Pathophysiology of lungs, liver, and kidneys in patients with mulibrey nanism

Mulibrey nanism (MUL) is a rare inherited disease caused by recessive mutations in the TRIM37 gene. MUL affects multiple organs and leads to growth retardation, infertility and early onset type 2 diabetes. Chronic heart failure and hepatopathy are major determinants of prognosis. In histological studies, kidneys of MUL patients have shown aberrative structure. In addition, the patients appear to suffer from airway obstruction related to infection or exercise, prompting the use of inhaled therapies. The aims of this study were to evaluate the pulmonary pathophysiology, characterize the structure and function of the kidneys and urinary tract, and study liver function and pathology in a national cohort of MUL patients. The study comprised altogether 101 Finnish MUL patients (age 0.2 to 76 years). Thirty-three patients (median age 20 years) were investigated with spirometry, diffusing capacity of the lungs, and body plethysmography. The ultrasound, MRI and autopsy findings of the kidneys and urinary tract were retrospectively analyzed from the whole cohort. Renal function of a cross-sectional cohort of 36 MUL patients (age 0.2–51 years) was examined using blood and urine biochemistry. Clinical, laboratory and imaging data of the liver were collected in a cross-sectional survey of 36 MUL patients and retrospectively from hospital records of the whole patient cohort. Kidney and liver histology and immunohistochemistry for 10 biomarkers were assessed from biopsy and autopsy samples. In lung function tests, total lung capacity (TLC) and forced vital capacity (FVC) were markedly reduced (p < 0.001, 51–63% of predicted) and forced expiratory volume in the first second (FEV1) was reduced (p < 0.001, 47–57%). No signs of airway obstruction were seen. Diffusing capacity (DLCO) was decreased (p < 0.001, 60–67%), but when related to alveolar volume (DLCO/VA), it was increased (p < 0.001, 130–148%). Bronchodilatation suggesting active asthma was found in only one patient. Structural anomalies of the kidneys and urinary tract were found in 13% of the MUL patients and renal tumors and macroscopic cystic lesions in 14% and 43% of the patients, respectively. The overall histology of the kidneys was well preserved, but glomerular cysts and prominent and abundant blood vessels with thick walls were seen. The expression of endothelial cell markers and angiogenic growth factors PDGF-B and FGF1 was significantly increased in MUL kidneys. Markers of fibrosis and epithelial-mesenchymal transformation were moderately up-regulated. Despite the radiological and histological changes, most MUL patients had normal kidney function. In liver biopsies, 21 MUL patients (age 1-51 years) with tumor suspicion showed moderate congestion, steatosis and fibrosis. Serum GGT, AST, ALT and AST to platelet ratio index (APRI) were marginally elevated in 20–66% of patients undergoing liver biopsy, and moderately elevated in 12–69% of 17 MUL patients prior to pericardiectomy. In the cross-sectional evaluation of 36 MUL outpatients, GGT, total bilirubin, and galactose half-life (Gal½) correlated with age. However, the frequency of clearly abnormal serum values in the 15 parameters analyzed was low even in patients with signs of restrictive cardiomyopathy. Transient elastography (TE) of the liver revealed elevated levels in 50% of the patients with signs of heart failure. Biomarkers of fibrosis, sinusoidal capillarization and hepatocyte metaplasia showed increased expression in autopsy liver samples. In conclusion, MUL patients typically have volume restriction of the lungs, but function of the pulmonary tissue remains intact. Evidence of asthma in lung function testing at adult age is rare. A genetic defect in TRIM37 protein leads to increased risk of kidney anomalies, renal tumors and solitary cysts as well as glomerular cystic lesions but not to progressive deterioration of renal function. Liver disease in MUL patients is characterized by sinusoidal dilatation, steatosis and fibrosis with individual progression to cirrhosis and moderate association of histology with cardiac function, liver biochemistry and elastography.