SOFT-TISSUE UPTAKE OF 99mTc-DIPHOSPHONATE

AND 99~c-PYROPHOSPHATE IN SYSTEMIC AA AND AL AMYLOIDOSIS

ABSTRACT

S. Janssen, D. A. Piers 1 ,

M. H. van Rijswijk, and E. Mandema

Department of Medicine and

lDepartment of Nuclear Medicine University Hospital Groningen, The Netherlands

Reviewing the literature it is difficult to assess the significance of soft-tissue uptake on scanning with 99mTc-1abe1ed phosphates in amyloidosis, because of differences with regard to the radiopharmaceutical and the scan­ning technique used, and because of lack of information concerning the type of amyloid involved.

A comparative, prospective study was made to determine the efficacy of 99mTc-methy1ene-diphosphonate (Tc-MDP) and 99mTc-pyrophosphate (Tc-PYP) in demonstrating soft-tissue uptake in AA and AL amyloidosis. The results of scintigraphic imaging with Tc-MDP and Tc-PYP were compared with the clinical pattern of organ involvement in 6 patients with systemic AA and 6 patients with systemic AL amyloidosis. Image quality (contrast) was generally better with Tc-MDP than with Tc-PYP, although there was no difference in the ex­tend or the intensity of the soft-tissue uptake. Tc-MDP can play an im­portant role in evaluating amyloid disease with regard to involvement of the thyroid gland, the oropharyngeal region, the nervous system, the liver, the spleen, and the intestinal tract. In contrast with previous reports we found echo cardiography to be more sensitive for demonstrating cardiac in­volvement than scintigraphy. Although nephropathy dominates the clinical scene in AA amyloidosis the scintigraphic pattern of organ involvement was compatible with the histological, multi-systemic, distribution of amyloid.

INTRODUCTION

Clinical manifestations of amyloid disease are variable and depend on the organs involved. The diagnosis of amyloidosis requires histological identification of amyloid material in biopsy specimens. Biopsy procedures are not without risk of hemorrhage. Bleeding may occur in the absence of abnormalities in the coagulation profile and is probably due to amyloid in­filtration of the wall of blood vessels (Yood et a1., 1983). Non-invasive tests would be helpful to evaluate the extend of organ involvement in cases of suspected or proven amyloidosis. Soft-tissue uptake of 99mTc-1abe1ed phosphates has been linked with the presence of amyloid in a number of

621 G. G. Glenner et al. (eds.), Amyloidosis© Plenum Press, New York 1986

cases of systemic amyloidosis, mainly of the AL type (Janssen et al., 1984). Lee et al. (1983) suggested that 99mTc-pyrophosphate (Tc-PYP) may be more sensitive in demonstrating cardiac and hepatic amyloidosis than 99Mrc_ methylene-diphosphonate (Tc-MDP).

The purpose of our study was 1) to establish the efficacy of whole body scintigraphy with "bone-scanning" agents as a non-invasive screening test for the extend of organ involvement in both AA and AL amyloidosis; 2) to establish the relative efficacy of Tc-MDP versus Tc-PYP.

MATERIAL AND METHODS

Between January 1983 and January 1984, 6 patients with systemic AA and 6 patients with systemic AL amyloidosis were entered into a prospective study. The diagnosis of amyloidosis was confirmed histologically by the apple-green birefringence with polarized light after Congo red staining of biopsy specimens. In all patients the effect of incubation with potassium permanganate (KMn04) on the affinity for Congo red was investigated.

A careful search for the presence of a monoclonal component was made. Diagnosis of renal amyloidosis was made in the presence of proteinuria and renal function loss. In 7 patients a renal biopsy specimen was obtained, all of which showed amyloid deposits. Diagnosis of cardiac amylOidosis was made if the patient had the typical echocardiographic appearance of amy­loidosis: increased thickness of septum and left ventricular wall with de­creased wall motion. The presence of amyloid neuropathy was established by measurement of nerve conduction velocity. Physical examination revealed the presence or absence of macroglossia and enlargement of the thyroid gland. Thyroid function tests (free thyroxine level; thyroid stimulating hormone) and liver function tests (alkaline phosphatase and transaminases) were made in all patients.

Whole body scintigraphy was performed 4 h after intravenous injection of 500 MBg (13.5 mCi) of Tc-MDP or Tc-PYP at 3 to 5 days intervals; scans were made in random order. Grading of soft-tissue uptake: 0 = normal: I = equivocal; 2 = positive with lower intensity than the ribs; 3 = positive with intensity equal to greater than the ribs, but lower than the sternum; 4 = positive and intensity greater than the sternum.

RESULTS

The clinical, laboratory, and scintigraphic data are summarized in Table 1. All patients had biopsy proven amyloidosis; 6 patients presented with systemic amylOidosis associated with overt or covert mUltiple myeloma (KMn04-resistant amyloid deposits); amyloidosis was associated with chronic inflammatory diseases in 6 patients (KMn04-sensitive amyloid deposits).

Tc-MDP images showed a better contrast than Tc-PYP images, although there was no obvious difference in the intensitI or the extend of soft­tissue uptake (Chi square test: p > 0.05). 991~c-labeled phosphates are excreted by the kidneys and this accounts for the visualization of the kid­neys on "bone-scanning." Abnormal soft-tissue uptake in the limbs was ob­served in 4/6 AA and 6/6 AL patients, 2 of whom suffered from severe poly­neuropathy with marked reduction of nervce conduction velocity. Soft­tissue uptake in the limbs was not correlated with renal function loss (Wilcoxon's rank sum test: p > 0.05). In both patients with macroglossia the scans showed marked uptake in the oropharyngeal region. Uptake in the thyroid gland was seen in 3 AA and 3 AL patients, all of whom had normal thyroid function tests. In patient 3 the thyroid gland was markedly en-

622

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N

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TAB

LE

1.

Cli

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L

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, an

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Fin

din

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in

6 P

ati

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ith

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and

6 P

ati

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AA

Am

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PAT

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NO

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PATH

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PYP

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+

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+

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nd

-2

nd

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nd

nd

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nd

-

4 nd

4

nd

.,

I 2

~74

AL

IgA~

+

... ±

2

3 +

2

2 -

I 0

0 N

:

1 2

0 0

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I "

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0 0

'" .. [G

oit

er]

:

2 3

654

AL

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+

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0

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2

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0 0

0 0

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3

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2 3

3 I

0 I

0 0

0 0

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: 0

0 -

0 0

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+

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-

-0

N

5 66

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0 0

0 0

I 0

0 -

0 0

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+

-2

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2

3 N

0

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co

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6 65

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0 0

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... I

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I

7 64

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0 -

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0 -

0 0

N

0 0

0 0

N

I 3

J -

0 0

8 I

: 0

0 ~J

AA

-+

ad

~ -

0 0

-I

2 1

-0

0 A

lk p

ht

J "

0 0

N

0 -

0 I

, : "

9

~61

AA

-+

I

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.>:

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I 3

3 -

0 0

Alk

ph

t 3

3 3

" N

"

-0

0 ,

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~ 0

10

672

AA

-+

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0 0

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2 2

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0

0 0

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3 -

2 2

I .....

. I

11

~53

AA

I I

" l 3

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I

0 0

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2 2

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3

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... .0

I

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I 12

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AA

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I~

-I

0 0

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0 0

-0

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0

I 0

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I I

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Exp

lan

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of

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-la

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g h

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one

TABLE 2. Soft Tissue Uptake of Bone-Seeking Radiopharmaceuticals in Amyloidosis; Review of the Literature

Tracer

Tc-MDP

Tc-MDP

Tc-MDP

Tc-MDP

Tc-MDP

Tc-MDP

Tc-PYP

Tc-PYP

Tc-MDP Tc-PYP

Tc-PYP

Tc-PYP Tc-PYP

Tc-PYP

Tc-MDP

Tc-PYP

Tc-MDP

624

Abnormal findings

Periarticular uptake

Hepatic uptake

Myocardial uptake

Skeletal-muscle uptake

"Soft tissue" uptake

Myocardial uptake

"Soft tissue" uptake

Uptake in skin nodules

Splenic uptake

Hepatic uptake

Splenic uptake

Myocardial uptake

Periarticular uptake

Hepatic uptake

Skeletal-muscle uptake

Myocardial uptake

Myocardial uptake

Myocardial uptake Myocardial uptake

Hepatic uptake Myocardial uptake

Hepatic uptake

Thyroid uptake

Uptake in:

-salivary glands

-thyroid gland

-heart

-liver/spleen

-intestine

-uterus

Number of patients

1

I

2

I

1

1

1

3

3

1

10

1

2

7

7

2

1

Probable Reference type of amyloid

AL Van Antwerp (1975)

AL Vanek (1977)

1 Heredi- Kula (1977)

tary and

1 AL

AL

AL

AL

AL

AL

AL

AL AL

AL AL AL

AL

1 AL

1 AA

AL

Bada (1977)

Braun (1979)

Moyle (1980)

Rao (1981)

Yood (1981)

Yood (1981)

Johnston (1982)

Wizenberg (1982)

Schiff (1982)

Sobol (1982)

Lee (1983)

Lee (1983)

Lee (1984)

Janssen (1984)

larged on palpation. Scintigraphic cardiac uptake was present in 5 patients (3 AL and 2 AA). There was no difference in septum and posterior wall thickness on echo cardiography between the patients with and without cardiac uptake (Wilcoxon's rank sum test: p > 0.05). Elevation of alkaline phos­phatase, which could not be explained by bone activity or active rheumatoid arthritis, was present in 3/5 patients with hepatic uptake. 2/5 patients with diffuse abdominal uptake had signs of malabsorption. Uncommon sites of soft-tissue uptake include the spleen, the uterus, the salivary glands, and the skin.

DISCUSSION AND CONCLUSIONS

Reviewing the published data, it is difficult to assess the true sig­nificance of soft-tissue uptake on "bone-scanning" in amyloidosis (Table 2). The case reports and small series published so far differ with regard to the radiopharmaceutical and the scaaning technique used.

In 63% of the cases there was no information concerning the staining technique used to confirm the diagnosis. In 79% there were no data on the type of amyloid. In 79% of the patients attention was focussed mainly on the heart and liver. Soft-tissue uptake on "bone-scanning" has been re­ported in 38 cases of systemic amyloidosis, 8 of which can be classified as AL amyloidosis associated with plasma cell dyscrasia. On clinical grounds 28 of the remaining cases can be classified as AL and 1 as AA amyloidosis. In 1 patient a diagnosis of heredofamilial amyloidosis was made. It is possible, however, that some reports, in whom the type of amyloid was not given, include patients with senile cardiac amyloidosis.

We tried to establish the efficacy of scanning with 99~c-labeled phos­phates in amyloidosis by comparing the results of scintigraphic imaging with the clinical pattern of organ involvement in 12 well-defined cases of sys­temic (AA and AL) amyloidosis. In contrast with previous reports we did find no difference in the extent or the intensity of soft-tissue uptake be­tween Tc-MDP and Tc-PYP images. Image quality (contrast) was generally better with Tc-MDP than with Tc-PYP. This may be explained by the biologic characteristics of the two agents (Rudd et al., 1977). Tc-PYP has slightly lower bone uptake than Tc-MDP and shows significant red cell labeling, whereas Tc-MDP is confined primarily to the plasma and has higher urinary excretion than Tc-PYP.

Our results clearly show that Tc-MDP scanning can play an important role in evaluating amyloid disease with regard to involvement of the thyroid gland, the oropharyngeal region, the nervous system, the liver, the spleen, and the intestinal tract.

In contrast, scintigraphy which has been claimed to be a sensitive test for demonstrating amyloid cardiomyopathy (Wizenberg et al., 1982; Lee et al., 1983) was negative in 3/7 patients with echocardiographic features of amy­loid heart disease and positive in 1 patient with a normal echocardiogram. A possible explanation for this finding might be a more massive deposition of amyloid in case of cardiac uptake. There was, however, no difference in diastolic septum and posterior wall thickness between patients with an without cardiac uptake on scintigraphy. The precise mechanism of amyloid affinity for phosphates is not known, but it may be explained by the high calcium content of amyloid, which is due to the presence of the non-fibril­lar protein AP. Protein AP is a common constituent of all types of amyloid and has been demonstrated to bind in vitro to isolated AA and AL fibrils in a strictly calcium-dependent way.

625

A B

Fig. 1. Ilhole body scintigraphy with 99mTc _I.ffiP in patient 1: A = anterior and B = posterior view showing intense uptake in the thyroid, oro­pharyngeal region, heart, liver, spleen, intestine and uterus.

SUMMARY

1. Scanning with 99mTc-labeled phosphates is a sensitive non-invasive screening test for the extend or organ involvement in both systemic AA and AL amyloidosis (see Fig. 1).

2. Echocardiography seems to be more sensitive for demonstrating cardiac involvement in systemic amyloidosis than Tc-MOP or Tc-PYP scin­tigraphy.

3. Tc-MOP images show a better contrast than Tc-PYP images, although there is no obvious difference in the extent or the intensity of soft­tissue uptake.

4. In AA amyloidosis the clinical scene is dominated by nephropathy; the scintigraphic pattern of organ involvement, however, is multisystemic, which is compatible with the histological distribution of amyloid.

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