Orthostatic Hypotension as a Clue to Primary

Systemic Amyloidosis

By ROBERT A. KYLE, M.D., BRUCE A. KOTTKE, M.D.,

AND ALEXANDER SCHIRGER, M.D.

ALTHOUGH HYPOTENSION has beenmentioned commonly in primary amy-

loidosis,1-3 reports of orthostatic hypotensionhave been infrequent.4-7 Extensive reviews ofsyncope or fainting do not mention primaryamyloidosis as a possible cause.8 9 We havebeen impressed with the presence of ortho-static hypotension in amyloidosis and havereviewed our experience in this regard.

MethodsWe reviewed the records of 138 patients with

primary systemic amyloidosis seen at the MayoClinic from 1935 through 1964. In all instances,the presence of amyloidosis was proved bytissue biopsy or postmortem examination. Thecriteria for the diagnosis of orthostatic hypoten-sion included a decrease in the standing bloodpressure from the recumbent blood pressure

of 30 mm Hg systolic and 20 mm Hg diastolicand the presence of light-headedness or syncope.

Our patients were not taking drugs associatedwith hypotension, had not had surgical sympa-

thectomy, and had no known diabetes mellitusor any other conditions reported to cause ortho-static hypotension. Amyloidosis was considered tobe the cause of the orthostatic hypotension inall cases.

Results (Table 1)Eleven of the 138 patients with primary

systemic amyloidosis fulfill the criteria oforthostatic hypotension and constitute the ma-

terial for this report. In addition, 26 otherpatients had systolic blood pressures of lessthan 100 mm Hg, but either there was no

evidence of orthostatic hypotension or theinformation was insufficient to make an un-

equivocal diagnosis of orthostatic hypoten-sion. Nine of the 11 patients were males,a greater predominance than was our general

experience with primary systemic amyloidosis.None of the patients had a family historysuggestive of amyloidosis, evidence of multi-ple myeloma, or any other underlying diseasethat might be associated with amyloidosis.The presenting complaint in three of the

11 patients was related to orthostatic hypo-tension and consisted of light-headedness,dizziness, syncope, or loss of consciousness.These symptoms tended to worsen as thedisease progressed. During the course oftheir illness, most of the remaining patientshad syncope or their activities were signifi-cantly hampered by dizziness or light-headed-ness. Three of the patients were unable tostand or walk at all because of syncope andthus were severely incapacitated. Four of the11 patients had systolic blood pressure of 120mm Hg or more when recumbent. One pa-

tient had markedly increased hypotensionafter successful treatment of edema with thia-zides, and another patient did not have symp-

toms of orthostatic hypotension until edemasecondary to a nephrotic syndrome was suc-

cessfully treated with thiazides and spirono-lactone. This suggests the importance of shiftsin body fluid. Symptoms of orthostatic hypo-tension preceded the diagnosis of amyloidosisin all patients in this series. In fact, symptomsof orthostatic hypotension antedated thediagnosis of amyloidosis by 6 months or more

in eight of the 11 patients.Diarrhea was a symptom in seven of the

11 patients, and steatorrhea was found in two

patients and was strongly suspected in one.

The incidence of diarrhea was much higherin this group than it was in the patientswith primary amyloidosis without orthostatichypotension (11 of 127 patients, 8.7%), possi-bly reflecting visceral neuropathy. Orthostatic

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From the Section of Medicine, Mayo Clinic andMayo Foundation, Rochester, Minnesota.

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KYLE ET AL.

Findings in Eleven Cases ofTable 1

Primary Amyloidosis and Orthostatic HypotensionBlood pressure( systolic \( diastolic) ,mm Hg

Case Recumbent Standing* Syncope*

Onset ofNephrotic Peripheral orthostatic

Diarrhea* syndrome* neuropathy* hypotension

112070120

28078

3_6096

464

90

1246

848870100

870

1349

100100

10 -

8011 -

60

806044

443450

603045

50368466504030

S

+ 0 0 Dec. 1961

+ 0 0 Mar. 1955

0 S 0 Sept. 1961

+ + 0 + Jan. 1950

0 + + 0 May 1960

+ + 0 0 July 1952

+ 0 S 0 Dec. 1951

0 0 0 1958

+ 0 + July 1958

+ + 0 0

S

1961

0 + 0 Mar. 1964

*+ present; 0 absent; ? not recorded; S suspected but inadequate data.

hypotension preceded the onset of diarrheain five of the seven patients.Impotence or decrease in libido was promi-

nent in only two patients. It is likely thatthis would have been found more often ifthese symptoms had been sought. Two pa-

tients presented with an anorexia nervosa-likesyndrome, whereas four others had frequentvomiting. Not surprisingly, loss of weight was

a prominent feature and ranged from 15 to100 lb in eight of 11 patients.A nephrotic syndrome was present in two

patients and strongly suspected in two othersin whom incomplete studies were performed.The fact that no patients in this group hadcongestive heart failure or the clinical featuresof multiple myeloma was rather unusual.The physical findings, aside from ortho-

static hypotension, were not different fromthe usual ones in primary amyloidosis.

Anemia had no part in the orthostatic hypo-tension or syncope, because the hemoglobinvalue was never less than 10.5 g/100 ml ofblood. Significant azotemia (urea value ofmore than 125 mg) was found in three pa-

tients, while three others had slightly elevatedconcentrations of urea (50 to 70 mg/100 mlof blood). Values for blood urea at the upper

limits of normal have been reported in ortho-static hypotension.10 Serum electrophoresiswas performed on nine patients. The albuminlevel was less than 1.9 g/ 100 ml of serum

in four patients and more than 3.0 g inthree. Four patients had hypogammaglobu-linemia (y-globulin value of 0.70 g or less/100ml of serum). One patient had a y-globulinconcentration of 1.43 g/100 ml of serum, andthis was distributed in a homogeneous spike.Although only one patient complained of

decreased sweating, this was found in allCirculation, Volume XXXIV, November 1966

Diagnosisof

amyloidosis

June 1962

Apr. 1956

Nov. 1961

Aug. 1962

Feb. 1961

Mar. 1953

Jan. 1952

Aug. 1959

Aug. 1958

June 1964

Sept. 1964

-.. I

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AMYLOIDOSIS

six patients in whom a sweating test wasperformed. There was no correlation betweenthe results of the sweating test and the severi-ty of orthostatic hypotension. The patchytype of distribution and lack of correlationare also seen in idiopathic hypotension. Pe-ripheral neuropathy was found in two patients.Postmortem examination was done in two

of our patients. In one patient, amyloid de-posits were found in the nerve bundles inboth autonomic and peripheral nerves. Thesedeposits distorted and compressed the nerves.In the second patient, large amounts ofamyloid were present in the walls of bloodvessels within the sciatic nerve as well asin the perineurium of the nerve.The drug 9-a-fluorohydrocortisone, fludro-

cortisone (Florinef), was used in treatmentof four patients. One patient responded wellfor a year but then became refractory tothe drug. Another obtained excellent controlof hypotension with this drug and was con-tinuing to do well after 8 months of therapy.One patient had some benefit initially, butthe follow-up was inadequate. Another patientobtained no benefit in spite of a large doseof Florinef.

DiscussionOrthostatic hypotension probably was first

mentioned by Piorry" in 1826, but Bradburyand Eggleston'0 presented the first definitedelineation of the condition nearly 100 yearslater. The latter emphasized the triad of lowblood pressure on standing, impotence, andanhidrosis. They stated that a compensatoryincrease in heart rate did not occur with thedecrease in blood pressure.Weakness and fatigue as well as impotence

and urinary incontinence frequently are theinitial symptoms of orthostatic hypotension.Not uncommonly, the patient experienceslight-headedness and fainting when standing.Prolonged syncope can produce convulsiveseizures.

Orthostatic hypotension may be idiopathicor it may be secondary to an underlyingdisease such as diabetes mellitus, Addison'sdisease, surgical sympathectomy, prolongedCirculation, Volume XXXIV, November 1966

recumbency, pregnancy, inadequate posturalreflex, hypotensive or tranquilizing drugs, hy-povolemia from anemia or dehydration, hypo-kalemia, Guillain-Barre syndrome and otherperipheral neuropathies, parkinsonism, tabesdorsalis, parasellar tumors, syringomyelia,transection of spinal cord, cerebrovascular in-sufficiency, encephalomalacia, abnormalities ofthe autonomic nervous system, and cachexiaas well as amyloidosis. Excellent referencesto these may be found in the reviews byWagner,5 Engel,8 and Schirger and associ-ates.'2Although the cause of idiopathic orthostatic

hypotension is unknown, the basic disturbanceis an autonomic dysfunction which resultsin decreased arteriolar constriction whenstanding. However, the excellent observationof Shy and Drager13 and the clinical observa-tions of members of our group14 are suggestiveof a more generalized process involving thecentral as well as the autonomic nervoussystem. Further evidence in this regard wasrecently presented.15The treatment of orthostatic hypotension

generally has been unsatisfactory. Elevationof the head of the bed, wrapping of the legswith elastic bandages, use of abdominal bind-ers, and a high intake of salt have been ofbenefit in some instances. Ephedrin, desoxy-cortisone acetate, and more recently Florinefhave shown promise.16

Hypotension is a common finding in pri-mary amyloidosis, and its incidence rangedfrom 11.8 to 44.0% in a large series of primaryamyloidosis.1-3 Orthostatic hypotension inprimary amyloidosis is much less common,and only a few cases have been reportedin the literature. Schneckloth and Page4 in1955 reported on a patient with orthostatichypotension who had a nepbrotic syndromeand primary amyloidosis. Four years laterWagner,5 in a review of orthostatic hypoten-sion, presented a patient with a nephroticsyndrome and orthostatic hypotension secon-dary to primary amyloidosis. Two cases ofpolyneuropathy and primary amyloidosis weredescribed by Munsat and Poussaint.6 Liskeand associates7 reported on a patient with

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primary amyloidosis and orthostatic hypoten-sion. In addition Ellis and Haynes,"1 in 1936,reported on a patient with orthostatic hypo-tension who, at postmortem examination,had amyloidosis of the adrenal glands andspleen. The small abscesses found in the renalcortex probably were not responsible for theamyloidosis. Although this patient probablyhad primary amyloidosis, Addison's diseasecannot be excluded. Weakness, diarrhea, andloss of weight are consistent with either pri-mary systemic amyloidosis or Addison's dis-ease.Primary systemic amyloidosis has been

recognized for more than 100 years, andalthough the clinical and laboratory findingsmay be striking, the diagnosis is frequentlyoverlooked. Weakness, fatigue, ankle edema,dyspnea, purpura, and loss of weight are thecommonest presenting complaints. Less com-mon but more suggestive of amyloidosis areperiorbital purpura, macroglossia, and bilater-al paresthesias of the hands (carpal tunnelsyndrome ).3 Splenomegaly is uncommon buthepatomegaly is seen in more than 50% ofthe patients. Submaxillary lymphadenopathy,usually associated with macroglossia, may bea prominent feature. The presence of refrac-tory, congestive heart failure, or a nephroticsyndrome should alert the physician to thepossibility of amyloidosis. Steatorrhea is un-common but may be a significant feature.Laboratory abnormalities including proteinu-ria or Bence Jones proteinuria, elevation oferythrocyte sedimentation rate and bloodurea, and increased sulfobromophthalein-dyeretention are common. Electrophoresis of theserum usually reveals hypoalbuminemia andfrequently normal or decreased amounts ofy-globulin. In some instances, a homogeneousserum-protein peak indistinguishable fromthat of myeloma is found. Plasma cells inthe marrow vary from a few mature cells tomany immature, atypical cells consistent withmultiple myeloma.Although these findings may be suggestive

of primary amyloidosis, an unequivocal diag-nosis must be obtained from tissue analysisat antemortem biopsy or postmortem examina-

tion. The liver'8 and kidney'9 have been pre-ferred sites for biopsy, but the risk of bleedingand the need for cooperation of the patientand an experienced physician make thesesites less than ideal for study. Peroral biopsyof the small bowel is a useful procedure20;but tissue cannot always be obtained, and theprocedure is uncomfortable for the patient.If involved with amyloid, biopsy specimensof the skin, lymph nodes, muscle, gum, ortongue will confirm the diagnosis. Rectal biop-sy appears to be the procedure of choice inthe diagnosis of primary amyloidosis.21 22Bone-marrow aspiration also may be helpful.23The mechanism of primary amyloidosis in

causing orthostatic hypotension is not clear.In some patients, amyloid deposits withinthe nerve, causing compression-neuropathy,could be responsible.24 Ischemia from depo-sition of amyloid in the walls of the bloodvessels supplying the nerves may have asignificant part.25 Both of these possibilitiesare supported by our findings. The possibilityof a toxic or metabolic factor26 has beenpostulated. In addition, the involvement ofthe heart and blood vessels with amyloidmight play some role.4 The small blood ves-sels involved with amyloid may not be ableto respond normally.

In six of 11 patients in our series, Addison'sdisease was seriously considered in the differ-ential diagnosis. The presence of weaknessand fatigue, nausea, vomiting, diarrhea, lossof weight, and hypotension all contributed tothe clinical impression of adrenal insufficiency.Adequate metabolic studies excluded Addi-son's disease in each instance.Although orthostatic hypotension is an un-

common feature of primary amyloidosis (11of 138 cases, 8.0%) and the incidence ofprimary systemic amyloidosis in orthostatichypotension is even less (five of 384 cases,1.3%), the association of these two uncommonentities appears greater than a chance re-lationship. In addition, the incidence of amy-loidosis in these patients with orthostatichypotension may be even greater because thepossibility of amyloidosis was not entertainedin all instances. Although recumbent blood

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AMYLOIDOSIS

pressure may be normal, the physicianshould look for orthostatic hypotension be-cause four of our patients had a recumbentblood pressure of 120/70 mm or greater.In our series, orthostatic hypotension wasdiagnosed 3 years before amyloidosis wasfound in one patient. Thus, the possibilityof amyloidosis should be considered in thedifferential diagnosis of any patient withidiopathic orthostatic hypotension.

SummaryData on 11 patients with orthostatic hypo-

tension and primary systemic amyloidosis havebeen presented. Dizziness and light-headed-ness or syncope significantly hampered theinvolved patients. Three were incapacitatedby orthostatic hypotension.

Diarrhea, nausea, vomiting, and loss ofweight were common, and adrenal insufficien-cy was seriously considered in the differentialdiagnosis of six of the 11 patients. Abnormalsweating was found in all six in whom thistest was done.The drug 9-a-fluorohydrocortisone showed

promise in symptomatic therapy of the con-dition.The possibility of primary systemic amy-

loidosis should be considered in the presenceof orthostatic hypotension. Rectal biopsy andbone-marrow aspiration are recommended asinitial biopsy procedures unless another organsuitable for biopsy is obviously involved.

References1. MATHEWS, W. H.: Primary systemic amyloido-

sis. Amer J Med Sci 228: 317, 1954.2. RUKAVINA, J. G., BLOCK, W. D., JACKSON,

C. E., FALLS, H. F., CAREY, J. H., AND CUR-TIS, A. C.: Primary systemic amyloidosis: Areview and an experimental, genetic, and clin-ical study of 29 cases with particular emphasison the familial form. Medicine (Balt) 35:239, 1956.

3. KYLE, R. A., AND BAYRD, E. D.: "Primary" sys-temic amyloidosis and myeloma: Discussionof relationship and review of 81 cases. ArchIntern Med (Chicago) 107: 344, 1961.

4. SCHNECKLOTH, R. E., AND PAGE, I. H.: Thenephrotic syndrome and chronic hypotensionassociated with primary systemic amyloidosis:Report of a case. Amer J Med Sci 230: 299,1955.

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5. WAGNER, H. N., JR.: Orthostatic hypotension.Bull Hopkins Hosp 105: 322, 1959.

6. MUNSAT, T. L., AND POUSSAINT, A. F.: Clinicalmanifestations and diagnosis of amyloid poly-neuropathy. Neurology 12: 413, 1962.

7. LisKE, EDWARD, CHOU, SHI-MING, AND THOMP-SON, H. G., JR.: Peripheral and autonomicneuropathy in amyloidosis. JAMA 186: 432,1963.

8. ENGEL, G. L.: Fainting, ed. 2. Springfield, Il-linois, Charles C Thomas, Publisher, 1962,196 pp.

9. WAYNE, H. H.: Syncope: Physiological consider-ations and an analysis of the clinical charac-teristics in 510 patients. Amer J Med 30: 418,1961.

10. BRADBURY, SAMUEL, AND EGGLESTON, CARY: Pos-tural hypotension: Report Of three cases. AmerHeart J 1: 73, 1925.

11. PIORRY, P. A.: Quoted by Wagner, H. N., Jr.512. SCHIRGER, ALEXANDER, HINES, E. A., JR., MOL-

NAR, G. D., AND THOMAS, J. E.: Current prac-tices in general medicine: XXII. Orthostatic hy-potension. Proc Mayo Clin 36: 239, 1961.

13. SHY, G. M., AND DRAGER, G. A.: Neurologicalsyndrome associated with orthostatic hypoten-sion: Clinical-pathologic study. Arch Neurol(Chicago) 2: 511, 1960.

14. THOMAS, J. E., AND SCHIRGER, ALEXANDER:Neurologic manifestations in idiopathic ortho-static hypotension. Arch Neurol (Chicago) 8:204, 1963.

15. FICHEFET, J. P., STERNON, J. E., FRANKEN, L.,DEMANET, J. C., AND VANDERHAEGHEN, J. J.:Etude anatomo-clinique d'un cas d'hypotensionorthostatique "idiopathique": Considerationspathogeniques. Acta Cardiol (Brux) 20: 332,1965.

16. SCHIRGER, ALEXANDER, HINES, E. A., JR., MOL-NAR, G. D., AND THOMAS, J. E.: Idiopathicorthostatic hypotension. JAMA 181: 822,1962.

17. ELLIS, L. B., AND HAYNES, FLORENCE W.: Pos-tural hypotension: With particular referenceto its occurrence in disease of the central ner-vous system. Arch Intern Med (Chicago) 58:773, 1936.

18. STAUFFER, M. H., GRoss, J. B., FOULK, W. T.,AND DAHLIN, D. C.: Amyloidosis: Diagnosiswith needle biopsy of the liver in eighteenpatients. Gastroenterology 41: 92, 1961.

19. MARTIN, J. H., BROWN, A. L., JR., AND DAUGH-ERTY, G. W.: Nonmyelomatous amyloid dis-ease of the kidney. Proc Mayo Clin 37: 567,1962.

20. GREEN, P. A., HIGGINS, J. A., BROWN, A. L.,JR., HOFFMAN, H. N., II, AND SOMMERVILLE,R. L.: Amyloidosis: Appraisal of intubation

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biopsy of the small intestine in diagnosis. Gas-troenterology 41: 452, 1961.

21. GAFNI, JOSEPH, AND SOHAR, EZRA: Rectal biopsyfor the diagnosis of amyloidosis. Amer J MedSci 240: 332, 1960.

22. KYLE, R. A., SPENCER, R. J., AND DAHLIN,D. C.: Value of rectal biopsy in the diagnosisof primary systemic amyloidosis. Amer J MedSci 251: 501, 1966.

23. KYLE, R. A., PEASE, GERTRUDE L., RICHMOND,HELEN, AND SULLIVAN, LOUISE: Bone marrowaspiration in the antemortem diagnosis of pri-

mary systemic amyloidosis. Amer J Clin Path45: 252, 1966.

24. DE NAVASQUEZ, S., AND TREBLE, H. A.: Case ofprimary generalized amyloid disease with in-volvement of the nerves. Brain 61: 116, 1938.

25. KERNOHAN, J. W., AND WOLTMAN, H. W.: Am-yloid neuritis. Arch Neurol Psychiat (Chicago)47: 132, 1942.

26. SULLIVAN, J. F., TWITCHELL, T. E., GHERARDI,G. J., AND VANDERLAAN, W. P.: Amyloidpolyneuropathy. Neurology 5: 847, 1955.

Centennial Second Edition of Thomas Peacock'sMalformations of the Human Heart

THOMAS B. PEACOCK: Malformations of the Human Heart, ed. 2. London, John Churchill& Sons, 1866.

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ROBERT A. KYLE, BRUCE A. KOTTKE and ALEXANDER SCHIRGEROrthostatic Hypotension as a Clue to Primary Systemic Amyloidosis

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1966 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.34.5.883

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