Q: What is ouch-ouch or itai-itai disease? A: Itai-itai translated from Japanese is literally "ouch-ouch." It refers to a syndrome that principally consists of a painful skeletal condition resulting from weak and deformed bones. The disease is characterized initially by complaints of spinal and leg bone pain, and an increasingly waddling gait due to bone deformities. These symptoms can persist and typically progress for several years, until the patient is eventually unable to walk and becomes bedridden. The clinical symptoms then progress rapidly, with eventually severe debilitating pain, multiple bone fractures from even mild traumas such as coughing, severe skeletal deformities, anemia, and severe kidney problems, leading to death. Itai-itai disease was first recognized in the 1940s and is a unique condition largely restricted to older, postmenopausal women in Japan in the Jinzu river basin region. The precise cause of this disease and the reason for its specificity to this subpopulation remains under investigation. However, now a great deal is known about its development.
It has long been suspected that one primary contributor to itai-itai disease was chronic cadmium poisoning. Cadmium is a relatively rare, tin-white, malleable, ductile "modern metal," having been discovered in 1817, and with little use until the past 60 years. It is used in the plating of iron and steel to protect them from corrosion, in various pigments and dyes, in nickel-cadmium (NiCad) batteries, and in electronic applications. It can also be an inadvertent contaminant of ores of other metals. The residents of the Jinzu river basin region were first exposed to cadmium in the 1930s as a result of industrial contamination of the environment from nearby intensive mining activities. The mining resulted in substantial pollution of the local river waters, which in turn led to pollution of the rice fields downstream with very high cadmium levels in both the water and soil. Cadmium is readily taken up by rice and other plants and by people from dietary sources. Since rice was and still remains a principal dietary component in rural Japan, this led to significant exposure of the residents to very high cadmium levels over a long period of time.
Cadmium is unusual even among the toxic heavy metals because of its very long half-life within the human body. It takes over 30 years for the average adult to excrete half a single dose of cadmium. Chronic exposure can result in the buildup of very high levels even though the daily exposure is very low, and such levels can quickly lead to toxic consequences. The body stores cadmium in the liver, kidney, and other tissues in a special protein called metallothionein, which normally stores the essential metals zinc and copper. But cadmium binds metallothionein even more tightly and displaces these metals. Cadmium can also substitute for zinc, copper, and other biologically important metals in many of the critical proteins of the cell that use these elements for their normal function, resulting in abnormal biochemical functioning of these proteins and cell toxicity or cell death. This eventually leads to a decrease in function of these tissues and organs. Chronic or high-dose cadmium exposure is particularly toxic to the kidney, and this can lead to poor absorption of calcium, which is required for healthy bones. Long-term cadmium exposure is also associated with increased risk of lung cancer in occupationally exposed people, as well as other clinical conditions.
However, it is now clear that there were other contributing factors that limited the development of the specific clinical condition known as itai-itai disease to this particular subset of Japanese women, since other individuals do not exhibit itai-itai disease even though they have signs of cadmium poisoning. Other factors likely include the general malnourishment and poor calcium metabolism of these women, their advanced age, and their gender. Postmenopausal women in general are at increased risk of osteoporosis and other calcium-related disorders. In particular, estrogen has been shown to play an important role in contributing to calcium metabolism, and poor nutrition can dramatically increase this risk. The diminutive size of these women may have also contributed, and for reasons that are not entirely clear, multiparous women (that is, women who had given birth to several children) in this population were at greatest risk of the disease. Recent studies in animal models have confirmed that exposure to cadmium alone can cause some aspects of this disease but that several of these other factors must also be present to elicit a syndrome more closely resembling the complete pattern of itai-itai disease. A recent animal study demonstrated that damage to the mitochondria of the kidney cells by cadmium was a key causal event in the progression of this disease.
Recognition of the etiology of itai-itai syndrome has led to decreased exposure to cadmium in this region, although the cadmium pollution levels remain very high compared with nonpolluted regions. Improved diet and health care have also reduced the occurrence of itai-itai disease in these women. However, the disease remains an important reminder of the potential impact of environmental pollution on human health. It also exemplifies the concept of highly susceptible subpopulations who may exhibit significant effects from environmental agents even when these effects are not observed in the general population.
Joshua W. Hamilton, Ph.D.
