nueva página del texto (beta)
Inglés (pdf)
Artículo en XML
Referencias del artículo
Traducción automática
Enviar artículo por email
Citado por SciELO 
Similares en
SciELO 
Permalink
Introduction
Cystic fibrosis (CF) is a disease of genetic origin, with autosomal recessive inheritance that is diagnosed mainly in children. It is caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR) gene. The main system affected is the respiratory tract and pancreas. There is also the involvement of the sweat glands, the intestine, the nasal mucosa, the salivary glands, and the reproductive system1.
The liver is a frequently compromised organ2, liver damage develops within the first 20 years of life and is usually stable, with a slowly progressive evolution3; however, some children may develop liver cirrhosis in early childhood or adolescence4. Determining the coexistence of liver disease is important, as it has a relevant implication in the short- and long-term prognosis of children with CF5.
The objective of this study was to determine the prevalence and characteristics of liver disease by evaluating liver function tests in a group of children with CF at the time of diagnostic confirmation.
Methods
A retrospective analytical study included 82 children with a confirmed genetic diagnosis of CF, treated in the Pediatric Gastroenterology and Nutrition service at Instituto Nacional de Pedriatría (Mexico City, Mexico). Baseline liver function tests (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltranspeptidase, alkaline phosphatase, albumin, lipids, bilirubin's, and INR) were collected. The cutoff point of the SAFETY study6 was used for the detection of chronic liver disease in children, considering the elevation of alanino aminotransferase (ALT) > 22.1 U/L in girls and 25.8 U/L in boys. The aspartato aminotransferasa (AST) to platelet ratio index (APRI) was calculated using the formula proposed by Wai et al.7. (APRI = [patient AST level/AST upper limit normal] × 100/platelet count 109/L), which was interpreted: < 0.5 = no significant fibrosis, 0.5-1.5 = probable fibrosis, and > 1. 5 = significant fibrosis.
Statistical analysis
The distribution of normality was evaluated with the Kolmogorov-Smirnov test. Subsequently, descriptive statistics were performed. The means were compared with the Mann-Whitney U test and correlations were made with the Sperson test. Statistical significance was established with an alpha error < 0.05. The analysis was performed in the SPSS version 22 software.
Results
A total of 82 children diagnosed with CF were included. The median age at diagnosis was 10 months (interquartile range = 30). 59.8% (n = 49) of the patients had elevated ALT in the first biochemical evaluation after diagnosis, the means of the other liver function tests are presented in table 1.
Table 1 Liver function tests and biochemical parameters in children with cystic fibrosis
| Parameters | Median and interquartile range |
|---|---|
| ALT | 32 (41) |
| AST | 49 (41) |
| ALP | 194 (166) |
| GGT | 33 (54) |
| Platelets | 350,000 (187,000) |
| Albumin | 3.30 (1.3) |
| INR | 1.03 (0.20) |
| BT | 0.57 (0.40) |
| BD | 0.17 (0.22) |
| Vitamin D | 18 (11) |
| CT | 111 (48) |
| Triglycerides | 98 (55) |
| APRI | 0.34 (0.38) |
ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; GGT: gamma-glutamyltranspeptidase; INR: International normalized ratio; BT: total bilirubin; BD: direct bilirubin; CT: total cholesterol; APRI: AST to platelet ratio index.
Of 69.5% (n = 57) had APRI between 0-0.5 (without fibrosis), 24.4% (n = 20) had APRI between 0.5-1.5, and 6.1% (n = 5) had APRI > 1.5. The correlation of APRI with ALT was 0.685 (p < 0.001), with AST 0.804 (p < 0.001), and with GGT 0.385 (p < 0.001), no correlation was found with other liver function tests (Table 2). When comparing liver function tests according to sex, we did not find significant differences, nor a greater association of ALT elevation in boys or girls (p = 0.159).
Table 2 APRI correlation tests with biochemical parameters and liver function tests
| ALT | AST | ALP | GGT | Albumin | Vit D | |
|---|---|---|---|---|---|---|
| Correlation | 0.685 | 0.804 | 0.47 | 0.385 | −0.068 | −0.248 |
| p | < 0.001 | < 0.001 | 0.675 | < 0.001 | 0.547 | 0.043 |
ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; GGT: gamma-glutamyltranspeptidase.
The most frequent genetic mutations were F508del (n = 14) and G542X (n = 9), no difference was found between the two groups in the comparison of liver function tests.
The children included in this study underwent liver ultrasound and 39% (n = 32) had alterations consistent with changes in liver echogenicity; however, when comparing the liver function tests of the children with and without liver ultrasound alterations, no differences were found (Table 3).
Table 3 Comparison of liver function tests according to liver ultrasound abnormalities in children with cystic fibrosis
| Altered USG | Normal USG | p | |
|---|---|---|---|
| ALT | 56.16 ± 69 | 38.73 ± 32 | 0.393 |
| AST | 121.16 ± 195 | 39.86 ± 12 | 0.119 |
| ALP | 187.91 ± 87 | 177.40 ± 87 | 0.759 |
| GGT | 82.58 ± 41 | 41 ± 37 | 0.219 |
| Platelets | 347,000 ± 94,000 | 402,000 ± 138,000 | 0.250 |
| Albumin | 3.3 ± 0.9 | 3.2 ± 0.7 | 0.692 |
| BT | 1.3 ± 1 | 0.5 ± 0.29 | 0.72 |
| APRI | 1.1 ± 2.2 | 0.29 ± 0.17 | 0.164 |
ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; GGT: gamma-glutamyltranspeptidase; INR: International normalized ratio; BT: total bilirubin; APRI: AST to platelet ratio index.
Discussion
In this study, we found that more than half of the children with the confirmatory diagnosis of CF had elevated transaminases. It has been described that CF-associated liver disease occurs due to alteration in the cholangiocyte transport protein, which results in chronic cholangiopathy secondary to a reduction in ductal bile flow, bile chloride, and bicarbonate secretion due to CFTR dysfunction8. However, the mechanism of liver injury is considered to be multifactorial, including the CFTR genotype, non-CFTR genetic variability, abnormal intracellular interactions, abnormal cholangiocyte function, impaired bile secretion, and pathological stimulation of the innate immune response with an abnormal response to endotoxins2,9.
The prevalence of liver disease in children with CF is varied and has been reported to occur in 5% to 68%, depending on the criteria used for its diagnosis10,11. Risk factors include male sex, the presence of severe mutations, the presence of the SERPINE 1Z allele, a history of meconium ileus, exocrine pancreatic insufficiency, and CF-associated diabetes12. In our study, we found no difference in the alteration of liver function tests according to sex. The most frequently reported mutations in patients were F508del and G542X, with no major difference in liver involvement observed according to the type of mutation.
In our study, we used the APRI to estimate the presence of liver fibrosis in children with CF. At present, there are different validated non-invasive methods to evaluate liver disease in the adult population13 and some have been used in the pediatric age with different results. APRI has shown good diagnostic performance in establishing the diagnosis of fibrosis in children with NAFLD (AUROC 0.619, 95% CI 0.556-0.679, p < 0.001)14; however, it seems to be superior in establishing liver involvement in children with CF. A study that evaluated the usefulness of non-invasive methods for diagnosing liver fibrosis in children with CF determined that the APRI is superior to the AST/ALT ratio, FIB-4 score, GGT, GGT/platelet ratio, and platelet count, showing an AUROC of 0.90; 95%CI = 0.830-0.970; p = 0.0380. The same study indicated that the elevation of the APRI cutoff point of ≥ 0.425 has an odds ratio of 23.8 (95%CI = 5.2-109.7; p < 0.001) for CF-associated liver disease15. Liver biopsy was not performed in our patients, which is a deficiency to be considered in this study; however, other studies in children with CF have indicated that APRI is a good surrogate marker to establish the presence of liver fibrosis16,17.
In the annual follow-up of children with CF, it is recommended that transaminases be evaluated and if alterations are found, hepatic ultrasound is initiated18. Partial or total hepatic hyperechogenicity is suggestive of steatosis and is the most common ultrasound finding in children with CF19. The patients included in this study were also evaluated by liver ultrasound, finding alteration of hepatic echogenicity in 39%; however, when comparing transaminases and other liver function tests, no difference was found, even though the percentage was lower in children with elevated transaminases. This is in contrast to other studies; abnormal echogenicity has been reported to precede biochemical or clinical evidence of liver disease. One study shows that two-thirds of children with abnormal hepatic echotexture and 50% with portal hypertension had no biochemical or clinical evidence of CF-associated liver disease at the time ultrasound changes were first observed20. It should be considered that ultrasound is an operator-dependent study and that there is intra- and interobserver variability in ultrasound images, and children with normal liver ultrasound may have advanced fibrosis, so a normal ultrasound does not exclude significant liver fibrosis3. A weakness of the study is that only biochemical tests of liver function and ultrasound were available, and ideally, elastography or other surrogate markers should be included for the evaluation of liver fibrosis and correlation tests should be performed to validate our findings.
Conclusion
In this study, we found that more than half of the children with CF at diagnosis may have elevated transaminases and according to the APRI estimate, 30.5% may have liver fibrosis, also observing a good correlation of APRI with other liver function tests. In this study, we observed that liver ultrasound may be normal, even when there is biochemical evidence of liver disease.
