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Liver stiffness measurement (LSM) by transient elastography (TE) predicts hepatic venous congestions and liver dysfunction but not liver fibrosis in children after Fontan procedure
Abstracts / Digestive and Liver Disease 49(4S) (2017) e243–e286
P016 Liver stiffness measurement (LSM) by transient elastography (TE) predicts hepatic venous congestions and liver dysfunction but not liver fibrosis in children after Fontan procedure K. Abukasm 1 , A. Fournier 2 , J. Mirò 2 , D. Dal Soglio 3 , C. Vincent 4 , J. Dubois 5 , M. Paganelli 1,6,∗ 1
Pediatric Hepatology, CHU Sainte-Justine, U. de Montréal, Canada 2 Pediatric Cardiology, CHU Sainte-Justine, U. de Montréal, Canada 3 Pathology, CHU Sainte-Justine, U. de Montréal, Canada 4 Hepatology, Centre Hospitalier de l’U. de Montréal, Canada 5 Radiology, CHU Sainte-Justine, U. de Montréal, Canada 6 Hepatology and Cell Therapy Lab, Sainte-Justine Research Center, Canada The Fontan procedure results in hepatic venous congestion, with consequent Fontan-associated liver disease (FALD). Biochemical markers are bad predictors of liver fibrosis and dysfunction in FALD. No intervention other than early heart transplant was shown to alter FALD progression. Aims: assessing LSM as (1) a predictor of liver fibrosis and dysfunction in children with FALD; (2) an indication for interventions to lower hepatic venous congestion. Methods: We retrospectively enrolled pediatric patients with history of Fontan procedure and LSM performed by TE (FibroScan, with adapted probes). Since no conversion scale is available for FALD, the grade of fibrosis was estimated from LSM using scales validated for other diseases. Fibrosis on transjugular liver biopsies was graded according to METAVIR. Results: Thirty-one consecutive patients were enrolled (21 M/10F, 10.9 ± 4.2 years old). Hepatomegaly and splenomegaly were noted in 74.2% and 25.8% of patients. Two had protein-losing enteropathy. Most patients had minimally elevated ALT and GGT levels. Factor V was low in 77.3% of patients, lymphocyte count in 55.6%, with normal total bilirubin and albumin levels in 80.6% and 93.5%. At TE performed 5.4 median years post-Fontan (mypF), LSM was 17.1 ± 7.4 kPa (median grade of fibrosis: 3.8/4). Presence of hepatomegaly did not influence LSM, whereas a non-significant trend was noted for splenomegaly. Portal fibrosis ≥F2 was evident in 13/14 patients who had liver biopsy (7.7 mypF), sinusoidal fibrosis in all, cirrhosis in 3 (12.8 mypF). LSM overestimated the grade of fibrosis compared to biopsy (p < 0.001). No significant correlation was found between fibrosis at biopsy and LSM. LSM was correlated to INR (p = 0.035), factor V level (p = 0.008), lymphocytes count (p = 0.006), and time since Fontan (p = 0.024). When high LSM was used as an indication to perform cardiac catheterization, pulmonary stenoses were found and dilated in 4/5 asymptomatic patients. LSM was significantly reduced at post-procedure TE (p = 0.012). Conclusions: Currently available scales to estimate fibrosis from LSM do not consider hepatic venous congestion and are inadequate for FALD. LSM in FALD is determined by lymphocyte count (an indirect marker of splanchnic venous congestion) and factor V level (a marker of hepatocellular dysfunction). LSM might be used as a predictor of liver dysfunction and venous congestion to guide vascular
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interventions. This approach led to a significant reduction of LSM in patients treated so far. Conflict of interest: None declared. http://dx.doi.org/10.1016/j.dld.2017.09.020 P017 Three patients with glycosylation deficiencies, chronically elevated transaminases, and low serum ceruloplasmin and copper, caused by mutations in the gene encoding the transmembrane protein TMEM199 M. Poeta 1,∗ , K. Zielinska 2 , M. Maccarana 2 , C. Mandato 1 , B.G. Ng 3 , A. Di Nuzzi 1 , E. D’Acunto 1 , L. Pierri 1 , E. Ecklund 2 , H. Freeze 3 , P. Vajro 1 1
Unit of Pediatrics, Dep. of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, Baronissi, SA, Italy 2 Division of Pediatrics, and Division of Clinical Chemistry, Dep. of Clinical Sciences, Lund University, Lund, Sweden 3 Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States Background: A decade ago we reported on four children with glycosylation deficiencies and a liver disease mimicking Wilsondisease, but without known genetic cause. Two (patients #1 and #2) were later diagnosed with phosphoglucomutase-1 deficiency. Aims: Here we present a long-term follow-up on the other two children (#3 and #4), and present data on a third, unrelated child (#5), all diagnosed with TMEM199-deficiency. Patients: Patients #3 and #4 are Italian healthy young adults investigated for hypertransaminasemia when they were 2 y.o. They also had increased values of total and LDL cholesterol, creatinine kinase, and alkaline phosphatase. Ceruloplasmin and serum copper were low in spite of a normal urinary basal and after penicillamine excretion. Liver biopsy confirmed ultrasonographic mild fibrosis/steatosis, with mildly increased copper content; Wilson-disease and aceruloplasminemia were ruled out by appropriate tests. Transferrin glycosylation was consistent with a CDG-II. Patient #5 (Italian, now 2 y.o.) presented a similar picture already at age 1 year; he did not undergo liver biopsy. Results: Exome-sequencing identified in all compound heterozygous mutations in TMEM199 (frameshift with a premature stop, and a missense change, respectively). Western Blot analysis showed absence of the TMEM199 protein in patient fibroblasts. Conclusions: Our patients present a recently described Wilson-disease mimicking rare disease with chronically elevated transaminases, low serum ceruloplasmin and copper, caused by mutations in gene encoding transmembrane protein TMEM199. The mechanisms potentially involve at least partial loss of either or both of the copper transporting proteins ATP7A and ATP7B. Conflict of interest: None declared. http://dx.doi.org/10.1016/j.dld.2017.09.021
P016 Liver stiffness measurement (LSM) by transient elastography (TE) predicts hepatic venous congestions and liver dysfunction but not liver fibrosis in children after Fontan procedure K. Abukasm 1 , A. Fournier 2 , J. Mirò 2 , D. Dal Soglio 3 , C. Vincent 4 , J. Dubois 5 , M. Paganelli 1,6,∗ 1
Pediatric Hepatology, CHU Sainte-Justine, U. de Montréal, Canada 2 Pediatric Cardiology, CHU Sainte-Justine, U. de Montréal, Canada 3 Pathology, CHU Sainte-Justine, U. de Montréal, Canada 4 Hepatology, Centre Hospitalier de l’U. de Montréal, Canada 5 Radiology, CHU Sainte-Justine, U. de Montréal, Canada 6 Hepatology and Cell Therapy Lab, Sainte-Justine Research Center, Canada The Fontan procedure results in hepatic venous congestion, with consequent Fontan-associated liver disease (FALD). Biochemical markers are bad predictors of liver fibrosis and dysfunction in FALD. No intervention other than early heart transplant was shown to alter FALD progression. Aims: assessing LSM as (1) a predictor of liver fibrosis and dysfunction in children with FALD; (2) an indication for interventions to lower hepatic venous congestion. Methods: We retrospectively enrolled pediatric patients with history of Fontan procedure and LSM performed by TE (FibroScan, with adapted probes). Since no conversion scale is available for FALD, the grade of fibrosis was estimated from LSM using scales validated for other diseases. Fibrosis on transjugular liver biopsies was graded according to METAVIR. Results: Thirty-one consecutive patients were enrolled (21 M/10F, 10.9 ± 4.2 years old). Hepatomegaly and splenomegaly were noted in 74.2% and 25.8% of patients. Two had protein-losing enteropathy. Most patients had minimally elevated ALT and GGT levels. Factor V was low in 77.3% of patients, lymphocyte count in 55.6%, with normal total bilirubin and albumin levels in 80.6% and 93.5%. At TE performed 5.4 median years post-Fontan (mypF), LSM was 17.1 ± 7.4 kPa (median grade of fibrosis: 3.8/4). Presence of hepatomegaly did not influence LSM, whereas a non-significant trend was noted for splenomegaly. Portal fibrosis ≥F2 was evident in 13/14 patients who had liver biopsy (7.7 mypF), sinusoidal fibrosis in all, cirrhosis in 3 (12.8 mypF). LSM overestimated the grade of fibrosis compared to biopsy (p < 0.001). No significant correlation was found between fibrosis at biopsy and LSM. LSM was correlated to INR (p = 0.035), factor V level (p = 0.008), lymphocytes count (p = 0.006), and time since Fontan (p = 0.024). When high LSM was used as an indication to perform cardiac catheterization, pulmonary stenoses were found and dilated in 4/5 asymptomatic patients. LSM was significantly reduced at post-procedure TE (p = 0.012). Conclusions: Currently available scales to estimate fibrosis from LSM do not consider hepatic venous congestion and are inadequate for FALD. LSM in FALD is determined by lymphocyte count (an indirect marker of splanchnic venous congestion) and factor V level (a marker of hepatocellular dysfunction). LSM might be used as a predictor of liver dysfunction and venous congestion to guide vascular
e249
interventions. This approach led to a significant reduction of LSM in patients treated so far. Conflict of interest: None declared. http://dx.doi.org/10.1016/j.dld.2017.09.020 P017 Three patients with glycosylation deficiencies, chronically elevated transaminases, and low serum ceruloplasmin and copper, caused by mutations in the gene encoding the transmembrane protein TMEM199 M. Poeta 1,∗ , K. Zielinska 2 , M. Maccarana 2 , C. Mandato 1 , B.G. Ng 3 , A. Di Nuzzi 1 , E. D’Acunto 1 , L. Pierri 1 , E. Ecklund 2 , H. Freeze 3 , P. Vajro 1 1
Unit of Pediatrics, Dep. of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, Baronissi, SA, Italy 2 Division of Pediatrics, and Division of Clinical Chemistry, Dep. of Clinical Sciences, Lund University, Lund, Sweden 3 Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States Background: A decade ago we reported on four children with glycosylation deficiencies and a liver disease mimicking Wilsondisease, but without known genetic cause. Two (patients #1 and #2) were later diagnosed with phosphoglucomutase-1 deficiency. Aims: Here we present a long-term follow-up on the other two children (#3 and #4), and present data on a third, unrelated child (#5), all diagnosed with TMEM199-deficiency. Patients: Patients #3 and #4 are Italian healthy young adults investigated for hypertransaminasemia when they were 2 y.o. They also had increased values of total and LDL cholesterol, creatinine kinase, and alkaline phosphatase. Ceruloplasmin and serum copper were low in spite of a normal urinary basal and after penicillamine excretion. Liver biopsy confirmed ultrasonographic mild fibrosis/steatosis, with mildly increased copper content; Wilson-disease and aceruloplasminemia were ruled out by appropriate tests. Transferrin glycosylation was consistent with a CDG-II. Patient #5 (Italian, now 2 y.o.) presented a similar picture already at age 1 year; he did not undergo liver biopsy. Results: Exome-sequencing identified in all compound heterozygous mutations in TMEM199 (frameshift with a premature stop, and a missense change, respectively). Western Blot analysis showed absence of the TMEM199 protein in patient fibroblasts. Conclusions: Our patients present a recently described Wilson-disease mimicking rare disease with chronically elevated transaminases, low serum ceruloplasmin and copper, caused by mutations in gene encoding transmembrane protein TMEM199. The mechanisms potentially involve at least partial loss of either or both of the copper transporting proteins ATP7A and ATP7B. Conflict of interest: None declared. http://dx.doi.org/10.1016/j.dld.2017.09.021