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About Porphyria

 Current research indicates that porphyria (poor-fear-e-uh) is a group of diseases

caused by a genetic mutation in which one of the enzymes in the heme pathway doesn’t work properly. Heme is a combination of iron and protoporphyrin IX which is essential for the function of all cells requiring oxygen and is made in every cell of the body, but mainly in the bone marrow and the liver. Two classifications of porphyria are acute hepatic porphyria (AHP) and erythropoietic porphyria (EP) depending on where heme synthesis is primarily affected in the body, in the bone marrow or the liver. When heme synthesis is affected in the bone marrow, the skin is primarily affected causing photosensitivity, which is a sensitivity to ultraviolet rays from the sun and fluorescent lighting (citation); when heme synthesis is affected in the liver, the whole body is affected causing a variety of symptoms. In each porphyria the activity of specific enzymes in the heme pathway is defective and leads to an accumulation of specific chemicals each in a distinctive pattern found in either plasma, erythrocytes, urine, and feces (Philips 2019). There are currently nine known types of porphyria, four acute hepatic porphyria's and five erythropoietic porphyria's. The types of acute hepatic porphyria (AHP) are Aminolevulinic Acid Dehydratase Porphyria (ALAD-P), Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), and Variegate Porphyria (VP). The types of Erythropoietic Porphyria are Congential Erythropoietic Porphyria (CEP), Porphyria Cutanea Tarda (PCT), Hepatoerythropoietic porphyria (HEP), Erythropoietic protoporphyria (EPP), X-linked Protoporphyria (XLP). A new porphyria was discovered only a few years ago, and we expect there to be more porphyria's discovered in the next few years.

 

 

Autosomal dominant and recessive 

 

These are then converted from one type of porphyrin to the next to form heme.


 

It was thought before that patients only had "attacks" or crises, it is now known that some patients have chronic signs and symptoms (citation).

Each type results from partial deficiency of one of the enzymes of heme biosynthesis (Deacon et al. 2001). Accumulation of the substrate of the defective enzyme produces a pattern of accumulation and excess excretion of heme precursors and their derivatives that characterizes each disorder (Deacon et al. 2001).

 

the principal site of accumulation of pathway intermediates

classification: location of defect (bone marrow or liver) and symptoms (photosensitivity and/or acute attack)

The classification is dependent on location of defect and symptoms experienced.

These current classifications are incomplete as there is cross over in some types (citation).

In some cases, particularly those without proper diagnosis and treatment, the disease can potentially cause life-threatening complications.

 

(technically 9, one is a dual version of one type and is called Hepatoerythropoietic Porphyria (HEP)

Criticism of the title acute as it is not always severe

 

Medical History, Signs and Symptoms, and Laboratory Findings

Medical History

Attacks can occur anytime in a person's life, even in infancy and childhood (citation). The patient may already have multiple diagnoses such as inappropriate sinus tachycardia, postural orthostatic hypotension, gastroparesis, constipation or irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, generalized anxiety disorder, also called panic disorder, bipolar disorder, somatization disorder, also called conversion disorder, major depressive disorder, schizophrenia, and premenstrual dysphoric disorder (Dhoble et al., 2009, Grigoriou et al., 2015, Peters et al., 2006, Laine et al., 2007, Tippett 2006, Crimlisk 1997, Singh et al. 2015, Patience et al., 1994, Ahangari 2015, Cederlöf et al., 2015). The patient may have seen multiple doctors, such as general practitioners, emergency physicians, gastroenterologists, psychiatrists, neurologists, cardiologists and had many tests (citation). Many patients fighting for their life during an attack have been denied medical treatment and sent to a psychologist or admitted to a mental hospital due to a lack of understanding of the disease and poor testing availability (citation). Adverse reactions to a variety of medications are a common finding, many medications can make an acute porphyria patient far sicker and must be stopped immediately, or as quickly as possible (citation). Please check the porphyria drugs database, porphyriadrugs.com, for any medication and always be very cautious with any new medication as safe medications have also triggered attacks. If you're starting a new medication it's a good idea to take the lowest dose or a fraction of the dose and wait several hours before taking any more/others. Many seizure medications, barbiturates, sulfa meds, hormonal medications and IUDs, SSRI's, many antibiotics, and anti-fungals, amphetamines, cocaine, lidocaine (use extreme caution with any "caine"), smoking, marijuana, alcohol, fasting including low carbohydrate diets, vaccines, caffeine, stress, painting with lead paint, and working with other paints, solvents or chemicals, hot or cold weather, certain foods (the website porphyria tripod has an extensive list), sun exposure, grief, physical exertion, and even flying in an air plane have all been documented to cause attacks.

Signs and Symptoms and Laboratory Findings

  • Pain in the abdomen, head, neckchestback, limbs, musclesbonesjoints

      or nerves 

Gounden V 2020, Stewart MF et al. 2007, Wang B et al. 2018, Indika NLR et al. 2018, Balwani M et al. 2016, Stein PE et al. 2012, Menegueti MG et al. 2011, Pichler G et al. 2015, Latina A et al. 2017, Al-Falahi et al. 2018, Messas N et al. 2016, Alqwaifly M et al. 2019, Chemmanur AT et al. 2004, Bloomer JR et al. 2007, Kent PM 2006Alfadhel M et al. 2014, Guan Liang Chen et al. 2013, Simon A et al. 2018 |  Dahlgren M et al. 2010, Balwani M et al. 2016 | Guan-Liang Chen et al. 2013 (neck pain) Guan-Liang Chen et al. 2013 (chest pain) | Guan-Liang Chen et al. 2013 (back pain), Simon A et al. 2018, Balwani M et al. 2016 | Guan-Liang Chen et al. 2013 (limb pain), Simon A et al. 2018, Stein PE et al. 2012 (limb pain), Balwani M et al. 2016 (limb pain), Patil AD et al.  2015, Simon A et al. 2018, Naef RW et al. 1959, Alfadhel M et al. 2014 (muscle pain), Wang B et al. 2018 (muscle pain), Cohen PL et al. 1997 (muscle pain), Simon A et al. 2018 (bone pain) Simon A et al. 2018 (joint pain), Wang B et al. 2018 (joint pain) Simon A et al. 2018 (nerve pain)

  • Fast heart rate also known as tachycardia 

         Stewart MF et al. 2007, Beattie AD et al. 1973De Block CEM et al. 1999, Menegueti MG et al. 2011, Messas N et al. 

       2016, Patil AD et al. 2015, Alfadhel M et al. 2014, Guan-Liang Chen et al. 2013, Stein PE et al. 

       2012, Balwani M et al. 2016, Indika NLR et al. 2018

  • Palpitations

       Balwani M et al. 2016, Indika NLR et al. 2018, Stewart MF et al. 2007, Gounden V 2020

  • High blood pressure, also known as hypertension or low blood pressure, also known as hypotension 

        Stewart MF et al. 2007, Stein PE et al. 2012, Messas N et al. 2016, De Block CEM et al. 1999, Beattie AD et al. 1973, Patil          AD et al. 2015, Menegueti MG et al. 2011, Latina A et al. 2017Pichler G et al. 2015, Alfadhel M et        al. 2014, Simon A et al. 2018, Balwani M et al. 2016, Indika NLR et al. 2018, Wang B et al. 2018 

       Nazila Rad et al. 2020

  • Heart rate and blood pressure that increase suddenly then decrease to normal also known as autonomic instability or dysautonomia 

      Chemmanur AT et al. 2004, Stewart MF et al. 2007, Nazila Rad et al. 2020, Messas N et al. 2016

  • Excessive sweating, also known as hyperhidrosis

       Stewart MF et al. 2007, Gounden V 2020

  • Seizures 

       Tran TPY et al. 2013, Rahim Vakili et al. 2016, Birchfield RI et al. 1966, Dawit S et al. 2019, 

       Alfadhel M et al. 2014, Guan-Liang Chen et al. 2013, Balwani M et al. 2016, Wang B et al. 2018, 

      Gounden V 2020

  • Tremors

       Indika NLR et al. 2018

  • Anxietydepression, irritability, hallucinations, paranoia, agitation, confusion, suicidal thoughts, emotional lability

       Stein PE et al. 2012, Simon A et al. 2018, Guan-Liang Chen et al. 2013, Burgoyne K et al. 1995, 

       Alfadhel et al. 2014, Stein PE et al. 2012,  Ghosh S et al. 2006Bloomer JR et al. 2007, Guan-                Liang Chen et al. 2013 (depression), Indika NLR et al. 2018 (irritability), Faoucher M et al. 2019González Arriaza HL et al. 2003 (hallucinations), | González Arriaza HL et al. 2003 (paranoia) | González Arriaza HL et al. 2003 (agitation) | Stein PE et al. 2012 (confusion) Millward LM et al. 2005Burgoyne K et al. 1995, Narang N et al. 2011Ware SK 2013Chemmanur AT et al. 2004, Dajer A et al. 2016Latina A et al. 2017, Millward LM et al. 2005BurgoyneK et al. 1995, Naef RW et al. 1959Altintoprak AE et al. 2009, Indika NLR et al. 2018 (confusion), Gounden V 2020 (confusion), González Arriaza HL et al. 2003 (suicidal thoughts), Indika NLR et al. 2018 (emotional lability) 

  • Constipation or diarrhea 

        Menegueti MG et al. 2011, Hadary A 2006, Chemmanur AT et al. 2004, Alfadhel et al. 2014,                   Simon A et al. 2018, Stein PE et al. 2012, Balwani M et al. 2016 (constipation), Indika NLR et al.             2018 (constipation), Wang B et al. 2018 (constipation), Indika NLR et al. 2018 (diarrhea), Gounden V 2020

  • Intestinal obstruction

       Indika NLR et al. 2018

  • Nausea and/or vomiting

        Messas N et al. 2016Rudnick SR 2020, Latina A et al. 2017, Al-Falahi et al. 2018, Alfadhel M et           al. 2014, Simon A et al. 2018, González Arriaza HL et al. 2003 (nausea), Wang B et al. 2018 (nausea), Indika NLR et al. 2018 (nausea), Gounden V 2020 (nausea), Stein PE et al. 2012  (vomiting), Balwani M et al. 2016 (vomiting), Indika NLR et al. 2018 (vomiting), Wang B et al. 2018 (vomiting)

  • Insomnia 

        Larion S et al. 2013Pérez-Carbonell L et al. 2018, Simon A et al. 2018, Balwani M et al. 2016               (insomnia)

  • Malaise, which is a general feeling of discomfort

       Stein PE et al. 2012

  • Fatigue

       Simon A et al. 2018

  • Muscle weakness 

        Menegueti MG et al. 2011, Pichler G et al. 2015, Indika NLR et al. 2018

  • Fever

       Balwani M et al. 2016, Indika NLR et al. 2018

  • Dizziness

       González Arriaza HL et al. 2003

  • Urinary retention, also known as oliguria or frequent urination also known as urinary incontinence

       Nazila Rad et al. 2020, Menegueti MG et al. 2011, Guan-Liang Chen et al. 2013, Balwani M et al.          2016, Indika NLR et al. 2018 (urinary retention or urinary incontinence)

  • Polydipsia, which is extreme thirst 

        González Arriaza HL et al. 2003

  • Skin issues may occur in HCP and VP - blistering, peeling, millia, scarring of skin which can present as hypopigmentation or hyperpimentation, fragility, itching, sores, particularly on sun exposed areas such as the face, and backs of hands, but can occur anywhere, and may have sun sensitivity. 

       González Arriaza HL et al. 2003

  • Foot and wrist drop

       Balwani M et al. 2016

  • Peripheral neuropathy

       Simon A et al. 2018, González Arriaza HL et al. 2003, Balwani M et al. 2016, Gounden V 2020 

  • Axonal motor neuropathy also known as motor sensory axonal polyneuropathy 

       Menegueti MG et al. 2011, Nazila Rad et al. 2020, Guan-Liang Chen et al. 2013, Balwani M et al.          2016, Wang B et al. 2018

  • Flaccid tetraparesis also known as quadriparesis, tetraplegia, or paresis which is paralysis that results in the partial or total loss of use of all four limbs and torso 

       Menegueti MG et al. 2011, Park EY et al. 2014, Barois A et al. 1977, Alfadhel M et al. 2014, Simon        A et al. 2018, K Beckh et al. 1990, Gounden V 2020

  • Elevated respiratory rate also known as tachypnea

       Patil AD et al. 2015, Menegueti MG et al. 2011, Messas N et al. 2016, Balwani M et al. 2016 

  • Respiratory failure

       Messas N et al. 2016, Guan-Liang Chen et al. 2013, Simon A et al. 2018

  • Memory Loss

       Simon A et al. 2018      ​​​

  • Urine may be dark (cola, bright red, red wine, whiskey, or orange colored) when exposed to sunlight for up to 72 hours

        Stein PE et al. 2012, Wang B et al. 2018

  • Gastroparesis 

        Steinberg JM et al. 2016

  • Weight gain or weight loss

       González Arriaza HL et al. 2003

  • Pallor which is paleness of the skin

  • Upper respiratory tract infection

       Balwani M et al. 2016

  • Urinary tract infection which is an infection in the urinary tract. Symptoms include burning feeling when peeing, frequent or intense urge to pee, even though little comes out when you do, and pain or pressure in your back or lower abdomen 

        Menegueti MG et al. 2011

  • Small amounts of blood in the urine (hematuria)

  • Kidney disease also called renal insufficiency or tubulointerstitial nephritis 

       Menegueti MG et al. 2011, De Block CEM et al. 1999, Messas N et al. 2016, Guan-Liang Chen et          al. 2013, Balwani M et al. 2016, Indika NLR et al. 2018​, Wang B et al. 2018

  • Liver failure

       Messas N et al. 2016

  • Hepatocarcinoma also known as hepatocellular carcinoma 

        Menegueti MG et al. 2011, Guan-Liang Chen et al. 2013, Balwani M et al. 2016​, Wang B et al.               2018

  • Metabolic acidosis

       Messas N et al. 2016, Indika NLR et al. 2018

  • Jaundice, which is yellowing of the skin caused by the buildup of bilirubin in the blood (Kapetanos D et al. 2001)

  • Takotsubo cardiomyopathy, also known as broken heart syndrome or stress cardiomyopathy, is a temporary heart condition that develops in response to intense emotional or physical stress

       Messas N et al. 2016, Madias JE 2016, Al-Falahi Z et al. 2018

  • Colonic diverticulosis also known as diverticular disease or diverticulitis which is a condition in which small, bulging pouches develop in the digestive tract      

       Latina A et al. 2017

  • Cholecystitis which is inflammation of the gallbladder

       Alfadhel M et al. 2014, Wang B et al. 2018 

  • Gallstones 

        Alfadhel M et al. 2014,

  • Posterior reversible encephalopathy syndrome (PRES) also called reversible posterior leukoencephalopathy syndrome which presents with headache, seizures, hypertension, altered consciousness, and visual disturbance (Arora H et al. 2019,

  • Syndrome of inappropriate antidiuretic hormone (SIADH), also referred to as hyponatremia, is a condition in which high levels of anti-diuretic hormone cause the body to retain water. Symptoms include nausea and vomiting, headache, 

      confusion, weakness, and fatigue

        De Block CEM et al. 1999, Ashawesh KA et al. 2005, Pichler G et al. 2015, Latina A et al. 2017               Montes AL et al. 2004, Alfadhel M et al. 2014, González Arriaza HL et al. 2003, Stein PE et 

        al. 2012, Balwani M et al. 2016, Indika NLR et al. 2018, Wang B et al. 2018

  • Postural orthostatic tachycardia syndrome (POTS) also known as orthostatic hypotension is a blood pressure that drops when standing up from a lying or sitting position and presents with  lightheadedness, dizziness, fainting, palpitations, and rapid heartbeat . It is defined as a fall in systolic blood pressure of at least 20 mm Hg or a fall in diastolic blood pressure of at least 10 mm Hg when a person assumes a standing position and an increase in the heart rate of more than 30 beats per minute, or a heart rate that exceeds 120 beats per minute, within 10 minutes of rising (citation).

  • Positive antinuclear antibodies also called ANA

       Patil AD et al. 2015, González Arriaza HL et al. 2003

  • Decreased hemoglobin

       Indika NLR et al. 2018

  • Normochromic, normocytic anemia

       Indika NLR et al. 2018

       Pischik 2015, De Block CEM et al. 1999, Dos Santos ARR et al. 2013

  • Decreased magnesium also know as hypomagnesemia

       Pischik 2015, Wang B et al 2018

  • Decreased chloride also known as hypochloremia 

  • Increased Ferritin

       Indika NLR et al. 2018

  • Increased white blood cells also known as leukocytosis

       Pichler G et al. 2015, Zakharov 2015, Dos Santos ARR et al. 2013, Balwani M et al. 2016

  • Increased antinuclear antibodies 

  • Increased catecholamines 

        De Block CEM et al. 1999

  • Increased creatine kinase which occurs in rhabdomyolysis

      Nazila Rad et al. 2020

  • Increased creatinine

      Indika NLR et al. 2018

  • Increased AST or ALT also known as aminotrasferase, transaminases, 

      transaminitis or hypertransaminasemia

       Pichler G et al. 2015, Guan-Liang Chen et al. 2013, Wang B et al. 2018

  • Increased cholesterol, also known as hypercholesterolemia

       De Block CEM et al. 1999, Shiue JW et al. 1989, Indika NLR et al. 2018

  • Increased aldosterone also known as hyperaldosteronism

        Pichler G et al. 2015

How Is Porphyria Diagnosed?

Testing for porphyria consists of testing blood, urine, and stool.

 

Blood tests for porphyria consists of total plasma porphyrins, fractionated plasma porphyrins, plasma fluorescence, erythrocyte porphyrins, enzyme activity, and DNA testing.

 

Urine tests for porphyria includes total urine porphyrins and urine precursors (ALA and PBG) and fractionated urine porphyrins.

 

Stool tests for porphyria includes total fecal porphyrins and fractionated fecal porphyrins.

The total plasma porphyrins test identifies the totality of porphyrins present in plasma (citation). The most common method for measuring total plasma porphyrins is (citation).

The fractionated plasma porphyrins test separates the totality of porphyrins present in plasma into individual components (citation). The most common method for separating porphyrins in plasma is high-performance liquid chromatography (HPLC), which is a laboratory technique used to separate, identify, and quantify each component in a mixture (citation). 

Erythrocyte Porphyrins. 

Enzyme activity. There are three enzyme activity tests available in the US: porphobilinogen deaminase (PBGD), uroporphyrinogen decarboxylase (UROD), and aminolevulinic acid dehydrastase (ALAD). There are multiple enzyme activity tests missing from the US which are offered in other countries that our organization would like to offer, they are coproporphyrinogen oxidase (CPOX), protoporphyrinogen oxidase (PPOX), uroporphyrinogen synthase (UROS), ferrochelatase (FECH). 

DNA testing. 

Total urine porphyrins 

Urine precursors (ALA and PBGA concerning number of HCP and VP patients are well documented in research papers to never have a positive urine PBG test in and out of an attack, it is simply incomplete and dangerous to do only urine testing and also illegal in the US as a non FDA approved test may not be used as a sole means of diagnosis under US Law. 

Total fecal porphyrins. The coproporphyrin in a fecal sample should be no more than 25% of the total fecal porphyrins.

Fractionated fecal porphyrins 

Coproporphyrin (CIII:CI) dominance

 

Unfortunately US labs are not currently flagging some abnormal results, if you see that your results are abnormal, but not flagged, we can help you report the lab to the proper governing body, please reach out to us.

Genetic testing (most mutations are family specific, a patient can have a negative DNA test and have porphyria, this happens in 1 of 5 patients, with just 1 type of porphyria test, according to one genetics lab, this is probably a much higher number, given there are 4 other tests, and only the urine test was used

Porphyrins are chemicals that help make hemoglobin, a type of protein in your red blood cells. Hemoglobin carries oxygen from your lungs to the rest of your body.

All samples must be protected from light; urinary porphyrin concentrations can decrease by up to 50% if kept in the light for 24 hours (Deacon et al. 2001).

Please see cautions below, there is a high rate of false negatives. 

1.) Fractionated Fecal Porphyrins (test must be High Performance Liquid Chromatography)

2.) Blood test of the Enzyme Porphobilinogen Deaminase and Aminolevulinic acid Dehydratase 

3.) Porphyrins Plasma fluorescence scan

4 & 5.) Urine Aminolevulinic acid (ALA) and Porphobilinogen (PBG)  

6.)

*These are not standard lab tests, we wince when people say "all my tests in the ER were normal", the truth is all routinely done tests were (close to) normal, these aren't routinely done tests. Our organization is in agreement with The Australian Porphyria experts to test each patients blood, plasma, urine, and stool. The "stepwise approach" (recommended elsewhere) is incredibly dangerous as it forces patients to wait for an attack, and tests only urine initially, which will miss younger patients, many latent patients, and may miss (a high percentage of) HCP, and VP, in life threatening attacks, according to Australian Porphyria expert Dr. Janus, and Dr. Blake's research findings in his paper "Fecal Coporporphyrin Isomers in HCP", and in the drug trial for Panhematin the paper entitled "Porphyria" noted the VP patient had a false negative PBG test. 

We give cautions and tips below, porphyria is a metabolic disease and false negatives often occur.

Cautions:

*The sample must be light protected (container wrapped in foil, or black container) immediately, and frozen or refrigerated per labs requirements. 

*Please NOTE: Coproporphyrin dominance (CIII:CI) is an ABNORMAL finding and is only seen in one Acute Porphyria, Hereditary Coproporphyria, and is also not seen in "non porphyric" humans. A normal fecal porphyrins profile according to the paper "Compound Heterozygous HCP" by Doss is the coproporphyrin (CIII:CI) is 16% of total porphyrins and 24% of Protoporphyrin.

*In the paper Variegate Porphyria, Anderson found that Copro dominance is seen only in HCP, 

*Patients with HCP may not have high porphyrin excretions in fecal testing per Blake's paper "Fecal Coproporphyrin Isomers in Hereditary Coproporphyria" 40% of one family with HCP did not have high fecal porphyrin excretion.

*Children may have false negative below the age of 12. 

Fecal testing in Blake's paper could detect even rather young patients. Allen in his paper "HCP comparison of molecular and biochemical investigations in large family" found by age 10 a CIII:CI ratio was detectable. 

Treatment success! Kuhnel in her Paper "HCP in Germany" found treating the patient with Normosang infusions of heme (The name for the non US version Panhematin) could reverse the abnormal fecal porphyrin profile in patients with HCP.

Blood

Enzyme Testing 

The PBGD whole blood enzyme test is tied with the PBG urine test as the best tests for AIP according to the research paper "196 patients with AIP". In the US there is currently only 2 of the 4 enzymes in the Acute Porphyria's that have testing: Aminolevulinic Acid Dehydratase whole blood ALAD (for ALAD) and Porphobilnigen Deaminase PBGD (for AIP). We are working to change this! You can donate to us we are working on bringing enzyme testing that is done in France to the US for HCP and VP. Enzyme testing for acute porphyria consists of testing four enzymes. The enzymes that are tested are Aminolevulinic acid dehydratase (ALAD) for aminolevulinic acid dehydratase deficiency porphyria (ADP), porphobilinogen deaminase (PBGD) for acute intermittent porphyria (AIP), coproporphyrinogen oxidase (CPOX) for hereditary coproporphyria (HCP), and protoporphyrinogen oxidase (PPOX) for variegate porphyria (VP). In those with acute porphyria, the enzyme are deficient by approximately half in a heterozygous carrier in AIP, HCP, and VP, to a almost a full loss of the enzyme function in ALAD and homozygous AIP HCP and VP. 

 

Cautions:

False negatives occur for the PBGD enzyme test in AIP in up to 16% of patients with AIP.

A low PBGD but not diagnostically low enough for AIP could indicate another porphyria is present, it was found that Variegate Porphyria and Hereditary Coproporphyria patients may also have low PBGD, our org has an HCP patients records who also had below normal PBGD, so please do thorough porphyria testing which is all available if a low enzyme is seen. Low PBGD has been documented in active HCP and VP.

May be a false negative if the patient is symptomatic and best done outside of an attack

*Must be refrigerated

Other illnesses may cause a low PBGD such as sideropenia, and the following illnesses may affect PBGD levels: anemia (this is often seen in Porphyria), uremia, malignicies, and hemodialysis. During an attack the level of PBGD can rise to reference levels creating a false negative. 

*Aminolevulinic Acid dehydratase Enzyme Whole Blood 

A test for ALAD porphyria.

must be refrigerated and best done outside of an attack. 

Cautions: about 1-2% of the population have below normal ALAD enzyme, please do a through work up on these patients, and take any signs and symptoms consistent with an attack seriously. 

Test name: 2 Plasma Porphyrins

Cautions: the sample must be light protected during collection, storage, and transport, and refrigerated. Plasma Fractionated porphyrins is the best test for VP when the patient is symptomatic.

Caution!

*Sample must be kept light protected at collection, storage, and shipping. Maybe negative outside of an attack or if improperly handled

 

Urine

Urine Aminolevulinic acid (ALA), urine Porphobilinogen (PBG), urine total porphyrins, urine fractionated porphyrins,

*ALA / PBG Urine first pee of the day, or 24 hr. test,

Aminolevuelinic acid is the best test for ALAD-P, and is also used in conjunction with PBG testing for AIP,

 

Cautions:

*Must be done during symptoms

*Must be light protected, and refrigerated. Improper lab handling or patient handling may also cause false negatives.

*May not ever be elevated in HCP, or if elevated may fall quickly, and VP may also have false negatives during an attack, or maybe elevated in VP in an attack, but fall quickly. Frequent false negatives occur in HCP whether the patient is in or outside of an attack, The Australian porphyria specialist state Ala/ Pbg may also be a negative during an in HCP both inside and outside of an attack, regardless of regardless of age. Levels quickly drop after an attack. 

*Patients with AIP may have a positive PBG test outside of an attack, in this case establish a baseline with testing outside of an attack, normal intraindividual increases in AIP range from 1.6-4 times. (196 patients with AIP)

 

*There can be a false negatives due to glucose infusion, or carbohydrate consumption, as well as lab mishandling. From the paper "Porphyria" 

*Treatment with Panhematin will cause false negatives as well as the Givorsiran drug. 

*Younger patients may have false negatives. The French Porphyria Center states patients 15 years and under in AIP may have false negatives, and The University Cape Town in S. Africa states testing done under age 22 in VP maybe a false negative.

*Signae Vitae's paper "Porphyria Diagnostic challenge in the ER" states the PBG test is prone to both false negatives and positives. 

*In the Spring of 2018 a Porphyria patient dropped a bombshell on the "Porphyria Sucks" face book support group publicly stating that a "porphyrin retainment" mutation was found in her DNA. Unfortunately when we reached out to the lab to obtain the RS # the lab cited HIPPA, and does not share their findings with the Human Genome Mutation Database, so we cannot independently verify what the mutation is, however it seems that about 17-30% of the patients in the paper "Fecal Isomers in HCP" had retention of porphyrins.

 

Other Biochemical testing

 

Serum porphobilinogen (PBG) is another way to test PBG in a patient, this is used in patients with renal failure.

Genetic Testing

Genetic testing is relatively new and not 100% reliable. Most porphyria mutations are "family specific" if your families mutation has not been found, you may have porphyria, but have a negative genetics test. A negative genetics test does not clear you of porphyria, one genetics counselor explained in their labs experience 20% of patients with a positive urine pbg test, had a negative genetics test, and 13% of the patients with out any positive biochemical testing, had a known pathogenic porphyria mutation. A negative genetics test- because they are not FDA approved, may not be used to deny treatment, or strip a diagnosis, it just means if you have porphyria that your variant has not been discovered yet. The DNA tests that are available are: next-generation sequencing, sanger sequencing, and microarray-based comparative genomic hybridization. 

 

A note about DNA Sequencing Analysis: It is important to note that labs that do not offer deletion and insertion testing will not find mutations with large deletions or insertions. At this time it is not clear how often deletion and insertion mutations occur. One source says that approximately fifteen percent of genetic mutations for hereditary coproporphyria are deletions or insertions, whereas another source says that approximately five percent of genetic mutations for acute intermittent porphyria are deletions or insertions. Heidi Rehm PhD, of Harvard stated that genetics testing may only catch 20% of gene carriers. All genetic testing in the US requires a Doctors signature. We encourage all the request your underlying DNA mutations, under HIPPA regulations you are legally entitled to receive those within 30-60 days of written request to the laboratory. Please contact the lab directly to ensure the testing has not changed. 

The genes are: ALAD, ALAS2, C15orf41, CPOX, FECH, HFE, HMBS, PPOX, SLC19A2, UROD, UROS.

If you feel you have had a problem with a lab, please file a Clinical Laboratory Improvement Amendments (CLIA) complaint to the Center for Disease Control in your state. Reasons to file a CLIA complaint are negligence, if your HIPPA rights were violated either by a lab disclosing your private information with out authorization or refusing to give you your underlying data please file a HIPPA complaint. And finally if a Dr. or medical professional interfered,compromised, or acted unsafely with your care please file a medical board complaint in your state. If you were stripped of your diagnosis based on a negative genetics test you may alsp file a FDA device complaint.

There are a limited number of laboratories in America that test for porphyria, so you or your doctor will have to send the samples to a laboratory or multiple laboratories that test for porphyria across the country. We want to make it very clear no one test is 100% accurate, and certain porphyria tests have false negative rates of close to 40%. Porphyria is an inborn error of metabolism and as such testing has to be compared to clinical history. As Acute Porphyria is a life threatening disease we encourage a full battery of testing which may have to be repeated until you the patient are satisfied. The current average time to an Acute Porphyria diagnosis is 15 years in the U.S.,our organization would like to shorten that to days.

The Porphyria's are diagnosed by several different laboratory tests, unfortunately at this time the US is missing several porphyria tests (our goal is to change that), so it is very important to do all available tests, as some tests are better for certain types, and other tests are better when not in an "attack".

How Is Porphyria Treated?

Treatment options for porphyria are Panhematindextroseand liver transplant. Panhematin is made of red blood cells processed from human blood, which is intended to limit the rate of heme synthesis possibly by inhibiting the enzyme aminolevulinic acid synthase 1. The risk factors associated with the use of Panhematin are allergic reactions, iron poisoning, and viral infection. Allergic reactions are usually due to the inactive ingredients in Panhematin such as sorbitol or sodium carbonate (cite source). Panhematin  can cause urinating less than usual or not at all, swelling, weight gain, feeling short of breath, fever, easy bruising or bleeding, or swelling, pain, or irritation around the IV needle. 

Panhematin is given at a dose of 1-4 milligrams per kilogram of body weight once daily for 3 to 14 days, based on clinical signs. Panhematin should not exceed 6 milligrams per kilogram of body weight per 24 hour period. Dextrose is intended to limit the rate of heme synthesis possibly by inhibiting the enzyme aminolevulinic acid synthase 1. Dextrose comes in a variety of options, 5% with saline, 10% with saline, and dextrose 50% with saline. Two litres of normal saline with 10% glucose given in divided doses of 500 ml over 24 hours through a central venous catheter. It is suggested that when patients cannot consume carbohydrates due to nausea or vomiting, glucose should be administered intravenously. Some physicians have prepared a standing order for patients who are prone to attacks to help facilitate intravenous glucose in the emergency room, which can prevent further hospitalization, however ideally patients in attacks are admitted and monitored in the ICU, attacks are serious and the mortality rate is 5-20% if the attack is undiagnosed and untreated. Side effects may include irritation of the vein in which it is given, high blood sugar, and swelling. Excess use may result in low blood sodium and other electrolyte problems. Liver transplant is curative. has been used successfully in a limited number of patients. The liver transplant must be done when the patient is strong enough to withstand the surgery and recovery, and must be a liver from a donor who does not have an acute porphyria.

 

Ordering Panhematin must be done quickly, most Hospital pharmacies do not stock Panhematin as it is an orphan drug, and it must be ordered from ASD pharmaceuticals (800) 746-6273 asd.customerservice@asdhealthcare.com in the U.S., as it can take 24-72 hours to be delivered. Another option is to see if a hospital near you has it in stock. 

What Are the Differential Diagnoses to Porphyria?

  • Diabetic Ketoacidosis

  • Pheochromocytoma

  • Familial Mediterranean Fever

  • Wilson's Disease

  • Huntington's Disease

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