正铁血红素治疗急性间歇性血卟啉症

目的 探讨正铁血红素对急性间歇性血卟啉症的治疗作用。方法 ２例ＡＩＰ均具有典型症状，尿Ｗａｔｓｏｎ－Ｓｃｈｗａｗｒｔｚ试验阳性，葡萄糖疗法对其明显效果，给予正铁血纱剂Ｐａｎｈｅｍａｔｉｎ治疗，２００ｍｇ／天，静脉输注，连用５天。结果 腹绞痛在用药２－３天后均迅速缓解。例１抽搐症状明显减轻，例１在６个月后症状复发，再次用药仍有效，随访２年昨发；例２接受随访１年，未见复发。     

Hepatocellular carcinoma in patients with acute hepatic porphyria: frequency of occurrence and related factors

BACKGROUND/AIMS: Previous retrospective studies have suggested an association between hepatocellular carcinoma and acute hepatic porphyrias. The incidence, the relative risk, the characteristics and the outcome of primary liver cancer were prospectively evaluated in patients with acute hepatic porphyrias; the molecular mechanism of carcinogenesis in these patients was also pointed out. METHODS: A cohort of 650 patients with acute hepatic porphyria was followed over 7 years. Standardized rate ratio was used to measure the relative risk of primary liver cancer after indirect standardization. Morphological and clinical aspects of primary liver cancer were investigated, and survival rates were calculated using the Kaplan-Meier method. Common etiological factors involved in liver carcinogenesis were screened. Excretion rates of porphyrin precursors, serum melatonin levels and mutations in the genes encoding for heme biosynthetic enzymes were studied. RESULTS: Hepatocellular carcinoma was found in four symptomatic and three asymptomatic patients (four female, three male). The overall standardized rate ratio was 36 (95% CI: 14-74). The 5-year disease-free survival was 43% in patients with hepatocellular carcinoma. Usual risk factors for primary liver cancer were not confounding factors. Hepatocellular carcinoma was not related to specific heme biosynthesis gene mutations. Heme precursors were significantly increased in porphyric patients with hepatocellular carcinoma, and serum melatonin levels were low. CONCLUSIONS: Acute hepatic porphyrias are risk factors for hepatocellular carcinoma. Hepatic porphyrias should be sought in patients with hepatocellular cancer without obvious etiology, and a periodic screening for hepatocellular carcinoma should be evaluated in these patients. Genes encoding for heme biosynthetic pathway may not act as tumor suppressor genes. Chronic increased levels of delta aminolevulinic acid could lead to the generation of free radicals and subsequently to hepatic carcinogenesis.     

Nitric oxide and the clinical manifestations of acute porphyria

The porphyrias comprise a clinically and genetically heterogenous group of diseases mostly arising from a genetically determined dysfunction of specific enzymes along the pathway of haeme biosynthesis. This leads to a pathological accumulation and measurable excretion of porphyrins and/or porphyrin precursors, which is considered the cause of the clinical features related to this group of diseases. However, acute porphyria can present with varied symptoms, which have some features in common with other diseases where nitric oxide has been shown to play a role. The article describes the possibility of nitric oxide depletion in porphyria contributing to its clinical manifestations.     

Renal symptomatology in patients with acute intermittent porphyria. A population-based study

OBJECTIVE: Can renal insufficiency in subjects with acute intermittent porphyria (AIP) be due solely to DESIGN: A population-based study. SUBJECTS: Subjects with AIP > or = 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.     

Effects of diabetes mellitus on patients with acute intermittent porphyria

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 Västerbotten, 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 PBG 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.     

肾功能与急性冠状动脉综合征患者住院期间不良事件相关性的研究

目的:探讨急性冠状动脉综合征(ACS)患者,不同程度的肾功能降低与住院期间不良事件的关系。方法:对连续入选的629例ACS患者进行回顾性分析,依据适合中国人的改良MDRD方程估算的肾小球滤过率(e GFR)水平,将患者分为肾功能正常(90 m L·min-1·1.73m-2)轻度降低(60~89 m L·min-1·1.73m-2)、中度降低(30~59 m L·min-1·1.73m-2)和重度降低(29 m L·min-1·1.73m-2)四组,分析不同程度肾功能损害患者住院期间不良事件发生率。结果:肾功能降低组(e GFR90 m L·min-1·1.73m-2)较肾功能正常组年龄偏大,多合并高血压、糖尿病,住院期间发生不良事件的比例明显高于正常组,两组比较差异有统计学意义。肾功能正常组与轻度、中度、重度降低组患者住院期间不良事件发生率分别为14.5%、25.8%、45.6%及44.4%,不良事件发生率随肾功能降低而呈逐渐增高趋势(P0.001)。Logistic回归分析证实肾功能降低是住院期间不良事件的独立危险因素(OR=2.224,95%CI:1.445~3.423,P0.001)。结论:肾功能降低ACS患者住院期间不良事件的发生率明显升高,且肾功能降低越显著,则不良事件的发生率越高;肾功能降低是住院期间不良事件的独立危险因素。     

Screening for hepatocellular carcinoma in acute intermittent porphyria: a 15-year follow-up in northern Sweden

Abstract. Innala E, Andersson C (Umeå University, Umeå, Sweden). Screening for hepatocellular carcinoma in acute intermittent porphyria: a 15‐year follow‐up in northern Sweden. J Intern Med 2011; 269 : 538–545. Objectives. To evaluate the benefit of screening for hepatocellular carcinoma (HCC) in gene carriers of acute intermittent porphyria (AIP) and estimate the annual incidence of HCC in this group. Subjects. All AIP gene carriers aged ≥55 years from the northernmost county in Sweden, Norrbotten, were invited for screening in this prospective study every 1–1.5 years during the period 1994–2009. We registered all HCC cases amongst AIP gene carriers in the northern region of Sweden (four counties). We compared gene carriers with repeated screening intervals of <2 years (Group A) with controls (Group B; i.e. gene carriers who had never been screened, those screened for the first time or screened at intervals of >2 years, or dropouts). The screening included radiological examination of the liver and relevant laboratory tests. Results. A total of 62 AIP subjects participated in the study, comprising 33% of the total AIP population aged >55 years in the northern region of Sweden. HCC was diagnosed in 22 AIP subjects (12 men and 10 women), mean age 69 (59–82) years. Amongst these subjects, 73% had experienced prior AIP attacks. The incidence rate ratio for HCC was 64 (52 in men and 93 in women). There were no cases of hepatitis B/C or alcohol abuse. Liver cirrhosis was rare. Liver resection could be performed in most subjects in Group A. Fourteen patients died of HCC, one in Group A and 13 in Group B. Compared with those who were not screened regularly, screening was associated with improved 3‐year and 5‐year survival (P = 0.005 and 0.038). Conclusions. Screening for HCC in carriers of AIP enables early diagnosis and a choice of potentially curative treatments with improved prognosis. We recommend annual screening using liver imaging for AIP gene carriers >50 years of age.     

Effect of aggressive versus conservative hydration for early phase of acute pancreatitis in adult patients: A meta-analysis of 3,127 cases

BackgroundThe advantages of aggressive hydration compared to conservative hydration within 24 h for acute pancreatitis (AP) remain controversial in adult patients. A meta-analysis was undertaken to investigate whether aggressive strategies are more beneficial.MethodsWe searched (on February 1, 2021) PubMed, Embase, and the Cochrane Library for eligible trials that assessed the two therapies and performed a meta-analysis. The primary endpoint was in-hospital mortality. Secondary outcomes were adverse events (e.g., renal failure and pancreatic necrosis) within 24 h of treatment.ResultsFive randomized controlled trials and 8 observational trials involving 3127 patients were identified. Patients with severe pancreatitis showed significant difference of in-hospital mortality (OR 1.75; 95% CI 1.32–2.33) in aggressive hydration group, which were less susceptible to study type and age. Patients with severe pancreatitis were likely to develop respiratory failure (OR 5.08; 95% CI 2.31–11.15), persistent SIRS (OR 2.83; 95% CI 1.58–5.04), renal failure (OR 2.58; 95% CI 1.90–3.50) with significant difference. A longer hospital stay was observed in patients with severe pancreatitis (WMD 7.61; 95% CI 5.51–9.71; P < 0.05) in the aggressive hydration group. Higher incidence of pancreatic necrosis (OR 2.34; 95% CI 1.60–3.42; P < 0.05) was major susceptible to observational studies, old patients and mild pancreatitis.ConclusionsCompared to conservative hydration, aggressive hydration increases in-hospital mortality and the incidence of renal failure, pancreatic necrosis with relatively strong evidence. Further investigation should be designed with a definitive follow-up period and therapeutic goals to address reverse causation bias.     

白细胞介素33水平对于急性缺血性脑卒中的临床意义

目的研究白细胞介素33（IL-33）在急性缺血性脑卒中患者中的水平变化及其与脑卒中患者临床预后的关系。 方法选择开平市中心医院内三科及江门市人民医院神经内科自2017年1月至2019年6月收治的192例急性缺血性脑卒中患者作为研究对象,并随机选择100例健康成年人作为对照组,比较缺血性脑卒中患者在治疗前和治疗后第1、3、7天时与健康成年人外周血IL-33的变化及差异,并将脑卒中患者根据IL-33水平从低到高排序,比较IL-33低水平组（四分位数P25以下）和IL-33高水平组（四分位数P75以上）患者治疗后第3个月的改良Rankin量表（mRs）评分、日常生活能力评分（ADL）评分不良事件发生率,同时通过受试者工作特征（ROC）曲线分析IL-33对缺血性脑卒中患者临床预后的预测价值。 结果IL-33在急性缺血性脑卒中患者中表达水平升高,入院时平均水平（575.36±200.75）pg/mL,入院后第1天平均水平（727.13±204.96）pg/mL,入院后第3天平均水平（647.92±228.41）pg/mL,入院后第7天平均水平（639.02±185.29）pg/mL,而健康成年人平均水平为（410.32±145.58）pg/mL,差异均有统计学意义（P<0.05）;IL-33高水平组患者在mRs评分、ADL评分中不良事件发生率均高于IL-33低水平组患者,差异有统计学意义（P<0.05）;mRs评分、ADL评分标准下IL-33作为临床预后评价指标的ROC曲线下面积分别为0.847和0.727。 结论急性缺血性脑卒中患者外周血清中IL-33的水平显著升高,并对患者的临床预后有较好的预测价值,IL-33水平升高越显著,患者的临床预后越差。     

Signs of neuropathy in the lower legs and feet of patients with acute intermittent porphyria

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.     

Comparing prophylaxis with episodic treatment in haemophilia A: implications for clinical practice

Summary. Recurrent haemarthroses in patients with severe haemophilia A often result in irreversible joint damage. Treatment using routine infusions of factor VIII (FVIII) concentrate, a therapy known as prophylaxis, is currently recommended for the prevention of haemarthroses and arthropathy in persons with severe haemophilia A. However, until recently, the body of evidence supporting prophylaxis in comparison with FVIII infusions given only at the time of haemarthroses was mostly retrospective and anecdotal. Recently, two prospective randomized clinical trials have been conducted to compare prophylaxis with on‐demand FVIII treatment for the prevention of arthropathy and haemarthroses in young children with haemophilia A. A third prospective, non‐randomized trial evaluated a strategy of escalating the dose frequency of prophylaxis. Data from these studies will provide objective evidence for the prevention of haemarthroses and arthropathy in children with severe haemophilia A.     

Human herpesvirus‐6 as an inducer of porphyria cutanea tarda: implications from a case

T. Weber, S. Theurich, M. Christopeit, T. Klapperstueck, G. Behre. Human herpesvirus‐6 as an inducer of porphyria cutanea tarda: implications from a case.
Transpl Infect Dis 2010: 12: 432–436. All rights reserved Abstract: Here we describe a case that might deliver a link between sporadic porphyria cutanea tarda (PCT) and human‐herpesvirus‐6 (HHV6) hepatitis. Sporadic PCT is a rare disease of the heme synthesis pathway. The pathogenesis has not been fully determined but iron overload and viral infections – e.g., hepatitis C virus – are thought to play an important role. We present the case of a patient suffering from myelo‐monocytic leukemia. He developed symptomatic sporadic PCT concomitant with HHV6‐associated subclinical hepatitis after allogeneic stem cell transplantation (SCT). Although HHV6 often reactivates after SCT and HHV6‐induced hepatitis can occur in immunocompromised patients, it has not been described that HHV6 might trigger PCT. A contribution of HHV6 to the pathogenesis of sporadic PCT could have dramatic implications on our current therapeutic approach.     

Efficacy and safety profile of dronedarone in clinical practice. Results of the Magdeburg Dronedarone Registry (MADRE study)

Background

Dronedarone is a new antiarrhythmic agent that has only recently been approved for the therapy of atrial fibrillation (AF). Results regarding a broader spectrum of patients and experience accumulated in clinical practice are still very scarce. Therefore, we prospectively investigated the efficacy and tolerance of dronedarone in a real life setting.

Methods and results

The study included 191 patients (85 women) aged 63 ± 9.9 years with a history of paroxysmal or persistent AF. Follow-up time was 14.3 ± 4.9 months. In patients with persistent AF, sinus rhythm was restored using electrical cardioversion prior to dronedarone administration. Each patient underwent standard ECG on a daily basis during the first 4 days of treatment, and on days 7, 30 and 90, resp. After that, the patients had a follow-up visit every three months. Creatinine, creatine kinase, and hepatic enzymes were closely monitored. Clinical history was meticulously taken at multiple follow-up visits. Dronedarone maintained sinus rhythm in 33.5% (95% CI: 27%–40%), and AF recurrence rate was high: 66.5% (95% CI: 60%–73%). Adverse effects occurred in 31.9% (95% CI: 27%–38%) of the patients and necessitated permanent discontinuation of dronedarone in 22% (95% CI: 17%–27%).

Conclusions

The results suggest that dronedarone may not be superior to available antiarrhythmic agents and caution against its use as a first line therapy in AF.     

Acute intermittent porphyria in women: clinical expression,use and experience of exogenous sex hormones. A population-based study in northern Sweden

OBJECTIVE: To describe the clinical expression of acute intermittent porphyria (AIP) in women, their use of exogenous sex hormones, and the effects on AIP. DESIGN: A retrospective population-based study. SUBJECTS: All women aged > or =18 years (n = 190) with DNA-diagnosed AIP in northern Sweden. RESULTS: A total of 166 women (87%) participated; 91 (55%) had manifest AIP. Severe attacks were reported by 82%; 39% reported recurrent premenstrual AIP attacks and 22% reported chronic AIP symptoms. Oral hormonal contraceptives had been used by 58% of all these women and by 50 with manifest AIP (57%). Twelve women (24%) associated oral contraceptives as precipitating AIP attacks; in nine cases their first attack. One woman experienced relief from AIP symptoms. On commencing their treatment, 72% of the women with manifest AIP had not yet suffered their first attack. Twenty-two women (25%) aged > or =45 years had used hormonal replacement therapy (HRT) at menopause to remedy climacteric symptoms (the percutaneous route was most frequently used); no AIP attack was precipitated. HRT to remedy vaginal dryness was used by 26 women (28%) aged > or =45 years without triggering an AIP attack. Miscarriages were more frequent in women with manifest AIP (50%) than in the latent group (30%, P = 0.014). CONCLUSIONS: About half of the women with AIP had used oral hormonal contraceptives. As 25% of women with manifest AIP reported attacks associated with such drugs, caution must still be recommended. Menopausal HRT only rarely affected the disorder. Miscarriage was more common amongst women with manifest AIP.     

Diagnosis of acute intermittent porphyria in northern Sweden: an evaluation of mutation analysis and biochemical methods

Abstract. Objective . To validate the use of a recently observed guanine to adenine mutation in exon 10 in the porphobilinogen deaminase (PBGD) gene as a diagnostic marker of acute intermittent porphyria (AIP). To evaluate the efficiency of the traditional biochemical diagnostic methods. Design . Matched and blinded case–control study (1:4). Setting . A primary health care centre in Arjeplog, the National Porphyria Research Unit and a department of clinical genetics in Stockholm. Subjects . A total of 48/49 (98%) patients over the age of 15 years living in Arjeplog with AIP, diagnosed according to standard clinical and biochemical criteria. For each AIP patient, four controls were matched for age, sex and geographical area and 164/196 (86%) participated. In the validity study, 35 patients were selected as indisputable AIP gene carriers, according to strict biochemical criteria, and 92 matched controls were selected with strict exclusion criteria. Main outcome measures . Validity, specificity and sensitivity of DNA diagnosis for this AIP mutation. Specificity and sensitivity of traditional biochemical methods. Results . Validity study: the mutation was found in all 35 individuals classified as carriers of AIP. None of the 92 controls had the mutation. Evaluation study: all 48 AIP gene carriers, diagnosed by traditional methods, had the mutation, as had one of the control persons. In an inconclusive group of five persons with heredity for AIP, two had a positive DNA test. Conclusions . The PBGD mutation analysis was found to have full specificity and sensitivity and can be used as the sole diagnostic method in the family complex studied, representing the major AIP mutation in Sweden. The traditional diagnostic methods, used in optimal combinations, work in most cases, but they do not show high precision. However, they must be used when the specific mutation in the PBGD gene is not known.     

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).
Design. A retrospective population-based mortality study.
Subjects. All inhabitants who died between 1978–1990 (2122) including 33 with AIP, in two municipalities in northern Sweden with a high prevalence of AIP.
Interventions. Death certificates and hospital records were examined. Histological re-examination of paraffin-embedded specimens from patients with HCC was performed and hepatitis B virus content analysed.
Results. HCC was found in 27% of patients with AIP versus 0.2% of the deceased non-AIP subjects, P< 0.0001. HCC was more common in women (men:women 1:2) and in manifest AIP (manifest: latent 2:1). Liver cirrhosis was more common in AIP patients (12%), especially in women, compared with controls (0.5%), P <0.0001.
Conclusions. AIP patients seem to have an increased risk of developing HCC. This tumour is more common in patients with manifest AIP and in women, a reversal of the usually reported gender ratio for HCC. No cause for developing HCC other than AIP was found. The pathogenesis may be explained by abnormalities in porphyrin metabolism and by intrinsic production of mutagenic substances, resulting in a condition of systemic overload of oxidative stress, enhancing mutation rate and liver cell injury. Liver cirrhosis appears to be more common in AIP patients and may be a preliminary stage to HCC. All AIP gene carriers aged 55 should be screened for HCC.