Endocrine complications in

Thalassemia major

SACHIN SONI

B- Thalassemia major• Point Mutations in genes presents on chromosome 11

• Severity depends on B- chain deletion-

-b0-no b-globin synthesis

-b+ reduced synthesis

• Disease results in an overproduction of a-globin chains

• Erythropoiesis increases, sometimes extramedullary

Types Of B-Thalassemia

• b-Thalassemia Minor - Minor point mutation- Minimal anemia; no treatment indicated

• b-Thalassemia Intermedia- Homozygous minor point mutation or more severe heterozygote- Do not require chronic transfusions

• b-Thalassemia Major-Cooley’s Anemia- Severe gene mutations- Need careful observation and intensive treatment

Pathophysiology• Reduced or nonexistent of b-globin

- Poor oxygen-carrying capacity of RBCs• Failure to thrive, poor brain development

- Increased alpha globin production • Bone marrow destruction of RBC precursors

• Increased splenic destruction of dysfunctional RBCs - Anemia, jaundice, splenomegaly

• Hyperplastic Bone Marrow - Ineffective erythropoiesis• Poor bone growth, frontal bossing, bone pain

- Increase in extramedullary erythropoiesis• Iron overload—increased absorption and transfusions

- Endocrine disorders, Cardiomyopathy, Liver failure

Endocrine Complications• Growth retardation-• Growth pattern relatively normal until age of 9-10 years

• Contributing factors include-• Chronic anaemia• Transfusional iron overload• Hypersplenism • Chelation toxicity

Diagnosis and investigations

• Slow growth rates-

Growth velocity below 1SD for age and sex• Short stature-

Height below 3rd centile for age and sex• Others- pituitary hormone deficiencies – Gonadotrophins

• First line investigation (six-monthly intervals) • Accurate measurement of standing and sitting height• Pubertal staging (Tanner)• Bone age- Examination of metaphysis

Treatment

• Anaemia- Regular blood transfusion

• Folate deficiency- Folic acid replacement

• Hypersplenism- Splenectomy

• On regular desferrioxamine- causes poor growth

Delayed puberty andHypogonadism

• Delayed puberty - Complete lack of pubertal development by age of 13 years in girls and 14 years in boys.

• Hypogonadism: Boys- Absence of testicular enlargement (less than 4 ml)

• Girls- Absence of breast development 16 years of age

• Arrested puberty- lack of pubertal progression over a year or more

-Testicular size remains 6-8 ml

-breast size at B3

Penile development Breast development Growth of pubic hair

P1: Prepubertal B1: Prepubertal PH1: Prepubertal

P2: Early puberty- scrotum and testes, 4-5 ml, little enlargement of penis)

B2: Early puberty (breast bud stage)

PH2: Early puberty(sparse growth)

P3: Mid-puberty- Penis and growth of testes, 8-12 ml

B3: Mid-puberty (breast and areolar

PH3:Mid-puberty (hair extends over the pubic junction)

P4:Advanced puberty penis length, breadth. pigmentation of scrotal skin and enlargement of testicles

B4: Advanced puberty(areola and nipple project separately from contour of the breast)

PH4: Advanced puberty(hair corresponds to adult growth but less extensive)

P5: Adult B5: Adult (Fully developed breast,the areola no longer projects separately from the breast

PH5: Adult

Investigations• Routine biochemical analysis• Bone age- X-ray wrist, hand• Thyroid function- TSH and FT4• Hypothalamic-pituitary-gonadal function:• Gn-RH, stimulation test for LH and FSH• Sex steroids- serum testosterone, serum17- Estradiol• Pelvic ultrasound - ovarian and uterine size• Transglutaminase antibodies• Others- Growth Hormone (GH) stimulation test, Insulin

Growth Factor-I(IGF-I), Insulin Growth Factor Binding Protein-3 (IGFBP-3), plasma zinc

Treatment• Girls- Ethinyl estradiol 2.5-5 mcg p.o. daily for six months

Hormonal reassessment spontaneous puberty

No response

Oral oestrogen increased dosages (ethinyl estradiol

5-10 mcg daily) for another 12 months

• No breakthrough uterine bleeding- low dose estrogen- progesterone hormone replacement

Males- Low dosages IM depot-testosterone esters(25mg) monthly for six months

Hormonal re-assessment Hypogonadotrophic hypogonadism

dose 50 mg per month can be continued • Fully virilising dose is 75-100 mg depot- testosterone esters every 10 Days IM.• Pubertal arrest- Testosterone esters or

topical testosterone gel

Hypothyroidism• Pre-clinical hypothyroidism- asymptomatic.• Mild and overt hypothyroidism-

-Growth retardation

-Decreased activity

-Above normal weight

-Constipation,

-Reduced school performance

-Cardiac failure, pericardial effusion • Thyroid gland not palpable• Thyroid antibodies negative • Thyroid ultrasonography- Irregular echo pattern, capsular• thickening

Investigation &Treatment

Hypo-thyroidism

Serum FT4 Serum TSH TSH Response to TRH

Treatment

Subclinical Normal Marginally Increased (TSH: 4.5-8mIU/l)

Increased Observation

Mild Marginally low

Elevated Exaggerated

L-Thyroxin

Overt Low Elevated Exaggerated

L-Thyroxin

Impaired carbohydratemetabolism

• Pathogenesis resembles type-2 diabetes• Age of onset early in second decade of life

• Type of glycaemia classified as-

Plasma glucose level

Diabetic type Normal type Borderline type

Fasting Plasma Glucose

≥7.0 mmol/l (126 mg/dl)

<6.1 mmol/l (110 mg/dl)

Neither diabetic nor normal types

2 h plasma glucose level

≥11.1mmol/l (200 mg/dl)

<7.8 mmol/l (140mg/dl)

According to cut-off values for venous PG

Investigations and Treatment• Oral Glucose Tolerance Test (OGTT) annually from age of

puberty• Children dose of glucose-1.75 g/kg (max 75g)

• Treatment-• Strict diabetic diet, weight reduction• Intensive iron chelation therapy• Symptomatic patient- Insulin• Hyperinsulinism- diet alone, Acarbose • Oral hypoglycaemic agents

Hypoparathyroidism

• Hypocalcaemia is late complication of iron overload • Onset after age 16 • Majority is having mild form of disease with paraesthesia• Severe cases may complicate- Tetany ,seizures, cardiac failure• Investigations- Serum calcium, phosphate and phosphate

balance. • Parathyroid hormone • 1,25 dihydroxycholecalciferol (vitamin D).

Treatment• Oral vitamin D • Calcitriol dose- 0.25-1.0 mcg, twice daily• Quarterly plasma and daily urinary calcium and phosphate• Phosphate binder• Tetany and cardiac failure require intravenous calcium

gluconate under• Careful cardiac monitoring followed by oral vitamin D

Osteoporosis• Definition- Characterised by low bone mass and

microarchitectural deterioration with a resulting increase in bone fragility and hence susceptibility to fracture

• osteopenia osteoporosis syndrome (OOS) – - Major cause of bone pain of hip and spine

Aetiopathogenesis• Multifactorial causes of OOS include-• Marrow expansion secondary to ineffective erythropoiesis • Anemia, transfusional haemosiderosis, delayed puberty• Use of chelation agents- eg: Desferroxamine • Multiple endocrinopathies-• Hypogonadothrophic hypogonadism, primary hypogonadism • low IGF1, low vitamin D levels ,Aberrant vitamin D-PTH axis • polymorphism VDR gene and COL 1• Diminished osteoblast function with reduced osteocalcin

increase in osteoclast activity • RANK/RANKL/osteoprotegerin pathway

Diagnosis and investigations• Commonest presentation- bone pain and backache with or

without fractures, asymptomatic in 20% cases.

(A) DEXA Scan-• The diagnosis is best confirmed by bone mineral density

(DEXA)• World Health Organisation (WHO) criteria for diagnosis of

OOS• Osteoporosis-• BMD > 2.5 SD below the young normal mean (T score) or• Standard deviations in relation to patient’s age (Z score)• Osteopenia-• BMD >1.5-2.5 SD below the young normal mean (T score)

MANAGEMENT1 Sex steroid replacement therapy• In symptomatic or asymptomatic patients sex hormone

replacement therapy for at least two years

2 Calcimimetics- Vitamin D oral dose-1000-1500 IU/day• calcium supplementation (500 mg-1G orally/day)

3 Anti-resorption agents- Bisphosphonates potent inhibitors of osteoclast function, used as second line therapy

• - Pamidronate 1-2 mg/kg body weight once a month as• IV infusion for 3-5 years• -Alendronate 70 mg orally per week• -Zolandronic 3-4 times in a year

4 Combination therapy- Bisphosphonate + HRT

Monitoring of Treatment• Biochemical parameters -bone and sex steroid profile• Annual DEXA scan-

- Spine and femoral neck to determine the T Score• long-term treatment for >5 years is not recommended• -may induce osteosclerosis of jaw• Biochemical correction of hypogonadism confirmed from

optimal peak and sex steroid levels.• Vitamin D replacement therapy- risk of nephrocalcinosis • Bisphosphonate- • -Patients on thyroxine and corticosteroid therapy