A breakdown of synthesis causes widespread symptoms of , an unusual comorbid disease in primary immunode ciencies.



MANY PATIENTS WITH a primary immunode ciency which primarily have skin manifestations, are caused by the (PI) and other diseases treated with immune globulin have buildup of photosensitizing in the skin. comorbidities.  ese diseases may be caused by the PI, or it may cause the PI or be entirely unrelated. In addition, Acute Hepatic many of these diseases are accompanied by nonspeci c and  e hepatic porphyrias that manifest with acute attacks are: overlapping symptoms. One of the most unusual of these • Acute intermittent porphyria (AIP) diseases is porphyria, which unlike many other diseases, can • Aminolevulinic acid dehydratase de ciency (ALAD) often be con rmed by a genetic diagnosis. porphyria (ADP) Porphyria is a group of diseases that cause the body to • Hereditary coproporphyria (HCP) incorrectly produce heme due to speci c enzymatic defects. • (VP) Heme is the substance that gives blood its red color. It is Enzyme activity in the heme synthesis pathway is reduced required to transport oxygen in the body and is essential for to about 50 percent of normal in AIP, HCP and VP, and all cells. Most heme comes from the bone marrow and the is less than 50 percent in ADP. Symptom onset of these liver, and it is used throughout the body, but especially for porphyrias is rare before puberty. Since hormones trigger red blood cell hemoglobinization (when red blood cells begin acute attacks, approximately 80 percent of those who su er producing a lot of haemoglobin inside them). Heme is from symptomatic acute hepatic porphyrias are women. produced in an eight-enzyme step process. Enzyme activity is All four acute porphyrias present with indistinguishable diminished in the heme synthesis steps for all but one of the symptoms during acute attacks that typically start with porphyrias, X-linked protoporphyria (XLP), in which enzyme activity is Figure: Acute Hepatic Porphyria Symptoms increased. In porphyria, cells fail to completely           metabolize porphyrins and    # '   precursors into heme. When these  "   Ĩ heme precursors build up in the body,    %  $!% they cause illness. Depending on the  !"       %     type of porphyria and enzymatic defect,  &"  these chemicals may collect in the liver     or the bone marrow.  "     Hepatic porphyrias are those in  !   !!   ! ! which there is an accumulation of heme       "  precursors in the liver. Most of these result in porphyrias with acute attacks thought      to be caused by neurotoxic e ects of   $     "  the heme precursors. In erythropoietic   # " porphyrias, heme precursors first     !   " (  %) accumulate in the bone marrow and red   ! blood cells.  e symptoms of porphyrias,

IG Living | June-July 2021 | IGLiving.com 37 brain fog, insomnia and fatigue, and they can progress over symptoms) hours or days to more severe symptoms. Without early and Acute porphyria attacks may require hospitalization to appropriate intervention, acute attacks can last for months stabilize the patient. Treatments can include: and can cause life-threatening complications, including • IV hemin respiratory failure, seizures, chronic kidney failure, liver • Pain medications damage and coma. • Nutrition and hydration Symptoms of acute attacks are nonspecic and aect the • Hypertonic saline to correct hyponatremia (low sodium) entire body (Figure): Frequent acute attacks may be decreased by suppressing • Widespread pain: Attacks can include severe abdominal pain, ovulation in women and avoiding porphyrogenic (nitrogen- chest pain, pain in the neck, lower back, buttocks, arms or legs. containing) drugs. • Gastrointestinal: Nausea, vomiting, constipation or diarrhea are common symptoms during attacks. Cutaneous Erythropoietic Porphyrias • Urological: Patients can present with dark (reddish or When the heme synthesis process breaks down in the brownish) urine and sometimes urinary retention during attacks. cutaneous erythropoietic porphyrias, excess heme precursors • Neurological and psychological: Symptoms of acute accumulate in the skin, causing photosensitivity. e attacks can include headache, anxiety, irritability and cutaneous erythropoietic porphyrias are: depression, psychosis, seizures and coma. • Congenital (CEP) • Peripheral nervous system: Numbness and tingling, • Erythropoietic protoporphyria (EPP) muscle weakness and sometimes diculty breathing can • X-linked protoporphyria (XLP) occur during attacks. Symptoms in all the cutaneous porphyrias include severe • Cardiovascular: Rapid heart rate, high blood pressure pain, itching, burning, swelling, edema and redness of the and cardiac arrhythmia can also occur. skin after exposure to light — sometimes as soon as a few • Solid organs: Over time, patients can develop liver or minutes after exposure. Most symptoms subside within 48 kidney damage from an accumulation of toxins in these hours, but pain and discoloration may last longer. e skin organs. may eventually take on a leathery appearance after repeated e acute symptoms of HCP and VP are identical to other exposure to sun. acute porphyrias. However, with HCP, blistering skin lesions Symptoms unique to each disease include: and fragile skin may occur with or apart from acute attacks. VP • CEP: Skin reactions can also include blistering and can also manifest with skin symptoms identical to those seen fragile skin. Patients can exhibit red or dark urine and in (PCT), which is explained below. anemia and may have an enlarged spleen. ey can also have Sometimes, skin manifestations are the only symptom of VP. skeletal changes such as bone loss and calcication. Some Many of the triggers of an acute porphyria attack act aected individuals may lose nails, lips or parts of the ears, by increasing the body’s demand for heme, as is the case nose and ngers. in metabolizing certain medications. With porphyria, the • EPP: Skin blistering isn’t common, but patients may production of heme is limited, porphyrin precursors in the develop mild anemia, gallstones and liver damage; some may body increase, the oending medication is not metabolized even have liver failure. properly, and an acute attack ensues. • XLP: is disease doesn’t involve blistering of the Triggers for the acute porphyrias include (but aren’t skin, but it can involve anemia. Patients with XLP can also limited to): develop gallstones and/or liver disease, including liver failure. • Alcohol All cutaneous porphyrias cause photosensitivity to sunlight; • Smoking patients may also be sensitive to some indoor lights such as • Certain drugs, especially P450 pathway drugs uorescents. • Stress e most eective treatments for the cutaneous erythropoietic • Dieting and fasting porphyrias include avoiding sunlight and wearing protective • Hormonal uctuations clothing. And, increasing skin pigmentation with afamelanotide • Exposure to sunlight (in the forms with cutaneous can increase sunlight tolerance.

38 IG Living | June-July 2021 | IGLiving.com Cutaneous Hepatic Porphyrias often used to rule in or out variants of the disease. The The cutaneous forms of porphyria that are also hepatic tests typically run for the porphyrias look for elevated are: levels of aminolevulinic acid (ALA), coproporphyrin • Porphyria cutanea tarda (PCT) (COPRO), porphobilinogen (PBG), protoporphyrin • Hepatoerythropoietic porphyria (HEP) and/or uroporphyrin (URO) in the urine, blood and/ PCT is the only form of porphyria that can develop or stool. in the absence of genetic mutation; it is the most Hyponatremia (low blood sodium) often occurs in the common type of porphyria. In PCT, uroporphyrinogen acute porphyrias. Liver enzymes (alanine transaminase and decarboxylase (UROD) de ciency and iron accumulation aspartate transaminase) may also be slightly elevated in in the liver play a role in the disease process. HEP also hepatic forms of porphyria, while other liver function tests stems from a UROD de ciency, but this type of porphyria remain normal. is very rare. With PCT, patients may experience photosensitivity, including blistering of the skin and extremely fragile skin,  excessive hair growth, especially on the face, and small skin bumps with a     white head, especially on the backs of  the hands. Patients may also develop liver abnormalities, including iron accumulations, fatty liver, inammation and scarring of the portal vein. Genetic testing is available for all types of porphyria In HEP, symptoms usually start within the rst two years discussed in this article. e tests may not detect all of life. Patients experience skin symptoms identical to PCT. genetic defects, and thus won’t detect all cases of porphyria. ey may also have anemia from premature destruction However, genetic testing can con rm clinical diagnoses in of red blood cells. Anemia associated with HEP may be many cases. It can also be useful to screen family members mild or severe. If the anemia is severe, it can cause fatigue, of aected individuals to see if they are carriers of porphyria pale skin, irregular heartbeat, chest pain, dizziness and — either aected or unaected; unaected carriers can pass abnormally cold hands and feet. Some patients may have the disease on to their ospring. e results of genetic tests an enlarged liver and/or spleen. should always be discussed with a geneticist or a trained Sun exposure triggers both HEP and PCT. In addition, genetics counselor. there are other triggers for PCT, including alcohol and smoking. References 1. Ogun, AS, Joy, NV, and Valentine, M. Biochemistry, Heme Synthesis. StatPearls Publishing [Internet]. July Treatments for the cutaneous hepatic porphyrias include 2020. Accessed at pubmed.ncbi.nlm.nih.gov/30726014. 2. Ramanuham, V-MS, and Anderson, KE. Porphyria Diagnostics Part 1: A Brief Overview of the Porphyrias. avoiding sunlight and wearing protective clothing. Also, Current Protocols in Human Genetics, 2015; 86: 17.20.1–17.20.26. Accessed at pubmed.ncbi.nlm.nih. gov/26132003. increasing skin pigmentation with afamelanotide can 3. National Institutes of Diabetes and Digestive and Kidney Diseases. Porphyria. Accessed at www.niddk.nih.gov/ health-information/liver-disease/porphyria. increase sunlight tolerance. 4. Kothadia, JP, LaFreniere, K, and Shah, JM. Acute Hepatic Porphyria. StatPearls Publishing [Internet]. May 2020. Patients with PCT who suer from iron accumulation 5. Pinpoint AHP: Acute Hepatic Porphria. Accessed at www.porphyria.com. in the liver can have blood extracted on a regular basis 6. National Organization for Rare Disorders (NORD). Porphyrias. Accessed at rarediseases.org/rare-diseases/ erythropoietic-protoporphyria. to reduce their blood iron levels. Patients with HEP and 7. e Porphyrias Consortium: Laboratory Diagnosis of the Porphyrias. Accessed at www.rarediseasesnetwork. org/cms/porphyrias/Healthcare_Professionals/diagnosis. anemia may need iron supplements or blood transfusions.

Testing for the Porphyrias CYNTHIA PERRY worked in the medical eld for eight years, interviewing doctors and conducting market research and strategic Clinical tests for the various porphyrias depend on the planning. She now writes articles and teaches classes focused on healthcare. suspected type of porphyria. Since there are overlapping Cynthia has been diagnosed with multiple chronic conditions and is a symptoms in many of the porphyria types, panels are breast cancer survivor.

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