KL-6 is a mucin-like high molecular weight glycoprotein found in 1988 by Kohno et al [6
]. This group also developed a monoclonal antibody against KL-6, which reacts with a sialylated carbohydrate antigen strongly expressed in Type II alveolar pneumocytes and bronchiolar epithelial cells, but not on granulomatous tissue. Several studies demonstrate that KL-6 is elevated in the bronchoalveolar lavage fluid and serum of patients with various types of interstitial pneumonia. The elevation of serum KL-6 levels is considered to be associated with increased permeability of the alveolar capillary barrier [20
]. It has also been reported that KL-6 induces chemotaxis of human fibroblasts in vitro
, suggesting that it may have a pathological role in fibrosing lung disease [21
]. Therefore, measurement of serum KL-6 is now widely accepted as a diagnostic marker for monitoring the activity of interstitial lung diseases, such as idiopathic interstitial pneumonia, and for the long-term management of various interstitial diseases [1
The clinical picture of sarcoidosis varies from that of a totally asymptomatic patient, with incidental radiographic findings of bilateral hilar lymphadenopathy, to a seriously dyspnoeic patient with acute respiratory distress syndrome. Alveolitis and subsequent granulomatous processes are important in the pathogenesis of sarcoidosis [22
]. Bronchoalveolar lavage studies have revealed that the alveolitis in sarcoidosis is characterised by lymphocytic infiltration of T helper cells. The activated T cells release various cytokines such as interleukin-2 and interferon-gamma, which are believed to play many important roles in the pathogenesis of sarcoidosis. Active alveolitis is often accompanied by pulmonary tissue injury or clinical deterioration.
In 1989, Kohno et al [1
] reported that serum KL-6 levels were elevated in 4 of 31 patients with sarcoidosis; however, further study was not performed. Kobayashi et al [16
] investigated the use of serum KL-6 as a marker for sarcoidosis activity in 47 patients, and found that serum KL-6 levels were significantly elevated in radiographic Type II and Type III patients compared with Type 0 and Type I cases. These observations are similar to those in our study. However, it was difficult to ascertain whether the pulmonary lesions in these patients were characterised by interstitial, granulomatous or fibrous changes.
Hiroshige et al [25
] presented a case report of a sarcoidosis patient with an elevated serum KL-6 level, where CT images showed panlobular ground-glass opacity with mosaic distribution. After steroid treatment the CT findings improved and serum KL-6 normalised.
However, no studies describing the radiological findings comparing thin-section CT images between patients with elevated KL-6 levels and those with normal KL-6 levels have been published in English. We retrospectively identified 101 patients with sarcoidosis who underwent chest thin-section CT examinations and had serum KL-6 measured.
Ground-glass opacity, traction bronchiectasis, architectural distortion, nodules, interlobular septal thickening and bronchial wall thickening were significantly more frequent in patients with elevated KL-6 levels than those with normal ones.
Pathologically, ground-glass opacity is considered to represent interstitial inflammatory infiltrate with marked thickening of alveolar septa by fibrous tissue [26
]. Lynch et al [27
] and Hiroshige et al [25
] reported that ground-glass opacities correlated with active diffuse alveolitis.
Traction bronchiectasis and architectural distortion are considered to represent the organisation and fibrosis of the lungs around the bronchi [26
]. Our results showed that increased KL-6 levels in sarcoidosis patients whose CT scans consisted of ground-glass attenuation, architectural distortion or traction bronchiectasis may have been caused by an increase in KL-6 production by regenerating alveolar Type II pneumocytes and/or an enhanced permeability following the destruction of the air–blood barrier in the affected lungs.
Bronchial wall thickening, interlobular septal thickening and nodules along bronchi, interlobular septa and pleural regions were also significantly observed more frequently in patients with an elevated KL-6 level than in those with a normal KL-6 level. CT findings are considered to correspond to granulomas, with or without perigranulomatous fibrosis, formed in the connective tissue sheath around the bronchial walls, pulmonary vessels and airways [29
]. Thus, our results might be due to perigranulomatous fibrosis with granulomas.
On the other hand, the present study showed that there was no significant difference in the frequency of consolidation between the two groups. Consolidation has revealed alveolitis with inflammatory exudates in alveolar spaces and/or accumulated granulomatous lesions [29
]. In the present report, biopsy specimens corresponding to consolidation could not be obtained, and whether consolidation shows alveolitis or granulomatous lesions remains unclear. This result may possibly be due to a low frequency of consolidation in this study compared with that of previous studies [31
]. Future work should confirm these findings by use of a greater sample size.
Finally, there were several limitations in our study. First, we undertook a retrospective study, and CT image interpretation was performed by consensus. Second, CT findings were not compared with pathological findings in all patients because some patients were asymptomatic and the diagnosis of sarcoidosis could be performed using clinical findings. Third, CT scans, measurement of KL-6 levels and histological specimens were not obtained on the same days. Fourth, CT images were obtained at several CT scans using different protocols. Furthermore, the relationship between the extent of abnormal findings and KL-6 levels was not evaluated.
In summary, thin-section CT findings of nodules, bronchial wall thickening, ground-glass opacity, traction bronchiectasis and architectural distortion were associated with elevated serum KL-6 levels. These results suggest that serum KL-6 levels may be a useful marker for indicating the severity of parenchymal sarcoidosis.