Severe homocysteinemia in two givosiran-treated porphyria patients: is free heme deficiency the culprit?

Givosiran is a novel approach to treat patients with acute intermittent porphyrias (AIP) by silencing of ∂-ALA-synthase 1, the first enzyme of heme biosynthesis in the liver. We included two patients in the Envision study who responded clinically well to this treatment. However, in both patients, therapy had to be discontinued because of severe adverse effects: One patient (A) developed local injection reactions which continued to spread all over her body with increasing number of injections and eventually caused a severe systemic allergic reaction. Patient B was hospitalized because of a fulminant pancreatitis. Searching for possible causes, we also measured the patients plasma homocysteine (Hcy) levels in fluoride-containing collection tubes: by LC–MS/MS unexpectedly, plasma Hcy levels were 100 and 200 in patient A and between 100 and 400 μmol/l in patient B. Searching for germline mutations in 10 genes that are relevant for homocysteine metabolism only revealed hetero- and homozygous polymorphisms in the MTHFR gene. Alternatively, an acquired inhibition of cystathionine-beta-synthase which is important for homocysteine metabolism could explain the plasma homocysteine increase. This enzyme is heme-dependent: when we gave heme arginate to our patients, Hcy levels rapidly dropped. Hence, we conclude that inhibition of ∂-ALA-synthase 1 by givosiran causes a drop of free heme in the hepatocyte and therefore the excessive increase of plasma homocysteine. Hyperhomocysteinemia may contribute to the adverse effects seen in givosiran-treated patients which may be due to protein-N-homocysteinylation.

Epirubicin-induced Kounis syndrome

Background Kounis syndrome is an acute coronary syndrome that appears in the setting of anaphylactic reaction or hypersensitivity. Many drugs and environmental exposures have been identified as potential offenders, and diagnosis and treatment can be challenging. Case presentation A 62-year-old man with recurrent bladder cancer underwent an intra-iliac artery epirubicin injection. After the injection, he developed chest pain and a systemic allergic reaction, with electrocardiographic alterations and elevated troponin-I levels. Emergent coronary angiography showed right coronary artery spasm and no stenosis of the other coronary arteries. This reaction was considered compatible with an allergic coronary vasospasm. A diagnosis of Kounis syndrome was made. Conclusions Kounis syndrome is common, but a prompt diagnosis is often not possible. This case is the first to suggest that an intraarterial epirubicin injection could potentially be one of its triggers. All physicians should be aware of the pathophysiology of this condition to better recognize it and start appropriate treatment; this will prevent aggravation of the vasospastic cardiac attacks and yield a better outcome.

A case report of Kounis syndrome presenting with a rash, very late stent thrombosis and coronary evaginations

Background Very late stent thrombosis (ST) is a concern in the era of drug-eluting stents (DESs), and ST is associated with peri-DES coronary artery aneurysmal lesions or coronary evaginations. An increasing number of cases of concurrent systemic allergic reaction and ST have been reported as Kounis syndrome (KS) in the literature. The number of patients with very late ST caused by KS is small, and further investigation of the potential pathophysiology is required. Case summary We report a case of KS that manifested as systemic urticaria followed by very late ST 14 years after placement of two sirolimus-eluting stents (SESs). Three months after the event of ST, coronary evaginations at the stented segments were detected on intravascular optical coherence tomography. Discussion Coronary evaginations are associated with local hypersensitivity, stent malapposition, uncovered strut, and flow disturbance that may predispose to ST. Systemic allergic reactions are known to promote platelet adhesion and aggregation. This case of KS suggests a pathophysiology in which the synergic effects between the coronary evaginations and a systemic allergic reaction may contribute to very late ST. For patients with Type 3 KS, performing follow-up intracoronary imaging tests may be important to confirm potential coronary evaginations, especially in patients with SESs.

Toxic epidermal necrolysis in the practice of a family doctor

Toxic epidermal necrolysis is a severe delayed-type systemic allergic reaction, in which there is a combined lesion of the skin and mucous membranes. 2 cases of toxic epidermal necrolysis from the practice of a family doctor are described in the article. Timely diagnosis and rational treatment of the disease in the first case led to a favorable outcome, in the second case, the outcome of the disease was unfavorable.

Anaphylactic reaction to ethylene oxide in a hemodialysis patient

We present the case of a patient who developed a severe systemic allergic reaction during initiation of hemodialysis. The reaction completely resolved by switching the dialysis filter sterilized by ethylene oxide to a steam sterilized filter. Ethylene oxide is used to sterilize heat sensitive medical devices, and although allergic reactions related to ethylene oxide have been reported before, awareness is lacking among providers in the inpatient setting, specifically in the intensive care unit setting.

Suspected anaphylaxis

A type I IgE-mediated systemic allergic reaction is characterized by a constellation of symptoms which are due to widespread histamine release and which comprise acute-onset urticaria, angioedema, bronchospasm, and hypotension. While a mild reaction may be limited to localized urticaria and/or angioedema, a full-blown allergic reaction associated with systemic features is best described as anaphylaxis. The term ‘anaphylactoid’, previously used to denote non-IgE-mediated systemic allergic reactions, is no longer recommended for use.

Myths, facts and controversies in the diagnosis and management of anaphylaxis

Anaphylaxis is a serious systemic allergic reaction that is rapid in onset and may cause death. Despite numerous national and international guidelines and consensus statements, common misconceptions still persist in terms of diagnosis and appropriate management, both among healthcare professionals and patient/carers. We address some of these misconceptions and highlight the optimal approach for patients who experience potentially life-threatening allergic reactions.