The Weltmann Test in Diseases of the liver* By

MANFRED KRAEMER, M.D. NEWARK, NEW JERSEY

T HE difficulty in making a positive clinical differen- tiation between a parenchymatous (catarrhal or

cirrhotic) and an obstructive jaundice is generally recognized. The many tests of liver function (1, 2, 3, 4, 5, 6) now in vogue suggest that likewise there is no absolute laboratory procedure which can tell us whether, in a given case of jaundice, we are dealing with a parenchymatous or an obstructive process.

Many authors (7, 8, 9) find the galactose tolerance test of Bauer most valuable in making a differentia- tion, but others, notably Banks, Sprague, and Snell (10) feel that its usefulness is very much limited. In private practice, and when performed promptly after the appearance of jaundice, our experience with Bauer's test has been favorable. However, in the wards of a public hospital the performance of the test is too time-consuming and expensive. Where chemicals are purchased by "bids," an impure galac- tose may be substituted for the more costly C.P. pro- duct. This use of impure galactose makes results very difficult to evaluate. The galactose test takes five hours for its completion and requires the collection of all urine passed within that time. In wards inade- quately staffed, patients unwittingly void specimens into urinals which are emptied into a toilet instead of being saved. In patients with associated prostatic disease, diabetes, or kidney disfunction, it is almost impossible to get an accurate idea of galactose utili- zation.

The above is my apologia for the discussion of a test for liver disease which may prove as valuable as the galactose tolerance test but which is both simpler and easier to perform and which can be carried out at a negligible cost.

Oskar Weltmann, a clinician and physiological chemist, who had for some time been studying liver disease (11, 12, 13, 14, 15) published in February, 1930, (16) the result of some researches on the effect of certain pathological processes on the coagulability of the blood serum. By October, 1930, (17) he had applied these changes in blood serum coagulability to a test for the differential diagnosis between obstruc- rive and parenchymatous states of the liver. He called his test the 'Serums Koagulations Band' and abbrevi- ated this title to 'K.B.' This test was later elaborated upon by Weltmann (18). European writers have used the test not only in differentiating hepatic diseases but also as an aid to the diagnosis of a great ~ variety of disease conditions. No reports have appeared in the English literature. In this !5aper, we shall confine ourselves to a description of the test, reports of the

* F r o m the Medical Se rv ice of Dr. F r e d e r i c k All ing, N e w a r k Ci ty Hos- pi ta l .

~ u b m i t t e d December 3, 1934.

14

literature, and a preliminary report of our findings with this test in hepatic diseases.

DESCRIPTION OF THE TEST If blood serum be diluted with distilled water and

boiled, the coagulability of the serum depends upon the presence of a certain minimal quantity of elec- trolytes. Thus, the protein in a 1:50 dilution of blood serum in distilled water does not coagulate by boiling, but coagulation immediately appears if a small amount of sodium chloride, calcium chloride or barium chlor- ide is added to the boiling dilution.

Weltmann determined that, in a boiling 1:50 dilu- tion of normal blood serum, the lowest concentration of calcium chloride solution in which coagulation of the serum protein takes place is from .03 to .04 per cent. That is, if 0.1 c.c. of normal blood serum is added to 5 c.c. of .02~-~ calcium chloride solution and boiled, no coagulation takes place. However, if 0.1 c.c. of normal blood serum is added to 5 c.c. of .04% calcium chloride solution and boiled, the serum pro- tein coagulates.

It was found that inflamatory and exudative pro- cesses (pneumonia) changed the blood serum so that the protein was coagulated in only the more highly concentrated solutions of boiled calcium chloride, as .08%. On the other hand, disease of the parenchyma of the liver, cardiac decompensation with stasis, and fibrous forms of tuberculosis so changed the blood serum that the protein was coagulated in much lower dilutions of boiled calcium chloride, e.g..02~/~. These observations have been confirmed by a number of in- vestigators to whom I shall refer later.

On the basis of these findings the Weltmann serum coagulation test was devised. The technic follows:

TECHNIC

In stock are kept eleven large (500 c.c.) bottles of the following solutions of anhydrous calcium chloride: 0.1c~, .09%, .08~, .07~, .06%, .05%, .04%, .035c/~, .03%, .02%, .01%. These bottles are numbered from 1 to 11. Number 1 corresponds to 0.1~ and number 11 to .01% dilution of calcium chloride.

Eleven test tubes are placed in a rack. To each tube 5 c.c. of a different one of the dilutions of calcium chloride is added. A different 5 c.c. volumetric pipette is used for each bottle. The tubes are numbered 1 to 11 to correspond to the stock bottles. Then to each test tube 0.1 c.c. of the serum to be tested is added, this serum having been collected by the usual method as for a Wasserman test. The tubes are shaken and then placed in a boiling water bath for fifteen minutes. A large water bath is used so that the entire test tube rack may be placed into the bath and removed with- out disturbing the position of the tubes. After fifteen minutes boiling, the tubes are removed from the water bath and the weakest solution of calcium chloride in

K R A E M E R - - T H E W E L T M A N N T E S T I N D I S E A S E S O F T H E L I V E R 1 5

which coagulation has taken place is determined. In the reading, lumping of the protein not turbidity is considered. The number of the tube containing the weakest solution in which lumping (coagulation) takes place determines the length of the coagulation band (C.B.).

In normal serum, the coagulation band has almost a constant length reaching to the 7th or 8th tube, corresponding to a calcium chloride dilution of .04 to .035%. In certain diseases the coagulation is either shortened (coagulation in less than 7 tubes) or length- ened (coagulation in more than 8 tubes). A short C.B. or no coagulation at all is observed in pneumonia, acute rheumatic fever, and in other infectious or exudative processes. A lengthened coagulation band occurs in cirrhosis of the liver, in all parenehymetous affections of the liver, and in all fibrous processes.

The method has its limitations in the eases in which exudative-inflamatory and fibrous procesess are asso- ciated. In these eases a normal C.B. may result from the antagonistic effect of the two processes. Thus extensive destruction of liver tissue by fibrosis follow- ing obstructions by a neoplasm may lead to a lengthen- ing of the band. (of. Table, Case 24)

REVIEW OF LITERATURE

As previously mentioned, the test has been found useful in the diagnosis and prognosis of several disc- ases. The value of the test in the differentiation of exudative and fibrous tuberculosis was first shown by Weltmann (16, 17) and has been confirmed by others. (19, 20, 21, 22, 23) Rohacova and Weicherz (21) and others (19, 22) found the C.B. of greater prognostic value in tuberculosis than the sedimentation rate of erythrocytes. Writers who have employed the test have found it of diagnostic and prognostic value in pleurisy (24), gynecological conditions (25, 26), and pneumonia (18). Klafton (27) has described changes in the C.B. in pregnancy associated with such compli- cations as pyelitis and mastitis or alterations in the liver. Kretz (28) studied the C.B. of 420 patients be- fore and after various abdominal operations and noted a shortening of the band post-operatively with a return to normal quite rapidly. Such complications of the recuperative processes as abscesses, and thrombophleb- iris caused continued shortening of the band.

The value of the coagulation band in the differential diagnosis of liver diseases has been established by many writers (16, 17, 18, 29, 30, 19, 31, 32, 33).

We have made no study as to the reasons for the phenomena observed in this test. Some function of the liver must be responsible for the changes found, because in other diseases in which hepatic function may be involved, as in pernicious anemia (cf. Table, Cases 19, 20 and 21), diabetes melitus, and chronic alcoholism the effect is the same as that observed in cirrhosis (3,~). Weltmann (18) and others (34) showed the reaction depends upon a change in the serum albumen, and not in a change in the serum cal- cium as suggested by Kaiser (20). Although the cause of the coagulation band is unsolved, its regular and constant changes in certain diseases and its simple technic may make it a useful diagnostic means, especi- ally in the field of liver pathology.

COMMENT Our results, which are shown in the accompanying

table, have in the main agreed with those of the

T A B L E I

The Coagulation Band (C.B.) In 25 Cases of Liver Disease.

Ict . Case A g e Sex I n d e x

. [__ l. 51 F. 22.5

2. 46 M. 10

3. 59 M. 33

4. 75 M. 10 5. 50 F.. 100

6. 40 M. 1S 7. 50 M. 10

~. 47 M. 10 .q. 72 M. 29

10. 33 F. 30

11. 45 M. 100

12. 26 M. 80 13. 59 F. 150 I4. 57 F. 30 15. 66 M. 30 16. 63 F. 15 17. 52 F. 31 1 8 . 3 9 M .

19. 30 M. 15 20. 30 M. 21. 53 22. 52 MI 4S

23. 36 M. 15 24. 5~ M. 75

25. 47 M. 50

C.B.

8

8

7

10 11

10 10

11

10

10 10 10 10 10 10 11

10 10

10

Diagnos i s

Stone in comon duct. ( L a p a r o t o m y )

P r o s t a t i c c a n c e r me t a s t a s i z in~ to l iver and o b s t r u c t i n g bil~! ducts. ( A u t o p s y ) I

Cancer of p a n c r e a s . ( L a p a r o t o m y ) ]

C i r rhos i s of l iver. I Pa ren .chymatous j aund ice and

c i r rhosis , j Ci r rhos i s of l iver. I ,Cirrhosis of l iver. (Esophagea l I var ices ) ]Cirrhosis o f l iver. I Ci r rhos i s of l iver. P a n c r e a t i c

cance r wi th ex t ens ive metas - I t a s i s to liver. ( A u t o p s y ) ]

Congen i t a l hemolyt ic ic terus . (Sp leenee tomy)

A r s p h o n a m i n e hepa t i t i s . ( A u t o p s y )

P a r e n c h y m a t o u s jaundice . P a r e n c h y m a t o u s jaundice . P a r e n e h y m a t o u s j aundice . P a r e n c h y m a t o u s jaundice . Cholangi t i s . ( L a p a r o t o m y ) Cholangi t i s . ( L a p a r o t o m y ) Cholangi t i s . Cholecyst i t i s .

( L a p a r o t o m y ) Pe rn ic ious a n e m i a . Pe rn ic ious a n e m i a , i Pe rn ic ious a nemia . P r i m a r y c a n c e r of bile ducts.

( L a p a r o t o m y ) Mi l ia ry tuberculosis , rl Cancer of head of pancreas , ]

w i th obstruetion~ of common I

duct of long dura t ion . I P r i m a r y cance r of l iver . I

( L a p a r o t o m y ) I

writers to whom we have referred. The test should prove valuable chiefly in determining whether or not a given case of jaundice is of an obstructive or of a parenchymetous nature. The cases of pernicious anemia and the case of familial hemolytic icterus showed results similar to those in parenchymatous jaundice, i.e. lengthening. The test does not aid in differentiating between an obstructive jaundice due to stone (Case 1) and one due to neoplasm. Case 3). In both the C.B. would be normal. In either case, however, surgical exploration is generally considered the proper procedure. Uniformly the patients with simple parenchymatous icterus (catarrhal jaundice) and those with cirrhosis with icterus showed lengthen- ing of the band. Unfortunately, the number of cases of early obstructive jaundice coming to our attention have been few--only three cases in the past year. Case 24, which was diagnosed as carcinoma of the head of the pancreas showed lengthening. The ob- struction, if this diagnosis was correct, (and we are not sure that it was, since the patient improved and left the hospital without a laparotomy) was of long standing and probably resulted in back-pressure on the liver with considerable parenchymatous damage, (as occurred in Case 9) which would have accounted for the lengthening of the band.

Our material has been too limited to enable us to evaluate this test properly. We present this prelimi- nary report in the hope that the use of this test will be investigated by others. We believe that fur ther use and study of the test in a large number of cases by critical investigators may elucidate a number of clinical problems.

ACKNOWLEDGMENT I wish to acknowledge the assistance rendered by

Dr. George Hewson.

16 AMERICAN JOURNAL OF DIGESTIVE DISEASES AND NUTRITION

R E F E R E N C E S

1. Strauss, H . : Zur Fufict ionsprufung der Leber, Deutsche recd. Wchnschr. 27: 757, 1901. 2. Bauer, Richard : Uber die Ass'imilatior~ von Galaktose und Milchzucker beim Gesunden und Kranken, Wien. med. Wehnsehr. 56: 20, 1906. 3. van den Bergh, A .A .H. : Presse ~ncd. 29:441, June 4, 1921. The Diazo Test for Bi]irubin in Blood. 4. Rosentha], N. and White, E. C. : Clinical Application of Bromsulphalein Test for Hepatic Function, J.A.M.A. 84:112, Apr~il 11, 1925. 5. Wallace, G. B., and Dimond, J . S. : The Significance of Urobiiinogen in the Urine as a Test of Liver Function, Arch. Int. Mcd. 35:698, June,

1925. 6. Lichtman, S. S. Cinchopen Oxidation Test of the Function of the Hepat'ic Cells, Arch. of Int, Meal. 48:98, July, 1931. 7. Shay. H a r r y and Schloss, Eugene : Painless Jaund ice : I ts Diffenential Diagnosis by Galactose Tolerance Test. J.A.M.A.. 98:1433, April 23,

1932. 8. Robertson, W. E., Swalm, W. A.. and Kanzelmann, F. W . : Functional Capacity of the Liver, J . A. M. A.. 99=2071, Dec. 17, 1932. 9. Rosenberg, D. H . : The Galactose and Urobilinogen Tests in the Differential Diagnosis of Obstructive and Int rahepat ic Jaundice, A~n. Int.

Med., 8:60, July, 1934. 10. Banks, B. M., Sprague, P. H.. and Snell, A. M.; Clinical Evaluation of the Galactose Tolerance Test, J . A. M. A.. 100:25. 1887. June 24, 1933. 11. Weltmann, O., aad Neumayer, K. : Das Fibrinogen in diagnostischen Kalkul der Leberkrankheiten, Med. Klin., 21:629, April 24, 1925. 12. Klimesch, E., and Weltmann, O. : The Clinical Value of the Determinat ion of Fibrinogen, Med. Klin., 23:1146, July 29. 1927. 13. Wel tmann, O., and Jost, F . : Uber die Adsorption des Bilirubins an das-Eiweiss, ihre Bes t immung und klinische Verwer tung, Dr utsches Arch.

f. Kiln. Med., 161:203, 1928. 14. Weltmann, Oska r : Die Differentialdiagnose des Ikterus, Praktische Arzt , 13:216-243, May and June, 1928. 15. Weltmann, O s k a r : The 'C~irrhoses of the Liver, Wien. klin. Wchnschr., 41:1301-1349, Sept. 13, 20, 1928. 16. Weltmann, O s k a r : Uber die Spiegelung exudativ-entzundlicher und fibroser Vorgange im Blutserum, Mcd. KIbl., 26:240, 1930. 17. Weltmann, Oska r : Pathology of the Liver, Wien. klin. Wchnsehr., 43:1301, Oct. 23, 1930. 18. Weltmann, Oskar and Medvei, C. V. : Invest igat ions on Serum Coagulation, Ztschr. f. klin. Med., 118:670, 1931. 19. Schneiderbauer, A. : The Coagulation Band and its Podition in the Clinic, Wien. klin. Wchnschr., 46:385, March 31. 1933. 20. Kaiser, T . : Bei t rag zur Weltmannschen Serumkoagulat ion bei Lungentuberkulose, Beitrage z. Kiln. d. Tuberk.. 83:271, May. 1933. 21. Rohacova, D., and Wcichherz, E. : Das Koagulationsband von Wel tmann bei Tuberkulose, Med. Klin., 29:1410, Oct. 13, 1933. 22. Mal4itra, A., and Tyndel, M.: Pract ical Value of Wel tmann 's Coagulation Band for Diagnosis and Frognosis of Tuberculosis, Beitragc z. Klin,

der Tuberkulose, 84:265, Feb. 22, 1934. 23. Dissmann, E. : Value of Wel tmann ' s Reaction in Est imation of Pulmonary Tuberculosis, Beitrage z. Klin. d. Tuberk., 84:270, Feb. 22, 1934. 24. D'A]essandro, R . : Wel tmann Coagulation Test in Pleurisy, Il Policlinico, 41:523, April 9, 1934. 25. Klaften, E . : Die Verwer tbarke i t und Entwicklung des Koagulationbandes, Zentralbl. f, Gynak., 56:939, 1932. 26. Purper , F. G.: Wel tmann ' s Coagulation Band in Inflammations of Adnexa. Monatsschr. f. Geburtshulfe u. Gynak., 97:138. June, 1934. 27. Klaften, E. : Die Verwer tbarke i t des Koagulationbandes in cler Geburtchilfe and Gynakologie, Med. Klin., 28:258, Feb. 19, 1932. 28. Kretz, J . : Das Verhalten des Weltmannschen KoaguIationsbandes nach operativen Eingriffen, Wein. ktin. Wchn~ehr.. 46:492, April 21, 1933. 29. Trost-Scherleitner, Pau la : Bei t rage zur Serumkoagulat ion nach Weltmann, Wein. reed. Wchnsehr., 82:1276, Oct. 1, 1932. 30. Skouge, E r l i n g : Der Wer t der Takata-Ara-Re~ktion und der Koagulat ionsbest immung bei Leberkrankheiten, KHn. Wchnschr.. 12:905, 1933. 31. Weltmann, O., and Sieder, B. : Significance of Wel tmann 's Coagulation Band for Diagnosis of Hepatic Diseases, W$en. Archiv f. innere Med.,

24:321, Feb. 10, 1934. 32. Massobrio, E., and de Michelis, U . : Serum Coagulation of Wel tmann in He!0atopathy in Relation to Protein Picture of Serum, Minerva

Medica, 1:147, Feb. 3, 1934. 33. Pellegrini, M., and Barsini , G. : Behavior and Significance of Wel tmann ' s Serum Reaction in Some Diseases: Research on Behavior of Elec-

trolytic Threshold of Coaguloflocculation to Heat of Exudates, Transudates, and of Normal and Pathologic Cerebrospinal Fluid, Mi,~erva Medica, 1:154, Feb. 3, 1934.

34. Medvei, C. V., and Paschkis, K. E. : Die Beeinflussung der Takata-Ara-Reakt ion und des Koagulationbandes durch Hepar in , Klin. Wchnschr., 12':1910, Dec. 9, 1933.

ABSTRACTS

G. M. DACK AND ELIZABETH PETRAN, Chicago, Ill.

Experimental Dysentery. P~ges 1-6, 1934, Vol. 55, No. 1.

A study was made of bacterial activity in two isolated segments of large intestine of monkeys into which dysen- tery bacilli were injected. This gave opportunity to de- termine bacterial changes in the absence of micro-organ- isms carried by the fecal stream. The opportunity for these dysentery bacilli to establish themselves may be quite variable. Freshly isolated virulent strains of these organisms, inoculated into isolated loops of colon in adult monkeys, produced an infection in the loops, which re- sulted in a profuse bloody mucous discharge. Marked systemic reaction accompanied the infection in the loops of intestine; this was characterized by pallor, loss of appe- tite, lenkopenia, loss of weight, and prostration. The acute symptoms appeared within forty-eight hours and lasted three to four days. Within a week the discharge from the fistulas had ceased and systemic symptoms had disap- peared. The severe systemic reactions may have been the result of absorption of toxins. Agglutinins for Bacterium dysenterae (Flexner) were demonstrated in the serum of the animals. No evidence of infection was apparent in that portion of the colon through which the fecal stream passed.

However, severe symptoms of dysentery developed in two large adult monkeys which were fed the same strains of organisms.

It would seem, then that the fecal strain is not essen- tial for the dysentery bacillus to establish itself and pro- duce infection.

J. Arnold Bargen, Rochester, Minn.

S C H I F F , LEON, AND SENIOR, F A N N Y A .

Jamzdice, With Particldar Reference to Galactose Tolera~tce, Jo~o ~. of the A. M. A., ldS:2924, Dec. 22, 1934.

The authors studied 100 eases of jaundice with partic- ular reference to galaetose tolerance.

There were 50 cases of catarrhal jaundice. In forty- seven of these cases a positive galactose test (excretion of three grams or more) was obtained on the first examina- tion. In two additional cases positive tests were obtained on second examination.

In fifteen cases of toxic hepatitis the test was positive in fourteen.

In a group of twenty cases of obstructive jaundice due to stone in common duct, cholangitis, pancreatitis, pan- creatic carcinoma, and pancreatic cyst, the galactose test was negative in all of these cases.

In ten cases of cirrhosis of the liver the galactose test was negative in six cases and positive in four.

In carcinoma of the liver, the galactose test was nega- tive in four out of five cases.

In the above study serum bilirubin determination and bromsulphalein retention tests were made. From compari- son of these studies the authors find that the galactose tolerance bears no relationship to the degree or duration of the jaundice or to the amount of bromsulphalein re- tention.

Discussions by Dr. Har ry Shay and Dr. F. C. Mann follow.

Francis D. Murphy, M.D., Milwaukee, Wis.