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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. Although historically the management of EPP and XLP (collectively termed protoporphyria) centered around avoidance of sunlight, novel therapies have recently been approved or are in development, which will alter the therapeutic landscape for these conditions. We present 3 patient cases, highlighting key treatment considerations in patients with protoporphyria, including (1) approach to photosensitivity, (2) managing iron deficiency in protoporphyria, and (3) understanding hepatic failure in protoporphyria.
The pathophysiology of erythropoietic protoporphyria and other protoporphyrias is based on disordered heme synthesis, porphyrin transport, and their effects on the skin and liver. Leaf and Dickey provide a comprehensive guide on how to approach the care of patients with these rare inherited diseases and an update on the recent development of novel therapies.
Update on the Porphyrias Dickey, Amy K; Leaf, Rebecca Karp; Balwani, Manisha
Annual review of medicine,
01/2024, Letnik:
75, Številka:
1
Journal Article
Recenzirano
Odprti dostop
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. Here, we review the porphyrias and describe their clinical presentation, diagnosis, and management. We discuss novel therapies that are approved or in development. Early diagnosis is key for the appropriate management and prevention of long-term complications in these rare disorders.
A 25-year-old woman with a history of acute intermittent porphyria was admitted with abdominal pain and jerking movements of the arm and leg. Symptoms did not abate with hemin treatment. A diagnosis ...was made.
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. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study of adolescent and adult (≥15 years) patients with EPP across the US conducted by a single academic hospital via a remotely administered survey, measurements of light sensitivity by light dosimetry and by text message symptom assessments. Data analyses were conducted from November 2020 to April 2022. EXPOSURES: Sunlight exposure. MAIN OUTCOMES AND MEASURES: Self-reported symptoms and association with measured light sensitivity. RESULTS: The study sample consisted of 35 patients with EPP (mean SD age, 39.1 (15.5) years; 21 60% female; 14 40% male; 35 100% White individuals). The patients’ median range skin tone was 3.0 (1.0-8.0), based on self-reporting from 1 (lightest) to 12 (darkest). A total of 24 participants completed the light dosimeter measurements. Phototoxic reactions were characterized by pain (97%; 34 patients), burning (97%; 34), tingling (97%; 34), pruritus (83%; 29), allodynia (89%; 31), improvement of symptoms with cold (89%; 31), achiness (24%; 12), fatigue (46%; 16), mild swelling (83%; 29), severe swelling (63%; 22), erythema (51%; 18), petechiae (40%; 14), skin cracking (43%; 15), scabbing (46%; 16), scarring (66%; 23), and other chronic skin changes (40%; 14). Patients with EPP reported that their hands, feet, and face were most sensitive to light and that their shoulders and legs were least sensitive; 25.7% (9 patient) reported no chronic skin changes, and 5.7% (2 patients) reported never having had any visible symptoms. None of these findings varied with the degree of light sensitivity except that lower overall light sensitivity was associated with lower ranked sensitivity of the neck and arms. CONCLUSIONS AND RELEVANCE: The findings of this cross-sectional study suggest that patients with EPP have distinctive cutaneous symptoms that may aid in identification of this underdiagnosed disease. Characteristic EPP symptoms include light-induced cutaneous burning pain and occasional swelling, particularly over the hands, with a prodrome of pruritus and paresthesias. Minimal skin changes or the absence of visible skin changes during reactions to light, including lack of erythema, do not exclude an EPP diagnosis nor suggest low EPP disease burden.
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. Bacterial clearance was transcriptionally and functionally associated with changes in macrophage cholesterol trafficking and lipid metabolism. To determine how these macrophage changes affected bacterial control, we performed the first Mtb CRISPR interference screen in an infection model, identifying Mtb genes specifically required to survive in ATRA-activated macrophages. These data showed that ATRA treatment starves Mtb of cholesterol and the downstream metabolite propionyl coenzyme A (propionyl-CoA). Supplementation with sources of propionyl-CoA, including cholesterol, abrogated the restrictive effect of ATRA. This work demonstrates that targeting the coupled metabolism of Mtb and the macrophage improves control of infection and that it is possible to genetically map the mode of bacterial death using CRISPR interference.
Tuberculosis, caused by the bacterium Mycobacterium tuberculosis, is a leading cause of death due to infectious disease. Improving the immune response to tuberculosis holds promise for fighting the disease but is limited by our lack of knowledge as to how the immune system kills M. tuberculosis. Our research identifies a potent way to make relevant immune cells more effective at fighting M. tuberculosis and then uses paired human and bacterial genomic methods to determine the mechanism of that improved bacterial clearance.
A 76-year-old woman presented with abdominal pain, anorexia, memory impairment, and suicidal ideation. CT of the abdomen and pelvis revealed multiple dilated, fluid-filled loops of small bowel ...measuring up to 4 cm in diameter, with air–fluid levels and a transition point in the right lower quadrant. The urinary porphyrin levels were elevated. A diagnosis was made.
Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present ...evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies.
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. We collected AMs by bronchoscopy performed in HIV-infected, antiretroviral therapy (ART)-naive and uninfected subjects. We found that viral constructs made with primary HIV envelope sequences isolated from both AMs and plasma were T-tropic and inefficiently infected macrophages. However, these isolates productively infected macrophages when co-cultured with HIV-infected CD4+ T cells. In addition, we provide evidence that T-tropic HIV is transmitted from infected CD4+ T cells to the AM cytosol. We conclude that AM-derived HIV isolates are T-tropic and can enter macrophages through contact with an infected CD4+ T cell, which results in productive infection of AMs. CD4+ T cell-dependent entry of HIV into AMs helps explain the presence of HIV in AMs despite inefficient cell-free infection, and may contribute to AM dysfunction in people living with HIV.
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