Studies in urticaria: The influence of metabolic factors

STUDIES IN URTICARIA: THE INFLUENCE OF METABOLIC FACTORS” t

LEO H. CRIEP, M.D., AND LAWRENCE WECHSLER, M.D. PITTSBURGH, PA.

U KTlCARIA is generally accepted to be a form of hypersensitiveness grouped with hay fever and bronchial asthma. Its causes

are varied. Urticarial manifestations may occur as a result of direct contact with offending substances such as furs or wool, or with physical agents such as sunlight or heat; from the ingestion of certain foods, or from the administration of sera and drugs; and, lastly, as is believed by some, from sensitization to bacteria found in foci of infection. But regardless of etiology, the pathologic physiology is always the same; the wheal is produced as a result of the irritation of the skin and the skin capillaries with subsequent oozing and localized edema.

Because clinically it is not always possible to determine the allergic nature of a large proportion of urticaria cases, there have been numer- ous attempts made to find other factors influencing its development. This paper concerns itself, however, only with factors which may be grouped as metabolic; it.s purpose is to consider the available literature on the subject, aud to report on a clinical and laboratory study of forty cases of urticaria wit,11 particular reference to the functional state of the gastrointestinal tract and the basal metabolism. A subsequent paper will report on other meta.bolic factors, such as the acid- base balance and blood chrmist,ry.

TABLE I

AGE OF PATIENTS AND III?RATIOX OF EQSEASE -

AGE NO. PTY. DURATIQK NO. PTs. DTTRA'MON NO. PT.?. __.-- 10-20 $‘. 3 1 y”. 1 7 yr. 1 20-30 yi-. 17 2 yr. 11 9 ?‘I-. 1 30-40 yr. 7 3 y”. 7 10 yr. 2 40-50 yr. 4 4 yr. 5 11 yr. 1 SO-60 pr. 7 r, pr. 3 1.5 y”. 1 60-70 yr. 2 6 9~. 2 - .__-

The group of patients formin, v the basis for t,hese observations is investigated first from the allergic viewpoint and present,s the following findings: The distribution of the patients with regard to age and the duration of the disease may be seen in Table I. Positive intra-

tRead before the Ninth Annual Meeting of Association for the Study of Allergy, Philadelphia. June 8, 1931.

*From the Clinic of Applied Immunology. Medical School, University of Pittsburgh, and the Medical Service of the Monteffol’e Hospital, Pittsburgh, Pa.

479

dermal tests are obtained in pract~icnlly all patients, but, in some, these reactions appear only as very doubtful. Only in nine patients, or 22 per cent, is a combined clinical and skin sensitivity found. Two patients, Cases 3 and 22, show allergy to physical agents such as heat and cold in addition to protein reactions. Trn patients have also other allergic manifestations such as eczema, hay fever, or asthma, and 14 give a positive history of familial allergy (Tables 11 ant1 V).

Intradermal skin tests positivr 40 100 Prol-ed clinical sensitiGtg Physical allerg! Other allergic manifestations Family historv positive

I. TTTE GASTIIOINTESTINAl, TKA(‘T

Lite~afIr,,c.--dcntr. transient, ttrticaria is frequently relieved by the administration of a brisk saline purge. This accounts partly for the prevalent opinion that even in chronic nrticaria disturbances in the function of the gastrointestinal tract and of the liver may be either direct or contributory etiologic factors. Thus, Eustis* reports that many urticaria patients have indican in the urine, illltl that this fintl- ing indicates absorption and subsectuent detoxificat,ion by the liver of products of intestinal putrefaction. During the process of putrefaction the amino acitts in the intestinal tract, are converted into car- bon dioxide and the correspondin, 0’ amine. and one of t,hese amines is histamine. Absorption of tlw lat,trr may play an important role in urticaria. for, as Lewis shows,’ in certain cases of physical allergy manifested by wheal formation, a hist,amine-like substance may be isolated from the skin; he believes that the liberation of this substance may hart something t,o do wit,h t.he pro(hwtiou of the wheal. Bassler’ also emphasizes the importance of papin, (I’ clown attention to the gastrointestinal function in allergy, and states that abnormal intestinal absorption and biologic disturbances in the intestinal tract are important fact,ors. Menagh’ concludes from a study of 260 cases of angio- neurotic edema and urticaria that in 48.8 per cent of his patients biliary tract disease is the only etiolopic factor. Disease of the gall bladder and ducts in these patients leads to absorption of bacterial proteins, and in 73 per cent, of his C’ilSPS positive skin t,ests ilrf? obtained with cultures derived by biliary drainage. Furthermore, treatment, directed toward the biliary tract and administrat,ion of vaccines from the bacteria isolated by drainage. resulted in the improvement of 88 per cent of the patients. TZarber and Oriel’ suggest that int,i- matelg associated with the allergic state is i l condition of hepatic in-

CRIEI’ .\SD \\‘ECHSI,ER : s’lTI)IES IS l’RTIC:tRI~~ 481

sufficiency. They arrive at this conclusion from a study of the blood amino acids which they take as a good index of liver function. Their results show that the amino acids of the blood are increased during the acute urticarial at,tack indicating in this may some disturbance of hepatic function. Normally, the amino acids are absorbed from the intestines, reach the liver where they are deaminatrd, and finally find their way to the tissues. In conditions where extensive liver damage occurs, such as in acute yellow atrophy, deamination does not occur due to massive liver destruction and tissue autolysis. In these cases the amino acid of the blood is high. Tn conditions where the liver damage is not quite so extensive, such as in cirrhosis, no such finding occurs. Since t,here is no demonstrable liver lesion in urt,icaria, it is difficult to see why it should be associated wit,h a high blood amino acid, and we believe t,hat such a finding when present should not necessarily be interpreted as a sign of hepatic deficiency. Procedures available for the determination of liver function ot,her than its bile forming abilit,y, are at, best not very usefnl. They are positive only after such extensive damage has occurred in t,he organ, that this damage is recognizable easily by clinical methods.

F&&ilzgs.-In order to determine the presence of an organic or functional gastrointestinal dist,urbance in urticaria, 40 patients are studied. This study includes a careful history and physical examination, and, with the excepGon of only several inst,ances, such laboratory invrsti- gations as gastric analysis, examination of feces, biliary drainage, icterus index, Van den Brrgh, bromsulphthalein excretion, cholecysto- gram, and complete roentgen-ray study of the gastrointestinal tract. The results of this investigation are shown in Table III. Of the entire group only eight patients, or 20 per cent, are free from any evidence of digestive disturbance. The rest present various t,ypes of involvement,. Thus, about one-third of t,he patient,s give a history of gastric upsets, constipation, and “indigestion. ” Twenty-one per cent have gastric hypoacidity and 23.7 per cent have achylia. On roentgen-ray study, 20 per cent show atony and ptosis, and 36.6 per cent show spas- ticity of the colon. Twent,y pat,icnts, or 50 per cent of the group, show some laboratory or clinical evidence of gall bladder tract, disease. It is t’rue that in only a much smaller number of cases is there a picture of clear-cut and definite cholecystitis. In many cases there are only isolated positive laboratory tests suggesting gall bladder involvement, the findings being as follows : Ten of 34 paGents, or 29 per cent, gave x-ray evidence of gall bladder disease; 13 of 25 patients, or 52 per cent, had an icterus index above seven indicating a slight degree of latent icterus, and three of 22 patients, or 13.6 per cent, had a positive Van den Bergh. Biliary drainage was done on 19 patients and the material was examined microscopically and cultured occasionally. [n

482 THE .JOURKAI, OP Al,I.ERGY

12 patients, or 63 per cent, there is evidence of some infection in the gall bladder as shown by the finding of many pus cells in the bile. In 11 patients, or 57.8 per cent, there is some disturbance in the function of the gall bladder concerned with bile metabolism as evidenced by the presence of cholesterol crystals (Table III). None of the patients so tested show liver insufficiency as tletrrminrd by the excretion of bromsulphthalrin (Table V). One patient shows prptie ulcer ; one’, colon mucorrhca ; three, chronic appendicitis ; and three’, manifestations of gastrointestinal allergy.

TABLE III

_-~ ___.-. PTS. EXAJI. NATURE OF DISTURBANCE NO. PTS. PER CENT

40

40 38 38 30 30 34 34 2 .j 22 19

19

40

40 40 40 40

Entirely free of any gastrointestinal or gall bladder disturbance 8

History of “indigestion, ’ ’ constipation, etc. 13 Gastric hypoacidity 8 Ac.hylia !j Atony and ptosis of stomach 6 Spastic, and hypermotile colon 11 Gall bladder disease : X-ray positive 6 Gall bladder disease : X-ray suggestive 4 Gall bladder disease: Ictcrus index above 7 13 Gall bladder disease: Van den Bergh positive 4 Gall bladder disease : Biliary drainage :

Tnfection 12 Gall blnddcr disease : Riliarq- drainage:

Disturbancae in pigment formation 11

Patients showing some rvidence of ga I1 bladder distnrhxnw 20

TJlcer 1 Colon mucorrhea 1 Chronic appendicitis 3 Gastrointestinal allergy 3

20 32.5 21 23.7 20 36.6 17.3 11.7 52 13.6

63

.i7.8

50 2.5 2.5 7,s) 7 3

A discussion of metabolism does not as a rule include consideration of gaslrointestinal fun&on, but for the purpose of the present paper it is taken up because it is so closely linked with other met,abolic factors related to urticaria. Furthermore, analysis of the findings obtained in the examination of the gastrointestinal tract, in this group indicates that the digestive tract is involved in a fairly large percentage of cases. This involvement, is entirely too frequent to be purely coincidental and must bear some indirect but contributory share in the production of t,he urticarial state. It is true that there may be a functional involvement of the gastrointestinal tract in ot,her- wise normal individuals but this fact would in no way affect the con- clusions to be derived from such an involvement in urticaria patients. Whereas incomplete digestion and imperfect nitrogen metabolism usu-

CRIEP AND WECHHI,ER : STUDIES IX PRTICARIA 483

ally may not give rise to any clinical manifestations, in urticaria such changes may affect the general state of susceptibility and produce symptoms. In an attempt to interpret the rather high incidence of achylia and hypoacidity in these cases, the possibility of senile atrophy of the gastric mucosa can be ruled out on account of t,be age of the patients in this series. A number of these individuals, however, have some associated biliary tract disturbance, and in this condition re- gurgitation of duodenal fluid is not uncommon. Furthermore, the presence of toxemia from foci of infection, the presence of congestion of the mucous membrane of the stomach, and nervous influences, particularly those of the sympathetic system, may play an important rcilc in this connection. Rut regardless of its mechanism of production, a deficiency in gastric acidity may, according to Beckman,” tlisturb the acid-base balance of the individual and thus contribut,e to the allergic state. Changes in motility, such as atony and spasm lead to constipation and st,asis, and this in ttun ma.y cause intest,inal absorption either of toxic substances or of incomplete split-up products of protein digestion. Such substances may produce urticaria either as a result of their irritative nature, or because the shock organ, that is, the skin, is actually sensitive to them. Derangement in the condition of the gall bladder may also be a factor, either because of interference with the supply of normal bile, which mould also affect digestion, or because of infect.ion. Whether the gall bladcler acts as a focus of infection and sensitizes the individual to bacterial proteins thus absorbed is a matter still open to question. The specificity of skin reactions to bacterial emulsions is not sufficiently established to render positive reactions obtainecl with vaccines prepared from bilia.ry drainage material as entirely convincing.

A great deal would be contributed toward a better understanding of possible etiology and treatment of some of the more obscure cases of urticaria if it were possible to prove its association with hepatic insufficiency, particularly with impairment of that function of the liver which is concerned with nitrogen metabolism. Such knowledge may reveal imperfect nitrogen metabolism in the liver as the factor responsible for the occurrence of incompletely metabolized substances to which the patient is sensitive.

TABLE IV

B.4811~ METABOLIC RATE IX THIBW-ONE CASES OF URTICAKIA .___.- ~-___

IVO. PTS. PER=- Total number ofsstudied-

- 31

Normal minus 10 to plus 17 20 64.5 Increased thyroid activity Decreased thvroid activi”ttv

8 26 3 !)

Total numbe; of disturbeb thyroid 11 35 ._-___-

484 THE JOURSAL OF ALLERGY

TABLE

THE, X6LE OF \JARIOUS MET4BOLIC

NO. AGE

z=z

--

WT.

-

D ‘J

--

,CRA SKIN PION !XST!

1 20 98 2 2 28 134 3

3 26 109 4 24 134

ii 6

42 49

118 141

2 4

7 28 124 5 8 35 122 2 9 21 129 5

10 39 150 7 11 21 115 4

12 24 142 4 13 29 129 2

14 19 114 15 25 120 16 51 180 17 17 122 18 31 96

1

1:

:

19 64 180 3 20 56 146 2 21 54 130 9 22 29 125 5

23 20 93 6

24 9 r r.1 26 27 28

r-

;6" 37 22 58

159 3 143 2 160 10 165 a 160 1:

29 <54 138 3 30 62 130 3 31 42 760 4 32 56 141 2 33 32 131 I.5 34 48 123 1: 3 *5 33 118 .5 36 11 110 4 37 29 91 11 38 21 140 3 39 24 120 3 40 23 124 2

-

i

-- I GASTROINTESnNAL

- ALLERGY

+ t

t s

t t

t 2 5 t +

k t

; 5 c ?

2 + -t

t+

2

t + t ? +

t t t + + + + t 2 + 5 +

--

; OTHER

ALLERGY

Asthma Sane

None Aug. IX. 1

None None

Eczema None1 Ang. K-. J NOW None

Eczema, None

No11e None Ang. N. J None Xone

None None None Sane

None

None None H. F. None None

None None None None None Drugs Kane H. F. Asthma None II. F. None

- STOMACH AND ________

l?. H. HISTORY SIGNS GASTRIC

EXAM. ICL T. A.

Keg. Constipation None f Neg. None

Neg. Constipation None Neg. None None

f None Tender G. B Neg. None None

t Constipation None Keg. None None

t None None

Neg. None None t None None

i- Pu’one Sane Neg. None Xone Neg. None None Neg. None None

t None None

Neg. None None Neg. None None Neg. Censtipatiou None

+ Constipation None

+ iYone None

Neg. None None Neg. Indigestion i None

t None I None Neg. None ’ None Neg. Nausea. Con- Tender G. B.

stipation Neg. None None Neg. Diarrhea , None

Tender G. B.

r\Tormal- 6 1X

IO 28 0 I.5

31 .x 0 21

11 ri o-x 14 12 29 14 31

Normal Normal

Normal Xorma I Normal Normal 0 0

Normal Normal 0 Normal’

I? 21

0 10 Normal

12 25 h-ormal 0 15

Neg. None I t None

1 None

i

None + None None

Neg. Indigestion None t Constipation None

Neg. None None ___~

Normal Normal

15 20 I1 20

3-4 16 Kormal 0 20 4 22 Normal 0 32 Normal

V

FAWCIRS IN URTICARIA

TRACT INTESTINES GALL RLADD

X-RAY SERIES FECES i X-RAY LROMSULPH- THALEIN D

-

CT. N- ‘EX

t5 f8

t9 f8

t5 t7

t5 ts $6 t6 t8

t9 t9

t6 t5 t9 t7 f8

$5

Good tonus Ptosis and atony.

Colon catarrh Normal Ptosis. ? k pasmotir

colon Normal Poor tonus. Spastic

colon Normal Stasis in colon Spastic pylorus Spastic colon Poor tonus. Spastic

c01011 Normal Fair tonus. Some

stasis Normal Normal Normal Normal Atony of stomach.

Hypermotility Normal CTastric ulcer Normal Hypermotility of

colon Ptosis and dilata-

tion colon Normal Pylorospasm Hypertonic

Spastic colon

Spastic colon. Stasis

Normal

Spastic colon

Neg. Faint shadow Neg. Faint shadow

Neg. Normal Neg. Normal


Neg. No shadow seen Neg. Normal Neg. Normal Neg. Normal Neg. Normal


Neg. Normal Neg. Normal Neg. Normal Neg. Normal Neg. Normal

Neg. Normal Neg. Normal Neg. Normal Neg. Normal

Neg. Normal

Neg. Large shadow Neg. Neg. Neg. ------ Neg. Faint outline

Neg. No shadow Neg. Neg. Neg. N’o shadow Neg. Normal Neg. Normal Neg. No shadow Neg. Neg. No shadow Neg. No shadow

-____ , less 15% f less 15%

less 15% : less 15%

I) less 15% 1, less 15%

I, les,s 15% I, less 15% I, lea,8 15% I) less 15% I, less 15%

I, less 157! I) less 1574

I, less 15% I, less 15yc I, less 157& 1, less 15% , less 15%

less 157& : less 15%

t3

ER

I VAN DEN BILIARY

BERGH DRAIN

DIR.

vsg. Xag.

Veg. YTeg.

Neg. Neg.

?Jsg. Neg. Neg. Neg. Ne’g.

1el. + lel. +

Neg. Neg. Neg. Neg. Neg.

Neg.

fig.

Neg. Neg.

- ND. - leg. reg

reg reg

Jeg Jeg

Teg Teg Jeg Jeg tl

Jeg t

t t t t t

Teg

- IP

.N

.N

.N

.N P

N N Ii

CF.

t t

t t

.eg. t

.eg. t

.eg. t t

leg. ‘OS.

reg. ieg. reg.

'IG- IENT ~-

t t

t t

Neg. t

Neg. t

Neg. t t

Neg. Neg.

Neg. Neg. Neg.

t

t

t

--

BASAL YETAB. OLISM

t5 t10

t17 t19

-3 -4

-5 t25 $23 -5 t19

t10 t10

t3 -24 t17 t19 t33

+I

t37

--

-9 -7 t12

t-a t13 -11 -26 t16 t21 Jr20 t5

186 THE ,JOl’RNAl, OF ,ZI,I,ERGY

IT. BASAL METABOLISM

Literature mad Finfiinys.-In a previous communication7 we pointed out that there is some disturbance in the basal metabolic rate in various allergic conditions : Roussrl” discusses such changes in chronic urticaria in t,he light of thyroid-adrenal dysfunction and indicates that it may be the cause of t,he vasomotor instability present in these individuals. The involuntary uervous system sends two nerve branches to the walls of the blood vessels. Stimulation of one branch leads to vasodilatation, stimulation of the other to vasoconstriction. Thyroid secretion stimulat.es the former and produces vasodilat,ation, while ad- renalin stimulates the latter and produces vasoconstriction. IIence, a tlctermination of the basal metabolism is of value, according to the above named writer, not only because it indicates which one of the conditions is present, but also because it may serve as a guide to treatment . Following is a report of basal metabolic determinations on 31 patients. The out,er limits of the normal rate is considered ranging between minus 10 and plus 17 per cent. The highest reading in this group is plus 37 per cent. Three patients, or 9 per cent, show a condition suggesting lessened thyroid activity, the lowest basal metabolic rate being minus 24 per cent. lt seems, therefore, that about 35 per cent of the patients studied in this group have some increase or de- crease in basal metabolic ral-t. (Tables IV and V.) These determinations are made more than once on each patient and are carefully checked. Clinically, most of the patients show slight hyperthyroid 01 hypothyroid signs and symptoms, but all except one are to be consitl- ered borderline cases. This patient presents the clinical picture of hypothyroidism. The etiologic importance of such deviations frorn the normal must, not. be given too much significance for patients with thyroid dysfunction do not usually present urticaria as an associated condition, and conversely, only a small percentage of urticaria patients have thyroid imbalance. This imbalance may rather contribute to the general make-up of t,he patient, rendering him less stable ant1 more susceptible to t,he exciting cause.

An analysis of the above findings leads one to the conclusion that changes in the gastrointestinal and thyroid function are for the most part either coexisting with, contributory to, or resulting from the urticarial state. They are not sufficiently specific to bear a direct causal relation to urticaria. They may increase an existing predisposition and contribute to the general state of susceptibility of the paGent. Urti- caria patients frequently give a positive familial allergic history. Thry frequently present manifestations of other allergic states. Their condition is traceable in a variable percentage of cases direct.ly to contact

with some specific substance. Hence the common denominator in these cases is hypersensitiveness.

CRIEP AND WECHSLER : STUDIES IS URTICARIA 487

REFERENCES

1. E&is: Relation of Intestinal Toxemia to Allergy, South. M. J. 23: 308, 1930. 2. Lewis, Thomas: The Blood Vesaels of the Human Skin and Their Responses,

1927. Chicano Medical Book Co. 3. Bassler, ‘Anthogy : Intestinal Toxemia, New York, 1930, F. A. Davis. 4. Mena&, Frank R.: The Etiology and Results of Treatment in Aneioneurotic

EIdema and Urtiearia, J. A. %. A. 90: 668, 1928. 5. Barber, W. H., and Oriel, H. G.: A Clinical and Biochemical Study of Allergy,

Lancet 41: 1009, 1928. 6. Beckman, Harry: Allergy and the Acid Base Balance, J. A. M. A. 95: 1582,

1930. 7. Criep, Leo H., and McElroy, William S.: Blood Calcium and Gastric Analysis,

Arch. Int. Med. 42: 865, 1928. 8. Roussel, J. N.: Chronic Urticaria, Thyroadrenal Syndrome; How to Determine

Direction of Dysfunction, and What Type of Agents to Employ in Treat.ment, South. M. J. 22: 668, 1929.

1004 MAY BUILDING. (For discussion, see page 507.)

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Studies in urticaria: The influence of metabolic factors