Sickle cell disease

Published on 02/04/2015 by admin

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Last modified 22/04/2025

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249 Sickle cell disease

Instruction

Examine this patient’s hands who has recurrent episodes of abdominal pain, precipitated by infection.

Salient features

History

• Bone pain

• Past history of strokes, fits

• Priapism

• Family history of similar problem

• Precipitating factors (infection, dehydration, cold, acidosis or hypoxia)

• Recurrent painful episodes.

Examination

• Afro-Caribbean patient

• Anaemia

• Digits of varying lengths (may be painful) (Fig. 249.1)

• Tell the examiner that you would like to examine the:

• urine for haematuria (renal papillary necrosis)
• leg for arterial ulcers
• abdomen for hepatomegaly
• heart for cardiomegaly and hyperdynamic circulation
• retina for neovascularization (which may cause blindness) (Fig. 249.2).
image

Fig. 249.1 Sickle-cell disease. Infarction in several of the metacarpals and proximal phalanges has resulted in bone destruction and swelling of the soft tissues.

(With permission from Adam et al. 2008.)

image

Fig. 249.2 Sickle-cell disease. (A) Macular ischaemia with the macular depression sign and perifoveal vascular remodelling. (B) Fluorescein angiogram of the same patient demonstrating an irregular and moth-eaten perifoveal capillary network and vascular telangiectasia.

(With permission from Yanoff, Duker 2008.)

Diagnosis

This black African patient has evidence of old dactylitis (lesions) caused by sickle cell anaemia (aetiology), which has caused severe deformity of the hand. She has difficulty buttoning her clothes (functional status).

Questions

What is the abnormality in this patient?

This patient has a structural abnormality of the haemoglobin chain (producing haemoglobin S (HbS)). A single base mutation from adenine to thymine results in substitution of valine for glutamine at the sixth residue of the β-globin chain. HbS polymerizes on deoxygenation and this results in the characteristic sickle appearance of haemoglobin. Sickling can produce a shortened red cell survival and impaired passage of cells through the microcirculation, leading to obstruction of small vessels and tissue infarction.

What do you know about the genetics of this syndrome?

In the homozygous state (sickle cell anaemia), both genes are abnormal (HbSS), whereas in the heterozygous state (sickle cell trait), only one chromosome carries the gene (HbAS). The disease does not manifest until the foetal form of haemoglobin (HbF) decreases to adult levels at about 6 months of age.

Does the haemoglobin level fall during a sickle cell crisis?

The patient has ‘steady-state’ anaemia and the haemoglobin level does not fall unless there is parvovirus-induced bone marrow aplasia, drug-induced haemolysis or sequestration of sickle cells in the liver and spleen.

Is the spleen enlarged in these patients?

The spleen may be enlarged in childhood as a result of haemolysis; in adult life, patients often undergo autosplenectomy (from infarcts), which increases their susceptibility to infection by Streptococcus pneumoniae (pneumonia, meningitis) and salmonella osteomyelitis.

What are the other complications of this disease?

Chronic leg ulcers (from ischaemia), pigmentary gallstones (from persistent haemolysis), chronic renal failure, aseptic necrosis of femoral heads, chronic renal disease, acute chest syndrome and pulmonary hypertension (appears to be a complication of chronic haemolysis, is resistant to hydroxyurea therapy and confers a high risk of death).

How would you investigate these patients?

• FBC: haemoglobin 60–80 g/l, with raised reticulocyte count

• Blood smear shows signs of hyposplenism (Howell–Jolly bodies, target cells)

• Sickling of red cells can be introduced by sodium metabisulfite but does not differentiate HbSS from HbAS

• Haemoglobin electrophoresis: there is no HbA, 80–95% HbSS and 2–20% HbF. High HbF levels are associated with a more benign progress. The parents of the patient will show features of sickle cell trait (remember that sickle cell trait protects against Plasmodium falciparum malaria).

How would you manage an acute sickle cell crisis?

Supportive therapy with intravenous fluids, oxygen, antibiotics and analgesia. Folic acid is given for those with severe haemolysis.

Is there any long-term treatment?

• Hydroxyurea and erythropoietin are given to increase synthesis of HbF.

• Allogenic bone marrow transplantation is being investigated as a possible ‘cure’ in severely affected individuals.

• Experimental therapy: induction of HbF by short-chain fatty acids, membrane-active drugs and other experimental treatments.

What is the role of blood transfusion in these patients?

• Steady-state anaemia requires no treatment and regular blood transfusions are given only when the anaemia is severe or if the patient has frequent episodes of crisis, particularly during pregnancy (to suppress endogenous production of HbS).

• Exchange transfusion is used for intractable pain crises, priapism and stroke.

What is the prognosis of this condition?

It is variable, with some having a normal lifespan while others succumb in the first few years of life to infection or episodes of sequestration. Median age of death is 42 years for homozygotes. The acute chest syndrome is the leading cause of death and its cause is unknown. The syndrome is precipitated by fat embolism and infection, particularly community-acquired pneumonia (N Engl J Med 2000;342:1855–65).

WH Howell (1860–1945), Professor of Physiology at Johns Hopkins Hospital, Baltimore, who also discovered and isolated heparin.

JMJ Jolly (1870–1953), French Professor of Histology.

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