**1. Introduction**

The inherited haemoglobinopathy thalassaemia major (also known as beta thalassaemia major) results from homozygous carriage of mutations at the betaglobin locus, resulting in defective haemoglobin synthesis and a severe hypochromic, microcytic anaemia. Epidemiologically, the largest incidence of thalassaemia major is in the Mediterranean countries and the Middle East, but demographic change and international migration have resulted in it posing a global health issue. Life expectancy has been radically increased by the advent of combined transfusion and chelation therapy, but this regimen is complicated by both citrate toxicity and the development of endocrine complications secondary to destructive haemosiderin deposition in glandular tissues, particularly during adolescence and young adulthood [1]. Pathologic iron deposition is concentrated in cardiac tissue, the liver parenchyma and endocrine glands [2], with the development of multiple endocrinopathies first being reported by Bannerman and colleagues in 1967 [3]. Determining the prevalence and onset patterns of endocrine disease in thalassaemia major remains a challenge, despite their high frequency; primarily, this related to variation in exposure to chelation therapy, compliance with chelation, and improved survival shedding light on new disease phenomena [4–8].

Chronic anaemia—and subsequent tissue hypoxia—results in compensatory increases in erythropoiesis and gastrointestinal iron absorption. In conjunction with regular blood transfusion, these processes conspire to produce massive iron deposition in thalassaemia. Iron is regulated exclusively at the level of absorption, with no excretory mechanism. Chelation therapies are available, but challenges in their administration, including via the parenteral route, and need for regular


*Key: OGTT: oral glucose tolerance test DM: diabetes mellitus IFG: impaired fasting glycaemia IGT: impaired glucose tolerance DKA: diabetic ketoacidosis PTH: parathyroid hormone.*

*ALP: alkaline phosphatase LH: luteinizing hormone FSH: follicle-stimulating hormone SHBG: sex-hormone binding globulin.*

*\*From puberty, or age 10 years if family history of DM.*

*••From age 12 years.*

*\*\*NICE 9 Key Care Processes: glycaemic control (via Fructosamine); blood pressure; cholesterol level; retinal screening; foot checks; urinary albumin testing; serum creatinine testing; weight monitoring; smoking status check. ‡ Including, for female patients, menstrual history; for male patients: history of impotence. • From age 2 years. UKTS (2016) guidelines recommend ~80 nmol/L optimal target following supplementation.*

**Table 1.**

*Summary of endocrine investigations in thalassaemia major [after UK Thalassaemia Standards, 2016].*

**61**

✦*Note.* ►

**Table 2.**

*Investigation and Management of Endocrinopathies in Thalassaemia Major*

• Impaired glucose regulation (IFG/ IGT) or Non-insulin treated Diabetes: Intensify chelation therapy, consider using combination chelation regimens • Diabetes: Referral to diabetes specialist. Managed according to NICE treatment targets and recommendations for type 1

• Hypogonadism: hormone (oestrogen/ testosterone) replacement • Females: combined oral contraceptive pill (when contraception is also required, or "post-menopausal" replace-

test: may consider GH therapy in

• Vitamin D replacement if required

• Bisphosphonates: considered for patients with low BMD for age►

adequate vitamin D levels

and interest in osteoporosis

fractures and/or falling BMD despite

supervised by a clinical with experience

*Key: DM: diabetes mellitus IFG: impaired fasting glycaemia IGT: impaired glucose tolerance DKA: diabetic* 

*Summary of endocrine treatments in thalassaemia major [after UK Thalassaemia Standards, 2016].*

• Adrenal insufficiency: Hydrocortisone

*Z-score <* −*2.0 if premenopausal or under 50, t-score <* −*2.5 if post-menopausal or over 50.* <sup>▷</sup>

: advisable that treatment is

and type 2 diabetes

Puberty • Suspicion of pubertal delay: Referral to paediatric endocrinologist

ment regime)

Growth • Positive growth hormone stimulation

childhood✥

• Denosumab<sup>▷</sup>

*ketoacidosis BMD: Bone Mineral Density GH: growth hormone.*

*Anti-RANKL monoclonal antibody.* ✥*some evidence for GH therapy in childhood only.*

supplementation

blood monitoring, hamper their acceptability. The primary endocrine complications found in thalassaemia, in the order reviewed in this chapter, are: disorders of growth; sexual development and fertility; abnormal bone mineralisation; diabetes

We have previously published an online Review of Endocrine Disorders in Thalassaemia in 2014 (Open Journal of Endocrine and Metabolic Diseases, 2014, 4, 25–34). In this book chapter, we have updated all the latest evidence and discuss current thoughts & details of the multi-system endocrine involvement in Thalassaemia. Finally, **Tables 1** and **2** summarise the investigations and treatment

> In patients with symptoms/signs of Diabetic Ketoacidosis (DKA) who are acutely unwell and plasma glucose>12 mmol; measure blood or

urinary ketones

function/rhythm

replacement.

2–3 years

available

✦Specialist endocrine review advised before initiation of hormone

• Bisphosphonate: should be reviewed after a maximum of 5 years for oral agents and 3 years for IV agents. Bisphosphonate 'holiday': is recommended after the above intervals for a period of

✦Adrenal dysfunction may be subacute (during acute illness), consider adrenal support, even before formal proof of insufficiency is

• Hypothyroidism: thyroxine replacement ✦Hypothyroidism may impair cardiac

, fragility

*DOI: http://dx.doi.org/10.5772/intechopen.93861*

of such patients.

Glycaemic Control

Thyroid Function

Gonadal Function

Bone Metabolism

Adrenal Function

mellitus; hypothyroidism; and hypoadrenalism [9].

*<sup>†</sup> From age 12 years.*

*Investigation and Management of Endocrinopathies in Thalassaemia Major DOI: http://dx.doi.org/10.5772/intechopen.93861*

blood monitoring, hamper their acceptability. The primary endocrine complications found in thalassaemia, in the order reviewed in this chapter, are: disorders of growth; sexual development and fertility; abnormal bone mineralisation; diabetes mellitus; hypothyroidism; and hypoadrenalism [9].

We have previously published an online Review of Endocrine Disorders in Thalassaemia in 2014 (Open Journal of Endocrine and Metabolic Diseases, 2014, 4, 25–34). In this book chapter, we have updated all the latest evidence and discuss current thoughts & details of the multi-system endocrine involvement in Thalassaemia. Finally, **Tables 1** and **2** summarise the investigations and treatment of such patients.


*Key: DM: diabetes mellitus IFG: impaired fasting glycaemia IGT: impaired glucose tolerance DKA: diabetic ketoacidosis BMD: Bone Mineral Density GH: growth hormone.*

✦*Note.*

*Human Blood Group Systems and Haemoglobinopathies*

Non-DM patients\*

Thyroid Function Tests (TFTs)†

TSH, free T3, free T4

assessment from age 10: Tanner staging

Growth 6-monthly: height/

Annual morning cortisol level

*tolerance DKA: diabetic ketoacidosis PTH: parathyroid hormone.*

*\*From puberty, or age 10 years if family history of DM.*

Annual clinical assessment‡ Men: annual morning testosterone Women: if normal menstrual history, no further investigations indicated

Puberty Systematic clinical

: free

OGTT and fructosamine DM: fructosamine and review as per NICE 9 Key Care Processes\*\*

Glycaemic Control

Thyroid Function

Gonadal Function

Bone Metabolism

Adrenal Function

*From age 12 years. ••From age 12 years.*

*globulin.*

*†*

*‡*

*•*

**Table 1.**

**Routine: annual Routine: other** 

:

**interval**

Chronic anaemia—and subsequent tissue hypoxia—results in compensatory increases in erythropoiesis and gastrointestinal iron absorption. In conjunction with regular blood transfusion, these processes conspire to produce massive iron deposition in thalassaemia. Iron is regulated exclusively at the level of absorption, with no excretory mechanism. Chelation therapies are available, but challenges in their administration, including via the parenteral route, and need for regular

> Male: if low testosterone ➔ measure LH/FSH/

weight/height velocity from diagnosis to attainment of final adult height

phosphate/ALP ➔ PTH if calcium level

*Key: OGTT: oral glucose tolerance test DM: diabetes mellitus IFG: impaired fasting glycaemia IGT: impaired glucose* 

*ALP: alkaline phosphatase LH: luteinizing hormone FSH: follicle-stimulating hormone SHBG: sex-hormone binding* 

SHBG

Vitamin D level• 6-monthly••: calcium/

low

*\*\*NICE 9 Key Care Processes: glycaemic control (via Fructosamine); blood pressure; cholesterol level; retinal screening; foot checks; urinary albumin testing; serum creatinine testing; weight monitoring; smoking status check.*

*From age 2 years. UKTS (2016) guidelines recommend ~80 nmol/L optimal target following supplementation.*

*Summary of endocrine investigations in thalassaemia major [after UK Thalassaemia Standards, 2016].*

*Including, for female patients, menstrual history; for male patients: history of impotence.*

DM: home capillary blood glucose as per individual management plan

**Specific circumstances**

• IFG or IGT: fructosamine at 6-monthly intervals • Symptomatic hyperglycaemia: random plasma glucose ± ketones to exclude DKA

• Clinical evidence of thyroid dysfunction: random TFTs

Female: if oligomenorrhoea/ amenorrhoea develop ➔ measure LH/FSH/oestradiol. Specialist endocrine review advised before initiation of hormone replacement.

If concerns regarding growth delay: bone age estimation (wrist plain radiographs) at 1–2 year

Faltering height velocity: growth hormone stimulation test

intervals

**60**

► *Z-score <* −*2.0 if premenopausal or under 50, t-score <* −*2.5 if post-menopausal or over 50.* <sup>▷</sup>

*Anti-RANKL monoclonal antibody.*

✥*some evidence for GH therapy in childhood only.*

#### **Table 2.**

*Summary of endocrine treatments in thalassaemia major [after UK Thalassaemia Standards, 2016].*
