porphyrias and approach in children ppt

Porphyrias are a group of inherited or acquired metabolic disorders resulting from a defect in the heme biosynthetic pathway, leading to accumulation of porphyrins or their precursors in tissues and body fluids.

Basic Concept:
• Heme is an essential component of hemoglobin, myoglobin, cytochromes, and various enzymes.
• It is synthesized mainly in the liver and bone marrow through a series of eight enzymatic steps.
• A deficiency or malfunction of any of these enzymes causes a build-up of intermediate compounds — these intermediates (porphyrins or their precursors) are toxic and lead to the clinical features of porphyria.

1. PORPHYRIAS Presenter – Dr. Mohid Syed Moderator- Dr.Ravindra Assistant professor

2. INTRODUCTION DEFINITION HEME BIOSYNTHETIC PATHWAY CLASSIFICATION CLINICAL FEATURES DIAGNOSIS APPROACH and TREATMENT OVERVIEW

3. Historical background Porphyria is named from the ancient Greek word porphura , meaning purple. referred to as a Vampire’s disease in medieval period .

4. The underlying mechanism of porphyria was first described by Felix Hoppe- Seyler in 1871. Acute porphyrias were described by the Dutch physician Barend Stokvis in 1889.

5. Definition : The porphyrias are rare inherited (or occasionally acquired) metabolic disorders due to deficiencies of enzymes in HEME synthesis . This leads to accumulation, increased excretion of porphyrins and its precursors. PORPHYRINS are organic compounds with four pyrrole rings. They are reffered to as ‘’PIGMENT OF LIFE’’.

6. Inherited enzyme deficiencies in which the enzyme substrate is usually excreted in excess in urine and/or feces. Defects of enzymes needed at various steps of heme synthesis result in distinct clinical syndromes known as porphyrias.

7. INCIDENCE The combined prevalence of the acute porphyrias is approximately 5 cases per 100,000 population. The prevalence of Erythropoietic porphyria in a study done by ‘European Dermatolgy Forum’ 2014 was estimated at 1.75 per 100,000 population.

8. Congenital erythropoietic porphyria is extremely rare. Less than 200 cases have been reported in the literature. [Source – annals of haematology 2012,kaplan]

9. There are high incidence reports of Acute Intermittent Porphyria in areas of India and Scandinavia. More than 200 genetic variants of AIP are known, some of which are specific to families, although some strains have proven to be repeated mutations.

10. Most commons & least common.. Porphyria cutanea tarda is the most common porphyria worldwide. Erythropoietic protoporphyria is the most common porphyria in pediatric age group. Congenital erytropoietic porphyria is the least common porphyria in incidence.

11. T he H eme biosynthetic pathway Porphyrins Containing ferrous ion in the center are called Heme and heme containing proteins are called hemeproteins. Heme is required for a variety of hemoproteins such as hemoglobin, myoglobin, respiratory cytochromes , and cytochrome P450 enzymes(CYPs ) in the liver. Synthesis of heme occurs in every human cell.

12. hemo p r o t ein

13. Hemoglobin synthesis in erythroid precursor cells accounts for approximately 85% of daily heme synthesis in humans. About 15-20% of heme synthesized in hepatocytes . Deficiency of each enzyme in the pathway is associated with a specific porphyria.

14. Biosynthesis of porphyrins Synthesized partly in Mitochondrion and partly in Cytosol of aerobic cells like developing erythrocytes and hepatic cells .

15. Stage 1- Synthesis of Aminolevulinic acid ALA ( Mitochndri a ) Stage 2- Synthesis of coproporphyrinogen III (major series) and coproporphyrinogen I (minor series) in cytosol. Stage 3- synthesis of protoporphyrin IX in m i tochondrion SYNTHESIS OF PORPHYRINS CAN BE DIVIDED INTO 3 STAGES

16. Heme is mainly required in bone marrow (for haemoglobin synthesis) and in liver (for cytochrome synthesis). On the basis of that, porphyrias are divided into Erythropoietic porphyrias Hepatic porphyrias . Hepatic porphyrias mainly affects nervous system, while Erythropoietic porphyrias primarily affects-skin.

17. Classification Based On Predominant Clinical Manifestations Neuropsychiatric : 1.Acute intermittent porphyrias(AIP) 2.ALA dehydratase porphyria(ALADP) Cutaneous (photosensitivity): 1.congenital erythropoietic porphyria(CEP) 2.porphyria cutanea tarda(PCT) 3.Erythropoietic porphyria(EPP) Mixed: 1.Hereditary copro-porphyria(HCP) 2.Variegate porphyria(VP)

18. Classification Based On Mode Of Presentation Of Disease Acute: 1.AIP 2.ALADP 3.HCP 4.VP Acute intermittent porphyria Aminolevulinic acid dehydratase def.P Hereditary coproporphyria Variegate porphyria Non acute (cutaneous): 1.PCT 2.EPP 3.CEP 4.HEP Porphyria cutanea tarda Eryhtropoietic protoporphyria Congenital erythropoietic porphyria Hepatoerythropoietic porphyria

19. Type o porphyria enzyme defect characteristics ERYTHROPOIETIC PORPHYRIA HEPATIC PORPHYRIA

20. Neuropsychiatric symptoms – minor behavioral problems to acute psychiatric symptoms like agitation, confusion, hallucinations, depression and altered consciousness, seizures may occur as neurologic manifestations due to hyponatremia.

21. URINE DURING ATTACK OF AIP

22. Porphyrias present in 2 distinct syndromes, ACUTE AND CHRONIC. ACUTE PORPHYRIAS The acute porphyrias are characterized by periodic acute attacks of neurovisceral symptoms and may stay occult for a long time. These porphyria syndromes are characterized by abdominal pain, neurologic deficits, psychiatric symptoms, and colored (red) urine.

23. CHRONIC PORPHYRIAS The chronic porphyrias are dermatologic diseases that may or may not involve the liver and nervous system .

24. ALA dehydratase deficiency porphyria Also known as Doss porphyria, plumbo porphyria is extremely rare. autosomal recessive. Caused by - severe deficiency of ALA dehydrase activity. Age – affects children & young adults equally.

25. Clinical features Abdominal pain and polyneuropathy are typical of this porphyria type. commonly affects - male adolescents. Infants presents with more severe disease, including failure to thrive beginning at birth. As there are multiple causes for deficient ALA dehydratase activity, It is important to confirm the diagnosis of ADP by mutation analysis .

26. DIAGNOSIS Urinary ALA and coproporphyrin are markedly increased. significantly elevated levels of plasma and urinary ALA and urinary coproporphyrin (COPRO) III. DIFFERENTIAL DIAGNOSIS includes Hereditary tyrosinemia type1 Lead poisoning

27. TREATMENT OF ALA DEHYDRATASE DEFICIENCY PORPHYRIA Severely affected infants - supported by hyperalimentation(TPN). Periodic blood transfusions. Intravenous hemin. Liver transplantation.

28. Acute intermittent porphyria This autosomal dominantly inherited disorder is characterized by a deficiency of porphobilinogen deaminase . This disorder is also termed pyrroloporphyria , Swedish porphyria , and intermittent acute porphyria and is the most common type of acute porphyria in most countries. Activation of the disease is often related to environmental or hormonal factors.

29. Clinical features AIP almost always latent before puberty – suggests adult levels of steroid hormones are important for clinical expression. Symptoms are more common in women, suggesting a role for estrogens or progestins .

30. Tachycardia/hypertension . Pain in the limbs, head, neck or chest. Proximal Muscle weakness . Sensory loss- axonal degeneration. Dysuria and urinary incontinence. Progression to respiratory and bulbar paralysis and death occurs especially when the diagnosis and treatment are delayed.

31. DIAGNOSIS Urine and Plasma ALA and PBG levels - are substantially ↑ during acute attacks, become normal only after prolonged latency. Diagnosis of an acute attack in a patient with biochemically proven AIP is based primarily on clinical features. Excretion of ALA and PBG decreases over a few days after intravenous hemin administration.

32. No history of symptoms -have normal urinary excretion of ALA and PBG. 1.Detection of the family’s HMBS mutation will diagnose asymptomatic family members. 2.Prognosis of individuals with HMBS mutations is generally favorable. Chronic, low-grade abnormalities in liver function tests are common, the risk of hepatocellular carcinoma is increased.

33. Treatment Treatment of seizures is difficult because most antiseizure drugs can exacerbate AIP. Excretion of ALA and PBG decreases over a few days after intravenous hemin administration. Allogeneic liver transplant .

34. HEREDITARY COPROPORPHYRIA (HCP) Hereditary coproporphyria(HCP) is a very rare, autosomal dominantly inherited variant of the acute porphyrias, characterized by a deficiency of coproporphyrinogen oxidase enzyme . The Acute attacks and cutaneous photosensitivity may occur together or separately .

35. CLINICAL FEATURES HCP is less common than AIP and VP. disease is latent before puberty, and symptoms, which are virtually identical to those of AIP, are more common in women. Blistering skin lesions are identical to PCT and VP and begin in childhood in rare homozygous cases.

36. Diagnosis COPRO III is markedly ↑ in the urine and feces in symptomatic patients. Often persists, especially in feces, when there are no symptoms. Urinary ALA and PBG levels ↑ during acute attacks, but may revert to normal when symptoms resolve.

37. The stool porphyrin profile commonly reveals coproporphyrin conc. higher than those measured for protoporphyrin . ALA and PBG levels ↑ during acute attacks, but may revert to normal when symptoms resolve. Diagnosis of HCP -confirmed by ↑ faecal porphyrins (consisting almost entirely of COPRO III, distinguishes it from other porphyrias).

38. Treatment Neurologic symptoms are treated as in AIP. Hemin administration has been tried. Phlebotomy and chloroquine are tried but not effective for the cutaneous lesions.

39. VARIEGATE PORPHYRIA (VP) Variegate porphyria is an autosomal dominant inherited trait that results in decreased activity of protoporphyrinogen oxidase . It is characterized clinically by photosensitive skin disease and a propensity to acute neurovisceral crises. Variegate porphyria is found worldwide but has an exceptionally high frequency in South Africa.

40. Clinical features Acute attacks identical to those in AIP , precipitated by same factors as AIP . Blistering skin lesions similar to PCT, but more difficult to treat ,usually of longer duration. Associated with photosensitivity & Neurologic symptoms. Developmental disturbances, including growth retardation, in infancy or childhood .

41. DIAGNOSIS ↑Urinary ALA and PBG during acute attacks, but return to normal more quickly than in AIP. ↑ fecal protoporphyrin and COPRO III ↑ urinary COPRO III are more persistent. Plasma porphyrin levels also ↑,particularly with cutaneous lesions. VP can be distinguished rapidly from all other porphyrias by examining the fluorescence emission spectrum of porphyrins in plasma. Increased erythrocyte levels of zinc protoporphyrin, characteristic finding in all homozygous porphyrias.

42. TREATMENT Acute attacks are treated as in AIP, and hemin should be started early in most cases. Other than avoiding sun exposure, β- Carotene for treating the skin lesions . phlebotomy, and chloroquine are not helpful.

43. Porphyria Cutanea Tarda Porphyria cutanea tarda (PCT) is characterized by the defective uroporphyrinogen III decarboxylase enzyme. patients present with skin fragility, erosions, vesicles, bullae, and milia in sun-exposed areas of the skin. Sometimes, there is the presence of periorbital mottled hyperpigmentation and hypertrichosis, sclerodermoid changes, and ulceration.

44. Clinical features Blistering skin lesions appears most commonly on the backs of the hands. These rupture and crust over, leaving areas of atrophy and scarring. Lesions may also occur on the forearms, face, legs, and feet.

45. Hypertrichosis and hyperpigmentation, especially of the face is seen. skin over sun-exposed areas becomes severely thickened, with scarring and calcification that resembles systemic sclerosis. Neurologic features are absent. Clinical features

46. Skin thickening, focal hypo- and hyperpigmentation, and hypertrichosis of the face and extremities are characteristic

47. P C T

48. Treatment A unit (450 mL) of blood can be removed every 1–2 weeks, to gradually reduce excess hepatic iron until the serum ferritin level reaches the lower limits of normal. Repeated phlebotomy, to reduce hepatic iron. Alcohol, estrogens, iron supplements, and if possible, any drugs that exacerbates the disease should be discontinued.

49. Congenital erythropoietic porphyria (Gunther's disease) Congenital erythropoietic porphyria, or Gunther's disease , is one of the least common porphyrias. It results from a deficient activity of uroporphyrinogen III synthase (URO- synthase). Hemolysis may be a feature in homozygous cases. Prolonged exposure to sunlight may precipitate a blistering rash, red urine, and even blindness.

50. Clinical features Severe cutaneous photosensitivity typically begins in early infancy. skin over light-exposed areas is friable and bullae and vesicles - prone to rupture and infection. Secondary infections of cutaneous lesions - lead to disfigurement of the face and hands. Hemolysis due to marked ↑ in erythrocyte porphyrins leads to splenomegaly .

51. Severe cutaneous photosensitivity typically begins in early infancy. Secondary infections of cutaneous lesions - lead to disfigurement of the face & hands. Hemolysis due to marked ↑ in erythrocyte porphyrins leads to splenomegaly .

52. odontoporphyri a Porphyrins are deposited in teeth and in bones; teeth are brownish and fluoresce on exposure to long-wave ultraviolet light.

53. Diagnosis of CEP can be confirmed by 1.Demonstration of markedly deficient URO synthase activity. 2 .Identification of specific mutations in the UROS gene .

54. Treatment Severe cases often require transfusions for anemia Chronic transfusions - to suppress erythropoiesis - effective in reducing porphyrin production Splenectomy -reduces hemolysis and ↓ transfusion requirements. Protection from sunlight & minor skin trauma prompt treatment of complicating bacterial infections.

55. Congenital erythropoietic porphyria . The diaper of an affected baby demonstrates the red color of urine. Vesicles, bullae, and crusts on sun-exposed areas. Brownish teeth that fluoresce under Wood lamp examination.

56. ERYTHROPOIETIC PROTOPORPHYRIA (EPP) In Erythropoietic porphyria, the protoporphyrin molecule accumulates and can be excited by absorbing light energy. This causes the generation of free radicals and, thereby, photosensitivity of all tissues exposed to light. In the dark, several other toxic mechanisms have been described. of protoporphyrin crystals in hepatocytes and bile canaliculi.

57. Clinical manifestations of erythropoietic porphyria are photosensitivity, insignificant hematologic abnormalities, and liver disease Most common porphyria in children.

58. Chronic skin changes include lichenification, leathery pseudovesicles, labial grooving, and nail changes.

59. Clinical Features Skin photosensitivity, usually begins in childhood. Asso.with substantial ↑ in erythrocyte protoporphyrin occurs only in patients with ferrochelatase activities below ~35% of normal. consists of pain, redness and itching-within minutes of sunlight exposure resemble angioedema Vesicular lesions are uncommon.

60. Clinical manifestations Of Porphyrias Clinical manifestations depend on the step in which the enzymatic defect occurs. If the enzymatic defects are in the initial steps of the metabolic cascade, early metabolic intermediates will accumulate ie, aminolevulinic acid [ALA] and porphobilinogen [PBG], which are responsible for attacks of neurologic dysfunction. If the enzymatic defects are in the final steps, sunlight-induced cutaneous lesions (photosensitivity) due to porphyrin accumulation in the skin will develop.

61. Physical Examination In acute porphyrias presenting as abdominal pain, attention should be paid to peritoneal signs. The presence of localized tenderness, rebound tenderness, genitourinary bleeding should raise "red flag“ suspicion. Jaundice may or may not be present. A focused neurologic examination should be performed to identify motor and sensory deficits and peripheral neuropathy.

62. Differential Diagnosis Acute abdomen. Hereditary tyrosinemia type I. Lead poisoning. Pseudoporphyria is a bullous photosensitivity, the commonest etiology being secondary to various ingested medications, such as voriconazole (a relatively new second-generation triazole antifungal ) Psychosis.

63. LABORATORY STUDIES Urine Urine porphyrin studies are the mainstay in the diagnosis of acute porphyria attacks. Establish the diagnosis promptly by testing for increased porphobilinogen in a single-void urine. An expert guidelines panel recommended the Trace PBG Kit

64. Patients with acute exacerbations of porphyria have increases (5-100 times) in metabolic precursors (ALA, PBG, etc). Minor elevations of these precursors are nondiagnostic and nonspecific. Significantly increased ALA and PBG in urine have 100% specificity for acute intermittent (hepatic) porphyria, variegate porphyria, and coproporphyria . A normal urine PBG result has a sensitivity of almost 100% in the diagnosis of porphyria in acutely symptomatic patients.

65. Stool Stool coproporphyrin and protoporphyrin are the most commonly measured porphyrins in feces. Erythrocyte uroporphyrinogen decarboxylase EUPD activity is a specific and intrinsic defect in porphyria cutanea tarda. measurement of this enzyme is a reliable diagnostic test for this disease.

66. C73R mutation Prenatal diagnosis is possible in some types of porphyria. For example, in congenital erythropoietic porphyria, pink fluorescence of the amniotic fluid examined fortuitously in sunlight is suggestive. DNA analysis may show the mutation C73R in the gene for URO-synthase.

67. Treatment Withdrawal of any culprit medications, drugs, toxins, is the key to therapy. Supportive care such as fluids, electrolytes, and nutrition is paramount. Monitor for hyponatremia or hypomagnesemia, and treat vigorously if found. Treatment of respiratory failure, which may ensue once muscle weakness involves the diaphragm, and ventilate in an ICU as appropriate.

68. Administer phenothiazines for nausea, vomiting, agitation, Treat tachycardia and/ hypertension with propranolol or nadolol, which can be safely used for beta blockade. Promptly start glucose infusion in the form of 10% dextrose. At least 300-400 g should be given in 24 hours.

69. Treat acute porphyria attacks with hemin (intravenous heme); 3-4 mg/kg/d for 3-5 days is the definitive treatment and mainstay of management. Thrombophlebitis is the major adverse effect. At least two thirds of the patients have a good response. Protoporphyrin appears to have a synergistic effect with hemin.

70. The cost for Panhematin intravenous powder for injection 313 mg is around $ 7,558 (5,04575 INR)

71. Recombinant PBG deaminase has been tested in phase I studies of acute hepatic porphyria and found to be effective . Hemodialysis has been used in circumstances when hemin was not available and showed some benefit. Avoidance of sunlight is the key in treating cutaneous porphyrias.

72. Magnesium sulfate has been used to control seizures, as many regular anti-seizure medications contraindicated. Hematopoietic stem cell transplantation (HSCT) has been applied with success in severe cases of congenital erythropoietic porphyria. Liver transplantation is an option in cases in which cirrhosis complicates hepatic porphyria.

73. Porphyria cutanea tarda can be effectively treated by phlebotomy. High-dose chloroquine therapy for porphyria cutanea tarda is rarely used now because of its hepatic side-effects.

74. TYPE OF PORPHYRIAS URINE FAECES 1.AIP PBG,COPROIII 2.VP PBG,COPROIII PROTOIX 3.HCP PBG,COPROIII COPROIII Diagnostic Pattern Of Conc. Of Heme Precursors In Acute Porphyrias Diagnostic Pattern Of Conc. Of Heme Precursors In cutaneous Porphyrias TYPE OF PO R P H Y R IA URINE FAECES ERYTHROCYTES 1.CEP UROI,COPROI COPROI 2.PCT UROPORPHYRIN ISOCOPRO 3.EPP PROTOPORPHYRIN

75. Drugs to Avoid Major culprits include barbiturates, anticonvulsants, progestins, rifampin & Pyrizinamide. Sulfonamide antibiotics. Angiotensin-converting enzyme inhibitors (especially enalapril) Ofloxacin, Ketoconazole Calcium channel blockers(especially nifedipine) Metoclopramide.

76. Smoking, which increases hepatic cytochrome P450 enzymes and presumably heme synthesis, is associated with more frequent porphyria attacks. Beta carotene containing foods have been used in cutaneous porphyrias and presumable success has been documented in various studies.

77. B ibliography Kaplans biochemistry – metabolic disorders. Porphyria Overview – BMJ Annals of European Dermatology Forum Piyush gupta pg textbook Nelsons pediatrics . - Thanks