Inherited and acquired disorders in which heme biosynthetic enzymes are partially or totally deficient.
Heme synthesis begins in the mitochondria with succinyl-CoA and glycine.
Heme synthesis involves eight steps, each with a unique enzyme that advances the precursor products along the pathway.
The enzyme that initiates the synthesis pathway, delta-aminolevulinic acid synthase differs in the liver and bone marrow as does the regulatory feedback control.
Disruptions in the pathway resulting from enzyme deficiencies cause precursors to accumulate.
The accumulation of porphyrin precursors delta aminolevulanic acid, porrphobilinogen, or porphyrins, uroporphyrin, coproporhyrin leads the clinical features of porphyria.
The most common are porphyria cutanea tarda,acute intermittent porphyria, and erythropoietic protopotphyria, in that order.
The accumulation of porphyrin precursors causes damage to neurons in the gut, brain, and peripheral nervous system and causes photo sensitivity and damage to the skin.
It is associated with CNS involvement that includes headaches, and abdominal pain and can cause hypertension and tachycardia.
Additional CNS effects include agitation, insomnia, hallucinations, and in many cases hyponatremia.
The majority of porphyrias disorders are inherited.
The subtypes of acute hepatic porphyria including acute intermittent porphyria, the most common sub type, hereditary coproporphyria, variegated porphyria, area, and Delta-aminolevulinicacid dehydratase-deficiency porphyria, are characterized by the occurrences of severe neurovisceral attacks.
Symptomatic attacks occur most frequently between ages 14 and 45 years and occur more often in female patients (4:1
Abdominal pain is usually the primary symptom and is typically located in the lower abdomen, is a colicky in nature and does not cause peritonitis.
Metabolic diseases that cause the accumulation of the intermediate compounds in heme biosynthesis.
It occurs mainly due to mutations in genes encoding enzymes involved in heme production.The genetic deficit causing acute hepatic porphyria reduces heme availability when there are increased heme demands, which leads to activation of the heme-synthesis pathway and upregulation of the first and rate limiting enzyme of the pathway, ALA synthase 1, which in turn leads to an increase in the production it and accumulation of neurotoxic metabolites aminolevulinic acid and porphobilinogen.
The elevation of aminolevulinic acid and porphobilinogen is accompanied by diffuse and severe abdominal pain, vomiting, tachycardia, and hypertension.
Rarely quadriparesis and even death can occur secondary to bulbar and respiratory paralysis.
Patients with recurrent attacks are at risk for long-term complications: hepatocellular carcinoma, chronic renal failure, chronic neuropathy, and hypertension.
Eight enzymes involved in the synthesis of heme.The 4 hepatic acute porphyrias: delta-aminolevulinate dehydratase deficiency, acute intermittent porphyria, hereditary coproporphyria, and variegated porphyria.
Estimates frequency of genetic defects in the HMBS gene 5-59/100,00.
Mutations in the gene that causes acute intermittent porphyria is relatively common approximately, one in 1600 white persons, but the disease penetrance among maturation carries is approximately 1% of the general population and up to 50% of families with a history of disorder.
Acute intermittent porphyria results from mutations in HMBS, the gene including hydroxymethylbilane synthase, which plays an integral role in heme synthesis.
Typical patient with AIP is a woman between ages of 18-45 years.
Common symptoms with AIP is abdominal pain at 74%, nausea and vomiting 73%, constipation 60%, and anxiety and depression 55%.
An enzymatic defect exists at all enzymatic steps, with the exception of the first step, leading to accumulation and excessive secretion of porphyrins or their precursors such associated δ-aminolevulinic acid and porphobilinogen.
The final product of porphyrin synthesis is heme and, otherwise porphyrin and its precursors are of no value and are toxic.
All forms affects fewer than 200,000 individuals in the US.
The prevalence of mutations among patients with acute intermittent porphyria, which is the most common subtype of acute hepatic porphyria, is approximately one and 1700 in western countries, although disease penetrance is low, with less than 10% of patients ever having disease symptoms develop.
Classified on the basis of clinical findings as photosensitive or neurological, or on the basis of the site of the expression of the enzyme defect as hepatic or erythropoietic, with some types showing overlapping.
Numerous types of mutations for each type of porphyria.
Occur as inherited disease, but can be acquired due to exposure to environmental chemicals or with other defects.
Unaffected gene carriers are at greater risk for infertility and chemical toxicity from lead or dioxin.
Diseases classified associated erythropoietic or hepatic, depending on the principal site of the expression of the specific enzymatic defect.
Erythropoietic types include: congenital erythropoietic porphyria, and erythropoietic protoporphyria.
Hepatic porphyrias are classified as acute or chronic.
Acute hepatic porphyrias are rare, serious, and life-threatening genetic diseases caused by mutations in hip Paddick team biosynthesis enzymes.
The neurotoxic heme intermediates delta aminolevulinic acid (ALA) and porphobilinigen accumulating in patients with acute hepatic porphyrias, leading to acute debilitating neurovisceral attacks and in some patients, disabling chronic symptoms.
Most symptomatic patients with acute hepatic porphyrias have only a few attacks in their lifetime, however, approximately 5-8% of symptomatic patients with acute intermittent porphyrias have recurrent attaks of four or greater attacks per year, which manifest primarily as severe diffusive abdominal pain typically requiring urgent medical attention or hospitalization.
When symptomatic patients with acute porphyrias present as acute attacks of pain, usually involving the abdomen, and often accompanied by symptomatic nervous system overactivity.
The latter includes systemic arterial hypertension, sweating, tachycardia, and sometimes there is neurologic manifestations such as weakness, delirium, and seizures.
A recent series report substantial preponderance of females (83%) (Bonkovsky HL et al).
Fewer than half patients with porphyria report a parent with known disease.
Onset of symptoms usually occurs in the 2nd to 4th decades of life.
Triggers of attacks include medications 37% a time and weight loss diets 22% of the time.
18 percent of patients suffer from chronic ongoing symptoms.
Associated with a high prevalence of chronic medical conditions including peripheral neuropathy, hypertension, chronic renal disease, previous abdominal surgeries such as appendectomy and cholecystectomy, seizures and psychiatric illnesses.
Patients have a much higher risk of having had a cholecystectomy in subjects with acute intermittent porphyria.
Disease manifestations are less frequent and less severe in patients with hereditary coproporphyria and variegate porphyria than in patients with acute intermittent porphyria.
Treatment for acute episodes is intravenous hematin.
Intravenous hematin associated with a 74% response rate foracute intermittent porphyria.
Intravenous hematin effective for prevention of acute attacks.
60% of patients can alter their intake of alcohol and certain medications and increase physical exercise with improved lifestyle benefits.
