Peiman Hematti
The porphyrias are a diverse group of uncommon metabolic disorders caused by inherited deficiencies of the enzymes involved in the heme biosynthetic pathway,1 except for one recently described porphyria syndrome due to a gain-of-function mutation. Mutations in the genes of all these heme-synthesizing enzymes have been identified at the molecular level. An exception to the genetic origin for these disorders is porphyria cutanea tarda (PCT), in which the enzyme deficiency in most cases is acquired. In all these ecogenic disorders, it is the interaction of genetic, physiologic, and environmental factors that causes disease in affected individuals. Each defective enzyme results in a characteristic clinical phenotype of porphyria, although disease mechanisms are not fully understood. Any patient with a long history of undiagnosed abdominal pain and/or atypical neuropsychiatric symptoms should have porphyria in their differential diagnosis, as simple tests can be used to confirm diagnosis in symptomatic patients and to screen family members to recognize asymptomatic carriers.2 Counseling about avoidance of precipitating factors can decrease clinical manifestations in the latter group.
EPIDEMIOLOGY
PCT is the most prevalent of the porphyrias, both genetic and acquired combined, but acute intermittent porphyria (AIP) is the most common of the genetic porphyrias. AIP has an estimated incidence of 5 in 100,000 in the United States and northern European countries. Approximately 90% of patients with this inherited enzyme deficiency remain symptom free throughout their life. In contrast, only six cases of δ-aminolevulinic acid dehydratase (ALAD) deficiency have been thus far reported.
PATHOPHYSIOLOGY
Heme is a complex of an iron atom and protoporphyrin IX. Heme is produced in a multistep biosynthetic pathway that functions mostly in the erythroid bone marrow and hepatocytes. Approximately 85% of the heme produced in the body is synthesized in erythroid cells to provide for hemoglobin formation; most of the remainder is produced in the liver to provide heme for cytochrome P-450 and other enzymes. Eight enzymes are involved in this tightly regulated biosynthetic pathway that sequentially converts glycine and succinyl CoA into heme (Fig. 5.1). In eukaryotic cells, the first and the last three steps of this pathway localize in mitochondria, while the others are cytoplasmic. Sequences of the genes for all these enzymes and their molecular defects have been well characterized.
The first enzyme active in the pathway, δ-aminolevulinic acid synthase (ALAS), is coded by two genes: ALAS1, which is expressed ubiquitously in all cells, and ALAS2, which is expressed only in erythroid cells. So far, no mutation has been identified in ALAS1, and until very recently all reported pathogenic mutations of ALAS2 were loss of function and resulted in recessive X-linked sideroblastic anemia, the only non-porphyria syndrome due to abnormalities in the heme biosynthetic pathway. Recently, gain-of-function mutations have been reported in the ALAS2 gene in eight families causing X-linked dominant protoporphyria (XLDPP). In general, mutations of these enzymes result in porphyria syndromes because of overproduction of metabolic precursors and intermediates and/ or their accumulation in tissues. All of these intermediate products are potentially toxic, and their overproduction causes the neurovisceral and/or photocutaneous symptoms characteristic of porphyria syndromes.
FIGURE 5.1 Classification of porphyrias based on their corresponding enzymatic deficiencies, mode of inheritance, major symptoms, and biochemical abnormalities.
Despite the characterization of these disorders at the molecular level, the exact pathophysiologic mechanisms responsible for specific organ manifestations are not fully understood.3 Porphyrias are heterogeneous at the molecular level, with numerous mutations found for each gene. There is a significant interaction between specific inherited genetic defects and acquired or environmental factors that result in a spectrum of clinical manifestations in affected patients. Patients with gene mutations for the acute hepatic forms of porphyrias may remain asymptomatic unless they are exposed to certain medications (Table 5.1) or hormones or are stressed by starvation, infection, surgery, or other intercurrent disorders. Under these environmental circumstances, affected patients develop characteristic neurologic disturbances. Photocutaneous hypersensitivity and skin damage occurs after exposure to ultraviolet light. When porphyrins absorb light of this wavelength, they produce free radicals that can induce oxidant tissue damage. Consequently, avoidance of precipitating factors is key in the therapy of porphyrias.4
CLASSIFICATION AND CLINICAL MANIFESTATIONS
For clinical purposes, porphyrias can be classified into hepatic and erythropoietic types depending on the major tissue site of production and accumulation of the heme precursors. The major manifestations of the hepatic porphyrias are neurovisceral symptoms, including abdominal pain, neurologic symptoms, and psychiatric disorders, whereas the erythropoietic porphyrias usually present primarily with cutaneous photosensitivity and hemolytic anemia. Porphyrias can be also classified according to their clinical presentations into a) acute porphyrias presenting with life-threatening neurovisceral manifestations and b) nonacute (or cutaneous) porphyrias characterized by photosensitivity syndromes, but there can be some overlap in clinical manifestations. However, because the porphyrias are well characterized at the molecular genetic level, they are better specifically classified by their unique enzyme deficiencies.5,6
DIAGNOSIS
Many symptoms of the porphyrias are nonspecific, and diagnosis requires a high index of suspicion. However, although the porphyrias are often suspected in a patient with vague and unexplained complaints, actual diagnosis is rare. A useful first step is to determine which one of the three major manifestations of the porphyrias—neurovisceral symptoms, photosensitivity, or hemolytic anemia—is present.7,8
Neurovisceral symptoms are present in ALAD deficiency porphyria (ADP), AIP, hereditary coproporphyria (HCP), and variegate porphyria (VP).
Photosensitivity is present in congenital erythropoietic porphyria (CEP), PCT, hepatoerythropoietic porphyria (HEP), HCP, VP, erythropoietic protoporphyria (EPP), and XLDPP.
Neurovisceral symptoms and photosensitivity are present in HCP and VP.
Hemolytic anemia is present in CEP, HEP, and EPP.
Laboratory testing is then required to confirm or exclude the various types of porphyrias. The diagnosis is made initially by detection of the metabolite(s) produced and/or excreted in excess in red blood cells, plasma, urine, and/or feces.7 Porphyrin precursors in urine and total porphyrins in plasma are the initial diagnostic tests for acute and cutaneous porphyrias, respectively. Today the diagnosis of many of porphyrias can be confirmed by measuring the enzymatic activity in the appropriate tissue directly or by specific molecular genetic testing. Family screening is advisable to prevent acute attacks in presymptomatic stages, with DNA analysis for the identification of the mutations being the gold standard.
SPECIFIC TYPES OF PORPHYRIAS
X-linked dominant protoporphyria
This most recently described syndrome is the only porphyria not caused by enzyme deficiency but by gain-of-function deletions in ALAS2.9 ALAS2 gain of function leads to excessive production of protoporphyrin in red blood cells and leads to a clinical presentation similar to EPP. Patients in these eight families all had photosensitivity; five of them also had overt liver disease, but they did not have anemia. Supportive and preventive interventions for these patients are similar to those for erythropoietic porphyrias.
δ-Aminolevulinic Acid Dehydratase Deficiency Porphyria
ADP is an autosomal-recessive porphyria caused by markedly deficient activity of ALA dehydratase, the second enzyme in the heme biosynthetic pathway. The diagnosis has been unequivocally confirmed only in a few cases. Clinical manifestations are primarily neurovisceral and their treatment and prevention are the same as for other acute porphyrias. Lead poisoning should be excluded, because it also diminishes activity of ALA dehydratase, may present as a clinical phenocopy, and is far more common.
Acute Intermittent Porphyria
AIP is inherited as an autosomal dominant condition resulting from a partial deficiency of porphobilinogen deaminase (PBGD) activity, the third enzyme of the pathway. Approximately 90% of heterozygotes remain biochemically normal and clinically asymptomatic throughout life. Clinical expression of the disease is usually the result of exposure to factors such as endogenous and exogenous corticosteroid hormones, a low-calorie diet, certain drugs (barbiturates and sulfonamide antibiotics are the most commonly implicated), alcohol ingestion, and stresses such as intercurrent illnesses, infection, and surgery. Symptoms usually develop after puberty and are more frequent in women. The pathophysiologic hallmark of the disease is neurologic dysfunction affecting peripheral, autonomic, and/or central nervous systems occurring as intermittent acute attacks. The most common symptom is acute abdominal pain (in 90% of cases), which may be generalized or localized, but tenderness, fever, and leukocytosis are absent because the symptoms are neurologic in origin, from the visceral autonomic nervous system involvement. Gastrointestinal manifestations also include abdominal distention, nausea, vomiting, diarrhea, or constipation. Peripheral sensory or motor neuropathy is another common feature of AIP. Psychiatric symptoms including hysteria, anxiety, apathy, depression, phobia, psychosis, agitation, disorientation, hallucinations, and schizophrenic-type behaviors can be the only manifestations of the disease. Acute attacks may be accompanied by seizures, either a manifestation of the porphyria itself or caused by hyponatremia (from inappropriate secretion of antidiuretic hormone), which also commonly occur during attacks. Sympathetic hyperactivity results in tachycardia (in 80% of cases), hypertension, tremors, and sweating. Because of the nonspecific nature of symptoms and signs, the use of highly sensitive and specific laboratory tests is essential to the diagnosis.
During acute attacks, symptomatic treatment may include narcotic analgesics, phenothiazines, low-dose benzodiazepines, and propranolol for hypertension and tachycardia. Although intravenous glucose (at least 300 g/day) can be effective in acute attacks of porphyria, intravenous heme is now considered the treatment of choice to reduce excretion of porphyrins. Infusion of heme should be initiated as soon as possible after onset of an attack, but the rate of recovery depends on the degree of neuronal damage and may take days to months. Human heme solution stabilized with arginine (Normosang) is widely available except in the United States, where the lyophilized form (PanHaematin) is FDA approved.6 Any intercurrent infection or disease should also be treated immediately. Identification and avoidance of precipitating factors is also essential for prevention. Cyclical attacks in some women associated with fluctuations in estrogen and progestins can be prevented with a long-acting gonadotropin-releasing hormone analogue.
Congenital Erythropoietic Porphyria
CEP, an autosomal-recessive disorder also known as Gunther’s disease, is caused by deficient activity of uroporphyrinogen III cosynthase (the fourth enzyme of the pathway) and is associated with hemolytic anemia and cutaneous lesions. Severe cutaneous photosensitivity usually begins in early infancy as blistering of sun-exposed areas of the skin. Recurrent vesicles, bullae, and secondary infection can lead to cutaneous scarring and deformities. Porphyrin deposition may also occur in bones, leading to brownish discoloration of teeth. Protecting skin from sunlight is essential.
Mild to severe hemolytic anemia and secondary splenomegaly are features of CEP, and anemia can be severe. Transfusion is effective but results in iron overload if chronic. Splenectomy may reduce hemolysis and decrease the transfusion requirement. In transfusion-dependent children, allogeneic stem cell transplantation can be considered.
Porphyria Cutanea Tarda
PCT, the most common of the porphyrias, is caused by acquired or inherited deficiency of uroporphyrinogen decarboxylase (the fifth enzyme of the pathway). The disease occurs worldwide but its exact incidence is not known. The disease can be sporadic (noninherited or type I, most common) or familial (types II and III), although these subtypes are not distinguishable clinically. The frequency of disease varies in relation to risk factors such as alcohol use, smoking, and hepatitis C and human immunodeficiency virus (HIV) infection. The hallmark of PCT is cutaneous photosensitivity presenting as chronic blistering lesions on sun-exposed areas of skin without neurologic manifestations.8 Chronic changes including cutaneous thickening, scarring, and calcification can mimic systemic sclerosis. Also common are facial hypertrichosis and hyperpigmentation. PCT is almost always associated with abnormalities in liver function tests, and the risk of developing hepatocellular carcinoma is significantly increased in this disease.
Alcohol ingestion, estrogens, iron supplements and, if possible, any other drugs that may exacerbate the disease, and sun exposure should be avoided. A complete response can usually be achieved by repeated phlebotomy to reduce hepatic iron and is still considered standard treatment. Low-dose chloroquine or hydroxychloroquine are also effective, especially when phlebotomy is not indicated. Chloroquine slowly mobilizes the porphyrins from the liver and increases their excretion into the urine. In contrast, similar skin lesions in VP, HCP, CEP, and HEP are unresponsive to these therapeutic interventions.
Hepatoerythropoietic Porphyria
This rare form of porphyria has been recently described. HEP is clinically indistinguishable from CEP and is caused by homozygous or compound heterozygous defects of the same enzyme involved in PCT. Patients usually present after birth with dark urine in the diapers followed by severe photosensitivity with blistering skin lesions and scleroderma-like scarring. Hemolytic anemia is often present with splenomegaly. The avoidance of sunlight is essential.
Hereditary Coproporphyria
HCP is an autosomal dominant porphyria resulting from deficiency of coproporphyrinogen oxidase (the sixth enzyme of the pathway). The neurovisceral symptoms and other manifestations as well as the precipitating factors are virtually identical to those of AIP but photosensitivity similar to PCT may also occur in one-third of the patients. Avoidance of precipitating factors as in AIP is important. Neurologic symptoms are treated as in AIP but in contrast to PCT, phlebotomy or chloroquine is not effective for cutaneous lesions.
Variegate Porphyria
This hepatic porphyria, the result of a mutation of the protoporphyria oxidase gene (the seventh enzyme in the pathway), is transmitted as autosomal dominant disorder and is particularly common in South African whites (prevalence of 3 in 1,000) because of a genetic founder effect from a couple who emigrated from Holland to South Africa in the late 1600s. The disease was termed variegate because it can present with either neurovisceral symptoms, cutaneous photosensitivity, or both. Neurovisceral symptoms are very similar to those of AIP and are provoked by the same precipitates. Acute attacks are treated with glucose and heme infusion as in AIP. Occurrence of skin manifestations is usually separate from the neurovisceral symptoms, and avoiding sun exposure is the only effective preventative measure for cutaneous photosensitivity.
Erythropoietic Protoporphyria
EPP, also known as protoporphyria, results from deficiency of ferrochelatase activity, the last enzyme in the heme biosynthetic pathway. EPP is the most common erythropoietic porphyria and the third most common porphyria in general. Skin photosensitivity beginning in childhood is typical of the disease but the skin lesions are different from other porphyrias. Erythema, burning, and itching accompanied by swelling can develop within minutes of sun exposure, but sparse vesicles and bullae are seen in only a minority of the cases. Chronic skin changes may occur but severe scarring is rare. Treatment involves avoidance of sun exposure and the use of topical sun screens. Oral β-carotene (120 to 180 mg/day) can be effective in many patients with EPP, in contrast to those with photosensitivity from other forms of porphyria. The mechanism of action of β-carotene is not clear but is attributed to its antioxidant effect. In some patients, accumulation of protoporphyrin causes chronic liver disease that can progress to hepatic failure and death. Neurovisceral symptoms are seen only in patients with severe hepatic complications. Protoporphyrin-rich gallstones may occur. Mild anemia is sometimes seen in patients with EPP, but hemolysis is either infrequent or very mild. Splenectomy may be helpful when the disease is accompanied by hemolysis and significant splenomegaly. Caloric restriction, drugs, and exogenous sex hormones should be avoided. Intravenous heme therapy is sometimes beneficial. Liver transplantation has been performed but the protoporphyrin-induced damage can recur in the donor liver.10
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