Acute Intermittent Porphyria: Response of Tachycardia and Hypertension to Propranolol

In four young adult patients with acute attacks of acute intermittent porphyria tachycardia and hypertension were prominent features of the illness. Urinary catecholamine excretion was increased in both patients in whom it was measured. The effect of the beta-adrenergic blocking drug propranolol was assessed in each case. The dose varied from 40 to 240 mg daily. A response in the form of a reduction in heart rate and blood pressure was noted in each case, and in one case a marked alleviation of abdominal pain followed administration of the drug.Propranolol, when given in high dosage to rats, did not induce an increase in hepatic delta-aminolaevulic acid synthetase, an enzyme which is raised in human and drug-induced animal porphyria. The use of propranolol is therefore unlikely to aggravate or precipitate an attack of acute intermittent porphyria.     

Acute porphyrias in the Argentinean population: a review.

The porphyrias are a group of inherited metabolic disorders of heme biosynthesis which result from a partial deficiency in one of its seven specific enzymes, after its first and rate limiting enzyme, delta-aminolevulinic acid synthetase. They can be classified on the basis of their clinical manifestations into cutaneous, acute and mixed disorders. Acute intermittent porphyria (AIP) is the most common type of hepatic acute porphyrias, inherited as an autosomal dominant trait, caused by a defect in the gene which codifies for the heme enzyme porphobilinogen deaminase. Its prevalence in the Argentinean population is about 1:125,000. A partial deficiency in another enzyme, protoporphyrinogen oxidase, produces variegate porphyria (VP), the second acute porphyria most frequent in the Argentinean population (1:600,000). Here, we review all the mutations we have found in 46 AIP and 9 VP unrelated Argentinean patients. To screen for mutations in symptomatic patients, we have proposed a geneticresearch strategy.     

Individualized workup: a new approach to the biochemical diagnosis of acute attacks of neuroporphyria

Porphyria experts concur that acute attacks of AIP, VP and HCP, are invariably associated with increases in urinary PBG. Reports differ, however, as to the amount of increase indicative of an acute attack. Some authors consider excretion of at least 25-fold the upper level of normal, as indicative, whereas others regard a 10-fold or even a 2-fold increase, as sufficient indication. An additional diagnostic difficulty arises from the fact that in many individuals known to have inherited one of the acute porphyrias, PBG is persistently raised also during remission. It may be markedly elevated even in asymptomatic carriers. In the absence of a universally accepted standard for interpreting PBG results, attribution of neurovisceral or neuropsychiatric symptoms in porphyrics to an acute attack of porphyria rather than to other causes, depends largely on clinical assessment. The aim of this work was to identify reliable criteria, which will enable establishing or excluding an acute attack, on a biochemical basis. The study summarizes and interprets data obtained during classical neurovisceral acute attacks and latent phases in 20 patients (10 with AIP, 6 with VP, and 4 with HCP). Calculated increases in urinary PBG, with the upper limit of normal excretion, (8.8 micromol/24 h), defined as 100 %, revealed an overlap between values in the acute and latent phases, (1 to 18.5-fold and 2.3 to 51-fold, respectively). This overlap indicates that the workup in each case needs to be individualized. We achieved this goal, by using another method of calculation, in which the PBG value measured during an acute attack in a particular patient was divided by the PBG value measured in that patient's latent phase. Increases of 2.3 to 50.5-fold were obtained, leading to the conclusion that any increase, calculated as above, of 2.3-fold and higher, may be taken as indicative of an acute attack. An additional finding, demonstrated in the study, which might be useful for supporting the diagnosis of an acute attack, is the distinct emission peak observed at 404/621 nm, in the plasma fluorometric scan of AIP and HCP patients, during an acute attack. We conclude that comparison of the urinary PBG level and plasma fluorometric scan in the acute phase to those of the latent phase in the individual patient is the key to correct, accurate and reliable biochemical diagnosis of an acute attack in a patient previously diagnosed as a porphyric. The additional tests required for confirming a patient's first acute attack, having no data to compare with, are discussed.     

Heme content of normal and porphyric cultured skin fibroblasts

Partial deficiencies in enzyme activities of the heme biosynthetic pathway have been demonstrated in cultured skin fibroblasts and other tissues from patients with protoporphyria (PP) and acute intermittent porphyria (AIP). We have quantitatively and qualitatively assessed the heme and free porphyrin content in cultured PP, AIP, VP (variegate porphyria, in which an enzymatic deficiency has not been identified), and normal skin fibroblasts during routine culture conditions in order to assess the overall metabolism of heme in these cells. The total heme concentration was not significantly different between control and porphyric lines; 189 +/- 15 pmoles/mg protein (mean +/- SEM) in controls, 154 +/- 17 in PP, 175 +/- 20 in AIP, and 181 +/- 81 in VP. The hemoprotein difference spectra were similar in all lines. Free porphyrins were not detected in any of the disorders. Despite partial deficiencies in enzyme activities of the heme pathway, porphyric fibroblasts thus maintain normal heme content during routine culture conditions without detectable porphyrin accumulation.     

血清PGRN、SFRP1、CCL26与支气管哮喘急性发作期患者肺功能和气道炎症的相关性研究

摘要 目的：探讨支气管哮喘（BA）急性发作期患者血清颗粒蛋白前体（PGRN）、分泌型卷曲相关蛋白1（SFRP1）、C-C基序趋化因子配体26（CCL26）与肺功能和气道炎症的相关性。方法：选取2021年1月～2022年6月我院收治的118例BA急性发作期患者作为急性发作期组,根据病情分级将BA急性发作期患者分为轻度亚组55例、中度亚组43例、重度亚组20例,另选取同期77例BA临床控制期患者（临床控制期组）和60例体检健康志愿者（对照组）分别作为对照。采用Pearson相关性分析BA急性发作期患者血清PGRN、SFRP1、CCL26水平与肺功能和气道炎症指标的相关性。结果：对照组、临床控制期组、急性发作期组血清PGRN水平和第1秒用力呼气容积占预计值百分比（FEV₁%pred）、峰值呼气流速（PEF）依次降低,SFRP1、CCL26水平和呼出气一氧化氮（FeNO）、外周血嗜酸性粒细胞（EOS）计数依次升高（P＜0.05）。轻度亚组、中度亚组、重度亚组血清PGRN水平和FEV₁%pred、PEF依次降低,SFRP1、CCL26水平和FeNO、外周血EOS计数依次升高（P＜0.05）。Pearson相关性分析显示,BA急性发作期患者血清PGRN水平与FEV₁%pred、PEF呈正相关,与FeNO、外周血EOS计数呈负相关（P＜0.05）,SFRP1、CCL26与FEV₁%pred、PEF呈负相关,与FeNO、外周血EOS计数呈正相关（P＜0.05）。结论：BA急性发作期患者血清PGRN水平降低,SFRP1、CCL26水平升高,与病情严重程度、肺功能和气道炎症有关,可能成为BA急性发作期患者新的治疗靶点。     

Survivors of Myocardial Infarction due to “Essential” Atherosclerosis

Currently, the porphyrias are classified in four main groups: congenital porphyria, acute intermittent porphyria, porphyria cutanea tarda hereditaria, and porphyria cutanea tarda symptomatica. The acquired form of porphyria (porphyria cutanea tarda symptomatica) occurs in older males and is nearly always associated with chronic alcoholism and hepatic cirrhosis. The main clinical changes are dermatological, with excessive skin fragility and photosensitivity resulting in erosions and bullae. Biochemically, high levels of uroporphyrin are found in the urine and stools. Treatment to date has been symptomatic and usually unsuccessful.A case of porphyria cutanea tarda symptomatica is presented showing dramatic improvement of both the skin lesions and porphyrin levels in urine and blood following repeated phlebotomy.Possible mechanisms of action of phlebotomy on porphyria cutanea tarda symptomatica are discussed.     

Molecular characterization of porphyrias in Italy: a diagnostic flow-chart.

The porphyrias are disorders associated with inherited or acquired enzyme deficiencies in the heme biosynthetic pathway. The differential diagnosis is often difficult since the phenotype is very similar in some forms and the biochemical tests are not commonly available. Here we provide an update on the molecular diagnosis of porphyrias in Italy and a flow-chart to facilitate the identification of mutations in heme biosynthetic genes. The molecular analysis has allowed us to identify the molecular defect underlying the disease in 66 probands with different porphyrias [acute intermittent porphyria (AIP), variegate porphyria (VP), porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP)]. No Italian patients with defects in coproporphyrinogen oxidise (CPOX) gene, responsible for hereditary coproporphyria (HCP), have been detected. The molecular characterization has been extended to 115 relatives with the identification of 55 asymptomatic mutation carriers and 60 normal subjects. We have so far identified 50 different mutations among 4 genes associated with the most common porphyrias showing a high molecular heterogeneity: 22 in the hydroxymethylbilane synthase (HMBS) gene (AIP), 7 in the protoporphyrinogen oxidase (PPOX) gene (VP), 16 in the uroporphyrinogen decarboxylase (UROD) gene (PCT) and 5 in the ferrochelatase (FECH) gene (EPP). Among the 50 molecular defects, 29 seem to be restricted to the Italian population.     

Lipid changes occuring in the course of hematological cancers

The relationship between plasma lipid levels and mortality from cardiovascular diseases has been shown in many studies, but there has been far less investigation into their relationship to non-cardiovascular diseases. The aim of this study was to investigate the lipid profile of individuals with hematological malignancies and its relationship to disease activity. 238 patients were included in the study: 84 with acute leukemia, 62 with non-Hodgkin lymphoma, 35 with Hodgkin's lymphoma, 32 with multiple myeloma, and 25 with myeloproliferative syndrome. The HDL cholesterol level of the patients differed to that of the individuals in the control group in the active disease period for all the analyzed disorders, but only remained statistically significant in the acute leukemia and non-Hodgkin lymphoma groups during the remission period. Smaller differences were observed for the remaining lipid fractions, except for the triglyceride level, which increased in the active disease period in all the analyzed disorders except non-Hodgkin lymphoma. The most pronounced changes in the lipid fractions occurred in the HDL cholesterol level, and were the most remarkable for acute leukemia.     

Elevated levels of circulating pancreatic polypeptide in inflammatory and infectious disorders

Circulating levels of pancreatic polypeptide (PP) were found to be elevated when compared to healthy controls in 54% of patients with chronic inflammatory connective tissue disorders (SLE, rheumatoid arthritis, scleroderma, mixed connective tissue disease and temporal arteritis) and in 96% of patients with acute viral or bacterial infections. Significant positive correlations were obtained between the serum values of PP and those of haptoglobin or orosomucoid. Accompanying successful anti-inflammatory treatment of patients with autoimmune disorders, a reduction of PP levels was observed. The findings suggest that the magnitude of increase in PP was associated with the degree of the inflammatory activity. Raised PP levels may contribute to the alterations in carbohydrate and lipid metabolism observed during active inflammatory diseases in man.     

支气管哮喘急性发作期患者呼出气一氧化氮的诊断价值及与肺功能和血清ECP、IL-13的关系研究

摘要 目的：研究支气管哮喘（BA）急性发作期患者呼出气一氧化氮（FeNO）的诊断价值及与其肺功能和血清嗜酸性粒细胞阳离子蛋白（ECP）、白细胞介素-13（IL-13）的关系。方法：将我院从2018年1月～2020年1月收治的78例BA患者纳入研究,将其按照病情的不同分成急性发作组（急性发作期）42例与非急性发作组（缓解期）36例。比较两组FeNO、肺功能指标水平和血清ECP、IL-13水平,并作相关性分析。此外,以受试者工作特征（ROC）曲线分析FeNO对BA急性发作期的有关诊断效能。结果：急性发作组FeNO水平高于非急性发作组,而最大呼气流量占预计值的百分比（PEF%pred）、第1秒用力呼气末容积占预计值的百分比（FEV₁%pred）及用力肺活量占预计值的百分比（FVC%pred）水平均低于非急性发作组（均P＜0.05）。急性发作组血清ECP、IL-13水平均高于非急性发作组（均P＜0.05）。经Pearson相关分析发现：BA急性发作期患者FeNO与PEF%pred、FEV₁%pred、FVC%pred均呈负相关,而与血清ECP、IL-13水平均呈正相关（均P＜0.05）。经ROC曲线分析发现：FeNO诊断BA急性发作期的曲线下面积为0.818,敏感度与特异度分别为75.51%、94.05%。结论：BA急性发作期患者FeNO水平显著升高,且和肺功能、血清ECP、IL-13密切相关,检测FeNO对BA急性发作期患者具有较高的诊断价值。     

A mouse model for South African (R59W) variegate porphyria: construction and initial characterization.

Variegate porphyria is inherited as an autosomal dominant disease with variable penetrance. It is characterized clinically by photocutaneous sensitivity and acute neurovisceral attacks, and biochemically by abnormal porphyrin excretion in the urine and feces. While the world-wide incidence of variegate porphyria is relatively low, in South Africa it is one of the most common genetic diseases in humans. Due to the large number of patients with variegate porphyria in South Africa, and the fact that variegate porphyria is representative of both the so-called "acute" and the "photocutaneous" porphyrias, it would be valuable to have an animal model in which to study the disease. In this study we have produced a mouse model of "South African" variegate porphyria with the R59W mutation in C57/BL6 mice via targeted gene replacement. Hepatic protoporphyrinogen oxidase activity was reduced by approximately 50% in mice heterozygous for the mutation. Urine and fecal samples from these mice, in the absence of exogenous inducers of hepatic haem synthesis, contain elevated concentrations of porphyrins and porphyrin precursors in a pattern similar to that found in human variegate porphyric subjects. Bypassing the rate-limiting step in haem biosynthesis by feeding 5-aminolevulinic acid to these mice, results in an accentuated porphyrin excretory pattern characteristic of the variegate porphyric phenotype and urinary porphobilinogen is increased significantly. This initial characterization of these mice suggest that they are a good model for variegate porphyria at the biochemical level.     

Ongoing Contact Activation in Patients with Hereditary Angioedema

Hereditary angioedema (HAE) is predominantly caused by a deficiency in C1 esterase inhibitor (C1INH) (HAE-C1INH). C1INH inhibits activated factor XII (FXIIa), activated factor XI (FXIa), and kallikrein. In HAE-C1INH patients the thrombotic risk is not increased even though activation of the contact system is poorly regulated. Therefore, we hypothesized that contact activation preferentially leads to kallikrein formation and less to activation of the coagulation cascade in HAE-C1INH patients. We measured the levels of C1INH in complex with activated contact factors in plasma samples of HAE-C1INH patients (N=30, 17 during remission and 13 during acute attack) and healthy controls (N=10). We did not detect differences in enzyme-inhibitor complexes between samples of controls, patients during remission and patients during an acute attack. Reconstitution with C1INH did not change this result. Next, we determined the potential to form enzyme-inhibitory complexes after complete in vitro activation of the plasma samples with a FXII trigger. In all samples, enzyme-C1INH levels increased after activation even in patients during an acute attack. However, the levels of FXIIa-C1INH, FXIa-C1INH and kallikrein-C1INH were at least 52% lower in samples taken during remission and 70% lower in samples taken during attack compared to samples from controls (p<0.05). Addition of C1INH after activation led to an increase in levels of FXIIa-C1INH and FXIa-C1INH (p<0.05), which were still lower than in controls (p<0.05), while the levels of kallikrein-C1INH did not change. These results are consistent with constitutive activation and attenuated depletion of the contact system and show that the ongoing activation of the contact system, which is present in HAE-C1INH patients both during remission and during acute attacks, is not associated with preferential generation of kallikrein over FXIa.     

Demystification of Chester porphyria: a nonsense mutation in the Porphobilinogen Deaminase gene

The porphyrias arise from predominantly inherited catalytic deficiencies of specific enzymes in heme biosynthesis. All genes encoding these enzymes have been cloned and several mutations underlying the different types of porphyrias have been reported. Traditionally, the diagnosis of porphyria is made on the basis of clinical symptoms, characteristic biochemical findings, and specific enzyme assays. In some cases however, these diagnostic tools reveal overlapping findings, indicating the existence of dual porphyrias with two enzymes of heme biosynthesis being deficient simultaneously. Recently, it was reported that the so-called Chester porphyria shows features of both variegate porphyria and acute intermittent porphyria. Linkage analysis revealed a novel chromosomal locus on chromosome 11 for the underlying genetic defect in this disease, suggesting that a gene that does not encode one of the enzymes of heme biosynthesis might be involved in the pathogenesis of the porphyrias. After excluding candidate genes within the linkage interval, we identified a nonsense mutation in the porphobilinogen deaminase gene on chromosome 11q23.3, which harbors the mutations causing acute intermittent porphyria, as the underlying genetic defect in Chester porphyria. However, we could not detect a mutation in the coding or the promotor region of the protoporphyrinogen oxidase gene that is mutated in variegate porphyria. Our results indicate that Chester porphyria is neither a dual porphyria, nor a separate type of porphyria, but rather a variant of acute intermittent porphyria. Further, our findings largely exclude the possibility that a hitherto unknown gene is involved in the pathogenesis of the porphyrias.     

Macrophage inflammatory protein-1α: A link between innate immunity and familial mediterranean fever?

The aim of this study is to investigate the relationship between chemokines and the inflammation in Familial Mediterranean Fever (FMF). Forty-nine patients with FMF (41 in remission and 8 in acute attack period) and 20 healthy controls were included in the study. Serum levels of macrophage inflammatory protein-1alpha (MIP-1alpha) were assessed in the patients and the controls, along with other parameters of disease activity, i.e., fibrinogen, C-reactive protein and erythrocyte sedimentation rate. Serum MIP-1alpha levels of the patients with FMF in acute attack period were significantly higher than the patients in remission and healthy controls (p=0.02 and p=0.038, respectively). MIP-1alpha levels were weakly correlated with CRP (r=0.32, p=0.032) levels. MIP-1alpha may have a role in the pathogenesis of FMF attacks. MIP-1alpha and other chemokines may constitute a link between the innate immune system and FMF.     

Osteopontin as two-sided mediator of intestinal inflammation

Osteopontin (OPN) is characterized as a major amplifier of Th1-immune responses. However, its role in intestinal inflammation is currently unknown. We found considerably raised OPN levels in blood of wild-type (WT) mice with dextran sodium sulfate (DSS)-induced colitis. To identify the role of this mediator in intestinal inflammation, we analysed experimental colitis in OPN-deficient (OPN(-/-)) mice. In the acute phase of colitis these mice showed more extensive colonic ulcerations and mucosal destruction than WT mice, which was abrogated by application of soluble OPN. Within the OPN(-/-) mice, infiltrating macrophages were not activated and showed impaired phagocytosis. Reduced mRNA expression of interleukin (IL)-1 beta and matrix metalloproteinases was found in acute colitis of OPN(-/-) mice. This was associated with decreased blood levels of IL-22, a Th17 cytokine that may mediate epithelial regeneration. However, OPN-(/-) mice showed increased serum levels of tumour necrosis factor (TNF)-alpha, which could be due to systemically present lipopolysaccharide translocated to the gut. In contrast to acute colitis, during chronic DSS-colitis, which is driven by a Th1 response of the lamina propria infiltrates, OPN(-/-) mice were protected from mucosal inflammation and demonstrated lower serum levels of IL-12 than WT mice. Furthermore, neutralization of OPN in WT mice abrogated colitis. Lastly, we demonstrate that in patients with active Crohn's disease OPN serum concentration correlated significantly with disease activity. Taken together, we postulate a dual function of OPN in intestinal inflammation: During acute inflammation OPN seems to activate innate immunity, reduces tissue damage and initiates mucosal repair whereas during chronic inflammation it promotes the Th1 response and strengthens inflammation.     

Identification of mutations in the uroporphyrinogen III cosynthase gene in German patients with congenital erythropoietic porphyria

The porphyrias are heterogeneous disorders arising from predominantly inherited catalytic deficiencies of specific enzymes along the heme biosynthetic pathway. Congenital erythropoietic porphyria is a very rare disease that is inherited as an autosomal recessive trait and results from a profound deficiency of uroporphyrinogen III cosynthase, the fourth enzyme in heme biosynthesis. The degree of severity of clinical symptoms mainly depends on the amount of residual uroporphyrinogen III cosynthase activity. In this study, we sought to characterize the molecular basis of congenital erythropoietic porphyria in Germany by studying four patients with congenital erythropoietic porphyria and their families. Using PCR-based techniques, we identified four different mutations: C73R, a well-known hotspot mutation, the promoter mutation -86A that was also described previously, and two novel missense mutations, designated G236V and L237P, the latter one encountered in the homozygous state in one of the patients. Our data from the German population further emphasize the molecular heterogeneity of congenital erythropoietic porphyria as well as the advantages of molecular genetic techniques as a diagnostic tool and for the detection of clinically asymptomatic heterozygous mutation carriers within families.     

Neuropathy in latent hereditary hepatic porphyria.

Peripheral nerve conduction velocoties were measured in 20 patients with acute intermittent porphyria and five with variegate porphyria and in 25 controls matched for age and sex. None of the porphyric patients had acute symptoms on examination, and nine had never had symptoms. Compared with the controls, patients had a significantly slower conduction velocity of the slower motor fibres of the ulnar nerve (P less than 0-001) and a slower sensory conduction velocity of the ulnar and median nerves (P less than 0-05). There was no significant difference between the patients and controls in the maximum motor conductionvelocity of the median, ulnar, deep peroneal, or posterior tibial nerves. Slight peripheral neuropathy seems to be associated with latent hereditary hepatic porphyria, even in patients who have never had symptoms.     

T suppressor (TG) lymphocytes fluctuate in parallel with changes in the clinical course of patients with multiple sclerosis.

Aberrant immune responses to several unrelated antigens observed in patients with multiple sclerosis have suggested faulty regulation of immunocompetent cells. Recently human T lymphocytes have been segregated into subpopulations. T lymphocytes that bear Fc receptors for IgG suppress B lymphocyte proliferation and the production of IgG. Here we report studies on the percentage of TG cells in the peripheral blood of 25 patients all of whom met stringent clinical criteria for the diagnosis of multiple sclerosis (MS). Many of these patients were followed for more than 14 months. In the total group, nine patients experienced definite acute exacerbations of disease followed by periods of remission. The mean percentages +/- 1 standard deviation of TG cells found in all MS patients during remission, 16 +/- 6 was significantly higher than the mean found in normal subjects, 12 +/- 2. In contrast, the mean found in patients experiencing an acute attack, 6 +/- 2 was significantly lower than the mean TG level of normal subjects. Moreover, when individual patients were followed through their clinical illness, levels of TG lymphocytes that were low during acute exacerbations invariably increased to relatively high levels with the onset of clinical remission.     

Radioimmunoassay of myelin basic protein in cerebrospinal fluid and its clinical application to patients with neurological diseases

A double antibody radioimmunoassay for myelin basic protein (BP) was developed that detects BP concentration greater than 0.5 ng/ml in cerebrospinal fluid ( CSF ). By this method, the amount of BP in CSF of 62 patients with various neurological disorders including 9 cases of multiple sclerosis was measured. The amount of BP in CSF obtained from 2 cases of multiple sclerosis in the exacerbation had significantly higher values than that in remission or during the gradual recovering stage. Also two of the 6 patients with myelopathy ( etiology unknown ) and one of the 11 patients with cerebrovascular disease, having acute attack, had significantly high BP values in CSF. The amount of BP in CSF from the other neurological patients showed normal level, compared with that from control patients. The presence of cross-reacting materials with bovine BP in CSF appears to be characteristic of acute myelin sheath destruction on not only patients with multiple sclerosis but also those with myelopathy and cerebrovascular disease.     

Disturbances of coagulation and fibrinolysis in patients with acute leukemia]

In 30 patients with acute leukemia--18 with myeloblastic acute leukemia, 1 with promyelocytic acute leukemia, 4 with myelo-monocytic acute leukemia, 4 with chronic myelocytic leukemia exacerbation--coagulation and fibrinolysis tests were performed in different stage of the disease. Most of the disorders were noted in the III period of the disease (significant levels of the factors II, IX decrease, clot contractility weakness and platelets count decrease). I in patients with manifestation of haemorrhagic diathesis and in patients without them disturbances in examined tests were similar, but platelets count in patients with bleeding was always significantly reduced. The main reasons of the bleeding in acute leukemias are thrombocytopenia together with the in coagulation factors.