Folke Lithner

Glibenclamide-associated hypoglycaemia: A report on 57 cases

SummaryIn the largest series of patients with glibenclamide-associated hypoglycaemia reported so far, 51 cases reported to the Swedish Adverse Drug Reactions Advisory Committee and six additional cases are reviewed and related to sales and prescription data of glibenclamide. Median age of the patients with hypoglycaemia was 75 years and 21% were 85 years or above. For comparison, the median age of a random sample (1 in 288 of all patients prescribed glibenclamide) was 70 years and only 5% were 85 years or older. In eight out of 40 cases where duration of glibenclamide treatment was recorded, the hypoglycaemic event occurred during the first month of treatment. The median daily dose of glibenclamide prescribed was 10 mg both in the hypoglycaemic cases and in the prescription sample. Coma or disturbed consciousness was the most common clinical presentation in this series and the minimum blood glucose value was 1.3 mmol/l (median). Twenty-two patients responded immediately to treatment, 24 had protracted hypoglycaemia of 12–72 h duration and 10 died. Fatal outcome was observed even with small doses of glibenclamide (2.5–5 mg/day). Previous strokes and cardiac disorders were isolated as two independent determinants of a serious course of the hypoglycaemia. Other contributing factors included impaired renal function, low food intake, diarrhoea, alcohol intake and interaction with other drugs. Thus, it is not uncommon for glibenclamide, like the first-generation sulphonylureas, to cause serious, protracted and even fatal hypoglycaemic events.

Value of basal plasma cortisol assays in the assessment of pituitary-adrenal insufficiency

A basal plasma Cortisol value taken in a physically unstressed state in 68 patients with or without hypothalamic‐pituitary‐adrenocortical disease was compared with the maximal plasma Cortisol concentration during an insulin tolerance test. There was a strong positive correlation between the values. Basal Cortisol levels above 300 nmol/1 (RIA method) almost excluded ACTH‐cortisol insufficiency and those below 100 nmol/1 strongly suggested dysfunction. A repeated basal Cortisol estimation within a month was especially valuable in categorizing patients with levels between 100 and 200 nmol/1. We suggest that a basal Cortisol measurement may be used as a first laboratory test in patients evaluated for possible hypothalamic‐pituitary‐adrenocortical insufficiency; in many patients, this approach obviates more sophisticated and expensive testing.

The Epidemiology of Foot Lesions in Diabetic Patients Aged 15–50 Years

All diabetic patients aged 15–50 years (n = 395) in the county of Umeå (population 118 500) were invited to have a standardized foot examination and 380 (96%) attended. Three‐quarters (78%) had Type 1 diabetes, 20% Type 2 diabetes, and 1% secondary diabetes. They were compared with 100 healthy control subjects. Both Type 1 and Type 2 diabetic patients had slight or moderate loss of forefoot arches more often than control subjects (57% and 60% vs 31%, p < 0.001). Callosities were not significantly more common in diabetic patients than in control subjects. Lesions observed on the lower legs and feet of the Type 1 and Type 2 diabetic patients were Melins shin spots (33% and 39%), dry feet (33% and 29%), yellow toenails (27% and 31%), purpura (9% and 5%), ulcers (3% and 0%), necrobiosis (3% and 0%), and diabetic osteopathy (2% and 0%). Intermittent claudication was present in 1% and 3%, respectively. Three Type 1 diabetic patients had undergone below‐knee amputation. Two of the control subjects had Melins shin spots. With the exception of necrobiosis which was only found in women with Type 1 diabetes and Melins shin spots which were twice as common in diabetic men as women, whether Type 1 or Type 2, lesions were equally distributed between the sexes. Sensory thresholds for vibration, perception, and pain were significantly elevated in Type 1 diabetic patients with dry feet, fallen forefoot arches or hammer toes compared with those without. They were not increased in Type 2 diabetic patients or control subjects with these lesions. In conclusion, foot deformity and lesions of skin and nails are common in the feet of diabetic patients in this age group while macroangiopathy appears to be uncommon.

Male predominance of type 1 (insulin-dependent) diabetes mellitus in young adults : results from a 5-year prospective nationwide study of the 15-34 year age group in Sweden

SummaryThe incidence of diabetes mellitus in Sweden in the 15–34 year age group was prospectively studied on a nationwide basis, beginning 1 January 1983. A total of 1,214 male and 720 female cases of newly-diagnosed (excluding gestational) diabetes were reported over a 5-year period. This corresponds to an incidence of 20.5 per 100,000/year in male subjects and 12.7 per 100,000/year in female subjects. Most cases were classified as Type 1 (insulin-dependent) diabetes, with an incidence of 15.9 in males and 8.6 in females. The incidence of Type 1 diabetes decreased gradually with age, while the incidence of Type 2 (non-insulin-dependent) diabetes increased. A male predominance was found in all age groups, with a male-to-female ratio of 1.8∶1 for Type 1 diabetes and 1.3∶1 for Type 2 diabetes. Maximum blood glucose concentration at diagnosis was significantly higher in males than in females in both Type 1 and Type 2 diabetic subjects. In contrast, the percent desirable weight was significantly higher in females, both in Type 1 and Type 2 diabetic subjects. The difference in diabetes incidence therefore cannot be attributed to any methodological error. The present finding of a marked male predominance after puberty in Type 1 diabetes in an ethnically quite homogeneous population supports the hypothesis that environmental risk factors and life-style are important for the development of the disease.

The epidemiology of hepatocellular carcinoma in patients with acute intermittent porphyria

Objective. To describe the epidemiology, pathogenesis and clinical features of hepatocellular carcinoma (HCC) in patients with acute intermittent porphyria (AIP).

Negative association between type 1 diabetes and HLA DQB1*0602-DQA1*0102 is attenuated with age at onset

HLA-associated relative risks of type 1 (insulin-dependent) diabetes mellitus were analysed in population-based Swedish patients and controls aged 0-34 years. The age dependence of HLA-associated relative risks was assessed by likelihood ratio tests of regression parameters in separate logistic regression models for each HLA category. The analyses demonstrated an attenuation with increasing age at onset in the relative risk for the positively associated DQB1*0201-A1*0502/B1*0302-A1*0301 (DQ2/8) genotype (P = 0.02) and the negatively associated DQB1*0602-A1*0102 (DQ6.2) haplotype (P = 0.004). At birth, DQ6.2-positive individuals had an estimated relative risk of 0.03, but this increased to 1.1 at age 35 years. Relative risks for individuals with DQ genotype 8/8 or 8/X or DQ genotype 2/2 or 2/X, where X is any DQ haplotype other than 2, 8 or 6.2, were not significantly age-dependent. An exploratory analysis of DQ haplotypes other than 2, 8 and 6.2 suggested that the risk of type 1 diabetes increases with age for DQB1*0604-A1*0102 (DQ6.4) and that the peak risk for the negatively associated DQB1*0301-A1*0501 haplotype is at age 18 years. There was also weak evidence that the risk for DQB1*0303-A1*0301 (DQ9), which has a positive association in the Japanese population, may decrease with age. We speculate that HLA-DQ alleles have a significant effect on the rate of beta cell destruction, which is accelerated in DQ2/8-positive individuals and inhibited, but not completely blocked, in DQ6.2-positive individuals.

Epidemiology and clinical characteristics of seizures in patients with acute intermittent porphyria

The objectives of this study were to investigate the lifetime prevalence of epileptic seizures in a population with acute intermittent porphyria (AIP) and to characterize the seizures and the seizure‐triggering factors. A letter was sent to all patients with known AIP in Sweden registered at the National Porphyria Center (n = 294). The medical records of patients who had had epileptic seizures were reviewed in detail. The letter was answered by 268 patients (91.2%). Ten patients (3.7%) reported epileptic seizures. Eight were women (mean age 54.1 years, range 30–81 years), and 2 were men (mean age 19 years, range 9–29 years). Six patients had tonic‐clonic seizures and 4 had partial seizures becoming secondarily generalized. Serum sodium levels were low in 3 patients (mean 110, range 103–120 mM), and normal in 5. Excretion of 5–aminolevulinic acid (ALA) in the urine was increased in 4 patients at the time of the seizures. In 6 patients, the seizures were associated with an acute attack of AIP (all patients with hyponatremia included). The lifetime prevalence of AIP‐associated seizures was 2.2% of all those with known AIP and 5.1% of all those with manifest AIP. Epileptic seizures among persons with AIP are less common than has been previously described.

Hypertension and renal disease in patients with acute intermittent porphyria

Abstract. Objectives. To assess the association between acute intermittent porphyria (AIP), hypertension and renal disease.

Difficulties in Classifying Diabetes at Presentation in the Young Adult

All newly diagnosed diabetic patients in Sweden aged 15–34 years have been registered since 1983. In this study the clinical characteristics initially and after 2.5‐3 years were evaluated by a questionnaire to the patients physician and by non‐fasting C‐peptide. The study comprised patients registered 1983‐84, and for 281 patients (37%), complete information was obtained. At diagnosis 75% were classified as Type 1, 19% as Type 2, and 6% as secondary diabetes or as uncertain by their physician. Twenty patients (7.1%) were reported to have ketoacidosis. Seventy‐five percent were treated with insulin, 7% with oral hypoglycaemic agents (OHG), and 18% with diet alone. At follow‐up 71% were classified as Type 1, 21% as Type 2, and 8% as secondary or uncertain while treatment was 82% insulin, 8% OHG, and 9% diet. During the follow‐up period 42% of the initially non‐insulin‐treated patients were put on insulin whereas only a few stopped insulin treatment. Patients treated with diet or OHG at follow‐up were older, had higher percent desirable weight, and lower blood glucose at diagnosis than patients treated with insulin. All except one patient had measurable random C‐peptide at follow‐up and mean values were for patients treated with insulin 0.55, OHG 1.41 and diet alone 1.29 nmol I−1. Random blood glucose results were similar. In conclusion the majority of newly diagnosed patients in the age group 15–34 years have the characteristics of Type 1 diabetes and Type 2 diabetes is rare before 25–30 years of age. Patients with biochemically mild hyperglycaemia are difficult to classify and there is a need for new guidelines for classification of diabetes which include aetiopathogenetic aspects.

The W198X and R173W mutations in the porphobilinogen deaminase gene in acute intermittent porphyria have higher clinical penetrance than R167W. A population-based study

In northern Sweden, 468 patients with DNA-verified acute intermittent porphyria (AIP) were registered. A higher prevalence of manifest AIP was found in patients with mutations W198X and R173W when separately compared with mutation R167W, indicating higher clinical penetrance. Signs of increased seriousness of the disease were also found in patients with the W198X and R173W mutations in relation to the number and duration of attacks, impaired renal function and chronic disability. One explanation could be lower PBGD enzyme activity resulting from the W198X and R173W mutations than from the R167W mutation, though other factors might also be the cause.In northern Sweden, 468 patients with DNA-verified acute intermittent porphyria (AIP) were registered. A higher prevalence of manifest AIP was found in patients with mutations W198X and R173W when separately compared with mutation R167W, indicating higher clinical penetrance. Signs of increased seriousness of the disease were also found in patients with the W198X and R173W mutations in relation to the number and duration of attacks, impaired renal function and chronic disability. One explanation could be lower PBGD enzyme activity resulting from the W198X and R173W mutations than from the R167W mutation, though other factors might also be the cause.