دزآزما

Description

• Group of      seven predominantly inherited metabolic disorders, caused by deficiencies      of enzymes of the heme biosynthetic pathway
• Symptoms      result from accumulation of precursors in heme biosynthesis
• Clinically      characterized by cutaneous and/or acute neuropsychiatric symptoms; such as      severe abdominal pain
• Cutaneous      porphyrias affect the skin causing cutaneous photosensitivity, which can      be severe
• Acute      neuropsychiatric porphyrias affect the nervous system and can be      life-threatening, but attacks can be aborted by early administration of      hemin
• Latency      is common, and some carriers only become symptomatic after exposure to      precipitating factors such as alcohol or certain drugs
• When a patient is diagnosed with porphyria, the whole family must be screened so that precipitating factors can be avoided in anyone found to be a carrier

Synonyms

• Delta-aminolevulinic      aciduria
• ALAD      porphyria
• Swedish      porphyria
• Pyrroloporphyria
• Intermittent      acute porphyria
• Gunther      disease
• Porphyria      variegata
• South      African porphyria
• Protocoproporphyria
• Royal      malady
• Protoporphyria
• Erythrohepatic      protoporphyria
• Toxic      porphyria

Immediate action

• Acute      symptoms may need immediate hospitalization
• If an      elevated urine porphobilinogen is detected, send a 24-h specimen for      quantitation and additional tests
• Intravenous      glucose for mild acute porphyria is appropriate; intravenous hemin therapy      should be instituted soon after and as soon as it is available

Key points

• A group      of metabolic disorders that present with gastrointestinal,      neuropsychiatric, and skin symptoms; can be divided into acute and      non-acute porphyrias
• Diagnosis      of acute neuropsychiatric porphyrias is supported by the finding of      elevated urine porphobilinogen on a single void urine specimen
• Intravenous      hemin treatment is the therapy of choice for acute neuropsychiatric      porphyrias along with glucose, intravenous fluids, and elimination of any      precipitating factors

Background

Cardinal features

• A group      of inherited metabolic disorders that are caused by a partial or nearly      complete deficiency of enzymes of the heme biosynthetic pathway
• Symptoms      result from accumulation of precursors in heme biosynthesis
• Seven      different kinds of porphyria have been distinguished, representing      discrete deficiencies of each of the seven enzymes beyond the first and      rate-limiting step of the pathway
• Dysfunction      of each specific enzyme causes a unique pattern of abnormally elevated      levels of porphyrins and/or their precursors to accumulate in tissues, and      to be excreted in urine and stool
• Clinical      presentation depends on associated enzyme and mode of inheritance, and is      often influenced by metabolic and environmental factors
• Clinically      characterized by cutaneous or acute neuropsychiatric symptoms and      syndromes, or both
• Cutaneous      manifestation is typically cutaneous photosensitivity, which can be severe
• Acute      neuropsychiatric manifestations are most typically abdominal pain,      constipation, dysesthesia, muscular paralysis, and respiratory failure      (which can be fatal); attacks can be aborted by early administration of      hemin
• Latency      is common and there can be asymptomatic or minimally symptomatic carriers
• Some      carriers only become symptomatic after exposure to an additional agent or      factor capable of inducing disease expression

Classification (from most to least common type):

• Porphyria      cutanea tarda (includes hepatoerythropoietic porphyria, a very rare type      of porphyria associated with hemolytic anemia)
• Acute      intermittent porphyria
• Erythropoietic      protoporphyria
• Variegate      porphyria
• Hereditary      coproporphyria
• Congenital      erythropoietic porphyria
• Aminolevulinic      acid dehydratase deficiency

Can also be categorized as:

• Hepatic      porphyrias (delta-aminolevulinic acid dehydratase deficiency porphyria,      acute intermittent porphyria, variegate porphyria, hereditary      coproporphyria, porphyria cutanea tarda), in which the excess porphyrin      production occurs in the liver
• Erythropoietic      porphyrias (erythropoietic protoporphyria, congenital erythropoietic      porphyria), in which excess porphyrin production occurs in the bone marrow

Can also be categorized as:

• Acute      porphyrias (delta-aminolevulinic acid dehydratase deficiency porphyria, acute      intermittent porphyria, variegate porphyria, hereditary coproporphyria),      which typically cause neuropsychiatric problems, often manifesting as a      severe abdominal pain and are associated with excess production and      excretion in urine of porphobilinogen and delta-aminolevulinic acid
• Nonacute      porphyrias (porphyria cutanea tarda, congenital erythropoietic porphyria,      erythropoietic protoporphyria), in which porphobilinogen and      delta-aminolevulinic acid are not produced in excess

Can also be categorized according to their mode of inheritance:

• Autosomal      dominant (acute intermittent porphyria, variegate porphyria, hereditary      coproporphyria, porphyria cutanea tarda (20% of cases are autosomal      dominant), erythropoietic protoporphyria)
• Autosomal      recessive (delta-aminolevulinic acid dehydratase deficiency porphyria,      congenital erythropoietic porphyria)

Causes

Common causes

The inherited mutant gene encodes the specific enzyme deficiency (in order of sequence of enzymes in the heme biosynthetic pathway):

• Delta-aminolevulinic      acid dehydratase deficiency causes delta-aminolevulinic acid dehydratase      deficiency porphyria
• Porphobilinogen      deaminase deficiency causes acute intermittent porphyria
• Uroporphyrinogen      III synthase deficiency causes congenital erythropoietic porphyria
• Uroporphyrinogen      decarboxylase deficiency (UROD) causes the familial type (approx. 20% of      cases) and sporadic type (80%) of porphyria cutanea tarda
• Coproporphyrinogen      oxidase deficiency causes hereditary coproporphyria
• Protoporphyrinogen      oxidase deficiency causes variegate porphyria
• Ferrochelatase      deficiency causes erythropoietic protoporphyria

The two autosomal recessive porphyrias, congenital erythropoietic porphyria and delta-aminolevulinic acid dehydratase deficiency porphyria are very rare; for each there is little or no production of normal enzyme.

The other five porphyrias are mainly inherited in an autosomal dominant manner, although more complex patterns of inheritance are possible.

• Signature      feature for each is low clinical penetrance
• Inheritance      of one copy of a mutant gene decreases enzyme activity by 50%, which is      sufficient for normal cellular metabolism
• Clinical      presentation requires additional factors (genetic or environmental) that      affect the heme pathway
• These      factors either increase the normal demand for heme production, cause a      decrease in enzyme activity, or are a combination of these effects

Porphyria cutanea tarda

Further variation is seen in porphyria cutanea tarda, the most common porphyria worldwide, and many risk factors precipitate the disease.

There are three clinically indistinguishable subtypes:

Type 1 (sporadic, no family history of porphyria) accounts for 80% of cases. UROD activity is inhibited (inactivated) only in the liver. Although sporadic cases do not have mutation in the UROD gene, there is association with mutations in the hemochromatosis (HFE) gene and other, as yet unknown, genetic causes. The disease is precipitated by various risk factors:

• Hepatitis      C infection
• Alcohol
• Oral      estrogens
• Hexachlorobenzene      and tetrachloridibenzo-p-dioxin
• Hepatic      tumors

Type 2 (familial, autosomal dominant) accounts for 20% of cases, and is caused by inherited mutations in the UROD gene.

• Distinguished      from sporadic cases by measuring erythrocyte UROD activity or by molecular      analysis
• Coinheritance      of UROD mutation and either homozygous or heterozygous HFE C282Y and H63D      mutations result in earlier onset of symptoms
• Manifestation      of disease requires precipitating factors, such as chronic exposure to      alcohol, hepatotropic viruses, excess iron intake or storage, and oral      estrogen use
• Additional      modifying genetic loci are implicated in the disease process

Type 3 (familial, very rare), results from other inherited mutations in the UROD gene.

Contributory or predisposing factors

All porphyrias:

• Liver      disease
• Hepatitis      C
• Infection
• Heavy      alcohol use
• Major      surgery

Acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, delta-aminolevulinic acid dehydratase deficiency porphyria:

• Drugs:      estrogen and progesterone from contraception and hormone replacement      therapies (although may be beneficial in some patients in prevention of      cyclic menstrual attacks); danazol; griseofulvin; rifampin, sulfonamides,      chloramphenicol and primidone; diclofenac; phenobarbital, carbamazepine,      valproic acid, clonazepam, chlordiazepoxide and meprobamate; imipramine;      chlorpropamide and metoclopramide; methyldopa and glutethimide;      ergotamine; pyrazinamide; carisoprodol; ethchlorvynol; and pentazocine,      mephenytoin, succinimides, and pyrazolones
• Steroids:      endogenous steroid hormones, sex steroid preparations
• Menstrual      cycle: in presence of high levels of progesterone
• Pregnancy
• Fasting
• Emotional      and physical stress
• Substance      abuse: particularly marijuana, ecstasy, amphetamines, and cocaine
• Tobacco

Porphyria cutanea tarda:

• Drugs:      nonsteroidal anti-inflammatory drugs, sulfonylureas, busulfan
• Estrogens,      especially from oral contraceptives
• Iron      supplements

Epidemiology

Incidence and prevalence

Prevalence

• Porphyria      cutanea tarda: 10 cases per 100,000 of population, including both      inherited and sporadic types
• Acute      intermittent porphyria, erythropoietic protoporphyria, variegate      porphyria: 1-10 cases per 100,000 of population
• Hereditary      coproporphyria: <1 case per 100,000 of population
• Delta-aminolevulinic      acid dehydratase deficiency porphyria, congenital erythropoietic      porphyria: very rare

Demographics

Age

• Congenital      erythropoietic porphyria: early childhood
• Erythropoietic      protoporphyria: older childhood
• Acute      intermittent porphyria, variegate porphyria, hereditary coproporphyria,      delta-aminolevulinic acid dehydratase deficiency porphyria: young adult
• Porphyria      cutanea tarda: typically after the fourth decade

Gender

• Erythropoietic      protoporphyria, congenital erythropoietic porphyria: males and females      equally affected
• Porphyria      cutanea tarda: generally more common in males; however, female incidence      is increasing in association with oral contraceptive and alcohol use
• Acute      intermittent porphyria, variegate porphyria, hereditary coproporphyria,      delta-aminolevulinic acid dehydratase deficiency porphyria: more common in      females

Race

More common in Caucasians than African-Americans or Asians.

Genetics

• The      seven porphyrias form a group of inherited metabolic disorders, with the      most common being porphyria cutanea tarda
• The      majority (80%) of patients have the sporadic (type 1) form of porphyria      cutanea tarda, in which UROD deficiency is restricted to the liver
• Familial      (type 2) porphyria cutanea tarda accounts for approx. 20%, and may be      distinguished from the sporadic cases by measuring erythrocyte UROD      activity or by molecular analysis of the UROD gene
• Four      additional porphyrias (acute intermittent porphyria, variegate porphyria,      hereditary coproporphyria, and erythropoietic protoporphyria) are mainly      inherited in an autosomal dominant manner, although more complex patterns      of inheritance are seen in some families
• The two      autosomal recessive porphyrias, congenital erythropoietic porphyria and      delta-aminolevulinic acid dehydratase deficiency porphyria, are very rare

A number of disease-specific mutations have been identified in each of the genes that encode the enzymes that are deficient in the porphyrias.

• Gene      testing identifies mutations in 90% or more of affected individuals with      the various inherited forms of porphyria
• Additional      modifier genes, such as the HFE gene for hemochromatosis, are associated      with some forms of porphyria, in particular porphyria cutanea tarda

Family screening and genetic counseling are important aspects of management for each of the porphyrias, and requires referral to a genetic specialist.

Geography

Variegate porphyria has a substantially higher incidence in South Africa of 3 per 1000; most cases have been traced to a single union between two Dutch settlers in 1680.

Codes

ICD-9 code

277.1 Disorders of porphyrin metabolism