The Challenges Of Testing For And Diagnosing Porphyrias

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emission of skin lesions in most cases. Phlebotomy produces remission by gradually reducing the hepatic iron overload. Serial serum ferritin (#8689 Ferritin, Serum) and plasma porphyrin (#8733 Porphyrins, Fractionation, Plasma) levels are useful in evaluating the efficacy of treatment. Low-dose chloroquine treatments have proven valuable as the drug complexes with excess porphyrins, promoting excretion. However, these therapies should only be initiated following biochemical confirmation of the clinical diagnosis, as they are not useful in other porphyrias presenting with cutaneous symptoms. Occurrences of dermatologic complications can be minimized through elimination or reduction of precipitating factors via sun avoidance and use of sunscreen, abstaining from alcohol, discontinuing estrogen therapy, or treatment of an underlying liver disorder. Even with these treatments, long-term follow-up is important for all patients as a means of monitoring for relapse through urine (#8562 Porphyrins, Quantitative, Urine) and plasma (#8733 Porphyrins, Fractionation, Plasma) porphyrin analysis, and for the management of any concomitant liver disease. Generally, PCT is not attributable to a single causal factor. Even in familial PCT, most patients have identifiable risk factors in addition to the hereditary enzyme deficiency. Therefore, all patients presenting with PCT should be evaluated for multiple risk factors, including testing for hepatitis C virus and screening for hemochromatosis, and treated accordingly. Hepatoerythropoietic Porphyria Hepatoerythropoietic porphyria (HEP) is a severe porphyria due to markedly deficient uroporphyrinogen decarboxylase activity or homozygous PCT. Onset of this rare porphyria usually occurs in infancy or childhood, although cases presenting in adulthood have been described. Patients experience severe photosensitivity leading to blistering lesions and scarring. Other complications include pink or red urine, hypertrichosis, erythrodontia (reddish discoloration of the teeth), hepatosplenomegaly, and hemolytic anemia. Treatment is limited to sun avoidance and the use of sunscreens. Erythropoietic Protoporphyria A deficiency of the enzyme ferrochelatase is observed in patients with erythropoietic protoporphyria (EPP). EPP is an autosomal dominant disorder with reduced penetrance. Only about 10% of individuals with an enzyme deficiency develop clinical symptoms. While onset usually occurs before 10 years of age, clinical presentation may occur during childhood or adulthood. Individuals with EPP are sensitive to most of the visible light spectrum. Such exposure causes burning, itching, and painful erythema and edema that can develop within minutes. Blistering and scarring is less common than in other dermatologic porphyrias. Repeated exposures may result in chronic changes giving the skin a waxy, thickened appearance with faint linear scars. Cutaneous photosensitivity is exacerbated in the spring and summer when exposure to sunlight is more likely. Patients are at an increased risk to develop hemolytic anemia. Gallstone formation is common, and some individuals with EPP experience mild hypertriglyceridemia. Liver dysfunction and hepatic failure are observed in up to 20% and less than 5% of patients, respectively. Patients with EPP accumulate protoporphyrin in erythrocytes, plasma, and feces. Other heme pathway intermediates do not accumulate, and protoporphyrin is not soluble in urine. For these reasons, urinary porphyrin, ALA, and PBG are not useful diagnostic tools for this disorder. When a diagnosis of EPP is suspected, the tests of choice are total porphyrins and protoporphyrin fractionation (#8536 Porphyrins, Total, Erythrocytes or #8739 Protoporphyrins, Fractionation, Erythrocytes) in erythrocytes. Unaffected individuals have approximately 60 µg/dL total protoporphyrin with approximately 85% being zinc-complexed and 15% or less free protoporphyrin. In EPP patients, the total erythrocyte protoporphyrin is significantly increased with values usually >200 µg/dL. Some patients have been observed with total protoporphyrin exceeding 1000 µg/dL. When the total protoporphyrin is fractionated, EPP patients exhibit more free than zinccomplexed protoporphyrin. However, iron deficiency, lead intoxication, or in very rare cases variegate porphyria should be suspected in patients who exhibit total protoporphyrin in excess of 200 µg/dL but have more zinc-complexed than free protoporphyrin. Although EPP is the third most common porphyria, treatment options are limited. Sun avoidance is essential, and protective clothing and sunscreen are recommended. Oral administration of beta-carotene allows for increased tolerance to sunlight in most patients. Although there are no other known precipitating factors, many advocate the avoidance of drugs and other elements that may induce crises in the acute porphyrias. Liver transplantation is an option for 4 11/02
the minority of patients who experience hepatic failure. However, this is not a cure as the excessive porphyrins are produced in the erythropoietic cells. Congenital Erythropoietic Porphyria Congenital erythropoietic porphyria (CEP), also known as Gunther disease, is an extremely rare and severe porphyria. It is an autosomal recessive condition resulting from markedly deficient uroporphyrinogen III cosynthase activity. Although the disorder typically manifests in early infancy, variability in the age of onset and severity are thought to be related to the level of residual enzyme activity. Prenatal manifestation of CEP presents as nonimmune hydrops fetalis (abnormal accumulation of serous fluid in fetal tissues) due to severe hemolytic anemia, whereas only cutaneous lesions are observed in the mildest cases manifesting in adulthood. Clinically, the majority of patients with CEP present in infancy with dermatological complications including photosensitivity, blistering, erythrodontia, and hypertrichosis. The skin may become thickened, and areas of hypopigmentation and hyperpigmentation are observed. Recurrent blistering and secondary infection may lead to significant scarring and mutilation. Exposure to sunlight and other sources of ultraviolet light exacerbate the severity of the cutaneous symptoms. In fact, some patients present at birth when undergoing phototherapy for hyperbilirubinemia. Ophthalmological findings include keratoconjunctivitis (inflammation of the conjunctiva and of the cornea), ulcerations, cataracts, and corneal scarring that can lead to blindness. Hemolytic anemia and other hematologic abnormalities accompanied by splenomegaly are common. To compensate for this, increased metabolic activity and expansion of the bone marrow may lead to pathologic fractures and vertebral compression or collapse. Many patients develop porphyrin-rich gallstones. Pink or reddish-brown urine is often observed as a result of the increased excretion of urinary porphyrins. Moreover, severely affected individuals exhibit growth and cognitive developmental delays and a decreased lifespan. A combination of urine (#8562 Porphyrins, Quantitative, Urine), erythrocyte (#8536 Porphyrins, Total, Erythrocytes and #8735 Porphyrins, Fractionation, Erythrocytes), and fecal (#81652 Porphyrins, Feces) porphyrin analyses can diagnose CEP. Porphyrins in urine are predominantly the I series isomers of uroporphyrin and coproporphyrin. Patients with CEP show elevated erythrocyte porphyrins consisting primarily of uroporphyrin I. Coproporphyrin I is detected in feces. The diagnosis of CEP should be confirmed by erythrocyte uroporphyrinogen III cosynthase enzyme analysis (#80288 Uroporphyrinogen III Synthase (Co- Synthase) (Upg III S), Erythrocytes). Enzyme analysis must be performed prior to blood transfusion to achieve the most accurate results. Furthermore, uroporphyrinogen III cosynthase testing is not useful for carrier testing, as CEP heterozygotes cannot be distinguished from unaffected individuals. Molecular studies are currently not available on a clinical basis, but may be obtained in a research setting. Treatment for CEP requires protection from ultraviolet light to reduce dermatological and ophthalmological complications. To minimize the risk of mutilation, secondary infections must be treated immediately. Blood transfusions and splenectomy are beneficial in some cases by decreasing porphyrin production and limiting hemolytic anemia. Allogenic bone marrow transplantation has proven curative for a handful of patients. However, this therapy carries a considerable risk for mortality. Acute Porphyrias The acute porphyrias include acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and 5-aminolevulinic acid dehydratase deficiency. Episodic neurovisceral symptoms that can be life threatening characterize the acute porphyrias. Cutaneous features also may manifest in some patients. Acute episodes can be precipitated by both endogenous and exogenous factors. These factors and clinical management are similar for all types of the acute porphyrias and are discussed following the clinical descriptions of each. Acute Intermittent Porphyria Acute intermittent porphyria (AIP), the second most common porphyria, results from a deficiency in the enzyme porphobilinogen deaminase (PBGD), also called uroporphyrinogen I synthase or hydroxymethylbilane synthase. AIP is aptly named for the intermittent episodes in which patients experience acute neuropathic symptoms. These acute episodes are potentially lifethreatening, highly variable, and although usually short in duration, may last from a few days to several months. 11/02 5
Page 1 and 2: Communiqué November 2002 AVolume 2
Page 3: Figure 1. Heme Biosynthetic Pathway
Page 7 and 8: activity, has been described. Patie
Page 9 and 10: Table 2. Informative Biochemical Fi
Page 11 and 12: Metanephrine/Normetanephrine Test A
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The Challenges Of Testing For And Diagnosing Porphyrias

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