The presence of Coomb’s negative hemolytic anemia suggested a non-immune
etiology of hemolysis. Her glucose-6-phosphate dehydrogenase (G6PD)
activity was normal. On suspicion of Wilson’s Disease, we sent a 24-hour
urine collection for copper quantification, which came out to be 298
mcg/24 hr. However, her ceruloplasmin was 76 mg/dl (20-60 mg/dl). The
patient deferred the liver biopsy. The abdominal ultrasonography
revealed a fetus of 28 weeks gestation with normal heart rate and fetal
movements, hepatomegaly with perihepatic cuffing suggestive of acute
hepatitis. With strong suspicion of Wilson’s disease, she was again sent
to a senior ophthalmologist for KF ring evaluation. She was then found
to have the KF ring on a slit-lamp examination.
Her treatment began with tab penicillamine 250 mg twice a day and tab
zinc 40 mg twice a day, where the gap of two hours between penicillamine
and zinc tablet administration was assured. She was also given a
pyridoxine tablet of 10 mg /day. She had gradual improvement in her
clinical symptoms of jaundice and anemia. Her hemoglobin level improved
to 8.2 g/dl, and her LFT and LDH were normalizing. After two years of follow-up,
she does not have jaundice or anemia, and her lab parameters are within
the normal range with no hemolytic features. She is currently under
penicillamine 250 mg once a day and a copper restricted diet. She had
pre-term delivery of a 2.3 kg baby by cesarean section at 34 weeks of
gestation. Her baby weighs 12 kg at present. The 24-hour urine copper
analysis could not be sent because of financial reasons. Neither the
genetic analysis could be done for the same reason.
Discussion
Progressive hepatolenticular degeneration or Wilson’s disease is a rare,
potentially treatable autosomal recessive disorder of the copper
transport caused by ATP7B gene mutation in the long arm of chromosome
13 [1]. WD’s prevalence was thought to be
1 in 100,000 people. However, with the advancement of studies, the
estimated prevalence is now considered 1 case per 30,000 live
births [1,2]. Although virtually no data
is available from Nepal but neighboring country India sheds some light on WD . Taly et al. have presented a cohort study
that reported approximately 15-20 cases of WD are registered annually at
one of India’s major neurological hospitals at NIMHAMS,
Bangalore [6].
Defective ceruloplasmin synthesis, impaired copper excretion, and
accumulation of copper in the tissues, mostly in the liver and brain, as
a result of a mutation in the ATP7B gene, are the main hallmarks of this
disease that presents itself as a broad spectrum of clinical
manifestations.
Acute intravascular Coombs negative hemolytic anemia is a characteristic
feature of acute hepatic failure in WD. Oxidative injury, altered
erythrocyte metabolism, and severely compromised antioxidant status is
caused by the toxic effects of copper that is released from necrotic
hepatocytes, which in turn results in Wilsonian
hemolysis [7,8]. WD has a myriad of clinical manifestations ranging from asymptomatic to
chronic liver diseases, neuropsychiatric diseases, acute liver failure,
hemolytic anemia, or combinations of these problems. It often poses as a
diagnostic challenge to the physicians. The finding of a KF rings is an essential indicator of critical copper
overload and is present in 95% of patients with neurological symptoms
and 50-60% of patients without neurological symptoms of
WD [4].
There is no single confirmatory test for WD; a score was developed at
the eighth International Conference of Wilson’s Disease based on
clinical and laboratory abnormalities, which helps diagnose
WD [9].
The presence of KF rings, low
serum ceruloplasmin levels, and high urine copper excretion is enough to
make a diagnosis of Wilson’s Disease [9].
WD is an easily overlooked rare clinical entity because it resembles
other common disorders like viral hepatitis. However, if detected early,
effective treatments are available to manage the disease that may help
prevent or reverse the many manifestations of Wilson’s disease.
The majority of patients with Wilson’s disease are diagnosed between 5
and 35 years of age, the mean age being 13.2
years [3]. Children are more likely to
present with hepatological symptoms considering the neurological
manifestations develop only after the slow accumulation of copper in the
brain [10]. The mean age at presentation
for patients with neurologic symptoms ranges between 15-21 years. Our
patient presented with hepatological symptoms of jaundice and
hepatomegaly, mimicking viral hepatitis. No neurological symptoms were
observed, but the classical ophthalmic manifestation of WD: the KF ring
was present at the age of 19 during the third trimester of her
pregnancy.
24-hour urine copper excretion >100 mcg holds an important
diagnostic aid and is also used for the therapeutic monitoring of
Wilson’s disease. The patient had elevated 24-hour urine copper
excretion, which can be seen in various liver diseases, but it is most
often below 100 mcg/24 hrs [11,12].
A liver biopsy could not be done, which is essential for quantifying the
hepatic copper concentration. The common observation in the liver
function test of a Wilson disease patient, as seen in this case, is the
elevated serum aminotransferase, which is typically less than 2000 with
an AST/ALT ratio of >2, wherein this patient AST/ALT ratio
is > 2.2 [11]. The ALP level
is usually normal or subnormal with an ALP: total bilirubin ratio of
<4 as seen in this particular
case [13].
Apart from the common liver diseases that present in pregnancy, such as
jaundice, hemolysis, elevated liver enzymes, and low platelets (HELLP)
syndrome, intrahepatic cholestasis, and viral hepatitis, Wilson’s
disease is also a very real possibility that may present itself as
hemolytic anemia with normal platelet count in pregnancy, as seen in
this case.
WD and pregnancy have a complicated relationship; the outcome of
pregnancy with WD in the past has not been great. Untreated WD can lead
to significant morbidity and mortality. Excessive copper accumulation in
the liver and uterus leads to metabolic disturbance and recurrent
miscarriage.
The normal range of ceruloplasmin in pregnancy is 300 to 1200 mg/L,
while it is 250 to 600 mg/L in a non-pregnant
adult [14]. Despite the less likelihood
of KF rings in a hepatic presentation; the patient was found to have
them.
During pregnancy, ceruloplasmin levels are elevated. Because of the
fetus, the physiological copper demand is also increased. There might be
an improvement in the symptoms of WD, and patients may experience a
period of remission [15]. However, in
symptomatic and asymptomatic patients alike, life-threatening
complications such as preeclampsia, placental abruption have been
experienced during pregnancy regardless of the
medications [16,17]. The exact mechanism
is not known, but it is believed that increased copper in the uterus
prevents the successful implantation of the fetus, similar to a
copper-containing intrauterine contraceptive
device [18]. The outcome of Wilson’s
disease in pregnancy has improved in recent years with the therapeutic
evolution and better understanding of the disease in asymptomatic
women [18]. Although a pre-term delivery,
this case is one such example of a successfully treated Wilson disease
diagnosed during pregnancy.
Currently, the treatment of WD consists of lifetime therapy aimed at
primarily copper detoxification by the chelators and prevention of
copper accumulation in the body by zinc salts or chelators themselves.
The primarily used chelator is D-penicillamine, while Trientine is
considered to be the second-line agent. Research suggests that although
teratogenous in animals, D-penicillamine is safe in pregnancy, which is
given with zinc acetate/ zinc sulfate, pyridoxine, and a low copper diet
for the maintenance of pregnancy [19,20].
We started the treatment of the patient with D-penicillamine and zinc. As
shown in this case, the correct diagnosis and appropriate management of
WD can lead to a favorable outcome even in pregnancy.
Conclusions
To sum up, WD is an inheritable metabolic liver disease associated with
the accumulation of copper in the human body. Pregnancies in patients
with WD are considered high risk, not only because it poses an obvious
risk to the mother but also because the accumulating copper could affect
the unborn fetus. The proper treatment of the mother with Zinc and
Penicillamine is said to be relatively safer and has a lower risk of
congenital disability. We have tried to establish that successful
pregnancy while suffering from WD is possible through the data collected
from our case, although it does require continuous treatment and good
compliance.
References
- Huster D: Wilson
disease. Best Pract Res Clin Gastroenterol. 2010,
24:531-539. 10.1016/j.bpg.2010.07.014
- Chu NS, Hung
TP: Geographic
variations in Wilson’s disease. J Neurol Sci. 1993,
117:1-7. 10.1016/0022-510x(93)90145-o
- Lin L-J, Wang D-X, Ding N-N, Lin Y, Jin Y, Zheng
C-Q: Comprehensive
analysis on clinical features of Wilson’s disease: an experience over
28 years with 133 cases. Neurol Res. 2014,
36:157-163. 10.1179/1743132813Y.0000000262
- Ferenci
P: Diagnosis
and current therapy of Wilson’s disease. Aliment Pharmacol Ther.
2004,
19:157-165. 10.1046/j.1365-2036.2003.01813.x
- Patil M, Sheth KA, Krishnamurthy AC, Devarbhavi
H: A Review and
Current Perspective on Wilson Disease. J Clin Exp Hepatol. 2013,
3:321-336. 10.1016/j.jceh.2013.06.002
- Taly AB, Prashanth LK, Sinha
S: Wilson’s disease:
An Indian perspective. Neurol India. 2009,
57:528. 10.4103/0028-3886.57789
- Anna
Członkowska: A
study of haemolysis in Wilson’s disease. Journal of the Neurological
Sciences. 1972, Volume 16, Issue 3:Pages
303-314. 10.1016/0022-510X(72)90194-3
- Attri S, Sharma N, Jahagirdar S, Thapa BR, Prasad
R: Erythrocyte
Metabolism and Antioxidant Status of Patients with Wilson Disease with
Hemolytic Anemia. Pediatr Res. 2006594,
1:593-597. 10.1203/01.pdr.0000203098.77573.39
- Ferenci P, Caca K, Loudianos G, et
al.: Diagnosis
and phenotypic classification of Wilson disease1. Liver Int. 2003,
23:139-142. 10.1034/j.1600-0676.2003.00824.x
- Saito T: Presenting
symptoms and natural history of Wilson disease. Eur J Pediatr. 1987,
146:261-265. 10.1007/BF00716470
- Frommer DJ: Urinary copper
excretion and hepatic copper concentrations in liver disease.
Digestion. 1981,
21:169-178. 10.1159/000198559
- Perman JA, Werlin SL, Grand RJ, Watkins
JB: Laboratory
measures of copper metabolism in the differentiation of chronic active
hepatitis and Wilson disease in children. J Pediatr. 1979,
94:564-568. 10.1016/S0022-3476(79)80011-6
- Roberts EA, Schilsky
ML: Diagnosis and
treatment of Wilson disease: An update. Hepatology. 2008,
47:2089-2111. 10.1002/hep.22261
- Tietz Textbook
of: Clinical
Chemistry and Molecular DiagnosticsAccessed September 18. 2020.
- Fukuda K, Ishii A, Matsue Y, Funaki K, Hoshiai H, Maeda
S: Pregnancy and
delivery in penicillamine treated patients with Wilson’s disease.
Tohoku J Exp Med. 1977,
123:279-285. 10.1620/tjem.123.279
- Sinha S, Taly AB, Prashanth LK, Arunodaya GR, Swamy
HS: Successful
pregnancies and abortions in symptomatic and asymptomatic Wilson’s
disease. J Neurol Sci. 2004,
217:37-40. 10.1016/j.jns.2003.08.007
- Malik A, Khawaja A, Sheikh
L: Wilson’s disease
in pregnancy: case series and review of literature. BMC Res Notes.
2013,
6:421. 10.1186/1756-0500-6-421
- Mustafa MS, Shamina
AH: Five
successful deliveries following 9 consecutive spontaneous abortions in
a patient with Wilson disease. Aust N Z J Obstet Gynaecol. 1998,
38:312-314. 10.1111/j.1479-828x.1998.tb03073.x
- Morimoto I, Ninomiya H, Komatsu K, Satho
M: Pregnancy
and Penicillamine Treatment in a Patient with Wilson’s Disease. Jpn J
Med. 1986,
25:59-62. 10.2169/internalmedicine1962.25.59
- Brewer GJ, Johnson VD, Dick RD, Hedera P, Fink JK, Kluin
KJ: Treatment of
Wilson’s disease with zinc. XVII: treatment during pregnancy. Hepatol
Baltim Md. 2000,
31:364-370. 10.1002/hep.510310216