PORPHYRIAS presentationsndclimical features.pptx

PORPHYRIAS

1. PORPHYRIA Moderator: Dr. Linda Marangmei Presenter: Dr. Vikashe Swu

2. PORPHYRIA Metabolic disorders Deficiency or increased activity of specific enzyme in Heme biosynthesis Inherited – AD, AR, X-linked Sporadic ( Eg : porphyria cutanea tarda )

3. Classification of Porphyrias Depending on whether the heme biosynthetic intermediates arise from the liver or erythrocyte precursors Hepatic porphyrias Erythropoietic porphyrias

4. Hepatic Porphyrias ALA-dehydratase deficient porphyria (ADP) Acute Intermittent porphyria (AIP) Porphyria cutanea tarda (PCT) Hereditary coproporphyria (HCP) Variegate porphyria (VP)

5. Erythropoietic Porphyria Congenital erythropoietic porphyria (CEP) Erythropoietic protoporphyria (EPP) X-linked protoporphyria (XLP)

6. Acute Intermittent Porphyria (AIP) AD, hepatic porphyria Most common acute porphyria Induction and increased expression of ALAS1 in heterozygotes Half-normal level of HMB-synthase activity

7. Triggers

8. Peripheral neuropathy due to axonal degeneration Primarily motor neurons Proximal muscles, often shoulders and arms Psychiatric manifestations – anxiety, depression, insomnia, hallucinations Seizures – neurologic or hyponatremia

9. Diagnosis High degree of suspicion Increased ALA and PBG in urine/plasma Urine for porphyrins commonly employed in India Two types of tests exist Qualitative analysis Quantitative analysis

10. Specific Therapies

11. Hemin Therapy 1st line for all acute attack Heme arginate , Heme albumin or lyophilized hematin are usually infused daily (3–4 mg/kg) into a large peripheral vein for 3–4 consequent days/clinical improvement

12. Dextrose Therapy If hemin not available IV Glucose, 300- 500g/day Mild acute attack

13. Orthotopic Liver Transplant Intractable attacks Refractory to hemin therapy

14. Supportive Treatment Abdominal pain - narcotic analgesics Nausea, vomiting - phenothiazines Insomnia- choral hydrate, low dose benzodiazepines Hyponatremia correction Avoidance of inciting factors

15. Emerging therapies GIVOSIRAN Hepatic-targeted RNA interference therapy Silence expression of ALAS1 mRNA – reduce ALA/PBG 2.5mg/kg monthly s/c injection Gene Therapy

16. ALA- dehyradatase -Deficient Porphyria (ADP) Rare AR, hepatic porphyria deficiency of ALA dehydratase activity in erythrocytes (<10%) Symptoms resemble AIP, including abdominal pain and neuropathy Diagnosis: Elevated levels of ALA – plasma/urine Elevated levels of COPRO) III - urine Prenatal diagnosis - determination of ALA-dehydratase activity/gene mutation in cultured chorionic villi or amniocytes Treatment: Similar to that of AIP

17. Porphyria Cutanea Tardea (PCT) Most common type of porphyria in adults Sporadic (type-1) and familial (type-2) Deficiency of Hepatic URO-decarboxylase Susceptiple factors – Hepatitis C, HIV, excess alcohol, elevated iron and estrogens C/F Blistering skin lesions (commonly on back of hands), Milia Hypertrichosis, hyperpigmentation on the face Chronic liver disease, risk of hepatocellular carcinoma

18. Diagnosis increased porphyrins in liver, plasma, urine and stool Isocoproporphyrins (feces; plasma/urine) – diagnostic for hepatic URO-decarboxylase deficiency Fluorometric scanning of diluted plasma can distinguish PCT and VP Treatment: Repeated phlebotomy – 450ml removed every 1-2 weeks until serum ferritin reaches the lower limit of normal Low dose chloroquine (125mg twice/week) or hydroxychloroquine

19. Hereditary Coproporphyria (HCP) AD hepatic porphyria Decreased activity of COPRO-oxidase Symptoms similar to AIP; but less severe More common in women

20. Diagnosis: Increased fecal porphyrins (COPRO III); distinguishes it from other porphyrias Treatment: Similar to AIP

21. Variegate Porphyria (VP) AD hepatic porphyria Deficient activity of PROTO-oxidase Particulary common in South Africa C/F: skin photosensitivity, acute neurovisceral crises acute attacks and precipitating are identical to AIP blistering skin lesions are same those of PCT – difficult to treat/ longer duration

22. Diagnosis: Urinary ALA and PBG levels are increased during attack but returns to normal more quickly than AIP Increased fecal protoporphyrin and COPRO III Increased urinary COPRO III Fluorescence emission spectrum of porphyrins in plasma - differentiates VP from other porphyrias Treatment: Acute attacks are treated same as AIP Hemin Givosiran

23. ERYTHROPOIETIC PORPHYRIAS Excess porphyrins from bone marrow precursors are transported via the plasma to the skin and leads to cutaneous photosensitivity

24. X-linked protoporhyria Deficient activity of the erythroid form of ALA-synthase 2 (ALAS2) Ineffective erythropoiesis C/F: Typically males Refractory anemia, weakness, pallor Secondary hypersplenism – iron overload and can develop hemosiderosis PBS - hypochromic microcytic anemia

25. Diagnosis: decreased ALAS2 activity in bone marrow BM exam – hypercellularity with a left shift Prussian blue-staining sideroblasts Treatment: Pyridoxine supplementation – cofactor for ALA-synthase activity Unresponsive patients – transfusion and chelation therapy

26. Congenital Erythropoietic Porphyria (CEP) Also known as Gunther’s disease AR deficient activity of URO-synthase – accumulation of URO-I and COPRO-I

27. C/F: Severe cutaneous photosensitivity (birth) – bullae, vesicles, skin thickening, hypo/hyperpigmentation, hypertrichosis Brownish teeth – deposition of porphyrins Splenomegaly due to marked increase in erythrocyte porphyrins – hemolysis Diagnosis: URO-I and COPRO-I – bone marrow, erythrocytes, plasma, urine and faeces In-utero – measuring porphyrins in amniotic fluid and URO-synthase activity in cultured amniotic cells or chorionic villi Treatment: Transfusion, Splenectomy, periodic phlebotomies, bone marrow and cord blood transplantation

28. Erythropoietic Porphyria (EPP) AR, deficient activity of FECH Most common erythropoietic porphyria in children Second most common porphyria in adults C/F: Skin photosensitivity – tingling, stinging, itching, or heat/burning sensation occurring within <10 to 30 mins of exposure Pain – out of proportion to visible skin involvement Chronic skin changes – lichenifiation , leathery pseudovesicles , labial grooving, and nail changes Severe abdominal and back pain (RUQ) CLD leading to liver failure

29. Diagnosis: Increased protoporphyrin IX - bone marrow, plasma, bile and feces ( hallmark of EPP ) erythrocyte in EPP exhibit red fluorescence under fluorescence microscopy decreased FECH activity in cultured lymphocytes or fibroblasts Treatment Afamelanotide – melanocyte stimulating hormone analogue Dersimelagon – selective melanocortin-1 receptor agonist Cholestyramine, porphyrin absorbents such as activated charcoal Plasmapheresis, IV hemin Liver transplantation

30. References: Harrison’s Principles of Internal Medicine; 21 st Edition

31. Thank You