- Last Update On : 2015-11-09
The heme biosynthetic pathway consists of 8 enzymes. The formation of heme begins with the condensation of glycine and succinyl coenzyme A to delta-aminolevulinic acid (ALA). A series of enzyme reactions converts ALA to porphobilinogen (PBG) and then to various porphyrinogens. Finally, iron is inserted into protoporphyrin by the enzyme ferrochelatase, forming heme.
The majority of heme is produced in erythropoietic cells where it is incorporated into hemoglobin. Hepatocytes also produce a significant amount for use in myoglobin, cytochromes, catalase and peroxidase.
Each porphyria is caused by a specific enzyme deficiency involved in the heme biosynthetic pathway. Accumulation of intermediary metabolites is responsible for the clinical manifestations.
Most types of porphyria, with the exception of congenital erythropoietic porphyria, are diagnosed in adulthood.
The simplest approach to classifying the porphyrias is on the basis of their clinical manifestations. Porphyrias can be divided into two general groups; those causing predominantly acute neurologic attacks and those causing chronic cutaneous photosensitivity.
|Acute Neurologic Disease||Chronic Cutaneous Disease|
|Acute Intermittent Porphyria (AlP)||Porphyria Cutanea Tarda (PCT)|
|Variegate Porphyria (VP)||Congenital Erythropoietic Porphyria (CEP)|
|Hereditary coproporphyria (HCP)||Hepatoerythropoietic porphyria (HEP)|
|Delta aminolevulinic acid dehydratase deficiency (ALA)||Erythropoietic protoporphyria (EPP)|
Chronic Cutaneous Porphyrias
The most common causes of chronic cutaneous photosensitivity are PCT, CEP, HEP, and EPP. A few of the acute neurologic porphyrias, such as VP, may express photosensitivity in addition to neurologic symptoms. Cutaneous photosensitivity is due to the accumulation of excessive amounts of porphyrins in the skin.
PCT is the most common porphyria and most responsive to treatment. Approximately 75% of cases are acquired and 25% are inherited. Acquired cases are precipitated by complications from hepatitis C, hemochromatosis, alcohol abuse, iron overload, smoking, estrogen therapy and occupational exposure to polychlorinated cyclic hydrocarbons. Familial PCT is caused by partial deficiency of uroporphyrinogen decarboxylase and is inherited as an autosomal dominant trait. It is characterized by photosensitivity and skin fragility. Sun exposed skin is most often affected. Hypertrichosis, hyperpigmentation, or alopecia may be observed. Liver function tests are usually abnormal as a result of uroporphyrinogen accumulation in the liver. PCT is diagnosed by demonstrating elevated uroporphyrin and heptacarboxylporphyrin in urine. Urine uroporphyrin is usually elevated more than 4 times the upper limit of normal. Heptaocarboxylporphyrin is usually 25% of the uroporphyrin level. Elevated uroporphyrin with normal heptacarboxylporphyrin is more indicative of an acute neurologic porphyria. Acquired versus familial PCT can be distinguished by measuring uroporphyrinogen decarboxylase levels in erythrocytes.
EPP is the third most common porphyria. It is caused by an autosomal recessive disorder due to deficiency of the enzyme ferrochelatase. Only about 10% of individuals with this deficiency develop clinical symptoms. Onset usually occurs before age 10. Sun exposure causes painful erythema, edema and itching. Blistering and scarring are less common than in the other cutaneous porphyrias. Patients have an increased risk of hemolytic anemia. Gallstone formation is common. Liver dysfunction is seen in 20% of patients. When ferrochelatase is deficient, protoporphyrin accumulates in erythrocytes, diffuses into plasma, is cleared by the liver, and secreted into bile. Excess protoporphyrin levels are detected in erythrocytes (free erythrocyte protoporphyrin), plasma and in feces. Urine levels are not elevated because protoporphyrin is not soluble in water. The tests of choice are total porphyrins and protoporphyrin fractionation in erythrocytes. Erythrocyte protoporphyrin levels in affected patients are usually above 300 ug/dL compared to less than 80 ug/dL in normal patients. Urine porphyrins, ALA and PBG are not useful and should not be ordered if EPP is suspected.
HEP is a rare but severe porphyria due to markedly deficient uroporphyrinogen decarboxylase activity. It is inherited as an autosomal recessive disorder. Onset usually occurs in infancy or childhood. Patients have severe photosensitivity leading to blistering and scarring. Hemolytic anemia and hepatosplenomegaly may also be present.
CEP, also known as Gunther’s Disease, is a very rare and severe disease that causes mutilating photodermatitis and excretion of dark red urine early in life. Most patients present in infancy with photosensitivity, blistering, erythrodontia and hypertrichosis. Scarring and mutilation may be seen. CEP may cause hemolytic anemia of the newborn and nonimmune hydrops fetalis. It is an autosomal recessive disorder caused by a deficiency of the erythrocyte enzyme, uroporphyrinogen III (UPG III) cosynthase, which results in the accumulation of an abnormal uroporphyrinogen I isomer that is oxidized to uroporphyrin and excreted into the urine. Urine, erythrocyte and fecal porphyrins are elevated. Porphyrins in the urine are predominantly the series I isomers of uroporphyrin and coproporphyrin..Coproporphyrin I is detected in feces. Demonstrating diminished erythrocyte uroporphyrinogen III (UPG III) cosynthase, enzyme activity confirms the diagnosis. Enzyme analysis must be completed prior to blood transfusion.
Acute Neurologic Porphyrias
AIP, HCP, VP and ALA are the most prevalent forms of acute neurologic porphyria and are characterized by acute episodic attacks of severe abdominal pain and psychiatric distress. Other symptoms include hypertension, paresthesias, seizures, and fever. Neuromuscular weakness can progress rapidly to paralysis and respiratory failure. Acute attacks are provoked by medications, such as barbiturates and antibiotics. Industrial or household chemicals, industrial chemical wastes, agricultural pesticides, garden chemicals, automotive degreasing solvents, and ceramic mineral pigments can also induce them.
AlP is the second most common porphyria and is inherited as an autosomal dominant trait with reduced penetrance. It is caused by mutations in the HMBS gene, resulting in a deficiency in the enzyme hydroxymethylbilane synthase, which is more commonly known as porphobilinogen deaminase (PBGD). Only 20% of individuals with this deficiency will become symptomatic during their lifetime.
AIP rarely presents prior to puberty, with onset most commonly between ages 20 and 40. It is aptly named for the intermittent episodes in which patients experience acute neuropathic symptoms. Episodes are highly variable, and although acute in duration, may last from days to several months. Patients experience episodes of severe abdominal pain, often in conjunction with nausea, vomiting and constipation. Peripheral neuropathy is common, but seldom occurs in the absence of abdominal pain. Psychiatric symptoms include psychotic episodes, depression and anxiety. Hypertension and tachycardia may be observed. Acute episodes may be life threatening due to seizures and respiratory paralysis.
Because of the PBGD deficiency, porphobilinogen cannot be assembled into the linear tetrapyrroles that ultimately form uroporphyrin. During acute episodes, PBG and ALA are excreted in excess amounts into the urine. During asymptomatic latent stages, urine PBG and ALA may remain elevated or return to normal. Erythrocyte PBG deaminase can be measured in asymptomatic individuals. Infants should be tested after one year of age, because enzyme levels fluctuate during the first year of life. Ten percent of asymptomatic individuals will have normal PBGD enzyme activity, so urine porphyrin levels should be measured simultaneously.
VP is an autosomal dominant acute porphyria that is caused by mutations in the PPOX gene. These mutations cause a deficiency in protoporphyrinogen oxidase activity. Highest prevalence occurs in individuals from South Africa and Finland. Symptoms rarely occur before puberty.
VP causes abdominal pain, vomiting, neuropathies and psychiatric sequelae. Cutaneous photosensitivity and sensitivity to mechanical trauma are more pronounced than in the other acute porphyrias. Neuropathic symptoms occur only during acute crisis, but photosensitivity remains a chronic symptom
Protoporphyrinogen oxidase is the next to the last enzyme involved in heme synthesis. Diagnosis of VP relies upon porphyrin analysis in urine and feces. ALA and PBG values are elevated up to 20 times the upper limit of normal during acute crises, but may be normal between attacks. Both fecal protoporphyrin IX & coproporphyrin are increased more than two times the upper limit of normal during acute crises. Fecal protoporphyrin is elevated more than coproporphyrin. The ratio of coproporphyrin III to coproporphyrin I ranges from 3 to 10, which is well above the normal ratio of 1.2. Fecal porphyrins may remain elevated for months after an acute episode, even thought the patient is asymptomatic. Protoporphyrinogen oxidase activity is not available for clinical use.
HCP is is one of the rarest forms of porphyria. It is an autosomal dominant disorder caused by mutations in the CPOX gene. These mutations result in a deficiency of coproporphyrinogen oxidase enzyme activity. Symptoms very rarely present before puberty. Clinical manifestations are predominantly neurovisceral. About one third of cases exhibit photosensitivity similar to PCT and VP. Patients without dermatologic findings are clinically indistinguishable from patients with AIP and VP. Correct diagnosis depends on porphyrin analysis The biochemical hallmark is elevated excretion of coproporphyrin in urine and feces similar to VP. Fecal porphyrin analysis allows for distinction between HCP from VP and AIP. In HCP, the fecal coproporphyrin III to 1 ratio is elevated much higher, into the 10 to 20 range, and protoporphyrin is not elevated. A laboratory test for coproporphyrinogen oxidase enzyme activity is not available.
Aminolevulinic acid dehydratase deficiency (ALAD) porphyria is a very rare autosomal recessive form of acute porphyria. Clinical manifestations are predominantly neuropathic and include abdominal pain, vomiting, and pain in the extremities. ALAD is differentiated from other acute porphyrias by normal or slightly elevated urinary PBG in the presence of significantly elevated ALA . ALAD enzyme activity is markedly decreased (<5%) in erythrocytes. Lead intoxication can also produce elevated ALA with normal PBG, so whole blood lead analysis should also be performed to rule out this possibility.
In general, the best initial test for porphyria is a random urine specimen for quantitative porphyrin analysis that includes porphobilinogen. If EPP is a possibility, erythrocyte protoporphyrin fractionation should be ordered. If urine porphyrin results are normal, additional testing of fecal, plasma and erythrocyte porphyrins is usually not recommended. If initial results are abnormal, then the most appropriate tests for each type of porphyria should be ordered.
|Porphyria||Enzyme Deficiency||Enzyme Assay||
|Erythrocyte Elevations||Plasma Elevations|
|Isocopro & Heptacarboxyl III||Not applicable||Uro & , Heptacarboxyl|
|HEP||Uroporphyrinogen decarboxylase||Yes||Uro & Heptacarboxyl||Isocopro, Heptacarboxyl III & Copro I||ZInc proto||Uro|
|CEP||Uroporphyrinogen III synthase||Yes||Uro & Copro||Copro I||Uro, Copro & Zinc proto||
|EPP||Ferrochelatase||No||Not applicable||Proto||Free Proto||Proto|
|ALAD||ALA dehyratase||Yes||ALA & copro||Not applicable||Zinc proto||Not applicable|
ALA, PBG, Uro &,
|HCP||Coproporphyrinogen oxidase||No||Copro, ALA & PBG||Coproporphyrin III/I ratio||Not applicable||Copro|
|VP||Protoporphyrinogen oxidase||No||Copro, PBG & ALA,||Proto>Copron III, Copro III/I ratio||Not applicable||Copro & Proto|
Patients should refrain from alcohol for at least 24 hours prior to urine collection since alcohol can affect enzyme activity in the heme biosynthetic pathway.
Mayo Medical Laboratories offers a multigene panel to differentiate the acute neurologic porphyrias. This panel includes HMBS, PPOX and CPOX genes. Biochemical testing should be performed prior to ordering this panel.