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WIDESPREAD ABNORMALITIES OF RADIOCOLLOID DISTRIBUTION IN PATIENTS WITH MUCOPOLYSACCHARIDOSES

WilliamC. KlingensmithIll, EdwardA. Eikman,IreneMaumenee,andHenryN. Wagner,Jr. The Johns Hopkins Medical Institutions, Baltimore, Maryland

Mucopolysaccharidoses (MPS) are inherited The mucopolysaccharidoses (MPS) are diseases disorders of lysosomal enzymes. We have ex caused by inherited enzyme deficiencies, which result amined the sites of accumulation of intrave in the accumulation of mucopolysaccharides within nously injected 99mTc.sulfur colloid in order to cells and body fluids in varying degrees. MPS are assess the regional dL@tribution of phagocytic subdividedaccordingto the urinary mucopolysaccha function in ten patients with MPS: three with ride excreted, mode of inheritance, and clinical fea Type 7 (Hurler), five with Type II (Hunter), tures (1 ) . Serial OomTcsujfur colloid liver—spleenand one with Type III (Sanfilippo), and one with studies were done to monitor the clini Type VI (Maroteaux-Lamy). Increased up cal response of ten patients with MPS of various take was observed in 22 of 40 studies (55%) types who were given a series -of plasma infusions in on the five patients with MPS Type H but in an attempt to correct the enzyme deficiency (2,3). none of the 38 studies on patients with other Although the effects of treatment remain inconclu MPS types. All MPS patients had diffuse recticu. sive, the findings with regard to the radiocolloid loendothelial (RE) marrow hypoplasia, despite distribution, both before and during treatment, were normal or nearly normal hematocrits and hemo of interest and have not been reported previously. levels, suggesting dissociation of the phagocytic and erythropoietic elements of the METhODS marrow. The eight patients with MPS Types I Of the ten patients, three had MPS Type I; five, and II all had hepatomegaly and increased Type II; one, Type Ill; and one, Type VI. All pa splenic uptake. Seven of these patients also had tients had a 9OmTo-sulf@@colloid liver— and . The two patients with MPS Types bone marrow study before receiving plasma infu III and Yl did not have . sions. Subsequently, the patients returned periodi These studies indicate that the lysosomal en zymic defect of MPS results in widespread abnormalities of the distribution of phagocytic Received March 20, 1975; revision accepted May 15, 1975. function in the , spleen, bone marrow,and For reprintscontact: WilliamC. KlingensmithflI, 615 N. probably the lung as well. Wolfe St., Baltimore,Md. 21205.

FIG. 1. Mild(A)andmoderate(B)in creased lung uptake of mTc@sulfurcolloid A in two patients with B Type II (Hunter).

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TABLE 1. RESULTSOF LIVER—SPLEENAND BONE MARROW STUDIESON PATIENTS WITH MUCOPOLYSACCHARIDOSES

marrowHepato

MPSLiver—spleen'Bone Patient type Age/SexStudies Lung uptaketsplenomegaly Spleen >liver* Studies Diffuse hypoplasia

Yes21 I 1/F 15 None Mild Yes(11/15) 12 Yes3 I 1/F 9 None Moderate Yes 9 Yes4 I 5/F 12 None Moderate Yes @3 Yes5 Il 2/M 4 Moderate(2/4) Moderate Yes 3 II 4/M 11 Mild (2/11) ModerateYes(liver Yes(5/11) 8 only)6 II 6/M 10 Mild (6/10) Moderate Yes 10 Initially normal,be hypoplastic7 came Yes8 II 10/M 7 Moderate(6/7) Marked Yes 7 Yes9 II 16/M 8 Moderate(6/8) Moderate Yes 7 Y@s10 Ill 18/F 1 None None Yes 1 VI 2/F Yes781 None None No 1

71*

studies.tFractions are given to indicate the number of positive studies in patients in whom the finding was not present on all patients.tMild and moderaterefer to predominantdegreeof lunguptakein corresponding Refersto splenicdensityas comparedto liverdensityin the anteriorscintigram.

type. With the imaging technique employed (4), TABLE 2. INCIDENCE OF INCREASED LUNG normal liver—spleenstudies usually show no activity UPTAKE IN MPS PATiENTS AND within the , or at most barely detectable ac CONTROL PATIENTS tivity. Increased lung uptake was determined from MPS of uptake the anterior and posterior views and classified as (%)II54022type- No. of patientsNo. studiesLung mild, moderate, or marked (Fig. 1 ) . The classifi (55)I, cation mild was used when the lung activity was only (0)ControlPatientsIII, VI5380 a small fraction of that in the liver and spleen. The uptakegroupsame doneNo. ofLung classification moderate was used when the border day asstudies(%) between the lung and liver or spleen began to be MPS II with lung 84 13 (15) obscured. In this study activity in the lung was never uptake marked, i.e., never comparable to that in the liver. 2 MPSII without lung 68 2(3) uptake The bone marrow studies were classified as nor 3 MPSotherthanTypeII 121 7 (6) mal, hyperplastic, diffusely hypoplastic, or centrally Total All MPStypes 273 22 (8) hypoplastic. Liver and spleen size were interpreted visually with the help of a costal-margin marker on one anterior view. Increased splenic uptake relative cally, usually monthly, for oomTc@sulfurcolloid studies to the liver was determined from the anterior view. and infusions. The duration of the study for each patient ranged from 1 to 26 months, with an aver RESULTS age of 13.5 months. Lung uptakeof radiocolloid.Increased(mild or A 9OmTc@sulfurcolloid dose of 5 mCi/m2 body moderate) lung uptake of 99mTc@sulfur colloid was surface area was used for the bone marrow studies, observed in all five patients with MPS Type H (Ta and a dose of 3 mCi/m2 was used when only a liver ble 1) . These patients had a total of 40 studies of spleen study was done. The bone marrow study con which 22 revealed increased activity within the lungs sisted of anterior and posterior rectilinear scans of (Table 2). There were 12 studies with mild lung the whole body, and scintillation camera views, with uptake and 10 with moderate lung uptake. None of preset time, of the lateral , anterior shoulders, the five patients showed increased lung uptake on anterior and posterior pelvis, and anterior femurs. every occasion, and there was no consistent temporal In addition, a 100,000-count scintigram of a 57Co pattern with the occurrence of lung activity, and no sheet source was taken as an image-density reference. relationship to treatment. The five patients with other The liver—spleen study consisted of anterior, pos MPS types, namely, I, III, and VI, had no increased tenor, and both lateral scintillation camera views. lung uptake in any of the 38 studies. The difference The 9OmTc_sulfurcolloid studies were interpreted between the Type II and Type I MPS patients was by one of us (WCK) without knowledge of MPS significant below the 0.001 level. However, the dif

Volume 16, Number I 1 1003 JCLINGENSMITH, EIKMAN, MAUMENEE, AND WAGNER ferences between the MPS Type II and MPS Types nificant at the 0.05 level while the difference between III and VI were not significant because the latter Group 3 and Groups 1 and 2 combined was not two patients had only one study each. The difference significant. between the incidence of lung uptake among the Bone marrow studies and hematologic findings. MPS Type II patients (55% ) and among all pa The bone marrow studies revealed diffuse hypoplasia tient controls examined with the same preparation of recticuloendothelial (RE) marrow in all studies of colloid as the MPS patients ( 8% ) was significant on all patients, with one exception. Patient 8, MPS below the O001 level. The fact that all MPS Type Type II, had a normal pattern initially that became II patients were males is explained by the x-linked progressively hypoplastic. Examples of a normal recessive mode of inheritance for this type, but the pediatric bone marrow study, and of diffuse hypo fact that the other five MPS patients were all females plasia in Patient 3, MPS Type I, are shown in Fig. 2. is probably coincidental and not related to the ab Hematologic values were available on all patients sence of lung uptake in these patients. except Patient 9. The remaining patients had normal Radiocolloid variability. The average number of or nearly normal hematocrits and levels liver—spleenstudies per day was five, with no in except Patient 10, who had a microcytic hypochromic stances of increased lung uptake in all patients on with a hematocrit of 29. This anemia was any one day. The contribution of radiopharmaceu probably secondary to poor eating habits and iron tical variability to the occurrence of increased lung deficiency. uptake was evaluated by determining the frequency Three of the five MPS Type II patients were con of lung uptake in three groups of patient controls sistently neutropenic (less than 3,000 neutrophils/ studied under the following circumstances: (A) on mm3) , with the degree of neutropenia correlating days when MPS Type II patients had lung uptake, with the frequency and degree of lung uptake and (B) on days when MPS Type II patients did not with the patient's age. The other two MPS Type II have lung uptake, and (C) on days when MPS pa patients, 5 and 6, did not have neutropenia, but they tients other than Type II were studied (Table 2). had only three white counts, two of which were The difference between Groups 1 and 2 was sig not at times when they showed lung uptake. For all

A C

FIG.2. Bonemarrowimagesofpelvis and knees in 6-year-old normal patient (A and B) and in 5-year-old MPS Type I (Hurler) patient with diffuse hypoplasia of D bone marrow(C and D).

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MPS Type II patients the correlation coefficient be tween neutropenia and frequency of lung uptake was 0.55, and between neutropenia and age was 0.68, . :@@:@‘_ ; but neither of these were significant at the 0.05 level *...@ in this small number of patients. Three of the four MPS patients other than Type II had normal neutro phil counts, and the fourth, Patient 1, was mildly ., neutropenic. J,_. Liver—spleen studies and liver function tests. The liver—spleen images revealed hepatosplenomegaly in all patients with MPS Types I and II except Patient 4, who had hepatomegaly only. The single studies of MPS Type III and VI did not show hepatospleno A megaly. In anterior scintigrams, increased splenic uptake of 9omTcsuffur colloid, relative to the liver, was present in all patients except the one with MPS Type VI. This finding tended to be progressive in Patients 1 and 4 (Table 1) , who did not show in creased splenic uptake on every study. Examples of increased splenic uptake in MPS Types I and II are shown in Fig. 3. All liver function tests were within @ . _re_.@-.@@:-. normal limits. ,,‘

DISCUSSION The mucopolysaccharidoses are a group of inherit B able diseases resulting from lysosomal enzyme defi FIG.3. (AandB)Hepatosplenomegalyandincreasedsplenic ciencies and characterized by accumulation of muco uptake of @@mTc.sulfurcolloid on anterior views in patients with polysaccharides in tissue lysosomes and body fluids mucopolysaccharidoses Types I and II, respectively. including the urine (5) . The accumulation occurs in a wide variety of cells and increases with time, resulting in progression of the disease with increasing Hepatosplenomegaly is usually present in MPS age. Mucopolysaccharides are synthesized in fibro Types I and II. This condition is usually only slight blasts and excreted extracellularly. Some of the sub to moderate in MPS Type III and, while it is a corn stance passes into the blood stream and appears in the mon finding in MPS Type VI after the age of 5, urine. Other cells take up the mucopolysaccharides our patient was studied at age 2 (1 ) . The hepato

- by endocytosis, i.e., pinocytosis and phagocytosis, splenomegaly is secondary to accumulation of muco with subsequent accumulation in lysosomes (6) . The polysaccharides in the lysosomes of the hepatocytes process is particularly prominent in RE cells and is and in of the liver and spleen (9). reflected:in the widespread abnormalities in radio Nevertheless, there is usually little functional im colloid studies found in this investigation. pairment of the liver in MPS (1 ) , and in our pa All ten patients with MPS had diffuse hypoplasia tients no significant abnormalities of liver function of the RE marrow despite the fact that erythron ab werefound. @ normalitiesare not a feature of MPS in general, and Increased splenic uptake of oomTc@sulfurcolloid the peripheral erythrocyte findings were normal or was present in all patients except the one with MPS

- nearly normal in the present study with one excep Type VI. This finding occurs most often in cases of tion. Dissociation of the degree of involvement of diffuse hepatic parenchymal disease, , and different marrow elements has previously been re diabetes mellitus ( 10) . In MPS it is probably related ported in severe hematologic disorders (7) and fol to diffuse hepatic parenchymal disease and spleno lowing irradiation (8) . In these cases, however, the megaly. RE marrow was usually preserved while the erythro The increased lung uptake of colloid was of par poietic marrow was impaired—exactly the opposite ticular interest. It has been observed in a number of of the findings in MPS. While radioactive iron studies diseases including malignant lymphomas (11,12), were not done in our MPS patients, the nearly normal metastatic carcinomas (12 ) , intra-abdominal infec peripheral RBC findings suggest that the erythro tions (12 ) , ( 13 ) , and liver transplants poietic marrow was relatively normal. (13). In the present study, significant lung uptake

. Volume 1 6, Number 11 1005 KLINGENSMITH, EIKMAN, MAUMENEE, AND WAGNER occurred in 55% of studies on the five patients with Genetics—given to the Department of Medical Genetics, MPS Type II (Hunter), but in none of 38 studies The Moore Clinic; Medical Genetics Training Grant 5 TO! GM 00795; OPD-CRC—1 MO! RR00722—Heritable Dis on the other five MPS patients. Increased lung up orders of Connective Tissue and Genetic Marker Studies; take is generally associated with a poor prognosis and Grant CRBS-322 from the National Foundation March in and cirrhosis (12) , yet MPS Type II of Dimes. (Hunter) has a significantly better prognosis than MPS Type I (Hurler) . Among the MPS Type II REFERENCES patients, however, the frequency and degree of lung 1. McKusicx VA: The mucopolysaccharidoses. In In uptake tended to increase with age and thus with heritable Disorders of Connective Tissue, McKusick VA, ed, St. Louis, Mosby, 1972, pp 521—686 progression of the disease. 2. DIFERRANTEN, NICHOLSBL, DONNELLY PV, et al: The mechanism of increased lung uptake is not Induced degradation of glycosaminoglysans in Hurler's and definitely known, although there are data against Hunter's syndromes by plasma infusion. Proc Nat! Acad the involvement of a plasma factor (14) and for Sci USA 68: 303—307,1971 gradual accumulation of the 99mTc@sulfurcolloid 3. HUSSELSIE, EIKMAN EA, KENYONKR, et a!: Treat ment of mucopolysaccharidoses. In Clinical Delineation of in the lung which would favor a phagocytic mech Birth Defects, Bergsma D, McKusick VA, eds, Baltimore, anism rather than embolization of macroaggre Williams & Wilkins, in press gates (1 1 ) . In animals, increased lung uptake has 4. LANGANJK, WAGNERHN: A systemto record, view, been produced by the intraperitoneal injection of store, and distribute nuclear medicine images and records. endotoxin (15,16) , and autoradiographic examina I Nucl Med 14:588—590,1973 5. DORFMAN A, MATALON R: The mucopolysacchari tion of the lungs of these animals demonstrated that doses. In The Metabolic Basis of Inherited Disease, Stan the 99mTc@sulfur colloid was associated with cells bury JB, Wyngaarden JB, Fredrickson DS, eds, New York, (15) . Therefore, the evidence to date suggests in McGraw-Hill, 1972, pp 1218—1272 creased RE activity in the pulmonary bed. 6. HERS HG: Concept of inborn lysosomal disease.In It has been suggested that the increased pulmonary Lysosomes and Storage Diseases, Hers HG, van Hoff F, eds, New York, Academic Press, 1973, pp 147—17! RE activity may reflect a monocytosis (17) and, in 7. VANDYKE D, SHxuRxiN C, PRICED, et a!: Differences general, there is a similarity between the diseases in distribution of erythropoietic and reticuloendothelial mar associated with lung uptake (12) and those associ row in hematologic disease. Blood 30: 364—374,1967 ated with monocytosis (18) . However, a significant 8. NELP WB, LARSONSM, BOWERRE, et a!: Tempo monocytosis was not found in the MPS Type II pa rary dissociation of RES and erythron activity in the mar row following irradiation. I NucI Med 8: 295, 1967 tients, although neutropenia, which was prevalent 9. v@u'iHOOF F: Mucopolysaccharidoses.In Lysosomes among these patients, is a known cause of monocy and Storage Diseases, Hers HG, van Hoof F, eds, New tosis (19). York, Academic Press, 1973, pp 242—243 The many studies done on each patient who had 10. WIisoN GA, KEYES JW: The significance of the increased lung uptake allowed us to test for colloid liver—spleenuptake ratio in liver scanning. I Nucl Med 15: variability. The 15 % incidence of lung uptake in 593—597,1974 11. KLINGENSMITHWC, RYERSONTW: Lung uptake of control patients, done on days when MPS Type II °@mTc-sulfurcolloid. I Nucl Med 14: 201—204,1973 patients had lung uptake, was significantly different 12. KEYES JW, WILSON GA, QUINONESTJD: An evalua from the 3 % incidence of lung uptake among pa tion of lung uptake of colloid during liver imaging. I Nucl tient controls done on days when MPS Type II pa Med 14:687—691,1973 tients did not have lung uptake. The overall incidence 13. KLINGENSMITH WC, RYERSONTW, CORMAN IL: Lung uptake of mmTc@sulfur colloid in transplanta of lung uptake among these patient controls, how tion.I NuclMed 14:757—759,1973 ever, was not significantly different from the mci 14. STEINBACHHL: Pulmonary accumulation of @@mtech@ dence among patient controls studied on days when netium-sulfur colloid during liver scanning. Tex Med 68: MPS patients other than Type II were studied. These 137—138,1972 findings support the concept that variation in oomTc@ 15. QUINONEST ID: Localization of technetium-sulfur colloid after RES stimulation. I Nuci Med 14: 443—444, sulfur colloid preparations influences the incidence 1973 of lung uptake in addition to endogenous factors. 16. KLINGENSMITHWC, LovErr VI : Lung uptake of “mTc-sulfurcolloid secondary to intraperitoneal endotoxin. ACKNOWLEDGMENT I Nucl Med 15: 1028—1031,1974 17. KLINGENSMITHWC: The Author's Reply. I Nucl Med Dr. Klingensmith is supported in part by USPHS Grant 15:727—728,1974 GM-10548 and NIH Fellowship 1 F22 HL 00014-01 RAD. 18. MALDONADOJE, HANLON DG: Monocytosis: A cur Dr. Maumenee is supported by Research Career Develop rentappraisal.Mayo ClinProc 40: 248—259,1965 ment Award GM 70124 from the National Institutes of 19. CASSILETHP: Monocytosis. In , Williams Health, Education, and Welfare; Grant-in-Aid from Fight WJ, Beutler E, Erslev Al, eds, New York, McGraw-Hill, For Sight, Inc.; Grant 5 P01 GM 19489—Studyof Human 1972,pp 855—858

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