Porphyria

BASICS

DESCRIPTION

Porphyrias: group of inherited or acquired metabolic disorders that involve defects in the pathway of heme biosynthesis (1,2)
Symptoms mediated by overproduction of porphyrins or precursors in heme biosynthetic pathway (1,2)
Heme biosynthesis (1,2)
- Involves eight enzymes (either cytoplasmic or mitochondrial) that are activated sequentially
- Occurs in all cells containing mitochondria, chiefly within bone marrow and liver
- Essential for erythropoietic hemoglobin and hepatic enzymes, for example, cytochrome p450 (cyp450)
Classification (1,2)
- See below for descriptions of each abbreviation.
- Acute porphyrias (AIP, VP, HCP, ADP)
  - Generally autosomal dominant inheritance (except ADP) with incomplete penetrance
  - Clinical manifestations typically expressed only in setting of increased heme requirements (e.g., cyp450 induction).
  - Key features: acute neurovisceral, neuropsychiatric, or dermatologic symptoms
- Chronic porphyrias (PCT, EPP, CEP, XLP)
  - Generally autosomal recessive inheritance (except PCT and XLP, see below)
  - Chronic in nature; severity of symptoms wax and wane over time
  - Do not present with acute attacks
  - Can lead to progressive hepatic impairment
Acute intermittent porphyria (AIP)
- Acute; autosomal dominant inheritance
- Deficient enzyme: no. 3 (porphobilinogen [PBG] deaminase, cytoplasmic), chromosome 11q
ALA dehydratase deficient porphyria (ADP)
- Acute; autosomal recessive inheritance
- Deficient enzyme: no. 2 (ALA dehydratase, cytoplasmic), chromosome 9q
Congenital erythropoietic porphyria (CEP)
- Chronic; autosomal recessive inheritance
- Deficient enzyme: no. 4 (uroporphyrinogen III synthase, cytoplasmic), chromosome 10q
Erythropoietic protoporphyria (EPP)
- Chronic; autosomal recessive inheritance
- Deficient enzyme: no. 8 (ferrochelatase, mitochondrial), chromosome 18q
Hereditary coproporphyria (HCP)
- Acute; autosomal dominant inheritance
- Deficient enzyme: no. 6 (coproporphyrinogen oxidase, mitochondrial), chromosome 1q
Porphyria cutanea tarda (PCT)
- Chronic; either acquired (type 1) or autosomal dominant with incomplete penetrance (type 2)
- Deficient enzyme: no. 5 (uroporphyrinogen decarboxylase, cytoplasmic), chromosome 1p
Hepatoerythropoietic porphyria (HEP): rare homozygous recessive uroporphyrinogen decarboxylase deficiency
Variegate porphyria (VP)
- Acute; autosomal dominant inheritance
- Deficient enzyme: no. 7 (protoporphyrinogen oxidase, mitochondrial), chromosome 3q
X-linked protoporphyria (XLP)
- Chronic; X-linked dominant inheritance
- Gain-of-function mutation in enzyme no. 1 (ALA synthase, mitochondrial), chromosome Xp

EPIDEMIOLOGY

PCT: prevalence 1/10,000 to 1/25,000 (3,4)
- Most common porphyria overall
- Onset: ages 20 to 50 years
HEP: very rare, onset in infancy (3,4)
AIP: prevalence 1/100,000 (3,4)
- Most common acute porphyria
- Onset: puberty to age 40 years
EPP: prevalence 1/140,000 (3,4)
- Most common pediatric porphyria
- Onset: ages 1 to 4 years
VP: prevalence 1/250,000 (3,4)
- Onset: puberty to age 30 years
CEP: ~150 cases reported (3,4)
- Onset: infancy to age 10 years
XLP: prevalence 1/700,000 (3,4)
- Onset: childhood
HCP: prevalence <50 cases reported (3,4)
- Onset: after puberty
ADP: prevalence <10 cases reported (3,4)
- Onset: both childhood and adulthood

ETIOLOGY AND PATHOPHYSIOLOGY

Acute porphyrias: overproduction of porphyrins or precursors (ALA, PBG) proximal to defect (1)
Chronic porphyrias: overproduction of porphyrins proximal to defect. Precursors are not increased (1).
Neurovisceral/psychiatric symptoms: caused by ALA interactions with GABA and glutamate receptors, thus specific to acute porphyrias (1)
Dermatologic symptoms: caused by UV-induced oxidative damage induced by porphyrins (4)
- Possible in all porphyrias except AIP and ADP

RISK FACTORS

Triggers of acute porphyria attack
- Cytochrome p450 inducers (rifampin, phenytoin, barbiturates, griseofulvin, carbamazepine)
- Sulfa drugs, estrogen, macrolides, steroids
- Pregnancy (however, porphyria does not complicate pregnancy or neonatal course)
- Starvation, alcohol, tobacco, viral infections
Porphyria cutanea tarda
- Iron overload (e.g., hemochromatosis)
- Exogenous estrogen
- Hepatitis C or HIV infection
- Alcohol (acute ingestion or chronic use)
- Chlorinated hydrocarbons (e.g., fungicides)

DIAGNOSIS

HISTORY

Symptoms of acute porphyria attacks (2,4,5)[C]
- Psychiatric: depression, disorientation, psychosis
- Gastrointestinal: abdominal pain (steady, poorly localized), vomiting, constipation
- Neurologic: proximal weakness, numbness, paresthesias, seizures
- Dermatologic: VP and HCP may have photosensitivity similar to chronic porphyrias.
- Other: Red/brown urine is sometimes present.
Symptoms of chronic porphyrias (2,4,5)[C]
- Dermatologic
  - Skin fragility, vesicles, scars, hypertrichosis, altered pigmentation (common in PCT)
  - Bacterial superinfection of skin lesions
  - Painful photosensitive skin (without significant blistering) is suggestive of EPP.
- Other (2,4,5)[C]
  - Red/brown urine
  - CEP: keratitis, erythrodontia, hepatosplenomegaly, jaundice

PHYSICAL EXAM

Signs of acute porphyria attacks (2,4,5)[C]

Tachycardia and hypertension
Altered mental status, including anxiety, depression, or frank psychosis
Respiratory distress, paralysis, or failure
Abdominal/neurovisceral disturbances
Motor neuropathies ± paresthesias (e.g., paresis, paralysis, hyporeflexia, urinary retention)

DIFFERENTIAL DIAGNOSIS

Heavy metal toxicity (e.g., lead poisoning) (2,6)[C]
Neuropsychiatric disturbances (e.g., intoxication, Guillain-Barre syndrome, delirium, psychosis, somatoform disorders) (2,6)[C]
Dermatologic disorders (e.g., epidermolysis bullosa, drug reactions, xeroderma pigmentosum) (4,6)[C]
Pseudoporphyria (identical presentation as PCT but with normal porphyrin levels) (6)[C]
- Disease-induced: renal/hepatic failure
- Drug-induced: NSAIDs, furosemide, fluoroquinolones, tetracyclines, retinoids

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

Nonspecific porphyria findings (2,5)[C]
- Hyponatremia in 40% of acute attacks
- Anemia (hemolytic in CEP, sideroblastic in XLP)
- Abdominal x-ray: normal or, possibly, ileus
Acute porphyria (2,4,5)[B]
- Spot (not 24 hour) urinary PBG ± ALA
- If elevated (>10 times upper limit normal): Begin empiric treatment after saving urine, blood, and stool specimens for further analysis.
- If VP is suspected: Consider plasma fluorescence emission spectroscopy.
- PBG/ALA levels normal during remission
- AIP: infrequently, only nonerythroid isoform enzyme mutation, so hepatic dysfunction but normal intra-RBC levels of PBG
Chronic porphyria (2,5)[B]
- Elevated serum and urine total porphyrins
  - EPP: urine porphyrins normal ¢ check total erythrocyte porphyrins or stool porphyrins
- If PCT or EPP suspected: consider plasma fluorescence emission spectroscopy

Follow-Up Tests & Special Considerations

DNA mutation analysis and genetic counseling helpful to identify family members carrying mutations (2,5)[B]
"Dual porphyria, " rare but possible, generally a gene defect coupled with acquired PCT (3)[C]

TREATMENT

GENERAL MEASURES

Neuropsychiatric: avoidance of precipitating factors (e.g., alcohol or offending drugs) (1,5)[C]
Searchable database of porphyria drugs at http://www.porphyriafoundation.com/drug-database/
- Dermatologic: protective clothing and eyewear, avoidance of UV exposure or trauma (1,5)[C]
Hepatic: avoidance of iron supplements, estrogens, or hepatotoxic agents, particularly in PCT (1,5)[C]

MEDICATION

First Line

Treatment of acute porphyria attacks (2,5)[B]
- Carbohydrate loading/oral glucose
  - Often sufficient for mild attacks (e.g., without neurologic signs or hyponatremia)
  - Typical dose: at least 300 g/day PO
- IV hemin
  - Initial treatment for attacks with neurologic signs or hyponatremia
  - 1:1 hemin dilution with 4 " 20% albumin has lower rates of postinfusion venous irritation.
  - Safe during pregnancy
  - Typical dose: 2 to 4 mg/kg/day IV for 3 to 14 days
Supportive treatment (2,5)[B]
- Opiates, phenothiazines, laxatives, ²-blockers, benzodiazepines as needed
  - Avoid use of calcium channel blockers, particularly nifedipine.
  - IV magnesium sulfate if adrenergic overdrive (tachycardia, hypertension, seizures)
Treatment of chronic porphyria (2,4,5,7)[B]
- Chloroquine
  - Increases porphyrin clearance in PCT (except in hepatoerythropoietic porphyria)
  - Consider for PCT if phlebotomy not feasible (see "Additional Therapies " )
  - Can trigger acute attacks; do not use to treat acute porphyrias such as VP.
  - Typical dose: 125 mg PO twice weekly
- Oral ²-carotene or melanocyte-stimulating hormone analogues such as afamelanotide
  - Increases tolerance to sunlight in EPP
  - Main side effect: skin discoloration

Second Line

IV glucose or 10 " 20% dextrose solution (2,5)[C]
- Consider in acute porphyria attacks.
- Risk of worsening hyponatremia, potentially leading to seizures
Gonadotropin-releasing hormone analogues (5)[C]
- Consider in women with recurrent premenstrual attacks of porphyria.
- Side effects may include infertility and osteopenia.

ADDITIONAL THERAPIES

Periodic phlebotomies (2,4,5)[B]
- Resolves PCT dermatologic symptoms and normalizes porphyrins, typically within 1 year
- Track total serum porphyrin and hemoglobin to monitor progress and avoid iatrogenic anemia.
- Typical regimens: 500 mL venesection every 2 weeks or 300 mL venesection weekly
Allogeneic liver transplantation (7)[C]
- Curative for AIP and VP but involves risks and morbidity of major surgery
- EPP: controversial, as disease may reoccur; may consider bone marrow transplant
- Perioperative lowering of poryphyrin levels is important to prevent light-induced tissue burns (complication: perforation) or posttransplant neuropathy requiring ventilation
Special treatments for CEP and EPP (2,5)[C]
- Activated charcoal binds porphyrins in gut.
- RBC transfusions for CEP (may be started in utero); monitor for long-term iron overload.
- Upfront iron chelation with deferasirox may benefit CEP patients (8)[C].
- Bone marrow transplant is often curative.
- Plasmapheresis may lower rates of disease recurrence in EPP after liver transplantation.

ISSUES FOR REFERRAL

Acute porphyrias (5)[C]
- Hematologic referral for administration and monitoring of IV hemin
- Genetic counseling is recommended after any diagnosis of acute porphyria.
- Referral to clinical psychologist for behavioral symptoms, psychosis, or adjustment disorder
Chronic porphyrias (3,5)[C]
- Hematologic referral recommended for monitoring of phlebotomies in PCT
- Genetic counseling generally not required for PCT unless HEP suspected

INPATIENT CONSIDERATIONS

Admission Criteria/Initial Stabilization

Admission criteria for acute porphyrias (5)[C]
- Any neurologic symptoms (e.g., seizures, respiratory insufficiency)
- Documented hyponatremia
- Intractable symptoms (e.g., pain or vomiting)
Inpatient monitoring for acute porphyrias (2,5)[C]
- Frequent neurologic exams
- Electrolyte measurements q8 " 12h
- Complete blood count, liver function tests, inflammatory markers (e.g., CRP) twice weekly

IV Fluids
Normal saline as needed to maintain adequate hydration while monitoring for appropriate rate of hyponatremia correction (5)[C]
Nursing
To prevent heme-related irritation with nonalbumin preparations, alternate between large veins and flush vein with 250 mL normal saline after infusion (5)[C].

ONGOING CARE

Patient Monitoring

Acute porphyrias: frequent neurologic exams and monitoring of electrolytes, blood counts, liver function, and inflammation markers (5)
PCT: Screen for other potential causes of hepatic dysfunction (hemochromatosis, viral hepatitis) (4,5).

DIET

Carbohydrate loading (see earlier discussion)
Nutrition/dietary consultation for patients with acute porphyria (5)

PATIENT EDUCATION

The American Porphyria Foundation: http://www.porphyriafoundation.com/ or (866)-APF-3635
The Drug Database for Acute Porphyria: http://www.drugs-porphyria.org/

PROGNOSIS

Acute attacks generally self-resolve within 1 to 2 weeks, with no effect on longevity (2)
<10% of patients with acute porphyria suffer recurrent acute attacks (2).
PCT responds well to phlebotomy, chloroquine, and UV/trauma avoidance (4,5).
Liver transplantation is curative for acute porphyrias but not for EPP (2,7).

COMPLICATIONS

Acute attack may lead to respiratory failure or permanent neurologic sequelae (5).
Increased risk of hepatocellular carcinoma from both acute porphyrias and PCT (2,5)
Long-term use of IV hemin can lead to iron overload or loss of venous access (5).

REFERENCES

11 Chiabrando D, Mercurio S, Tolosano E. Heme and erythropoiesis: more than a structural role. Haematologica. 2014;99(6):973 " 983.22 Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Blood. 2012;120(23):4496 " 4504.33 Whatley SD, Badminton MN. Role of genetic testing in the management of patients with inherited porphyria and their families. Ann Clin Biochem. 2013;50(Pt 3):204 " 216.44 Schulenburg-Brand D, Katugampola R, Anstey AV, et al. The cutaneous porphyrias. Dermatol Clin 2014;32(3):369 " 384.55 Stein P, Badminton M, Barth J, et al. Best practice guidelines on clinical management of acute attacks of porphyria and their complications. Ann Clin Biochem. 2013;50(Pt 3):217 " 223.66 Turnbull N, Callan M, Staughton RCD. Diclofenac-induced pseudoporphyria: an under-recognized condition? Clin Exp Dermatol. 2014;39(3):348 " 350.77 Singal AK, Parker C, Bowden C, et al. Liver transplantation in the management of porphyria. Hepatology. 2014;60(3):1082 " 1089.88 Egan DN, Yang Z, Phillips J, et al. Inducing iron deficiency improves erythropoiesis and photosensitivity in congenital erythropoietic porphyria. Blood. 2015;126(2):257 " 261. doi:10.1182/blood-2014-07-584664.

ADDITIONAL READING

Bonkovsky HL, Maddukuri VC, Yazici C, et al. Acute porphyrias in the USA: features of 108 patients from porphyrias consortium. Am J Med. 2014;127(12):1233 " 1241.
Bissell DM, Lai JC, Meister RK, et al. Role of delta-aminolevulinic acid in the symptoms of acute porphyria. Am J Med. 2015;128(3):313 " 317.

CODES

ICD10

E80.20 Unspecified porphyria
E80.29 Other porphyria
E80.21 Acute intermittent (hepatic) porphyria
E80.0 Hereditary erythropoietic porphyria
E80.1 Porphyria cutanea tarda

ICD9

277.1 Disorders of porphyrin metabolism

SNOMED

porphyria (disorder)
Porphyria cutanea tarda (disorder)
Acute intermittent porphyria
Erythropoietic protoporphyria (disorder)

CLINICAL PEARLS

Symptoms of acute porphyria classically include severe nonfocal gastrointestinal pain and neuropsychiatric disturbances.
Once the diagnosis of acute porphyria is made with elevated urinary PBG and/or ALA, empiric treatment with oral glucose (if mild) or IV hemin (if severe) should be initiated.
PCT, the most common porphyria, classically manifests with dermatologic symptoms that respond well to phlebotomy or chloroquine.
For patients newly diagnosed with porphyria, counseling is important regarding diet, medications, and family screening.

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