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The acute porphyrias are comprised of four disorders caused by different enzyme deficiencies, and are distinctive for neurologic symptoms that usually occur as acute exacerbations during adult life. Similar symptoms occur in lead poisoning, hereditary tyrosinemia type I, and in some reported cases of porphyria with dual enzyme deficiencies.
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δ-AMINOLEVULINIC ACID DEHYDRATASE PORPHYRIA
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Definition and History
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ADP is an autosomal recessive disorder resulting from severe deficiency of ALAD activity (see Table 58–1 and Fig. 58–1). This is the rarest of the porphyrias, with only six cases documented at the molecular level.50,168
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All reported cases were males.164,166,167,168,169 Compound heterozygosity for two distinct ALAD mutations was documented in five cases (see Fig. 58–4, step 2).167,168 Four (three in Germany and one in the United States) experienced onset of symptoms in their teens, whereas one Swedish case developed severe symptoms in infancy.166 The sixth patient was a Belgian male who developed ADP at age 63 years and was found to have two inherited base transitions in one allele, and was therefore heterozygous for ALAD deficiency.164,169 He also developed polycythemia vera and his erythrocyte ALAD activity was less than 1 percent of normal, while lymphocyte ALAD activity was greater than 20 percent of normal. Heterozygous ALAD deficiency was apparently clinically silent in this patient until there was expansion of a clone of erythroid cells that carried the mutant ALAD allele.169
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Thus ADP is highly heterogeneous at the molecular level, with a total of 11 mutant alleles identified in these 6 patients.168 An additional mutation was found in a healthy Swedish girl with markedly decreased ALAD activity (12% of normal), which was detected by ALAD measurement during neonatal screening for hereditary tyrosinemia.170 The same mutation was found in a U.S. male patient with acute porphyria who also had a CPO mutation and an unusual pattern of porphyrin precursors and porphyrins reflecting dual enzyme deficiencies.171 Thus, heterozygous ALAD deficiency may rarely be combined with another enzyme deficiency, or may itself cause porphyria if a marrow disorder leads to clonal expansion of the mutant ALAD allele.
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Human ALAD consists of eight identical oligomers, each with two zinc-binding sites. Lead can bind at least one of these sites and impair enzyme activity. Some mutations found in ADP may affect zinc binding, or favor assembly of a hexameric enzyme with decreased activity. Thus ADP has been described as a conformational disease.50
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ADP is classified as one of the hepatic porphyrias because it closely resembles the other acute porphyrias. However, the site of overproduction of ALA is not established, and the Swedish infant with severe, early onset disease did not benefit from liver transplantation.172 Substantial increase in erythrocyte zinc protoporphyrin also suggests an erythroid component. The excess urinary coproporphyrin III in ADP may originate from metabolism of ALA to porphyrinogens in a tissue other than the site of ALA overproduction. Indeed, ALA loading in normal subjects was shown to cause substantial coproporphyrinuria.173 The pathogenesis of the neurologic symptoms is poorly understood, as in other acute porphyrias.
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The four adolescent males had intermittent symptoms resembling other acute porphyrias, including abdominal pain, vomiting, extremity pain, and motor neuropathy, although exacerbating factors were less evident.168,174 Two German cases had initial acute attacks and then remained well during 20 years of followup.175 The third German case176 and the U.S. case168 had further attacks and were maintained on prophylactic hemin infusions. The Swedish infant had more severe neurologic disease, including failure to thrive, and died after liver transplantation.177 The 63-year-old man in Belgium, developed an acute motor polyneuropathy concurrently with a myeloproliferative disorder.88,164,178
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A biochemical diagnosis of ADP includes demonstration of markedly deficient erythrocyte ALAD activity, marked elevation in urinary ALA and coproporphyrin III and erythrocyte zinc protoporphyrin, with little or no increase in urinary PBG. Erythrocyte ALAD activity is approximately half-normal in both parents. Lead poisoning is differentiated by increased blood lead and restoration of ALAD activity in vitro by reduced glutathione or dithiothreitol.167,179 Although biochemical measurements can strongly suggest ADP, the diagnosis must be confirmed by DNA studies.
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Patients with hereditary tyrosinemia type I may also have ALAD inhibition and increased excretion of ALA. 43 Dioxoheptanoic acid (succinylacetone), a structural analogue of ALA and a potent ALAD inhibitor, accumulates as a result of an inherited deficiency of fumarylacetoacetate hydrolase in these patients. The presence of this inhibitor can be demonstrated in urine by measuring ALAD activity in normal blood after addition of a patient’s urine. ALAD protein is not reduced in this disease.180
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Because few cases have been documented, treatment recommendations are based on limited experience. Hemin was beneficial in the four male patients, but there was little or no response to glucose. A long-term preventive hemin regimen was effective in two of these patients. The Swedish infant did not respond to glucose or hemin, and did not improve greatly after liver transplantation.172 Whether transplantation would benefit less severe cases is unknown. Hemin produced a biochemical response but no clinical improvement in the late-onset case in Belgium, who had a peripheral neuropathy but no acute attacks.178
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ACUTE INTERMITTENT PORPHYRIA
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Definition and History
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AIP is an autosomal dominant disorder caused by a partial deficiency of PBG deaminase (see Table 58–1 and Fig. 58–1). Symptoms usually occur as acute attacks and are neurologic in origin. In most countries this is the most common acute porphyria and the second most common porphyria. Most individuals who inherit the enzyme deficiency (probably more than 90 percent) never develop symptoms, but are at some risk to develop symptoms after puberty. The first case of acute porphyria was described in 1889 by Stokvis5 who noted a relationship of the symptoms to the drug sulfonal, which is related to the barbiturates.
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Prevalence of AIP was estimated to be 1 to 2 per 100,000 population in Europe,181 and 2.4 per 100,000 population in Finland.182 Up to 300 PBGD mutations have been described in AIP, with many found in only one or a few families.183,184 The disease occurs in all races, but clusters as a result of founder effects occur in some countries. A founder mutation in northern Sweden is associated with a disease prevalence of 1 per 1500 population.185 The prevalence of low PBG deaminase activity, which includes latent gene carriers of AIP, is as high as 1 per 500 in the general population of Finland.186 Based on DNA studies, the minimal prevalence of the AIP-associated genes in France has been calculated to be 1 per 1675 population.187
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PBG deaminase is also known as HMB synthase, and formerly as uroporphyrinogen I synthase. PBGD mutations have been classified based in part on the presence or absence of cross-reactive immunologic material (CRIM), which indicates the presence of inactive enzyme protein. Type I mutations are CRIM-negative, with reduction of both enzyme activity and protein to approximately 50 percent of normal in heterozygotes. Type II mutations are associated with reduced PBGD activity only in nonerythroid tissue. These patients with “variant AIP” comprise less than 5 percent of AIP patients, and have normal erythrocyte PBGD activity and decreased hepatic activity because, as explained earlier in the section on hydroxymethylbilane synthase, transcription of the gene to form the erythroid-specific enzyme starts downstream of the site of the mutation. Type III are CRIM-positive mutations that result in decreased activity with structurally abnormal enzyme protein.188
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Pathogenesis of the Clinical Findings
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A partial deficiency of PBGD rarely causes clinical expression of AIP, and most individuals who inherit this enzyme deficiency remain healthy with normal porphyrin precursor excretion throughout life. Certain drugs and hormones that exacerbate AIP can directly induce ALAS27 and also increase the demand for heme by inducing CYP enzymes, which turn over rapidly and use most of the heme synthesized in the liver.189
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When heme synthesis is stimulated, the partial enzyme deficiency in AIP apparently impairs heme synthesis sufficiently to compromise negative feedback by the regulatory heme pool, which controls synthesis of the rate-limiting enzyme ALAS1. This leads to marked induction of ALAS1 and overproduction of ALA, PBG and porphyrins in the liver.
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It is generally accepted, although not proven, that hepatic PBGD remains constant at approximately 50 percent of normal activity during exacerbations and remissions of AIP, as in erythrocytes. An early report suggested that the enzyme activity is considerably less than half-normal in liver during an acute attack,14 but additional data is lacking. It has been suggested that once the disease becomes activated, excess PBG may interfere with assembly of the dipyrromethane cofactor for this enzyme.
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Clinical improvement and normalization of porphyrin precursor excretion after liver transplantation in patients with severe AIP is a clear indication that the liver plays an essential role in neuropathic processes in the acute porphyrias.190 Proposed explanations for neurologic dysfunction in the acute porphyrias include the following. (1) Heme pathway intermediates or products derived from them may be neurotoxic. This hypothesis is most favored, although the evidence is not conclusive. (2) PBG deaminase deficiency in the nervous system tissues may limit heme synthesis and formation of important hemoproteins. For example, decreased activity of the hemoprotein nitric oxide synthase might decrease production of nitric oxide and cause vasospasm, which might account for some cerebral manifestations of AIP,191,192 and possibly compromise intestinal blood flow.193 However, regulation of heme and hemoprotein synthesis in nervous tissue and blood vessels is difficult to study, and convincing evidence is lacking. (3) Impaired hepatic heme synthesis during an attack may lead to decreased activity of hepatic tryptophan pyrrolase, which might increase levels of tryptophan in plasma and brain, leading to increased synthesis of the neurotransmitter 5-hydroxytryptamine.
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ALA is increased in a number of disorders with similar neurologic manifestations, including all four of the acute porphyrias, lead poisoning, and hereditary tyrosinemia type I, which favors a neuropathic role for this porphyrin precursor or perhaps a derivative. ALA can enter cells readily and be converted to porphyrins, which, in turn, may have toxic potential.194 ALA is also structurally similar to γ-aminobutyric acid and can interact with γ-aminobutyric acid receptors.195,196 However, studies of ALA loading have not shown adverse effects.
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Impaired motor function with ataxia develops in mice with PBGD deficiency resulting from compound heterozygous or homozygous mutations induced by gene targeting.197 Induction of hepatic CYPs is impaired in these animals and corrected by heme.198 But motor neuropathy can develop even with normal or only slightly increased ALA in plasma and urine, suggesting a primary role for heme deficiency in porphyric neuropathy in this murine model.199
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Precipitating Factors
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Acute attacks are precipitated in some heterozygotes by various endogenous or exogenous factors that are additive. Additional unknown genetic factors are also likely to contribute. Some individuals remain susceptible to repeated attacks even after avoidance of known precipitants. Many precipitating factors cause induction of hepatic ALAS1, which is closely associated with induction of CYPs and leads to overproduction of ALA and other pathway intermediates.
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Drugs and Other Exogenous Chemicals
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Most drugs that are harmful in acute porphyrias are known inducers of hepatic CYPs. These drugs increase de novo heme synthesis, thereby derepressing hepatic ALAS1, and also directly induce this rate-limiting enzyme.27 Table 58–4 identifies some drugs that are known to be harmful or safe. Information regarding safety of many drugs in clinical practice is uncertain or lacking. More extensive drug safety databases are available at the websites of the American Porphyria Foundation (www.porphyriafoundation.com) and the European Porphyria Initiative (www.porphyria-europe.com). These drug classifications are often based on limited evidence and may be controversial. Ethanol and other alcohols are inducers of hepatic ALAS1 and some CYPs.200 Smoking is known to increase CYPs in humans, probably from effects of polycyclic aromatic hydrocarbons, and has been associated with more frequent symptoms of acute porphyria.201
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Rarity of symptoms before puberty and more common clinical expression in women point to hormonal factors as important contributors in AIP. Although estrogens are considered harmful, it is likely that progesterone is mostly responsible for cyclic premenstrual attacks that occur in some women. Progesterone, certain metabolites of testosterone, and synthetic progestins are potent inducers of ALAS1. Thus administration of progestational agents should be avoided. Diabetes mellitus is not known to precipitate attacks of porphyria, and has been observed to decrease the frequency of attacks and lower porphyrin precursor levels, possibly in relation to high circulating glucose levels.202
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Pregnancy is usually well tolerated.203 Attacks during pregnancy are sometimes a result of harmful drugs or reduced caloric intake. Metoclopramide, considered at least by some a contraindicated drug, is associated with exacerbation of the disease when used to treat hyperemesis gravidarum.204,205 But for reasons that are not clear, some women experience attacks during pregnancy even when harmful factors are avoided.
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Reduced intake of calories and carbohydrate can exacerbate acute porphyrias. This may occur from efforts to lose weight, bariatric surgery or from metabolic stress from an illness or surgery. Under these conditions, upregulation of PGC-1α can lead to induction of ALAS1, increases in ALA and PBG, and symptoms of acute porphyria, and these effects are reversed by administration of carbohydrate.30,206 Starvation, may also induce hepatic heme oxygenase,207 which may deplete hepatic heme and contribute to ALAS1 induction.
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Various forms of physical or psychological stress may exacerbate acute porphyrias, although the mechanisms are not well defined. Medical illnesses, fever, infections, alcoholic excess, and surgery may decrease food intake and contribute to induction of hepatic ALAS1 and heme oxygenase. Psychological stress may also lead to decreased food intake and have other metabolic effects.
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Symptoms are almost never seen before puberty, and most commonly develop in women in the third or fourth decade of life. Acute attacks are life-threatening but rarely fatal if promptly recognized and treated. Frequently recurring attacks and chronic symptoms can develop and be disabling. Although the most prominent symptoms are a result of effects on the nervous system, liver and kidney damage may be important in the long-term. In very rare homozygous cases, severe neurologic manifestations are seen early in childhood, and acute attacks are not prominent.207a,209
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Symptoms and signs are nonspecific and highly variable. Abdominal pain is the most common symptom, occurring in 85 to 95 percent of cases.210 It is usually severe, steady, and poorly localized, but may be cramping, and is often accompanied by nausea, vomiting, constipation, and abdominal distention because of ileus. Pain in the chest and extremities are also common. Tachycardia is the most common physical sign, occurring in up to 80 percent of acute attacks,211 and often accompanied by hypertension, sweating, tremors, and other effects of sympathetic overactivity and excess catecholamine production. There is little or no abdominal tenderness, fever, or leukocytosis because inflammation is not prominent. Bowel sounds are usually decreased, but are sometimes increased with diarrhea. The urine is often dark (because of porphobilin, a degradation product of PBG) or reddish (because of porphyrins, including uroporphyrin formed nonenzymatically from PBG). Urinary hesitancy and dysuria may occur as a consequence of bladder dysfunction. Acute mental symptoms may include insomnia, anxiety, restlessness, disorientation, paranoia, and hallucinations.
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Paresis because of peripheral motor neuropathy usually occurs with prolonged, severe attacks, but is sometimes an early or even initial manifestation.212,213 Porphyric neuropathy is primarily motor and results from axonal degeneration, which may be followed by demyelinization.214 Muscle weakness may not be detected until it is quite advanced because it usually begins in the proximal muscles of the upper extremities. Paresis is usually symmetrical, but may be asymmetrical or focal. Course tremors, clonus and increased reflexes are sometimes prominent. Magnetic resonance imaging may demonstrate cortical densities resembling the posterior reversible encephalopathy syndrome.192 Sensory loss may develop, especially in the distal extremities. Cranial nerve involvement and cortical blindness have been described.
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Motor neuropathy may progress to respiratory and bulbar paralysis and death especially if diagnosis and treatment are delayed and harmful drugs continued. Death may also result from respiratory arrest or cardiac arrhythmia.214,215 Most attacks treated promptly resolve within days or even hours. Advanced neuropathy from a severe attack is potentially completely reversible, with improvement continuing for up to 1 to 2 years.216
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Hyponatremia is common during severe attacks and is sometimes a result of hypothalamic involvement and the syndrome of inappropriate antidiuretic hormone secretion. However, hyponatremia may be accompanied by reductions in blood volume,217 indicating that increased antidiuretic hormone secretion in this setting is an appropriate physiologic response.215 Hyponatremia may sometimes result from gastrointestinal loss, poor intake, and excess renal sodium loss.215,218 A possible nephrotoxic effect of ALA may explain renal tubular sodium loss and impaired renal function in some patients.218 Other electrolyte abnormalities may include hypomagnesemia and hypercalcemia.219 Seizures may result from hyponatremia or represent a neurologic effect of acute porphyria.
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Chronic mental symptoms, such as depression, are difficult to attribute to AIP. But chronic pain accompanied by depression develops in some patients after frequent exacerbations, and risk for suicide is increased. The disease also predisposes to chronic arterial hypertension and impaired renal function.203,220,221 The latter may progress and require renal transplantation.222,223
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Mild abnormalities in serum transaminases are common in AIP.224 More advanced liver disease may develop and the risk of hepatocellular carcinoma is greatly increased (60- to 70-fold) in AIP, and is not related to specific PBGD mutations. Serum α-fetoprotein was not increased and the uninvolved liver was not cirrhotic in most acute porphyria cases with liver cancer reported as of this writing. Increased serum thyroxin levels because of increased thyroxin-binding globulin occurs in some patients with AIP, and occasionally hyperthyroidism and porphyria occur together.225 Elevated low-density lipoprotein cholesterol is apparently less commonly observed in this disorder than in the past.226
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A high index of suspicion and knowing when to suspect these diseases contributes to making an initial diagnosis of acute porphyria. Because the disease so often remains latent, there is often no family history of porphyria. Acute porphyria should be considered in patients with unexplained abdominal pain or other characteristic symptoms when initial evaluation does not suggest another more common explanation, and ruled in or out by rapid assessment of urinary PBG, which is both sensitive and specific. A substantial increase in PBG, which can be determined rapidly by a commercial kit,227 establishes that a patient has either AIP, HCP, or VP. Consensus recommendations are that all major medical centers should retain the capacity for rapid urinary PBG testing on single-void urine specimens, as collection of 24 hour urines and reliance on outside laboratories for screening can greatly delay diagnosis and treatment. The urine specimen should be saved for later quantitative measurement of PBG, ALA, and total porphyrin levels. If PBG is substantially increased, samples of plasma, erythrocytes and feces should also be obtained prior to treatment with hemin. This approach provides for rapid initial diagnosis of AIP, HCP, and VP, subsequent biochemical differentiation of these conditions and diagnosis of ADP. In patients with renal failure, PBG can be measured in serum by a specialized laboratory. Figure 58–6 presents a diagnostic flow chart for use when acute porphyria is suspected.
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PBG excretion is generally 50 to 200 mg/day (normal range: 0 to ~4 mg/day) during acute attacks of AIP. Excretion of ALA is usually about half that of PBG (expressed as mg/day). Increases in ALA and PBG can persist for prolonged periods between attacks, especially in AIP. Increases in ALA and PBG are less striking during acute attacks of HCP and VP and often decrease more rapidly.
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The diagnosis of an acute attack is largely clinical, and is not based on a specific level of ALA or PBG. Levels of ALA and PBG during an acute attack may be increased compared to baseline levels, which fluctuate considerably and can be difficult to establish between attacks. Intravenous hemin causes dramatic, rapid but often transient decreases in these levels.
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Urinary porphyrins are increased in AIP, are predominantly uroporphyrin and account for reddish urine (ALA and PBG are colorless). Uroporphyrin can form nonenzymatically from PBG in urine even prior to excretion. However, there is evidence that porphyrins in this condition are predominantly type III, which may be formed enzymatically,228 perhaps from ALA transported to tissues other than the liver.194 Total fecal porphyrins and plasma porphyrins are normal or slightly increased in AIP, and erythrocyte zinc protoporphyrin concentrations may be nonspecifically increased.
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Erythrocyte PBGD activity is approximately half-normal in most (70 to 80 percent) patients with AIP. However, this measurement is not definitive for confirming or excluding the diagnosis. As described earlier, some PBGD mutations cause the enzyme to be deficient only in nonerythroid tissues. Moreover, the ranges of activity for normals and AIP are wide and overlapping, and the erythrocyte enzyme is highly age-dependent, such that an increase in the proportion of younger cells in the circulation can raise the activity into the normal range in AIP patients with a concurrent condition such as hemolytic anemia or hepatic disease.229,230 A decrease in this enzyme also does not distinguish between latent and active disease. For these reasons, and because it does not detect other acute porphyrias, erythrocyte PBGD measurement in not useful for initial diagnosis of ill patients.
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Once the diagnosis of AIP is established by biochemical methods, the underlying PBGD mutation should be identified. This confirms the diagnosis and, most importantly, enables reliable and definitive identification of other gene carriers by DNA testing. Erythrocyte PBGD measurement is useful for screening of asymptomatic family members if a known case in the family has low erythrocyte enzyme activity, but is less dependable than DNA testing. PBGD deficiency can be documented in the fetus by measuring the enzyme activity or by identifying the maternal or paternal mutation in amniotic fluid cells. However, prenatal diagnosis is usually not indicated because the great majority of heterozygous carriers of PBGD mutations have a good prognosis.
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Hospitalization is usually required for treatment of attacks, although well-characterized patients with frequently recurring attacks that respond rapidly to treatment are sometimes managed as outpatients. Hospitalization facilitates treatment of severe symptoms, intravenous therapies and monitoring of respiration, electrolytes and nutritional status. Admission to intensive care is warranted if the vital capacity is impaired. Harmful drugs should be discontinued whenever possible. Pain, nausea, and vomiting are generally severe and require narcotic analgesics, chlorpromazine or another phenothiazine, or ondansetron. Low doses of short-acting benzodiazepines are probably safe for anxiety and insomnia. β-Adrenergic blocking agents may be useful to control tachycardia and hypertension, but may be hazardous in patients with hypovolemia or incipient cardiac failure.231 Seizures are treated by correcting hyponatremia, if present. Almost all anticonvulsant drugs have at least some potential for exacerbating acute porphyrias. Clonazepam may be less harmful than phenytoin, barbiturates, or valproic acid.232,233 Bromides, gabapentin, and vigabatrin are safe.
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Glucose and other carbohydrates repress hepatic ALAS1 and reduce porphyrin precursor excretion, but the effects are weak compared to those of hemin. Attacks with mild pain and without severe manifestations such as paresis and hyponatremia may be treated with carbohydrate loading. Oral glucose polymer solutions may be given if tolerated. Intravenous treatment with 300 to 500 g of intravenous glucose, usually administered as a 10 percent solution, is recommended. However, the dilutional effects of a large volume of free water may increase risk of hyponatremia. A more complete parenteral nutrition regimen may be needed if oral or enteral feeding is not possible.
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Hemin is much more potent in reducing levels of ALA and PBG compared to glucose. Although controlled clinical trials are lacking for all current therapies for acute attacks of porphyria, consensus recommendations are that the clinical benefits of hemin are superior to other available therapies.234,235,243a Hemin is available in the United States as a lyophilized hematin preparation (Panhematin, Recordati Rare Diseases, Northfield, IL), and was the first drug approved under the Orphan Drug Act. Heme arginate (Normosang, Orphan Europe, Paris, France), which is a stable preparation of heme and arginine, is available in Europe and South Africa.235,236 Hemin, when infused intravenously as hematin or heme arginate, becomes bound to circulating hemopexin and albumin and is then taken up primarily by hepatocytes. It then enters and reconstitutes the regulatory heme pool and represses the synthesis of hepatic ALAS1. This results in a dramatic reduction in porphyrin precursor excretion. The standard regimen for treatment of acute attacks is 3 to 4 mg/kg daily for 4 days. Treatment may be extended if a response is not observed within this time. Hemin has been administered safely during pregnancy.235,236,243a
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Product labeling recommends reconstitution of hematin with sterile water. But it was subsequently discovered that degradation products of hematin begin to form immediately upon reconstitution with water, and these are responsible for phlebitis at the site of infusion, which occurs frequently and can lead to loss of venous access with repeated dosing, and a transient anticoagulant effect.236a Stabilization of hematin with 25 percent human albumin can prevent these adverse effects,238 and is currently recommended.239 Uncommon side effects include fever, aching, malaise, hemolysis, anaphylaxis, and circulatory collapse.240,241 Excessive dosing caused reversible acute renal tubular damage in one case.242
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Controlled trials comparing initial treatment with either glucose or hemin are lacking, except for one randomized, double-blind, placebo-controlled trial of heme arginate for acute attacks of porphyria, which was underpowered (only 12 patients). Although treatment with hemin was delayed for 2 days, striking decreases in urinary PBG and trends in clinical benefit were noted.243 In contrast, a larger uncontrolled study enrolled 22 patients who had 51 acute attacks, and heme arginate was initiated within 24 hours of admission in 37 attacks (73 percent); all patients responded and hospitalization was less than 7 days in 90 percent of cases.235 Therefore, based on this and numerous other uncontrolled clinical studies, it is now recommended that most acute attacks of porphyria be treated promptly with intravenous hemin, without an initial trial of intravenous glucose.235,243a Response to hemin may be delayed or incomplete when there is advanced neurologic damage. Subacute or chronic symptoms are unlikely to respond.
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Liver Transplantation
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Liver transplantation has been highly effective in several patients who were disabled by recurrent attacks of AIP.190 This may be an option for severely affected patients.
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Cimetidine has been recommended for human acute porphyrias based on uncontrolled observations in small numbers of patients.244,245 This drug inhibits hepatic CYPs, and can prevent experimental forms of porphyria induced by agents such as allylisopropylacetamide that undergo activation by these enzymes.246 However, these mechanisms are not immediately relevant to inherited porphyrias in humans. Therefore, cimetidine cannot be recommended as an alternative to hemin.
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Prevention of Acute Attacks
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Multiple inciting factors must be avoided especially in patients who continue to have repeated attacks. Consultation with a dietitian may be useful to identify dietary indiscretions, and to help maintain a well-balanced diet somewhat high in carbohydrate (60 to 70 percent of total calories). There is little evidence that additional dietary carbohydrate helps further in preventing attacks. Iron deficiency, if present, should be corrected. Patients who wish to lose excess weight should do so gradually and when they are clinically stable.
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Gonadotropin-releasing hormone analogues can prevent repeated attacks that are confined to the luteal phase of the menstrual cycle,247,248 but are less effective in patients with attacks partially associated with the cycle. If treatment is effective after several months, low-dose estradiol, preferably by the transdermal route, or a bisphosphonate may be added to prevent bone loss and other side effects, or treatment changed to a low-dose oral contraceptive. Hemin administered once or twice weekly can prevent frequent, noncyclic attacks of porphyria in some patients.249
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Patients with acute porphyrias are at risk for renal damage and hepatocellular carcinoma. Renal function should be monitored, hypertension controlled, and nephrotoxic drugs avoided. Current recommendations are that patients with acute porphyrias who are older than age 50 years, and especially those with continued elevations of ALA and PBG, be screened at least annually by ultrasonogram or an alternative imaging method to detect hepatocellular carcinoma at an early stage.243a
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HEREDITARY COPROPORPHYRIA AND VARIEGATE PORPHYRIA
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These closely related hepatic porphyrias are caused by deficiencies of CPO and PPO, the sixth and seventh enzymes of the heme biosynthetic pathway. They present with neurovisceral symptoms, as in AIP, or with blistering skin lesions identical to those seen in PCT. Cutaneous manifestations are much more common in VP than in HCP. The enzyme deficiency in each is inherited as an autosomal dominant trait with variable penetrance (see Table 58–1 and Fig. 58–1). As in AIP, most individuals who inherit the trait remain asymptomatic. Both disorders are less common and generally less severe than AIP in most countries. The incidence of HCP was estimated to be 2 per 1,000,000 population in Denmark,250 and the incidence of VP in Finland reported at 1.3 per 100,000 population.251
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Because of a founder effect, VP is especially common among whites of Dutch descent in South Africa, where almost all cases share the same PPO mutation (R59W). The incidence of VP in that country was estimated at 3 per 1000 population.252 Very rare cases of homozygous HCP and VP are manifested by severe neurologic impairment early in life, but not acute attacks, and severe photosensitivity.253
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Like other porphyrias, HCP and VP are heterogeneous at the molecular level. At least 43 CPO mutations, mostly missense mutations, have been identified in HCP,254 and 130 PPO mutations in VP (see Table 58–1). Clinical expression is variable and onset of neurologic manifestations is influenced by the same factors that are important in AIP.
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CPO catalyzes the two-step decarboxylation of coproporphyrinogen III to yield protoporphyrinogen IX, with intermediate formation of harderoporphyrinogen, a tricarboxyl porphyrinogen. A single active site carries out both decarboxylations, and most of the harderoporphyrinogen formed is not released before being further decarboxylated to protoporphyrinogen IX. However, a variant form of HCP, termed harderoporphyria, is a result of CPO mutations that favor premature release of harderoporphyrinogen from the enzyme.255
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Neurovisceral manifestations are identical to those in other acute porphyrias. Although both HCP and VP are generally less severe than AIP, attacks may be life-threatening. Blistering skin lesions may be seen, and are much more common in VP than in HCP. Factors that contribute to attacks, including drugs, hormones, and dietary factors, are also the same as in AIP. Oral contraceptives may precipitate cutaneous manifestations of VP. Risk of chronic hypertension, renal disease, and hepatocellular carcinoma are increased, as in AIP.
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Urinary PBG is elevated during acute attacks, and usually is the basis for diagnosis of these acute porphyrias. However, increases in PBG may be less than in AIP, and more transient. Levels of coproporphyrin III are markedly increased in urine and feces, whereas in AIP fecal porphyrins are normal or only slightly increased. Fecal porphyrins in HCP are almost entirely coproporphyrin III, whereas in VP both coproporphyrin III and protoporphyrin are approximately equally increased. The fecal coproporphyrin III:I ratio is sensitive for diagnosis of HCP, even in asymptomatic stages of the disease.256 Plasma porphyrin concentration is commonly increased in VP, seldom increased in HCP unless there are cutaneous manifestations, and are normal or only slightly increased in AIP. A characteristic plasma porphyrin fluorescence maximum observed at neutral pH is a very specific marker for VP, and is believed to represent protoporphyrin bound covalently to plasma proteins.257 The fluorescence maximum as at approximately 626 nm in VP, approximately 634 in EPP, and approximately 620 in other porphyrias. This fluorometric method is more effective than examination of fecal porphyrins for detecting asymptomatic VP,257 and is useful for rapidly differentiating VP and PCT. Erythrocyte PBG deaminase activity is normal in HCP and VP, and usually deficient in AIP. Assays for CPO and PPO are not widely available. DNA studies are most reliable for identifying asymptomatic carriers, once the mutation affecting the family is identified.
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Harderoporphyria is a variant form of HCP that results from a homozygous defect of a structurally altered CPO, such that harderoporphyrinogen is released prematurely from the enzyme. This variant is identified by finding a predominance of harderoporphyrin in urine and feces. Neonatal hemolytic anemia is a distinctive feature of this condition.258 Increases in porphyrin precursors and porphyrins may be more severe in homozygous HCP and VP, with substantial increases in erythrocyte zinc protoporphyrin.
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The identification and avoidance of precipitating factors is essential. Treatment of acute attacks is the same as in AIP. Treatment of the phototoxic manifestations is not satisfactory. Although the lesions are identical to the blistering skin lesions seen in PCT, there is no response in HCP and VP to phlebotomies or low-dose chloroquine or hydroxychloroquine. Therefore, avoidance of sunlight and use of protective clothing is most important. Yearly screening for hepatocellular carcinoma by imaging is recommended after age 50 years, especially in individuals with persistent increases in porphyrin precursors or porphyrins.
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PORPHYRIA CUTANEA TARDA AND HEPATOERYTHROPOIETIC PORPHYRIA
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PCT is caused by a deficiency of hepatic UROD activity and is manifested by the development of chronic, blistering skin lesions on the dorsal aspects of the hands and other sun-exposed areas of skin in middle or late life. This iron-related disorder is the most common and readily treated form of porphyria (see Table 58–1 and Fig. 58–1). The enzyme deficiency develops specifically in the liver as a result of generation of a UROD inhibitor in the presence of multiple susceptibility factors. The disease has been classified as types 1 to 3, based on the presence or absence of heterozygous UROD mutations and other unknown inherited factors. Patients with familial (type 2) PCT are heterozygous for UROD mutations, which are inherited as an autosomal dominant trait with low penetrance. HEP is the homozygous (or compound heterozygous) form of familial (type 2) PCT, which usually presents in childhood and resembles CEP clinically. Rarely, hepatocellular carcinomas may secrete porphyrins and simulate PCT; however the enzyme defect was not established in such cases.259
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PCT must be differentiated from other porphyrias that cause identical blistering skin lesions and from pseudoporphyria (also known as pseudo-PCT). The latter is a poorly understood condition that presents with lesions that closely resemble PCT, but with plasma porphyrins that are not significantly increased. Potentially photosensitizing drugs, such as nonsteroidal antiinflammatory agents, are sometimes implicated.
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UROD sequentially decarboxylates uroporphyrinogen (which has eight carboxyl side chains) to yield coproporphyrinogen (with four carboxyl groups). When hepatic UROD is profoundly inhibited, the substrate and the intermediate and final products of the reaction accumulate as the oxidized porphyrins in the liver (mostly uroporphyrin and heptacarboxylporphyrin), and then appear in plasma and urine. Photosensitivity results from activation of porphyrins in the skin by long-wave ultraviolet light and generation of reactive oxygen species.
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Hepatic UROD activity is inhibited to less than approximately 20 percent of normal in all patients with PCT. Types 1, 2, and 3 are not fundamentally different or clinically distinguished from each other. Patients with type 1 or “sporadic” PCT have no UROD mutations and no family history of PCT. Approximately 80 percent of patients fall into this category. Type 2 or “familial” PCT comprises approximately 20 percent of cases who are heterozygous for UROD mutations; but because the penetrance of this trait is low there are usually no other documented cases in the family. In families with type 3, which is rare, more than one member has PCT, but there is no UROD mutation; these familial cases presumably share other inherited or environmental susceptibility factors.
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Although hepatic UROD activity must be reduced to approximately 20 percent of normal for PCT to be manifest, the amount of enzyme protein, when measured immunochemically in liver, remains at its genetically determined level, which in type 2 cases is approximately 50 percent of normal.260 Mice heterozygous for mutant UROD alleles are much more sensitive to porphyrinogenic stimuli than wild-type animals.261 In heterozygous mice that display porphyric phenotypes, hepatic UROD protein is half normal, but the catalytic activity of the enzyme is reduced to approximately 20 percent, suggesting the existence of an inhibitor of hepatic UROD.261
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Although iron does not directly inhibit UROD, there is considerable evidence that PCT is an iron-related disease, with hepatic siderosis seen in many cases. This explains why HFE (hemochromatosis gene) mutations that lead to increased intestinal iron absorption predispose to development of PCT (Chap. 42). Individuals who inherit a UROD mutation have approximately 50 percent of normal enzyme activity from birth, such that a UROD inhibitor can more readily reduce enzyme activity to less than approximately 20 percent of normal. How iron and other known or suspected susceptibility factors such as alcohol, smoking, estrogens, hepatitis C, HIV, hepatic steatosis, and other suspected factors contribute to the development of PCT is less-well understood, but these may act in part by increasing oxidative stress in hepatocytes. A deficiency of ascorbic acid,261a and perhaps other antioxidants,263 may play a role in some patients. Smoking may also act by inducing hepatic CYPs, including CYP1A2, which is essential for causing uroporphyria in rodent models,264,265 and may produce a UROD inhibitor, which has been characterized as a uroporphomethene. This substance is a product of partial oxidation of uroporphyrinogen, and is found in the liver of mice that are heterozygous for a UROD mutation, homozygous for an HFE mutation (C282Y), and develop uroporphyria spontaneously.62 Other potential mechanisms for lowering of hepatic UROD activity in PCT, such as oxidative damage to UROD active site residues, are less favored but have not been excluded.266
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At least 70 different UROD mutations have been identified in type 2 PCT and HEP (see Table 58–1). These reduce UROD activity and immunoreactivity to approximately 50 percent of normal in all tissues from birth. Most are missense mutations, with each occurring in one or a few families. Homozygosity for a null UROD mutation is lethal in early neonatal life. Therefore, in HEP at least one of the mutant UROD alleles must preserve at least some catalytic activity. Knowledge of the crystal structure of UROD allows mapping of specific mutations and prediction of their impact on enzyme structure and function. Expression studies in eukaryotic cells suggest that some mutations may destabilize the enzyme protein in a tissue-specific manner.267
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Pathogenesis of the Clinical Findings
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A distinctive feature of PCT is massive accumulation of porphyrins in the liver. As a result, fresh hepatic tissue shows strong red fluorescence on exposure to long-wave ultraviolet light. Microscopic, birefringent, needle-like inclusions are found in lysosomes, and paracrystalline inclusions in mitochondria. Increased stainable iron is very common. Other nonspecific hepatic findings are probably partly a result of the disease itself, although the effects of associated factors such as alcohol and hepatitis C are difficult to differentiate. Liver histopathology includes hepatocyte necrosis, inflammation, increased iron, and increased fat. Mild abnormalities in liver function tests, especially serum transaminases and γ-glutamyltranspeptidase, are present in almost all cases, but cirrhosis is unusual. The risk of hepatocellular carcinoma is increased, especially in those with more prolonged disease, cirrhosis, or other risk factors such as hepatitis C or alcoholic liver disease.268,269,270
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Excess porphyrins are transported in plasma from the liver. Skin histopathology includes subepidermal blistering and deposition of periodic acid-Schiff–positive material around blood vessels and fine fibrillar material in the upper dermis and at the dermoepithelial junction. Immunoglobulin G, other immunoglobulins, and complement are deposited around dermal blood vessels and at the dermoepithelial junction. Splits in the lamina lucida of the basement membrane lead to formation of fluid-containing bullae.271 These histologic changes are found in other cutaneous porphyrias, as well as pseudoporphyria, and are not diagnostic for PCT. Activation of the complement system after irradiation has been demonstrated in PCT patients both in vivo and in vitro in sera,272 and is thought to result from generation of reactive oxygen species.
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Susceptibility Factors
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PCT is a highly heterogeneous disease, with multiple susceptibility factors expected in the individual patient.273 Multiple factors are important in familial as well as sporadic PCT, because heterozygosity for a UROD mutation is a susceptibility factor that does not of itself reduce hepatic enzyme activity sufficiently to cause the disease. The environmental, infectious, and inherited factors discussed below, none of which is invariably present, are known or suspected to play an important role. Their prevalence may show considerable geographic variation in PCT patients as well as healthy subjects.
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PCT has long been associated with excess alcohol use. Alcohol and its metabolites may induce ALAS1 and CYP2E1, generate active oxygen species that contribute to oxidative damage, cause mitochondrial injury, deplete reduced glutathione and other antioxidant defenses, increase production of endotoxin, activate Kupffer cells, decrease the iron regulatory hormone hepcidin274 and increase iron absorption.
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Smoking and Cytochrome P450 Enzymes
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Smoking is less extensively studied as a risk factor but is commonly associated with alcohol use in PCT.273 Smoking may increase oxidative stress in hepatocytes, and induces CYP1A2, which is essential to the development of uroporphyria in rodent models. CYP levels have been found to be increased in liver in human PCT, but it is not clear which CYP might be important in pathogenesis of the human disease. A study of caffeine metabolism did not find evidence for increased CYP1A2 activity in vivo in PCT, even when smokers and nonsmokers were analyzed separately.275 However, a more inducible polymorphism of CYP1A2 has been found to be more common in PCT than in normal subjects.276
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Estrogen use is very common in women with PCT.273,277,278 In the past, some men developed the disease after treatment of prostate cancer with estrogens.277 Female rats or males treated with estrogens are more susceptible to development of chemically induced uroporphyria than untreated males.279 The mechanism is not established, although estrogens can generate reactive oxygen species in some experimental systems.266
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Reported prevalence of hepatitis C in PCT has ranged from 21 to 92 percent in various countries, and greatly exceeds the prevalence of this viral infection in healthy subjects, which shows considerable geographic variation. Hepatitis C is associated with excess fat, some iron accumulation, mitochondrial dysfunction, and oxidative stress in hepatocytes, which may contribute to the development of PCT. Dysregulation of hepcidin may contribute to iron accumulation in hepatitis C.280
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Human Immunodeficiency Virus
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PCT is less commonly associated with HIV infection than with hepatitis C.281 Occasionally PCT is the initial manifestation of this infection. The mechanism is unknown.
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Iron and HFE Mutations
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Mild to moderate iron overload is found in most patients with PCT, and iron deficiency is protective. The importance of iron has been confirmed in animal models, such as rodents treated with hexachlorobenzene and other halogenated polyaromatic hydrocarbons.266 Mice with disruption of one UROD allele (UROD[+/–]) and two disrupted HFE alleles (HFE[–/–]) develop uroporphyria without administration of exogenous chemicals.261 Prevalence of the C282Y mutation of the HFE gene, which is the major cause of hemochromatosis in whites, is increased in both sporadic and familial PCT, and 10 to 20 percent of patients may be C282Y homozygotes (Chap. 43).282 In southern Europe, where the C282Y is less prevalent, the H63D mutation is more commonly associated with PCT.283 Excess iron may contribute to UROD inhibition by providing an oxidative environment that is apparently needed for generation of a UROD inhibitor. Hepatic hepcidin expression is reduced in hemochromatosis, and is also reduced in PCT patients without hemochromatosis genotypes when compared to patients without PCT and comparable iron overload, suggesting that reduced expression of this peptide is important in causing hepatic siderosis in PCT.274
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Substantial reductions in plasma levels of ascorbate and carotenoids have been noted in some patients with PCT.263 Ascorbate deficiency in rodents enhances susceptibility to development or uroporphyria, and ascorbate decreases uroporphyrin accumulation except in animals treated with large amounts of iron.262
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A large outbreak of PCT occurred during a period of food shortage in a population in eastern Turkey in the 1950s from consumption of seed wheat treated with the fungicide hexachlorobenzene.11 Smaller outbreaks and individual cases have occurred after exposures to other chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin).284 These chemicals were subsequently shown to cause hepatic UROD deficiency and biochemical features resembling PCT in laboratory animals, and many studies that followed have greatly increased our understanding of this acquired enzyme deficiency.266,285 But such exposures are rarely identified in PCT patients in current clinical practice.
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Disease onset is usually in the fourth or fifth decade of life, and is more common in men. Onset may occur earlier in familial (type 2) disease or in cases with the C282Y/C282Y HFE genotype.286 Fluid-filled vesicles develop most commonly on the backs of the hands (Fig. 58–7A). Skin friability is increased and blisters often follow minor trauma. These also occur on the forearms, face, ears, neck, legs, and feet. The blisters often rupture, crust over, and are prone to infection before healing slowly. Milia may precede or follow vesicle formation. Facial hypertrichosis and hyperpigmentation are particularly noticed by female patients (Fig. 58–7B). Severe thickening of affected areas of skin is termed pseudoscleroderma and resembles systemic scleroderma.
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Blistering skin lesions in VP and HCP are identical to those in PCT. Those in CEP and HEP resemble PCT but are usually much more severe and mutilating. Mild or moderate erythrocytosis is common in PCT, and is not well explained. Chronic lung disease from smoking may contribute.
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Drugs that exacerbate the acute porphyrias are only occasionally reported to play a role in PCT.287 PCT may occur with other conditions predisposing to iron overload such as myelofibrosis288,289 and end-stage renal disease,290 and with diabetes mellitus270 and cutaneous and systemic lupus erythematosus. PCT associated with end-stage renal disease is usually more severe, sometimes with severe mutilation. Lack of urinary porphyrin excretion in these patients leads to much higher concentrations of porphyrins in plasma, and the excess porphyrins are poorly dialyzable.290 The disease occasionally develops during pregnancy, perhaps related to effects of estrogen.
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The clinical manifestations of HEP usually resemble CEP, with onset of blistering skin lesions, hypertrichosis, scarring, and red urine in infancy or childhood. Sclerodermoid skin changes are sometimes prominent. Excess porphyrins originate mostly from the liver in this condition. Unusually mild cases have been described.291
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A diagnosis of PCT is established by finding a substantial elevation of porphyrins in urine or plasma, with a predominance of highly carboxylated porphyrins (uroporphyrin and hepta-, hexa-, and pentacarboxylporphyrins); coproporphyrins are also increased. Levels of PBG are normal, and urinary ALA is normal or slightly increased. The pattern of porphyrins in feces is complex, and includes heptacarboxylporphyrins and isocoproporphyrins. The latter are overproduced in the presence of UROD deficiency because pentacarboxylporphyrinogen is a substrate for CPO, leading to formation of dehydroisocoproporphyrinogen, which is excreted in bile and undergoes oxidation by intestinal bacteria to isocoproporphyrins.292
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Measurement of plasma porphyrins and determination of the fluorescence emission peak at neutral pH is especially useful for screening patients with blistering skin lesions. A substantial increase with a peak at approximately 620 nm is most commonly caused by PCT, and excludes VP and pseudoporphyria, which are the most common conditions that mimic PCT clinically.292a Plasma porphyrin measurements are essential for diagnosis of PCT in patients with advanced renal disease; the reference range is higher in patients with renal failure than in normals.293
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Erythrocyte porphyrins are substantially increased in CEP and HEP, but are normal or only modestly increased in PCT. Rare cases of HCP with blistering lesions are identified by a predominance of coproporphyrin III in urine and especially feces. Familial (type 2) cases are identified by half-normal erythrocyte UROD activity or preferably by DNA studies to identify a UROD mutation. Erythrocyte UROD activity is 5 to 30 percent of normal in HEP, and DNA studies reveal that a UROD mutation is inherited from each parent.
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Biochemical findings in HEP resemble PCT, with predominant accumulation and excretion of highly carboxylated porphyrins and isocoproporphyrins. However, in contrast to PCT, erythrocyte zinc protoporphyrin is substantially increased. At least one genotype may be associated with predominant excretion of pentacarboxylporphyrin.291
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Treatment is highly effective but specific in both sporadic and familial PCT, and therefore should be initiated only after the diagnosis is well established. It is sometimes reasonable to start treatment after PCT is validated with a plasma porphyrin screen and excludes VP and pseudoporphyria (see “Diagnosis” above). Patients should be questioned and tested for all known susceptibility factors, including use of alcohol, tobacco, and estrogens, hepatitis C, HIV, HFE mutations, and inherited UROD deficiency (erythrocyte UROD activity or, preferably, UROD mutations), because their presence influences management. Serum ferritin should be measured before starting treatment. Patients are advised to stop drinking and smoking and to discontinue estrogens. A nutritionally adequate intake of ascorbic acid and other nutrients should be assured, but this vitamin should not be administered as primary therapy.
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Improvement may occur after removing one or more susceptibility factor, but without phlebotomy or low-dose hydroxychloroquine recovery is unpredictable or slow.294 Repeated phlebotomy is the preferred treatment at most centers. The original rationale proposed by Ippen in 1961 was to decrease the commonly associated mild or moderately increased hemoglobin, stimulate erythropoiesis, and perhaps channel excess heme pathway intermediates to hemoglobin synthesis.295 However, the oxidized porphyrins that accumulate in PCT cannot reenter the heme biosynthetic pathway and be converted to heme, and it is now understood that phlebotomy is effective by reducing body iron stores and liver iron content. Treatment with an iron chelator such as desferrioxamine is less efficient than phlebotomies in reducing iron, but may be tried when the latter are contraindicated.296
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Approximately 450 mL of blood is removed, usually at 2-week intervals. In one series an average of 5.4 phlebotomies was required for remission, but many more are needed in some patients with coexisting hemochromatosis and marked increases in serum ferritin levels. Hemoglobin or hematocrit levels are followed as safety (not therapeutic) targets, to prevent symptomatic anemia. Usually, the hemoglobin should not fall below 10 to 11 g/dL, but the baseline value and the age and clinical condition of the patient are also considered. The therapeutic target is a serum ferritin near 15 ng/mL, which is close to the lower limit of normal and associated with tissue iron depletion but usually not anemia. Additional iron depletion is not beneficial, and causes anemia. Treatment is also guided by plasma (or serum) porphyrin levels, which are more convenient to measure repeatedly than urine porphyrins, and fall more slowly than the serum ferritin. Plasma porphyrins usually decline from initial levels of 10 to 25 mcg/dL during treatment, to below the upper limit of normal (~1 mcg/dL) within weeks after phlebotomies are completed.297 New skin lesions are generally decreased at the end of treatment, but some may occur for a few weeks after plasma porphyrin levels become normal. Severe sclerodermatous changes and liver function abnormalities can also improve.
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After a remission, continued phlebotomies are generally not needed. However, relapses may occur, especially in patients who resume use of alcohol, and are treated by another course of phlebotomies. For patients with the C282Y/C282Y or C282Y/H63D HFE genotypes, management guidelines for hemochromatosis should be followed. Continued phlebotomies as needed to maintain a serum ferritin below approximately 50 ng/mL may also be beneficial in patients who have experienced recurrences of PCT, although published experience is limited. It is also advisable to follow porphyrin levels and reinstitute phlebotomies promptly if porphyrin levels begin to rise. Liver imaging and a serum α-fetoprotein determination should be repeated as screening for hepatocellular carcinoma. After remission, transdermal estrogen can be resumed in women, if needed, with little risk for recurrence of PCT.275
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A low-dose regimen of hydroxychloroquine or chloroquine is also effective,266,298,299,300,301,302,303 and most appropriate when phlebotomy is contraindicated or poorly tolerated, if iron overload is not severe. However, this treatment is preferred at some centers because it is more convenient and much less expensive. These 4-aminoquinoline antimalarials do not appear to deplete hepatic iron, and the mechanism for their effect in PCT is not fully understood. Full therapeutic doses of these drugs exacerbate photosensitivity in PCT, induce fever, malaise, and nausea, markedly increase urinary and plasma porphyrins, and increase serum transaminases, other liver function tests, and ferritin. This reaction can even unmask previously unrecognized PCT.304 Although these adverse effects, which are unique to PCT, are followed by complete remission,305 they should be avoided by a low-dose treatment regimen (hydroxychloroquine 100 mg or chloroquine 125 mg—one-half of a standard tablet—twice weekly) at least until plasma or urine porphyrins are normalized.298,301,302 However, some patients may respond poorly and require later treatment with larger doses, or phlebotomy.305 There is a small risk of retinopathy,306 which may be lower with hydroxychloroquine. A recent prospective study found that time to biochemical remission with low-dose hydroxychloroquine was comparable to that with phlebotomy.307 In a retrospective study, low-dose chloroquine was ineffective in patients homozygous for the C282Y mutation of the HFE gene,308 which suggests that the degree of excess hepatic iron may influence response to this treatment.
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These 4-aminoquinolines are not effective in other porphyrias, and do not mobilize all types of porphyrins from liver and other tissues.309 Chloroquine may form complexes with a variety of porphyrins, which might promote their mobilization from liver,310,311 but this does not appear to explain the effects in PCT. It was suggested that mobilization of hepatic iron may be important,302,312,313 but serum ferritin concentrations do not change significantly during treatment. Most likely, these drugs colocalize with excess porphyrins in lysosomes and other intracellular organelles and promote their release by a process that involves transient cell damage.
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PCT may improve after treatment of coexisting hepatitis C. However, for several reasons PCT should be treated first and hepatitis C later in most cases. First, PCT is usually more symptomatic and can be treated more quickly and effectively. Second, there is some evidence that treatment of hepatitis C may be more effective after iron reduction. Third, interferon and ribavirin commonly cause anemia, which usually precludes phlebotomy for PCT. Hydroxychloroquine may be an option during treatment with interferon and ribavirin, but initial worsening of liver function tests, even with a low-dose regimen, may cause concern. It is reasonable to consider continuing low-dose hydroxychloroquine after PCT is in remission to avoid a reoccurrence of PCT during treatment of hepatitis C, but there is little experience with this approach. Reports that PCT patients are often resistant to treatment of hepatitis C,314,315 contrast with reports of successful treatment, and prospective studies are needed. Studies are needed with newer and more effective agents for hepatitis C as these become available.
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Treatment of PCT associated with end-stage renal disease is more difficult, as phlebotomy is often contraindicated by anemia. Erythropoietin administration can correct anemia, mobilize iron, and support phlebotomy in many cases.290,316,317 High-flux hemodialysis may remove porphyrins from plasma and provide some benefit.318 PCT is not a contraindication to renal transplantation, which is likely to lead to remission319 partly because of resumption of endogenous erythropoietin production. The level of plasma porphyrins are often especially high in these patients, and should be assessed prior to surgery, because there may be some risk of skin and peritoneal burns from exposure to operating room lights.
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Management of HEP emphasizes avoiding sunlight, as in CEP. Oral charcoal was helpful in a severe case associated with dyserythropoiesis.98 Phlebotomy has shown little or no benefit. Retrovirus-mediated gene transfer can correct porphyria in cell lines from patients with this disease, which suggests that gene therapy may be applicable in the future.320