AJR 2004; 183:1339-1342
© American Roentgen Ray Society
Wilson's Disease with Chronic Active Hepatitis: Monitoring by In Vivo 31-Phosphorus MR Spectroscopy Before and After Medical Treatment
W. C. W. Chu1,
T. F. Leung2,
K. F. Chan3,
D. K. W. Yeung1,
T. K. Yeung1,
H. M. Cheung2,
E. K. L. Hon2,
C. T. Liew3 and
W. W. M. Lam1
1 Department of Diagnostic Radiology and Organ Imaging, Faculty of Medicine, The
Chinese University of Hong Kong, Prince of Wales Hospital, Ngan Shing St.,
Shatin, New Territories, Hong Kong.
2 Department of Paediatrics, The Chinese University of Hong Kong, Prince of
Wales Hospital, Shatin, Hong Kong.
3 Department of Anatomical and Cellular Pathology, The Chinese University of
Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
Received November 4, 2003;
accepted after revision December 23, 2003.
Address correspondence to W. C. W. Chu.
Introduction
Wilson's disease is an autosomal recessive disorder of copper
metabolism resulting from the absence or dysfunction of a copper-transporting
P-type adenosinetriphosphatase encoded on chromosome 13. Pediatric patients
can present with hepatic impairment without neurologic or psychiatric features
[1]. Correct diagnosis followed
by proper treatment is of vital importance to avoid the development of lethal
complications.
Recently, in vivo hepatic phosphorus-31 MR spectroscopy has been shown to
provide information about the pathophysiology of liver injury and may
contribute to the assessment of hepatic functional state in chronic liver
disease. In this case report, we describe the serial findings on
31P MR spectroscopy before and at 3 and 7 months after medical
therapy in a child with Wilson's disease. The patient presented with chronic
active hepatitis and early cirrhosis and was successfully treated with medical
therapy. The results of MR spectroscopy correlated with liver biopsy and blood
biochemistry results and showed normalization of metabolites along with the
clinical course. We propose that 31P MR spectroscopy provides a way
to either eliminate the need for biopsy or at least follow up the
posttreatment evolution of the disease in a noninvasive manner.
Case Report
A 9-year-old girl presented with insidious onset of bilateral ankle
swelling and facial puffiness with gradual deterioration for 3 weeks before
assessment. She was afebrile the entire period. Physical examination revealed
mild ascites but no hepatosplenomegaly or neurologic manifestation.
Preliminary investigations revealed hypoalbuminemia, biochemical hepatitis,
and a prolonged clotting profile. Her coagulopathy remained static despite
repeated IV injections of vitamin K.
Investigations for causes of subacute hepatitis showed that her serum
ceruloplasmin level was undetectable. Serum copper was reduced to 6.2
µmol/L (normal range, 10.7-25.2 µmol/L), whereas urine copper excretion
increased to 3.4 µmol per day (normal, < 1 µmol per day).
Ophthalmologic assessment revealed the presence of Kayser-Fleischer rings,
further confirming the diagnosis of Wilson's disease. The patient and her
asymptomatic 7-year-old brother had MRI and 31P MR spectroscopy
performed on a 1.5-T whole-body MRI system (Gyroscan ACSNT, Philips Medical
Systems). The subjects fasted overnight to standardize the MR spectroscopy
examinations. Turbo spin-echo T1-weighted (TR/TE, 450/15) and T2-weighted
(1,800/90) axial images were obtained for characterizing the morphology of the
liver. Phosphorus-31 spectra were obtained for the right lobe of the liver and
skeletal muscle (for later correction of muscle contamination during liver
spectroscopy).
MRI revealed numerous tiny hypointense nodules in the liver on the
T2-weighted image. The liver nodules ranged from 2 mm to 1 cm in diameter. A
moderate amount of ascitic fluid was also present
(Fig. 1A). The major
disturbance of 31P MR spectra was an elevation in the
phosphomonoester (PME) resonance and a reduction in the phosphodiester (PDE)
resonance (Fig. 1B). The
PME/PDE ratio was markedly elevated (1.16). The inorganic phosphate energy
balance in terms of nucleotide triphosphates and intracellular acid base
appeared to be maintained.
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Fig. 1A. —9-year-old girl with Wilson's disease. T2-weighted axial MR
image (TR/TE, 1,800/90) of liver shows numerous tiny hypointense nodules in
liver at presentation before medical treatment. Note hyperintense ascitic
fluid (arrow) around edge of liver.
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Fig. 1B. —9-year-old girl with Wilson's disease. Graph shows
representative serial phosphorus-31 MR liver spectra before and after 3 and 7
months of medical treatment. Elevation in phosphomonoester (PME) resonance
(long arrow) is concurrent with reduction in phosphodiester (PDE)
resonance (short arrow) at presentation, followed by gradual reversal
change in subsequent 3- and 7-month spectra. NTP = nucleotide triphosphate, Pi
= inorganic phosphate, PCr = phosphocreatine.
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Sonographically guided liver biopsy was performed targeting the right lobe
of the liver using a 20-gauge biopsy needle. Histology showed a moderate to
severe degree of portal inflammation with accompanying interphase hepatitis.
Moderate acinar inflammation with lymphocytic infiltrate and scattered spotty
necrosis was present. Lobular disarray with moderate to severe hydropic
degeneration of the hepatocytes involving 80-90% of lobules was noted (Figs.
1C,
1D,
1E). Increased cytoplasmic
copper deposit in periportal hepatocytes was also observed in orcein-stained
sections, which supported the clinical diagnosis of Wilson's disease.
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Fig. 1C. —9-year-old girl with Wilson's disease. Photomicrographs of
serial liver biopsies show portal tracts present in upper portion of images at
presentation (C), and at 3 (D), and 7 (E) months after
treatment. Gradual reduction is seen in necroinflammatory activity in terms of
portal inflammation, interphase hepatitis, and lobular inflammation. Latter is
evident by reduction in hydropic hepatocytes degeneration
(arrowheads, C and D) and spotty necrosis
(arrows, C and D). (H and E, x20)
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Fig. 1D. —9-year-old girl with Wilson's disease. Photomicrographs of
serial liver biopsies show portal tracts present in upper portion of images at
presentation (C), and at 3 (D), and 7 (E) months after
treatment. Gradual reduction is seen in necroinflammatory activity in terms of
portal inflammation, interphase hepatitis, and lobular inflammation. Latter is
evident by reduction in hydropic hepatocytes degeneration
(arrowheads, C and D) and spotty necrosis
(arrows, C and D). (H and E, x20)
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Fig. 1E. —9-year-old girl with Wilson's disease. Photomicrographs of
serial liver biopsies show portal tracts present in upper portion of images at
presentation (C), and at 3 (D), and 7 (E) months after
treatment. Gradual reduction is seen in necroinflammatory activity in terms of
portal inflammation, interphase hepatitis, and lobular inflammation. Latter is
evident by reduction in hydropic hepatocytes degeneration
(arrowheads, C and D) and spotty necrosis
(arrows, C and D). (H and E, x20)
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A daily regimen of oral penicillamine (21 mg/kg in three divided doses) and
vitamin K (5 mg) was then started. Peripheral edema and ascites resolved after
2 months of therapy.
A repeat MRI study 3 months after the initial study revealed marked
reduction in the number of regeneration nodules and resolution of the ascites
(Fig. 1F). Phosphorus-31 MR
spectra showed normalization of PME and PDE resonance. The PME/PDE ratio was
0.50. No significant change in the energy balance and intracellular acid-base
status was seen. Simultaneous liver biopsy showed a reduction of
necroinflammatory activity. Hydropic degeneration of the hepatocytes was
reduced to involvement of only 70% of lobules
(Fig. 1D).
With the continued administration of penicillamine, biochemical parameters
gradually returned to normal over the subsequent 4 months. Liver biopsy showed
further improvement in the necroinflammatory activity, with only 10% of
lobules showing hydropic degeneration of the hepatocytes
(Fig. 1F). Further reduction of
the PME/PDE ratio (0.24) was observed in the 31P MR spectra. The
overall spectra pattern now resembled that of the patient's brother
(Fig. 2), whose urinary copper
excretion, liver function test, and liver imaging remained normal.
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Fig. 2. —Graph shows phosphorus-31 MR liver spectrum of 7-year-old boy
(patient's younger brother) with normal liver function test who is confirmed
not to be carrier of Wilson's disease, hence serving as healthy control
subject. Spectrum is similar to 7-month spectrum of patient in
Figure 1B. PME =
phosphomonoester, PDE = phosphodiester, NTP = nucleotide triphosphate, Pi =
inorganic phosphate, PCr = phosphocreatine.
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Representative 31P liver spectra obtained before and at 3 and 7
months after penicillamine treatment are shown in
Figure 1B.
Discussion
Hepatic dysfunction is the most common manifestation of Wilson's disease in
childhood, usually presenting at age 10-13 years
[1]. Liver disease ranges from
mild elevation of the serum transaminases in asymptomatic individuals to
chronic active hepatitis and cirrhosis. Most patients have some evidence of
cirrhosis on initial liver biopsy that progresses to chronic hepatitis with
nodular regeneration [2].
The diagnosis of Wilson's disease in our patient was made from the findings
of undetectable serum ceruloplasmin, reduced serum copper level, increased
urinary copper excretion, and the presence of Kayser-Fleischer rings on eye
examination. The definitive staging and grading of Wilsonian liver involvement
were established by liver biopsy, which is currently the gold standard for
monitoring disease progression and treatment response. Liver biopsy carries
significant morbidity and a small but defined mortality
[3]. Thus, it is desirable to
have a noninvasive method that can reliably characterize the severity of liver
disease and monitor therapy response.
Previous studies showed correlation in histologic scores from liver biopsy
with in vivo 31P MR spectra in patients with hepatitis C
virus-related liver disease
[4]. The increase in PME
resonance, reduction in PDE resonance, and hence an increase in the PME/PDE
ratio correlated with the increase in the disease severity
[4]. A statistically
significant difference was seen in the PME/PDE ratios among patients with mild
hepatitis, moderate hepatitis, and cirrhosis. A possible explanation for the
observed change in 31P MR spectroscopy is that the liver attempts
to regenerate after injury, thus giving rise to increased turnover of cell
membrane synthetic and degradation products. The ratio of PME to PDE has
therefore been viewed traditionally as an indirect measure of disease severity
within the liver [5]. This view
explains the observed reduction of the PME/PDE ratio and normalization of
spectra with gradual reduction of necroinflammatory activity in our patient.
Although inorganic phosphate has been reported to reflect hepatic inflammation
[6,
7], the significant reduction
in total hepatic adenosine triphosphate levels observed in cirrhoses of
differing origins could be related to a reduced total liver mass or to
different hepatic bioenergetics in a cirrhotic liver
[8]. The inorganic phosphate
and nucleotide triphosphates appeared to be static throughout serial MR
spectroscopy studies in our case.
Phosphorus-31 MR spectroscopy thus provides an alternative noninvasive test
for assessing disease severity and a possible means for measuring the response
of the liver to treatment. These findings need to be evaluated in a
prospective study to determine the true value of this technique for evaluating
the disease. In our patient, the presence of diffuse hypointense nodules that
represented early cirrhotic transformation in the liver resolved on serial
scans, and this change showed good correlation with the histopathologic
resolution after copper chelation therapy. MR spectroscopy can provide
information on hepatic architecture from a large volume within the liver in
contrast to the small tissue sample and the risk of sampling error obtained at
biopsy for histologic characterization. MR spectroscopy might therefore
provide a more accurate picture of diffuse hepatic disease.
On the basis of our findings, we suggest that 31P MR
spectroscopy has a potential role in grading and disease monitoring in
patients with Wilson's disease. This noninvasive technique may reduce the
necessity for liver biopsy in monitoring liver involvement in pediatric
patients and those at risk of complications (e.g., coagulopathy) from biopsy.
We recommend baseline 31P MR spectroscopy for patients with
Wilson's disease at initial diagnosis and follow-up studies 3-6 months
thereafter for monitoring the progress of the disease.
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Introduction
Case Report
