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Bayramova S, Koç Yekedüz M, Köse E, Eminoğlu FT. Retrospective assessment of hepatic involvement in patients with inherited metabolic disorders: nine-year single-center experience. J Pediatr Endocrinol Metab 2025; 38:465-475. [PMID: 39995240 DOI: 10.1515/jpem-2024-0511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 01/31/2025] [Indexed: 02/26/2025]
Abstract
OBJECTIVES This study aimed to identify clinical, laboratory, and radiological features that could serve as red flags for diagnosing inherited metabolic disorders (IMDs) with hepatic involvement in childhood. METHODS We retrospectively reviewed the medical records of 1,237 children from a pediatric metabolism department, with suspected or diagnosed IMDs. Patients with hepatic involvement were divided into two groups: Group 1 (diagnosed with IMDs) and Group 2 (undiagnosed). Demographic, clinical, laboratory, and radiological data were compared between the groups. RESULTS Hepatic involvement was observed in 415 patients (33.5 %), with 206 (49.2 %) diagnosed with IMDs. Group 1 had higher rates of consanguineous marriage and affected siblings. Complex molecule disorders (20.4 %), mitochondrial (16.0 %), and lipid metabolism disorders (16.0 %) were the most common IMDs. Dysmorphic findings were more frequent in Group 1 (28.2 vs. 16.3 %, p=0.004), while diarrhea was less common (4.4 vs. 12.0 %, p=0.005). Ammonia and lactate levels were higher in Group 1 (p<0.001 and p=0.032, respectively). Hepatomegaly was more frequent in Group 1 (53.3 vs. 22.6 %, p<0.001). Pathological abdominal ultrasonography was the only significant multivariate predictor (OR: 89.377, p=0.026). Overall survival was 87.7 %, with no difference between groups. CONCLUSIONS Consanguineous marriage, affected siblings, dysmorphic findings, absence of diarrhea, and pathological abdominal USG are key predictors of IMDs in hepatic involvement cases.
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Affiliation(s)
- Samira Bayramova
- Ankara University Faculty of Medicine, Department of Pediatrics, Ankara, Türkiye
| | - Merve Koç Yekedüz
- Ankara University Faculty of Medicine, Department of Pediatric Metabolism, Ankara, Türkiye
- Harvard Medical School, Boston Children's Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, Boston, MA, USA
| | - Engin Köse
- Ankara University Faculty of Medicine, Department of Pediatric Metabolism, Ankara, Türkiye
- Ankara University Rare Disease Application and Research Center, Ankara, Türkiye
| | - Fatma Tuba Eminoğlu
- Ankara University Faculty of Medicine, Department of Pediatric Metabolism, Ankara, Türkiye
- Ankara University Rare Disease Application and Research Center, Ankara, Türkiye
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Rouhafshari M, Hadi Imanieh M, Khazaei M, Radaei Z, Barzegar H. An Unusual Presentation of Tyrosinemia Type 1 in a Pediatric Patient: Case Report and Comprehensive Review. Clin Case Rep 2025; 13:e70384. [PMID: 40177161 PMCID: PMC11961375 DOI: 10.1002/ccr3.70384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 03/15/2025] [Accepted: 03/24/2025] [Indexed: 04/05/2025] Open
Abstract
Tyrosinemia type 1 often manifests with liver, renal, or peripheral neuropathy disorders. Before therapies like nitisinone, management was limited to dietary modifications and liver transplantation. We present a 19-month-old girl who developed respiratory distress requiring intubation, with abnormal laboratory findings, including liver function tests. Further work-up, including succinylacetone testing, confirmed tyrosinemia. She responded remarkably to nitisinone treatment.
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Affiliation(s)
- Mahsa Rouhafshari
- Department of Pediatric GastroenterologyShiraz University of Medical SciencesShirazIran
| | - Mohammad Hadi Imanieh
- Department of Pediatric Gastroenterology, Gastroenterohepatology Research Center of Nemazee HospitalShiraz University of Medical SciencesShirazIran
| | - Mahdi Khazaei
- Department of Internal MedicineShiraz University of Medical SciencesShirazIran
| | - Zahra Radaei
- Department of Pediatric GastroenterologyShiraz University of Medical SciencesShirazIran
| | - Hamide Barzegar
- Neonatal Research CenterShiraz University of Medical SciencesShirazIran
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Evaluation of dynamic thiol/disulfide homeostasis in hereditary tyrosinemia type 1 patients. Pediatr Res 2022; 92:474-479. [PMID: 34628487 DOI: 10.1038/s41390-021-01770-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/29/2021] [Accepted: 08/08/2021] [Indexed: 11/08/2022]
Abstract
BACKGROUND Despite successful treatment with nitisinone, the pathophysiology of long-term complications, including hepatocellular carcinoma and mental decline in tyrosinemia type 1 patients, is still obscure. Oxidative stress may play a role in these complications. While increased fumarylacetoacetate and maleylacetoacetate cause oxidative stress in the liver, increased tyrosine causes oxidative stress in the brain. The aim of this study is to evaluate dynamic thiol/disulfide homeostasis as an indicator of oxidative stress in late-diagnosed tyrosinemia type 1 patients. METHODS Twenty-four late-diagnosed (age of diagnosis; 14.43 ± 26.35 months) tyrosinemia type 1 patients (19 under nitisinone treatment and 5 with liver transplantation) and 25 healthy subjects were enrolled in the study. Serum native thiol, total thiol, and disulfide levels were measured, and disulfide/native, disulfide/total, and native thiol/total thiol ratios were calculated from these values. RESULTS No significant difference was observed in native, total, and disulfide thiol levels between the groups and no increase in disulfide/native, disulfide/total, and native/total thiol ratios was detected, despite significantly higher plasma tyrosine levels in the nitisinone-treated group. CONCLUSIONS We suggest that providing sufficient metabolic control with good compliance to nitisinone treatment can help to prevent oxidative stress in late-diagnosed tyrosinemia type 1 patients. IMPACT Despite successful nitisinone (NTBC) treatment, the underlying mechanisms of long-term complications in hereditary tyrosinemia type 1 (HT1), including hepatocellular carcinoma and mental decline, are still obscure. Oxidative stress may play a role in these complications. Thiol/disulfide homeostasis, which is an indicator of oxidative stress, is not disturbed in hereditary tyrosinemia patients under NTBC treatment, despite higher plasma tyrosine levels and patients who had liver transplantation. This is the first study evaluating dynamic thiol/disulfide homeostasis as an indicator of oxidative stress in late-diagnosed HT1 patients.
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Hereditary Tyrosinemia Type 1 in Jordan: A Retrospective Study. Int J Pediatr 2021; 2021:3327277. [PMID: 34899923 PMCID: PMC8660245 DOI: 10.1155/2021/3327277] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 11/23/2022] Open
Abstract
Background Hereditary tyrosinemia type 1 (HT1) is a recessively inherited inborn error of metabolism affecting the final step of tyrosine catabolism. The accumulation of tyrosine toxic metabolites leads to progressive hepatic, renal, and neurological manifestations. Treatment of HT1 consists of tyrosine-restricted diets and nitisinone. The untreated disease progresses into life-threatening liver failure with an increased risk of hepatocellular carcinoma. Methods From April 2010 to March 2021, eighteen patients were diagnosed with HT1 in the metabolic department at Queen Rania Al Abdullah Hospital for Children in Jordan. Patients were reviewed retrospectively regarding their clinical features, laboratory data, and sociodemographic history. Results The mean age of nine boys and nine girls was 6.03 years (SD ± 3.85). The mean age for symptom onset was 5.61 months (SD ± 6.02). However, the diagnosis was belated from the onset by 10.50 months (±10.42). Nitisinone treatment was delayed from diagnosis around 12.28 months (SD ± 25.36). Most of the patients (66.7%) had acute onset of the disease. Two children (11.1%) died due to hepatic complications. Positive family history was identified in 61.1% of patients, and a similar percentage were born to parents with consanguineous marriage. The most common presentation was abdominal pain, vomiting, and fever. Hepatomegaly and abdominal distention were the most common findings. Six patients' (42.9%) first presentation was rickets. Conclusion HT1 diagnosis is usually delayed because it is not part of newborn screening and nonfamiliarity with the clinical features of the disease. Therefore, nationwide newborn screening should be expanded to include HT1.
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Sintusek P, Phewplung T, Sanpavat A, Poovorawan Y. Liver tumors in children with chronic liver diseases. World J Gastrointest Oncol 2021; 13:1680-1695. [PMID: 34853643 PMCID: PMC8603454 DOI: 10.4251/wjgo.v13.i11.1680] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/27/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Liver tumors are rare in children, but the incidence may increase in some circumstances and particularly in chronic liver diseases. Most liver tumors consequent to chronic liver diseases are malignant hepatocellular carcinoma. Other liver tumors include hepatoblastoma, focal nodular hyperplasia, adenoma, pseudotumor, and nodular regenerative hyperplasia. Screening of suspected cases is beneficial. Imaging and surrogate markers of alpha-fetoprotein are used initially as noninvasive tools for surveillance. However, liver biopsy for histopathology evaluation might be necessary for patients with inconclusive findings. Once the malignant liver tumor is detected in children with cirrhosis, liver transplantation is currently considered the preferred option and achieves favorable outcomes. Based on the current evidence, this review focuses on liver tumors with underlying chronic liver disease, their epidemiology, pathogenesis, early recognition, and effective management.
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Affiliation(s)
- Palittiya Sintusek
- Thai Pediatric Gastroenterology, Hepatology and Immunology Research Unit, Department of Pediatrics, Division of Gastroenterology, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok 10330, Thailand
| | - Teerasak Phewplung
- Department of Radiology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Anapat Sanpavat
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Chulalongkorn University, Bangkok 10330, Thailand
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Yilmaz O, Daly A, Pinto A, Ashmore C, Evans S, Gupte G, Jackson R, Yabanci Ayhan N, MacDonald A. Physical Growth of Patients with Hereditary Tyrosinaemia Type I: A Single-Centre Retrospective Study. Nutrients 2021; 13:3070. [PMID: 34578949 PMCID: PMC8472760 DOI: 10.3390/nu13093070] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/26/2021] [Accepted: 08/30/2021] [Indexed: 12/23/2022] Open
Abstract
In a retrospective review, we aimed to assess long-term growth in 17 patients (n = 11 males) with hereditary tyrosinaemia type I (HTI). Median age at assessment was 15.6 years (5.7-26.6 years) and median age at diagnosis was 1 month (range: 0-16 months), with 35% (n = 6/17) symptomatic on presentation. From the age of 8 years, there was a noticeable change in median height, weight, and body-mass-index [BMI]-z-scores. Median height-for-age z-scores were consistently ≤ -1 (IQR -1.6, -0.5) during the first 8 years of life but increased with age. Weight-for-age z-scores ranged between -1 to 0 (IQR -1.2, 0.1) in the first 8 years; then increased to > 0.5 (IQR -0.3, 1.3) by age 16 years, and BMI-for-age z-scores ranged from 0 to 1 (IQR -0.7, 1.3) up to 8 years, and >1 (IQR -0.2, 1.9) until 16 years. The percentage of overweight and obesity was lowest in children aged < 5 years, and consistently > 40% in patients aged between 7 to 16 years. The prescribed total protein intake was associated with improved height growth (p < 0.01). Impaired growth in early life improved with age achieving normal population standards. Further studies are needed to investigate factors that influence growth outcome in HTI patients.
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Affiliation(s)
- Ozlem Yilmaz
- Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK; (O.Y.); (A.D.); (A.P.); (C.A.); (S.E.); (G.G.)
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Ankara Yildirim Beyazit University, Ankara 06760, Turkey
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Ankara University, Ankara 06290, Turkey;
| | - Anne Daly
- Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK; (O.Y.); (A.D.); (A.P.); (C.A.); (S.E.); (G.G.)
| | - Alex Pinto
- Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK; (O.Y.); (A.D.); (A.P.); (C.A.); (S.E.); (G.G.)
| | - Catherine Ashmore
- Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK; (O.Y.); (A.D.); (A.P.); (C.A.); (S.E.); (G.G.)
| | - Sharon Evans
- Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK; (O.Y.); (A.D.); (A.P.); (C.A.); (S.E.); (G.G.)
| | - Girish Gupte
- Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK; (O.Y.); (A.D.); (A.P.); (C.A.); (S.E.); (G.G.)
| | - Richard Jackson
- Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool, Liverpool L69 3GL, UK;
| | - Nurcan Yabanci Ayhan
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Ankara University, Ankara 06290, Turkey;
| | - Anita MacDonald
- Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK; (O.Y.); (A.D.); (A.P.); (C.A.); (S.E.); (G.G.)
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Abstract
PURPOSE Pediatric hepatocellular carcinoma is rarely seen in childhood. It constitutes approximately 1% of childhood solid organ malignancies. Pediatric hepatocellular carcinoma is the second most common malignant liver tumor after hepatoblastoma in children. In this review, we aimed to review the diagnosis and treatment of pediatric hepatocellular carcinoma in the light of the latest literature. METHODS We reviewed the literature in terms of the diagnosis and treatment of pediatric hepatocellular carcinoma. RESULTS Hepatocellular carcinoma (HCC) and hepatoblastoma constitute 0.5-1.5% of all childhood malignant tumors. HCC is responsible for 27% of all liver tumors and 4% of all pediatric liver transplantations. While 99.6% of HCC is seen in adults, only 0.4% of it is seen in pediatric patients. Etiological predisposition and biological behavior are different from adults. In a child with cirrhosis or liver disease, HCC should be suspected in the presence of a high level of AFP and an abnormal nodule on ultrasonography. Hepatoblastoma should be considered first in the differential diagnosis. CONCLUSION Treatment of pediatric HCC is challenging. Complete surgical resection is essential for the cure. To this end, different neoadjuvant chemotherapy protocols have been designed to convert non-resectable tumors into resectable tumors. For tumors that cannot be resected, liver transplantation for each patient with childhood HCC should be decided individually.
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Affiliation(s)
- Fatma İlknur Varol
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Faculty of Medicine, Inonu University, 244280, Malatya, Turkey.
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Dweikat I, Qawasmi N, Najeeb A, Radwan M. Phenotype, genotype, and outcome of 25 Palestinian patients with hereditary tyrosinemia type 1. Metabol Open 2021; 9:100083. [PMID: 33598652 PMCID: PMC7868710 DOI: 10.1016/j.metop.2021.100083] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/22/2021] [Accepted: 01/23/2021] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Tyrosinemia type 1 (hepatorenal tyrosinemia, HT1) is a rare autosomal recessive inborn error of tyrosine metabolism caused by deficiency of the last enzyme in the tyrosine catabolic pathway, fumarylacetoacetate hydrolase (FAH) leading to severe hepatic, renal and peripheral nerve damage if left untreated. Early treatment may prevent acute liver failure, renal dysfunction, liver cirrhosis, hepatocellular carcinoma (HCC) and improves survival. MATERIAL AND METHODS A retrospective single center study was carried out based on the clinical and biochemical presentation, therapy and outcome of 25 Palestinian patients with HT1 diagnosed during the last 25 years. RESULTS HT1 is not included in newborn screening program in Palestine. The mean age at diagnosis was 8 months and the main clinical manifestations were coagulopathy, hepatomegaly, splenomegaly and renal tubular dysfunction. The main biochemical abnormalities were elevated plasma tyrosine, serum transaminases and prothrombin time, and low serum phosphorous with elevated alkaline phosphatase compatible with hypophosphatemic rickets secondary to renal tubular dysfunction. All patients were treated with nitisinone. The mean duration of nitisinone treatment was 74 months and the mean dosage was 0.89 mg/kg/day. None developed HCC or neurological crisis. CONCLUSIONS Most patients present with liver failure and renal tubular dysfunction. Nitisinone treatment was effective therapy in all patients and improved both short- and long-term prognosis of HT1. Renal tubular dysfunction improved in all patients within the first week of starting nitisinone. Early diagnosis is necessary because delay in the treatment increases the risk of progressive liver failure HCC, progressive renal disease and neuropathy.
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Affiliation(s)
- Imad Dweikat
- Metabolic Department Arab American University, PO Box 240 Jenin, 13 Zababdeh, Palestine
| | - Nada Qawasmi
- Pediatric Department, Makassed Hospital, Palestine
| | - Aysha Najeeb
- Pediatric Department, Makassed Hospital, Palestine
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Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I. Int J Mol Sci 2021; 22:ijms22041789. [PMID: 33670179 PMCID: PMC7916972 DOI: 10.3390/ijms22041789] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 02/07/2021] [Accepted: 02/08/2021] [Indexed: 12/30/2022] Open
Abstract
Fumarylacetoacetate hydrolase (FAH) is the fifth enzyme in the tyrosine catabolism pathway. A deficiency in human FAH leads to hereditary tyrosinemia type I (HT1), an autosomal recessive disorder that results in the accumulation of toxic metabolites such as succinylacetone, maleylacetoacetate, and fumarylacetoacetate in the liver and kidney, among other tissues. The disease is severe and, when untreated, it can lead to death. A low tyrosine diet combined with the herbicidal nitisinone constitutes the only available therapy, but this treatment is not devoid of secondary effects and long-term complications. In this study, we targeted FAH for the first-time to discover new chemical modulators that act as pharmacological chaperones, directly associating with this enzyme. After screening several thousand compounds and subsequent chemical redesign, we found a set of reversible inhibitors that associate with FAH close to the active site and stabilize the (active) dimeric species, as demonstrated by NMR spectroscopy. Importantly, the inhibitors are also able to partially restore the normal phenotype in a newly developed cellular model of HT1.
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Mirani S, Poojari V, Shetty NS, Shah I. Outcome of Tyrosinemia Type 1 in Indian Children. J Clin Exp Hepatol 2021; 11:9-13. [PMID: 33679043 PMCID: PMC7897851 DOI: 10.1016/j.jceh.2020.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 07/05/2020] [Indexed: 12/12/2022] Open
Abstract
AIM The objective of this study was to determine the outcome of children with tyrosinemia type 1 from India. METHODS A retrospective observational study was conducted on 11 patients diagnosed with type I tyrosinemia under our care. Age at symptoms, age at diagnosis, age at starting 2-nitro-4-trifluoromethylbenzoyl-1,3-cyclohexanedione (NTBC), duration between diagnosis and initiation of NTBC, dose given, total duration of NTBC, and outcomes were noted. RESULTS Eleven children with a median age of 1.1 years (0.51-1.52) at onset of symptoms were included in the study. The median age at diagnosis was 1.76 years (0.95-2.43). Their current median age is 5.44 (2.36-8.80) years. Common clinical features at presentation were chronic liver disease in 8 (72.72%), rickets in 2 (18.18%), and fulminant liver disease in 1 (9.09%) patient. Hepatomegaly was observed in all children, growth retardation in 9 (81.81%), coagulopathy in 8 (72.72%), and abdominal distention in 6 (54.54%) patients. The median duration of NTBC therapy was 13.5 (7-21.25) months. The median dose of NTBC was 1 (0.77-1) mg/kg/day. One (9.09%) patient died due to liver cell failure. However, she had received NTBC only for a month. Another patient developed hepatocellular carcinoma (HCC) and underwent liver transplantation. He could receive NTBC only for 2 months, although he was diagnosed to have tyrosinemia for over a 1 year. Eight patients are on treatment with NTBC and are doing well, and 1 patient is not on NTBC and continues to have renal tubular acidosis. CONCLUSION NTBC therapy is effective and improves the prognosis of tyrosinemia. A long-term follow-up is required to determine progression to HCC and need for liver transplantation.
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Key Words
- AFP, Alpha-feto Protein
- ALP, Alkaline Phosphatase
- CLD, Chronic Liver Disease
- GGPT, γ-glutamine Transaminase
- HCC, Hepatocellular Carcinoma
- INR, International Normalized Ratio
- LFT, Liver Function Test
- NTBC
- NTBC, 2-nitro-4-trifluoromethylbenzoyl-1,3-cyclohexanedione
- RTA, Renal Tubular Acidosis
- SA, Succinylacetone
- SGOT, Aspartate Transaminase
- SGPT, Alanine Transaminase
- Tyrosinemia type 1
- hepatocellular carcinoma
- liver transplant
- succinylacetone
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Affiliation(s)
- Sonal Mirani
- Department of Pediatric Gastroenterology and Hepatology, B J Wadia Hospital for Children, Mumbai, India
| | - Vishrutha Poojari
- Department of Pediatric Gastroenterology and Hepatology, B J Wadia Hospital for Children, Mumbai, India
| | - Naman S. Shetty
- Department of Pediatric Gastroenterology and Hepatology, B J Wadia Hospital for Children, Mumbai, India
| | - Ira Shah
- Department of Pediatric Gastroenterology and Hepatology, B J Wadia Hospital for Children, Mumbai, India,Consultant in Pediatric Gastroenterology and Hepatology, Nanavati Hospital, Mumbai, India,Address for correspondence. Ira Shah, Head, Department of Pediatric Gastroenterology and Hepatology, B J Wadia Hospital for Children, Mumbai, India.
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Colemonts-Vroninks H, Neuckermans J, Marcelis L, Claes P, Branson S, Casimir G, Goyens P, Martens GA, Vanhaecke T, De Kock J. Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation. Genes (Basel) 2020; 12:E3. [PMID: 33375092 PMCID: PMC7822164 DOI: 10.3390/genes12010003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/17/2020] [Accepted: 12/18/2020] [Indexed: 12/14/2022] Open
Abstract
Hereditary tyrosinemia type 1 (HT1) is an inherited condition in which the body is unable to break down the amino acid tyrosine due to mutations in the fumarylacetoacetate hydrolase (FAH) gene, coding for the final enzyme of the tyrosine degradation pathway. As a consequence, HT1 patients accumulate toxic tyrosine derivatives causing severe liver damage. Since its introduction, the drug nitisinone (NTBC) has offered a life-saving treatment that inhibits the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), thereby preventing production of downstream toxic metabolites. However, HT1 patients under NTBC therapy remain unable to degrade tyrosine. To control the disease and side-effects of the drug, HT1 patients need to take NTBC as an adjunct to a lifelong tyrosine and phenylalanine restricted diet. As a consequence of this strict therapeutic regime, drug compliance issues can arise with significant influence on patient health. In this study, we investigated the molecular impact of short-term NTBC therapy discontinuation on liver tissue of Fah-deficient mice. We found that after seven days of NTBC withdrawal, molecular pathways related to oxidative stress, glutathione metabolism, and liver regeneration were mostly affected. More specifically, NRF2-mediated oxidative stress response and several toxicological gene classes related to reactive oxygen species metabolism were significantly modulated. We observed that the expression of several key glutathione metabolism related genes including Slc7a11 and Ggt1 was highly increased after short-term NTBC therapy deprivation. This stress response was associated with the transcriptional activation of several markers of liver progenitor cells including Atf3, Cyr61, Ddr1, Epcam, Elovl7, and Glis3, indicating a concreted activation of liver regeneration early after NTBC withdrawal.
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Affiliation(s)
- Haaike Colemonts-Vroninks
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium; (H.C.-V.); (J.N.); (P.C.); (S.B.); (T.V.)
| | - Jessie Neuckermans
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium; (H.C.-V.); (J.N.); (P.C.); (S.B.); (T.V.)
| | - Lionel Marcelis
- Laboratoire de Pédiatrie, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Université Libre de Bruxelles (ULB), Avenue J.J. Crocq 1-3, 1020 Brussels, Belgium; (L.M.); (G.C.); (P.G.)
| | - Paul Claes
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium; (H.C.-V.); (J.N.); (P.C.); (S.B.); (T.V.)
| | - Steven Branson
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium; (H.C.-V.); (J.N.); (P.C.); (S.B.); (T.V.)
| | - Georges Casimir
- Laboratoire de Pédiatrie, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Université Libre de Bruxelles (ULB), Avenue J.J. Crocq 1-3, 1020 Brussels, Belgium; (L.M.); (G.C.); (P.G.)
| | - Philippe Goyens
- Laboratoire de Pédiatrie, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Université Libre de Bruxelles (ULB), Avenue J.J. Crocq 1-3, 1020 Brussels, Belgium; (L.M.); (G.C.); (P.G.)
| | - Geert A. Martens
- Department of Laboratory Medicine, AZ Delta General Hospital, Deltalaan 1, 8800 Roeselare, Belgium;
- Center for Beta Cell Therapy in Diabetes, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Tamara Vanhaecke
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium; (H.C.-V.); (J.N.); (P.C.); (S.B.); (T.V.)
| | - Joery De Kock
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium; (H.C.-V.); (J.N.); (P.C.); (S.B.); (T.V.)
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Thompson WS, Mondal G, Vanlith CJ, Kaiser RA, Lillegard JB. The future of gene-targeted therapy for hereditary tyrosinemia type 1 as a lead indication among the inborn errors of metabolism. Expert Opin Orphan Drugs 2020; 8:245-256. [PMID: 33224636 PMCID: PMC7676758 DOI: 10.1080/21678707.2020.1791082] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction Inborn errors of metabolism (IEMs) often result from single-gene mutations and collectively cause liver dysfunction in neonates leading to chronic liver and systemic disease. Current treatments for many IEMs are limited to maintenance therapies that may still require orthotropic liver transplantation. Gene therapies offer a potentially superior approach by correcting or replacing defective genes with functional isoforms; however, they face unique challenges from complexities presented by individual diseases and their diverse etiology, presentation, and pathophysiology. Furthermore, immune responses, off-target gene disruption, and tumorigenesis are major concerns that need to be addressed before clinical application of gene therapy. Areas covered The current treatments for IEMs are reviewed as well as the advances in, and barriers to, gene therapy for IEMs. Attention is then given to ex vivo and in vivo gene therapy approaches for hereditary tyrosinemia type 1 (HT1). Of all IEMs, HT1 is particularly amenable to gene therapy because of a selective growth advantage conferred to corrected cells, thereby lowering the initial transduction threshold for phenotypic relevance. Expert opinion It is proposed that not only is HT1 a safe indication for gene therapy, its unique characteristics position it to be an ideal IEM to develop for clinical investigation.
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Affiliation(s)
| | - Gourish Mondal
- Department of Surgery, Research Scientist, Mayo Clinic, Rochester, MN, USA
| | | | - Robert A Kaiser
- Department of Surgery, Research Scientist, Mayo Clinic, Rochester, MN, USA.,Midwest Fetal Care Center, Childrens Hospital of Minnesota, MN, USA
| | - Joseph B Lillegard
- Midwest Fetal Care Center, Childrens Hospital of Minnesota, MN, USA.,Assistant Professor of Surgery, Mayo Clinic, Rochester, MN, USA
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13
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Neeleman RA, Wilson JHP, Williams M, Langendonk JG. Heme as an initial treatment for severe decompensation in tyrosinemia type 1. Genet Med 2020; 22:437-438. [PMID: 31570800 DOI: 10.1038/s41436-019-0658-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 09/10/2019] [Accepted: 09/10/2019] [Indexed: 12/19/2022] Open
Affiliation(s)
- Rochus A Neeleman
- Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disorders, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - J H Paul Wilson
- Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disorders, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Monique Williams
- Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disorders, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Pediatrics, Center for Lysosomal and Metabolic Disorders, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Janneke G Langendonk
- Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disorders, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
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14
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van Ginkel WG, Rodenburg IL, Harding CO, Hollak CEM, Heiner-Fokkema MR, van Spronsen FJ. Long-Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1. Paediatr Drugs 2019; 21:413-426. [PMID: 31667718 PMCID: PMC6885500 DOI: 10.1007/s40272-019-00364-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Tyrosinemia type 1 (TT1) is a rare metabolic disease caused by a defect in tyrosine catabolism. TT1 is clinically characterized by acute liver failure, development of hepatocellular carcinoma, renal and neurological problems, and consequently an extremely poor outcome. This review showed that the introduction of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) in 1992 has revolutionized the outcome of TT1 patients, especially when started pre-clinically. If started early, NTBC can prevent liver failure, renal problems, and neurological attacks and decrease the risk for hepatocellular carcinoma. NTBC has been shown to be safe and well tolerated, although the long-term effectiveness of treatment with NTBC needs to be awaited. The high tyrosine concentrations caused by treatment with NTBC could result in ophthalmological and skin problems and requires life-long dietary restriction of tyrosine and its precursor phenylalanine, which could be strenuous to adhere to. In addition, neurocognitive problems have been reported since the introduction of NTBC, with hypothesized but as yet unproven pathophysiological mechanisms. Further research should be done to investigate the possible relationship between important clinical outcomes and blood concentrations of biochemical parameters such as phenylalanine, tyrosine, succinylacetone, and NTBC, and to develop clear guidelines for treatment and follow-up with reliable measurements. This all in order to ultimately improve the combined NTBC and dietary treatment and limit possible complications such as hepatocellular carcinoma development, neurocognitive problems, and impaired quality of life.
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Affiliation(s)
- Willem G van Ginkel
- Department of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
| | - Iris L Rodenburg
- Department of Dietetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Cary O Harding
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, USA
| | - Carla E M Hollak
- Deparment of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - M Rebecca Heiner-Fokkema
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Francjan J van Spronsen
- Department of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.
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15
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Abstract
Inborn errors of metabolism comprise a wide array of diseases and complications in the pediatric patient. The rarity of these disorders limits the ability to conduct and review robust literature regarding the disease states, mechanisms of dysfunction, treatments, and outcomes. Often, treatment plans will be based on the pathophysiology associated with the disorder and theoretical agents that may be involved in the metabolic process. Medication therapies usually consist of natural or herbal products. Established efficacious pediatric doses for these products are difficult to find in tertiary resources, and adverse effects are routinely limited to single case reports. This review article attempts to summarize some of the more common inborn errors of metabolism in a manner that is applicable to pharmacists who will provide care for these patients.
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Khanna R, Verma SK. Pediatric hepatocellular carcinoma. World J Gastroenterol 2018; 24:3980-3999. [PMID: 30254403 PMCID: PMC6148423 DOI: 10.3748/wjg.v24.i35.3980] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 07/11/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
Pediatric hepatocellular carcinoma (HCC) is the second common malignant liver tumor in children after hepatoblastoma. It differs from the adult HCC in the etiological predisposition, biological behavior and lower frequency of cirrhosis. Perinatally acquired hepatitis-B virus, hepatorenal tyrosinemia, progressive familial intrahepatic cholestasis, glycogen storage disease, Alagille’s syndrome and congenital portosystemic shunts are important predisposing factors. Majority of children (87%) are older than 5 years of age. Following mass immunization against hepatitis-B, there has been a drastic fall in the incidence of new cases of pediatric HCC in the Asia-Pacific region. Management is targeted on complete surgical removal either by resection or liver transplantation. There is a trend towards improving survival of children transplanted for HCC beyond Milan criteria. Chemotherapeutic regimens do not offer good results but may be helpful for down-staging of advanced HCC. Surveillance of children with chronic liver diseases with ultrasound and alpha-fetoprotein may be helpful in timely detection, intervention and overall improvement in outcome of HCC.
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Affiliation(s)
- Rajeev Khanna
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
| | - Sanjeev Kumar Verma
- Department of Pediatrics, King George Medical University, Uttar Pradesh 226003, India
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Abstract
Hereditary tyrosinemia type 1 (HT1, OMIM 276700) is a rare autosomal recessively inherited inborn error of metabolism in the tyrosine catabolic pathway due to deficiency of the enzyme fumarylacetoacetate hydrolase. The clinical features of HT1 are widely heterogenous even within the same family members. Clinical features includes acute or chronic liver disease with increased risk of hepatocellular carcinoma, hypophosphatemic rickets due to renal tubular dysfunction, glomerulosclerosis, failure to thrive, neurological porphyria-like crisis, hypertrophic cardiomyopathy and hypoglycemia due to hyperinsulinism. Currently, the treatment in HT1 consists of two principles: inhibition of the formation of toxic metabolites by nitisinone [2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione; NTBC] and reduction of tyrosine levels by dietary treatment. In this chapter besides presenting the data for 42 patients that had been followed up by Pediatric Metabolic Diseases and Nutrition Unit, Cerrahpasa Medical Faculty, Istanbul University, we also evaluated the data abstracted from the previously published case studies in order to better understand the disease course and gain further insight in the current diagnosis and treatment for HT1 in Turkey.
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Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations. Genet Med 2017; 19:S1098-3600(21)04765-1. [PMID: 28771246 PMCID: PMC5729346 DOI: 10.1038/gim.2017.101] [Citation(s) in RCA: 137] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 04/28/2017] [Indexed: 12/19/2022] Open
Abstract
Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure with comorbidities involving the renal and neurologic systems and long term risks for hepatocellular carcinoma. An effective medical treatment with 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione (NTBC) exists but requires early identification of affected children for optimal long-term results. Newborn screening (NBS) utilizing blood succinylacetone as the NBS marker is superior to observing tyrosine levels as a way of identifying neonates with HT-1. If identified early and treated appropriately, the majority of affected infants can remain asymptomatic. A clinical management scheme is needed for infants with HT-1 identified by NBS or clinical symptoms. To this end, a group of 11 clinical practitioners, including eight biochemical genetics physicians, two metabolic dietitian nutritionists, and a clinical psychologist, from the United States and Canada, with experience in providing care for patients with HT-1, initiated an evidence- and consensus-based process to establish uniform recommendations for identification and treatment of HT-1. Recommendations were developed from a literature review, practitioner management survey, and nominal group process involving two face-to-face meetings. There was strong consensus in favor of NBS for HT-1, using blood succinylacetone as a marker, followed by diagnostic confirmation and early treatment with NTBC and diet. Consensus recommendations for both immediate and long-term clinical follow-up of positive diagnoses via both newborn screening and clinical symptomatic presentation are provided.
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19
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Ibarra-González I, Ridaura-Sanz C, Fernández-Lainez C, Guillén-López S, Belmont-Martínez L, Vela-Amieva M. Hepatorenal Tyrosinemia in Mexico: A Call to Action. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 959:147-156. [PMID: 28755193 DOI: 10.1007/978-3-319-55780-9_14] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Hepatorenal tyrosinemia is a treatable metabolic disease characterized by progressive liver failure, renal damage and pronounced coagulopathy. Its clinical diagnosis is difficult because of its low prevalence and heterogeneous symptoms. In developed countries, expanded newborn screening, based on succinylacetone quantification by tandem mass spectrometry, has been very valuable in the early detection of hepatorenal tyrosinemia, providing the opportunity for rapid treatment of affected patients. In developing countries without systematic expanded newborn screening, however, diagnosis and treatment of this disease remain major challenges, as genetic diseases in these countries are not a health priority and there are few referral centers for infants with inherited errors of metabolism. This chapter describes the diagnosis, follow-up and outcome of 20 Mexican patients with hepatorenal tyrosinemia. This chapter also constitutes a call to action to pediatricians, gastroenterologists, geneticists and other health professionals, and to academic organizations, health authorities and patient advocacy groups, to promote early patient detection and treatment, reducing the unacceptably high mortality rate (75%) in Mexican infants with this potentially deadly but eminently treatable condition.
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Affiliation(s)
| | - Cecilia Ridaura-Sanz
- Departamento de Patología, Instituto Nacional de Pediatría, Ciudad de México, México
| | - Cynthia Fernández-Lainez
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Av. IMAN #1, piso 9, Insurgentes-Cuicuilco, CP 04530, Ciudad de México, México
| | - Sara Guillén-López
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Av. IMAN #1, piso 9, Insurgentes-Cuicuilco, CP 04530, Ciudad de México, México
| | - Leticia Belmont-Martínez
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Av. IMAN #1, piso 9, Insurgentes-Cuicuilco, CP 04530, Ciudad de México, México
| | - Marcela Vela-Amieva
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Av. IMAN #1, piso 9, Insurgentes-Cuicuilco, CP 04530, Ciudad de México, México.
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20
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Mathes T, Pieper D. Clarifying the distinction between case series and cohort studies in systematic reviews of comparative studies: potential impact on body of evidence and workload. BMC Med Res Methodol 2017; 17:107. [PMID: 28716005 PMCID: PMC5513097 DOI: 10.1186/s12874-017-0391-8] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 07/10/2017] [Indexed: 12/15/2022] Open
Abstract
Distinguishing cohort studies from case series is difficult.We propose a conceptualization of cohort studies in systematic reviews of comparative studies. The main aim of this conceptualization is to clarify the distinction between cohort studies and case series. We discuss the potential impact of the proposed conceptualization on the body of evidence and workload.All studies with exposure-based sampling gather multiple exposures (with at least two different exposures or levels of exposure) and enable calculation of relative risks that should be considered cohort studies in systematic reviews, including non-randomized studies. The term "enables/can" means that a predefined analytic comparison is not a prerequisite (i.e., the absolute risks per group and/or a risk ratio are provided). Instead, all studies for which sufficient data are available for reanalysis to compare different exposures (e.g., sufficient data in the publication) are classified as cohort studies.There are possibly large numbers of studies without a comparison for the exposure of interest but that do provide the necessary data to calculate effect measures for a comparison. Consequently, more studies could be included in a systematic review. Therefore, on the one hand, the outlined approach can increase the confidence in effect estimates and the strengths of conclusions. On the other hand, the workload would increase (e.g., additional data extraction and risk of bias assessment, as well as reanalyses).
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Affiliation(s)
- Tim Mathes
- Institute for Research in Operative Medicine, Chair of Surgical Research, Faculty of Health, School of Medicine, Witten/Herdecke University, Ostmerheimer Str. 200, 51109 Cologne, Germany
| | - Dawid Pieper
- Institute for Research in Operative Medicine, Chair of Surgical Research, Faculty of Health, School of Medicine, Witten/Herdecke University, Ostmerheimer Str. 200, 51109 Cologne, Germany
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21
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Corneal Pseudodendritic Lesions Masquerading as Herpetic Keratitis in a Patient With Tyrosinemia Type I. Eye Contact Lens 2017; 43:e7-e9. [DOI: 10.1097/icl.0000000000000187] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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22
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Belfiori-Carrasco LF, Marcora MS, Bocai NI, Ceriani MF, Morelli L, Castaño EM. A Novel Genetic Screen Identifies Modifiers of Age-Dependent Amyloid β Toxicity in the Drosophila Brain. Front Aging Neurosci 2017; 9:61. [PMID: 28352227 PMCID: PMC5349081 DOI: 10.3389/fnagi.2017.00061] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 02/28/2017] [Indexed: 11/13/2022] Open
Abstract
The accumulation of amyloid β peptide (Aβ) in the brain of Alzheimer's disease (AD) patients begins many years before clinical onset. Such process has been proposed to be pathogenic through the toxicity of Aβ soluble oligomers leading to synaptic dysfunction, phospho-tau aggregation and neuronal loss. Yet, a massive accumulation of Aβ can be found in approximately 30% of aged individuals with preserved cognitive function. Therefore, within the frame of the "amyloid hypothesis", compensatory mechanisms and/or additional neurotoxic or protective factors need to be considered and investigated. Here we describe a modifier genetic screen in Drosophila designed to identify genes that modulate toxicity of Aβ42 in the CNS. The expression of Aβ42 led to its accumulation in the brain and a moderate impairment of negative geotaxis at 18 days post-eclosion (d.p.e) as compared with genetic or parental controls. These flies were mated with a collection of lines carrying chromosomal deletions and negative geotaxis was assessed at 5 and 18 d.p.e. Our screen is the first to take into account all of the following features, relevant to sporadic AD: (1) pan-neuronal expression of wild-type Aβ42; (2) a quantifiable complex behavior; (3) Aβ neurotoxicity associated with progressive accumulation of the peptide; and (4) improvement or worsening of climbing ability only evident in aged animals. One hundred and ninety-nine deficiency (Df) lines accounting for ~6300 genes were analyzed. Six lines, including the deletion of 52 Drosophila genes with human orthologs, significantly modified Aβ42 neurotoxicity in 18-day-old flies. So far, we have validated CG11796 and identified CG17249 as a strong candidate (whose human orthologs are HPD and PRCC, respectively) by using RNAi or mutant hemizygous lines. PRCC encodes proline-rich protein PRCC (ppPRCC) of unknown function associated with papillary renal cell carcinoma. HPD encodes 4-hydroxyphenylpyruvate dioxygenase (HPPD), a key enzyme in tyrosine degradation whose Df causes autosomal recessive Tyrosinemia type 3, characterized by mental retardation. Interestingly, lines with a partial Df of HPD ortholog showed increased intraneuronal accumulation of Aβ42 that coincided with geotaxis impairment. These previously undetected modifiers of Aβ42 neurotoxicity in Drosophila warrant further study to validate their possible role and significance in the pathogenesis of sporadic AD.
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Affiliation(s)
- Lautaro F Belfiori-Carrasco
- Laboratorio de Amiloidosis y Neurodegeneración, Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Buenos Aires, Argentina
| | - María S Marcora
- Laboratorio de Amiloidosis y Neurodegeneración, Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Buenos Aires, Argentina
| | - Nadia I Bocai
- Laboratorio de Amiloidosis y Neurodegeneración, Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Buenos Aires, Argentina
| | - M Fernanda Ceriani
- Laboratorio de Genética del Comportamiento, Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Buenos Aires, Argentina
| | - Laura Morelli
- Laboratorio de Amiloidosis y Neurodegeneración, Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Buenos Aires, Argentina
| | - Eduardo M Castaño
- Laboratorio de Amiloidosis y Neurodegeneración, Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Buenos Aires, Argentina
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Long-term cognitive functioning in individuals with tyrosinemia type 1 treated with nitisinone and protein-restricted diet. Mol Genet Metab Rep 2017; 11:12-16. [PMID: 28377889 PMCID: PMC5369864 DOI: 10.1016/j.ymgmr.2017.01.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 01/24/2017] [Accepted: 01/26/2017] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION Tyrosinemia Type 1 (HT1) is an autosomal recessive disorder caused by a defect in the enzyme fumarylacetoacetate hydroxylase in the tyrosine pathway. Implementation of nitisinone (NTBC) treatment has dramatically improved survival rate of individuals with HT1, yet recent reports on cognitive impairment in treated patients exist. AIMS Describe long-term neurocognitive outcome individuals with HT1 treated with nitisinone and protein restricted diet. METHODOLOGY Twelve individuals with HT1 were analyzed with respect to psychomotor development and cognitive functioning using standardized psychometric tests. Plasma tyrosine and phenylalanine concentrations were also collected and analyzed, as part of the regular HT1 follow up program in our clinic. RESULTS Delayed performance in Bayley scale mental developmental index (MDI) was identified in 29% to 38% of the patients assessed at different ages. At preschool age, mean full scale IQ (FSIQ) was 88 ± 16; six out of nine assessed children preformed within normal range, and one child presented with intellectual disability. At school age mean FSIQ was 79 ± 18, three out of nine children preformed within normal range and two showed intellectual disability. Repeated measures showed IQ decline over time in four out of eight patients, all of whom presented with symptoms in their first months of life. Patients that showed no progressive IQ decline were 8 months or older at diagnosis, with a mean age of 17 months. Significant correlation between Phe/Tyr ratio and FSIQ at school age was identified (r = - 0.689; p < 0.044). CONCLUSION Some patients with HT1 treated with nitisinone and protein restricted diet are at risk of presenting developmental delay and impaired cognitive functioning. Patients with early onset of symptoms could be at risk for progressive cognitive functioning decline over time.
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Palaniappan K, Borkar VV, Safwan M, Vij M, Govil S, Shanmugam N, Rela M. Pediatric hepatocellular carcinoma in a developing country: Is the etiology changing? Pediatr Transplant 2016; 20:898-903. [PMID: 27392999 DOI: 10.1111/petr.12754] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/07/2016] [Indexed: 12/26/2022]
Abstract
HCC is the second most common malignant liver tumor of childhood. It typically affects children with a median age of 10-14 yr on background hepatitis B-related liver disease and is often metastatic or locally advanced at diagnosis. Children below the age of five yr typically constitute <10% of all children with HCC. In these children, it occurs on a background of congenital or metabolic liver disease. The records of all children with HCC who presented to our department over a six-yr study period were reviewed. Twelve patients with a median age of 5.9 yr (range 1.6-15.4) were diagnosed to have HCC. All patients underwent liver transplantation, and none were resected. Eleven patients had background congenital or metabolic liver disease. All five of those with hereditary tyrosinemia type 1 who presented to us were found to have HCC. No patient had hepatitis B-related liver (HBV) disease. Eight (66.7%) patients had incidentally discovered HCC on examination of the explant. Incidentally discovered HCC were smaller, well differentiated, and did not show microvascular invasion compared to those diagnosed preoperatively. There was no recurrence with a median follow-up of five months. The patient demographic for pediatric HCC is changing probably as a consequence of successful immunization against HBV. Younger patients with congenital and metabolic liver disease in whom liver transplantation is the ideal treatment are likely to constitute an ever-increasing proportion of patients with pediatric HCC as HBV disease is controlled or eradicated.
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Affiliation(s)
- Kumar Palaniappan
- Institute of Liver Disease and Transplantation, Global Health City, Chennai, India
| | - Vibhor V Borkar
- Institute of Liver Disease and Transplantation, Global Health City, Chennai, India
| | - Mohamed Safwan
- Institute of Liver Disease and Transplantation, Global Health City, Chennai, India
| | - Mukul Vij
- Institute of Liver Disease and Transplantation, Global Health City, Chennai, India
| | - Sanjay Govil
- Institute of Liver Disease and Transplantation, Global Health City, Chennai, India
| | - Naresh Shanmugam
- Institute of Liver Disease and Transplantation, Global Health City, Chennai, India
- National Foundation for Liver Research, Chennai, India
| | - Mohamed Rela
- Institute of Liver Disease and Transplantation, Global Health City, Chennai, India.
- National Foundation for Liver Research, Chennai, India.
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Önenli Mungan N, Yıldızdaş D, Kör D, Horoz ÖÖ, İncecik F, Öktem M, Sander J. Tyrosinemia type 1 and irreversible neurologic crisis after one month discontinuation of nitisone. Metab Brain Dis 2016; 31:1181-3. [PMID: 27188289 DOI: 10.1007/s11011-016-9833-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 05/02/2016] [Indexed: 01/04/2023]
Abstract
Tyrosinemia type I is an autosomal recessively inherited metabolic disease of tyrosine metabolism due to the deficiency of fumarylacetoacetate hydrolase. Clinical manifestations include hepatic failure, cirrhosis, hepatocellular carcinoma, renal fanconi syndrome, and neurologic crisis. With the introduction of 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione treatment the prognosis improved with reduced rate of complications. "Neurologic crisis" of tyrosinemia type I is a rare complication seen after discontinuation of treatment characterized with anorexia, vomiting, and hyponatremia in the initial phase continuing with paresthesia and paralysis of the extremities and the diaphragm. Here, we report a tyrosinemia type I patient who admitted to the hospital with nonspecific symptoms such as vomiting, anorexia, weakness, and restlessness only after one month discontinuation of nitisone and diagnosed as neurological crisis.
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Affiliation(s)
| | - Dinçer Yıldızdaş
- Department of Pediatrics, Cukurova University Faculty of Medicine, Adana, Turkey
| | - Deniz Kör
- Department of Pediatrics, Cukurova University Faculty of Medicine, Adana, Turkey
| | - Özden Özgür Horoz
- Department of Pediatrics, Cukurova University Faculty of Medicine, Adana, Turkey
| | - Faruk İncecik
- Department of Pediatrics, Cukurova University Faculty of Medicine, Adana, Turkey
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Gokay S, Ustkoyuncu PS, Kardas F, Kendirci M. The outcome of seven patients with hereditary tyrosinemia type 1. J Pediatr Endocrinol Metab 2016; 29:1151-1157. [PMID: 27682708 DOI: 10.1515/jpem-2015-0471] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 07/18/2016] [Indexed: 11/15/2022]
Abstract
BACKGROUND Hereditary tyrosinemia type 1 (HT1) is a rare, inborn error of tyrosine metabolism. It is a fatal disorder without treatment. Early treatment may prevent acute liver failure, renal dysfunction, liver cirrhosis, hepatocellular carcinoma (HCC) and improves survival. The aim of the present study is to describe the clinical, biochemical, imaging and follow-up of seven patients with HT1 and to define the consequences of the late and interrupted treatment. METHODS A retrospective study was carried out with seven HT1 patients. RESULTS The median age at onset of clinical symptoms was 11.2 months (range, 3-28 months) and the median age at diagnosis was 22 months (range, 6-58 months). Liver enzymes and coagulation parameters were back to normal in all symptomatic patients in about 2 weeks. Alfa-fetoprotein (AFP) levels were normalized within the first year of therapy. Hypoechoic nodule formation was detected in two of the seven patients despite drug treatment without an increase of AFP and any dysplastic changes in the biopsies. One patient died due to metastatic HCC because of the late diagnosis and the poor compliance of the follow-up. CONCLUSIONS This study showed once again that adherence to the treatment and a follow-up schedule of the patients are very important. Also it should not be forgotten that nodule formation can occur despite nitisinone treatment without an increase of AFP. Despite nitisinone treatment, HT1 patients still carry the risk of HCC. HCC must be detected before metastasis to other organs otherwise, patients may lose the chance for liver transplantation.
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