bubble_chart Overview

Kashin-Beck disease is an endemic osteoarthropathy characterized primarily by cartilage necrosis. The disease often affects multiple, symmetrically distributed endochondral bones, leading to impaired endochondral ossification, shortened tubular bones, and secondary degenerative joint disease. It predominantly occurs in children and adolescents, with clinical manifestations including joint pain, thickening and deformation, muscle atrophy, and movement disorders. The internationally recognized English name for this disease is Kashin-Beck disease.

bubble_chart Epidemiology

1. Historical Background

In Russia, it is generally believed that the disease was first discovered in 1849 by the land surveyor Yurenski. However, some argue that the Irkutsk doctor Filatov first identified the existence of "deforming arthritis" among residents of Zabaikaye as early as 1830. In China, records resembling this disease have been documented in local chronicles since the 17th century. Reports on the disease began to appear in the Chinese medical community in 1934.

2. Distribution of Endemic Areas

In China, the disease is distributed across a broad belt stretching from the northeast to the southwest, encompassing 302 counties in 14 provinces, municipalities, and autonomous regions: Heilongjiang, Jilin, Liaoning, Inner Mongolia, Shanxi, Hebei, Beijing, Henan, Shandong, Shaanxi, Gansu, Qinghai, Sichuan, and Tibet. It primarily occurs in rural areas, affecting approximately 1.7 million people.

In Russia, the disease is found in southeastern Siberia, with two endemic zones: a larger one in Chita Oblast and a smaller one in Amur Oblast, bordering China's Heilongjiang and Inner Mongolia. The Chita endemic area is located in the Urov River basin, a tributary of the Argun River, hence the disease is also known as Urov disease in Russia. According to data from Chita Medical Institute, the detection rate of the disease was 31.0±0.4% in 1924 but dropped to 6.3±0.4% by 1983. Based on a 1991 investigation by Yang Jianbo and colleagues in the Chita endemic area, typical cases of Kashin-Beck disease were only observed among individuals over 60 years old, with no new cases detected among adolescents. This indicates that the disease has been controlled in the former Soviet Union.

In North Korea, the disease is distributed in the northern mountainous regions, specifically in areas adjacent to China, such as North Hamgyong Province, South Hamgyong Province, and North Pyongan Province.

Literature also mentions sporadic cases of the disease in some countries in Asia, Europe, and even Africa. In summary, current data indicate that this is a distinctly regional endemic disease occurring in China, southeastern Siberia in Russia, and northwestern North Korea.

3. Endemic Areas of Kashin-Beck Disease in China

These areas are generally located in the transitional zone between the warm, humid southeastern region and the cold, arid northwestern region. The disease is more common in mountainous, semi-mountainous, and hilly areas, with higher prevalence in low-lying, damp regions such as valleys, river basins, and marshes. On the Loess Plateau in the northwest, it is more prevalent in gully areas. In the Songnen Plain and Songliao Plain of Northeast China, heavily affected villages can also be found in certain locations.

The endemic areas largely coincide with low-selenium soil zones and overlap significantly with the distribution of Keshan disease (a type of endemic cardiomyopathy).

4. Focal Distribution

Whether in the former Soviet Union or China, the disease not only occurs in specific regions but also exhibits significant disparities in prevalence among different settlements within the same endemic area. Sometimes, two villages in close proximity may have vastly different prevalence rates—one very high and the other very low. Occasionally, "healthy islands" with almost no cases may exist within heavily affected regions, or conversely, isolated "disease islands" may appear in otherwise non-endemic areas. This focal or patchy distribution remains relatively stable over long periods, though natural expansion or contraction of endemic areas can sometimes occur.

5. Classification of Endemic Areas

The disease often has an insidious onset and progresses slowly, with many cases persisting for life. Therefore, it is not appropriate to judge the severity of an endemic area during a specific period solely based on prevalence rates. Recently, Chinese epidemiologists have proposed the concept of "active endemic areas," classifying regions into the following three categories based on disease activity:

⑴ Active endemic areas: Characterized by a high number of new cases among children, with X-ray images of fingers predominantly showing rapidly changing metaphyseal alterations indicative of active lesions.

⑵ Inactive endemic areas: Characterized by the absence of new cases among children, with X-ray images of fingers mainly showing slowly changing epiphyseal alterations indicative of chronic lesions.

(3) Relative venous disease area; between the above two, fewer newly discovered cases among children, finger X-ray images show more changes in the bone ends than in the metaphysis

6. This disease mainly occurs among farmers in endemic areas who consume locally produced corn and wheat, especially impoverished farmers.

⑴ Age: It primarily affects growing children and adolescents, with very few new cases occurring in adults. Children typically begin to show symptoms at 7–8 years of age, though onset may be earlier in severely affected areas. In Shaanxi, an infant aged 3 months and 7 days was reported to exhibit X-ray changes in the metaphysis similar to those of this disease. During the scientific investigation of Kashin-Beck disease in Yongshou County, a 3-year-old child was pathologically confirmed to have the disease. However, examinations of 140 fetuses from endemic areas revealed no typical pathological changes of the disease.

⑵ Gender: There is no significant difference in incidence between males and females.

⑶ Ethnicity: The disease affects Han, Manchu, Hui, Mongol, Korean, Tibetan, and Daur ethnic groups in China, as well as Russians and Japanese living in endemic areas, with no apparent racial susceptibility. Differences observed among ethnic groups in some surveys may actually reflect disparities in living conditions. For example, in some northeastern endemic areas, Han residents suffer more severely while Koreans are less affected, likely due to differences in staple diets. Severely affected Han residents primarily consume corn, whereas less affected Korean residents mainly eat rice. However, Koreans who consume corn as their staple food show similar disease prevalence to Han residents.

⑷ Familial clustering: It is common to find two or more cases within the same family residing long-term in endemic areas. This may be due to equal exposure to disease-causing factors under similar living conditions and does not necessarily indicate genetic involvement.

bubble_chart Etiology

The cause of Kashin-Beck disease has not yet been elucidated. Currently, there are three main disease cause theories domestically and internationally.

1. **Biogeochemical Theory**

Initially proposed by scholars from the former Soviet Union, this theory suggests that the disease is caused by an excess, deficiency, or imbalance of one or several elements. Early hypotheses linked it to low calcium and high strontium and barium levels in water and soil. Later, it was proposed that excessive phosphorus and manganese in the local diet and environment were responsible. However, no definitive evidence has been found in patients or experimental studies to support these claims.

Chinese scientists discovered a close relationship between Kashin-Beck disease and environmental selenium deficiency: ① The distribution of disease-endemic areas in China largely coincides with low-selenium soil regions. Most endemic areas have soil selenium levels below 0.15 mg/kg, and grain selenium content is often lower than 0.020 mg/kg. ② Selenium levels in blood, urine, and hair of residents in endemic areas are lower than those in non-endemic areas. Patients exhibit metabolic changes associated with selenium deficiency. ③ As hair selenium levels rise in endemic populations, disease incidence declines. ④ Selenium supplementation reduces the incidence of new cases and promotes the repair of metaphyseal lesions.

However, some important facts do not support selenium deficiency as the primary cause: ① Some low-selenium regions, such as Yulin and Luonan in Shaanxi, and certain Keshan disease-endemic areas in Sichuan and Yunnan, do not report Kashin-Beck disease. Conversely, some areas with relatively higher selenium levels, like Yidu in Shandong, Zuoquan and Huoxian in Shanxi, Ankang in Shaanxi, and Banma in Qinghai, still experience the disease. ② Selenium supplementation does not completely prevent new cases. ③ Cell culture studies show that chondrocyte growth does not specifically depend on selenium. ④ Animal experiments with selenium deficiency fail to replicate the cartilage necrosis seen in the disease.

Currently, many researchers believe that selenium deficiency is merely a contributing factor rather than the sole cause.

2. **Mycotoxin Theory**

This theory posits that grains in endemic areas are contaminated by certain Fusarium fungi, which produce heat-resistant toxic substances. Residents contract the disease by consuming these mycotoxin-contaminated foods. First proposed by Soviet scholars between 1943 and 1945, this theory was not widely accepted. In the 1960s, Chinese researcher Yang Jianbo and others continued investigating this hypothesis. They noted that Fusarium oxysporum was the most frequently detected fungus in corn from endemic areas. Additionally, significant amounts of Fusarium metabolites, such as threitol and xylitol, were found in corn and wheat flour from these regions, showing a "dose-effect" relationship with disease severity. When chickens were fed grain inoculated with Fusarium isolated from endemic areas (10% mixed into normal feed), they developed band-like necrosis in the knee joint epiphyseal cartilage.

Key challenges for the mycotoxin theory include: ① Difficulty explaining the patchy distribution of endemic areas epidemiologically, as factors like temperature, humidity, and grain storage conditions do not provide convincing explanations. ② The dominant fungal species vary across endemic areas (e.g., Alternaria alternata instead of Fusarium in some regions), with no consistent pattern between endemic and non-endemic zones. ③ Cell culture studies show that Fusarium toxins (e.g., TDP-1 from Fusarium graminearum or T-2 from Fusarium sporotrichioides) lack selective toxicity to chondrocytes.

3. **Organic Matter Poisoning Theory**

This theory attributes the disease to drinking water contaminated by humic substances. In many Chinese endemic areas, locals have long blamed poor water quality for the disease. Japanese researcher Takizawa and colleagues studied the relationship between plant-derived organic matter in water and Kashin-Beck disease, suggesting that ferulic acid and p-hydroxycinnamic acid might be causative agents.

During the 1979-1982 scientific investigation of Kashin-Beck disease in Yongshou County, our country found that the total amount of humic acid and hydroxyl humic acid in water was positively correlated with the prevalence rate of Kashin-Beck disease, and negatively correlated with selenium content. In recent years, the separation and identification of organic matter in drinking water from endemic areas have shown that there is no significant difference in the core structure of humic acid between endemic and non-endemic areas. However, small-molecule organic compounds such as phenolic quinones, sulfur- and nitrogen-containing benzothiazole compounds are more frequently found in drinking water from endemic areas. Using electron spin resonance (ESR) for detection, significant free radical signals were observed in the drinking water of endemic areas.

In recent years, some scholars have suggested that low selenium, fungal toxins, and organic matter in drinking water may have an intrinsic connection in the onset of this disease. Specifically, the combined effects of fungal contamination in grains and organic pollution in drinking water both generate exogenous free radicals (semiquinone free radicals). The increased free radicals entering the human body can injure chondrocytes; in the absence of sufficient selenium protection in the endemic environment, this leads to the onset of the disease.

The main issue with this perspective is why free radicals and peroxidative injury selectively target chondrocytes without causing significant damage to other tissues.

IV. Research on Experimental Animal Models

To explore the disease etiology and pathogenesis, many scholars both domestically and internationally have dedicated years to studying experimental animal models of this disease.

Chinese researchers generally use cartilage damage as the basic morphological criterion for determining animal models. However, past experiments using rats or dogs mostly revealed scattered chondrocyte necrosis, matrix degeneration, and small acellular areas—grade I changes lacking distinctive features—with no qualitative differences compared to control groups, making it difficult to assess their value. More recently, experiments using young rhesus monkeys fed with endemic-area food and water have been relatively successful. After 6 or 18 months of consuming endemic-area water or food, most monkeys exhibited focal or band-like necrosis in the deep layers of articular and epiphyseal plate cartilage, along with a series of secondary changes post-necrosis, essentially replicating the pathological progression and main lesion characteristics of Kashin-Beck disease. The results suggest that both water and food from endemic areas contain disease-causing factors. The pathogenic effects of these factors on experimental animals did not weaken as the disease prevalence in the endemic area declined. Even using endemic-area water alone could induce significant cartilage necrosis, indicating that the primary etiology is unlikely to be a deficiency of certain trace elements.

To date, no naturally occurring Kashin-Beck disease has been proven in the animal kingdom. Previously reported joint swelling and lameness in livestock or dogs from endemic areas are far from resembling human Kashin-Beck disease. Internationally, two conditions have been proposed as comparable:

(1) Osteochondrosis in livestock: This disease shares similarities with Kashin-Beck disease, such as necrosis in articular and epiphyseal plate cartilage and potential progression to secondary osteoarthritis. However, its most typical feature is impaired chondrocyte differentiation and localized hypertrophic chondrocyte accumulation, which differs from Kashin-Beck disease. Although uneven epiphyseal plate thickness is observed in Kashin-Beck disease, existing evidence does not support hypertrophic chondrocyte accumulation as a precursor to cartilage necrosis.

(2) Tibial dyschondroplasia in birds: The primary lesion is the failure of epiphyseal plate cartilage matrix to calcify, halting endochondral ossification. Although sometimes equated with osteochondrosis in livestock, the absence of cartilage necrosis and unaffected articular cartilage make it unrelated to human Kashin-Beck disease.

bubble_chart Pathological Changes

I. Basic Pathological Changes of Cartilage

This disease primarily affects endochondral ossification bones, especially the limb bones, manifesting as degeneration and necrosis of hyaline cartilage accompanied by absorption and reparative changes. Chondrocytes often exhibit coagulative necrosis, with pyknosis, fragmentation, and dissolution of nuclei, leaving behind red-stained cellular shadows. Subsequently, these shadows disappear, and the matrix becomes red-stained, forming focal or band-like acellular areas. The necrotic areas may further disintegrate and liquefy. Chondrocytes surrounding the necrotic foci often show reactive hyperplasia, forming clusters of varying sizes. Near the bone tissue, pathological calcification may occur in the necrotic areas; blood vessels and connective tissue from the primary marrow invade the necrotic foci, leading to organization and ossification, eventually being replaced by bone tissue.

Cartilage necrosis primarily affects maturing chondrocytes (hypertrophic chondrocytes), showing a juxta-osseous distribution. When necrosis expands, it may also involve chondrocytes in other layers. Necrotic foci are often multiple, varying in size, appearing as punctate, patchy, or band-like formations.

II. Lesions of Epiphyseal Plate Cartilage

Necrosis of the epiphyseal plate cartilage mainly occurs in the hypertrophic cell layer, and in severe cases, it may extend through the entire epiphyseal plate. After necrosis occurs in the deep layer of the epiphyseal plate, blood vessels from the metaphysis cannot invade this area, halting normal endochondral ossification. However, surviving proliferative layer chondrocytes above the necrotic foci can continue to proliferate and differentiate, leading to localized thickening of the epiphyseal plate. Degenerative calcification often occurs at the osseous margin of the necrotic foci, and bone deposition may occur along the metaphyseal edge of the necrotic foci, forming irregular bone fragments or transverse bone trabeculae, indicating a halt in the normal ossification process. Meanwhile, ossification continues in other parts of the epiphyseal plate, resulting in uneven thickness of the epiphyseal plate and irregular ossification lines.

When necrosis extends through the entire epiphyseal plate, absorption, organization, and ossification of the necrotic material proceed from both the epiphyseal plate and metaphysis, eventually leading to premature bony closure of the epiphyseal plate. This causes early cessation of longitudinal growth in the affected tubular bone, resulting in brachydactyly or limb shortening deformities.

The correspondence between the pathology of epiphyseal plate cartilage and X-ray changes is shown in Table 102-1.

Table 102-1 Correlation Between Pathological Changes of the Epiphyseal Plate and X-ray Findings

Pathological Changes	X-ray Findings
Focal or small necrotic foci in the deep layer of the epiphyseal plate, not affecting its thickness	Normal epiphyseal line, no visible changes
Necrosis involving the lowest layer of the epiphyseal plate cartilage, with localized disappearance of the provisional calcification zone	Blurring, interruption, or disappearance of the metaphyseal provisional calcification zone
Localized thickening of the epiphyseal plate cartilage above the necrotic area	Depressed shadow in the metaphysis
Pathological calcification at the osseous margin of the necrotic foci	Sclerotic shadow in the metaphysis
Formation of transverse bone trabeculae at the metaphyseal edge of the necrotic foci, shifting toward the diaphysis	Growth arrest line
Multiple layers of scar-like bone tissue at the metaphyseal edge of the necrotic foci	Thickening of the sclerotic shadow in the metaphysis
Necrosis extending through the entire epiphyseal plate, with absorption, organization, and ossification	Premature closure of the epiphyseal line

Due to the rich vascular supply in the metaphysis, the absorption, organization, and ossification of necrotic epiphyseal cartilage progress relatively rapidly. As a result, its X-ray imaging can show significant worsening or improvement and recovery within a short period (several months to 1 year).

III. Articular Cartilage Lesions

Similar to the necrotic foci in the epiphyseal plate cartilage, lesions in the articular cartilage also exhibit a near-bone distribution, meaning that the deep-layer maturing chondrocytes are affected first. Due to the slow absorption of necrotic material in this area and the prolonged presence of necrosis, the proliferative masses of chondrocytes around the necrotic foci often become more noticeable. In larger necrotic foci, when the necrotic material disintegrates and liquefies, fissures or cystic cavities form. Under mechanical forces such as gravity and friction, the superficial cartilage tissue is prone to flaking off in patches (osteochondritis dissecans), forming joint loose bodies (joint mice), while the local joint surface leaves ulcers of varying sizes. In severe cases, the articular cartilage in the affected area may be completely destroyed and disappear, exposing large areas of bone. At the marginal parts of the joint surface, cartilage necrosis is often accompanied by a proliferative response, leading to thickening of the joint margins, which may ossify and form bony marginal outgrowths. This results in enlargement of the bone ends, joint deformity, and restricted movement. In the late stage [third stage], proliferation, calcification, and ossification of the synovial membrane connective tissue further exacerbate joint enlargement. Due to the repeated processes of degeneration, necrosis, disintegration, flaking, and reparative proliferation of the articular cartilage, advanced-stage cases exhibit changes resembling degenerative joint disease. However, bony ankylosis has never been observed.

The correspondence between the pathological changes in the articular cartilage and the radiographic findings in this disease is shown in Table 102-2.

Table 102-2 Relationship Between Articular Cartilage Lesions and Radiographic Findings

Pathological Changes	Radiographic Findings
Deep-layer necrosis of articular cartilage, calcified zone and underlying bone unaffected	No changes
Destruction of the calcified zone of articular cartilage, erosion and absorption of the underlying bone plate	Thinning, roughness, and interruption of the bony joint surface
Organization of necrotic areas, connective tissue proliferation, pushing of the underlying bone plate	Flattening or depression of the bony joint surface
Formation of scarred bone tissue in necrotic areas	Sclerotic shadow
Cartilage proliferation and ossification at joint margins	Enlargement of bone ends, thickening of joints
Microfractures and collapse of subchondral trabecular bone	Joint deformity

The absorption and organization of articular cartilage necrosis can only begin at the normal defect sites of the bone plate, with relatively weak reparative responses and slow progression of the lesions. Therefore, radiographic changes in the joint surface (bone ends) often appear later than those in the metaphysis, and the repair process develops slowly, showing minimal changes over an extended period.

IV. Mechanisms of Cartilage Damage

Currently, there are three main perspectives:

One view holds that the biochemical basis of cartilage damage in this disease is a disorder of sulfur metabolism. Chondroitin sulfate (ChS) is a crucial component of cartilage matrix. Researchers supporting this perspective have found that patients with this disease exhibit increased urinary excretion of ChS, reduced sulfation, decreased molecular weight, and an imbalance in the proportions of various glycosaminoglycans in urine. They believe these changes indicate a disorder in sulfur utilization. The sulfation of ChS in the body is regulated by sulfation factors (SF) produced by organs such as the liver and kidneys. These researchers discovered that serum SF activity in affected children is significantly lower than in healthy local control children, who in turn have lower levels than non-endemic control children. They propose that the sulfur metabolism disorder results from reduced SF activity, and that the pathogenic factor of this disease induces a series of cartilage damages by interfering with the biological function of SF.

Another opinion suggests that the defective state of the cell membrane constitutes the biochemical basis for the onset of this disease. They found that in the membrane lipid composition of red blood cells in affected children, phospholipids were reduced, and the molecular ratio of cholesterol/phospholipids increased. Among the phospholipids, phosphatidylcholine (PC) decreased significantly, while sphingomyelin (SM) showed minor changes, leading to an elevated molecular ratio of SM/PC. These changes indicate aging of the biological membrane. Similar findings were observed in cartilage analysis from autopsy materials of affected children. They believe that the combined effects of low-temperature environments, low selenium levels, and monotonous diets (insufficient phospholipid intake) lead to membrane system fragility and reduced antioxidant capacity, thereby triggering the disease.

Another view posits that exogenous free radical sources can cause both chondrocyte necrosis and abnormal chondrocyte metabolism. The latter would synthesize and secrete abnormal matrix rich in type I collagen, resulting in rapid, small-grained, and low-crystallinity abnormal mineralization, thereby initiating the pathochemical process of this disease. Feeding mice with grain and water from endemic areas revealed an increase in type I collagen in the cartilage matrix, along with a higher type I/type II ratio.

The aforementioned changes in glycosaminoglycans, collagen, and the cell membrane system provide valuable clues for exploring the mechanisms of cartilage damage. However, there remains a significant gap in reasonably explaining how the disease cause selectively targets specific regions of cartilage and initiates a series of characteristic changes.

bubble_chart Clinical Manifestations

1. Symptoms and Signs

The disease often begins insidiously, with patients in the initial stage [first stage] possibly experiencing a lack of self-awareness, weakness in the limbs, abnormal skin sensations (such as crawling or numbness), muscle soreness, pain, etc. These symptoms are often inconsistent and not pronounced. The main and typical clinical manifestations are closely related to osteochondral damage and joint function.

1. Early Manifestations

Before obvious joint enlargement or the appearance of brachydactyly (short fingers/toes), early symptoms and signs often lack specificity. Based on extensive surveys and follow-up observations, the following manifestations warrant attention.

(1) Joint pain: Often multifocal and symmetrical, typically first appearing in highly active finger joints and weight-bearing joints like the knees and ankles. Patients describe it as distending pain, soreness, or "bone-crack pain."

(2) Terminal finger bending: The distal phalanges of the 2nd, 3rd, and 4th fingers bend toward the palm, often exceeding 15º. This is the earliest sign of the disease and holds diagnostic significance in endemic areas. However, mild terminal finger bending (less than 15º) can occur in non-endemic areas, and the disease may develop in endemic-area adolescents without terminal finger bending. Terminal finger bending often coexists with finger deviation, most commonly in the index finger, followed by the middle and ring fingers.

(3) Arched fingers: Fingers bend in an arch-like fashion toward the palm.

(4) Fusiform joint thickening: Usually occurs in the middle phalanges.

2. Manifestations After Disease Progression

As the disease progresses, in addition to worsening early symptoms like joint pain, the following signs and symptoms emerge:

(1) Joint thickening: Most commonly manifests as multifocal, symmetrical thickening of the interphalangeal joints, often first appearing in the proximal interphalangeal joints of the 2nd, 3rd, and 4th fingers. Generally, joint thickening is more pronounced in the right hand than the left, and joints subjected to mechanical injury or those of women who wear thimbles show more severe thickening.

(2) Joint mobility impairment: In the hands, this manifests as morning stiffness, difficulty making a tight fist, inability to touch the palm with fingertips, or delayed extension after making a fist. Elbow flexion and extension become limited, leading to flexion contractures. Shoulder involvement may prevent patients from reaching the opposite ear from behind the head or even washing their forehead. The knees may develop varus or valgus deformities, resulting in bowlegs or scissor-like legs. Due to flexion deformities in the knees and hips, patients struggle to squat, with compensatory lumbar lordosis and gluteal protrusion, leading to a small, waddling, or limping gait ("duck walk"). Ankle metatarsal flexion and dorsiflexion are impaired. Pain and mobility issues often worsen after rest or in the morning, improving slightly with activity. Many patients need to "walk around" by holding onto the bed edge before taking steps.

(3) Joint crepitus: Ranges from fine crepitus to coarse grinding sounds, caused by irregular joint surfaces, synovial membrane villi hyperplasia, or detachment.

(4) Joint loose bodies: May originate from detached articular cartilage fragments or shed synovial membrane villi, the latter often appearing as small rice-like particles. Loose bodies may become lodged in the joint cavity, causing locking and severe pain, which resolves when the loose body dislodges with joint movement.

(5) Skeletal muscle atrophy: Muscles in the limbs, especially the flexor muscles of the calves and forearms, often atrophy, sometimes even before obvious joint changes. In the late stage [third stage], atrophy worsens due to pain, restricted joint movement, and disuse.

(6) Brachydactyly (short fingers/toes): Phalanges are shorter than normal, resulting in small, square-shaped hands. Alternatively, uneven developmental impairment of fingers/toes disrupts their normal proportional lengths.

(7) Short-limbed deformity, short stature: The degree of developmental disorder in each tubular bone is often uneven. In some patients, the radius stops growing early, the ulna is relatively long, the ulnar styloid process shifts downward and dorsally, and the hand tilts toward the radial side, resulting in Madelung's deformity. If the disease occurs at a young age and the lesions are severe, it can lead to large joint nature of disease dwarfism. The patient's limbs are disproportionate to the head and trunk, with the upper arms significantly shorter than the forearms, the lower legs significantly shorter than the thighs, and the trunk close to normal.

3. Staging and Grading of the Disease

Based on the severity of the condition, the disease can be classified into early stage, Grade I, Grade II, and Grade III. The main clinical manifestations are shown in Table 102-3. According to a retrospective survey of patients with large joint disease over 15 years, some early-stage patients may recover to normal, while others may progress to Grade I, Grade II, or even Grade III. However, no cases developed into Grade III if the onset occurred after the age of 7. Early clinical signs are reversible, whereas patients with Grade I or above may remain unchanged or continue to worsen. Therefore, treatment for early-stage patients is extremely important.

Table 102-3 Grading of Large Joint Disease and Its Clinical Manifestations

Symptoms and Signs	Early Stage	I	II	III
Joint Pain	+	++	++	++
Finger Joint Palmar Flexion	+	+	+	+
Morning Stiffness of Joints	±	+	++	+++
Joint Thickening	±	+	++	++
Joint Dysfunction	±	+	++	+++
Joint Crepitus	±	+	++	+++
Joint Loose Bodies	-	-	++	++
Short Finger (Toe) Deformity	-	-	+	+++
Elbow Joint Flexion	-	+	++	+++
Bone Atrophy	-	+	++	+++
Short Limb Deformity, Short Stature	-	-	-	+++
Decreased Work Capacity	-	+	++	+++

Note: Symbol meanings, -, none; ±, suspicious; +, grade I; ++, grade II; +++, grade III.

As shown in Table 102-3, the main distinction between the early stage and Stage I lies in whether multiple finger joints are thickened; the main distinction between Stage I and Stage II is the presence of brachydactyly; and the main distinction between Stage II and Stage III is the presence of limb shortening and short stature.

II. X-ray Classification

The radiographic manifestations of bone changes secondary to cartilage necrosis are listed in Tables 102-1 and 102-2. Due to differences in the patient's age of onset, affected sites, and disease progression stages, X-ray findings vary. Scholars from the former Soviet Union and China primarily classified this disease based on hand X-ray changes into the following types.

(1) Metaphyseal Type: Mainly characterized by metaphyseal changes, including thinning, blurring, interruption, or disappearance of the provisional calcification zone, as well as metaphyseal depression and sclerosis. The metaphyseal type occurs in preschool and school-aged children, reflecting secondary changes after necrosis of the epiphyseal plate cartilage, representing earlier damage in large joint disease. Clinical symptoms are mostly negative or very mild. Except for pronounced sclerosis, which is less common in non-endemic areas, other metaphyseal X-ray signs can also appear in children from non-endemic areas. Therefore, in the absence of typical Stage I or above cases in the same region, a diagnosis should not be made solely based on a few metaphyseal X-ray changes. The so-called large joint disease discovered in Japan, as previously mentioned, was due to insufficient attention to this point.

(2) Metaphyseal-Epiphyseal Type: In addition to the metaphyseal changes mentioned above, the epiphysis also shows abnormalities, such as a conical or other deformed shape, embedding into the depressed metaphysis. This type mostly occurs in school-aged children and adolescents, reflecting full-thickness necrosis of part of the epiphyseal plate cartilage, with concurrent growth disorders and bone changes on both the metaphyseal and epiphyseal sides, leading to early perforation and ossification of the local epiphyseal plate. This represents further progression of the metaphyseal type.

(3) Epiphyseal Type: Primarily characterized by changes in the bone ends, including irregularity, thinning, interruption, depression, sclerosis, or even fragmentation of the articular surface. This type mostly occurs in school-aged children to post-adolescents, reflecting secondary bone changes due to deep-layer necrosis of articular cartilage. Epiphyseal changes develop slowly and are often associated with other joint damage. The diagnostic significance of epiphyseal changes is more important and specific than metaphyseal changes.

(4) Osteoarthritic Type: Seen after the closure of the epiphyseal line and disappearance of the epiphyseal plate cartilage, including severe destruction of the articular surface, unevenness, hyperplasia and sclerosis, osteophyte formation, bone fragmentation, cystic changes, and deformity of enlarged bone ends. It often involves multiple joints, with X-ray findings resembling degenerative (proliferative) arthropathy, representing the advanced stage of the disease.

In addition to the above four types, some researchers have recently proposed additional classifications, such as the metaphyseal-epiphyseal type and the metaphyseal-epiphyseal-epiphyseal type.

Although this classification system is still used by radiologists today, this descriptive classification based on anatomical location is neither convenient for combining with clinical staging nor effective in reflecting the nature of the lesions. Moreover, when multiple joints are involved, the manifestations at each affected site vary, making this classification method highly limited in practical application.

bubble_chart Auxiliary Examination

In addition to osteochondral damage and skeletal muscle atrophy, no regular changes have been proven in other tissues or organs so far. Currently, there is a lack of reliable and simple laboratory detection methods for cartilage necrosis and secondary bone changes. Moreover, the skeletal lesions caused by this disease can persist for life. Early researchers conducted some laboratory tests on this disease, but it remains difficult to distinguish which findings are inherent to the disease and which are secondary reactions or results of concurrent diseases. In recent years, some tests have been conducted to study the {|###|}mechanism of disease{|###|}, which are meaningful for observing groups but have limited value for individuals. Here, we introduce some major research findings from recent years.

1. Examinations related to bone and cartilage metabolism

⑴ Plasma alkaline phosphatase (ALP) activity is elevated, especially in children with large joint disease showing typical X-ray changes, significantly higher than in healthy controls from both endemic and non-endemic areas. In the absence of obvious liver or kidney damage, ALP mainly originates from bones, reflecting active osteoblast function.

⑵ Urinary hydroxylysine is significantly increased and rises with the severity of the disease as reflected by X-rays. In contrast, hydroxyproline, another collagen degradation product, shows less consistent changes. Some reports indicate a trend of increased urinary hydroxyproline in active, severe endemic areas, while others report {|###|}antagonism{|###|}.

⑶ The excretion of urinary chondroitin sulfate (Chs) is elevated, reflecting increased degradation of cartilage matrix. The degree of sulfation in Chs is reduced. Using cellulose acetate membrane electrophoresis, the electrophoretic mobility of Chs in patients' urine is significantly increased, indicating a decrease in the molecular weight of Chs.

⑷ Blood sulfation factor activity is low (as mentioned earlier).

2. Examinations related to muscle metabolism

Since skeletal muscle atrophy appears early in patients with this disease, some components reflecting muscle metabolism have been measured for a long time. Results from early and recent tests are largely similar. The basic changes include reduced blood levels of creatine and creatinine, significantly increased urinary creatine, and slightly decreased or unchanged urinary creatinine.

3. Changes in erythrocyte formation and function

Under light microscopy, the frequency of target erythrocytes in the blood of affected children is increased. Under scanning electron microscopy, deformed erythrocytes (acanthocytes and stomatocytes) are more numerous. These findings suggest structural and functional abnormalities in the erythrocyte {|###|}membrane{|###|} of patients. As previously mentioned, the total phospholipid content in the erythrocyte {|###|}membrane{|###|} of affected children is reduced, and the proportions of various phospholipid components are abnormal, indicating alterations in the lipid bilayer structure of the erythrocyte {|###|}membrane{|###|}. Functionally, the activity of Na⁺, K⁺-ATPase on the erythrocyte {|###|}membrane{|###|} shows a declining trend, while actin—one of the erythrocyte cytoskeletal proteins—tends to increase. Fluorescence polarization measurements indicate a slight decrease in the fluidity of the erythrocyte {|###|}membrane{|###|}.

4. Blood enzyme profiles

Using automated analyzers for {|###|}generation and transformation{|###|}, it was found that plasma levels of aspartate aminotransferase, lactate dehydrogenase, and hydroxybutyrate dehydrogenase in affected children are higher than in controls. Although these changes are mild, they are statistically significant and reproducible across multiple endemic areas. These alterations suggest that, in addition to bone and cartilage involvement, there may be mild, reversible damage to other tissue cells.

5. Changes related to selenium metabolism

Patients with this disease show no reduction in blood, hair, urine, or erythrocyte selenium levels, but the activity of the selenium-containing blood glutathione peroxidase (GSH-Px) is decreased. Correspondingly, blood lipid peroxide levels are significantly higher than in non-endemic control populations. It should be noted that these changes mainly reflect differences between endemic and non-endemic populations. Among those living in endemic areas, no regular differences are observed between mild cases, severe cases, or healthy controls.

6. Immune function status

The Yongshou County large joint disease scientific investigation's tests showed that the patients' immunoglobulins IgG, IgA, and IgM exhibited no significant changes. However, reports from Inner Mongolia indicated that the IgM levels in affected children were significantly lower than those in the control group.

During the investigation in Yongshou County, tests for nine antibodies in patient serum (including anti-cartilage cell antibody, anti-myocardial antibody, anti-mitochondrial antibody, anti-skeletal muscle antibody, etc.) all yielded negative results. This suggests that the disease is unlikely to be an autoimmune disorder.

bubble_chart Diagnosis

In the endemic area of large joint disease, clinically diagnosing patients with degrees I, II, and III based on symptoms and signs is not difficult, with the main diagnostic challenge lying in early-stage patients.

The scientific investigation of large joint disease in Yongshou County proposed the following reference indicators for early diagnosis: ① bending of the distal phalanx; ② bow-shaped fingers; ③ suspected thickening of finger joints; ④ pain in the ankle or knee joints. For children who have resided in the endemic area for more than six months, the presence of two or more of the above signs (inclusive) with symmetry holds diagnostic significance. If accompanied by X-ray changes, the case can be confirmed as early-stage. If only one of the metaphyseal X-ray changes or clinical findings is positive, the individual should be considered an early-stage observation case, with an observation period of six months.

The scientific investigation of large joint disease in Yongshou County established the following principles for X-ray diagnosis: ① the presence of any one X-ray sign at the bone end; ② multiple other X-ray signs; ③ a single-site X-ray sign combined with clinical diagnosis or additional imaging of other sites—positive cases are diagnosed, while negative cases are observed; ④ cases with unclear X-ray signs but clinical manifestations are designated as observation cases. It was also stipulated that in non-endemic areas, large joint disease cannot be diagnosed solely based on X-ray signs.

The scientific investigation of large joint disease in Yongshou County proposed X-ray diagnostic criteria based on X-ray images of the metacarpal and phalangeal bones, carpal bones, talus and calcaneus, and metatarsal bones. Based on comparative studies of X-ray and pathological findings, 23 fundamental X-ray signs were established for these regions. These can be summarized into the following five categories: ① thinning, blurring, interruption, or disappearance of the calcification zone; ② depressed sclerosis; ③ reappearance of the calcification zone; ④ epiphyseal deformation or premature closure of the epiphyseal line; ⑤ joint thickening and brachydactyly. Here, the "calcification zone" refers both to the provisional calcification zone in the deep layer of the epiphyseal plate cartilage and the calcification zone around the hypertrophic chondrocytes in the ossification nuclei of the epiphysis and carpal or tarsal bones. "Reappearance of the calcification zone" typically indicates that the chondrocytes above (epiphyseal side) the necrotic lesion in the epiphyseal plate cartilage continue to grow and differentiate, re-forming a hypertrophic cell layer with calcified matrix, thus reappearing as a calcification zone on X-ray. This is a healing phenomenon, indicating that cartilage necrosis no longer occurs at this site.

bubble_chart Treatment Measures

1. Drugs targeting potential disease causes and mechanisms of disease

These drugs are suitable for early-stage patients, aiming to block disease progression and promote lesion repair. Commonly used drugs include:

(1) Sodium selenite and vitamin E: Used for patients with low selenium levels and membrane injury manifestations. Sodium selenite tablets are generally taken orally, with each tablet containing 1mg of sodium selenite. The dosage is typically 1 tablet per week for children under 10 years old and 2 tablets per week for children over 10 years old, taken for at least 6 months. Concurrent administration of vitamin E, 10-20mg daily, can enhance the effect. The Yongshou joint disease study showed that, based on X-ray changes in the metaphysis, the efficacy reached 81.9% after one year of medication, similar to the lesion repair process observed when patients moved from endemic to non-endemic areas. Due to the narrow physiological range of selenium dosage, strict control is necessary to avoid abuse.

(2) Chondroitin sulfate tablets (Kangdeling): Used for patients with chondroitin sulfate metabolic disorders. Each tablet contains 0.12g, with a dosage of 5 tablets per dose, twice daily, for a 3-month treatment course.

(3) Sulfates: Also used for sulfur metabolism disorders. Commonly used compound sodium sulfate tablets contain 0.36g of anhydrous sodium sulfate, 0.09g of citric acid, and excipients such as starch and magnesium stearate. The dosage is 4 tablets daily for children under 10, 5 tablets for ages 10-15, and 6 tablets for those over 15, taken twice daily after meals. The treatment course lasts 6-8 months. Magnesium sulfate tablets can also be used, with dosages of 2g daily for children under 10, 3g for ages 10-15, and 4g for those over 15, taken twice daily after meals for 6-8 months. Alternatively, 1% dilute sulfuric acid can be taken orally once daily, 5-10mg per dose, mixed with 200ml of warm water after meals.

2. Drugs targeting joint pain and mobility impairment

There are many symptomatic treatment drugs in this category, applicable to patients at various stages. Commonly used drugs include:

(1) Salicylates: Enteric-coated aspirin tablets or other salicylate preparations can be used. Reports indicate not only analgesic effects but also inhibition of proteolytic enzymes, promoting cartilage lesion repair. However, long-term use should consider side effects.

(2) Chinese medicinals: Commonly used include Youwu Pills (composed of Aconite Mother Root, kusnezoff monkshood root, etc.), nux vomica pills, Shangtong Huoxue Powder, and Small Collaterals-Activating Pill.

3. Acupuncture and physical therapy

Acupuncture and physical therapy are also symptomatic treatments for pain relief, spasmolysis, and joint function improvement. In addition to traditional acupuncture, cupping, and tuina, treatments can be adapted to local conditions using mud therapy, wax therapy, mineral baths, thermoelectric stimulation therapy, or iontophoresis. The solution for iontophoresis can be 5% sodium thiosulfate.

4. Surgical treatment

For patients with severe joint deformities, joint contractures, or frequent joint locking (grades II and III), orthopedic surgery can be performed to remove loose bodies, clean the joint interior, and correct deformities, often yielding good results.

bubble_chart Prevention

1. Improve Water Quality

In response to the low mineralization and severe natural pollution of drinking water in endemic areas, efforts should be made to improve water quality. In areas with favorable conditions, deep wells can be drilled based on local hydrogeological conditions, or high-quality spring water can be channeled into villages. Protection of drinking water sources should be strengthened to prevent contamination. For areas with poor water quality and high organic content, treatment in accordance with local conditions can be implemented by constructing filtration facilities for centralized filtration and unified water supply.

2. Enhance Grain Quality

To address the monotonous diet and dietary imbalances among residents in endemic areas, diversification of crop cultivation and food variety should be promoted. In northern endemic areas with irrigation capabilities, dry farmland can be converted into paddy fields, shifting the staple diet from corn or wheat to rice. From harvesting to transportation and storage, grains should be thoroughly dried or exposed to sunlight in a timely manner to prevent mold growth. Before and after milling, grains must also be kept sufficiently dry to inhibit fungal proliferation and toxin production.

3. Selenium Supplementation

This measure targets the low selenium levels in the soil and crops of endemic areas. For large-scale selenium supplementation, foliar spraying on crops can be considered. For example, sodium selenite solution can be sprayed on wheat or corn leaves 2–3 times during the flowering period, with each application containing 10–25 mg of solution per acre, including 1 g of sodium selenite. Additionally, nitrogen, phosphorus, and selenium compound fertilizers can be applied to selenium-deficient soil, equivalent to about 15 g of sodium selenite per acre. Preliminary trials show that a single application can increase selenium levels in grains for up to three years, eliminating the need for annual fertilization. However, monitoring selenium levels in soil and grains is necessary to ensure rational fertilizer use.

Large-scale selenium supplementation can also be achieved by adding selenium to table salt. The preparation method involves mixing 15 g of sodium selenite per ton of salt, ensuring thorough blending. Similar to iodized salt for preventing iodine deficiency disorders, this is a simple and practical approach.

bubble_chart Differentiation

Clinically, diseases that need to be differentiated from large joint disease mainly fall into two categories: one includes diseases that cause joint enlargement and pain, and the other includes diseases that cause endochondral ossification disorders, short limb deformities, and short stature. The key to differentiation lies in understanding the characteristics of each disease, as well as the regional features of large joint disease.

(1) Degenerative osteoarthropathy (osteoarthritis, proliferative arthritis): It shares similarities with advanced-stage large joint disease in terms of degenerative changes and destruction of articular cartilage, leading to joint pain, stiffness, joint enlargement, and limited mobility. The differences from large joint disease include: ① It mostly occurs in adults over 40 years old, rarely in young adults, and almost never in children; ② There are no short fingers (toes) or short limb deformities; ③ Joint involvement is asymmetric; ④ Muscle atrophy is not significant.

(2) Osteochondritis dissecans: It shares similarities with advanced-stage large joint disease in that partial separation of articular cartilage forms loose bodies in the joint, leading to joint locking. The main differences are: ① The affected areas are primarily the knees or a single joint (e.g., the ankle), with rare finger involvement; ② It does not affect epiphyseal plate cartilage growth, so there are no short fingers or short limb deformities; ③ There is often a history of trauma.

(3) Rheumatoid arthritis: It shares some similarities with large joint disease in that it often occurs in adolescents, initially involving small finger joints, with multiple, symmetric joint swelling and pain. The significant differences are: ① There are inflammatory manifestations such as swelling and heat in the soft tissues around the affected joints, with spindle-shaped joint swelling; ② Severe cases often result in fibrous ankylosis; ③ There are no short fingers (toes) deformities; ④ Rheumatoid factor (IgM) is positive in 70–80% of patients; ⑤ 20–25% of patients have subcutaneous rheumatoid nodules.

(4) Gout: Although it also involves multiple joints with swelling and pain in the hands, wrists, feet, and ankles, it differs significantly from large joint disease in the following ways: ① The onset age is mostly under 40; ② There is often a family history; ③ The affected joints show acute inflammatory manifestations such as redness, swelling, heat, and pain, with sudden onset and severe pain; ④ There are gouty tophi under the skin of joints or other areas, and ulcerated skin may discharge white urate crystals; ⑤ Joint damage is asymmetric; ⑥ During acute episodes, there are systemic reactions such as fever, chills, and elevated white blood cell count; ⑦ Symptoms rapidly improve with colchicine treatment. Therefore, it is easily distinguishable from large joint disease.

(5) Fluorosis: In advanced stages, fluorosis can also cause widespread joint degeneration, osteophyte formation at joint margins, restricted joint movement, and unsteady gait. However, it differs from large joint disease in many ways, such as: ① The affected regions differ, with little overlap between the two diseases; ② The onset age is usually adulthood; ③ Dental fluorosis is common; ④ The spine and large joints of the limbs are primarily affected; ⑤ Skeletal lesions are mainly characterized by osteosclerosis, accompanied by extensive calcification and ossification of periarticular soft tissues; ⑥ Spinal canal stenosis and reduced intervertebral foramina can cause spinal cord and nerve root injury. Therefore, it is not difficult to differentiate from large joint disease.

(6) Achondroplasia: It needs to be differentiated from large joint disease in terms of short limb deformities and short stature. The main differences are: ① It is congenital, with short limbs and slow growth from birth; ② There is prominent forehead and deep nasal bridge depression; ③ X-rays show achondroplastic deformities in multiple parts of the body; ④ The epiphyses are enlarged in a trumpet shape, with significant bilateral expansion of long bones; ⑤ There is little or no joint pain.

(7) Rickets: Although severe cases can also affect bone growth and development, it mostly occurs in infants and young children. It has characteristic features such as delayed fontanel closure, square skull, pigeon breast, and rachitic rosary. X-rays show thickened epiphyseal lines with a brush-like appearance, and the long bones of the lower limbs bend, forming "X" or "O" legs. These features are distinctly different from large joint disease.

⑻ Cretinism: Although it also presents with short stature, it shows delayed growth and development shortly after birth; there are obvious intellectual and sexual dysfunctions; varying degrees of hearing and language impairments; X-ray bone age is significantly delayed, with delayed closure of the epiphyses. It is easily distinguished from large joint disease.

In our country and abroad, there are several endemic osteoarthropathies that share some similarities with Kashin-Beck disease. For example: ① Pazi disease: mainly prevalent in rural areas of Dayi and Guanghan in the western Sichuan plain, as well as Neijiang, Zizhong, Ziyang, and Jianyang in the hilly regions of southern Sichuan; ② Mseleni disease: occurring in Mseleni and its neighboring areas in South Africa's Zululand; ③ Malnad disease (familial arthritis): found in over 40 villages in the Malnad region of southern India. These three endemic diseases share many similarities with Kashin-Beck disease, such as onset predominantly in children and adolescents, occurrence in impoverished farming households, and causing skeletal growth disorders, joint mobility impairments, and disproportionately shortened limbs. Unlike Kashin-Beck disease, these three conditions primarily affect the large joints of the limbs, particularly the hip joints, while the small finger (toe) joints are either mildly affected or spared. Since the endemic areas of these diseases are relatively limited, there is practically no issue of differential diagnosis with Kashin-Beck disease. They might be considered "sister diseases" to Kashin-Beck disease. The fact that these three diseases occur in vastly distant countries yet exhibit such striking similarities raises the intriguing question of whether they share common etiological factors—a topic well worth exploring.