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Der Internist Sep 2021Porphyrias are caused by enzyme defects along the heme biosynthetic pathway. The first line diagnosis of porphyria is based on specific biochemical patterns of elevated...
Porphyrias are caused by enzyme defects along the heme biosynthetic pathway. The first line diagnosis of porphyria is based on specific biochemical patterns of elevated porphyrins and porphyrin precursors in urine, feces, and blood. In clinically active disease accumulated porphyrin precursors and/or porphyrins lead to abdominal, neurologic, psychiatric, endocrine and cardiovascular symptoms, liver damage and/or skin photosensitivity. Porphyrias are classified into acute and nonacute forms. Patients with symptomatic (clinically active) acute hepatic porphyria, e.g. acute intermittent porphyria, porphyria variegata, hereditary coproporphyria, and aminolevulinic acid dehydratase deficiency porphyria, display accumulation of porphyrin precursors, 5‑aminolevulinic acid and porphobilinogen due to regulation disorder. In the non-acute forms of porphyria, such as porphyria cutanea tarda, erythropoietic porphyria, X‑linked protoporphyria and congenital erythropoietic porphyria, accumulated porphyrins lead to skin photosensitivity and occasionally also to severe liver damage. Several different options for treatment, proven and innovative ones, are available for most porphyrias.
Topics: Humans; Porphyria Cutanea Tarda; Porphyria, Acute Intermittent; Porphyrias; Porphyrias, Hepatic; Porphyrins
PubMed: 34185109
DOI: 10.1007/s00108-021-01066-1 -
Molecular Genetics and Metabolism Nov 2019Porphyrias, is a general term for a group of metabolic diseases that are genetic in nature. In each specific porphyria the activity of specific enzymes in the heme... (Review)
Review
Porphyrias, is a general term for a group of metabolic diseases that are genetic in nature. In each specific porphyria the activity of specific enzymes in the heme biosynthetic pathway is defective and leads to accumulation of pathway intermediates. Phenotypically, each disease leads to either neurologic and/or photocutaneous symptoms based on the metabolic intermediate that accumulates. In each porphyria the distinct patterns of these substances in plasma, erythrocytes, urine and feces are the basis for diagnostically defining the metabolic defect underlying the clinical observations. Porphyrias may also be classified as either erythropoietic or hepatic, depending on the principal site of accumulation of pathway intermediates. The erythropoietic porphyrias are congenital erythropoietic porphyria (CEP), and erythropoietic protoporphyria (EPP). The acute hepatic porphyrias include ALA dehydratase deficiency porphyria, acute intermittent porphyria (AIP), hereditary coproporphyria (HCP) and variegate porphyria (VP). Porphyria cutanea tarda (PCT) is the only porphyria that has both genetic and/or environmental factors that lead to reduced activity of uroporphyrinogen decarboxylase in the liver. Each of the 8 enzymes in the heme biosynthetic pathway have been associated with a specific porphyria (Table 1). Mutations affecting the erythroid form of ALA synthase (ALAS2) are most commonly associated with X-linked sideroblastic anemia, however, gain-of-function mutations of ALAS2 have also been associated with a variant form of EPP. This overview does not describe the full clinical spectrum of the porphyrias, but is meant to be an overview of the biochemical steps that are required to make heme in both erythroid and non-erythroid cells.
Topics: Animals; Biosynthetic Pathways; Environment; Heme; Humans; Liver; Mice; Mutation; Porphobilinogen Synthase; Porphyria, Acute Intermittent; Porphyrias; Porphyrias, Hepatic; Uroporphyrinogen Decarboxylase
PubMed: 31326287
DOI: 10.1016/j.ymgme.2019.04.008 -
Brain and Behavior Nov 2021Acute hepatic porphyrias (AHP) can cause severe neurological symptoms involving the central, autonomic, and peripheral nervous system. Due to their relative rarity and... (Review)
Review
Acute hepatic porphyrias (AHP) can cause severe neurological symptoms involving the central, autonomic, and peripheral nervous system. Due to their relative rarity and their chameleon-like presentation, delayed diagnosis and misdiagnosis are common. AHPs are genetically inherited disorders that result from heme biosynthesis enzyme deficiencies and comprise four forms: acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and ALA-dehydratase porphyria (ALADP). Depending on the clinical presentation, the main differential diagnoses are Guillain-Barré syndrome and autoimmune encephalitis. Red flags that could raise the suspicion of acute porphyria are neurological symptoms starting after severe (abdominal) pain, in association with reddish urine, hyponatremia or photodermatitis, and the presence of encephalopathy and/or axonal neuropathy. We highlight the diagnostic difficulties by presenting three cases from our neurological intensive care unit and give a comprehensive overview about the diagnostic findings in imaging, electrophysiology, and neuropathology.
Topics: Humans; Nervous System Diseases; Porphobilinogen Synthase; Porphyria, Acute Intermittent; Porphyrias; Porphyrias, Hepatic
PubMed: 34661997
DOI: 10.1002/brb3.2389 -
Emergency Medicine Clinics of North... Nov 2021Abdominal pain is a common reason for emergency department visits, with many patients not receiving a definitive diagnosis for their symptoms. Non-gastrointestinal... (Review)
Review
Abdominal pain is a common reason for emergency department visits, with many patients not receiving a definitive diagnosis for their symptoms. Non-gastrointestinal causes need to be considered in the workup of abdominal pain. A high index of suspicion is needed in order to develop a broad differential, and a thorough history and physical examination is paramount. This article will discuss some of these diagnoses, including can't miss diagnoses, common non-abdominal causes, and rare etiologies of abdominal pain.
Topics: Abdominal Pain; Acute Coronary Syndrome; Adrenal Gland Diseases; Anemia, Sickle Cell; Angioedemas, Hereditary; Aortic Diseases; COVID-19; Diabetic Ketoacidosis; Diagnosis, Differential; Emergency Service, Hospital; Female; Heart Failure; Herpes Zoster; Humans; IgA Vasculitis; Lead Poisoning; Migraine Disorders; Ovarian Torsion; Pelvic Inflammatory Disease; Pneumonia; Porphyria, Acute Intermittent; Pregnancy; Pregnancy, Ectopic; Pulmonary Embolism; Thyrotoxicosis; Uremia
PubMed: 34600641
DOI: 10.1016/j.emc.2021.07.003 -
Current Protocols in Human Genetics Jul 2015Porphyria diseases are a group of metabolic disorders caused by abnormal functioning of heme biosynthesis enzymes and characterized by excessive accumulation and... (Review)
Review
Porphyria diseases are a group of metabolic disorders caused by abnormal functioning of heme biosynthesis enzymes and characterized by excessive accumulation and excretion of porphyrins and their precursors. Precisely which of these chemicals builds up depends on the type of porphyria. Porphyria is not a single disease but a group of nine disorders: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), δ-aminolevulinic acid dehydratase deficiency porphyria (ADP), porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP), congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), and X-linked protoporphyria (XLP). Each porphyria results from overproduction of heme precursors secondary to partial deficiency or, in XLP, increased activity of one of the enzymes of heme biosynthesis. Taken together, all forms of porphyria afflict fewer than 200,000 people in the United States. Based on European studies, the most common porphyria, PCT, has a prevalence of 1 in 10,000, the most common acute porphyria, AlP, has a prevalence of ∼1 in 20,000, and the most common erythropoietic porphyria, EPP, is estimated at 1 in 50,000 to 75,000. CEP is extremely rare, with prevalence estimates of 1 in 1,000,000 or less. Only six cases of ADP are documented. The current porphyria literature is very exhaustive and a brief overview of porphyria diseases is essential in order for the reader to better appreciate the relevance of this area of research prior to undertaking biochemical diagnostics procedures. This unit summarizes the current knowledge on the classification, clinical features, etiology, pathogenesis, and genetics of porphyria diseases.
Topics: Comorbidity; Diagnosis, Differential; Humans; Inheritance Patterns; Porphyrias; Prevalence; Risk Factors
PubMed: 26132003
DOI: 10.1002/0471142905.hg1720s86 -
JHEP Reports : Innovation in Hepatology Aug 2021Gene therapy is becoming an increasingly valuable tool to treat many genetic diseases with no or limited treatment options. This is the case for hundreds of monogenic... (Review)
Review
Gene therapy is becoming an increasingly valuable tool to treat many genetic diseases with no or limited treatment options. This is the case for hundreds of monogenic metabolic disorders of hepatic origin, for which liver transplantation remains the only cure. Furthermore, the liver contains 10-15% of the body's total blood volume, making it ideal for use as a factory to secrete proteins into the circulation. In recent decades, an expanding toolbox has become available for liver-directed gene delivery. Although viral vectors have long been the preferred approach to target hepatocytes, an increasing number of non-viral vectors are emerging as highly efficient vehicles for the delivery of genetic material. Herein, we review advances in gene delivery vectors targeting the liver and more specifically hepatocytes, covering strategies based on gene addition and gene editing, as well as the exciting results obtained with the use of RNA as a therapeutic molecule. Moreover, we will briefly summarise some of the limitations of current liver-directed gene therapy approaches and potential ways of overcoming them.
PubMed: 34159305
DOI: 10.1016/j.jhepr.2021.100300 -
Biomedica : Revista Del Instituto... Mar 2020The term ‘porphyria’ comes from the Greek ‘porphyra’. It refers to a heterogeneous group of metabolic disorders caused by the enzymatic deficiency in the...
The term ‘porphyria’ comes from the Greek ‘porphyra’. It refers to a heterogeneous group of metabolic disorders caused by the enzymatic deficiency in the biosynthesis of the heme group. Acute intermittent porphyria is caused by a deficiency of the porphobilinogen deaminase enzyme. A 40-year-old woman presented with abdominal pain for ten days (which required laparotomy that evidenced no surgical pathology), severe hydroelectrolytic disorder due to hyponatremia and resistant hypokalemia, persistent tachycardia and hypertension. Seven days later, she developed acute flabby quadriparesis and presented a single generalized tonic-clonic convulsive crisis. Neurophysiological studies supported mixed axonal polyneuropathy and urine results of porphobilinogen and porphyrins were elevated. After acute intermittent porphyria was diagnosed, hemin was administered, which stabilized the patient’s clinical signs and normalized the porphobilinogen. The prevalence of this entity is 1 in 2,000 people. It is an autosomal dominant disease, which affects mainly women between 20 and 40 years of age. This entity manifests with neurological and visceral symptoms. Management consists of hematin and dextrose administration avoiding hypotonic solutions because of the risk of exacerbating hyponatremia.
Topics: Delayed Diagnosis; Female; Gastrointestinal Diseases; Hemin; Humans; Neurons; Porphobilinogen; Porphyria, Acute Intermittent; Porphyrins; Prevalence; Quadriplegia; Respiration, Artificial; Respiratory Insufficiency; Seizures; Symptom Assessment; Water-Electrolyte Imbalance; Young Adult
PubMed: 32220159
DOI: 10.7705/biomedica.4767 -
AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review.Gastroenterology Mar 2023The acute hepatic porphyrias (AHP) are rare, inborn errors of heme-metabolism and include acute intermittent porphyria, hereditary coproporphyria, variegate porphyria,... (Review)
Review
DESCRIPTION
The acute hepatic porphyrias (AHP) are rare, inborn errors of heme-metabolism and include acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and porphyria due to severe deficiency of 5-aminolevulinic acid dehydratase. Acute intermittent porphyria is the most common type of AHP, with an estimated prevalence of patients with symptoms of approximately 1 in 100,000. The major clinical presentation involves attacks of severe pain, usually abdominal and generalized, without peritoneal signs or abnormalities on cross-sectional imaging. Acute attacks occur mainly in women in their childbearing years. AHP should be considered in the evaluation of all patients, and especially women aged 15-50 years with recurrent severe abdominal pain not ascribable to common causes. The screening tests of choice include random urine porphobilinogen and δ-aminolevulinic acid corrected to creatinine. All patients with elevations in urinary porphobilinogen and/or δ-aminolevulinic acid should initially be presumed to have AHP. The cornerstones of management include discontinuation of porphyrinogenic drugs and chemicals, administration of oral or intravenous dextrose and intravenous hemin, and use of analgesics and antiemetics. Diagnosis of AHP type can be confirmed after initial treatment by genetic testing for pathogenic variants in HMBS, CPOX, PPOX, and ALAD genes. AHP is also associated with chronic symptoms and long-term risk of systemic arterial hypertension, chronic renal and liver disease, and hepatocellular carcinoma. Patients who have recurrent acute attacks (4 or more per year) should be considered for prophylactic therapy with intravenous hemin or subcutaneous givosiran. Liver transplantation is curative and reserved for patients with intractable symptoms who have failed other treatment options.
METHODS
This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Women aged 15-50 years with unexplained, recurrent severe abdominal pain without a clear etiology after an initial workup should be considered for screening for an AHP. BEST PRACTICE ADVICE 2: Initial diagnosis of AHP should be made by biochemical testing measuring δ-aminolevulinic acid, porphobilinogen, and creatinine on a random urine sample. BEST PRACTICE ADVICE 3: Genetic testing should be used to confirm the diagnosis of AHP in patients with positive biochemical testing. BEST PRACTICE ADVICE 4: Acute attacks of AHP that are severe enough to require hospital admission should be treated with intravenous hemin, given daily, preferably into a high-flow central vein. BEST PRACTICE ADVICE 5: In addition to intravenous hemin, management of acute attacks of AHP should include pain control, antiemetics, management of systemic arterial hypertension, tachycardia, and hyponatremia, and hypomagnesemia, if present. BEST PRACTICE ADVICE 6: Patients should be counseled to avoid identifiable triggers that may precipitate acute attacks, such as alcohol and porphyrinogenic medications. BEST PRACTICE ADVICE 7: Prophylactic heme therapy or givosiran, administered in an outpatient setting, should be considered in patients with recurrent attacks (4 or more per year). BEST PRACTICE ADVICE 8: Liver transplantation for AHP should be limited to patients with intractable symptoms and significantly decreased quality of life who are refractory to pharmacotherapy. BEST PRACTICE ADVICE 9: Patients with AHP should be monitored annually for liver disease. BEST PRACTICE ADVICE 10: Patients with AHP, regardless of the severity of symptoms, should undergo surveillance for hepatocellular carcinoma, beginning at age 50 years, with liver ultrasound every 6 months. BEST PRACTICE ADVICE 11: Patients with AHP on treatment should undergo surveillance for chronic kidney disease annually with serum creatinine and estimated glomerular filtration rate. BEST PRACTICE ADVICE 12: Patients should be counseled on the chronic and long-term complications of AHP, including neuropathy, chronic kidney disease, hypertension, and hepatocellular carcinoma, and need for long-term monitoring.
Topics: Humans; Female; United States; Middle Aged; Porphyria, Acute Intermittent; Porphobilinogen Synthase; Porphobilinogen; Hemin; Aminolevulinic Acid; Carcinoma, Hepatocellular; Antiemetics; Creatinine; Quality of Life; Porphyrias, Hepatic; Heme; Hypertension; Liver Neoplasms; Renal Insufficiency, Chronic; Abdominal Pain
PubMed: 36642627
DOI: 10.1053/j.gastro.2022.11.034 -
Annual Review of Medicine Jan 2024The 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... (Review)
Review
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.
Topics: Humans; Porphyrias; Heme
PubMed: 37540847
DOI: 10.1146/annurev-med-042921-123602