British Journal of Haematology, 1999, 106, 812±816
Is there a correlation between degree of splenomegaly, symptoms and hypersplenism? A study of 218 patients with Gaucher disease Y U VA L G I E L C H I N S KY, 1 D E B O RA H E L S TE IN , 1 I RI TH H A DA S -H A L P E R N , 2 A M N O N L A H AD , 3 AYA L A A B R AH A M OV 4 1,5 1 A ND A R I Z I M R A N Gaucher Clinic, Departments of 5Medicine, 4Paediatrics and 2Diagnostic Radiology, Shaare-Zedek Medical Centre, and 3Department of Family Medicine, Hadassah Medical Centre, Jerusalem, Israel Received 5 February 1999; accepted for publication 11 June 1999
Summary. Despite the prevalence of splenomegaly as a sign in many disorders, there have been no studies that correlate the degree of organomegaly with the symptoms generally ascribed to splenic enlargement. The degree of splenomegaly was compared with ®ve overt symptoms of mechanical displacement, i.e. chronic abdominal pain, abdominal discomfort, early satiety, pain while lying on the side, or attacks of acute (colicky) left upper quadrant pains. We have also employed splenomegaly as seen in Gaucher disease as a paradigm to determine whether there is a correlation
between the degree of splenomegaly and the parameters of hypersplenism. Although there was a statistically signi®cant correlation between degree of splenomegaly and blood counts, this proved to be clinically negligible. Surprisingly, there was also no correlation between degree of splenomegaly and any of symptoms investigated.
Splenomegaly is a common physical sign that is often associated with symptoms such as chronic abdominal pain, abdominal discomfort, early satiety, pain while lying on the side, or attacks of acute (colicky) left upper quadrant pains; there may or may not be laboratory ®ndings of hypersplenism. Despite the high frequency of this ®nding, which generally instigates a thorough haematological evaluation, very little is known about the relationship between the degree of splenic enlargement and the severity of the associated symptoms and/or degree of cytopenia (Nathan, 1996; Erslav, 1995). Splenomegaly is usually the ®rst discernible feature and an almost universal ®nding in patients with Gaucher disease. Increased volume may only be detected in many cases via sophisticated imaging techniques (such as ultrasound or radioisotope scan) (Hill et al, 1986), or may evolve to enormous size, extending to the right lower quadrant or to the true pelvis (Beutler et al, 1995). The introduction of enzyme replacement therapy for Gaucher disease, wherein organomegaly is a primary response parameter (Grabowski et al, 1995; Zimran et al, 1995), underlined the importance
of accurate imaging modalities for organ volume assessment (Glenn et al, 1994; Elstein et al, 1997), since repeat evaluations over time are required for follow-up. In our clinic we routinely follow our patient population with (minimally) annual evaluations by ultrasound which is safe as well as reproducible in experienced hands. We have shown that the index volumes of spleen and liver correlate with those of computed tomography over a wide range in all body types and can be converted via an algorithm to those of computed tomography (Elstein et al, 1997). In the present study 218 Gaucher patients with intact spleens were investigated to ascertain if there is a correlation between degree of splenomegaly and the severity of hypersplenism and the putatively associated symptoms of mechanical discomfort.
Correspondence: Dr Deborah Elstein, Gaucher Clinic, Shaare Zedek Medical Center, P.O. Box 3235, Jerusalem 91031, Israel. e-mail:
[email protected].
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Keywords: splenomegaly, hypersplenism, ultrasound, Gaucher disease, abdominal pain.
PATIENTS AND METHODS In our clinic, which is a referral centre for Gaucher disease in Israel, >400 patients are routinely followed, of whom 225 patients have not undergone partial or total splenectomy up to September 1997. All 35 patients between the ages of 2 and 10 years, and seven who were under the age of 2 years, were excluded from the study. Of the 183 patients above the q 1999 Blackwell Science Ltd
Splenomegaly, Symptoms, and Hypersplenism Table I. Haematological parameters, body weight and splenic excess of all patients. Variable
Mean 6 SD
Range
Haemoglobin (g/dl) Leucocyte counts ´ 109/l Platelet counts ´ 109/l Body weight (kg) Splenic excess
11´9 6 1´6 5´7 6 1´9 110´4 6 62´2 59´6 6 16´0 24´3 6 21´5
7´6±16´3 1´6±12´1 18´0±456´0 24´0±103´0 1´3±115´9
Table II. Patients complaining of abdominal symptoms. Symptom
N
%
Asymptomatic Abdominal pain Abdominal discomfort Early satiety Pain lying Colicky pain
123 19 13 14 1 13
67 10 7 8 0´5 7
age of 10 years, 111 were female and 72 male. The diagnosis of Gaucher disease was con®rmed in all patients by low enzymatic activity of b-glucocerebrosidase. The splenic volume was determined by ultrasound index volume, and the degree splenomegaly was expressed as fold-increase (`excess') relative to the predicted normal spleen volume which is calculated as 0´2% body-weight (Elstein et al, 1997, 1998). All ultrasound examinations were done by a senior radiologist. The mean values for the haematological
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parameters (haemoglobin, white blood cell [WBC] counts and platelet counts), body weight and splenic excess are presented in Table I. Five symptoms related to splenomegaly: chronic abdominal pain, abdominal discomfort, early satiety, pain while lying on the side, or attacks of acute (colicky) left upper quadrant pains, were recorded (Table II). All patients were studied on the day of their ®rst evaluation in the clinic; none had been on enzyme therapy at that time. The senior physician asked speci®c questions to which the patient was to give yes/no answers without providing a subjective evaluation of the severity of the symptom. The patients were to refer to the symptom as having occurred within the last interval since seen by a physician, but no longer than in the previous 6 months. Ultrasound evaluation and all blood tests were performed on the same day as the survey of symptoms. Statistical analysis. This study asked the question of whether splenomegaly is correlated with hypersplenism as expressed by blood counts. To test the effect of splenic volume on haemoglobin level, WBC counts and platelet counts, multiple regression was used; other variables that were controlled for included age and sex; age was controlled for as a continuous linear variable. The splenic volume, added last to the regression, was the independent variable and the haematological parameters were the dependent variables. A decision was made not to control for severity using the classic Severity Score Index (Zimran et al, 1989), in that the degree of splenomegaly is an integral part of the index. In all analyses, values for splenic excess >60 were counted as 60, in that these extreme values of splenic index volume were probably due to idiosyncratic distortions that may appear on ultrasound as long axes but in fact have little cubic volume. It has also been shown that the volumes derived for these hugely enlarged organs evaluated by various imaging techniques correspond less well with each other (Elstein
Fig 1. Changes in haemoglobin (g/dl) with increases in splenic-fold excess. q 1999 Blackwell Science Ltd, British Journal of Haematology 106: 812±816
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et al, 1997). In that these outliers comprise only a small percentage of the total and the statistical manipulation affected the results only slightly, this condensation was allowed to stand. This study also asked the question of whether splenomegaly is correlated with speci®c abdominal symptoms, and therefore the independent variable in all statistical manipulations was the splenic excess and the dependent variable was each symptom. In asking the obverse question, i.e. whether the presence of symptoms highlight the presence of splenomegaly, a Wilcoxon rank sum test was used where the
independent variable was each of the symptoms and the splenic excess was the dependent variable. RESULTS The correlation between splenic volume and haemoglobin level, WBC counts and platelet counts are presented in Figs 1, 2 and 3, respectively. There was a statistically signi®cant negative correlation between the size of the spleen and the degree of anaemia: with each one-fold increase in splenic excess there was a decrease in haemoglobin level by 0´04 g/dl
Fig 2. Changes in WBC (leucocyte) counts (´109/l) with increases in splenic-fold excess.
Fig 3. Changes in platelet counts (´109/l) with increases in splenic-fold excess. q 1999 Blackwell Science Ltd, British Journal of Haematology 106: 812±816
Splenomegaly, Symptoms, and Hypersplenism Table III. Correlation of massive splenomegaly with symptoms in the 33 patients with splenic excess greater than 40-fold. Symptom
N
%
Asymptomatic Abdominal pain Abdominal discomfort Early satiety Pain lying Colicky pain
18 1 4 5 4 1
55 3 12 15 12 3
(P < 0´0001). There was no correlation between the size of the spleen and the degree of leucopenia: with each one-fold increase in splenic excess there was a decrease in WBC count of 0´000051 ´ 109/l, which was not statistically signi®cant. There was also a negative correlation between the size of the spleen and the degree of thrombocytopenia: with each onefold increase in splenic excess there was a decrease in platelet count of 1´464 ´ 109/l. This trend, which was statistically signi®cant (P < 0´0001), was unrelated to the age of the patients. There was no correlation between the size of the spleen and any one of the ®ve symptoms studied; moreover there was no correlation between symptoms even in the patients with splenic excess greater than 40-fold (Table III). Finally, there was no statistically signi®cant correlation between the symptoms and the splenomegaly using the Wilcoxon rank sum test. DISCUSSION Our study presents for the ®rst time an attempt to correlate the physical ®nding of splenomegaly with the putatively associated symptoms as well as the signs of secondary hypersplenism. Although intuitively one may assume that the larger the splenic volume the more overt the symptoms associated with mechanical displacement, our data shows this not to be the case. Indeed, it is surprising that even massive splenic enlargement is completely disassociated from the symptoms classically attributable to organomegaly. Interestingly, we have a patient who presented with massive splenomegaly (8 kg), who did not complain of abdominal discomfort. After nearly 2 years on enzyme replacement therapy, the splenomegaly proved to be refractory to treatment and hence splenectomy was necessary to manage the hypersplenism (Krasnewich et al, 1998). The current study, using ultrasound assessment of splenomegaly, ®nds a statistically signi®cant negative correlation between splenic excess and haemoglobin and platelet counts but not WBC counts. A recent ultrasound study in patients with portal hypertension showed a negative correlation between splenic volume and WBC counts (Shah et al, 1996) but no correlation with haemoglobin or platelet counts. However, an early study in a large cohort of patients undergoing shunt procedures for portal hypertension and variceal bleeding, reported a signi®cant correlation
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between spleen size measured by computed tomography, and both platelet and WBC counts (El-Khishen et al, 1985). This latter study indicated that non-alcoholic patients with portal hypertension tended to have larger spleens and more commonly suffered from secondary hypersplenism than alcoholic patients. The discrepancy between the degree of hypersplenism secondary to the splenomegaly of portal hypertension versus that due to other causes is unexplained. Albeit, very early studies implied that enlarged spleens concentrate platelets to a disproportionate degree compared to the amount of blood they contain (Aster, 1966), and that this phenomenon may be ascribed to increased blood ¯ow consequent to a trebling of the percentage of cardiac output in hypersplenic patients (Kaplan & Jandl, 1963). If so, the discrepant results between our results and those in patients with portal hypertension may be postulated to be due to dissimilar degree of pooling of blood in portal hypertension relative to splenomegaly due to other causes. The relatively minor change in cell counts per foldincrease is of little, if any, clinical importance. For example, a palpable change, as from 2-fold to 20-fold in splenic volume, would be associated with relatively negligible changes in the haematological parameters: a mean decrease of 0´36 g/dl in haemoglobin, a mean decrease of 0´00042 ´ 109/l in leucocyte counts and a mean decrease of 10 ´ 109/l in thrombocyte counts. Although our ®ndings related to splenomegaly in Gaucher disease may be extrapolated to the splenomegaly seen in other chronic/congestive disorders, this may not necessarily be comparable to acute and/or transient splenic enlargement. Nonetheless, it is noteworthy that (even massive) splenomegaly per se does not predictably induce hypersplenism or abdominal discomfort in a linear fashion. REFERENCES Aster, R.H. (1966) Pooling of platelets in the spleen: role in the pathogenesis of `hypersplenic' thrombocytopenia. Journal of Clinical Investigation, 45, 645±657. Beutler, E., Demina, A., Laubscher, K., Garver, P., Gelbart, T., Balicki, D. & Vaughn, L. (1995) The clinical course of treated and untreated Gaucher disease: a study of 45 patients. Blood Cells and Molecular Disease, 21, 86±108. El-Kischen, M.A., Henderson, J.M., Millikan, W.J., Jr, Kutner, M.H. & Warren, W.D. (1985) Splenectomy is contraindicated for thrombocytopenia secondary to portal hypertension. Surgery, Gynecology and Obstetrics, 160, 233±238. Elstein, D., Hadas-Halpern, I., Azuri, Y., Abrahamov, A., Bar-Ziv, Y. & Zimran, A. (1997) Accuracy of ultrasonography in assessing spleen and liver size in patients with Gaucher disease: comparison to computed tomographic measurements. Journal of Ultrasound Medicine, 16, 209±211. Elstein, D., Hadas-Halpern, I. & Zimran, A. (1998) Ultrasonography in assessing spleen and liver volume in Gaucher disease. Medical Imaging International, 1, 12±15. Erslav, A.J. (1995) Hypersplenism and hyposplenism. Williams Hematology, 5th edn (ed. by E. Beutler, M. A. Lichtman, B. S. Coller and T. J. Kipps), pp. 709±711. McGraw-Hill, New York. Glenn, D., Thurston, D., Garver, P. & Beutler, E. (1994) Comparison of magnetic resonance imaging and ultrasound in evaluating liver size in Gaucher patients. Acta Haematologica, 92, 187±189.
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