Challenges in diagnosis and management of acute hepatic porphyrias: from an uncommon pediatric onset to innovative treatments and perspectives

Abstract

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, $$\delta$$ δ -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

“…In AHPs, the accumulation of toxic non-porphyrin heme precursors ( -aminolevulinic acid—ALA and porphobilinogen—PBG) is deemed to cause most clinical manifestations, including those with possible vascular involvement (arterial hypertension, headache, neurological symptoms, kidney impairment) [ 9 , 10 , 15 , 16 , 17 , 18 ]. Symptomatic patients with AHPs often undergo an off-label maintenance therapy with heme arginate, which aims to reduce the frequency of APAs [ 19 ]. Alternatively, monthly infusions of intravenous (IV) hypertonic (10–20%) glucose can be attempted as an off-label maintenance therapy in symptomatic patients with mild-to-moderate manifestations of AHPs.…”

An Overview of Acute Hepatic Porphyrias: Clinical Implications, Diagnostic Approaches, and Management Strategies

“…Individuals who are free of symptoms and carrying pathological mutation are named as “latent patients.” Environmental factors and existence of modifier genes are thought to have a pivotal role in determination of the phenotype. 3 …”

“…Severe abdominal pain, hyponatremia, hypertension, tachycardia, and constipation are the cardinal signs of an acute neurovisceral attack caused by an affected autonomic nervous system involvement. 3 , 9 …”

“…Hypertension, tachycardia, correction of hyponatremia, and gastrointestinal symptoms such as nausea and vomiting should be treated appropriately. 3 …”

“…In this review, clinical manifestations, diagnostic approaches, and management strategies of acute hepatic porphyrias (AHP), acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and aminolevulinic acid dehydratase deficiency porphyria (ADP) are discussed. 3 , 4 …”