38 research outputs found
The Acute Porphyric Attack: A Difficult Diagnosis for a Potential Lethal Event in Emergency Medicine
The porphyrias are a heterogeneous group of metabolic
disorders due to an inherited (but in some forms the disturbance may
also be acquired) enzymatic deficiency in the metabolic pathway
of heme biosynthesis. The variable degree of block in the heme
biosynthetic pathway due to the enzyme deficiency results in
accumulation of different metabolic intermediates, whose toxicity is
responsible for the peculiar (cutaneous and/or neurovisceral) clinical
pictures observed in each of these diseases. According to the clinical
features, the porphyrias are classified as \u201cacute\u201d (or neuropsychic)
[characterized by acute neurovisceral crises (the acute porphyric
attack) involving the autonomic and/or central nervous system, but
also the liver and the kidney] and \u201con acute\u201d (or dermatological)
(mostly presenting with cutaneous lesions, due to photosensitivity).
The acute porphyrias are often misdiagnosed diseases: the acute
porphyric attack may in fact mimic many other more common medical
and neuropsychiatric conditions; its delayed diagnosis and treatment
(or its inappropriate treatment) may result in a fatal outcome. For
these reasons, many different specialists, such as surgeons,
psychiatrists, gastroenterologists, neurologists, emergency
physicians and dermatologists may be variably involved in the
diagnostic process, especially in those cases presenting with
acute and life-threatening clinical features. An early and definitive
diagnosis is mandatory to improve outcomes and to assure that
potentially harmful drugs are avoided. To date, the availability of an
adequate treatment has significantly improved the outcome of the
acute porphyric attacks, so the knowledge about the management of
these events may be relevant for the physicians working in internal
and emergency medicine units
Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications
Porphyrias are a group of rare disorders originating from an enzyme dysfunction in the
pathway of heme biosynthesis. Depending on the specific enzyme involved, porphyrias manifest
under drastically different clinical pictures. The most dramatic presentation of the four congenital
acute hepatic porphyrias (AHPs: acute intermittent porphyria—AIP, ALAD deficiency, hereditary
coproporphyria—HCP, and porphyria variegata—VP) consists of potentially life-threatening neurovisceral
attacks, for which givosiran, a novel and effective siRNA-based therapeutic, has recently
been licensed. Nonetheless, the clinical manifestations of acute porphyrias are multifaceted and do
not limit themselves to acute attacks. In particular, porphyria-associated kidney disease (PAKD) is a
distinct, long-term degenerating condition with specific pathological and clinical features, for which a
satisfactory treatment is not available yet. In PAKD, chronic tubule-interstitial damage has been most
commonly reported, though other pathologic features (e.g., chronic fibrous intimal hyperplasia) are
consistent findings. Given the relevant role of the kidney in porphyrin metabolism, the mechanisms
possibly intervening in causing renal damage in AHPs are different: among others, d-aminolevulinic
acid (ALA)-induced oxidative damage on mitochondria, intracellular toxic aggregation of porphyrins
in proximal tubular cells, and derangements in the delicate microcirculatory balances of the kidney
might be implicated. The presence of a variant of the human peptide transporter 2 (PEPT2), with
a greater affinity to its substrates (including ALA), might confer a greater susceptibility to kidney
damage in patients with AHPs. Furthermore, a possible effect of givosiran in worsening kidney
function has been observed. In sum, the diagnostic workup of AHPs should always include a baseline
evaluation of renal function, and periodic monitoring of the progression of kidney disease in patients
with AHPs is strongly recommended. This review outlines the role of the kidney in porphyrin
metabolism, the available evidence in support of the current etiologic and pathogenetic hypotheses,
and the known clinical features of renal involvement in acute hepatic porphyrias
Challenges in diagnosis and management of acute hepatic porphyrias: from an uncommon pediatric onset to innovative treatments and perspectives
Acute hepatic porphyrias (AHPs) are a family of four rare genetic diseases resulting from a deficiency in one of the
enzymes involved in heme biosynthesis. AHP patients can experience potentially life-threatening acute attacks,
characterized by severe abdominal pain, along with other signs and symptoms including nausea, mental confusion,
hyponatraemia, hypertension, tachycardia and muscle weakness. Some patients also experience chronic manifestations
and long-term complications, such as chronic pain syndrome, neuropathy and porphyria-associated kidney
disease. Most symptomatic patients have only a few attacks in their lifetime; nevertheless, some experience frequent
attacks that result in ongoing symptoms and a significant negative impact on their quality of life (QoL). Initial diagnosis
of AHP can be made with a test for urinary porphobilinogen, -aminolaevulinic acid and porphyrins using a
single random (spot) sample. However, diagnosis is frequently missed or delayed, often for years, because the clinical
symptoms of AHP are non-specific and mimic other more common disorders. Delayed diagnosis is of concern as
some commonly used medications can trigger or exacerbate acute attacks, and untreated attacks can become severe,
potentially leading to permanent neurological damage or fatality. Other attack triggers include hormonal fluctuations
in women, stress, alcohol and low-calorie diets, which should be avoided in patients where possible. For the management
of attacks, intravenous hemin is approved, whereas new therapeutic approaches are currently being investigated
as a baseline therapy for prevention of attacks and improvement of QoL. Among these, a novel siRNA-based
agent, givosiran, has shown very promising results in a recently concluded Phase III trial and has been approved for
the management of AHPs. Here, we propose a challenging case study-with a very unusual pediatric onset of variegate
porphyria-as a starting point to summarize the main clinical aspects (namely, clinical manifestations, diagnostic challenges,
and therapeutic management) of AHPs, with a focus on the latest therapeutic innovations
Endothelial Dysfunction in Acute Hepatic Porphyrias
Background Acute hepatic porphyrias (AHPs) are a group of rare diseases caused by
dysfunctions in the pathway of heme biosynthesis. Although acute neurovisceral attacks are the
most dramatic manifestations, patients are at risk of developing long-term complications, several of
which are of a vascular nature. The accumulation of non-porphyrin heme precursors is deemed to
cause most clinical symptoms. AimWe measured the serum levels of endothelin-1 (ET-1) and nitric
oxide (NO) to assess the presence of endothelial dysfunction (ED) in patients with AHPs. Forty-six
patients were classified, according to their clinical phenotype, as symptomatic (AP-SP), asymptomatic
with biochemical alterations (AP-BA), and asymptomatic without biochemical alterations (AP-AC).
Results Even excluding those under hemin treatment, AP-SP patients had the lowest NO and highest
ET-1 levels, whereas no significant differences were found between AP-BA and AP-AC patients.
AP-SP patients had significantly more often abnormal levels of ED markers. Patients with the highest
heme precursor urinary levels had the greatest alterations in ED markers, although no significant
correlation was detected. Conclusions ED is more closely related to the clinical phenotype of AHPs
than to their classical biochemical alterations. Some still undefined disease modifiers may possibly
determine the clinical picture of AHPs through an effect on endothelial functions
Inflammation: an important parameter in the search of prostate cancer biomarkers
Background
A more specific and early diagnostics for prostate cancer (PCa) is highly desirable. In this study, being inflammation the focus of our effort, serum protein profiles were analyzed in order to investigate if this parameter could interfere with the search of discriminating proteins between PCa and benign prostatic hyperplasia (BPH).
Methods
Patients with clinical suspect of PCa and candidates for trans-rectal ultrasound guided prostate biopsy (TRUS) were enrolled. Histological specimens were examined in order to grade and classify the tumor, identify BPH and detect inflammation. Surface Enhanced Laser Desorption/Ionization-Time of Flight-Mass Spectrometry (SELDI-ToF-MS) and two-dimensional gel electrophoresis (2-DE) coupled with Liquid Chromatography-MS/MS (LC-MS/MS) were used to analyze immuno-depleted serum samples from patients with PCa and BPH.
Results
The comparison between PCa (with and without inflammation) and BPH (with and without inflammation) serum samples by SELDI-ToF-MS analysis did not show differences in protein expression, while changes were only observed when the concomitant presence of inflammation was taken into consideration. In fact, when samples with histological sign of inflammation were excluded, 20 significantly different protein peaks were detected. Subsequent comparisons (PCa with inflammation vs PCa without inflammation, and BPH with inflammation vs BPH without inflammation) showed that 16 proteins appeared to be modified in the presence of inflammation, while 4 protein peaks were not modified. With 2-DE analysis, comparing PCa without inflammation vs PCa with inflammation, and BPH without inflammation vs the same condition in the presence of inflammation, were identified 29 and 25 differentially expressed protein spots, respectively. Excluding samples with inflammation the comparison between PCa vs BPH showed 9 unique PCa proteins, 4 of which overlapped with those previously identified in the presence of inflammation, while other 2 were new proteins, not identified in our previous comparisons.
Conclusions
The present study indicates that inflammation might be a confounding parameter during the proteomic research of candidate biomarkers of PCa. These results indicate that some possible biomarker-candidate proteins are strongly influenced by the presence of inflammation, hence only a well-selected protein pattern should be considered for potential marker of PCa
Sustaining the Continued Effectiveness of an Antimicrobial Stewardship Program in Preterm Infants
Background: There are wide variations in antibiotic use in neonatal intensive care units (NICUs). Limited data are available on antimicrobial stewardship (AS) programs and long-term maintenance of AS interventions in preterm very-low-birth-weight (VLBW) infants. Methods: We extended a single-centre observational study carried out in an Italian NICU. Three periods were compared: I. "baseline" (2011-2012), II. "intervention" (2016-2017), and III. "maintenance" (2020-2021). Intensive training of medical and nursing staff on AS occurred between periods I and II. AS protocols and algorithms were maintained and implemented between periods II and III. Results: There were 111, 119, and 100 VLBW infants in periods I, II, and III, respectively. In the "intervention period", there was a reduction in antibiotic use, reported as days of antibiotic therapy per 1000 patient days (215 vs. 302, p < 0.01). In the "maintenance period", the number of culture-proven sepsis increased. Nevertheless, antibiotic exposure of uninfected VLBW infants was lower, while no sepsis-related deaths occurred. Our restriction was mostly directed at shortening antibiotic regimens with a policy of 48 h rule-out sepsis (median days of early empiric antibiotics: 6 vs. 3 vs. 2 in periods I, II, and III, respectively, p < 0.001). Moreover, antibiotics administered for so-called culture-negative sepsis were reduced (22% vs. 11% vs. 6%, p = 0.002), especially in infants with a birth weight between 1000 and 1499 g. Conclusions: AS is feasible in preterm VLBW infants, and antibiotic use can be safely reduced. AS interventions, namely, the shortening of antibiotic courses in uninfected infants, can be sustained over time with periodic clinical audits and daily discussion of antimicrobial therapies among staff members
Ponatinib as a Prophylactic or Pre-Emptive Strategy to Prevent Cytological Relapse after Allogeneic Stem Cell Transplantation in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Transplanted in Complete Cytological Remission
The bone marrow represents an enrichment site of specific T lymphocytes against filamentous fungi
Bone marrow has already been described as an enrichment site for several antigen-specific T lymphocytes, but the presence of mould-specific T cells has never been investigated in the bone marrow. We have previously demonstrated that mould-specific T cells emerge in the peripheral blood of patients with invasive fungal infections (IFI) but tend to become undetectable after disease resolution. In seven patients with a history of IFI, we investigated the presence of mould-specific T cells secreting different cytokines in bone marrow and peripheral blood paired samples. The results showed that the frequencies of mould-specific T cells secreting the protective cytokine IFNI3 are significantly higher in bone marrow (BM) and are mainly represented by CD8+ T lymphocytes with effector phenotype. A putative disappearance of such protective BM responses after myeloablative therapy could contribute to the increased risk of IFI in hematologic patients
Clinical and molecular epidemiology of erythropoietic protoporphyria in Italy
Background: Erythropoietic protoporphyria (EPP) is a rare inherited disease associated with heme metabolism, characterized by severe life-long photosensitivity and liver involvement. Objectives: To provide epidemiological data of EPP in Italy. Materials and Methods: Prospective/retrospective data of EPP patients were collected by an Italian network of porphyria specialist centres (Gruppo Italiano Porfiria, GrIP) over a 20-year period (1996-2017). Results: In total, 179 patients (79 females) with a clinical and biochemical diagnosis of EPP were assessed, revealing a prevalence of 3.15 cases per million persons and an incidence of 0.13 cases per million persons/year. Incidence significantly increased after 2009 (due to the availability of alfa-melanotide, which effectively limits skin photosensitivity). Mean age at diagnosis was 28 years, with only 22 patients (12.2%) diagnosed 6410 years old. Gene mutations were assessed in 173 (96.6%) patients; most (164; 91.3%) were FECH mutations on one allele in association with the hypomorphic variant, c.315-48C, on the other (classic EPP), and nine (5.2%) were ALAS2 mutations (X-linked EPP). Only one case of autosomal recessive EPP was observed. Of the 42 different FECH mutations, 15 are novel, three mutations collectively accounted for 45.9% (75/164) of the mutations (c.215dupT [27.2%], c.901_902delTG [11.5%] and c.67\u2009+\u20095G\u2009>\u2009A [7.2%]), and frameshift mutations were prevalent (33.3%). A form of light protection was used by 109/179 (60.8%) patients, and 100 (56%) had at least one \u3b1-melanotide implant. Three cases of severe acute liver involvement, requiring OLT, were observed. Conclusions: These data define, for the first time, the clinical and molecular epidemiology of EPP in Italy
Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis
We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation