The syndrome of benign recurrent cholestasis

The Syndrome of Benign Recurrent Cholestasis* WILLIAM H . J . SUMMERSKILL, D .M ., M .R .C .P . Rochester, Minnesota

1959 Summerskill and Walshe [1] described two cases of a benign disorder not susceptible to classification within the current concepts or nomenclature of hepatic disease and characterized by recurrent episodes of jaundice with cholestatic features . Subsequently, patients with very similar clinical, biochemical and histologic changes have been described by Tygstrup [2], De Groote and associates [3] and Schapiro and Isselbacher [4] . Thus, in over four years seven examples of the syndrome (Cases 1 to 7 herein) have been recorded in the world literature ; an eighth will be added in this report . However, the true incidence of the disorder is obscure, as examples documented previously have been in the form of one or two case reports, originating from those primarily interested in hepatic disease, and unpublished instances of the syndrome have been observed recently by Sherlock [5] and Tygstrup [6]. Adequate information is now available to differentiate the syndrome from other idiopathic, constitutional or recurrent hyperbilirubinemias and other hepatobiliary disorders . It is the purpose of this paper to present the characteristic features of the syndrome, based on both published [1-4] and unpublished data [5-8], the latter including clinical details and special studies relevant to a new instance of the disease, as well as follow-up information relating to all cases reported earlier . In addition, observations regarding hepatic function between episodes of jaundice, the effect of challenges with hepatotoxic drugs, trials of therapy and certain apparently characteristic features revealed by electron microscopy will be presented .

I

N

CASE REPORT

Report of a New Case (Case 8) . A fifty-nine year old widow began to experience occasional episodes of mild discomfort in the right upper quadrant late in 1958 . A single stone was observed in the gallbladder, and since exploration of the bile duct proved negative, a cholecystectomy was performed . Later review of the gallbladder tissue showed no significant pathologic change . Following surgery intermittent abdominal discomfort continued and in June 1959 began to be associated with obvious jaundice . Subsequently, the patient experienced six episodes of jaundice until February 1961, when she first presented at our clinic . At that time laparotomy was recommended . Exploration of the bile ducts, followed by T tube cholangiography, was performed, with negative results . Two episodes of jaundice occurred later in 1961, and a single attack took place in 1962 . The latest recurrence of jaundice in May 1963 resulted in the patient's admission to this hospital for special studies . The attacks were characterized by sudden onset without any identifiable precipitating factor, initial fatigue, nervous tension, anorexia and vague abdominal discomfort of variable location and intensity which was usually described as a steady ache across the right upper part of the abdomen . Dark urine, together with pale, loose feces, was noted within three days of the attacks and was quickly followed by jaundice, occasionally with nausea, and rarely with vomiting . Pyrexia was never recorded and pruritus did not occur . The jaundice lasted for two to six weeks. Abdominal symptoms subsided as the jaundice began to clear, and the weight loss was approximately 2 to 3 pounds per week. Despite multiple efforts at medication, the patient could specify no measure of benefit and believed that the attacks "just run their course ." The positive findings on physical examination were jaundice, abdominal tenderness which was greater over the right upper quadrant and lower part of the

* From the Gastrointestinal Research Unit, Mayo Clinic and Mayo Foundation, Rochester, Minnesota . This investigation was supported in part by Research Grant AM-06908 from the National Institutes of Health, Public Health Service . Manuscript received March 6, 1964. 298

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2(y)

Benign Recurrent Cholestasis--Surrvnerskill TABLE I REPORTED CASES OF BENIGN RECURRENT OpOLESTASIS

Age (yr .) Source

Origin

Summerskill, Walshe [7] Case 1 Case 2 Tygstrup [2] Case 3 Case 4 De Groote et al . [3] Case 5 Case 6 Schapiro, Isselbacher [4] Case 7 Present Report Case 8

,

OF

THE

nset Onset

Initial Report

Follow-

F M

9 17

44 33

49 38

M M

2 1

Faroe Islands

FEBRUARY

No .

;

Duration (mo .)

7 22

2-18 1-6

4 7

2-3 2-3

I

18 18

i

Belgium M M

19 7

29 25

33 28

F

3

40

41

9 5

1-4 3-10

United States 1-3 I

United States

F

SYNDROME

I .)

38

I

Up

England

Besides the present case seven previous instances of the syndrome (Cases 1 to 7) have been reported from England, the Faroe Islands, Belgium and the United States . (Table In all, there were five male and three female subjects . The first episode of jaundice occurred before the age of twenty in all but the present patient (Case 8) and before the age of ten in five patients . Despite careful investigation in four cases, no family history of jaundice was obtained ; Tygstrup [2] alluded to probable but unproved consanguinity between his patients . In Case 8 responses to inquiries regarding knowledge of jaundice or other features of hepatobiliary diseases in the family were received from all sixteen living blood relatives of known location . None of these responses was positive . Precipitating factors for the attacks are unknown . No occupational hazard existed and no seasonal incidence for jaundice was recorded other than a predilection for autumn months in one instance (Case 7) . In one patient the consumption of eggs or milk was followed by vomiting, diarrhea and eosinophilia [2], but no other patient had a history of allergy . Drug sensitivity, V OF .

. aundice

Sex

abdomen, and modest enlargement of the liver . Details relevant to additional clinical findings, laboratory tests, roentgenologic investigations, histologic findings, trials of therapy and other factors are included later under the appropriate section . REVIEW

Episodes of ~

1965

59

63

10

1-2

alcoholism and toxic exposure were not implicated in any case . Since similar cholestatic features develop in rare instances during the last trimester of pregnancy [9], it is relevant that of the two patients who had pregnancies one (Case 7) had no jaundice, and the other (Case 1) had jaundice coincident with only one of six pregnancies . In Case 8 the urinary excretion of estrogens and gonadotropins was within the normal range during an episode of jaundice . The duration and number of attacks varied considerably, from seven episodes in forty years (Case 1) to ten in five years (Case 8) . The greatest number of jaundice attacks (twentyseven in thirty-seven years) occurred in Case 7, and the least (four episodes in thirteen years) in Case 3 . On the average, jaundice is anticipated rather more frequently than every other year . The length of attacks is also unpredictable, ranging from eighteen months (Case 1) to two weeks (Case 8) ; considerable variation in duration occurs in individual patients . The usual duration has been between three and four months . The periodicity of the attacks is hard to evaluate, but the greatest regularity was observed in Cases 1, 3, 4 and 5 . The symptoms that occurred during the episodes of jaundice had many common features [1-4] . Fatigue was prominent and the majority of patients were aware of increased nervous tension . Anorexia occurred in most patients, nausea in at least half and vomiting was experienced by three . Loss of



3 00

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FIG . 1 .

(Case 8 .) Tests of hepatic function and their relationship to the administration of drugs .

FIG . 2 .

weight varied from 50 pounds in seven months (Case 1) to 8 pounds in eight months (Case 7) . Abdominal pain was present in half the patients, located primarily in the right upper quadrant . The severity of symptoms was variable and occasionally striking, comparable to that with severe viral hepatitis [6] . Invariably the urine became dark and the feces light with the onset of jaundice, and in all but two patients troublesome itching developed at the height of the attack . The patients were all afebrile . Hemorrhagic tendencies, which included bruising, epistaxis and vaginal or gingival bleeding, occurred during prolonged attacks of jaundice in three patients (Cases 1, 2 and 7) . In addition to jaundice, the physical findings included abdominal tenderness, greatest over the right upper quadrant, in at least half the patients . In four patients the liver was considered to be enlarged during an attack (Cases 1, 5, 7 and 8) . Bruising was observed in three patients and itching resulted in skin excoriations, which sometimes became infected, in another three . No additional physical stigmata of hepatic or biliary tract disease have been reported .

line phosphatase concentrations also increased invariably ; values greater than twice normal at their height occurred in all but one patient (Case 5), the greatest being observed in Cases 3 and 8 (94 and 92 King-Armstrong units) and Case 7 (17 .6 Bodansky units) . Serum albumin and serum globulin concentrations were within the normal range . Electrophoretic patterns of serum globulin concentrations during episodes of jaundice, obtained in five instances, did not show any significant abnormality . Serum cholesterol levels were very high in one instance (Case 4) and somewhat elevated in three (Cases 1, 7 and 8) . In Case 8 the serum cholesterol level fell from 274 to 195 mg . per 100 ml . following an attack of jaundice . In this case plasma fatty acids (517 mg . per 100 ml .), phospholipids (345 mg . per 100 ml .) and total lipids (791 mg . per 100 ml.) also increased with jaundice . Serum glutamic oxalacetic transaminase activity was recorded in four cases (1, 3, 4 and 8) and increased modestly to two to six times normal (Case 8) during an attack of jaundice . Various flocculation tests were performed in six patients (Cases 1, 2, 5, 6, 7 and 8), including thymol turbidity, cephalin cholesterol and zinc sulfate tests, all of which yielded negative results . Prothrombin time, recorded in four patients (Cases 1, 2, 7 and 8), was prolonged in three, all of whom manifested hemorrhagic phenomena which responded to the administration of vitamin K. Urobilin was present in the urine in all four patients thus tested during an attack. Information recorded previously regarding hepatic function between attacks of jaundice is

TESTS OF HEPATIC FUNCTION

Standard tests of liver function showed identical cholestatic features during episodes of jaundice in all patients [1-4] . The increases in serum bilirubin concentrations involved primarily the conjugated fraction ; the highest values of total bilirubin ranged from 40 (Case 1) to 11 .3 mg. per 100 ml . (Case 8) . Serum alka-

(Case 8 .) Removal rates of injected bilirubin and bromsulfalein from the blood between attacks ofjaundice.

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Benign Recurrent Cholestasis-Summerskill limited to the normal values for serum bilirubin reported in three cases (Cases 1, 2 and 7) . In Case 8 serum bilirubin concentrations decreased to normal, as did serum alkaline phosphatase activity, which decreased from 92 .0 to 9 .1 KingArmstrong units . (Fig . 1 .) Simultaneously, serum glutamic oxalacetic transaminase activity decreased from 10 .0 to 0 .9 µM per nil . per hour (normal < 1 .44), and serum lipid fractions all reverted to normal following recovery from jaundice . (Fig . 1 .) Further evidence of apparently normal hepatic function between attacks of jaundice was indicated by the normal removal rates of injected bilirubin and sulfobromophthalein (bromsulphalein) from the blood in Case 8 . (Fig . 2 .) STUDIES OF THE BILIARY SYSTEM

Since patients with this syndrome manifest several clinical, biochemical and histologic features similar to those characteristic of mechanical obstruction of the hepatic biliary system before the pattern of recurrent jaundice is established [1], a laparotomy was performed in all but one patient (Case 5) . It is doubtful whether a diagnosis can be made early or with confidence without exploration of the biliary system . In fact, the diagnostic problems presented by such patients have led to multiple procedures in the treatment of the majority . Thus, cholecystectomy was performed in three patients (Cases 4, 7 and 8) and explorations of the common bile duct were carried out in six (Cases 1, 2, 3, 6, 7 and 8) . More than one exploration of the common duct was believed necessary in four cases, and the procedure was repeated on three occasions in Case 2 . Surgical cholangiography, particularly necessary to exclude extrahepatic obstruction, was performed with negative results in five patients (Cases 1, 2, 3, 7 and 8) . In contrast to patients with recurrent jaundice due to the Dubin-Johnson syndrome [10], visualization of the gallbladder and bile ducts by the use of opaque media has always been possible, in the absence of jaundice, in patients with the present syndrome . Normal appearances of the gallbladder were observed by oral cholecystography in all four patients thus studied (Cases 1, 2, 5 and 8), and satisfactory intravenous cholangiograms were obtained in each of three patients (Cases 2 . 5 and 8) . In Case 8 a hepatic scintigram excluded ductal obstruction by an extrinsic mass within the hepatic parenchyma. VOL . 38, FEBRUARY

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Further investigations of the biliary system have also supported the concept of an intrahepatic lesion . In two cases (2 and 7) T tube drainage did not have an evidentt effect on the degree of jaundice . Duodenal intubation in Case 8 yielded a profuse recovery of bile-stained fluid (pH 9, bilirubin content 11 .0 mg . per 100 ml .), although little bile was aspirated [6] during an attack of jaundice in another patient (Case 6) . Additional evidence exonerating mechanical extrahepatic obstruction includes the failure of substances thought to act on the biliary system and sphincter of Oddi (papaverine, meperidine [Demerol ® 1, amyl nitrite, atropire and magnesium sulfate) to affect the course of jaundice in Case 2 . In Case 8 the administration of morphine (20 mg.), which induced nausea and vomiting, did not cause any change in serum bilirubin and alkaline phosphatase concentrations or in the serum activity of glutamic oxalacetic transaminase and amylase curing the subsequent four hours . HISTOLOGIC FEATURES

Biopsy specimens of the liver obtained during attacks of jaundice were examined by light microscopy in all but one instance (Case 4) . Invariably, nonspecific cholestatic features comprising bile stasis in the canaliculi and round cell infiltration in the portal tracts were reported [1-4] . In addition, isolated necrotic cells and discrete increases in fibrous tissue (Case 6) were observed occasionally . In no instance were changes suggestive of extrahepatic obstruction reported nor was there any irretersible change in hepatic architecture despite recurrent episodes of jaundice for periods up to forty and thirty-seven years (Cases 1 and 7) . As examination of tissue between attacks of jaundice was made only once previously (Case 7), biopsy material was also studied when the results of liver function tests were normal in Case 8 . No abnormality was demonstrated is either of these cases . Since studies of hepatic tissue with the electron microscope had not been reported previously for this syndrome, they were carried out in Cases 1 and 8 [11] . During episodes of jaundice, numerous vesicles containing material of low to medium density were present . They were mainly intracellular and of variable size, the largest approximately twenty times the size of mitochondria [11 ] . (Fig . 3 .) These changes were found in every section but not in every cell ;

302

Benign Recurrent Cholestasis-Sumrnerskill

(Case 8 .) Ultrastructural appearances of hepatic tissue . Note the numerous intracellular and exracellular vesicles. v = vesicle ; rbc = erythrocyte ; b = bile canaliculus ; nu = nucleus ; ne = nucleolus ; m = mitochondrion . Electromicroscopic view, original magnification X 10,832 . FIG . 3 .

following recovery from jaundice in Case 8, they were no longer apparent, and no other abnormality was observed . The vesicles could not be identified by light microscopy, and lipid staining gave negative results . Additional but less specific ultrastructural changes were present in Case 1 during an attack of jaundice and comprised variable dilatation of the bile canaliculi with blunting and shortening of the microvilli of the canalicular membrane . MISCELLANEOUS TESTS

Steatorrhea was demonstrated in all patients in whom fecal fat studies were reported (Cases 1, 3 and 4), the highest amount excreted being 48 gm . fat in 24 hours during an episode of jaundice . Malabsorption is probably an important factor in the production of hypoprothrom-

binemia, hemorrhaging and loss of weight . No evidence of a. hemolytic component of the jaundice was encountered and the results of hematologic studies were normal in all patients thus investigated (Cases 1, 2, 3, 7 and 8) . No clinical, roentgenologic or surgical evidence of pancreatic disease was observed in any patient, and the values for serum and urinary amylase during jaundice were normal in Cases 7 and 8 . Additional studies in Case 8 yielded negative results for bacterial cultures of hepatic biopsy tissue, examinations of the feces for parasites and ova, excretion of porphyrins in the urine and a lupus erythematosus clot test . DIFFERENTIAL DIAGNOSIS

The syndrome can be differentiated from other diseases with features of cholestasis [1,71 . AMERICAN JOURNAL OF MEDICINE

Benign Recurrent Cholestasis Semi rnen kill The recurrence of attacks and absence of identifiable precipitating factors prevent confusion with cholcstatic hepatitis associated with drugs, pregnancy or viral infection . Extrahepatic obstructive jaundice is excluded by appropriate roentgenologic and surgical investigation . Hepatic biopsy and other standard procedures allow distinction, when necessary, from fatty liver, cirrhosis, metastatic liver disease and other conditions with cholestatic features . Differentiation from other types of recurrent or idiopathic jaundice thus far recognized is also relatively straightforward [1,7] . The presence of conjugated bilirubin in serum and urine contrasts with the jaundice of Gilbert's disease (constitutional hepatic dysfunction) or of hemolytic anemias . More careful discrimination may be necessary to exclude the rare instances of idiopathic jaundice involving impaired hepatic excretion of conjugated bilirubin which have been described by Rotor and associates [12], Dubin and Johnson [10] and Sprinz and Nelson [13] . However, in benign recurrent cholestasis, jaundice is deeper and of longer duration, itching is frequent and serum alkaline phosphatase concentrations are much greater [1] ; in addition, a family history of jaundice is not to be expected . Moreover, it is possible to visualize the gallbladder and bile ducts roentgenologically between attacks of jaundice, and serum disappearance curves of injected bromsulphalein or bilirubin appear normal . (Fig . 2 .) Finally, the cholestatic features present on hepatic biopsies are not found in the other conditions, although lipochrome-like pigment in hepatic tissue may be present in some [10] . Electron microscopy may prove specific in diagnosis since the vesicles observed were not noted in other conditions with cholestasis [11] . PROGNOSIS AND TREATMENT

Although temporarily incapacitating, the disorder is benign in that no serious complications, long-term disability or irreversible change in hepatic function or histologic structure have resulted from episodes of jaundice in any patient over follow-up periods up to forty years . No specific treatment which reduces the incidence or duration has been found effective . Earlier reports (Cases 1, 2, 4 and 5) failed to substantiate any consistent therapeutic effect of steroid medication in regard to symptomatology or the degree of bilirubinemia . Recently, a third course of treatment with prednisone was preVOL . 38, FEBRUARY 1965

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o<„

FIG. 4 .

(Case 1 .) Therapeutic effect of the administration of prednisone and cholestyramitic .

scribed in Case 1 with no evident effect (Fig . 4), and neither the clinical course nor the results of tests of hepatic function have been affected by prednisone in Case 8 . (Fig . 1 .) There is some evidence that the bile acid exchange resin, cholestyramine, may improve symptoms and hepatic function in some patients with cholestatic jaundice [14] . However, :here was no striking change in bilirubinemia in Case 1 (Fig . 4) with this medication, although the drug may partially have relieved pruritus, a finding similar to that noted by Sherlock [5] . For general management during attacks of jaundice, there is no evidence that bed rest is beneficial, unless dictated by the severity of the symptoms . Because of nutritional problems developing from anorexia and malabsorption during long periods of icterus, a diet high in calories and proteins and low in fat is preferable and supplemental vitamins, particularly A, D and K, are indicated [1] . The findings in Case 8 (Fig . 1) did not contraindicate the use of methyltestosterone (for the management of pruritus) or chlorpromazine (for antiemetic and tranquilizing purposes) despite their potential hepatotoxic actions . Subsequently, prochlorperazine was administered for several weeks to the patient with no ill effects . COMMENT ON ETIOLOGY

Subsequent evidence [2-4] supports the original impression [ 1 ] that cholestasis is a benign disorder of intrahepatic origin, resulting from a defect affecting primarily the physicochemical

3 04

Benign Recurrent Cholestasis-Summerskill

processes involved in excreting conjugated bilirubin and other substances from the liver cells and bile canaliculi . Comments on the cause of such changes are based on the assumption that the number of similarities demonstrated by these patients implies a common cause or mechanism . Infectious, neoplastic, infiltrative and autoimmune processes can be excluded with confidence on available data . The onset of jaundice usually in childhood or adolescence is compatible with a genetically determined abnormality ; the failure to extract significant family histories and the wide geographic distribution of the syndrome do not exclude this possibility, although a recessive gene with poor penetrance is implied . Tygstrup [2] postulated a relationship between his patients and subsequently examined kindred with a similar type of jaundice [6] . Schapiro and Isselbacher [4] emphasized the seasonal incidence of jaundice in their patients, and Tygstrup commented on the apparent regularity of the attacks in his cases . In Case 8 symptoms similar to those later associated with jaundice recurred for several months before icterus was apparent, suggesting the possibility that jaundice may not always develop with the disorder . The normality of hepatic function and structure between attacks of jaundice is compatible with an allergic or toxic reaction . Such a hypothesis cannot be supported at present, since only one patient had evidence of allergic phenomena [2] . None of the patients studied responded convincingly to the administration of steroids, and no toxic factor was identified . Studies in Case 8 showed that both norethandrolone and chlorpromazine, which may cause toxic and allergic lesions of the liver, respectively [15], were tolerated without deterioration in hepatic function . The significance of the histologic changes cannot yet be interpreted . The cholestatic features on light microscopy and the alterations of the bile canaliculi and microvilli of the canalicular membrane observed on the electron microscopy are relatively nonspecific and can occur with either hepatotoxic agents or extrahepatic obstruction [16] . On the contrary, the ultrastructural abnormality of intracellular and extracellular vesicles in Cases 1 and 8 during an episode of jaundice, but not between attacks, appears to be more characteristic . Changes of a comparable degree have not been identified by us in patients with cholestatic jaundice of dif-

ferent types or in other conditions, and we have not found any reference to them by others . The presence of such vesicles is consistent with retention of a metabolic product, abnormal in character or amount, accumulating within the liver as a result of a disordered excretory function of an unknown nature . SUMMARY

The syndrome of benign recurrent cholestasis is defined by summarizing published and unpublished data relevant to cases previously reported and by the findings, which include special studies, in a new instance of the disease . Clinical, biochemical, roentgenologic and histologic characteristics are further defined ; differential diagnosis and possible etiologic factors, together with responses to therapy or challenge tests, are described in relation to these findings . The disorder is benign and cholestasis appears to be of intrahepatic origin with no demonstrable disorder of hepatic function between episodes of jaundice . Examination of liver tissue by electron microscopy revealed ultrastructural changes which may be characteristic of the condition . Acknowledgment: I am indebted to Dr . F . Avery Jones and Dr . J . Fletcher for arranging the latest studies in Case 1 ; to Dr. E . R . Dickson for interpretation of the ultrastructural findings ; and to those physicians who observed examples of the syndrome and kindly communicated their findings to me .

REFERENCES

and WALSHE, J . M. Benign recurrent intrahepatic "obstructive" jaundice .

1 . SUMMERSKILL, W . H . J .

Lancet, 2 : 686, 1959 . 2 . Tvosnxur, N . Intermittent 3.

possibly familial intrahepatic cholestatic jaundice. Lancet, 1 : 1171, 1960 . DE GRooTE, J ., GOUEEAU, P. and VANDENEROUCRE, J . IctIre cholostatique rEcidivant . Acta gastro-

enterol . berg ., 23 : 747, 1960 . 4 . SCHAPIRO, R. H . and ISSELBACHER, K . J. Benign recurrent intrahepatic cholestasis . New England J. Med., 268 : 708, 1963 . 5 . SHERLOCK, S . Personal communication . 6 . TVGSTRDP, N . Personal communication . 7 . DE GROOM, J . Personal communication . 8 . ISSELBACHER, K . J . Personal communication . 9 . SVANEORO, A . and OHLSSON, S. Recurrent jaundice of pregnancy : a clinical study of twenty-two cases . Am . J. Med., 27 : 40, 1959 . 10 . DuarN, I . N. and JOHNSON, F . B. Chronic idiopathic

jaundice with unidentified pigment in liver cells : a new clinicopathologic entity with a report of 12 cases. Medicine, 33 : 155, 1954. AMERICAN JOURNAL OP MEDICINE



Benign Recurrent Cholestasis-Summerskill 11 . SUMMERSIILL, W . H . J ., DICxsON, E . R . and FLETCHER, J . Unpublished data . 12 . ROTOR, A . B ., MANAHAN, L . and FLORENTIN, A .

13 .

Familial non-hemolytic jaundice with direct van den Bergh reaction . Aria rned. pailippina, 5 : 37,1949 . SPRnNZ, H1 and NELSON, R . S . Persistent nonhemolytic hyperbilirubinemia associated with lipochrome-like pigment in liver cells : report of 4 cases . Ann . Int . Med ., 41 : 952, 1954 .

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B . . JR. and KRIVIT, W, Cholestyramine therapy in a case of intra-lobular biliary atresia . (_Abstract .) Gastroenteroiogv, 44 : 475, 1963 . SHERLOCx, S . Jaundice . Brie . Al. J., 1 : 1559, 1962 . SHAFFNER, F ., POPPER, H . and PEREZ . V . Changes in bile canaliculi produced by norethandrolone : electron microscopic study of human and rat liver . J. Lab . & Clin . Med., 56 : 623, 1960 .

LOTTSFELDT, F. L., CARRY, J .