Chapter 13 - Other organ involvement and clinical aspects of Wilson disease

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Abstract

Wilson disease (WD) is a rare disorder of copper metabolism that presents mainly with hepatic and neuropsychiatric features. Copper accumulates not only in the liver and brain, but also in other organs. Liver injury can also be the cause of secondary impairment of other tissues. Therefore, the clinical manifestation of WD may be renal, cardiac, skin, osteoarticular, or endocrinologic and include other organ disturbances. Renal abnormalities include tubular dysfunction (e.g., renal tubular acidosis, aminoaciduria) and nephrolithiasis. Bone demineralization is a common manifestation in patients with WD. Cardiac injury may include arrhythmia, cardiomyopathy, and autonomic dysfunction. Different endocrine system manifestations, such as infertility or repeated miscarriages, growth and puberty disturbances, and hypoparathyroidism, are observed. Other important clinical aspects of WD include pancreas involvement, immunologic abnormalities, the presence of lipomas, and skin changes. Although other organ involvement is not common in WD and usually not severe, delayed diagnosis may lead to irreversible changes in organs and tissues. Therefore, awareness of other possible WD presentations is important in the differential diagnosis of WD.

Introduction

Wilson disease (WD) is known for its diverse clinical symptoms and signs, but it typically presents with hepatic and neuropsychiatric features due to copper accumulation in the liver and brain. However, copper also accumulates in other organs and may cause other manifestations of WD.

Very high copper content is detected in the kidneys of WD patients. In 8 untreated patients described by (Scheinberg and Sternlieb, 1984), the copper concentration in the kidneys was very high compared to a control group (904 μg/g dry tissue vs. 15 μg/g dry tissue). The copper content in the hearts of WD patients is also higher (average 157 μg/g dry tissue) than in healthy people (average 17 μg/g dry tissue). Increased copper concentrations have also been detected in the bones of WD patients (5.5 μg/g wet tissue vs. 0.8 μg/g wet tissue), and copper deposition has been reported in cartilage biopsies from WD patients (Menerey et al., 1988). In addition, 1 out of 5 WD patients has an increased copper concentration in the pancreas (Scheinberg and Sternlieb, 1984).

In this chapter we will discuss the various less typical, but still important, clinical features of WD, which may be caused by copper toxicity but may also be sequels of liver disease or anticopper therapy. For management of some of the other organ symptoms, see also Chapter 17.

Section snippets

The kidneys

In WD, excess copper is eliminated by the kidneys, resulting in increased urinary copper excretion (Scheinberg and Sternlieb, 1984, European Association for the Study of the Liver, 2012). As with the liver and brain, copper accumulates in the kidneys and may impair renal function.

Normal urinary copper excretion is < 50 μg/24 hours. In patients with WD, copper excretion is often > 100 μg/24 hours (EASL, 2012). Increased urinary excretion is also detected in primary biliary cirrhosis, hepatitis,

The osteoarticular system

Osteoarticular manifestations are a common feature of WD and mainly involve osteopenia, osteoporosis, and arthropathy (Warnock, 1952, Feller and Schmuacher, 1972, Kaklamanis and Spengos, 1973, Golding and Walshe, 1977, Lugassy et al., 1988). Bone demineralization is frequently observed in WD patients and possibly results from hypercalciuria and hyperphosphaturia. Joint problems may be caused by copper deposition (Canelas et al., 1978, Menerey et al., 1988). Osteoporosis may also result from

Cardiovascular system

Another manifestation of WD is cardiac involvement, including arrhythmias, cardiomyopathy, and autonomic dysfunction. However, this manifestation rarely results in clinical problems. The average copper content in the heart is much higher in WD patients (157 μg/g dry tissue) than in healthy people (17 μg/g dry tissue) (Scheinberg and Sternlieb, 1984). Myocardial copper accumulation may cause cardiomyopathy and arrhythmias (Factor et al., 1982, Kuan, 1982). The number of studies evaluating the

Endocrinology

The endocrine manifestations of WD may include disorders of growth and puberty, hypothyroidism, hypoparathyroidism, infertility, or repeated miscarriages (Frydman et al., 1991, Sinha et al., 2004, Leggio et al., 2007, European Association for the Study of the Liver, 2012). The frequency of endocrinologic manifestation is difficult to establish because single cases have mainly been reported (Klee, 1979, Krysiak et al., 2012).

The most common cause of gonadal dysfunction in patients with WD is

Hematology

Hematologic symptoms include acute Coombs-negative hemolytic anemia, leukopenia, anemia, and thrombocytopenia (EASL, 2012). Acute Coombs-negative hemolytic anemia with hemolytic jaundice may be an initial symptom of WD in 10–15% of patients (Yarze et al., 1992) and precede the onset of neurologic or hepatic symptoms (Hoogenraad, 1996). Among 276 cases, 19 (6.8%) had hemolytic anemia confirmed by laboratory tests at admission. However, in a group of patients presenting with jaundice, 28% also

Dermatology

Dermatologic signs in WD include those that occur during the course of disease as well as complications after DPA treatment. Skin changes may occur as result of liver cirrhosis and involve mainly vascular spiders and palmar erythema (Wiliam et al., 2011). Cutaneous findings in WD include hyperpigmentation of the lower extremities (Fig. 13.4), azure lunulae (“sky-blue moon”) (Fig. 13.5) of the nails, anetoderma, xerosis, acatnosis nigricans, and dermatomyositis (Wiliam et al., 2011, Ivanova et

Lipomas

As we observe at our center, WD patients often present with lipomas (Fig. 13.6). Schaefer et al. (2015a) reported a high frequency of subcutaneous lipomas in a cohort of WD patients; among 80 patients with WD, lipomas were found in 26% during examination. Multiple subcutaneous lipomas were noted in 16 (76%) of the 21 affected patients. Lipomas were present mainly on the trunk and extremities. Histologic examination was performed in 3 patients and revealed typical lipoma tissue. Neither initial

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