Gallstone disease in Swedish twins: risk is associated with ABCG8 D19H genotype

Abstract. Katsika D, Magnusson P, Krawczyk M, Grünhage F, Lichtenstein P, Einarsson C, Lammert F, Marschall H‐U (Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden; and Saarland University Hospital, Homburg, Germany). Gallstone disease in Swedish twins: risk is associated with ABCG8 D19H genotype. J Intern Med 2010; 268 : 279–285. Objective. Recently, variants of the hepatocanalicular cholesterol hemitransporters ABCG5/8 were linked to gallstone disease; ABCG8 D19H in Caucasians and ABCG5 Q604E in Chinese. We investigated these polymorphisms in Swedish twins by merging the Swedish Twin Registry with the Hospital Discharge and Causes of Death Registries for gallstone disease‐related diagnoses. Design. All monozygotic (MZ) twins with gallstone disease alive in the Stockholm area were invited to participate. Gallstone disease was defined by entry in all above mentioned registries, questionnaire or abdominal ultrasound. Subjects. ABCG5 Q604E and ABCG8 D19H genotyping was performed in 24 unique MZ and eight dizygotic (DZ) twins from concordant pairs. Screening of the TwinGene database for gallstone disease resulted in an additional 20 concordant MZ and 54 twins from concordant DZ pairs. We included 109 concordantly stone‐free MZ and 126 stone‐free independent DZ twins as controls. Results. Amongst the 341 twins, 20.8% carried at least one D19H allele as compared to 9.4% of stone‐free controls. The association analysis showed that D19H positivity significantly increased the risk of gallstone disease [odds ratio (OR), 2.54; 95% confidence interval (CI), 1.33–4.82; P = 0.004]. We also found a trend for a positive association between gallstone disease and the Q604E variant (OR, 1.47; 95% CI, 1.00–2.16; P = 0.052). Conclusion. Twins carrying a heterozygous or homozygous ABCG8 D19H genotype have a significantly increased risk of gallstone disease. Our study confirms the ABCG8 D19H genotype as a major risk factor for gallstone disease.     

Biochemical and molecular diagnosis of erythropoietic protoporphyria in an Ashkenazi Jewish family

Erythropoietic protoporphyria (EPP) is a rare hereditary disorder due to a partial deficiency of ferrochelatase (FECH). The genotype of EPP patients features a mutation on one allele of the FECH gene and a common hypomorphic FECH IVS3-48c on the other allele (M/c). The resulting enzyme activity in patients is ～35% of that in normal individuals. Ferrochelatase deficiency results in the accumulation of protoporphyrin in the skin, which is responsible for the clinical symptom of cutaneous photosensitivity in patients. In this study, we report the identification of a novel FECH mutation delT23 in an 11-member EPP family of Jewish origin. Two EPP siblings shared an identical genotype of delT23/IVS3-48c (M/c). They were both photosensitive and showed highly increased erythrocyte protoporphyrin. The genotype of the patients' mother, who did not present with any EPP clinical symptoms, was delT23/IVS3-48t (M/t). The patients' father, an offspring of consanguineous parents, was homozygous IVS3-48 c/c. He exhibited a mild photosensitivity, and an increase of 4-fold in erythrocyte protoporphyrin. His FECH mRNA amount was 71% of that of genotype t/t. It is the first reported case of an individual with c/c genotype who exhibits both biochemical and clinical indications of EPP. These results suggest that IVS3-48c is a functional variant of ferrochelatase. The clinical symptoms and biochemical abnormalities in the patients' father could be the result of an interaction between genetic and environmental factors. In addition, the frequency of IVS3-48c in the Ashkenazi Jewish population was estimated at 8%, which is similar to that in the European populations.     

Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 2006

Abstract. Holmqvist ME, Wedrén S, Jacobsson LTH, Klareskog L, Nyberg F, Rantapää‐Dahlqvist S, Alfredsson L, Askling J (Institute of Environmental Medicine, Karolinska Institutet, Stockholm; Karolinska Institutet/Karolinska Hospital, Stockholm; Malmö University Hospital, Malmö; AstraZeneca R&D, Mölndal; and Umeå University Hospital, Umeå, Sweden) Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 2006. J Intern Med 2010; 268 : 578–585. The risk of ischaemic heart disease (IHD), and in particular myocardial infarction (MI), is increased amongst patients with established rheumatoid arthritis (RA). Few studies have included contemporary patients with RA. We recently reported that the risk of IHD is not elevated before the onset of RA symptoms. However, when, in relation to RA diagnosis, the risk is increased is unknown. Objective. To assess the risk of MI and other IHD events amongst patients diagnosed with RA during the last decade and within 18 months following RA symptom onset, compared to the general population, by time since RA diagnosis, year of RA diagnosis and by rheumatoid factor (RF) status. Methods and patients. A Swedish inception cohort of RA (n = 7469) diagnosed between 1995 and 2006 and a matched general population comparator cohort (n = 37 024), was identified and linked to national registers of morbidity and mortality from IHD. Relative risks (RRs) of MI and other IHD events were estimated using Cox regression. Results. During follow‐up, 233 patients with RA and 701 controls developed a first MI, corresponding to an overall RR of MI of 1.6 (95% confidence interval 1.4, 1.9). Increased risks of MI were already detected within 1–4 years following RA diagnosis, as well as in patients diagnosed with RA during the last 5 years, in RF‐negative patients and for transmural as well as nontransmural MIs. Conclusions. MI risk increases rapidly following RA diagnosis, suggesting the importance of additional mechanisms other than atherosclerosis. The elevated short‐term risk is present amongst patients diagnosed in recent years, underscoring the importance of MI prevention from the time of RA diagnosis.     

The incidence of inherited porphyrias in Europe

Retrospective estimates of the prevalence of porphyrias have been reported but there has been no large scale prospective study of their incidence. The European Porphyria Network collected information prospectively over a 3 year period about the number of newly diagnosed symptomatic patients with an inherited porphyria (335 patients from 11 countries). Prevalence was calculated from the incidence and mean disease duration. The incidence of hepato-cellular carcinoma (HCC) in acute hepatic porphyria and the prevalence of patients with recurrent acute attacks of porphyria were also investigated. The incidence of symptomatic acute intermittent porphyria (AIP) was similar in all countries (0.13 per million per year; 95 % CI: 0.10 – 0.14) except Sweden (0.51; 95 % CI: 0.28–0.86). The incidence ratio for symptomatic AIP: variegate porphyria: hereditary coproporphyria was 1.00:0.62: 0.15. The prevalence of AIP (5.4 per million; 95 % CI: 4.5–6.3) was about half that previously reported. The prevalence of erythropoietic protoporphyria (EPP) was less uniform between countries and, in some countries, exceeded previous estimates. Fourteen new cases of HCC (11 from Sweden) were reported in patients with acute porphyria. Sixty seven patients (3 VP; 64 AIP: 53 females, 11 males) with recurrent attacks of acute porphyria were identified. The estimated percentage of patients with AIP that will develop recurrent acute attacks was 3–5 %. In conclusion, the prevalence of symptomatic acute porphyria may be decreasing, possibly due to improved management, whereas the prevalence of EPP may be increasing due to improved diagnosis and its greater recognition as a cause of photosensitivity.     

No survival benefit from early‐start dialysis in a population‐based,inception cohort study of Swedish patients with chronic kidney disease

Abstract. Evans M., Tettamanti G., Nyrén O., Bellocco R., Fored C.M., Elinder C.‐G. (Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden; University of Milano‐Bicocca, Milan, Italy; Karolinska Institutet, Stockholm, Sweden) No survival benefit from early‐start dialysis in a population‐based, inception cohort study of Swedish patients with chronic kidney disease. J Intern Med 2010; 269 : 289–298. Objective. To investigate how the timing of dialysis initiation is associated with mortality. Design. Population‐based, prospective, observational cohort study. Setting. Clinical laboratories (n = 69) provided information on all patients in Sweden whose serum creatinine level for the first time and exceeded 3.4 mg dL^?1 (men) or 2.8 mg dL^?1 (women) between 20 May 1996 and 31 May 1998. Subjects. All patients (n = 901), aged 18–74 years, in whom the cause of serum creatinine elevation was chronic kidney disease, were included in the study; participants were interviewed and followed for 5–7 years. Main outcome measures. Information on date of death was obtained from a national Swedish population register. Early‐start dialysis [estimated glomerular filtration rate from serum creatinine (eGFR) ≥7.5 mL min^?1 per 1.73 m²] was compared to late start of dialysis (eGFR <7.5 mL min^?1 per 1.73 m²), and no dialysis. Relative risk [hazard ratio (HR)] of death was modelled with time‐dependent multivariate Cox proportional hazards regression. Results. Mean eGFR was 16.1 mL min^?1 per 1.73 m² at inclusion and 7.6 mL min^?1 per 1.73 m² at the start of dialysis. Among the 385 patients who started dialysis late, 36% died during follow‐up compared to 52% of 323 who started early. The adjusted HR for death was 0.84 [95% confidence interval (CI) 0.64, 1.10] among late versus early starters. The mortality among nondialysed patients increased significantly at eGFR below 7.5 mL min^?1 per 1.73 m² (HR 4.65; 95% CI 2.28, 9.49; compared to eGFR 7.5–10 mL min^?1 per 1.73 m²). After the start of dialysis, the mortality rate further increased. Compared to nondialysed patients with eGFR ≤15 mL min^?1 per 1.73 m², adjusted HR was 2.65 (95% CI 1.80, 3.89) for patients receiving dialysis. Conclusion. We found no survival benefit from early initiation of dialysis.     

Letter to the editor: Diagnosis of erythropoietic protoporphyria with severe liver injury-a case report

Erythropoietic protoporphyria(EPP)is an extremely rare disease which is often unrecognized as diagnosis.In the recent article Lui et al describe a patient with a new diagnosis of EPP with severe liver injury.Approximately 5%-20%of patients with EPP develop liver manifestations.The most severe complication of EPP is an hepatic crisis,which is a medical emergency requiring urgent treatment.Intensive treatment should consist of(exchange)transfusions and preferably in a center that performs liver transplantations.     

以肝硬化合并急性腹痛为表现的红细胞生成性原卟啉病1例

红细胞生成性原卟啉病(erythropoietic protoporphria,EPP)是临床上罕见的一种遗传代谢性疾病,以血红素合成过程中的亚铁螯合酶活性缺陷,致体内原卟啉IX水平升高为发病原理.该病临床表现形式多样,常累及皮肤、血液、神经系统,但以肝功能严重受损和急性腹痛为主要临床表现的较为罕见.本文现对1例以肝硬化合并急性腹痛为主要临床表现的EPP病例进行报道,为临床诊治该类疾病提供借鉴及参考.     

Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study

Abstract. Hooshmand B, Solomon A, Kåreholt I, Rusanen M, Hänninen T, Leiviskä J, Winblad B, Laatikainen T, Soininen H & Kivipelto M (Aging Research Center, Karolinska Institutet, Stockholm, Sweden; KI Alzheimer’s Disease Research Center (KI‐ADRC), Karolinska Institutet, Stockholm, Sweden; National Institute for Health and Welfare (THL), Helsinki, Finland; University of Eastern Finland, Institute of Clinical Medicine, and University Hospital, Kuopio, Finland). Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study. J Intern Med 2012; 271 : 204–212. Objectives. To examine the associations between serum homocysteine (tHcy), holotranscobalamin (holoTC, the biologically active fraction of vitamin B12) and folate and cognitive functioning in a longitudinal population‐based study of Finnish elderly subjects. Subjects and design. tHcy, holoTC and folate were measured at baseline in 274 dementia‐free subjects aged 65–79 years from the Cardiovascular Risk Factors, Aging and Dementia study. Subjects were re‐examined 7 years later, and global cognition, episodic memory, executive functioning, verbal expression and psychomotor speed were assessed. Results. Higher baseline tHcy levels were associated with poorer performance in global cognition, relative difference: 0.90 [95% confidence interval (CI) 0.81–0.99]; episodic memory: 0.87 (95% CI 0.77–0.99); executive functions: 0.86 (95% CI 0.75–0.98); and verbal expression: 0.89 (95% CI 0.81–0.97) at follow‐up. Increased holoTC levels were related to better performance on global cognition: 1.09 (95% CI 1.00–1.19); executive functions: 1.11 (95% CI 1.01–1.21); and psychomotor speed: 1.13 (95% CI 1.01–1.26). After excluding 20 cases of incident dementia, increased tHcy remained associated with poorer performance in episodic memory, execution functions and verbal expression. Higher holoTC levels tended to be related to better performance in executive functions and psychomotor speed, while elevated serum folate concentrations were significantly related to higher scores in global cognition and verbal expression tests. Conclusions. tHcy, holoTC and folate levels are related to cognitive performance 7 years later even in nondemented elderly subjects. Randomized trials are needed to determine the impact of vitamin B12 and folate supplementation on preventing cognitive decline in the elderly.     

Association of boiled and filtered coffee with incidence of first nonfatal myocardial infarction: the SHEEP and the VHEEP study

Abstract. Hammar N, Andersson T, Alfredsson L, Reuterwall C, Nilsson T, Hallqvist J, Knutsson A, Ahlbom A (Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Stockholm Center of Public Health, Stockholm, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Västernorrland County Council, Sundsvall, Division of Social Medicine, Karolinska Institutet, Stockholm, Norrland University Hospital, Umeå, Sweden) Association of boiled and filtered coffee with incidence of first nonfatal myocardial infarction: the SHEEP and the VHEEP study. J Intern Med 2003; 253: 653–659. Objectives. To evaluate the influence of consumption of filtered and boiled coffee, on the incidence of first nonfatal myocardial infarction. Design. Population‐based case–control study. Setting and subjects. The study base consisted of the population 45–65/70 years‐old in two Swedish counties, Stockholm and Västernorrland, 1992/93–94. In all, 1943 cases of first nonfatal myocardial infarction were identified. For each case one control was selected from the study base concurrently with disease incidence by matching the sex, age and place of residence of the case. Information about coffee consumption and other factors was obtained by mailed questionnaire and a medical examination. The participation rate was 85% amongst cases and 74% amongst controls. Results. Men with a reported consumption of 7–9 dL filtered coffee per day showed an increased incidence of first myocardial infarction compared with consumers of 3 dL day^?1 or less (RR: 1.32; 95% CI: 1.03–1.70). A consumption of at least 10 dL day^?1 was associated with an RR of 1.93 (95% CI: 1.42–2.63) for filtered and 2.20 (95% CI: 1.17–4.15) for boiled coffee. Amongst women, no clear association was seen between consumption of filtered coffee and myocardial infarction but consumption of boiled coffee tended to be related to an increased incidence. Comparing subjects drinking boiled coffee with those drinking filtered coffee and adjusting for the amount consumed gave an increased incidence for boiled coffee amongst both men (RR: 1.41; 95% CI: 1.07–1.80) and women (RR: 1.63; 95% CI: 1.04–2.56). Conclusions. Consumption of boiled coffee appears to increase the incidence of first nonfatal myocardial infarction. This increased incidence is consistent with randomized trials showing an adverse impact of boiled coffee on blood lipids.     

Increased plasma transferrin, altered body iron distribution, and microcytic hypochromic anemia in ferrochelatase-deficient mice

Patients with deficiency in ferrochelatase (FECH), the last enzyme of the heme biosynthetic pathway, experience a painful type of skin photosensitivity called erythropoietic protoporphyria (EPP), which is caused by the excessive production of protoporphyrin IX (PPIX) by erythrocytes. Controversial results have been reported regarding hematologic status and iron status of patients with EPP. We thoroughly explored these parameters in Fechm1Pas mutant mice of 3 different genetic backgrounds. FECH deficiency induced microcytic hypochromic anemia without ringed sideroblasts, little or no hemolysis, and no erythroid hyperplasia. Serum iron, ferritin, hepcidin mRNA, and Dcytb levels were normal. The homozygous Fechm1Pas mutant involved no tissue iron deficiency but showed a clear-cut redistribution of iron stores from peripheral tissues to the spleen, with a concomitant 2- to 3-fold increase in transferrin expression at the mRNA and the protein levels. Erythrocyte PPIX levels strongly correlated with serum transferrin levels. At all stages of differentiation in our study, transferrin receptor expression in bone marrow erythroid cells in Fech(m1Pas) was normal in mutant mice but not in patients with iron-deficiency anemia. Based on these observations, we suggest that oral iron therapy is not the therapy of choice for patients with EPP and that the PPIX-liver transferrin pathway plays a role in the orchestration of iron distribution between peripheral iron stores, the spleen, and the bone marrow.     

Unexplained musculoskeletal pain in people of South Asian ethnic group referred to a rheumatology clinic - relationship to biochemical osteomalacia, persistence over time and response to treatment with calcium and vitamin D

BACKGROUND: Hypovitaminosis D continues to be a problem for South Asian people living in the UK. This study investigates the association between widespread unexplained pain and biochemical osteomalacia in this group of people. METHODS: All South Asian patients attending with unexplained widespread pain (CWP) over a two-year period had biochemical tests for osteomalacia: calcium, phosphate, alkaline phosphatase, vitamin D (25OHD), and parathyroid hormone (PtH). For comparison, a control group consisted of patients in whom a specific rheumatic diagnosis (SRD) had been made. A follow up questionnaire was sent enquiring about pain, disability and dietary habits. A small proportion of the responders attended for a further set of biochemical tests for osteomalacia. RESULTS: The majority of patients in both groups had a raised PtH (124/220, 57%) and a low 25OHD (117/160, 73%). Where data on both PtH and 25OHD were available, 47% (64/137) had a combination of reduced 25OHD and raised PtH. Few of these patients had abnormal calcium, phosphate or alkaline phosphates.From the postal questionnaire the prevalence of disability and continuing pain was high in both groups, with the majority of respondents complaining of difficulty with activities and nearly half needing help. Pain was widespread, the same or worse and graded above 7/10 for 69% and 78% of respondents in the CWP and SRD groups respectively. Overall, sixty one percent of respondents thought their gait pattern had changed in the last year. No significant differences were seen between respondents based on diagnosis (CWP or SRD), initial or subsequent PtH levels, or current calcium and vitamin D consumption. At the time of the second blood test, 52% of those with an elevated PtH on the first test now had a normal PtH value but 31% of those with a normal PtH first time had an elevated PtH. CONCLUSION: This observational study conducted in a rheumatology clinic in the north of England has shown high levels of biochemical osteomalacia in people of South Asian origin and high levels of persistent pain and disability, unrelated to diagnosis, biochemical status or treatment with calcium and vitamin D.     

Seasonal and regional variations of asthma and association with osteoporosis: possible role of vitamin D in asthma

Background. Based on the evidence that vitamin D is involved in the development of immune system and vitamin D receptor gene is associated with asthma, we supposed that vitamin D is related to the development of asthma. Methods. Asthma patients were identified from the Swedish Hospital Discharge Register and the hospitalization rate was examined by different seasons and regions. Standardized incidence ratios (SIRs) for asthma were examined among patients hospitalized for osteoporosis compared with the general population. Results. A total of 172,384 patients were hospitalized for asthma in Sweden during 1965–2007. More patients were hospitalized in winter and North Sweden than in summer and South Sweden. The risk of asthma after osteoporosis was significantly increased, giving an overall SIR of 2.93. The risk was higher in male patients when compared with female subjects. Patients hospitalized for osteoporosis at age younger than 55 showed a high risk. Reversing the analyses and examining the risk of osteoporosis after hospitalization of asthma, SIR was significantly increased (3.54). Conclusion. Our study suggests that vitamin D, as indicated by the high risk of asthma after osteoporosis and the seasonal and regional variations of hospitalization, could play an important role for the development of asthma.     

Production and characterization of erythropoietic protoporphyric heterodimeric ferrochelatases

Mutations resulting in diminished activity of the dimeric enzyme ferrochelatase are a prerequisite for the inherited disorder erythropoietic protoporphyria (EPP). Patients with clinical EPP have only 10% to 30% of normal levels of ferrochelatase activity, and although many patients with EPP have one mutant allele and one "low-expression" normal allele, the possibility remains that, for some, low ferrochelatase activity may result from an EPP mutation that has an impact on both subunits of the wild-type/mutant heterodimer. Here we present data for 12 ferrochelatase wild-type/EPP mutant heterodimers showing that some mutations result in heterodimers with the residual activity anticipated from individual constituents, whereas others result in heterodimers with significantly lower activity than would be predicted. Although the data do not allow an a priori prediction of heterodimeric residual activity based solely on the in vitro activity of EPP homodimers or the position of the mutated residue within ferrochelatase, mutations that affect the dimer interface or [2Fe-2S] cluster have a significantly greater impact on residual activity than would be predicted. These data suggest that some EPP mutations may result in clinically overt EPP in the absence of a low-expression, wild-type allele; this is of potential significance for genetic counseling of patients with EPP.     

Brief interventions in routine health care: a population-based study of conversations about alcohol in Sweden

Aims To investigate how brief alcohol interventions are delivered in routine practice in the Swedish health‐care system. Design, setting and participants A cross‐sectional sample of 6000 individuals representative of the adult population aged 18–64 years registered in the Swedish total population register was drawn randomly. Data were collected in 2010 by means of a mail questionnaire. The response rate was 54%. Measurements The questionnaire consisted of 27 questions, of which 15 variables were extracted for use in this study. Whether alcohol had been discussed and the duration, contents, experiences and effects of any conversations about alcohol, as reported by patients themselves, were assessed. Findings Sixty‐six per cent of the respondents had visited health‐care services in the past 12 months and 20% of these had had one or more conversations about alcohol during these visits (13% of the population aged 18–64 years). The duration of the conversations was generally brief, with 94% taking less than 5 minutes, and were not experienced as problematic. The duration, contents, experiences and effects of these conversations generally varied between abstainers, moderate, hazardous and excessive drinkers. Twelve per cent of those having a conversation about alcohol reported that it led to reduced alcohol consumption. Reduced alcohol consumption was more likely when conversations lasted for 1–10 minutes rather than less than 1 minute and included advice on how to reduce consumption. Conclusions Population survey data in Sweden suggest that when health‐care professionals give brief advice to reduce alcohol consumption, greater effects are observed when the advice is longer and includes advice on how to achieve it.     

Revalidation of description of constipation in terms of recall bias and visual scale analog questionnaire

Background and Aim: The present study was designed to identify a cut‐off value to define subjective and relatively objective criteria of constipation using the visual scale analog questionnaire (VSAQ) in healthy subjects. In addition, the importance of recall bias when evaluating constipation was investigated by repeating the questionnaire and ensuring the subjects maintained diaries. Methods: Seven hundred and sixty healthy hospital personnel were questioned by means of a standard questionnaire. Subjects were initially asked if they were constipated (self‐reported) and their daily defecation frequencies. Severity of the parameters of constipation, the consistency of defecation in the form of hard stools, straining and incomplete evacuation were also investigated using a VSAQ (0–10). Subjects were asked to complete a standard form about their daily bowel habits in the subsequent 7 days (diary). At the end of this series, the questionnaire forms completed at the beginning were readministered. Using the criteria of functional constipation, the prevalence of self‐reported, symptom‐based (≥2 criteria) and diary‐based (≥2 criteria in the diary) were defined. Results: Of the subjects, 48.5% (369/760) completed diaries regarding their bowel habits and completed the questionnaire for the second time (198 female, 171 male; mean age 31.6 ± 7.1 years). According to only interrogation, 29.8% of subjects reported that they were constipated; however, this number increased to 39.6% when symptom‐based constipation (≥2 criteria) was considered. Significant agreement was observed between the results of self‐reported constipation in form I and II, and symptom‐based and diary‐based constipation (concordance = 77.7–98.6%, k = 0.47–0.97). Furthermore, 98.1% of the subjects who reported that they were not constipated scored 3 on the VSAQ; conversely, 91.8% who accepted being constipated scored >3 for the same question. A total of 76.1% subjects who had symptom‐based constipation scored 3 on the VSAQ, 97.3% of those who had <2 criteria scored 3. When asked ‘Are you constipated?’ 1.2% of subjects with none of the criteria for diary‐based constipation, and 10.7% of subjects who had one criteria scored >3 on the VSAQ. Also, 91.8% of those with three criteria and 100% of those with four criteria had a score >3 on the VSAQ for the same question. Conclusions: The prevalence of constipation in the questionnaire form based on self‐reported, symptom‐based and diary‐based criteria were highly compatible with the result obtained on readministration. Recall bias was negligibly low. Also, the present results suggest that the diagnosis of constipation is more accurate when >2 criteria are present. In addition, the VSAQ seems to be sensitive enough to differentiate subjects with constipation from those without, when a score of 3 has been chosen as the cut‐off value for discrimination. However, this sensitivity was less in the group who stated they were constipated.     

Paradoxical Esterification of Plasma Cholesterol in Fish Eye Disease

ABSTRACT. Carlson LA, Holmquist L. (King Gustaf V Research Institute and Department of Internal Medicine, Karolinska Hospital and Karolinska Institute, Stockholm, Sweden.) Paradoxical esterification of plasma cholesterol in fish eye disease. The activity of lecithin: cholesterol acyl transferase (LCAT), the enzyme which catalyses the esterification of human plasma cholesterol, has been measured by two independent methods in plasma from the two known living Swedish patients with fish eye disease. The enzyme activity was in both cases about 15% of that of normal plasma. Paradoxically, however, the percentage of plasma cholesterol which was esterified was almost normal in both patients. In addition, a normal spectrum of the fatty acids of the cholesteryl esters was present indicating a normal cholesterol esterification pathway in vivo. Incubation experiments in vitro of plasma from the two patients also yielded normal cholesterol esterification rates when measured by two different methods. These paradoxical results for cholesterol esterification are discussed on the basis of the present biochemical knowledge of fish eye disease and LCAT deficiency.     

Heterogeneity of penetrance in familial amyloid polyneuropathy,ATTR Val30Met,in the Swedish population

Transthyretin (TTR) familial amyloid polyneuropathies (FAP) are autosomal dominant devastating afflictions. They were first described in Portugal, later in Japan and Sweden and are now recognized worldwide. The TTR Val30Met mutation is the most common, and depending on the geographic origin, a wide variation in age at onset of the disease is observed. In Europe, northern Sweden is the second most prevalent area of the disease, and a late age of onset of 56 years has been reported. The present study aims to estimate the penetrance in TTR Val30Met Swedish families. Genealogical investigations, clinical data and genotyping were obtained in 77 TTR-Val30Met Swedish families. The penetrance in Val30Met carriers and variation within the endemic area, according to gender and transmitting parents were calculated by a newly developed bias-free method. The penetrance estimates were low, i.e. 1.7% and 22% at age 30 and 60 years, respectively, and far from complete (69%) by age 90 years. Differences between Piteå and Skellefteå regions were observed. Moreover, penetrance was significantly higher when the mutation was inherited from the mother than from the father. The low penetrance observed in TTR FAP kindreds and its variations is important information for the genetic counseling and treatment of Swedish FAP patients and their families.     

Risk of ischaemic heart disease and cardiomyopathy in patients with haemochromatosis and in their first-degree relatives: a nationwide, population-based study

Abstract. Elmberg M, Hultcrantz R, Simard JF, Stål P, Pehrsson K, Askling J (Karolinska University Hospital and Karolinska Institutet, Solna; Karolinska Institutet, Huddinge; Karolinska Institutet, Solna; Karolinska Institutet, Huddinge, Karolinska University Hospital; Karolinska Institutet, Solna; Sweden). Risk of ischaemic heart disease and cardiomyopathy in patients with haemochromatosis and in their first‐degree relatives: a nationwide, population‐based study. J Intern Med 2012; 272 : 45–54. Background Iron‐loaded macrophages increase atherosclerosis formation. Genetic haemochromatosis (GH) is an autosomal recessive disease characterized by iron overload, for example in the myocardium, but the reticuloendothelial system is depleted of iron. In contrast to the elevated risk of cardiomyopathy in GH, the risk of ischaemic heart disease (IHD) may therefore not be increased. Little is known of these risks among heterozygotes also being first‐degree relatives (FDRs), thus sharing other factors for phenotypic expression of GH. Objective To assess the risks of IHD and cardiomyopathy among haemochromatosis patients and their FDRs. Design Population‐based cohort study. Setting and subjects A total of 3531 haemochromatosis patients and 11 794 FDRs were identified using nationwide, population‐based health and census registers. Matched (1:10) population controls were randomly selected. Individuals with a record of IHD and cardiomyopathy during 1997–2005 were identified through linkage with the National Patient Register. Relative risks were estimated using Cox proportional hazard regression. Results Of the 3531 patients, 259 were diagnosed with IHD compared with 3077 of the 37 369 controls [hazard ratio (HR) = 1.17; 95% CI, 1.03–1.33]. Based on 30 patients versus 115 controls, the HR for cardiomyopathy was 3.21 (95% CI, 2.15–4.81). Of 11 794 FDRs of haemochromatosis patients, 582 were registered with IHD compared with 6197 among FDRs of controls (HR = 1.05; 95% CI, 0.97–1.15). Based on 28 FDRs of patients versus 291 FDRs of controls registered with cardiomyopathy, the HR for cardiomyopathy was 1.06 (95% CI, 0.72–1.56). Conclusions In patients with haemochromatosis, the increased risk of cardiomyopathy is much more pronounced than that of IHD, which is barely elevated. FDRs of haemochromatosis patients are not at increased risk of cardiomyopathy or IHD.     

A "null allele" mutation is responsible for erythropoietic protoporphyria in an Israeli patient who underwent liver transplantation: relationships among biochemical,clinical, and genetic parameters

Mutations in the human ferrochelatase gene (FECH) are the primary cause of the inborn disorder erythropoietic protoporphyria (EPP). While the majority of the EPP patients exhibit only photosensitivity, a small percentage of patients (approximately 2%) develop liver complications in addition to the cutaneous symptoms. In this study, the FECH gene of an Israeli EPP patient who suffered from EPP-related liver complications was sequenced. A splicing defect IVS10+1, g-->t, which is known to cause the deletion of exon 10, was identified in the index patient as well as in his symptomatic older sister and his asymptomatic mother. Like the other 12 known FECH mutations associated with liver complications, IVS10+1, g-->t is a "null-allele" mutation. Although the two siblings with overt EPP share an identical genotype with respect to both the mutation on one FECH allele and three intragenic single nucleotide polymorphisms, -251G, IVS1-23T, and IVS3-48C on the other allele, the sister of the index patient has so far shown no signs of liver involvement, suggesting that additional factors might account for the liver disease in EPP.