Liver function tests in the differential diagnosis of jaundice

Liver Function

Tests in the Differential

Diagnosis T.

of Jaundice*

L. ALTHAUSEN,

M.D.

San Francisco, California

I

N a paper Meeting

read before the 1946 Annual of

Association

clinical

the the

diagnosis

attention

American author

with

TABLE OF CASES

struction

ObstructiveJaundice Common duct stone.. . . . . Carcinoma of the pancreas.

effective

39 44

. . .

and

2

-

Hemolytic Jaundice Congenital hemolytic

icterus

very

42 3

. .

. .

.

-

.

..

190

The present paper is devoted

discussion

of the value of various laboratory

and

contains

diagnosis

an analysis

cases

is

is placed

between

obstructive

jaundice.

Hemolytic

operation

is rarely

jaundice.

on the

considered.

biliary

In addition

findings which,

are characteristic These findings

of hemoare: An

large amounts of urobilinogen in the urine, “indirect” reaction with the qualitative Van

to a

den

Bergh

test,

and

an increased

reticu-

locyte count in the blood.

of jaundice

of 190

treatment

icteric index under 50 units, a normal amount of bile pigment in the stools, absence of bilirubin with the presence of

2

patients.’

tests in the differential

ill so that

in the aggregate, lytic

102

. . ......

is the only

in cases of par-

surgical

there are several laboratory

47 5 3 1

Total

parenchymatous

passages

1

. .

jaundice

of

jaundice is uncommon and patients suffering from chronic hemolytic icterus are not

86 ParenchymatousJaundice Portal cirrhosis. . . . . . . Biliary cirrhosis. ... . Xanthomatous biliary cirrhosis. . Acute hepatitis. . . . Drug toxicity. . . . . Acute yellow atrophy of the liver. Primary carcinoma of the liver

anastomosis

whereas

on the differentiation

1

.

Stricture of the common duct.

of the ob-

to the duodenum

treatment,

lies in

jaundice

for removal

useless and contraindicated. In this discussion the emphasis

OF JAUNDICE

..

patient

or for a palliative

enchymatous TO TYPES

in a given

operation

the gallbladder

from of 100

I

ACCORDING

Lymphosarcoma . . .

surgical

special

examination

present

the fact that in cases of obstructive

the

to the value of data obtained

the history and physical DISTRIBUTION

Medical

discussed

of jaundice

jaundice

Liver

in

function

two classes.

which the diagnosis was definitely established by operation, autopsy or clinical course. (Table I.) The conventional classification of jaundice into “hemolytic,” “obstructive,” and “parenchymatous” types according to the original cause ‘of jaundice is followed in this paper.2 The importance of making a differential diagnosis at least as to the type of

so-called

In

tests can be divided the

“excretory”

first class

into

belong

the

tests in which a patent

biliary system is necessary for the normal outcome of the test. An example of this class is the Rose Bengal dye excretion test. In the second class belong the so-called “metabolic” tests which are independent of the state of the bile passages. An example of this class is the galactose tolerance test.

* From the Division of Medicine, University of California Medical School, San Francisco, California. the First Mexican Congress of Medicine, Mexico City, August 4-10, 1946. 208

AMERICAN

JOURNAI.

OF

Read before MEDICINE

209

Liver Function Tests-Athausen In the differential we can

rule

excretory

out

liver

qualitative

diagnosis at once

function

Van

indicates

except

test. The

the liver to excrete bilirubin

is impaired

for this reason

expect

excretion

of other substances

used to estimate must leave

hepatic

various substances

common The

tinguishes which

enters

to excrete

this may be block of the changes

den ,Bergh test dis“indirect”

the blood cells

and

from

bilirubin the reticulo-

“direct”

bilirubin

which enters the blood with the bile, having previously been excreted by the liver. In hemolytic jaundice which is caused by excessive

hemolysis

“indirect” because reaction

for

this

many

During

the hepatic liver

overproduction test

of

is of value

in most cases it gives the “indirect”

enchymatous the

and

bilirubin

jaundice.

weeks the

jaundice

after

early

qualitative

For

diagnosis

to

this reason

Van den Bergh

the differential

the “direct” the

test is useful for of jaundice

the first week of jaundice,

only

except

in

jaundice. underlying

the use of met-

abolic liver function tests in the differential diagnosis of jaundice is that in obstruction of the common chyma forms

bile duct the hepatic

is usually of acute

intact

cells resulting necrosis.

whereas

or chronic

paren-

in various

hepatitis

there

lesions in the hepatic

in more

or less widespread

On the basis of this principle,

in

an ideal case we should with the use of any metabolic

test get normal

in obstructive patic function

hepatic

function

jaundice and impaired hein parenchymatous jaundice.

However, these ideal conditions prevail only during the first few days after the onset of jaundice. Unfortunately, usually elapse before the

several patient

days or his

of

family notice the yellow color of the sclerae

of par-

and skin and then more time is lost because,

onset

stage

cloudy

cells diminishes to take

type.

“biphasic”

Ac-

the Van

this is also changed

are diffuse pathologic Van

between

endothelial

the

jaundice

test at first gives

but later

The principle

cells.

qualitative

den Bergh reaction

in the blood.

in obstructive

cases of hemolytic

Moreover,

bile duct or to pathologic

also accumulates

cordingly

during

is of no help in

diagnosis because to an extrahepatic

in the hepatic

and

normal

function-which

by way of the bile.

differential due either

of

such as dyes-

the fact that the liver is unable normally

the pres-

that the ability

we cannot

latter

use of all

tests

den Bergh

ence of jaundice

of jaundice

the

swelling

of

unless pain is also present, jaundice

the ability

of

ently does not alarm most patients who often wait for weeks and sometimes months

up “indirect”

bilirubin

appar-

which then accumulates in the blood. Later necrosis of some of the cells of the liver

before

takes

jaundice causes damage to the hepatic cells and a week or at the most ten days after

place

of the bile

leaving

openings

capillaries

in the walls

through

which

bile

the

seeking

back

medical advice. As a result pressure of bile in obstructive

the obstruction

becomes

established

most

begins to enter the blood bringing with it “direct” bilirubin. Accordingly in the early

metabolic

stage of parenchymatous

the Van

function.

reaction

of the metabolic liver function tests for the differential diagnosis of jaundice is lost soon

jaundice

den Bergh test gives the “indirect”

whereas later a mixed or “biphasic” reaction is the rule. In obstructive jaundice bile with “direct” bilirubin enters the blood from the first. Later as the back pressure of bile begins to ‘injure the hepatic cells they are no longer able to take up normal amounts of “indirect” bilirubin and the AMERICAN JOURNAL

OF

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after

the

tests begin to register

diminished

In this way the usefulness

onset

of jaundice.

of most

Among

the

otherwise useful tests which in my experience are of little value for this purpose are the hippuric acid test, the cephalin flocculation test, determinations of total cholesterol, of alkaline phosphatase and of

Liver Function

210 urobilinogen method

in the urine according

of Wallace

Fortunately

there are two metabolic

of liver function

which enable

to distinguish

between

enchymatous

jaundice

of cases.

These

galactose

tolerance

prothrombin 1. The

in a large the

Intravenous

several

diag

lies in the observation

to metabolize

very little

The

Test.

months’

duration.

performed

on the fasting patient,

but in our

experience

such food as toast and coffee has no rise in the galactose

level

With this method almost all patients obstructive

jaundice

with

of less than six months’

duration

had less than

galactose

in the blood seventy-five

after the injection

of

20 mg. per cent of

of galactose

minutes

while a large

majority

of patients

of the liver the

jaundice

had more than 20 mg. of galactose

is impaired

jaundice

paper* we called attention

is usually

that

galactose

by obstructive

The

have been

test

the blood.

in the differential

method

elsewhere.6

produced

K.

unlike most other functions

to the Folin-Wu

majority

intravenous

Galactose

tation

described

and par-

test and the response of

to vitamin

nosis of.jaundice

tests

the physician

obstructive

tests are

value of galactose

ability

to the

and Diamond.3

Tests-AMzausen

In

of even

a previous

to the unreliable

with

parenchymatous

in the blood. In the present

series all except

tient with uncomplicated

one pa-

obstructive

dice due to stone in the common

jaun-

bile duct

results obtained with the conventional oral galactose test which, in addition to the

had less than 20 mg. per cent of galactose in the blood at the end of tbe test. In the

ability

one exception

of the liver to metabolize

is influenced sorption

galactose,

by the rates of intestinal

and renal

excretion

ab-

of this sugar.

At the same time the following

method

for

doing the test was described: After-an obtained,

oxalated

of 1 cc. of a 50

the blood Eight

repeated

patients attacks

with jaundice,

had

chills

of galactose

per kilogram

was easy to distinguish

of body

is injected

intravenously

from patients tive jaundice.

over a period of four to five minutes with a 100 cc. syringe with excentric tip, fitted with a short No. 19 gauge needle.

Another

was 28

with choledo-

clinical

colic

and fever,

history

of

associated so that

this group clinically

of biliary

by operation

cirrhosis

was

and in half of them

oxalated blood sample is secured seventyfive minutes after the injection. Glucose is

in addition by biopsy of the liver. In all but three patients with uncompli-

removed from the blood samples by fermentation with yeast according to Raymond

cated obstructive

and

under 20 mg. per cent.

Blanco’s5

modification

of Somogyi’s

method. The filtrates are analyzed for the non-fermentable reducing substance by the Hagedorn-Jensen method. In order to obtain the galactose content of the blood, the figure for reducing substances in the fasting blood is subtracted from the corresponding figure in the seventy-five-minute specimen. A correction of 24 per cent must be added if conversion tables for glucose are used. The details of the procedure and its adap-

of the

it

with uncomplicated obstrucIn all of these patients the

diagnosis

confirmed

a long

of biliary

per cent solution weight

galactose

patients

cholithiasis and superimposed biliary cirrhosis had higher galactose values. All of the latter

blood sample has been

a dose consisting

mg. per cent.

pancreas

jaundice the

due to carcinoma

blood

galactose

was

In the three excep-

tions the blood galactose was under 30 mg. per cent. Three patients with carcinoma of the pancreas had considerably higher values for galactose. Two of them also had cirrhosis of the liver as shown by operation and biopsy, and the third patient had massive metastatic growths in the liver. Two patients with jaundice due to benign postoperative stricture of the common duct had a normal galactose tolerance. Seven paAMERICAN JOURNAL

OF

MEDICINE

Liver Function tients had obstructive

jaundice

from various

such as ascites,

causes longer than six months and in four of

cutaneous

them considerable

diagnosis

tolerance In

impairment

of galactose

was found.

summary

(95 per cent)

RESULTS

“spider”

collateral

(Table patients

practically

II),

all

with uncomplicated

OF THE INTRAVENOUS IN 188

PATIENTS

GALACTOSE WITH

acute

angiomas

circulation

per cent

hepatitis

the with

blood level

in excess of 20 mg. per cent. Twenty-three

TEST

OBSTRUCTIVE

II AND

OF THE

PROTHROMBIN

OR PARENCHYMATOUS

RESPONSE

TO VITAMIN

K

JAUNDICE

Prothrombin Response to Vitamin K

No. of

Type of Jaundice

Parenchymatous .Jaundice

of patients

had a galactose

I.V. Galactose Test

Obstructive Jaundice

and submade

clear.

Seventy-seven

TABLE THE

211

Tests-Althausen

Cases

Allcases* ....................... Uncomplicated cases.

............ -.__-_ .. . .

All cases t . . . .. . Cases with icteric index over 50 units

86 68

Under 20 mg. (per cent)

___-

102 80

82 95

__

24 4

* Including cases with biliary cirrhosis. t Including cases with jaundice which was slight (icteric index under 50 units) or of short duration.

obstructive rectly

jaundice

were

by the intravenous

diagnosed galactose

cortest. If

per cent had less than

20 mg. per cent of

we are to include in the group of obstructive

galactose in the blood. In the latter group, in all but three cases the hepatitis was mild

jaundice cirrhosis

of short

tases

the cases complicated by hepatic and the case with massive metas-

to the

liver,

we still

get

a correct

answer in 82 per cent of the cases. The mean galactose obstructive

blood

level

jaundice

of all patients

with

was 14 mg. per cent.

(with

an icteric duration

improvement

at

index and the

under

50 units)

undergoing time

the

or

rapid

test

was

performed. Three

patients

with acute yellow atrophy

of the liver had a striking

inability

to me-

Seventy-six per cent of patients with cirrhosis of the liver had more than 20 mg.

tabolize galactose. Their blood galactose levels were 129, 139 and 145 mg. per cent.

per cent of galactose in the blood. All but one of these patients had an icteric index over 50 units. Twenty-four per cent of pa-

The highest figure for galactose

tients with cirrhosis of the liver had less than 20 mg. per cent of galactose in the blood and all of them had an icteric

index

in the blood

observed by us in acute hepatitis with recovery was 116 mg. per cent and the highest figure obtained in cirrhosis of the liver was 92 mg.

per cent.

This

limited

experience

mild

suggests that galactose levels over 125 mg. per cent are of grave prognostic significance.

degree of icterus which usually robs the case of urgency because surgical intervention is not contemplated, in most of the latter cases the presence of other signs pointing to parenchymatous hepatic disease

This finding is of all the more value since in two of the three cases extremely hi& values for galactose were obtained by us before other indications of the gravity of the situation appeared and while the patients had

under

AMERICAN

50 units.

JOURNAL

In

addition

OF

MEDICINE

to the

Liver Function

212 few subjective cases

complaints.

the outcome

In one of these

of vitamin

a close relative

tive jaundice

in bringing

distant

part of the country

from a

to the patient’s

cinchophen,

with slight jaundice

caused

of drugs (two cases due to

two due to sulfonamides

and

K from

ciency.

of an adequate the intestine.

with intestinal

K and creating Such

binemia

hours) by parenteral

the intravenous

test. Two of these

hypoprothrombinemia

patients

had a galactose

blood level of more

the ability

Consequently

than 20 mg. These

tion of vitamin

galactose

test is unreliable

of jaundice

induced

in the diagnosis

by drugs.

this is not very important of preceding

medication

since with

produces

by interfering

with

in the latter case administra-

prothrombin

K either level

does not raise the

at all or does so only

slowly, and then the prothrombin

a history

decreases

of the

of vita-

jaundice

However, one

in six

of the liver to form prothrombin.

than 20 mg. and three had a level of less results suggest that the

(often

administration

min K. Parenchymatous

of

K defi-

hypoprothrom-

rapidly

were studied with

level

absorption

a vitamin

a deficiency

is corrected

one due to arsphenamine) galactose

supply Obstruc-

lowers the prothrombin

by interfering vitamin

bedside before death occurred. by toxic action

only in the Presence

of the test was instru-

mental

Five patients

Tests-Althausen

again

ministration

in spite

of vitamin

level often

of continued

ad-

K. This difference,

hepatotoxic drugs is relatively easy to obtain. In summary (Table II), 76 per cent of

as has been repeatedly pointed out,*i3 can be used for the differential diagnosis between

all patients

obstructive

with parenchymatous

jaundice

and parenchymatous

were identified correctly by means of the intravenous galactose test. Were we to ex-

In Ievel

clude from our material

with mild

Quick.r4

The

jaundice (with an icteric index under 50 units) or with jaundice lasting less than a

injection

of 1 mg. of vitamin

week,

the accuracy

chymatous

jaundice

patients

Combining

determined hours later.

would

rise to 96 per

prothrombin

level

level of the blood

obtained

the results

comparable galactose

test.

of the intravenous

test in all cases of jaundice,

it is

seen that the outcome of the test alone made the differentiation between obstructive and parenchymatous

was then

to forty-eight

results with the intravenous galactose

prothrombin

patient

test in paren-

of all patients with parenchymatous jaundice was 56 mg. per cent. King and Aitken7 as well as Maclagan*

the present study the prothrombin was determined by the method of

of the

cent. The mean galactose

jaundice

in our series in

three out of four cases. When certain

simple

cant

jaundice.

Elevation

was considered

only if the original

our

patients

an

and the

again twenty-four of the signifi-

level was 70 per

cent or less and the increase more. Among

given

K*

20 per cent or

with

obstructive

jaundice, 91 per cent responded with a significant increase of an initially low prothrombin concentration. Among those failing to respond, superimposed biliary cirrhosis, the presence of which was easy to determine from the history, accounted for one-half

of the cases. A11en15 also found that

additional clinical data are taken into consideration; it becomes possible to determine correctly thel’type of jaundice in almost all cases. 2. Protfirombin :Response to Vitamin K.

the presence of cholangitis with fever impaired the prothrombin response. In the group of our patients with parenchymatous jaundice, 96 per cent showed no increase in the prothrombin Ievel. These figures indi-

Maintenance of a ‘normal prothrombin level in the plasma is one of the functions of the liver,
* “H Ykinone” ampules by Abbott Co. were used in this work but any other preparation of vitaniin K suitable for parenteral ad&i&r&on can be employed. AMERICAN

JOURNAL

OF

MEDICINE

Liver Function cate a very satisfactory of the prothrombin in the

accuracy response

differentiation

parenchymatous

vitamin

K

from

of jaundice.

correlation

results of the intravenous the response

to vitamin

of obstructive

types

was also excellent

on the part

There

between

the

galactose

test and

of a low prothrombin

level to

with

the

history

possess a high differential

ever possible,

physical

degree

of accuracy

for the

it is advisable,

when-

to do both tests in every pa-

Technically and

after

the galactose

a little of known in

equipped

laboratory

tests

results

they

where workers. experienced

liver

do not take the place a careful patients

physical

aid but

of a good history

examination.

with jaundice alone.

In

the correct

can be made from the history examination

function

or

hand,

usually

In an additional

num-

accurate

require

determinations

be is

prothrombin

a larger

perform

laboratory

in prothrombin

the tests.

SUMMARY

diagnosis

ber of cases ordinary laboratory studies and roentgenologic examinations will answer the

can which

are fairly difficult and reliable

many

and physical

galactose

to do blood sugar determinations.

jaundice

diagnostic

with

concentration

any

On the other determinations

in particular,

test is simple

practice

In the diagnosis of diseases of the liver in general and in the differential diagnosis of are an important

findings,

tient with jaundice.

performed

COMMENTS

and

diagnosis,

solutions

K.

213

Tests-Althausen

1.

The pathologic

types of jaundice

physiology

and its relation

tory” and “metabolic” discussed. 2. The

results

of different to “excre-

liver function

of the

tests is

intravenous

gal-

question whether the jaundice is due to extrahepatic block and surgical intervention is necessary, or whether it is due to

actose test and of the response of prothrombin to vitamin K in the differential diagnosis

parenchymatous

of 190 patients

medical nary

disease

treatment

studies

in ruling

However, to liver

and Ordi-

particularly jaundice.

in most cases final recourse is made function

tests.

in patients

metabolic

are

out hemolytic

bered that excretory useless

liver

alone is indicated.

laboratory

helpful

of the

functions

It must be remem-

liver function with jaundice.

tests are Among

of the liver most deci-

sive for the differentiation

between

tive and parenchymatous

jaundice,

obstrucin my

experience, is the ability of the liver to metabolize galactose and to produce prothrombin following an injection of vitamin K. If these functions of the liver are not impaired

or are impaired

only slightly,

the

case is in the domain of the surgeon. If they are markedly impaired, the case is almost always strictly a medical problem. Although the results of either the intravenous galactose test or of the prothrombin response to vitamin K, especially if taken in conjunction AMERICAN

JOURNAL

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MEDICINE

3. The

with jaundice

importance

tween obstructive cal operation

are analyzed.

of distinguishing

jaundice

is the only effective

and parenchymatous

jaundice

stitutes a strictly medical

be-

for which surgi-

problem

treatment which

con-

is pointed

out. 4. The usefulness

of the intravenous

gal-

actose test is demonstrated by the fact that, when taken alone, it made possible the differentiation chymatous

between jaundice

obstructive and parenin three out of four

cases. When taken in conjunction with certain simple additional clinical data, this test allowed the identification of the type of jaundice 5. The thrombin

in almost all cases. diagnostic accuracy response to vitamin

of the proK is shown

by the fact that it was present in nine of ten patients with obstructive jaundice and was absent in the same proportion of patients with parenchymatous jaundice.

214

Liver Function CONCLUSIONS

Appropriate liver function tests are an important aid in the differential diagnosis of jaundice when taken in conjunqtion with data from the history, physical findings and ordinary laboratory studies. 2. With the help of the intravenous galactose test and the response of prothrombin to vitamin K it is possible to arrive at a correct diagnosis as to the type of jaundice in over 90 per cent of cases. 1.

REFERENCES 1. GIANSIR~~CUSA, J. E. and ALTHAUSEN,T. L. Diagnostic management of patients with jaundice, J. A. M. A., 134: 589, 1947. 2. MARTIN, L. Jaundice. Internat. Clin., 1: 19, 1934. 3, WALLACE, J. B. and DIAMOND,J. S. The significance of urobilinogen in the urine as a test of liver function. Arch. Znt. Med., 35: 698, 1925. 4. BASSETT,A. M., ALTHAWSEN,T. L. and COLTRIN, G. C. A new galactose test for the differentiation of obstructive from parenchymatous jaundice. Am. 3. Digest. Dir., 8: 432, 1941.

Tests-Athausen 5. RAYMOND, A. L. and BLANCO, J. G. ,Blood sugar determinations and separation of sugars with live yeast. 3. Biol. Chem., i9: 649, 192%. 6. ALTHAUSEN.T. L.. LOCKHART. 1. C. and SOLEY. M. A new diagnostic test (galaiyose) for thyroid’disease. Am. 3. M. SC., 199: 432, 1940. 7. KING, E. J. and AITKEN, R. S. An intravenous galactose tolerance test. Lance& 2: 543, 1940. 8. MACLAGAN, N. F. Laboratory tests in the diagnosis of liver disease. Brit. M. J., 2: 363, 1944. 9. ALLEN, J. G. The diagnostic value of prothrombin response to vitamin K therapy as a means of differentiating between intrahepatic and obstructive jaundice. Internat. Abstr. Surg., 76: 401, 1943. 10. LORD, J. W. and ANDRUS, W. D. Differentiation of intrahepatic and extrahepatic jaundice. Arch. Znt. Med., 68: 199, 1941. 11. OLWIN, J. H. Differentiation of surgical jaundice from severe damage of liver. Arch. Surg., 43: 633, 1941. 12. ALLEN, J. G. and JULIAN, 0. C. Prothrombin and hepatic function. Arch. Surg., 45: 691, 1942. 13. LUCIA, S. P. and AGGELER, P. M. The influence of liver damage on the plasma prothrombin concentration and the response to vitamin K. Am. 3. M. SC., 201: 326, 1941. 14. AGGELER, P. M., HOWARD, J., LUCIA, S. P., CLARK, W. and ASTAFF, A. Standardization of the Quick prothrombin test. Blood, 1: 220, 1946. 15. ALLEN, J. G. The clinical value of the functional tests of the liver. Gastroenterology, 3: 490, 1944.

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