Extra Topic 3.3 -- Porphyria

Question 1

What is the pathogenesis of acute porphyrias?

(A 38-year-old female with a history of acute intermittent porphyria presents for an excision of a left breast mass.)

Answer 1

The porphyrias result when one of the enzymes in the heme biosynthetic pathway is deficient, resulting in overproduction of porphyrias.

The accumulation of these precursors is responsible for the clinical manifestations of the various forms of porphyria.

The type of porphyria that develops depends on the specific enzyme deficiency, as deficiencies at different points in the pathway lead to the accumulation of different precursors

(there is an accumulation of the chemicals in the heme biosynthetic pathway that immediately precede the enzymatic block).

Only the acute forms of porphyria are “inducible” by exposure to various drugs, potentially resulting in a life-threatening condition characterized by –

severe abdominal pain, nausea, vomiting, psychiatric disturbance, autonomic nervous system instability, electrolyte disturbances, hypovolemia, seizures, skeletal muscle weakness, quadriparesis, and respiratory failure (bulbar paralysis).

Clinical Notes:

• The combination of autonomic neuropathy, hypovolemia, and CNS involvement may result in cardiovascular instability
  
  • (usually tachycardia and hypertension, but sometimes hypotension).
• The most abundant form of porphyrin in the human body is found in the form of – heme, which is bound to proteins to form hemoglobin and cytochrome-P450 proteins.
  
  • Production of heme is controlled by the activity of the enzyme aminolevulinic acid (ALA) synthetase.
  • In patients susceptible to porphyria, any increase in heme requirements such as anemia or cytochrome-P450 metabolism (since heme is inserted into newly produced cytochrome P450 proteins, the demand for heme is increased with induction of the cytochrome P450 system) may trigger an acute attack of porphyria by reducing the feedback inhibition of ALA synthetase (resulting in increased activation of ALA synthetase).
• Types of Porphyria:
  
  • Acute Porphyrias include:
    
    • Plumboporphyria (aminolevulinic acid dehydratase porphyria)
    • Acute Intermittent Porphyria
    • Hereditary Coproporphyria
    • Variegate Porphyria
  • Other Porphyrias:
    
    • Congenital Erythropoietic Porphyria
    • Porphyria Cutanea Tarda
    • Erythropoietic Uroporphyria
    • Erythropoietic Protoporphyria

Question 2

How would you evaluate this patient preoperatively?

(A 38-year-old female with a history of acute intermittent porphyria presents for an excision of a left breast mass.)

Answer 2

I would focus my preoperative evaluation on the severity and susceptibility of porphyria in this patient.

Therefore, I would perform a careful history and physical to determine –

• the last time she experienced an acute attack,
• the precipitating factor,
• the subsequent treatment, and
• the presence of any current symptomatology.

Specifically, I would evaluate the patient for the presence of –

• peripheral neuropathy,
• autonomic nervous system instability (hypertension and tachycardia),
• skeletal muscle weakness,
• cranial nerve dysfunction,
• fluid imbalance, and
• electrolyte abnormalities.

Clinical Notes:

• When the family history suggests possible porphyria susceptibility, a thorough physical exam should be performed to identify –
  
  • any skin lesions,
  • peripheral neuropathy,
  • autonomic nervous system instability,
  • skeletal muscle weakness, or
  • cranial nerve dysfunction.
    
    • The most appropriate screening test is a determination of erythrocyte porphobilinogen activity.
• When there are signs of an acute exacerbation in the preoperative period:
  
  • Elective surgery should be postponed.
  • An assessment of skeletal muscle strength and cranial nerve function should be performed
    
    • (cranial nerve dysfunction and diminished skeletal muscle strength are associated with an increased risk of aspiration and impending respiratory failure).
  • Tachycardia, hypertension, hypovolemia, and electrolyte disturbances should be identified and treated/corrected.

Question 3

What steps would you take to reduce the risk of triggering a porphyric crisis?

(A 38-year-old female with a history of acute intermittent porphyria presents for an excision of a left breast mass.)

Answer 3

To reduce the risk, I would attempt to – AVOID and/or MINIMIZE factors that can lead to hormonal fluctuations suspected of potentially inducing a porphyric crisis, such as – fasting, dehydration, stress, and infection.

Therefore, I would ensure – adequate hydration, administer versed for anxiolysis, and consider administering 10% glucose in saline to provide a source of carbohydrates, which have been shown to suppress porphyrin synthesis.

I would also avoid drugs suspected to have porphyrinogenic potential (drugs that induce the activity of ALA synthetase or interfere with negative feedback control – (i.e. drugs that require P-450 for their metabolism), such as Thiopental, Thiamylal, Methohexital, Etomidate, Ketorolac, Phenacetin, and Nifedipine.

I would also keep in mind that the administration of multiple potential enzyme-inducing drugs is more dangerous than exposure to any one drug and remember that repeated or prolonged use of one of these drugs may further increase the risk of inducing a crisis.

Clinical Notes:

• Lists of “safe” and “unsafe” anesthetic drugs are unreliable because they are based on animal or cell culture experiments.
  
  • Moreover, it is difficult to attribute an acute perioperative exacerbation to any given drug because there are a number of other factors that could potentially precipitate an event such as stress, fasting, or sepsis.
• Anesthetic agents that are “likely safe” include – propofol, ketamine, nitrous oxide, volatile agents, most analgesics (except ketorolac), and neuromuscular blocking drugs.
• Regional anesthesia has been safely utilized in porphyric patients, however:
  
  • It should probably be avoided during an acute exacerbation of acute intermittent porphyria due to the hemodynamic instability, porphyria-related neuropathy, and mental confusion often associated with an acute attack.
  • A prior neurologic exam should be performed in order to reduce the risk in that an exacerbation of a neuropathy will be inappropriately attributed to the regional anesthetic.

Question 4

The post-op nurse calls you and reports that the patient is experiencing nausea, vomiting, and abdominal pain.

What would you do?

(A 38-year-old female with a history of acute intermittent porphyria presents for an excision of a left breast mass.)

Answer 4

This patient’s symptomatology is consistent with a porphyric crisis.

Therefore, I would:

1. discontinue any porphyrinogenic drugs;
2. ensure adequate ventilation, oxygenation, hydration, analgesia, and anxiolysis;
3. administer carbohydrates (initiate an infusion of 10% glucose in saline);
4. treat any nausea and vomiting with an antiemetic;
5. control any tachycardia and/or hypertension with B-blockers;
6. correct any electrolyte disturbances; and
7. treat the development of any seizure activity with a benzodiazepine or propofol (traditional anticonvulsants are considered unsafe). If she showed no improvement after 1-2 days of conservative therapy, I would –
8. administer hematin to supplement the intracellular pool of heme, thereby suppressing ALA synthetase activity (3 to 4 mg/kg IV over 20 minutes).