serum proteins and liver function in sarcoidosis

Acta Medica Scandinavica. Vol. 180, fasc. 4, 1966

From the Department of Pulmonary Diseases (Head: E. von Rosen, M. D.) and the Depart- ment of Clinical Chemistry (Head: C. G. Holmberg, M. D.), University of Lund, Lund,

Sweden

Serum Proteins and Liver Function in Sarcoidosis’

BY

R. INCESTAD and N. TRYDING

In patients with sarcoidosis decreased serum albumin and increased serum globulins are very commonly found (5, 15, 17, 19, 20, 24). This paper is mainly concerned with the electrophoretic serum-protein pattern in different roentgenologic stages of sarcoidosis. In an attempt to ascertain whether patients with sarcoidosis have a constitutional tendency to hypergammaglobulinaemia, it was decided to examine the electrophoretic serum protein pattern, especially the gamma-globulin concentration, in relatives of patients with sarcoidosis and with tuberculosis respectively. In addition, liver function in patients with sarcoidosis was studied with the bromsulphthalein test.

Material The miterial was selected at random from that used in an investigation by Ingestad and consisted of 115 patients with roent- g:nolo,oic evidence of pulmonary sarcoidosis, 50 males and 65 females. Histologic examination of biopsy specimens from one or more

Submitted for publication May 2, 1966.

organs revea!ed sarcoid tissue in 99 of the 115 patients. The study also covered 93 siblings and 51 children of our patients. For comparison 53 siblings and 19 children of patients with tuberculosis were examined. The sex and age distribution of the subjects is given in table IV. Among the above- mentioned relatives, 4 siblings of patients with sarcoidosis had allergic diseases (2 hay fever and 2 bronchial asthma). None of the relatives had tuberculosis, sarcoidosis or “collagen disease” in their history. General physical examination and radiography revealed no abnormalities of relevance.

Methods

Paper electrophoresis was done according to Laurel1 ct al. (13). The normal ranges are given in table I. The blood samples were collected in the fasting state. The serum samples were stored at -20” C until analysed.

The ESR was done according to Wester- gren’s method in association with collections of the sample for electrophoresis.

Liver function test: The bromsulphthalein test was done with 5 mg per kg body-weight.

* A preliminary report was presented at the Third International Conference on Sarcoidosis, Stockholm, September 11-14, 1963.

449 5-663002. A d a Med. Scand. Vo l . 180: 4

450 R. INGESTAD AND N. TRYDING

TABLE I. Paper electrophoresis of serum from patients with sarcoidosis in different roentgenological

Alb. a1

N Age (g/ 1cJo ml) (g/100 ml)

Group J 9 m S Mdn Variation Mdn Variation ~

Stage I 15 21 36.0 12.3 4.77 3.41-5.61 0.27 0.18-0.48 Stage I1 18 22 43.4 14.1 4.45 2.64-5.93 0.32 0.20-0.68 Stage 111 12 24 52.4 10.1 4.65 3.73- 5.76 0.28 0.22 -0.43 Healed 13 14 39.5 12.2 5.12 3.99-5.84 0.25 0.17-0.33 Normal ranges 4.8 - 5.8 0.20- 0.32

Statistical analysis: (Konskal-Wallis one-way analysis of variance) (The Mann-Whitney U test) Albumin H=28.34 df=3 P <.001

Stage 1-11 2-1.39 P >.05 1-111 z=O.lO P <.05 I-healed z= 3.44 P > 001 11-111 z= 1.66 P >.05 11-healed z=4.79 P <.001 111-healed z=6.67 P <.001

When retention exceeded 10 yo after 30 min. the test was said to be positive. The deter- mination of alkaline phosphatase was done according to Bessey et al. ( l ) , and serum bilirubin ad modum Nosslin (21).

The serum calcium was measured with an Eppendorf flame photometer.

Statistical analysis: The differences were examined by the X2 test.

Results

Serum protein electrophoresis Altogether 139 samples tients with sarcoidosis

from 1 15 pa- were studied

a1

H=23.15

Stage 1-11 1-111 I-healed 11-111 11-healed 111-healed

aa H= 18.17

Stage 1-11

df=3

z=2.16 z=0.34 z=2.52 2-1.84 z=4.51 z=2.76

df= 3

z=1.37

P <.001

P <.05 P >.05 P <.05 P >.05 P <.001 P <.01

P <.001

P >.05

electrophoretically. The results are sum- marized in table I.

The serum albumin was abnormally low in all 3 roentgenological stages of the disease and was lowest in stage 11. The difference observed in the albumin concentration between active sarcoidosis (stages I, I1 and 111) and roentgenologically healed sarcoidosis was significant.

The alpha,-, alpha,- and beta-globulin concentrations were significantly higher in stages I, I1 and I11 than in the roentgenologically healed group. The highest individual concentrations were found in stage 11.

SARCOIDOSIS 45 1

stages

a, P Y Total protein (g/lOOml) (g1100 ml) (g/100 ml) k / 1 0 0 ml)

Mdn Variation Mdn Variation Mdn Variation Mdn Variation

0.54 0.36-1.09 0.72 0.54-1.03 1.11 0.75-2.02 7.5 6.3-8.5 6.0 - 9.0

0.50 0.31 -0.68 0.65 0.50-0.86 0.98 0.70-1.70 7.6 6.6 - 8.6

0.62 0.39-1.29 0.76 0.51-1.19 1.34 0.86-2.12 7.6 0.57 0.39-0.75 0.74 0.55-1.05 1.35 0.72-2.33 7.7 5.9-9.0

0.32-0.54 0.43 -0.85 0.61 - 1.17 6.8 - 8.2

1-111 I-healed 11-111 I1 -healed 111-healed

B

Stage 1-11 1-111 I-healed 11-111 11-healed 111-healed

H=18.76

z=0.36 z=2.08 z=1.89 z=4.03 z=2.56

df= 3

z = 1.74 z=0.95 z=2.51 z=0.57 z=3.73 z=3.06

P >.05 P <.05 P >.05 P <.001 P <.05

P <.001

P >.05 P >.05 P <.05 P x . 0 5 P <.001 P <.001

The gamma-globulin fraction was likewise increased in stages I, I1 and 111, especially in stages I1 and 111.

In the roentgenologically healed cases the median values found for the various fractions fell within the normal range of variation, but some of the individual globulin values exceeded the normal limits, which suggested that the disease had not completely healed despite the absence of any roentgenographic changes in the lungs.

The patients in stage I produced different clinical symptoms and two principal groups may be distinguished :

Y H = 27.64

Stage 1-11 1-111 I-healed 11-111 I I-healed 111-heeled

df= 3 P <.001

z=2.59 P <.01 z=2.39 P <.02 z=2.12 P <.05 z=0.33 P >.70 z=4.56 P <.001 z=4.39 P <.001

P <.05 probably significant P < .01 significant P < .001 highly significant

1. Patients with acute onset of the disease with erythema nodosum.

2. Patients with insidious onset of the disease without erythema nodosum.

The serum gamma- and beta-globulin concentrations in patients belonging to these two groups were found to be largely the same. The alpha-globulins were significantly higher and the albumin was lower in the group of erythema nodosum (table 11). Only patients in whom the roentgenographic changes regressed were compared.

In several patients the roentgenographic appearance of the lungs varied


TABLE 11. Serum proteins and ESR of sarcoid patients in stage I, with and without erythema nodosum ~

Alb. a1

N Age (g/lOOml) (g/100 ml) -- Group 6 9 m S Mdn Variation Mdn Variation

Stage I

Stage I without E.N. 8 7 29.4 11.0 4.98 4.24-5.29 0.26 0.18-0.33

with E.N. 5 9 38.6 1 1 . 1 4.00 3.41-5.26 0.34 0.24-0.48

Statistical analysis: Albumin: U = 36.0 P < .002 al: U=34.5 P<.OO2 a,: U=48.0 P<.O2 p: U=105.0 P>.O5 y : U=97.5 P > . 0 5

TABLE 111. Serum proteins and ESR of sarcoid patients in stage I1 with progressive and regressive

Group $ . ? m S Mdn Variation Mdn Variation

Stage I1

Stage I1 (+ 111) 4 4 47.5 10.4 4.32 3.73-4.69 0.33 0.26-0.36

(+ healed) 7 10 38.2 14.1 4.46 3.38-5.95 0.32 0.23 - 0.48

Statistical analysis: Albumin: U=46.5 al: U=59.0 a,: U=65.0

in the course of the investigation. In some cases in stage I1 the roentgenographic changes advanced to stage 111, while in others they regressed. In order to get a clinically equivalent comparison between progressive and regressive cases in stage 11, only patients with insidious onset without erythema nodosum were included in the two groups. I t is clear from table I11 that the gamma-globulin concentration determined in stage I1 was generally somewhat lower in those

P > .0.5 P >.05 P >.05

cases in which the disease healed than in those in which it progressed to stage 111, but for none of the serum protein fractions is the difference significant. Thus the gamma-globulin concentration in stage I1 appears to be of no prognostic significance in the individual case.

Erythrocyte sedimentation rate In the patients with sarcoidosis the ESR showed a wide range of variation

SARCOIDOSIS 453

a, B Y ESR (g/ 100 ml) ( g l 100 ml) ( g / 100 ml) (mm / hour)


0.69 0.36-1.09 0.73 0.57-0.87 1.20 0.79-2.02 71 40- 124

0.49 0.37-0.76 0.72 0.54-1.03 1 . 1 1 0.75-1.98 10 4- 33

ESR: U=O.O P<.OOl P < .05 probably significant P < .O 1 significant P < .001 highly significant

course, respectively

a2 B Y ESR (91100ml) (g/100 ml) k / 1 0 0 ml) (mm / hour)


0.62 0.42-0.70 0.75 0.65-1.19 1.47 1.07-1.98 23 5-68

0.62 0.39-1.19 0.80 0.51-1.13 1.29 0.87-2.12 12 2-52

8: U=68.0 P> .05 y : U=54.5 P >.05 (no significance)

(table IV). The median values were increased in all the 3 stages. The highest individual values were noted in stage I. In several of these active cases the ESR was normal. The median ESR in the roentgenologically healed group was normal.

In stage I the median ESR was significantly higher in patients with erythema nodosum than in those with an insidious onset of the disease (table 11).

The median ESR determined in stage I1 was largely the same in those patients in whom the disease healed as in those in whom it progressed to stage 111 (table 111).

Findings in relatives o f patients with sarcoidosis The serum gamma-globulin concentrations found in the patients with sarcoidosis in various roentgenologic stages as


TABLE IV. Serum y-globulin values and ESR of patients with sarcoidosis in different roentgenological stages as well as of relatives of patients with sarcoidosis and with tuberculosis

ESR Serum y-globulins (mm / hour)

N Age (81 100 ml) Varia-

Group $ 8 m s Mdn Variation Mdn tion

Patients with sarcoidosis

Stage I Stage I1 Stage I11 Healed

Siblings of sarc. pat. Children of sarc. pat. Siblings of tuberc. pat. Children of tuberc. pat.

15 21 36.0 12.3 1.11 18 22 43.4 14.1 1.34 12 24 52.4 10.1 1.35 13 14 39.5 12.2 0.98 45 48 40.8 14.0 1.04 19 32 21.5 10.0 0.94 23 30 39.6 11.3 0.97 10 9 25.3 15.1 0.93

0.75-2.02 16.5 2-124 0.86 -2.12 20.1 2-84 0.72-2.33 15.0 2-93 0.70-1.70 6.2 1-20 0.57-1.60 6.4 1-36 0.51 - 1.67

0.66- 1.36 0.68- 1.64 6.0 2-28

Statistical analysis: (The Mann-Whitney U test)

y Stage I - siblings of sarcoid patients Stage I1 - siblings of sarcoid patients Stage I11 - siblings of sarcoid patients Healed - siblings of sarcoid patients

ESR Stage I - I1 Stage I - 111 Stage I - healed Stage I1 - 111 Stage I1 - healed Stage I11 - healed

P g.05 probably significant P g.01 significant P g.001 highly significant

well as in relatives of patients with sarcoidosis or tuberculosis are given in table IV.

The median serum gamma-globulin concentration in the roentgenologically healed patients did not differ significantly from that noted in the relatives of patients with sarcoidosis and tuberculosis, respectively. Each of these 3

z=3.11 z=5.74 z=6.69 z=o.21

z=0.56 z=0.35 z=3.90 z=1.43 z= 5.29 z=4.01

P < ,002 P <.001 P <.001 P >.80

P >.50 P >.70 P <.001 P >.lo P <.001 P <.001

groups included a few members with hypergammaglobulinaemia. With but few exceptions the persons with hypergammaglobulinaemia did not belong to the same family. Nor was any significant difference in the ESR found between the roentgenologically healed sarcoidosis group and the siblings of patients with sarcoidosis or tuberculosis.

SARCOIDOSIS 455

Liver function tests Liver function was studied in 66 of the patients with sarcoidosis, 25 males and 41 females. None of them had any known disease of the liver or the heart. In 20 of the patients studied the bromsulphthalein test was positive. The positive tests were noted mostly in patients in stage I1 of the disease. In table V the results of the bromsulphthalein tests are related to the serum alkaline phosphatase, to the serum protein values and to the results of histologic examination of biopsy specimens of the liver. The serum alkaline phosphatase was found to be increased in 3 out of 38 patients studied. In all 3 the disease was in stage I1 and the bromsulphthalein test was positive, but the serum bilirubin concentration was not increased in these or in other patients studied. Abdominal palpation revealed no enlargement of the liver in any of the 66 patients.

Liver biopsy ad modum Radner was done in 30 cases. Among these, the bromsulphthalein test was positive in 11 and negative in 19. The biopsy specimen showed signs of sarcoid tissue in 6 cases. The bromsulphthalein test was positive in 3 of these cases and negative in the remaining 3. All these 6 cases were in stage I1 or 111. There thus appeared to be no correlation between positive bromsulphthalein test and positive histologic findings in the liver. Roentgenographic hepatomegaly was verified in 2 of the 30 cases examined. In both cases the bromsulphthalein test was positive, but the liver biopsy specimen showed no sarcoid tissue. A slight correlation between the bromsulphthalein test and the serum gamma-

globulin concentration was found. The other serum globulins did not vary with the results of the bromsulphthalein test.

Serum calcium content Only in 2 of the patients studied (35 males and 52 females) was the calcium content found to be increased, and then only slightly (5.4 and 5.5 mEq/l). In one patient, who proved to have renal sarcoidosis, the serum calcium (5.2 mEq/l) bordered the upper normal limit. Histologic examination of a biopsy specimen of kidney tissue showed the characteristics of sarcoid lesions and interstitial nephritis but no signs of nephrocalcinosis.

Discussion

An increase of the total serum protein content in patients with sarcoidosis was first demonstrated by Salvesen (22). Harrel and Fischer (6), Harrel (7), and Seibert etal. (23) found hyperprotein- aemia and hyperglobulinaemia in patients with active sarcoidosis. The abnormality disappeared when the disease healed. Murray et al. (19) studied 12 cases of histologically confirmed sarcoidosis in different stages. In 4 of the patients with no signs of active disease the serum protein pattern was largely normal. In patients with active sarcoidosis, however, the concentration of the gamma-globulin was increased, while that of the albumin was decreased. Sunderman and Sunder- man (24) found by paper electrophoretic studies an increased concentration of total protein in the serum, diminished concentration of albumin and step-like

456 R. INCESTAD AND N. TRYDING

TABLE V. Relation between liver biopsy, liver function and serum proteins

Serum protein con-

Alb. N Age (g/100 ml)

Bromsulph- Liver Alk. thalein test d ? m S biopsy phosf. Mdn Variation

Positive

Negative (> lo%) 7 13 50.8 16.7 3/11 3/12 4.55 2.64-5.40

( 2 1 0 % ) 18 28 41.1 10.9 3 /19 0 /26 4.78 3.12 -5.76

Statistical analysis : Bromsulphthalein test positive - bromsulphthalein test negative :

increases in the concentrations of alpha,-, beta-, and gamma-globulin ( “sarcoid steps”).

Levitt (15) studied the paper electrophoretic protein pattern in 25 patients with histologically confirmed sarcoidosis. The alpha,-, beta-, and especially the gamma-globulin fractions were found to be increased, while the serum albumin was definitely decreased.

Norberg (20) recently reported 82 histologically confirmed cases of sarcoidosis in which the serum protein pattern was studied in various stages of the disease according to th,e same prin- ciple as that used by us. The total serum protein was increased in the patients with progressive lesions, but was normal or only slightly increased in those with stationary lesions. In all the groups the mean relative albumin concentration was lowered. The mean alpha,-globulin level was elevated in all of the groups, especially in the progressive cases. In several cases of each groups the beta-globulin was also increased. The mean relative gamma-globulin

concentration was increased only in the groups with progressive lesions.

I t is well known that the serum protein values are higher in ambulant than in non-ambulant patients. According to Lange (1 l ) , the difference is approxima- tely 9 yo. In Norberg’s study (20) this difference was 8.3 yo in the controls and 14.5 yo in the cases with sarcoidosis. In our material, both the patients with sarcoidosis and the relatives, almost all the samples were taken from ambulant persons and therefore the results in the different groups may be considered comparable.

Like Norberg (20), we found decreased serum albumin and increased alpha,- and beta-globulines in all stages of active sarcoidosis. The gamma-globulin concentration was especially elevated in stages I1 and 111.

The great ESR differences between patients in stage I with erythema nodosum and those with insidious onset is not correlated to any differences in the gamma-globulin concentration. The patients in the erythema nodosum group,

SARCOIDOSIS 457

~ ~

centration


0.30 0.21 -0.68 0.57 0.36-1.29 0.80 0.51-1.05 1.47 0.79-2.2 1

0.28 0.20-0.44 0.54 0.37-1.04 0.74 0.57-0.93 1.19 0.83-2.12

a,, a,, B : (no significance) y : z=2.21

however, had significantly lower serum albumin and higher alpha-globulin values.

A comparison between progressive and regressive cases in stage I1 showed no significant difference to the serum protein fractions. Thus, like Greenberg et al. ( 5 ) we found no prognostic significance in the serum protein values.

Dieckmann (4) pointed out that granulomatosis of the sarcoid type can be seen in patients with agamma- globulinaemia. According to him, the serum gamma-globulin concentration is of no diagnostic or prognostic value in sarcoidosis.

It is, however, well established that hypergammaglobulinaemia is a common accompaniment of active sarcoidosis and of systemic lupus erythematosus (SLE). In an investigation of relatives of patients with SLE Larsson and Leonhardt (12) and Leonhardt (14), found hypergammaglobulinaemia to be fairly common in relatives of the patients. I t was concluded that the tendency to hypergammaglobulinaemia

P =.027 (probably significant)

in the relatives of patients with SLE is probably a constitutional abnormality of the immunologic system. As in SLE, a familial occurrence of sarcoidosis has been reported (8,9, 18). Our study of the serum globulin content in siblings and children of patients with sarcoidosis did not, however, produce any evidence of a constitutional tendency to hypergammaglobulinaemia in sarcoidosis.

According to Branson et al. (2), the liver is affected in 65 yo of all patients with sarcoidosis. Cheitlin and Sullivan Jr. (3) surveyed published cases of liver cirrhosis due to sarcoidosis, to which they added one of their own. In our investigation the bromsulphthalein test showed impairment of liver function in 20 out of 66 patients examined in this respect. Little correlation between the result of the bromsulphthalein test and the serum gamma- globulin concentration was found.

Only in 2 out of 20 patients with sarcoidosis did roentgenography show hepatomegaly. In neither of them did liver biopsy specimen show sarcoid


lesions. Nor was any correlation found tern. For comparison, relatives of patients between the histologic findings in the liver biopsy specimens and the results of the bromsulphthalein tests.

Summary

One hundred and fifteen patients with roentgenologic evidence of pulmonary sarcoidosis were subjected to tissue biopsy, mainly of the lymph nodes (scalene fat-pad biopsy). Histological examination revealed sarcoid lesions in 99 of the patients. Paper electrophoresis of the serum proteins in these patients showed a strongly significant increase of the globulin fractions during stage I1 and stage I11 of the disease. In stage I the serum globulin values were only slightly elevated, and there was no difference in serum gamma-globulin concentration between patients with and without erythema nodosum, but the serum albumin was lower and the alpha- globulins higher in the group of erythema nodosum. As a rule the roentgenographic and the electrophoretic abnormalities disappeared roughly simultaneously in those cases that healed. Some patients were followed from roentgenologic stage I1 up to complete disappearance of the roentgenographic changes or to a stage of pulmonary fibrosis. The values of the serum protein fractions and the ESR in stage I1 did not allow any prognostic conclusions.

In order to check whether patients with sarcoidosis have any constitutional tendency to hypergammaglobulinaemia, siblings and children of patients with sarcoidosis were studied with regard to the electrophoretic serum protein pat-

with pulmonary tuberculosis were also studied. No significant difference was found in the concentration of the serum gamma-globulins between the groups of relatives and the patients with roentgenologically healed sarcoidosis. Thus, no evidence of familial occurrence of hypergammaglobulinaemia was produced.

The liver function of 66 patients with pulmonary sarcoidosis was studied with the bromsulphthalein test. The retention of the dye was increased in as many as 20. A correlation was found between impairment of liver function and the increase of the serum gamma-globulin concentration.

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