Keywords:
hepatolenticular degeneration - therapeutics - penicillamine
Palavras-chave:
degeneração hepatolenticular - terapêutica - penicilamina
Wilson's disease (WD) is a rare autosomal recessive metabolic disease resulting from
mutations in the ATP7B gene, which has been mapped to chromosome 13q14[1],[2]. The ATP7B gene encodes a copper-transporting adenosine triphosphatase (ATPase) protein, which
is expressed most abundantly in the liver and is responsible for biliary copper excretion.
Because of defects in this gene, copper accumulates in several organs, especially
the liver, brain (basal ganglia) and corneas[1],[2]. Clinically, patients present with predominantly hepatic, psychiatric and neurological
symptoms, particularly dystonia, tremor and parkinsonism. The Kayser-Fleischer ring
is an important physical sign, and the most important laboratory tests are serum ceruloplasmin
and urine copper levels[1],[2]. The worldwide prevalence of WD is 1:30,000 and more than 400 distinct disease-causing
mutations in the ATP7B gene associated with WD have been identified[1],[2]. Treatment options for WD patients include copper chelating agents such as penicillamine,
trientine, ammonium tetrathiomolybdate and zinc salts[1],[3]. First used in patients with WD 60 years ago, penicillamine is considered the most
effective treatment for the condition[1],[3]. This review describes historical aspects of WD and emphasizes the important contribution
made by Professor Walshe to the treatment of this disease with his pioneering use
of penicillamine.
WILSON's DISEASE – HISTORICAL MILESTONES
WILSON's DISEASE – HISTORICAL MILESTONES
Samuel Alexander Kinnier Wilson (1878-1937) published his masterpiece “Progressive
lenticular degeneration: a familial nervous disease associated with cirrhosis of the
liver” in 1912[1],[3]. He described twelve patients: four cases he had seen himself, two additional cases
from the records of the National Hospital, Queen Square, London, UK, and six cases
previously published in the literature[1]. From 1913 to 1952, several researchers published important contributions to the
understanding of WD, including: Rumpel (described excess copper in the liver), Gerlach
and Rohrscheiner (reported excess copper in corneal rings), Kayser, Fleischer (Kayser-Fleischer
corneal ring), Hall (introduced the term hepatolenticular degeneration), Cumings (suggested
treatment with British antilewisite), Bearn and Kunkel, and Schieberg and Gitlin (reported
deficiency of ceruloplasmin in the serum)[1],[3]. Three years later, Walshe proposed the use of penicillamine for WD treatment, and
his seminal paper was published in 1956[1],[4],[5]. Five years after that, Schouwink described the use of zinc salts in the treatment
of WD[1],[3], and in 1969 and 1984, Walshe reported the use of trientine and tetrathiomolybdate,
respectively, for this condition[1],[3]. In 1982, Starzl et al. published the first report of liver transplantation for
WD[1],[3], and in 1993, three different groups identified the gene responsible for WD on chromosome
13q14[1],[3].
JOHN M. WALSHE AND PENICILLAMINE
JOHN M. WALSHE AND PENICILLAMINE
Walshe ([Figure 1]) worked with penicillamine (dimethylcysteine), a product of the hydrolysis of penicillin,
in the early 1950s in Prof. Charles Dent's laboratory at University College Hospital,
London, UK[1],[3],[4]. He subsequently moved to the liver unit in the Thorndike Memorial Laboratory at
Boston City Hospital, Boston, USA, where he worked under the supervision of Prof.
Charles Davidson[1],[3],[4]. In the same hospital, Prof. Denny-Brown was working on WD and treating patients
with British antilewisite, a drug with important side effects[1],[4]. Based on his previous studies, Walshe suggested to Prof. Davidson that penicillamine
could be used as a copper-chelating drug[4]. Following this suggestion, penicillamine was used in one patient with WD, and an
increase in his urinary copper excretion was observed. However, because of various
problems, additional tests proved inconclusive[1],[4]. Walshe then returned to the UK and restarted his studies with penicillamine in
WD patients. The first WD patient to use penicillamine regularly was Ms S.F., who
started treatment in 1955, and after one year of follow-up, clinical examination showed
that penicillamine had been effective[1],[4]. In 1956, Walshe published a paper in the American Journal of Medicine under the title “Penicillamine, a new oral therapy for Wilson's disease”[5] ([Figure 2]). Penicillamine was the first effective treatment for patients with WD. However,
initial reactions from other researchers studying WD were less than enthusiastic,
and both Denny-Brown in the USA and Cumings in London were very critical of Walshe's
discovery[4]. In 1960, Walshe published another paper on the treatment of WD with penicillamine
in The Lancet
[6]. Ten years after penicillamine was first used to treat WD, its toxicity became evident
and several side effects were observed. These were related to immunologically-mediated
reactions, including skin lesions (elastosis perforans serpiginosa, epidermolysis
bullosa), systemic lupus erythematosus, nephrotic syndrome, Goodpasture syndrome,
Ehlers-Danlos syndrome, myasthenia gravis, polymyositis, thrombocytopenia and agranulocytosis[4],[7]. In some patients using penicillamine, a worsening of the neurological clinical
picture (dystonia, parkinsonism) was observed[4],[7]. Walshe and Yealland found these unexplained side effects in 11 of 137 patients
with predominantly neurological signs. Various hypotheses have been put forward to
explain this paradoxical worsening of neurological symptoms, including a sudden release
of ionic copper, the redox potential of copper, a low level of urate in the plasma
following treatment with penicillamine and genetic mechanisms (unfavorable mutations
in the ATP7B gene)[4],[7]. The neurotoxicity and reversible side effects of penicillamine motivated various
researchers, including Prof. Walshe, to look for new drugs to treat WD[3],[4], and their efforts led to trientine, thiomolybdate and zinc therapy being used to
treat this condition[3],[4],[7]. Although penicillamine still remains the drug of choice for the treatment of WD,
in recent years it has become the subject of some controversy because of its well-known
side effects, particularly worsening of the neurological symptoms[4],[7]. In 1999, the journal Movement Disorders published three very interesting papers about this controversial issue by Prof. Walshe
(“Penicillamine: the treatment of first choice for patients with WD”), Prof. Brewer
(“Penicillamine should not be used as initial therapy in WD”) and Prof. LeWitt (“Penicillamine
as a controversial treatment for WD”), but no consensus about its use was reached,
and penicillamine continues to be a treatment option for WD patients[8]
-
[10].
Figure 1 J. M. Walshe (1920-).(Courtesy of Professor Walshe)
Figure 2 Walshe´s first paper about Penicillamine for treatment of Wilson´s disease (1956)
in the American Journal of Medicine.(Reproduced from reference 5)
CONCLUSION
Professor John Walshe pioneered the treatment of WD and discovered various drugs that
can be used to treat the condition, including penicillamine, trientine and thiomolybdate.
His seminal paper published 60 years ago described the first study in which penicillamine
was used as oral therapy for WD. Penicillamine remains an effective drug for treating
patients with WD. However, neurologists should be aware of the advantages and disadvantages
associated with its use[3],[4],[7]
-
[10].
