Complications
Lung disease. Progressive interstitial changes in the lung are frequently detected from early years without overt clinical symptoms. Progression to severe pulmonary alveolar proteinosis (PAP) is a well-known life-threatening complication, occurring as early as childhood in many individuals with LPI [Valimahamed-Mitha et al 2015, Mauhin et al 2017]. Pulmonary fibrosis may develop independently from PAP.
PAP usually presents with progressive exertional dyspnea, tachypnea, and cough that are exacerbated by respiratory infections and complicated by viral or bacterial pneumonia. Diminished breath sounds, inspiratory crackles, subcostal and suprasternal retractions, cyanosis, and, more rarely, digital clubbing can be found on physical examination.
Bạn đang xem: Bookshelf
Diffuse reticulonodular densities are common on radiologic evaluation. Chest high-resolution computed tomography reveals ground-glass opacities with superimposed smooth septal thickening.
The pathogenesis of the PAP in LPI is poorly understood, but may be associated with intracellular nitric oxide accumulation [Mauhin et al 2017].
Renal involvement. Glomerular and tubular involvement is common. Isolated mild proteinuria is the initial sign of renal disease leading to proximal tubular dysfunction and nephrocalcinosis [Estève et al 2017, Mauhin et al 2017]. Serum creatinine concentration and cystatin C concentration are frequently increased. In a study on 39 Finnish individuals with LPI, proteinuria and hematuria were observed in 74% and 38%, respectively. Elevated blood pressure, mild to moderate renal insufficiency, and, in some cases, end-stage renal disease were also reported in this cohort [Tanner et al 2007]. Urine beta2-microglobulin may serve as an early marker of renal involvement in LPI [Kärki et al 2016].
Xem thêm : 10 Dos and Don’ts to Treat Sunburn at Home—and When to Visit the Burn Center
Renal tubular acidosis or findings consistent with reduced phosphate reabsorption and generalized aminoaciduria indicate underlying complex proximal tubular disease (Fanconi syndrome).
Kidney histology reveals immune-mediated glomerulonephritis as well as chronic tubulointerstitial nephritis with glomerulosclerosis in the absence of immune deposits [Estève et al 2017].
The pathogenesis of the renal involvement is unknown but may be associated with nitric oxide overproduction [Nicolas et al 2016].
Hematologic complications and bone marrow anomalies. A clinical presentation resembling hemophagocytic lymphohistiocytosis/macrophagic activation syndrome has been repeatedly observed.
Erythroblastophagocytosis and decreased megakaryocytes may be found in bone marrow aspirate. Hematologic findings also include slight normochromic or hypochromic anemia, leukopenia, thrombocytopenia, and subclinical intravascular coagulation.
Hypercholesterolemia and hypertriglyceridemia. Increased plasma concentrations of cholesterol and triglycerides are relatively common in individuals with LPI [Tanner et al 2010]. No clear explanation has been proposed for this dyslipidemic state; a higher-carbohydrate diet may contribute to the increased plasma concentration of triglycerides, but it is not sufficient to explain either the hypercholesterolemia or the severe hypertriglyceridemia (triglycerides >1,000 mg/dL or >11 mmol/L).
Xem thêm : Síntomas de un ataque cardíaco: conoce qué es una emergencia médica
Autoimmunity and immunologic abnormalities. Various immunologic abnormalities including impaired function of lymphocytes, the presence of lupus erythematosus cells, antinuclear and anti-DNA antibodies, hypergammaglobulinemia or low serum immune globulin concentrations, hypocomplementemia, and life-threatening varicella and bacterial infections can be observed.
Growth, growth hormone deficiency. Growth retardation is commonly observed in children with LPI and is usually related to protein malnutrition. In some cases, growth hormone deficiency or arginine depletion causing impaired secretion of growth hormone is observed. Growth hormone has been used in several individuals with good response [Niinikoski et al 2011].
Pancreatitis. Acute pancreatitis is a life-threatening complication in some persons with LPI. A clear relationship with severe hypertriglyceridemia has not been defined.
Pregnancy and childbirth. A Finnish study demonstrated that maternal LPI is associated with increased risk of anemia and toxemia during pregnancy and increased risk of bleeding complications during delivery. Intrauterine growth retardation was noted in a significant number of unaffected neonates born to mothers with LPI [Tanner et al 2006].
Pathophysiology. LPI is an inborn error of metabolism caused by pathogenic variants in SLC7A7, the gene encoding the light chain of system y+L. This system mediates the transport of cationic amino acids at the basolateral membrane of enterocytes and renal tubular cells. Most of the clinical findings of LPI may be related to the metabolic abnormality originating from altered absorption and reabsorption of cationic amino acids. In this respect, hyperammonemia is caused by functional impairment of the urea cycle probably resulting from an intracellular deficiency of ornithine in the liver. However, nutritional imbalance of cationic amino acids does not explain the complex multiorgan involvement of LPI, especially the complications affecting lung, kidney, and immune and hematologic systems.
System y+L activity has been shown to be markedly reduced in monocytes and alveolar macrophages from an individual with LPI [Barilli et al 2010]. This could explain the pathogenesis of the severe complications of LPI including those affecting lung and kidney. A paradox may occur in LPI: on one hand, pathogenic variants in SLC7A7 cause a general depletion of cationic amino acid secondary to defective intestinal uptake and renal reuptake; additionally, in immunocompetent cells the impairment of system y+L activity may cause intracellular arginine accumulation, with a potential risk of surcharging the nitric oxide pathway [Sebastio et al 2011]. A lower dosage of citrulline supplementation is now recommended, given that citrulline is converted into arginine, notably in kidney.
Nguồn: https://blogtinhoc.edu.vn
Danh mục: Info