This issue of the AJRCCM (pp. 70–77) contains a meticulously illustrated article on hard metal lung disease (HMLD) (1), an uncommon and still somewhat mysterious occupational interstitial lung disease that affects people exposed to dust from hard metal objects. The disease has been known by various names: hard metal pneumoconiosis, tungsten carbide pneumoconiosis, hard metal lung, giant cell interstitial pneumonitis (GIP), and cobalt lung (2).

The clinical presentation of HMLD is similar to that of hypersensitivity pneumonitis, with some patients having episodes of work-related subacute disease and some patients evolving, more or less rapidly, to lung fibrosis. However, the pathology of HMLD is unique in that it is characterized, at least in typical cases, by the presence of “cannibalistic” multinucleated giant cells in airspaces (and bronchoalveolar lavage) (3).

The term “hard metal” has nothing to do with the “heavy metals” lead, cadmium, and mercury. Hard metal is generally produced by compacting powdered tungsten carbide (WC) and cobalt (Co) (+ some other agents) into a polycrystalline material, a process called sintering, hence the term “sintered carbides” (or cemented carbides). This composite material has a hardness almost that of diamond; it is used to make machine parts that require high heat resistance, or to make tools used for drilling, cutting, machining, or grinding. Industrial diamond tools are not hard metal tools (since they do not contain WC), but may also contain Co as a binder. The discovery that the use of diamond tools could lead to the same pathology as that of HMLD confirmed that Co plays a dominant role in HMLD (4).

That GIP (first described by Liebow [5]) is pathognomonic for HMLD was discovered when it emerged that nearly all subjects diagnosed with GIP in Liebow's collection had evidence of past exposure to WC (6). Although Co is always present in hard metal and is critical in the pathogenesis of GIP, this element is only detected in approximately 10% of lung tissue samples from patients with HMLD (7), presumably because it is highly soluble in body fluids. The mechanisms by which Co-containing dusts cause this peculiar interstitial disease are still largely unknown (2, 8).

One important aspect of HMLD is that the disease may occur after a short duration of exposure, thus suggesting that individual susceptibility, rather than cumulative exposure, plays a major role (9). The early occurrence of disease led Jobs and Ballhausen to publish, in 1940, their discovery of a new lung disease in workers from a hard metal factory in Krefeld, Germany: “[Es ist] außerordentlich auffallend, daß die Veränderungen sichtbar sind nach relative kurzer Arbeitszeit, einer Arbeitszeit, die sogar wesentlich kürzer ist …, als wir es bei der Silikose gewohnt sind” (It is extremely remarkable that the [radiological] changes are visible after a relatively short working time, a working time that is substantially shorter than we are used to seeing in silicosis) (10).

The article by Moriyama and collaborators (1) describes novel findings in archival lung tissue specimens from 17 patients with HMLD, which is a large series considering the rarity of the condition. Most of these biopsies exhibited typical GIP, but there were four patients with “atypical” GIP also showing fibroblastic foci as in usual interstitial pneumonia. Detection and characterization by microanalysis of particles retained in the lung of persons with suspected occupational/environmental exposures is not new, but Moriyama and colleagues (1) remind us that it is a powerful method to investigate mechanisms not only in HMLD but in other (interstitial) lung diseases. Although the presence and concentration of W-containing particles in GIP has previously been reported using scanning electron microscopy with energy dispersive spectrometry (SEM/EDS) (7), Moriyama and colleagues (1) describe the histologic distribution of elements, especially W, in the lung parenchyma by means of electron probe microanalysis. They showed that W was mainly distributed in the areas of peribronchiolar fibrosis, where it colocalized with CD163⁺ monocytes/macrophages and CD8⁺ lymphocytes, thus revealing a close spatial relationship between the inhaled particles of hard metal (at least their main constituent, W) and immunological cells, especially the monocytes/macrophages having acquired a phenotype of giant cells. In GIP/HMLD, these giant cells, which were described by Liebow as “cannibalistic,” showing individually discernable cells apparently in the process of being engulfed into the multinucleated cells, are often described as “bizarre” (5), but this feature, although illustrated, is not specifically mentioned in the article of Moriyama and colleagues (1).

The process by which these giant cells are produced and the role of Co, if any, in this process are still unknown. The presence of giant cells has only been observed rarely in animals exposed to hard metal dusts or their components (11), and the phenomenon has not been reproduced in vitro. Cobalt is a well-known skin sensitizer, causing allergic contact dermatitis, and it can also cause occupational asthma, but there is no convincing evidence for a cell-mediated immunologic reaction against Co in HMLD (2), although this issue would merit being revisited. Thus, HMLD differs from chronic beryllium lung disease, which is a granulomatous lung disease that can be diagnosed by a lymphocyte proliferation test using a Be salt as the antigen (12). As a transition metal, Co has prooxidant properties (13), and these are enhanced by WC (14). Consequently, it is conceivable that the individual susceptibility to develop HMLD is related to an innate or acquired inability to deal with oxidant injury. Another property that has, so far, not been pursued in the field of HMLD is that Co ions are potent inducers of hypoxia-inducible factor (HIF)–1, an important intracellular regulator of numerous genes involved in glucose metabolism, angiogenesis, cell survival, proliferation, and apoptosis (15). HIF-1 is activated during macrophage differentiation (16), but the effects of such activation in dust-laden alveolar macrophages are unknown. Perhaps macrophages are stimulated by Co and WC to become the bizarre, cannibalistic, multinucleated giant cells that are so characteristic of GIP/HMLD. In demonstrating the CD163⁺ macrophages in HMLD, Moriyama and coworkers (1) open another direction for investigating the pathogenesis of GIP, an interstitial lung disease that is still hard to understand.

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