Epidemiologic Surveys and Intervention of Endemic Goiter in China

Outline

Endemic goiter can be divided into two forms, i.e., the iodine-deficiency goiter and the iodine-excess goiter. The iodine-deficiency goiter was prevalent in northern mountainous areas and the iodine-excess goiter was prevalent in the eastern coastal areas, Hebei Province, China. In 1962, a site of intervention and treatment for endemic goiter was established in Chengde City, one of nine prefecture-level cities in Hebei, located in the north of the province, to comprehensively study its etiology, including geographic, environmental and epidemiologic characteristics, and clinical features of endemic goiter. Findings of the study indicated that Chengde City was severely deficient in iodine, with water iodine concentrations of 0.33-0.86 micrograms/liter (μg/L), individual iodine intake of 13.36 μg/d on average, and individual urine iodine excretion of 13.36 μg/d. The prevalence was 25.17% for endemic goiter (visible goiter), 44.35% for thyroid swelling (visible and touchable enlargement), and 2.38% for endemic cretinism. Since 1963, iodized salt (supplemented with 50 parts per million, ppm, of potassium iodide) has been provided to prevent from goiter caused by iodine deficiency, and its interventional effect was evaluated by comparison of prevalence of goiter in the iodine-supplementation group to that in the control group. Further investigations conducted in 1988 found that the prevalence of endemic goiter dramatically reduced from 25.17% in 1963 to 2.38% in 1988, similar to the national level of an area with low-prevalence (3.0%) of endemic goiter; the prevalence of thyroid swelling remarkably reduced from 44.35% to 4.49% during the same period, reaching the international level of an area of non-endemic goiter (a prevalence less than 10%). However, no significant change was found in the control group. The proportion of persons suffered from diffused goiter among those with goiter decreased from 91.67% to 58.67%, but the proportion of persons with nodal goiter increased from 8.31 to 41.12%, and the ratio of male to female subjects with goiter increased from 1:1.60 to 1:2.28 during the same period. The data also indicated that tablets of iodide and dried thyroid had no therapeutic effect on endemic cretinism, but intervention with salt supplemented with iodine can prevent against endemic cretinism caused by iodine deficiency. With the iodized-salt intervention in areas prevalent with endemic goiter, the intelligence quotient (IQ) of affected children there still lagged behind those in non-endemic areas, but the urine level of iodine in the general population in the areas prevalent with endemic goiter had reached the level of an area of non-endemic goiter. Isotope ¹³¹I uptake by the thyroid of persons in these areas had reduced to the normal range, and the iodine deficiency status had been dramatically improved in local residents by the iodized-salt intervention.

Endemic goiter also occurred in residents living in Huanghua County, coastal areas of Bohai Bay, Hebei in 1970’s. Since 1978, epidemiological studies had been conducted, and the results indicated that the prevalence of goiter was 1.52% in local residents drinking shallow-well water with an average iodine concentration of 27.2 (μg/L), compared with 7.3% in those drinking deep-well water with an iodine concentration of 661.2 μg/L, reaching the national criteria for an area of endemic goiter with a prevalence of goiter 3.0%. Experimental studies in Leghorn chickens indicated
that chickens would suffer from goiter after drinking shallow-well water added with potassium iodide at the iodide level of the deep-well water. Experiments in Kunming mice further showed that the weight of the thyroid in mice and the proportion of mice with goiter increased with their iodine intake of varied doses of iodine. All these findings concluded that endemic goiter in this area was consistently associated with chronic exposure to excessive iodine in its drinking water.

Endemic goiter is one of endemic diseases distributed widely in both China and the rest of the world, affecting many people, which is common in remote inland areas with no sea foods available and very low level of iodine in diet. For example, the prevalence of endemic goiter can vary from 5% to 90% in some remote mountainous or hilly areas. The cause of endemic goiter was thought to be iodine deficiency only in history. Chengde City, located in mountainous area of north Hebei, was an area prevalent with goiter for a long time, having a high prevalence ranging from 1.6% to 2.0%[1], but its prevalence was relatively low with sporadic cases along the coast of the Bohai Bay in Hebei Province before 1970s. During 1962-1969, Suzuki, et al.[2] conducted an investigation on goiter in fishermen in Hokkaido, Japan. Results showed that the prevalence of goiter (visible) in students varied from 6.6% to 8.9%, up to 25.0% in certain areas. The cause of goiter there was because that local residents usually took laminaria, a kind of seaweed, containing 0.8-4.5 g/kg (dry weight) of iodine. Iodine metabolism tests showed that they took 8-45 milligrams of iodine daily per person, as estimated by the daily intake of 10 grams of laminaria per person, even their actual intake was of 10-40 grams of laminaria daily per person, approximately equal to 53-300 times of their normal daily iodine requirement (150 μg/d). They usually appeared to be of diffused enlargement of the thyroid, and the prevalence of goiter increased with age after their sixth birthday and reached the peak at age of 14 years, higher in males than in females. Plasma concentration of inorganic phosphorus (IP) and absolute iodine uptake (AIU) in the thyroid was higher, and urine excretion of iodine was 8-24 mg daily; ¹³¹I uptake in the thyroid in 24 hours was 11.7%. Pathological examinations showed that goiter tissue was formed of follicles filled with colloid and flat epithelial cells. In this paper, we present findings in two parts from epidemiologic studies carried out by the Department of Environmental Health, School of Public Health, Hebei Medical University, one is the iodine-deficiency goiter in northern mountainous areas of Chengde City, Hebei, and the other is the iodine-excess goiter in Huanghua County, a coastal area of eastern Hebei.

I. Epidemiological studies on the iodine-deficiency goiter and population intervention

1. Background

1.1 Geographic Environment

Chengde City located in the north of Hebei at the intersection of 41 degrees north latitude and 117 degrees east longitude, neighboring with Inner Mongolia Plateau in the north and Yanshan Mountain in the south. The City is a small basin surrounded by hilly areas of 371-490 meters above the sea level and river valley of 329-343 meters above the sea level. Wulie (previously called Rehe) River flows pass the City from the north to the south and converges with Luan River within the City. The study sites, Lamasi and Erdaohe Villages located on the flood land of Wulie River and Shiziyuan and Luohantang Villages located in low hilly areas. The geographic area has a continental climate with an annual average temperature of 8.7°C and
an annual precipitation of 560 millimeters concentrated in three months from July to September with pelting and violent rain. There is little plant coverage on its hilly top. The slope of the land is steep there, with a thin layer of the surface less than 1.4 meters of thickness composed of a mixture of sand and loam and a mixture of sand and pebble below the surface. So, iodine deficiency environment is formed there because of the following geographic features: (1) the airflow containing more iodine from the sea and ocean is blocked by the Yanshan Mountain so that little iodine is present in the rain, (2) iodine in the soil is easy to be washed away due to heavy rain in the three months and the steep slope of the land, and (3) iodine can not be adhered and deposited due to its big granule and larger holes in the soil.

Table 5.1 Comparison of iodine concentrations in the water, soil, grains and vegetables between Chengde City and Shijiazhuang City

Samples sources		Places samples collected	Iodine concentrations	Ratio of iodine concentration in Chengde to that in Shijiazhuang
Water (μg/L)	Shallow well water	Chengde	0.3	1:7.3
		Shijiazhuang	2.4
	Deep well water	Chengde	0.9	1:5.1
		Shijiazhuang	4.4
Soil (mg/kg)		Chengde	0.6	1:12.2
		Shijiazhuang	7.6
Grain (mg/kg)	Millet	Chengde	3.3	1:3.8
		Shijiazhuang	12.9
	Sorghum (setaria italica)	Chengde	3.9	1:1.5
		Shijiazhuang	5.6
	Corn	Chengde	8.0	1:3.5
		Shijiazhuang	26.8
Vegetables (ug/100g)	Summer squash (Cucurbita pepo L)	Chengde	7.1	1:2.2
		Shijiazhuang	15.6
	Large green Chinese onion	Chengde	9.9	1:1.2
		Shijiazhuang	15.2
	Chinese cabbage. (Brassica sinensis L)	Chengde	14.2
	Goosefoot	Chengde	1.6

1.2 Iodine Concentration in Environment

In general, iodine contents in the water, soil, grains and vegetables in the study sites of Chengde City are significantly lower, compared with those in Shijjiazhuang City (Table 5.1 )[3].

1.3 Nutritional Status and Iodine Intake in Local Residents

Studies carried out in suburban areas of Chengde in 1962 showed that staple food of the residents mainly was corn and sorghum (setaria italica) with a monthly
quota of 14 kilograms (kg) and subsidiary food included pakchoi, pickle and wild vegetables. Protein intake of the labor force was about 80 grams (g) daily per person, which was all from plant sources. Intake of fat, carbohydrate and gross calorie were 30 g, 670 g and 13681.68 kilojoule (kJ), respectively. Vitamin B₂ deficiency was common in the pupils of primary schools, and 10% of them had obvious symptoms of vitamin A deficiency. Nutritional investigation and analysis of iodine contents in staple food and vegetables showed that intake of iodine was 35.95 μg per day per person for the residents living in the suburb of Chengde City, about 23.97% of the recommended daily intake. All these conditions mentioned above led to a high prevalence of endemic goiter and cretinism in that area.

1.4 Intervention Measures

Intervention was implemented by providing iodized salt with a concentration of 1:20,000 (50 parts per million, ppm) of potassium iodide, covering 30 million residents of both urban and suburban areas of Chengde City, and pregnant women with established diagnosis of endemic cretinism in Lmasi Village were provided with tablets of dried thyroid by country doctors, except for those in Erdaohe Village where non-iodized salt was supplied as a control site from 1963 to 1965. Intervention using iodized salt was unexpectedly interrupted by several important events in recent Chinese history. For example, the residents in the urban areas had consumed “washed salt” without iodine for several years during the ten-year turmoil of the Cultural Revolution from 1966 to 1976. In late 1980s, the intervention with iodized salt was also interrupted for several years when China started to adopt new economic policy, in a transition to a market economy system from the planned economy system.

2. Prevalence of Endemic Goiter and Cretinism before Intervention

2.1 Prevalence of Endemic Goiter in the Suburb of Chengde City

A study on 3,156 residents in four villages (Lamasi, Erdaohe, Shiziyuan and Luohantang) of the suburb of Chengde demonstrated that the overall prevalence of thyroid swelling (enlargement) in them was 44.33% (1399/3156), 34.48% for males and 55.76% for females. The ratio of males with thyroid swelling to females was 1:1.60. Endemic goiter occurred in people at all ages with a higher prevalence in olderage and female groups. The prevalence of thyroid swelling was lower in males aged less than 20 years, showing an increasing tendency with age. The prevalence of thyroid swelling gradually decreased in males after 20 years of age, but it still increased with age in females and stabilized at a level of more than 10% (Table 5.2 and Figure 5.1). All these findings suggested that this area (Chengde) had been affected severely by the disease for a long term.

2.2 Prevalence of Endemic Cretinism in the Suburb of Chengde City

There were 76 patients with endemic cretinism in the four villages mentioned above, with an overall prevalence of 2.38% (76/3193), 2.52% for males and 2.30% for females, and the difference was not reaching a level of statistical significance.
Endemic cretinism was found among all age-groups except for the 0-year group, and the peak of occurrence of the cases was in 7-year and 12-year age-groups, accounting for 81.58% (62/76) of the total cases, with an age-specific prevalence of 7.94% for 7-year and 12-year groups. All these children were born during the periods of Chinese civil war (1945-1949) and the Korean War (1950-1953). It was suggested that endemic cretinism could be related with multiple factors other than iodine deficiency, e.g., severe malnutrition and psychological trauma during pregnancy caused by wars. The distribution of endemic cretinism varied in the four villages, the highest (2.87%) in Erdaohe Village, followed by 2.40% in Lamasi Village and 1.89% in Luohantang and Shiziyuan Villages. It is worthy noting that with the same living standard and cultural background, the prevalence of endemic cretinism was lower in Luohantang and Shiziyuan Villages, a valley area with inconvenient transportation, compared with Lamasi and Erdaohe Villages that lied on the bank of a river with better transportation. Therefore, it is suggested that there existed some factors other than iodine deficiency for the occurrence of endemic cretinism.

Table 5.2 Prevalence of endemic goiter and cretinism in Chengde suburb in 1962

Age (yrs.)	No. subjects studied			Endemic goiter (%)			Endemic cretinism (%)
Age (yrs.)	male	female	total	male	Female	total	male	female	total
0-	181	183	364	6.08	9.29	7.67	0.00	0.00	0.00
3-	268	245	513	26.86	30.61	28.65	0.75	0.00	0.38
7-	261	224	485	32.95	33.04	32.99	10.34	9.38	9.90
12-	154	142	296	33.77	59.15	45.95	2.60	7.04	4.63
18-	123	140	263	47.97	80.71	65.40	0.81	0.00	0.38
25-	160	252	412	45.00	82.14	67.72	1.88	0.79	1.21
35-	140	188	328	42.88	85.64	67.38	0.71	1.60	1.22
45+	262	223	485	34.73	73.99	52.78	0.38	0.45	0.41
total	1459	1607	3156	34.48	55.76	44.33	2.52	2.30	2.38

Figure 5.1 Prevalence of endemic goiter and endemic cretinism in suburb of Chengde City

3. Prevalence of Endemic Goiter and Cretinism in an Era of Intervention by Supplementation with Iodine

3.1 Changes in the Prevalence of Endemic Goiter

3.1.1 Comparison between Intervention and Control Groups

A three-year prospective cohort study (Table 5.3 ) showed that the prevalence of hypothyroidism goiter in the intervention groups of Lamasi and Shiziyuan reduced dramatically by 9.53% and 11.15%, respectively, after a two-year iodine supplementation, with a statistical significance compared with that before the intervention. No statistically significant difference in the prevalences of endemic goiter was found between these intervention groups and the control group of Erdaohe Village.

3.1.2 Impact of Stopping and Resuming Iodine Supplementation on the Prevalence of Endemic Goiter[3]

The prevalence of thyroid swelling among 3,692 students in three primary schools and two secondary schools in Chengde City was 50.87% before iodine supplementation intervention. After supplying iodized salt, the prevalence of thyroid swelling there dropped annually,

reducing to 6.81% in 1965. However, the monitoring and follow-up of its prevalence during the “Cultural Revolution in 1966-1975 indicated that iodine supplementation was interrupted in the urban areas of Chengde. The prevalence of goiter in the pupils of primary schools dramatically increased to 29.58% in 1967 from 16.81% in 1965. The prevalence of goiter dropped to 21.22% again in 1975, when in Changde City 1/2,000.000 (0.5 ppm) iodized salt was provided to the pupils of primary schools (Figure 5.2 and Table 5.4 ).

Table 5.3 Comparison of prevalence of thyroid swelling between iodine supplementation and control groups[5]

Groups	Villages	Pre-intervention (1962)		Post-intervention (1965)
Groups	Villages	person-years of participants	% thyroid swelling	person years of participants	% thyroid swelling
Iodine supplementation	Lamasi	1158	42.72	1588	33.19
Iodine supplementation	Shiziyuan and Luohantang	951	41.22	1277	30.07
Control	Erdaohe	1079	48.75	1567	51.51
(Note: This table needs some statistics to show the comparisons)

3.1.3 Prevalence of Endemic Goiter after 25-year Iodine Supplementation

The four villages in Chengde were supplied with iodized salt since 1963 and changes in the prevalence of goiter during 1962-1988 are listed in Figure 5.3 and Table 5.5 After iodine supplementation intervention, the prevalence of thyroid swelling and prevalence goiter declined annually, with the prevalence of goiter reduced to 2.38% in 1988 from 25.17% in 1962, the prevalence of thyroid swelling reduced to 4.79% from 44.33%, and the sex ratio of the prevalence of thyroid swelling changed to 1:2.28 from 1:1.60 during the same period. Although the prevalence continued to drop, the overall declining trend slowed down in the areas with a previously high prevalence and gone up in the areas with a previously low prevalence, e.g, the prevalence in Shiziyuan and Luohantang Villages reached a normal level in 1983, but Lamasi and Erdaohe Villages did not reach such a level until 1988, where patients with huge, nodular goiter were not treated or could not be cured.

Table 5.4 Impact of iodine supplementation on the prevalence of goiter

Iodine supplementation	No. participants			% thyroid swelling			Prevalence of goiter (%)
Iodine supplementation	Male	Female	Total	Male	Female	Total	Male	Female	Total
Before iodine supplementation in 1963	1919	1773	3692	42.00	60.18	50.87	14.33	27.92	22.34
One year after iodine supplementation in 1964	2189	2028	4217	24.23	42.12	32.36	4.72	8.37	6.54
Two years after iodine supplementation in 1965	2323	2289	4612	11.97	21.84	16.81	2.06	4.90	3.47
No iodine supplementation in 1975	1902	1996	3898	26.70	32.36	29.58	2.79	5.06	3.95
Resumption of iodine supplementation in 1979	2069	2176	4245	16.48	25.72	21.22	1.30	3.08	2.21
(Note: This table needs some statistics to show the comparisons)

Figure 5.2 Changes in the prevalences of goiter in primary schools in Chengde City

Table 5.5 Prevalences of thyroid swelling in four villages and the suburb of Chengde City in 1962-1988[6]

Years	Lamasi			Luohansi, Shiziyuan
Years	No. examined	Prevalence of goiter (%)	Prevalence of thyroid swelling (%)	No. examined	Prevalence of goiter (%)	Prevalence of thyroid swelling (%)
1962	1126	28.42	42.72	951	20.61	41.22
1965	1588	17.70	33.19	1277	10.81	30.07
1975	1697	8.31	23.57	1286	7.30	17.11
1983	1933	4.29	9.67	1562	2.88	9.09
1988	2093	1.58	3.31	1698	2.59	5.77
Years	Erdaohe			Total
Years	No. examined	Prevalence of goiter (%)	Prevalence of thyroid swelling (%)	No. examined	Prevalence of goiter (%)	Prevalence of thyroid swelling (%)
1962	1097	28.90	48.67	3174	25.17	44.33
1965	1567	26.42	51.12	4432	13.64	34.11
1975	1983	14.37	39.89	4966	10.47	28.41
1983	2083	6.37	16.18	5578	4.70	11.83
1988	2085	2.88	5.72	5876	2.38	4.79

Figure 5.3 Changes in the prevalences of goiter in the four villages of Chengde City in 1962˜1988

3.1.4 Clinical Types of Goiter after Iodine Intervention

During the period of iodine supplementation in 1962-1988, clinical characteristics of goiter changed dramatically. The number of cases with goiter reduced, and the prevalence of diffuse goiter decreased gradually. On the other hand, the prevalence of nodular, mixed type of goiter increased (Table 5.6 ). Even though, diffuse goiter is still prevalent. Since diffuse goiter is easy to be discovered, it is predictable that the prevalence of goiter could be reduced further with continuous iodine supplementation.

Table 5.6 Clinical types of endemic goiter in the suburb of Chengde during 1962 to 1988[6]

Year	No. goiter cases	Clinical types (%)
Year	No. goiter cases	Diffuse	Nodular	Mixed
1962	481	91.62	4.78	3.53
1975	400	62.50	22.75	4.75
1983	262	37.40	58.39	4.19
1988	140	58.57	30.71	10.71

3.1.5 Impact of Iodine Supplementation on Goiter

3.1.5.1 Prevention Efficacy

With iodine supplementation in low prevalent areas, the prevalence of goiter maintained in a range from 2.56% to 8.89%. The prevalence of goiter was 4.60% for the pupils of intervention group (95% confidence interval [CI] of 4.01-5.04), and 42.06% in the control group (95% CI of 36.00-49.00%). It was obvious that the prevalence of goiter in the pupils with iodine supplementation was significantly lower than that in the controls without intervention. (Table 5.7 )

Effects of iodine supplementation on the prevalence of goiter in males and females and various age groups are shown in Table 5.8. The prevalence of goiter was 4.60% for 1,022 teenagers, 2.87% for males and 6.40% for females, with a statistical significance in all age groups, especially in 18-21 years group (zero in male and 1.47% in female). Goiter occurs in all ages of females of 9-12 years, but the prevalence of
goiter reduced with age, with a coefficient of correlation r of 0.98 (P<0.01), in contrast to the previous concept that “goiter prevalence increased with age before the era with iodine intervention. This finding is consistent with a previous report entitled “Swelling Rate of Endemic Goiter in Four Villages in Outskirts of Chengde City, which indicated that all new cases of goiter were basically palpable “swelling, accounting for 91.49% of all the cases, but the cases of “goiter accounted for only 8.51% of them, all with swelling of a second degree of the thyroid. This showed that the swollen thyroid formed under iodine supplementation was not so severe as previously seen before the intervention.

Table 5.7 Intervention efficacy of iodine supplementation on goiter in general population[6]

Study groups and period	No. participants	Prevalence of goiter % (95% CI)^A	P-Value
Residents
1963-1975	932	4.08 (2.90-5.55)	<0.001^B
1975-1983	1864	8.89 (7.65-10.29)
1983-1988	3711	2.56 (2.08-3.12)
Students
1963-1965	1022	4.60 (3.40-4.60)
Controls
1963-1965	236	42.06 (36.00-49.00)
^A CI: confidence interval.
^B: As compared with that of control group without iodine supplementation.