Elsevier

The Lancet

Volume 360, Issue 9347, 30 November 2002, Pages 1742-1745
The Lancet

Mechanisms of Disease
Hyperzincaemia and hypercalprotectinaemia: a new disorder of zinc metabolism

https://doi.org/10.1016/S0140-6736(02)11683-7Get rights and content

Summary

Background

Calprotectin (complex of S100A8 and S100A9) is the major calcium and zinc-binding protein of phagocytes. We report a new syndrome with recurrent infections, inflammation, and hyperzincaemia associated with excessively high plasma concentrations of calprotectin.

Methods

We measured calprotectin in plasma and protein fractions by ELISA assay and zinc by atomic absorption spectrometry. Plasma proteins were fractionated by size exclusion chromatography and electrophoresis. Mass spectra of purified proteins were determined by MALDI-TOFMS.

Findings

We assessed five patients, two of whom are related. All patients had much the same biochemical findings of hyperzincaemia (77–200 μmol/L, reference range 11–18 μmol/L) and raised plasma calprotectin concentrations (1·4–6·5 g/L, reference range <1 mg/L). All patients presented with recurrent infections, hepatosplenomegaly, anaemia, and evidence of systemic inflammation. Three patients had cutaneous inflammation and three presented in infancy with severe growth failure. Size exclusion chromatography showed that zinc and calprotectin were associated in a broad fraction with molecular weight range 100–300 kDa. Analysis by electrophoresis and mass spectrometry showed that the patients' protein contained normal S100A8 and S100A9 subunits.

Interpretation

Dysregulation of zinc metabolism associated with accumulation in plasma of S100A8 and S100A9 defines a new disease, which encompasses a pathological role for dysregulation of two members of the large S100 protein family.

Introduction

The importance of trace elements for normal physiology is shown by the severe clinical manifestations of defects in their metabolism. The best characterised disorders are Wilson's disease and Menkes disease.1 The only known disorder of zinc metabolism is acrodermatitis enteropathica, a disorder of intestinal zinc uptake.1 Without zinc supplementation these patients have features of zinc deficiency, including a characteristic rash, growth failure, diarrhoea, and impaired immunity.

Two cases of familial hyperzincaemia have been reported previously;2, 3 one was not associated with any clinical features, and the other was associated with pyoderma gangrenosum.4 We previously identified a patient with very high concentrations of zinc in plasma but with clinical features of zinc deficiency. Biochemical analysis showed that the patient had high concentrations of an unidentified zinc binding protein,5 which was subsequently identified as calprotectin (MRP8, S100A8/MRP14, S100A9 complex).6 We are now able to report four more patients. Two of the newly described patients are related (mother and son).

Calprotectin is known mainly for its association with inflammatory conditions,7, 8, 9 its antimicrobial properties,10 and its possible role in regulation of leukocyte adhesion.11 We describe five patients with a defect in calprotectin metabolism and with similar biochemical and clinical features.

Section snippets

Patients

To date, we have identified five cases. The first (patient 1), previously described elsewhere,5, 6 is a boy now 18 years old. Two further cases with similar clinical features have also been identified; one (patient 2) is a girl aged 9 years and the other (patient 3) is a boy aged 14 years. Patient 4 is the mother of patient 3, aged 35 years.12 Patient 5 is a man aged 21 years with a milder phenotype than the other cases. The local ethics committees approved the study for all patients, and all

Results

Table 1 shows the clinical and laboratory data of patients, with the patient described by Hambidge and colleagues4 included for comparison. All patients presented with recurrent infections, hepatosplenomegaly, arthritis, anaemia, and persistently raised concentrations of C-reactive protein. All patients except patients 2 and 3 had inflammatory skin lesions. Patients 1–3 had also had severe growth failure in early infancy—below the 3rd centile for weight and height for age; patients 1 and 5 had

Discussion

Calprotectin (also known as the S100A8/9 or MRP8/14 complex) is a major calcium-binding protein in the cytosol of neutrophils, monocytes,7, 8 and keratinocytes.17, 18, 19 Although serum concentrations are known to be raised in many inflammatory conditions,7, 9 they are generally lower than 10 mg/L, and thus far below the concentrations we recorded in our patients. All disorders in which plasma calprotectin concentrations are raised are associated with an acute phase response, and hence with

GLOSSARY

calprotectin
A 36 kDa calcium and zinc binding protein constituting about 60% of total proteins in the cytosol of neutrophil granulocytes. Calprotectin has antimicrobial properties and can induce zinc-reversible apoptosis.
ef hand protein
EF hand is a structural motif in proteins consisting of two perpendicularly placed α helices and an interhelical loop which form a calcium binding site. The feature is named after the E and F helices in pavalbumin in which it was first described.
electrothermal

References (32)

  • SmithJC et al.

    Elevated plasma zinc. A heritable anomaly

    Science

    (1983)
  • FaillaML et al.

    Characterization of zinc binding proteins of plasma in familial hyperzincemia

    J Lab Clin Med

    (1982)
  • SampsonB et al.

    A case of hyperzincaemia with functional zinc depletion: a new disorder?

    Pediatr Res

    (1997)
  • RichmondP et al.

    Dysregulation of calprotectin metabolism is associated with a multisystem autoimmune vasculitis

    Arch Dis Child

    (1999)
  • JohneB et al.

    Functional and clinical aspects of the myeolomonocyte protein calprotectin

    Mol Path

    (1997)
  • HessianPA et al.

    MRP-8 and MRP-14, two abundant Ca(2+)-binding proteins of neutrophils and monocytes

    J Leukoc Biol

    (1993)
  • Cited by (104)

    • Zinc

      2021, Handbook on the Toxicology of Metals: Fifth Edition
    • HSCT is effective in patients with PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome

      2021, Journal of Allergy and Clinical Immunology
      Citation Excerpt :

      A recent gene-based disease names classification uses PSTPIP1-associated inflammatory disorder (PAID) term as a universal description of all allelic variants of the disease.2 Yet, a small group of patients, currently with only 2 PSTPIP1 mutations reported (p.E250K and p.A230T),3 has been recently described to have a distinct clinical phenotype, predominantly characterized by skin vasculitis/nonpyogenic dermatitis, hepatosplenomegaly, lymphadenopathy, and cytopenia, as well as hypercalprotectinemia and hyperzincemia.4-6 The disease was termed PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome.3

    • The redox biology of redox-inert zinc ions

      2019, Free Radical Biology and Medicine
      Citation Excerpt :

      For example, cases of unusually high serum zinc concentrations have been reported. One condition is due to calprotectinemia, elevation of a protein of the S100 family, the expression of which is controlled by zinc in myeloid cell lines [185,186]. Investigations in two areas influenced our knowledge about zinc as a cellular toxin: exposure of the lung to inhaled zinc-polluted air and intrinsic dislocation of zinc ions damaging neurons in the brain.

    • The role of zinc in calprotectin expression in human myeloid cells

      2018, Journal of Trace Elements in Medicine and Biology
    View all citing articles on Scopus
    View full text