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Anemia, paresthesias, and gait ataxia in a 57-year-old denture wearer.

CASE

A 57-year-old man developed numbness and tingling in his toes, which progressed over 3 to 4 months to involve his legs, hands, and lower torso. He then developed trouble walking owing to imbalance and had increasingly frequent falls. His hands felt clumsy, and he began dropping objects. He reported several instances of urinary incontinence in the weeks before presentation, but no bowel symptoms. He denied focal weakness or changes in speech, swallowing, or breathing. His sisters brought him to the emergency room after a fall in which he hit his head on a kitchen stool, and he was admitted to the neurology service for further evaluation.

The patient's medical history included longstanding tobacco use, chronic obstructive pulmonary disease, and low back pain. In addition, 5 months before the onset of his paresthesias, he was discovered to have a macrocytic anemia that did not respond to treatment with vitamin [B.sub.12] and folate. He was subsequently treated with periodic blood transfusions.

The general physical examination was unremarkable. On neurologic examination, the patient's mental status and cranial nerves were normal. A motor examination revealed spasticity without weakness in the legs. There was severe loss of vibratory and joint position sensation in the upper and lower extremities in a stocking-glove distribution; pain and temperature sensation were relatively spared. Reflexes were normal to brisk throughout, and there was no extensor toe sign. Finger tapping and toe tapping were mildly slowed. The Romberg sign was present. The patient's gait was slow, stiff-appearing, and ataxic, with a widened base and marked truncal instability. The constellation of lower extremity-predominant spasticity and proprioceptive defects suggested an abnormality in the region of the cervical spinal cord.

A laboratory workup on the patient's admission revealed macrocytic anemia (Table 1). The vitamin [B.sub.12] concentration was in the upper part of the reference interval, and the concentrations of cobalamin pathway metabolites homocysteine and methylmalonic acid were within reference intervals. Despite the normal [B.sub.12] concentration, [B.sub.12] repletion was instituted, but symptoms did not improve. An MRI evaluation of the spinal cord excluded compression but identified abnormal T2 signal along the posterior regions of the cervical and upper thoracic cord. Nerve-conduction studies showed a mild sensory peripheral neuropathy. Further questioning revealed that the patient had worn dentures for 10 years and that family members frequently chided him for excessive use of denture adhesive to the extent that it sometimes accumulated at the corners of his mouth.

PATIENT FOLLOW-UP

The patient's brisk reflexes, spastic gait, proprioceptive loss, and history of urinary incontinence were clues toward a predominantly spinal cord localization of his symptoms (i.e., a myelopathy). The differential diagnosis of acquired noncompressive myelopathies is broad, including toxic, nutritional, infectious, autoimmune, vascular, and structural causes (Table 2). The prominent sensory ataxia with only mild motor findings pointed toward a lesion of the posterior columns. This finding, in conjunction with a history of macrocytic anemia, suggested the subacute combined degeneration syndrome of vitamin B12 deficiency. This patient's anemia persisted, however, and his neurologic syndrome worsened while he was receiving [B.sub.12] supplementation.

Owing to the patient's excessive use of denture adhesive, which contains zinc, serum concentrations of copper and zinc were measured. The patient's serum zinc concentration was 1.42 [micro]g/mL (21.7 [micro]mol/L) (reference interval, 0.66-1.1 [micro]g/mL), and his copper concentration was <0.1 [micro]g/mL(<1.6 [micro]mol/L) (reference interval, 0.75-1.45 [micro]g/mL). The patient was diagnosed with copper deficiency myeloneuropathy due to zinc toxicity from his denture adhesive. Intravenous copper repletion with cupric sulfate (2 mg/day) was administered for 5 days, followed by long-term oral copper gluconate supplementation (2 mg/day). The patient also began using a different brand of denture cream. At follow-up 2 months later, the patient's blood cell counts, mean corpuscular volume, and copper concentration had completely normalized, while the zinc concentration remained slightly increased. He reported near-resolution of his paresthesias and bladder symptoms, and on examination his gait was markedly steadier.

DISCUSSION

Over the last decade, the relationship between acquired copper deficiency and neurologic disease has become firmly established. Myeloneuropathies with a varying combination of sensory and motor involvement have now been described. A spastic ataxia syndrome with prominent posterior column findings mimicking cobalamin deficiency (1) remains the archetypal and probably the most common neurologic presentation of copper deficiency. In about half of such cases, neuroimaging reveals a pattern of abnormal T2 signal in the midline and posterior columns of the cervical and thoracic spine that is nearly identical to the radiographic findings in [B.sub.12] deficiency (2). Although minor subjective and objective responses are not uncommon, clinically significant neurologic improvement after copper treatment is atypical; most patients experience a stabilization of their disease. Several variant neurologic presentations of copper deficiency have now been reported in detail (3-7). In all of these cases, neurologic findings stabilized or slightly improved with treatment.

A variety of reversible hematologic abnormalities--such as anemia (macrocytic, normocytic, and microcytic), leukopenia, neutropenia, and thrombocytopenia, as well as pancytopenia--may result from copper deficiency. These abnormalities typically, but not always, occur in the context of neurologic presentations. Among the cases described in the neurology literature, swift and complete reversal of accompanying hematologic abnormalities is the norm. Halfdanarson and colleagues (8) reviewed 40 cases of acquired copper deficiency with low hematologic indices, with 22 (55%) of the patients having no other identifiable potential causes for their cytopenia. Of the patients for whom treatment data were available, 89% had complete or partial normalization of hematologic parameters after copper supplementation. Bone marrow biopsies from 23 patients showed characteristic patterns of granulocytic hypoplasia (100%), vacuolization in myeloid precursor cells, erythroid hyperplasia, increased iron staining within macrophages and plasma cells, and ringed sideroblasts. In many cases, biopsies were initially interpreted as reflecting myelodysplastic or toxic syndromes, again attesting to the tendency of copper deficiency to masquerade as a different, better-known entity.

The etiology of acquired copper deficiency ultimately derives from impaired copper absorption from the gastrointestinal tract. Dietary copper is absorbed into enterocytes of the stomach and duodenum via the CTR1 copper import protein and possibly via DMT1 (divalent metal transporter 1) or other less well-characterized transmembrane routes (9). Intracellular copper binds to various cytosolic chaperone proteins and then is pumped into the trans-Golgi endoplasmic reticulum via the copper transporter ATP7A (copper-transporting ATPase 1). From there it is distributed to cuproenzymes or secreted across the basolateral membrane and into the portal circulation, where it is taken up by the liver and either incorporated into ceruloplasmin or excreted (via ATP7B) into bile and ultimately feces. The most commonly identified mechanism of acquired copper deficiency relates to an altered gastroduodenal anatomy, such as occurs after bariatric or peptic ulcer surgery, in which the surface area for copper absorption is reduced. More recently, malabsorption of copper due to celiac disease has also been reported (10). In any potential malabsorption scenario, other concomitant vitamin and mineral deficiencies should be investigated, such as vitamins [B.sub.1], [B.sub.6], [B.sub.12], D, and E, folic acid, and iron. Copper-deficiency states also lead to a reduction in serum ceruloplasmin, and concentrations of this protein may be monitored as a marker of the therapeutic response once copper repletion has begun.

In the presence of a normal anatomy, a second well-described mechanism of copper malabsorption relates to excess zinc intake causing a secondary hypocupremia. Cytosolic zinc within enterocytes causes upregulation of metallothioneins, which are chelators that normally serve to scavenge excess copper but that lead to intracellular copper sequestration and functional malabsorption when overproduced (9), with copper-sequestering enterocytes eventually sloughing off. As with the present patient, many reported cases of acquired copper deficiency feature a concomitant hyperzincemia that is presumably causal. Perhaps the most common way for excess zinc ingestion to occur is through overzealous use of denture adhesives, which contain high concentrations of zinc (6), although some cases have been attributed to excessive zinc ingestion for dubious purported health benefits (e.g., warding off colds). There are also a few reported cases of patients with the dual hit of having undergone gastric bypass and having taken zinc (but not copper) supplementation in a well-meaning attempt to avoid post-bypass nutritional deficiencies. Interestingly, a large fraction of copper-deficiency cases (including some with associated hyperzincemia) remains idiopathic, emphasizing our incomplete knowledge of the etiology of this disorder.

QUESTIONS TO CONSIDER

1. What is in the differential diagnosis of a noncompressive myelopathy?

2. What are some causes of macrocytic anemia?

3. Could the excessive use of dental adhesive contribute to the patient's symptoms?

POINTS TO REMEMBER

* Copper deficiency can be a treatable cause of neurologic syndromes, including ataxia, neuropathy, spasticity, optic neuropathy, and motor neuron degeneration resembling amyotrophic lateral sclerosis.

* Copper deficiency is caused by copper malabsorption secondary to altered gastrointestinal tract anatomy (e.g., after bariatric surgery) or upregulation of copper-chelating proteins by excess zinc (e.g., from denture adhesive), although a significant percentage of cases remain idiopathic.

* A history of gastrointestinal surgery, as well as of denture adhesive use or zinc supplementation, should be routinely obtained in evaluating patients with sensorimotor neurologic disorders.

* Serum copper should also be measured in patients with unexplained cytopenia or a suspected myelodysplastic syndrome.

* Zinc and ceruloplasmin concentrations should also be checked when copper deficiency is suspected.

* When copper deficiency is identified in a patient with a history of gastrointestinal resection, other concomitant nutritional deficiencies should also be investigated.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

References

(1.) Kumar N, Gross JB, Ahlskog JE. Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 2004;63:33-9.

(2.) Kumar N, Ahlskog JE, Klein CJ, Port JD. Imaging features of copper deficiency myelopathy: a study of 25 cases. Neuroradiology 2006;48:78-83.

(3.) Schleper B, Stuerenberg HJ. Copper deficiency-associated myelopathy in a 46-year-old woman. J Neurol 2001;248:705-6.

(4.) Prodan CI, Holland NR, Wisdom PJ, Burstein SA, Bottomley SS. CNS demyelination associated with copper deficiency and hyperzincemia. Neurology 2002;59:1453-6.

(5.) Weihl CC, Lopate G. Motor neuron disease associated with copper deficiency. Muscle Nerve 2006;34:789-93.

(6.) Nations SP, Boyer PJ, Love LA, Burritt MF, Butz JA, Wolfe GI, et al. Denture cream: an unusual source of excess zinc, leading to hypocupremia and neurologic disease. Neurology 2008;71:639-43.

(7.) Naismith RT, Shepherd JB, Weihl CC, Tutlam NT, Cross AH. Acute and bilateral blindness due to optic neuropathy associated with copper deficiency. Arch Neurol 2009;66:1025-7.

(8.) Halfdanarson TR, Kumar N, Li CY, Phyliky RL, Hogan WJ. Hematological manifestations of copper deficiency: a retrospective review. Eur J Haematol 2008;80:523-31.

(9.) Van den Berghe PVE, Klomp LWJ. New developments in the regulation of intestinal copper absorption. Nutr Rev 2009;67:658-72.

(10.) Goodman BP, Mistry DH, Pasha SF, Bosch PE. Copper deficiency myeloneuropathy due to occult celiac disease. Neurologist 2009;15:355-6.

Commentary

Jonathan D. Gitlin *

Copper is an essential nutrient, readily available in the diet and rapidly absorbed through the gastrointestinal tract. Copper is abundant in dietary foods and water sources, and copper deficiency in humans is therefore uncommon. Nevertheless, acquired copper deficiency may occur when gastrointestinal uptake is impaired. The most common manifestations of copper deficiency are a decreased serum ceruloplasmin and anemia, neutropenia, or thrombocytopenia. If prolonged, copper deficiency will produce neurologic signs and symptoms that include sensory ataxia, hyperreflexia, and a spastic gait. If the deficiency is detected early, copper supplementation always resolves the serum and hematologic manifestations and prevents further neurologic deterioration. Neurologic recovery may be slow, however, and preferentially involves the sensory symptoms. Thus, copper deficiency is an important clinical problem that must be recognized early by the physician.

This case report raises several fascinating clinical issues. The reported findings are similar to those observed in patients with megaloblastic anemia and subacute combined degeneration due to vitamin B12 deficiency. The mechanisms of bone marrow dysplasia and neurologic degeneration in copper deficiency are unknown, and these findings remind us of the unexplored relationship between cobalamin and copper metabolism. This patient was also reported to have increased serum zinc, presumably from chronic ingestion of dental adhesive. Zinc ingestion is associated with copper deficiency, and patients have been identified with acquired copper deficiency of unknown etiology and increased serum zinc in the absence of exogenous zinc ingestion. These findings remind us that we have much to learn about the interplay of copper and zinc homeostasis and suggest that the resulting copper deficiency is likely more complex than the proposed interference with gastrointestinal tract absorption.

In the final analysis, case reports of rare diseases sharpen our diagnostic skills and reveal the hidden mysteries that remain to be explored in much of human physiology and disease.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

Jonathan D. Gitlin *

Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN.

* Address correspondence to the author at: Department of Pediatrics, Vanderbilt University School of Medicine, 2200 Children's Way, Nashville, TN 37232. E-mail jonathan.d.gitlin@vanderbilt.edu.

Received March 11, 2011; accepted March 21, 2011.

DOI: 10.1373/clinchem.2011.163485

Commentary

William L. Roberts *

This clinical case study is timely and interesting. A recent TV advertisement from a law firm aired in Utah and targeted victims who might have been harmed by zinc-containing denture adhesives. An Internet search on zinc toxicity identified 2 law firms that handle these cases and an advertisement for a zinc-free denture adhesive. Zinc toxicity may have causes other than excessive use of zinc-containing denture adhesives. Pennies minted in the US since 1983 contain 97.5% zinc. Zinc is highly reactive with gastric acid. Ingestion can cause local corrosion and systemic toxicity. Massive ingestion can be fatal (1). Acute toxicity has resulted from storage of food or drink in galvanized containers. Toxicity due to ingestion of very large doses of zinc remains quite uncommon (2). Pharmacologic intake of zinc (100-300 mg Zn/day) over a long period can lead to severe copper deficiency, like that described in this clinical case study. Ingestion of between the Recommended Daily Allowance of 15 mg/day and pharmacologic doses of 100 mg/day has been associated with adverse consequences (2). Excessive absorption of zinc can also suppress iron absorption (2).

Zinc is an essential cofactor in a number of cellular processes. A review of the literature on zinc and human health demonstrates that dietary zinc deficiency is a major health problem worldwide, with nearly 2 X [10.sup.9] people affected (3). Zinc deficiency is particularly problematic in infancy, with nearly 1 X [10.sup.6] excess deaths due to pneumonia, diarrhea, and malaria occurring worldwide annually in children under 5 years. Adequate intake from foods can be difficult without fortification. Fortification programs are difficult to implement for the rural poor of less-developed countries. Obtaining an adequate intake of zinc in children is a major challenge worldwide, in contrast with the excessive intake from supplements and zinc-containing products in developed countries.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:

Employment or Leadership: W.L. Roberts, Academy of Clinical Laboratory Physicians and Scientists, and College of American Pathologists.

Consultant or Advisory Role: W.L. Roberts, ARUP Laboratories.

Stock Ownership: None declared.

Honoraria: None declared.

Research Funding: None declared.

Expert Testimony: None declared.

References

(1.) Bennett DR, Baird CJ, Chan KM, Crookes PF, Bremner CG, Gottlieb MM, Naritoku WY. Zinc toxicity following massive coin ingestion. Am J Forensic Med Pathol 1997;18:148-53.

(2.) Fosmire GJ. Zinc toxicity. Am J Clin Nutr 1990;51:225-7.

(3.) Prasad AS. Zinc deficiency. BMJ 2003;326:409-10.

William L. Roberts *

ARUP Laboratories, Salt Lake City, UT.

* Address correspondence to the author at: ARUP Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108. Fax 801-584-5207; e-mail william. roberts@aruplab.com.

Received March 15, 2011; accepted March 21, 2011.

DOI: 10.1373/clinchem.2011.163493

R. Brian Sommerville [1] * and Robert H. Baloh [1,2] *

[1] Department of Neurology, Neuromuscular Division, and [2] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO.

* Address correspondence to: R.B.S. at Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8111, St. Louis, MO 63110. E-mail sommervilleb@neuro.wustl.edu. R.H.B. at Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8111, St. Louis, MO 63110. E-mail rbaloh@wustl.edu.

Received September 3, 2010; accepted October 26, 2010.

DOI: 10.1373/clinchem.2010.156364
Table 1. Patient laboratory results. (a)

Analyte                            Result

WBC (b)              4200/[micro]L (4.2 X [10.sup.9]/L)
Hemoglobin           9.8 g/dL (98 g/L)
Hematocrit           28.3%
Platelets            272 X [10.sup.3]/[micro]L
                       (272 X [10.sup.9]/L)
MCV                  113 fL
Vitamin [B.sub.12]   834 pg/mL (615 pmol/L)
Homocysteine         5.2 [micro]mol/L
MMA                  235 nmol/L

Analyte                           Reference interval

WBC (b)              3800-9800/[micro]L (3.8-9.8 X [10.sup.9]/L)
Hemoglobin           13.9-17.2 g/dL (139-172 g/L)
Hematocrit           40.7-50.3%
Platelets            140-440 X [10.sup.3]/[micro]L
                       (140-440 X [10.sup.9]/L)
MCV                  80-97.6 fL
Vitamin [B.sub.12]   211-911 pg/mL (156-672 pmol/L)
Homocysteine         5.1-13.9 [micro]mol/L
MMA                  73-271 nmol/L

(a) Values in boldface are outside the reference interval.

(b) WBC, white blood cells; MCV, mean corpuscular volume;
MMA, methylmalonic acid.

Table 2. Acquired noncompressive myelopathies.

Etiology                                       Description

Nutritional
  Cobalamin deficiency              Subacute combined degeneration of
                                      posterior columns and
                                      peripheral sensory neurons
                                      (myeloneuropathy)
  Nitrous oxide inhalation          Can induce acute cobalamin
                                      deficiency
  Copper deficiency                 Subacute combined degeneration,
                                      spastic ataxia, lower motor
                                      neuron syndrome

Infectious
  HTLV-1                            Chronic progressive spastic
                                      paraparesis
  HIV                               Chronic vacuolar myelopathy
  Syphilis                          Tabes dorsalis (now quite rare)

Immune/inflammatory
  Demyelinating diseases            Multiple sclerosis, transverse
                                      myelitis, acute disseminated
                                      encephalomyelitis,
                                      neuromyelitis optica
  Sarcoidosis                       Variable presentations; may mimic
                                      tumor, demyelinating disease,
                                      or HIV myelopathy;
                                      leptomeningeal involvement
                                      also is common
  Sjogren syndrome                  Usually transverse myelitis

Vascular
  Dural arteriovenous fistula       Spinal angiography should be
                                      considered for unexplained
                                      myelopathies
  Venous hypertensive myelopathy    Obstructed venous drainage
                                      associated with mild central
                                      disc herniation

Other structural
  Syringomyelia                     Progressive cord cavitation with
                                      or without associated Chiari I
                                      malformation
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Title Annotation:Clinical Case Study
Author:Sommerville, R. Brian; Baloh, Robert H.
Publication:Clinical Chemistry
Article Type:Clinical report
Geographic Code:1USA
Date:Aug 1, 2011
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