Porphyria

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Porphyria

• Hematology Grand Rounds
• May 16, 2003

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Case Presentation

• 53 y/o man with recently diagnosed PCT
  transferring his care from private hematologist
  to VAMC for insurance reasons
• Diagnosis prompted by new development of bullous
  lesions in sun-exposed areas, fatigue

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Case Presentation

• Initial work-up
• Hb 15.5
• Hct 45.2
• WBC 4,400
• Plt 137,000
• LFTS AST 116, ALT 113, t.bili 0.6
• Iron studies Total iron 63, TF sat 37, TIBC
  250

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Case Presentation

• 24 hour urine porphyrin fraction panel
• Octacarboxylporphyrin 7492 (0-46)
• Heptacarboxylporphyrin 4154 (0-13)
• Hexacarboxylporphyrin 650 (0-5)
• Pentacarboxylporphyrin 821 (0-4)
• Tetracarboxylporphyrin 439 (0-96)
• Porphobilinogen 0.3 (0-1.4)
• (carboxylate porphyrins 5-8)

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Case Presentation

• Hepatitis panel negative
• Pt phlebotomized x 3 units prior to transferring
  care

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Case Presentation

• Physical Exam Chronically ill-appearing man
  with multiple bullous lesions on face, scalp,
  hands, and arms. Oropharyngeal exam revealed
  oral thrush.

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Case Presentation

• Repeat hepatitis panel negative
• HIV 1,2 Ab positive
• Initial viral load 325,000
• Initial CD4 133
• Pt phlebotomized and started on HAART with good
  clinical improvement. Most recent CD4 414, VL
  undetectable.

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Overview of Porphyrias

• Metabolic disorders involving defects in heme
  biosynthesis
• May be inherited or acquired
• Most inherited forms are autosomal dominant, some
  are autosomal recessive

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Heme Biosynthesis
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ALA
Plumboporphyria
X-linked hereditary sideroblastic anemia
Porphobilinogen
ALA
Acute intermittent porphyria
Glycine succinyl CoA
Hydroxymethylbilane
Heme
Congenital porphyria
Erythropoietic protoporphyria
Protoporphyrin IX
Uroporphyrinogen III
Variegate porphyria
Protoporphyrinogen
Porphyria cutanea tarda
Hereditary coproporphyria
Coproporphyrinogen III
ALA 5-aminolevulinate
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Overview of Porphyrias

• Classified into acute and non-acute
• Acute
• Acute intermittent porphyria
• Variegate porphyria
• Hereditary coproporphyria
• Non-acute
• Porphyria cutanea tarda
• Erythropoietic protoporphyria
• Congenital Porphyria
• Porphyrinurias lead, alcohol, iron-deficiency
  anemia, liver disease

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Overview of Porphyrias

• Each type is caused by absence or deficiency of
  an enzyme in the heme biosynthetic pathway
• Leads to increase in amount and excretion of heme
  precursors (in the case of acute porphyrias) or
  porphyrins (in the case of non-acute porphyrias)

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Acute Intermittent Porphyria

• The most severe of the acute porphyrias
• Autosomal dominant inheritance
• Manifestations
• Colicky abdominal pain (95), sometimes with
  nausea, vomiting, and constipation.
• Motor neuropathy (66), usually ascending
  paralysis. May also have sensory involvement
  with paresthesias.
• Psychiatric disturbances with anxiety,
  depression, or psychosis

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Acute Intermittent Porphyria

• Diagnosis Affected pts will excrete large
  amounts of ALA and porphobilinogen in the urine
  during acute attacks.
• Dx can be difficult between attacks when levels
  are usually normal.

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Acute Intermittent Porphyria

• Precipitants of Attacks
• Drugs (most common)
• EtOH
• Reduced caloric intake
• Infection
• Smoking
• Pregnancy, oral contraceptives
• Stress

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Acute Intermittent Porphyria

• Treatment
• Intravenous hematin (heme arginate, 3 mg/kg/day
  for 4 days) if within 2-4 days of onset of attack
  to reduce production of porphyrins and precursors
• Oral or intravenous glucose to reduce porphyrin
  synthesis
• BMJ, 3201647-1651, 2000

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Acute Intermittent Porphyria

• Prevention
• Avoidance of known precipitants
• LHRH antagonists to prevent ovulation,
  menstruation

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Porphyria Cutanea Tarda

• a.k.a. cutaneous hepatic porphyria
• Most common form of porphyria, prevalence
  15000-125,000
• Either inherited or acquired
• Familial form is autosomal dominant, 33 of cases
• Both forms caused by diminshed activity of
  hepatic uroporphyrinogen decarboxylase
• Iron, halogenated hydrocarbons can diminish the
  activity of this enzyme
• Blood, Vol 95 No 5, 2000

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PCT cont

• Clinically manifests as bullous dermatitis in
  sun-exposed areas
• Photosensitivity is caused by presence of
  uroporphyrin partially decarboxylated
  porphyrins in the skin
• May scar or be associated with hirsutism, skin
  fragiligy
• Not associated with neurologic sx, psychiatric
  disturbance, or abdominal pain

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PCT and Associated Conditions

• Alcohol is well known precipitant
• Hepatitis C
• HIV
• HFE gene mutations
• Hepatocellular carcinoma
• Exposure to halogenated hydrocarbons

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PCT and Iron

• Fe in liver generates reactive oxygen species,
  which oxidate uroporphyrinogen to uroporphyrin
• Uroporphyrin is not a substrate for enzyme
  activity, and may inhibit its acitivity
• Hematologica, 84248, 1999

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Treatment of PCT

• Weekly phlebotomy until remission of symptoms or
  hemoglobin lt 12.0 g/dl
• Chloroquine 125 mg bi-weekly enhances urinary
  clearance of porphyrin
• If phlebotomy cant be done, ? Desferal
• Avoidance of sunlight and alcohol

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PCT and HIV

• Over 60 case reports since 1987
• Many patients coinfected with HIV and HCV
• One study with 10 pts
• Average duration of HIV infection was 4.8 years
• 7 had CD4 lt 200
• 9 had elevated LFTs
• 5 had HCV
• 8 admitted to EtOH abuse
• All were prescribed hepatotoxic drugs
• Eur J. Dermatology, 8(7) 1998

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PCT and HIV

• One case report of pt without HCV documented
  clinical remission with HAART only
• Theory infection with HIV causes damage to
  hepatocytes and unmasks latent hepatic
  uroporphyrinogen decarboxylase deficiency

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PCT and HCV

• Prevalence of HCV infection in pts with PCT
  varies by region
• 71-91 in southern Europe
• 0-18 in Australia, New Zealand, central Europe
• 56 in United States
• 15 of pts in one study with HCV had elevated
  urine porphyrins without clinical PCT

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Study Evaluating Risk Factors for PCT

• 39 consecutive patients
• 95 Caucasian
• 72 male
• 74 infected with HCV
• 86 smoked
• 79 used EtOH
• 65 had HFE mutations
• 25 infected with HIV
• Digestive Diseases and Sciences, 472, 2002

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PCT and HFE

• 108 patients evaluated for PCT, HCV, EtOH intake,
  iron phenotype (HIV not tested)
• Worst iron overload observed in pts with
  C282Y/C282Y and was clearly a risk factor for
  dvmt of PCT (OR 60)
• Unable to evaluate HCV and EtOH as independent
  risk factors for PCT because all HCV pts c HFE
  mutations in study drank gt 70 g EtOH/day
• Blood, 955, 2000

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PCT and Risk Factors

• Conclusion Most patients with porphyria cutanea
  tarda have multiple risk factors for development
  of disease
• Some authors advocate testing all pts presenting
  with PCT for HCV, HIV, and HFE mutations counsel
  EtOH cessation