Thalassaemia Case Scenarios

Dr Emma Drasar Haematology Consultant The Whittington Hospital

With transfusion and chelation therapy, thalassemia patients can be expected to have a normal life, shifting the focus to managing the disease complications

IOL, iron overload; TDT, transfusion-dependent thalassemia.

Borgna-Pignatti C, et al. Haematologica. 2004;89:1187-93. Musallam KM, et al. Haematologica. 2013;98:833-44.

Non-transfusion-dependent thalassemias (NTDT)

β-thalassemia major (regularly transfused, TDT)

Silent cerebral ischemia

Pulmonary hypertension Right-sided heart failure

Splenomegaly

Gallstones

Hepatic fibrosis, cirrhosis, and cancer

Extramedullary hemopoietic pseudotumors

Leg ulcers

Venous thrombosis

Osteoporosis

Cardiac siderosis Left-sided heart failure

Hepatic failure Viral hepatitis

Diabetes mellitus

Hypogonadism

Hypothyroidism Hypoparathyroidism

Osteoporosis

Disease-related Disease- and IOL-related

Surv

ival

pro

bab

ility

p < 0.00005

0

1.00

0.75

0.50

0.25

0 5 10 15 20 25 30 Age (years)

Birth cohort

1960–1964 1965–1969 1970–1974 1975–1979 1980–1984 1985–1997

Guidance for the clinician

Yardumian et al. Standards for the Clinical Care of Children and Adults with Thalassaemia in the UK. 3rd Edition 2016. The United Kingdom Thalassaemia Society .

Cappellini MD, et al. Guidelines for the management of transfusion dependent thalassaemia (TDT). 3rd ed. Thalassaemia International Federation Publication No. 20; 2014.

Available from: http://www.thalassaemia.org.cy/educational-programmes/publications?issuu=18570602/30656661

Complication 1 • 26 year old man

• Attends for routine cross match

• Mentions to Thalassaemia nurse that he was found on the floor last night by flat mates

• Has no memory of what happened.

• What would you do?

Complication 1

• Now feels fine • Does say has had

sensation of “skipped beats” for last month.

• Poorly compliant with chelation

Next investigations?

Complication 1 • ECG • 48 hour tape • Admit and IV desferral with view to introducing

deferiprone ASAP

Mildly dilated LV with impairment, EF 52%. Severe liver (0.86ms) and myocardial (2.1ms) iron loading. Both on 2-point curve. “We see one such severe cardiac iron overload every 3-5 years”.

Complication 1

Why does iron overload in the heart matter?

Guidelines for Iron Assessment Myocardial loading

Myocardial T2*(ms)

Hepatic loading

Hepatic T2* (ms)

Dry weight (Anderson)

None >20ms None >6.3ms <2mg/g

Mild >14-20ms Mild >2.7- 6.3ms 2->5mg/g

Moderate 10-14ms Moderate 1.4-2.7ms 5-10mg/g

Severe* <10ms Severe <1.4ms >10mg/g

Anderson LJ, et al. Eur Heart J. 2001;22:2171-9. Kirk P, et al. Circulation. 2009;120:1961-8.

LVEF, arrhythmia and cardiac failure associated with cardiac IOL Arrhythmia

0.15 0.10 0.05 0

0.20

0.25

0.30 < 10 ms

10–20 ms

> 20 ms

Pro

po

rtio

n o

f p

atie

nts

w

ith

arr

hyt

hm

ia

60 0 120 180 240 300 360

p < 0.001

Cardiac failure

Pro

po

rtio

n o

f p

atie

nts

d

evel

op

ing

card

iac

failu

re

0.1

0.3 0.2

0

0.4

0.5

0.6

< 6 ms

6–8 ms

8–10 ms

> 10 ms

Follow-up time (days)

60 0 120 180 240 300 360

p < 0.001

LVEF

(%

)

0

50

70

40

30

20

10

60

80

90

0 20 40 60 90 80 100 10 30 50 70 Cardiac T2*, ms

Cardiac T2* value of 37 ms in a normal heart

Cardiac T2* value of 4 ms in a significantly iron-overloaded heart

Normal T2* range

Normal LVEF range

Myocardial T2* values < 20 ms are associated with a progressive and

significant decline in LVEF

• The age at the time of death from cardiac

mortality increased in parallel with the

decrease of cardiac mortality

• The prognosis of β-TM patients

significantly improved with

– non-invasive methods to measure organ iron

– new chelators

– increased blood safety measures

Significant reduction in cardiac mortality in the past two decades with new chelators and diagnostics

Origa R, et al. Expert Rev Hematol. 2015;8:851-62. M

ean

age

at

de

ath

(y

ear

s)

0

8

24

32

40

16

Even

ts pe

r 1,0

00

pt/yr

1989– 1995

1996– 2000

2000– 2003

2004– 2006

2005– 2010

2010– 2014

0

3

9

12

15

6

Increase of the age at death (line) and decrease in cardiac deaths (bar chart) reported in Cagliari, Italy,

over 24 years

Complication 2

• 45 year old beta thal major patient presents to A&E with nausea, confusion and polyuria and polydypsia.

• How would you investigate them?

• What is the underlying cause?

Complication 2 • Treat as you would any other patient with HHS

but think about cardiac function • Screening for DM and control – annual OGTTs

and regular fructosamines • Role of joint clinics and MDT to improve

compliance • Diabetes nurse reviewing patient while they

have their transfusion • Phone clinics

Endocrinopathies increase with age in TDT patients

Cunningham MJ, et al. Blood. 2004;104:34-9.

Pro

po

rtio

n o

f th

e p

atie

nts

(%

)

Older thalassaemia major patients

Ang et al 2013 EJH

60%

Complication 3

Complication 3 • What is this and what could have led to

its development in a patient with thalassaemia?

• What can we do to prevent it from happening to future patients?

Liver complications are becoming more prominent

• Voskaridou E, et al. Ann Hematol. 2012;91:1451-8.

0

5

10

15

20

25

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Heart disease

Liver disease

Year of death

Pat

ien

ts (n

) n = 4,506, of whom 2,485 (52.3%) with TM

HCC is a major cause of death in HH and NTDT • HCC generally occurs on a cirrhotic substrate

– yearly incidence rate approximately 3% in HH; no data for NTDT

• HCC is the main cause of morbidity and mortality in adult HH and is increasing in thalassaemia (particularly NTDT)

– of 36 thalassaemic patients with HCC, 22 (61%) had β-TI, including 6 who were HCV negative (probably almost all had liver cirrhosis)

• Reasons for increased risk

– IOL remains unnoticed and untreated

• patients are asymptomatic

• iron burden was underestimated in β-TI patients

– patients with an adult form of HH and β-TI patients survive longer

• higher risk of cirrhosis and more time for HCC development HCC, hepatocellular carcinoma; TI, thalassaemia intermedia.

• Borgna-Pignatti C, et al. Br J Haematol. 2004;124:114-7. • Fargion S, et al. Hepatology. 1994;20:1426-31. Fracanzani AL, et al. Hepatology. 2010;51:501-10.

Maakaron JE, et al. Ann Hepatol. 2013;12:142-6. Restivo Pantalone G, et al. Br J Haematol. 2010;150:245-7.

Recommendations? • All patients who have EVER had a liver biopsy with

evidence of cirrhosis or fibrosis should be on surveillance for HCC – Six monthly ultrasound scans – Endoscopy annually

• Any patients with severe iron overload at any time in the past should be tested to identify fibrosis/cirrhosis (fibroscan or other method) and then enter survailence

Complication 4 • 42 year old thalassaemia major patient

presents with high temperature, unwell with loin to groin pain.

• What could be causing this?

• Renal function has been deteriorating over past 5 years. What could be contributing to this situation?

Complication 4

• Renal complications increasingly common in thalassaemia:

– Renal tubulopathy

– Renal stones

– Renal cell carcinoma

Renal stones

Probability of forming a stone – Asia 1–5%

– Europe 5–9%

– North America 13%

– Saudi Arabia 20%

1–2% occurrence in children

Types – Ca2+ oxalate/phosphate 50–70%

– uric acid 10–23%

– struvite 5–10%

– cysteine 1–2%

Idiopathic hypercalciuria

Hyperparathyroidism

Sarcoidosis

Vitamin D intake

Distal renal tubular acidosis

Lithium

Hypercalcaemic syndromes – tumour, etc.

Hereditary

1. Ryall R, et al., editors. Urolithiasis 2. New York: Plenum Press; 1994.

Nephrolithiasis

Mussalam KM, Taher AT. J Am Soc Nephrol. 2012;23:1299-302.

Mechanisms of renal disease in thalassaemia

Vascular resistance

Renal plasma flow

GFR

Endothelial and epithelial

damage

Transudation of

macromolecules

Mesangial dysfunction GFR

Tubular cell damage

Epithelia–mesenchymal

transdifferentiation

Tubulointerstitial injury

Glomerular sclerosis GFR

GFR Iron overload Chronic anaemia or hypoxia

Chronic anaemia or hypoxia

Tubular cells

Iron overload

Oxidative stress

Lipid peroxidation

Cellular damage

Relative iron depletion

Abnormal mitochondrial

function and arachidonic acid

cascade

Tubuloglomerular feedback

and haemodynamic change GFR

Iron chelation

Nephrotoxicity

Iron chelation

Conclusion • New complications developing as well as the

preexisting ones

• Thalassaemia patients are reaping the benefits of longer survival but also a whole new lot of complications

• Long term impact of iron overload is resulting in new problems

Thanks