An 11-year-old boy develops vomiting, weakness, weight loss and a neck mass

Michael Shannon
Children's Hospital
Boston, MA

Int J Med Toxicol 1998; 1(2): 14

These case conferences are supported by a grant from Orphan Medical, Inc.

See also NEW CASE - SUMMARY - 1998; 1(2): 13, NEW CASE - FURTHER DISCUSSION - 1998; 1(2): 15

In summary this 11 year old boy with blindness and developmental delay presented with a three week history of vomiting, a 5-10 pound weight loss and a 2 week history of fatigue, anorexia and an enlarging midline neck mass. Upon presentation to the emergency department he was noted to be tachycardic and tachypneic, but afebrile and normotensive. He displayed evidence of moderate dehydration (sunken eyes, tachycardia). He was also noted to have hepatomegaly and a midline neck mass that was almost certainly thyroid tissue. Laboratory tests were remarkable for polycythemia, a mild compensated, anion gap metabolic acidosis (pH 7.36, PCO2 27 mm Hg and serum bicarbonate 13 mEq/L) with surprisingly normal renal function tests (BUN, creatinine and urinalysis) that contradicted the clinical diagnosis of severe dehydration. The day following his admission, the child developed worsening acidosis and manifestations of congestive heart failure with a gallop, cardiomegaly, left ventricular dilation and a diminished shortening fraction. These findings led to the diagnosis of thyrotoxicosis and prompted the administration of propranolol. However, this pharmacotherapy failed to improve his clinical status; in fact his metabolic acidosis and congestive heart failure worsened. Surprisingly, his thyroid function tests subsequently revealed a low thyroxine (2.4 µg/dL, normal 5-11 µg/dL) and a elevated TSH (26 µU/mL, normal 0.4-4.8 µU/mL).

Many of the clinical features of this case including the fatigue, enlarging neck mass and thyroid hormone profile were consistent with the diagnosis of primary hypothyroidism presenting as goiter. Goiter or thyroid enlargement results from inadequate production of thyroid hormone with inhibition of the negative feedback loop to the central nervous system, resulting in increased secretion of thyroid stimulating hormone. Increased TSH secretion produces hyperplasia of the thyroid follicles, manifested as neck swelling. Goiter, a once epidemic disease results most commonly from inadequate dietary intake of iodine, the mineral which is the essential precursor to thyroid hormone production. Before the addition of iodine to salt, “goiter belts” were prevalent around the world. The child's developmental delay might have some importance in explaining etiology; children with such handicaps often have unusual or restrictive diets which can lead to nutritional diseases such as hypothyroidism or rickets. Medical conditions associated with hypothyroidism include autoimmune thyroiditis (which is relatively uncommon in males) and infiltrative diseases of thyroid such as histiocytosis X.

In addition to iodine deficiency there are medications and environmental toxins which can produce hypothyroidism. These so-called goitrogens include pharmaceutical agents that inhibit iodide transport into the thyroid (e.g., thiocyanate) those that inhibit iodide organification (propylthiouracil, sulfonamides, methimazole), those that inhibit thyroid hormone release (lithium), and drugs that induce hepatic microsomal enzymes, thereby increasing metabolism of thyroid hormone (e.g., barbiturates, steroids, calcium channel blockers, polychlorinated biphenyls and chlorinated hydrocarbons such as DDT or chlordane). Other agents which can produce hypothyroidism after repeated use are radioactive iodine, amiodarone, iodinated contrast agents, and iodine-containing antiseptics such as povidone-iodine (Betadine). Finally, intoxications by metals and minerals including copper, zinc, cobalt and even iodide itself can produce hypothyroidism. There is no history of exposure to any of the above mentioned agents in the child's past medical history.

Despite clinical and laboratory evidence of hypothyroidism the boy had several findings atypical for this diagnosis. First, his degree of vomiting was greater than that normally associated with thyroid deficiency. He was not described as having the coarse hair, diminished reflexes and hypothermia that are characteristic of hypothyroidism. His tachycardia, tachypnea and congestive heart failure were more consistent with thyrotoxicosis, a life-threatening endocrine emergency that carries substantial morbidity. It is undoubtedly because he had features of hyperthyroidism that propranolol therapy was initiated since this diagnosis has a worse prognosis if not promptly treated.

The elevated hematocrit was an extremely unusual finding which could not be accounted for by hemoconcentration from intravascular fluid loss. In children, polycythemia typically results from chronic cardiopulmonary disease. For example, congenital heart diseases which produce left-to-right shunting such as tetralogy of Fallot, truncus arteriosus, transposition of the great vessels and total anomalous pulmonary venous return can all produce an elevated hematocrit if uncorrected. Although he was indeed found to have a congestive cardiomyopathy, there was no past history suggestive of cyanotic heart disease and he had no murmur (although cardiac lesions such as total anomalous pulmonary venous return can produce cyanosis without a murmur). Chronic lung diseases such as cystic fibrosis can also lead to polycythemia as progressive lung failure ensues. Again the absence of a past history suggestive of cardiopulmonary disease makes these medical diagnoses unlikely.

In terms of his apparently new-onset cardiomyopathy there are again a number of diagnostic possibilities. These include infectious illnesses such as myocarditis, metabolic abnormalities such as mitochondrial defects, nutritional deficiency such as beriberi (thiamine deficiency) and drug intoxication. Common causes of toxin induced cardiomyopathy are ethanol, amphetamines, cocaine, arsenic, and selenium, none of which are completely consistent with the child's clinical picture.

Finally, he had a worsening metabolic acidosis which was unexplained. The differential for metabolic acidosis is also extensive with the most common etiologies being medical illnesses such as uremia (renal failure), diabetic ketoacidosis and shock, none of which seemed to be present. Exogenous sources are also numerous but include methanol, salicylates, and ethylene glycol. Again, there is no history of exposure to toxins and his clinical findings did not fit any of these poisonings.

Among toxins which can produce such an unusual constellation of features, the poisoning which most closely fits this child's illness is cobalt intoxication, which is the likely diagnosis in this case. With an atomic weight of 58.933 and an atomic number of 27, cobalt is found in the first transition section of the periodic table. Cobalt is extensively mined because of valuable properties including high resistance to high temperatures and ferromagnetic properties. In the industrial setting cobalt is used in the production of superalloys designed to withstand high temperatures (e.g., those found in jet aircraft, machine tools and construction equipment). Because of its ferromagnetic features, cobalt is also commonly used in the manufacture of magnets.

Cobalt is also an essential micronutrient, contained in cyanocobalamin (Vitamin B-12), the vitamin which protects against pernicious anemia. Before its toxicity was recognized, cobalt was once used widely as a pharmaceutical agent, prescribed to treat conditions of anemia such as renal failure, sickle cell disease and thalassemia; goiter was a recognized complication of this therapy when given to children with sickle cell disease. The metal appeared to have a large margin of safety which permitted ingestion of large amounts daily. Fatalities from acute cobalt overdose have been reported only rarely.

Cases of chronic cobalt intoxication can be found throughout the 20th century medical literature. The classic toxidrome which has come to be associated with cobalt poisoning is the tetrad of goiter, polycythemia, cardiomyopathy and metabolic acidosis. Historically cobalt was responsible for many epidemics of cardiomyopathy because of the once widespread practice of adding the metal to beer as a foam stabilizer. This was done because the advent of soaps and detergents used to clean beer mugs rapidly resulted in a loss of the beer's “head”. Clusters of idiopathic cardiomyopathy among beer drinkers occurred in Nebraska, Belgium, Quebec and other countries from 1930-1970 without identification of an etiologic agent. Initially attributed to ethanol-induced myocardial toxicity or beriberi this cardiomyopathy was finally traced to the addition of cobalt sulfate to the beer. The syndrome disappeared once cobalt was removed from beer in the 1970s. Victims of beer cardiomyopathy also had a remarkable degree of polycythemia, metabolic acidosis and enlarged thyroid glands, leading to the term “cobalt-induced goiters”.

Mechanisms of cobalt toxicity are only partially explained. It is known that this metal inhibits conversion of pyruvate to acetyl CoA and blocks certain Krebs cycle enzymes; these effects result in metabolic acidosis. Cobalt blocks iodine uptake into the thyroid resulting in functional iodine deficiency, resulting in increased TSH stimulation and thyroid hyperplasia; however, cobalt has also been theorized to inhibit tyrosine iodinase, reducing synthesis of thyroid hormone by this mechanism. Cobalt is known to deposit in the myocardium where it impairs myocardial contractility and produces cardiomyopathy. The polycythemia of cobalt intoxication is the result of stimulation of erythropoietin production.

In terms of providing an explanation for the appearance of cobalt intoxication in a child whose past medical history is remarkable for visual impairment and developmental delay, the likely etiology is pica (repetitive ingestion of non-nutritive objects). Children who have developmental delay often have pica which is aggressive and persistent. I suspect that the child was ingesting a cobalt containing substance. The most common cobalt containing material found in a home would be magnets, for example from electronic parts (e.g., a small speaker). Another possibility is his parents were administering a cobalt-containing alternative medicine (although I am not aware of any such product in existence).

The diagnosis of cobalt intoxication is best established by measurement of urinary cobalt concentration since kidneys are a major route of this metal's elimination from the body. Normal urinary cobalt concentrations in adults are 0.1-0.2 ng/mL. Serum cobalt levels can also be measured; the normal range is 2-17 nmol/L. Another potentially valuable diagnostic tool in this case would be an abdominal X-ray in search of radiodense material consistent with cobalt. Parenthetically, radiographic imaging with magnetic resonance in someone who has ingested ferromagnetic elements (iron, nickel, or cobalt) would be disastrous.

Treatment of cobalt intoxication involves a termination of exposure and, if warranted on the basis of clinical illness, chelation therapy. Both CaNa2EDTA and dimercaprol (BAL) have been shown in animal models to be effective chelators of cobalt. However, there is limited experience in humans with chelation therapy for this intoxication and its efficacy has not been rigorously proven outside of animal studies. Nonetheless in this patient, a brief trial of CaNa2EDTA might produce salutary results in terms of improving cardiac contractility.

In summary, this case is most consistent with chronic or sub-acute cobalt intoxication. In a child with developmental delay, this is best explained either by his ingestion of a cobalt containing agent or administration of an cobalt-containing alternative medicine by a parent. The test of choice would be an abdominal radiograph to identify radiopaque material and a urine collection for cobalt measurement. This would be followed by consultation with a toxicologist in order to discuss the potential value of chelation therapy. If there was evidence that the child had a retained abdominal foreign body a gastroenterology consultation for possible removal would be appropriate.

Clinical Diagnosis: Cobalt intoxication resulting in hypothyroidism, polycythemia, cardiomyopathy and metabolic acidosis.


Int J Med Toxicol 1998; 1(2): 14

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