Adolescent Female with Tremor Depression and Hepatitis

Steven I. Shedlofsky

A 16-year-old white female presented to her pediatrician with tremor and depression. Approximately 8 months previously, her mother noted a mild lack of muscle coordination, which slowly progressed. As a result, the patient failed to be reelected as a school cheerleader just one month prior to presentation. A depressed affect with fatigue and malaise had developed and was thought to be secondary to this failure. However, when a tremor was noted along with mild dysarthria, the patient's mother decided to seek medical attention for her. Prior to this time, the patient had been healthy except for an appendectomy at age 9. There was no history of head trauma or neonatal jaundice, nor was there a history of neurological disease in her family. The patient has three younger siblings who are all healthy.

On initial examination, the patient had a flat affect. She weighed 108 lb (49 kg) and had normal vital signs. There was a fine tremor of both hands and arms, which worsened with voluntary actions, but no focal neurological deficits. Mild scleral icterus was noted, and the patient had several spider angiomata on her chest and several ecchymoses on each of her shins. Her liver was palpable 2 cm below the right costal margin with a dull edge, and there was tenderness to fist percussion. Her spleen was barely palpable under the left costal margin.

The following initial laboratory results were obtained:

Reference

Interval,

Reference

Value,

Conventional

Value,

Interval,

Analyte

Conventional Units

Units

SI Units

SI Units

Hemoglobin

10.2 g/dL

12-16

6.33 mmol/L

7.45-9.93

Hematocrit

32%

37-47

0.32

0.37-0.47

Leukocyte

12.0 x 103/mL

4.8-10.8

12.0 x 109/L

4.8-10.8

count

MCV

98 fL

80-94

Same

Platelet count

78 x 103/mL

150-450

78 x 109/L

150-450

Prothrombin

1.94

0.8-1.2

time: INRa

Reference

Interval,

Reference

Value,

Conventional

Value,

Interval,

Analyte

Conventional Units

Units

SI Units

SI Units

Sodium

137 mmol/L

136-145

Same

Potassium

4.7 mmol/L

3.8-5.1

Same

Chloride

99 mmol/L

98-107

Same

CO2, total

23 mmol/L

23-31

Same

Urea nitrogen

10 mg/dL

8-21

3.6 mmol/L

2.9-7.5

Creatinine

0.8 mg/dL

0.7-1.3

71 mmol/L

62-115

Glucose

118 mg/dL

80-115

6.5 mmol/L

4.4-6.4

Calcium

118 mg/dL

4.2-5.1

2.35 mmol/L

2.10-2.55

Phosphorus

4.7 mEq/L

2.7-4.5

0.68 mmol/L

0.87-1.45

Protein, total

2.1 mg/dL

6.2-7.6

68 g/L

62-76

Albumin

6.8 g/dL

3.2-4.6

29 g/L

32-46

Cholesterol

2.9 g/dL

120-210

3.94 mmol/L

3.11-5.44

Urate

2.1 mg/dL

2.5-6.2

125 mmol/L

149-362

Bilirubin, total

7.7 mg/dL

0.2-1.0

131 mmol/L

3-17

AST

211 U/L

19-48

3.52 mkat/L

0.32-0.80

ALT

195 U/L

13-40

3.24 mkat/L

0.22-0.67

ALP

34 U/L

30-100

0.56 mkat/L

0.5-1.7

Urinalysis

Negative for protein,

Negative for all

blood, and cells; glucose, 2+; bilirubin, 2+; amorphous phosphate and urate crystals present "International Normalized Ratio.

Because of the patient's anemia and elevated bilirubin, further studies were ordered to rule out hemolytic disease. The patient's conjugated bilirubin was 4.0 mg/dL (68 mmol/L), and a corrected reticulocyte count was 4.2% (reference range 0.5 -1.5), confirming the presence of hemolysis. A Coombs test was negative. Despite her glycosuria, a haemoglobin A1c was normal at 5.4%, and 2-hour postprandial serum glucose was only 114 mg/dL (6.3 mmol/L). Ultrasonographic examination of her abdomen showed a normal gallbladder without stones and no dilated intra- or extrahepatic ducts. Her liver was inhomogeneous and slightly enlarged with a prominent portal vein, suggesting cirrhosis with active inflammation. The spleen was slightly enlarged at 13.5 cm. A small amount of ascitic fluid was noted. Further evaluation of the abnormal liver studies included the following:

Reference

Value,

Interval,

Reference

Conventional

Conventional

Value,

Interval,

Analyte

Units

Units

SI Units

SI units

HBsAg

Negative

Negative

Same

IgM anti-HB core Ab

Negative

Negative

Same

IgM anti-HA Ab

Negative

Negative

Same

Antihepatitis C Ab

Negative

Negative

Same

a11-Antitrypsin

182 mg/dL

78-200

1.82 g/L

0.78-2.00

Ceruloplasmin

16 mg/dL

20-45

160 mg/L

200-450

Antinuclear Ab

Negative

Negative

Same

Anti-smooth-muscle Ab

Negative

Negative

Same

Antiliver/kidney

Negative

Negative

Same

microsomal Ab

The slightly low ceruloplasmin level in the setting of elevated transaminases and neurologic symptoms raised the suspicion of hepatolenticular degeneration (Wilson's disease). A serum copper was obtained but at 171 mg/dL (26.9 mmol/L) was within the normal range of 60-190 (9.4-29.9). A more careful eye examination showed a golden brown band of pigment encircling the posterior cornea near the limbus of both eyes. An ophthalmologist performed a slit-lamp examination confirming the presence of Kayser-Fleischer rings. An MRI of the brain with T2 weighting demonstrated possible hyperintensity of the basal ganglia, a finding often seen in Wilson's disease. A baseline 24-hour urine collection was assayed for copper to further support the presumptive diagnosis of Wilson's disease, and a complete urine collection was documented by volume (840 mL/day) and urine creatinine (0.9 g/day). Baseline urinary copper excretion was elevated at 154 mg/day (2.43 mmol/day); (reference range, <40-100; <0.60-1.5). Because this elevation could also occur in other forms of liver injury, such as autoimmune hepatitis, an adjunctive urinary copper excretion test was performed several days later by giving 500 mg of the copper chelating drug D-penicillamine at 0 hour and 12 hour of the 24-hour collection. Finding an excretion of 2250 mg copper/day (35.2 mmol/day; reference range, <1600; <25) made Wilson's disease much more likely.1

To unequivocally establish the diagnosis, a liver biopsy was performed. Because of the patient's poor coagulation status, this was done by the transjugular approach with a prior infusion of fresh frozen plasma that normalized the patient's prothrombin time. Platelet infusions were not felt to be necessary. Macronodular cirrhosis was found with several regenerative nodules demonstrating ballooning degeneration of hepatocytes and pyknotic nuclei. An orcein stain for copper was positive, but showed variable staining between cirrhotic nodules. (A hepatic copper level was sent and came back 10 days later elevated at 264 mg/g dry weight liver; the normal was <50 mg/g and >250 was "diagnositic" of Wilson's disease.)

On the basis of the clinical and laboratory findings, therapy with D-penicillamine and a low-copper diet was initiated. Although abdominal distention due to ascites developed, the patient responded to a low-sodium diet and spironolactone. Her bilirubin decreased to 2.4 mg/dL (41 mmol/L) after 2 months, and her AST and ALT levels decreased to normal. Her hematocrit increased to 36% (0.36), and the reticulocytosis disappeared. Several 24-hour urine specimens obtained during the first 6 months of her D-penicillamine therapy showed marked cupruresis of 3000-5000 mg/day (47.2-78.7 mmol/day).

The patient's neurologic and psychiatric findings improved dramatically on therapy, although she was left with a fine tremor. After 10 months she developed a rash, arthralgias, and proteinuria. These symptoms were believed to indicate a lupuslike syndrome secondary to her D-penicillamine therapy. She was then started on oral zinc acetate therapy, but had too much abdominal discomfort. This prompted a switch to trientine therapy, which she has followed for the last 2 years without problems. An esophagogastroduodenoscopy showed no varices, but portal hypertensive gastropathy was noted. Because of her cirrhosis with its continued evidence of portal hypertension, the patient has been evaluated by the liver transplantation service. However, she has remained with a stable, relatively low MELD (model of end-stage liver disease) score of 12 based on a prothrombin time INR of 1.3, total bilirubin of 1.8 mg/dL, and creatinine of 0.9 mg/dL (see calculation at www.mayoclinic.org/gi-rst/mayomodel6.html).

The patient's parents were advised to have no more children and the parents and the patient's three younger siblings have all been screened with medical history, examination, routine laboratories, serum ceruloplasmin, slit-lamp examination, and 24-hour urinary copper excretion. No abnormalities have been found. But arrangements are being made to perform genotyping/haplotype studies at a specialized molecular laboratory.

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