In a retrospective study over a 20-year period we found in the Umeå region in Sweden 11 patients (7 women and 4 men, mean age 67 years) with both hepatocellular carcinoma and acute intermittent porphyria. This coincidence was highly significant. Concomitant existence of portal cirrhosis of the liver was demonstrated in those 5 patients in whom it could be examined.

OBJECTIVES:To detect post-operative sequelae of sural nerve biopsy.MATERIALS AND METHODS:A questionnaire mailed to type 1 diabetic patients (n = 24; male/female 23/1; reply n = 23) 2 years after biopsy.RESULTS:Type 1 diabetic patients (age 56 [11]; median [interquartile range]) had a long duration of diabetes (DM; 20 [19] years) and all had neuropathy. Three out of 24 patients developed infection (two superficial and one deep) and one had a post-operative bleeding. Less frequent pain among the patients were reported from one centre. About one-third or more of the patients still complained of pain, mostly mild, in the biopsy area and paraesthesia in the foot 2 years after surgery. More than two-thirds of the patients were reluctant for further biopsy; a crucial information in drug trial planning.CONCLUSIONS:Sequelae of a sural nerve biopsy occur in type 1 DM. The risk for wound infections should be considered.

Objectives. To study the effects of diabetes mellitus in patients with acute intermittent porphyria (AIP).Haeme deficiency in the liver of AIP patients stimulates an increase in ALA-synthase which triggers an escalating metabolic chain reaction, leading to an increase in the porphyrin content. This reaction can be reduced by treating AIP patients with haeme arginate or with glucose.Design. A population-based study of all patients >18 years of age having DNA-verified AIP (n = 328) living in the two most northerly counties of Sweden (Norrbotten and Vasterbotten, with 550 000 inhabitants) of whom 16 had type 2 diabetes. Prevalence of diabetes was studied retrospectively in 26 AIP patients with hepatocellular carcinoma (HCC).Results. None of the patients showed symptoms of AIP after the onset of their diabetes. Three patients had had recurrent, severe attacks for many years but when their diabetes became manifest, their urinary ALA and PBC levels decreased and the AIP symptoms resolved, to the relief of the patients. Amongst the 26 AIP patients with HCC, only one with signs of diabetes was identified (impaired glucose tolerance test).Conclusions. This study raises the possibility that diabetes mellitus may be beneficial for patients with severe AIP.

Abdominal pain is by far the most serious symptom in attacks of acute intermittent porphyria (AIP). Its cause is unknown. This case suggests visceral ischemia as a possible cause of the abdominal pain. A 31-year-old woman with recurrent bouts died during an attack; the autopsy revealed a 20 cm necrotic gangrene in the ileum. A protracted intestinal vasospasm could have been the immediate cause of death. The question as to whether intestinal angina could be the cause of abdominal pain in acute intermittent porphyria is discussed.

In AIP attacks there is an escalating metabolic chain reaction leading to heme deficiency and increased levels of porphyrin precursors. This reaction is inhibited by treatment with glucose or heme arginate. In a population-based study in the two most northerly counties of Sweden (Norrbotten and Västerbotten), out of 319 patients > 18 years of age with DNA-verified AIP, 16 had type-2 diabetes. None of the 16 patients showed AIP symptoms after the onset of their diabetes. Three patients had suffered recurrent, severe attacks for many years, but after onset of diabetes their ALA and PBG levels decreased and the AIP symptoms resolved, to the relief of the patients. In a study of the 30 AIP patients with hepatocellular carcinoma (HCC) none had diabetes. This implies that diabetic metabolism may prevent the development of HCC in patients with AIP. The prevalence of AIP patients with diabetes was lower than the prevalence of diabetic patients in the general population. This study shows that diabetes mellitus may be beneficial for patients with severe AIP.

OBJECTIVESTo study, prospectively, in young adult patients, the mortality during the first years after the diagnosis of diabetes.DESIGNThe Diabetes Incidence Study in Sweden (DISS) aims to register all incident cases aged 15-34 years. During a 10-year period all deaths were identified by record linkage to the national Cause of Death Registry.SUBJECTSDuring the period, 4097 new cases were registered and classified as type 1 diabetes (73%), type 2 (16%), secondary (2%) and unclassified (9%). The median follow-up was 5 years (21 001 person-years).MAIN OUTCOME MEASURESCalculation of the standardized mortality ratio (SMR) and 95% confidence interval (CI). Evaluation of all deceased by scrutiny of clinical records, death certificates and autopsy protocols.RESULTSFifty-eight patients died, corresponding to an SMR of 3.5 (CI=2.7-4.5), which increased from 1.5 at 15-19 years to 4.1 at 30-34 years. SMR was 2.7 in primary diabetes: 2.3 (1.6-3.3) in type 1 and 4.1 (2.6-6.7) in type 2. In secondary diabetes, alcohol-associated pancreatitis a common cause, SMR was 32 (CI=24-45). Evidence of alcohol or drug misuse, mental dysfunction or suicide was found in 40 of all 58 deceased cases. Less often, hypoglycaemia (n=7) or hyperglycaemia-ketoacidosis (n=11) was present at death. Unexplained 'dead in bed' was found once.CONCLUSIONSIn the investigated population-based cohort the early mortality was about threefold increased. Hypoglycaemia and ketoacidosis per se played a relatively small role compared with a heavy impact from social and mental dysfunction, and from careless use of alcohol or drugs.

Distal neuropathy was assessed in 339 patients with acute intermittent porphyria (AIP). The chronic neurological signs were symmetrical and similar to those in Type 1 diabetic patients. Significant impairment was found concerning perception, extensor digitorum brevis test, lower leg pain, ankle and knee tendon reflexes but not concerning dry feet, loss of forefoot arch and hammer toes, when comparing patients with manifest vs. latent AIP. The neurological signs were more severe in the diabetic patients (n = 298). Five AIP patients had permanent quadriplegia and renal failure after severe attacks. Patients with manifest AIP had significantly more signs of distal chronic, symmetrical neuropathy of axonal type than had patients with latent AIP. More serious neurological lesions appear to develop after severe attacks.

This study presents a 2-yr follow-up of 281 patients, aged 15-34 yr, diagnosed with diabetes between 1992 and 1993. At diagnosis, 224 (80%) patients were positive for at least one of the following autoantibodies: islet cell antibodies (ICAs), glutamic acid decarboxylase antibodies (GADAs), or tyrosine phosphatase antibodies (IA-2As); the remaining 57 (20%) patients were negative for all three autoantibodies. At diagnosis, C-peptide levels were lower (0. 27; 0.16-0.40 nmol/L) in autoantibody-positive patients compared with autoantibody-negative patients (0.51; 0.28-0.78 nmol/L; P: < 0. 001). After 2 yr, C-peptide levels had decreased significantly in patients with autoimmune diabetes (0.20; 0.10-0.37 nmol/L; P: = 0. 0018), but not in autoantibody-negative patients. In patients with autoimmune diabetes, a low initial level of C-peptide (odds ratio, 2. 6; 95% confidence interval, 1.7-4.0) and a high level of GADAs (odds ratio, 2.5; 95% confidence interval, 1.1-5.7) were risk factors for a C-peptide level below the reference level of 0.25 nmol/L 2 yr after diagnosis. Body mass index had a significant effect in the multivariate analysis only when initial C-peptide was not considered. Factors such as age, gender, levels of ICA or IA-2A or insulin autoantibodies (analyzed in a subset of 180 patients) had no effect on the decrease in beta-cell function. It is concluded that the absence of pancreatic islet autoantibodies at diagnosis were highly predictive for a maintained beta-cell function during the 2 yr after diagnosis, whereas high levels of GADA indicated a course of decreased beta-cell function with low levels of C-peptide. In autoimmune diabetes, an initial low level of C-peptide was a strong risk factor for a decrease in beta-cell function and conversely high C-peptide levels were protective. Other factors such as age, gender, body mass index, levels of ICA, IA-2A or IAA had no prognostic importance.

OBJECTIVE:To assess signs of distal neuropathy in patients with acute intermittent porphyria (AIP). DESIGN:A population-based study. SUBJECTS:All patients with DNA-verified AIP >/= 18 years of age in the four most northerly counties of Sweden. INTERVENTION:Validated neuropathic signs and tests such as monofilament test, neuropathic pain, dry feet, extensor digitorum brevis (EDB) test, loss of forefoot arch, hammer toes and ulceration. RESULTS:A total of 356 patients were registered and 339 of them (95%) participated in the neuropathy study. The chronic neurological signs were symmetrical and similar to those in type 1 diabetic patients. Significant impairment was found concerning perception, EDB test, lower leg pain, ankle and knee tendon reflexes, but not concerning dry feet, loss of forefoot arch and hammer toes, on comparing patients with manifest versus latent AIP. The neurological signs were more severe in the diabetic patients (n = 298). Five AIP patients had permanent quadriplegia after severe attacks. CONCLUSIONS:Patients with manifest AIP had significantly more signs of distal chronic, symmetrical neuropathy of axonal type than did patients with latent AIP. More grave neurological lesions appear to develop after severe attacks.

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.

The aim of this study was to elucidate the experiences of the women with severe, recurrent attacks of porphyria and how they coped with them successfully. A total of five women were interviewed and were encouraged to describe their experiences. Thematic content analysis was used to interpret the significance of their narratives. The result demonstrated that the women's experience was of living in deepest darkness with inexpressible pain, both physical and mental. Coming into contact with health care had its good and bad points. It was often difficult to cope with life during severe periods of the disease. The process of maturation towards a more positive existence seemed to follow a pattern of accepting the disease, continuing the fight until it was finally possible to discover a pattern and meaning in life that suited the individual concerned.

Objective. Can renal insufficiency in subjects with acute intermittent porphyria (AIP) be due solely to AIP?Design. A population-based study.Subjects. Subjects with AIP greater than or equal to 18 years of age (n = 386) in the four most northerly counties of Sweden.Interventions. Screening with creatinine clearance at 24 h. Patients below the lower reference level underwent a repeat clearance test and, if still low, also chromEDTA clearance.Results. 286 (74%) subjects performed the creatinine clearance test and in 57 clearance was low; the second clearance proved normal in 23 who were then excluded. Eighteen subjects with other possible medical reasons for renal insufficiency, ethical reasons or refusing further examinations were also excluded. The 16 remaining subjects with no explanation for their renal insufficiency other than AIP were then studied in detail. All 14 women, mean age 52 years, and two uraemic men, 58 and 67 years, had manifest AIP. Twelve patients had hypertension (HT) and four were normotensive in spite of renal insufficiency. Histological findings of renal biopsies revealed diffuse glomerulosclerotic and interstitial changes with additional ischaemic lesions.Conclusion. Protracted vasospasm in attacks of AIP may be a cause of renal lesions. This is discussed.

Abdominal pain is by far the most serious symptom in attacks of acute intermittent porphyria. Its cause is unknown. This case study suggests visceral ischaemia as a possible cause of the abdominal pain. A 31-year-old woman with recurrent bouts died during an attack; the autopsy revealed a 20-cm necrotic gangrene in the ileum. A protracted intestinal vasospasm could have been the immediate cause of death. It is discussed whether intestinal angina could be the cause of the abdominal pain in acute intermittent porphyria.

A group of 15 diabetic persons with different degrees of diabetes complications, including skin changes, was studied by Fourier Transform Near Infrared (FT-NIR) spectroscopy. Skin reflectance spectra were measured with a fibre-optic probe in four locations (sites): hand, arm, leg and foot. For reference, a group of 28 healthy controls was also measured, Multivariate analysis of the NIR spectra obtained shows a high potential for classification and discrimination of the skin conditions. Valuable indications for future experiments can be observed.

PURPOSE:To study possible associations between serum lipid levels and degree of retinopathy in a population-based study on a specific age-group of patients with diabetes mellitus in the county of Umeå, Sweden.METHODS:All patients with diabetes mellitus aged 15-50 years living in the county of Umeå were invited to the study. The participating subjects had a standard clinical examination and an eye examination performed. Seven-field stereoscopic photographs were taken of each eye, and the photos were sent to Grading Center, Hammersmith Hospital, London, U.K. for grading of the retinopathy. Blood samples were drawn for analysis of lipoprotein(a), high density lipoprotein (HDL) cholesterol, cholesterol and triglycerides. Univariate and multivariate statistical analyses were performed.RESULTS:In the present study only patients with type 1 diabetes mellitus were included, and 285 of the invited 308 diabetic subjects (93%) took part. When univariate analysis was applied we found statistically significant associations between higher lipoprotein(a) levels, higher triglyceride levels, higher cholesterol levels, lower HDL cholesterol/total cholesterol ratios and increasing severeness of retinopathy. However, in the multivariate analysis triglyceride levels lost their importance while all other significant associations were still present.CONCLUSION:Associations were found between higher levels of serum total cholesterol, declining ratios of high density lipoprotein (HDL) cholesterol/total cholesterol, higher levels of serum lipoprotein(a) and more severe retinopathy in diabetes mellitus type 1. No such association was found between serum triglycerides and degree of retinopathy.

Islet cell antibodies (ICA) and glutamic acid decarboxylase antibodies (GAD65Ab) are often present at diagnosis of insulin dependent diabetes mellitus (type I diabetes) and are supposed to decline in level and frequency during the first years of disease. We have analysed ICA and GAD65Ab at onset and after one year in 395 population based randomly selected 15-34 year old patients newly diagnosed with diabetes mellitus, to study how these autoantibodies persist, disappear and appear and their relation to C-peptide levels. Of the 395 samples 212 (54%) were positive for ICA, 250 (63%) were positive for GAD65Ab and 170 (43%) were positive for both. At follow up after one year, 27/183 (15%) of the ICA negative patients and 25/145 (17%) of the GAD65Ab negative patients had converted to positivity. Among the 103 patients negative for both ICA and GAD65Ab, 16 turned positive for one or both antibodies after one year. Patients converting to positivity for one or the other antibody after one year, had lower C-peptide levels after one year than patients who initially were and remained negative, supporting the hypothesis that these patients have a genuine type I diabetes. In conclusion, newly diagnosed patients may be negative for autoantibodies at diagnosis but develop these antibodies later on during the disease.

OBJECTIVE To clarify the predictive value of islet cell antibody (ICA) and GAD65 antibody (GADA) present at diagnosis with respect to the need for insulin treatment 6 years after diagnosis in young adults initially considered to have type 2 or unclassifiable diabetes. RESEARCH DESIGN AND METHODS The patient material was representative of the entire Swedish population, consisting of patients who were 15-34 years old at diagnosis of diabetes in 1987-1988 but were not considered to have type 1 diabetes at onset. At follow-up, 6 years after the diagnosis, it was noted whether the patient was treated with insulin. The presence of ICA was determined by an immunofluorescence assay, and GADAs were measured by a radioligand assay. RESULTS Six years after diagnosis, 70 of 97 patients were treated with insulin, and 27 of 97 patients were treated with oral drugs or diet alone. At diagnosis, ICAs and GADAs were present in 41 (59%) of 70 patients and 41 (60%) of 68 patients, respectively, of those now treated with insulin, compared with only 1 (4%) of 26 patients and 2 (7%) of 27 patients who were still not treated with insulin. For either ICA or GADA, the corresponding frequencies were 50 (74%) of 68 for patients who were later treated with insulin and 3 (12%) of 26 for those who were still not treated with insulin, respectively. The sensitivity for later insulin treatment was highest (74%) for the presence of ICA or GADA, and the specificity was highest (100%) for ICA and GADA. The positive predictive value was 100% for the combination of ICA and GADA, 98% for ICA alone, and approximately 95% for GADA alone. CONCLUSIONS Determination of the presence of ICA and GADA at diagnosis of diabetes improves the classification of diabetes and predicts the future need of insulin in young adults.