Porphyrias Victor Gordeuk, MD Thursday, August 13, 2020 © 2020

Porphyrias Thursday, August 13, 2020 Victor Gordeuk, MD

Outline 1. General considerations; heme synthesis 2. Acute hepatic porphyrias 3. Cutaneous porphyrias 4. Summary 5. Case reports 5 ‐ Porphyria Victor R. Gordeuk, MD

Porphyrias • Disorders of heme synthesis • Defect of specific enzyme in heme biosynthetic pathway – overproduction of heme precursors formed prior to defect –  activity of rate‐controlling ALA synthase

Enzymes of Heme Biosynthesis Porphyrins and Precursors Enzyme Chromosome Porphyria with defect 1ALA synthase 2 Xp11.2 X‐linked protopophyria • Measure in urine (water • Measure in feces (fat 2ALA dehydratase 9q32 Plumboporphyria soluble) soluble) 3PBG deaminase 11q23.3 Acute intermittent porphyria – ALA (aminolevulinic acid) – Coproporphyrin 4 Uroporphyrinogen III synthase 10q26.2 Congential erythropoietic porphyria – PBG (porphobilinogen) – Protoporphyrin 5 Uroporphyrinogen decarboxylase 1q34.1 Porphyria cutanea tarda – Uroporphyrin, • Measure in RBCs Coproporphyrin 6 Coproporphyrinogen oxidase 3q12.1 Hereditary coproporphyria – Protoporphyrin

7 Protoporphyrinogen oxidase 1q23.3 Variegate porphyria

8 Ferrochelatase 18q21.31 Erythropoietic protoporphyria

Broad Classification Acute Porphyrias

• Acute hepatic porphyrias • Non‐acute or cutaneous 1. Autosomal dominant – Porphyrins proximal to – Porphyrins proximal to defect • But rare ALA dehydratase deficiency is recessive defect increased increased 2. Heterogeneous mutations – Earliest porphyrin precursors – But, ALA and PBG not • Deletion, alternative splicing,  mRNA stability, missence (ALA, PBG) increased increased 3. Long quiescent periods and neurovisceral ‘attacks’ caused by hepatic overproduction: • ALA (γ‐aminobutyric acid analog) and/or • PBG (interacts with GABA or glutamate receptors)

Acute Porphyrias Acute Porphyrias‐ Presenting Symptoms

Type Enzyme defect Inheri‐ Age Biochemistry System Symptom or Sign Incidence tance onset Plumboporphyria ALA dehydratase Autosomal Child Urine: ALA Gastrointestinal Abdominal pain 85‐95% Recessive Acute PBG deaminase Autosomal Adult Urine: PBG and ALA Vomiting 43‐88% intermittent Dominant porphyria Constipation 48‐84% Hereditary Copropor‐ Autosomal Adult Urine: ALA, PBG, Diarhea 5‐12% coproporphyria phyrinogen Dominant coproporphyrin oxidase Stool: copropor. Cardiovascular Tachycardia 28‐85% Variegate Protopor‐ Autosomal Adult Urine: ALA, PBG, porphyria phyrinogen Dominant coproporphyrin Systemic hypertension 36‐55% oxidase Stool: coproporyrin, protoporphyrin Anderson et al. Ann Intern Med 2005;142:439‐450.

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Acute Porphyrias‐ Presenting Symptoms Acute Porphyrias‐ Precipitating Factors

System Symptom or Sign Incidence 1. Drugs Neurologic Pain – www.porphyriafoundation.org (extremities, back, chest, head) 50‐70% – www.drugs‐porphyria.org Paresis 42‐68% Respiratory paralysis 9‐20% 2. Others – Females of child‐bearing years Mental symptoms 40‐58% – Fasting, dieting, stress, smoking Convulsions 10‐20%

Anderson et al. Ann Intern Med 2005;142:439‐450.

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Acute Hepatic Porphyrias Drugs and Acute Porphyrias Early Dx of AHP in Symptomatic Patient (see www.porphyriafoundation.org and www.drugs‐porphyria.org)

Unsafe Unsafe Unsafe Safe Safe Urine PBG (protect from light) and ALA Alcohol Ergots Primidone Acetominophen Insulin – PBG Increased in AIP, hereditary coproporphyria, variegate Barbiturates Glutethimide Progesterone Aspirin Penicillin Carbamazepine Griseofulvin Pyrazinamide Atropine Penicillin derivatives porphyria Carisoprodol Mephenytoin Pyrazolones Bromides Phenothiazines – PBG Levels of 20‐200 mg/L (normal <2.5 mg/L) Clonazepam Meprobamate Rifampin Cimetidine Ranitidine Danazol Methyprilon Succinimides Erythropoietin Streptomycin – ALA increased in all four acute hepatic porphyrias Diclofenac, Metoclopramide Sulfonamides Gabopentin – Measure in an acute, symptomatic attack NSAIDS Phenytoin Valproic acid Glucocorticoids

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Acute Hepatic Porphyrias Acute Hepatic Porphyrias Acute Porphyrias‐ Rx of Acute Attack Acute Porphyrias‐ Rx of Acute Attack

1. Hospitalize, withdraw 3. Use meds known to be 4. Begin hemin urgently 6. Monitor patient closely: unsafe meds safe • Inhibits delta‐amiolevulinic • PFTs: if vital capacity 2. Provide nutrition and • narcotics for pain acid synthetase impaired, place pt in ICU supportive Rx • phenothiazines for nausea or • 3‐4 mg/d for 3‐14 d • neurologic status, especially vomiting • IV fluids for dehydration, 5. IV glucose proximal muscle strength electrolyte imbalances • beta blockers for • serum electrolytes, hypertension, tachycardia • administer while awaiting • seizure precautions if pt delivery of hemin creatinine, Mg daily hyponatremic • 10% solution, at least 300 g daily • watch for bladder distention.

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Acute Hepatic Porphyrias Acute Hepatic Porphyrias Acute Hepatic Porphyrias‐ Chronic Rx Acute Intermittent Porphyria

1. Manage chronic pain. Address depression or other • Autosomal dominant deficiency neuropsychiatric problems of PBG deaminase 2. Prevent acute attacks - >375 mutations 3 • Avoid unsafe drugs • Prevalence • Maintain adequate intake of carbohydrates - ~1/10,000 European ancestry 3. Pharmacologic options to prevent acute attacks - Also present in African Americans • Gonadotropin‐releasing hormone analogues to suppress ovulation • Clinical expression in <10% of • Regular transfusion of hemin those with mutation • Givosiran, approved by FDA 2019. siRNA directed at ALAS1 mRNA. Given by S.C. injection once per month.

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Acute Hepatic Porphyrias Acute Hepatic Porphyrias Acute Intermittent Porphyria AIP‐ Diagnosis • Urine • Symptoms and signs – Clear but darkens with light exposure – GI (95%) – Large excess PBG, ALA – Neuropathy (66%) • Blood – Cardiovascular (70%) – Low RBC PBG deaminase (~50%) confirms dx – Hyponatremia in severe attack – ~10% of pts have nl RBC PBG deaminase but decreased hepatic – Photosensitivity not present activity • Long term‐ increased risk of hepatocellular CA • Differential Diagnosis – Guillain‐Barre; heavy metal poisoning; PNH

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Acute Hepatic Porphyrias Acute Hepatic Porphyrias Hereditary Coproporphyria Hereditary Coproporphyria • Diagnosis – Urine ALA and PBG increased 6 – RBC PBG deaminase not decreased • Autosomal dominant deficiency copro‐porphyrinogen III –  Stool coproporphyrin (> stool protoporphyrin) oxidase; >60 mutations –  Urine coproporphyrin • AIP sx’s plus photosensitivity • Neurovisceral attacks and skin lesions usually occur together

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Acute Hepatic Porphyrias Acute Hepatic Porphyrias Variegate Porphyria Variegate Porphyria • Diagnosis • Autosomal dominant deficiency protopor‐phyrinogen oxidase; – Urine ALA and PBG elevated >160 mutations 7 – RBC PBG deaminase not decreased • 1/400 white South Africans –  Stool protoporphyrin (> stool coproporphyrin) • AIP sx’s plus photosensitivity, –  Urine coproporphyrin (> urine uroporphyrin) scarring • Neurovisceral attacks and skin lesions may occur separately

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Acute Hepatic Porphyrias Acute Hepatic Porphyrias ALA Dehydratase Deficiency Acute Porphyria Management Summary 1. Spot urine PBG level for 4. Avoid precipitating factors 2 rapid Dx if possible – Suppress ovulation with 2. Carbohydrates to  LHRH agonists • Rare homozygous defect; 12 mutations porphyrin synthesis 5. Consider IV hematin or SC • Diagnosis – PO 1500‐2000 kcal/24 h – Urine ALA elevated givosiran – Urine PBG not increased – IV 10‐ 20% dextrose 6. Mutation analysis in pts and • Differential Diagnosis 3. IV hematin (early) family – Tyrosinemia; plumbism (lead posoning) – 3‐4 mg/kg IV qd

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Cutaneous Porphyrias Cutaneous Porphyrias Cutaneous Porphyrias Cutaneous Porphyrias

Type Enzyme defect Inheritance Age Biochemistry • Variable inheritance onset Porphyria cutanea tarda Uroporphyrinogen Autosomal Adult Urine: • Cutaneous photoxicity (PCT) decarboxylase dominant uroporphyrin – Porphyrins deposited in upper layers of skin Hepatoerythropoietic Uroporphyrinogen autosomal Infant Urine: porphyria decarboxylase recessive uroporphyrin – Reactive oxygen species Erythropoietic Ferrochelatase autosomal Child to RBC: – Oxidative membrane damage to mast cells protoporphyria dominant adult protoporphyrin Congenital erythropoietic Uroporphyrinogen III autosomal Infant Urine, stool: copro‐ – Complement activation porphyria synthase recessive porphyrin 1 X‐linked protoporphyria Aminolevulinic acid X‐linked Child to RBC: synthase 2 adult protoporphyrin

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Cutaneous Porphyrias Cutaneous Porphyrias Porphyria Cutanea Tarda Porphyria Cutanea Tarda 1. Sx’s when hepatic uroporphyrinogen decarboxylase activity ≤20% of nl urine darker than control 2. Type 1 acquired form is most common 5 – Nl URO‐D activity when asymptomatic

Blistering and scarring of 3. Type 2 hereditary form; <100 mutations Fluorescence sun‐exposed skin – Autosomal dominant after acidification – ~50% URO‐D activity when asymptomatic Hyper‐ trichosis Cloeren and Craig. 4. Manifestations precipitated by co‐factors NEJM 2001;245 no. 14

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Cutaneous Porphyrias Cutaneous Porphyrias Porphyria Cutanea Tarda Porphyria Cutanea Tarda 5. Most common porphyria 7. Down‐regulation of hepcidin may underlie increase in – 1‐5 cases/25,000 iron stores 6. Precipitating factors oxidize uroporphyrinogen, which 8. Manifestations inhibits URO‐D – Bullous dermatosis (blistering skin lesions) –  iron stores; HFE, African iron overload – Scarring – Hepatitis C (>50% of pts +), HIV – Hyperpigmentation – Alcohol, estrogens – Hypertrichosis – Exposure to fungicide hexachlorobenzene (Turkey, 1956)

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Cutaneous Porphyrias Cutaneous Porphyrias Porphyria Cutanea Tarda Porphyria Cutanea Tarda 9. Evaluation 10. Treatment – Elevated urinary total porphyrins (uroporphyrin >>> – Avoid precipitating factors coproporphyrin) – Avoid sun and use opaque sun‐block if outdoors: (responsible – Genetic testing light is at 400 nm and not blocked by most sunscreens) – Screen for HFE C282Y homozygosity and other forms of iron – Phlebotomy 500 ml/wk until remission overload – Iron chelation if phlebotomy not possible – Evaluate for viral hepatitis/other liver disease; R/O hepatocellular carcinoma

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Cutaneous Porphyrias Cutaneous Porphyrias Hepatoerythropoietic Porphyria Erythropoietic Protoporphyria

• Biallelic URO‐D mutations • Management • Deficiency of ferrochelatase (homozygous PCT) – Avoid sunlight including – Autosomal dominant; >135 mutations – URO‐D activity 3‐10% of nl; dx longwave UV light that passes – Sxs begin from childhood to adulthood through glass in childhood – ~10% with mutant allele develop sxs; 8 –  uroporphyrin and – Use opaque sunscreens related to RNA output of non‐mutated heptacarboxylporphyrin in (contain zinc oxide and allele titanium dioxide) urine • More common than congenital –  Zn‐protoporphyrin in RBCs – Avoid alcohol, estrogens, erythropoietic protoporphyria smoking, drugs that induce cytochrome P450

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Cutaneous Porphyrias Cutaneous Porphyrias Erythropoietic Protoporphyria Erythropoietic Protoporphyria

• Symptoms & signs • Diagnosis • Treatment – Photoprotection – Erythrema, urticaria, – Massive increase pruritus, burning sensation erythrocyte protoporphyrin – Beta carotene may protect from dermal toxicity of sun‐exposed skin – Cholestyramine may interrupt protoporphyrin enterohepatic recycling – Hepatic dysfunction later in life from porphyrin – Liver transplant for hepatic failure deposition in the liver, may be fatal

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Cutaneous Porphyrias Cutaneous Porphyrias X‐LInked Protoporphyria Congenital Erythropoietic Porphyria

• Gain of function mutation in • Uroporphyrinogen III ALAS2 synthase deficiency – Autosomal recessive, rare • Clincal findings identical to but >35 mutations 4 erythropoietic – Upregulation of ALAS2 protoporphyia • Typical onset at birth

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Cutaneous Porphyrias Cutaneous Porphyrias Congenital Erythropoietic Porphyria Congenital Erythropoietic Porphyria • Uroporphyrin 1 in RBCs, plasma, • Hemolytic anemia, urine, skin splenomegaly • Treatment – severe cutaneous photosensitivity – Avoidance of sun or sunscreens – Scarring – RBC Tx’s to reduce erythropoiesis – Most disfiguring porphyria – Chloroquine, hematin, hydroxyurea • Uroporphyrin 1 deposits in teeth – Allogeneic hemopoietic stem cell transplant – Discoloration of teeth – Iron chelation

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Porphyria: Clinical Approach Summary Clinical Approach Summary

1. General principles 2. Acute hepatic porphyria 3. Cutaneous porphyria 4. Mutation analysis (neurovisceral sx’s) (photosensitivity) • Symptomatic porphyria • Mount Sinai Genetic Testing Lab‐ always has  heme • Measure urinary PBG‐  in • PCT‐  urinary Porphyria DNA Testing 866‐322‐ precursors; absence AIP, VP, HCP uroporphyrin indicates sx’s not due to 7963; [email protected] • Measure RBC PBG porphyria. • EPP‐  RBC free deaminase; if nl, measure protoporphyrin • Alnylam Pharmaceuticals, Inc. • During asymptomatic stool coproporphyrin and 1.800.436.3037 periods, individuals with protoporphyrin • CEP‐  uroporphyrin 1 in enzymatic defect may have plasma and urine nl heme precursor levels.

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Clinical Case 1: Clinical Case 1: • Hx: 24‐yo female; abd. pain; progressive weakness in • Findings suggestive of AIP extremities, mild resp. distress. • Further work‐up: rapid screen of urine shows  PBG. RBC • Past Hx: multiple admissions for abd. pain; moderate PBG deaminase level 50%. alcohol; estrogen‐containing OCT. • Management: 10% dextrose; panhematin; narcotics; Correct • PE: diffuse abd. tenderness; generalized motor weakness; hyponatremia. Monitor resp. status and urine ALA, PBG. poor resp. effort. • Prevention: avoid alcohol, estrogen, smoking, certain other • Lab: Na+ 129 mEq/L. meds; monitor for hepatoma. • Course: intubation, mech. ventilation in 12 h.

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Clinical Case 2: Clinical Case 2: • Hx: 52‐yo female; life‐long painful photosensitivity • Findings of eyrthropoietic protoporphyria • Past Hx: Pt. protects herself from sunlight; no alcohol; no • Management: protection from sunlight; trial of beta‐ meds. carotene was given. • PE: no chronic skin changes or hepatomegaly. • Clinical course: progressive hepatic dysfunction; liver bx showing cirrhosis and hepatocellular accumulation of • Lab: AST 96 U/L. Urine ALA, PBG, uroporph. Nl; RBC crystalline pigment. protoporphyrin 18,900 ug/dL (nl <90).

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Clinical Case 3: Clinical Case 3: • Hx: 48‐yo male; blistering lesions on sun‐exposed areas 2 y; • Findings suggest PCT. sunscreens do not help; no abd pain. • Further work‐up: Urinary ALA and PBG nl; urinary • Past Hx: Hepatitis C pos; HIV neg; regular alcohol uroporphyrin increased; neg for HFE C282Y consumption. • Management: use of opaque sunscreen; avoid alcohol; • PE: blistering and scarring on dorsum of hands. phlebotomy; screen for hepatoma. • Lab: CBC and LFT’s nl. Ferritin 500 ng/ml. • Clinical course: resolution of symptoms after four phlebotomies.

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