INTRODUCTION

TOP ABSTRACT INTRODUCTION CASE REPORT DISCUSSION REFERENCES

Keywords: Niemann-Pick Type B disease; pulmonary involvement; whole-lung lavage

Niemann-Pick disease is a lipid storage disorder caused by an absence or deficiency of the enzyme acid sphingomyelinase. Patients with Type A Niemann-Pick disease usually die within a few years of birth, but in Type B disease, in which there is phenotypic variability and some residual enzyme activity, patients often survive into adulthood. In more severely affected patients with Type B disease, diagnosis in childhood usually follows the development of hepatic and splenic disease, but in later life, progressive pulmonary infiltration tends to be the cause of mortality and major morbidity (1). To date, no treatment specific for pulmonary involvement by Type B Niemann-Pick disease has been reported. We present the case of a patient with Niemann-Pick Type B disease resulting in severe ischemic heart disease and extensive lipoid pneumonia, in whom life-threatening hypoxia was successfully alleviated by bilateral whole-lung lavage.

	CASE REPORT

TOP ABSTRACT INTRODUCTION CASE REPORT DISCUSSION REFERENCES

A 48-yr-old man presented with substantial exertional dyspnea following an inferior myocardial infarction. The patient had had no previous respiratory systems or other medical history. Examination revealed a normotensive patient in sinus rhythm, with no abnormal chest sounds. There was no hepatosplenomegaly. Hematologic and basic biochemical parameters were within normal limits. Cardiac catheterization revealed global impairment of left ventricular function, with marked anteroseptal and inferior hypokinesis. The patient was also found to have significant coronary artery lesions, with a tight left main-stem stenosis and occlusion of the right coronary artery, which were considered suitable for coronary artery bypass surgery. A chest radiograph showed diffuse ground-glass opacification thought to be due to pulmonary edema, although superimposed coarse reticular shadowing raised the possibility of a coexistent diffuse parenchymal lung disease (Figure 1).

View larger version (150K): [in this window] [in a new window]   Figure 1.   A chest radiograph shows diffuse bilateral and mid-zone ground-glass shadowing, with thickening of the horizontal fissure and a superimposed reticulonodular pattern in the lower zones.

Because the patient's coronary artery disease was life-threatening, he underwent urgent surgical revascularization, at which time an open lung biopsy specimen was taken from the left lower lobe. Histologically, the alveolar architecture was wholly preserved, with the alveolar spaces filled by abundant, finely vacuolated foamy macrophages. There was little inflammation and no extracellular lipoid material within the interstitium, although a mild degree of interstitial fibrosis was present (Figure 2). Histochemical staining for fungal organisms was negative. A diagnosis of endogenous lipoid pneumonia was made. There was no history of aspiration or ingestion of drugs known to cause lipoid pulmonary infiltration: medication prior to presentation comprised dipyridamole and omeprazole only, with no history of amiodarone therapy. On clinicopathologic review, the possibility of an underlying inborn error of metabolism was considered. Further biochemical investigation identified a reduction of serum high-density lipoprotein (HDL) cholesterol to less than 50% of the normal reference interval, with an accompanying normal total serum cholesterol concentration. Ultrastructural analysis of the macrophages obtained at biopsy showed giant lamellar structures within the cytoplasm, consistent with a lipid storage disease (Figure 3). Diagnostic confirmation was achieved by analysis of white blood cell lysosomal enzyme activity. Sphingomyelinase activity was 0.3 nmol/h/mg white cell protein (reference interval: 0.74 to 7.01 nmol/h/mg). This result was consistent with Niemann-Pick disease, and given the age of the patient and the presence of residual enzyme activity, the patient was diagnosed as having the Type B form of the disease. Gaucher's disease and GM₁-gangliosidosis were excluded by the finding of normal enzyme activities of -glucosidase and -galactosidase.

View larger version (118K): [in this window] [in a new window]   Figure 2.   The alveolar spaces are filled by finely vacuolated alveolar macrophages characteristic of endogeous lipoid pneumonia, with mild fibrotic thickening of the interstitium (Elastic van Gieson stain).

View larger version (191K): [in this window] [in a new window]   Figure 3.   Utrastructural analysis shows giant lamellar structures within the cytoplasm of alveloar macrophages, consistent with Niemann-Pick disease.

High-resolution computed tomography (HRCT) (Figure 4) at the time of the surgical lung biopsy had shown extensive bilateral ground-glass attenuation, with some focal areas of consolidation and thickening of the interlobular septa. Formal pulmonary function tests (Table 1) had disclosed a restrictive functional deficit, severe depression of total gas transfer, and marked resting hypoxia on room air (arterial oxygen tension [Pa_O2] 6.6 kPa). Because of the high risk of ongoing myocardial ischemia from severe impairment of pulmonary function, and the possibility that intense macrophage infiltration might be modulated pharmacologically, empiric steroid therapy was begun. Six weeks of prednisolone at a daily dose of 40 mg was associated with a significant improvement in pulmonary function indices (Table 1), although the patient still had substantial residual functional impairment and radiographic shadowing. The dose of prednisolone was gradually tapered, but in view of the initial response, the patient remained on 20 mg daily over the next 6 mo. However, during this period there was a significant decline in pulmonary function (Table 1), with a reduction in resting Pa_O2 on breathing of air from 9.4 kPa to 8.4 kPa, and a recurrence of exertional angina, in association with oxygen desaturation. Repeat HRCT showed minor regression of ground-glass attenuation at the lung apices, but a striking increase in density at the lung bases (Figure 5A). Because steroid therapy had failed to prevent pulmonary macrophage accumulation, no alternative pharmacologic treatment could be justified, and because the patient's increasing hypoxia was clearly life-threatening, empiric whole-lung lavage was performed. Because this treatment was unprecedented in lipoid pneumonia, a personalized consent form was devised to highlight the urgent need for a therapeutic response, the lack of a recognized treatment, the novelty of the proposed intervention, the potential benefits of the procedure, and the likelihood of increased risks of whole-lung lavage in cardiac disease.

View larger version (154K): [in this window] [in a new window]   Figure 4.   HRCT shows extensive bilateral ground-glass shadowing, some focal consolidation, coarse reticular shadowing, and thickening of interlobular septa.

View larger version (162K): [in this window] [in a new window]   View larger version (164K): [in this window] [in a new window]   Figure 5.   (A) HRCT at 6 mo shows increased intensity of ground-glass attenuation in both lungs, most obvious in the dependent lung. Following lavage (B), there is a significant decrease in the density of the parenchyma.

The lungs were sequentially lavaged, with a 2-wk interval between the two procedures, using a technique described previously for the treatment of alveolar proteinosis (2). The procedure consisted of single-lung anesthesia, with degassing of the excluded lung by use of a volume of warm neutral saline equal to the predicted FRC for that lung and subsequent tidal lavage volumes of 500 to 800 ml. The initial returns were heavily laden with pinkish-grey proteinaceous debris. A total of 18 L of saline was used for the right lung (over a 53-min period of single-lung ventilation), and 21 L for the left lung (with 63-min of single-lung ventilation), after which the returns were mostly clear. All residual fluid was drained and accounted for, and the treated lung was reventilated, with the double-lumen tube replaced by an endotracheal tube for postoperative ventilation in recovery.

Postoperatively, HRCT showed a marked reduction in ground-glass opacification within the lung parenchyma (Figure 5B) in association with a marked increase in exercise tolerance. On pulmonary function testing (Table 1), the resting Pa_O2 with breathing of room air rose to 10.3 kPa, with a corresponding decrease in the calculated alveolar-arterial oxygen gradient from 5.8 kPa to 4.0 kPa. There were marginal but not significant improvements in lung volumes and gas transfer levels.

	DISCUSSION

TOP ABSTRACT INTRODUCTION CASE REPORT DISCUSSION REFERENCES

Niemann-Pick disease is one of several inborn errors of metabolism that cause clinical disease in the lung, with other such diseases including Gaucher's disease (3), lysinuric protein intolerance, cholesterol ester storage disease, and Fabry's disease (1, 3, 4). In most patients, pulmonary involvement by all of these disorders is asymptomatic. Among the various diseases, alveolar accumulation of excess protein and/or lipid occurs in lysinuric protein intolerance, in which there is an alveolar proteinosis-like picture, and in both Gaucher's disease (3) and Niemann-Pick disease Types A and B, in which alveolar filling by foamy macrophages is a recognized feature (5, 6). In Niemann- Pick Type B disease, imaging features are described as a diffuse or finely nodular reticular infiltration in chest radiographs (1), and areas of nodular, centrilobular ground-glass opacification in the upper and mid-zones of the lung, plus thickening of the interlobular septa on HRCT (5). In asymptomatic children, the presence of these pulmonary infiltrates should raise the possibility of a metabolic storage disease (7), but it is rare for a patient to reach adulthood without hepatic or splenic symptoms leading to a prior diagnosis, even in the presence of significant pulmonary disease (8). In the present patient, cardiac disease, presumably due to edema precipitated by the patient's infarct, either compounded the patient's pulmonary disease or acted as a co-factor for its exacerbation. Indeed, the underlying coronary artery disease was itself most likely related to the patient's lipid storage disorder.

Although a defect in exogenous cholesterol trafficking is characteristic of Type C Niemann-Pick disease, cholesterol (in addition to sphingomyelin) accumulates in tissues in patients with Types A and B of the disease (9). It has not been described that cholesterol accumulation in Type A or Type B Niemann- Pick disease is mirrored by changes in serum total cholesterol concentrations, but there are reports in the literature of reductions in serum HDL cholesterol concentrations, as in the present patient (9, 10). The clinical significance of this is not clear.

With regard to treatment, there is no precedent for the use of whole-lung lavage in Niemann-Pick disease, although bone marrow transplantation has been successful in reducing liver volume and pulmonary infiltration in the disease (11), and gene therapy with hemopoietic stem cells may become available in the future (12, 13). However, our patient was not a candidate for such procedures, owing to his severe cardiac disease, and had unequivocal deterioration despite high-dose maintenance steroid therapy. A decision was therefore made to undertake whole-lung lavage. This decision was based on the precedent of successful treatment of other alveolar filling disorders, such as alveolar proteinosis (2); in this case, as in alveolar proteinosis, lipid accumulation was wholly intraalveolar, with no loss of architecture. From an ethical viewpoint, the risks of this procedure were considered, in particular the possibility that the material in the lung might be too dense to clear, and also that the whole-lung instillate might be difficult to retrieve, thus triggering further myocardial ischemia. However, it was felt that the probable benefit of successful lavage outweighed the risksa belief that was supported by the procedure leading to significant clearing of shadowing on HRCT and a marked improvement in resting Pa_O2 on breathing of air to 10.3 kPa from 8.4 kPa.

In conclusion, whole-lung lavage appears to be a potentially useful treatment modality for patients with pulmonary involvement by Niemann-Pick Type B disease. Its application to other alveolar filling defects, not amenable to established therapies, should be considered.