ORIGINAL ARTICLE
Acute Hemolytic Anemia as an Initial Presentation of Wilson Disease in Children Mona S. El Raziky, MS, MD,* Amal Ali, MD,w Amira El shahawy, MSc,w and Mona M. Hamdy, MD*
Background: Wilson disease (WD) is an inherited disorder of copper metabolism. Hemolytic anemia in WD occurs in up to 17% of patients at some point during their illness. Aim: To screen for WD among children presenting with hemolytic anemia. Methodology: Twenty cases (mean age, 8.8 ± 3.9 y) with Coombsnegative hemolytic anemia, attending the hematology clinic of children hospital, Cairo University, were screened for WD by serum ceruloplasmin level, 24 hours urinary copper before and after D-penicillamine challenge test, and slit-lamp examination for detecting Kayser-Fleischer rings. Results: No case had low ceruloplasmin, whereas bilateral KayserFleischer rings was detected in 5% of our cases. Urinary copper was elevated in 5% before and in 40% after D-penicillamine challenge test. According to the scoring system used, 1 case had definite WD and 7 cases were likely to have WD. These 8 (40%) cases were referred to as group B. Group B had a significantly lower hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, and reticulocytes (P = 0.04, 0.001, 0.04, and 0.04, respectively) and a significantly higher urinary copper after penicillamine (P = 0.000) when compared with group A (unlikely WD). Conclusion: WD is not uncommon in children with hemolytic anemia after exclusion of other common causes. Key Words: Wilson disease, hemolytic anemia, screening
(J Pediatr Hematol Oncol 2014;36:173–178)
W
ilson disease (WD) is an autosomal recessive disorder of copper metabolism resulting in pathologic accumulation of copper in many organs and tissues. The incidence of WD was estimated to be at least 1:30,000 to 50,000. The gene defect lies in the WD protein, ATP7B, a copper-transporting ATPase that is highly active in hepatocytes.1 Other genes may also be involved in the pathogenesis of WD.2 WD is a lethal condition in the absence of adequate treatment. The prognosis for survival depends on the severity of liver and neurological disease and compliance with drug treatment. With chelation treatment and liver Received for publication May 3, 2012; accepted January 17, 2014. From the *Pediatric Department, Cairo University; and wPediatric Department, National Hepatology and Tropical Medicine Institute, Cairo, Egypt. The authors have participated in the concept and design, analysis and interpretation of data, drafting and revision of the manuscript, and are approving the manuscript submitted. The authors declare no conflict of interest. Reprints: Mona M. H. Mahmoud, MD, Pediatric Department, Cairo University, 30, Tarablos street, Nasr city, Cairo, 11371, Egypt (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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transplantation, prolonged survival has become the norm.3,4 Thus, early identification of WD leads to a better possible outcome in patients with this condition; hence, WD should certainly be ruled out in any young patient presenting with findings suggestive of hemolytic anemia of uncertain etiology, as the disease can be successfully treated in the early stages.5 Over 80% of patients become symptomatic within the first 3 decades of life and about 40% to 70% of overall initial WD manifestations involve the liver. Clinical presentation can vary widely, but the key features of WD are liver disease and cirrhosis, neuropsychiatric disturbances, Kayser-Fleischer (KF) rings in Desc¸emet’s membrane of the cornea, and acute episodes of hemolysis often in association with acute liver failure.6 The hepatic manifestations of WD are diverse. The diagnosis of WD is often delayed.7,8 The differential diagnosis of hemolytic anemia is extensive and WD is generally not the first condition to be considered. It can be difficult to diagnose due to the low specificity of the presenting symptoms. However, because of the potentially fatal consequences, an early diagnosis is of utmost importance.9 Hemolytic anemia in WD occurs in up 17% of patients at some point in time during the natural course of illness; it is uncommon as the initial presentation. It occurs as a result of oxidative injury, altered erythrocyte metabolism, and severely compromised antioxidant status caused by toxic effects of copper that is released from necrotic hepatocytes.10
AIM Our aim is to check for WD among children presenting with hemolytic anemia.
PATIENTS AND METHODS This cohort study was carried out on children attending the Hematology Clinic of the Children Hospital, Cairo University, during the period from October 2010 to September 2011. Inclusion criteria were: children from both sexes 3 to 18 years of age (WD is uncommon below this age), with Hb < 10 mg/dL, reticulocytic count >2%, Coombs negative test, normal Hb electrophoresis, normal G6PD activity, and normal osmotic fragility test. Subjects with previously diagnosed liver disease were excluded from the study. Before enrollment, an informed consent was obtained from the parents. The Institutional Ethics Review Committee approved the study protocol. All subjects enrollment in the study were evaluated at baseline. A detailed medical history was obtained and a complete physical examination www.jpho-online.com |
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was conducted on all study participants. Laboratory investigations included: (1) Liver biochemical profile including AST, ALT, bilirubin total and direct, alkaline phosphatase, serum albumin, prothrombin time, and INR. (2) Serum ceruloplasmin level (normal range, 20 to 65 mg/ dL) for which blood was collected after an overnight fast. Sera were collected and stored at 801C until assayed. Total serum ceruloplasmin concentration was analyzed using an immunonephelometric assay with anti-serum to human ceruloplasmin (Dade Behring, Marburg, Germany) on BNII nephelometer (Dade Behring). The assay was used in line with the manufacturer’s instructions. (3) Urinary copper levels in 24-hour collection before and after a D-penicillamine challenge test in which urinary copper excretion was determined in all patients using an “Atomic energy spectrophotometer” from the Atomic Energy Centre Laboratory, Dhaka. Penicillamine challenge test is standardized in children; 500 mg Dpenicillamine is given orally at the beginning and again 12 hours later during the 24-hour collection irrespective of body weight. Slit-lamp examination for detecting KF rings using Slit-Lamp 3C model by Topcon Corporation. Patients were considered as having WD according to the following scoring system of the 8th International Conference on Wilson’s Disease, 2001.11
Scoring System This scoring system has high sensitivity and specificity for the diagnosis of WD. A combination of clinical and biochemical tests with a score ranging from 0 to 4 for each test were developed (Table 1).11 The patients with a total score of at least 4 were diagnosed with WD. The patients with a total score of 3 were considered as “likely to have Wilson’s disease, yet more investigations had to be performed.” The diagnosis of WD was judged to be improbable for scores between 0 and 2.12 With respect to molecular analysis, it should be noted that >200 different mutations have been identified. It has been difficult to devise a simple genetic screening test for the disease. Thus only the H1069Q (exon 14) was researched.
Statistical Methods Data were collected and tabulated. Statistical Package for Social Science program version 17.0 was used for data analysis. Mean and SD were estimates of quantitative data, whereas frequency and percentage were estimates of qualitative data. Differences in clinical and biochemical characteristics were tested by the Student t test for quantitative data and by the w2 test for nonparametric (qualitative) data. A 2-sided P value 5ULN (250 mg/g) 50-250 mg/g Normal (< 50 mg/g) Rhodamine-positive granules Urinary Cu ( in absence of acute hepatitis)
Score
2 1 1 1
0
Absent
0
Total score Z4 3 r2
Normal 1-2ULN > 2ULN Normal but >5 ULN > after penicillamine Mutation analysis
0 1 2 2
Mutation on both chromosomes Mutation only on 1 chromosome No mutations detected Evaluation Diagnosis established Diagnosis possible, more tests needed Diagnosis very unlikely
4 1 0
ULN indicates upper limit of normal.
We further classified the studied children into group A (mean age, 8.8 ± 4.4 y; 75% males) including those unlikely to have WD (score: 0, 1, and 2) and group B (mean age, 9.9 ± 3.1 y; 62.5% males) including 1 case with definite WD (score 5) and 7 cases likely to have WD (score 3). Jaundice was evident in 4 cases (50%) in group B, whereas pallor and history of previous hemolytic attacks were present in all cases (100%). Hepatic and splenic enlargements were detected in 1 case only (12.5%). No significant difference was observed between the 2 groups in relation to history and clinical examination. Cases in group B had a significantly lower hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and reticulocytes than those in group A (P = 0.04, 0.001, 0.04, and 0.04, respectively) (Table 3). Significantly higher urinary copper after penicillamine was observed in group B than group A (P = 0.000) (Table 4). Among cases in group B, there was a significant correlation between serum ceruloplasmin level and AST (P = 0.005), although correlation between ceruloplasmin and ALT was P = 0.07. No significant correlation was observed between urinary copper before and after D-penicillamine and liver enzymes tests.
DISCUSSION Many recent findings come in accordance with the old recommendation: “It is imperative that all children over 6 or 7 years of age who develop acute hemolytic anemia of obscure etiology be investigated for Wilson disease”.13 WD r
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TABLE 2. Scoring for Diagnosis of Wilson Disease in All Studied Cases
Case No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Ceruloplasmin (mg/dL)
Slit-Lamp Examination
Urinary Copper Before D-Penicillamine
Urinary Copper After D-Penicillamine
Score
39.00 29.00 45.80 59.10 51.90 38.30 59.70 34.60 33.80 29.80 65.00 29.9 50.40 53.00 71.90 47.40 64.90 41.30 52.10 34.00
Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Abnormal Normal Normal Normal Normal Normal
65 14 20 4.2 118 86 7 6.6 20 38 30 7.5 41 5 36 18 4.5 36 60 56
433 72 336 49 544 1225 50 668 497 285 306 52 59 530 576 585 629 745 88 90
1 1 1 1 3 3 1 3 1 1 1 1 1 3 5 3 3 3 1 1
is itself quite uncommon and its rapid diagnosis is life saving; hence, Balkema et al9 recommended considering WD in any patient with hemolytic anemia, liver dysfunction, or neuropsychiatric symptoms of unknown cause, whereas Singh et al5 recommended that WD should certainly be ruled out in any young patient presenting with liver disease either clinical or subclinical and other findings TABLE 3. Hematological Findings and Liver Biochemical Profile of Groups A and B
Group A (N = 12) WBCs, median (IQR) 6.5 (2.9) ( 10/cmm) Hemoglobin, mean ± SD 10.4 ± 1.5 (g/dL) MCV, mean ± SD (fL) 86.7 ± 11.9 MCH, median (IQR) (pg) 28.6 (4.3) Platelet, median (IQR) 263.5 (127.8) ( 10/cmm) Retics, median (IQR) (%) 6.1 (6.8) Aspartate transaminase, 28.5 (35.5) median (IQR) (U/L) Alanine transaminase, 20.5 (35) median (IQR) (U/L) Alkaline phosphatase, 239 (69.5) median (IQR) (U/L) Gamma glutamyl 15.8 ± 2.9 transpeptidase, mean ± SD (U/L) Serum albumin, mean ± SD 4.4 ± 0.4 (g/dL) Total bilirubin, median 1.9 (1.4) (IQR) (mg/dL) Direct bilirubin, median 0.3 (0.4) (IQR) (mg/dL) Prothrombin time, 15.04 ± 2.4 mean ± SD (/s)
Group B (N = 8)
P
8.95 (9.03)
0.5
7.98 ± 2.7
0.04*
64.4 ± 11.1 0.001* 23.9 (4.6) 0.04* 642.5 (569.3) 0.1 2 (2.4) 26 (11.5)
0.04* 0.4
19 (11.8)
0.3
278.5 (213.5) 0.8 15.5 ± 4.9
0.8
4.1 ± 0.7
0.5
1.1 (1.5)
0.2
0.2 (0.3)
0.4
14.6 ± 1.6
0.6
*Significant P < 0.05. IQR indicates interquartile range; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume;WBC, white blood cells.
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suggestive of hemolytic anemia; Kitazawa et al14 confirmed that a possible diagnosis of WD should be considered in patients presenting with fulminant hepatic failure with evidence of Coombs-negative hemolytic anemia. To the best of our knowledge, no single study has discussed such number of patients. Reviewing all case reports from 1965 to 2011 discussing hemolytic cases diagnosed as WD (Table 5), we found 20 reports that, after exclusion of patients older than 18 years, discussed only 1 case, 2 that discussed 3 cases, and 1 that discussed 2 cases. The collective data of 25 cases of WD gathered from 20 publications can be summarized as follows. About 68% of cases were females, 84% had a history of single hemolytic attack, and the rest had >1 hemolytic attack (Table 5). On physical examination, there was severe pallor along with hepatomegaly in 64% (16/25) and/or splenomegaly in 40% (10/25). CNS manifestation was reported in only 12% (3/25) in the form of asterixis, a confusion that progressed to coma and death (Table 5). Laboratory investigations revealed normocytic-normochromic anemia in most reports. ALT was normal, whereas AST was elevated in some of the case reports.15–18 These data are in disagreement with the rest of reviewed case reports where 80% of their cases had elevated ALT TABLE 4. Levels of Serum Ceruloplasmin and Urinary Copper of Groups A and B
Group A (N = 12) Ceruloplasmin, mean ± SD (mg/dL) Urinary copper before D-penicillamine, median (IQR) (mg/d) Urinary copper after D-penicillamine, median (IQR) (mg/d)
43.97 ± 13.1 25 (43.1) 89 (274.8)
Group B (N = 8)
P
50.4 ± 12.9 0.3 27 (68.1)
0.8
607 (173.8) 0.000*
*Significant P < 0.05. IQR indicates interquartile range.
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TABLE 5. Summary of Case Reports on Children With Wilson Disease Presenting With Hemolytic Anemia (1965 to 2011)
Age Hemolytic Neuro. K-F Aspartate Alanine Alkaline (years) Attacks Jaundice Sympt. Hepatomegaly Splenomegaly Ring Transaminase Transaminase Phosphatase This study (1 case + 7 likely to be) Agrawal et al15 (1 case) Sharma et al21 (1 case) Singh et al5 (1 case) Prochazkova et al22 (1 case) Asfaha et al23 (1 case) Christl et al24 (1 case) Kitazawa et al14 (1 case) Chand et al25 (1 case) Brouwer et al16 (1 case) Michel et al17 (1 case) Kim et al26 (1 case) Ozer et al27 (1 case) Kawahara et al28 (1 case) Degenhardt et al18 (1 case) Tseng et al29 (1 case) Kraut and Yogev30 (1 case) Roche-Sicot and Benhamou31 (3 cases) Robitaille et al32 (3 cases) Buchanan13 (2 cases) Carr-Saunders33 (1 case)
+ in 1
m in 1
N
m in 1
+
m
N
k
+
m
m
k
+
m
m
m
+
m
m
k
m
m
k
m
m
k
m
m
k
k
k
k
+
m
N
k
+
+
m
N
N/A
1
+
+
m
m
N/A
9
1
+
+
m
m
N/A
16
1
+
+
m
m
N/A
18
1
+
m
N
k
10
1
+
+
m
m
N/A
11
1
+
+
m
m
N/A
12
3
+
14.6
1
11.5 10
9.9
+
+ in 4
16
1
+
4.5
1
+
16
1
16
1
+
18
1
+
16
1
+
14
1
+
18
1
+
16
1
+
17
1
16
+ in 1
+
+
+ in 1
+
+ + +
+
+
+
+
+
+
+
+ in 2
+
m
m
N/A
+
+
+ in 2
+
N
N
N/A
1
+
+
+
+
m
m
N
2
+
+
+
N
N
N/A
+
N indicates normal; N/A, not available.
and AST. Agrawal et al15 in 2011 reported that episodes of low alkaline phosphatase tend to occur during the hemolytic event and then improve. Table 5 shows the criteria for diagnosis of WD: low serum level of ceruloplasmin in 92% (23/25), high serum level of copper and high urinary copper level in 92% (23/25), bilateral KF rings by slit-lamp examination in 68% (17/25), and copper content of dried liver weight in liver biopsy in 40% (10/25). Our results proved that 40% of cases presented by Coombs-negative hemolytic anemia are likely to have WD, which was described by Buchanan13 in 1975 to be secondary to the release of large quantities of hepatic copper intermittently
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into the bloodstream of WD patients, resulting in a transient elevation of erythrocytic and urinary copper and in an acute episode of hemolysis. When the copper release ceases, as it usually does within a few days, the hemolysis abates and within several weeks the patient becomes hematologically normal again. Such episodes may antedate clinical signs of significant liver disease, sometimes by months or even years. It is presumably caused by excess copper released from the liver due to apoptosis/necrosis of copper-loaded hepatocytes, possibly triggered by external stimuli. This may have direct toxic effects on erythrocytes, resulting in hemolysis.10 The key to diagnosis of WD is a high index of suspicion, which can increase only on greater awareness of the r
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disorder in the medical fraternity. A well known but tricky presentation of WD is acute or recurrent Coombs-negative hemolytic anemia with or without associated liver dysfunction. In the present study, no cases had low ceruloplasmin. This is similar to the results of Degenhardt et al,18 but disagrees with results of reviewed case reports where 92% of their cases had low ceruloplasmin (Table 5). In children with WD, 15% to 36% had ceruloplasmin in the normal range.19,20 Using serum ceruloplasmin to identify patients with WD is further complicated by overlap with some heterozygotes. Approximately 20% of heterozygotes have decreased levels of serum ceruloplasmin.34,35 Bilateral KF rings was detected in 1 (12.5%) of our 8 positive cases that may be due to short duration of presentation. In contrast, 68% of reviewed case reports had bilateral KF rings on slit-lamp examination (Table 5). ElKaraksy et al36 in 2011 found KF rings in 33% of children presenting with liver disease and in 62.5% of Egyptian children presenting with neurological presentation and also found that the combination of low ceruloplasmin and KF rings was present in 31.5% of patients. Neither the absence of KF rings nor normal values of serum copper or ceruloplasmin can exclude WD.37–39 Elevated levels of urinary copper before and after Dpenicillamine was observed in all 8 cases (100%) and with a significantly higher levels than group A (P = 0.000). Recent reevaluation of the penicillamine challenge test in children found it valuable for the diagnosis of WD in patients with active liver disease (sensitivity 92%), but poor for excluding the diagnosis in asymptomatic siblings (sensitivity only 46%).40 Wilson et al41 in 2000 reported that WD may present symptomatically at any age, although the majority presents between ages 5 and 35. The youngest patient reported with cirrhosis due to WD was 3 years old. In our cases which are likely to be WD, the mean age was 9.9 + 3.1 years, whereas the mean age was 14 years (Table 5). Our positive cases were 62.5% males and 37.5% females. Our data disagree with that of Table 5 in which 68% of them were females and 32% were males, but our results are in concordance with the male predominance of Egyptian WD cases reported by El-Karaksy et al36 in both hepatic and neurologically presented cases. Some studies reported a predominance of males in WD,42,43 whereas other studies reported female predominance.3,44,45 Previous hemolytic attacks were present in 100%, whereas results of the reviewed case reports was 84% had a history of single hemolytic attack and the rest had >1 hemolytic attack (Table 5). History of jaundice was present in 50% of our positive cases. Data from the reviewed case reports showed history of jaundice in 100% of their cases (Table 5). Hepatomegaly was observed in 1 case (12.5%) and splenomegaly in 1 case (12.5%), lower than that of reviewed case reports where 64% showed hepatomegaly and 44% showed splenomegaly (Table 5). None of our positive cases showed neurological manifestations on the history or physical examination. This disagrees with results of reviewed case reports where 12% had neurological manifestations (Table 5). Cases likely to have WD have a significantly lower hemoglobin, MCV, and MCH than those unlikely to have WD (P = 0.04, 0.001, and 0.04, respectively), and have a significantly lower reticulocytes. Data of reviewed case reports showed low Hb level in 100% of cases with elevated MCV in 40%. MCV and MCH were normal in the study r
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conducted by Singh et al5 in 2009. MCH was normal according to the study by Ozer et al27 in 1999 and was low according to the study by Kitazawa et al14 in 2004. ALT was normal in all cases, whereas AST was elevated in 12.5% of cases. Similar data were reported in some of the case reports.15–18 Mild elevation of serum transaminases in one third and prolonged prothrombin time in two thirds of WD patients was reported.46 This is in contrast to the collective data of all case reports where 80% of their cases had elevated ALT and AST (Table 5). In our positive cases, alkaline phosphatase was normal in all cases. This is different from data of Table 5 where 36% of cases had low alkaline phosphatase. Agrawal et al15 in 2011 reported that episodes of low alkaline phosphatase tend to occur during the hemolytic event and then improve. Limitation of this study was the inaccessibility to perform liver biopsy for the children included due to the unavailability of the Rodamine stain and the dried liver weight as well for the copper content. We concluded that WD in not uncommon in children with hemolytic anemia after exclusion of common causes. The diagnosis of Coombs-negative hemolytic anemia in any child between 3 and 18 years should alert pediatricians to the possibility of the presence of WD. ACKNOWLEDGMENT The authors thank Dr Mohamed Hashem, Department of Epidemiology & Public Health, University of Maryland School of Medicine Baltimore, MD, for language revision. REFERENCES 1. Bull PC, Thomas GR, Rommens JM, et al. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993;5:327–337. 2. De Bie P, van de Sluis B, Burstein EJ, et al. Distinct Wilson’s disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B. Gastroenterology. 2007;133:1316–1326. 3. Merle U, Schaefer M, Ferenci P, et al. Clinical presentation, diagnosis and long-term outcome of Wilson’s disease: a cohort study. Gut. 2007;56:115–120. 4. Czlonkowska A, Tarnacka B, Litwin T, et al. Wilson’s disease—cause of mortality in 164 patients during 1992–2003 observation period. J Neurol. 2005;252:698–703. 5. Singh T, Chaturvedi MK, Banerjee S, et al. Wilson’s disease presenting as haemolytic anaemia. J Assoc Physicians India. 2009;57:775. 6. Ferenci P, Czlonkowska A, Merle U, et al. Late onset Wilson disease. Gastroenterology. 2007;132:1294–1298. 7. Kong HL, Yap IL, Kueh YK. Wilson’s disease presenting as haemolytic anaemia and its successful treatment with penicillamine and zinc. Singapore Med J. 1996;37:670–672. 8. Ala A, Walker AP, Ashkan K, et al. Wilson’s disease. Lancet. 2007;369:397–408. 9. Balkema S, Hamaker ME, Visser HPJ, et al. Haemolytic anaemia as a first sign of Wilson’s disease. Neth J Med. 2008;66:344–347. 10. Attri S, Sharma N, Jahagirdar S, et al. Erythrocyte metabolism and antioxidant status of patients with Wilson disease with hemolytic anemia. Pediatr Res. 2006;59:593–597. 11. Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int. 2003;23:139–142. 12. EASL (European Association for the Study of the Liver). Clinical practice guidelines: Wilson’s disease. J Hepatol. 2012;56:671–685. 13. Buchanan GR. Acute hemolytic anemia as a presenting manifestation of Wilson disease. J Pediatr. 1975;86:245–247.
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14. Kitazawa J, Kaizuka M, Kasai M, et al. Hemolytic crisis with fulminant hepatic failure in Wilson disease without consanguinity. Pediatr Int. 2004;46:726–729. 15. Agrawal AK, Haddad FG, Matsunaga A. Acute nonimmune hemolytic anemia without fulminant hepatitis in Wilson disease. J Pediatr Hematol Oncol. 2011;33:163–165. 16. Brouwer RE, Manten A, van Leeuwen AM. An adolescent with hemolytic anemia and coagulation disorders as manifestation of Wilson’s disease, treated with liver transplantation. Ned Tijdschr Geneeskd. 2001;145:316–322. 17. Michel M, Lafaurie M, Noe¨l V, et al. Hemolytic anemia disclosing Wilson’s disease. Report of 2 cases. Rev Med Interne. 2001;22:280–283. 18. Degenhardt S, Blomhard G, Hefter H. A hemolytic crisis with liver failure as the first manifestation of Wilson’s disease. Dtsch Med Wochenschr. 1994;119:1421–1426. 19. Perman JA, Werlin SL, Grand RJ, et al. Laboratory measures of copper metabolism in the differentiation of chronic active hepatitis and Wilson disease in children. J Pediatr. 1979;94: 564–568. 20. Sanchez-Albisua I, Garde T, Hierro L, et al. A high index of suspicion: the key to an early diagnosis of Wilson’s disease in childhood. J Pediatr Gastroenterol Nutr. 1999;28:186–190. 21. Sharma S, Toppo A, Rath B, et al. Hemolytic anemia as a presenting feature of Wilson’s disease: a case report. Indian J Hematol Blood Transfus. 2010;26:101–102. 22. Prochazkova D, Pouchla S, Mejzlik V, et al. Haemolytic anaemia and acute liver failure—the initial manifestations of Wilson’s disease. Bratisl Lek Listy. 2008;109:434–437. 23. Asfaha S, Almansori M, Qarni U, et al. Plasmapheresis for hemolytic crisis and impending acute liver failure in Wilson disease. J Clin Apher. 2007;22:295–298. 24. Christl SU, Flieger D, Keller R, et al. Acute liver failure and hemolysis in a 16-year-old woman. First manifestation of Wilson’s disease. Med Klin Munich. 2005;100:579–582. 25. Chand VK, Morgan WA, Miller DK. Fulminant hepatic failure with hemolytic anemia: an unusual presentation of Wilson’s disease. Gundersen Lutheran Med J. 2003;2:41–42. 26. Kim JY, Na KS, Kim SH, et al. A case of Wilson’s disease presenting and flare-up as acute hemolytic anemia and fulminant hepatitis features. Korean J Hematol. 2000;35:167–170. 27. Ozer A, Kasırga E, Ozer E, et al. Wilson’s disease presenting with severe hemolytic anemia. East J Med. 1999;5:29–30. 28. Kawahara S, Morimoto K, Nakazawa H, et al. Severe hemolytic anemia with tear drop red cells as initial manifestation of Wilson’s disease. Rinsho Ketsueki. 1998;39:665–669. 29. Tseng CL, Tsai SL, Lin KH. Wilson disease presenting as fulminant hepatic failure, acute hemolytic anemia and renal failure: report of one case. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1990;31:266–271.
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30. Kraut JR, Yogev R. Fatal fulminant hepatitis with hemolysis in Wilson’s disease. Criteria for diagnosis. Clin Pediatr (Phila). 1984;23:637–640. 31. Roche-Sicot J, Benhamou JP. Acute intravascular hemolysis and acute liver failure associated as a first manifestation of Wilson’s disease. Ann Intern Med. 1977;86:301–303. 32. Robitaille GA, Piscatelli RL, Majeski EJ, et al. Hemolytic anemia in Wilson’s disease. A report of three cases with transient increase in hemoglobin A2. JAMA. 1977;237:2402. 33. Carr-Saunders E. Wilson’s disease presenting as an acute haemolytic anemia. Proc R Soc Med. 1965;58:614–615. 34. Dhawan A, Taylor RM, Cheeseman P, et al. Wilson’s disease in children: 37-year experience and revised King’s score for liver transplantation. Liver Transpl. 2005;11:441–448. 35. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47:2089–2111. 36. El-Karaksy H, Fahmy M, El-Raziky MS, et al. A clinical study of Wilson’s disease: the experience of a single Egyptian Paediatric Hepatology Unit. Arab J Gastroenterol. 2011; 12:125–130. 37. Gibbs K, Walshe JM. A study of the ceruloplasmin concentrations found in 75 patients with Wilson’s disease, their kinships and various control groups. Q J Med. 1979;48: 447–463. 38. Stremmel W, Meyerrose KW, Niederau C, et al. Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med. 1991;115:720–726. 39. Schilsky ML, Sternlieb I. Overcoming obstacles to the diagnosis of Wilson’s disease. Gastroenterology. 1997;113: 350–353. 40. Mu¨ller T, Koppikar S, Taylor RM, et al. Re-evaluation of the penicillamine challenge test in the diagnosis of Wilson’s disease in children. J Hepatol. 2007;47:270–276. 41. Wilson DC, Phillips MJ, Cox DW, et al. Severe hepatic Wilson’s disease in preschool-aged children. J Pediatr. 2000; 137:719–722. 42. Jha SK, Behari M, Ahuja GK. Wilson’s disease: clinical and radiological features. J Assoc Physicians India. 1998;46: 602–605. 43. Taly AB, Meenakshi-Sundaram S, Sinha S, et al. Wilson disease description of 282 patients evaluated over 3 decades. Medicine. 2007;82:112–121. 44. Maier-Dobersberger T, Ferenci P, Polli C, et al. Detection of the His1069Gln mutation in Wilson disease by rapid polymerase chain reaction. Ann Intern Med. 1997;127:21–26. 45. Wang XH, Cheng F, Zhang F, et al. Living related liver transplantation for Wilson’s disease. Transpl Int. 2005;18: 651–656. 46. Kalra V, Khuana D, Mittal R. Wilson’s disease—early onset and lessons from a pediatric cohort in India. Indian Pediatrics. 2000;37:595–601.
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Acute Hemolytic Anemia as an Initial Presentation of Wilson Disease in Children Mona S. El Raziky, MS, MD,* Amal Ali, MD,w Amira El shahawy, MSc,w and Mona M. Hamdy, MD*
Background: Wilson disease (WD) is an inherited disorder of copper metabolism. Hemolytic anemia in WD occurs in up to 17% of patients at some point during their illness. Aim: To screen for WD among children presenting with hemolytic anemia. Methodology: Twenty cases (mean age, 8.8 ± 3.9 y) with Coombsnegative hemolytic anemia, attending the hematology clinic of children hospital, Cairo University, were screened for WD by serum ceruloplasmin level, 24 hours urinary copper before and after D-penicillamine challenge test, and slit-lamp examination for detecting Kayser-Fleischer rings. Results: No case had low ceruloplasmin, whereas bilateral KayserFleischer rings was detected in 5% of our cases. Urinary copper was elevated in 5% before and in 40% after D-penicillamine challenge test. According to the scoring system used, 1 case had definite WD and 7 cases were likely to have WD. These 8 (40%) cases were referred to as group B. Group B had a significantly lower hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, and reticulocytes (P = 0.04, 0.001, 0.04, and 0.04, respectively) and a significantly higher urinary copper after penicillamine (P = 0.000) when compared with group A (unlikely WD). Conclusion: WD is not uncommon in children with hemolytic anemia after exclusion of other common causes. Key Words: Wilson disease, hemolytic anemia, screening
(J Pediatr Hematol Oncol 2014;36:173–178)
W
ilson disease (WD) is an autosomal recessive disorder of copper metabolism resulting in pathologic accumulation of copper in many organs and tissues. The incidence of WD was estimated to be at least 1:30,000 to 50,000. The gene defect lies in the WD protein, ATP7B, a copper-transporting ATPase that is highly active in hepatocytes.1 Other genes may also be involved in the pathogenesis of WD.2 WD is a lethal condition in the absence of adequate treatment. The prognosis for survival depends on the severity of liver and neurological disease and compliance with drug treatment. With chelation treatment and liver Received for publication May 3, 2012; accepted January 17, 2014. From the *Pediatric Department, Cairo University; and wPediatric Department, National Hepatology and Tropical Medicine Institute, Cairo, Egypt. The authors have participated in the concept and design, analysis and interpretation of data, drafting and revision of the manuscript, and are approving the manuscript submitted. The authors declare no conflict of interest. Reprints: Mona M. H. Mahmoud, MD, Pediatric Department, Cairo University, 30, Tarablos street, Nasr city, Cairo, 11371, Egypt (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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transplantation, prolonged survival has become the norm.3,4 Thus, early identification of WD leads to a better possible outcome in patients with this condition; hence, WD should certainly be ruled out in any young patient presenting with findings suggestive of hemolytic anemia of uncertain etiology, as the disease can be successfully treated in the early stages.5 Over 80% of patients become symptomatic within the first 3 decades of life and about 40% to 70% of overall initial WD manifestations involve the liver. Clinical presentation can vary widely, but the key features of WD are liver disease and cirrhosis, neuropsychiatric disturbances, Kayser-Fleischer (KF) rings in Desc¸emet’s membrane of the cornea, and acute episodes of hemolysis often in association with acute liver failure.6 The hepatic manifestations of WD are diverse. The diagnosis of WD is often delayed.7,8 The differential diagnosis of hemolytic anemia is extensive and WD is generally not the first condition to be considered. It can be difficult to diagnose due to the low specificity of the presenting symptoms. However, because of the potentially fatal consequences, an early diagnosis is of utmost importance.9 Hemolytic anemia in WD occurs in up 17% of patients at some point in time during the natural course of illness; it is uncommon as the initial presentation. It occurs as a result of oxidative injury, altered erythrocyte metabolism, and severely compromised antioxidant status caused by toxic effects of copper that is released from necrotic hepatocytes.10
AIM Our aim is to check for WD among children presenting with hemolytic anemia.
PATIENTS AND METHODS This cohort study was carried out on children attending the Hematology Clinic of the Children Hospital, Cairo University, during the period from October 2010 to September 2011. Inclusion criteria were: children from both sexes 3 to 18 years of age (WD is uncommon below this age), with Hb < 10 mg/dL, reticulocytic count >2%, Coombs negative test, normal Hb electrophoresis, normal G6PD activity, and normal osmotic fragility test. Subjects with previously diagnosed liver disease were excluded from the study. Before enrollment, an informed consent was obtained from the parents. The Institutional Ethics Review Committee approved the study protocol. All subjects enrollment in the study were evaluated at baseline. A detailed medical history was obtained and a complete physical examination www.jpho-online.com |
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was conducted on all study participants. Laboratory investigations included: (1) Liver biochemical profile including AST, ALT, bilirubin total and direct, alkaline phosphatase, serum albumin, prothrombin time, and INR. (2) Serum ceruloplasmin level (normal range, 20 to 65 mg/ dL) for which blood was collected after an overnight fast. Sera were collected and stored at 801C until assayed. Total serum ceruloplasmin concentration was analyzed using an immunonephelometric assay with anti-serum to human ceruloplasmin (Dade Behring, Marburg, Germany) on BNII nephelometer (Dade Behring). The assay was used in line with the manufacturer’s instructions. (3) Urinary copper levels in 24-hour collection before and after a D-penicillamine challenge test in which urinary copper excretion was determined in all patients using an “Atomic energy spectrophotometer” from the Atomic Energy Centre Laboratory, Dhaka. Penicillamine challenge test is standardized in children; 500 mg Dpenicillamine is given orally at the beginning and again 12 hours later during the 24-hour collection irrespective of body weight. Slit-lamp examination for detecting KF rings using Slit-Lamp 3C model by Topcon Corporation. Patients were considered as having WD according to the following scoring system of the 8th International Conference on Wilson’s Disease, 2001.11
Scoring System This scoring system has high sensitivity and specificity for the diagnosis of WD. A combination of clinical and biochemical tests with a score ranging from 0 to 4 for each test were developed (Table 1).11 The patients with a total score of at least 4 were diagnosed with WD. The patients with a total score of 3 were considered as “likely to have Wilson’s disease, yet more investigations had to be performed.” The diagnosis of WD was judged to be improbable for scores between 0 and 2.12 With respect to molecular analysis, it should be noted that >200 different mutations have been identified. It has been difficult to devise a simple genetic screening test for the disease. Thus only the H1069Q (exon 14) was researched.
Statistical Methods Data were collected and tabulated. Statistical Package for Social Science program version 17.0 was used for data analysis. Mean and SD were estimates of quantitative data, whereas frequency and percentage were estimates of qualitative data. Differences in clinical and biochemical characteristics were tested by the Student t test for quantitative data and by the w2 test for nonparametric (qualitative) data. A 2-sided P value 5ULN (250 mg/g) 50-250 mg/g Normal (< 50 mg/g) Rhodamine-positive granules Urinary Cu ( in absence of acute hepatitis)
Score
2 1 1 1
0
Absent
0
Total score Z4 3 r2
Normal 1-2ULN > 2ULN Normal but >5 ULN > after penicillamine Mutation analysis
0 1 2 2
Mutation on both chromosomes Mutation only on 1 chromosome No mutations detected Evaluation Diagnosis established Diagnosis possible, more tests needed Diagnosis very unlikely
4 1 0
ULN indicates upper limit of normal.
We further classified the studied children into group A (mean age, 8.8 ± 4.4 y; 75% males) including those unlikely to have WD (score: 0, 1, and 2) and group B (mean age, 9.9 ± 3.1 y; 62.5% males) including 1 case with definite WD (score 5) and 7 cases likely to have WD (score 3). Jaundice was evident in 4 cases (50%) in group B, whereas pallor and history of previous hemolytic attacks were present in all cases (100%). Hepatic and splenic enlargements were detected in 1 case only (12.5%). No significant difference was observed between the 2 groups in relation to history and clinical examination. Cases in group B had a significantly lower hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and reticulocytes than those in group A (P = 0.04, 0.001, 0.04, and 0.04, respectively) (Table 3). Significantly higher urinary copper after penicillamine was observed in group B than group A (P = 0.000) (Table 4). Among cases in group B, there was a significant correlation between serum ceruloplasmin level and AST (P = 0.005), although correlation between ceruloplasmin and ALT was P = 0.07. No significant correlation was observed between urinary copper before and after D-penicillamine and liver enzymes tests.
DISCUSSION Many recent findings come in accordance with the old recommendation: “It is imperative that all children over 6 or 7 years of age who develop acute hemolytic anemia of obscure etiology be investigated for Wilson disease”.13 WD r
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TABLE 2. Scoring for Diagnosis of Wilson Disease in All Studied Cases
Case No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Ceruloplasmin (mg/dL)
Slit-Lamp Examination
Urinary Copper Before D-Penicillamine
Urinary Copper After D-Penicillamine
Score
39.00 29.00 45.80 59.10 51.90 38.30 59.70 34.60 33.80 29.80 65.00 29.9 50.40 53.00 71.90 47.40 64.90 41.30 52.10 34.00
Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Abnormal Normal Normal Normal Normal Normal
65 14 20 4.2 118 86 7 6.6 20 38 30 7.5 41 5 36 18 4.5 36 60 56
433 72 336 49 544 1225 50 668 497 285 306 52 59 530 576 585 629 745 88 90
1 1 1 1 3 3 1 3 1 1 1 1 1 3 5 3 3 3 1 1
is itself quite uncommon and its rapid diagnosis is life saving; hence, Balkema et al9 recommended considering WD in any patient with hemolytic anemia, liver dysfunction, or neuropsychiatric symptoms of unknown cause, whereas Singh et al5 recommended that WD should certainly be ruled out in any young patient presenting with liver disease either clinical or subclinical and other findings TABLE 3. Hematological Findings and Liver Biochemical Profile of Groups A and B
Group A (N = 12) WBCs, median (IQR) 6.5 (2.9) ( 10/cmm) Hemoglobin, mean ± SD 10.4 ± 1.5 (g/dL) MCV, mean ± SD (fL) 86.7 ± 11.9 MCH, median (IQR) (pg) 28.6 (4.3) Platelet, median (IQR) 263.5 (127.8) ( 10/cmm) Retics, median (IQR) (%) 6.1 (6.8) Aspartate transaminase, 28.5 (35.5) median (IQR) (U/L) Alanine transaminase, 20.5 (35) median (IQR) (U/L) Alkaline phosphatase, 239 (69.5) median (IQR) (U/L) Gamma glutamyl 15.8 ± 2.9 transpeptidase, mean ± SD (U/L) Serum albumin, mean ± SD 4.4 ± 0.4 (g/dL) Total bilirubin, median 1.9 (1.4) (IQR) (mg/dL) Direct bilirubin, median 0.3 (0.4) (IQR) (mg/dL) Prothrombin time, 15.04 ± 2.4 mean ± SD (/s)
Group B (N = 8)
P
8.95 (9.03)
0.5
7.98 ± 2.7
0.04*
64.4 ± 11.1 0.001* 23.9 (4.6) 0.04* 642.5 (569.3) 0.1 2 (2.4) 26 (11.5)
0.04* 0.4
19 (11.8)
0.3
278.5 (213.5) 0.8 15.5 ± 4.9
0.8
4.1 ± 0.7
0.5
1.1 (1.5)
0.2
0.2 (0.3)
0.4
14.6 ± 1.6
0.6
*Significant P < 0.05. IQR indicates interquartile range; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume;WBC, white blood cells.
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suggestive of hemolytic anemia; Kitazawa et al14 confirmed that a possible diagnosis of WD should be considered in patients presenting with fulminant hepatic failure with evidence of Coombs-negative hemolytic anemia. To the best of our knowledge, no single study has discussed such number of patients. Reviewing all case reports from 1965 to 2011 discussing hemolytic cases diagnosed as WD (Table 5), we found 20 reports that, after exclusion of patients older than 18 years, discussed only 1 case, 2 that discussed 3 cases, and 1 that discussed 2 cases. The collective data of 25 cases of WD gathered from 20 publications can be summarized as follows. About 68% of cases were females, 84% had a history of single hemolytic attack, and the rest had >1 hemolytic attack (Table 5). On physical examination, there was severe pallor along with hepatomegaly in 64% (16/25) and/or splenomegaly in 40% (10/25). CNS manifestation was reported in only 12% (3/25) in the form of asterixis, a confusion that progressed to coma and death (Table 5). Laboratory investigations revealed normocytic-normochromic anemia in most reports. ALT was normal, whereas AST was elevated in some of the case reports.15–18 These data are in disagreement with the rest of reviewed case reports where 80% of their cases had elevated ALT TABLE 4. Levels of Serum Ceruloplasmin and Urinary Copper of Groups A and B
Group A (N = 12) Ceruloplasmin, mean ± SD (mg/dL) Urinary copper before D-penicillamine, median (IQR) (mg/d) Urinary copper after D-penicillamine, median (IQR) (mg/d)
43.97 ± 13.1 25 (43.1) 89 (274.8)
Group B (N = 8)
P
50.4 ± 12.9 0.3 27 (68.1)
0.8
607 (173.8) 0.000*
*Significant P < 0.05. IQR indicates interquartile range.
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TABLE 5. Summary of Case Reports on Children With Wilson Disease Presenting With Hemolytic Anemia (1965 to 2011)
Age Hemolytic Neuro. K-F Aspartate Alanine Alkaline (years) Attacks Jaundice Sympt. Hepatomegaly Splenomegaly Ring Transaminase Transaminase Phosphatase This study (1 case + 7 likely to be) Agrawal et al15 (1 case) Sharma et al21 (1 case) Singh et al5 (1 case) Prochazkova et al22 (1 case) Asfaha et al23 (1 case) Christl et al24 (1 case) Kitazawa et al14 (1 case) Chand et al25 (1 case) Brouwer et al16 (1 case) Michel et al17 (1 case) Kim et al26 (1 case) Ozer et al27 (1 case) Kawahara et al28 (1 case) Degenhardt et al18 (1 case) Tseng et al29 (1 case) Kraut and Yogev30 (1 case) Roche-Sicot and Benhamou31 (3 cases) Robitaille et al32 (3 cases) Buchanan13 (2 cases) Carr-Saunders33 (1 case)
+ in 1
m in 1
N
m in 1
+
m
N
k
+
m
m
k
+
m
m
m
+
m
m
k
m
m
k
m
m
k
m
m
k
k
k
k
+
m
N
k
+
+
m
N
N/A
1
+
+
m
m
N/A
9
1
+
+
m
m
N/A
16
1
+
+
m
m
N/A
18
1
+
m
N
k
10
1
+
+
m
m
N/A
11
1
+
+
m
m
N/A
12
3
+
14.6
1
11.5 10
9.9
+
+ in 4
16
1
+
4.5
1
+
16
1
16
1
+
18
1
+
16
1
+
14
1
+
18
1
+
16
1
+
17
1
16
+ in 1
+
+
+ in 1
+
+ + +
+
+
+
+
+
+
+
+ in 2
+
m
m
N/A
+
+
+ in 2
+
N
N
N/A
1
+
+
+
+
m
m
N
2
+
+
+
N
N
N/A
+
N indicates normal; N/A, not available.
and AST. Agrawal et al15 in 2011 reported that episodes of low alkaline phosphatase tend to occur during the hemolytic event and then improve. Table 5 shows the criteria for diagnosis of WD: low serum level of ceruloplasmin in 92% (23/25), high serum level of copper and high urinary copper level in 92% (23/25), bilateral KF rings by slit-lamp examination in 68% (17/25), and copper content of dried liver weight in liver biopsy in 40% (10/25). Our results proved that 40% of cases presented by Coombs-negative hemolytic anemia are likely to have WD, which was described by Buchanan13 in 1975 to be secondary to the release of large quantities of hepatic copper intermittently
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into the bloodstream of WD patients, resulting in a transient elevation of erythrocytic and urinary copper and in an acute episode of hemolysis. When the copper release ceases, as it usually does within a few days, the hemolysis abates and within several weeks the patient becomes hematologically normal again. Such episodes may antedate clinical signs of significant liver disease, sometimes by months or even years. It is presumably caused by excess copper released from the liver due to apoptosis/necrosis of copper-loaded hepatocytes, possibly triggered by external stimuli. This may have direct toxic effects on erythrocytes, resulting in hemolysis.10 The key to diagnosis of WD is a high index of suspicion, which can increase only on greater awareness of the r
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disorder in the medical fraternity. A well known but tricky presentation of WD is acute or recurrent Coombs-negative hemolytic anemia with or without associated liver dysfunction. In the present study, no cases had low ceruloplasmin. This is similar to the results of Degenhardt et al,18 but disagrees with results of reviewed case reports where 92% of their cases had low ceruloplasmin (Table 5). In children with WD, 15% to 36% had ceruloplasmin in the normal range.19,20 Using serum ceruloplasmin to identify patients with WD is further complicated by overlap with some heterozygotes. Approximately 20% of heterozygotes have decreased levels of serum ceruloplasmin.34,35 Bilateral KF rings was detected in 1 (12.5%) of our 8 positive cases that may be due to short duration of presentation. In contrast, 68% of reviewed case reports had bilateral KF rings on slit-lamp examination (Table 5). ElKaraksy et al36 in 2011 found KF rings in 33% of children presenting with liver disease and in 62.5% of Egyptian children presenting with neurological presentation and also found that the combination of low ceruloplasmin and KF rings was present in 31.5% of patients. Neither the absence of KF rings nor normal values of serum copper or ceruloplasmin can exclude WD.37–39 Elevated levels of urinary copper before and after Dpenicillamine was observed in all 8 cases (100%) and with a significantly higher levels than group A (P = 0.000). Recent reevaluation of the penicillamine challenge test in children found it valuable for the diagnosis of WD in patients with active liver disease (sensitivity 92%), but poor for excluding the diagnosis in asymptomatic siblings (sensitivity only 46%).40 Wilson et al41 in 2000 reported that WD may present symptomatically at any age, although the majority presents between ages 5 and 35. The youngest patient reported with cirrhosis due to WD was 3 years old. In our cases which are likely to be WD, the mean age was 9.9 + 3.1 years, whereas the mean age was 14 years (Table 5). Our positive cases were 62.5% males and 37.5% females. Our data disagree with that of Table 5 in which 68% of them were females and 32% were males, but our results are in concordance with the male predominance of Egyptian WD cases reported by El-Karaksy et al36 in both hepatic and neurologically presented cases. Some studies reported a predominance of males in WD,42,43 whereas other studies reported female predominance.3,44,45 Previous hemolytic attacks were present in 100%, whereas results of the reviewed case reports was 84% had a history of single hemolytic attack and the rest had >1 hemolytic attack (Table 5). History of jaundice was present in 50% of our positive cases. Data from the reviewed case reports showed history of jaundice in 100% of their cases (Table 5). Hepatomegaly was observed in 1 case (12.5%) and splenomegaly in 1 case (12.5%), lower than that of reviewed case reports where 64% showed hepatomegaly and 44% showed splenomegaly (Table 5). None of our positive cases showed neurological manifestations on the history or physical examination. This disagrees with results of reviewed case reports where 12% had neurological manifestations (Table 5). Cases likely to have WD have a significantly lower hemoglobin, MCV, and MCH than those unlikely to have WD (P = 0.04, 0.001, and 0.04, respectively), and have a significantly lower reticulocytes. Data of reviewed case reports showed low Hb level in 100% of cases with elevated MCV in 40%. MCV and MCH were normal in the study r
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conducted by Singh et al5 in 2009. MCH was normal according to the study by Ozer et al27 in 1999 and was low according to the study by Kitazawa et al14 in 2004. ALT was normal in all cases, whereas AST was elevated in 12.5% of cases. Similar data were reported in some of the case reports.15–18 Mild elevation of serum transaminases in one third and prolonged prothrombin time in two thirds of WD patients was reported.46 This is in contrast to the collective data of all case reports where 80% of their cases had elevated ALT and AST (Table 5). In our positive cases, alkaline phosphatase was normal in all cases. This is different from data of Table 5 where 36% of cases had low alkaline phosphatase. Agrawal et al15 in 2011 reported that episodes of low alkaline phosphatase tend to occur during the hemolytic event and then improve. Limitation of this study was the inaccessibility to perform liver biopsy for the children included due to the unavailability of the Rodamine stain and the dried liver weight as well for the copper content. We concluded that WD in not uncommon in children with hemolytic anemia after exclusion of common causes. The diagnosis of Coombs-negative hemolytic anemia in any child between 3 and 18 years should alert pediatricians to the possibility of the presence of WD. ACKNOWLEDGMENT The authors thank Dr Mohamed Hashem, Department of Epidemiology & Public Health, University of Maryland School of Medicine Baltimore, MD, for language revision. REFERENCES 1. Bull PC, Thomas GR, Rommens JM, et al. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993;5:327–337. 2. De Bie P, van de Sluis B, Burstein EJ, et al. Distinct Wilson’s disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B. Gastroenterology. 2007;133:1316–1326. 3. Merle U, Schaefer M, Ferenci P, et al. Clinical presentation, diagnosis and long-term outcome of Wilson’s disease: a cohort study. Gut. 2007;56:115–120. 4. Czlonkowska A, Tarnacka B, Litwin T, et al. Wilson’s disease—cause of mortality in 164 patients during 1992–2003 observation period. J Neurol. 2005;252:698–703. 5. Singh T, Chaturvedi MK, Banerjee S, et al. Wilson’s disease presenting as haemolytic anaemia. J Assoc Physicians India. 2009;57:775. 6. Ferenci P, Czlonkowska A, Merle U, et al. Late onset Wilson disease. Gastroenterology. 2007;132:1294–1298. 7. Kong HL, Yap IL, Kueh YK. Wilson’s disease presenting as haemolytic anaemia and its successful treatment with penicillamine and zinc. Singapore Med J. 1996;37:670–672. 8. Ala A, Walker AP, Ashkan K, et al. Wilson’s disease. Lancet. 2007;369:397–408. 9. Balkema S, Hamaker ME, Visser HPJ, et al. Haemolytic anaemia as a first sign of Wilson’s disease. Neth J Med. 2008;66:344–347. 10. Attri S, Sharma N, Jahagirdar S, et al. Erythrocyte metabolism and antioxidant status of patients with Wilson disease with hemolytic anemia. Pediatr Res. 2006;59:593–597. 11. Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int. 2003;23:139–142. 12. EASL (European Association for the Study of the Liver). Clinical practice guidelines: Wilson’s disease. J Hepatol. 2012;56:671–685. 13. Buchanan GR. Acute hemolytic anemia as a presenting manifestation of Wilson disease. J Pediatr. 1975;86:245–247.
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