Acquired hypocupremia

Acquired hypocupremia refers to an acquired serum copper deficiency. With many causes, it most commonly results from malabsorption following bariatric surgery. Its hematological and neurological manifestations, which can be severe, are similar to those of vitamin B12 deficiency. Since the clinical progression is generally insidious, the diagnosis is often made late (several months to several years after the onset of symptoms).

Copper metabolism and pathophysiology elements

Copper is absorbed in the stomach and duodenum, then binds to albumin and circulates through the portal system. In hepatocytes, it binds to ceruloplasmin and is then available in general circulation. Copper is primarily excreted via bile.

The recommended daily dose is 1.5 to 3 mg/day.

Hypotheses regarding the pathophysiology of copper deficiency include:

• Copper acts as a cofactor for various enzymes, including cytochrome oxidase (complex IV of the mitochondrial respiratory chain) involved in oxidative metabolism.
• A methylation cycle dysfunction is believed to be common to both hypocupremia and vitamin B12 deficiency. This cycle includes enzymes dependent on copper and cobalamin (e.g., methionine synthase) and catalyzes the transfer of a methyl group from methyltetrahydrofolate to various macromolecules, including myelin.

Etiologies

• Frequently undetermined
• 1^st cause: Bariatric surgery. Copper absorption occurs in the stomach and proximal duodenum. The exact mechanism of copper malabsorption after this type of surgery remains unclear. The time between surgery and the onset of neurological symptoms varies from less than a year to 24 years.
• Excessive zinc absorption (denture adhesive, acne creams, etc.), which leads to upregulation of metallothionein production in enterocytes. Metallothionein is an intracellular ligand with a higher affinity for copper than zinc → copper is sequestered in the enterocytes and excreted in the stool during apoptosis.
• Excessive iron intake: Paradoxical situations have been described where iron supplementation, initiated for suspected iron-deficiency anemia, worsens hematological pathology. The mechanism by which iron interferes with copper absorption in humans is unknown.
• Celiac disease and other causes of malabsorption
• Other: nephrotic syndrome, glomerulonephritis (excessive urinary excretion of copper), infant malnutrition, prolonged parenteral nutrition, Wilson’s disease, etc.

Clinical features

Neurological manifestations

The most common manifestation is myelopathy with or without peripheral polyneuropathy. Generally, the neurological presentation mimics the combined cord syndrome induced by vitamin B12 deficiency.

The typical complaint is a subacute or chronic onset of gait disturbance (sensory ataxia due to posterior cord involvement with or without a spastic-paraparetic component due to pyramidal tract involvement). Hyperreflexia with bilateral Babinski sign is frequent but can be masked by peripheral involvement (hyporeflexia in polyneuropathy).

Less common: bladder dysfunction, optic neuritis, lower motor neuron involvement (differential diagnosis: ALS).

Hematological manifestations

Possible nonspecific symptoms of anemia. More rarely, leukopenia may be observed, and even more rarely thrombocytopenia.

Complementary tests

Biology

Anemia is almost constant, leukopenia (++ neutrophils), and rarely thrombocytopenia.

Electrophysiology

Useful only in case of clinical uncertainty regarding the reality of neurological involvement, or for NCS when there is etiological uncertainty.

• EMG and NCS → frequent axonal involvement (rarely demyelinating), generally motor or mixed, rarely purely sensory.
• SEP → frequent nonspecific abnormalities.

Radiological tests

Spinal MRI

Sometimes normal. The most common abnormality: T2 hyperintensity in the posterior columns at the cervical and/or thoracic level. Possible involvement of both the posterior and lateral columns. No contrast enhancement. Essential for differential diagnosis to exclude other causes of myelopathies.

Brain MRI

Possible nonspecific T2 hyperintensities. However, the distribution of certain lesions may suggest a multilacunar syndrome (role of hypocupremia in cerebrovascular diseases?). Useful only in cases of diagnostic doubt.

Bone marrow biopsy

→ vacuolization of erythroid and myeloid precursors + presence of ringed sideroblasts. Not pathognomonic but highly suggestive.

Therapeutic management - Treatments

Based on copper administration. No consensus regarding dose, duration, and route of administration. Oral supplementation appears sufficient except in cases of malabsorption or jejunostomy. 2 mg/day PO/IV seems adequate. Some recommend 6 mg/day for 1 week, then 4 mg/day for 1 week, then 2 mg/day. Peripheral copper dosage for follow-up. Recommend a copper-rich diet (chocolate, vegetables, seafood, nuts, liver, etc.).

In zinc intoxication → stop exposure + copper supplementation via parenteral route (delay due to slow zinc elimination).

Hematological recovery is rapid and often complete. Neurologically, stabilization is always achieved, but clinical and complementary test improvement is rare.

Bibliography

EMC, Hématologie, Elsevier, 2018