalassemia

As well as alpha and beta chains being present in hemoglobin about 3% of adult hemoglobin is made of alpha and delta chains. Just as with beta thalassemia, mutations can occur which affect the ability of this gene to produce delta chains.

In combination with other hemoglobinopathies

Thalassemia can co-exist with other hemoglobinopathies. The most common of these are:

hemoglobin E/thalassemia: common in Cambodia, Thailand, and parts of India; clinically similar to β thalassemia major or thalassemia intermedia.

hemoglobin S/thalassemia, common in African and Mediterranean populations; clinically similar to sickle cell anemia, with the additional feature of splenomegaly

hemoglobin C/thalassemia: common in Mediterranean and African populations, hemoglobin C/βo thalassemia causes a moderately severe hemolytic anemia with splenomegaly; hemoglobin C/β+ thalassemia produces a milder disease.

Cause

Thalassemia has an autosomal recessive pattern of inheritance

α and β thalassemia are often inherited in an autosomal recessive fashion although this is not always the case. Cases of dominantly inherited α and β thalassemias have been reported, the first of which was in an Irish family who had a two deletions of 4 and 11 bp in exon 3 interrupted by an insertion of 5 bp in the β-globin gene. For the autosomal recessive forms of the disease both parents must be carriers in order for a child to be affected. If both parents carry a hemoglobinopathy trait, there is a 25% chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families that carry a thalassemia trait.

There are an estimated 60-80 million people in the world who carry the beta thalassemia trait alone.[citation needed] This is a very rough estimate and the actual number of thalassemia major patients is unknown due to the prevalence of thalassemia in less developed countries.[citation needed] Countries such as India and Pakistan are seeing a large increase of thalassemia patients due to lack of genetic counseling and screening.[citation needed] There is growing concern that thalassemia may become a very serious problem in the next 50 years, one that will burden the world's blood bank supplies and the health system in general.[citation needed] There are an estimated 1,000 people living with thalassemia major in the United States and an unknown number of carriers.[citation needed] Because of the prevalence of the disease in countries with little knowledge of thalassemia, access to proper treatment and diagnosis can be difficult.[citation needed]

Treatment

Patients with thalassemia minor usually do not require any specific treatment.[citation needed] Treatment for patients with thalassemia major includes chronic blood transfusion therapy, iron chelation, splenectomy, and allogeneic hematopoietic transplantation.[citation needed]

Medication

Medical therapy for beta thalassemia primarily involves iron chelation. Deferoxamine is the intravenously or subcutaneously administered chelation agent currently approved for use in the United States. Deferasirox (Exjade) is an oral iron chelation drug also approved in the US in 2005. Deferoprone is an oral iron chelator that has been approved in Europe since 1999 and many other countries. It is available under compassionate use guidelines in the United States.

The antioxidant indicaxanthin, found in beets, in a spectrophotometric study showed that indicaxanthin can reduce perferryl-Hb generated in solution from met-Hb and hydrogen peroxide, more effectively than either Trolox or Vitamin C. Collectively, results demonstrate that indicaxanthin can be incorporated into the redox machinery of β-thalassemic RBC and defend the cell from oxidation, possibly interfering with perferryl-Hb, a reactive intermediate in the hydroperoxide-dependent Hb degradation.[6]

Carrier detection

A screening policy exists in Cyprus to reduce the incidence of thalassemia, which since the program's implementation in the 1970s (which also includes pre-natal screening and abortion) has reduced the number of children born with the hereditary blood disease from 1 out of every 158 births to almost zero.[7]

In Iran as a premarital screening, the man's red cell indices are checked first, if he has microcytosis (mean cell hemoglobin < 27 pg or mean red cell volume < 80 fl), the woman is tested. When both are microcytic their hemoglobin A2 concentrations are measured. If both have a concentration above 3.5% (diagnostic of thalassemia trait) they are referred to the local designated health post for genetic counseling.[8]

In 2008, in Spain, a baby was selectively implanted in order to be a cure for his brother's thalassemia. The child was born from an embryo screened to be free of the disease before implantation with In vitro fertilization. The baby's supply of immunocompatible cord blood was saved for transplantation to his sister. The transplantation was considered successful.[9] In 2009, a group of doctors and specialists in Chennai and Coimbatore registered the successful treatment of thalassemia in a child using a sibling's umbilical cord blood.[10]

Epidemiology

Generally, thalassemias are prevalent in populations that evolved in humid climates where malaria was endemic. It affects all races, as thalassemias protected these people from malaria due to the blood cells' easy degradation.

Thalassemias are particularly associated with people of Mediterranean origin, Arabs, and Asians.[11] The Maldives has the highest incidence of Thalassemia in the world with a carrier rate of 18% of the population. The estimated prevalence is 16% in people from Cyprus, 1%[12] in Thailand, and 3-8% in populations from Bangladesh, China, India, Malaysia and Pakistan. There are also prevalences in descendants of people from Latin America and Mediterranean countries (e.g. Greece, Italy, Portugal, Spain, and others). A very low prevalence has been reported from people

in Northern Europe (0.1%) and Africa (0.9%), with those in North Africa having the highest prevalence. It is also particularly common in populations of indigenous ethnic minorities of Upper Egypt such as the Beja, Hadendoa, Sa'idi and also peoples of the Nile Delta, Red Sea Hill Region and especially amongst the Siwans.

Benefits

Epidemiological evidence from Kenya suggests another reason: protection against severe anemia may be the advantage.[13]

People diagnosed with heterozygous (carrier) β thalassemia have some protection against coronary heart disease.[14]

References

1. ̂ Hemoglobinopathies and Thalassemias2. ̂ Weatherall David J, "Chapter 47. The Thalassemias: Disorders of Globin Synthesis" (Chapter). Lichtman

MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal, JT: Williams Hematology, 8e: http://www.accessmedicine.com/content.aspx?aID=6123722.

3. ̂ Online 'Mendelian Inheritance in Man' (OMIM) 1418004. ̂ Online 'Mendelian Inheritance in Man' (OMIM) 1418505. ̂ Online 'Mendelian Inheritance in Man' (OMIM) 1419006. ̂ Tesoriere L, Allegra M, Butera D, Gentile C, Livrea MA (July 2006). "Cytoprotective effects of the

antioxidant phytochemical indicaxanthin in beta-thalassemia red blood cells". Free Radical Research 40 (7): 753–61. doi:10.1080/10715760600554228. PMID 16984002.

7. ̂ Leung TN, Lau TK, Chung TKh (April 2005). "Thalassaemia screening in pregnancy". Current Opinion in Obstetrics & Gynecology 17 (2): 129–34. doi:10.1097/01.gco.0000162180.22984.a3. PMID 15758603.

8. ̂ Samavat A, Modell B (November 2004). "Iranian national thalassaemia screening programme". BMJ (Clinical Research Ed.) 329 (7475): 1134–7. doi:10.1136/bmj.329.7475.1134. PMID 15539666.

9. ̂ Spanish Baby Engineered To Cure Brother10. ̂ His sister's keeper: Brother's blood is boon of life, Times of India, 17 September 200911. ̂ E. Goljan, Pathology, 2nd ed. Mosby Elsevier, Rapid Review Series.12. ̂ http://www.dmsc.moph.go.th/webrOOt/ri/Npublic/p04.htm13. ̂ Wambua S, Mwangi TW, Kortok M, et al. (May 2006). "The effect of alpha+-thalassaemia on the

incidence of malaria and other diseases in children living on the coast of Kenya". PLoS Medicine 3 (5): e158. doi:10.1371/journal.pmed.0030158. PMID 16605300.

14. ̂ Tassiopoulos S, Deftereos S, Konstantopoulos K, et al. (2005). "Does heterozygous beta-thalassemia confer a protection against coronary artery disease?". Annals of the New York Academy of Sciences 1054: 467–70. doi:10.1196/annals.1345

The disease

Thalassemia is a group of inherited blood disorders characterised by mild to severe anaemia caused by haemoglobin deficiency in the red blood cells. In individuals with thalassemia, the

production of the oxygen-carrying blood pigment haemoglobin is abnormally low, or the molecule structure of the haemoglobin is altered.

There are two main types of thalassemia: alpha thalassemia and beta thalassemia. In each variant a different part of the haemoglobin protein is defective. Individuals with mild thalassemia may be practically symptom-free throughout their lives. Intermediate to severe cases are associated with a variety of symptoms, such as anaemia, enlarged liver and spleen, increased susceptibility to infection, slow growth, thin and brittle bones, and heart failure.

Occurrence

A national survey carried out in 2004 identified approximately 35 individuals with severe beta thalassemia in Sweden. The disorder is common in parts of the world with a history of malaria epidemics, and it is estimated that about 3 per cent of the world's population are carriers of a gene for thalassemia.

In a WHO survey carried out in 1994, it was estimated that about 26,000 babies are born with severe beta thalassemia each year, while 4,500 are affected by the most severe form of alpha thalassemia, resulting in foetal or neonatal death. Alpha thalassemia primarily occurs in individuals with Southeast Asian ancestry, and the beta type is common in the Mediterranean region, North Africa, the Middle East, India and Southeast Asia.

Screening programmes detecting carriers of the genetic trait for beta thalassemia and the availability of prenatal diagnostics (for example in Greece and Italy) have significantly reduced the number of infants born with beta thalassemia. As a result of immigration flows to northern Europe, more children are currently born with the condition in this area than in the Mediterranean region.

Cause 

Haemoglobin (Hb) is a protein pigment in the red blood cells that delivers oxygen to peripheral tissues in the body and makes the blood red. After the neonatal period, the predominant type of haemoglobin is haemoglobin A (HbA). Each haemoglobin A molecule consists of four protein chains: two alpha globin chains and two beta globin chains (a2b2). In healthy individuals, the rate at which beta and alpha chains are produced is regulated so that proportional amounts of each type of globin are available to form haemoglobin.

In alpha or beta thalassemia, very little or no alpha or beta globin is produced, or the protein is structurally defective. The cause of the abnormality is an alteration (a mutation) in the genes that regulate globin chain production. Alpha thalassemia results from deficient or structurally abnormal alpha chains, and beta thalassemia results from deficient or structurally abnormal beta chains. The severity of the symptoms in the two forms of thalassemia mainly depends on how much the production of globins is reduced, or the extent to which the structure of the protein is altered and its function impaired.

Alpha thalassemia: Four genes located on chromosome 16 control the production of alpha globin. Alpha thalassemia results when one or more of these genes, or parts of them, are missing (a deletion) or carry a point mutation (a change in a single base pair of DNA). Deletions impair the production of alpha chains. A point mutation may also impair the production or slightly alter the protein structure, resulting in a dysfunctional alpha chain. Alpha thalassemia is often clinically divided into subcategories that reflect the severity of the symptoms:

1. A "silent carrier" is a person with thalassemia who is symptom free 2. Alpha thalassemia minor (two genes involved)

Hb-H disease (three-gene deletion alpha thalassemia) 3. Hydrops fetalis (four genes involved)

The characteristic symptoms of alpha thalassemia are mainly caused by low haemoglobin levels resulting from reduced alpha chain production. The loss of three out of four genes only results in moderate anaemia. If all four genes are deleted, however, the foetus often dies in the womb owing to severe anaemia and oedema (swelling), a condition known as hydrops fetalis.

Beta thalassemia: There is one beta globin gene on each copy of chromosome 11. As many as 200 mutations in these genes either suppress the production of beta chains or alter the globin structure, thereby impairing its function. Individuals with only one defective gene have beta thalassemia minor, while those with two mutated genes have beta thalassemia major. The severity of the disorder also depends on the type of gene mutation that causes the condition. Another factor that determines the severity is whether the individual, in addition to beta Thalassemia, is also affected by the alpha variant, and on his or her capacity to produce other globin chains (especially foetal haemoglobin gamma chains). Like alpha thalassemia, beta thalassemia is clinically divided into four subcategories:

1. Symptom-free "silent carriers" 2. Beta thalassemia minor 3. Beta thalassemia intermedia 4. Beta thalassemia major

Symptoms arise when the low beta globin chain production causes a surplus of alpha chains in the red blood cells. The excess alpha chains form insoluble aggregates that damage the red cell membrane, leading to premature red blood cell breakdown (haemolysis). The production of red blood cells in the bone marrow is also impaired, and many blood cells fail to mature (inefficient erythropoiesis).

In thalassemia major the body tries to compensate for the impaired maturation process by accelerating the pace of red blood cell production in the bone marrow. The liver and the spleen, which do not normally produce red blood cells, are also activated. As a result of this extreme activity, the bone marrow cavities expand and the liver and spleen are enlarged. The blood volume increases, and as a consequence the heart is under great pressure. The low haemoglobin concentration also lowers the oxygen level in the bloodstream. This is a serious condition that increases the risk of heart failure and is fatal if not treated.

For unknown reasons, iron absorption in the gastro-intestinal tract is often enhanced in individuals with beta thalassemia. This may lead to iron overload and subsequent organ damage.

Heredity

Alpha thalassemia: Two genes on each chromosome 16 contain the blueprint for alpha globin production. As one chromosome is inherited from the mother and one from the father, each parent contributes two alpha globin genes to the child. Around 30 mutations causing alpha thalassemia are currently known, usually involving the loss of alpha globin genes in one or both chromosomes.

Thalassemia minor, caused by deletion of two genes on the same chromosome, is particularly common in Southeast Asia. Despite the fact that individuals with thalassemia minor have few if any symptoms, there is an increased risk that they will give birth to children with Hb-H disease or hydrops fetalis. These disorders are rare in people originating from Africa or the Mediterranean region, where only one gene on each chromosome is usually deleted.

Beta thalassemia: One gene on each copy of chromosome 11 contributes to the production of beta globin chains. Over 200 mutations are currently identified as impairing the production of beta globin protein. The mutations lead either to partial or total failure of beta globin production, the beta globin chain being structurally and functionally altered.

If beta globin protein is completely absent, the mutated gene is known as beta0, while beta+ is a gene that produces a small amount of normal beta protein or structurally impaired beta globin.

If one of the beta globin genes is normal, the individual is affected by beta thalassemia minor. In cases where the beta genes in both chromosomes 11 are mutated, the symptoms vary depending on how the globin synthesis is affected (b+b+, b+b0 or b0b0). The severity of symptoms also depends on the individual's inherited capacity to produce other haemoglobin chains, and on whether alpha globin synthesis is also disturbed.

Symptoms

Alpha thalassemia: People with alpha thalassemia minor are only mildly anaemic and their general health is usually not affected. Individuals with Hb-H disease have moderate or severe anaemia with haemoglobin values between 70- 100 g/l (a normal value is 120-160 g/l). Although characteristic symptoms may present, they do not necessarily affect the person's life greatly. Individuals with Hb-H disease are often affected by liver and spleen enlargement or jaundice (icterus), caused by the rapid breakdown of haemoglobin. In some cases, gall bladder disease, leg ulcers and folic acid deficiency also present. Acute anaemia (haemolytic crises) may occur as a result of infection or when taking certain medications, such as sulpha. As a consequence, the breakdown of red blood cells increases.

Beta thalassemia: Individuals with beta thalassemia minor are only mildly anaemic and are usually symptom-free. The anaemia is exacerbated by iron and folic acid deficiencies as well as by infection. Approximately 10 per cent are affected by liver and spleen enlargement. In beta

thalassemia major, the symptoms usually present during the first year of life. Anaemia causes pallor, fatigue, slow growth and delayed intellectual and motor development. If the condition is left untreated during the first few years, the bone marrow cavities may expand, and the cortex of the long bones may become abnormally thin. The bones become frail and brittle and the risk of bone fracture increases. As a consequence of the upper jaw bone expanding, the face develops abnormally with an overbite, protruding teeth in the upper jaw and widely set eye sockets.

Erythrocytes (cells in the bone marrow that produce red blood cells) may also aggravate in the chest and in the liver and spleen, which become abnormally enlarged. If blood transfusions are not carried out, most children with the disorder die between the ages of two to three as a consequence of heart failure caused by the large blood volume, or oxygen deprivation caused by anaemia.

Today, blood transfusions are a standard treatment and as a result the anaemic symptoms can be almost completely relieved. Instead, iron overload causes the most pronounced symptoms. All individuals with beta thalassemia who are on chronic blood transfusion therapy are affected by iron overload. Excess iron accumulates in the cells and causes organ damage. If the condition is not treated (using iron chelation therapy), life-threatening progressive heart failure develops by the age of 10-15. The endocrine glands are also affected, which may cause diabetes, hypothyroidism, growth hormone deficiency, delayed puberty or parathormone deficiency. To prevent progression of iron-induced organ damage, chelating agents, mainly desferrioxamine are used. However, treatment with chelators does not completely eliminate iron accumulation, and over time iron toxicity may be fatal.

In thalassemia intermedia the anaemia is less severe, and the haemoglobin level normally remains above 70g/l. In these cases, the individual child's growth, skeletal development and heart condition should be taken into account when determining the need for regular transfusions. Just as in beta thalassemia, there is a risk that iron overload caused by blood transfusions and increased intestinal absorption may lead to heart failure and endocrine dysfunction.

Diagnosis

Alpha thalassemia: The most severe forms of alpha thalassemia are symptomatic at birth and the moderate cases manifest in early infancy. Mild cases of alpha thalassemia may be difficult to diagnose as the blood test known as haemoglobin electrophoresis, which analyses the prevalence of different types of haemoglobin molecules, does not indicate any abnormalities. To establish the diagnosis, one often has to rely on haematological findings characteristic of the disorder, ethnic origin, absence of beta thalassemia and family history of the disease. Hb-H disease is easier to diagnose, as the electrophoresis will detect the presence of abnormal haemoglobin (beta 4), which is characteristic of the disorder.

Beta thalassemia: In children the condition usually presents as anaemia, and the age of onset is between six months and two years. A detailed disease history that includes family occurrences and ethnic origin is often helpful when making the diagnosis. In a medical examination it is particularly important to observe signs of slow growth and physical development, and to look for liver or spleen enlargement. In most cases of thalassemia, the individual is affected by anaemia,

which manifests clinically as small red blood cells with low haemoglobin content. It is important to detect cases of iron deficiency, not only because the condition may cause anaemia, but also because it may mask the diagnosis of mild beta thalassemia.

The diagnosis is usually confirmed in a haemoglobin electrophoresis test. In beta thalassemia minor, the HbA2 (a2d2) level rises when the child is between one and a half and two years old, and in many cases the HbF (a2g2) level is also abnormally high. In severe beta thalassemia, these indications are more pronounced.

In both alpha and beta thalassemia it is possible to determine the exact genetic mutation that causes the disorder. This genetic information is particularly useful as it allows prenatal diagnosis by carrying out a placental biopsy (chorionic villus sampling). The type of gene defect will also help predict the clinical severity, although there is no clear connection between genotype and clinical outcome.

Treatment/interventions

Alpha thalassemia: Even individuals with very low alpha globin production are normally not anaemic to the extent that the condition interferes with their daily lives, and blood transfusions are generally not required. However, infections may cause the haemoglobin concentration to drop dramatically, in which case transfusions are needed. Folic acid deficiency is common as a result of chronic red blood cell destruction and the compensatory production increase it induces. Individuals with alpha thalassemia should therefore take folic acid supplements. Gall bladder disease, leg ulcers and increased susceptibility to infection are also common symptoms that require adequate medical treatment.

Beta thalassemia: In general, individuals with beta thalassemia minor require no treatment, but children may need to take folic acid supplements until they are fully grown. Like individuals with mild alpha thalassemia, people with beta thalassemia may under certain conditions be affected by severe anaemia requiring treatment. Individuals with beta thalassemia minor should be offered information and genetic counselling, as there is a risk that they will have children with severe beta thalassemia. Genetic testing of family members may be necessary.

Individuals with beta thalassemia intermedia should be examined regularly to monitor their growth, skeletal development, and heart and circulatory status. As the years go by, they should also undergo regular examination to detect any complications arising owing to iron overload. As the Hb level may decline with age, it should be tested regularly in order to assess the need for blood transfusions.

Thalassemia major should be diagnosed as early as possible in order to prevent growth restriction, frail bones and infections in the first year of life. It may be difficult to distinguish thalassemia major from thalassemia intermedia, and the infant's haemoglobin levels and development should therefore be monitored closely. If Hb is lower than 70 or the child shows signs of poor growth and development, regular transfusion is the treatment of choice. According to the WHO, the aim of this treatment is to retain a median haemoglobin value of 115-120g /l. This can usually be achieved by carrying out transfusions of concentrated red blood cells at

intervals of every three to four weeks. An alternative treatment regime, advocated by many practitioners in several large medical centres, is to schedule transfusions so as to prevent the Hb level from dropping below 90.

Multiple transfusions result in gradual iron build-up. Sooner or later, treatment with iron-binding chelators (usuallyrioxamine) will be required in order to prevent organ damage. The WHO recommends iron chelator therapy after 10-15 blood transfusions, or when the iron level, measured as ferritin value in the bloodstream, exceeds 1000 ng/ml. Unfortunately, this is a demanding treatment as the current principal chelator should be administered either through intravenous infusion or subcutaneously (into the fat tissues under the skin). A common treatment regime is to administer the drug subcutaneously via a mechanical pump for 10 to 12 hours, five to six days a week. Today, iron chelators are also available as tablets (defer="defer"="defer="defer""riprone) that are an option in some cases, preferably in combination with desferrioxamine treatment.

When children with thalassemia major are treated, it is important to monitor their growth and development. The effects of the iron chelator treatment should be evaluated regularly by using various techniques to measure iron storage, and assessing potential injury to vital organs such as the heart and liver. There is no good correlation between ferritin value, the iron content in a liver biopsy, or an MRT (magnetic resonance imaging) that assesses the amount of iron deposition in the liver or heart. People are differently predisposed to iron absorption in different organs. This means that an assessment of iron in the liver is not valid for the heart or vice versa. As desferrioxamine has side effects affecting vision and hearing, it is important to have the eyes and ears examined annually.

Before hypertransfusions and iron chelator therapy were available, individuals with thalassemia died during infancy. Today the situation is different, and many people who have received these treatments from an early age are now in their thirties or forties. There are any indications that the intensive iron chelation therapy currently in use significantly increases the life span and improves the quality of life of individuals with thalassemia. However, the treatment requires that the patients are cared for by experienced medical staff.

Active psychological and social support is essential, especially during the teens when identification with one's peers is particularly important for establishing a sense of self. This process often causes a need to test limits and to challenge constraints imposed both by the disease and the child's parents. The experience of feeling different often weakens the motivation to be treated, and as a result interventions may be less successful and the risk of organ damage increases. Psychological support from a psychologist or counsellor may be very helpful, both for the individual with thalassemia and for close relations.

Today thalassemia major can be cured by stem cell transplantation. A prerequisite is usually that the affected individual has siblings with identical tissue type (HLA type). If this is the case, a transplantation of blood stem cells (a haematopoietic transplantation, often referred to as a "bone marrow transplant"), can be carried out. All blood cells are produced by stem cells in the bone marrow in the cavities of the bone. In a stem cell transplantation, diseased stem cells are replaced by stem cells from a healthy donor. The HLA tissue type is inherited from the parents, and each

sibling has a 25 per cent chance of inheriting the same type as the affected child. The results of the transplantation are usually very satisfactory if the intervention is carried out before any organ injury has presented. However, as the procedure is still associated with risks, there are no general guidelines that determine who should receive a transplant. In cases where there is a sibling with identical HLA, transplantation should be seriously considered after the parents have been well informed about the intervention. In the near future, transplants from unrelated donors are likely to become more common in cases of thalassemia.

Practical advice

Individuals who have been diagnosed with thalassemia minor should receive a letter from their doctor containing information about their condition, in order to prevent unnecessary investigation of their anaemia.

National and regional resources in Sweden

There are physicians with competence in thalassemia treatment at Swedish regional paediatric clinics.

Resource personnel

Resource personnel for children:

Senior Physician Jonas Abrahamsson, Queen Silvia Children's Hospital, SE-416 85 Göteborg, Sweden. Tel +46 (0)31-343 40 00, email: [email protected].

Professor Rolf Ljung, Paediatric Clinic, Malmö University Hospital, SE-205 02 Malmö, Sweden. Tel +46 (0)40-33 10 00, email: [email protected].

Professor Ildiko Marky, Queen Silvia Children's Hospital, SE-416 85 Göteborg, Sweden. Tel +46 (0)31-343 40 00, email: [email protected].

Resource personnel for adults:

Professor Robert Hast, Haematological Clinic, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel +46 (0)8-517 726 02, email: [email protected].

Courses, exchanges of experience, recreation

The Thalassemia International Federation (the address is listed under Organisations for the disabled/patient associations) organises courses and other activities.

Organizations for the disabled/patient associations

The Thalassemia International Federation is an international patient association. Address: P.O. Box 28807, Nicosia, Cyprus, email: [email protected], Internet: www.thalassemia.org.cy.

Courses, exchanges of experience for personnel

Network for paediatric nurses. Contact person: Anna Hansson, Paediatric Clinic, ward 3, MAS University Hospital, Malmö, Sweden. Tel +046 (0)40-33 16 43.

The Swedish Paediatric Haematology Health Care Planning Group (Vårdplaneringsgruppen för pediatrisk hematologi, VPH), belonging to the Swedish Paediatricians´ Section for Haematology and Oncology (http://orebroll.se/vph), have put together a "mini care programme for thalassemia 2003".

Research and development (R&D)

Research on thalassemia is closely associated with basic research in molecular biology. There is intensive ongoing work to learn more about the mechanisms that govern the expression of haemoglobin genes from the foetal stages to old age. The aim is to find ways of increasing the production of foetal haemoglobin in individuals with beta thalassemia, as this is one way of relieving the symptoms. Researchers are also looking intensively for new iron chelators that can be administered orally, as available therapies are very taxing for the patients. Finally, methods for blood stem cell transplantation are continuously being developed. In the future it is likely that more stem cell donors will be available, and the procedure will be safer with fewer side effects.

Information material

An information folder on Thalassemia, which summarises the information in this database text, is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2002-12-148). Address: SE-120 88 Stockholm, Sweden. Tel +46 (0)8-779 96 66, fax +46 (0)8-779 96 67, email: [email protected]. Postage will be charged for bulk orders.

A "Mini care programme for thalassemia 2003" (written by Rolf Ljung, listed under Resource personnel). Published by the Swedish Paediatric Haematology Health Care Planning Group (Vårdplaneringsgruppen för pediatrisk hematologi, VPH), belonging to the Swedish Paediatricians´ Section for Haematology and Oncology. The "Mini care programme" (in Swedish) is available at: http://www.orebroll.se/vph.

There are several excellent websites, both for professional caregivers and for other categories:

In the international patient association's webpage: www.thalassemia.org.cy, there is, for example, books are available for download, for example "What is Thalassemia".

Cooley's Anemia Foundation: www.thalassemia.org.

United Kingdom Thalassemia Society, London, UK: www.ukts.org.

Joint Center for Sickle Cell and Thalassemic Disorders: http://sickle.bwh.harvard.edu/index.html.

Thalassemia On-Line, Melbourne, Australia: www.geocities.com/HotSprings/5917/.

Literature

Cao A, Rosatelli MC, Monni G, Galanello R. Screening for thalassemia: a model of success. Obstet Gynecol Clin North Am 2002; 29: 305-328.

Galanello R. A thalassemic child becomes adult. Rev Clin Exp Hematol 2003; 7: 4-21.

Gaziev J, Lucarelli G. Stem cell transplantation for hemoglobinopathies. Curr Opin Pediatr 2003; 15: 24-31.

Chui DH, Fucharoen S, Chan V. Hemoglobin H disease: not necessarily a benign disorder. Blood 2003; 101:791-800.

Gu X, Zeng Y. A review of the molecular diagnosis of thalassemia. Hematology 2002; 7: 203-209.

Guidelines for clinical management of thalasseamia samt Compliance to iron chelation therapy with desferrioxamine. Utgivna av International Thalassaemia Federation (www.thalassaemia org.cy/)

Mancuso L, Panzarella G, Bartolotta TV, Midiri M, Renda D, Maggio A. Cardiac complications in thalassemia: noninvasive detection methods and new directions in the clinical management. Expert Rev Cardiovasc Ther 2003; 1: 439-452.

Nathan and Oski's Hematology of infancy and childhood 5th edition. Editors: Nathan DG, Orkin SH. W.B. Sa

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Thalassemia AnatomyTo better understand thalassemia , it helps to understand the anatomy and composition of blood.

Blood is a circulating tissue that carries nourishment and oxygen to the cells and tissue.

Blood is composed of 3 cell types that are suspended in a protein-rich fluid called plasma:

Red blood cells (erythrocytes)

White blood cells (leukocytes) Platelets (thrombocytes)

Red Blood CellsRed blood cells contain hemoglobin, which is the molecule that carries oxygen to the tissues. A decrease in the number of red blood cells reduces the amount of oxygen that can be carried by the bloodstream. This can result in poor exercise tolerance and fatigue.

Normal ranges for the total number of red blood cells in adults are:

4.6-6.2 million per cubic millimeter (males) 4.2-5.4 million per cubic millimeter (females)

White Blood CellsWhite blood cells are an important part of the immune system. There are several types of white cells (leukocytes) present in the blood. These cells mainly function to fight infection. Normal total ranges for white blood cells are: 4,500 - 11,000 (per cubic millimeter). Slightly higher counts are normal in children.

A white blood cell differential reports the percentages of the different types of white blood cells that comprise the total white blood cell count. These values are reported as a percentage of the total number of cells.

Cell Type % Of Total WBC'sNeutrophils 47% to 77% (elevated in infection, inflammation, and stress)

Bands 0% to 3% (elevated in some cases of bacterial infection)Lymphocytes 16% to 43% (elevated in some cases of viral infection and some leukemias)Monocytes 0.5% to 10% (elevated in some viral, fungal & TB infections, lupus, cancer)Basophils 0.3% to 2% (elevated in some leukemias, some cancers, and hypothyroidism)

Eosinophils0.3% to 7% (elevated in some allergies, cancer, leukemia, Hodgkin's disease,

autoimmune disease)

PlateletsPlatelets are the smallest of the blood cells. They play an essential role in the blood clotting system. A platelet count: 150,000-400,000 per cubic millimeter is considered a normal range.

Last Updated: Feb 11, 2010 ReferencesAuthors: Stephen J. Schueler, MD; John H. Beckett, MD; D. Scott Gettings, MDCopyright 1989-2011DSHI Systems, Inc. Powered by: FreeMD - Your Virtual Doctor

PubMed Thalassemia References

1. Cohen AR, Galanello R, Pennell DJ, Cunningham MJ, Vichinsky E. Thalassemia. Hematology (Am Soc Hematol Educ Program). 2004;:14-34. [15561674]

2. Gu X, Zeng Y. A review of the molecular diagnosis of thalassemia. Hematology. 2002 Aug;7(4):203-9. [14972782]

3. Mohammadian S, Bazrafshan HR, Sadeghi-Nejad A. Endocrine gland abnormalities in thalassemia major: a brief review. J Pediatr Endocrinol Metab. 2003 Sep;16(7):957-64. [1451387]

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Pathophysiology

Treatment of nephrotic syndrome is directed toward the resolution of proteinuria and edema. Edema occurs

due to a decrease in intravascular oncotic pressure secondary to urinary protein losses and the inability to

increase synthesis to compensate for such losses, leading to reduced plasma albumin levels. Reduced plasma

albumin leads to intravascular hypovolemia, increased aldosterone, antidiuretic hormone secretion, and

subsequent renal salt and water retention.[19, 23, 24]

Proteinuria occurs due to increased glomerular permeability of proteins resulting from the loss of fixed negative

charges and inability of the proximal tubules to reabsorb all of the filtered proteins. Mean glomerular pore size

or density may be altered due to lack of electrostatic interaction between glomerular capillaries and polyionic

plasma proteins, such as albumin.[25] In addition, the type of proteinuria appears to correlate with response to

therapy. Patients with highly selective proteinuria respond better to corticosteroids and are more likely to have

minimal change disease than those with nonselective proteinuria. In highly selective proteinuria, only

intermediate-sized proteins (< 100 kD), such as albumin and transferrin, leak through the glomerulus; in

nonselective proteinuria, a large range of proteins leak through the glomerulus.[9] In the modern era, use of

protein selectivity to predict response to therapy has been replaced by observation of the response to

corticosteroids in favorable populations, and renal biopsy and electron microscope results in patients in less

favorable su

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Nephrotic syndrome is a pattern of presentation of renal disease, rather than a single

pathological entity or diagnosis. Nephrotic syndrome is also known as nephrosis and is

defined by the presence of nephrotic-range proteinuria, oedema, hyperlipidemia, and

hypoalbuminaemia. It has serious complications and must be on the differential diagnosis

for any patient presenting with new onset oedema.1

Pathophysiology

It comprises the following elements:

Features of the nephrotic syndrome:

Glomerular dysfunction leading to excessive urinary protein excretion (formerly defined as >3.5 g/day but there appears to be individual variation around this cut-off figure)

Hypoalbuminaemia as a result of urinary protein loss (albumin levels usually in range <25–30 g/l) Peripheral oedema due to hypoalbuminaemia Hypercholesterolaemia/dyslipidaemia Normal detoxifying renal function, at least initially

The primary abnormality in nephrotic syndrome is thought to be loss of a layer of negatively-charged heparin sulphate within the glomerular basement membrane, that allows the increased passage of large amounts of low-molecular weight anionic proteins during ultrafiltration. However, recent research has shown that the loss of albumin in the urine may not be due to excessive filtration across the glomerular basement membrane as was previously supposed, rather a failure to reabsorb albumin after its ultrafiltration. It appears that renal disease may cause an impairment of the ability of cells in the proximal renal tubules to endocytose albumin that has been filtered across the glomeruli, and deliver it back into the blood supply around the renal tubules.2

Oedema is thought to occur due to the loss of plasma oncotic pressure secondary to hypoalbuminaemia, causing accumulation of fluid in the extracellular space; a decrease in intravascular volume is thought to cause renal hypoperfusion further enhancing salt and water retention. However, this model cannot fully explain all the pathophysiological and clinical features of the nephrotic syndrome and other, as yet unelucidated, intra- and extra-renal mechanisms may be responsible for the combination of biochemical and clinical features seen in nephrotic syndrome. Hypercholesterolaemia is thought to be caused by:

Stimulation of the liver to increase synthesis of all plasma proteins (including the lipoproteins), due to their low level in the blood.

Reduction of lipoprotein catabolism due to reduced levels of lipoprotein lipase in blood.

Other consequences of nephrotic syndrome:3

Decreased resistance to infections due to urinary immunoglobulin loss. Increased risk of arterial and venous thrombosis due to loss of anti-thrombin III and plasminogen in the urine,

combined with an increase in hepatic synthesis of clotting factors. Increased risk of osteitis fibrosa cystica and osteomalacia due to loss of vitamin D-binding protein and its

complexes in the urine, through a combination of calcium malabsorption and secondary hyperparathyroidism.

Epidemiology

Nephrotic syndrome is a relatively rare but important manifestation of kidney disease.

In the US, its annual incidence among children is reported to be 2–7 cases per 100,000.3

Incidence varies among adults depending on the incidence of underlying causes for the

condition, particularly diabetes mellitus. Nephrotic syndrome has an incidence of around

three new cases per 100 000 each year in adults.1

Commoner causes of the nephrotic syndrome

It can be caused by a wide range of primary (idiopathic) and secondary glomerular diseases.

Primary renal diseases

Minimal-change nephrotic syndrome (~85% of childhood cases) Focal segmental glomerulosclerosis (~9% of childhood cases) Mesangial proliferative glomerulonephritis (~2% of childhood cases) Membranous nephropathy (~3% of childhood cases) Membranoproliferative glomerulonephritis

Secondary renal diseases

Postinfectious causes, e.g. Group-A beta-haemolytic streptococci, TB, malaria, syphilis, viruses such as VZV, HBV, HIV, infectious mononucleosis

Collagen vascular diseases, e.g. SLE, rheumatoid arthritis, polyarteritis nodosa, Henoch-Schönlein purpura, vasculitides

Metabolic diseases, e.g. diabetes mellitus, amyloidosis Inherited disease, e.g. Alport's syndrome, hereditary nephritis, sickle cell

disease Malignant disease, e.g. multiple myeloma, leukaemia, lymphoma, carcinoma

of breast/lung/colon/stomach Medications, e.g. NSAIDs, captopril, lithium, gold, diamorphine, interferon-

alpha, penicillamine, probenecid and many others Toxins, e.g. bee sting, snake bites, phytotoxins Pregnancy, e.g. pre-eclampsia Transplant rejection

Presentation

Symptoms

In children facial swelling is a common presenting feature, with periorbital oedema often being the first evidence that something is wrong; oedema may progress to involve the whole body.

Adults tend to present with peripheral oedema affecting the ankles and legs, which may progress to involve the whole body.

Some patients may notice frothiness of their urine. Hypercoagulability may manifest as venous or arterial thrombosis, e.g. DVT, MI. Recurrent infections and/or general fatigue, lethargy, poor appetite, weakness or

episodic abdominal pain may cause presentation to a doctor.

Signs

Clinical signs of nephrotic syndrome:1

Oedema o Periorbital oedema

o Lower limb oedema

o Oedema of the genitals

o Ascites

Low albumin o Tiredness

o Leukonychia

Breathlessness o Pleural effusion

o Fluid overload (high jugular venous pressure)

o Acute renal failure

Breathlessness with chest pain o Thromboemboli

Dyslipidaemia o Eruptive xanthomata

o Xanthelasmata

Other

Frothy urine

Oedema of dependent parts or generalised oedema are the main clinical findings. Facial oedema may be found in children. Occasionally, severely hypoalbuminaemic cases may have pleural effusions or

ascites. Urinalysis will reveal gross proteinuria. Hypertension and haematuria are not usually found but may affect a minority of

cases.

Investigations

The aim of investigations is to find the underlying cause, direct future management,

establish a baseline of severity and monitor response to treatment. The initial sequence is:1

Confirm proteinuria present: urine dipstick positive Check for concomitant invisible (microscopic) haematuria: urine dipstick positive Exclude urine infection:urine microscopy/culture and sensitivity Measure amount of proteinuria:

o Early morning urinary protein:creatinine ratio or albumin:creatinine ratio (mg/mmol)

o Typically >300-350 mg/mmol in nephrotic syndrome Basic blood testing:

o Full blood count and coagulation screeno Renal function including plasma creatinine and estimated glomerular

filtration rateo Liver function tests to exclude concomitant liver pathologyo Bone profile—corrected (for albumin) plasma calcium

Check for other systemic diseases and causes of nephrotic syndrome: o C reactive protein and erythrocyte sedimentation rateo Glucose

o Immunoglobulins, serum and urine electrophoresiso Autoimmune screen if an underlying autoimmune disease is suspected—

antinuclear antibody (ANA), anti-double stranded DNA antibody (dsDNA), and complement values (C3 and C4)

o Hepatitis B and C and HIV (after obtaining informed consent) Chest x ray and abdominal or renal ultrasound scan (especially if renal function is

abnormal): o To check for pleural effusion or asciteso To check for the presence of two kidneys, their size and shape, and the

absence of obstructiono To exclude malignancy and exclude other causes of oedema

Be vigilant for complications such as thromboembolism: o Doppler ultrasound of leg veins in suspected deep vein thrombosiso Abdominal ultrasound, renal vein Doppler scan, venography of the inferior vena

cava, computed tomography and magnetic resonance imaging of the abdomen if renal vein thrombosis is suspected

o V/Q nuclear medicine lung scan, computed tomography pulmonary angiography for pulmonary embolism

Investigate the underlying renal and systemic cause of nephrotic syndrome: o Renal biopsy under ultrasound (to assess size and structural condition of

kidneys)o Obstructed or small kidneys may contraindicate renal biopsyo Make histological preparations for light microscopy, immunofluoresence or

immunoperoxidase, electron microscopy

Most cases will require renal biopsy to determine the exact underlying cause of the

condition; children under 8 years old usually have minimal-change nephrotic syndrome and

so may be spared this investigation, especially if they are steroid-responsive. Adults with an

obvious cause (e.g. diabetes with evidence of other complications) may be spared a biopsy

at the discretion of a renal specialist. Other investigations to diagnose less usual causes

such as abdominal fat/gingival biopsy to detect amyloidosis may be needed in place of or in

addition to a renal biopsy.

Diagnosis

Diagnostic criteria for nephrotic syndrome:1

Proteinuria greater than 3-3.5 g/24 hour or spot urine protein:creatinine ratio of >300-350 mg/mmol

Serum albumin <25 g/l Clinical evidence of peripheral oedema Severe hyperlipidaemia (total cholesterol often >10 mmol/l) is often present

Initial management

Initial management should focus on investigating the cause, identifying complications, and

managing the symptoms of the disease.1 All patients should be referred to a nephrologist for

further investigation, which often includes a renal biopsy.1

Indications for acute admission include:

Severe generalised oedema, particularly if pleural effusion/oedema causing respiratory compromise Tense scrotal/labial oedema Complications of the nephrotic state (e.g. sepsis, pneumonia, MI, DVT, growth failure) Inability to comply with therapy/inability to cope with condition in family/independently Any features of a possible nephritic syndrome such as haematuria, hypertension and impaired renal function

parameters

Most cases do not require acute hospitalisation. Reduce salt intake in diet (avoid processed foods and adding salt to food). Give diet with adequate calorific intake and sufficient protein content (1–2 g/kg

daily).4

Hyperlipidaemia – does not initially require therapy but may do so if prolonged.4

Fluid restriction is not usually necessary (if severe enough to need this then may need admission).4

Referral to a renal service for urgent outpatient assessment is advisable, to confirm the mode of presentation and direct any future investigations/therapy.

Oedema is treated through diuretic therapy with furosemide (~1 mg/kg/day) ± spironolactone (~2 mg/kg/day).

Check weight regularly to assess response to diuretics and ensure fluid retention is not worsening, or that patient is over-diuresed.

Patients with very low albumin levels may not respond to diuretics and may require admission to receive intravenous albumin therapy.

Some children with severe oedema may be prescribed antibiotic prophylaxis against infection and this should usually be on the advice of a renal specialist.

Most children will have minimal-change nephrotic syndrome and usually respond to a trial of steroid therapy under the direction of a renal specialist.

Other forms of nephrotic syndrome are less treatment responsive; ACE inhibitors are frequently used in adults to some effect.

In children who do not respond to steroids, and in some adults, treatment may be with other immunomodulatory drugs such as cyclophosphamide, ciclosporin, tacrolimus and levamisole.4

Prognosis

This is highly variable depending on the underlying cause. Congenital nephrotic syndrome usually carries a very poor prognosis. Outlook for the vast majority of children with minimal-change nephrotic syndrome is

excellent; response to steroids is the norm, although there may be relapses and a need to use alternative immunomodulatory drugs. Since the introduction of corticosteroids, the overall mortality of primary nephrotic syndrome has decreased dramatically from over 50% to approximately 2-5%.

Adult prognosis is variable and largely related to the underlying cause, its severity, progression and response to any treatment used to modify it.

Document references

1. Hull RP, Goldsmith DJ; Nephrotic syndrome in adults. BMJ. 2008 May 24;336(7654):1185-9.

2. Russo LM, Sandoval RM, McKee M, et al; The normal kidney filters nephrotic levels of albumin retrieved by proximal tubule cells: Retrieval is disrupted in nephrotic states. Kidney Int. 2007 Jan 17;. [abstract]

3. Agraharkar M, Gala G, Gangakhedkar AK; Nephrotic Syndrome. eMedicine, February 2007.

4. Lane J; Nephrotic Syndrome. eMedicine, Dec 2008; Paediatric overview.

Internet and further reading

Medline Plus - Acute Nephritic Syndrome Medline Plus - Nephrotic syndrome. EdREN, website of renal unit of the Royal Infirmary of Edinburgh, information for

patients on the nephrotic syndrome, 2006. Loghman-Adham M; Evaluating proteinuria in children. Am Fam Physician. 1998 Oct

1;58(5):1145-52, 1158-9. [abstract] Carroll MF, Temte JL; Proteinuria in adults: a diagnostic approach. Am Fam

Physician. 2000 Sep 15;62(6):1333-40. [abstract] Lane J; Nephrotic Syndrome. eMedicine, Dec 2008; Paediatric overview. Hogg RJ, Portman RJ, Milliner D, et al; Evaluation and management of proteinuria

and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the National Kidney Foundation conference on proteinuria, albuminuria

INTRODUCTION

Edema is a clinical condition characterized

by an increase in interstitial fluid volume

and tissue swelling that can either be

localized or generalized. Severe

generalized edema is known as anasarca.

More localized interstitial fluid collections

include ascites and pleural effusions.

Optimizing the diagnostic approach to

edema is based upon a thoughtful

approach to the pathogenesis of its

formation. Once a diagnosis is

established, specific treatment of the

underlying disorder can be given. If

specific therapy is not available, general

treatment, such as fluid management, can

be provided.

The pediatric disease processes

associated with edema and the

pathogenesis of edema will be described

in this topic review. More detailed

discussions of evaluation and

management of edema in children as well

as the pathophysiology of edema are

presented separately. (See "Evaluation

and management of edema in children".)

OVERVIEW OF PATHOPHYSIOLOGY

Normal physiology — Edema does not occur in normal subjects because of the

tight balance of hemodynamic forces along the capillary wall and the intact function

of the lymphatic system. While capillary hydrostatic pressure favors transcapillary

fluid movement into the interstitium, the colloid oncotic pressure across the capillary

favors the retention of fluid within the vessel (figure 1). Under normal circumstances,

these competing forces result in a small net movement of fluid into the interstitium.

The lymphatic vessels return this interstitial fluid to the venous system.

Pathophysiology of edema — The following physiologic processes result in edema

formation:

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about a kidney disease called the nephrotic syndrome. This illness also is called nephrosis or minimal change disease. The brochure will give you and your family information about your child's illness. It will tell you what will happen with this illness. You also should talk to your doctor. The more you know, the more you can help your child.

What do the kidneys do?

The kidneys are two fist-sized organs found in the lower back. When they are working well, they clean the blood, and get rid of waste products, excess salt and water. When diseased, the kidneys may get rid of things that the body needs to keep, such as blood cells and protein.

What is the nephrotic syndrome?

This is an illness where the kidney loses protein in the urine. This causes protein in the blood to drop, and water moves into body tissues, causing swelling (edema). You will see the swelling around the child's eyes, in the belly, or in the legs. Your child will not go to the bathroom as often as usual and will gain weight with the swelling.

Do other kidney diseases cause edema and protein in the urine?

Yes. Edema and protein in the urine are common in other types of kidney disease, especially a disease called glomerulonephritis.

What causes the nephrotic syndrome?

In the majority or cases, the cause is not known. The National Kidney Foundation has active research programs into causes and treatments of the nephrotic syndrome.

Who gets it?

Usually, young children between the ages of 1 1/2 and 5. It happens twice as often in boys as girls. However, children of all ages and adults also can get it.

How can you tell if your child has it?

You may see that your child has swelling around the eyes in the morning. You may think that your child has an allergy. Later, the swelling may last all day, and you may see swelling in your child's ankles, feet and belly. Also, your child may be:

• more tired & more irritable• eating less• pale looking

The child may have trouble putting on shoes or buttoning clothes because of swelling.

How is the nephrotic syndrome treated?

The treatment will try to stop the loss of protein in the urine, and increase the amount of urine. Usually, the doctor will start your child on a drug called prednisone. Most children get better with this drug.

What does prednisone do?

Prednisone is used to stop the loss of protein from the blood into the urine. After one to four weeks of treatment, your child should begin going to the bathroom more often. As your child makes more urine, the swelling will go away.

When there is no protein in the urine, the doctor will begin to reduce the amount of prednisone over several weeks. The doctor will tell you exactly how much prednisone to give your child each day. Never stop prednisone, unless the doctor tells you to do so. If you stop this drug or give your child too much or too little, he or she may get very ill.

Sometimes, your child will stay healthy after treatment. Your child may relapse (get sick again) at any time, even after a long time with good health. Getting sick may happen after a viral infection, such as a cold or the flu.

What problems call occur with prednisone?

Prednisone can be a very good drug, but it has a number of side effects. Some of these side effects are:

• being hungry• gaining weight • acne (pimples)• mood changes (very happy, then very sad)• being overactive

* more chance of infection• slowing of growth rate

Side effects are more common with larger doses and if it is used for a long time; once prednisone is stopped, most of these side effects go away.

What if prednisone does not work?

If prednisone does not work for your child or if your child has serious side effects, the doctor may order another kind of medicine, called an immunosuppressive drug. These drugs decrease the activity of the body's immune system. They are effective in most, but not all, children. Your doctor will discuss in detail with you the good and bad things about the drug. The side effects of these drugs include: increased susceptibility to infections, hair loss and increased blood cell production.

Parents also should be aware that children taking immunosuppressive drugs may become ill if they develop chicken pox. Therefore, you should notify your doctor any time that your child is exposed to chicken pox while on these medications.

Your child also may be given diuretics (water pills). These drugs help the kidney get rid of salt arid water. The most common water pill used in children is called furosemide. If your child starts to have a problem with vomiting or diarrhea, you should call your doctor as the child can lose too much fluid and become even sicker. Once protein disappears from the urine, diuretics should  stopped.

What other problems happen with the nephrotic syndrome?

Most children will have problems only with swelling. However, a child with nephrotic syndrome can develop a serious infection in the belly. If your child has a fever or starts complaining of severe pain in the belly, you should call your doctor at once.

Sometimes, children with nephrotic syndrome get blood clots in their legs. If this happens, your child will complain of:'

• severe pain in arm or leg• swelling of arm or leg• changes in color or  temperature of arm or leg

If any of these things happens, you should call your doctor right away.

What can parents do?

Much of your child's care will be given by you. Pay attention to your child's health, but do not overprotect the child. If your child is ill or taking prednisone, the doctor will recommend a low salt diet. This type of diet will make your child more comfortable by keeping the swelling down. Try to give your child foods that he or she likes, but that are low in salt. Ask the dietitian for suggestions.

Usually, the child will be allowed to drink as much as he or she wants. A child's natural thirst is the best guide as to how much to drink. You should also weigh your child and keep a record of weight to spot a change in the disease.

The first sign that your child is getting sick again is the return of protein in the urine. Because of this, many doctors ask you to check your child's urine regularly. To do this, a special plastic strip with a small piece of paper on the end is dipped into the urine. The paper will change color when protein is in the

urine. This test can be done easily at home and it can detect a relapse before any swelling is seen. Check with your doctor to learn how to do the test and how often to do it.

When there is swelling, check that your child's clothing is not too tight because the clothing can rub the child's skin over the swollen areas. This can make the skin raw, and it may get infected.

Your child will probably have this disease several years. It is very important to treat your child as normally as possible. Your child needs to continue his or her usual activities, such as going to school and seeing friends. Your child should be treated just like other children in the family in terms of discipline. Occasionally, your child may not go to school for a time. Your doctor will let you know if this is necessary. Keeping your child out of school or not letting him or her see friends will not change the illness.

Does the disease ever go away?

Sometimes. Even though the nephrotic syndrome does not have a specific cure, the majority of children "outgrow" this disease in their late teens or early adulthood. Some children will have only one attack of the nephrotic syndrome. If your child does not have another attack for three years after the first one, the chances are quite good that he or she will not get sick again.

Still, most children will have two or more attacks, The attacks are more frequent in the first one to two years after the nephrotic syndrome begins. After ten years, less than one child in five is still having attacks. Even if a child has a number of attacks, most will not develop permanent kidney damage. The major problem is to control their accumulation of fluid using prednisone and diuretics. Children with this disease have an excellent long-term outlook.

What else should I know?

1. Most children with the nephrotic syndrome respond to treatment.

2. Most children with the nephrotic syndrome have an excellent long-term outcome.

3. You should feel free to ask your child's doctor any questions.

What if I have more questions?

If you have more questions, you should speak to your doctor. You also can get additional information by contacting your local National Kidney Foundation Affiliate.

What is The National Kidney Foundation and how does it help?

Twenty million Americans have some form of kidney or urologic disease. Millions more are at risk. The National Kidney Foundation, Inc., a major voluntary health organization, is working to find the answers through prevention, treatment and cure. Through its 50 Affiliates nationwide, the Foundation conducts programs in research, professional education, patient and community services, public education and organ donation. The work of The National Kidney Foundation is funded entirely by public donations.

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Nephrotic Syndrome

Nephrotic syndrome is a group of symptoms including protein in the urine (more than 3.5 grams per day), low blood protein levels, high cholesterol levels, high triglyceride levels, and swelling.

Causes

Nephrotic syndrome is caused by various disorders that damage the kidneys, particularly the basement membrane of the glomerulus. This immediately causes abnormal excretion of protein in the urine.

The most common cause in children is minimal change disease, while membranous glomerulonephritis is the most common cause in adults.

This condition can also occur as a result of infection (such as strep throat, hepatitis, or mononucleosis), use of certain drugs, cancer, genetic disorders, immune disorders, or diseases that affect multiple body systems including diabetes, systemic lupus erythematosus, multiple myeloma, and amyloidosis.

It can accompany kidney disorders such as glomerulonephritis, focal and segmental glomerulosclerosis, and mesangiocapillary glomerulonephritis.

Nephrotic syndrome can affect all age groups. In children, it is most common from age 2 to 6. This disorder occurs slightly more often in males than females.

Assessment

1. Perform physical examination including assessment of the extent of edema.

2. Get your medical history carefully, particularly those associated with weight gain this time, renal dysfunction.

3. Observation of the manifestation of nephrotic syndrome : o Weight gaino Edemao Face puffy : Especially around the eyes Arising in the morning when you wake up Reduced daytimeo Swelling of the abdomen (ascites)o Difficulty breathing (pleural effusion)o Swelling labial (scrotal)o Intestinal mucosal edema that causes : Diarrhea Anorexia Intestinal absorption of poorlyo Pale skin extreme (often)o Be sensitive excitatoryo Easily tiredo Lethargyo Blood pressure is normal or slightly decreasedo Susceptibility to infectiono Change the urine : Decrease the volume Dark Smelly fruit Help with diagnostic and testing procedures, such as urine analysis will be a protein, cylinders and red blood cells;

analysis of blood for serum proteins (total, ratio of albumin / globulin, cholesterol), the number of red blood, serum sodium.

Nursing Diagnosis

Excess fluid volume (total body) associated with the accumulation of fluid in the network and the third space.

Purpose

The patient showed no evidence of accumulation of fluid (patients receive the appropriate volume of liquid)

Intervention

Review input relative to output accurately.Rational : need to determine kidney function, fluid replacement needs and reducing the risk of excess fluid.

Weigh weight per day (or more often if indicated).Rational : assess fluid retention

Review the change of edema: abdominal circumference measured at the umbilicus and Receptions edema around the eyes.Rational : to assess because of ascites and edema are common side.

Set the input fluid carefully.Rational : that does not get more than the amount needed

Monitor the intra-venous infusionRational : to maintain the prescribed input

Provide appropriate provisions corticosteroids.Rational : to reduce the excretion of proteinuria

Give diuretic if instructed.Rational : to provide temporary disappearance of the edema.

Source : http://www.nlm.nih.govhttp://nursing-all.blogspot.com