Porphyria cutanea tarda: a unique iron-related disorder.

The porphyrias are a group of disorders of heme biosynthesis, each characterized by an enzymatic defect in the heme biosynthetic pathway. Porphyria cutanea tarda (PCT) arises due to the inhibition of uroporphyrinogen decarboxylase (UROD) in the presence of hepatic iron and oxidative stress. Most patients with PCT have evidence of siderosis on liver biopsy, and the disease resolves with iron depletion.

Givosiran: a targeted treatment for acute intermittent porphyria.

The acute hepatic porphyrias (AHPs) are a family of rare genetic diseases associated with attacks of abdominal pain, vomiting, weakness, neuropathy, and other neurovisceral symptoms. Pathogenic variants in 1 of 4 enzymes of heme synthesis are necessary for the development of AHP, and the onset of acute attacks also requires the induction of δ-aminolevulinic acid synthase 1 (ALAS1), the first and rate-limiting step of heme synthesis in the liver. Givosiran is an RNA interference medication that inhibits hepatic ALAS1 and was designed to treat AHP.

Potential Biomarkers for the Earlier Diagnosis of Kidney and Liver Damage in Acute Intermittent Porphyria.

Acute intermittent porphyria (AIP) is an inherited metabolic disorder associated with complications including kidney failure and hepatocellular carcinoma, probably caused by elevations in the porphyrin precursors porphobilinogen (PBG) and delta-aminolevulinic acid (ALA). This study explored differences in modern biomarkers for renal and hepatic damage between AIP patients and controls. Urine PBG testing, kidney injury panels, and liver injury panels, including both routine and modern biomarkers, were performed on plasma and urine samples from AIP cases and matched controls (50 and 48 matched pairs, respectively).

Tobacco smoke exposure recruits inflammatory airspace monocytes that establish permissive lung niches for .

Tobacco smoking doubles the risk of active tuberculosis (TB) and accounts for up to 20% of all active TB cases globally. How smoking promotes lung microenvironments permissive to () growth remains incompletely understood. We investigated primary bronchoalveolar lavage cells from current and never smokers by performing single-cell RNA sequencing (scRNA-seq), flow cytometry, and functional assays.

Acute hepatic porphyrias: Recommendations for diagnosis and management with real-world examples.

Acute hepatic porphyria (AHP) is a group of four rare inherited diseases, each resulting from a deficiency in a distinct enzyme in the heme biosynthetic pathway. Characterized by acute neurovisceral symptoms that may mimic other medical and psychiatric conditions, lack of recognition of the disease often leads to a delay in diagnosis and initiation of effective treatment. Biochemical testing for pathway intermediates that accumulate when the disease is active forms the basis for screening and establishing a diagnosis.

Update on the Porphyrias.

The porphyrias are a group of rare diseases, each resulting from a defect in a different enzymatic step of the heme biosynthetic pathway. They can be broadly divided into two categories, hepatic and erythropoietic porphyrias, depending on the primary site of accumulation of heme intermediates. These disorders are multisystemic with variable symptoms that can be encountered by physicians in any specialty.

How I treat erythropoietic protoporphyria and X-linked protoporphyria.

Erythropoietic protoporphyria (EPP) is an inherited cutaneous porphyria caused by reduced expression of ferrochelatase, the enzyme that catalyzes the final step in heme biosynthesis. The resultant accumulation of protoporphyrin IX leads to severe, painful cutaneous photosensitivity, as well as potentially life-threatening liver disease in a small percentage of patients. X-linked protoporphyria (XLP) is clinically similar to EPP but results from increased activity of δ-aminolevulinic acid synthase 2, the first step in heme biosynthesis in the bone marrow, and also causes protoporphyrin accumulation.

Quantifying the impact of symptomatic acute hepatic porphyria on well-being via patient-reported outcomes: Results from the Porphyria Worldwide Patient Experience Research (POWER) study.

Acute hepatic porphyria (AHP) is a group of rare genetic diseases of heme biosynthesis resulting in severe neurovisceral attacks and chronic complications that negatively impact patients' well-being. This study evaluated the impacts of AHP on patients' physical and emotional health from a global perspective. Adult patients from the United States, Italy, Spain, Australia, Mexico, and Brazil with AHP with >1 porphyria attack within the past 2 years or receiving intravenous hemin and/or glucose for attack prevention completed an online survey assessing demographics, health characteristics, and patient-reported outcomes.

Light-Related Cutaneous Symptoms of Erythropoietic Protoporphyria and Associations With Light Sensitivity Measurements.

Importance: Erythropoietic protoporphyria (EPP) is a rare and underdiagnosed genetic disease characterized by painful sensitivity to light. A better understanding and characterization of its light-induced cutaneous symptoms may aid in the identification of EPP in patients.

Objectives: To describe the cutaneous symptoms of erythropoietic protoporphyria (EPP) and to determine if these symptoms are associated with the degree of light sensitivity.

Dental and Periodontal Health in Acute Intermittent Porphyria.

In the inherited metabolic disorder acute intermittent porphyria (AIP), high sugar intake prevents porphyric attacks due to the glucose effect and the following high insulin levels that may lower AIP disease activity. Insulin resistance is a known risk factor for periodontitis and sugar changes diabetogenic hormones and affects dental health. We hypothesized differences in homeostasis model assessment (HOMA) scores for insulin resistance in AIP cases vs.

CRISPR Interference Reveals That All--Retinoic Acid Promotes Macrophage Control of Mycobacterium tuberculosis by Limiting Bacterial Access to Cholesterol and Propionyl Coenzyme A.

Macrophages are a protective replicative niche for Mycobacterium tuberculosis (Mtb) but can kill the infecting bacterium when appropriately activated. To identify mechanisms of clearance, we compared levels of bacterial restriction by human macrophages after treatment with 26 compounds, including some currently in clinical trials for tuberculosis. All--retinoic acid (ATRA), an active metabolite of vitamin A, drove the greatest increase in Mtb control.

Smoking and Human Immunodeficiency Virus 1 Infection Promote Retention of CD8 T Cells in the Airway Mucosa.

Smoking and human immunodeficiency virus 1 (HIV-1) infection are risk factors for chronic obstructive pulmonary disease (COPD), which is among the most common comorbid conditions in people living with HIV-1. HIV-1 infection leads to persistent expansion of CD8 T cells, and CD8 T cell-mediated inflammation has been implicated in COPD pathogenesis. In this study, we investigated the effects of HIV-1 infection and smoking on T-cell dynamics in patients at risk of COPD.

T cell-tropic HIV efficiently infects alveolar macrophages through contact with infected CD4+ T cells.

Alveolar macrophages (AMs) are critical for defense against airborne pathogens and AM dysfunction is thought to contribute to the increased burden of pulmonary infections observed in individuals living with HIV-1 (HIV). While HIV nucleic acids have been detected in AMs early in infection, circulating HIV during acute and chronic infection is usually CCR5 T cell-tropic (T-tropic) and enters macrophages inefficiently in vitro. The mechanism by which T-tropic viruses infect AMs remains unknown.

Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria.

Purpose: Erythropoietic protoporphyria (EPP), characterized by painful cutaneous photosensitivity, results from pathogenic variants in ferrochelatase (FECH). For 96% of patients, EPP results from coinheriting a rare pathogenic variant in trans of a common hypomorphic variant c.315-48T>C (minor allele frequency 0.

Flagellin-independent effects of a Toll-like receptor 5 polymorphism in the inflammatory response to Burkholderia pseudomallei.

Background: Toll-like receptors (TLRs) are sentinel receptors of the innate immune system. TLR4 detects bacterial lipopolysaccharide (LPS) and TLR5 detects bacterial flagellin. A common human nonsense polymorphism, TLR5:c.