Together with hereditary coproporphyria (HCP), acute intermittent porphyria (AIP), and δ-aminolevulinic acid dehydratase porphyria (ADP), variegate porphyria (VP) belongs to the group of acute hepatic porphyrias, as mitochondrial protoporphyrin oxidase (PPOX), the enzyme affected in VP and necessary for the seventh step in heme synthesis, performs its respective function of converting protoporphyrinogen IX to protoporphyrin IX in the liver [1] [2]. In VP, autosomal dominant gene mutations of the PPOX lead to its insufficient activity and the onset of cutaneous and neurovisceral symptoms [1] [2] [3]. Chronic blistering lesions in the form of erosions, bullae, and ulcerations with crusting and slow recovery are principal manifestations on the skin [2] [4]. Lesions are usually seen in childhood on the hands and face [2] [4]. The trauma of the skin that is exposed to sunlight seems to be the major risk factor for their appearance [4] [5]. Hypertrichosis and either hyper or hypopigmentation, as well as thickening of the skin are other notable findings [2]. On the other hand, vomiting, constipation, tachycardia, fever, fatigue, abdominal pain, muscle weakness, seizures, mental instability, paresis and neuromuscular deficits are hallmarks of an "acute neurovisceral attack" that is typical for patients suffering from VP [2] [3] [4]. Due to the fact that respiratory paralysis is a known complication, but also because the diagnosis is often delayed, a 10% mortality rate from acute attacks is observed [2] [6]. Patients may exhibit either of the two types of symptoms or both, whereas growth retardation and significant developmental disturbances are seen in the rare homozygous forms of VP [5].

• Weakness

  Weakness of limbs, tremor of the legs while walking and brachydactyly were the other findings in this case. [ijponline.biomedcentral.com]

  Psychiatric disturbances, autonomic neuropathy and muscle weakness have been reported in some patients. [clinuvel.com]

  Muscle weakness, seizures, and increased heart rate and blood pressure may also occur. [rarediseases.info.nih.gov]

  Symtpoms include abdominal pain, vomiting, diarrhea, constipation, muscle weakness, seizures, and mental changes such as anxiety and hallucinations. Some people with variegate porphyria have skin that is overly sensitive to sunlight. [smpdb.ca]

• Falling

  Hot water baths or showers may lessen nausea temporarily, but can present a risk of burns or falls. [house.wikia.com]

  During clinical remissions, these abnormal levels fall to normal. [albertaporphyriasociety.weebly.com]

  VAN DER BERGHGROTEPASS AW: Ein bemerkenswerter Fall von Porphyrie. Wien Klin Wochenschr 50:830-831, 1937 Google Scholar 2. BARNES H: Further South African cases of porphyrinuria. S Afr J Clin Sci 2:117-169, 1951 MedlineGoogle Scholar 3. [acpjournals.org]

  These fall under the broad designation: “secondary porphyrinurias.” [clinicaladvisor.com]

  Pathophysiology When hepatic UROD activity falls below the critical threshold, porphyrin by-products of the heme biosynthetic pathway with 4-8 carboxyl group substituents are overproduced. [emedicine.medscape.com]

• Surgical Procedure

  A surgical procedure. Sometimes, infection somewhere in the body. There are certain medicines that you should avoid if you have this type of porphyria. Recommended lists of medicines to avoid are available. [patient.info]

  The most frequent triggers of a porphyria attack are various drugs, surgical procedures, fasting, smoking, and physical or psychological stressors (Sassa, 2006; Zürich and Endokrinologie, 2018). [frontiersin.org]

• Malingering

  Because these attacks will often not involve any obvious visible signs of acute illness, such as fever, healthcare providers such as ER staff may not fully understand how much pain patients are experiencing, may think that patients are malingering or [www1.rarediseasesnetwork.org]

• Abdominal Pain

  The congenital form is more serious, resulting in crises of acute abdominal pain and certain neurological complications. [medical-dictionary.thefreedictionary.com]

  Attacks can persist for several weeks and manifest as intense abdominal pain, and neurological and psychological symptoms. The abdominal pain is often associated with lumbago irradiating to the thighs, and with nausea, vomiting and constipation. [orpha.net]

• Vomiting

  People with variegate porphyria can also have neurological symptoms in the form of episodes (acute attacks) of severe stomach pain, nausea and vomiting. [1] [2] Symptoms usually begin in adulthood. [rarediseases.info.nih.gov]

  Common neurological symptoms include abdominal pain, nausea, vomiting, constipation, extremity pain and weakness, anxiety, restlessness and convulsions. [porphyriafoundation.org]

  Abstract Variegate porphyria (VP), a low-penetrant autosomal dominant inherited disorder of haem metabolism, is characterised by photosensitivity (Fig. 1) and a propensity to develop acute neuropsychiatric attacks with abdominal pain, vomiting, constipation [ncbi.nlm.nih.gov]

  Symtpoms include abdominal pain, vomiting, diarrhea, constipation, muscle weakness, seizures, and mental changes such as anxiety and hallucinations. Some people with variegate porphyria have skin that is overly sensitive to sunlight. [smpdb.ca]

• Constipation

  She was admitted in an acute attack and developed severe dysautonomia manifested clinically by postural hypotension, tachycardia and constipation with severe abdominal pain. [ncbi.nlm.nih.gov]

  Symtpoms include abdominal pain, vomiting, diarrhea, constipation, muscle weakness, seizures, and mental changes such as anxiety and hallucinations. Some people with variegate porphyria have skin that is overly sensitive to sunlight. [smpdb.ca]

  The abdominal pain is often associated with lumbago irradiating to the thighs, and with nausea, vomiting and constipation. [orpha.net]

• Nausea

  People with variegate porphyria can also have neurological symptoms in the form of episodes (acute attacks) of severe stomach pain, nausea and vomiting. [1] [2] Symptoms usually begin in adulthood. [rarediseases.info.nih.gov]

  Common neurological symptoms include abdominal pain, nausea, vomiting, constipation, extremity pain and weakness, anxiety, restlessness and convulsions. [porphyriafoundation.org]

  The abdominal pain is often associated with lumbago irradiating to the thighs, and with nausea, vomiting and constipation. [orpha.net]

• Abdominal Cramps

  Symptoms present as an acute attack, often as severe abdominal cramping with vomiting and constipation. Acute intermittent porphyria Acute intermittent porphyria (AIP) is a deficiency of the enzyme hydroxymethylbilane synthase (HMBS). [healthline.com]

  Masters suggested Ryan's abdominal bleeding might be caused by acute intermittent porphyria, but there were no abdominal cramps to go along with it. [house.wikia.com]

• Hypertension

  Papers PDF Open Access More filters Journal Article•DOI• TL;DR: Patients with AIP or VP showed increased incidences of hepatocellular carcinoma, and probably also chronic renal failure and hypertension and hypertension. ...read moreread less Abstract: [typeset.io]

  Other long-term complications include chronic arterial hypertension and subsequent renal impairment. [clinicaladvisor.com]

  […] porphyria (VP), a low-penetrant autosomal dominant inherited disorder of haem metabolism, is characterised by photosensitivity (Fig. 1) and a propensity to develop acute neuropsychiatric attacks with abdominal pain, vomiting, constipation, tachycardia, hypertension [ncbi.nlm.nih.gov]

  […] severe, poorly localized Another cause of acute abdomen Associated nausea and vomiting Endometriosis/pelvic inflammatory disease Absence of fever or leucocytosis Irritable bowel syndrome Opiate addiction Cardiovascular signs Tachycardia Tachyarrhythmia Hypertension [academic.oup.com]

• Tachycardia

  She was admitted in an acute attack and developed severe dysautonomia manifested clinically by postural hypotension, tachycardia and constipation with severe abdominal pain. [ncbi.nlm.nih.gov]

  Other useful clues are a history of dark urine, especially reddish urine, tachycardia, and systemic arterial hypertension during attacks. [clinicaladvisor.com]

  Acute porphyria should be excluded in any case of unexplained severe abdominal pain, especially if associated with tachycardia and neurological symptoms. [academic.oup.com]

  On the other hand, vomiting, constipation, tachycardia, fever, fatigue, abdominal pain, muscle weakness, seizures, mental instability, paresis and neuromuscular deficits are hallmarks of an "acute neurovisceral attack" that is typical for patients suffering [symptoma.com]

• Photosensitivity

  The patients with the I12T mutation experienced no photosensitivity and acute attacks were rare (8%). [ncbi.nlm.nih.gov]

  Two are extremely severely affected with photosensitivity from birth and neurological and skeletal developmental abnormalities including severe brachydactyly. [porphyria-professionals.uct.ac.za]

• Blister

  Erythropoietic porphyrias are characterized by increased sensitivity to sunlight that causes chronic blistering ( Figure 1 ) ( Signal, 1993 ). [bcm441.kericolabroy.bergbuilds.domains]

  Patients are forced to lead a life sheltered from light and to avoid any mechanical contact with their skin surface or risk triggering wounds and long-lasting blistering. [clinuvel.com]

  Sun sensitivity, blisters, sores and discoloration after sun exposure are the most common type of skin symptoms in patients with VP. [ijponline.biomedcentral.com]

  They were advised on the importance of sun protection to avoid triggering skin blisters. [porphyrianews.com]

  PCT, HCP and VP are known as bullous porphyrias, as they all can lead to skin blistering. [porphyria-australia.org]

• Cutaneous Manifestation

  Our patient, a 36-year-old woman, has severe cutaneous manifestations. [ncbi.nlm.nih.gov]

  Phlebotomy and taking chloroquine are rarely effective at treating cutaneous manifestations. Micro-phlebotomy is beneficial for some patients. It is necessary to protect the skin from sources of light. [orpha.net]

• Hyperpigmentation

  We present the case of two sisters showing cutaneous signs typical of PCT: blisters, photosensitivity, hyperpigmentation, hypertrichosis, cutaneous fragility, and no acute symptomatology. [porphyria.eu]

  He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin. The weakness of limbs and brachydactyly were observed. [ijponline.biomedcentral.com]

  It is characterized by skin hyperpigmentation and hypertrichosis, abdominal pain, tachycardia, hypertension and neuromuscular disturbances. [uniprot.org]

  Hyperpigmentation and hypertrichosis of the face are possible side effects. Cutaneous manifestations may improve during the winters and be less common in northern areas and those with dark skin. [news-medical.net]

• Skin Rash

  Cutaneous porphyrias This type of porphyria mainly affects the skin, causing skin rashes and other problems. The excess porphyrins that build up can interact with light, making the skin light-sensitive. [patient.info]

  Reactions such as dizziness, feeling faint, allergies or short-lived skin rashes (which may occur immediately or very soon after taking the drug) are common after taking drugs and rarely have anything to do with porphyria. [porphyria.org.uk]

  [ more ] 0008066 Cutaneous photosensitivity Photosensitive skin Photosensitive skin rashes Photosensitivity Sensitivity to sunlight Skin photosensitivity Sun sensitivity [ more ] 0000992 5%-29% of people have these symptoms Abdominal pain Pain in stomach [rarediseases.info.nih.gov]

• Psychiatric Manifestation

  Much the same way as previously diagnosed patients with MCSS showed similarities with somatization disorders, the psychiatric manifestations of acute porphyria may also be confused with various psychiatric disorders (especially when combined with an isolated [clinicaladvisor.com]

  Santosh PJ, Malhotra S: Varied psychiatric manifestations of acute intermittent porphyria. Biol Psychiatry 1994; 36:744-747Crossref, Medline, Google Scholar 36. [ajp.psychiatryonline.org]

  Depression and other chronic psychiatric manifestations may occur, but are usually not attributable to VP, except in patients with frequent recurring attacks and chronic pain [56,63]. Monitoring of such patients for depression is recommended. [medilib.ir]

• Seizure

  He was also admitted to a local hospital and received anti-seizure drug due to episodes of generalized tonic-clonic seizure (GTC). She had also a history of delayed developmental milestones and started walking by 3 years old. [ijponline.biomedcentral.com]

  Hepatic porphyrias, on the other hand, involve attacks of intense abdominal pain and neurological dysfunction, such as seizures ( Signal, 1993 ). [bcm441.kericolabroy.bergbuilds.domains]

  In acute porphyric attacks, seizures can be treated with intravenous diazepam, levetiracetam or propofol if status epilepticus develops; a single or few seizures may not require antiepileptic drug treatment in the long term, provided the porphyria itself [pn.bmj.com]

  We delineate a syndrome principally characterized by growth retardation, developmental delay, epileptic seizures, photosensitivity and an abnormal porphyrin excretion pattern. [ncbi.nlm.nih.gov]

• Confusion

  For a long time, this disease has caused confusion among the porphyrias because it presents with clinical symptoms and biochemical findings that can be similar to those found in other types of porphyrias. [ncbi.nlm.nih.gov]

  Psychological symptoms are variable: irritability, emotionality, depression, considerable anxiety and, more rarely, auditory and visual hallucinations, disorientation, mental confusion. [orpha.net]

• Neurologic Manifestation

  Variegate porphyria (VP) is an autosomal dominant disease characterized in adults by mechanical fragility and blistering of sun-exposed skin or acute visceral and neurological manifestations. [ncbi.nlm.nih.gov]

  Neurological manifestations can affect the central nervous system as much as the peripheral nervous system and can lead to severe complications such as motor paralysis. [orpha.net]

• Personality Change

  Those with acute forms of porphyria develop numbness, tingling, paralysis, cramping, vomiting, constipation, personality changes or mental disorders, and/or pain in the abdomen, chest, limbs, or back. [medicinenet.com]

  The imbalance can contribute to some of these symptoms: Abdominal pain, often severe Chest pain Increased heart rate and blood pressure Limb and back pain Muscle weakness Tingling Loss of sensation Cramping Vomiting and constipation Personality changes [webmd.com]

  Personality changes developed along with mood lability, intermittent suicidal ideation, and behavioral dyscontrol. At times he withdrew to his home, exhibiting anhedonia and psychomotor slowness. [ajp.psychiatryonline.org]

• Agitated Delirium

  For an attack requiring hospitalization, opioids, or other intravenous medication, or accompanied by nausea and vomiting, motor neuropathy, paresis, seizures, agitation, delirium, psychosis, ileus that prevents oral intake, or hyponatremia, we recommend [medilib.ir]

  Clinical Manifestations Reported clinical manifestations of acute porphyria include neuropsychiatric symptoms and clinical signs (hysteria, anxiety, depression, phobias, psychosis, agitation, delirium, restlessness, seizures, neuropathy, sensory involvement [ajp.psychiatryonline.org]

• Dark Urine

  The patient recalled passing dark urine after surgery and was subsequently hospitalized for 3 months. [medicaljournals.se]

  Urine needs to be transported to the laboratory in a container protecting it from light, otherwise false positive results can arise. [health24.com]

  In addition, she repeatedly observed that her urines were dark-colored. [frontiersin.org]

  Other useful clues are a history of dark urine, especially reddish urine, tachycardia, and systemic arterial hypertension during attacks. [clinicaladvisor.com]

• Red Urine

  Porphyrins are substances that represent the building blocks of hemoglobin, the red-colored protein in red blood cells that transport oxygen. [utswmed.org]

  Some signs and symptoms of an acute attack are: pain, red, burning or blistering skin, red urine, neurological changes, or psychological changes. Resources BOOKS Deats-O'Reilly, Diana. Porphyria: The Unknown Disease. [healthofchildren.com]

  In some forms of porphyria, accumulated heme precursors excreted in the urine may cause various changes in color, after exposure to sunlight, to a dark reddish or dark brown color. Even a purple hue or red urine may be seen. [house.wikia.com]

Early recognition of VP, particularly when patients develop neurovisceral attacks, can be life-saving, which is why a thorough workup is necessary. The first step is obtaining a detailed patient and family history, given the autosomal dominant nature of the disease. Furthermore, the population of Dutch descendants living in South Africa is at the greatest risk for developing VP due to the founder effect [2] [3] [5]. After history taking, the physical examination, if done properly, could identify typical skin lesions and assess their progression, thus a provisional diagnosis of VP can be made. Laboratory studies are the mainstay in diagnosing porphyrias, and the following tests should be implemented when a suspicion toward VP exists:

• Stool analysis - The levels of protoporphyrin and coproporphyrin in feces are very high during acute attacks, and are one of the most reliable indicators when it comes to identifying VP as the possible cause [2] [6]. However, normal levels are observed during remissions and milder attacks in some patients and the diagnosis can be missed [2] [6].
• Serum and urine testing - If patients present with cutaneous lesions, serum levels of porphyrin might be elevated, whereas the urinary determination of aminolevulinic acid dehydratase (ALA) and porphobilinogen (PBG) may be a useful tool during acute attacks [5]. However, one of the most specific forms of testing is the plasma fluorescence emission spectrum analysis, which reveals a unique fluorescence emission peak at 626 nm in a neutral pH [2] [5] [6].

A definite diagnosis, however, is made after conducting genetic studies on the PPOX gene located on chromosome 1, or by detecting a lower PPOX activity in lymphocytes [4] [5] [6].

• Hyponatremia

  We hypothesize that brainstem dysfunction in VP patients with a history of porphyric crises may be due to neurotoxic effects of porphyrin precursors as well as subclinical osmolarity changes due to hyponatremia. [ncbi.nlm.nih.gov]

  Indeed, hyponatremia is common enough in acute attacks that its presence may help support suspicion of underlying porphyria. [clinicaladvisor.com]

  Our patient presented repeatedly with hyponatremia. Marked hyponatremia frequently complicates acute porphyrias (4, 5, 7, 31, 34, 45). [ajp.psychiatryonline.org]

  It is very important to monitor patients with hyponatremia because they can develop seizures. [hematologyandoncology.net]

Recent advances in VP treatment demonstrate that antioxidants such as vitamins E and C can help reduce the occurrence and severity of hepatic attacks ( Ferrer et al. 2013 ). [bcm441.kericolabroy.bergbuilds.domains]

Scenarios/symptoms Treatment Definitive treatment of any acute attack: 1. Identification and removal of known precipitants. Removal of unnecessary undocumented medications or possible precipitants.2. [clinicaladvisor.com]

"Recommendations for the diagnosis and treatment of the acute porphyrias". Ann Intern Med. 142 (6): 439–50. PMID 15767622. Chemmanur AT, Bonkovsky HL (2004). "Hepatic porphyrias: diagnosis and management". Clin Liver Dis. 8 (4): 807–38, viii. [wikidoc.org]

The material is in no way intended to replace professional medical care by a qualified specialist and should not be used as a basis for diagnosis or treatment. [orpha.net]

The incidence of serious complications and mortality in this series was low, confirming a trend to an increasingly good prognosis for patients with acute porphyria who receive expert treatment. [ncbi.nlm.nih.gov]

Prognosis With early diagnosis and treatment acute attacks are rarely fatal and the disease is rarely progressive. However, variegate porphyria is a risk factor for the development of hepatocellular carcinoma. [orpha.net]

Etiology Variegate porphyria is caused by a deficiency in protoporphyrinogen oxidase (PPOX; the penultimate enzyme in the heme biosynthesis pathway) that leads to an accumulation of porphyrins and their precursors in the liver (delta-aminolevulinic acid [orpha.net]

Inglês : BL blood CF cerebrospinal fluid CI chemically induced CL classification CO complications CN congenital DI diagnosis DG diagnostic imaging DH diet therapy DT drug therapy EC economics EM embryology EN enzymology EP epidemiology EH ethnology ET etiology [decs.bvs.br]

Cutaneous porphyrias part I: epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Int J Dermatol. 2013;52(12):1464-1480. doi:10.1111/ijd.12305. Singal AK, Anderson KE. Variegate Porphyria. [clinuvel.com]

Summary Epidemiology Prevalence is around 1/100,000 in European countries and much higher in South Africa due to a founding effect. Clinical description Generally the disease manifests after puberty and preferentially affects women. [orpha.net]

The article provides a brief description of heme biosynthesis and the pathophysiology that underlie an acute attack. [clinicaladvisor.com]

Pathophysiology and Epidemiology In people suffering from variegate porphyria porphyrins (protoporphyrin and coproporphyrin) accumulate in the body because of inadequate heme synthesis. [ic.steadyhealth.com]

Porphyrias are classified in two ways, by symptoms and by pathophysiology. Symptomatically, acute porphyrias primarily present with nervous system involvement, often with severe abdominal pain, vomiting, neuropathy and mental disturbances. [indigitrax.org.au]

IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Milan, Italy Michela Brena, MD,Post-Graduate School of Dermatology and Venereology, University of Milan, Italy Carlo Gelmetti, MD,chairman of the Pediatric Dermatology Unit, Department of Pathophysiology [routledge.com]

Pathophysiology Inherited as an autosomal dominant trait, variegate porphyria is biochemically characterized by accumulations of the photosensitizing porphyrins protoporphyrin and coproporphyrin. [5] In addition, abnormally high levels of the porphyrin [emedicine.medscape.com]

In the event of an attack, patients are often administered glucose and/or hemin intravenously, which work to stop heme synthesis and prevent the accumulation of unused metabolites ( Signal, 1993 ). [bcm441.kericolabroy.bergbuilds.domains]

Future attacks can be prevented by avoiding triggering factors. Frequent attacks that are cyclic can be prevented by administration of a GnRH analogue. [porphyriafoundation.org]

Recognition of the carrier status is the first step of an efficient preventive care. This could be achieved by measurement of PO activity which is a sensitive and specific but tedious method. [ncbi.nlm.nih.gov]

Management includes both the prevention of attacks (warning against triggering factors) and pain relief (opiates). Phlebotomy and taking chloroquine are rarely effective at treating cutaneous manifestations. [orpha.net]

1. Stojeba N, Meyer C, Jeanpierre C, et al. Recovery from a variegate porphyria by a liver transplantation. Liver Transpl. 2004;10(7):935-938.
2. Ramanujam V-MS, Anderson KE. Porphyria Diagnostics – Part 1: A brief overview of the porphyrias. Curr Protoc Hum Genet. 2015;86:17.20.1-17.20.26.
3. Christiansen AL, Aagaard L, Krag A, Rasmussen LM, Bygum A. Cutaneous Porphyrias: Causes, Symptoms, Treatments and the Danish Incidence 1989-2013. Acta Derm Venereol. 2016;96(7):868-872
4. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically Important Features of Porphyrin and Heme Metabolism and the Porphyrias. Fuller M, ed. Metabolites. 2014;4(4):977-1006.
5. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.
6. Horner ME, Alikhan A, Tintle S, Tortorelli S, Davis DM, Hand JL. Cutaneous porphyrias part I: epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Int J Dermatol. 2013;52(12):1464-1480.