# 45 - 427 Wilson’s Disease

### 427 Wilson’s Disease

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■ROLE OF HFE MUTATIONS IN OTHER 

LIVER DISEASES

There is considerable interest in the role of HFE mutations and 
hepatic iron in several other liver diseases. Several studies have 
shown an increased prevalence of HFE mutations in PCT patients. 
Iron accentuates the inherited enzyme deficiency in PCT and clinical 
manifestations of PCT. The situation in metabolic dysfunction–
associated steatohepatitis is less clear, but some studies have shown an 
increased prevalence of HFE mutations. Available evidence does not 
support a role for phlebotomy therapy unless there is a proven increase 
in hepatic iron stores.
HFE mutations are not increased in frequency in alcoholic liver 
disease. However, alcohol does reduce hepcidin expression, which 
accounts for increased iron absorption and hepatic iron sometimes 
seen in alcoholic liver disease. Hemochromatosis in a heavy drinker 
can be distinguished from alcoholic liver disease by the presence of the 
C282Y mutation.
PART 12
Endocrinology and Metabolism
End-stage liver disease may also be associated with iron overload 
of the degree seen in hemochromatosis. The mechanism is uncertain, 
although studies have shown reduced hepcidin and intestinal iron 
transporter expression. Hemolysis also plays a role. HFE mutations are 
uncommon.
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■GLOBAL CONSIDERATIONS
The HFE mutation is of northern European origin (Celtic or Nordic) with 
a heterozygous carrier rate of ~1 in 10 (1 in 8 in Ireland). Thus, HFEassociated hemochromatosis is quite rare in non-European populations, 
e.g., Asia. However, non-HFE-associated hemochromatosis resulting 
from mutations in other genes involved in iron metabolism (Fig. 426-1) is 
ubiquitous and should be considered when one encounters iron overload.
African iron overload occurs primarily in sub-Saharan Africa and 
was previously thought to be due to the consumption of an iron-rich 
fermented maize beverage. However, recent evidence suggests that it is 
primarily the result of a non-HFE-related genetic trait that is exacer­
bated by dietary iron loading. A similar form of iron overload has been 
described in African Americans.
Acknowledgment
The authors extend their gratitude to the late Professor Lawrie W. Powell 
and recognize his outstanding contributions to previous versions of this 
chapter.
■
■FURTHER READING
Adams PC et al: Haemochromatosis. Lancet 401:1811, 2023.
Anderson GJ, Bardou-Jacquet E: Revisiting hemochromatosis: 
Genetic vs. phenotypic manifestations. Ann Transl Med 9:731, 2021.
Girelli D et al: Hemochromatosis classification: Update and recom­
mendations by the BIOIRON Society. Blood 139:3018, 2022.
Olynyk JK, Ramm GA: Hemochromatosis. N Engl J Med 387:2159, 
2022.
Powell LW et al: Haemochromatosis. Lancet 388:706, 2016.
Stephen G. Kaler

Wilson’s Disease
Wilson’s disease is an autosomal recessive inherited disorder of cop­
per transport that primarily impacts the liver and brain. This reflects 
the critical need for homeostatic mechanisms to properly utilize this 
trace metal, both systemically and in the central nervous system. Since 
the initial detailed clinical description in 1912, Wilson’s disease has 
emerged as arguably one of the best-characterized and most effectively 
managed human inborn errors of metabolism. The condition results 

from variants in ATP7B, a highly evolutionarily conserved P-type 
ion-motive ATPase that normally mediates copper removal from the 
liver via biliary excretion and prevents brain copper accumulation. 
Prompt diagnosis in the presymptomatic or early symptomatic phase 
of the illness and lifelong treatment are needed to prevent premature 
mortality in affected individuals.
HISTORY OF WILSON’S DISEASE
Wilson’s disease (hepatolenticular degeneration) was first described 
in 1912 by neurologist S.A.K. Wilson, who recognized the heritable 
aspect of the condition. In 1948, the pathologist J.N. Cumings pro­
posed an etiologic connection with copper overload. Several years 
later, a metal chelator developed to counteract an arsenic-based chem­
ical warfare agent (lewisite) was used to successfully treat advanced 
Wilson’s disease. In 1956, copper chelation by d-penicillamine was 
introduced and found preferable to anti-lewisite with respect to 
route of administration and side effect profile. In the early 1970s, an 
alternative copper chelator, triethylene tetramine, became the second 
U.S. Food and Drug Administration (FDA)–approved treatment for 
Wilson’s disease. Also in the early 1970s, the first liver transplants 
were performed for Wilson’s disease, with resultant correction of 
both hepatic failure and crippling neurologic impairments in patients 
unresponsive to medical therapies. The treatment potential of zinc 
salts to reduce gastrointestinal copper absorption in Wilson’s dis­
ease was recognized in the early 1960s, eventually leading to FDA 
approval for this indication. Tetrathiomolybdate, which forms a 
tripartite complex with copper and albumin, and a bacterial peptide, 
methanobactin, which traverses mitochondrial membranes, are more 
recently proposed copper chelators with potential for treatment of 
Wilson’s disease.
In 1993, the gene for Wilson’s disease was identified and found to 
encode a copper-transporting ATPase, ATP7B, expressed primarily 
in liver and kidney. In addition to providing a molecular basis for 
diagnosis and genotype-phenotype correlations, the finding presents 
current opportunities for viral gene therapy that could impact future 
management of this illness.
PHENOTYPES
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■CLINICAL
Presenting clinical features of Wilson’s disease include nonspecific 
liver disease, neurologic abnormalities, psychiatric illness, hemolytic 
anemia, renal tubular Fanconi syndrome, and various skeletal abnor­
malities. Age influences the specific presentation in Wilson’s disease. 
Nearly all individuals who present with liver disease are <30 years of 
age, whereas those presenting with neurologic or psychiatric signs 
may range in age from the first to the fifth decade. This reflects the 
sequence of events in the pathogenesis of the illness. However, regard­
less of clinical presentation, some degree of liver disease is invariably 
present.
Hepatic Presentation 
With hepatic presentations, signs and 
symptoms include jaundice, hepatomegaly, edema, or ascites. Viral 
hepatitis and cirrhosis are often initial diagnostic considerations in 
individuals who, in fact, have Wilson’s disease.
Neurologic Presentation 
In patients with neurologic presenta­
tions, abnormalities include distinctive speech difficulties (dysar­
thria), dystonia, rigidity, tremor (e.g., wing-beating) or choreiform 
movements, abnormal gait, and uncoordinated handwriting. Wilson’s 
disease can properly be classified as a movement disorder. The neu­
rologic signs and symptoms reflect the predilection for basal ganglia 
(e.g., caudate, putamen) involvement in the brains of affected persons. 
Wilson’s disease may be mistakenly diagnosed as Parkinson disease or 
other movement disorders.
Psychiatric Presentation 
In psychiatric presentations, changes 
in personality (irritability, anger, poor self-control) or school perfor­
mance, depression, and anxiety are common symptoms. Typically, 
patients presenting in this fashion are in their late teens or early

FIGURE 427-1  Kayser-Fleischer ring in Wilson’s disease, representing copper 
deposition in Descemet membrane of the cornea. (Image courtesy of Tjaard U. 
Hoogenraad MD, PhD, Department of Neurology, University Medical Centre Utrecht, 
Utrecht, The Netherlands.)
twenties, a period during which substance abuse is also a diagnostic 
consideration. Wilson’s disease should be formally excluded in all teen­
agers and young adults with new-onset psychiatric signs.
Ocular Manifestations 
The eye is a primary site of copper 
deposition in Wilson’s disease, producing a pathognomonic sign, the 
Kayser-Fleischer ring (Fig. 427-1), a golden to greenish-brown band 
in the peripheral cornea. This important diagnostic sign first appears 
as a superior crescent, then develops inferiorly, and ultimately becomes 
circumferential. Slit-lamp or optical coherent tomography examina­
tions are required to detect rings in their early stage of formation. 
Copper can also accumulate in the lens and produce “sunflower” cata­
racts. Approximately 95% of Wilson’s disease patients with neurologic 
signs manifest the Kayser-Fleischer ring compared to two-thirds of 
those with hepatic presentations. Copper chelation therapy causes fad­
ing and eventual disappearance of corneal copper.
Other Clinical Manifestations 
Secondary endocrine effects of 
Wilson-associated liver disease may include delayed puberty or amen­
orrhea. Renal tubular dysfunction in Wilson’s disease leads to abnormal 
losses of amino acids, electrolytes, calcium, phosphorus, and glucose. 
Presumably, this effect is related to renal copper toxicity; high copper 
levels have been noted previously in the kidneys of patients with 
Wilson’s disease. Treatment with copper chelation often improves the 
renal disturbances. There also can be skeletal effects of Wilson’s disease, 
including osteoporosis and rickets, which  may be attributable to renal 
losses of calcium and phosphorus. Osteoarthritis, primarily affecting 
the knees and wrists, may involve excess copper deposition in the bone 
and cartilage.
Hemolytic anemia due to the direct toxic effects of copper on red 
blood cell membranes is usually associated with release of massive 
quantities of hepatic copper into the circulation, a phenomenon that 
can be sudden and catastrophic.
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■BIOCHEMICAL
Laboratory findings that support the diagnosis of Wilson’s disease 
include low levels of serum copper and serum ceruloplasmin, elevated 
hepatic transaminase levels, aminoaciduria, and hemolytic anemia. 
Incorporation of radiolabeled 64Cu into serum ceruloplasmin, mea­
sured as the appearance of copper in the serum after an oral load, is a 
highly specific diagnostic test; patients with Wilson’s disease incorpo­
rate very little 64Cu into ceruloplasmin.
Increased urinary excretion of copper (>100 μg/24 h) is an easily per­
formed and important diagnostic test for Wilson’s disease. Acid-washed 
(copper-free) collection containers should be used. The penicillamine 

challenge is a variation using serial urine copper measurements in 
which 500 mg of penicillamine are administered orally after collecting 
a baseline 24-h urine. The penicillamine dose is repeated after 12 h, the 
midpoint of the second 24-h urine collection. A several-fold increase in 
copper excretion in the second collection suggests the diagnosis.

Although invasive, percutaneous needle liver biopsy for mea­
surement of hepatic copper remains a gold standard technique for 
biochemical diagnosis of Wilson’s disease. Hepatic copper values 
>200 μg per gram of dry weight (normal 20–50 μg) are characteristic 
of Wilson’s disease. Inductively coupled plasma mass spectrometry 
and atomic absorption spectrometry are preferred quantitative meth­
ods; histochemical staining for copper in liver biopsy specimens is 
considered less reliable.
Wilson’s Disease
CHAPTER 427
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■MOLECULAR
Wilson’s disease is caused by loss-of-function variants in ATP7B. 
Despite similar genomic structures, large deletions are much less 
common in ATP7B than in ATP7A, the closely related X-linked gene 
responsible for Menkes disease. Several ATP7B missense variants are 
common (H1069Q, M645R, and R778L), with various allelic frequen­
cies reflecting geographic, racial, and/or ethnic differences. Major 
ATP7B databases list >650 pathogenic or likely pathogenic variants. 
Population-based and genomic-based estimates of prevalence range 
from 1 in 7000 to 1 in 30,000, with genome-based ascertainments sup­
porting the higher prevalence. This disparity may reflect incomplete 
penetrance, although there is little doubt that some affected individuals 
unfortunately escape medical attention. Advances in the application of 
whole genome sequencing (and/or measurement of ATP7B peptides) 
from newborn dried blood spots may transform presymptomatic diag­
nostic screening for Wilson disease in the future.
DIAGNOSIS
Currently, a formal diagnosis of Wilson’s disease relies on a combina­
tion of clinical, biochemical, and molecular features (Table 427-1). A 
scoring system (Leipzig) that weights and collates various signs and 
symptoms was produced by an international expert group in 2001 and 
remains a valuable guide to diagnosis that is endorsed by the European 
Association for the Study of the Liver (EASL).
TABLE 427-1  Main Diagnostic Features of Wilson’s Disease
CLINICAL SIGNS AND 
SYMPTOMS
BIOCHEMICAL 
FINDINGS
MOLECULAR 
FINDINGS
Hepatic:
  Jaundice
  Anorexia
  Vomiting
  Ascites and/or edema
  Splenomegaly
Neurologic:
  Dysarthria
  Facial grimace (risus sardonicus)
  Drooling
  Dysphagia
  Dysgraphia
  Dystonia
  Tremor (“wing-beating”)
  Ataxia
  Seizures (rare)
Ocular:
  Kayser-Fleischer ring
  Sunflower cataract (rare)
Psychiatric:
  Decline in school performance
  Personality change
  Mood disorder
  Schizophrenia
Low serum copper
Low serum 
ceruloplasmin
Increased urinary 
copper excretion
Elevated liver 
enzymes
Hypoalbuminemia
Increased liver 
copper
Fatty liver
Cirrhotic liver
Hemolytic anemia
Renal Fanconi 
syndrome
Variants in 
ATP7B on both 
chromosomes
Variants or 
polymorphisms in 
other genes (e.g., 
CAT, SOD2, MTHFR) 
may influence 
clinical expression 
of Wilson’s disease 
in some individuals