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The outcome of brittle type 1 diabetes—a 20 year study

A. Cartwright, M. Wallymahmed, I.A. MacFarlane, A. Wallymahmed, G. Williams, G.V. Gill
DOI: http://dx.doi.org/10.1093/qjmed/hcr010 575-579 First published online: 1 February 2011

Abstract

Aims: To determine the long-term (20 years from presentation) outcome of brittle type 1 diabetes characterized by recurrent episodes of ketoacidosis (DKA).

Methods: The cohort studied was a group of brittle diabetic patients from various parts of UK originally identified between 1979 and 1985. Patients were traced, where possible, via their diabetic clinics and/or general practitioners. Data on survival or otherwise were obtained from hospital case notes and information from diabetes care team members. For survivors, clinical and demographic information obtained included complication status and whether they still had brittle characteristics. They were also compared with a matched case–control group of type 1 patients with no history of brittle behaviour.

Results: The original cohort comprised 33 patients— all female and mean ± SD, aged 18 ± 5 years and diabetes duration 8 ± 4 years. Thirteen were not traceable and 10 of the remaining 20 (50%) had died during the mean 22 years of follow-up. Deaths occurred evenly throughout the period, and causes were chronic renal failure (3), DKA (3), hypoglycaemia (2), subarachnoid haemorrhage (1) and uncertain (1). Age at death ranged from 27 to 45 years. Of the 10 survivors, none remained brittle, but they had a substantial burden of complications. Compared with the non-brittle control group, there was a significant excess of nephropathy and autonomic neuropathy.

Conclusions: We conclude that brittle diabetes characterized by recurrent DKA has high long-term outcome mortality. These deaths were premature and almost all diabetes related. Those who survived had resolution of brittleness, but suffered a significant complication burden.

Introduction

The term ‘brittle’ is used to describe an unusual subgroup of type 1 diabetic patients whose lives are disrupted by glycaemic instability with repeated (and often prolonged) hospitalization.1–3 Such patients generally defy conventional attempts at recontrol with multiple injection therapy, or continuous subcutaneous insulin infusion (CSCII),4 and place a heavy burden on their health-care teams.5 Type 1 patients with brittle behaviour most frequently have recurrent admissions with diabetic ketoacidosis (DKA),2,6,7 and such patients are usually young and female, overweight and insulin resistant.8 Though the aetiology of the ‘syndrome of recurrent DKA’7 is not always clear, in at least some cases self-induction of instability has been demonstrated.8–10 In a series of such patients in the USA, (all thought to have ‘subcutaneous insulin resistance’11), careful and supervised tests of insulin absorption and activity demonstrated entirely normal insulin absorption and pharmacokinetics.11

Whatever the cause, brittle type 1 diabetes is very difficult to treat.7 Thankfully, most cases resolve spontaneously with the passage of time, often coinciding with positive life events.3,6 However, outcome studies up to 10 years of follow-up have shown a relatively high mortality from potentially preventative causes (e.g. DKA and hypoglycaemia), as well as an excess of microvascular complications and adverse pregnancy outcome.3

In this article, we report on the long-term outcome (20 years) of a cohort of type 1 patients originally presenting in the second and third decades of their lives with recurrent DKA.

Patients and methods

Patient cohort

We followed the progress and survival of an original cohort of 33 ‘brittle’ type 1 diabetic patients from various parts of UK, originally recruited between 1979 and 1985 at two academic UK diabetes centres with an interest in unstable type 1 diabetes (Freeman Hospital, Newcastle upon Tyne and Guys Hospital, London). All patients had been intensively investigated at these centres, and they fulfilled the contemporary diagnostic criterion of life-disrupting glycaemic instability,1 as well as later accepted characteristics including recurrent and/or prolonged hospitalizations,3 and glycaemic instability despite intensive subcutaneous insulin therapy (including subcutaneous pump treatment).4 Their hospitalizations were almost entirely due to recurrent DKA.2

Follow-up procedure

Two of us (G. Gill and G. Williams) had been involved with the initial assessment of the cohort7, 8 and also at 10-year follow-up assessment.3 Patient contact information from these studies was updated by detailed enquiries involving hospital diabetes clinics and general practitioners. As well as the long time span of follow-up, other tracing difficulties included changes of name by marriage, change of location, and lack of NHS number details on the original records. Of the original 33 patients, 13 could not be traced, leaving a study cohort of 20 (including deceased and survivors) in whom we were able to obtain accurate information. Data were obtained from hospital case notes, supplemented by information from diabetes consultants. An experienced research nurse (A. Cartwright) obtained and recorded this information by personally visiting the appropriate hospitals. Full agreement for data collection was obtained from hospital consultants and also from surviving patients. For those who had died, the year and cause of death was obtained and enquiries if necessary included approaches to pathologists or coroner’s records. The follow-up was carried out at a mean of 22 years since the patients were first identified.

Status of survivors

Information gathered on survivors included age, diabetes duration, body mass index (BMI), glycated haemoglobin (HbA1c, all measurements DCCT aligned), total and HDL cholesterol, insulin dose, complication status, and hospitalisations (with reasons) in the last 12 months. To compare with ‘non-brittle’ type 1 patients, a case–control group was recruited. These were from a type 1 diabetes data base of our own clinic (Aintree University Hospital, Liverpool, UK), and consisted of type 1 patients who did not meet accepted definitions of ‘brittle’ diabetes3. They were also matched for age, sex and diabetes duration, but not HbA1c or complication status. Two case–controls were collected for each brittle case, by consecutive visual inspection of our database. Data recorded for this group were the same as for the brittle survivors.

Ethical approval

The study was approved as a national project by the Sefton Local Research Ethics Committee. Full permission for the study was obtained from all patients and consultants (for both cases and controls).

Statistical analysis

Crude mortality rate (MR) over the follow-up period was calculated, with details of cause and year of death. Numerical data were compared between the brittle and control groups by Student’s unpaired t-test, and proportionate data by the chi-squared test. Paired t-tests (where appropriate) were used for within group comparisons in the brittle patients. The Statistical Package for Social Sciences (SPSS version 14.0) was used.

Results

Mortality and causes

Of the original cohort of 33, 13 subjects were untraceable and 10 of the remaining 20 patients had died (mortality 50% of those traced). Causes of death (Table 1) were uncertain (1), subarachnoid haemorrhage (1) and all others (8) were diabetes related. Three died of chronic renal failure (CRF), two of hypoglycaemia and three of DKA. Five died in the first 10 years and five in the second 10 years of follow-up. Four deaths were sudden and unexpected (two hypoglycaemia, one DKA and one due to hyperkalaemia related to CRF). One woman dying from renal failure had refused any supportive therapy. The age at death ranged from 27 to 45 years.

View this table:
Table 1

Causes of death among 10 brittle type 1 diabetic patients during 20 years of follow-up

CRF3
DKA3
Hypoglycaemia2
Subarachnoid haemorrhage1
Uncertain1

Status of survivors

Table 2 shows demographic and other details at baseline, at 10 years follow-up,3 and at the current assessment over 20 years from recruitment. Brittle behaviour declined to none (0%) of the 10 final patients studied. BMI rose (24.7 ± 3.2 to 28.3 ± 4.6, P < 0.01) but insulin dose fell (124 ± 55 to 51 ± 33, P < 0.01). Rates of hospital admission and DKA fell to negligible levels at the final follow-up. All survivors were affected by diabetic complications—7 (70%) had nephropathy or microalbuminuria, 9 (90%) had retinopathy of any degree and all (100%) had neuropathy—see Table 3.

View this table:
Table 2

Details of the brittle cohort at baseline and at 10 and 20 years follow-up

Initial study 1979–81, (n = 33)Follow-up (1) 1991–92, (n = 20)Follow-up (2) 2005–06, (n = 10)
Age (years)18 ± 5 (12–44)29 ± 6 (22–44)42 ± 4 (36–50)
Duration of diabetes (years)8 ± 4 (2–19)18 ± 5 (10–31)32 ± 5 (24–40)
Number of brittle (%)21 (100)2 (10)0 (0)
Diabetic complications (%)0 (0)14 (67)10 (100)
BMI (kg/m2)24.7 ± 3.225.1 ± 3.528.3 ± 4.6a,b
Insulin dose (u/day)124 ± 5577 ± 39c51 ± 33a,b
Admissions in last year (mean per person)1220
DKA in last year (mean per person)810
  • Results expressed as mean ± SD (range) or actual number (%). aP < 0.01 initial vs. follow-up (2). bP < 0.05 follow-up (1) vs. follow-up (2). cP < 0.01 initial study vs. follow-up (1).

View this table:
Table 3

Complications of brittle diabetic patients compared with case–controls

Brittle (n = 10)Controls (n = 20)Significance
Nephropathy
    None315
    Microalbuminuria12
    Proteinuria23
    Renal impairment30
    End-stage renal failure10
    Total renal disease75P < 0.05
Retinopathy
    None13
    Retinopathy no laser112
    Retinopathy with laser65
    Partially sighted10
    Registered blind10
    Total retinopathy917p NS
Peripheral neuropathy
    None314
    Diagnosed neuropathy  (no treatment)35
    Diagnosed painful  neuropathy (treated)41
    Total peripheral  neuropathy76pNS (0.56)
Autonomic neuropathy
    None520
    Gastro-paresis40
    Postural hypotension10
    Total autonomic  neuropathy50P < 0.002
Large vessel disease
    None917
    IHD11
    CVD01
    PVD01
    Total13pNS
  • CVD, cerebrovascular disease; IHD, ischaemic heart disease; NS, not significant; PVD, peripheral vascular disease.

Case–control comparison

Table 4 compares demographic and other data with the brittle group at follow-up and the non-brittle case–controls. It can be seen that BMI, HbA1c and insulin dose were not significantly different between the two groups. Complication comparisons between the groups are in Table 3. Retinopathy rates were not significantly different, but more of the brittle group had laser treatment or were currently visually impaired. Similarly, though peripheral neuropathy was not significantly different, painful and autonomic syndromes were commoner in the brittle group. The latter patients also had more diabetic renal disease (70 vs. 25%, P < 0.05), and four of the brittle group (40%) had renal impairment or failure, compared with none in the case–controls. Serum creatinine also differed between the groups—mean 156 ± 117 in the brittle patients and 82 ± 10 μmol/l in controls (P = 0.009).

View this table:
Table 4

Demographic and other data among the brittle survivors (n = 10), and the non-brittle case–controls

Brittle (n = 10)Case– controls (n = 20)Significance
Age (years)42 ± 446 ± 6NS
Duration (years)32 ± 530 ± 6NS
BMI (kg/m2)28.3 ± 4.630.0 ± 5.4NS
HbA1c (%)9.4 ± 1.58.8 ± 1.0NS
Cholesterol4.3 ± 0.44.5 ± 0.9NS
HDL cholesterol1.8 ± 0.41.6 ± 0.4NS
Insulin dose (u/day)51 ± 3359 ± 33NS
  • Results expressed as mean ± SD; NS, not significant.

Discussion

We believe that this is the longest outcome study (over 20 years) of a group of patients with severely brittle diabetes characterized by recurrent DKA. Our previously reported 10 year follow-up study of the same cohort showed a 19% MR, though of the survivors only 10% showed brittle characteristics.3 The present study has demonstrated an overall 50% morality during the 20-year follow-up period, though none of the survivors were brittle. There was also an associated steady decline in hospitalization rates and DKA episodes during follow-up (Table 2). Of the 10 deaths in the brittle patients, 8 were diabetes related; 6 of these were due to either renal failure or DKA, but surprisingly 2 were due to hypoglycaemia (Table 1). Perhaps reduced hypoglycaemia awareness (we noted a 50% rate of autonomic neuropathy in our surviving group), may have been linked to a risk of fatal hypoglycaemia.

We accept that the numbers of patients studied are small, and that no originally recruited comparative control group was available for mortality comparison. Over such a long period of follow-up, we also had a high number we could not contact. Nevertheless, the death of half of those we were able to trace is concerning. A recent Norwegian outcome study of type 1 patients suggests that an expected mortality over such a period would be about 5%.12 The accuracy of our mortality figure is of course potentially affected by the untraceable patients. If all 13 of these had survived, the mortality would be 30% and if all had died it would be 69%–both figures still excessive.

We also compared our long-term survivors with a matched case–control group of stable type 1 patients, and this showed the brittle survivors to have significantly more diabetes-related renal disease and autonomic neuropathy (Table 3). HbA1c, BMI and insulin doses were not significantly different between cases and controls. As mentioned, an ideal control group would have been one recruited at the time of original identification of the brittle patients. An alternative would have been case–controls for each survivor from their own clinic, but this was made difficult by the lack of patient registers in some clinics. Our final control choice was the same as we used in our 10-year follow-up study.3

Resolution of brittleness has been reported before in shorter term follow-up studies.3 Sometimes it has been related to positive life events (marriage, employment, children, etc.), but there may also be a ‘survivor effect’ whereby the most severe cases are more likely to die during follow-up.

This long-term outcome study has confirmed the dangerous nature of the ‘recurrent DKA’ subgroup of brittle type-1 diabetes. As well as leading to an increased burden of microangiopathic complications, the condition has a high mortality (50% in 20 years), most of which is diabetes related. The deaths occurred in relatively young women (aged 17–45 years) and four of the deaths were sudden and unexpected, representing tragic outcome to this difficult condition.

Funding

The research was funded by a grant from Diabetes UK.

Conflict of interest: None declared.

Acknowledgements

We are grateful to all the patients who participated in this study, as well as the clinic doctors and nurses who helped with the data collection.

References

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