The Hepatic Porphyrias: Revealing the Complexities of a Rare Disease.

The porphyrias are a group of metabolic disorders that are caused by defects in heme biosynthesis pathway enzymes. The result is accumulation of heme precursors, which can cause neurovisceral and/or cutaneous photosensitivity. Liver is commonly either a source or target of excess porphyrins, and porphyria-associated hepatic dysfunction ranges from minor abnormalities to liver failure. In this review, the first of a three-part series, we describe the defects commonly found in each of the eight enzymes involved in heme biosynthesis. We also discuss the pathophysiology of the hepatic porphyrias in detail, covering epidemiology, histopathology, diagnosis, and complications. Cellular consequences of porphyrin accumulation are discussed, with an emphasis on oxidative stress, protein aggregation, hepatocellular cancer, and endothelial dysfunction. Finally, we review current therapies to treat and manage symptoms of hepatic porphyria.

Brazilian registry of patients with porphyria: REBRAPPO study.

BACKGROUND: Porphyrias are a rare group of disease due to inherited defects of heme synthesis with important systemic manifestations and great burden of disease for patients and families due to the exceptional course of disease with disabling chronic symptoms interposed by life-threatening acute attacks. Unfortunately, the porphyrias are usually underrecognized reflecting a lack of medical and disease awareness as well as few studies about natural history in large cohorts of patients. The main aim of this article is present consistent data about natural history and burden of disease in a large Brazilian cohort. METHODS: We conducted a national cross-sectional registry with retrospective clinical data of Brazilian patients with porphyria collected with Brazilian patients Association with Porphyria in collaboration with a tertiary care center for rare diseases. RESULTS: A cohort of 172 patients was analyzed in which 148 (86%) patients had the diagnosis of acute hepatic porphyria [AHP] that needed a mean of 62.04 medical visits and 9.6 years to achieve a definitive diagnosis. About AHP cohort, the most common first clinical manifestation were abdominal pain in 77 (52%) patients and acute muscle weakness in 23 (15.5%) with 73 (49.3%) patients presenting only one attack during disease course and 37 (25%) exhibiting 4 or more attacks in the last year. Of note, 105 patients with AHP reported chronic manifestations and the scores for quality of life are lower when compared with general healthy population. CONCLUSIONS: Brazilian patients with AHP had a higher prevalence of chronic disabling manifestations and a poor quality of life like other cohorts and a higher proportion of patients with recurrent attacks than previously reported.

Single-incision laparoscopic partial cecectomy for appendiceal mucocele in a patient with porphyria photosensitivity.

Erythropoietic protoporphyria (EPP) is a rare hereditary subtype of cutaneous porphyria characterized by photosensitivity. Increased exposure to light irradiation may precipitate acute liver failure, and surgical light-induced intestinal burns and perforations are known to occur. We report a case of EPP in a patient who underwent laparoscopic partial cecectomy for appendiceal mucocele. A 55-year-old man with EPP was presented for treatment of appendiceal mucocele. A light test using two types of laparoscopes (Companies O and S) was performed preoperatively. Light from the laparoscope manufactured by Company O caused photosensitivity; this effect was not observed with light from the laparoscope manufactured by Company S. Therefore, we performed laparoscopic partial cecectomy through a single umbilical incision using the laparoscope from Company S. Except for the incision site, the patient's skin was completely covered using surgical drapes. No intra- or postoperative complications were observed. Histopathological examination of the resected specimen revealed a low-grade appendiceal mucinous neoplasm.

Porphyria: a case report.

BACKGROUND: Prompt diagnosis of metabolic disorders in a resource-limited country like Nepal is daunting. Acute intermittent porphyria is a rare but common hepatic porphyria mostly seen in females of the reproductive age group. As its incidence is quite uncommon, conjectures about porphyria diagnosis are often duped into a diagnostic conundrum. CASE PRESENTATION: Here we unravel a case of a 15-year-old Hindu Nepalese girl distraught by the myriad of symptoms in the setting of severe abdominal pain accompanied by constipation and limb pain as the chief complaints. She presented with acute severe hypertension with marked persistent hyponatremia (up to 109 mEq/L). Despite conservative management of hypertension and electrolytes, unresolved electrolyte imbalance led us to the speculation of disturbance in the renin-angiotensin-aldosterone system. Due to her exacerbating neurovisceral status, she also required intensive care during the disease course. After thorough investigations and exemption of presumed provisional diagnoses, based on sustained symptomatic presentation, the clinical suspicion was driven towards a diagnosis of porphyria-related disorders. Positive Watson-Schwartz test substantiated the diagnosis of acute intermittent porphyria. Her symptoms gradually abated after the consumption of high carbohydrate diets. CONCLUSION: This case highlights the baffling amalgamation of symptoms that simulate common diseases of concern yet are buried in the realm of porphyric disorders. Porphyria can be diagnosed using simple screening tools and timely treatment can diminish serious consequences.

Photodermatoses: what's new.

PURPOSE OF REVIEW: The purpose of this review is to summarize and highlight the recent literature in photodermatoses. In the past year, there have been many developments in this heterogeneous group of conditions. RECENT FINDINGS: This review is divided by photodermatoses type, which include idiopathic photodermatoses, photodermatoses secondary to exogenous agents, photodermatoses secondary to endogenous agents (the porphyrias), and genodermatoses. The idiopathic photodermatoses section focuses on case series and reports highlighting new disease presentations or further disease characterization and new treatment strategies for these disorders. The second section discusses a unique case and has a brief update on photoallergens. Clinical, diagnostic, and treatment updates for porphyrias are discussed in Section 3. For genodermatoses, we discuss complications and neoplastic risk of xeroderma pigmentosum and a few highlights from other rare disorders. Finally, we conclude with a brief overview of photoprotection updates, from assessing sun-damaged skin to the most effective photoprotective agents. SUMMARY: Up-to-date information will help providers identify and manage this rare group of disorders.

Neurological Manifestations of Acute Porphyrias.

PURPOSE OF REVIEW: Porphyrias constitute a group of rare metabolic disorders that result in a deficiency of the heme biosynthetic pathway and lead to the accumulation of metabolic intermediaries. Patients with porphyria can experience recurrent neurovisceral attacks which are characterized by neuropathic abdominal pain and acute gastrointestinal symptoms, including nausea, vomiting, and constipation. Depending on the type of porphyria, patients can present with cutaneous manifestations, such as severe skin photosensitivity, chronic hemolysis, or evidence of neurologic dysfunction, including alterations in consciousness, neurovascular involvement, seizures, transient sensor-motor symptoms, polyneuropathy, and behavioral abnormalities. RECENT FINDINGS: More recently, cases of posterior reversible encephalopathy syndrome, cerebral vasoconstriction, and acute flaccid paralysis have also been described. While the exact pathogenic mechanisms linking the accumulation of abnormal heme biosynthetic intermediaries to neurologic manifestations have not been completely elucidated, it has been proposed that these manifestations are more common than previously thought and can result in permanent neurologic injury. This article reviews the basic principles of heme synthesis as well as the pathogenic mechanism of disease, presentation, and treatment of acute hepatic porphyrias with emphasis on those with neurologic manifestations.

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, [Formula: see text]-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.

[Flaccid paralysis and abdominal pain, an approach to porphyrias: a literature review and case series]. / Dolor abdominal y parálisis flácida, una aproximación a las porfirias: serie de casos y revisión de la literatura.

Porphyrias are inherited metabolic disorders caused by enzymatic deficiencies of HEM group biosynthesis. Most common in childhood at the third and fourth decade of life. They are characterized by increased levels of porphyrins, and various cutaneous, neurological, and visceral manifestations. We describe a series of 3 cases of female patients in the third decade of life with abdominal pain and a wide range of clinical manifestations and short and long-term complications. Our review contributes to the early recognition of these diseases to establish early specific managements to impact on irreversible outcomes.

Acute Neurological Manifestations of Porphyrias and its Types: A Systematic- Review.

INTRODUCTION: Acute porphyrias cause life-threatening attacks of neurovisceral non-specific symptoms, so this condition mimics many acute medical and psychiatric diseases. The disease is very misdiagnosed, probably due to its low incidence and non-pathognomonic symptoms, this delays the effective treatment onset. Early diagnosis and treatment highly improve the prognosis and can prevent the development of neuropathic manifestations. METHODS: We assembled a systematic review, following the PRISMA guidelines and using Pubmed as our database. Our aim was to show some peculiarities among patients that present neurological manifestations in acute porphyria attack. We obtained the patients' age, sex, clinical presentation, eurological manifestations and porphyria type of 16 patients. We also evaluated the time between symptoms onset and neurological manifestations. The average age was 28,4 ± 11,1; 50% of patients were male. RESULTS: AIP was the most prevalent porphyria type. The average time between symptoms onset and neurological manifestations was of 9,53 ± 11,6 days. Abdominal pain; nausea and vomiting and psychiatric manifestations were the most common symptoms preceding neurological attacks. Seizures and consciousness disturbance were the most prevalent findings within an attack. We also presenting a case to illustrate how difficult this diagnosis can be.

Porphyria-induced posterior reversible encephalopathy syndrome and central nervous system dysfunction.

BACKGROUND AND AIM: An association between neuropsychiatric manifestations and neuroimaging suggestive of posterior reversible encephalopathy syndrome (PRES) during porphyric attacks has been described in numerous case reports. We aimed to systematically review clinical-radiological features and likely pathogenic mechanisms of PRES in patients with acute hepatic porphyrias (AHP) and porphyric attacks. METHODS: PubMed, Scopus, Ovid MEDLINE, and Google Scholar were searched (July 30, 2019). We included articles describing patients with convincing evidence of an AHP, confirmed porphyric attacks, and PRES in neuroimaging. RESULTS: Forty-three out of 269 articles were included, which reported on 46 patients. Thirty-nine (84.8%) patients were women. The median age was 24 ±â€¯13.8 years. 52.2% had unspecified AHP, 41.3% acute intermittent porphyria, 4.3% hereditary coproporphyria, and 2.2% variegate porphyria. 70.2% had systemic arterial hypertension. Seizures, mental changes, arterial hypertension, and hyponatremia occurred more frequently than expected for porphyric attacks (p < .001). Seizures and hyponatremia were also more frequent than expected for PRES. The most common distributions of brain lesions were occipital (81.4%), parietal (65.1%), frontal (60.5%), subcortical (40%), and cortical (32.5%). Cerebral vasoconstriction was demonstrated in 41.7% of the patients who underwent angiography. 19.6% of the patients had ischemic lesions, and 4.3% developed long-term sequelae (cognitive decline and focal neurological deficits). CONCLUSIONS: Brain edema, vasoconstriction, and ischemia in the context of PRES likely account for central nervous symptoms in some porphyric attacks.

Reversible encephalopathy syndrome in acute porphyria attack / Síndrome de encefalopatía reversible en el ataque de porfiria aguda

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Neurological and neuropsychiatric manifestations of porphyria.

Porphyrias are inherited disorders of the heme biosynthetic pathway, usually characterized by dermatological changes due to the accumulation of byproducts in the pathway. Select porphyrias also affect the nervous system, namely hereditary coproporphyria, acute intermittent porphyria and variegate porphyria. Complications include paralysis, hyponatremia which can risk central pontine myelinolysis, seizures and coma. Neurological complications usually result from severe episodes of acute attacks. Acute attacks may also elicit neuropsychiatric symptoms such as confusion, hallucinations, anxiety and psychosis. However, these manifestations are generally self-limiting. Due to the generally low incidence of porphyria and full knowledge the associated neurological and psychiatric manifestations, we review the relevant porphyrias along with their clinical manifestations, evaluation, and management to raise its awareness in the clinical picture and to prevent misdiagnosis. Porphyria should be considered within the differential diagnosis for unexplained neurological symptoms.

Clinical Guide and Update on Porphyrias.

Physicians should be aware of porphyrias, which could be responsible for unexplained gastrointestinal, neurologic, or skin disorders. Despite their relative rarity and complexity, most porphyrias can be easily defined and diagnosed. They are caused by well-characterized enzyme defects in the complex heme biosynthetic pathway and are divided into categories of acute vs non-acute or hepatic vs erythropoietic porphyrias. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and aminolevulinic acid dehydratase deficient porphyria) manifest in attacks and are characterized by overproduction of porphyrin precursors, producing often serious abdominal, psychiatric, neurologic, or cardiovascular symptoms. Patients with variegate porphyria and hereditary coproporphyria can present with skin photosensitivity. Diagnosis relies on measurement of increased urinary 5-aminolevulinic acid (in patients with aminolevulinic acid dehydratase deficient porphyria) or increased 5-aminolevulinic acid and porphobilinogen (in patients with other acute porphyrias). Management of attacks requires intensive care, strict avoidance of porphyrinogenic drugs and other precipitating factors, caloric support, and often heme therapy. The non-acute porphyrias are porphyria cutanea tarda, erythropoietic protoporphyria, X-linked protoporphyria, and the rare congenital erythropoietic porphyria. They lead to the accumulation of porphyrins that cause skin photosensitivity and occasionally severe liver damage. Secondary elevated urinary or blood porphyrins can occur in patients without porphyria, for example, in liver diseases, or iron deficiency. Increases in porphyrin precursors and porphyrins are also found in patients with lead intoxication. Patients with porphyria cutanea tarda benefit from iron depletion, hydroxychloroquine therapy, and, if applicable, elimination of the hepatitis C virus. An α-melanocyte-stimulating hormone analogue can reduce sunlight sensitivity in patients with erythropoietic protoporphyria or X-linked protoporphyria. Strategies to address dysregulated or dysfunctional steps within the heme biosynthetic pathway are in development.

Photoonycholysis: new findings.

First described in 1961, photoonycholysis (PO) is a rare nail alteration that may result from drug intake, from topical aminolevulinate photodynamic therapy or from photosensitive conditions such as porphyria or pseudoporphyria. Spontaneous PO is rare. This review updates the numerous causes of PO and highlights some new ways producing this condition. Four different types of PO are clearly recognized without relationship with the responsible drug. An updated list of potential inducing drug is provided. Some practical points on PO have been raised. The inability to reproduce photoonycholysis experimentally should be emphasized, and the pathogenesis of PO still needs to be clarified.

Loss of hepatocyte ß-catenin protects mice from experimental porphyria-associated liver injury.

BACKGROUND & AIMS: Porphyrias result from anomalies of heme biosynthetic enzymes and can lead to cirrhosis and hepatocellular cancer. In mice, these diseases can be modeled by administration of a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which causes accumulation of porphyrin intermediates, resulting in hepatobiliary injury. Wnt/ß-catenin signaling has been shown to be a modulatable target in models of biliary injury; thus, we investigated its role in DDC-driven injury. METHODS: ß-Catenin (Ctnnb1) knockout (KO) mice, Wnt co-receptor KO mice, and littermate controls were fed a DDC diet for 2 weeks. ß-Catenin was exogenously inhibited in hepatocytes by administering ß-catenin dicer-substrate RNA (DsiRNA), conjugated to a lipid nanoparticle, to mice after DDC diet and then weekly for 4 weeks. In all experiments, serum and livers were collected; livers were analyzed by histology, western blotting, and real-time PCR. Porphyrin was measured by fluorescence, quantification of polarized light images, and liquid chromatography-mass spectrometry. RESULTS: DDC-fed mice lacking ß-catenin or Wnt signaling had decreased liver injury compared to controls. Exogenous mice that underwent ß-catenin suppression by DsiRNA during DDC feeding also showed less injury compared to control mice receiving lipid nanoparticles. Control livers contained extensive porphyrin deposits which were largely absent in mice lacking ß-catenin signaling. Notably, we identified a network of key heme biosynthesis enzymes that are suppressed in the absence of ß-catenin, preventing accumulation of toxic protoporphyrins. Additionally, mice lacking ß-catenin exhibited fewer protein aggregates, improved proteasomal activity, and reduced induction of autophagy, all contributing to protection from injury. CONCLUSIONS: ß-Catenin inhibition, through its pleiotropic effects on metabolism, cell stress, and autophagy, represents a novel therapeutic approach for patients with porphyria. LAY SUMMARY: Porphyrias are disorders resulting from abnormalities in the steps that lead to heme production, which cause build-up of toxic by-products called porphyrins. Liver is commonly either a source or a target of excess porphyrins, and complications can range from minor abnormalities to liver failure. In this report, we inhibited Wnt/ß-catenin signaling in an experimental model of porphyria, which resulted in decreased liver injury. Targeting ß-catenin affected multiple components of the heme biosynthesis pathway, thus preventing build-up of porphyrin intermediates. Our study suggests that drugs inhibiting ß-catenin activity could reduce the amount of porphyrin accumulation and help alleviate symptoms in patients with porphyria.

Porphyrias and photosensitivity: pathophysiology for the clinician.

Porphyrias are disorders caused by defects in the biosynthetic pathway of heme. Their manifestations can be divided into three distinct syndromes, each attributable to the accumulation of three distinct classes of molecules. The acute neurovisceral syndrome is caused by the accumulation of the neurotoxic porphyrin precursors, delta aminolevulinic acid, and porphobilinogen; the syndrome of immediate painful photosensitivity is caused by the lipid-soluble protoporphyrin IX and, the syndrome of delayed blistering photosensitivity, caused by the water-soluble porphyrins, uroporphyrin, and coproporphyrin. Porphyrias can manifest with one, or with a combination, of these syndromes, depending on whether one or more types of molecules are being accumulated. Iron plays a significant role in some of these conditions, as evidenced by improvements in both clinical manifestations and laboratory parameters, following iron depletion in porphyria cutanea tarda, or iron administration in some cases of X-linked erythropoietic protoporphyria. While the pathophysiology of a specific type of porphyrias, the protoporphyrias, appears to favor the administration of zinc, results so far have been conflicting, necessitating further studies in order to assess its potential benefit. The pathways involved in each disease, as well as insights into their pathobiological processes are presented, with an emphasis on the development of photosensitivity reactions.

Porphyria: often discussed but too often missed.

The diagnosis of acute intermittent porphyria (AIP) is often overlooked. We describe a patient with this condition who had all the 'bells and whistles', in whom the diagnosis was only made after considerable delay. Far from an esoteric condition haunting examination candidates, AIP is an important cause of a broad spectrum of neurological symptoms. Its early recognition allows the astute clinician to prevent potentially devastating sequelae. We provide practical guidance on the investigation and management of this complex disorder. With a 'back to basics' approach to the underlying genetics and biochemistry, we hope to dispel some of the confusion that may obstruct a timely diagnosis.