Diseases of Tetrapyrrole Metabolism - Refsum Disease and the Hepatic Porphyrias Clinical Presentation

Updated: Jun 28, 2018
  • Author: Norman C Reynolds, Jr, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA  more...
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Family history is critical in diagnosis. In Refsum disease, manifest cases are homozygous recessive. If the key symptoms of failing vision and cerebellar ataxia are present, consanguinity should be considered. On the other hand, sporadic cases might occur with heterozygotes who are on selective diets high in beef and dairy products.

The porphyrias express an autosomal-dominant pattern, and the typical family has a history of combinations of photodermatitis and abdominal crises, concomitant mental and neurologic symptoms, and urine of a reddish-brown, fluorescent color.

Patients typically have a history of remissions and exacerbations (exacerbations - several days to 2 weeks; memissions - months to years)

Patients may have a history of drug-induced exacerbations (partial or significant) in the hepatic porphyrias but not in erythropoietic protoporphyria, which has obvious cutaneous photosensitivity and normal urine color during exacerbations without neurologic sequelae.




Findings in Refsum disease include the following:

  • Ocular changes - Retinitis pigmentosa, cataracts

  • Sensorimotor polyneuropathy

  • Nonspecific ECG changes

  • Anosmia

  • CN VIII deafness

  • Ichthyosis (can be widespread or limited to the palms)

  • Signs of epiphyseal dysplasia (eg, syndactyly, pes cavus, hammer toes)

Findings in hepatic porphyrias include the following:

  • During remissions: Signs are limited to residual axonal polyneuropathy and skin sensitivity to mechanical trauma and photodermatitis; these are often disabling in porphyria cutanea tarda but rare in acute intermittent porphyria. In erythropoietic protoporphyria, scarred, thickened skin is due to multiple sun-exposure reactions.

  • During acute attacks: Eighty percent of patients initially present with an acute abdomen, 20% ushered in with agitated and hysterical behavior. Other manifestations are autonomic instability (tachycardia, labile blood pressure), generalized pain, segmental sensorimotor polyneuropathy, urinary frequency, and diarrhea. Occasionally, patients present with seizures or coma. Acute attacks in erythropoietic protoporphyria involve rapid-onset burning and edematous, blistering lesions.

  • In erythropoietic protoporphyria, exacerbations are characterized uniquely by acute cutaneous eruptions immediately after ultraviolet light exposure, including that from operating room lights. Ironically, chronic disease may lead to hepatic failure, which can be fatal.

  • In general, the hepatic porphyrias are not associated with hepatic failure but only liver-based aberrant porphyrin metabolism.



Both Refsum disease and the hepatic porphyrias can be exacerbated by nonspecific causes, particularly environmental stress and prolonged or severe illness.

Causes unique to Refsum disease include the following:

  • Dietary intake of phytol and phytanic acid (from beef and milk)

  • Paradox: Liberal intake of chlorophyll-containing foods is perfectly safe, because hydrolysis to free phytol occurs only in the ruminant gut, not in the human digestive tract.

Causes unique to hepatic porphyrias include the following:

  • Prolonged fasting, hypoglycemia

  • Long-term drug use that leads to increased cytochrome P450 activity: This increases delta-ALA synthase activity, the hepatic, rate-limiting enzyme for the heme/porphyrin pathway. Depending on the inherited enzyme deficiency, specific characteristic porphyrins may build up.

  • Other drugs with acute inducing capability: Experienced patients learn to avoid these.

  • Light (especially UV) can induce skin eruptions in porphyric patients with photocutaneous sensitivity. [9] This sensitivity can be seen in several hepatic porphyrias, particularly porphyria cutanea tarda, but it is the sine qua non of erythropoietic protoporphyria and is the dominant, often sole, clinical problem in this nonhepatic porphyria.

  • Endogenous hormones: Some women have catamenial patterns of exacerbation initiated during the luteal phase of normal menstrual periods or during pregnancy.