DOWNLOAD PDF DIAGNOSIS AND THERAPY OF PORPHYRIAS AND LEAD INTOXICATION

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1 Chapter 1 : Porphyria - Wikipedia Diagnosis and Therapy of Porphyrias and Lead Intoxication and millions of other books are available for Amazon Kindle. Learn more Enter your mobile number or address below and we'll send you a link to download the free Kindle App. X X Porphyrias are usually classified based either on the predominant site of overproducution of heme precursors hepatic vs. Of the six hepatic porphyrias, four are considered "acute" because they may present with sudden attacks of clinically indistinguishable neurologic manifestations. With the exception of ADP, all acute porphyrias are inherited in an autosomal dominant fashion and are of low penetrance. Cutaneous porphyrias, in turn, may be divided into hepatic and erythropoietic types. PCT is considered a prototypic chronic hepatic porphyria, whereas HEP may be classified in both categories. EPP and CEP, on the other hand, are considered erythropoietic porphyrias because, in them, the overproduction of porphyrins is limited to developing red blood cells RBCs. However, in EPP secondary liver disease hepatic fibrosis or cirrhosis due to protoporphyrin, accumulation may develop. Heme synthesis and regulation In eukaryotes, the first and last three steps of the pathway are located in the mitochondria while the remainder occurs in the cytoplasm. Regardless of the catalyst involved, biosynthesis of all tetrapyrroles begins with the synthesis of 5-aminolevulinic acid ALA. The subsequent three steps that follow are common to the biosynthesis of all tetrapyrroles. After the formation of uroporphyrinogen III, the pathways for vitamin B12, coenzyme F, heme d1, and siroheme formation branch off from the pathway, leading to the formation of other tetrapyrrole compounds of biological importance e. ALAS has two different isoforms coded by separate genes: ALAS2 gene is an erythroid-specific isozyme located on chromosome X, whereas ALAS1 is a ubiquitous housekeeping enzyme coded by a gene on chromosome 3. Each ALAS gene is under different regulatory control mechanisms. Indeed, ALAS2 is induced only during active heme synthesis, where the rate is limited by the availability of iron and is not inhibited by heme. In contrast, ALAS1 is the rate-limiting enzyme in hepatic heme production and is controlled by the uncommitted regulatory heme pool. In addition, heme inhibits the uptake of a precursor ALA synthase into the mitochondria and, as recently shown in our laboratory, is also capable of decreasing stability of the ALAS1 protein in the mitochondria. Finally, heme-oxygenase 1 HMOX1 may indirectly exert control on the regulatory hepatic heme pool by catalyzing heme degradation. Thus, the level of heme in hepatocytes plays a critical role in regulating levels of ALAS I and the flux of intermediates in the pathway. Once formed, ALA exits the mitochondria. The latter compound readily cyclizes nonenzymatically to form uroporphyrinogen I. However, in the presence of normal activity of uroporphyrinogen III co -synthase, hydroxymethylbilane is converted to uroporphyrinogen III. Protoporphyrinogen oxidase PPOX then catalyzes a dehydrogenation reaction that leads to the formation of protoporphyrin IX. Only six cases have been reported in Europe and the United States. These heterozygotes may have a higher likelihood of developing biochemical and clinical manifestations if exposed to environmental toxins, such as lead, that inhibit ALAD. To accomplish this, it requires a divalent zinc cation and an intact sulfhydryl group per subunit. Lead potently inhibits ALAD activity by displacement of zinc from the enzyme. In lead poisoning, urinary ALA and coproporphyrin may be markedly increased and neurological symptoms resembling acute porphyric attacks may occur. The biochemical and clinical features it shares with lead poisoning have led some to use the term "plumboporphyria" to describe ADP. Similarly, hereditary tyrosinemia type I may lead to acute porphyric-like symptoms via the production of succinylacetone 4,6-dioxoheptanoic acid, a potent inhibitor of ALAD. Hence, it is important to rule out these two conditions before making a diagnosis of ADP. The identical clinical manifestations of AIP and ADP along with the porphyric symptoms in lead poisoning and hereditary tyrosinemia type I, suggests that ALA or its metabolite s is the neurotoxic agent that underlies acute porphyrias. Indeed, elevated urinary ALA is the common biochemical marker found in all of the four acute porphyrias and in symptomatic lead poisoning and hereditary tyrosinemia type I. It is widespread in the Northern European countries of Scandinavia, Sweden, Page 1

2 Britain, and Ireland, with an estimated prevalence of 60 to per, In the United States, its prevalence is lower and thought to be around 5 to 10 per, The two isozymes ubiquitous and erythroid of the protein arise from the alternative splicing of an identical gene transcript, with the latter missing exon 2. Thus, the erythroid-specific PBGD is composed of amino acid residues, whereas there are in the ubiquitous isoform. Thus, the decreased activity is found only in nonerythroid cells. Although biochemically distinct, the clinical importance of these subgroups is still unclear. Yet just as in ADP, biochemically active AIP also presents with an elevation of certain urinary porphyrins, namely, uroporphyrin and coproporphyrin. This is partially explained by nonenzymatic conversion of PBG to uroporphyrin. This pattern is sufficiently characteristic such that if it is not seen, a diagnosis other than AIP is more likely. Hereditary coproporphyria HCP Similar to most of the acute porphyrias, HCP is an autosomal dominant hepatic porphyria with variable penetrance. It is characterized by a to fold increase in urinary and fecal coproporphyrin III, compared with controls. The CPOX gene has been mapped to chromosome 3q12 and is about 14 kb in length. Its expression is regulated in a tissue-specific manner. HCP is known to be associated with a number of mutations with variable phenotypes. The most frequent of these is due to the substitution of lysine residue by glutamic acid KE. This mutation leads to increased fecal harderoporphyrin tricarboxylate porphyrin and coproporphyrin, hence, was aptly named harderoporphyria. Although it is generally thought that the neurovisceral manifestations of HCP are milder than those of AIP, fatalities from respiratory paralysis have been reported. Variegate porphyria VP VP has also been called the "royal" malady due to its possible connection with European aristocracy, protocoproporphyria, neurocutaneous porphyria, and South African porphyria. This is due to a founder effect and can be traced to a couple from the Netherlands who emigrated and married in in what is now South Africa. For this reason, VP is the most common acute porphyria in South Africa in comparison to other countries where AIP is the predominant form. It was first reported in that the gene that encodes the human PPOX is located on chromosome 1q Since its discovery, many different mutations have been documented. Patients present with the neurovisceral symptoms common to all acute porphyrias but may also present with cutaneous symptoms similar to PCT. During acute attacks, VP is characterized by increased fecal protoporphyrin and coproporphyrin. Usual signs and symptoms of acute porphyria A prodrome consisting of minor behavioral changes usually precedes an acute episode and includes anxiety, restlessness, or insomnia. For most sufferers, this is followed by major neurologic manifestations of acute porphyrias that include abdominal pain, peripheral neuropathy, and psychiatric disturbances. In addition, gastrointestinal complaints, various neuropathies, and psychiatric disturbances are also observed. More specifically, nausea, vomiting, and constipation are common. Cardiovascular manifestations due to sympathetic overactivity or autonomic neuropathy include tachycardia and systemic arterial hypertension. Initial attacks usually occur in the early third decade of life and can be fatal. Porphyric episodes may be exacerbated by drugs such as sulfonamides, phenobarbital, or phenytoin, which, sometimes, have been administered inadvisedly to treat manifestations of the disease e. See Table II for a listing of presenting signs and symptoms of acute porphyric attacks. Presenting signs and symptoms of acute porphyric attacks Signs and symptoms. Page 2

3 Chapter 2 : Lead Poisoning and Porphyria On the occasion of the th anniversary of Philipp University, the porphyrin research group of. the Department of Clinical Biochemistry in the Faculty of Medicine organized an international symposium. Pathogenesis[ edit ] Heme synthesisâ note that some reactions occur in the cytoplasm and some in the mitochondrion yellow In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, and P liver cytochromes. The body requires porphyrins to produce heme, which is used to carry oxygen in the blood among other things, but in the porphyrias there is a deficiency inherited or acquired of the enzymes that transform the various porphyrins into others, leading to abnormally high levels of one or more of these substances. Porphyrias are classified in two ways, by symptoms and by pathophysiology. Physiologically, porphyrias are classified as liver or erythropoietic based on the sites of accumulation of heme precursors, either in the liver or in the bone marrow and red blood cells. Heme function plays a central role in cellular metabolism. This is not the main problem in the porphyrias; most heme synthesis enzymes â even dysfunctional enzymes â have enough residual activity to assist in heme biosynthesis. The principal problem in these deficiencies is the accumulation of porphyrins, the heme precursors, which are toxic to tissue in high concentrations. The chemical properties of these intermediates determine the location of accumulation, whether they induce photosensitivity, and whether the intermediate is excreted in the urine or feces. There are eight enzymes in the heme biosynthetic pathway, four of whichâ the first one and the last threeâ are in the mitochondria, while the other four are in the cytosol. Defects in any of these can lead to some form of porphyria. The hepatic porphyrias are characterized by acute neurological attacks seizures, psychosis, extreme back and abdominal pain, and an acute polyneuropathy, while the erythropoietic forms present with skin problems, usually a light-sensitive blistering rash and increased hair growth. Variegate porphyria also porphyria variegata or mixed porphyria, which results from a partial deficiency in PROTO oxidase, manifests itself with skin lesions similar to those of porphyria cutanea tarda combined with acute neurologic attacks. All other porphyrias are either skin- or nerve-predominant. Porphyrin studies[ edit ] Porphyria is diagnosed through biochemical analysis of blood, urine, and stool. As a result of feedback, the decreased production of heme leads to increased production of precursors, PBG being one of the first substances in the porphyrin synthesis pathway. The urine screening test has been known to fail in the initial stages of a severe, life-threatening attack of acute intermittent porphyria. The exception to this may be latent post-puberty genetic carriers of hereditary coproporphyria. In general, testing involves sending samples of blood, stool, and urine to a reference laboratory. Samples should be taken during an acute attack; otherwise a false negative result may occur. Samples must be protected from light and either refrigerated or preserved. A careful medication review often will find the cause of pseudoporphyria. Additional tests[ edit ] Further diagnostic tests of affected organs may be required, such as nerve conduction studies for neuropathy or an ultrasound of the liver. Basic biochemical tests may assist in identifying liver disease, hepatocellular carcinoma, and other organ problems. Acute porphyria[ edit ] Carbohydrates and heme[ edit ] Often, empirical treatment is required if the diagnostic suspicion of a porphyria is high since acute attacks can be fatal. However, this can worsen hyponatraemia and should be done with extreme caution as it can prove fatal. These drugs need to be given very early in an attack to be effective; effectiveness varies amongst individuals. They are not curative drugs but can shorten attacks and reduce the intensity of an attack. Side effects are rare but can be serious. These heme-like substances theoretically inhibit ALA synthase and hence the accumulation of toxic precursors. Pain should be treated as early as medically possible. Nausea can be severe; it may respond to phenothiazine drugs but is sometimes intractable. Hot baths and showers may lessen nausea temporarily, though caution should be used to avoid burns or falls. Early identification[ edit ] It is recommended that patients with a history of acute porphyria, and even genetic carriers, wear an alert bracelet or other identification at all times. This is in case they develop severe symptoms, or in case of accidents where Page 3

4 there is a potential for drug exposure, and as a result they are unable to explain their condition to healthcare professionals. Some drugs are absolutely contraindicated for patients with any form of porphyria. This is thought to be due to axonal nerve deterioration in affected areas of the nervous system and vagal nerve dysfunction. Pain treatment with long-acting opioids, such as morphine, is often indicated, and, in cases where seizure or neuropathy is present, Gabapentin is known to improve outcome. Some psychotropic drugs are porphyrinogenic, limiting the therapeutic scope. Other psychiatric symptoms such as anxiety, restlessness, insomnia, depression, mania, hallucinations, delusions, confusion, catatonia, and psychosis may occur. Most seizure medications exacerbate this condition. Treatment can be problematic: Some benzodiazepines are safe and, when used in conjunction with newer anti-seizure medications such as gabapentin, offer a possible regimen for seizure control. Gabapentin has the additional feature of aiding in the treatment of some kinds of neuropathic pain. The addition of hematin or heme arginate has been used during status epilepticus. These include hemochromatosis and hepatitis C. Treatment of iron overload may be required. Other typical risk factors for liver cancer need not be present. However, oral contraceptives have also triggered photosensitivity and withdrawal of oral contraceptives has triggered attacks. Androgens and fertility hormones have also triggered attacks. The pain, burning, swelling, and itching that occur in erythropoietic porphyrias generally require avoidance of bright sunlight. Most kinds of sunscreen are not effective, but SPF-rated long-sleeve shirts, hats, bandanas, and gloves can help. Chloroquine may be used to increase porphyrin secretion in some EPs. The rarest is congenital erythropoietic porphyria C. The signs may present from birth and include severe photosensitivity, brown teeth that fluoresce in ultraviolet light due to deposition of Type 1 porphyrins, and later hypertrichosis. Hemolytic anemia usually develops. Pharmaceutical-grade beta carotene may be used in its treatment. More than genetic variants of AIP are known, some of which are specific to families, although some strains have proven to be repeated mutations. The underlying mechanism was first described by Felix Hoppe-Seyler in, [38] and acute porphyrias were described by the Dutch physician Barend Stokvis in In the early s, patients with porphyrias occasionally referred to as "porphyric hemophilia" [41] and severe symptoms of depression or catatonia were treated with electroshock therapy. Vampires and werewolves[ edit ] Porphyria has been suggested as an explanation for the origin of vampire and werewolf legends, based upon certain perceived similarities between the condition and the folklore. In January, L. Later, Nancy Garden argued for a connection between porphyria and the vampire belief in her book, Vampires. The Aetiology of European Metamorphosis Legends," gained widespread media coverage, popularizing the idea. The theory has been rejected by a few folklorists and researchers as not accurately describing the characteristics of the original werewolf and vampire legends or the disease, and as potentially stigmatizing people with porphyria. As it was believed that the folkloric vampire could move about freely in daylight hours, as opposed to the 20th century variant, congenital erythropoietic porphyria cannot readily explain the folkloric vampire but may be an explanation of the vampire as we know it in the 20th century. In addition, the folkloric vampire, when unearthed, was always described as looking quite healthy "as they were in life", while due to disfiguring aspects of the disease, sufferers would not have passed the exhumation test. Individuals with congenital erythropoietic porphyria do not crave blood. The enzyme hematin necessary to alleviate symptoms is not absorbed intact on oral ingestion, and drinking blood would have no beneficial effect on the sufferer. Finally, and most important, the fact that vampire reports were literally rampant in the 18th century, and that congenital erythropoietic porphyria is an extremely rare manifestation of a rare disease, makes it an unlikely explanation of the folkloric vampire. The first, written in, thirty-five years after his death, concluded that he had acute mania. Guttmacher, in, suggested manic-depressive psychosis as a more likely diagnosis. Many psychiatrists disagreed with the diagnosis, suggesting bipolar disorder as far more probable. The theory is treated in Purple Secret, [47] which documents the ultimately unsuccessful search for genetic evidence of porphyria in the remains of royals suspected to have had it. In, an exhaustive analysis of historical records concluded that the porphyria claim was based on spurious and selective interpretation of contemporary medical and historical sources. The closing credits of the film include the comment that the illness that King Page 4

5 George had has been attributed to porphyria and that it is hereditary. It is assumed she inherited the disorder, if indeed she had it, from her father, James V of Scotland. Both father and daughter endured well-documented attacks that could fall within the constellation of symptoms of porphyria. Maria I of Portugal in a c. Maria I of Portugal â known as "Maria the Pious" or "Maria the Mad" because of both her religious fervor and her acute mental illness, which made her incapable of handling state affairs after â is also thought to have had porphyria. Francis Willis, the same physician who treated George III, was even summoned by the Portuguese court but returned to England after the court limited the treatments he could oversee. Page 5

6 Chapter 3 : Lead poisoning - Diagnosis and treatment - Mayo Clinic On the occasion of the th anniversary of Philipp University, the porphyrin research group of. the Department of Clinical Biochemistry in the Faculty of Medicine organized an international symposium. This was held between June 28 and July 1,, under the joint chairmanâ ship of Professor. The American Academy of Pediatricians recommends that doctors and parents follow the recommendations of their state or local health department. Some areas, such as those with older homes, have a higher lead exposure risk, so more frequent testing might be recommended for children who live in those areas. A simple blood test can detect lead poisoning. A small blood sample is taken from a finger prick or from a vein. There is no safe blood level of lead. Children whose blood tests at those levels should be tested periodically. Treatment The first step in treating lead poisoning is to remove the source of the contamination. Your local health department can recommend ways to identify and reduce lead in your home and community. For children and adults with relatively low lead levels, simply avoiding exposure to lead might be enough to reduce blood lead levels. Treating higher levels For more-severe cases, your doctor might recommend: EDTA is given by injection. Request an Appointment at Mayo Clinic Preparing for your appointment If you think you or your child has been exposed to lead, see your doctor or contact your local public health department. A blood test can help determine blood lead levels. What you can do Make a list of: What tests are needed? Is this condition likely temporary or chronic? Are there brochures or other printed material I can have? What websites do you recommend? What to expect from your doctor Your doctor is likely to ask you questions, including: Have you recently moved to a different home or changed schools? When was your house built? Do you have a new job that might expose you to lead? Does your child have a sibling or playmate who has had lead poisoning? Chapter 4 : Acute porphyrias - Cancer Therapy Advisor Note: Citations are based on reference standards. However, formatting rules can vary widely between applications and fields of interest or study. The specific requirements or preferences of your reviewing publisher, classroom teacher, institution or organization should be applied. Chapter 5 : - NLM Catalog Result Fifty-three papers originally presented as a meeting held in the summer of at Philipp University, Marburg. The topics range well beyond that suggested by the title, to basic biochemical background, genetics, epidemiology, and analytical methods. Not a good investment for physicians interested. Page 6