• Information
  1. Heme Biosynthesis
  2. Types of Porphyrias
  3. Pathogenesis of Acute Attack
  4. Symptoms
  5. Diagnosis
  6. Management
  7. Porphyria cutanea tarda

A. Heme Biosynthesis [1,2]

1. Heme is synthesized in every human cell
   1. ~85% synthesized in red blood cells (RBC)
   2. The majority of the heme in RBC is used in hemoglobin synthesis
   3. Most remaining heme is produced in the liver; 80% is used for cytochrome synthesis
   4. Each cell requires heme for cytochrome (electron transport chain) synthesis
2. Porphyrias are inherited metabolic disorders resulting from partial deficiency in enzymes involved in heme biosynthesis
3. Seven enzymes are involved in heme biosynthesis
   1. Porphyrias corresponding to abnormalities in each of these enzymes have been found
   2. Porphyrias are overproduction syndromes with the formation of toxic heme precursors
4. Enzymes in Heme Biosynthesis
   1. Delta-Aminolevulinic acid (DALA) synthase (ALAS): glycine + succinyl-CoA forms DALA
   2. Aminolevulinate dehydratase: DALA to porphobilinogen
   3. Prophobilinogen deaminase (ALAD): porphobilinogen to hydroxymethylbilane
   4. Uroporphyrinogen III synthase: hydroxymethylbilane to uroporphyrinogen III (UP3)
   5. Uroporphyrinogen decarboxylase: UP3 to coproporphyringoen III (CPP3)
   6. CPP3 oxidase: CPP3 to protoporphyrinogen IX
   7. Protoporphyrinogen oxidase: protoporphyrinogen IX to protoporphyrin IX
   8. Ferrochelatase: protoporphyrin IX + iron (Fe) to Heme
5. Regulation of heme synthesis controlled by ALAS enzymes
   1. Two tissue specific ALAS isozymes exist
   2. In liver, heme represses synthesis of ALAS
   3. Many drugs induce ALAS in liver
   4. In erythroid cells, heme induces hemoglobin synthesis (more complex regulation)

B. Types of Porphyrias (Enzyme Deficiency) [2,3,4]

1. Overall prevalence is about 1:100,000 (range 0.5-10) persons; no ethnic predisposition
2. Most are inherited as autosomal dominant with incomplete penetrance
3. Clinically classified as Acute versus Cutaneous
4. Four Acute Prophyrias
   1. Acute Intermittent Porphyria (AIP, auotomsal dominant)
   2. Hereditary Copoporphyria (HCP, auotomsal dominant)
   3. Variegate Porphyria (auotomsal dominant)
   4. 5-Aminolevulinic acid dehydratase (ALAD) deficient prophyria (autosomal recessive)
5. Neuroporphyrias (mutated gene in disease)
   1. AIP (Porphobilinogen Deaminase)
   2. Plumboporphyria (Alanine Dehydratase)
6. Neurocutaneous Porphyrias
   1. HCP (Copoporphyrinogen Oxidase)
   2. Variegate Porphyria (Protoporphyrinogen Oxidase >> Ferrochelatase)
7. ALAD deficient prophyria - (ALAD); four families reported
8. Cutaneous Porphyrias
   1. Porphyria cutanea tarda (Uroporphyrinogen Decarboxylase)
   2. Congenital Erythropoietic Porphyria (Uroporphyrinogen III Cosynthase)
   3. Erythropoietic Protoporphyria (Ferrochelatase)

C. Pathogenesis of Acute Attack [1,2]

1. During acute attack, DALA and porphobilinogen excreted massively from the liver
2. This is because of induction of heme biosynthesis
3. DALA and porphobilinogen are neurotoxic
4. Due to blood brain barrier, these neurotoxins have more effects on peripheral and autonomic
5. Hypothalamus and limbic areas are more susceptible to neurotoxic heme precursors
6. These compounds can also cause vascular injury, impaired permeability, and brain edema

D. Symptoms [2,3]

1. Usually occur after puberty
2. Abdominal Symptoms
   1. Pain - usually diffuse, chronic (~90%)
   2. Vomiting ~60%
   3. Constipation ~60%
   4. Diarrhea ~10%
3. Neurologic Symptoms [2]
   1. Similar with all porphyria types
   2. May involve central, peripheral, and/or autonomic nervous systems
   3. Pain in extremities, back, chest, neck, or head ~60%
   4. Peripheral, usually motor neuropathy ~67%
   5. usually symmetric weakness
      1. usually limb and girdle muscles
   6. Seizures: ~20% of acute cases
   7. treatment with usual anti-convulsants may exacerbate symptoms
      1. best therapy is magnesium sulfate
   8. Psychoses / Severe Anxiety: ~20% of cases
   9. Autonomic dysfunction may occur
   10. Mental changes ~45% including behavrioal changes, agitation, depression, confusion
4. Skin Lesions (porphyria cutanea tarda and others)
   1. HCP ~ 30% of cases
   2. PV >80% of cases
   3. Usually occur in sun-exposed areas
   4. Dermal abrasions, erosions, blister formation
   5. May be accompanied by hyponatremia due to dehydration
5. Cardiovascular - hypertension (45%), tachycardia (50%)

E. Diagnosis

1. High level of suspicion: chronic neuropathy, abdominal pain, and/or acute attacks
   1. Consider diagnosis in patients with chronic unexplained abdominal pain
   2. Vomiting is also common 60-85%
   3. Constipation occurs in 40-80%
2. Acute attacks occur only with certain porphyrias [2,4]
   1. These include AIP, hereditary coproporphyria, variegate porphyria, ALAD deficiency
   2. Urinary porphyrin levels always elevated in attacks (may be normal between attacks)
   3. Attacks may be related to menstrual cycle
3. Stool porphyrins are always elevated in patients with porphyria
4. Best test is urinary prophobilinogen level during acute attack
   1. Urinary porphyrin elevations usually 20-50 fold higher than normal levels
   2. Levels of 20-200mg/L may be seen in AIP, HCP, variegate prophyria
   3. In some patients with high baseline levels, porphyrin levels during acute attack increase 2X
   4. Aminolevulinate level usually also elevated
5. Drugs which induce hepatic P450 system can often induce acute attacks
6. Specific Diagnosis
   1. Series of secondary tests can be used to distinguish main types of acute porphyrias
   2. Erthyrocyte porphobilinogen deaminase levels decreased ~50% in 90% of AIP
   3. Urine uroporphyrin increased in AIP
   4. Urine coproporphyrin increased in HCP and variegate prophyria
   5. Fecal prophyrin levels markedly increased in HCP and variegate porphyria
   6. Plasma prophyrin levels markedly increased in variegate porphyria only

F. Management [5]

1. Identical in all cases of acute hepatic porphyrias
   1. Initially, fluids with glucose are recommended
   2. Measure urine porphobilinogen excretion to confirm diagnosis
   3. Admission to hospital is usually requred
2. Attacks usually precipitated by certain drugs; these should be stopped in most cases:
   1. Ethanol
   2. Progesterone and synthetic progestins
   3. Phenylbutazone
   4. Tetracyclines
   5. Theophylline
   6. Tolbutamide
   7. Phenobarbital
   8. Valproate
   9. Sulfonamide antibiotics
   10. Rifampin
   11. Pyrazinamide
   12. Metoclopramide
   13. Phenytoin
   14. Primodone
3. Hematin
   1. Infused 4mg/kg over 10-15 minutes q12 hours
   2. Moderate to highly efficacious; must be started early in course of acute attack
   3. Main side effect is thrombophlebitis
   4. Transitory side effects: oliguric renal failure, circulatory collapse, coagulopathy
4. Other
   1. Careful fluid and electrolyte monitoring
   2. Low magnesium ± sodium common; azotemia may occur
   3. Hypertension and tachycardia treated with ß-blocking agents
   4. Attacks related to menstrual cycle may be suppressed with GNRH agonists
   5. Acute attacks may be associated with increased risk of hepatocellular carcinoma

G. Porphyria cutanea tarda

1. Most common and readily treated form of porphyria in humans
   1. More common form is sporadic (Type 1) and only affects liver
   2. Less common form is autosomal dominant (Type 2)
   3. Type 2 affects liver, erythrocytes, other cells
2. Deficiency of uroporphyrinogen decarboxylase with levels ~50% of normal
3. Sporadic form (Type 1) is restricted to liver
   1. Can lead to liver failure (cirrhosis)
   2. Strongly associated with Hepatitis C Virus (HCV) infection (RNA) and antibodies [4]
4. Cutaneous Photosensitivity [6]
   1. Likely due to action of environmental radiation on metal-free porphyrins
   2. Leads to formation of highly reactive singlet oxygen
5. Iron levels typically very high; remove iron with phlebotomy, induce enzyme
6. Complication of chronic renal failure / dialysis
7. Recently reported that recombinant erythropoietin can treat disease

References

1. Kauppinen R. 2005. Lancet. 365(9454):241
2. Bonkovsky Hl, Siao P, Roig Z, et al. 2008. NEJM. 358(26):2813 (Case Record)
3. Ahmed I. 2002. May Clin Proc. 77(8):825
4. Anderson KE, Bloomer JR, Bonkovsky HL, et al. 2005. Ann Intern Med. 142(6):439
5. Gumbar S and Chopra S. 1995. Ann Intern Med. 123(8):615
6. Babior BM. 2000. Am J Med. 109(1):33