250
ARAYA FT AL..
creased absorption of vitamin (2.4 The present study provided no evidence that malabsorption was responsible for the Ion vitamin C levels. The three children who had zero plasma levels of Litamin C on admission (one of them after recovery as well) and the two children with clinical signs of hypovitaminosis were all
VOI,.
5.
No.
3
Aboriginals. Since multiple biochemical deficiency appears to be a common finding in Aboriginal children4, ' ', these low figures could be due to a chronic poorer vitamin nutrition in this ethnic group rather than due to a more marked response to a simple episode of diarrhoea. X.
References
J M.and WiIinilOi \b, R. I1 119661: HeiSht and acight siandard charts prmted hy Creascys of HeLtford Ltd.. England. JPI LIFH. D 8. (19661-The assessment of the nutritional stntm or t h e conimunit?. World Health O r g a n v a r ~ mGenera. . 10 Interdepartmental Committee on Nutrition for h'atiunal DcicncrIlTN31)) itional Surveys. 2nd edition, National Institute
I. SC.KIMIIIAW. U. 5 , Tnrriin. C F and (ionno\. J 1 1 Y h P J . Interaction. of nutrition and infection Monograph Series N o 57. 'A H 0 CieneLa. 2 W o i i i . M G and (;OOI)H~RT.P S 11971) Modern \utntion an Health and D i w ~ q eAth c d I ea and Febiger. Phllddelphia Pen" 3 HARK\.J (1968) Vitamin< i n health and disease A modern reappraisal J : ~ n dA Churchill. London 4 . K a l o n r x r l r l ~ ,A . (1969). Some aSDects of aborieinal infant mortality.
T&\xFK.
9
NOHII t . S (1974) Vitaniin blood ana se? in Aboriginal children and then mothers in Western Kew South Wale March. 19:2. Met?. J A:ial 1, 601 I?.TtllJMI'Yl*.. J . N..ERIllJil>. P..B R l . R. and ML!RRAY. T. K 11971) Fluorometnc determination of vitamin A in human blood and liver. Eiuchem Medicine. 5. 6 7 . 0. R . (19661: Rapid dcterrnlnation of 13. H A ~ H I SS.I .A and SCIILTTRIWXR. tocopherol In macro- and microquantities of plasma Results ohtamed 111 ..Lrlou, r.otritiLln ; , r , ~ I n c t d ~ o ~ l! i, ~ ~ , ~ i , ,4mr.t ~,, .I , ,v,,It 19. 17II
Aust. N.Z. J. Med. ( 1 9 7 3 , 5, pp. 250-255
A Family Study of Coeliac Disease Richard 1.Shipman', Alan
L. Williams+, Rosa Kay:
and R. R . W. Townley"'
From the Departments of Gastroenterology and Pathology, Royal Children's Hospital, Melbourne, Vi cto r i a
Summary:
A family study of coeliac disease.
R T. Shiprnan, A. L. Williams, Rosa Kay and R R. W. Townley, Aust. N.Z J. Med., 1975, 5, pp. 250-255.
Studies by Thompson', Carter et a/.2, MacDonald et a/.3 and McCrae" have all shown a high familial frequency of coeliac disease (CD). The diagnostic criteria differed in each study; in Thompson's patients the diagnosis was based on clinical or historical ~ ~ ~ _ - _ _ _ _ ~
___
'Research Fellow, Department of Gastroenterology. I n receipt of a grant from the Department of Health Research and Planning, Ontario, Canada. Current address, Paediatric Centre. 505 O ' c o n n o r Street. Ottawa 1 , Ontario, Canada. tDirector, Department of Pathology. :Histology Technologist, Department of Gastroenterology '*Director, Department of Gastroenterology. Correspondence' Dr. R. R. W. Townley, Department of Gastroenterology. Royal Children's Hospital, Flernington Road, Parkville, Victoria 3052. Accepted for publication: 6 November. 1974.
I
1
data alone; in Carter's study response to a gluten-free diet was required, while in MacDonald's and McCrae's studies the diagnostic criteria included the demonstration of the lesion of CD by small bowel biopsy. In MacDonald's study some asymptomatic cases were discovered and a few of these had normal fat balance results. No hereditary pattern emerged from these studies though MacDonald postulated a dominant gene with variable penetrance while McCrae suggested that susceptibility to CD is inherited multifactorially and that environmental factors other than dietary gluten are of aetiological importance. Hoffman et a / . 5 , on the other hand, have described discordance for CD in identical twins.
We sought to re-examine the familial nature of CD and to establish the frequency of the disorder
in siblings using intestinal biopsy t o study relatives of children with CD diagnosed at the Royal Children’s Hospital, Melbourne. Incidentally we gathered information about blood group and secretor status, and the presence in the family of other diseases which have been claimed by others to be associated with CD.6-12 Definirions In this report, “patients with CD” and “affected relatives” have been defined as follows: Patients with CD have a malabsorptive disorder presenting usually with the clinical features described by Gee’3 and have characteristic abnormalities of the small bowel m u c o ~ a . ’Thc ~ clinical features of the disease remit following the exclusion of wheat gluten from the diet. “Affected relatives” are blood relatives of a proband, with the small bowel lesion of CD, whether or not they have clinical features.
TABLE 1 Rlood group. birth order and iiiteWnal hiopry findingi m member\ 0132 families with a proband with CD
Birth order . .
4
Family 1 7
o+
3 4
5 6 7
o t lo+
A t
+ +
A 0 O f A+ A+
A+
!A-
A+
\A+
l? 14
BC
OL
I5
4
16 17 18
o+
1’) 20
A+ 0+
21 22 23 24 25 26 27 28
A+
8 9
I0 11
I2
29
30 31
32
OT A+
o+ jo+ o+ lo+*
o+: lo+ ,R+
>
A?
4
6
11 7
Material and Methods
Patients and their Families Relatives of 32 patients with CD were studied. Sixteen of the 32 families were selected as follows. One of the authors (R.T.S.) examined the histology of all small bowel biopsy specimens obtained at the hospital from July 1965 to December 1968, without the knowledge of any clinical details of the patients. Sixty-two were considered to show the characteristic lesion of CD. This included “flattening” of the mucosa, with diminished height and irregularity of the surface epithelium and increased infiltration of the lamina propria with plasma cells and less frequently eosinophils. The case records of these 62 patients were then examined. There were 24 patients who fulfilled the above criteria of CD and whose physicians had given us permission to approach the family seeking to investigate its members. Eight of the 24 families were unable or unwilling to he examined. In these eight families there were 18 siblings. and no relative was known to be affected. Of the remaining 16 families (Nos. 1Ll6, Table 1) who co-operated, two were already aware of a sibling with C D at the time of diagnosis of the proband, though in only one had the diagnosis been confirmed by small bowel biopsy. In a third family the mother was known to be affected, and in a fourth family a cousin was affected. We also studied a second group of 16 families (Nos. 17-32, Table I) of patients attending the hospital with CD. In these families the date of diagnosis of the proband fell outside the period of July, 1965 to December, 1968. The basis for selection for these families was merely that they were available and willing to be studied. No measures were taken to avoid or assess bias caused by the inclusion of patients known to have a positive family history. Two of these second 16 families were aware of an affected sibling. two others were aware of an affected parent and in a fifth family the father had suffered from “fat intolerance in infancy”. In these two groups of 16 families, there were 80 living siblings, two of whom were under six months of age. Two siblings had died in infancy. All the parents were alive and there was no blood relationship between the parents in any of the families studied.
0 t:
+
R+
7
0+:
o+
A t A+“
o+ lo+
A+
AR4
+
A+ A+
A+
*
O f
[Oi
n-: n+
A+:
B+* 0A+
R+
R-
Br
IA+
A+
R+ ARt
A t
O+
B t B*
6-+
Clinical Information We obtained detailed family histories of the proband and personal medical histories of the first degree relatives by questionnaire and checked the information at direct interview with the parents. The personal histories included dietary information so that an assessment of gluten intake could be made. Relatives were weighed and measured and when available infant welfare clinic records were examined to determine growth during infancy. Family histories taken from the parents of our probands covered the diseases of parents, siblings, grandparents, uncles, aunts and first cousins. The information available was almost certainly incomplete. The 32 pairs of parents were aware of 405 cousins (194 paternal, 211 maternal), 106 uncles (60 paternal, 46 maternal), 103 aunts (54 paternal, 49 maternal), eight siblings and. of course, 128 grandparents.
~
* Mucosal lesion of CD t Propositus :No biopsy X Dead Blood group unknown **Extra marital paternity presumed
Techniques and Laboratory Methods Biopsy specimens were obtained under radiographic control using the Watson paediatric capsule. A small sample of intestinal content was obtained for microscopy by applying gentle aspiration to the oral end of the tubing attached to
the capsule for 30-60 seconds before the capsule knife was “fired” by vigorous suction. The biopsy specimen, usually obtained from the third part of the duodenum, but occasionally from the junction of the second and third parts, was taken from the capsule immediately, spread out on nylon mesh. and then transferred into buffered formol saline or Bouin fixative. The tissue was mounted in paraffin wax blocks with care to ensure correct orientation for sectioning. Sections were stained with haematoxylin and eosin. A few relatives had had small bowel biopsies before this study commenced. All slides, including those of specimens obtained prior to this study, were coded and examined independently by the four authors. Only well-oriented sections were accepted for diagnosis of the lesion of CD. A drop of intestinal content from the capsule tubing was examined microscopically for trophozoites of Giurdirr lamhlia. Blood was taken by venipuncture for grouping and saliva was collected into sterile glass bottles at the time the families attended the hospital. Saliva specimens were stored at -20°C and tested for secretor status by the Hyland “Anti H” method. Srntistical analysis: Calculation of x2 were made on a Monroe Epic 3000 calculator using Yates correction.
Results
Intestinal Biopsy Findings We obtained biopsies from 78 siblings, 27 mothers, 26 fathers and 1 1 non-first degree relatives. Findings in the two groups of families were similar. The four authors independently diagnosed the lesion of C D in the biopsies of 15 of the 142 relatives. In addition, the authors considered about 100,;; of the remaining biopsies to show minor abnormalities which were not considered to be diagnostic of CD. In some of these, the changes were probably due to giardiasis since parasites were visible microscopically in intestinal content and in histological sections. Siblings Ten siblings aged between two and 16 years had mucosal changes characteristic of C D (Table l), and of these only four had clinical features of CD. The other six were not only asymptomatic, but also could not be distinguished from their unaffected siblings by growth pattern or current height and weight percentiles. The mucosal histology in one of these six is shown in Figure 1. Pnrents Two mothers and two fathers, each from a different family, were affected. The two mothers had each been considered to have C D in child-
FIGURE 1 Histological appearanceof duodenal biopsy specimen from an asymptomatic sibling of a child wlth coeliac disease (Haematoxylin and eosin x 80)
hood although in neither had the diagnovis been confirmed by biopsy or response to a gluten-free diet until adult life. In one mother (family 14) the diagnosis was confirmed at the age of 36 years by biopsy shortly after the diagnosis of her daughter. She had been asymptomatic since childhood. Thc other mother (family 20) was considered well during the second decade of life, but suffered from weight loss, diarrhoea and megaloblastic anaemia leading to her investigation and confirmation of the diagnosis of C D at 23 years of age. Subsequently her daughter was found to have CD. One father (family 27) had been healthy until about 24 years of age when he commenced five years of ill-health with diarrhoea and weight loss which improved spontaneously. He was well at 36 years of age when his daughter was diagnosed. His biopsy was taken following the diagnosis of C D in his daughter. The other father (family 30) had suffered “fat intolerance” in infancy, but had otherwise maintained good health and was asymptomatic at the time his biopsy was taken during this study when he was 37 years of age. Twins There was one pair of twins in the study. The proband in family 7 had a non-identical twin sister whose biopsy was normal at 33 years of age.
~~~
- - - _ ~ _ ~ _ _ _
.-
~
~
~~
Nowfirst DP
ARAYA FT AL..
creased absorption of vitamin (2.4 The present study provided no evidence that malabsorption was responsible for the Ion vitamin C levels. The three children who had zero plasma levels of Litamin C on admission (one of them after recovery as well) and the two children with clinical signs of hypovitaminosis were all
VOI,.
5.
No.
3
Aboriginals. Since multiple biochemical deficiency appears to be a common finding in Aboriginal children4, ' ', these low figures could be due to a chronic poorer vitamin nutrition in this ethnic group rather than due to a more marked response to a simple episode of diarrhoea. X.
References
J M.and WiIinilOi \b, R. I1 119661: HeiSht and acight siandard charts prmted hy Creascys of HeLtford Ltd.. England. JPI LIFH. D 8. (19661-The assessment of the nutritional stntm or t h e conimunit?. World Health O r g a n v a r ~ mGenera. . 10 Interdepartmental Committee on Nutrition for h'atiunal DcicncrIlTN31)) itional Surveys. 2nd edition, National Institute
I. SC.KIMIIIAW. U. 5 , Tnrriin. C F and (ionno\. J 1 1 Y h P J . Interaction. of nutrition and infection Monograph Series N o 57. 'A H 0 CieneLa. 2 W o i i i . M G and (;OOI)H~RT.P S 11971) Modern \utntion an Health and D i w ~ q eAth c d I ea and Febiger. Phllddelphia Pen" 3 HARK\.J (1968) Vitamin< i n health and disease A modern reappraisal J : ~ n dA Churchill. London 4 . K a l o n r x r l r l ~ ,A . (1969). Some aSDects of aborieinal infant mortality.
T&\xFK.
9
NOHII t . S (1974) Vitaniin blood ana se? in Aboriginal children and then mothers in Western Kew South Wale March. 19:2. Met?. J A:ial 1, 601 I?.TtllJMI'Yl*.. J . N..ERIllJil>. P..B R l . R. and ML!RRAY. T. K 11971) Fluorometnc determination of vitamin A in human blood and liver. Eiuchem Medicine. 5. 6 7 . 0. R . (19661: Rapid dcterrnlnation of 13. H A ~ H I SS.I .A and SCIILTTRIWXR. tocopherol In macro- and microquantities of plasma Results ohtamed 111 ..Lrlou, r.otritiLln ; , r , ~ I n c t d ~ o ~ l! i, ~ ~ , ~ i , ,4mr.t ~,, .I , ,v,,It 19. 17II
Aust. N.Z. J. Med. ( 1 9 7 3 , 5, pp. 250-255
A Family Study of Coeliac Disease Richard 1.Shipman', Alan
L. Williams+, Rosa Kay:
and R. R . W. Townley"'
From the Departments of Gastroenterology and Pathology, Royal Children's Hospital, Melbourne, Vi cto r i a
Summary:
A family study of coeliac disease.
R T. Shiprnan, A. L. Williams, Rosa Kay and R R. W. Townley, Aust. N.Z J. Med., 1975, 5, pp. 250-255.
Studies by Thompson', Carter et a/.2, MacDonald et a/.3 and McCrae" have all shown a high familial frequency of coeliac disease (CD). The diagnostic criteria differed in each study; in Thompson's patients the diagnosis was based on clinical or historical ~ ~ ~ _ - _ _ _ _ ~
___
'Research Fellow, Department of Gastroenterology. I n receipt of a grant from the Department of Health Research and Planning, Ontario, Canada. Current address, Paediatric Centre. 505 O ' c o n n o r Street. Ottawa 1 , Ontario, Canada. tDirector, Department of Pathology. :Histology Technologist, Department of Gastroenterology '*Director, Department of Gastroenterology. Correspondence' Dr. R. R. W. Townley, Department of Gastroenterology. Royal Children's Hospital, Flernington Road, Parkville, Victoria 3052. Accepted for publication: 6 November. 1974.
I
1
data alone; in Carter's study response to a gluten-free diet was required, while in MacDonald's and McCrae's studies the diagnostic criteria included the demonstration of the lesion of CD by small bowel biopsy. In MacDonald's study some asymptomatic cases were discovered and a few of these had normal fat balance results. No hereditary pattern emerged from these studies though MacDonald postulated a dominant gene with variable penetrance while McCrae suggested that susceptibility to CD is inherited multifactorially and that environmental factors other than dietary gluten are of aetiological importance. Hoffman et a / . 5 , on the other hand, have described discordance for CD in identical twins.
We sought to re-examine the familial nature of CD and to establish the frequency of the disorder
in siblings using intestinal biopsy t o study relatives of children with CD diagnosed at the Royal Children’s Hospital, Melbourne. Incidentally we gathered information about blood group and secretor status, and the presence in the family of other diseases which have been claimed by others to be associated with CD.6-12 Definirions In this report, “patients with CD” and “affected relatives” have been defined as follows: Patients with CD have a malabsorptive disorder presenting usually with the clinical features described by Gee’3 and have characteristic abnormalities of the small bowel m u c o ~ a . ’Thc ~ clinical features of the disease remit following the exclusion of wheat gluten from the diet. “Affected relatives” are blood relatives of a proband, with the small bowel lesion of CD, whether or not they have clinical features.
TABLE 1 Rlood group. birth order and iiiteWnal hiopry findingi m member\ 0132 families with a proband with CD
Birth order . .
4
Family 1 7
o+
3 4
5 6 7
o t lo+
A t
+ +
A 0 O f A+ A+
A+
!A-
A+
\A+
l? 14
BC
OL
I5
4
16 17 18
o+
1’) 20
A+ 0+
21 22 23 24 25 26 27 28
A+
8 9
I0 11
I2
29
30 31
32
OT A+
o+ jo+ o+ lo+*
o+: lo+ ,R+
>
A?
4
6
11 7
Material and Methods
Patients and their Families Relatives of 32 patients with CD were studied. Sixteen of the 32 families were selected as follows. One of the authors (R.T.S.) examined the histology of all small bowel biopsy specimens obtained at the hospital from July 1965 to December 1968, without the knowledge of any clinical details of the patients. Sixty-two were considered to show the characteristic lesion of CD. This included “flattening” of the mucosa, with diminished height and irregularity of the surface epithelium and increased infiltration of the lamina propria with plasma cells and less frequently eosinophils. The case records of these 62 patients were then examined. There were 24 patients who fulfilled the above criteria of CD and whose physicians had given us permission to approach the family seeking to investigate its members. Eight of the 24 families were unable or unwilling to he examined. In these eight families there were 18 siblings. and no relative was known to be affected. Of the remaining 16 families (Nos. 1Ll6, Table 1) who co-operated, two were already aware of a sibling with C D at the time of diagnosis of the proband, though in only one had the diagnosis been confirmed by small bowel biopsy. In a third family the mother was known to be affected, and in a fourth family a cousin was affected. We also studied a second group of 16 families (Nos. 17-32, Table I) of patients attending the hospital with CD. In these families the date of diagnosis of the proband fell outside the period of July, 1965 to December, 1968. The basis for selection for these families was merely that they were available and willing to be studied. No measures were taken to avoid or assess bias caused by the inclusion of patients known to have a positive family history. Two of these second 16 families were aware of an affected sibling. two others were aware of an affected parent and in a fifth family the father had suffered from “fat intolerance in infancy”. In these two groups of 16 families, there were 80 living siblings, two of whom were under six months of age. Two siblings had died in infancy. All the parents were alive and there was no blood relationship between the parents in any of the families studied.
0 t:
+
R+
7
0+:
o+
A t A+“
o+ lo+
A+
AR4
+
A+ A+
A+
*
O f
[Oi
n-: n+
A+:
B+* 0A+
R+
R-
Br
IA+
A+
R+ ARt
A t
O+
B t B*
6-+
Clinical Information We obtained detailed family histories of the proband and personal medical histories of the first degree relatives by questionnaire and checked the information at direct interview with the parents. The personal histories included dietary information so that an assessment of gluten intake could be made. Relatives were weighed and measured and when available infant welfare clinic records were examined to determine growth during infancy. Family histories taken from the parents of our probands covered the diseases of parents, siblings, grandparents, uncles, aunts and first cousins. The information available was almost certainly incomplete. The 32 pairs of parents were aware of 405 cousins (194 paternal, 211 maternal), 106 uncles (60 paternal, 46 maternal), 103 aunts (54 paternal, 49 maternal), eight siblings and. of course, 128 grandparents.
~
* Mucosal lesion of CD t Propositus :No biopsy X Dead Blood group unknown **Extra marital paternity presumed
Techniques and Laboratory Methods Biopsy specimens were obtained under radiographic control using the Watson paediatric capsule. A small sample of intestinal content was obtained for microscopy by applying gentle aspiration to the oral end of the tubing attached to
the capsule for 30-60 seconds before the capsule knife was “fired” by vigorous suction. The biopsy specimen, usually obtained from the third part of the duodenum, but occasionally from the junction of the second and third parts, was taken from the capsule immediately, spread out on nylon mesh. and then transferred into buffered formol saline or Bouin fixative. The tissue was mounted in paraffin wax blocks with care to ensure correct orientation for sectioning. Sections were stained with haematoxylin and eosin. A few relatives had had small bowel biopsies before this study commenced. All slides, including those of specimens obtained prior to this study, were coded and examined independently by the four authors. Only well-oriented sections were accepted for diagnosis of the lesion of CD. A drop of intestinal content from the capsule tubing was examined microscopically for trophozoites of Giurdirr lamhlia. Blood was taken by venipuncture for grouping and saliva was collected into sterile glass bottles at the time the families attended the hospital. Saliva specimens were stored at -20°C and tested for secretor status by the Hyland “Anti H” method. Srntistical analysis: Calculation of x2 were made on a Monroe Epic 3000 calculator using Yates correction.
Results
Intestinal Biopsy Findings We obtained biopsies from 78 siblings, 27 mothers, 26 fathers and 1 1 non-first degree relatives. Findings in the two groups of families were similar. The four authors independently diagnosed the lesion of C D in the biopsies of 15 of the 142 relatives. In addition, the authors considered about 100,;; of the remaining biopsies to show minor abnormalities which were not considered to be diagnostic of CD. In some of these, the changes were probably due to giardiasis since parasites were visible microscopically in intestinal content and in histological sections. Siblings Ten siblings aged between two and 16 years had mucosal changes characteristic of C D (Table l), and of these only four had clinical features of CD. The other six were not only asymptomatic, but also could not be distinguished from their unaffected siblings by growth pattern or current height and weight percentiles. The mucosal histology in one of these six is shown in Figure 1. Pnrents Two mothers and two fathers, each from a different family, were affected. The two mothers had each been considered to have C D in child-
FIGURE 1 Histological appearanceof duodenal biopsy specimen from an asymptomatic sibling of a child wlth coeliac disease (Haematoxylin and eosin x 80)
hood although in neither had the diagnovis been confirmed by biopsy or response to a gluten-free diet until adult life. In one mother (family 14) the diagnosis was confirmed at the age of 36 years by biopsy shortly after the diagnosis of her daughter. She had been asymptomatic since childhood. Thc other mother (family 20) was considered well during the second decade of life, but suffered from weight loss, diarrhoea and megaloblastic anaemia leading to her investigation and confirmation of the diagnosis of C D at 23 years of age. Subsequently her daughter was found to have CD. One father (family 27) had been healthy until about 24 years of age when he commenced five years of ill-health with diarrhoea and weight loss which improved spontaneously. He was well at 36 years of age when his daughter was diagnosed. His biopsy was taken following the diagnosis of C D in his daughter. The other father (family 30) had suffered “fat intolerance” in infancy, but had otherwise maintained good health and was asymptomatic at the time his biopsy was taken during this study when he was 37 years of age. Twins There was one pair of twins in the study. The proband in family 7 had a non-identical twin sister whose biopsy was normal at 33 years of age.
~~~
- - - _ ~ _ ~ _ _ _
.-
~
~
~~
Nowfirst DP
