LATENT LIVER DISEASE IN PERSONS RECOVERED FROM CATARRHAL JAUNDICE
   AND IN OTHERWISE NORMAL MEDICAL STUDENTS AS REVEALED
              BY THE BILIRUBIN EXCRETION TEST

                       BY ARTHUR KORNBERG
    (From the Department of Medicine, University of Rochester School of Medicine and Dentistry
          and the Medical Clinics, Strong Memorial and Rochester Municipal
                  Hospitals, Rochester, New York)

              (Received for publication December 29, 1941)

The frequency with which chronic non-hemoly-
tic jaundice occurs in otherwise healthy young
persons is not commonly recognized, nor 'is it
usually appreciated how often an uncomplicated
attack of catarrhal jaundice is followed by residual
liver dysfunction which persists long after the
acute episode.
The present study was prompted by the acci-
dental discovery of a relatively large number of
medical students with chronic jaundice and a
history of a previous attack of catarrhal jaundice
in two of them. A group of persons long recov-
ered from catarrhal jaundice was investigated and
also a control group of persons presumably nor-
mal.  The bilirubin excretion test was used in all
cases because of its reliability in detecting lesser
degrees of liver dysfunction.

METHODS

Bilirubin excretion test. The method of Von Bergmann
and Eilbott (1,2) was used with modifications.  Bilirubin
(Eastman Kodak) was given under basal conditions in
a dose of 1.5 mgm. per kilogram of body weight.  No
untoward reactions were observed when fresh materials
were used.  A retention at 4 hours in excess of 15 per
cent was regarded as abnormal.

Bilirubin determination, qualitative and quantitative.
The photoelectrometric method of Malloy and Evelyn (3)
was used.  Hemolysis was avoided and analyses which
failed to check within 2 per cent were rejected.  The
Evelyn colorimeter manual gives the range of normal
serum values for direct bilirubin as 0.1 to 0.4 mgm. per
cent and for indirect (total) bilirubin as 02 to 0.7 mgm.
per cent.  The ratio of the direct to indirect bilirubin is
given clinical significance when elevated values occur.
The ratio is high (0.60 to 0.80) in obstructive jaundice,
intermediate (025 to 0.55) in diffuse parenchymal damage,
and low (0.15) in hemolytic jaundice.

Bromsulphalein excretion test.  A dose of 5 mgm. per
kilogram of body weight was injected intravenously and
a retention in excess of 10 per cent at 30 minutes was
regarded as abnormal. Galactose toleranre test. Forty
grams of the sugar were given orally; a urinary output
of more than 3 grams within 5 hours after ingestion was

regarded as indicative of liver damage.  Cholecystogram.
A dose of tetraiodophenolphthalein was administered
orally 18 and 12 hours before the test.  Fragility of red
blood cells to hypotonic solutions of sodium chloride.
The method of Waugh and Asherman (4) was used
with saline. Determinations were made with the Evelyn
colorimeter. Sedimentation rate. The Wintrobe method
was used.  Values from 0 to 9 mm. per hour were re-
garded as normal for males. Reticulocyte count. The
"wet" method was used.  A drop of capillary ear blood
was placed on a dry film of cresyl blue (in saturated
alcohol solution), and the reticulocytes in 1000 red blood
cells were counted.  The normal range was considered to
be 0 to 2.5 per cent. Urobilin. The Schlessinger reaction
was used for the qualitative determination of urobilin in
the urine.  A definite fluorescence in the filtrate was a
positive test. Urobilinogen. Ehrlich's aldehyde method
was employed for the detection of excess urobilinogen in
the urine. A red color in a dilution greater than 1: 10
was a positive test.  Vitamin A absorption test and plant
pigment determination.  The method of Chesney and Mc-
Coord was used.  Fish liver oil containing 7000 U.S.P.
vitamin A units for each kilogram of body weight was
given.  The vitamin A content of the blood was measured
by the McCoord and Luce-Clausen (5) modification of
the Carr and Price technique. The analysis for the
carotenoids or plant pigments (xanthophyll and carotene),
which was necessary for the correction of vitamin A
results, was done by the method of Clausen and Mc-
Coord (6).

RESULTS

1. Persons presumed to be normal.  For this
group, subjects were selected who gave no indi-
cation of liver dysfunction by history or physical
examination. They were in the younger age
groups and were recovering from minor surgical
operations.

The basal serum bilirubin concentrations which
were generally below 0.8 mgm. per cent are in
Table I, and the individual values during the ex-
cretion test are in Table 11. Of 22 persons tested,
95 per cent retained less than 15 per cent of the
injected bilirubin and 73 per cent retained less
than 10 per cent.  The sole person who retained

299

300 ARTHUR KORNBERG

~ 0.396*0.034 0.460 17
12.760fO.106 0.181 16
I 1.320f0.065 0.268 17
0.710f0.048 0.366 17
0.490f0.039 0.408 17
0.240f0.030 0.584 17

TABLE I

Distribution of basal bilirubin values in *sons presumed to
              be normal

Range:   0.114 mgm. per cent to 0.900 mgm. per cent
Mean concentration:         0.398 mgm. per cent
Standard deviation:         0.184 mgm. per cent

0.616f0.061
2.940f0.080
1.650f0.085
1.120f0.085
0.870f0.085
0.540f0.073

Serum bilirubin Number of - Per ant of total

0.408
0.109
0.212
0.312
0.402
0.506

mv. pc* cenl

0.000-0.199           3 10
0.200-0.399          11 38
0.400.599           12 41
0.600-0.799           2 7
0.8OO-O.999           1 4

Total 29 100

0.264
0.400
0.645
0.522
0.592
0.418
0.574
0.490
0.430
0.131
0.500
0.214
0.282
0.503
0.900

~~~~~~ ~~~~~ ~ ~

TABLE I1

Indidual bilirubin axretion test dues in *sons #e-
           sud to be normal
Per cent retention at 240 minutes

                    8.8
2.810 1.240 0.863 0.628 0.503 9.4
3.250 1.560 1.010 0.790 0.538 4.9
3.920 2.400 1.590 1.300 0.975 10.1
3.860 2.160 1.360 1.070 0.682 4.8
4.200 2.450 1.630 1.320 0.900 8.6
3.060 1.520 0.938 0.718 0.645 8.7
3.770 2.100 1.440 1.090 0.918 10.6
3.350 2.030 1.340 1.070 0.790 10.5
3.330 2.030 1.430 1.110 0.830 13.8
2.380 1.010 0.592 0.434 0.204 3.6
3.120 1.590 1.010 0.790 0.540 1.5
3.460 1.610 1.002 0.790 0.522 9.6
3.060 1.740 1.010 0.700 0.452 6.1
4.610 2.590 1.730 1.350 0.955 11.0
4.320 2.960 2.430 2.080 1.560 19.6

0.538.3.710 2.170 1.420 1.120 0.790 7.7

-
-

CWb2
num.
ber

-

1
2
3
4
5
6
7
8
9

10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29

0.347
0.330
0.420
0.247
0.214

-
-

4-

-

!am

5
29
28
31
16
16
14
13
13
20
14
23
19
23
20
33
25
23
24
22
20
20
7
5
5
9
10
14
21
-

2.060 1.080 0.760     0.450`
2.780 1.420 0.880     0.540
3.240 1.460 0.810     0.560

1.090 0.647 0.469
1.078 0.594 0.358

0.307
0.264
0.264
0.486
0.718

1.550 1.097 0.857
1.710 1.024 0.724
1.540 1.070 0.770
1.840 1.280 0.975
2.120 1.520 1.200

in excess of 15 per cent of the injected bilirubin
was the one who had the extreme basal bilirubin
value of 0.900 mgm. per cent.  Mean bilirubin val-
ues at various time intervals during the test are

TABLE 111

Man bilirubin excretion test values in

sons pesumed to

be wd and othcrs long recover $" from cutarrhai

jaundicc

The values at 0 minutes are the basal bilirubin levels.
Ci - CO = Concentration at time, "i," minus basal
bilirubin concentration, "0".  The mean bilirubin values
are followed by their standard errors.  The mean values
for the two groups were significantly different at each time
period except the one at 5 minutes.

min-
uus

0
5
30
60
90

240

"Normal" proup

"Post-catarrhal jaundice"
      POUV

Coef-


ation

29
22
29
29
26
22

in Table 111. Figure 1 contains a composite
curve of these mean bilirubin values, and Figure
2 shows the linear relationship which is obtained
when these values are plotted against the logarithm
of time.
2. Persons long recovered from catarrhal jaun-
dice.  The subjects for this group were chosen
completely at random from the hospital records
of adequately studied and confirmed cases of
acute catarrhal jaundice.  They were generally
children or young adults who, during their acute
episode of jaundice, had symptoms of malaise,
nausea, and abdominal pain.  There was a sudden
onset of jaundice which often coincided with
symptomatic improvement. A familial incidence
was noted in half of the cases.  Fever, hepato-
megaly, leukopenia with an increase in the per-
centage of mononuclear cells, bilirubinuria, and
acholic stools were found in most cases.  Hyper-
bilirubinemia was always present with an imme-
diate direct van den Bergh reaction when tested.
Treatment was symptomatic and recovery in each
case was rapid and uneventful, with a prompt fall
of the serum bilirubin level to near normal limits.

Individual serum bilirubin values during the
excretion test are shown in Table IV, and the
mean values in Table 111.  The latter have been
shown to differ significantly from those for the
"normal" group.  Of 16 persons tested, 63 per
cent retained more than 15 per cent of the in-

LATENT LIVER DISEASE

301

2

I-
f
W
c-
W
p:

k
2
w
0

W
a.

0

a

e CHRONIC NON-HEMOLYTIC JAUNDl CE
o CATARRHAL  JA U N DIC E
o NORMAL

a I I a I I I

60 12 0 180 2h

. TIME. (MINUTES)


EXCRETION TEST

FIG. 1.  COMPOSITE CURVES OF MEAN SERUM BILIRUBIN VALUES DURING THE

jected bilirubin and 95 per cent retained more
than 10 per cent.  Composite curves for the data
in Table I11 are in Figures 1 and 2.

Among the 10 persons who showed an abnormal
bilirubin excretion curve, a history at the time of
the test revealed 4 with symptoms suggestive of
liver dysfunction (Cases 30, 33, 40, 45), 3 with
only vague abdominal pains or anorexia (Cases 35,
37, 44), and 3 without any symptoms (Cases 31,
32, 36). The pertinent clinical data of 5 of
these 10 patients are presented here.

Care 30.  A 12-year-old boy has been followed in the
pediatric clinic since the age of 6 years for enuresis, habit
spasms, and temper tantrums.  His father has a convul-
sive disorder, and the home environment is unstable.  In
October 1940 he had an attaclc of catarrhal jaundice and
was discharged after 5 days.  In the Out-Patient Depart-

ment he complained of anorexia, fatigue, malaise, right
upper quadrant tenderness, and mild epigastric pain.
Four months after discharge he was readmitted to the
hospital for severe paraumbilical pain, nausea, vomiting,
marked distension, and foul flatus. The only positive
findings were a flat glucose tolerance curve and an ab-
normal excretion of bilirubin despite normal basal bili-
rubin values.  Supportive care eased the symptoms, and
he was discharged with the diagnosis of aerophagia.  He
continued to be irritable, became fatigued easily, and
complained of diffuse abdominal pain, nausea, flatulence,
headaches, and severe constipation.  Two weeks later he
returned to the hospital with frank jaundice, an enlarged
tender liver, and a readily palpable spleen.  Again com-
plete hematological, chemical, and x-ray studies were
entirely negative, except for a basal bilirubin level of 122
mgm. per cent and a bilirubin retention of 41.8 per cent.
Other tests of liver function were repeatedly negative.
After a 2-week dietary regime of low fat and high car-

302

10-

ARTHUR KORNBERG '

\*

FIG. 2. COMPOSITE CURVES OF MEAN SERUM BILIRUBIN VALUES DURING THE
     EXCRETION TEST PL~ AGAINST THE LOGARITHM OF TIME

bohydrate and protein intake, he was discharged as
improved.
Caw 31. This 49-year-old laborer had catarrhal jaun-
dice in August 1940.  A gastro-intestinal series revealed
a tender, incompletely filled duodenal cap; other studies
were negative.  Eight months later his basal bilirubin
level was 122 mgm. per cent with a D/I (direct : indi-
rect) ratio of 0.38 and a +hour bilirubin retention of 47.8
per cent.  His liver was firm and palpable 5 an. below
the costal margin, but he was asymptomatic.  He admitted
moderate alcohol ingestion.

Case 33.  This *year-old male has been studied in
this clinic since the age of 14.  His most frequent com-
plaints were malaise and shifting abdominal pains.  In
September 1938 he was hospitalized for a 2-day episode
of unexplained diarrhea with high fever and in April
1940 for catarrhal jaundice.  Three months later he re-
turned to the Out-Patient Department with complaints of
epigastric distress and flatulence. A gastro-intestinal
series revealed a slightly irritable cap.  The diagnosis was

psychoneurosis.  One year after his episode of jaundice,
he still complained of malaise, anorexia, flatulence, irri-
tability, and persistent pain in the upper abdominal quad-
rants.  The basal bilirubin level was 0.860 mgm. per cent
with a D/I ratio of 0.31 and a 4-hour retention of 21.1
per cent.  A gallbladder series was normal.

Case 40.  This 29-year-old hospital orderly had catar-
rhal jaundice in September 1939.  He had residual belch-
ing, flatulence, abdominal distension, and a dull achihg
pain in the right upper quadrant.  He could obtain no
medical relief and resorted to herb remedies. He felt
irritable and tired, and drank moderate amounts of al-
cohol.  One and a half years after his jaundice, the basal
bilirubin level was 0.520 mgm. per cent, and he still re-
tained 182 per cent of the injected bilirubin at 4 hours.
His liver was tender and palpable 2 cm. below the costal
margin.

Care 45.  This 16-year-old boy had catarrhal jaundice
in February 1938.  He visited the Out-Patient Depart-
ment a few months after his recovery with complaints

LATENT LIVER DISEASE 303

I years

11

49
10
19
12
23
13
15
20
13
29
7
8
15
11
15
22

TABLE IV

    Indidual bilirubin excretion test values in persons long recover& from catarrhal jaundice, March 1941
The basal bilirubin values ranged from 0.264 to 1.280 mgm. per cent with a mean value of 0.616 mgm. per cent and a
                 standard deviation of 0.252 mgm. per cent.

I months Imgm.ww

Casenumber

Interval

since catarrhal 1
jaundice o minuter

Age

30(2/2)
(217)
(311)
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46

4

5
8
10
11
13
13
13
14
16
16
18
23
25
24
26
38
42

0.628
0.503
1.280
1.220
0.682
0.863
0.332
0.660
0.660
1.010
0.682
0.522
0.520
0.400
0.231
0.574
0.264
0.503
0.556

5 minuter

m#m. &r unl

3.040
3.360
5.090
4.170
3.950
3.980
2.990
3.550
3.120
3.740
3.430
3.400
3.710

2.490
3.580
2.870
3.660
3.630

of fatigue, abdominal and chest pain, headaches, severe
constipation, and inability to attain his former proficiency
at school. Three years later the basal bilirubin level was
0.503 mgm. per cent, and he retained 16.1 per cent of
the injected pigment at 4 hours.  The above mentioned
symptoms were persistent.

3. Persons with chronic non-hemolytic jaundice.
This group consists of 7 medical students and 1
graduate chemistry student (Case 54).  It arose
as a result of casual observations of less than
100 medical students and a selection of those who
appeared to have an icteric tint to their sclerae.
The laboratory studies of these individuals re-
vealed the basal bilirubin level to be consistently
elevated over a period of many months with a van
den Bergh reaction indirect in type.  The bili-
rubin excretion was markedly retarded in every
instance, and in several individuals other tests of
liver function yielded positive results.  The hema-
tological, x-ray, blood chemical, and urinary studies
were uniformly negative.  In Table V are the
assembled data for this group, and in Figures 1
and 2 the composite bilirubin excretion curves are
shown.  Figure 3 contains the results of vitamin
A absorption tests.'

1At present a further group is being investigated.
Among the first and second year medical classes, com-
prising approximately 120 persons, routine icterus indices

Saum bilirubin

30 minutea

rim. iter ccd
2.490
2.360
3.920
3.180
2.890
2.780
1.590
2.540
2.030
2.910
2.120
2.030
2.240
1.360
1.320
2.260
1.710
2.380
2.260

60 minuter

cgm. prr unl
2.030
1 .860
3.520
2.870
2.300
2.100
0.992
1.930
1.690
2.570
1.400
1.420
1.820
0.920
0.920
1.510
1.240
1.670
1.630

90 minuter

atm. 9n ulrl
1.950
1.580
3.220
2.490
1.970
1.990
0.808
1.660
1.380
2.400
1.180
1.190
1.380
0.770
0.700
1.190
1.010
1.460
1.440

~~~

240 minuter

vtm. pcr rarl

1.560
1.200
2.870
2.630
1.360
1.520
0.610
1.140
1.180
1.650
1.030
0.881
1.100
0.522
0.452
0.937
0.736
1.010
0.937

Per cent
retention
at 240 min.

37.6
24.5
41.8
47.8
20.8
21.1
10.5
16.6
21.1
23.4
12.7
12.8
18.2

9.7
12.3
18.2
16.1
12.4

Some interesting data were obtained from chi-
d histories and physical examinations of these 8
individuals and they are summarized here.

Care 47. This 26-year-old male had catarrhal jaundice
in September 1938.  His icterus index upon discharge was
18 units. In October 1939 he had unexplained abdominal
cramps and diarrhea for several days and a palpable liver
and spleen. In October 1940 his basal bilirubin level
was 1.5 mgm. per cent, he was asymptomatic, and his
liver and spleen were no longer palpable.

Case 48.  This 25-year-old male, at the age of 8, had
the "yellow jaundice."  At the age of 17 he was exposed
to carbon tetrachloride for 6 weeks, while working in a
cleaning plant.  He had drunk raw milk, and his -agglu-
tinin titre for Brucella melitensis was 1 : 80 in 1938.  In
1939, he had a tuberculous pleural effusion with recovery,
following a year of sanitorium care.  Subicteric sclerae
were noted in January 1940.  In October 1940 his basal
bilirubin level was 1.36 mgm. per cent.

Care 49.  This 29-year-old male recalled having had
"dirty-looking" eyes for many years.  At the age of 19
he worked in a gasoline filling station for one year.
At 21 years he had acute appendictis, generalized peri-
tonitis, pelvic abscess, and finally recovered without re-

revealed 10 with elevated values. Bilirubin excretion
tests on 6 of these persons, performed by Dr. E. B. Mil-
lard, Jr., demonstrated basal bilirubin values of 1.45, 1.59,
1.62, 1.63, 1.67, and 1.75 mgm. per cent with 4-hour
retention percentages of 792, 70.7, 58.9, 70.9, 31.5, and
47.9 respectively.

TABLE V

&sults of tb bilitubin w&h kt ad other stdics in prisons raith chronic nim-hcmdjrlic jaundice, March 1941

Ill I

ub

1.m

1.a

1440

1m

1.910

2.680

2.m

am

06
mtn-mb
   uor

--

rqrrmm.
#rv-
WCd

1.W

1.600

4.m

6.W

4.980

ldob

6.lM

0.100

pb mlt
rstsntian

I

24
born

-

a4

19.4

27.2

6.0

2S.O

17.6

soox)

46.2

mu
PI pl
oal OJ

0.486 0.87 0.638 0.01 0

0.418 0.8 0.7@ OB 6

a623 0s 0.808 0.aa 0

am 0.20 om O.M 4

0.770 0.40 0.610 038 0

0.790 0.88 0.7S8 0.28 0

0.918 OS 0.100 0.16 0

0.718 0.22 0.W 0.11 0

.----

pum
PIlV
daw

0.0 6.2 43

0.w 6J k.4

430 Nod 6.8 6.1

2m 6.a 4.a



2.00 NO-I 7.a 4.2



a.w  NO^ 7.s 6.4

430 Nod 65 43

1.86 Nod 6.7 4.6

-

3

51
4

3-8
BS

-

a.a



a.2

21

2.2

1.8

1.a

20

2.7

-

I
E

--

-0lOu
PIW
OJOJ

M 0344

as 0670

aa Osul

a4oJw

M om

ai 0.m

m om

8 om

--

    v-
    o*u

Nod 0.1

Nod

Nod

Nod 14

 NO^ 1.11



 NO^ 0.a

Nod 2.S

--

L.

--

Nod 0

Nod

Nod 0

Nod

Nod 0

Nod 0

Nod 0

Nd 0

LATENT LIVER DISEASE

305

--.-CASE 49
-0- '1 50
-0- II 51
-A- 'I 52
-0- !I 53
-x- 54
- --A--- NORMAL CHILDREN
--*--NORMAL ADULTS

--------- - ---

4

* I EVELYN PHOTOELECTRIC UNIT = APPROXIMATELY 3.1

INTERNATIONAL UNITS

FIG. 3.  VITAMIN A ABSORPTION TEST

sidua. Subicteric sclerae were noted in 1939. In OC-
tober 1940 his icterus index was 14 units.
Care 50. This 26-year-old male had jaundice neo-
natally and once or twice in childhood.  Since 1938 he
has had flatulence, constipation, occasional vomiting, and
generalized discomfort after eating.  These symptoms are
aggravated by emotional upsets.  He has chronic sinusitis.
In October 1940 his icterus index was 14 units.

Care 51. This 25-year-old male had typhoid fever at
5 years.  The icteric tint of his sclerae was noted in
October 1940.  In March 1941 his liver was tender and
palpable 3 cm. below the costal margin.  He complained
of occasional drawing right upper quadrant pains. A
maternal grandmother died of obstructive jaundice.

Care 52.  This 25-year-old male at 16 years aspirated
a mercurial solution.  This was followed by severe diar-
rhea for several days and then recovery.  At 19 he had
an appendectomy for chronic abdominal pain with some

relief. At 20 a physician casually observed his sclerae
to be yellow. The jaundice has been more notable during
exacerbations of sinus disease.  In April 1940 his icterus
index was 22 units. All diagnostic procedures directed
at the etiology of his jaundice during a hospital study
were negative. Blood bilirubin levels of his family
showed normal values for all but his mother, who had
a level of 126 mgm. per cent with a D/I ratio of 0.36.
A maternal grandmother died of hepatic cirrhosis at 72
years after a lifetime of jaundice.2

Case 53. A 23-year-old male, whose jaundice was
noted in November 1939, had at that time an icterus in-
dex of 14 units.  He complained of flatulence, a partial

2A bilirubin excretion test in November 1941 revealed
a basal value of 225 mgm. per cent with a 4-hour reten-
tion of 64.3 per cent as compared with 612 per cent in
March 1941.

306

years
60
18
15
59
44
65

i 57
67
10

~ 55

I 36

ARTHUR KOPNBERG

mm.m

Unl
5.920
1.390
1.230
1.990
1.820
1.500
1.860
6.790
2.440
1.910
1.650

TABLE VI

Indwidwd bilirubin cze*ction tcsf ducs in pcrsons with miscellaneous condirions

mcm.prr

cml
5.310
1.080
0.753
1.300
1.360
0.968
1.320
6.200
1.850
1.400
1.090

61
62
64
65
66
67
68
69
70
71
72

mcm.$er

cad
5.190
0.920
0.592
1.090
0.992
0.835

m8m.W
UrJ

4.980

0.556
0.880
0.863

Carcinoma of pancreas
Hodgkin's disease
Lymphosarcoma
L phosarcoma
Cgnic lym hatic leukemia
Chronic myefqenous leukemia
Carcinoma of liver
Portal cirrhosis
Portal cirrhosis
Paroxysmal hemoglobinuria
Hepatitis, convalescent

1.140
5.880
1.610
1.090
0.937

mm. PII

4.550
0.538
0.366
0.500
0.503
0.468
0.592
4.840
0.736
0.418
0.592

cad

5.340
1.260
0.881
0.825

intolerance to fatty and fried foods, occasional shifting
abdominal pains, and several episodes of unexplained
diarrhea.  Icterus levels were followed closely during the
next year and varied between 10 and 20 units.  Repeated
x-rays of the gallbladder and intestinal tract, and hema-
tological and blood chemical studies were negative.  His
mother died of an operative complication of cholecystec-
tomy for chronic cholecystitis and cholelithiasis.  A sister
has symptoms of gallbladder disease.  A maternal aunt
had a cholecystectomy many years ago and is jaundiced
at present.

Case 54. Jaundice was discovered in this 24-year-old
male during the routine blood chemical studies of indi-
viduals doing research with arsenical gases.  Traces (1
gamma or less) of arsenic were found in the urine, hair,
blood seruxn, and cells.  Cadmium appeared as a trace in
the urine, in a concentration of 3 gamma in the hair, and
10 gamma per cc. in the blood serum.  He remembered
volatilizihg cadmium and sulphur in a crucible 1 year ago.
There was no known exposure to free arsenical fumes.

4. Persons with miscellaneous conditions.  The
bilirubin excretion test was performed on a varied
group of persons suspected of liver dysfunction.
Positive results were obtained in 1 person with
chronic leukemia, 2 persons with portal cirrhosis,
and in 1 person with paroxysmal hemoglobinuria.
Bilirubin excretion within normal limits occurred
in 2 persons with lymphosarcoma and in 1 person
recovering from jaundice coincident with pneu-
monia.

DISCUSSION

Observations of 29 presumably normal indi-
viduals indicate that the basal serum bilirubin
level is generally below 0.8 mgm. per cent.  Bili-
rubin injected in a dose of 1.5 mgm. per kilogram

5
minuter

rynr. *

raJ
6.920
2.170
2.490
3.300
2.700
2.610
2,990
7.180
3.920
2.780
3.090

of body

Serum bilirubin

30 I 60
minutea   minuter

90 1 240

minuter minutcr

Per qnt

rrtcntlm
at 240
minute#

18.2

8.2
13.5
16.3

21.4
16.4
19.5
9.6

weight is excreted by these subjects in

a relatively uniform way, the retention at 4 hours
after injection never exceeding 15 per cent.  A
comparison of these results with those in the
literature is difficult because of the diverse tech-
niques employed.

A group of individuals, otherwise random, who
were long recovered from a well-studied attack of
catarrhal jaundice, differed significantly from these
nod subjects.  Of 16 individuals tested, 10
gave evidence of abnormal excretion of bilirubin
and 4 of these 10 described symptoms of liver
dysfunction, which prior to the test had been
unexplained.  Their complaints were vague ab-
dominal pains, flatulence, anorexia, and general
malaise. Hepatomegaly and jaundice occurred in
several individuals. These laboratory and clinical
findings are in close agreement with those de-
scribed by Kalk (7) and Soffer (8) and sene to
emphasize, along with the more recent concept of
the pathogenesis of catarrhal jaundice, that this
disease is not so completely benign as it is com-
monly regarded.  Rather it is seen that long-
lasting impairment of liver function, often asso-
ciated with a suggestive symptom complex, is a
frequent residuum of an uncomplicated episode of
catarrhal jaundice.

Eight cases of chronic non-hemolytic jaundice
were discovered in a small body of medical stu-
dents.  Comparable experiences have been de-
scribed by others. Polack (9) found 8 cases of
jaundice in young persons which he ascribed to
chronic hepatitis resulting from antecedent acute

LATENT LIVER DISEASE 307

episodes. Meulengracht (10) saw 24 persons be-
tween the ages of 15 and 30 years who had mild
chronic jaundice.  He regarded the abnormality
as a benign hepatic disorder rather than hemolytic
jaundice, chronic hepatitis, or "physiological hy-
perbilirubinemia."  A high incidence of medical
students and physicians was noted in these groups,
and it was attributed to the greater acuity of these
persons in detecting slight degrees of jaundice.

A careful study of the individuals in the present
series revealed a uniformly marked inability to
excrete intravenously injected bilirubin. Galac-
tose was excreted in excessive amounts in several
members of the group, and one subject was unable
to absorb ingested vitamin A.  Bromsulphalein,
x-ray, hematological, blood chemical, and urinary
studies were negative. The etiology and the pre-
cise nature of these disorders are not clear. Prob-
ably they are examples of low-grade parenchymal
dysfunction which have arisen from one or sev-
eral causes, such as exposure to poisons or inflam-
matory disease.

Soffer (11) and others have stated that the
bilirubin excretion test is contraindicated in the
presence of hyperbilirubinemia, because of the
manifest inability of the individual to excrete
bilirubin. While these theoretical objections may
possibly hold in purely obstructive types of jaun-
dice, they do not apply with equal force to other
types of jaundice.  In the present study useful
information has been derived from the application
of the test to persons with low-grade chronic
non-hemolytic jaundice. Methods of calculation
(Weech et d., 12) designed to eliminate the ef-
fect of elevated basal bilirubin levels, yield results,
in this group of individuals, which do not differ
from those reported here with the use of the con-
ventional retention formula, originally proposed
by Von Bergmann and Eilbott ( 1,2).  Also there
are several reports (13, 2, 7, 14) of normal ex-
cretion in the presence of jaundice.

Von Bergmann and Eilbott found the rate of
bilirubin excretion to be proportional to the con-
centration in the blood at any particular time.
This relationship was not obtained from the pres-
ent data.  From the linear relation of the serum
bilirubin values to the logarithm of time (Figure
Z), it can be inferred that within limits the excre-
tory rate varies inversely with time.  Although

simple, this relation gives little information about
the kinetics of bilirubin removal.
Weech et d. (12) propose a formula for the
measurement of bilirubin excretion based on the
assumption that within certain defined limits the
excretory rate is approximately proportional to
the square of the plasma concentration.  This for-
mula was applied to the data of the present in-
vestigation, and the results were compared with
those obtained with the conventional retention
formula. The coefficient of correlation, "r"
(product moment), for the entire body of data
was 0.68 and that for the group with chronic non-
hemolytic jaundice, separately, was 0.86.

Dragstedt and Mills (15) in studying the re-
moval of intravenously injected bilirubin in dogs
were puzzled by the low concentrations present in
the serum 5 minutes after injection.  They ob-
tained only 40 per cent of the concentration calcu-
lated to be there if the material were distributed
solely in the plasma, whereas in the present studies
of human subjects these 5-minute values were
usually close to 100 per cent.  These workers
(16) also concluded as a result of reticulo-endo-
thelial cell blockade experiments in dogs, that
bromsulphalein retention occurred whenever jaun-
dice was present.  However, the group of indi-
viduals with chronic non-hemolytic jaundice in
this study showed no pathological retention of
bromsulphalein.

CONCLUSIONS

1. Persons long recovered from catarrhal jaun-
dice show an abnormal retention of bilirubin and
possess symptoms of liver dysfunction in a con-
siderable percentage of the cases.
2. Chronic non-hemolytic jaundice occurs in
otherwise healthy young persons much more fre-
quently than has been commonly recognized.
3. Presumably normal persons have basal bili-
rubin values which fall within a narrow range
and excrete intravenously injected bilirubin in a
relatively uniform way.
4. The bilirubin excretion test is a reliable and
sensitive test of liver function.

I wish to express my gratitude to Professor William
S. McCann whose encouragement made this work pos-
sible. I am also indebted to Mr. A. V. Wolf for his
helpful advice throughout the course of this work.

308

ARTHUR KORNBERG

BIBLIOGRAPHY

1. Von Bergmann, G., Zyr Funktionellen Pathologie der
  Leber insbesondere der Alkohol-Atiologie der Cir-
   rhose.  Klin. Wchnschr., 1927, 6, 776.

2. Eilbott, W., Funktionspriifung der Leber Mittels
  Bilirubinbelastung. Ztschr. f. klin. Med., 1927,
  106, 529.

3. Malloy, H. T., and Evelyn, K. A., The determination
  of bilirubin with the photoelectric colorimeter.  J.
  Biol. Chem., 1937, 119, 481.

4. Waugh, T. R., and Asherman, E. G., The use of an
  index of hemolysis in expressing the fragility of
  erythrocytes. J. Lab. and Clin. Med., 1938, 23, 746.

5. McCoord, A. B., and Luce-Clausen, E. M., The stor-
  age of vitamin A in the liver of the rat.  J. Nutri-
  tion, 1934, 7, 557.

6. Clausen, S. W., and McCoord, A. B., The determina-
  tion of carotene and xanthophyll by a single dis-
  tribution between liquid phases.  J. Biol. Chem.,
  1936, 113, 89.

7. Kalk, H., Klinische Untersuchungen iiber die Frage
  des latenten Leberschadens. I. Untersuchungen mit
  der Bilirubinbelastungsprobe beim Ikterus Catar-
   rhalis. Deutsche med. Wchnschr., 1932, 58, 1078;
  11. Klinische Untersuchungen bei den sogenannten
  Hepatopathien ~ch iiberstandenem Ikterus Catar-
  rhalis. Ibid., 1932, 58, 1119.

8. Soffer, L. J., and Paulson, M., Residual hepatic dam-
  age in catarrhal jaundice as determined by the
  bilirubin excretion test.  Arch. Int. Med., 1934, 53,
   809.

9. Polack, E., Chronic hepatitis in young persons with
  or without intermittent jaundice.  Acta med. Scan-
  dinav., 1938, 93, 614.

10. Meulengracht, E., Icterus Intermittens Juvenilis
  (Chronischer Intermittierender Juveniler Subik-
  terus). Klin. Wchnschr., 1939, 18, 118.

11. Soffer, L. J., and Paulson, M., Comparative advan-
  tages and further modifications of the bilirubin
  excretion test for hepatic function. Am. J. M. SC.,
  1936, 192, 535.

12. Weech, A. A., Vann, D., and Grillo, R. A., The
  clearance of bilirubin from the plasma.  A meas-
  ure of the excreting power of the liver.  J. Clin.
  Invest., 1941, 20, 323.

13. Damashek, W., and Singer, K., Familial nonhemolytic
  jaundice. Arch. Int. Med., 1941, 67, 259.
14. Lm, H., and Eastman, N. J., The behavior of intra-

venously injected bilirubin in newborn infants.
Am. J. Obst. and Gynec., 1937, 33, 317.

15. Dragstedt, C. A., and Mills, M. A., The removal of
  intravenously injected bilirubin from the blood
   stream in the dog. Am. J. Physiol., 1937, 119, 713.

16. Dragstedt, C. A., and Mills, M. A., Bilirubinemia and
  bromsulphalein retention.  Proc. SOC. Exper. Biol.
  and Med., 1936, 34, 467.