Benign transient hyperphosphatasemia of infancy and early childhood is a self-limiting condition characte-rized by transiently increased serum alkaline phosphatase in the absence of liver, kidney or metabolic bone diseases. It is often accidentally found in children under five years old and it might be associated with a variety of underlying clinical disorders. Its pathophysiology remains unclear. Herein, we report a case of a 4-year-old girl with a 1-year history of persistent oligoarticular Juvenile Idiopathic Arthritis, who was found to have transient hyperphosphatasemia during a periodic check-up. This clinical case underlines the importance of promptly recognizing this benign condition, which avoids unnecessary extensive investigations.publishersversionpublishe

Branco, J. C.

Costa, M.

Mourão, A. F.

Neto, A.

English

Branco, Jaime

Repositório da Universidade Nova de Lisboa

ÓRgÃO OFICIAL DA SOCIEDADE PORTUgUESA DE REUMATOLOgIA317CASE BASED REVIEWS1. Serviço de Reumatologia, Hospital de Egas Moniz, CentroHospitalar de Lisboa Ocidental, Lisboa;2. Serviço de Reumatologia, Hospital Central do Funchal, Madeira;3. Centro de Estudos de Doenças Crónicas (CEDOC), NOVA MedicalSchool, Faculdade de Ciências Médicas, Universidade NOVA deLisboa, Lisboa.its real prevalence is difficult to estimate since ALP le -vels are not routinely measured in all children, espe-cially in those who are asymptomatic6,7. Studies ad-dressing gender distribution are contradictory: somehave shown that BTHI affects both sexes equally1,5,8,while others have reported a male predominance2. The diagnosis is confirmed by the spontaneous re-turn of ALP to normal levels within weeks or monthsof initial observation. It has no adverse long-term con-sequences.BTHI was first described by Bach in 19549, and sincethen, some case reports and few case series have beenpublished in the literature. It remains a relatively un-recognized condition and it might be a potential, yetavoidable, concern for physicians when faced with amarked elevation of ALP levels.cAse report A 4-year-old girl with a 1-year history of persistentoligoarticular Juvenile Idiopathic Arthritis (JIA) pre-sented to our Pediatric Rheumatology department fora routine follow-up visit. She was in clinical remissionfor at least 6 months, following two single intra-articularcorticosteroid injections of both knees. She was not ta -king any medication.At the time of visit, she was asymptomatic and herphysical examination was unremarkable. Laboratorytests showed a normal blood count, an erythrocyte sed-imentation rate of 19 mm/h and a C-reactive protein of0.1 mg/dL. However, alkaline phosphatase wasmarkedly increased (1578 U/L; normal age-related val-ue 150-380 U/L). Alanine-aminotransferase (ALT), as-partate-aminotransferase (AST), gamma-glutamyltranspeptidase (GGT) and total bilirubin were withinnormal reference ranges, as well as renal function, cal-cium and phosphorus levels.Her parents were healthy and reported no com-plaints or abnormalities in their routine laboratory tests. ACTA REUMATOL PORT. 2019;44:317-319Benign transient hyperphosphatasemia in juvenile idiopathic arthritis: a case reportNeto A1,2,3, Costa M1, Branco JC1,3, Mourão AF1,3AbstrActBenign transient hyperphosphatasemia of infancy andearly childhood is a self-limiting condition characte -rized by transiently increased serum alkaline phos-phatase in the absence of liver, kidney or metabolicbone diseases. It is often accidentally found in childrenunder five years old and it might be associated with avariety of underlying clinical disorders. Its pathophys-iology remains unclear.Herein, we report a case of a 4-year-old girl with a1-year history of persistent oligoarticular Juvenile Id-iopathic Arthritis, who was found to have transient hy-perphosphatasemia during a periodic check-up. Thisclinical case underlines the importance of promptly rec-ognizing this benign condition, which avoids unnec-essary extensive investigations. Keywords: Hyperphosphatasemia; Juvenile idiopa thicarthritis.IntroductIonBenign transient hyperphosphatasemia of infancy andearly childhood (BTHI) is a self-limiting condition cha -racterized by a sudden and temporary increase of serumalkaline phosphatase (ALP) in the absence of liver, kid-ney or metabolic bone diseases1,2. It predominantly af-fects children, especially those aged less than 5 years,though it has also been reported in adults3-5. BTHI is often accidentally detected when laborato-ry tests are required in healthy children or in childrendiagnosed with a variety of unrelated disorders. It canbe found in 1.5% up to 5.1% of the infants, althoughÓRgÃO OFICIAL DA SOCIEDADE PORTUgUESA DE REUMATOLOgIA318Benign transient hyperphosphatasemia in juvenile idiopathic arthritis: a case reportSince there were no other findings suggestive of li -ver, kidney or metabolic bone disease either in physi-cal examination or in the laboratory tests, BTHI wassuspected and a “wait-and-see” strategy was adopted.After two months, there was a spontaneous reductionof ALP to normal levels (201 U/L), while all the otherlaboratory tests remained normal, supporting the di-agnosis of BTHI.dIscussIonALP is a glycoprotein that can be synthetised through-out the body in a variety of isoenzymes, dependingupon the site of origin. In humans, there are four isoen-zymes: tissue-nonspecific (liver, bone, kidney), in-testinal, placental and germ cell ALP3,10,11. In the pedi-atric population, under physiological conditions, thebone and liver fractions contribute 85% and 15% tothe total serum ALP pool, respectively11.Serum ALP level varies according to age. It is ge -nerally higher in children than in adults, particularlyduring the rapid growth phases of infancy and puber-ty, due to increased rates of osteoblastic activity11.In this report, we describe a transient increase inALP levels in an asymptomatic 4-year-old child. Theserum level of ALP was increased four to five timesabove the upper reference limit for age, which is typi-cally seen in BTHI, although elevations up to 20 timesthe upper standard value have been described12.In 1985, Kraut et al. proposed the following diag-nostic criteria for BTHI13: 1) age less than 5 years; 2)variable clinical picture, ranging from asymptomatic tovariable unrelated symptoms; 3) no evidence of boneor liver disease on physical examination; 4) no bio-chemical or laboratory evidence of bone or liver dis-ease, except for the severe isolated rise in serum ALP;5) elevation in both bone and liver fractions of ALP; 6)return to normal ALP values within four months. Inour clinical case, all these diagnostic criteria were met,except for the identification of ALP isoenzymes, whoseanalysis was not performed. However, some studieshave shown that the characteristic isoenzyme patternis not always observed in infants with otherwise typi-cal features of BTHI1,2,14. This could be explained bydifferences in laboratory methods, lack of experiencein interpreting results or by a late performance of thetest during the course of the condition when the isoen-zyme pattern has returned to normality1. Therefore,failure to meet the fifth criterion described by Krautshould not preclude the establishment of the diagno-sis.Kraut’s criteria have been further contested because,as previously stated, BTHI has been observed in olderchildren and adults3-5 and its duration can exceed thetime limit of four months in nearly 20% of cases5,15. Inour clinical case, ALP levels returned to normal aftertwo months, portraying the classic natural history ofBTHI.The pathophysiology of BTHI remains poorly un-derstood. The most plausible explanation for the risein ALP levels is a delayed clearance of ALP from circu-lation due to excessive sialylation13,16. Still, the cause ofthis abnormal sialylation is also unclear. Viral infec-tions (cytomegalovirus, herpes virus, adenovirus, Ep-stein-Barr virus, rotavirus, enterovirus, among others)have been suggested as potential triggering factors1,2,14.In fact, several studies have found a temporal associa-tion between the development of BTHI and a previousor concomitant viral infection, especially in the upperrespiratory or gastrointestinal tracts. In our patient, nohistory of any recent infection was described.Although most children are healthy, BTHI has beenlinked with a variety of underlying clinical conditions,such as gastrointestinal diseases (Celiac disease,Crohn’s disease1,2, multiple congenital anomalies1,phenylketonuria1, hemophilia1, congenital HIV infec-tion17, malignancies (leukemia, lymphoma, rhab-domyosarcoma)18, post liver and kidney transplant19,20or seizure disorders13. Our patient had a history ofoligoarticular JIA, with 1-year evolution. In the litera-ture, this association with JIA is rare but has alreadybeen described. In 1985, Jerry Jacobs reported the oc-currence of BTHI in two girls with polyarticular JIA21.In these cases, the elevation of ALP occurred 2 and 16months after the onset of JIA. Nonetheless, we hy-pothesize that this apparent association may be a tem-poral coincidence rather than a causal relationship, re-flecting more frequent monitoring of JIA patients.The differential diagnosis of increased ALP in child-hood should include bone disorders (such as rickets,healing fractures, juvenile Paget’s disease, fibrous dys-plasia of bone, bone tumors), hepatic disorders(cholestasis, malignancy) and kidney disorders (chron-ic renal failure, tubulopathies)22,23. However, these dis-eases are usually accompanied by other clinical ele-ments or laboratory abnormalities. Our patient wastotally asymptomatic and there was no other evidenceof hepatic or bone disease in the physical examinationor in the laboratory tests. ÓRgÃO OFICIAL DA SOCIEDADE PORTUgUESA DE REUMATOLOgIA319neto a et alDrugs such as cotrimoxazole, cyclosporin A, anti-convulsants and chemotherapy can also cause an in-crease in ALP13,14,16 but, as mentioned, our patient wason no medication.Benign familial hyperphosphatasemia (BFH) alsoneeds to be considered in the differential diagnosis.BFH is an inherited disease characterized by the pres-ence of persistently elevated levels of serum ALP in theabsence of other cause of hyperphosphatasemia24,25.BFH was excluded in our clinical case by the sponta-neous reduction of ALP to normal levels and by the factthat the child’s parents are healthy, with no history ofhyperphosphatasemia. In conclusion, the incidental finding of isolated hy-perphosphatasemia in children should raise the possi-bility of BTHI. A careful clinical history, physical ex-amination and routine laboratory tests are usuallysufficient to rule out other possible causative illnesses.Given the benign nature and self-limiting evolution ofthis condition, monitoring of ALP levels is recom-mended before any further diagnostic steps are under-taken. The occurrence of BTHI in JIA patients is rareand it may be found by chance.correspondence toAgna NetoHospital de Egas Moniz Rua da Junqueira 126, 1349-019 LisboaE-mail: agnaneto@gmail.comreferences 1. Stein P, Rosalki SB, Foo AY, Hjelm M. Transient hyperphos-phatasemia of infancy and early childhood: clinical and bio-chemical features of 21 cases and literature review. Clin Chem.1987 Feb;33(2 Pt 1):313-318.2. Carroll AJ, Coakley JC. Transient hyperphosphatasaemia: animportant condition to recognize. J Paediatr Child Health. 2001Aug;37(4):359-362.3. Jassam NJ, Horner J, Marzo-Ortega H, Sinclair M, Barth JH.Transient rise in alkaline phosphatase activity in adults. BMJCase Rep. 2009;bcr09.2009.2250. doi:10.1136/bcr.09.2009.22504. Rosalki SB, Foo AY, Went J, Williams R, Baker DM. "Transienthyperphosphatasemia of infancy and childhood" in an adult.Clin Chem. 1991 Jun;37(6):1137-1138.5. Gualco G, Lava SA, Garzoni L, Simonetti GD, Bettinelli A, Mi-lani GP et al. Transient benign hyperphophatasemia. J PediatrGastroenterol Nutr. 2013 Aug;57(2):167-171.6. Huh SY, Feldman HA, Cox JE, Gordon CM. Prevalence of tran-sient hyperphosphatasemia among healthy infants and toddlers.Pediatrics. 2009;124(2):703–709.7. Asanti R, Hultin H, Visakorpi JK. Serum alkaline, phosphatasein healthy infants. Occurrence of abnormally high values with-out known cause. Ann Paediatr Fenn. 1966;12:139–142.8. Çakir BÇ, Kirsaçlio lu CT, Tartıcı EK, Demirel F. Transient hy-perphosphatasemia in infants and children: a retrospectivestudy of 43 cases. J Contemp Med 2017; 7(2): 138-1429. Bach U. Das verhalten der alkalischen serum-phosphatase beiFruhgeborenen, Rachitikern und Spasmophilen. Z. Kinder-heilkd. 1954; 74: 593–609. 6 Kraut JR, Metrick M 10. Sharma U, Pal D, Prasad R. Alkaline phosphatase: an overview.Indian J Clin Biochem. 2014;29(3):269–278. doi:10.1007/s12291-013-0408-y 11. Turan S, Topcu B, Gökçe İ, Güran T, Atay Z, Omar A et al. Serumalkaline phosphatase levels in healthy children and evaluationof alkaline phosphatase z-scores in different types of rickets. JClin Res Pediatr Endocrinol. 2011;3(1):7-11.12. Behúlová D, Bzdúch V, Holesová D, Vasilenková A, Ponec J.Transient hyperphosphatasemia of infancy and childhood:study of 194 cases. Clin Chem. 2000 Nov;46(11):1868-1869.13. Kraut JR, Metrick M, Maxwell NR, Kaplan MM. Isoenzyme stud-ies in transient hyperphosphatasemia of infancy. Ten new casesand a review of the literature. Am J Dis Child. 1985Jul;139(7):736-740. 14. Alves C, Arruti R. Benign transient hyperphosphatasemia ofchildhood. Acta Ortopédica Brasileira. 2009; 17(1), 55-57.15. Schonhaut L, Rocha A. Benign transient hyperphosphatasemiain infants, clinical series. Rev Chil Pediatr. 2017;88(1):176-181.16. Crofton PM. What is the cause of benign transient hyperphos-phatasemia? A study of 35 cases. Clin Chem. 1988 Feb;34(2):335-340.17. Fennoy I, Laraque D. Benign transient hyperphosphatasia andHIV infection. Clin Pediatr (Phila). 1989 Apr;28(4):180-184.18. Steinherz PG, Steinherz LJ, Nisselbaum JS, Murphy ML. Tran-sient, marked, unexplained elevation of serum alkaline phos-phatase. JAMA. 1984 Dec 21;252(23):3289-3292.19. Arikan C, Arslan MT, Kilic M, Aydogdu S. Transient hyper-phosphatasemia after liver transplantation. Pediatr Int 2006;48:390-392.20. Yoshimaru K, Matsuura T, Hayashida M, Kinoshita Y, TakahashiY, Yanagi Y et al. Transient hyperphosphatasemia after pediatricliver transplantation. Pediatr Int 2016 Aug;58(8):726-731.21. Jacobs JC. Reply to the editor: Transient hyperphosphatasemiaof infancy. The Journal of Pediatrics 1985 Nov;107(5):829. 22. Roberson JR, Kaste SC, Santana VM, Furman WL. Differentialdiagnosis and work-up of elevations of alkaline phosphatasefollowing therapy for pediatric cancer. Pediatr Blood Cancer.2008 Dec;51(6):840-842.23. Otero JL, González-Peralta RP, Andres JM, Jolley CD, NovakDA, Haafiz A. Elevated Alkaline Phosphatase in Children: An Al-gorithm to Determine When a "Wait and See" Approach is Op-timal. Clin Med Insights Pediatr. 2011 Jun 22;5:15-18.24. Navarro Despaigne D, Moro Alvarez MJ, Díaz Curiel M. Benignfamilial hyperphosphatasemia. A report of one case and diag-nostic considerations. An Med Interna. 2007 Aug;24(8):387--389.25. Siraganian PA, Mulvihill JJ, Mulivor RA, Miller RW. Benign fa-milial hyperphosphatasemia. JAMA. 1989 Mar 3;261(9):1310--1312.

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