Study objectives: To evaluate the pulmonary manifestations and the course of acute respiratory insufficiency associated with lysinuric protein intolerance (LPI).
Design: Retrospective review of clinical data and chest radiographs (total 225) obtained during the lifetime followup of 31 LPI patients. About half of the 25 patients without respiratory symptoms underwent high-resolution computed tomography (HRCT) of the lungs, radionuclide perfusion imaging, whole body plethysmography, and diffusing capacity measurements.
Patients: Thirty-one Finnish patients with LPI.
Results: During the follow-up period, four children with LPI died in respiratory insufficiency, and another had chronic symptoms, whereas 25 patients remained symptom-free. The radiologic findings in acute progressive respiratory insufficiency were uniform: at first, reticulonodular interstitial densities and, later on, progressive airspace disease. At autopsy, three patients showed pulmonary alveolar proteinosis and one had pulmonary hemorrhage and cholesterol granulomas. One adult had reversible respiratory insufficiency with signs of bronchiolitis obliterans, another adult had recurrent episodes of chest pain, dyspnea, and hypoxia. Of the symptom-free patients, one third (8 of 25) had signs suggestive of pulmonary fibrosis evidenced on chest radiographs and two thirds (8 of 14) had signs evidenced by HRCT films. Most symptom-free patients showed mild abnormalities either in perfusion imaging (9 of 12) or in function tests (8 of 12).
Conclusion: In childhood, patients with LPI are highly predisposed to develop pulmonary hemorrhages and alveolar proteinosis. Interstitial lung densities may precede the acute phase. Most adult LPI patients show radiologic signs of interstitial lung disease but only a few show clinical impairment.
Lysinuric protein intolerance (LPI) is an autosomally, recessively inherited metabolic disease in which the transport of cationic amino acids is defective. The basolateral transport defect is expressed in the epithelial cells of the intestine and the kidney tubules, hepatocytes, and skin fibroblasts. The intracellular functional deficiency of cationic amino acids affects the urea cycle function, and usual amounts of dietary protein may lead to hyperammonemia.
The first Finnish LPI patients were identified in 1965. To date, about 80 cases have been diagnosed worldwide, 38 of them in Finland, where the prevalence is about 1 in 60,000. Lysinuric protein intolerance patients present with failure to thrive, growth retardation, protein aversion, osteoporosis, fractures, muscular hypotony, and enlargement of the liver and spleen. Urinary excretion of lysine, arginine, and ornithine is massively increased, their absorption from the intestine is decreased, and their plasma concentrations are subnormal. The concentrations of ferritin and the activity of lactate dehydrogenase in the serum are increased.
As a systemic disease, LPI has manifestations in all organ systems. The only reported life-threatening complication of LPI is acute progressive respiratory insufficiency.[3-5]
The present study evaluated potential contributory factors, preceding signs, and the course of the acute respiratory insufficiency associated with LPI. The extent, type, and prognostic value of pulmonary manifestations in symptom-free LPI patients also were studied.
MATERIAL AND METHODS
We analyzed clinical data accumulated on 31 of the 38 known Finnish LPI patients (12 men and 19 women; age range, 3.7 to 48.9 years; mean age, 26.9 years [Table 1]). The mean follow-up time was 17.5 years (range, 3.7 to 26.5 years). The patients were divided into groups according to the existence of respiratory symptoms: patients with fatal respiratory insufficiency (study group A), patients with serious respiratory complications (study group B), and patients without respiratory symptoms (study group C).
A diagnosis of LPI was made based on evidence of massively increased urinary excretion of lysine, arginine, and ornithine, decreased plasma concentrations of these cationic amino acids, increased serum concentrations of ferritin, increased activity of lactate dehydrogenase in the plasma, postprandial hyperammonemia, and clinical findings of LPI.
In addition to LPI, one patient had hypothyroidism, one had rheumatoid arthritis, one had systemic lupus erythematosus (SLE), one had congenital rubella syndrome, and five were hypertensive. Seven patients of 31 had generalized hypotonia needing physiotherapy; of them, 4 were children under the age of 15 years. All patients had been on a protein-restricted diet (protein, about 1 g/body weight/d) and receiving L-citrulline (0.1 to 0.5 g/body weight/d) in an attempt to increase their protein tolerance. In group A, three patients (cases 2, 3, and 4) were given corticosteroids (prednisolone 1 mg/body weight/d) in their final course; in group B, 1 patient (case 5) had a 12-month period of high-dose corticosteroid treatment (prednisolone 100 mg/d for 2 weeks, then a gradual decrease to 60 mg/d in 2 months, and finally 10 mg/d) because of acute respiratory insufficiency; and in group C, 1 patient (case 24) had corticosteroid treatment for 6 months because of rheumatoid arthritis.
Two patients were smokers (cases 17 and 21), and three had given up smoking. The remaining patients had no smoking history.
All available chest radiographs accumulated during the follow-up period (a total of 255 studies) were reviewed by a radiologist who was unaware of other aspects of the patients' clinical status.
Radiographic studies were done on 17 patients (mean age, 27.1 years). High-resolution computed tomography (HRCT) was performed using a CT PACE tomograph (General Electric Medical Systems, Milwaukee) with 1-mm collimation and 2 s scan time at 120 kilovolt and 160-ma settings and 3-cm intervals (5 to 6 sections for each patient) at full inspiration. The images were reconstructed using a bone algorithm and targeted separately at both lungs with a field of view of 25 cm.
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Fourteen patients (mean age, 31.3 years) underwent radionuclide imaging of lung perfusion using intravenous technetium 99 m-labeled macroaggregated albumin.
Lung Function Measurements and Bronchoalveolar Lavage
The pulmonary function of 13 patients (mean age, 30.8 years) was measured by means of constant-pressure body plethysmography and expressed as a percentage of the predicted values. Diffusing capacity for carbon monoxide was determined by the single-breath method and compared with predicted values.
Four patients underwent fiberoptic bronchoscopy and segmental bronchoalveolar lavage (BAL). Total cell counts were done on an aliquot of fluid using a hemocytometer; the differential cell count was done on cytocentrifuge preparations.
Patients With Fatal Respiratory Insufficiency (Study Group A)
During the follow-up, four patients developed fatal respiratory insufficiency; all of them were children aged less than 15 years. The autopsy specimens of one patient showed massive pulmonary hemorrhage and cholesterol granulomas; the three other patients showed evidence of pulmonary hemorrhage and alveolar proteinosis.
In addition to LPI, two patients had a second systemic disease (SLE and hypothyroidism). Patients with fatal respiratory insufficiency did not differ from the patients without respiratory manifestations in the duration or success of the diet therapy; the diagnosis of LPI was established at the mean age of 5.8 years (range, 1.0 to 10.0 years) in patients with fatal respiratory insufficiency and 8.4 years (range, 0.1 to 30.6 years) in LPI patients without respiratory symptoms, respectively.
The concentration of immunoglobulin A in serum was normal in three patients and marginally increased in one patient. The concentrations of immunoglobulins G and M were normal in one patient and slightly increased in three patients. The subgroups of immunoglobulin G were measured in only one patient and they were normal. One patient had slightly decreased activity of natural killer cells, the ratio of T helper to T suppressor lymphocytes was 1:1.
All patients had interstitial densities evidenced on chest radiographs at an early age, seen the first time at a mean age of 4.9 years (range, 1.2 to 10.2 years). Two patients developed acute respiratory insufficiency 2 months after detection of the interstitial densities. One patient had interstitial densities for 2.4 years before the acute phase; another had them for 12.1 years.
One patient (case 1) underwent pulmonary investigations 2 months before the appearance of acute respiratory insufficiency. The patient had no clinical respiratory symptoms; blood gas values were normal and chest radiographs showed reticular interstitial densities and HRCT ventral consolidation. Massive pulmonary hemorrhage and cholesterol granulomas were seen at autopsy.
In the acute phase, the radiologic course was very similar in all patients: at first, patients developed diffuse, reticulondular interstitial densities; later on, a rapidly progressing airspace disease was seen (Fig 1, top and center). In one patient, the lung biopsy specimen taken at the time of the appearance of the reticulonodular densities showed pulmonary alveolar proteinosis (Fig 1, bottom).
Patients With Serious Respiratory Complications (Study Group B)
Two adult patients had severe respiratory symptoms during the follow-up period. One of them (case 5) developed acute respiratory insufficiency presenting with cough, fever, dyspnea, and hemoptysis at the age of 23 years. Chest radiographs showed interstitial densities and airspace disease (Fig 2, top). Lung function tests showed minimal obstruction of the distal airways, and the diffusing capacity was normal. Extensive microbiologic investigations produced no evidence of infection. Lung biopsy specimens showed bronchiolitis obliterans with signs of interstitial pneumonia: granulation tissue polyps obstructed the bronchiolar lumen, and thickened interalveolar septa, lymphocyte and macrophage infiltrations, as well as alveolar hemorrhage also were seen (Fig 2, bottom). No vasculitis or signs of alveolar proteinosis were seen. In the cytocentrifuge preparation made from a lung biopsy specimen, macrophages accounted for 57 percent, neutrophils for 15 percent, and lymphocytes for 26 percent of the total cell count. The ratio of T helper to T suppressor lymphocytes was 0.81. The symptoms and radiographic signs disappeared after 2 months of high-dose corticosteroid treatment. After 8 months, hemoptysis recurred; the symptoms, however, responded to increased corticosteroid dosing. Five years later, at the time of the study, the patient was symptom-free; chest radiographs showed some interstitial linear densities, HRCT showed no abnormalities, radionuclide imaging showed slightly uneven perfusion, pulmonary function tests were within normal limits, and with the exception of an increased erythrocyte count, the proportions of cells in the BAL fluid were normal.
Another patient (case 6) had chronic, slowly progressing pulmonary insufficiency. During 6 years he had 7 exacerbations presenting with severe dyspnea, cough, chest pain, hypoxia, and hypercapnia with the first episode occurring at the age of 42 years. After BAL was performed, the clinical symptoms disappeared within hours. Chest radiographs showed increasing interstitial linear and nodular densities. Six years after emergence of the initial symptoms, radionuclide perfusion imaging showed a segmental defect and uneven perfusion. Pulmonary function tests showed slight restriction and a normal diffusing capacity. No abnormalities were disclosed when HRCT was performed. Bronchoscopy showed signs of chronic bronchitis; the proportions of cells in the BAL fluid were normal. Between the exacerbations, the patient was symptom-free and the blood gas values were normal.
Patients Without Respiratory Symptoms (Study Group C)
Sixty percent (15 of 25) of the patients without clinical respiratory symptoms showed radiologic signs of interstitial lung disease, as evidenced on chest radiographs during the follow-up period. Thirty-two percent (8 of 25) had interstitial densities that persisted at least for 4 years. Transient interstitial densities were seen in 11 patients during a total of 15 periods, but only 5 of these were clearly related to respiratory infection. The mean age of the appearance of the interstitial densities was 25.5 years. Ten patients showed linear densities; the remaining patients had reticular, nodular, and reticulonodular interstitial densities. Ten patients showed no parenchymal changes. Seven patients had a bell-shaped thorax, presumably due to muscular hypotony.
In 4 of the 14 patients studied, HRCT showed no abnormalities (Table 2). The changes found in the other ten patients were slight and nonspecific: irregularities in the walls of the bronchial tree (6 of 14), thickening of interlobular septa (5 of 14) or pleura (2 of 14), emphysematous bulla (2 of 14), ground-glass opacities (2 of 14), and bronchiectasis (1 of 14). Only one third of patients did not show signs of pulmonary fibrosis.
Radionuclide perfusion imaging gave normal results in 3 of the 12 patients studied (Table 2). Of the other nine patients, one had perihilar and apical lobar perfusion defects and eight had a nonuniform pattern of pulmonary perfusion.
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Twelve patients underwent whole body plethysmography and diffusion capacity measurements (Table 2). The mean of total lung capacity (TLC) was 76.6 percent of predicted values (range, 52.3 to 107.6 percent). The means of forced vital capacity (FVC) and [FEV.sub.1] were 86.3 and 87.0 percent of predicted values (ranges, 72.8 to 102 percent and 67.9 to 115.3 percent), respectively. The mean peak expiratory flow (PEF) was 87.1 percent of the predicted value (range, 49.7 to 126.1 percent). The diffusion capacity for carbon monoxide also was normal with a mean of 116.6 percent of the predicted value (range, 82.5 to 136 percent). The calculated mean of total lung resistance was 198.1 percent of the predicted value (range, 60.2 to 492.8 percent).
Two patients without pulmonary symptoms underwent BAL. The total cell counts were within normal limits in both cases. The proportions of lymphocytes were 46 and 59 percent, while those of macrophages were 52 and 38 percent.
All patients were physically active and the blood gas values were normal.
Infections in patients with LPI were sometimes complicated with unusually severe respiratory problems. Of the 31 patients, 15 had at least 1 episode of maxillary sinusitis; 2 patients had pansinusitis. Six patients had pneumonia severe enough to indicate hospitalization and parenteral administration of medication; two of these cases were caused by varicella. Cases of pneumonia caused by gastroesophageal reflux and aspiration were not seen.
In the current study, the early radiologic findings of acute respiratory insufficiency associated with LPI included interstitial reticulonodular densities and progressive airspace disease. These nonspecific abnormalities are easily misinterpreted as signs of cardiac insufficiency and infection. The possibility of alveolar proteinosis and alveolar hemorrhage should be considered at an early stage.
Alveolar proteinosis is a disease of unknown origin characterized by the accumulation of large amounts of phospholipids and amorphous proteinaceous material in the alveoli and distal airways of the lungs. Generally it is considered as a nonspecific alveolar reaction to severe damage. Also, it is seen secondary to obstructive processes and pulmonary hypertension. Alveolar proteinosis associated with LPI could be the end-state of a sequel of alveolar damage, inflammation, and increased permeability of the alveolar membrane. Experimentally, phospholipidosis can be induced by cationic amphiphilic drugs.[11,12] The increased concentrations of cationic amino acids in the alveolar epithelial lining of patients with LPI might also affect the metabolism of surfactant and surfactant proteins and predispose the patient to alveolar proteinosis.
Immunologic abnormalities have been reported in one Japanese LPI patient, but generally the immunologic responses in LPI are not well-known. In our material, one patient had SLE, one had rheumatoid arthritis, and one had hypothyreosis. One adult patient had an episode fulfilling the criteria of bronchiolitis obliterans. Earlier bronchiolitis obliterans has been reported to be associated with immunologic disorders such as rheumatoid arthritis, Sjogren's syndrome, and SLE. Also, the favorable response to corticosteroid treatment in our patient suggests immunologic etiology. The markedly increased lymphocyte counts in the BAL fluid of two symptom-free patients are suggestive of subclinical alveolitis, which is a common finding in several systemic immunologic disorders. The increased concentrations of cationic amino acids in alveolar lining or in instances of alveolar hemorrhage associated with infection could trigger alveolar epithelial damage and lead to an exaggerated inflammatory reaction in alveolar spaces.
Experimental pulmonary lesions evolve through damage to alveolar epithelial cells, denudation of the epithelial basement membrane, and alveolitis leading to fibrosis.[20,21] In our study, 39 percent (12 of 31) of the LPI patients showed signs of fibrosis as evidenced on chest radiographs, and 47 percent (8 of 17) showed these signs by means of HRCT. Several other inherited diseases, such as familial idiopathic pulmonary fibrosis, idiopathic disease, and Hermansky-Pudlak syndrome, also are associated with interstitial lung densities and eventual fibrosis.
A childhood history of interstitial densities was associated with an unfavorable prognosis. Five patients less than 10 years old showed interstitial densities (detected at a mean age of 5.6 years). Four of them died in a state of pulmonary insufficiency, whereas 1 was still symptom-free at the age of 18 years. The situation was different in adulthood. Ten adult patients showed signs suggestive of fibrosis (seen at a mean age of 29.5 years); two of them had clinical respiratory symptoms, whereas eight remained symptom-free. Similar differences between children and adults in the severity of symptoms can be seen in all organ systems, eg, 75 percent of fractures associated with osteoporosis in LPI occur in patients less than 15 years of age. One explanation could be that the inevitable protein restriction is most harmful in the period of active growth.
We conclude that patients with LPI have a marked tendency to develop pulmonary hemorrhages and alveolar proteinosis in childhood. Interstitial lung densities may precede the acute phase, which is radiologically characterized by reticulonodular interstitial densities and by airspace disease. Even though most adult LPI patients show radiologic signs of interstitial lung disease, only a few of them have clinical impairment.
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