DIFFERENTIAL DIAGNOSIS BETWEEN MEDICAL

AND SURGICAL JAUNDICE BY LABORATORY

TESTS *
By HANS POPPER, M.D., Ph.D., F.A.C.P., and FREDERICK STEIGMANN,
M.D., M.S., F.A.C.P., Chicago, Illinois

DESPITE the great strides of laboratory medicine in the past two decades
and the subsequent elaboration of many liver function tests, the jaundiced
patient still presents today a challenging diagnostic problem. There is little
difficulty in recognizing the hemolytic variety of jaundice (retention type)
primarily by the absence of bile from the urine, the low or absent direct
serum bilirubin and evidence of hemolysis. However, to differentiate the
two types of regurgitation jaundice, the medical (due to acute or chronic
hepatitis or to cirrhosis) from the surgical (due to stones, tumors or stric-
tures), is often difficult. Even the experienced clinician concedes a relatively
high number of diagnostic failures as evidenced by superfluous as well as by
delayed operations. The hope of improving this unsatisfactory situation by
developing new liver function tests has to date only partly materialized.
The performance of a number of different liver function tests was there-
fore recommended—a "composite" study of liver function.1 This created a
problem of how to dovetail the results of the different tests into a unified
diagnostic approach. Among several presented attempts,2'3'4'5> 6 ' 7 ' 8 the
profile derived from graphic recording of the results of liver function tests
in a given case as described by Watson and Hoffbauer * appeared promising.9
Nevertheless, to date, profiles characteristic of individual conditions are not
as yet available. Moreover, profound knowledge of the physiologic basis
is needed for the interpretation of the "composite" study of liver function.
Another approach to be presented below is to trace the thought processes
which lead to a diagnosis in a jaundiced patient, and to analyze the role
which the results of liver function tests play in them. To simplify this other-
wise unwieldy problem, the approach was limited to the differentiation
between medical and surgical jaundice. Only the initial series of liver
function tests was taken into consideration and thus the duration of jaundice
was not taken into account. Experiences with a group of 285 jaundiced
patients served as the basis for this attempt.
This analysis had a twofold purpose: first, to develop a graphic scheme
which may facilitate the recognition of the diagnostic problems in jaundice,
and secondly, to evaluate empirically which liver function tests in use, with-
* Received for publication December 2, 1947.
From the Hektoen Institute for Medical Research, the Departments of Pathology and
Internal Medicine, Cook County Hospital; Department of Pathology, Northwestern Uni-
versity School of Medicine and the Department of Internal Medicine, University of Illinois
College of Medicine, Chicago, Illinois.
Aided by a grant from the Dr. Jerome D. Solomon Memorial Research Foundation.
469

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 470 HANS POPPER AND FREDERICK STEIGMANN

out reference to their physiologic basis, were, from a practical standpoint

most helpful in determining the diagnosis.

MATERIAL AND METHOD

The material studied consisted of 285 cases of various types of jaundice

excluding the hemolytic variety. It included only cases in whom the diag-
nosis was definitely established by the follow-up course, subsequent biopsy,
operation and/or necropsy findings. The patients were observed in a large
general charity hospital. This is reflected by the distribution of the various
types (table 1). Cirrhosis was relatively common. Acute hepatitis as well
as obstructive jaundice was usually seen in somewhat advanced stages.

TABLE I
Final Diagnoses in 285 Analyzed Cases of Jaundice
Acute Benign Malignant
Hepatitis Cirrhosis Obstruction Obstruction
83 122 44 36

The examined cases fell into two groups: Group I consisted of 125 cases
studied between 1941 and 1943, while Group II comprised 160 cases, studied
during 1946 and 1947. In the first group, the following determinations
were performed: (a) total serum protein; (b) albumin-globulin ratio; (c)
serum non-protein nitrogen; (d) cephalin-cholesterol flocculation10; (e)
total serum cholesterol; (/) cholesterol ester/cholesterol ratio 11 ; (g) serum
alkaline phosphatase12; (h) hippuric acid synthesis after oral administra-
tion 13; (i) urinary urobilinogen in a 24 hour specimen 14; (/) concentration
of fecal urobilinogen15; (k) plasma vitamin A 1 6 ; (/) bromsulfalein reten-
tion 45 minutes after administration of 5 mg. per kg. body weight (in cases
with only slight jaundice) ; and (m) total serum bilirubin.
In the second group, the same tests were performed with the following
exceptions: the thymol turbidity was determined in all instances.17'18'19 The
hippuric acid synthesis after intravenous administration 20 (replacing the
oral method) and the plasma vitamin A determinations were done only in
selected cases; moreover, in the majority of these patients the urinary uro-
bilinogen was determined as units in a two hour afternoon specimen.21
These examinations were supplemented with the usual clinical observa-
tion, additional laboratory studies, biopsy findings, and in some instances
with the findings at operation or necropsy.
The final diagnosis was obviously not made in all cases after the primary
workup because the analytical thought processes described below were not
correctly applied. A number of diagnostic failures—not quite 5 per cent—
occurred, many of which might have been avoided according to retrospective
analysis.
The described thought processes will be composed of a number of steps.
In the description of each step, two points will be made: (1) analysis of the

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 MEDICAL AND SURGICAL JAUNDICE 471

function tests which are taken into consideration in making this step, and (2)
discussion of the cases in which this step was not justified.

DIAGNOSTIC ROUTE

The first problem in the differential diagnosis of the jaundiced patient is

the distinction between presence or absence of liver cell damage and of
marked interference with the bile flow. Some interference with the bile flow
is found in every patient with regurgitation jaundice. There are gradual
transitions from slight interference to complete exclusion of bile from the
duodenum, as is typically seen in complete extrahepatic mechanical biliary
obstruction. Therefore, arbitrarily the term "marked interference with the
bile flow," as used hereafter, has been defined by the results of function tests
as characteristically found in established extrahepatic biliary obstruction.
On this basis, in general, the patient with medical jaundice has liver cell
function impairment; the patient with surgical jaundice marked interference
with the bile flow.
The liver function tests used can be divided into two groups: (a) those
TABLE II
Pathologic Levels Chosen in Liver Function Tests
Which Are Grouped as to Their Significance

Tests Indicating

Liver Cell Damage Marked Bile Flow Interference

Test Pathologic Level Test Pathologic Level

Cephalin cholesterol Above 2 + Urinary urobilinogen Less than 1.0 mg. 24

flocculation reduced hrs. or less than 0.5
U in 2 hrs.
Thymol turbidity Above 4 U Fecal urobilinogen Less than 10 mg. %
reduced
Albumin-globulin Below 1.25 Serum alkaline phos- Above 15 Bodansky
ratio phatase units
Cholesterol ester/ Below 50% Serum total choles- Above 300 mg. %
cholesterol ratio terol
Urinary urobilinogen Above 3 mg./24 hrs.
(elevated) or above 3 U in 2 hrs.
Hippuric acid
Oral test Below 3 gm.
Intravenous test Below 0.7 gm.
Non-protein nitrogen Above 40 mg.%
Plasma vitamin A Below 15 micrograms
Bromsulfalein Above 6% retention
in 45 min. after in-
jection of 5 mg./kg.

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 472 HANS POPPER AND FREDERICK STEIGMANN

which indicate liver cell damage; and (b) those which indicate marked im-
pairment of bile flow (table 2).
The classification in table 2 agrees to some extent with that recently
presented by Watson and Hoffbauer * in which the tests are divided as
indicating hepatocellular or cholangiolar dysfunction. Regurgitation jaun-
dice appears to be a cholangiolar disturbance resulting in back flow of bile
through the smallest bile ducts. The previously held view that dissociation
of the liver cell cords is responsible has been given up since the latter is
usually a postmortem phenomenon.22 Total serum bilirubin is elevated and
bilirubinuria is present in every regurgitation jaundice. Though, therefore,
hyperbilirubinemia and bilirubinuria appear to be due to cholangiolar dys-
function they are found in both types—in medical and surgical jaundice—
and obviously from the practical standpoint are not characteristic for either
group.
A decrease of prothrombin may be due to both exclusion of bile from
the duodenum and liver cell damage. The prothrombin test was therefore
omitted from table 2. Bromsulfalein retention may be due to both liver
cell damage and marked bile flow interference. However in the presence
of a mild degree of jaundice (the only time it was utilized in this series)
bromsulfalein retention was only due to the former. The level of total
cholesterol chosen is higher than the usually accepted pathologic borderline.
However, only the high levels indicate marked bile flow interference since
levels up to 300 mg. per cent are not infrequently found in other conditions.
The occasional reduction of total cholesterol in hepatitis was not taken into
consideration. A level of serum alkaline phosphatase between 4 and 15
Bodansky units is definitely pathologic in the adult. Such an elevation
is very commonly found in all types of medical jaundice 28 and therefore can
hardly serve as a differential diagnostic criterion between surgical and medi-
cal jaundice. Levels above 15 units have been selected since they are com-
monly seen in conditions in which a mechanical interference with the bile
flow can be demonstrated. Since the cause of the elevation of the alkaline
phosphatase level in jaundice is as yet not established, it is questionable
whether the levels between 4 and 15 units represent lesser degrees of bile flow
interference or liver cell damage. In contrast to the older concept that the
elevation is due only to reduced excretion of alkaline phosphatase in the bile,
increased formation in overstimulated pathologic liver cells has also been
claimed to be responsible.24'25'26'27
It is generally accepted that almost every one of the mentioned tests for
liver cell damage may yield false positive results. It was, therefore, felt
advisable to start under the assumption that liver cell damage is present in
a jaundiced patient only if at least two of the given tests were positive. For
the establishment of marked impairment of the bile flow in the presence of
jaundice, one positive test was considered necessary. The correctness of
these assumptions were attested by the results mentioned below.

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 MEDICAL AND SURGICAL JAUNDICE 473

FIG. 1. Diagram demonstrating the route of the thought processes in the differential
diagnosis between medical and surgical jaundice based primarily on laboratory examination.
The width of the individual lanes indicates the number of cases in each. "L" indicates tests
for liver cell damage; "B" tests for marked interference with bile flow.

On this basis, the cases studied were initially divided into three groups
(figure 1) :
(a) Those having liver cell damage without marked bile flow inter-
ference (L + B—) (151 cases).
(b) Those having marked interference with bile flow but no liver cell
damage (L — B + ) (34 cases).
(c) Those having both (L + B + ) (98 cases).
A. Cases with Liver Function Impairment but without Interference with
Bile Flow. A priori the cases of this group were considered as medical
jaundice.
1. Analysis of tests.
A variable number of the function tests indicating liver cell damage was
positive in each individual case. Four cases in which only one test was

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 474 HANS POPPER AND FREDERICK STEIGMANN

FIG. 2. Columns demonstrating the number of

cases in which liver cell damage was correctly
diagnosed by at least two of the listed tests. They
show the increase produced by taking into account
additional tests. The cases of the period 1941-
1943 (without thymol turbidity test) are separated
from those of 1946 and 1947 (with thymol turbidity
test).

positive had to be included on the basis of the clinical picture. In the over-
whelming majority, however, two or more tests revealed pathologic results.
Most commonly three tests were positive, rarely five or six, but never more.
It seems, therefore, that in the presence of jaundice one pathologic liver
function test may occasionally indicate liver cell damage, but that in general,
pathologic results in at least two tests should be required to indicate it.

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 MEDICAL AND SURGICAL JAUNDICE 475

It is not easy to decide which combination of tests is most helpful in

establishing liver cell damage, since in the cases examined 67 variations in
the results of the different liver function tests were encountered. The 147
cases with two or more pathologic liver function tests were divided into two
groups:
(a) 81 cases belonging to the previously described group I (without
thymol turbidity test).
(b) 66 cases belonging to group II in whom the thymol turbidity test
was performed.
Six tests were necessary (cephalin-cholesterol flocculation, albumin/
globulin ratio, cholesterol ester/cholesterol ratio, hippuric acid synthesis,
plasma vitamin A, serum non-protein nitrogen) for the inclusion of all cases
into Group I (figure 2). However, 72.8 per cent of the cases could have
been accounted for by the albumin/globulin ratio and cephalin-cholesterol
flocculation alone. The additional use of the cholesterol ester/cholesterol
ratio increased the percentage of correct diagnosis. In only a few cases were
additional tests needed.
In Group II also six tests were necessary to envelop all cases (cephalin-
cholesterol flocculation, thymol turbidity, albumin/globulin ratio, urinary
urobilinogen, cholesterol ester/cholesterol ratio and bromsulfalein retention).
The majority (76.2 per cent) were correctly classified by the cephalin-
cholesterol flocculation and thymol turbidity tests. The addition of the
albumin/globulin ratio substantially increased the percentage of correct
diagnosis (81.8 per cent) while additional tests were necessary in a few more
cases.

2. Evaluation of diagnostic results.

Of the 151 cases comprising this group (L + B —) 148 remained in the
medical jaundice group, while three proved to be surgical in nature repre-
senting patients with incomplete obstruction and associated liver damage in
whom none of the signs of marked bile flow interference were positive on
admission. Two factors were diagnostically helpful in directing these three
cases from the medical to the surgical group:
(a) Fluctuating urinary urobilinogen levels as found by repeated quali-
tative or quantitative determinations of urinary urobilinogen in two cases.
It is known that in calculous jaundice the urinary urobilinogen excretion may
vary on consecutive days or longer periods from diminished to highly ele-
vated levels.28'29 In one of these two cases a negative cephalin-cholesterol
flocculation was an additional support.
(b) A mass in the gall-bladder region, suggesting a hydrops of the gall-
bladder on the basis of cholelithiasis, directed the third case to the surgical
group.

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 476 HANS POPPER AND FREDERICK STEIGMANN

B. Cases with Marked Bile Flow Interference without Liver Cell

Damage. Cases characterized by marked interference with bile flow and
absence of significant liver cell damage belong primarily to the group of
surgical jaundice.
1. Analysis of tests.
In 35 cases, one or none of the tests for liver function impairment and
one or more of the tests for marked interference with bile flow were positive.
In the majority of the cases only one of the latter tests and only rarely all
four were positive. Marked bile flow interference was indicated in the ma-
jority of the cases by a markedly elevated alkaline phosphatase. The latter
test together with the absence of urinary urobilinogen accounted for almost
all cases in this group. Elevated total cholesterol levels added only a few re-
maining cases (figure 3). Demonstration of reduced fecal urobilinogen did

FIG. 3. Columns demonstrating the num-

ber of cases in whom marked interference
with bile flow was correctly diagnosed by
at least one positive test. They show the
increase produced by taking into account
additional tests.

not improve the grouping of these cases since fecal urobilinogen is usually
reduced when urinary urobilinogen is absent. This statement can be gen-
eralized with the exception of the rare cases in which severe renal insuffi-
ciency due to chronic glomerulonephritis with deficient filtration may cause
absence of urobilinogen from urine in the presence of urobilinogen in
stool.80'81 In 24 of these 35 cases, one of the tests indicating liver cell
damage was also positive. The test for liver cell damage most frequently
positive was reversal of the albumin/globulin ratio (11 times).
2. Evaluation of diagnostic results.
Of the 35 cases, 32 proved to belong to the surgical and three to the
medical group. One of two factors may divert such cases to the medical
side.

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 MEDICAL AND SURGICAL JAUNDICE 477
(a) History of Treatment with Arsenicals as Part of an Antiluetic
Therapy.
After such treatment jaundice may occur which is characterized by evi-
dence of biliary obstruction but absence of detectable liver cell damage.82
This represents a fairly acute condition in which both obstruction and nor-
mal liver cell function are seen at the onset of the disease. Of the three
cases in our material, belonging to this category, one had a pathologic hip-
puric acid synthesis, another a positive thymol turbidity, while in the third
case no indication for liver cell damage was found in any of the tests
performed.
(6) Cholangiolitic Cirrhosis.
According to Watson and Hoffbauer,33 after the defervescence of an
acute hepatitis with typical liver cell damage, a protracted condition of nor-
mal liver cell function but marked interference with bile flow may occur
which they designated as cholangiolitic cirrhosis. Such cases are recog-
nized by a careful history and evaluation of clinical and biopsy findings.
We had opportunities to study cases belonging to this category, but none
were observed long enough to be used in the present analysis.
C. Cases Revealing Liver Cell Damage and Marked Interference with
Bile Flow. In the material examined, there were 99 cases in whom at least
two of the tests indicating liver cell damage and one of the tests indicating
marked interference with bile flow were positive. Such cases, a priori,
could be due either to a primary involvement of the liver or to an extra-
hepatic biliary obstruction associated with liver cell damage. In such in-
stances, the results of the cephalin-cholesterol flocculation test served as the
key criterion. This test has been described as permitting differentiation of
surgical from medical jaundice in a relatively high percentage of cases since
it is, as a rule, negative in the surgical group. 10 ' 19 ' 34 ' 35 ' 36 ' 37

I. GROUP WITH NEGATIVE CEPHALIN-CHOLESTEROL FLOCCULATION TEST

The negative cephalin-cholesterol flocculation test directed 38 cases of

this group to the surgical side.
1. Analysis of tests.
In the majority of cases, only two of the tests indicating liver cell damage
were positive (figure 4 ) . The tests most commonly giving pathologic re-
sults were the albumin/globulin ratio, thymol turbidity and the cholesterol
ester/cholesterol ratio. In most of the cases, two or three of the tests in-
dicating marked bile flow interference were positive. In almost all of them,
the serum alkaline phosphatase was markedly elevated, while urinary uro-
bilinogen was absent in about two-thirds of the cases.

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 478 HANS POPPER AND FREDERICK STEIGMANN

2. Evaluation of diagnostic results.

The presence of liver cell damage in these cases which presented both
marked bile flow interference and negative cephalin-cholesterol flocculation
will first suggest a biliary hepatitis, i.e., liver cell damage produced by
protracted biliary obstruction.88'89 The development of biliary hepatitis
depends upon the degree and the duration of the obstruction and is, there-

FIG. 4. Number of patients (indicated by black column) with evidence of liver cell
damage and marked interference with bile flow, revealing pathologic results in a given
number of liver function tests. The cases are separated according to the results of the
cephalin-cholesterol flocculation test.

fore, more commonly seen in complete obstruction due to tumors than in

incomplete obstruction due to stones. This is also borne out by the inci-
dence in this series since 19 of the 33 cases remaining on the surgical side
were due to malignant obstruction. Common exceptions to the rule that a
negative cephalin-cholesterol flocculation is indicative of surgical jaundice
are about 30 per cent of the cases of toxic hepatitis.38 If in the latter, the
laboratory tests indicative of marked interference with the bile flow are
positive, these cases are presumptively directed into the surgical group.
However, evidence of a toxic etiologic factor should direct them to the

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 MEDICAL AND SURGICAL JAUNDICE 479

medical side. In problematic cases, the histologic picture as seen in biopsy

specimens may help in the differential diagnosis between toxic hepatitis and
extrahepatic obstructive jaundice. In our material five such cases were
met. Their histories revealed either exposure to arsenicals or sulfonamides,
acute alcoholism, or preceding pneumonia. In all these cases, two of the
tests for liver cell damage and one or two of the tests for marked bile flow
interference were positive. In two of them, the non-protein nitrogen was
elevated, as often seen in patients with toxic hepatitis.40

II. GROUP WITH POSITIVE CEPHALIN-CHOLESTEROL FLOCCULATION TESTS

Positive cephalin-cholesterol flocculation diverted 61 cases to the medical

side since a priori such cases should be considered as primary hepatitis with
marked interference with bile flow.
1. Analysis of tests.
In the majority of these cases (figure 4) three or four tests indicative
of liver cell damage gave pathologic results and in contrast to the previous
group often five or more were positive. In addition to the cephalin-choles-
terol flocculation, the albumin/globulin ratio, thymol turbidity and choles-
terol ester/cholesterol ratio were most often positive. In contrast to the
group with negative cephalin-cholesterol flocculation, marked bile flow inter-
ference was here primarily indicated by absence of urinary urobilinogen (46
out of 61), whereas the total serum cholesterol and serum alkaline phos-
phatase were less often markedly elevated.
2. Evaluation of diagnostic results.
Positive results of tests indicative of marked interference with the bile
flow (in the presence of liver cell damage) should first suggest intrahepatic
biliary obstruction as may occur in any type of acute (infectious or toxic)
hepatitis or of cirrhosis. This phenomenon, at least in certain stages of
hepatitis, is relatively frequent.33'41'42'43 However, there are certain ex-
ceptions to this assumption:
(a) Purulent Hepatitis.
In cases of extrahepatic mechanical biliary obstruction, either an ascend-
ing or more commonly a hemolymphatic infection of the portal triads may
lead to what has been called purulent hepatitis associated with liver cell
damage.38'44 This condition is not dependent upon duration or degree of
the obstruction but rather upon the presence of a complicating infection.
It is therefore more often a complication of benign rather than of malignant
obstruction, found especially in cholelithiasis and cholecystitis. In such
instances, the cephalin-cholesterol flocculation is or may become positive
in a case of surgical jaundice. Obviously, such conditions will at first fall
into the group of medical jaundice. They can be diverted to the surgical

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 480 HANS POPPER AND FREDERICK STEIGMANN

side, where they belong, by the clinical evidence of a bacterial infection, i.e.,
fever, chills and leukocytosis, and by the typical histologic picture of the
liver biopsy specimen. In our material nine cases were thus brought to the
surgical side, despite liver function tests similar to those of the medical
cases. One of those nine cases, despite the characteristic findings of a
septicemia, did not belong in the surgical group: it represented one of the
rare instances of a protracted cholangiolitis without obstruction but with
transition into cirrhosis. The results of the liver biopsy as well as the
fact that almost all tests indicating liver cell damage were positive brought
this case back to the medical side.
(b) Biologically false positive tests.
There are rare instances of biliary hepatitis without complicating infec-
tion which have a positive cephalin-cholesterol flocculation test and which
could possibly be considered as false positive. In two cases in our series
such possibilities arose. They or similar ones might be correctly diagnosed
by the palpatory findings in the abdomen (mass), signs of metastases, his-
tory of repeated attacks, roentgen-ray findings, etc.

EVALUATION OF TESTS INDICATIVE OF LIVER CELL DAMAGE

The follow-up of a large number of jaundiced patients with established

diagnosis permits an evaluation of the liver function tests. It has been
postulated above that in general at least two of the tests indicating liver cell
damage should be positive for such damage to" be entertained. This was
done because practically every one of the function tests used may occasionally
yield biologically false results; usually without available explanation. In
four of the examined jaundice cases, however, liver cell damage had to be
conceded because of clinical findings although only one of the tests for liver
cell damage was positive.
The question now arises which of the tests should be selected from
experience gained in practical use. Some information concerning this ques-
tion was provided by the results of function tests in the above discussed
smaller group of cases with liver cell damage but without marked bile flow
interference. Now, all cases showing positive results in at least two tests
indicating liver cell damage will be considered. These 246 cases were also
divided into the two groups mentioned: Group I in which the thymol tur-
bidity test was not performed and Group II in which this test was performed.
In 135 cases of Group II (table 3) a combination of the thymol turbidity
test with either the cephalin-cholesterol flocculation or the albumin/globulin
ratio permitted recognition of liver cell damage in two-thirds of the cases.
A combination of the cephalin-cholesterol flocculation plus the albumin/
globulin ratio permitted this in a slightly smaller number. In the above
percentages, results of other tests are not considered. If two positive results
in all three above-mentioned tests were accepted, 83 per cent of the cases

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 MEDICAL AND SURGICAL JAUNDICE 481
TABLE III
Percentage of Cases with Liver Cell Damage Correctly Grouped on Basis of at Least Two
Positive Tests for Liver Cell Damage, and the Increase in This Percentage
Due to Inclusion of Additional Tests
Cases Examined
With Thymol Turbidity Test Without Thymol Turbidity Test
Per Cent Per Cent
Cephalin-cholesterol flocculation plus
albumin/globulin ratio 61.7
Thymol turbidity test plus albumin/
globulin ratio 66.0
Cephalin-cholesterol flocculation plus Cephalin-cholesterol flocculation plus
thymol turbidity test 66.7 albumin/globulin ratio 69.4
Cephalin-cholesterol flocculation plus Cephalin-cholesterol flocculation plus
thymol turbidity test plus albumin/ albumin/globulin ratio plus choles-
globulin ratio* 83.6 terol ester/cholesterol ratio 84.7
The above tests plus cholesterol ester/ The above tests plus oral hippuric
cholesterol ratio 93.3 acid 92.8
The above tests plus urinary urobi- The above tests plus non-protein
linogen 98.5 nitrogen 97.3
The above tests plus bromsulfalein.. 99.2 The above tests plus vitamin A 98.2
The above tests plus oral hippuric acid 100.0 The above tests plus bromsulfalein.. 99.1
The above tests plus urinary urobi-
linogen 100.0
* For instance pathologic results in cephalin-cholesterol flocculation and in albumin/
globulin ratio but normal in thymol turbidity, or as another example all 3 being positive.

were correctly classified. The addition of the cholesterol ester/cholesterol

ratio, i.e., at least two positive results in four tests, raised the percentage
further to a significant degree. The additional consideration of the results
of urinary urobilinogen determination, bromsulfalein retention or hippuric
acid synthesis added only a few more cases. On this basis, it appears that,
in the vast majority of the cases, liver cell damage can be diagnosed with four
tests: cephalin-cholesterol flocculation, thymol turbidity, albumin/globulin
ratio and cholesterol ester/cholesterol ratio. However, for correct evalua-
tion of all of the cases in our material three more tests were necessary.
The great significance of the thymol turbidity test is indicated by com-
paring the above group with 111 cases of Group I which were observed
before the thymol turbidity test was available. In the latter cases, the
majority were "diagnosed" by the cephalin-cholesterol flocculation, the
albumin/globulin ratio, the cholesterol ester/cholesterol ratio and hippuric
acid synthesis whereas five additional tests were required to diagnose the
remaining four cases. In our material, therefore, the thymol turbidity test
reduced the number of other more complicated tests required to group the
cases correctly. Additional flocculation tests may possibly further reduce
the necessity for the more complicated tests and thus simplify the differential
diagnosis of jaundice.

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 482 HANS POPPER AND FREDERICK STEIGMANN

In no case were all tests indicative of liver cell damage positive (figure
5). In most instances, two to four tests were positive, whereas a higher
number was rarely encountered even in severe cases.

FIG. 5. Columns indicating the number

of cases in whom a given number of tests
indicative of liver cell damage were positive.
The cross hatched part of the columns repre-
sents patients in whom no thymol turbidity
tests were performed.

EVALUATION OF TESTS FOR MARKED BILE FLOW INTERFERENCE

One test denoting marked bile flow interference was considered sufficient
to indicate that phenomenon. On this basis, the latter was diagnosed in 134
cases. In one-third of them absence of urinary urobilinogen was the only
positive test; in combination with other tests, this absence was demonstrable
in two-thirds of the cases (table 4). Marked elevation of the serum alkaline
phosphatase alone was found in a relatively small percentage. If one positive
test in the determination of either urinary urobilinogen or of serum alkaline

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 MEDICAL AND SURGICAL JAUNDICE 483
TABLE IV
Percentage of Cases with Marked Interference with Bile Flow Correctly Grouped on Basis of
Single or Groups of Tests Denoting Marked Bile Flow Interference
Absence of urinary urobilinogen alone 29.8%
Serum alkaline phosphatase elevation alone 16.4%
Total serum cholesterol elevation alone 5.3%
All cases showing absence of urinary urobilinogen 67.1 %
All cases showing absence of urinary urobilinogen and/or elevation or alkaline phos-
phatase. 94.7%
All cases showing absence of urinary urobilinogen or elevated alkaline phosphatase or
elevated cholesterol or combination of them 100.0%

phosphatase or of both was used as criterion, almost all cases of this group
were accounted for. Only a few more were included because of a markedly
elevated total cholesterol. In only 17 per cent of the cases were all three
tests positive. The determination of the fecal urobilinogen added little in
this type of analysis.
COMMENT

This study attempts first to analyze the thought processes used in the
differential diagnosis of jaundice based primarily upon laboratory deter-
minations, and secondly, to evaluate the liver function tests from the prac-
tical point of view by deliberately giving less emphasis to their physiologic
meaning. The teaching of clinical diagnosis might be considered as the
presentation of analytic thought processes which lead over various "cross-
ings" to the correct diagnosis. In this study, an attempt was made to illus-
trate graphically such analytic thought processes in a case of jaundice
(figure 1). The main "crossings" were provided by (1) liver cell damage,
(2) marked interference with bile flow and (3) results of the cephalin
cholesterol flocculation reaction in the cases in which the two former were
positive. Further "crossings" were based on a history of exposure to hepa-
toxic substances especially the arsenicals—pointing to a toxic hepatitis.
Similarly, septic manifestations served to separate the purulent hepatitis with
positive cephalin-cholesterol flocculation from primary hepatitis with marked
interference with bile flow. The presence of an abdominal mass, or a his-
tory typical of biliary colics helped in the recognition of the cases in which
the cephalin-cholesterol flocculation reaction might be considered as biologi-
cally false positive. In some instances, the result of the liver biopsy may be
the only criterion directing the case into the right group.
As mentioned previously, we did not initially diagnose all cases cor-
rectly. Some were put in this schematic arrangement by hindsight rather
than foresight. Obviously, even in following the described lines, one may
not always reach the correct diagnosis at first.
In evaluating liver function tests, one should be aware of the fact that
almost every one of them may occasionally yield a pathologic result if done
on a large series of so-called normal controls. Such pathologic results have
to be considered biologically false positive since no other evidence for liver
function impairment exists, either on the basis of clinical or other laboratory

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 484 HANS POPPER AND FREDERICK STEIGMANN

examination. There is probably a biologic reason for the positive results

in such instances, but it is apparently not related to the liver. This reason
may be obvious in instances of pathologic albumin/globulin ratio or non-
protein nitrogen levels, but is usually obscure in the case of cephalin-choles-
terol flocculation or thymol turbidity. The term biologically false positive
is used in analogy with the sero-diagnosis of syphilis where it applies to
positive reactions in the absence of syphilis. According to the presented
concept, the cephalin-cholesterol flocculation reaction is negative in obstruc-
tive jaundice with and without biliary hepatitis, except in the purulent form.
It is positive in most types of primary hepatitis and cirrhosis. To allow for
biologically false positive results, consideration of an abdominal mass, or
typical history had to be introduced. Moreover, the possibility of biologi-
cally false positive tests was the reason for insisting on two positive tests
as indicative of liver cell damage. It should be stressed that not too often
were more than three tests for liver cell damage positive, even in quite
severe cases of hepatitis. Similarly only in relatively few instances were
all tests indicating marked bile flow interference positive.
The number of positive tests in a patient without consideration for their
individual physiologic basis is apparently of some significance. The higher
the number of positive tests the more marked is the liver cell damage. As
long as the physiologic basis for many of the tests remains obscure, such an
assumption may be helpful. Thus, for instance, in the group in which both
liver cell function and bile flow were impaired, the sub-group with positive
cephalin-cholesterol flocculation, which as a whole presents primarily medical
jaundice, had a much higher number of positive tests than the sub-group
with negative flocculation in which biliary hepatitis is prominent. In the
latter group more of the tests indicating marked bile flow interference were
positive, whereas in the former group, only urinary urobilinogen was absent
in most instances. Since this absence is only temporary, serial observations
of urobilinogen excretion would eliminate many cases from this group and
line them up with uncomplicated cases of medical jaundice which showed
only liver cell damage on admission.
There may also be biologically false positive results in the tests indicating
marked bile flow interference. Obviously, the total cholesterol may be
elevated due to reasons not connected with the jaundice and the serum al-
kaline phosphatase may be markedly increased, e.g., due to bone lesions.
However, these factors are readily recognized by clinical observation. In
the presence of jaundice, therefore, one positive test for marked bile flow
interference is sufficient, provided other disturbing factors are taken into
account.
In reviewing the entire material, one is struck by the frequent concur-
rence of both liver cell damage and marked bile flow interference (34.7 per
cent of the cases). This indicates that the usually held premise from which
this study also started, namely, that medical jaundice has only liver cell
damage, and surgical jaundice as a rule only marked bile flow interference

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 MEDICAL AND SURGICAL JAUNDICE 485

is incorrect in a significant number of cases. Of the medical cases, 26.3 per

cent were complicated by marked interference with the bile flow, something
of the nature of what has been previously called intrahepatic biliary obstruc-
tion. In the majority of cases with surgical jaundice (60 per cent) liver
cell damage was found. The latter was due in 47.5 per cent to biliary
hepatitis (secondary liver cell damage due to prolonged obstruction) and in
12.5 per cent to purulent hepatitis caused by bacterial infection of the portal
triads. Nevertheless, the above-mentioned premise proved to be a good
starting point for a diagnostic analysis.
On the basis of the material presented here, the performance of the fol-
lowing liver function tests can be recommended for the differential diagnosis
between medical and surgical jaundice: cephalin-cholesterol flocculation,
thymol turbidity, albumin/globulin ratio, cholesterol ester/cholesterol ratio,
urinary urobilinogen and serum alkaline phosphatase. To group all cases,
it may be advantageous to add the bromsulfalein retention and the hippuric
acid synthesis.
Obviously, more laboratory determinations than these considered in this
study are in clinical use, e.g., urinary and serum bilirubin, galactose tolerance
test, total serum protein (especially for control of therapy), urinary amino
acid excretion, prothrombin time and sedimentation rate. They give im-
portant information and may determine the diagnosis in some patients.
Most of them were determined in our cases, but were omitted from the
discussion for the sake of simplicity. It should also be stressed that only
the initial determination was taken into account and that, for instance, the
follow-up of the serum bilirubin concentration was not taken into considera-
tion. Similarly, the degree of alteration from the normal was not con-
sidered. Thus the thymol turbidity, although positive in a significant num-
ber of cases of surgical jaundice, seldom rises above 10 units in the latter
condition, in contrast to medical jaundice.
SUMMARY
It is attempted to present a schematic plan of the thought processes
applied in the differential diagnosis between medical and surgical jaundice.
It uses primarily laboratory findings but takes into account, to some extent,
clinical history and/or physical findings. It is based primarily upon the
recognition of liver cell damage and marked interference with the bile flow.
The cases revealing both are further subdivided by the results of the cephalin-
cholesterol flocculation test.
The analysis of these thought processes provides an opportunity for
evaluating the efficiency of the liver function tests for practical purposes
without emphasis upon their physiological basis. It appears that at least
two positive tests are necessary to establish liver cell damage, but only one
to recognize marked bile flow interference. Only rarely are all tests in-
dicating either of the two phenomena positive and the number of positive
tests appears to parallel the severity of the pathologic process.
The overwhelming majority of cases will be guided into the right direc-

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 486 HANS POPPER AND FREDERICK STEIGMANN

tion if cephalin-cholesterol flocculation, thymol turbidity, albumin/globulin

ratio, total serum cholesterol, and cholesterol esters, serum alkaline phos-
phatase and urinary urobilinogen are determined. The addition of the hip-
puric acid synthesis and bromsulfalein retention tests permitted, in the final
evaluation, correct grouping of all cases in this series.
The addition of the thymol turbidity test has markedly decreased the
need for the more complicated liver function tests in the differential diagnosis
of jaundice. It may, therefore, be expected that additional flocculation or
precipitation tests may further simplify the laboratory diagnosis of jaundice.

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