Chiara Patelli
MAD HATTER SYNDROME
1. INTRODUCTION: MERCURY
Mercury in elemental form is a silver-colored metal that exists as a thick liquid at room temperature, familiar to most people as the silver liquid inside mercury thermometers. Mercury is transported in the environment by air and water, as well as by biological organisms through the food-chain. Off-gassed mercury vapour from the soil and water enters the air, where it may be transported and redistributed over the Earth’s surface. Upwelling along the continental shelves helps to bring minerals to the surface, where mercury can enter the air as a vapour, settle to the bottom sediment, be absorbed by phyto-plankton, or be ingested by zooplankton, other micro-organisms, or fish. Over geologic time, volcanic activity may bring mercury from below the Earth’s crust to the surface, where it may either enter the atmosphere as a vapour or be redistributed to soil or bodies of water. Mercury can chemically combine with other elements to form organic (carbon-containing) and inorganic (not containing carbon) compounds. Biotransformation of inorganic mercury to methyl-mercury by aqueous microorganisms is very important,as methylmercury bioaccumulates.
Mercury is a naturally-occurring metal that is used in man-made products and processes, and is emitted into air from industrial sources. Human exposure to mercury occurs from a variety of sources, e.g., breathing mercury-containing air, using commercial products that contain mercury, and ingesting some types of fish that contain methylmercury.
Inorganic mercury describes a category of mercury compounds that includes mercuric chloride, mercuric acetate, mercuric sulfide, and other compounds. Of the inorganic mercury compounds, mercuric chloride is more common than other compounds. Mercuric chloride is a white powder that is soluble in water. Exposure of children to inorganic mercury above levels of concern is uncommon, and most likely to occur following ingestion of items containing inorganic mercury, such as some batteries; or use of some homeopathic remedies or skin bleaching creams. Mercuric chloride exposure can be toxic to the kidney, stomach, and intestines and can lead to increased blood pressure. Experimental animal studies have shown embryotoxic effects, including increased rates of miscarriage and stillbirths, following mercuric acetate exposure or mercuric chloride exposure during pregnancy. Autoimmune kidney damage has also been reported in adult rats following mercuric chloride exposure. But mostly mercury is a neurotoxicant, and may affect many areas of the brain.
- Toxicological Profile for Mercury. 1999
- World Health Organization Geneva. 2003. “Concise International Chemical Assessment
Document 50 : Elemental Mercury and inorganic mercury compounds: human health aspects.”
2. NEUROTOXICITY
The central nervous system is probably the most sensitive target for elemental mercury vapour exposure. Similar effects are seen after all durations of exposure; however, the symptoms may intensify and/or become irreversible as exposure duration and/or concentration increase. A wide variety of cognitive, personality, sensory, and motor disturbances have been reported. Prominent symptoms include tremors (initially affecting the hands and sometimes spreading to other parts of the body), emotional lability (characterized by irritability, excessive shyness, confidence loss, and nervousness), insomnia, memory loss, neuromuscular changes (weakness, muscle atrophy, muscle twitching, electromyographic abnormalities), headaches, polyneuropathy (paraesthesia, stocking-glove sensory loss, hyperactive tendon reflexes, slowed sensory and motor nerve conduction velocities), and performance deficits in tests of cognitive function. Some long-term exposures to elemental mercury vapour have resulted in unsteady walking, poor concentration, tremulous speech, blurred vision, performance decrements in psychomotor skills (e.g., finger tapping, reduced hand–eye coordination), decreased nerve conduction, and other signs of neurotoxicity. Children and adults exposed to mercury, including inorganic mercury, have been reported to develop a disorder called acrodynia, or “pink disease”. Symptoms include leg cramps, irritability and redness and peeling of the skin of hands, nose, and soles of the feet; itching, fever, sweating, salivating, rashes, sleeplessness, and/or weakness have also been reported.
- titolo, ann
3. BIOMOLECULAR MECHANISM
Pyruvate dehydrogenase complex (PDC) is a complex of three enzymes that convert pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the citric acid cycle.
Pyruvate dehydrogenase (E1) is the first component and it performs the first two reactions within the PDC: a decarboxylation of pyruvate and a reductive acetylation of lipoic acid. Lipoic acid is covalently bound to dihydrolipoamide acetyltransferase (E2), which is the second catalytic component enzyme of PDC.
p=. 
Lipoic acid (LA), also known as α-lipoic acid and alpha lipoic acid (ALA) and thiotic acid is an organosulfur compound derived from octanoic acid, it is present in almost all foods, but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract and is essential for aerobic metabolism. As a cofactor, LA is covalently attached by an amide bond to a terminal lysine residue of the enzyme’s lipoyl domains that transfers acyl groups in 2-oxoacid dehydrogenase complexes.
In conclusion, higly toxic properties of mercury are due to the fact it leads binds with the sulfur groups of the lipoic acid mainly, so they can’t lead binds with acyls and neither ferry them on coenzyme A, causing the ending block of the pyruvate dehydrogenate complex.
- " I principi di biochimica di Lehninger " , David L. Nelson, Michael M. Cox,
Ed. Zanichelli, Giugno 2014
4. MAD HATTER SYNDROME
This peculiar preference for tiolic enzymes can explain the connection between the mercury poisoning and a particular syndrome called “mad hatter’s syndrome” indeed.
Mad hatter disease, or mad hatter syndrome, is a commonly used name for occupational chronic mercury poisoning among hatmakers whose felting work involved daily prolonged exposure to mercury vapours: the metal which accumulated within their bodies over time, causing some workers to develop dementia. The neurotoxic effects included tremor and the pathological shyness and irritability characteristic of erethism.
Use of inorganic mercury in the form of mercuric nitrate to treat the fur of small animals for the manufacture of felt hats seems to have begun in 17th-century France and from there spread to England by the end of the century with the Huguenots. By the Victorian era the hatters' condition had become proverbial, as reflected in popular expressions like "mad as a hatter", that was is a colloquial phrase used in conversation to refer to a crazy person.
To make felt, hatters separated fur from the skin of small animals with the use of mercury nitrate. In the process, the fur became darker, coiled and more easily removed. Prior to the use of mercury, hatters used urine (especially camel urine, but often their own) for this purpose, as the nitrogen-containing urea caused denaturation of the protein in the fur. Supposedly it was recognized that mercury would work well for this purpose when it was noticed that the urine of workers who were being treated for syphilis with mercury compounds consistently produced superior fur. It was recognized that this was due to mercury in the urine of these workers. The process was called “carroting” because the nitrous gas released from mercury nitrate turned the fur an orange color.
The first description of symptoms of mercury poisoning among hatters appears to have been made in St Petersburg, Russia, in 1829. In France, the National Academy of Medicine described the health hazards in 1869, and in 1898 a law was passed to protect hatmakers from the risks of mercury exposure. In Britain, mercury poisoning among hatters had become a rarity by the turn of the 20th century. In the United States, where the occupational illness was thoroughly described in New Jersey in 1860 by Addison Freeman in the Transaction of the Medical Society of New Jersey, the practice continued until 1941, when the United States Public Health Service banned the use of mercury in the felt industry in this country; mercury poisoning in the hatmaking industries of Danbury, Connecticut gave rise to the expression the Danbury shakes. Hatmakers in Tuscany, Italy, were also affected and exposed workers received financial compensation.
Symptoms and effects of the disease are commonly characterized through:
- behavioral changes and emotional disturbances such as marked irritability, low self-confidence, depression, apathy, and pathological shyness and timidity, and in some extreme cases with prolonged exposure to mercury vapors, mental confusion, delirium, hallucinations, dizziness and memory loss or also suicidal tendency and erethism (the set of neurological symptoms characteristically associated with mercury poisoning, because of people find it difficult to interact socially with others, with behaviors similar to that of a social phobia).
- Although most of the effects of erethism are neurological, some physical problems arise as well. Signs and symptoms can include red fingers, red toes, red cheeks, sweating, loss of hearing, bleeding from the ears and mouth, loss of appendages such as teeth, hair, and nails, lack of coordination, including a decrease in physical strength, headaches, general pain, as well as irregular heartbeat and tremors, called hatter’s shakes. With continuing exposure, a fine tremor develops, initially involving the hands and later spreading to the eyelids, lips, and tongue, causing violent muscular spasms in the most severe cases. The tremor is reflected in the handwriting which has a characteristic appearance. In milder cases, erethism and tremor regress slowly over a period of years following removal from exposure. Decreased nerve conduction velocity and kidney demage can also occur.
As we can see, symptoms are carefully described in the following article:
“The man affected is easily upset and embarrassed, loses all joy in life and lives in constant fear of being dismissed from his job. He has a sense of timidity and may lose self control before visitors. Thus, if one stops to watch such a man in a factory, he will sometimes throw down his tools and turn in anger on the intruder, saying he cannot work if watched. Occasionally a man is obliged to give up work because he can no longer take orders without losing his temper or, if he is a foreman, because he has no patience with men under him. Drowsiness, depression, loss of memory and insomnia may occur, but hallucinations, delusions and mania are rare.
The most characteristic symptom, though it is seldom the first to appear, is mercurial tremor. It is neither as fine nor as regular as that of hyperthyroidism. It may be interrupted every few minutes by coarse jerky movements. It usually begins in the fingers, but the eyelids, lips and tongue are affected early. As it progresses it passes to the arms and legs, so that it becomes very difficult for a man to walk about the workshop, and he may have to be guided to his bench. At this stage the condition is so obvious that it is known to the layman as "hatter's shakes."
Buckell et al, "Chronic Mercury Poisoning" (1946)
At last, talking about the mad hatter disease, we must mention Lewis Carroll and his 'Hatter' character from Alice's Adventures in Wonderland, 1865, which is of course the best-known mad hatter of them all. Many people think this occupational disease of hat makers, that was very common in England around Carroll’ time, clearly inspired the author in creating his character, with his erratic and flamboyant behavior. Furthermore, there are many other portrayals of “The Hatter” in the popular culture, for example the Tim Burton’s one in “Alice in Wonderland” movie, that were conditioned by this interpretation, in fact even the make up used by the character of the hatter, played by Johnny Depp, recalls in a way some symptomatic aspects typical of the mercury-intoxication, as the orange marks on the skin, around the eyes and in the fingernails, and of course the orange of his hair.
- Mad as a hatter
- Waldron HA (1983). "Did the Mad Hatter have mercury poisoning?".
British Medical Journal (Clinical Research Edition)
- Buckell et al, Chronic Mercury Poisoning (1946)
