Heavy metals are not musical, hard rock bands, but they are sometimes found in bands of hard rock. They are a group of about 40 electropositive elements that are natural constituents of the earth's crust and have a density greater than five. This somewhat arbitrary definition lumps together elements of widely different chemical properties and degrees of toxicity. For example, small amounts of zinc, iron or copper are essential for life, but each is toxic in excessive amounts. Molybdenum and titanium have very little biological activity, good or bad. Mercury, lead and cadmium are invariably toxic and a source of concern in the environment.
In the technical jargon, acute toxicity refers to the syndrome resulting from a single massive exposure to a poison. Chronic toxicity results from long term, low level exposure, perhaps over years, at a rate where no single dose would result in signs or symptoms of poisoning. Eventually, however, the cumulative body burden results in an intoxication syndrome. Chronic toxicity is a result of exposure to chemicals that have one or the other of two fundamental properties. Either they accumulate in the body as a result of repeated exposures, or they induce cumulative damage that is irreversible, or only very slowly reversible. Thus, the lesion outlasts the physical presence of the chemical. Carcinogens are the example par excellence of "hit and run" poisons that produce damage that may not be manifest for many years. Lead poisoning is invariably a chronic intoxication, but mercury can produce both acute and chronic forms of poisoning.
One of the most difficult concepts for the public to grasp is that there is no simple relationship between acute and chronic toxicity. A single large dose of cyanide can be rapidly fatal; yet, doses close to the single fatal dose can be tolerated indefinitely on a daily basis. That is because the body has an almost infinite capacity to repeatedly convert cyanide to thiocyanate, a less toxic chemical, and rapidly excrete it. If part of a single large dose of lead is actually retained instead of being dispelled by vomiting and defecation, it sometimes results in the slow development of a syndrome that is indistinguishable from the syndrome resulting from long term, low level exposure.
To further complicate matters, the chemical form of the metal greatly influences the course of the poisoning. Exposure to liquid, elemental mercury is quite a different kettle of fish from exposure to a salt, such as mercuric chloride, and neither is much like the syndrome produced by exposure to an organic form of mercury, such as methyl mercury. Although heavy metals may change their chemical form in the environment, they tend to persist in one form or another, and some constitute significant environmental hazards. They may taken up by lower life forms such as algae. When the algae are consumed by the next feeding level, the metal may become concentrated. This concentration as the metal is passed through natural food webs presents a special threat to the longer lived species at the top. They consume the most heavily contaminated food, and they do so over their longer life spans. They are us.
The story, "Cinnabar" can be found in Roueché, B., The Man Who Grew Two Breasts, Truman Talley Books/Plume, New York, New York, 1995.
As pointed out in the story, lead poisoning has been recognized since antiquity. There is some evidence that poisoning of epidemic proportions may have contributed to the downfall of the Roman Empire. It was the practice at that time to boil down fruit juices to make syrups in lead pots for flavoring other drink or food. In terms of human morbidity and mortality, lead poisoning is unquestionably the most important of the heavy metals in the United States. Whereas, we no longer use lead in water pipes or as pigments in household paints, these sources are still found in abundance in large city slums, and even in older middle-class suburban homes. We did not have a Lead Paint Poisoning Prevention Act until 1971, nearly a half century after Greece and Poland. In the words of one expert, lead poisoning could be eradicated "if we could eliminate slums". A geophagic subject was mentioned in the story. Pica as exhibited by many children includes not only earthy substances, but any abnormal material, such as lead-containing paint chips. A history of pica is a useful contribution to the diagnosis of lead poisoning.
Because of its ubiquitous distribution each of us carries an appreciable body burden of lead stored in our skeletons and, to some extent in soft tissues. Lead has properties in common with calcium in that it is a "bone seeker". If calcium absorption from the gastrointestinal tract is increased because of increased need, as in pregnancy, lead absorption is increased also. If calcium mobilization from the skeleton is increased, lead will be mobilized also. It was once thought that this lead store in bones and teeth was of no consequence when there were no clinical signs of lead poisoning. It has now been established through studies on primary (baby) teeth, that there are deleterious effects on cognitive function and classroom behavior of subclinical lead exposure in children. Some problems ascribed to "attention deficit disorder" are possibly due to low level lead exposure.
In an odd chapter of biomedical progress, the investigator in this landmark study on primary teeth was accused of scientific misconduct in a suit brought by parties with connections to the lead industry. After twelve years of rancorous feuding over the investigator's methods, the Office of Scientific Integrity of the National Institutes of Health asked the University of Pittsburg to initiate a misconduct probe. It was one of the first such actions initiated by the National Institutes of Health. There were many aspects to this case that had a chilling effect on investigative scientists in the United States, including the very long delay between the actual conduct of the study and the hearing. During that period the original data had undergone extensive scientific review by many agencies. The study was initially conducted under the auspices of Harvard University, yet the hearing was at the University of Pittsburg, where the investigator had relocated. The OSI had not been in existence at the time of the study, and there were no rules about scientific misconduct at that time. According to the protocol drawn up by Pittsburg, requests for such actions were supposed to be initiated within the institution, not by OSI. Finally, several other studies in the interim had not only corroborated the original conclusions, but extended them to even lower levels of lead exposure. Thus, the conclusions were a moot point, and the allegations of misconduct concerned only the methods by which this particular investigator reached those conclusions. Fortunately, the accused was eventually cleared of all charges, and the procedures for initiating misconduct allegations were thoroughly revised. If the IQ difference between the "high" and "low" lead exposed groups was only five points, it would have little change in outcome on the "normal" range of IQs. However, at the extremes of IQ there could be a three-fold increase in retardation, and a loss of two-thirds of the extremely gifted (J. Pharmacol. Exp. Therap. 285:942, 1998).
Tetraethyl lead is a particularly virulent neurotoxin that penetrates rapidly the intact skin and the blood brain barrier to produce insomnia, fatigue, nightmares, weakness, staggering gait, tremors, psychosis, and convulsions. Such signs and symptoms are also seen as a consequence of inorganic lead exposure in young children, and more rarely in adults. The end stages often involve cerebral edema and hydrocephalus. The treatment of these conditions is still unsatisfactory, and patients have a high mortality or incur permanent brain damage. Before leaded gasoline was banned in the United States in 1983, teenage "sniffers" contracted poisonings when tetraethyl lead vapors were inhaled along with the hydrocarbons in gasoline.
At one time tetraethyl lead accounted for as much as twenty per cent of the total lead production in the United States, but because it was exhausted directly into the atmosphere, leaded gasoline may well have been the major source of environmental contamination. Recent measurements showing that atmospheric lead levels had declined by 90% indicate the success of the ban. Another source associated with automobiles, the storage battery, not only remains, but may increase in the future depending on the popularity of electric cars, and on our ability to find a substitute for the traditional lead storage battery. Another way in which automobiles may be involved indirectly in lead poisoning is through their radiators, which often have been soldered or brazed with lead-containing materials. Such radiators may be reincarnated as serviceable condensers for illicit stills. It is thought that the majority of the moonshine produced in the United States is contaminated with lead. Poisonings have also occurred as a result of lead bullets or shot left in the body in inoperable areas months or years after the shooting.
The clinical course of Mrs. McBride is more typical of moderate to severe, inorganic, lead poisoning in adults. The anemia, which was so prominent in her case, has several causes. Lead interferes to varying degrees at many points in the biosynthetic pathway for heme, needed for red cell hemoglobin. It interferes with iron transport to ferrochelatase, which normally inserts the iron into the porphyrin ring, and the enzyme begins inserting zinc instead. Abnormal zinc porphyrins then accumulate. Red cell production may not be able to keep pace with peripheral destruction, and cells that are released to the circulation may be pale, because of a low hemoglobin content, and other defects. In an effort to boost red cell production, the marrow begins exporting immature cells to the blood (reticulocytosis). Basophilic stippling represents an aggregation of ribosomes, which occurs in normal red cells during fixing and staining. In lead poisoning and thalassemia, the ribosomes have a greater tendency to aggregate during the same processes, so that the granules are larger and may be referred to as coarse basophilic stippling. Lead induces changes in red cell membrane proteins making the cells more fragile. Such cells are apt to be destroyed in the spleen. They are not pliable enough to fit through narrow channels lined with white cells, whose mission it is to eliminate older or defective red cells. Thus, Mrs. McBride's spleen, in trying to do its normal job, was actually working against her to cause the anemia. This increased activity of the spleen, resulted in an increase in its size (splenomegaly), and Dr. Wallace was able to feel it through the abdominal wall. The anemia of lead poisoning is therefore, a result of both decreased red cell production and increased red cell destruction.
Lead has a "spasmogenic" effect on the intestines and vascular smooth muscle. Intestinal spasms were the cause of Mrs. McBride's painful cramps. Contraction of vascular smooth muscle together with the anemia accounts for a frequently observed pallor. There is also skeletal muscle weakness apparently due to an incompletely understood impairment of cholinergic transmission at the myoneural junction. Wrist drop is a common sign in adult lead poisoning. Although neither seems to have occurred in Mrs. McBride, hypertension is a frequent complication of lead poisoning, and kidney damage happens occasionally
Mrs. McBride had several relapses even after her exposure to lead had been terminated. These were undoubtedly caused by the mobilization of skeletal lead stores for one reason or another. When she was given a blood transfusion, her blood concentration of lead must have fallen. The blood concentration exists in equilibrium with the concentration in bone, so bone lead was released to bring the blood concentration back to equilibrium. Similarly, chelation therapy lowered the blood concentration, and resulted in lead mobilization, at least until the bone stores were depleted relative to the blood concentration.
Chelating agents are tricky to design. For one thing, they must have a higher affinity for the heavy metal in question than natural binding sites in the body. If that is not true, the chelator simply won't work. There are many chemically different binding sites for heavy metals in the body, and with time, the metal will shift from lower affinity binding sites to higher affinity binding sites. Thus, the longer the metal is in the body, the more intense becomes the competition between chelator and endogenous binding. As a general rule, the earlier chelation therapy is attempted, the more successful it is apt to be.
Secondly, the chelator must bind the toxic heavy metal specifically, over natural and essential elements such as iron. If that is not true, a deficiency syndrome may be precipitated concomitant with the intoxication syndrome. Let us call the lead chelator "edetate" for short. The story points out that it is given in lead poisoning in the form of a disodium/calcium salt. Salts of organic chemicals are more soluble in water than free forms. Edetate prefers lead to calcium, but it can still bind calcium tightly. If given only as the sodium salt, it may encounter calcium first, chelate it, and be excreted in the urine. This could result in dangerously low blood levels of calcium. When lead is encountered by the preformed calcium salt, the lead displaces calcium. The body is easily able to deal with any excess calcium in blood. Finally, the chelator should have as few toxic "side effects" as possible, and that is always difficult to avoid. Edetate does have occasional toxic side effects, and the risks of any drug must be weighed against the potential benefits.
Edetate does not penetrate the blood brain barrier, and, thus, it is of little value in removing lead from the brain in young children and the occasional adult, who has central nervous system involvement. In such cases, another chelator, BAL, which crosses the blood brain barrier, is sometimes used in combination with edetate. Neither of these chelators is effective against organolead compounds, such as tetraethyl lead, which does not bear an electrochemical charge.
The Eagle-Pitcher Industries, Inc. of Cincinnati went bankrupt in 1996, because of a series of lawsuits involving personal injuries alleged to have been caused by asbestos products and lead-based pigments made by the firm. A $680 million dollar trust fund was created from their assets of which $2.5 million was set aside for research on lead poisoning. The trustees recently requested proposals for methods to link the pigments in lead paint samples to a specific date of production and one of the half-dozen companies that might have manufactured it. Such precise identification would help to determine who should receive compensation and who should be responsible for providing it. Isotopic ratios of lead have already been used in attempts to identify the mines from which lead samples originated, but whether or not this technology can be applied to the identification of specific manufacturers is questionable.
Hungarians are the world's leading producers, consumers and exporters of paprika. Government licensed mills in southern Hungary produce products that are regularly tested. In 1994, government officials discovered some paprika marketed locally was adulterated with lead oxide, a red to red-yellow pigment. At least fifty people were hospitalized with intestinal cramps, paralysis and other signs of lead poisoning. Unscrupulous private manufacturers had added the lead pigment to heighten the color of the paprika, which is an indication of its freshness. There may be hazards to the unrestrained consumption of goulash, but presumably lead poisoning is no longer one of them.
The explanation for how the cinnabar came to be contaminated with lead that satisfied Dr. Fischbein and Dr. Wallace, namely that it was deliberately added to increase the weight (density) of the cinnabar to increase its market value, seems rather unlikely when one actually does the mathematics. According to the 73rd edition of the CRC Handbook of Chemistry and Physics, the density of cinnabar (mercuric sulfide) is 8.1 (g/ml), whereas the density of red lead (lead tetroxide) is 9.1. If 99 parts of cinnabar are mixed with 1 part of red lead, the density of the mixture would be 8.11. That would be a trivial increase in density of 0.1%; hardly a profitable alteration. Cinnabar is a mineral, not a pure chemical substance. Minerals often contain natural contaminants, and the contaminants vary from deposit to deposit. It seems far more likely that the cinnabar was contaminated with red lead even before it was extracted from its deposit.
Goyer, R. R. Lead toxicity: Current Concerns. Environ. Health Perspect. 100:177-187, 1993.
The story, "The Huckleby Hogs" can be found in Roueché, B., The Medical Detectives, Truman Talley Books/Plume, New York, New York, 1991.
Also found in Rouché, B., The Orange Man and Other Narratives of Medical Detection, Little Brown and Company, 1971. (Out of Print)
"The Huckleby Hogs" Addendum
Mercury is found in many natural sources such as coal. Thus, it is a part of the emissions from coal-burning power plants, but combustion of almost any material as in waste incinerators is apt to release elemental mercury to the atmosphere where it is distributed globally. On return to the earth, in aquatic environments it is converted to inorganic mercury. and this can be converted to organic forms by microorganisms.
All forms of mercury are toxic, but it is a chameleon among poisons. As pointed out in the story the inorganic salts produce very different syndromes depending on whether the exposure is due to a single large dose (acute), or multiple small doses (chronic). Neither of these clinical pictures is quite like methylmercury poisoning. Liquid elemental mercury is also a horse of a different color. It is sufficiently volatile, that poisonings most commonly occur as a result of inhalation of the vapors. It is not absorbed from the gastrointestinal tract. The signs referable to mercury vapor exposure are initially those of central nervous system involvement with late kidney damage. Disturbed individuals have injected themselves intravenously with liquid mercury. If one survives the acute insult, which may result in a fatal pulmonary embolism, lung X-rays show a bizarre distribution of small opaque bodies, as if the patient had been shotgunned. Today, mercury thermometers and other laboratory apparatus that used the liquid form have largely been replaced with alternatives.
Dental amalgams contain silver, copper, tin and mercury. Under the pressures of chewing small amounts of mercury vapor are released. Although no adverse health effects have ever be demonstrated from amalgams, some unscrupulous dentists have persuaded patients to have all such fillings replaced with gold, ceramic or porcelain. The poisonings among dentists and hygienists that have resulted from amalgams have arisen from discarded material that accumulated in sink traps or behind cabinets and released mercury vapor for inhalation.
The citizens of the United States have been extremely fortunate in that this story details the circumstances of the only "mini-epidemic" of methylmercury poisoning within our borders. Other nations have not been so lucky. The episode in Minamata Bay, Japan, first recognized in 1958, was not, as indicated in the story associated with the discharge of "organic-mercury-containing effluent from chemical factories". The industries were actually discharging inorganic mercury wastes. Anaerobic bacteria in the detritus on the floor of the bay were able to convert inorganic mercury into methylmercury. The methylmercury became concentrated as it was passed along natural food webs. It found its way into fish and shellfish that were consumed by people living around the bay. The biomagnification in food chains may be as high as a millionfold, and today the only source of methylmercury exposure in humans is through food.
The Alamogordo incident was in 1970. In 1971-72, a major outbreak occurred in Iraq in which 6,530 persons were hospitalized and almost 500 died. The circumstances were somewhat like those of the cases in the United States. In a well-intentioned humane response to famine in Iraq, several nations shipped wheat grain intended for planting. Just as in this story, the seeds had been treated with a methylmercury-containing fungicide to hold down mold growth and preserve the viability of the seeds. The seeds were also dyed red to serve as a warning, and attempts were made to inform the natives of the hazards of eating the seeds directly. Unfortunately, the warnings on the bags were in Spanish, because some of the grain had originated in Mexico, and the skull and crossbones, recognized by westerners as meaning poison, meant nothing to the Iraqis. In the face of starvation many families milled the seeds directly into flour, and made and consumed the contaminated bread. There would have been no danger in eating grain grown from the treated seeds, because the subsequent crop would contain little or no methylmercury. As indicated in the story, the use of methylmercury as a fungicide was suspended, and since this was the only commercial use for the chemical, it is no longer manufactured in the United States. It is, however, still found in the environment as a result of bacterial methylation of inorganic mercury.
There are a number of populations in the world consuming mercury contaminated fish that are at risk. One example is the indigenous population of the province of eastern Quebec, Canada, consisting of Cree and Inuit Native Americans. Some of these were displaced in a huge project to develop hydroelectric power. During the James Bay project by Hydro-Québec, the rerouting of rivers and massive flooding of previously dry lands mobilized environmental mercury that had always been in the soil. Bacterial action resulted in the transformation of some of that pool into methylmercury, and it began to accumulate in natural food chains. Much of this population exists at a subsistence level, and freshwater fish are a staple in their diet. The provincial government has been forced to institute monitoring programs of hair analyses to protect this population.
Methylmercury is also found in saltwater fish, again posing a dilemma to public health officials. The health benefits of even modest fish consumption are well known, particularly in the prevention of cardiovascular disease, so there is a delicate balance between achieving those benefits and the risk of chronic intoxication. The Native American population of Quebec consume fish primarily during the summer months, and the mercury content of their hair reflects peak concentrations during the summer and valleys during the winter. In contrast, populations that depend on ocean fish as their main source of protein tend to have relatively stable elevated levels of mercury in their hair. Fortunately, limited studies in both types of consumers suggest that they are not exhibiting even the most subtle signs of poisoning.
Methylmercury is a virulent teratogen, and infants in utero may be ten times more sensitive to it than adults. Mrs. Huckleby's baby had a violent convulsion shortly after birth, and later developed an irreversible syndrome similar to cerebral palsy. The developmental defects are believed to be due to the induction of abnormal migration patterns of nerves, and deranged organization of neuronal clusters in the brain. The neurotoxic effects in adults are less well understood, but may be related to binding to sulfhydryl groups or an interference with DNA and RNA synthesis.
Twenty-two years after this incident all surviving members of the family were carefully examined and tested. In this interim the two youngest children had died, and autopsy and toxicological findings were available from one of these. Both were left in a vegetative state until their deaths. Some recovery did occur in the older children, but the visual defects including blindness in one and constricted visual fields in the other did not improve. Neither parent showed signs of poisoning, although both were exposed. Toxicological studies suggested that methylmercury, which readily crosses the blood-brain-barrier, is converted to inorganic mercury in the brain. Since inorganic mercury does not readily cross biological membranes, it is effectively trapped in the brain, but it is not clear which of the two species is responsible for the brain pathology.
Although chelation therapy is effective in inorganic mercury and lead (as indicated in "Cinnabar") poisoning, it is not particularly helpful in methylmercury poisoning. Methylmercury is excreted in the bile, and subsequently reabsorbed from the intestine (enterohepatic recycling). This process can be interrupted by surgically inducing gall bladder drainage. Nonabsorbable resins that bind methyl-mercury to enhance intestinal excretion were used with some success in Iraq, but they are no longer commercially available.
In August of 1996, a much admired professor of chemistry at Dartmouth College was using as a reagent, a very similar compound, dimethylmercury. She spilled a tiny drop of the liquid on her LatexR glove. She washed her hands, cleaned up the lab, and went home. In January, five months after the initial exposure, she was taken to the hospital after several episodes of bumping into doors, unsteady gait, falls and difficulty in speaking. Chemical analysis of blood samples confirmed the presence of mercury. Indeed, the technology is such that mercury concentrations along the length of a single shaft of hair can be determined. Knowing the normal rate of hair growth, the exposure can be pinpointed in time. The measurements confirmed a single exposure five months previously. Despite heroic intervention, she died within a few weeks. It was later determined that LatexR gloves, intended to prevent the transmission of bacteria and viruses, afforded no more protection against dimethylmercury "than a KleenexR".
This tragic case and others from the literature illustrate certain principles. Even a single, brief skin exposure to dimethylmercury can be fatal. After absorption, dimethylmercury is converted to methylmercury in the body, hence, the striking similarities between the two intoxication syndromes. Methylmercury finds its way into hair surprisingly quickly. The half-life of uptake into hair is about 6 days, whereas the half-life in the body is about 80 days. Although chelation therapy increased the urinary excretion and shortened the half-life, it appeared to be of little or no clinical benefit. Still unanswered are questions about the reason(s) for the long delay in this case between the exposure and the appearance of clinical signs and symptoms, and the wide, apparently individual differences in sensitivity to absorbed methylmercury alluded to in the story and illustrated by the Huckleby family.
Nierenberg, D. W., R. E. Nordgren, M. B. Chang, R. W. Siegler, M. B. Blayney, F. Hochberg, T. Y. Toribara, E. Cernichiari and T. Clarkson. Delayed cerebellar disease and death after accidental exposure to dimethylmercury. New Engl. J. Med. 338:1672-1676, 1998.
Davis, L. E., M. Kornfield, H. S. Mooney, K. J. Fiedler, K. Y. Haaland, W. W. Orrison, E. Cernichiari and T. W. Clarkson. Methylmercury poisoning: long-term clinical, radiological, toxicological and pathological studies of an affected family. Ann. Neurol. 35:680-688, 1994.
The story, "Live and Let Live" can be found in Roueché, B., The Medical Detectives, Truman Talley Books/Plume, New York, New York, 1991.
"Live and Let Live" Addendum
If one starts out feeding a diet that is entirely free of copper to pigs or sheep (below), the animals will all eventually die. If one adds a small amount of copper to the diet, the animals will survive, but they will exhibit suboptimal growth and development (copper deficiency state). If more copper is added, a concentration will eventually be reached that is optimal for normal growth and development, and the animals will flourish. The addition of still more copper will result in accumulation, and signs of copper poisoning. A sufficiently high concentration in the diet will eventually result in death. This is typical for essential trace elements that also have toxic effects. It would also be true of iron. It is a gloomy bell-shaped curve with death at either extreme.
A single large dose of copper results in a somewhat different syndrome. The first signs are gastrointestinal with prompt vomiting. Copper was once used an emetic agent. There is burning pain in the mouth, throat and stomach. Diarrhea with colicky pain may be delayed. There are signs of circulatory shock, which can result in death. If the victim survives the shock phase, they may die as a result of liver or kidney failure. Suicidal ingestion of copper salts is common in undeveloped countries for want of more sophisticated poisons.
The history of Mrs. Terry is eerily reminiscent of the unfortunate circumstances surrounding Sheila Allen in "Hoofbeats of a Zebra". Once a suspicion of a psychiatric disorder gets into a patient's medical records, it can have an unfortunate effect on subsequent consultations. Should that suspicion be repeated again by others, the stain becomes almost indelible. Not only was the true diagnosis delayed, but Mrs. Terry was subjected to expensive drug therapy, which helped little and may have caused harm. ThorazineR (chlorpromazine) was among the first of the synthetic antipsychotic drugs. As pointed out in the story, it has antimuscarinic side effects, and in large doses a normal person should have dry mouth ("Something a Little Unusual") instead of drooling. TofranilR (imipramine) is used to treat depression, as also is electroshock. SinequanR (doxepin) is a somewhat similar antidepressant. l-DOPA (levodopa) is used in the management of Parkinson's disease. There were some features in this patient that resemble signs in parkinsonism such as the mask-like face and the "pill-rolling" tremor of the fingers. Moreover, one of the places where copper particularly concentrates in the brain is a region known as the basal ganglion. This structure is specifically affected in parkinsonism. The lack of a dramatic response to levodopa, however, ruled out parkinsonism.
In addition to the basal ganglion, excessive copper is also stored in the rear of the cornea of the eye as golden deposits (Kayser-Fleischer rings). These depots do not interfere with vision, but they often indicate that the copper has already caused brain damage. They are often first discovered during routine eye examinations. The liver, however, is the first organ to begin copper storage, and some type of liver damage is usually the first clinical manifestation. This sign most commonly appears in mid-adolescence, and many patients die of some form of liver failure. Mrs. Terry's liver involvement, e. g., elevated SGOT, was noted on every one of her hospitalizations, but either ignored or misinterpreted.
For those patients who do not present initially with liver disease, the next most common clinical manifestations are neurologic or psychiatric. As already indicated, some of the neurologic signs are reminiscent of parkinsonism: resting and intention tremors, rigidity, and drooling. Most patients with neurologic signs also have psychiatric disturbances. These may resemble some forms of schizophrenia or manic depressive psychoses. Most commonly, however, they exhibit bizarre behavior that cannot be classified. Hence, Mrs. Terry's inexplicable attempt at suicide. While there are never psychiatric complications of myasthenia gravis ("Hoofbeats of a Zebra"), they are to be expected in Wilson's disease.
Only a small fraction of dietary copper is essential for normal growth and development. Recently absorbed copper is transported from the intestine to the liver in the blood plasma by albumin, transcuprein and ceruloplasmin. Later, copper is also transported by ceruloplasmin from the liver to other organs. Liver copper is also excreted in the bile, apparently in a form that resists reabsorption. Both copper and ceruloplasmin are also found in cerebrospinal and amniotic fluids.
In patient's with Wilson's disease, copper accumulates in the liver. A specific copper-transporting protein (copper-ATPase) in the liver is thought to be involved in the biliary excretion of copper, but the exact details are still lacking. It is apparently the absence of this specific protein in Wilson's disease that is critical, not the characteristically low plasma levels of ceruloplasmin. The latter may be only an incidental finding. When the liver can store no more copper, it escapes to the blood, with disastrous consequences for the central nervous system. Normal infants under one year of age have low ceruloplasmin levels in plasma and high liver levels of copper. Both of these move toward normal adult levels over the first year of life. In infants with Wilson's disease these abnormalities continue throughout life.
Although BAL treatment first proved the point that the usually inexorable course of the disease can be reversed by chelation therapy, it is so unpleasant to the patient, that it has been replaced entirely by penicillamine. Potassium sulfide is no longer used as part of the treatment regimen. In the body potassium sulfide is converted immediately to hydrogen sulfide, a gas that is as highly toxic as hydrogen cyanide, acts by the same mechanism and shares a common antidote, sodium nitrite (addendum to "Eleven Blue Men"). Fortunately, the body has the capacity to inactivate both of these poisons rapidly. So long as a critical threshold dose is not reached, small doses of either can be given almost indefinitely. Never-the-less, Wilson's disease can be satisfactorily managed by penicillamine alone. Penicillamine causes pyridoxine (vitamin b6) deficiency, so pyridoxine is given at the same time. In some patients, penicillamine can cause life-threatening side effects such as bone marrow damage. In that situation, another chelator, trientine, should be substituted for penicillamine.
Trientine was one of the first products to result from the so-called orphan drug amendment of 1983 to the Federal Food, Drug and Cosmetic Act. Orphan drugs are effective or even life-saving in rare diseases. Because the diseases are rare, the market for the drug is small. Perhaps so small that the manufacturer may not even be able to recover the costs of research and development, let alone make a profit. The amendment provided financial incentives for the development of drugs for which less than 200,000 patients may have the disease at any one time. The world-wide incidence of Wilson's disease is about 1 in 30,000. It occurs in every ethnic and geographic population. In the United States today that amounts to something on the order of 9,000 cases. Chelation therapy with either agent must be continued for life. Compliant patients can be maintained indefinitely in a disease-free remission.
Hereditary hemochromatosis is a disease that is analogous to Wilson's disease with the accumulation of excessive levels of iron in the liver and other organs. The disease is caused by an inappropriate level of iron absorption from the intestine. In normal people, iron absorption from the gut is tightly regulated in such a way that iron absorption is equal to iron losses from the body. The basic defect leading to increased iron absorption in hemochromatosis is unknown. If the condition is untreated patients die from heart failure, liver failure or liver cancer. Deferoxamine is a highly effective iron chelator, but when given in doses that can be safely tolerated, it removes only a fraction of the iron that can be gotten out by once weekly donations of a unit of blood. The hemoglobin in that one pint unit contains 250 mg of iron.
Linder, M. C., L. Wooten, P. Cervza, S. Cotton, R. Shulze and N. Lomeli. Copper transport. Am. J. Clin. Nutr. 67 (suppl), 965S-971S. 1998.
Bingham, M. J., T.-J. Ong, K. H. Summer, R. B. Middleton and H. J. McArdle. Physiologic function of the Wilson disease gene product, ATP7B. Am. J. Clin. Nutr. 67 (suppl), 982S-987S, 1998.