The clinical presentation is quite similar across all types of acute hepatic porphyrias. The "acute attacks" are the hallmark of these disorders, most frequently encountered after puberty in women [5]. Most important symptoms are related to the gastrointestinal tract and include intense and nonspecific abdominal pain that may be cramping, constipation, nausea, vomiting, decreased bowel sounds and diarrhea in some patients [1] [3] [5]. Head, neck and chest pain are seen in approximately 50% of cases, as are hypertension, tachycardia, mental changes (restlessness, anxiety, insomnia, disorientation, paranoia and hallucinations) and convulsions [1] [9]. Muscle weakness, tremor, diaphoresis, dysuria, dark urine, bladder distension and severe neuropathy may be encountered as well [5], and a missed diagnosis may lead to severe and irreversible motor neuropathy [2]. In addition to acute attacks, some forms may be accompanied by cutaneous symptoms, such as HCP, in which photosensitivity and blistering skin lesions (vesicles, bullae and erosions with scarring) are constitutive features [1] [5].

• Pain

  paralysis, fatigue, respiratory paralysis Autonomic2,4,10 nausea and vomiting, hypertension, tachycardia, constipation, severe diffuse abdominal pain, diarrhea, pain in back or chest Cutaneous symptoms1,5 lesions on sun-exposed skin occur only in hereditary [porphyria.ca]

  The pain of acute attacks can be severe, requiring hospitalisation for pain management and a lead-up to other possible causes of pain. Severe electrolyte imbalance, respiratory distress, or seizures should prompt admission to intensive care. [dermnetnz.org]

  When these are found in patients with diverse symptoms, including abdominal pain, joint pain, muscle pain, fibromyalgia, anxiety and chronic fatigue syndrome, such patients, unfortunately, are labeled as having porphyria when they do not. [aasldpubs.onlinelibrary.wiley.com]

  Rapid heart rate High blood pressure 4 Cutaneous (Skin) Symptoms* Leisons or blisters on sun-exposed skin 5 Gastrointestinal Constipation or diarrhea 6 Autonomic Nervous System Unexplained abdominal pain Pain in back or chest Nausea and vomiting Other [porphyria.com]

  AHP is life-threatening due to the possibility of paralysis and respiratory arrest during attacks and debilitating in the long term because of symptoms such as pain, nausea, seizures and skin blistering. [io.nihr.ac.uk]

• Weakness

  Severe, Diffuse Abdominal Pain1-5 1 Or More Of The Following PERIPHERAL Nervous System Limb weakness or pain CENTRAL Nervous System Anxiety Confusion AUTONOMIC Nervous System Nausea Vomiting CUTANEOUS† Skin lesions on sun- exposed areas *There are 4 AHP [porphyria.ca]

  Weakness or paralysis. AHP can affect the nerves that control your muscles. You may get weakness in your legs, belly, and arms. Without treatment, you may lose the ability to move. Continued Mood changes. [webmd.com]

  AHPs are associated with potentially life-threatening acute attacks characterised by a range of debilitating symptoms including severe, diffuse abdominal pain, nausea, weakness and constipation. [medthority.com]

  Clinical description All acute hepatic porphyrias can be accompanied by neuro-visceral attacks that appear as intense abdominal pain (in 85-95% of cases) over one to two weeks, neurological symptoms (muscular weakness, sensory loss or convulsions) and [orpha.net]

• Anemia

  Four new chapters cover anemias unique to the newborn period, pathology of LHC and other histiocytic disorders, tumors of the spleen, and pathology and classification of myeloproliferative disorders and mast cell disease. [books.google.com]

  During childhood and adulthood a mild residual anemia is chronically observed. In our case the girl suffering from abdominal and cerebral pain, only one we find skin alteration, without any apparent clinical or ematological sign of anemia. [clinicsinsurgery.com]

  However, in this study, the patient had normocytic and normochromic type of anemia. [scielo.br]

  P74 ) Endocrine, nutritional and metabolic diseases E70-E88 2019 ICD-10-CM Range E70-E88 Metabolic disorders Type 1 Excludes androgen insensitivity syndrome ( E34.5- ) congenital adrenal hyperplasia ( E25.0 ) Ehlers-Danlos syndrome ( Q79.6 ) hemolytic anemias [icd10data.com]

  The patient on routine labs was also found to have an acute on chronic anemia (hemoglobin baseline 10-11 g/dL, Hgb on admission 9.7 g/dL with an MCV of 92.6 and an RDW of 19.9). Further evaluation was consistent with a hemolytic anemia (Table 2). [hindawi.com]

• Fatigue

  CHRONIC AHP SYMPTOMS Chronic symptoms, such as anxiety, nausea, pain, and fatigue can take a serious toll on some people with AHP. [porphyria.com]

  RESULTS: All patients identified prodromal symptoms that began days prior to acute severe pain; the most common included confusion ("brain fog"), irritability, and fatigue. [ncbi.nlm.nih.gov]

  Common symptoms of AHP include severe, diffuse abdominal pain, weakness, nausea, and fatigue. Long term symptoms and complication can include chronic neuropathic pain, hypertension, chronic kidney disease and liver disease. [trialsitenews.com]

  Other AEs included rash, serum creatinine increase, transaminase elevations, and fatigue. [ajmc.com]

  Common symptoms of AHP are severe, diffuse abdominal pain, weakness, nausea and fatigue. The disease has four subtypes, each caused by a genetic defect that causes deficiency in one of the enzymes of the heme biosynthesis pathway in the liver. [biospace.com]

• Fever

  VP), hereditary coproporphyria (HCP), and the extremely rare ALA dehydratase-deficiency porphyria (ADP).1,6,7 †Cutaneous symptoms occur only in HCP and VP.5 AHP Features a combination of Symptoms In addition to severe, diffuse abdominal pain without fever [porphyria.ca]

  In the case of acute abdominal pain with fever, the suspicion of appendicitis is obvious. An appendectomy scar is thus often found amongst porphyria patients. [lecturio.com]

  Because the pain is neuropathic, it often is not accompanied by fever or leukocytosis. Patients also may experience nausea, vomiting, constipation, or pain in the chest or back. [hematologyandoncology.net]

  She did not present vomit or alteration of alvo or fever. Neurological examination was normal. [clinicsinsurgery.com]

  The patient also endorsed one episode of “grape-juice-colored” urine the day prior to admission in the context of dysuria, without concurrent fever or chills. [hindawi.com]

• Dyspnea

  Some patients have prolonged symptoms of lesser intensity (eg, obstipation, fatigue, headache, back or thigh pain, paresthesia, tachycardia, dyspnea, insomnia, depression, anxiety or other disturbances of mood, seizures). [msdmanuals.com]

• Abdominal Pain

  AHP can be diagnosed using a PBG urine test, and testing should be considered in all patients presenting with recurrent abdominal pain of unknown origin. [medthority.com]

  Clinical description All acute hepatic porphyrias can be accompanied by neuro-visceral attacks that appear as intense abdominal pain (in 85-95% of cases) over one to two weeks, neurological symptoms (muscular weakness, sensory loss or convulsions) and [orpha.net]

  Patients usually present with abdominal pain, impaired intestinal motility, neurological and psychiatric symptoms, hypertension, tachycardia, hyponatriemia and reddish urine. [ncbi.nlm.nih.gov]

  pain Neurological symptoms that occurred around the time of severe abdominal pain (i.e. muscle weakness, sensory loss, confusion, hallucinations, seizures) Gastrointestinal manifestations that occurred around the time of severe abdominal pain (i.e. nausea [invitae.com]

• Vomiting

  Additional treatments include painkillers and antiemetics (to treat nausea and vomiting), chemically-induced menopause with hormonal suppression therapy, and liver transplantation. [ema.europa.eu]

  Severe, Diffuse Abdominal Pain1-5 1 Or More Of The Following PERIPHERAL Nervous System Limb weakness or pain CENTRAL Nervous System Anxiety Confusion AUTONOMIC Nervous System Nausea Vomiting CUTANEOUS† Skin lesions on sun- exposed areas *There are 4 AHP [porphyria.ca]

  Gastrointestinal disorders Irritable bowel syndrome (IBS) Acute gastroenteritis with vomiting Hepatitis Crohn's disease Neurological/neuropsychiatric disorders Fibromyalgia Guillain-Barré syndrome Psychosis Gynecological disorders Endometriosis Abdominal [mygi.health]

  As a result, substances for making haem accumulate in the body (particularly in the liver) and become toxic, causing attacks of severe abdominal pain, vomiting and nervous system disorders, such as seizures (fits), depression and anxiety. [io.nihr.ac.uk]

  Gastrointestinal disorders Irritable bowel syndrome (IBS) Acute gastroenteritis with vomiting Hepatitis Crohn’s disease Neurological/neuropsychiatric disorders Fibromyalgia Guillain-Barré syndrome Psychosis Gynecological disorders Endometriosis Abdominal [porphyria.com]

• Nausea

  Severe, Diffuse Abdominal Pain1-5 1 Or More Of The Following PERIPHERAL Nervous System Limb weakness or pain CENTRAL Nervous System Anxiety Confusion AUTONOMIC Nervous System Nausea Vomiting CUTANEOUS† Skin lesions on sun- exposed areas *There are 4 AHP [porphyria.ca]

  The most common adverse events were nausea (27% on givosiran compared to 11% on placebo), and reactions at the injection site (16.7% on the drug and 0% on placebo). [biospace.com]

  CHRONIC AHP SYMPTOMS Chronic symptoms, such as anxiety, nausea, pain, and fatigue can take a serious toll on some people with AHP. Signs and Symptoms of AHP The symptoms of AHP can vary from person to person and change over time. [mygi.health]

  AHP is life-threatening due to the possibility of paralysis and respiratory arrest during attacks and debilitating in the long term because of symptoms such as pain, nausea, seizures and skin blistering. [io.nihr.ac.uk]

  CHRONIC AHP SYMPTOMS Chronic symptoms, such as anxiety, nausea, pain, and fatigue can take a serious toll on some people with AHP. [porphyria.com]

• Constipation

  AHPs are associated with potentially life-threatening acute attacks characterised by a range of debilitating symptoms including severe, diffuse abdominal pain, nausea, weakness and constipation. [medthority.com]

  Constipation or diarrhea. You may have trouble pooping. Less often, you may poop too much. Pee changes. Your urine may look dark or reddish. You could have a hard time peeing. Numbness or tingling. [webmd.com]

  Nervous System Limb weakness or pain Numbness Fatigue Tiredness Paralysis Respiratory paralysis Sensory loss 3 Cardiovascular Rapid heart rate High blood pressure 4 Cutaneous (Skin) Symptoms* Leisons or blisters on sun-exposed skin 5 Gastrointestinal Constipation [porphyria.com]

  Central2,4 anxiety, depression, confusion, seizures, hallucinations, insomnia Peripheral2,4 muscle weakness, neuropathic pain in limbs, sensory loss, paralysis, fatigue, respiratory paralysis Autonomic2,4,10 nausea and vomiting, hypertension, tachycardia, constipation [porphyria.ca]

  The pain may extend to other parts of your body, such as your: arms legs back An AHP attack can also cause: breathing difficulties, such as wheezing or a tight feeling in your throat constipation dark-colored urine difficulty urinating high blood pressure [healthline.com]

• Severe Abdominal Pain

  As a result, substances for making haem accumulate in the body (particularly in the liver) and become toxic, causing attacks of severe abdominal pain, vomiting and nervous system disorders, such as seizures (fits), depression and anxiety. [io.nihr.ac.uk]

  abdominal pain Neurological symptoms that occurred around the time of severe abdominal pain (i.e. muscle weakness, sensory loss, confusion, hallucinations, seizures) Gastrointestinal manifestations that occurred around the time of severe abdominal pain [invitae.com]

  This can cause attacks of severe abdominal pain, vomiting and nervous system disorders, such as seizures, depression and anxiety. AHP is life-threatening due to the possibility of paralysis and respiratory arrest during attacks. [ema.europa.eu]

  Depending on the specific type, AHP patients can suffer from a range of symptoms including acute and/or recurrent life-threatening attacks with severe abdominal pain, peripheral and autonomic neuropathy, neuropsychiatric manifestations, cutaneous lesions [clinicaladvisor.com]

  According to the National Institutes of Health, severe abdominal pain is the most common symptom of an impending AHP attack. [healthline.com]

• Jaundice

  Renal tubular disorders and renal stone disease 168 Clinical biochemistry of nutrition 180 Nutritional disorders and their management 200 Clinical biochemistry of the gastrointestinal tract 214 Assessment of hepatic function and investigation of jaundice [books.google.com]

  M. was born after a natural childbirth with a weighed of 2.810 gr; she manifested light asphyxia and jaundice at birth, for this reason she were recovered in UTIN, where she was in observation for three days. [clinicsinsurgery.com]

  壊血病 scorbutus 核黄疸 Kernikterus (独), kernicterus, nuclear jaundice 家族性アミロイドーシス familial amyloidosis 家族性アミロイドポリニューロパチー familial amyloidotic polyneuropathy 家族性LCAT欠損症 familial lecithin cholesterol acyltransferase deficiency 家族性高コレステロール血症 familial hypercholesterolemia [jsge.or.jp]

  A 27-year-old man was admitted to our hospital for evaluation and treatment of liver dysfunction with jaundice and hepatosplenomegaly. The patient had severe photosensitivity from childhood. [ci.nii.ac.jp]

  […] disease-causing mutation will express symptoms. [2] Individuals who are homozygous for a specific mutation (K404E) or compound heterozygous with a null allele in CPOX have a more severe erythropoietic porphyria, harderoporphyria, [5] characterized by neonatal jaundice [ippn.info]

• Hypertension

  Patients usually present with abdominal pain, impaired intestinal motility, neurological and psychiatric symptoms, hypertension, tachycardia, hyponatriemia and reddish urine. [ncbi.nlm.nih.gov]

  […] lead to a diagnosis1,2: Central2,4 anxiety, depression, confusion, seizures, hallucinations, insomnia Peripheral2,4 muscle weakness, neuropathic pain in limbs, sensory loss, paralysis, fatigue, respiratory paralysis Autonomic2,4,10 nausea and vomiting, hypertension [porphyria.ca]

  Content is provided from medical therapies to surgery on the patient with portal hypertension. [books.google.com]

  Long term symptoms and complication can include chronic neuropathic pain, hypertension, chronic kidney disease and liver disease. Currently, there are no treatments approved to prevent attacks or to treat the chronic manifestations of the disease. [trialsitenews.com]

  They also can have significant autonomic dysfunction, including tachycardia and hypertension. [hematologyandoncology.net]

• Tachycardia

  Patients usually present with abdominal pain, impaired intestinal motility, neurological and psychiatric symptoms, hypertension, tachycardia, hyponatriemia and reddish urine. [ncbi.nlm.nih.gov]

  Tachycardia and hyponatremia are often present in acute attacks of AHP.1,2,7 These symptoms reflect neurotoxic effects across the autonomic, peripheral, and central nervous systems. [porphyria.ca]

  and no fever Skin is never affected HCP Autosomal dominant inheritance Symptoms include acute-onset abdominal pain with nausea, vomiting, constipation, and tachycardia (identical to those of AIP) Skin symptoms are rare but can present with or without [arupconsult.com]

• Chest Pain

  Generally, the most common symptoms being abdominal pain (74%), back pain (56%), chest pain (58%), and nausea and vomiting (73%) 8,10, however, there can be a wide range of neuropsychiatric and cutaneous manifestations as well. [radiopaedia.org]

  Head, neck and chest pain are seen in approximately 50% of cases, as are hypertension, tachycardia, mental changes (restlessness, anxiety, insomnia, disorientation, paranoia and hallucinations) and convulsions. [symptoma.com]

  Pronunciation or Specialty Hematology, dermatology, neurology Symptoms Depending on subtype– abdominal pain, chest pain, vomiting, confusion, constipation, fever, seizures, blisters with sunlight . Templeton Press. ISBN 978-0954558918. [en.wikipedia.org]

  The symptoms can include: Belly pain, often severe Chest pain Faster heart rate and higher blood pressure Limb and back pain Muscle weakness Tingling and loss of sensation Cramping Vomiting and constipation You may notice changes in your personality or [webmd.com]

  Symptoms of an attack include abdominal pain, chest pain, vomiting, confusion, constipation, fever, high blood pressure, and high heart rate. The attacks usually last for days to weeks. [clinicsinsurgery.com]

• Muscle Weakness

  Patients may experience one characteristic symptom or multiple symptoms that may lead to a diagnosis1,2: Central2,4 anxiety, depression, confusion, seizures, hallucinations, insomnia Peripheral2,4 muscle weakness, neuropathic pain in limbs, sensory loss [porphyria.ca]

  Peripheral motor neuropathy, characterized by muscle weakness which begins in the proximal upper extremities, may also develop. δ-Aminolevulinic acid dehydratase deficiency porphyria (ADP) is characterized by adolescent-onset attacks of abdominal pain [invitae.com]

  tachycardia, hypertension), muscle weakness; sensory loss; and pain in the back, chest, and extremities. Unfortunately, physical findings are often minimal, and even severe symptoms may be discounted as a result. [ncbi.nlm.nih.gov]

• Back Pain

  Generally, the most common symptoms being abdominal pain (74%), back pain (56%), chest pain (58%), and nausea and vomiting (73%) 8,10, however, there can be a wide range of neuropsychiatric and cutaneous manifestations as well. [radiopaedia.org]

  The acute hepatic porphyrias are described by neurological attacks (seizures, psychosis, severe abdominal and back pain, and an acute polyneuropathy), and, to a lesser extent, present with cutaneous manifestations, usually a photosensitive blistering [ncbi.nlm.nih.gov]

• Myalgia

  Possibly or definitely related AEs reported in two or more cases were injection site reactions and myalgia; all of these events were mild. [businesswire.com]

  Four patients were assessed as having AEs possibly related to study drug, including injection site reaction (mild and self-limiting), hypersensitivity, myalgia, headache, moderate renal impairment (in a patient with a history of moderate renal impairment [dddmag.com]

• Neck Pain

  Her medical history includes hypertension, generalized seizures, cardiac arrythmia, and chronic neck pain. She had been hospitalized previously with episodes of abdominal pain and generalized seizures. [karger.com]

• Photosensitivity

  Differential diagnoses for variagate porphyria and hereditary coproporphyria also include photosensitivity. [orpha.net]

  Indications for Testing Diagnostic testing for porphyrias should be performed in individuals who present with severe, diffuse neuropathic abdominal pain and accompanying symptoms and in individuals with cutaneous photosensitivity. [arupconsult.com]

  Hereditary coproporphyria (HCP) and variegate porphyria (VP) are characterized by neurovisceral attacks as well as cutaneous manifestations including blistering or non-blistering skin lesions, which are caused by photosensitivity. [invitae.com]

  They present similarly except that HCP and VP are also associated with cutaneous photosensitivity. [epilepsy.com]

• Blister

  For individuals with blistering or non-blistering skin lesions, total plasma porphyrins or erythrocyte porphyrins should be tested. [invitae.com]

  AHP is life-threatening due to the possibility of paralysis and respiratory arrest during attacks and debilitating in the long term because of symptoms such as pain, nausea, seizures and skin blistering. [io.nihr.ac.uk]

  The roof of the blisters has eosinophilic, PAS , and diastase resistant linear globules. History and Physical Acute and chronic symptoms due to effects on the central and peripheral nervous system characterize acute hepatic porphyrias. [ncbi.nlm.nih.gov]

  Some people with AHP get blisters on your skin when they're out in the sun. In rare cases, the muscles that control your lungs may stop working, which can affect your breathing. This is life-threatening and requires medical attention right away. [webmd.com]

• Cutaneous Manifestation

  Management includes the prevention of attacks (by avoiding causal factors) and the protection of skin from the light in cases of cutaneous manifestations. [orpha.net]

  This panel may be appropriate for individuals with signs and symptoms of an acute hepatic porphyria with or without cutaneous manifestations. [invitae.com]

  Generally, the most common symptoms being abdominal pain (74%), back pain (56%), chest pain (58%), and nausea and vomiting (73%) 8,10, however, there can be a wide range of neuropsychiatric and cutaneous manifestations as well. [radiopaedia.org]

  Of the acute hepatic porphyrias, cutaneous manifestations in sun exposed areas are usually seen in VP and HCP. Thus, these two are sometimes referred to as the neurocutaneous porphyrias. [hindawi.com]

• Hypertrichosis

  Over time, in CEP, HEP and PCT scarring, pigment changes, infection, and excessive hair growth (hypertrichosis) can occur. [aasldpubs.onlinelibrary.wiley.com]

  […] hepatic porphyrias are described by neurological attacks (seizures, psychosis, severe abdominal and back pain, and an acute polyneuropathy), and, to a lesser extent, present with cutaneous manifestations, usually a photosensitive blistering rash or hypertrichosis [ncbi.nlm.nih.gov]

• Hyperpigmentation

  Secondary infections can cause areas of hypo- or hyperpigmentation or sclerodermatous changes and may result in the development of alopecia at sites of repeated skin damage. [mayomedicallaboratories.com]

  Similarly, patients show increased hair growth (hypertrichosis) and hyperpigmentation. The skin manifestation of the PCT can be presumed without a prophylaxis disfiguring extent. [lecturio.com]

  […] therapy Sunlight exposure Pathophysiology Clinical findings Cutaneous manifestations Increased fragility of sun-exposed skin blistering and impaired healing ( blistering photosensitivity ) Healing results in scarring and milia formation Hypertrichosis Hyperpigmentation [amboss.com]

  There was neither hyperpigmentation nor hypertrichosis. A urinalysis was done which was significant for blood, trace leukocyte esterase, negative nitrite, 478 WBCs, and 297 RBCs (Figure 2). WBC count was elevated at 12.6. [hindawi.com]

• Psychiatric Manifestation

  Psychiatric manifestations accompany acute attacks in up to 80% of the cases. Symptoms include anxiety, depression, hallucinations, paranoia, and mental status changes (ranging from mild confusion to encephalopathy and coma). [hindawi.com]

  Managing Chronic Problems The suicide rate in patients with acute porphyria is increased significantly compared with the rate in the general population, possibly owing to depression caused by ongoing psychiatric manifestations or because of chronic pain [cghjournal.org]

  Clinical conditions involve autonomic neuropathy, peripheral neuropathy and brain dysfunction, progressing generally in the following order: first, severe abdominal pain; second, psychiatric manifestations and finally neurological disorders (Blom 1996 [scielo.br]

  manifestations.10 Therefore clinicians must maintain a high index of suspicion for the disease, as patients can present with symptoms that can be attributed to an alternative disease process. [dovepress.com]

  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 [cancertherapyadvisor.com]

• Delusion

  Sleep disturbance, anxiety, delirium, hallucinations, depressed mood, and paranoid delusions may be present.81,82 Lethargy and coma occur rarely. Peripheral motor neuropathies may lead to foot or wrist drops. [epilepsy.com]

  Rarely these are more severe with psychosis, delusions and hallucinations. Mental changes resolve completely on remission. [onlinelibrary.wiley.com]

• Mood Swings

  He suffered from mood swings, abdominal pain and occasional paranoia. He was initially diagnosed with stress. Acute intermittent porphyria (AIP) is a rare sub-type that can be passed on by receiving one copy of the faulty gene from a single parent. [house.fandom.com]

  He suffered from mood swings, abdominal pain and occasional paranoia. He was initially diagnosed with stress. [house.wikia.com]

• Urinary Retention

  Other symptoms may include (7): nausea vomiting constipation pain in the back, arms and legs muscle weakness (due to the effects on nerves supplying the muscles) urinary retention palpitation (due to a rapid heart rate and often accompanied by an increased [content.sciendo.com]

  Neuropathy may progress rapidly to give complete paralysis, incontinence or urinary retention, swallowing difficulties and respiratory failure. [journals.sagepub.com]

  The most typical clinical signs include nausea, vomiting, constipation, diarrhea, urinary retention, tachycardia, hypertension, mental symptoms, and muscle pain and weakness. [revistanefrologia.com]

  Bladder dysfunction can present with urinary retention, urinary incontinence, or dysuria.9 Renal Manifestations Porphyria related nephropathy is due to genetic variations in renal transporters. [dovepress.com]

• Dark Urine

  You could also have: Dark urine Sensitive skin Belly pain Nausea Seizures An attack usually starts with severe stomach pain and can last for days. You'll usually need to go to the hospital for treatment. [webmd.com]

  Signs and Symptoms Diagnosis Treatment Symptoms vary depending on the type of porphyria, but some of the more common include: Dark urine Skin sensitivity, including blistering, of areas exposed to the light, such as the face and back of hands Pain in [ucsfhealth.org]

  Muscle weakness, tremor, diaphoresis, dysuria, dark urine, bladder distension and severe neuropathy may be encountered as well, and a missed diagnosis may lead to severe and irreversible motor neuropathy. [symptoma.com]

  Pain can also affect back, legs and other sites; Nausea, vomiting, constipation; Dark urine – colour darkens to orange or red on exposure to light; Hypertension, tachycardia, and rarely, arrhythmias; Agitation, insomnia, confusion, psychosis with hallucinations [journals.sagepub.com]

• Dysuria

  Bladder dysfunction (urinary retention, incontinence, and dysuria) Endorsed dysuria on some admissions. HTN Noted in our patient. Chronic kidney disease Present, necessitating dialysis. [hindawi.com]

  Muscle weakness, tremor, diaphoresis, dysuria, dark urine, bladder distension and severe neuropathy may be encountered as well, and a missed diagnosis may lead to severe and irreversible motor neuropathy. [symptoma.com]

  Bladder dysfunction can present with urinary retention, urinary incontinence, or dysuria.9 Renal Manifestations Porphyria related nephropathy is due to genetic variations in renal transporters. [dovepress.com]

  They include abdominal pain which is severe and poorly localized (most common, 95% of patients experience), Urinary symptoms (Dysuria, urinary retention/incontinence or dark urine), peripheral neuropathy (patchy numbness and paresthesias), Proximal motor [house.fandom.com]

  Additional common manifestations include nausea; vomiting; tachycardia; hypertension; mental symptoms; extremity, neck, or chest pain; headache; muscle weakness; sensory loss; tremors; sweating; dysuria; and bladder distention. [ashpublications.org]

• Red Urine

  AIP Cutaneous Porphyrias PCT Mainly an acquired condition presenting in middle age Most common porphyria Characterized by photosensitivity that manifests with blisters CEP Extremely rare, severe multisystem disease Usually presents soon after birth Red [arupconsult.com]

  Red urine that fluoresces in nappies can allow an easy bedside diagnosis. [ 3 ] There is severe photosensitivity. Pruritus and erythema followed by vesicle and bullous formation occur on exposure to sunlight. [patient.info]

  Clinical features include blistering skin lesions, hypertrichosis, and red urine. [31] See the image below. [emedicine.medscape.com]

  Even a purple hue or red urine may be seen. DiagnosisEdit Porphyrin studiesEdit Porphyria is diagnosed through biochemical analysis of blood, urine, and stool. [house.fandom.com]

  Even a purple hue or red urine may be seen. Diagnosis Edit Porphyrin studies Edit Porphyria is diagnosed through biochemical analysis of blood, urine, and stool. [house.wikia.com]

• Bladder Distention

  Additional common manifestations include nausea; vomiting; tachycardia; hypertension; mental symptoms; extremity, neck, or chest pain; headache; muscle weakness; sensory loss; tremors; sweating; dysuria; and bladder distention. [ashpublications.org]

• Seizure

  We studied one patient with major motor seizures and acute intermittent porphyria. The seizure disorder was exacerbated by phenytoin and did not respond to a high-carbohydrate diet or to intravenous hematin. [ncbi.nlm.nih.gov]

  AHP is life-threatening due to the possibility of paralysis and respiratory arrest during attacks and debilitating in the long term because of symptoms such as pain, nausea, seizures and skin blistering. [io.nihr.ac.uk]

• Confusion

  Severe, Diffuse Abdominal Pain1-5 1 Or More Of The Following PERIPHERAL Nervous System Limb weakness or pain CENTRAL Nervous System Anxiety Confusion AUTONOMIC Nervous System Nausea Vomiting CUTANEOUS† Skin lesions on sun- exposed areas *There are 4 AHP [porphyria.ca]

  RESULTS: All patients identified prodromal symptoms that began days prior to acute severe pain; the most common included confusion ("brain fog"), irritability, and fatigue. [ncbi.nlm.nih.gov]

  […] attacks that appear as intense abdominal pain (in 85-95% of cases) over one to two weeks, neurological symptoms (muscular weakness, sensory loss or convulsions) and psychological symptoms (irritability, anxiety, auditory or visual hallucinations, mental confusion [orpha.net]

  It’s also common to worry a lot or feel depressed and lose interest in activities or get confused. You could also see things that aren’t there or get really paranoid. Less energy. Chronic fatigue could happen. [webmd.com]

• Agitation

  You may get irritated, agitated, or feel like you need to move around. It’s also common to worry a lot or feel depressed and lose interest in activities or get confused. You could also see things that aren’t there or get really paranoid. [webmd.com]

  […] diarrhea Port wine-colored urine Diffuse musculoskeletal pain Neurologic symptoms Headache Sensory loss (40%) An indication of a severe and potentially life-threatening attack Neuropathy can progress to respiratory failure in hours or days Bladder paresis Agitation [wikem.org]

  Patients also may develop paresis or acute motor neuropathy, and may experience changes in mental status, such as behavioral changes, agitation, or hallucinations. [hematologyandoncology.net]

  […] anxiety/depression along with some agitation episodes.   [hindawi.com]

  Central nervous system symptoms include agitation, confusion, and depression. Convulsions occur in 10%–20% of patients. [cghjournal.org]

• Peripheral Neuropathy

  Features of Textbook of Peripheral Neuropathy Include : ̈ Practical yet comprehensiveóan accessible ìgo-toî reference for clinicians ̈ Covers all clinically relevant peripheral neuropathies ̈ Clinical Pearls and Key Points are set off from the text for [books.google.com]

  AHP is characterized by attacks of gastrointestinal disturbances, abdominal colic, paralyses and peripheral neuropathy. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors. [uniprot.org]

  Peripheral neuropathy. 3rd edition. Saunders, Philadelphia1992: 1161-1168 Bonkovsky H.L. Barnard G.F. Diagnosis of porphyric syndromes: a practical approach in the era of molecular biology.Semin Liver Dis. 1998; 18: 57-65 Grandchamp B. [liver.theclinics.com]

  Acute intermittent porphyria with peripheral neuropathy: a follow-up study after hematin treatment. J Neurol Sci. 2007 Sep;260(1-2):231–5. Wu CL, Ro LS, Jung SM, Tsai TC, Chu CC, Lyu RK, et al. [karger.com]

  Peripheral neuropathy is the most common central nervous system manifestation. Motor symptoms tend to affect the proximal muscles, more frequently the upper extremities. [hindawi.com]

• Insomnia

  Insomnia. That means you’ll have trouble falling or staying asleep. Low levels of electrolytes. Low sodium levels, or hyponatremia, can be an early sign of AHP. You could also get low levels of magnesium in your blood. [webmd.com]

  Signs and Symptoms of AHP 1 Central Nervous System Confusion Anxiety Seizures Insomnia Hallucinations Depression 2 Peripheral Nervous System Limb weakness or pain Numbness Fatigue Tiredness Paralysis Respiratory paralysis Sensory loss 3 Cardiovascular [porphyria.com]

  Patients may experience one characteristic symptom or multiple symptoms that may lead to a diagnosis1,2: Central2,4 anxiety, depression, confusion, seizures, hallucinations, insomnia Peripheral2,4 muscle weakness, neuropathic pain in limbs, sensory loss [porphyria.ca]

  Porphyrias can also lead to other mental health conditions, such as: anxiety depression hysteria phobias Keep your healthcare providers updated on any mental health symptoms you might be experiencing, such as: fear insomnia irritability loss of interest [healthline.com]

  Mental symptoms, such as irritability, restlessness, insomnia, agitation, tiredness, and depression, are common. Nervous system symptoms are numerous. [merckmanuals.com]

To make the diagnosis of acute hepatic porphyrias, a thorough patient history that will reveal presence of any of the mentioned porphyrias (having in mind the autosomal dominant pattern of inheritance), recent use of drugs or habits that may have precipitated the attacks, as well as history of similar symptoms, is essential. Together with a thorough physical examination, sufficient information can be gathered to suspect porphyria as an underlying cause. To confirm the diagnosis, urine and fecal testing for heme precursors and toxic metabolites should be performed. A distinction between subtypes can be made based on the obtained findings. AIP is suspected when markedly higher levels (20-100x higher) of ALA, PBG and uroporphyrin are found in urine, whereas detection of high coproporphyrin III levels in urine and stool, in addition to ALA and PBG in urine, is highly specific for HCP [5]. VP, on the other hand, is distinguished from HCP by confirming the presence of protoporphyrin in stool [5]. Urine and stool samples should be obtain during or right after the acute attacks [2]. A definite diagnosis is made through genetic tests, specifically polymerase chain reaction (PCR), which will detect the exact type of mutation [1].

• Hyponatremia

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

  Tachycardia and hyponatremia are often present in acute attacks of AHP.1,2,7 These symptoms reflect neurotoxic effects across the autonomic, peripheral, and central nervous systems. [porphyria.ca]

  Common laboratory abnormalities observed in the setting of acute attacks of porphyria include hyponatremia (most common). In some circumstances, hyponatremia may be severe and contribute to the development of seizures. Hypomagnesemia is also common. [aasldpubs.onlinelibrary.wiley.com]

  Basic metabolic panel: Hyponatremia is common. The probable mechanism includes: SIADH due to central nervous system (CNS) involvement, gastrointestinal or renal sodium loss. [ncbi.nlm.nih.gov]

  Low sodium levels, or hyponatremia, can be an early sign of AHP. You could also get low levels of magnesium in your blood. Your doctor may call that hypomagnesia. Sun sensitivity. [webmd.com]

• Coproporphyrin Increased

  increase only with hepatopathy Protoporphyrin* X-EPP Free and zinc protoporphyrin Protoporphyrin ( 634 nm)** Urine porphyrins (especially coproporphyrin) increase only with hepatopathy Protoporphyrin* What other diseases, conditions, or complications [cancertherapyadvisor.com]

• Protoporphyrin Increased

  increased in blood HIV, human immunodeficiency virus. [gastrojournal.org]

Initial therapeutic measures of acute hepatic porphyrias are focused on symptom alleviation - management of tachycardia, electrolyte dysbalance (hyponatremia is common, and often the cause of seizures) and gastrointestinal irritation [8]. Phenytoin or valproic acid should be avoided in management of seizures, as they may cause more severe symptoms [2]. Instead, benzodiazepines, gabapentin, magnesium and propofol (in the setting of refractory seizures) are used. Intravenous administration of hemin (a synthetic form of heme), however, is the mainstay of treatment, especially when dealing with acute attacks [2] [10]. Hemin is able to expand the pool of heme in hepatocytes, which produces a negative feedback mechanism that will reduce the production of heme precursors, most notably ALA [2]. Intravenous infusions will lead to resolution of symptoms within 3-4 days, and the lipophilic form (hematin), or heme arginate, is given in doses of 3 mg/kg per 24 hours as a single dose for 4 days [9]. For more severe enzyme deficiencies that cause recurrent life-threatening attacks and predispose patients to progressive motor neuropathies, liver transplantation may be indicated, but proper follow-up and rigorous anticoagulant therapy is mandatory, since a very high risk for hepatic artery thrombosis has been noted [9].

Before the introduction of modern critical care and directed therapy, mortality rates exceeded 35%, but with early identification and increased awareness of the disorder, patients achieve a good prognosis through long-term monitoring and avoidance of factors that are known to induce acute attacks [2]. However, numerous complications may arise, especially if the diagnosis is made late, most important being irreversible nerve degeneration (characteristic for AIP), renal insufficiency, chronic hypertension and hepatocellular carcinoma, which seems to be age-related and more commonly encountered among patients suffering from ongoing liver disease [2] [6].

Acute hepatic porphyrias are all caused by genetic deficiencies of enzymes involved in one of the steps of heme synthesis, many of which occur in the liver. Although only 15% of total heme is synthesized in the liver, genetic mutations reduce enzymatic activity by 50% in AIP, HCP and VP, whereas 95% reduction is seen in ADP [5]. Apart from an autosomal recessive pattern of inheritance seen in ADP, all hepatic porphyrias are caused by autosomal dominant mutations, leading to accumulation of neurotoxic substances in the liver, presumably γ-aminobutyric acid analogs and/or porphobilinogen (PBG) [5].

Prevalence rates of acute hepatic porphyrias significantly vary across different types and geographical regions. Overall prevalence rate of AIP in Europe is estimated at 1 in 75,000 individuals, ranging from 1 in 1,000 in northern Sweden to 2 in 100,000 in Finland, while Argentina reports rates of 1 in 125,000 individuals [1]. On the other hand, valegriate porphyria (VP) is most commonly encountered in South Africa, where 1 in 300 individuals suffer from this type of porphyria due to founder effect [6]. Other countries report much lower rates (2 per 100,000 in Finland and 1 per 600,000 in Argentina) [1]. Up to 2015, only 6 cases of ADP are reported [6]. Numerous precipitating factors or events are well-established inducers of acute attacks: lipophilic drugs (rifampicin, sulfonamide antibiotics, barbiturates and hydantoins) [6], corticosteroids, androgens, alcohol, organic solvents, pesticides, but also profound emotional stress, caloric deprivation that leads to severe fasting and physical effort [1] [6]. It must be noted that some types of hepatic porphyria, such as AIP, are more prevalent among women [6].

Heme formation is a complex metabolic pathway involving eight different enzymes, all being potential targets for genetic mutations and the occurrence of porphyrias [7]. 85% of heme is formed in erythrocytes, and only 15% in the liver, but about 80% of heme synthesized in this organ is necessary for activity of cytochromal P450 enzymes and the electron transport chain in the TCA cycle, which are essential for degradation of toxic chemical and energy formation, respectively [1]. In the setting of genetic mutations that cause deficiencies of enzymes involved in heme synthesis, the pathogenesis of porphyrias stems from insufficient heme production and consequent hepatic accumulation of its precursors, in the attempt to accelerate the production of heme. As enzyme deficiencies impair the ability of the liver to produce heme, these precursors accumulate and become toxic (presumably γ-aminobutyric acid analogs, ALA, and/or porphobilinogen) and their deleterious effects develop through interaction with γ-aminobutyric acid (GABA) or glutamate receptors, the sites where main neuronal transmitters exert their effects [2] [5]. For symptoms to appear, however, the accumulation of these metabolites is not sufficient, but intake of certain drugs, stress, or severe caloric deprivation causes further saturation of cytochromal enzymes and even larger accumulation of toxic metabolites, eventually breaching the threshold of tolerance by the body resulting in the onset of symptoms.

Genetic counselling may be highly recommended for families with a positive history for porphyrias. For those in whom the diagnosis is confirmed, several preventive measures may be of significant benefit [2] [8]:

• Avoiding use of hazardous drugs and exposure to substances that are known inducers of acute attacks.
• Avoid periods of starvation and profound fasting.
• Prophylactic therapy with hematin.
• Regular screening - Abdominal ultrasonography and serum alpha-fetoprotein levels performed on an annual basis after 50 years of age is recommended, primarily to identify early signs of liver disease and hepatocellular carcinoma.

Porphyrias are a group of genetic disorders that arise as a result of deficiency of enzymes involved in the formation of heme, a vital constituent of hemoglobin and cytochromal enzymes that participate in metabolism of numerous drugs in the liver and in the tricyclic acid cycle (TCA), where they are necessary cofactors in the electron transport chain [1]. Based on the onset of symptoms, porphyrias are generally divided into acute and non-acute, and a further classification according to the type of symptoms (neurovisceral and/or cutaneous) can be made as well [1] [2]. Additionally, porphyrias can be classified into hepatic and erythropoietic, depending the site of overproduction of toxic metabolites [3], and four hepatic porphyrias are recognized in literature [4] [5] [6]:

• δ-aminolevulinic acid dehydratase deficiency (ADP) porphyria - Only a six cases of ADP have been described in literature up to today, in which the second step of heme synthesis (condensation of two molecules of δ-aminolevulinic acid - ALA into porphobilinogen) is affected by autosomal recessive mutations [2].
• Acute intermittent porphyria (AIP) - Considered as one of the most common forms of porphyria, AIP is inherited through autosomal dominant patterns, and is caused by mutations in hydroxymethylbilane synthase (HMB-synthase) gene, responsible for the third step of heme synthesis - conversion of porphobilinogen (PBG) into uroporphyrinogen [2]. The clinical presentation appears in only 10% of mutation carriers and comprises typical acute attack consisting of nonspecific abdominal pain, nausea, tachycardia, vomiting, constipation, mental changes, convulsions, hypertension and pain in the head, neck and/or thorax [1].
• Hereditary coproporphyria (HCP) - Deficiency of coproporphyrinogen oxidase (CPOX), necessary for the sixth step of heme formation - conversion of coproporphyrinogen III to protoporphyrinogen IX, through autosomal dominant mutations of the CPOX gene is the mechanism of disease in this type of porphyria [1]. The majority of patients exhibit acute attacks, while 20% can also present with skin-related symptoms, such as photosensitivity and blistering skin lesions [1].
• Variegate porphyria (VP) - Like AIP and HCP, variegate porphyria (VP) is inherited by autosomal dominant transfer of mutated genes that code for protoporphyrinogen oxidase (PPOX), which is necessary for the conversion of protoporphyrinogen to protoporphyrin, the seventh and second-last step in heme synthesis [6]. Adult-onset of cutaneous blistering lesions (subepidermal vesicles, erosions, bullae) of the sun-exposed skin and acute attacks of abdominal and chest pain, constipation, muscle weakness that can be severe enough to cause paralysis of the limbs and respiratory muscles, as well as psychiatric disturbances are main symptoms of VP [7].

Two main features are shared by all porphyrias. Firstly, the onset of symptoms stems from accumulation of toxic substances of the heme pathway due to enzyme deficiencies; and secondly, these metabolites are not sufficient by themselves to cause symptoms [4]. Acute attacks are precipitated by various factors and events, including alcohol, pesticides, organic solvents, caloric deficiency, corticosteroids, and numerous lipophilic drugs (barbiturates, rifampicin, sulfonamide antimicrobials etc.) [1] [6]. For this reason, the diagnosis of hepatic porphyrias can be made by detecting heme precursor metabolites in urine or feces after use of certain drugs, substances or nutritional-related effects. Treatment principles comprise discontinuation of potentially hazardous drugs, administration of hematin (a synthetic form of heme that inhibits production of toxic metabolites), dextrose, symptomatic care, and in most severe cases, liver transplantation [8].

Porphyrias are a group of inherited disorders that cause insufficient formation of heme, a precursor of hemoglobin and a vital constituent of various liver enzymes involved in metabolism of numerous drugs and toxic substances. Based on their clinical features and site of occurrence, they can be divided into acute or non-acute, hepatic or erythropoietic (originating from the liver or red blood cells, respectively) and neurovisceral or cutaneous, implying that symptoms may be related either to the nervous system and internal organs or the skin. Acute hepatic porphyrias are a group of disorders in which enzyme deficiencies cause insufficient formation of heme in the liver and subsequent accumulation of toxic metabolites of this pathway in the same organ. Delta-aminolevulinic acid dehydratase deficiency (ADP) porphyria, acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP) are representatives of this group. For symptoms to appear, enzyme deficiencies are not sufficient by themselves, but additional factors are necessary to trigger their onset. Examples are use of drugs metabolized by enzymes that use heme as its substrate, such as rifampicin, barbiturates, and sulfonamide antibiotics, whereas corticosteroids and androgens, profound fasting due to starvation, emotional stress, exposure to organic solvents, pesticides, and alcohol are other notable examples. The hallmark of hepatic porphyrias are "acute attacks" of nonspecific and intense abdominal pain accompanied by nausea, vomiting, cramping, constipation and deceased bowel sounds, hence the term acute hepatic porphyria. Additional signs include head, neck and chest pain, hypertension, seizures, mental changes (restlessness, anxiety, confusion, insomnia, disorientation), and neuropathies that can induce severe muscle weakness. The diagnosis can be made by detecting toxic metabolites in urine or feces and genetic testing may be performed as a confirmation. Treatment initially focuses on alleviation of symptoms through stabilizing blood pressure and seizures, as well as gastrointestinal complaints. The mainstay of therapy, however, is administration of synthetic heme (known as hematin or heme arginate), which increases the pool of heme in the liver, thus reducing the production of toxic metabolites. Because acute attacks may be recurrent and severe, and even life-threatening, liver transplantation may be considered. For the same reason, a late diagnosis is detrimental, as current therapeutic modalities and preventive strategies (avoiding use of drugs or other factors that can precipitate the onset of symptoms) can successfully treat the condition and prevent long-term sequelae.

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