Acute Porphyria

Acute Porphyrias result from lack of certain enzymes in the heme biosynthesis, leading to an accumulation of the heme precursors which cause intermittent attacks of abdominal pain and neurological symptoms. The attacks are triggered by certain medications and other factors. The diagnosis based on the detection of elevated levels of Porphyrinvorläufers ?-aminolevulinic acid in urine and porphobilinogen during a seizure. The attacks are with glucose, or in severe cases with an i.v. Administration of heme treated. Symptomatic treatment to the analgesia counts is administered as needed.

Among the acute porphyria (overview of porphyria) include, in order of prevalence:

Acute Porphyrias result from lack of certain enzymes in the heme biosynthesis, leading to an accumulation of the heme precursors which cause intermittent attacks of abdominal pain and neurological symptoms. The attacks are triggered by certain medications and other factors. The diagnosis based on the detection of elevated levels of Porphyrinvorläufers ?-aminolevulinic acid in urine and porphobilinogen during a seizure. The attacks are with glucose, or in severe cases with an i.v. Administration of heme treated. Symptomatic treatment to the analgesia counts is administered as needed. Among the acute porphyria (overview of porphyria) include, in order of prevalence: acute intermittent porphyria (AIP) porphyria variegata (VP) Hereditary coproporphyria (HC) ?-aminolevulinic acid dehydratase deficiency porphyria (ALAD) patients with VP and HCP with or without neurovisceral symptoms bullous eruptions may develop, especially on the hands, forearms, face, neck, or other areas of exposed skin to sunlight. The heterozygotes acute porphyria show rarely before puberty a manifestation; and after puberty in only 2 to 4% of cases. In homozygotes and compound heterozygotes of onset usually in childhood, and the disease course is usually heavy. There are many triggering factors triggering factors, typically accelerate these factors, the heme synthesis on the catalytic capacity of the defective enzyme addition. This results in an accumulation of the Porphyrinvorläufer porphobilinogen (PBG) and ?-aminolevulinic acid (ALA), or in the case of ALA dehydratase (ALAD) deficiency porphyria only an accumulation of ALA. The attacks are probably caused by different, sometimes by non-identifiable factors. Identified triggering factors include: Hormonal changes in women drug calorie, low carbohydrate diet alcohol exposedness to organic solvents infections and other diseases Surgical procedures Emotional stress Hormonal factors play an important role. Women show frequent attacks than men, especially in times of hormonal changes (eg. As in the second phase of the menstrual cycle, during use of oral contraceptives, in the first weeks of pregnancy or during the time immediately after birth). Nevertheless pregnancy is not contraindicated. Other triggering factors include drugs (including barbiturates, hydantoins, other anticonvulsant drugs and sulfonamide antibiotics-see Table: Drugs and Porphyria *) and hormones of the reproductive cycle (progesterone and related steroids), especially those that hepatic ALA synthase and the enzymes of the cytochrome induce P-450 system. The attacks usually occur within 24 hours after exposure to the triggering medication. Exposure to sunlight triggers cutaneous symptoms in PV and HKP. Drugs and Porphyria * Category / Unsure disorder to be treated Certainly Probably safe painkiller dextropropoxyphene † diclofenac meprobamate propoxyphene tramadol aspirin Buprenorphine caffeine codeine morphine propofol atropine dexibuprofen † fentanyl, hydromorphone ketobemidone † ketoprofen naproxen anesthetic (local) Lidocaine Bupivacaine Articaine anesthetic (premedication, induction or maintenance) barbiturates atropine morphine propofol Alfentanil Fentanyl isoflurane desflurane droperidol remifentanil scopolamine, sufentanil antidepressants – Lithium fluoxetine Antidiarrheal agents – carbon loperamide – Antiemetics – chlorpromazine granisetron tropisetron, ondansetron, scopolamine † anticonvulsant barbiturates, carbamazepine Methadone (Para methadone †, Trimethadon) felbamate lamotrigine mephenytoin † phenytoin primidone succinimides (ethosuximide, mesuximide) valproate – clonazepam, diazepam (active seizure) gabapentin, levetiracetam, topiramate, vigabatrin antidiabetics metformin, sulfonylureas, acarbose insulin Anti-infectives chloramphenicol clindamycin erythromycin indinavir, ketoconazole mecillinam † Nitrofurantoin pivampicillin † Pivmecillinam † rifampicin ritonavir sulfonamides trimethoprim acyclovir amikacin amoxicillin Amoxicillin with a ?-lactamase inhibitor ampicillin Cloxacillin † dicloxacillin fusidic † ganciclovir gentamicin immunoglobulin immune sera hexamethylenetetramine netilmicin † oseltamivir Penicillin G Penicillin V Piperacillin teicoplanin † Tobramycin vaccinations valaciclovir zanamivir vancomycin amphotericin B azithromycin bacampicillin † cephalosporins, ciprofloxacin, ethambutol didanosine ertapenem famciclovir flucytosine foscarnet fosfomycin Imipenem / cilastatin Levofloxacin Meropenem moxifloxacin, norfloxacin † ofloxacin piperacillin with tazobactam ribavirin anti-inflammatory agents or anti-inflammatory drugs – hyaluronic acid penicillamine salicylic abacavir dexibuprofen † ibuprofen ketoprofen lamivudine lornoxicam † naproxen piroxicam tenofovir tenoxicam † zalcitabine † anxiolytics, sedatives / hypnotics or antipsychotics ethchlorvynol † glutethimide † hydroxyzine meprobamate chlorpromazine droperidol fluoxetine fluphenazine, haloperidol levomepromazine † prochlorperazine Propiomazine † alprazolam clozapine dixyrazine † eszopiclone lorazepam olanzapine oxazepam perphenazine triazolam Cardiovascular disease dihydralazine † ergoloid mesylate hydralazine lidocaine methyldopa, nifedipine, spironolactone, amiloride ?-blocker cholestyramine colestipol digitalis glycosides diltiazem Enalapril adrenaline heparins lisinopril, losartan niacin Organic nitrates adenosine amrinone bendroflumethiazide bezafibrate † bumetanide digoxin, dobutamine dopamine dopexamine † doxazosin ethacrynic Etilefrin † fenofibrate furosemide hydrochlorothiazide milrinone phenylephrine prostaglandins quinidine Danazol hormones progesterone Synthetic progestins non-reproductive hormones, including glucocorticoids Natural estrogens laxatives – bisacodyl Cascara Sagrada fiber lactitol † lactulose sodium lauryl Psyllium Senna glycosides docusate sodium Natriumpicosulfat † sorbitol – migraine ergot – – Muscle relaxants Carisoprodol Orphenadrine atracurium mivacurium Cisatracurium † pancuronium rocuronium, succinylcholine (suxamethonium) vecuronium Baclofen osteoporosis – bisphosphonates calcium supplements – gastric and duodenal ulcer – alginic acid calcium containing antacids cimetidine magnesium containing antacids, sucralfate famotidine, misoprostol, nizatidine ranitidine Respiratory clemastine, dimenhydrinate, albuterol (salbutamol) alimemazine † codeine corticosteroids dipalmitoylphosphatidylcholine dornase alfa ephedrine ethylmorphine Ipratropium phenylpropanolamine † phospholipid surfactant bambuterol † cromolyn desloratadine fenoterol † fexofenadine, formoterol levocabastine † lidocaine (gargle solution) loratadine mizolastine † oxymetazoline salmeterol terbutaline tiotropium * Classification of the drugs on the list based on a combination of clinical observations, case reports in the literature and theoretical considerations derived from the structure and St offwechsel the substances. However, clinical observations in many cases can be unreliable. The biochemical and molecular biological models for the activation of the disease are incomplete. This list is intended only as a guide and is applicable to all patients in whole or in. Drugs must always be used with caution in people who carry genes for acute porphyria. For questions about specific medications doctors can consult www.drugs-porphyria.org. † Not available in the US. Symptoms and signs The symptoms and complaints of acute porphyria affect the nervous system, the abdomen or both (neurovisceral symptoms). The attacks develop over hours or days and may continue for several weeks. Most carriers of the gene to experience life few or no seizures. Others suffer from ever-recurring symptoms. In women recurrent attacks often occur in connection with the second phase of the menstrual cycle (luteal phase) on. The acute Porphyrieanfall constipation, fatigue, irritability and insomnia go ahead an acute attack typically. The most common symptoms of an attack include abdominal pain and vomiting. The pain is often unbearable and bear no relation to painful abdominal rigidity or other physical complaints. The abdominal manifestations probably resulting from irritation visceral nerve or a local vasoconstrictive ischemia. Since no inflammation is present, the abdomen is soft and there are no signs of peritonitis. Temperature and white blood cell counts are normal or only slightly elevated. A voltage increase in the intestine can occur due to a paralytic ileus. The urine is red or reddish-brown and PBG is detectable during the seizure. All parts of the peripheral nervous system and the central nervous system can be affected. A motor neuropathy with severe and persistent seizures is frequent. The muscle weakness usually starts in the extremities, but can each motor neuron or any cranial nerve and relate to quadriplegia progress. A bulbar involvement can cause respiratory paralysis. The involvement of the CNS can cause seizures or mental disorders (eg. As apathy, depression, agitation, psychosis, hallucinations). Seizures, psychotic behavior and hallucinations may be difficult or due to hyponatremia or hypomagnesemia, which can also contribute to Arrhythmieentstehung. Hyponatremia can during an acute attack due to excessive release of vasopressin (antidiuretic hormone [ADH]) and / or the administration of hypotonic infusion solutions (5% or 10% dextrose in water), a standard treatment for acute attacks occur. Excessive catecholamine generally caused restlessness and tachycardia. Rarely performs a catecholamine-induced arrhythmias to sudden death. The labile hypertension with transient high blood pressure can cause vascular changes and untreated cause irreversible hypertension. Renal failure in acute porphyria has many causes; acute hypertension (possibly chronic hypertension) is probably the most important Auslöser.Subakute or sub-chronic symptoms Some patients show over a long period subacute symptoms (eg. as constipation, fatigue, headaches, back and thigh pain, paresthesia, tachycardia, dyspnea, insomnia, depression, anxiety or other impairment of mood, seizures) .Symptome the skin in PV and HKP photodermatosis and bullous lesions may develop on sun-exposed areas of skin, even in the absence of visceral neurotic symptoms. Often patients do not notice the connection with the exposure to sunlight. Cutaneous manifestations are identical to those of porphyria cutanea tarda; Lesions usually occur on the dorsal aspects of the hands and forearms, face, ears and neck auf.Späte manifestations of acute porphyria Involvement of motor skills during the acute attack may also lead between attacks to persistent muscle weakness and muscle atrophy. Cirrhosis, hepatocellular carcinoma, systemic hypertension and renal impairment are more likely to reach the middle age at AIP, and probably also in PV and ICPs, particularly in patients with a history of seizures as part of a porphyria. Diagnostic examination of urine PBG If the results of the urine sample are positive, quantitative ALA and PBG determination to confirm the AIP, measurement of the PBG deaminase in erythrocytes Genetic analysis if the type must be identified acute attack misdiagnosis is common, because the symptoms of acute attack resemble other causes of acute abdominal pain (sometimes resulting in unnecessary surgery leads) or primarily neurological or psychiatric disorders. However, for patients who are known as gene carriers already or a positive family history in terms of porphyria have to be thought of porphyria. However, other causes must be considered even in a gene carriers. Red or reddish-brown urine, which by the time the first symptoms was undetectable and now shows during a severe attack, is a very important note. In all patients with abdominal pain of unknown origin, a urine sample should be done, especially if severe constipation, vomiting, tachycardia, muscle weakness, bulbar involvement or psychological symptoms. If the suspicion of a porphyria is, the urine is examined for PBG. Here we use a qualitative or semiquantitative dipstick. A positive result or strong clinical suspicion of making a quantitative ALA and PBG measurement, most of the same urine sample necessary. PBG and ALA levels that are> 5 times higher than the standard value, show an acute Porphyrieanfall on if it is not the patient is a gene carrier in which the excretion of Porphyrinvorläufern even during the latent phase of the disease on similar level occurs. If the PBG and ALA levels are normal in the urine, an alternative diagnosis should be considered. Measuring total porphyrins in the urine and a high-performance liquid chromatography of these porphyrins are helpful. Elevated levels in the urine sample for ALA and coproporphyria with normal or only slightly elevated PBG indicate a lead poisoning, ALAD deficiency porphyria, or hereditary tyrosinemia type. 1 A 24-hour urine analysis is not necessary. Instead, any urine sample can be examined, and the PBG and ALA levels should be corrected by means of Creatininspiegels in the sample with regard to a possible dilution. Electrolytes and magnesium should be measured. Hyponatremia can conditionally sein.Bestimmung of acute Porphyrietyps Because the treatment does not depend on the type of acute porphyria by excessive vomiting or diarrhea after hypotonic fluid replacement or by a syndrome of inappropriate antidiuretic hormone secretion (SIADH), identification of the specific Porphyrietyps is above particularly interesting for the search for other gene carriers in the relationship. If the type and mutation is already known from previous tests of relatives, the diagnosis is clear, but can be confirmed by gene analysis. The activity of the enzyme ALAD and PBGD in red blood cells is easy to measure and can be helpful for each of the founding of the diagnosis in ALAD deficiency porphyria and acute intermittent porphyria. The PBG deaminase levels in red blood cells, which are increased by about 50%, indicate a AIP. If there is no family history that guides the diagnosis, the various forms of acute porphyria are the characteristic patterns of Porphyrinakkumulation (or by the accumulation of precursor stages) are differentiated and their elimination in plasma, urine and stool. If the urine test, elevated levels of ALA and PBG shows, the porphyrins can be determined in the stool. The porphyrins in stool are normal usually in the AIP or only minimally increased, while showing increased at HKP and PV values. Often, these markers are not detectable in the resting phase of the disease. The plasma fluorescence emission after excitation with Soret band (~ 410 nm) can be used to HKP and PV, which have different highest emissions to unterscheiden.Familienuntersuchungen in acute porphyria children of a gene carrier (for an autosomal dominant form of acute porphyria AIP , ICPs PV) have a 50% risk of inheriting the disease. In contrast, children of patients with ALAD deficiency porphyria (autosomal recessive inheritance) obligate carriers, but develop very unlikely a clinical disease. Since early diagnosis followed by advice to reduce the morbidity risk, children should be tested in affected families before the onset of puberty. A genetic test is performed when the gene mutation in the index case is known. If not, the corresponding enzyme activities are measured in erythrocytes and leukocytes. Genetic analysis can also be used for intrauterine diagnosis (amniocentesis or chorionic villus sampling means), but is rarely indicated due to the very good prognosis for most gene carriers. Prognosis The advances in medical care and self-care have improved the prognosis of acute porphyria for symptomatic patients. However, some patients develop recurrent seizures and a progressive disease with persistent paralysis and kidney failure. Also, the frequent need for opioid analgesics may lead to opioid dependence. Therapy trigger if possible eliminate dextrose (oral or iv) iv Heme Treatment of acute attack is the same for all acute porphyria. Possible triggers (eg. As excessive drinking, drugs) will be identified and eliminated. Except for a very mild attack, the patient is hospitalized in a darkened, quiet single room. The heart rate, blood pressure and fluid and electrolyte balance are monitored. The neurological status, bladder function, the function of muscles and tendons, respiratory function and O2 saturation are monitored continuously. Symptoms (. Eg pain, vomiting) are treated as needed with nichtporphyrinogenen drugs (see Table: Drugs and Porphyria *). Dextrose 300-500 g daily hepatic ALA synthase regulates down (ALAS 1) and improves the symptoms. Glucose can be administered orally, if patients do not vomit; otherwise it will i.v. administered. The usual therapy is 3 l of 10% glucose solution, administered through a central venous catheter for 24 h (125 ml / h). In order to prevent overhydration with subsequent hyponatremia, may instead be used 1 l of a 50% dextrose solution. Iv Heme is more effective than dextrose and should be given immediately in severe attacks, electrolyte imbalance or muscle weakness. Heme improves the symptoms usually within 3-4 days. If the Hämtherapie uses delayed nerve damage are more pronounced and the recovery is slower and may be incomplete. Heme is available in the US as a lyophilized hematin, which is prepared in sterile water in a glass vial again. The dose is 3-4 mg / kg i.v. once a day for 4 days. An alternative is hemin arginate, which is administered in the same dose, with the exception that it is diluted in 5% dextrose, or half or a quarter of the normal saline. Hematin and hemin arginate can cause venous thrombosis and / or thrombophlebitis. The risk of these side effects seems to be lower when heme is administered bound to human serum albumin. Such binding reduces the speed of development of hematin aggregates. Therefore, most experts recommend administration of hematin or hemin arginate with human serum albumin. Recurrent seizures in patients with severe recurrent seizures, which have a risk of kidney damage or permanent neurological damage, liver transplantation is an option. Successful liver transplantation results in permanent cure of all acute porphyria except ALAD deficiency porphyria. Patients with acute porphyria should not be used as liver donors, even though their liver may appear structurally normal (ie no cirrhosis..) Because the recipients have developed syndromes of acute porphyria; such a result helped determine that the acute porphyria are liver diseases. Kidney transplant, with or without simultaneous liver replacement should be considered in patients with active disease and ESRD into account, because there is a significant risk that progress nerve damage at the start of dialysis. Prevention carrier of acute porphyria should avoid: Potentially harmful drugs (see Table: Drugs and Porphyria *) Heavy alcohol consumption Physical or emotional stress or exhaustion exposure to organic solvents (eg in the case of painting or dry cleaning.) Crash diets starvation diets reduction of overweight should have a gradual weight loss goal and only be carried out during periods of remission. Carrier of the gene for PV or HKP should minimize their exposure to sunlight; a sunscreen that filters out only UVB light, is ineffective, but opaque Titaniumdioxidzubereitungen are useful. Supporting organizations such as the American Porphyria Foundation and the European Porphyria Network can provide written information and direct advice. Patients should receive clear labeling with regard to their Genträgerstatus in its file. they should constantly carry an identification card with a list of emergency measures to be taken and with precautions regarding the prevention of an attack with him as well. A high-carbohydrate diet can reduce the risk of an acute attack. Some patients can sometimes be treated by increasing the intake of dextrose or glucose slight acute attacks. Long-term use should be avoided because of the risk of obesity and dental caries. Patients who constantly recurring seizures or foreseeable suffering (typically women whose seizures linked to the menstrual cycle occur), may benefit from treatment with prophylactic Hämgabe administered shortly before the expected attack. A standardized therapy concept does not exist; in any case, a specialist should be consulted. Common premenstrual seizures in some women may be prevented with low-dose estrogen by administration of gonadotropin-distributing hormone agonists in combination. Low-dose oral contraceptives are used occasionally successful, but the progesterone component provoked often a Porphyrieanfall. To prevent kidney damage, chronic hypertension should be treated aggressively (with safe medicines). Patients with evidence of renal impairment are referred to a nephrologist. Current individual experiences show that tolvaptan, an ADH-blockers, is helpful in the management of hyponatremia during acute attacks. The incidence of hepatocellular cancer is high among the carriers of acute porphyria, particularly in patients with active disease. Patients who are> 50 years old should undergo an annual or semi-annual monitoring, including liver screening with ultrasound. Early intervention can be beneficial and increases life expectancy. Summary Acute porphyria cause intermittent bouts of abdominal pain and neurological symptoms; some species have cutaneous manifestations, which are triggered by sunlight. The attacks have many triggers, including hormones, drugs, low-calorie and low-carbohydrate diet and alcohol consumption. Seizures typically include severe abdominal pain (with a tense abdomen) and vomiting, each component of the peripheral and central nervous system may be affected, but muscle weakness is widespread. during an attack, the urine is often reddish brown. Perform a qualitative urine test for PBG and confirm a positive result with quantitative ALA and PBG measurements Treat acute seizures with oral or iv administered dextrose and severe bouts with i.v. administered heme. More information American Porphyria Foundation European Porphyria Network The Drug Database for Acute Porphyria

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