J Chron Dis 197’). Vol. 32. pp. 499 to 504 Purgamon Press Ltd Prmtrd m Great Brafain

PREVALENCE OF INTRAHEPATIC CHOLESTASIS OF PREGNANCY IN LA PAZ, BOLIVIA* HUMBERTO

Departments

REYES,~GONZALOTABOADA

and

JOSE RIBALTA

of Medicine and Experimental Medicine (Santiago University of Chile School of Medicine and Institute of Human Genetics. Universidad Mayor de San Andres. La Paz, Bolivia

Eastern

Campus).

Abstract-A past history of intrahepatic cholestasis of pregnancy--either as cholestatic jaundice or as pruritus gravidarum-was inquired in 304 pregnant women examined in La Paz. Bolivia. Pruritus gravidarum was detected in 9.2% of them but no cases of cholestatic jaundice of pregnancy were found in the sample studied. This prevalence rate of pruritus gravidarum is considerably greater than that reported in European and North American populations (0.2-3.0%) but smaller than in Araucanian Indian-mixed (22.1%) and in Caucasoids (12.6%) previously studied in Chile. No significant differences in prevalence rates of pruritus gravidarum were found between the four ethnic groups (Aimara Indian, Quechua Indian, Indian-mixed and Caucasoids) in which Bolivian women were classified. Bolivian and Chilean Caucasoids showing a greater degree of ethnic admixture with South American Indian groups in their ancestry, had a greater prevalence and recurrence rate of intrahepatic cholestasis of pregnancy than Caucasoid women showing a smaller degree of ethnic admixture with native Indian groups. We propose that the prevalence of intrahepdtic cholestasis of pregnancy in Bolivia and in Chile is influenced by a genetic predisposition related to ethnic admixture wrth some South American Indian groups. Still unidentified environmental factors may modify the expressivity of the disease.

INTRODUCTION

A RARE form of intrahepatic cholestasis of unknown cause can be recognized clinically in pregnant women, either as cholestatic jaundice or as pruritus gravidarum. Widespread pruritus appearing during a pregnancy (generally during the last trimester), lasting until delivery and disappearing in the first hours (or days) post-partum, is the most striking clinical manifestation in pruritus gravidarum and in cholestatic jaundice of pregnancy. Laboratory alterations indicative of cholestasis (increased serum alkaline phosphatases, 5’ nucleotidase, bile acids, lipoprotein X, and sulfobromophthalein retention in plasma) can be detected in both forms of the disease. In clinical practice, increased serum total and direct reacting bilirubin is the main characteristic allowing a distinction between cases with cholestatic jaundice of pregnancy and those with pruritus gravidarum. In both clinical pictures the liver biopsy shows a mild nonspecific cholestasis. Both forms of intrahepatic cholestasis of pregnancy tend to recur in subsequent pregnancies of an affected woman, and both may alternate in different pregnancies of the same woman [l-6]. Although clinical and laboratory abnormalities return to normal immediately after delivery or in the forthcoming 2-3 weeks, this disorder is important because the *Grants ICYT), Bolivia. *Reprint 16038;

from the University of Chile (M0399782). the Comision National de Investigation Cientifica (CONChile, and the ComitC National Coordinador del Desarrollo de Ciencias Biologicas (CQNDEClB). requests: Humberto Santiago 9. Chile.

Reyes, M.D.; Universidad

de Chile:

499

Facultad

dc Medicina,

Sede Orientc:

Casilla

500

HUMBERTOREYES,GONZALO TABOADA and JOSE RIBALTA

affected women have a greater rate of still-births and premature deliveries [3,7,8], a higher risk of developing cholestatic jaundice during the use of contraceptive drugs containing estrogens [9-141 and a higher prevalence of cholesterol gallstones [14]. The disease is currently considered to represent an abnormal reaction of the maternal liver to endogenous estrogens or to their metabolites [13,15]. The aggregation of cases among blood relatives [3,5, 16-22) and the l&20-fold greater prevalence of the disease in well-defined geographic areas, such as Chile [23], Poland [24] and the Scandinavian countries [l-3,5, 14, 161, suggest that a genetic predisposition could play an important role in its pathogenesis. No common environmental factors have yet been identified as influencing the disease. We have recently demonstrated that the prevalence of both clinical forms of idiopathic intrahepatic cholestasis of pregnancy in Chile is significantly greater in women with overt Araucanian-Indian admixture (27.6%) than in Caucasoid women (15.1%) [23]. The apparently low prevalence of the disease in Spain and in Latin American countries, where different (non-Araucanian) aborigine groups have contributed to the ethnic admixture, supports the hypothesis that an ethnic predisposition to develop intrahepatic cholestasis of pregnancy is associated with the Araucanian Indians. However, in the same study, pruritus gravidarum was detected in 11.2% of a small group of Aimara Indians living at sea level in northern Chile. This prevalence-although smaller than in Araucanian-Indian-mixed women-is clearly higher than the prevalence reported in Europe and in North America. Thus, it seemed important to obtain more definitive information about the prevalence of intrahepatic cholestasis of pregnancy in the Aimaras, who live primarily in the Bolivian High Andean Plateau. This South American Indian group has contributed greatly to the ethnic admixture of the Bolivian population, and to a smaller extent, in some neighboring countries such as Chile. A prospective study was then done in Bolivia, where Aimara Indians live in a completely different geographic environment than in northern Chile and have access to different food supplies.

MATERIAL

AND

METHODS

The study was performed in the city of La Paz, Bolivia (Latitude 16”3O’S, Longitude 68”10’, Altitude 3600m, Population 600,000). From 15 May until 15 June, 1976, every pregnant woman hospitalized for a delivery in each of the two main obstetric wards available to the population of this city (Hospital de Clinicas and Caja National de Seguro Social) was examined. Using the same methodology as in our studies done in Chile [23,25], every woman was examined 15-40 hr after delivery. The data collected included the patient’s identification, ethnic characteristics, past obstetrical history, the presence or absence of idiopathic cholestatic jaundice or pruritus gravidarum in the recent as well as in previous pregnancies, a past history of jaundice with or without pruritus during non-pregnant periods, and physical examination. Serum bilirubin measurements were done in every patient in whom jaundice was clinically suspected. Diagnostic criteria for cholestatic jaundice of pregnancy and pruritus gravidarum were based in the commonly accepted clinical characteristics of the disease, and similar to those adopted in previous studies done by the authors [22,25]. Pruritus gravidarum was diagnosed in women with widespread pruritus, without jaundice nor hyperbilirubinemia, that appeared during pregnancy, lasted until delivery, and was clearly attenuated in the subsequent hours; these women should have no skin lesions (except those due to scratching), no biliary colicky pain during pregnancy, no past history of pruritus (with or without jaundice) in non pregnant periods, and no other symptoms nor physical signs of other liver or skin diseases. The diagnosis of cholestatic jaundice of pregnancy requires the coexistence of jaundice, dark urine, and generalized pruritus, all appearing during the second half of pregnancy, with a clear decline of itching immediately after delivery. As with pruritus gravidarum, the absence of jaundice and pruritus

Intrahepatic

Cholestasis

501

of Pregnancy

in non-pregnant periods and of symptoms or physical signs suggesting other liver diseases were mandatory requisites. Every individual was classified into one of the following ethnic groups, using phenotypical, socio-cultural and geographic characteristics as ethnic markers:

(1) Aimaras:

Indian facial traits, with both maternal and paternal surnames being Aimara, born in zones of the Bolivian High Andean Plateau (‘Altiplano’) close to the Lake Titicaca (where the Aimaras are predominantly located), and whose native language was the Aimara. (2) Quechuas: Indian facial traits, with both maternal and paternal surnames being Quechua, born in zones of Bolivia where the predominant Indian population is Quechua (Oruro. Potosi, Cochabamba) and whose native language was the Quechua. (3) Caucasoids : Caucasian facial traits, with both maternal and paternal surnames being European, and whose native language was the Spanish. (4) Indian-mixed (‘mestizos’): Indian facial traits, one parent being Indian (either Aimara or Quechua), the other having a Spanish surname. In this group, native language and birthplace were considered unimportant. After the population sample was classified in ethnic groups. the presence or absence of ‘shovel-shaped teeth was used to estimate the degree of South American Indian admixture in each group. Shovel-shaped teeth are inherited as an autosomal dominant morphologic trait; they are present in SO-100% of individuals in the Mongolian population in Asia and in most aborigine groups in North, Central and South America [26-281. They are found in (.X200/, of Caucasian individuals in Europe and can be used as a genetic marker in population studies of ethnic origin and admixtures. The results were statistically analyzed using the Yates’ correction of the x2 test [29]. Differences with a p value equal to or smaller than 0.05 were accepted as significant. RESULTS

A quantity of 304 women were examined, 179 at the Hospital de Clinicas and 125 at the Caja National de Seguro Social (CNSS). The proportion of primiparous women (33.6%) was similar in both hospitals. No cases of cholestatic jaundice of pregnancy were observed among these women, judged by the absence of jaundice, dark urine and generalized pruritus during the recent pregnancy, and the finding of serum total bilirubin concentration below 1.2mg/dl in blood samples taken 15-40 hr after delivery in women suspected of being icteric. Pruritus gravidarum was detected in 28 women (9.2x), 15 at the Hospital de Clinicas and 13 at the CNSS. In 23 cases (82.1%. of the affected women) pruritus gravidarum started between the sixth and eigth month of pregnancy, and in 17 of them, in the seventh month. The earliest dates of beginning of pruritus gravidarum were the second and third month of gestation (one case for each date). Table 1 shows that age and parity were comparable in women with and without pruritus gravidarum.

TABLE I.AGE ANDPARITY

Pruritus

IN BOLIVIAN WOMEN GRAVIDARUM

gravidarum No. 28

WITH AND WITHOUT

Without

pruritus gravidarum No. 276

Age (yr) Mean

25.1

Median Range Parity Mean Median Range

24.4 15-43 2.8 2 I-10

PRUHITUS

25.6 25.4 1544 2.8 2 I- 1I

502

HUMBERTO

REYES, GONZALO

TABOADA

and JOSE RIBALTA

TARLE 2. PREVALENCI: OF PRURITUS GRAVIDARUM FIED ACCORDING

IN BOLIVIAN WOMEN

Sample size Ethnic

group

Aimaras Quechuas Indian-mixed Caucasoids Total

CLASSI-

TO THEIR ETHNIC ORIGIN* Pruritus

gravidarum

(No.)

(No.)

1%)

94 23 110 77 304

13

13.8 4.3 7.3 7.8 9.2

I 8 6 28

*I’ test for pruritus gravidarum: between the four ethnic groups p z 0.05; between Aimaras and Indian-Mixed p > 0.05; between Aimaras and Caucasoids p > 0.05.

In the total sample, 94 women were ethnically classified as Aimaras, 23 as Quechuas, 110 as Indian-mixed and 77 as Caucasoids. The frequency of shovel-shaped teeth in Aimaras (97.6x), Quechuas (92.9%) and Indian-mixed women (89.0%) was significantly higher than in Caucasoids (63.6%) (p < 0.01). The prevalence of pruritus gravidarum in Bolivian women classified according to ethnic origin is shown in Table 2. There was a higher prevalence of the disease in Aimara women than in the other ethnic groups, but the difference was not statistically significant. Other clinical characteristics of the disease, such as date of beginning of pruritus during pregnancy and recurrence in previous pregnancies, were similar in the four ethnic groups. In Caucasoid women with shovel-shaped teeth the prevalence of pruritus gravidarum was 8.2x, and in Caucasoid women without shovel-shaped teeth it was 5.0%. The number of individuals in both sub-groups of Caucasoid women was too small to allow a meaningful statistical comparison. DISCUSSION

The prevalence of pruritus gravidarum detected in inhabitants from the Bolivian High Andean Plateau is higher than that reported in comparable studies from Sweden [S, 63,

TARLI. 3. PREVALENCI: OF INTRAHEPATIC CHOLESTASIS ot I'RM;NANCY* DIFFERENT COUNTRIES AND IN SOME ETHNIC OROUPS

Countries, ethnic groups and reference sources of data U.S.A. [lg. 191 Canada [20] Australia [3l] France [I 7.301 Switzerland [7] Poland [24] Sweden [I. 3.5.6. I63 Bolivia [this paper] Caucasoids Aimara Indians Quechua Indians Indian-mixed (‘mestizos’) Chile [23,25] Caucasoids Aimara Indians Araucanian Indian-mixed

Cholestatic jaundice of pregnancy

Pruritus gravidarum

f?,)

G)

0.003~.0 0.036 0.13 0.024 0.035 I.16 1.20 ‘) ? ‘, ‘) ‘i 2.4 2.5 ‘) 5.5

I

IN

‘) ‘, 0:ll 0.2 0 ‘> l63.0 9.2 7.8 13.8 4.3 7.3 13.2 12.6 I I.8 22. I

*Estimated as the proportion of affected cases in relationship to the total number of deliveries attended in general hospitals. Numbers in square brackets indicate the reference sources of data. Under the term “lntrahepatic Cholestasis of Pregnancy” we include cases with cholestatic jaundice of pregnancy and cases with pruritus gravidarum. as stated in the Introduction. ? = unknown prevalence.

Intrahepatic Cholestasis of Pregnancy

503

France [30] and Australia [28], but it is lower than in the general population in Chile [23,25] (Table 3). Both forms of intrahepatic cholestasis of pregnancy have been recognized in almost every European country and in the Americas, but in most countries the actual prevalence rate of pruritus gravidarum has not been measured. The clinical variability of the disease and the possibility of an alternation of cholestatic jaundice and pruritus gravidarum in different pregnancies of the same woman [6,15,23,32]. makes it difficult to estimate the relative frequency of these disorders in a population. Only a few publications specifically report the prevalence of pruritus gravidarum but most conclude in that it is more frequent than the icteric form of this disease. In the present work, no cases of cholestatic jaundice of pregnancy were detected among 304 women examined consecutively. Since the patients were studied only 15-40 hr post-partum, and the jaundice may subside rapidly after parturition, the presence of a slight hyperbilirubinemia before delivery may have been missed. Therefore, we may be underestimating the frequency of cholestatic jaundice of pregnancy. This may be important because the results were compared with a previous study done in Chile [25]. in which case bilirubin measurements were done in every patient with widespread pruritus during a recent pregnancy, thus revealing slight hyperbilirubinemias in women with a declining jaundice, already undetectable on physical examination. We had the opportunity to examine two Bolivian women (one Caucasoid and one Aimara-mixed) who had clearly developed cholestatic jaundice during their pregnancies. Both women had their deliveries a few days before we started our survey, therefore they were not included in it. However, these two examples show that the icteric form of intrahepatic cholestasis of pregnancy is also present in women from the Bolivian High Andean Plateau. Considering the number of women sampled in this study, we can roughly estimate the frequency of cholestatic jaundice of pregnancy as lower than l”, of pregnant women in this geographic zone. Two South American Indian groups with a relatively high degree of ethnic purity represented 38.5% of the total population sample examined in La Paz. Another large group (36.2%) consisted of women with a high degree of Indian admixture, as judged by their facial traits, surnames and the frequency of shovel-shaped teeth. The remaining women, although classified as predominantly Caucasoids by their facial traits and surnames, also seemed to have a large degree of Indian admixture, suggested by a high frequency of shovel-shaped teeth. Thus, the general population examined in La Paz has a high degree of ethnic admixture between South American Indian groups (mainly Aimaras and in a lower proportion Quechuas) and Europeans (mainly Spaniards). The present and previous studies 123,251 indicate that, in comparison with European and North American populations (including the Scandinavian countries), the prevalence of intrahepatic cholestasis of pregnancy is: (1) higher in riatives from the Bolivian High Andean Plateau, mainly in the Aimaras; (2) even higher in the Chilean population: (3) the highest figures have been found in Chilean women with an overt Araucanian Indian descent. The extremely different environments in which these populations live, with few common characteristics, suggests the rdle of genetic factors in the ethnic predisposition to develop intrahepatic cholestasis of pregnancy. Furthermore, when Caucasoid women studied in Bolivia and in Chile are pooled (n = 671) and their degree of ethnic admixture with South American Indians is estimated by the presence or absence of shovel-shaped teeth, both the prevalence and recurrence of intrahepatic cholestasis of pregnancy were significantly higher in women with shovel-shaped teeth (prevalence: 17.0%; recurrence in multiparous women: 61.9%) than in women without this ethnic marker (11.37; and 26.9?,,, respectively) (p < 0.05). It is also important to emphasize that the prevalence of pruritus gravidarum was similar in Aimara women living at a high altitude, in the Andean Plateau, compared with Aimara women living at a lower altitude, in the valleys close to the city of Arica [25] (Table 3). However, the influence of non-genetic factors. such as diet, in these ethnic differences has not beEn thoroughly evaluated and they should be studied in detail. Environmental factors, superimposed on a genetic predisposi-

504

HUMBERTO REYES, GONZALO TALIOADAand JOSE RIBALTA

tion, may have an important effect on the occurrence of intrahepatic cholestasis of pregnancy.

and especially the expressivity

AcknoM,/e~~rrllc,nts-We are grateful to Dr. Luis Felipe Hartmann. Director. Institute of Human Genetics. U.M.S.A., La Paz, Bolivia. for his help in coordinating this research project. and to Drs. Fred Kern. Jr. (Denver. Colorado. USA) and Ricardo Cruz Coke (Santiago. Chile) for their critical review of the manuscript. We also thank our colleagues in the Hospital de Clinicas and the C.N.S.S. in La Paz for their permission to investigate patients admitted under their care. REFERENCES I. 2. 3. 4. 5. 6. 7. 8. 9. 10. Il. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 21. 28. 29. 30. 31. 32.

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