Diseases of Tetrapyrrole Metabolism - Refsum Disease and the Hepatic Porphyrias Treatment & Management

No specific treatments are indicated in Refsum disease, other than dietary restrictions of beef and milk products. On the other hand, judicious medication choices are key elements in managing the porphyrias.

• Any drug used over the long term has the risk of inducing increased cytochrome P450 activity and increased production of the heme group. Increased production of heme groups accelerates delta-ALA synthase activity in the rate-limiting step for the porphyrin pathway. This results in excessive porphyrins in response to inherited low enzyme activity at specific points in the heme biosynthetic pathway. Lists of safe and unsafe drugs can be found through the American Porphyria Foundation (or European Porphyria Network). A drug risk profile can be found by entering the generic or brand name for the drug of interest.

  • Long-term care of concomitant idiopathic epilepsy is especially challenging, leaving only bromide (which should be administered only in cooperation with an experienced pharmacist) and gabapentin^[10] as reasonable treatment options. New anticonvulsants that are tolerated for several months are not a sign of safety since the induction of higher levels of delta-ALA synthase may occur gradually over time. Other more immediate toxic responses occur with medications that induce cytochrome P450.
  • Short-term care is not as risky as long-term care, especially if the medications used are excreted by the kidneys. Experience teaches patients with latent porphyria which medications to avoid. Special care should be exercised in planning general anesthesia so that the anesthesiologist is alerted to special medication requirements and is aware of the risks of inducing acute attacks that may occur postoperatively.
• Phlebotomy for porphyria cutanea tarda

  • Therapeutic phlebotomy is the treatment of choice to control the photocutaneous manifestations of porphyria cutanea tarda.
  • Effective blood loss is defined as reducing serum porphyrins to 20% of prephlebotomy levels over 2-3 months, which allows a period of remission lasting 6-12 months.
  • In the treatment of erythropoietic protoporphyria, not blood loss but rather ultraviolet light avoidance is recommended. Sunscreens and possibly oral use of beta-carotene can improve sunlight tolerance.

Patients with acute porphyria are at risk for exploratory laparoscopy for an acute abdomen that is unique because of the absence of rebound tenderness.

• A high preoperative urinary PBG level should reduce the pressure to explore the abdomen surgically; this finding is especially compelling if an abdominal CT scan is not conclusive.
• For other surgical procedures, the risk of anesthesia exacerbating acute attacks in Refsum disease or in the porphyrias, either as a nonspecific stress or in porphyria as a metabolic challenge to cytochrome P450, should be considered. The anesthesiologist should be alerted to the risk of exacerbation due to fasting or general anesthesia in patients with porphyria and be prepared to use glucose loading postoperatively when acute attacks appear likely or in progress.

Although a gastroenterologist or a physician with specific interest in porphyria may be helpful in planning disease management, a doctoral level clinical pharmacist or pharmacologist is especially helpful in making choices of safe drug combinations. Medical geneticists can help establish diagnostic histories and help to order the appropriate diagnostic tests as well as provide genetic counseling.

Dietary management is a major part of treating Refsum disease and hepatic porphyrias. Inappropriate dietary choices may result in exacerbations.

• In Refsum disease, dietary intake of phytol and phytanic acid must be restricted. Monitor serum phytanic acid levels to ensure that levels remain low.

  • The rule of thumb in dietary control is that vegetables are unrestricted (only ruminants can hydrolyze phytol from chlorophyll in the gut).
  • Phytol is converted readily to phytanic acid in all mammals. Both phytol and phytanic acid are found among the other fatty acids, therefore both are absorbed from ruminant fat stores and fatty fractions (eg, fat, beef, dairy products).
  • Without dietary restrictions, the phytanic acid level may comprise as much as one third of the total fatty acids of the plasma; healthy individuals have only trace levels.
• The "glucose effect" is a major modulator of metabolic control of extremes in porphyrin synthesis. Fasting or hypoglycemia is a well-known precipitant of acute attacks, whereas oral or intravenous (IV) 10% dextrose solution is useful in averting or reversing acute attacks.

Avoiding direct sunlight is necessary in preventing photosensitive dermatitis, especially in PCT.