Target Health Blog

The Porphyrias are Generally Considered Genetic in Nature

April 9, 2018


A skin rash in a person with porphyria: From Wikimedia Commons, the free media repository

Porphyria is the name for certain medical conditions or diseases, which have been known since the days of Hippocrates. Those who suffer from the disease can not make certain substances in the blood. They have disorders of certain 1) _____ which normally work in the production of porphyrins and heme. The condition is usually caused by a genetic deficiency, but chemicals which affect metabolism may also cause it. Arsenic is an example. It can be triggered by various drugs or by some environmental conditions. The disease causes skin problems, or some diseases of the nervous system, or both. Severe pain is often present. When someone is affected by porphyria they will start to lose their 2) ____ about two weeks after having an attack. There is no cure for the hair loss.

In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, and P450 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.

There are eight enzymes in the heme biosynthetic pathway, four of which - the first one and the last three - 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.

The first reports of clinical porphyria appeared in the 1870's, describing patients who excreted porphyrin-like chemicals and had symptoms ranging from abdominal pain to photosensitivity. Some had disfiguring photocutanous damage with loss of tissue from the ears, eyelids and fingers, in association with very high urine porphyrins. One patient was hired as a laboratory assistant for Hans Fischer, a German physician and chemist, and provided urine from which the chemical structure of uroporphyrin was deduced. Fischer then synthesized the compound de novo. In the process he established the structures of bilirubin and heme, respectively, work for which he received the Nobel Prize in Chemistry in 1930. Studies of heme synthesis in living organisms followed, starting in the 1940s, facilitated by the advent of isotopic tracer techniques.  By the 1960s, the pathway was well delineated, allowing predictions of the specific enzyme deficiency associated with each of the porphyrias. The predictions were confirmed initially with assay of the individual enzymes, then by deoxyribonucleic acid (DNA) analysis of the relevant genes.

Three of the acute hepatic porphyrias (acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP)) are autosomal dominant disorders, affecting males and females equally. A fourth type, delta-aminolevulinic aciduria (ALAD), is autosomal recessive and very rare. For the three dominant types, family studies with DNA analysis have indicated multiple mutations. While enzyme activity varies with the nature of the mutation, on average it is roughly 50% of normal. Efforts to associate specific mutations with clinical manifestations have been largely negative. Regardless of genotype, the vast majority (perhaps 90%) of confirmed genetic carriers never experience an attack. In families with multiple documented genetic carriers, symptoms often are limited to one or two individuals.

People with symptoms, represent only a small fraction of those who carry a relevant mutation and are at risk of an attack. In one study of mutation prevalence from France, 3,350 healthy blood donors were screened for HMBS (PBG deaminase) deficiency. The test was positive in four, and a known AIP mutation was documented in two. Thus, the prevalence of mutations in this group was at least 1:1,675 (60:100,000) - far larger than is generally assumed. Another study from northwestern Russia (St. Petersburg) and Finland screened patients who were admitted to a neurology ward with acute polyneuropathy or encephalopathy and abdominal pain. Out of 108 patients, 11% proved to have previously undiagnosed acute porphyria. While these studies are small, they suggest that people coming to an Emergency Department (ED) with recent onset abdominal pain may have a mutation for AIP more often than is generally assumed.

The most common acute symptom is abdominal 3) ____, which is usually diffuse. In some patients, it is localized to the back or an extremity. By the time the patient is seen, pain has increased relentlessly for several days, not hours, often accompanied by nausea, vomiting, and constipation. Fever and leukocytosis are not present in the absence of an accompanying infectious process. Mild elevation of the transaminases is common. Hyponatremia may be seen and occasionally is severe. Because patients tend to present dehydrated after several days of nausea and inadequate oral intake, hyponatremia may be masked initially by hemoconcentration but can develop rapidly after rehydration with dextrose in water.

In an attack that has not been recognized and treated, acute visceral symptoms may progress to motor neuropathy, which is manifested initially as weakness of the proximal limb muscles but in advanced cases the respiratory muscles as well. Seizures occur in 10-20% of cases. Patients presenting with seizure represent a difficult challenge for the consulting neurologist. If acute porphyria is not considered, the treatment may include medications such as phenytoin or valproic acid, which intensify the attack with potentially disastrous results. For this reason, early diagnosis is critical, followed by definitive treatment with intravenous hemin. Seizures in acute porphyria can be controlled with a short-acting benzodiazepine, gabapentin, or magnesium.

For people who are known carriers of a porphyria 4) _____ determining whether symptoms represent a porphyria exacerbation or are due to a more common problem can be a diagnostic challenge. In those with recurrent attacks, the pattern of symptoms is largely reproduced with each episode, but urine PBG still should be evaluated for biochemical confirmation. A random urine sample is adequate, provided a urine creatinine is obtained, so that results can be expressed per gram creatinine. The sample should be collected prior to intravenous (IV) fluid resuscitation. If it is very dilute, it could yield a false-negative result.

Typically, acute 5) ____ porphyria is considered only after a patient has made several visits to the ED. What is needed is a standard quantitative test that is available on an urgent or expedited basis. The concern of the laboratories is the cost of providing a service that may be requested only occasionally. However, the actual cost per positive test of implementing rapid PBG screening is unknown, because very little information exists on the prevalence of acute porphyria in the urgent care setting. An analysis from the Mayo 6) ____ concluded that a rapid PBG test would be cost-effective.45 While additional studies are needed, it should be noted that the cost of a delayed diagnosis is also high: multiple unnecessary procedures, prolonged hospitalization, and treatment for an erroneous diagnosis, including intensive care unit (ICU) care for those in neurological crisis.

Misdiagnosis also occurs but in the outpatient rather than the ED. It arises when the gamut of tests and procedures has failed to identify a reason for the patient's chronic abdominal pain. Rare diseases then come under consideration, and a porphyrin screen is ordered. The latter consists of fractionated urine porphyrins only; it does not include ALA and PBG, which must be ordered separately. In some cases, the report shows elevation of several porphyrin fractions, predominantly COPROs. Although the changes are quantitatively minor (2- to 4-fold the upper limit of normal) and well below the threshold for symptoms for cutaneous porphyria, the patient receives a diagnosis of porphyria and feels relief at having, at last, a name for the recurring symptoms. 

Initial management is focused on eliminating factors that may be contributing to an attack, including inducer medications, caloric deprivation, and dehydration. Medications considered risky for genetic 7) ____ of acute porphyria and all nonessential medications are discontinued. The American Porphyria Foundation (APF) and the European Porphyria Network (EPNET) maintain lists of drugs that are considered safe or hazardous. If possible, calories and rehydration are administered orally to reverse the fasting state; otherwise, 10% dextrose in 0.45% normal saline is administered IV. Although this therapy has not been tested in controlled trials, it does stop the attack for some patients. Hyponatremia may be severe, requiring urgent 8) _____ administration. A protocol that minimizes the risk of brainstem damage should be followed.47 Pain relief generally requires opiates, often in large doses, while waiting for porphyria-specific therapy to take effect. 

Fifty years ago, the outlook for acute porphyria with neurological complications was poor, with a reported mortality of 35%. Although the prognosis remains guarded, the number of cases progressing to advanced disease has declined, as a result of heightened awareness, early identification of genetic carriers, and specific therapy in the form of hemin infusion. In patients with neuropathy who respond to treatment, motor deficits resolve slowly but usually completely, over an average of 10-11 months. Because the manifestations of an attack can include an altered 9) ____ state, there has been speculation that people with undiagnosed acute porphyria may be institutionalized for psychiatric reasons. One study indeed found an unexpectedly high prevalence of elevated urine 10) ____ in residents of a mental health facility, without symptoms suggestive of acute porphyria. When the question was reexamined, abnormal tests were no more frequent than expected.  In patients with known porphyria who have been monitored long-term, to date there has been no evidence for excess chronic mental illness. 

ANSWERS:  1) enzymes; 2) hair; 3) pain; 4) mutation; 5) porphyria; 6) clinic; 7) carriers; 8) saline; 9) mental; 10) PGB

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