RESPIRATORY MEDICINE (1997) 91, 616-623
Serum lactate dehydrogenase and its isoenzyme pattern in ex-coalminers
N. A. M. COBBEN”, M. DRENT”, A. M. W. J. SCHOLS”, R. J. S. LAMERS+, E. F. M. WOUTERS” AND M. P. VAN DIEIJEN-VISSER*
Departments of “Pulmonology, ‘Diagnostic Radiology and *Clinical Chemistry, University Hospital Maastricht, The Netherlands
Serum lactate dehydrogenase (LDH) activity, a marker of cell damage, is increased in several pulmonary disorders, especially when fibrosis is involved. In rats exposed to silica, high levels of LDH activity were found. A rise of serum LDH, has been associated with lung tissue injury. The aim of this study was to investigate the serum LDH isoenzyme pattern after coal-dust exposure and the possible relation to pulmonary function tests. Ex-coalminers (72=201), with a history of coal-dust exposure more than 20 yr ago, were admitted to the authors’ hospital for a medical check-up and were included in the study. The serum LDH activity was found to be elevated in 79.1% of the ex-coalminers (634 f 245 U l- ‘). Moreover, in 196 of the 201 cases (97.5%), a high LDH, level (31 * 4%) was demonstrated. A moderate negative relation was found between the forced expiratory volume in 1 s (FEV,) and the LDH activity (v= - 0.26; P
RESPIR. MED. (1997) 91, 616-623
Introduction coniotic abnormalities. Until now, however, no clinical parameter was reported to identify the Occupational exposure to mineral dusts can cause relation between pulmonary function impairment and pulmonary fibrosis. Several animal studies described silica exposure (3). the pathogenesis of pulmonary silicosis (1,2). More- In the pathogenesis of lung fibrosis, complicated over, it was demonstrated that this cytotoxic effect for processes are involved. These processes include inter- alveolar macrophages (AMs) persists after cessation cellular communication by peptides released from of exposure. It is now evident that coalworkers’ and to various immune cells and lung target cells in pneumoconiosis (CWP) can become apparent or a phenomenon referred to as the ‘cytokine network’. progress further after cessation of exposure of silica. It has been shown that silica, as well as coal dust, Besides pneumoconiosis accumulation of coal dust in can stimulate the release of monocyte-/macrophage- the lungs, other non-pneumoconiotic effects such as derived pro-inflammatory cytokines, such as tumour chronic airway obstruction, bronchitis and emphy- necrosis factor (TNF)-a, IL-lp, IL-6 and the macro- sema may occur, both in smokers and non-smokers, phage inflammatory proteins la and 2 (4). More irrespective of the extent of possible pneumo- recently, elevated messenger ribonucleic acid (mRNA) levels of TNF and IL-6 have been observed Received 1 August 1996 and accepted in revised form in bronchoalveolar lavage fluid (BALF) obtained 21 November 1996. from pneumoconiosis patients (4,5). Correspondence should be addressed to: M. Drent, Univer- Cellular enzymes in the extracellular space can sity Hospital of Maastricht, Department of Pulmonology, serve as indicators for disturbances of the cellular PO Box 5800, 6202 AZ Maastricht, The Netherlands. integrity induced by pathological conditions (6).
0954.6111/97/100616+08 $12.00/O 0 1997 W. B. SAUNDERS COMPANY LTD LDH PATTERN IN EX-COALMINERS 617
TABLE 1. Characteristics of the studied cases of ex-coalminers
Age Weight Height Underground Smoking Group n (years) (kg) (cm> years (pack years)
Total group 201 72 (52-92) 76 (46-117) 170 (153-194) 25.8 (1042) 29.9 (3-90) Group I 42 70 (56685) 77 (46-102) 171 (1577184) 26.2 (1241) 31.0 (10-80) Group II 159 72 (50-92) 75 (77-117) 169 (153-194) 25.7 (1042) 29.6 (3-90)
Data are expressed as means with ranges in parentheses. Group I, normal serum lactate dehydrogenase (LDH) activity; Group II, high serum LDH activity. Note: no significant differences between the groups.
Lactate dehydrogenase (LDH) is a cytoplasmatic chest X-ray was classified as abnormal showing enzyme present in essentially all major organ systems. abnormalities varying between few nodules, normal The extracellular appearance of LDH is used to lung markings visible and numerous opacities, and detect cell damage or death and is abnormal in a host normal markings totally obscured (n= 149; 74%) of disorders (6-9). The total serum LDH activity is (23). The characteristics of the studied population elevated in several pulmonary disorders associated are summarized in Table 1. The population of with fibrosis, and has been suggested to be a useful ex-coalminers was divided into two categories, based monitor of disease activity (8,10-16). Elevation of on the serum LDH activity. Group I consisted of LDH activity in BALF has been described after ex-coalminers with a normal serum LDH activity exposure to silica, in humans as well as in rats (n=42; LDH I 450 U 1 - ‘), and Group II consisted (17-19). However, the serum LDH activity is a highly of cases with an elevated serum LDH activity (n = 159; sensitive, but non-specific, parameter for pulmonary LDH >450 U 1- ‘). disease. Besides the elevated serum LDH activity, a A group of 48 healthy control subjects, all men (age high LDH, activity has also been reported to be 58 & 13 years), without a relevant medical history, related to lung injury (12). Although the serum LDH- was used to assess normal values of serum LDH and isoenzyme pattern has a slightly better specificity, the its isoenzyme activity pattern. Of this latter group, clinical value is still rather low. The LDH isoenzyme the total protein, albumin, y-glutamyl transferase pattern of the lung is characterized by proportional (y- GT), alanine aminotransferase (ALT) and creatine increases in isoenzymes 3,4 and 5 as compared to the kinase (CK) were within normal limits. serum isoenzyme pattern (7,12,16,20-22). The aim of this study was to investigate whether the serum LDH activity and its isoenzyme pattern RESPIRATORY FUNCTION TESTS was related to pulmonary damage caused by silica Pulmonary function tests were assessed. Forced exposure. Therefore, the relationship between serum expiratory volume capacity (FVC) and forced expira- LDH activity, its isoenzyme pattern and pulmonary tory volume in 1 s (FEV,) were determined using function impairment was investigated in patients with a spirometer (Jaeger, Masterlab, Wuerzburg, a history of coal-dust exposure. Germany). Diffusion capacity (DCO) was obtained by the single breath method and corrected for Methods haemoglobin. The predicted values for each subject, based on sex, age and height, were obtained from PATIENTS standard tables (24). Data were expressed as The study was performed in a population of percentages of the predicted values. ex-coalminers (n=201), all men. They were admitted to the authors’ hospital for a medical check-up. All had a history of coal-dust exposition, more than LABORATORY TESTS 20 yr ago. Their medical history revealed no other Simultaneously with pulmonary function tests, blood relevant pulmonary disorders. The majority of the samples were taken and serum was stored frozen at ex-coalminers (n= 182, 90%) were smokers, having - 70°C until actual measurement of LDH and its had a smoking history of many years. The chest isoenzyme pattern. In the authors’ laboratory, LDH X-ray was classified as normal in 52 cases (26%). The activity is measured at 37°C by an enzymatic rate 618 N. A. M. COBBEN ET AL.
TABLE 2. Results of laboratory tests of the studied cases of ex-coalminers
Reference Total group Group I Group II Parameters value (n=201) (n=52) (n= 159)
Albumin (g 1 - ‘) 35.0-55.0 39 It 3 (38.9) 38 It 3 (389) 38 I+:3 (38.8) Ureum (mm01 1~ ‘) 3.0-7.0 6.0 i 2 (6.0) 6.0 * 1.6 (6.0) 6.3 f 2 (6.0) Creatine (mm01 1 - ‘) 71-110 100 ZIZ60 (95) 93 5 19 (16.0) 102 f 67 (94) ALT (Ul-‘) 5540 19Zt 10 (17) 19 * 7 (19.0) 19* 10 (17) y-GT (U 1 - ‘) 2-50 31f43 (23) 30% 37 (22) 31 f 44 (23) CK (U 1-r) 40-240 96*78 (76) 80*43 (69) 100 + 84 (77) LDH (Ul-‘) 361 & 59 633 zt 245 (573)s 371 f 55 (372) 703 k 229 (632)* LDH, (%) 21 f 3.4 15 i: 4 (lS.O)§ 19 f 3 (19.5) 14 * 3 (13.9)$,§ LDH, (%) 39.7 f 2.5 37 If 4 (37.0)§ 40 Ik 4 (40.9) 36 f 3 (36.4)$,§ LDH, (%) 18.6 f 1.9 31 * 4 (31.9)§ 26 * 4 (25.4)§ 33 4 3 (32.5)$,$ LDH, (%) 8.7 f 1.4 11 f 3 (11.2)s 9~t2 (8.6) 12 Et 3 (11.9)$,§ LDH, (%) 11.8 f 3.2 5 f 2 (4.6)§ 6 + 2 (5.4)9 5 * 2 (W-t,§
Data are expressed as means f SD, with median values in parentheses. Group I, normal serum lactate dehydrogenase (LDH) activity; Group II, high serum LDH activity; ALT, alanine aminotransferase; y-CT, y-glutamyl transferase; CK, creatine phosphokinase; LDH,-,, LDH isoenzymes. t-test Group I vs Group II: “P~0.05, tPCPO.01, $P
function tests, creatine kinase and creatinine) were within normal ranges (Table 2). In Table 3, the results of the pulmonary function tests of the different groups are summarized. Negative relations between the FEV, and the total LDH activity (r= - 0.26, P TABLE 3. Results of pulmonary function tests of the studied cases of ex-coalminers Flow volume Total group Group I Group II (BTPS) (n=201) (n=42) (n= 159) FEV, (1) 1.91 f 0.69 2.16 5 0.7 1.84 i 0.67” FEV, of norm (%) 69 zt 22 75 f 21 68 f 227 FVC (1) 3,38 f 0.78 3.65 iz 0.74 3.31 & 0.78” FVC of norm (%) 96&31 98zt 16 96 f 34 FEV,/FVC (%) 56 zk 14 58~t 11 55 f 15 n=190 n=40 n= 150 DC0 (%) 68 * 20 70521 68 f 20 Data are expressed as means f SD. Group I, normal serum lactate dehydrogenase (LDH) activity; Group II, high serum LDH activity; BTPS, body temperature and pressure, saturated with water vapour; FEV,, forced expiratory volume in 1 s; FVC, forced expiratory volume; Dco, diffusion capacity measured by single breath method. “PcO.05 Group I w II, tW0.001 Group I vs Group II. adequately differentiate the contribution of dust between ex-coalminers with a normal chest X-ray vs exposure as cause of the pulmonary function impair- those with an abnormal chest X-ray concerning the ment (23). In line with this, differences were not found LDH activity and its isoenzyme pattern. In several pulmonary disorders associated with cell death or cell damage, elevated serum LDH activities 1400 r (a) ’ 0 have been reported. De Remee (14) reported elevated & 1200 . serum LDH in five cases of interstitial pneumonitis. . l . 2 . . . Matusiewicz et al. (8) reported serum LDH to be a x 1000 simple, though non-specific, test which appears to 3E 800 reflect changes of disease activity in patients with cryptogenic fibrosing alveolitis (CFA), extrinsic g2 600 allergic alveolitis (EAA) and hypersensitivity pneu- 72 s 400 monitis, but not in sarcoidosis. Recently, Drent et al. 200 L (22) described a similar increase of the LDH iso- 20 40 60 80 100 120 140 enzyme pattern in serum as well as in BALF obtained Percentage FEV, of norm from a patient with a lipoid pneumonia. Moreover, a 50, , high LDH activity has been reported in Pneumocystic 1(b) carinii pneumonia (22,28), pulmonary alveolar pro- teinosis (10) and desquamative interstitial pneumo- nitis (11,13,14). So, several pulmonary disorders have been associated with elevated serum LDH activity. An increase in airway LDH activity might arise from diverse sources, including rupture (necrosis) of the airway and/or alveolar epithelial cells, AMs or other pulmonary cell types, increased flux of plasma- 101 I I 1 I I derived LDH through an air/blood barrier rendered 20 40 f5jl 80 100 120 140 more permeable by pulmonary injury (e.g. oedema, Perckntage FEV, of norm haemorrhage), and elevated plasma LDH concen- FIG. 2. Relations between (a) the forced expiratory tration resulting in an increased plasma/alveolus con- volume in 1 s (FEV,) and serum lactate dehydroge- centration gradient, with a consequent increased rate nase isoenzyme (LDH), and (b) FEV, and LDH, of passage of LDH across the air/blood barrier of a activity in the total group of ex-coalminers. normal lung (16,29). Thus, LDH might be released LDH PATTERN IN EX-COALMINERS 621 TABLE 4. Pearson coefficient of correlation testing a relation between the total lactate dehydrogenase (LDH) activity in serum and pulmonary function tests of ex-coalminers FEV, of norm FVC of norm Dco W> Wo> v4 Correlation with total LDH Y= - 0.26 r= - O-06 r= - 0.06 P NS, not significant; FVC, forced expiratory volume; FEV,, forced expiratory volume in 1 s; Dco, diffusion capacity measured by single breath method; Y, coefficient of correlation. from injured cells of the lung into the pulmonary participating in the inflammatory and fibrogenesis interstitium and alveoli, or from damaged inflam- processes (34). When AMs ingest silica, they release matory cells that infiltrate the lung after treatment. chemical attractants, thereby inducing the required However, less is known about the utility of the LDH amplification of macrophage production and release. isoenzyme pattern in the assessment of pulmonary This process is perpetuated by serial ingestion, cell function impairment. killing, release of crystals and rephagocytosis (35-38). The LDH isoenzyme pattern of the lung is charac- This accounts for the continuously high output of terized by proportionally high LDH, and LDH, AMs, even after a brief exposure of silica. Brown compared to the normal serum isoenzyme pattern. A et al. (39) demonstrated that supernatants of human high serum LDH, activity was reported just after AMs stimulated with silica contained large amounts pulmonary embolism (12). Release of LDH, from of apparent growth factor activity for human lung injured pulmonary parenchyme presumably produces fibroblasts. Since all miners in the present study were the observed rise in serum LDH, activity. However, retired, acute effects of coal-dust exposure were during acute rejection of a pulmonary graft in man, excluded; repeated ingestion of old silica particles, serum LDH, and LDH, were increased (30). Bansal still present in the lung, giving cell death after more et al. (17) found that AMs contained all five LDH than 20 yr, seems to be the cause of the elevated levels isoenzymes, with LDH, being the most prominent. of serum LDH in this group of retired miners. Animal studies confirmed observations that the Bowden et al. (40) studied the fibroblast proliferation intrapulmonary instillation of silica particles results of silica- stimulated human AMs in vivo. By determi- in an immediate severe inflammatory reaction. This nation of hydroxyproline, they found a significant early structural damage was followed by reparative increase in collagen. Taken in conjunction with the processes that were manifested by replication of epi- morphological data, it is reasonable to conclude that thelial cells, endothelial cells and fibroblastic cells as the cellular granulomas subside, the residuum of (31). Furthermore, a focal centrilobular necrosis of collagen becomes incorporated into the peribron- type I pneumocytes cells was accompanied by a chiolar connective tissues. The localization of this fibrinous exudate. This focal necrosis was rapidly excess of collagen, and the absence of significant repaired by proliferation of type II pneumocyte cells. scarring on the walls of peripheral air sacs, may An increase in cuboidal cells after silica exposure was account for the remarkable paucity of symptoms in first described by Policard et al. (32). At present, type many people who are exposed to silica, and for the II cell hyperplasia is generally regarded as the stan- poor correlation between the radiologic demon- dard reparative reaction after type I cell injury. stration of peribronchial scars and the lack of signifi- Melloni et al. (33) showed LDH release from AMs in cant impairment of pulmonary function. Moreover, supernatants in vitro after 24 h of incubation with simple mineral dust exposure, in the absence of mineral dust. The latter group found that AMs were smoking, pneumoconiosis, or both, did not increase an important source of factors that normally stimu- the prevalence of emphysema, seen by HRCT (41). late type II cell proliferation, and that this prolifer- In agreement with Dubar et al. (42), the present ative activity was enhanced by in vitro silica exposure. authors did not find differences between smokers and The cytotoxicity of silica for AMs has been consid- non-smokers. The latter group (42) studied the im- ered to be a major component in the development of mediate affect of cigarette smoke on cell injury, cell fibrosis. Cell death induced the release of mediators viability and cytokine secretion by AMs from guinea 622 N. A. M. COBBEN ET AL. pigs and healthy human subjects. They measured 3. Wouters EFM, Yorna THJM, Westenend M. Respir- LDH release in a culture medium after smoke expo- atory effects of coal dust exposure: clinical effects and sure together with measurement of IL-6 and TNF-a diagnosis. Exp Lung Res 1994; 20: 3855394. activities. The release of LDH from AMs in the 4. Schins RPF, Borm JA. Plasma levels of soluble tumour culture medium was unchanged both immediately necrosis factor receptors are increased in coalminers after tobacco smoke exposure and at the time of the with pneumoconiosis. Eur Respir J 1995; 8: 165881663. 5. Vanhee D, Gosset P, Marquette CH et al. Secretion cytokine evaluation (1 S-20 h later). 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