A D U L T N I E M A N N - P I C K DISEASE-A
CASE R E P O R T
W. C. CHAN,K. S . LAIAND D. TODD The Departments of Pathology and Medicine, University of Hong Kong
PLATE LXXXVI NIEMANN-PICK disease is known to occur most frequently in Jewish children, and is excessively rare in adults. The usual presenting features include hepatosplenomegaly, xanthomata on a waxy skin, mental retardation, radiological changes in lungs and long bones, and the presence of lipoid-laden cells in the bone marrow and other organs. Diagnosis is confirmed by the demonstration of increased sphingomyelin (relative or absolute) in these organs. An adult form of the disease has been reported on several occasions (Dusendschon, 1946; Pfandler, 1946; Terry et al., 1954; Lynn and Terry, 1964). We now present the results of various studies in a southern Chinese woman with biochemical confirmation of Niemann-Pick disease. CASEREPORT Clinical features The patient, W.Y., was a Cantonese (southern Chinese) housewife born in Saigon, Vietnam, on 27 Apr. 1918. She first attended the Radiotherapy Department, Queen Mary Hospital, on 3 Nov. 1965. She then had a Stage IV nasopharyngeal carcinoma presenting with nasal obstruction and sero-sanguinous discharge for 8 mth and cervical lymphadenopathy mainly on the left side for 5 mth. Physical examination confirmed a large primary growth covering the roof and posterior wall of the nasopharynx. Liver and spleen were not palpable. Biopsy of the growth showed poorly differentiated carcinoma, apparently of the squamous type, infiltrating fibrous tissue. A 6-wk course of radiotherapy combined with 4 g of cyclophosphamide given in 20 intravenous injections brought completed regression of all signs of malignancy. The patient was seen again in July 1967, when she had n o symptoms but the right lobe of the liver was noted to be enlarged to 8 cm below the costal margin at the mid-clavicular line; it was firm and smooth. Recurrence was thought to be the most likely cause and no active treatment given. Six months later the patient began to have intermittent puffiness of the face, ankle oedema, and abdominal distension. Symptoms persisted and the patient was admitted to a hospital in Vietnam in July 1968 after 3 days of fever, cough and vomiting. She was told that she had " pericardial effusion " and improved with conservative measures. After 5 mth of relative freedom from symptoms, patient noticed epigastric discomfort and dull aching in the right upper quadrant of the abdomen. She returned to the follow-up clinic of the Radiotherapy Department in May 1969 and was transferred to the care of the University Department of Medicine on 16 May 1969. There was n o history of fever, jaundice or chest symptoms. Past health and family history were unremarkable. Patient had four normal children (now aged 21-27 yr) by full-term pregnancies and spontaneous delivery. Physical examination revealed a thin woman weighing 82 Ib. She was pale but had no jaundice, skin lesions, oedema, lymphadenopathy, or bleeding tendency. Her blood pressure Received 25 April 1976; accepted 7 June 1976. I. PATH.-VOL.
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measured 120/80 mm Hg. The abdomen was mildly distended with some ascites. The right lobe of the liver had shrunken to extend only 4 cm below the costal margin, but the left lobe now measured 8 cm below the xiphoid process; it was very firm and irregular on the surface. The spleen tip was palpable. All the other systems,,including the cardiovascular, showed no abnormality. The nasopharynx was clear. Invesfigations Haemoglobin 9.9 g per cent., white cell count 2‘745/cu. mm, with 66 per cent. neutrophils, 24 per cent. lymphocytes, and 8 per cent. monocytes; all cells appeared normal. Platelets 52,000/c.mm, reticulocytes 1 per cent., erythrocyte sedimentation rate 90 mm in the 1st hr. Urine contained trace protein and 5-15 pus cells/h.p.f. and scanty growth of E. coli on culture. Ova of Clonorchis sinensis were found in the stool. Serum bilirubin ranged from 0.7 mg per cent. to 1.3 mg per cent. alkaline phosphatase 8617-6KA units, acid phosphatase 41.0 KA units (repeat: 32.6 KA units), glutamic oxaloacetic transaminase 198 King’s units, glutamic pyruvic transaminase 108 King’s units, prothrombin time 13-24 s (control: 12 s). Urea 39 mg per 100 ml, Naf 140 mEq/l., K+ 4.2 mEq/l., cholesterol 106 mg per 100 ml, fasting glucose 90 rrig per 100 ml. Total serum proteins 5.6 g per lOOml: albumin 2.1 g, globulin 3-5 g, comprising c(1 9.1 per cent., c(2 9.1 per cent., /3 9-1 per cent. and y 39.3 per cent. by paper electrophoresis. Immuno-electrophoresis: increase in all immune globulins tested-IgA, IgM, and IgG. Urinary excretion of acid mucopolysaccharide expressed as glucuronic acid = 4.32 mg/24 hr (normal range: 2.73-5.4 mg/24 hr). Indium113 scanning of the liver demonstrated a large zone of deficient uptake occupying much of the right lobe and a major portion of the left lobe. A percutaneous needle biopsy of the liver was taken from the “ filling defect ” in the right lobe. An aspiration biopsy of sternal and later iliac crest marrow showed active normoblastic erythropoiesis and normal granulopoiesis and megakaryocytes but some large cells with small nuclei containing coarse chromatin, and plentiful vacuolated cytoplasm, appearing to be lipid-laden. X-ray of the chest showed slight increase in the i.ransverse diameter of the cardiac shadow but normal lung fields. At cardioscopy, there was marked limitation of cardiac pulsations, and subsequent cardiac catheterisation demonstrated a thickness of over 2.5 cm from the right cardiac border to the right atrial lumen. The electrocardiagram was normal. Skeletal survey revealed extensive rarefaction in the lateral half of the proximal third of the left humerus and both ends of both femora and a suggestion of destruction in the iliac wings of the pelvis, especially the right side. The skull X-ray was normal. At pericardiostomy, 200 ml of serous fluid was drained; the pericardium appeared normal except for seven to eight greyish-white nodules, each measuring 2-3 mm in diameter, over the visceral pericardium; these were biopsied. For special studies, a wedge biopsy of the liver was also taken by a short extension of the incision. Management and subsequent course The ascites was controlled with difficulty by frusemide and ethacrynic acid. Anorexia, general weakness and constipation was prominent. Patient developed a dental abscess from the right lower second premolar, with cellulitis of the face, responding to extraction of the offending tooth and a 5-day course of tetracycline. A combination of prednisone 15 mg q.i.d. orally and cyclophosphamide 200 mg intravenously daily was tried but patient became mentally confused on the 4th day of therapy, went downhill steadily despite withdrawal of the drugs and died on 1 Sept. 1969, Pathology First liver biopsy. There are groups of cells with foamy cytoplasm in the sinuses with compression of liver cords (fig. 1). These cells appear to originate from Kupffer cells. They are PAS -ve and stand out strikingly among liver cells which are strongly PAS +ve.
ADULT NIEMANN-PICK DISEASE
179
Second liver biopsy. In the wedge of liver, similar foamy cells are present in groups in sinusoids. Nodules removed from epicardium are composed of aggregates of cells with foamy and vacuolated cytoplasm. There is a basophilic tinge of the cytoplasm. Autopsy finding The body is emaciated. Moderate autolysis is evident in all organs. Significant gross findings are present in the liver, the heart and the spleen. Heart. There are 30 cc of serous fluid in the pericardial cavity. The epicardium is studded with about ten brownish nodules, the largest of which is 5 mm in diameter. The myocardium and heart valves are not remarkable. Liver. The liver weighs 1300 g. It is pale yellow and shows an increase in consistency. The surface is smooth. Cut surface shows irregular pale yellowish areas which are confluent in the right lobe. Tiny brownish-yellow specks are scattered sporadically. Mild thickening of intrahepatic bile-ducts is present. Spleen. Weighs 275 g. The capsule is thickened. Cut surface shows brownish flecks similar to those described in the liver.
TABLE Percentage wet weight Total Total phospholipid Sphingomyelin Cholesterol
Liver 1 *72 1.31 (75% of total lipid) 1.07 (82% of phospholipid) 0.18 (10% of lipid)
Spleen
2.06 1.13 (54% of total lipid) 0.85 (75% of phospholipid) 0.23 (20% of lipid)
There is less than 0.2 per cent. dry weight of cerebroside in the two organs.
Histology Histology of post-mortem material is poor because of autolysis. Apart from the liver and nodules of the epicardium which have been examined histologically before death, infiltrations of foamy cells are found in all tissues examined. They include the thyroid, the adrenals, the spleen, the kidneys, the lungs, various lymph nodes and vertebral bone marrow. In the lungs, foamy cells are present in alveoli. The nasopharynx was carefully sectioned and examined. N o residual tumour was found. There are groups of similar foamy cells in the wall of the nasopharynx. Review of the original biopsy of the nasopharynx confirms the presence of a poorly differentiated squamous carcinoma. Electron microscopy The 2nd liver biopsy was fixed in 1 per cent. osmium tetroxide and processed for ultrastructural study. The Kupffer cells contain vacuoles of varying sizes. Most of their cytoplasm is displaced by these vacuoles and the nucleus is often compressed (fig. 2). The content of these vacuoles is lightly electron dense. In occasional vacuoles, electron-dense material in small clumps is present. There are no lamellated structures seen. Mitochondria, GER and microsomes are displaced. The liver cells also contain similar vacuoles, but their sizes are generally smaller than those in the Kupffer cells (fig. 2). A few cells show small clear zones in the cytoplasm, in which no organelles are seen.
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Chemical analysis
The liver and spleen were analysed chemically for lipids and sphingomyelin. The results are in the table.
DISCUSSION Niemann-Pick (NP) disease is characterised by the accumulation in tissue of sphingomyelin (Klenk, 1934). It is primarily a disease of childhood. Since the study in 1946 of two Swiss brothers independently by Dusendschon and Pfandler, an adult variant distinct from the usual infantile type emerged. Terry et al. (1954) described a 54-yr-old man suffering from the disease and Lynn and Terry (1964) studied by histochemical and ultrastructural methods a 19-yrold Puerto Rican boy. In the latter study, a lymph node and also marrow smears were examined. The material concerned was found to be a phospholipid and PAS positive. Ultrastructurally, the material in the lymph node was represented by lamellated, membranous bodies. Tanaka et al. (1963) found similar bodies in three cases and one was a 19-yr old. Lynn and Terry claimed that these bodies were more common in the adult type of the disease. In the present case, histological and ultrastructural studies were made on liver tissue of a 54-yr-old woman suffering from the disease. The results differed from those of Lynn and Terry. Unlike the NP cell in the lymph node of their case, the accumulated substance in our patient was PAS negative as is most phospholipids. Lamellated membranous bodies were not found. Instead, amorphous, lightly electron-dense material was found in vacuoles, reflecting the light microscopic picture. These vacuoles were plentiful in the Kupffer cells and to a lesser degree in the liver parenchyma cells. Chemically, using autopsy material, there is little doubt that the sphingomyelin content is markedly elevated in the liver and spleen. The absolute amount is increased, but more important is the high percentage of sphingomyelin in total phospholipid. The distribution of the NP cells was generalised; this and the fatal outcome are features of the infantile form. Another unusual feature in the present case is the markedly elevated serum acid phosphatase, confirmed on two occasions. This finding has been reported in Gaucher’s disease (Crocker and Landing, 1960) but not in Niemann-Pick disease. Brady et al. (1966) demonstrated that the primary lesion in Niemann-Pick disease is a biochemical one. It is due to a deficiency in the enzyme sphingomyeljnase. This enzyme is concerned with the catabolic breakdown of sphingomyelin, the source of which is mainly in cell membranes, particularly of the red cells, and the red cell stroma. Normal liver contains the highest activity. Because of the deficiency of this catabolic enzyme, sphingomyelin accumulates. There are several possible reasons why our ultrastructural findings differ from those of Lynn and Terry’s. The first is obvious. The material used is different. They studied lymph node, while we studied the liver. It is rather unfortunate that lymph-nodal tissue was not available for ultrastructural study until after death. Attempt at electron microscopy of the post-mortem lymph
CHAN,LAI A N D TODD
PLATE XXXVI ADULTNIEMANN-PICK
DISEASE
FIG. 1. ---Enlarged and foamy Kupffer cells compress liver cords. (HE). x140.
Fici.
Haematoxylin and eosin
2.-The Kupffer cells contain many vacuoles with lightly electron-dense material. Part of a red blood cell is seen among thc vacuoles. Electron micrograph (EM). x 6800.
A D ULT NIEMANN-PICK DISEASE
181
node was unsatisfactory. The second possibility is that although the two cases were both lipidosis, the metabolic defects were different. It is possible that the histological picture of NP cells may be the result of more than one biochemical lesion in the metabolism of lipids. The appearance of lamellated membrane structures may represent either an increase in biosynthesis of membrane or a blockage in the degradation at a higher level than found in our case. The difference in the PAS staining in the two cases lends support to the idea that the abnormal phospholipids were actually two different substances. Chemical data were not presented in Lynn and Terry’s article. The relationship between the NP disease and the preceding disease of nasopharyngeal carcinoma and irradiation is conjectural. The complete eradication of the tumour by irradiation and chemotherapy is remarkable in itself. It is, however, not unknown in this locality, for long survival after radiotherapy is commonplace (Ho, H. C.). It is possible that irradiation and/or chemotherapy may either initiate or unmask the deficiency of sphingomyelinase. On the other hand the metabolic defect may be the result of the presence of the carcinoma due to some unknown mechanism.
SUMMARY
A case is presented of the rare adult form of Niemann-Pick disease occurring in a Cantonese. The diagnosis was verified by biochemical analysis of the affected tissues. We thank Dr H. J. Lin, Senior Hospital Biochemist, for the chemical analysis. Mr K. H. Lau and Mr J. F. Ning gave valuable technical assistance. REFERENCES BRADY, R. O.,KANFER, J. N., MOCK,M. B., AND FREDRICKSON, D. S. 1966. The metabolism of sphingomyelin. 11. Evidence of an enzymatic deficiency in Niemann-Pick disease. Proc. Nut. Acad. Sci. US.,55, 366. CROCKER, H. C., AND LANDING, B. H. 1960. Phosphatase studies in Gaucher’s disease. Metabolism, 9, 341. Ho, H. C. Personal communication. DUSENDSCHON, A. 1946. Deux cas familiaux de maladie de Niemann-Pick chez l’adulte. Thesis, Faculte de Medicine, University of Geneva. KLENK,E. Z. 1934. Cited by Brady et aZ., 1966. LYNN,R., AND TERRY,R. D. 1964. Lipid histochemistry and electron microscopy in adult Niemann-Pick disease. Am. J. Med., 37, 987. U. 1946. La maladie de Niemann-Pick dans le cadre des lipoidoses. Schweiz. PFANDLER, med. wchnschr., 76, 1128. TANAKA, Y.,BRECHER, G., AND FREDRIKSON, D. S. 1963. Cellules de la maladie de NiemannPick et de quelques autres lipoidoses. Nouv. rev. Franc. d’tiemat., 3, 5. R. D., SPERRY, W. M., AND BRODOFF, B. 1954. Adult lipoidoses resembling NiemannTERRY, Pick disease. Am. J. Path., 30, 263.
CASE R E P O R T
W. C. CHAN,K. S . LAIAND D. TODD The Departments of Pathology and Medicine, University of Hong Kong
PLATE LXXXVI NIEMANN-PICK disease is known to occur most frequently in Jewish children, and is excessively rare in adults. The usual presenting features include hepatosplenomegaly, xanthomata on a waxy skin, mental retardation, radiological changes in lungs and long bones, and the presence of lipoid-laden cells in the bone marrow and other organs. Diagnosis is confirmed by the demonstration of increased sphingomyelin (relative or absolute) in these organs. An adult form of the disease has been reported on several occasions (Dusendschon, 1946; Pfandler, 1946; Terry et al., 1954; Lynn and Terry, 1964). We now present the results of various studies in a southern Chinese woman with biochemical confirmation of Niemann-Pick disease. CASEREPORT Clinical features The patient, W.Y., was a Cantonese (southern Chinese) housewife born in Saigon, Vietnam, on 27 Apr. 1918. She first attended the Radiotherapy Department, Queen Mary Hospital, on 3 Nov. 1965. She then had a Stage IV nasopharyngeal carcinoma presenting with nasal obstruction and sero-sanguinous discharge for 8 mth and cervical lymphadenopathy mainly on the left side for 5 mth. Physical examination confirmed a large primary growth covering the roof and posterior wall of the nasopharynx. Liver and spleen were not palpable. Biopsy of the growth showed poorly differentiated carcinoma, apparently of the squamous type, infiltrating fibrous tissue. A 6-wk course of radiotherapy combined with 4 g of cyclophosphamide given in 20 intravenous injections brought completed regression of all signs of malignancy. The patient was seen again in July 1967, when she had n o symptoms but the right lobe of the liver was noted to be enlarged to 8 cm below the costal margin at the mid-clavicular line; it was firm and smooth. Recurrence was thought to be the most likely cause and no active treatment given. Six months later the patient began to have intermittent puffiness of the face, ankle oedema, and abdominal distension. Symptoms persisted and the patient was admitted to a hospital in Vietnam in July 1968 after 3 days of fever, cough and vomiting. She was told that she had " pericardial effusion " and improved with conservative measures. After 5 mth of relative freedom from symptoms, patient noticed epigastric discomfort and dull aching in the right upper quadrant of the abdomen. She returned to the follow-up clinic of the Radiotherapy Department in May 1969 and was transferred to the care of the University Department of Medicine on 16 May 1969. There was n o history of fever, jaundice or chest symptoms. Past health and family history were unremarkable. Patient had four normal children (now aged 21-27 yr) by full-term pregnancies and spontaneous delivery. Physical examination revealed a thin woman weighing 82 Ib. She was pale but had no jaundice, skin lesions, oedema, lymphadenopathy, or bleeding tendency. Her blood pressure Received 25 April 1976; accepted 7 June 1976. I. PATH.-VOL.
121 (1977)
177
M
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W. C. CHAN, K . S. LA1 AND D. TODD
measured 120/80 mm Hg. The abdomen was mildly distended with some ascites. The right lobe of the liver had shrunken to extend only 4 cm below the costal margin, but the left lobe now measured 8 cm below the xiphoid process; it was very firm and irregular on the surface. The spleen tip was palpable. All the other systems,,including the cardiovascular, showed no abnormality. The nasopharynx was clear. Invesfigations Haemoglobin 9.9 g per cent., white cell count 2‘745/cu. mm, with 66 per cent. neutrophils, 24 per cent. lymphocytes, and 8 per cent. monocytes; all cells appeared normal. Platelets 52,000/c.mm, reticulocytes 1 per cent., erythrocyte sedimentation rate 90 mm in the 1st hr. Urine contained trace protein and 5-15 pus cells/h.p.f. and scanty growth of E. coli on culture. Ova of Clonorchis sinensis were found in the stool. Serum bilirubin ranged from 0.7 mg per cent. to 1.3 mg per cent. alkaline phosphatase 8617-6KA units, acid phosphatase 41.0 KA units (repeat: 32.6 KA units), glutamic oxaloacetic transaminase 198 King’s units, glutamic pyruvic transaminase 108 King’s units, prothrombin time 13-24 s (control: 12 s). Urea 39 mg per 100 ml, Naf 140 mEq/l., K+ 4.2 mEq/l., cholesterol 106 mg per 100 ml, fasting glucose 90 rrig per 100 ml. Total serum proteins 5.6 g per lOOml: albumin 2.1 g, globulin 3-5 g, comprising c(1 9.1 per cent., c(2 9.1 per cent., /3 9-1 per cent. and y 39.3 per cent. by paper electrophoresis. Immuno-electrophoresis: increase in all immune globulins tested-IgA, IgM, and IgG. Urinary excretion of acid mucopolysaccharide expressed as glucuronic acid = 4.32 mg/24 hr (normal range: 2.73-5.4 mg/24 hr). Indium113 scanning of the liver demonstrated a large zone of deficient uptake occupying much of the right lobe and a major portion of the left lobe. A percutaneous needle biopsy of the liver was taken from the “ filling defect ” in the right lobe. An aspiration biopsy of sternal and later iliac crest marrow showed active normoblastic erythropoiesis and normal granulopoiesis and megakaryocytes but some large cells with small nuclei containing coarse chromatin, and plentiful vacuolated cytoplasm, appearing to be lipid-laden. X-ray of the chest showed slight increase in the i.ransverse diameter of the cardiac shadow but normal lung fields. At cardioscopy, there was marked limitation of cardiac pulsations, and subsequent cardiac catheterisation demonstrated a thickness of over 2.5 cm from the right cardiac border to the right atrial lumen. The electrocardiagram was normal. Skeletal survey revealed extensive rarefaction in the lateral half of the proximal third of the left humerus and both ends of both femora and a suggestion of destruction in the iliac wings of the pelvis, especially the right side. The skull X-ray was normal. At pericardiostomy, 200 ml of serous fluid was drained; the pericardium appeared normal except for seven to eight greyish-white nodules, each measuring 2-3 mm in diameter, over the visceral pericardium; these were biopsied. For special studies, a wedge biopsy of the liver was also taken by a short extension of the incision. Management and subsequent course The ascites was controlled with difficulty by frusemide and ethacrynic acid. Anorexia, general weakness and constipation was prominent. Patient developed a dental abscess from the right lower second premolar, with cellulitis of the face, responding to extraction of the offending tooth and a 5-day course of tetracycline. A combination of prednisone 15 mg q.i.d. orally and cyclophosphamide 200 mg intravenously daily was tried but patient became mentally confused on the 4th day of therapy, went downhill steadily despite withdrawal of the drugs and died on 1 Sept. 1969, Pathology First liver biopsy. There are groups of cells with foamy cytoplasm in the sinuses with compression of liver cords (fig. 1). These cells appear to originate from Kupffer cells. They are PAS -ve and stand out strikingly among liver cells which are strongly PAS +ve.
ADULT NIEMANN-PICK DISEASE
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Second liver biopsy. In the wedge of liver, similar foamy cells are present in groups in sinusoids. Nodules removed from epicardium are composed of aggregates of cells with foamy and vacuolated cytoplasm. There is a basophilic tinge of the cytoplasm. Autopsy finding The body is emaciated. Moderate autolysis is evident in all organs. Significant gross findings are present in the liver, the heart and the spleen. Heart. There are 30 cc of serous fluid in the pericardial cavity. The epicardium is studded with about ten brownish nodules, the largest of which is 5 mm in diameter. The myocardium and heart valves are not remarkable. Liver. The liver weighs 1300 g. It is pale yellow and shows an increase in consistency. The surface is smooth. Cut surface shows irregular pale yellowish areas which are confluent in the right lobe. Tiny brownish-yellow specks are scattered sporadically. Mild thickening of intrahepatic bile-ducts is present. Spleen. Weighs 275 g. The capsule is thickened. Cut surface shows brownish flecks similar to those described in the liver.
TABLE Percentage wet weight Total Total phospholipid Sphingomyelin Cholesterol
Liver 1 *72 1.31 (75% of total lipid) 1.07 (82% of phospholipid) 0.18 (10% of lipid)
Spleen
2.06 1.13 (54% of total lipid) 0.85 (75% of phospholipid) 0.23 (20% of lipid)
There is less than 0.2 per cent. dry weight of cerebroside in the two organs.
Histology Histology of post-mortem material is poor because of autolysis. Apart from the liver and nodules of the epicardium which have been examined histologically before death, infiltrations of foamy cells are found in all tissues examined. They include the thyroid, the adrenals, the spleen, the kidneys, the lungs, various lymph nodes and vertebral bone marrow. In the lungs, foamy cells are present in alveoli. The nasopharynx was carefully sectioned and examined. N o residual tumour was found. There are groups of similar foamy cells in the wall of the nasopharynx. Review of the original biopsy of the nasopharynx confirms the presence of a poorly differentiated squamous carcinoma. Electron microscopy The 2nd liver biopsy was fixed in 1 per cent. osmium tetroxide and processed for ultrastructural study. The Kupffer cells contain vacuoles of varying sizes. Most of their cytoplasm is displaced by these vacuoles and the nucleus is often compressed (fig. 2). The content of these vacuoles is lightly electron dense. In occasional vacuoles, electron-dense material in small clumps is present. There are no lamellated structures seen. Mitochondria, GER and microsomes are displaced. The liver cells also contain similar vacuoles, but their sizes are generally smaller than those in the Kupffer cells (fig. 2). A few cells show small clear zones in the cytoplasm, in which no organelles are seen.
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Chemical analysis
The liver and spleen were analysed chemically for lipids and sphingomyelin. The results are in the table.
DISCUSSION Niemann-Pick (NP) disease is characterised by the accumulation in tissue of sphingomyelin (Klenk, 1934). It is primarily a disease of childhood. Since the study in 1946 of two Swiss brothers independently by Dusendschon and Pfandler, an adult variant distinct from the usual infantile type emerged. Terry et al. (1954) described a 54-yr-old man suffering from the disease and Lynn and Terry (1964) studied by histochemical and ultrastructural methods a 19-yrold Puerto Rican boy. In the latter study, a lymph node and also marrow smears were examined. The material concerned was found to be a phospholipid and PAS positive. Ultrastructurally, the material in the lymph node was represented by lamellated, membranous bodies. Tanaka et al. (1963) found similar bodies in three cases and one was a 19-yr old. Lynn and Terry claimed that these bodies were more common in the adult type of the disease. In the present case, histological and ultrastructural studies were made on liver tissue of a 54-yr-old woman suffering from the disease. The results differed from those of Lynn and Terry. Unlike the NP cell in the lymph node of their case, the accumulated substance in our patient was PAS negative as is most phospholipids. Lamellated membranous bodies were not found. Instead, amorphous, lightly electron-dense material was found in vacuoles, reflecting the light microscopic picture. These vacuoles were plentiful in the Kupffer cells and to a lesser degree in the liver parenchyma cells. Chemically, using autopsy material, there is little doubt that the sphingomyelin content is markedly elevated in the liver and spleen. The absolute amount is increased, but more important is the high percentage of sphingomyelin in total phospholipid. The distribution of the NP cells was generalised; this and the fatal outcome are features of the infantile form. Another unusual feature in the present case is the markedly elevated serum acid phosphatase, confirmed on two occasions. This finding has been reported in Gaucher’s disease (Crocker and Landing, 1960) but not in Niemann-Pick disease. Brady et al. (1966) demonstrated that the primary lesion in Niemann-Pick disease is a biochemical one. It is due to a deficiency in the enzyme sphingomyeljnase. This enzyme is concerned with the catabolic breakdown of sphingomyelin, the source of which is mainly in cell membranes, particularly of the red cells, and the red cell stroma. Normal liver contains the highest activity. Because of the deficiency of this catabolic enzyme, sphingomyelin accumulates. There are several possible reasons why our ultrastructural findings differ from those of Lynn and Terry’s. The first is obvious. The material used is different. They studied lymph node, while we studied the liver. It is rather unfortunate that lymph-nodal tissue was not available for ultrastructural study until after death. Attempt at electron microscopy of the post-mortem lymph
CHAN,LAI A N D TODD
PLATE XXXVI ADULTNIEMANN-PICK
DISEASE
FIG. 1. ---Enlarged and foamy Kupffer cells compress liver cords. (HE). x140.
Fici.
Haematoxylin and eosin
2.-The Kupffer cells contain many vacuoles with lightly electron-dense material. Part of a red blood cell is seen among thc vacuoles. Electron micrograph (EM). x 6800.
A D ULT NIEMANN-PICK DISEASE
181
node was unsatisfactory. The second possibility is that although the two cases were both lipidosis, the metabolic defects were different. It is possible that the histological picture of NP cells may be the result of more than one biochemical lesion in the metabolism of lipids. The appearance of lamellated membrane structures may represent either an increase in biosynthesis of membrane or a blockage in the degradation at a higher level than found in our case. The difference in the PAS staining in the two cases lends support to the idea that the abnormal phospholipids were actually two different substances. Chemical data were not presented in Lynn and Terry’s article. The relationship between the NP disease and the preceding disease of nasopharyngeal carcinoma and irradiation is conjectural. The complete eradication of the tumour by irradiation and chemotherapy is remarkable in itself. It is, however, not unknown in this locality, for long survival after radiotherapy is commonplace (Ho, H. C.). It is possible that irradiation and/or chemotherapy may either initiate or unmask the deficiency of sphingomyelinase. On the other hand the metabolic defect may be the result of the presence of the carcinoma due to some unknown mechanism.
SUMMARY
A case is presented of the rare adult form of Niemann-Pick disease occurring in a Cantonese. The diagnosis was verified by biochemical analysis of the affected tissues. We thank Dr H. J. Lin, Senior Hospital Biochemist, for the chemical analysis. Mr K. H. Lau and Mr J. F. Ning gave valuable technical assistance. REFERENCES BRADY, R. O.,KANFER, J. N., MOCK,M. B., AND FREDRICKSON, D. S. 1966. The metabolism of sphingomyelin. 11. Evidence of an enzymatic deficiency in Niemann-Pick disease. Proc. Nut. Acad. Sci. US.,55, 366. CROCKER, H. C., AND LANDING, B. H. 1960. Phosphatase studies in Gaucher’s disease. Metabolism, 9, 341. Ho, H. C. Personal communication. DUSENDSCHON, A. 1946. Deux cas familiaux de maladie de Niemann-Pick chez l’adulte. Thesis, Faculte de Medicine, University of Geneva. KLENK,E. Z. 1934. Cited by Brady et aZ., 1966. LYNN,R., AND TERRY,R. D. 1964. Lipid histochemistry and electron microscopy in adult Niemann-Pick disease. Am. J. Med., 37, 987. U. 1946. La maladie de Niemann-Pick dans le cadre des lipoidoses. Schweiz. PFANDLER, med. wchnschr., 76, 1128. TANAKA, Y.,BRECHER, G., AND FREDRIKSON, D. S. 1963. Cellules de la maladie de NiemannPick et de quelques autres lipoidoses. Nouv. rev. Franc. d’tiemat., 3, 5. R. D., SPERRY, W. M., AND BRODOFF, B. 1954. Adult lipoidoses resembling NiemannTERRY, Pick disease. Am. J. Path., 30, 263.
