Scintigraphic Findings in Primary Amyloidosis
Nuclear Medicine
An Analysis of 7 Cases1 Samuel Sostre, Maj., MC USAF, 2 Nell D. Martin, Col., MC USAF, Richard N. Lucas, Col., MC USAF, and H. William Strauss, M.D.
Images of 7 patients with primary amyloidosis revealed organomegaly with regions of decreased tracer accumulation due to infiltration and replacement of normal tissue by the amyloid complex. These scintigraphic changes in the clinical setting of multisystem disease should suggest amyloidosis as a'possible diagnosis. INDEX TERMS: Amyloidosis. Kidneys, radionuclide studies. Liver, radionuclide studies• Spleen, radionuclide studies. Thyroid, radionuclide studies
Radiology 115:675-677, June 1975
AMYLOIDOSIS is a disease of unknown etiology characterized by the deposition of an abnormal protein mucopolysaccharide complex within tissue parenchyma and around blood vessels (1-3), eventually compressing and replacing the normal tissue and interfering with cellular and organ function (4). Due to the varied clinical presentation, diagnosis is often difficult and is sometimes made only at autopsy. In many cases, radionuelide studies are necessary in order to determine the nature of the disease process. We wish to describe the scintigraphic findings in 7 patients with multisystem disease studied between 1968 and 1972 who subsequently proved to have primary amyloidosis. Three were studied at the David Grant USAF Medical Center and 4 at Johns Hopkins Hospital.
(e) Bone-marrow scans were performed by the technique of Mcintyre (5), using 12 mCi of 99mTc-sulfur colloid. All studies were performed with a rectilinear scanner (Picker) having either a 7.6-cm (3-in.) or 12.7-cm (5-in.) crystal or with a Pho-Gamma 3 gamma camera. Except for the total-body bone scans, no contrast enhancement was employed. The diagnosis of primary systemic amyloidosis was established by autopsy in 5 patients and percutaneous liver biopsy in 2. A total of 15 imaging procedures were performed.
METHOD
The liver and spleen were studied in 5 patients, all of whom demonstrated histological involvement of the liver by amyloid. The scintigraphic appearance of the liver was normal in 1, enlarged with homogeneous uptake in 2, and enlarged with heterogeneous uptake in 2. None had focal defects. Histological sections of the liver were evaluated by the Pathology Department and graded from 0 (no involvement) to 4+ (virtually complete replacement of the liver by amyloid). The degree of histological involvement correlated with the radionuclide findings (TABLE I). The spleen was normal in 1, enlarged with increased uptake in 2, enlarged with decreased uptake in 1, and "absent" in 1, although it was palpable on physical examination and massively enlarged at autopsy. Histologically it was infiltrated by amyloid, with virtually complete replacement of the normal tissue (Fig. 1).
K
RESULTS
Liver and Spleen
Five types of radionuclide studies were performed: (a) The liver, reticuloendothelial system, and spleen
were given intravenous injections of 3 mCi of 99mTc_ sulfur colloid (Tesuloid, Squibb) and imaged in the anterior, posterior, and both lateral positions. (b) Thyroid uptake was evaluated either 2 and 24 hours after administration of 50 Jl,Ci of Na 131 1by mouth or 20-30 minutes after intravenous administration of 5 mCi of 99mTc-pertechnetate. (c) Renal scans were obtained 1 hour after intravenous administration of 150 Jl,Ci of 197Hg-chlormerodrin, followed by renography using 300 Jl,Ci of 1311-iodohippurate. (d) Bone scans were obtained 2 hours after intravenous administration of 4 mCi of 18F.
1 From the Department of Radiology and the Division of Nuclear Medicine (S. S., H. W. S.), Johns Hopkins Medical Institutions, Baltimore, Md., and the Departments of Nuclear Medicine (N. D. M.) and Pathology (R. N. L.), David Grant USAF Medical Center, Travis AFB, Calif. Accepted for publication in October 1974. Supported by USPHS grants GM 01496 and GM 10548. 2 Present address: Department of Nuclear Medicine, USAF Medical Center-SGHA, Wright-Patterson AFB, Ohio 45433. sjh
675
676
June 1975
SAMUEL SOSTRE AND OTHERS
Table I:
Scintigraphic and Histological Findings in the Liver and Spleen in Patients with Amyloidosis -------Liver
Case
Scan Findings
I. II.
Normal Enlarged with homogeneous uptake Enlarged with homogeneous uptake Enlarged with heterogeneous uptake Enlarged with heterogeneous uptake
III.
IV.
V.
Spleen---·---Degree of Histological Involvement
1+ 1-2+ 2+ 2+ 3+
Scan Findings
Degree of Histological Involvement
Normal Enlarged with increased uptake Enlarged with decreased uptake Enlarged with increased uptake Absent
2+ 2+ Not examined Not examined
4+
B. Liver-spleen scan (anterior and posterior views), showing an enlarged liver and lack of splenic uptake.
Fig. 1. A. Gross specimen of the spleen obtained at autopsy from a patient with an "absent" spleen on the liver-spleen scan.
Thyroid
Four thyroid studies were performed, including 2- and 24-hour uptake, thyroid scanning, T3 resin uptake, and total T 4. All 4 patients were clinically and chemically euthyroid. The radionuclide images showed normal structure in 2, diffuse enlargement in 1, and an enlarged, apparently multinodular gland in 1. There was histological evidence of diffuse thyroidal invasion in the first 3 patients; the fourth patient had nodular amyloid invasion with atrophic compression of the surrounding tissue.
Renal
Renal scans and renograms were obtained in 2 patients. The first patient had nephrotic syndrome and had undergone unilateral nephrectomy. Both radionuclide images and renograms were normal, and the creatinine clearance was 90 ml/min. The second patient was uremic, and his kidneys could not be seen on the scan, while the renogram showed marked functional reduction. Autopsy demonstrated marked involvement of both glomeruli and tubular cells by amyloid. Miscellanepus
Two bone scans, one bone-marrow scan, and one
c. Histological section of the spleen, showing marked splenic involvement by amyloid with virtually complete replacement of the normal structure. brain scan were performed in a total of 4 patients. All four studies were normal. DISCUSSION
Although we found no pathognomonic scintigraphic findings in our series, there are some findings which may suggest the diagnosis in the appropriate clinical setting. These are the result of compression, displacement, or replacement of normal tissue, most frequently that of mesenchymal origin, by the amyloid complex (6). Hepatic involvement is very common and may be present in up to 80 % of patients with amyloidosis. Progressive deposition of amyloid in the space of Disse may result in enlargement of the liver and compression of the vascular sinusoids, biliary passages, and liver parenchyma (7). These changes can be seen on images of the liver and spleen. If hepatic involvement is minimal, the liver may appear normal, as was true in CASE I (TABLE I); amyloid infiltration in this patient was not sufficient to enlarge or compress the liver. As amyloid infiltration progresses, less resistant structures (in this case the sinusoids) will be compressed, resulting in decreased blood flow to the liver, increased portal pres-
Vol. 115
SCINTIGRAPHIC FINDINGS IN PRIMARY AMYLOIDOSIS
sure, and some vascular engorgement of the spleen. One would expect to find either a normal or enlarged liver and a large spleen with increased uptake on images of these organs. Marked hepatic infiltration with some parenchymal compression would be seen as a large liver with either homogeneous or heterogeneous uptake depending on whether amyloid deposition was diffuse or focal. Intrahepatic obstructive jaundice caused by amyloidosis is rare (8) and was not observed in any of our patients. Another cause of enlargement of the liver and spleen with heterogeneous uptake is congestive heart failure (9, 10). Since cardiac involvement occurs in most patients with amyloidosis, and since congestive failure is a common manifestation of this state, it is possible that cardiac failure alone could cause the liver image- to be abnormal; however, all patients with an abnormal liver image in this series had hepatic involvement. An enlarged spleen with increased uptake correlates with the degree of hepatic amyloid involvement and probably reflects a secondary increase in portal pressure. This is certainly not unique to amyloidosis, as the same pattern is also seen in cirrhosis (10). On the other hand, one of our patients had no splenic uptake on both the posterior and left lateral views, while in another it was decreased. Of these, only the patient with the "absent" spleen was autopsied; his spleen was found to be massively infiltrated by amyloid. Hence decreased splenic uptake may reflect the degree of direct amyloid invasion. Judging by the 3 patients whose spleens were examined histologically, it appears that such infiltration must be quite marked before splenic uptake decreases. Other conditions known to produce apparent asplenia on radionuclide images include congenital asplenia, complete replacement of the spleen by tumor, and sickle-cell anemia (11). Although thyroidal invasion by amyloid has been regarded as an infrequent finding (12), it was present in 4 patients in this series. The radionuclide pattern in such cases is probably more representative of the degree of involvement than of the presence of the disease. Amyloid involvement of the thyroid should be included in the differential diagnosis of diffusely enlarged or multinodular goiter. Amyloid involvement apparently must be massive before thyroid function decreases, as all 4 of our patients were euthyroid. Renal involvement is potentially the most serious manifestation of amyloidosis. It can lead to nephrotic syndrome and uremia and predisposes to renal-vein thrombosis (3). Involvement is primarily glomerular, with a lesser degree of accumulation in the peritubular basement membrane. Atrophic tubules may be seen late in the disease. One patient with nephrotic syndrome had normal
677
Nuclear Medicine
renal scans and renograms. This is not surprising, since amyloid is deposited early in the glomeruli and the renogram represents predominantly tubular function. The second patient was markedly uremic; the renogram was abnormal, and no definite renal function was demonstrable by chlormerodrin studies. Histologically, this patient had marked involvement of both glomeruli and tubular cells. The only brain study done was normal. A seizure disorder had developed, and the electroencephalogram was abnormal, with a focus in the right temporal lobe. Autopsy revealed amyloid involvement of the neurofibrillar tangles on the temporal lobes. It is possible that brain scans may not be sensitive enough to evaluate amyloid involvement of the central nervous system. Amyloid involvement of bone and bone marrow is rare (13). Two bone scans and one bone-marrow scan were performed in this series, and all 3 were normal. ACKNOWLEDGMENTS: We are indebted to Harry P. Wells, MSgt., MC USAF, David Grant USAF Medical Center, and James K. Langan, Johns Hopkins, under whose direction the scintigraphic studies were performed. Department of Nuclear Medicine USAF Medical Center-SGHA Wright-Patterson AFB, Ohio 45433
REFERENCES 1. Glenner GG, Ein D, Terry WD: The immunoglobulin origin of amyloid. Am J Med 52:141-147, Feb 1972 2. Abruzzo JL: Amyloidosis. A study of its pathogenesis and the role of humoral immunity. Arthritis Rheum 14:451-456, Jul-Aug 1971 3. Barth WF, Willerson JT, Waldmann TA, et al: Primary amyloidosis. Clinical, immunochemical and immunoglobulin metabolism studies in fifteen patients. Am J Med 47:259-273, Aug 1969 4. Pear BL: The radiographic manifestations of amyloidosis. Am J RoentgenoI111:821-832, Apr 1971 5. Mcintyre PA: Visualization of the reticuloendothelial system. Hosp Practice 5:77-87, 1971 6. Calkins E, Cohen AS: Diagnosis of amyloidosis. Bull Rheum Dis 10:215-218, Apr 1960 7. Stauffer MH, Dahlin DC: Amyloidosis of the liver. [In] Schiff L, ed: Diseases of the Liver. Philadelphia, Lippincott, 3d Ed, 1969, Chapt 27, pp 965-973 8. Levy M, Fryd CH, Eliakim M: Intrahepatic obstructive jaundice due to amyloidosis of the liver. A case report and review of the literature. Gastroenterology 61:234-238, Aug 1971 9. Gould L, Collica C, Comprecht RF, et al: Scintiphotography in congestive heart failure. The disappearing flying bat pattern. JAMA 219:1734-1737, 27 Mar 1972 10. McAfee JG, Ause RG, Wagner HN Jr: Diagnostic value of scintillation scanning of the liver. Follow-up of 1,000 studies. Arch Intern Med 116:95-110, Jul 1965 11. Pearson HA, Spencer RP, Cornelius EA: Functional asplenia in sickle-cell anemia. N Engl J Med 281 :923-926, 23 Oct 1969 12. Shapiro ST, Kohut RI, Potter JM:· Amyloid goiter. New associations and surgical treatment. Arch Otolaryngol 93:203-208, Feb 1971 13. Axelsson U, Hallen A, Rausing A: Amyloidosis of bone. Report of two cases. J Bone Joint Surg [Br] 52-B:717-723, Nov 1970
Nuclear Medicine
An Analysis of 7 Cases1 Samuel Sostre, Maj., MC USAF, 2 Nell D. Martin, Col., MC USAF, Richard N. Lucas, Col., MC USAF, and H. William Strauss, M.D.
Images of 7 patients with primary amyloidosis revealed organomegaly with regions of decreased tracer accumulation due to infiltration and replacement of normal tissue by the amyloid complex. These scintigraphic changes in the clinical setting of multisystem disease should suggest amyloidosis as a'possible diagnosis. INDEX TERMS: Amyloidosis. Kidneys, radionuclide studies. Liver, radionuclide studies• Spleen, radionuclide studies. Thyroid, radionuclide studies
Radiology 115:675-677, June 1975
AMYLOIDOSIS is a disease of unknown etiology characterized by the deposition of an abnormal protein mucopolysaccharide complex within tissue parenchyma and around blood vessels (1-3), eventually compressing and replacing the normal tissue and interfering with cellular and organ function (4). Due to the varied clinical presentation, diagnosis is often difficult and is sometimes made only at autopsy. In many cases, radionuelide studies are necessary in order to determine the nature of the disease process. We wish to describe the scintigraphic findings in 7 patients with multisystem disease studied between 1968 and 1972 who subsequently proved to have primary amyloidosis. Three were studied at the David Grant USAF Medical Center and 4 at Johns Hopkins Hospital.
(e) Bone-marrow scans were performed by the technique of Mcintyre (5), using 12 mCi of 99mTc-sulfur colloid. All studies were performed with a rectilinear scanner (Picker) having either a 7.6-cm (3-in.) or 12.7-cm (5-in.) crystal or with a Pho-Gamma 3 gamma camera. Except for the total-body bone scans, no contrast enhancement was employed. The diagnosis of primary systemic amyloidosis was established by autopsy in 5 patients and percutaneous liver biopsy in 2. A total of 15 imaging procedures were performed.
METHOD
The liver and spleen were studied in 5 patients, all of whom demonstrated histological involvement of the liver by amyloid. The scintigraphic appearance of the liver was normal in 1, enlarged with homogeneous uptake in 2, and enlarged with heterogeneous uptake in 2. None had focal defects. Histological sections of the liver were evaluated by the Pathology Department and graded from 0 (no involvement) to 4+ (virtually complete replacement of the liver by amyloid). The degree of histological involvement correlated with the radionuclide findings (TABLE I). The spleen was normal in 1, enlarged with increased uptake in 2, enlarged with decreased uptake in 1, and "absent" in 1, although it was palpable on physical examination and massively enlarged at autopsy. Histologically it was infiltrated by amyloid, with virtually complete replacement of the normal tissue (Fig. 1).
K
RESULTS
Liver and Spleen
Five types of radionuclide studies were performed: (a) The liver, reticuloendothelial system, and spleen
were given intravenous injections of 3 mCi of 99mTc_ sulfur colloid (Tesuloid, Squibb) and imaged in the anterior, posterior, and both lateral positions. (b) Thyroid uptake was evaluated either 2 and 24 hours after administration of 50 Jl,Ci of Na 131 1by mouth or 20-30 minutes after intravenous administration of 5 mCi of 99mTc-pertechnetate. (c) Renal scans were obtained 1 hour after intravenous administration of 150 Jl,Ci of 197Hg-chlormerodrin, followed by renography using 300 Jl,Ci of 1311-iodohippurate. (d) Bone scans were obtained 2 hours after intravenous administration of 4 mCi of 18F.
1 From the Department of Radiology and the Division of Nuclear Medicine (S. S., H. W. S.), Johns Hopkins Medical Institutions, Baltimore, Md., and the Departments of Nuclear Medicine (N. D. M.) and Pathology (R. N. L.), David Grant USAF Medical Center, Travis AFB, Calif. Accepted for publication in October 1974. Supported by USPHS grants GM 01496 and GM 10548. 2 Present address: Department of Nuclear Medicine, USAF Medical Center-SGHA, Wright-Patterson AFB, Ohio 45433. sjh
675
676
June 1975
SAMUEL SOSTRE AND OTHERS
Table I:
Scintigraphic and Histological Findings in the Liver and Spleen in Patients with Amyloidosis -------Liver
Case
Scan Findings
I. II.
Normal Enlarged with homogeneous uptake Enlarged with homogeneous uptake Enlarged with heterogeneous uptake Enlarged with heterogeneous uptake
III.
IV.
V.
Spleen---·---Degree of Histological Involvement
1+ 1-2+ 2+ 2+ 3+
Scan Findings
Degree of Histological Involvement
Normal Enlarged with increased uptake Enlarged with decreased uptake Enlarged with increased uptake Absent
2+ 2+ Not examined Not examined
4+
B. Liver-spleen scan (anterior and posterior views), showing an enlarged liver and lack of splenic uptake.
Fig. 1. A. Gross specimen of the spleen obtained at autopsy from a patient with an "absent" spleen on the liver-spleen scan.
Thyroid
Four thyroid studies were performed, including 2- and 24-hour uptake, thyroid scanning, T3 resin uptake, and total T 4. All 4 patients were clinically and chemically euthyroid. The radionuclide images showed normal structure in 2, diffuse enlargement in 1, and an enlarged, apparently multinodular gland in 1. There was histological evidence of diffuse thyroidal invasion in the first 3 patients; the fourth patient had nodular amyloid invasion with atrophic compression of the surrounding tissue.
Renal
Renal scans and renograms were obtained in 2 patients. The first patient had nephrotic syndrome and had undergone unilateral nephrectomy. Both radionuclide images and renograms were normal, and the creatinine clearance was 90 ml/min. The second patient was uremic, and his kidneys could not be seen on the scan, while the renogram showed marked functional reduction. Autopsy demonstrated marked involvement of both glomeruli and tubular cells by amyloid. Miscellanepus
Two bone scans, one bone-marrow scan, and one
c. Histological section of the spleen, showing marked splenic involvement by amyloid with virtually complete replacement of the normal structure. brain scan were performed in a total of 4 patients. All four studies were normal. DISCUSSION
Although we found no pathognomonic scintigraphic findings in our series, there are some findings which may suggest the diagnosis in the appropriate clinical setting. These are the result of compression, displacement, or replacement of normal tissue, most frequently that of mesenchymal origin, by the amyloid complex (6). Hepatic involvement is very common and may be present in up to 80 % of patients with amyloidosis. Progressive deposition of amyloid in the space of Disse may result in enlargement of the liver and compression of the vascular sinusoids, biliary passages, and liver parenchyma (7). These changes can be seen on images of the liver and spleen. If hepatic involvement is minimal, the liver may appear normal, as was true in CASE I (TABLE I); amyloid infiltration in this patient was not sufficient to enlarge or compress the liver. As amyloid infiltration progresses, less resistant structures (in this case the sinusoids) will be compressed, resulting in decreased blood flow to the liver, increased portal pres-
Vol. 115
SCINTIGRAPHIC FINDINGS IN PRIMARY AMYLOIDOSIS
sure, and some vascular engorgement of the spleen. One would expect to find either a normal or enlarged liver and a large spleen with increased uptake on images of these organs. Marked hepatic infiltration with some parenchymal compression would be seen as a large liver with either homogeneous or heterogeneous uptake depending on whether amyloid deposition was diffuse or focal. Intrahepatic obstructive jaundice caused by amyloidosis is rare (8) and was not observed in any of our patients. Another cause of enlargement of the liver and spleen with heterogeneous uptake is congestive heart failure (9, 10). Since cardiac involvement occurs in most patients with amyloidosis, and since congestive failure is a common manifestation of this state, it is possible that cardiac failure alone could cause the liver image- to be abnormal; however, all patients with an abnormal liver image in this series had hepatic involvement. An enlarged spleen with increased uptake correlates with the degree of hepatic amyloid involvement and probably reflects a secondary increase in portal pressure. This is certainly not unique to amyloidosis, as the same pattern is also seen in cirrhosis (10). On the other hand, one of our patients had no splenic uptake on both the posterior and left lateral views, while in another it was decreased. Of these, only the patient with the "absent" spleen was autopsied; his spleen was found to be massively infiltrated by amyloid. Hence decreased splenic uptake may reflect the degree of direct amyloid invasion. Judging by the 3 patients whose spleens were examined histologically, it appears that such infiltration must be quite marked before splenic uptake decreases. Other conditions known to produce apparent asplenia on radionuclide images include congenital asplenia, complete replacement of the spleen by tumor, and sickle-cell anemia (11). Although thyroidal invasion by amyloid has been regarded as an infrequent finding (12), it was present in 4 patients in this series. The radionuclide pattern in such cases is probably more representative of the degree of involvement than of the presence of the disease. Amyloid involvement of the thyroid should be included in the differential diagnosis of diffusely enlarged or multinodular goiter. Amyloid involvement apparently must be massive before thyroid function decreases, as all 4 of our patients were euthyroid. Renal involvement is potentially the most serious manifestation of amyloidosis. It can lead to nephrotic syndrome and uremia and predisposes to renal-vein thrombosis (3). Involvement is primarily glomerular, with a lesser degree of accumulation in the peritubular basement membrane. Atrophic tubules may be seen late in the disease. One patient with nephrotic syndrome had normal
677
Nuclear Medicine
renal scans and renograms. This is not surprising, since amyloid is deposited early in the glomeruli and the renogram represents predominantly tubular function. The second patient was markedly uremic; the renogram was abnormal, and no definite renal function was demonstrable by chlormerodrin studies. Histologically, this patient had marked involvement of both glomeruli and tubular cells. The only brain study done was normal. A seizure disorder had developed, and the electroencephalogram was abnormal, with a focus in the right temporal lobe. Autopsy revealed amyloid involvement of the neurofibrillar tangles on the temporal lobes. It is possible that brain scans may not be sensitive enough to evaluate amyloid involvement of the central nervous system. Amyloid involvement of bone and bone marrow is rare (13). Two bone scans and one bone-marrow scan were performed in this series, and all 3 were normal. ACKNOWLEDGMENTS: We are indebted to Harry P. Wells, MSgt., MC USAF, David Grant USAF Medical Center, and James K. Langan, Johns Hopkins, under whose direction the scintigraphic studies were performed. Department of Nuclear Medicine USAF Medical Center-SGHA Wright-Patterson AFB, Ohio 45433
REFERENCES 1. Glenner GG, Ein D, Terry WD: The immunoglobulin origin of amyloid. Am J Med 52:141-147, Feb 1972 2. Abruzzo JL: Amyloidosis. A study of its pathogenesis and the role of humoral immunity. Arthritis Rheum 14:451-456, Jul-Aug 1971 3. Barth WF, Willerson JT, Waldmann TA, et al: Primary amyloidosis. Clinical, immunochemical and immunoglobulin metabolism studies in fifteen patients. Am J Med 47:259-273, Aug 1969 4. Pear BL: The radiographic manifestations of amyloidosis. Am J RoentgenoI111:821-832, Apr 1971 5. Mcintyre PA: Visualization of the reticuloendothelial system. Hosp Practice 5:77-87, 1971 6. Calkins E, Cohen AS: Diagnosis of amyloidosis. Bull Rheum Dis 10:215-218, Apr 1960 7. Stauffer MH, Dahlin DC: Amyloidosis of the liver. [In] Schiff L, ed: Diseases of the Liver. Philadelphia, Lippincott, 3d Ed, 1969, Chapt 27, pp 965-973 8. Levy M, Fryd CH, Eliakim M: Intrahepatic obstructive jaundice due to amyloidosis of the liver. A case report and review of the literature. Gastroenterology 61:234-238, Aug 1971 9. Gould L, Collica C, Comprecht RF, et al: Scintiphotography in congestive heart failure. The disappearing flying bat pattern. JAMA 219:1734-1737, 27 Mar 1972 10. McAfee JG, Ause RG, Wagner HN Jr: Diagnostic value of scintillation scanning of the liver. Follow-up of 1,000 studies. Arch Intern Med 116:95-110, Jul 1965 11. Pearson HA, Spencer RP, Cornelius EA: Functional asplenia in sickle-cell anemia. N Engl J Med 281 :923-926, 23 Oct 1969 12. Shapiro ST, Kohut RI, Potter JM:· Amyloid goiter. New associations and surgical treatment. Arch Otolaryngol 93:203-208, Feb 1971 13. Axelsson U, Hallen A, Rausing A: Amyloidosis of bone. Report of two cases. J Bone Joint Surg [Br] 52-B:717-723, Nov 1970
