Copper deficiency

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Classification according to ICD-10
E61.0 Copper deficiency
E64.8 Consequences of other nutritional deficiencies
ICD-10 online (WHO version 2019)

If there is a copper deficiency , the body does not have sufficient amounts of the essential trace element copper . Copper is found in numerous enzymes and is partly responsible for the absorption of iron in the gastrointestinal tract. The decreased level of copper in the blood is known as hypocupraemia .

Copper metabolism

The copper requirement can be covered by food. It is found in meat, poultry, fish and seafood, nuts, beans, dried vegetables, raisins, dark chocolate, and grain products. A person's daily requirement is 1.5–3 mg.

Copper is absorbed through the gastrointestinal tract. Of the copper supplied with food, 40–70%, around 2–5 mg daily, is actively absorbed; this occurs primarily in the proximal duodenum . Responsible is the copper transport protein CTR-1 ( high affinity copper uptake protein 1 ), which absorbs copper from the intestine into the cells on the luminal (intestinal) side of the enterocytes , but also for the copper transport into the cell expressed throughout the body and encoded by the SLC31A1 gene.

After being absorbed into the intestinal cells ( enterocytes ), copper is bound to metallothionein there . Zinc also binds to it, but with less affinity. Metallothionein with a positive feedback leads to the fact that the enterocytes form more metal thionein, which then binds more copper and this is not released into the bloodstream. Therefore, an increased zinc level leads to the fact that the body loses the copper-laden enterocytes as part of the constant renewal of the intestinal cells and cannot mobilize enough copper, which can result in a copper deficiency.

First, the copper is transported from the intestinal cells to the liver via the portal vein , where it is bound to albumin , amino acids and transcuprein. In the liver, it is also bound in the hepatocytes to metallothionein, superoxide dismutase and newly formed ceruloplasmin . In the blood, copper circulates 95% bound to ceruloplasmin and 5% bound to albumin, amino acids and transcuprein.

With a total content of 70–150 mg, copper is the third most common trace element in humans after iron and zinc. Copper is mainly stored in the skeleton, the brain, the muscles and the liver (around 15%). 80% of copper is excreted via the bile , whereby the copper is firmly bound to biliary proteins that are not reabsorbed, so that there is no enterohepatic circulation . Another 20% is excreted through tissue loss, especially the mucous membrane cells , while urine excretion is marginal. Copper is also found in breast milk . ATP- dependent transport systems are responsible for regulating the copper concentration within the cells (e.g. the liver ) .

causes

A copper deficiency can be triggered by insufficient oral intake (malnutrition) as well as by insufficient intake, a malabsorption . The main cause is currently gastric bypass surgery ( bariatric surgery ), especially in the case of Roux-en-Y gastric bypass with elimination of the duodenum and inadequate substitution of copper.

In addition, other diseases with gastrointestinal malabsorption, such as celiac disease and an increased zinc level, can also lead to a copper deficiency. Zinc can be increased in the blood through excessive intake of food supplements , foods containing zinc or through the use of adhesive creams for dentures. Due to a pathologically increased zinc uptake, the copper ions in the enterocytes are increasingly bound to the metallothioneins and excreted with them as part of the renewal of the intestinal wall. On the other hand, increased blood zinc levels are very often found without any pathological zinc absorption, for which the cause is not known.

Taking the anti- epileptic valproic acid also leads to a copper deficiency via a mechanism that has not yet been clarified.

The rare Menkes syndrome is a congenital metabolic disorder with a copper deficiency that leads to developmental delays, seizures and progressive weakness even in young children.

Even with permanent parenteral nutrition , insufficient administration of copper can lead to deficiency symptoms.

In about 20% of all patients there is no cause of the copper deficiency, it is idiopathic.

Disease emergence

Copper-dependent reactions are essential for electron transport and oxidative phosphorylation in the mitochondrial respiratory chain , as well as in antioxidative protective reactions, in catecholamine synthesis and in the post-translational modification of neuropeptides and peptide hormones , and also in iron homeostasis in the brain.

Concretely, copper is a co-factor in enzymes in energy metabolism, such as cytochrome oxidase , catalase , peroxidase , tyrosinase , monoamine oxidase , superoxide Dysmutase (protection against reactive oxygen ), dopamine β-hydroxylase (dopamine formation), uricase , lysyl oxidase ( Elastin - and collagen synthesis ) and ascorbic acid oxidase . It is important for the formation of the red blood pigment (oxygen carrier - hemoglobin ) and the function of the cytochromes in the mitochondria .

Copper is also important for the absorption of iron from food ( absorption in the gastrointestinal tract). In the case of copper deficiency, symptoms of iron deficiency and impaired function of the corresponding enzymes occur.

Clinical manifestations

If there is a copper deficiency, neurological and haematological changes occur in particular .

Neurologically, paresthesias , weakness in arms and legs and an unsteady gait are in the foreground. The muscle weakness is usually more pronounced in the legs.

Electrophysiologically, there is often a mixed sensory-motor polyneuropathy , and the findings may be similar to those of amyotrophic lateral sclerosis . Purely motor or purely sensory neuropathy are also possible.

In addition, damage to the optic nerve and the spinal cord ( myelopathy ) can occur, which is often similar to myelopathy with vitamin B 12 deficiency. The copper deficiency myelopathy was first described in 2001 by Schleper and Stuerenburg. There are shown in the magnetic resonance imaging in the T2-weighted sequences hyperintense changes in the spinal cord in the thoracic and cervical spine, especially in the dorsal midline region, in the area of the dorsal horn, forward in the ascending nerve fibers sensory signals to the brain. The dorsal horn dysfunction results in sensory ataxia , hyposensitivity of the feet and hands (which is stocking-like and glove-shaped in its spread) and sometimes spastic paraparesis. Often there are also pyramidal tract signs , peripheral neuropathies, and hyporeflexia.

Hematological changes usually precede neurological changes. There is often anemia in the blood count , which is typically macrocytic, but can also be normocytic or sideroblastic due to the secondary iron deficiency . In addition, there may be a lack of blood platelets and, more rarely, of white blood cells , the latter probably due to reduced cell division and a differentiation block of CD34- positive haematopoietic stem cells .

Bone marrow biopsies show an increased number of myeloid and erythroid progenitor cells with vacuoles , with ring-shaped sideroblasts and a dysplasia of numerous hematopoiesis cell lines, which can resemble a myelodysplastic syndrome . Insufficiently differentiated neutrophils can also occur, the bilobular form of which, as a "pseudo- Pelger-Huët anomaly ", can also indicate a myelodysplastic syndrome.

The copper level in the blood and the concentration of the main transport protein ceruloplasmin are reduced in all patients with copper deficiency . The urinary excretion of copper can be reduced, especially if the zinc level is increased at the same time.

In addition, a long-standing copper deficiency can also lead to osteoporosis . The sugar level can also be increased, as can the cholesterol levels in the blood, and there is an increased risk of cardiovascular disease .

Investigation methods

The normal serum copper concentration is between 75 and 80 µg / dl as the lower limit and 140–145 µg / dl as the upper limit, or 11.8–22.8 µmol / l. Of this, 4 percent are bound to serum albumin and 96 percent to ceruloplasmin .

Since ceruloplasmin is rapidly broken down without copper binding, its blood level is also reduced if there is a copper deficiency. (Normal value 20–60 mg / dl)

If a pathologically increased zinc intake is the cause, the histological examinations must show more copper ions in the enterocytes, otherwise an increased zinc level is not the cause.

Prevention and treatment

Treatment and prevention usually consist of sufficient oral administration of copper. Copper should also be taken after bariatric surgery. In the rare case of malabsorption, parenteral administration is indicated. In parenteral nutrition, copper must also be substituted as a trace element.

In the case of iron deficiency anemia , the parenteral administration of iron may also be indicated symptomatically, since its absorption from the gastrointestinal tract is significantly restricted in the case of copper deficiency.

After the start of treatment, the haematological changes usually regress quickly, while the neurological changes respond only very slowly and variably to the copper substitution and often remain irreversible. In two observational studies with 16 and 55 patients, the changes in the blood count were corrected in 93% in the first study after three months, while the neurological changes only improved partially in 25% and 49%, and no longer increased in 42% and 51%, and even got worse in 33% in the first study. Neurological improvements were observed at the earliest after six weeks and up to two and a half years after the start of therapy.

history

The occurrence of copper in biological organisms was already known in the middle of the 19th century. Even then, its importance as an essential trace element was discussed.

See also

Literature and Sources

Individual evidence

  1. ↑ a b c d Mounica Vallurupalli, Sanjay Divakaran, Aric Parnes, Bruce D. Levy, Joseph Loscalzo: The Element of Surprise , New England Journal of Medicine 2019, Volume 381, Issue 14 of October 3, 2019, pages 1365-1371, DOI: 10.1056 / NEJMcps1811547
  2. ↑ Michael P. Bowley, William S. David, Tracey A. Cho, Anand S. Dighe: Case 35-2017: A 57-year-old woman with hypoaesthesia and weakness in the legs and arms. New England Journal of Medicine 2017, Volume 377, Issue 20 November 16, 2017, pages 1977-1984, DOI: 10.1056 / NEJMcpc1710564
  3. ↑ a b c Danielle L. Saly, Ursula C. Brewster, Gordon K. Sze, Elan D. Louis, Anushree C. Shirali: An element of unsteadiness. New England Journal of Medicine 2017, Volume 377, Issue 14, October 5, 2017, pages 1379-1385, DOI: 10.1056 / NEJMcps1701934
  4. ^ Meinhard Classen , Volker Diehl , Kurt Kochsiek : Internal Medicine , Verlag Urban & Schwarzenberg , Munich 1991, ISBN 3-541-11671-4 , pages 766-767
  5. ↑ a b c d T. Kreutzig: Short textbook biochemistry. Urban & Fischer-Verlag, 2006, ISBN 3-437-41774-6 , pp. 186-187. (on-line)
  6. ↑ a b T. Brandenburger among others: Case book biochemistry. Georg Thieme Verlag, 2006, ISBN 3-13-140191-5 , pp. 45-46. (on-line)
  7. ↑ B. Schleper, HJ Stuerenburg: Copper deficiency-associated Myelopathy in a 46-year-old woman. In: Journal of neurology. Volume 248, Number 8, August 2001, pp. 705-706, ISSN  0340-5354 . PMID 11569901 .
  8. ↑ V. Kletzinsky include: Compendium of biochemistry. Volume 1–2, Verlag W. Braumüller, 1858, p. 49. (online)