Splenic enlargement in adults with homozygous sickle cell disease: the Jamaican experience

Abstract

Objective

It is quite rare to find splenomegaly or its various complications in adults with homozygous sickle cell (SS) disease. Splenomegaly in adults may indicate a differential severity of disease, when compared with those who have had ‘autosplenectomy’.

Methods

We studied the clinical and haematological profiles of all SS patients (n = 25) in our database who have had splenomegaly in their adulthood (group 1) and compared with a random sample of age- and gender-matched persons (n = 75) who did not have splenomegaly in adulthood (group 2).

Results

Group 1 persons had higher foetal haemoglobin, lower platelets and white blood cells, and greater prevalence of gall bladder disease and hospitalizations. Seven of the 25 persons in group 1 had acute splenic sequestration and the rest had hypersplenism.

Conclusions

Splenic enlargement occurring during adulthood may imply lower severity of disease and clinicians should consider this diagnosis even in persons with SS genotype.

Keywords:

• Splenic enlargement
• Adults
• Homozygous sickle cell disease
• Jamaica
• Clinical profile

Introduction

The natural history of splenomegaly in homozygous sickle cell (SS) disease is for a transient, modest splenic enlargement in early childhood to be followed by a progressive splenic fibrosis,¹ due to repeated episodes of vaso-occlusion and infarctions, ultimately leading to autosplenectomy. Occasionally splenomegaly persists, and may be associated with sequestration either chronically (hypersplenism, HS) or acutely (acute splenic sequestration, ASS). Haematological abnormalities are uncommon.

In the patients with splenomegaly, the persistence of a high foetal haemoglobin level and the concomitant presence of alpha-thalassemia (both of which inhibit sickling) may be involved in predisposing the patients to sequestration.^2,3 In fact, there are isolated reports of splenic regeneration after hydroxyurea therapy⁴ (which increases foetal haemoglobin levels), as well as after chronic transfusion therapy^5,6 (which presumably reduces levels of sickling in the blood). Even though splenomegaly in adults with SS is more common in other parts of the world,^7–11 it is very infrequently described in the western hemisphere. Importantly, the presence of splenomegaly in adults may indicate a differential severity of disease when compared with those who have had ‘autosplenectomy’, as the latter will likely have greater immune dysfunction due to the absence of the spleen.¹²

The Sickle Cell Unit in Jamaica has one of the largest clinic populations of persons with sickle cell diseases and has been operating over a period greater than 40 years. There have been infrequent reports of adult splenomegaly in SS patients¹ at this Unit as well. In this study, we seek to describe the clinical manifestations and the haematological parameters of those Jamaican patients with SS disease in our database who have had persistent childhood splenomegaly or developed splenomegaly in their adulthood, i.e. over the age of 18 years, as well as compare these parameters to those in an age- and gender-matched SS control group who have never had an episode of adult splenomegaly.

Methods

Ethics statement

The Sickle Cell Unit in Jamaica is a specialized unit within the University of the West Indies, and is dedicated to research. Therefore, all patients who attend are aware that their medical information and notes, which are stored in a fully protected database, may be used for research. No registration numbers, names, or other information that may potentially identify the patient is recorded from the database. Hence, individual patient consent was not required for this study. However, all strict confidentiality criteria were met and this study was granted ethical approval by the UHWI/UWI/FMS Ethics Review Committee. All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki.

This was a retrospective study requiring a chart review of all patients of the Sickle Cell Unit, Jamaica, who had a diagnosis of SS disease and had a documentation of splenomegaly (spleen palpated below the left costal margin) recorded (labeled ‘group 1’ hereafter) in the database after age 18 years. Clinical features such as frequency of painful crises, acute chest syndrome, presence/absence of renal disease, leg ulcerations and gall bladder disease were recorded from their patient files. Steady state and acute state haematological parameters such as haemoglobin levels, steady state mean cell volume levels, haemoglobin F levels, haemoglobin A2 levels, alpha-thalassemia status, white cell counts and reticulocyte counts, were also extracted from the database. Once cases were identified, three age- and sex-matched adult patients, with nil history of splenectomy and who were never detected as having splenic enlargement after age 18 years, (labeled ‘group 2’ hereafter) were also randomly selected from the database to serve as controls for each index case and similar clinical data were extracted for them. Further data collected on group 1 included number of blood transfusions they were given for the episodes, what was coded as the cause for their splenic enlargement, and whether they ended up with a splenectomy.

Statistics

Data were analysed using STATA™ 10.0 (StataCorp, College Station, Texas, USA).

Descriptive statistics are reported as frequency for categorical data and mean and standard deviation for continuous data. Conditional logistic regressions were conducted for univariate analyses of differences between groups, and are reported as odds ratios (ORs) with 95% confidence intervals.

Results

A total of 25 persons (of a total of 3304 persons in SCU database) were identified as having had splenomegaly in adulthood from the database. Their mean age at the time of first presentation with splenic enlargement was 28.2 years with a range of 18.1–58.5 years and consisted of 10 male and 15 female individuals. None of the persons in group 1 or 2 were on a chronic transfusion programme or hydroxyurea therapy.

Group 1 vs. group 2

Interestingly, a much larger proportion of persons in group 1 had childhood splenomegaly recorded than did those in group 2 (18/25 vs. 5/75; OR: 5.79, P < 0.001). There were some significant differences in the haematological profile of both groups (Table 1), where steady state platelet counts (312.9 ± 122.9 vs. 419.5 ± 119.2; OR: 0.99, P < 0.001), and white cell counts (10.3 ± 3.0 vs. 13.0 ± 11.9; OR: 0.8, P: < 0.05) were significantly lower, and the steady state foetal haemoglobin level (9.4 ± 5.5 vs. 7.2 ± 4.2; OR: 1.1, P < 0.05) was higher in group 1.

Table 1. Steady-state haematological and historical variables compared between cases and controls

	Group 1 (n = 25)	Group 2 (n = 75)	OR (CI)
Hemoglobin, gm/dl (mean ± SD)	8.2 ± 1.3	8.1 ± 1.1	1.1 (0.7–1.6)
Reticulocytes, % (mean ± SD)	11.0 ± 4.0	10.9 ± 3.1	1.1 (0.9–1.2)
WBC (×10^9/L) (mean ± SD)	10.3 ± 3.0	13.0 ± 11.9	0.8* (0.67–0.97)
Platelets (×10^9/L) (mean ± SD)	312.9 ± 122.9	419.5 ± 119.2	0.99**(0.98–0.99)
MCV, fl (mean ± SD)	85.3 ± 9.0	88.8 ± 8.0	0.95 (0.89–1.01)
Haemoglobin F, % (mean ± SD)	9.4 ± 5.5	7.2 ± 4.2	1.1* (1.0–1.2)
Haemoglobin A2, % (mean ± SD)	2.8 ± 0.6	3.0 ± 0.5	0.56 (0.22–1.44)
Freq Alpha Thal Status, n			0.92 (0.78–1.09)
(α -/α -)	4	0
(α -/α α)	5	9
(α α/α α)	6	15
History childhood splenomegaly, n			5.79** (2.6–12.9)
Yes	18	5
No	4	66
Unknown	3	4

WBC, white blood cells; CI, confidence interval.

*P < 0.05.

**P < 0.001.

A significantly greater proportion of persons in group 1 had a history of gall bladder disease (8/25 vs. 11/75; OR: 1.8, P < 0.05) and had more frequent hospitalizations (18/25 in group 1 vs. 70/75 in group 2 had lower frequency of hospitalizations; OR: 0.28, P < 0.05) as compared with controls (Table 2). More persons in group 2 gave a history of having a leg ulcer (58% in group 2 vs. 39% in group 1), even though the difference was not statistically significant There were no differences in frequency of pain or acute chest syndrome events within the two groups.

Table 2. Clinical outcomes compared between cases and controls

	Group 1 (n = 25)	Group 2 (n = 75)	OR (CI)
Freq of painful crises, n			0.81 (0.3–2.0)
Once a month or more	11	37
Rarely or never	14	38
History of leg ulcers, n			0.7 (0.4–1.1)
Yes	9	43
No	14	31
Unknown	2	0
Freq of ACS, n			0.78 (0.2–2.9)
≥ 3 events –	4	16
0–2 events	18	58
History of renal disease, n			1.0 (0.5–2.0)
Yes	2	9
No	19	60
Unknown	4	6
History of gallbladder disease, n			1.8* (1.06- 3.06)
Yes	8	11
No	14	61
Unknown	3	3
Frequency of hospitalizations, n			0.28* (0.09–0.9)
Once every 3–5 years or less	18	70
Once a year or more	6	5

CI, confidence interval.

*P < 0.05.

Group 1

The number of independent episodes of splenomegaly after achieving adulthood ranged from one episode to seven episodes, with a median of three episodes. The mean spleen size was 7.2 cm below the left costal margin, with a range of 3–15 cm. The mean change in haemoglobin levels was a fall of 2.1 gm/dl, with a maximum drop of 5.3 gm/dl. The reticulocytes count increased for most cases, ranging from an increase of 17% to a fall of 6%, the mean change being an increase by 2.9%. Not many episodes were managed with a blood transfusion, four persons had 2 units of packed cells transfused and one case had 1 unit transfused. Six had a splenectomy done after two to four episodes of splenic enlargement, the status of splenectomy was not known for three cases, and the remaining persons have not had a splenectomy to date.

Seven of the persons were diagnosed with ASS, whereas the rest had a diagnosis of HS. As expected, those with ASS had a greater fall in their haemoglobin (3.2 gm/dl vs. 1.6 gm/dl; P = 0.047); a greater increase in their reticulocytes count (7% vs. 0.8%; P = 0.008); and more of them required a splenectomy (3/7 vs. 3/18; Fisher's exact: 0.045) when compared with those with HS. There were no differences in steady-state haematological parameters in those with ASS and HS, nor in their clinical outcomes, except that those with ASS had a greater frequency of hospitalizations when compared with those diagnosed with HS.

Discussion

This is the largest series, to our knowledge, reported of splenic enlargement occurring in adults with SS disease. A normally functioning spleen is an important component of a person's immune system, involved in antigen processing and antibody synthesis.⁵ In this study, however, it is not clear whether splenic function was maintained for the persons with splenomegaly in adulthood, as no investigations for splenic function were available for them. However, most of them had splenic enlargement during their childhood as well and we may assume that these persons never actually had a period of splenic atrophy. This may imply milder disease in the cases, as splenic atrophy is a result of repeated attacks of vaso-occlusion and resulting infarctions in the spleen. Also the loss of spleen early in life poses greater risk for severe infections and hence greater morbidity, and hence retention of normal splenic sizes may mean retention of splenic function and hence lower risk of such infections.

Alpha-thalassemia is known to inhibit in vivo sickling in SS disease and may be an important genetic determinant of its haematologic severity.¹³ It is also known to be associated with a higher frequency of splenomegaly.^1,3,14 The alpha-thalassemia status was not known for all persons in this paper, and even though the difference among those where it was known, was not significant, it is to be noted that only a few persons in group 2 had any alpha-gene deletions whereas many of the persons in group 1 had homozygous or heterozygous alpha-thalassemia. Foetal haemoglobin levels were significantly higher and white blood cells were significantly lower in group 1 and generally speaking higher foetal haemoglobin, lower white cell counts^15,16 and presence of alpha-thalassemia are all usually associated with milder disease^17,18.

In conclusion, whereas it is not fully clear what causes some adults with SS disease to have splenomegaly whereas most will lose their spleen in childhood, what is clear is that splenic enlargement occurring during adulthood is an important phenomenon to consider a possibility. The disease severity may also be lower in those whose spleens persist into adulthood, but these observations needs to be supported by further studies. Also, whereas most clinicians may be aware of the possibility of splenic crises in adults with sickle-haemoglobin C or sickle-beta thalassemia diseases,¹⁹ they may not consider this in persons with SS disease. Splenectomy should be considered, especially in those who have had splenic sequestration crises, as many will otherwise go on to have recurrent episodes.

Acknowledgements

M.A. and M.R. designed the study; M.A. and A.W. collected and entered the data; M.A. and M.R. performed the analysis; and all three authors wrote and approved the manuscript.