PAPERS

Effects of social class, sex, and region of residence on age atdeath from cystic fibrosis

John R Britton

AbstractTo determine the time trend in age at death fromcystic fibrosis and the independent effects of socialclass, sex, and region of residence mortality data forEngland and Wales from 1959 to 1986 were analysed.Median age at death increased from 6 months in 1959to 17 years in 1986 and was higher in most years from1970 in male patients (by one to six years) andin social classes with non-manual occupations (byone to 12 years). Independent odds ratios fordeath above the median age for the year of death(calculated for years from 1974, when regions ofresidence were coded by regional health authorityarea) were 1-47 (95% confidence interval 1- 16 to 1.87)in male compared with female patients and 2 -75 (2 - 16to 3.52) in non-manual compared with manual socialclasses. The independent odds of death at above themedian age also varied significantly among regionsof residence by a ratio of up to 2-67.

Social class, sex, and region of residence are allpotential determinants of survival of patients withcystic fibrosis. Social class is particularly likely toconfound the effect of management in specialistcentres on survival.

IntroductionThirty years ago most patients with cystic fibrosis

were expected to die in infancy or childhood.' 2 Nowmost can expect to survive into adulthood.3'3 Thisdramatic change, attributed to developments indiagnosis and management of cystic fibrosis,'4 hasbeen particularly noticeable among patients attendingcentres specialising in caring for those with cysticfibrosis.7'2 '7 Consequently, many doctors supportthe expansion of the role of specialist centres.79 15

Concentration of resources into specialist centresmay be one means of providing the skill and supportrequired in managing cystic fibrosis, but a dis-advantage is that the clinics tend to be less accessiblethan more localised forms of health care. As a resultthe patients who attend specialist clinics may tendto be fairly affluent or more motivated to comply withtreatment. One recent description of the character-istics of patients attending such a clinic in Englandclearly showed a social class bias, with 56% of patientscoming from social classes I and II against an expectedproportion of 20%. '8 If social class is related tosurvival with cystic fibrosis then part of the apparentlybetter performance of specialist clinics may be due toconfounding by social class. The effect of social classhas not, however, been controlled in comparisons ofsurvival between clinic populations, and the extent ofthe effect of social class on survival with cystic fibrosisis not known.The present study used data on mortality from cystic

fibrosis in England and Wales to establish whether

social class is an independent determinant of age atdeath from cystic fibrosis and therefore a potentialconfounder of the effect of management in specialistclinics on survival. The study also documented timetrends in age at death in England and Wales after 1959and estimated the independent effects of patients' sexand the regional health authority in which they lived.

MethodsMortality data for cystic fibrosis were obtained for

England and Wales for 1959 to 1986 from the Office ofPopulation Censuses and Surveys. Underlying causeof death, age at death, and sex had been codedthroughout this period; social class from 1970; andregional health authority of usual residence from 1974.

Underlying cause of death was coded by theInternational Classification of Diseases (ICD) categoryapplying to cystic fibrosis. From 1959 to 1967 this wascategory 587.2, which also included other diseases ofthe pancreas. ' In 1968 the diseases of the pancreaswere assigned to category 577.9 and a code exclusive tocystic fibrosis was created, being 273.0 between 1968and 1978 and 277.0 thereafter.202' The distribution ofages at death from cystic fibrosis and from otherdiseases of the pancreas in categories 273.0 and 577.9for the three years after the change in coding showed aclear age distinction between the categories, with onlyone death from cystic fibrosis occurring above and fivedeaths not from cystic fibrosis occurring below the ageof 50.22.24 Deaths recorded before 1968 were thereforeadjusted for the inclusion of deaths from otherpancreatic diseases coded in the same ICD category byexcluding deaths at or over age 50.Age at death for people surviving beyond their first

birthday was coded as age in years at the last birthday,and for those dying before 1 year in days for thefirst week, weeks for the first month, and monthsthereafter. Social class of those who died aged < 16 wascoded by the mother's occupation or, if the mother hadno paid occupation, that of the father; for those whodied aged - 16 it was coded by their own occupation orthat of the spouse. People in the armed forces werecoded separately by codes that did not distinguishmanual from non-manual occupations.

Data were entered into and analysed on mainframecomputers at Nottingham University. Descriptivestatistics were produced with the statistical package forthe social sciences (SPSS X)25 and logistic analyseswith generalised linear interactive modelling (GLIM).26Social class was classified into non-manual and manualcategories in all analyses. As the distributions of ages atdeath were not normal in any year and no singletransformation achieved normality the data weredescribed in terms of median age at death by year, sex,and social class. The independent effects of sex, socialclass, and region of residence on the odds of death at

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Respiratory Medicine Unit,City Hospital, NottinghamNG5 1PBJohn R Britton, MD, lecturer

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above the median age for the year of death wereanalysed in a multiple logistic regression analysis of thedeaths that occurred after the introduction of the newregional health authority areas in 1974 with male sex,non-manual social class, and residence in the NorthernRegional Health Authority as the reference point.The median and 25th centile of the distribution of

age at death were estimated for birth cohorts from 1959from published numbers of live births in England andWales by year,2 with the assumptions that one in2500 liveborn infants would have cystic fibrosis,29 thatcystic fibrosis would be registered as the underlyingcause of death in all of these cases, and that nodeaths from other causes were misclassified in theregistrations of death from cystic fibrosis.

ResultsAfter the effect of including deaths from causes

other than cystic fibrosis in ICD category 587.2from 1959 to 1967 had been allowed for 4107 people(2069 boys or men and 2038 girls or women) inEngland and Wales were estimated to have died fromcystic fibrosis from 1959 to 1986. The total number ofdeaths each year declined over the period (table I) andranged from an estimated maximum of 185 in 1963 to aminimum of 94 in 1982. The distribution of age atdeath from cystic fibrosis changed with time, deathsbefore 1 year of age decreasing from 106 in 1959 to fourin 1986. Median age at death increased from 6 monthsin 1959 to 17 years in 1986 (fig 1), and the range of ageat death between the 25th and 75th centiles increasedfrom 2 to 14 years. Median age at death was similar inthe sexes until the 1970s but thereafter was higherin male patients in most years by one to six years(fig 2). From 1970 median age at death was higher innon-manual social classes than in manual classes inmost years (fig 3) by one to 12 years.

After the introduction of coding of region ofresidence by regional health authority area in 1974there were 1734 deaths from cystic fibrosis, for 160 ofwhich no information on social class was known; a

TABLE i-Number of deaths by age and International Classification of Diseases (ICD) categors' 1959-86

Age (years)Adjusted

<1 1- 5- 10- 15- 20- 25- 30- 35- 40- 45- '50 Total total*

ICD category 587.21959 106 44 18 4 2 2 2 17 195 1781960 122 30 19 7 2 2 3 28 213 1851961 97 30 10 8 2 1 1 18 167 1491962 107 35 19 7 2 2 1 24 197 1731963 102 50 19 9 1 1 15 197 1851964 86 40 22 13 4 1 2 1 16 185 1701965 73 31 20 10 8 2 2 1 1 13 161 1481966 78 34 27 14 6 3 1 1 24 188 1651967 63 28 28 15 8 3 1 11 157 147

ICD categorm- 2 73. 0

1968 74 31 31 11 11 1 1591969 46 29 31 22 7 3 1 1391970 50 29 31 22 6 2 1 1 1421971 58 24 31 18 10 2 2 1 3 1491972 41 27 38 20 9 3 1 1 4 1441973 40 14 32 29 11 7 3 1 3 1401974 29 21 33 27 8 7 4 1 1301975 24 19 35 33 19 10 2 2 1441976 23 17 34 34 20 5 12 1451977 24 13 26 26 22 12 4 1 128

ICI) category 2 7 7. 0

1978 20 14 22 40 25 12 5 1 1391979 21 20 36 29 30 15 3 1 2 4 1611980 10 9 28 33 32 14 7 1 1 1351981 12 11 23 38 23 20 5 1 3 1361982 10 8 20 20 11 18 6 1 941983 10 12 24 35 35 19 9 3 1471984 7 6 12 28 22 27 9 3 3 2 1191985 12 10 11 32 41 17 11 2 1 2 1391986 4 7 21 16 25 23 14 1 2 113

*Excluding deaths of people aged -50.

25-

20-

- 15-

10-

.....,,,"

5-

0--

1958 1962 1966 1970 1974 1978 1982 1986

Year of death

FIG 1-Ages at death from cystic fibrosis in England and Wales1959-86. ----=25th Centile, =median. .....= 75th centile

20-

10

1958 1962 1966 1970 1974 1978 1982 1986

Year of death

FIG 2-Median age at death from cysticfibrosis by sex in England andW'ales 1959-86. X, =Boys and men, A =girls and women

m(1)-.t.r-mQ)-o

m(LIZ0)cm

-0CL)2

20-

10-

0 l1969 1974 1979 1984

Year of death

FIG 3-Median age at death from cystic fibrosis by social class inEngland and Wales 1970-86. EL=Non-manual occupations,*=manual occupations

further 290 subjects were coded as having no paidoccupation and 20 as being in the armed forces; six hadno area code. Thus there were complete data for 1258deaths (605 boys or men and 653 girls or women).Occupation was coded as non-manual for 463 andmanual for 763. For deaths coded by the occupation ofthe father or spouse the 25th, 50th, and 75th centiles ofthe distribution of ages at death in pooled data for 1974to 1986 were all higher in non-manual than in manualcategories (table II). For deaths coded by own class the75th centile was higher for manual occupations. All15 deaths coded by the occupation of the mother werein the non-manual category.

Independent odds ratios for death at age above themedian for the year ofdeath were 1 47 (95% confidenceinterval 1 16 to 1-87, p<0 005) for male comparedwith female patients and 2 75 (2 16 to 3 52, p<0 0001)for non-manual compared with manual social class.

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After the effects of sex and social class had beenallowed for there were significant differences (p<0005)in the odds of death at above the median age for theyear among the areas of England and Wales, themaximum difference being a ratio of 2-67 between theNorthern region and Wales (table III).

Estimated median survival based on estimates of thenumbers of children affected by cystic fibrosis borneach year increased from five years for the 1959 cohortto 15 years for children born in 1971. From 1972 less

TABLE iI-Number of deaths among people with cvstic fibrosis and 25th, 50th, and 75th centiles ofdistribution ofages at death in non-manual and manual social classes. Data are for 1974-86

Age at death (years)No of

Social class deaths 25th Centile 50th Centile 75th Centile

No who died aged < 16:Coe vfather's ocuain Non-manual 327 4 9 12(Codedby father'soccupation MAlanual 682 3 7 11

Coded bv mother's occupatioii Non-manual 15 15 15 15o,^dc>ccupationl 1tManual 0No who died aged a 16:

Coded b%Jown occupation Non-manual 138 20 22 25Moaanual 64 19 22 28

J Non-manual 16 24 26 43C>oded byspouse's occupation 1tManual 16 20 25-5 35

TABLE III-Odds of death from cystic fibrosis in England and Wales at above median age in any year1974-86

Estimate Standard error Odds ratio X df

Intercept (male sex, non-manual social class, residence inNorthern Regional Health Authority) 0-84 0-24

Femalesex -0-39 0-12 0-68 9-9 1Manualsocialclass -1-01 0-12 0-36 67-2 1Region of residence 34-8 14

South East Thames -0-13 0-30 0-88North East Thames -0 20 0-29 0-82South Western -0-21 0-33 0-81South West Thames -0-37 0-36 0-69East Anglian -0-39 0-39 0-67Wessex -0 40 0-34 0-67West Midlands -0 69 0-29 0-50M,ersey -0-89 0-34 0-41Oxford -0-91 0-36 0-40Yorkshire -0-92 0-32 0-40North Western -0-93 0-30 0-39Trent -0-93 0-31 0-39North West Thames -0-96 0-32 0-38Wales -0-98 0-34 0-38

TABLE IV-Estimated number of births of infants with cystic fibrosiseach year in England and Wales, number (percentage) ofdeaths fromcysticfibrosis in each birth cohort, and estimated 25th and 50th centilesofages at death bvyear of birth 1959-85

Estimated No of No of deaths in Estimated age at death (years)births affected by cohort with

Year cystic fibrosis* cystic fibrosis (%) 25th Cenitile 50th Centile

1959 300 216 (72)1960 314 260 (82)1961 325 256 (79)1962 336 266 (79)1963 342 244(71)1964 351 242 (69)1965 346 195 (56)1966 340 200(59)1967 333 184(55)1968 328 203 (62)1969 320 141(44)1970 314 136(43)1971 314 157(50)1972 290 127(44)1973 271 91 (34)1974 256 83(32)1975 242 75(31)1976 234 59(25)1977 228 56(25)1978 238 43(18)1979 255 41(16)1980 262 21 (8)1981 254 27(11)1982 250 18 (7)1983 252 15 (6)1984 255 10 (4)1985 262 12 (5)

0-40-30-60-40-51-02-01-03-01-06-05-05-06-08-08-07-010-0

5-04-08-07-09-012-016-014-017-013-0

>17-0>16-0

15-0

*One birth in 2500.

than half of the estimated birth cohort for each yeardied from cystic fibrosis. The estimated 25th centile ofthe age at death in these cohorts increased from5 months in 1959 to 10 years in 1976 (table IV).

DiscussionThis study was conducted primarily to determine

whether the effect of social class is likely to confounddifferences in survival between patients with cysticfibrosis cared for in a specialist clinic and thosereceiving care locally. Mortality data from the Office ofPopulation Censuses and Surveys were chosen as theyare the only population based data available for cysticfibrosis in England and Wales that include details ofsocial class. Data on social class were available for ahigh proportion of deaths after coding began in1970; an occupation code was present for 86% andnon-manual or manual occupation could be identifiedfor over 70%.As cystic fibrosis was coded with other diseases of

the pancreas before 1968 the numbers of deaths fromcystic fibrosis each year from 1959 to 1967 wereestimated by excluding deaths at age 50 or over. In thethree years immediately after the segregation of deathsfrom cystic fibrosis into an exclusive code in 1968 theproportion of deaths misclassified by this processwould have been less than 2% of the total; thus it isunlikely that the estimates of numbers and median ageat death before 1968 were seriously distorted.The extent to which the data comprise a complete

record of mortality from cystic fibrosis is determXinedby the degree of misclassification, under-reporting andunderdiagnosis of the disease. Misclassification ofreported deaths from cystic fibrosis into other diseasecategories is unlikely to have been a major influence,'6but the degree of misclassification of deaths fromother causes into the category for cystic fibrosis or ofunder-reporting or underdiagnosis of cystic fibrosis isless clearly established. In the present study thediscrepancy between the expected number of childrenborn with cystic fibrosis each year from 1959 to 1962and the observed number of deaths from cystic fibrosisin the birth cohorts registered by the end of 1986 wasabout 20%, suggesting that unless these people are stillalive, contrary to estimates of life expectancy at thetime of birth,' 2 up to 20% in the early cohorts may havedied with unrecognised or unreported disease.The data were analysed by median age at death so

that all information on social class of people who diedafter 1970 could be used. The alternative approachwould be to use birth cohort analysis; the disadvantagesof this method in the present study are that the analysiswould be restricted to mortality at relatively early agesin the small numbers of deaths in people born atter1970; inclusion of the effects of region of residencewould further restrict the analysis to those born after1974; differences in existing methods of collecting datawould mean that data for deaths and for the populationat risk would not be reliably linked for social class;and cohort analysis requires an unsubstantiatedassumption that the incidence of cystic fibrosis is thesame in all social classes. A shortcoming of theapproach used, however, was that the data did notinclude information on current survivors with cysticfibrosis, so that generalisation of the effects of socialclass, sex, and region of residence from the presentstudy assumes that effects among those who died alsoapply to current and future survivors.The most striking observation from the data is the

increase in median age at death, from 6 months in 1959to 17 years in 1986 (fig 1). The increase was apparentlylinear from the late 1960s. The estimates of survival insuccessive birth cohorts (table IV) show a similartrend, though these figures may be overestimates

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because of underdiagnosis and under-reportingof cystic fibrosis. Several factors are thought toaccount for the increasing life expectancy, includingimprovements in the management of meconiumileus,5 '')"3Ithe introduction of effective antibioticsfor staphylococcal and pseudomonal infections and ofvitamin and pancreatic enzyme supplementation,'4 andthe increased ascertainment of milder forms of cysticfibrosis in adults.'

Since the mid-1970s median age at death has tendedto be higher in male patients and in patients with non-manual occupations. The odds of death at above themedian age for the year of death were independentlyrelated from 1974 to sex, social class, and region ofresidence. Some reports have noted significantlylonger survival in male patients 66" and others havenot,4""13 31 3' 38 perhaps because the difference in age atdeath (about two years in the present study) is fairlysmall. The reason for the male advantage is not clear,and confounding of increasing age at death with timemakes it uncertain whether the increased survival inmale patients is due to a differential effect of treatmentor to more rapid deterioration in female patients afterlate childhood."9

After the effects of sex had been allowed for socialclass had a strong and independent effect on age atdeath. The effect of social class in the present study isopen to bias by reverse causation (that is, cystic fibrosisdetermining social class) and by confounding by themethod of coding social class. Reverse causation isparticularly likely in adults, who represent a success insurvival, and may because of respiratory disability tendto select non-manual occupations. This influence willbe offset to some extent by the fact that adults inmanual occupations are likely to be those with the leastdisability and the best prognosis. For deaths underage 16 coding of social class by the mother's occupationmay be associated with prolonged survival as mothersmay be unlikely to take paid work of any categoryunless their child is old enough and well enough toattend school. Father's social class is likely to be theleast biased indicator of family lifestyle but is availablein data from the Office of Population Censuses andSurveys only if death occurred below age 16 and in theabsence of a working mother.The social class of most (83%) of those who died was

coded by the father's or spouse's occupation; thisshowed a consistent trend towards a higher age at deathin non-manual occupations (table II). In deaths codedfor own occupation the age at death represented by the75th centile was higher in the manual category,supporting the suggestion that adults who choosemanual occupations tend to have a better prognosis.The small number of deaths with social class coded bythe mother's occupation were all in the non-manualcategory, and age at death was higher than in groupscoded by the father's occupation. This supports theassociation of working mothers with older children,and although the group was small, the fact that all ofthe mothers had non-manual occupations suggests thatthese older children tended to come from families of ahigher social class. Thus despite the bias inherent inthe methods of recording social class the consistenteffect of social class suggests that the observed relationbetween higher social class and higher age at death isvalid. The lower ages at death in the lower social classesmay be caused either by a lack of resources to permitvisits to hospitals or the local doctor or to providemedicines and dietary supplements, or by factorssuch as increased parental smoking, poor quality orovercrowded housing, and lower levels of education.40'

After the effects of sex and social class were allowedfor there were appreciable differences in the odds ofdeath at above median age among the regions ofEngland and Wales. The differences had no clear

geographical pattern. Climate, air pollution, theavailability and nature of health services, and thedifferential effects of social class are all potentialcontributors to these differences.

This study showed that the prognosis of cysticfibrosis improved greatly in England and Wales overthe past 30 years and that social class, sex, and region ofresidence were all independent determinants of ageat death. Given the disproportion of non-manualoccupations among patients attending at least onespecialist clinic in England," social class is particularlylikely to confound the association between attendanceat specialist clinics and improved survival. The reasonsfor the effect of social class on survival with cysticfibrosis should be investigated further to determinewhether alternative, possibly less centralised, forms ofhealth care might be more effective for patients fromlower social classes. Current plans to provide facilitiesto care for the growing numbers of patients with cysticfibrosis should take particular account of the effect ofsocial class.

I thank Richard Somerville and Nirupha Lakhani from theOffice of Population Censuses and Surveys for supplying theraw data, Antoni Wisniewski for help with entering data, DrDavid Strachan for advice in preparing the paper, ProfessorAnne Tattersfield for comments on the manuscript, and theMedical Research Council for financial support.

1 Andersen DH. Cvstic fibrosis of the pancreas. ] Chronic D)is 1958 ;7:58-90.2 Polgar G, D)enton R. Cystic fibrosis in adults. Am Rev, Respir Dis 1962;85:

3 19-27.3 Pogue RE, Wlarwick W'J. Cystic fibrosis. A new challenge to internal medicine.

Mtinn Med 1969;52:1551-5.4 Huang NN, Macri CN, Girone J, Sproul A. Survival of patients with cystic

fibrosis. A.m j Dis Chtld 1970;120:289-95.5 George 1, Norman AP. Life tables for cystic fibrosis. Arch D)is (hild

1971;46:139-43.6 Warwick WJ, IPogue RE, Gerber HU, Nesbitt CJ. Survival patterns in cystic

fibrosis. ] Chronic Dis 1975;28:609-22.7 Dynesen H, Flensborg EW'. P'rognosen for cystisk fibrose lDallmark

1945-1974. t1geskr Laeger 1978;140:463-70.8 Phelan lPD), Allan JL, Landau LI, Barnes GL. Improved survival if patients

with cystic fibrosis. Medj Aust 1979;1:261-3.9 Warwick WI. IPrognosis for sursival with cystic fibrosis: the effects of carlI

diagnosis atld cystic fibrosis center care. Acta Paediatr Stand [Suppl]1982;301:27-3 1.

10 Nielsen OH, Schiotz PO. Cystic fibrosis in Denmark in the period 1945-1981.Evaluation of centralised treatment. Acta Palaedi'atr Scatad [Suppl] 1982;301:107- 19.

11 Hill D)JS, Martin AJ, lDavidson (ill, Smith GS. Survival of cystic fibrosispatients in South Australia. Medj Aust 1985;143:230-2.

12 Geddes I)M, I)odge JA. Improving prognosis for cystic fibrosis in the UK1977-1985. 7'horax 1988;43:838.

13 Hudson 1, Phelan PD. Arc sex, age at diagnosis, or mode of presentationprognostic f:actors for cystic fibrosis? Peditaitr Pulmonol 1987;3:288-97.

14 Wood RE, Boat TF, Doershuk CF. Cvstic fibrosis. 3Am Rev, Respir D)is1976;113:833-78.

15 Stern RC, Boat TF, Doershuk CF, Tucker AS, Primiano FP, iNMatthews LW.Course of cystic fibrosis in 95 patients. ] Pediatr 1976;89:406-1 1.

16 Phelan P, Hey E. Cystic fibrosis mortality in England and Wales and inVictoria, Australia 1976-80. Arch Dis Child 1984;59:71-83.

17 Corey M, McLaughlin FJ, Williams M, Levison H. A comparison ot survival,growth and pulmonary function in patients with cystic fibrosis itt Btoston andToronto. Journal ofClinical Epidemi'ologv 1988;41:583-91.

18 IPenketh ARL, Wise A, Mearns MB, Hodson IE, Batten JC. Cystic fibrosis inadolescents and adults. Thorax 1987;42:526-32.

19 World Health Orgattisation. Manual ol thhe niernational statistical classificationoJ diseases, injuries and causes of death. 7ih Revision, 1955. (Geneva: WHON,1957.

20 World Health Organisation. Manual of/the international statistical classlficationsI'diseases, insurnes and causes ssf death. 8th Revision, 1965. (Getneva: WHO,1967.

21 World Health Organisation. Mfanual oJ the internatilcnal siatistical classificationol diseases, injuries and causes of death. 9ih Revision, 1975. Geneva: WHO,1977.

22 Office of Plopulation Ccnsuses and Surveys. Registrar feneral's statisticall review-Fof England atid Wa'les f)or the rear 1968. I'art I: tables, medical. I.ondon:HMSO, 1970.

23 Office of Population Censuses and Surveys. Registrar General's statistical review,of England and Wlales for the Year 1969. Part I: tables, medical. London:HMIISO, 1971.

24 Office of Population Censuses and Surveys. Registrar General's statistical reviewvof England and Wales for the Year 1970. Part 1: tables, medical. London:HMSO, 1972.

25 SPSS-X Inc. SPSS-X users guide. 2nd cd. New York: McGraw Hill, 1986.26 Numerical Algorithms Group. Generalised linear interactivecmodelling system,

release 3. 77. Oxford: Royal Statistical Society, 1986.27 Office of l'opplation Censuses and Surveys. sirtis statistics 1975. Lontdon:

HMSO, 1978. (Series FMI No 2.)28 Office of P'opulation Censuses and Surveys. Blirth statisti(cs 1985. Londoss:

HMSO, 1986. Scries FMI No 12.)29 Allan Jl,, Robbic Ml, Phelan PD, D)anks DMI. TIhe incidence and prcscntation

osf cystic fibrosis its Victoria 1955-1978. Aust Paedicatrj 1980;16:270-3.

486 BMJ VOLUME 298 25 FEBRUARY 1989

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30 McPartlin JF, Dickson JAS, Swain V'AJ. Meconium ileus. Immediate andlong-term survsial. Arch Dis Child 1972;47:207- 10.

31 Wilmott RW, Tyson SL, Dinwiddie R, Matthew DJ. Survival rates in cysticfibrosis. Arch Dis Child 1983;58:835-6.

32 Shwachman H, Doolev RR, Guilmette F, Patterson PR, W'eil C, LeubnerH. Cystic fibrosis of the pancreas with v-arying degrees of pancreaticinsufficiency. Amj Dis (Child 1956;92:347-68.

33 Karlish AJ, Tarnokv AL. lucoviscidosis as a factor in chronic lung disease inadults. Lancet 1960;ii:514-5.

34 Anderson EG, Laszlo G, Brown HM. A case of mucoviscidosis in an adult. Br]Dis Chesi 1965;59:173-6.

35 (iracey M, Andcrson CMN. Cystic fibrosis of the pancreas in adolescence andadulthood. Australian Annals of Medicine 1969;18:91- 101.

36 'l'omashefski JF, Christoforidis AJ, Abdullah AK. Cystic fibreosis in youngadults. Chest 1970;57:28-36.

37 Knoke JD, Stern RC, Doershuk CF, Boat TF, Mlatthews LW. Cystic fibrosis:the prognosis for five-year survival. Pediatr Res 1978;12:675-9.

38 Wilmott RW, T'lyson SL, Matthew DJ. Cystic fibrosis survival rates. AmJ DisChild 1985;139:669-71.

39 Corey AM, Levison H, Crozier D. Five- to seven-year course of pulmonaryfunction in cvstic fibrosis. Am Rev Respir Dis 1976;114:1085-92.

40 Black D, Morris JN, Smith C, Townsend P. The Black report. In: TownsendP, Davidson N, eds. Inequalities in health. Harmondsworth: Penguin,1982:39-233.

(Accepted 2 December 1988)

Plasma lipid and coagulation factor concentrations in insulindependent diabetics with microalbuminuria

S L Jones, C F Close, M B Mattock, R J Jarrett, H Keen, G C Viberti

Unit for MetabolicMedicine, United Medicaland Dental Schools, Guy'sHospital, London SEI 9RTS L Jones, MRCP, researchregistrar in metabolic medictneC F Close, MRCP, researchregistrar in metabolic medicineM B Mattock, PHD, principalbiochemistR J Jarrett, FFCM, professor ofclinical epidemiologyH Keen, FRCP, professor ofhuman metabolismG C Viberti, MRCP, professorofdiabetic medicine

Correspondence to:Professor Viberti.

BrMedj 1989;298:487-90

AbstractObjective-To determine whether insulin depend-

ent diabetics with microalbuminuria have significantabnormalities in concentrations of lipoproteins, apo-lipoproteins Al and B, fibrinogen, and clotting factorVII which could result in increased cardiovascularrisk.Design-Case-control study.Setting-Outpatient department of a metabolic

ward.Patients-Group of 20 insulin dependent dia-

betics with urinary albumin excretion rates greaterthan 30 [tg/min (microalbuminuria) and 20 indi-vidually matched insulin dependent diabetics withnormal urinary albumin excretion rates (below30 Fg/min) matched for age, sex, and duration ofdiabetes.

Interventions-Fasting venous blood sampleswere taken for determination of concentrations ofglucose, glycated haemoglobin, lipoproteins, apo-lipoproteins Al and B, fibrinogen, and factor VII.Height, weight, arterial pressure, and usual insulindose were recorded, and each patient was given adietary questionnaire to be completed at home.End point-Comparison of blood pressure and

concentrations of lipoproteins, apolipoproteins AIand B, and fibrinogen in the diabetics with micro-albuminuria and the controls.Measurements and main results- Patients with

microalbuminuria had significantly higher concen-trations of low density lipoprotein cholesterol (mean3*33 (SE 0.20) v 2-84 (0-12) mmol/l) and very lowdensity lipoprotein cholesterol (0.30 (0.05) v 0-17(0.03) mmol/l) than controls but significantly lowerconcentrations of high density lipoprotein 2subfraction cholesterol (0-32 (0.04) v 0*54(0.04) mmol/l). Concentrations of total triglyceride(1-11 (0-14) v 0*68 (0.08) mmol/l), very lowdensity lipoprotein triglyceride (0-56 (0.10) v 0 30(0.05) mmol/l), apolipoprotein B (0-88 (0.06) v 0-67(0 03) g/l) and fibrinogen (2-2 (0 1) v 1-9 (0-1) g/W), anddiastolic arterial pressure (80 (2) v 74 (2) mm Hg),were also higher in patients with microalbuminuria.

Conclusions-Cardiovascular risk factors-namely, disturbances in lipoprotein and apolipo-protein concentrations, increased fibrinogenconcentration, and increased arterial pressure-arealready present in insulin dependent diabetics withmicroalbuminuria. The increased risk of coronaryheart disease in patients with clinical proteinuriamay result from prolonged exposure to these riskfactors, which are present before any impairment ofrenal function.

IntroductionInsulin dependent diabetics who develop clinical

proteinuria have a much greater risk of prematuredeath from cardiovascular complications than thosewithout proteinuria. 2 A subclinical increase in urinaryexcretion of albumin (microalbuminuria) predicts thedevelopment of persistent clinical proteinuria andrenal failure in insulin dependent diabetics.'-' In bothprospective and cross sectional studies of non-insulindependent diabetics microalbuminuria stronglyindicated an increased risk of death from cardio-vascular complications,79 and it may also do so in non-diabetics.' "

At the stage of clinical proteinuria and progressiverenal failure changes in plasma lipoprotein concentra-tions,'2-'4 an increase in systemic blood pressure,'2and haemorrheological changes' 16 have each beenproposed as contributing to the increased cardio-vascular risk. The situation is less clear in patients withmicroalbuminuria, in whom renal function is normalor even supranormal. Several workers have shown araised arterial blood pressure at this stage,46"7 andcontrol of blood glucose concentration has also beenreported to be worse."' Reports have suggested thatprofiles of lipoprotein concentrations are changed indiabetics with microalbuminuria and lie between thosein diabetics with normal albuminuria and diabeticswith clinical proteinuria. 1' 1' The differences, however,were not significant and could have been accounted forby the poorer glycaemic control in the diabetics withmicroalbuminuria."3

In this case-control study we compared concentra-tions of lipoproteins, apolipoproteins, fibrinogen,and factor VII in insulin dependent diabetics withmicroalbuminuria and diabetics with normal albuminexcretion rates with similar control of their bloodglucose concentration.

Patients and methodsTwenty insulin dependent diabetics with micro-

albuminuria were matched individually for age, sex,and duration of diabetes with 20 insulin dependentdiabetics shown to have normal rates of albuminexcretion. All were less than 65 years old and had haddiabetes since before the age of 35. All patients wereEuropids and received the standard dietary advicegiven to diabetics. None were taking drugs otherthan insulin apart from two patients with micro-albuminuria, who were receiving long term thyroxineand cortisol replacement treatment. No patient had ahistory of renal disease or of drug or alcohol abuse.As part of a collaborative screening programme" we

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