The Porphyrias

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Chapter 85 The Porphyrias

Porphyrias are metabolic diseases resulting from altered activities of specific enzymes of the heme biosynthetic pathway. These enzymes are most active in bone marrow and liver. Erythropoietic porphyrias, in which overproduction of heme pathway intermediates occurs primarily in bone marrow erythroid cells, usually present at birth or in early childhood with cutaneous photosensitivity, or in the case of congenital erythropoietic porphyria, even in utero as nonimmune hydrops. Most porphyrias are hepatic, with overproduction and initial accumulation of porphyrin precursors or porphyrins occurring 1st in the liver. Regulatory mechanisms for heme biosynthesis in liver are distinct from those in the bone marrow and appear to account for activation of hepatic porphyrias during adult life rather than childhood. Homozygous forms of the hepatic porphyrias may manifest clinically prior to puberty, and asymptomatic heterozygous children may present with nonspecific and unrelated symptoms. Parents often request advice about long-term prognosis and information about management of these disorders and drugs that can be taken safely to treat other common conditions.

The DNA sequences and chromosomal locations are established for the human genes of the enzymes in this pathway, and multiple disease-related mutations have been found for each porphyria. The inherited porphyrias display autosomal dominant or recessive inheritance, and recently an X-linked form of erythropoietic porphyria has been identified. Although initial diagnosis of porphyria by biochemical methods remains essential, it is especially important in children to confirm the diagnosis by demonstrating a specific gene mutation(s).

The Heme Biosynthetic Pathway

Heme is required for a variety of hemoproteins such as hemoglobin, myoglobin, respiratory cytochromes, and cytochrome P450 enzymes (CYPs). It is believed that the 8 enzymes in the pathway for heme biosynthesis are active in all tissues. Hemoglobin synthesis in erythroid precursor cells accounts for about 85% of daily heme synthesis in humans. Hepatocytes account for most of the rest, primarily for synthesis of CYPs, which are especially abundant in the liver endoplasmic reticulum (ER), and turn over more rapidly than many other hemoproteins, such as the mitochondrial respiratory cytochromes. As shown in Figure 85-1, pathway intermediates are the porphyrin precursors δ-aminolevulinic acid (ALA, also known as 5-aminolevulinic acid) and porphobilinogen (PBG), and porphyrins (mostly in their reduced forms, known as porphyrinogens). At least in humans, these intermediates do not accumulate in significant amounts under normal conditions or have important physiologic functions.

A deficiency of each enzyme in the pathway is associated with a specific porphyria (Table 85-1). The 1st enzyme, ALA synthase (ALAS), occurs in 2 forms. An erythroid specific form, termed ALAS2, is deficient in X-linked sideroblastic anemia, due to mutations of the ALAS2 gene on chromosome Xp11.2. Gain of function mutations of ALAS2 due to deletions in the last exon have been found in a variant form of erythropoietic protoporphyria (EPP). The housekeeping or ubiquitous form of this enzyme, termed ALAS1, is found in all tissues including liver, and its gene is located on chromosome 3p21.1. Disease-related mutations of ALAS1 have not been described.

Regulation of heme synthesis differs in the 2 major heme-forming tissues. Liver heme biosynthesis is primary controlled by ALAS1. Synthesis of ALAS1 in liver is regulated by a “free” heme pool (see Fig. 85-1), which can be augmented by newly synthesized heme or by existing heme released from hemoproteins and destined for breakdown to biliverdin by heme oxygenase.

In the erythron, novel regulatory mechanisms allow for the production of the very large amounts of heme needed for hemoglobin synthesis. The response to stimuli for hemoglobin synthesis occurs during cell differentiation, leading to an increase in cell number. Also, unlike the liver, heme has a stimulatory role in hemoglobin formation, and the stimulation of heme synthesis in erythroid cells is accompanied by increases not only in ALAS2, but also by sequential induction of other heme biosynthetic enzymes. Separate erythroid-specific and nonerythroid or “housekeeping” transcripts are known for the 1st 4 enzymes in the pathway. The separate forms of ALAS are encoded by genes on different chromosomes, but for each of the other 3, erythroid and nonerythroid transcripts are transcribed by alternative promoters in the same gene. Heme also regulates the rate of its synthesis in erythroid cells by controlling the transport of iron into reticulocytes.

Intermediates of the heme biosynthetic pathway are efficiently converted to heme and, normally, only small amounts of the intermediates are excreted. Some may undergo chemical modifications before excretion. Whereas the porphyrin precursors ALA and PBG are colorless, nonfluorescent, and largely excreted unchanged in urine, PBG may degrade to colored products such as the brownish pigment called porphobilin or spontaneously polymerize to uroporphyrins. Porphyrins are red in color and display bright red fluorescence when exposed to long wavelength ultraviolet light. Porphyrinogens, which are colorless and nonfluorescent, are the reduced form of porphyrins, and when they accumulate are readily autoxidized to the corresponding porphyrins when outside the cell. Only the type III isomers of uroporphyrinogen and coproporphyrinogen are converted to heme (see Fig. 85-1).

ALA and PBG are excreted in urine. Excretion of porphyrins and porphyrinogens in urine or bile is determined by the number of carboxyl groups. Those with many carboxyl groups, such as uroporphyrin (octacarboxyl porphyrin) and heptacarboxyl porphyrin, are water soluble and readily excreted in urine. Those with fewer carboxyl groups, such as protoporphyrin (dicarboxyl porphyrin), are not water soluble and are excreted in bile and feces. Coproporphyrin (tetracarboxyl porphyrin) is excreted partly in urine and partly in bile. Because coproporphyrin I is more readily excreted in bile than is coproporphyrin III, impaired hepatobiliary function may increase total coproporphyrin excretion and the ratio of these isomers.

Classification and Diagnosis of Porphyrias

Two classification schemes reflect either the underlying pathophysiology or clinical features, and both are useful for diagnosis and treatment (see Table 85-1). In hepatic and erythropoietic porphyrias, the source of excess production of porphyrin precursors and porphyrins is the liver and bone marrow, respectively. Acute porphyrias cause neurologic symptoms that are associated with increases of 1 or both of the porphyrin precursors ALA and PBG. In the cutaneous porphyrias, photosensitivity results from transport of porphyrins in blood from the liver or bone marrow to the skin. Dual porphyria refers to the very rare cases of porphyria with deficiencies of 2 different heme pathway enzymes.

It is notable that acute intermittent porphyria (AIP), porphyria cutanea tarda (PCT), and erythropoietic protoporphyria (EPP), the 3 most common porphyrias, are very different in clinical presentation, precipitating factors, methods of diagnosis, and effective therapy (Table 85-2). Two of the 4 acute porphyrias, hereditary coproporphyria (HCP) and variegate porphyria (VP), can also cause lesions indistinguishable from PCT (see Table 85-1). Congenital erythropoietic porphyria (CEP) causes more severe blistering lesions, often with secondary infection and mutilation. EPP is distinct from the other cutaneous porphyrias in causing nonblistering photosensitivity that occurs acutely after sun exposure. EPP is also the most common porphyria to become manifest before puberty.

First-Line Laboratory Diagnostic Testing

A few sensitive and specific first-line laboratory tests should be obtained whenever symptoms or signs suggest the diagnosis of porphyria. If a first-line or screening test is significantly abnormal, more comprehensive testing should follow to establish the type of porphyria. Overuse of laboratory tests for screening can lead to unnecessary expense and even delay in diagnosis. In patients who present with a past diagnosis of porphyria, laboratory reports that were the basis for the original diagnosis must be reviewed, and if these were inadequate, further testing considered.

Acute porphyria should be suspected in patients with neurovisceral symptoms such as abdominal pain after puberty, when initial clinical evaluation does not suggest another cause, and urinary porphyrin precursors (ALA and PBG) should be measured. Urinary PBG is virtually always increased during acute attacks of AIP, HCP, and VP, and is not substantially increased in any other medical conditions. Therefore, this measurement is both sensitive and specific. A method for rapid, in-house testing for urinary PBG, such as the Trace PBG kit (Thermo Scientific, 1-800-640-0640), should be available in-house at all major medical facilities. Results from spot (single void) urine specimens are highly informative because very substantial increases are expected during acute attacks of porphyria. A 24 hr collection can unnecessarily delay diagnosis. The same spot urine specimen should be saved for quantitative determination of ALA and PBG, in order to confirm the qualitative PBG result, and also detect patients with ALA dehydratase porphyria. Urinary porphyrins may remain increased longer than porphyrin precursors in HCP and VP. Therefore, it is useful to measure total urinary porphyrins in the same sample, keeping in mind that urinary porphyrin increases are often nonspecific. Measurement of urinary porphyrins alone should be avoided for screening, because these are often increased in many disorders other than porphyrias, such as chronic liver disease, and misdiagnoses of porphyria can result from minimal increases in urinary porphyrins that have no diagnostic significance.

PBG is a colorless pyrrole that forms a violet pigment with Ehrlich reagent (p-dimethylaminobenzaldehyde). Other substances, principally urobilinogen, also react with Ehrlich aldehyde. A reliable quantitative method for both ALA and PBG, which uses small anion and cation exchange columns to separate interfering substances before adding Ehrlich reagent, has been available for many years. ALA is reacted to form a pyrrole, which is then also measured using Ehrlich reagent. The Trace PBG kit to detect increased PBG is based on this method.

δ-Aminolevulinic Acid Dehydratase Porphyria (ADP)

This porphyria is sometimes termed Doss porphyria after the investigator who described the 1st cases. The term plumboporphyria emphasizes the similarity of this condition to lead poisoning, but incorrectly implies that it is due to lead exposure.

Pathology and Pathogenesis

ALAD catalyzes the condensation of 2 molecules of ALA to form the pyrrole PBG (see Fig. 85-1). The enzyme is subject to inhibition by a number of exogenous and endogenous chemicals. ALAD is the principal lead-binding protein in erythrocytes, and lead can displace the zinc atoms of the enzyme. Inhibition of erythrocyte ALAD activity is a sensitive index of lead exposure.

To date, all ADP cases inherited a different ALAD mutation from each parent. Eleven abnormal ALAD alleles, most with point mutations, have been identified, some expressing partial activity, such that heme synthesis is partially preserved. The amount of residual enzyme activity may predict the phenotypic severity of this disease. Immunochemical studies in 3 cases demonstrated nonfunctional enzyme protein that cross-reacted with anti-ALAD antibodies. One late-onset case was associated with a myeloproliferative disorder and expansion of an affected clone of erythroid cells.

ADP is often classified as a hepatic porphyria, although the site of overproduction of ALA is not established. A patient with severe, early-onset disease underwent liver transplantation, without significant clinical or biochemical improvement, which might suggest that the excess intermediates did not originate in the liver. Excess urinary coproporphyrin III in ADP might originate from metabolism of ALA to porphyrinogens in a tissue other than the site of ALA overproduction. Administration of large doses of ALA to normal subjects also leads to substantial coproporphyrinuria. Increased erythrocyte protoporphyrin may, as in all other homozygous porphyrias, be explained by accumulation of earlier pathway intermediates in bone marrow erythroid cells during hemoglobin synthesis, followed by their transformation to protoporphyrin after hemoglobin synthesis is complete. The pathogenesis of the neurologic symptoms is poorly understood.

Acute Intermittent Porphyria (AIP)

This disorder is also termed pyrroloporphyria, Swedish porphyria, and intermittent acute porphyria and is the most common type of acute porphyria in most countries.

Etiology

AIP results from the deficient activity of the housekeeping form of PBG deaminase (PBGD). This enzyme is also known as hydroxymethylbilane (HMB) synthase; the prior term uroporphyrinogen I synthase is obsolete. PBGD catalyzes the deamination and head-to-tail condensation of 4 PBG molecules to form the linear tetrapyrrole, HMB (also known as preuroporphyrinogen; see Fig. 85-1). A unique dipyrromethane cofactor binds the pyrrole intermediates at the catalytic site until 6 pyrroles (including the dipyrrole cofactor) are assembled in a linear fashion, after which the tetrapyrrole HMB is released. The apo-deaminase generates the dipyrrole cofactor to form the holo-deaminase, and this occurs more readily from HMB than from PBG. Indeed, high concentrations of PBG may inhibit formation of the holo-deaminase. The product HMB can cyclize nonenzymatically to form nonphysiologic uroporphyrinogen I, but in the presence of the next enzyme in the pathway is more rapidly cyclized to form uroporphyrinogen III.

Erythroid and housekeeping forms of the enzyme are encoded by a single gene on human chromosome 11 (11q24.1→q24.2), which contains 15 exons. The 2 isoenzymes are both monomeric proteins and differ only slightly in molecular weight (approximately 40 and 42 kd, respectively), and result from alternative splicing of 2 distinct mRNA transcripts arising from 2 promoters. The housekeeping promoter functions in all cell types, including erythroid cells.

The pattern of inheritance of AIP is autosomal dominant, with very rare homozygous cases that present in childhood. More than 300 PBGD mutations, including missense, nonsense, and splicing mutations and insertions and deletions have been identified in AIP, and in many population groups, including blacks. Most mutations are found in only 1 or a few families. But due to founder effects, some are more common in certain geographic areas such as northern Sweden (W198X), Holland (R116W), Argentina (G116R), Nova Scotia (R173W), and Switzerland (W283X). De novo mutations may be found in about 3% of cases. Chester porphyria was initially described as a variant form of acute porphyria in a large English family but was found to be due to a PBGD mutation. The nature of the PBGD mutation does not account for the severity of the clinical presentation, which varies markedly within families.

Most mutations lead to approximately half-normal activity of the housekeeping and erythroid isozymes and half-normal amounts of their respective enzyme proteins in all tissues of heterozygotes. In approximately 5% of unrelated AIP patients, the housekeeping isozyme is deficient, but the erythroid-specific isozyme is normal. Mutations causing this variant are usually found within exon 1 or its 5′ splice donor site or initiation of translation codon. Immunochemical methods can distinguish mutations that are CRIM-positive (i.e., having excess cross-reactive immunologic material [CRIM] relative to the mutant enzyme activity), whereas CRIM-negative mutations either do not synthesize a mutant enzyme protein, or the protein is not stable and not immunologically detectable using anti-PBGD antibodies. A child with homozygous AIP was found to have inherited a different CRIM-positive mutation from each parent.

Pathology and Pathogenesis

Induction of the rate-limiting hepatic enzyme ALAS1 is thought to underlie acute exacerbations of this and the other acute porphyrias. AIP remains latent (or asymptomatic) in the great majority of those who are heterozygous carriers of PBGD mutations, and this is almost always the case before puberty. In those with no history of acute symptoms, porphyrin precursor excretion is usually normal, suggesting that half-normal hepatic PBGD activity is sufficient and hepatic ALAS1 activity is not increased. Many nongenetic factors that lead to clinical expression of AIP, including certain drugs and steroid hormones, have the capacity to induce hepatic ALAS1 and CYPs. Under conditions in which heme synthesis is increased in the liver, half-normal PBGD activity may become limiting and ALA, PBG, and other heme pathway intermediates may accumulate. In addition, heme synthesis becomes impaired and heme-mediated repression of hepatic ALAS1 is less effective.

It is not proven, however, that hepatic PBGD remains constant at about 50% of normal activity during exacerbations and remission of AIP, as in erythrocytes. An early report suggested that the enzyme activity is considerably less than half-normal in the liver during an acute attack. Hepatic PBGD activity might be reduced further once AIP becomes activated if, as suggested, excess PBG interferes with assembly of the dipyrromethane cofactor for this enzyme. It also seems likely that currently unknown genetic factors play a contributing role in, for example, patients who continue to have attacks even when known precipitants are avoided.

The fact that AIP is almost always latent before puberty suggests that endocrine factors, and especially adult levels of steroid hormones, are important for clinical expression. Symptoms are more common in women suggesting a role for female hormones. Premenstrual attacks are probably due to endogenous progesterone. Acute porphyrias are sometimes exacerbated by exogenous steroids, including oral contraceptive preparations containing progestins. Surprisingly, pregnancy is usually well tolerated, suggesting that beneficial metabolic changes may ameliorate the effects of high levels of progesterone.

Drugs that are unsafe in acute porphyrias (Table 85-3) include those having the capacity to induce hepatic ALAS1, which is closely associated with induction of CYPs. Some chemicals (e.g., griseofulvin) can increase heme turnover by promoting the destruction of specific CYPs to form an inhibitor (e.g., N-methyl protoporphyrin) of ferrochelatase (FECH, the final enzyme in the pathway). Sulfonamide antibiotics are harmful but apparently not inducers of hepatic heme synthesis. Ethanol and other alcohols are inducers of ALAS1 and some CYPs.

Table 85-3 DRUGS REGARDED AS UNSAFE AND SAFE IN ACUTE PORPHYRIAS

UNSAFE SAFE
Barbiturates Narcotic analgesics
Sulfonamide antibiotics* Aspirin
Meprobamate* (also mebutamate,* tybutamate*) Acetaminophen
Carisoprodol* Phenothiazines
Glutethimide* Penicillin and derivatives
Methyprylon Streptomycin
Ethchlorvynol* Glucocorticoids
Mephenytoin Bromides
Phenytoin* Insulin
Succinimides Atropine
Carbamazepine* Cimetidine
Clonazepam Ranitidine
Primidone* Acetaminophen (paracetamol)
Valproic acid* Acetazolamide
Pyrazolones (aminopyrine, antipyrine) Allopurinol
Griseofulvin* Amiloride
Ergots Bethanidine
Metoclopramide* Bumetanide
Rifampin* Cimetidine
Pyrazinamide* Coumarins
Diclofenac* Fluoxetine
Progesterone and synthetic progestins* Gabapentin
Danazol* Gentamicin
Alcohol Guanethidine
ACE inhibitors (especially enalapril) Ofloxacin
Calcium channel blockers (especially nifedipine) Propranolol
Ketoconazole Succinylcholine
Rifampin Tetracycline

This partial listing does not include all available information about drug safety in acute porphyrias. Other sources should be consulted for drugs not listed here.

* Porphyria is listed as a contraindication, warning, precaution, or adverse effect in U.S. labeling for these drugs. Estrogens are also listed as harmful in porphyria, but have been implicated as harmful in acute porphyrias mostly based only on experience with estrogen-progestin combinations. While estrogens can exacerbate PCT, there is little evidence they are harmful in the acute porphyrias.

Porphyria is listed as a precaution in U.S. labeling for this drug. However, this drug is regarded as safe by other sources.

Nutritional factors, principally reduced intake of calories and carbohydrates, as may occur with illness or attempts to lose weight, can increase porphyrin precursor excretion and induce attacks of porphyria. Increased carbohydrate intake may ameliorate attacks. Hepatic ALAS1 is modulated by the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), which is an important link between nutritional status and exacerbations of acute porphyria.

Other factors have been implicated. Chemicals in cigarette smoke, such as polycyclic aromatic hydrocarbons, can induce hepatic CYPs and heme synthesis. A survey of AIP patients found an association between smoking and repeated porphyric attacks. Attacks may result from metabolic stress and impaired nutrition associated with major illness, infection, or surgery.

The additive effect of multiple predisposing factors, including drugs, endogenous hormones, nutritional factors, and smoking, is suggested by clinical observations. Exposure to drugs and other precipitating factors is less likely to cause an attack in patients who have had no recent symptoms than in those with recent and frequent porphyric symptoms.

Clinical Manifestations

Neurovisceral manifestations of acute porphyrias may appear any time after puberty, but rarely before. Very rare cases of homozygous AIP develop severe neurologic manifestations early in childhood.

In affected heterozygotes, acute attacks are characterized by a constellation of nonspecific symptoms, which may become severe and life-threatening. Abdominal pain occurs in 85-95% of cases, is usually severe, steady, and poorly localized, but sometimes cramping, and accompanied by signs of ileus, including abdominal distention and decreased bowel sounds. Nausea, vomiting, and constipation are common, and increased bowel sounds and diarrhea may occur. Bladder dysfunction may cause hesitancy and dysuria. Tachycardia, the most common physical sign, occurs in up to 80% of attacks. This is often accompanied by hypertension, restlessness, coarse or fine tremors, and excess sweating, which are attributed to sympathetic overactivity and increased catecholamines. Other common manifestations include mental symptoms; pain in the extremities, head, neck, or chest; muscle weakness; and sensory loss. Because all these manifestations are neurologic rather than inflammatory, there is little or no abdominal tenderness, fever, or leukocytosis.

Porphyric neuropathy is primarily motor and appears to result from axonal degeneration rather than demyelinization. Sensory involvement is indicated by pain in the extremities, which may be described as muscle or bone pain, and by numbness, paresthesias, and dysesthesias. Paresis may occur early in an attack, but is more often a late manifestation in an attack that is not recognized and adequately treated. Rarely, severe neuropathy develops when there is little or no abdominal pain. Motor weakness most commonly begins in the proximal muscles of the upper extremities and then progresses to the lower extremities and the periphery. It is usually symmetric, but occasionally asymmetric or focal. Initially, tendon reflexes may be little affected or hyperactive and become decreased or absent. Cranial nerves, most commonly X and VII, may be affected, and blindness from involvement of the optic nerves or occipital lobes has been reported. More common central nervous system manifestations include seizures, anxiety, insomnia, depression, disorientation, hallucinations, and paranoia. Seizures may result from hyponatremia, porphyria itself, or an unrelated cause. Chronic depression and other mental symptoms occur in some patients, but attribution to porphyria is often difficult.

Hyponatremia is common during acute attacks. Inappropriate antidiuretic hormone (ADH) secretion is often the most likely mechanism, but salt depletion from excess renal sodium loss, gastrointestinal loss, and poor intake have been suggested as causes of hyponatremia in some patients. Unexplained reductions in total blood and red blood cell volumes are sometimes found, and increased ADH secretion might then be an appropriate physiologic response. Other electrolyte abnormalities may include hypomagnesemia and hypercalcemia.

The attack usually resolves quite rapidly, unless treatment is delayed. Abdominal pain may resolve within a few hours and paresis within a few days. Even severe motor neuropathy can improve over months or several years, but may leave some residual weakness. Progression of neuropathy to respiratory and bulbar paralysis and death is uncommon with appropriate treatment and removal of harmful drugs. Sudden death may result from cardiac arrhythmia.

Laboratory Findings

Levels of ALA and PBG are substantially increased during acute attacks and these may decrease after an attack but usually remain increased unless the disease becomes asymptomatic for a prolonged period. A population-based study in Sweden indicated that symptoms suggestive of porphyria may occur in heterozygotes during childhood, in contrast to adults, even when urinary porphyria precursors are not elevated. This study lacked a comparison with the frequency of such nonspecific symptoms in a control group of children.

Porphyrins are also markedly increased, which accounts for reddish urine in AIP. These are predominantly uroporphyrins, which can form nonenzymatically from PBG. But because the increased urinary porphyrins in AIP are predominantly isomer III, their formation is likely to be largely enzymatic, which might occur if excess ALA produced in the liver enters cells in other tissues and is then converted to porphyrins via the heme biosynthetic pathway. Porphobilin, a degradation product of PBG, and dipyrrylmethenes appear to account for brownish urinary discoloration. Total fecal porphyrins and plasma porphyrins are normal or slightly increased in AIP. Erythrocyte protoporphyrin may be somewhat increased in patients with manifest AIP.

Erythrocyte PBGD activity is approximately half-normal in most patients (70-80%) with AIP. The normal range is wide and overlaps with the range for AIP heterozygotes. As noted, some PBGD gene mutations cause the enzyme to be deficient only in nonerythroid tissues. PBGD activity is also highly dependent on erythrocyte age, and an increase in erythropoiesis due to concurrent illness in an AIP patient may raise the activity into the normal range.

Diagnosis and Differential Diagnosis

An increased urinary PBG establishes that a patient has 1 of the 3 most common acute porphyrias (see Table 85-2). Measuring PBG in serum is preferred when there is coexistent severe renal disease but is less sensitive when renal function is normal. Measurement of urinary ALA is less sensitive than PBG and also less specific but will detect ADP, the fourth type of acute porphyria. Erythrocyte PBGD activity is decreased in most AIP patients and helps confirm the diagnosis in a patient with high PBG. A normal enzyme activity in erythrocytes does not exclude AIP.

Knowledge of the PBGD mutation in a family enables reliable identification of other gene carriers. PBGD deficiency can be documented in a fetus by measuring the enzyme activity in amniotic fluid cells, or more reliably by finding a PBGD mutation in these cells.

Treatment

Hemin

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