What is the pathophysiology of erythromelalgia?

Updated: Sep 17, 2018
  • Author: Antoine N Saliba, MD; Chief Editor: Emmanuel C Besa, MD  more...
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The first insights into the pathophysiology of erythromelalgia associated with thrombocythemia were gained when skin biopsy samples revealed arteriolar fibrosis and occlusion with platelet thrombi. [4] In this setting, platelets may have abnormal hyperaggregability. Platelet kinetic studies show decreased platelet survival, predominantly due to consumption. Prostaglandins and cyclooxygenase apparently play an important pathogenetic role.

For erythromelalgia not associated with thrombocythemia, the pathophysiology is less clear, but it is known not to involve platelet-mediated inflammation and thrombosis. This is the major reason why Drenth and Michiels distinguished primary erythromelalgia (erythermalgia) from secondary erythromelalgia. [3, 5] Factors postulated to contribute to primary erythromelalgia include the following:

  • Postganglionic sympathetic dysfunction

  • Hypersensitivity of C-fibers [6]

  • Maldistribution of skin perfusion resulting from arteriovenous shunting, which leads to an imbalance between thermoregulatory and nutritive perfusion [7, 8]

Molecular biology may provide the key to understanding this disorder. [9] Drenth et al examined 5 kindreds with familial erythermalgia and found a linkage to chromosomal arm 2q. [10] Novel mutations of voltage-gated sodium channels that are selectively expressed in peripheral nerves have been discovered. [11, 12, 13, 14]

Han et al, in a study investigating whether a genotype-phenotype association exists in early- and late-onset inherited erythromelalgia, found a shift in the patient’s mutation hyperpolarization activation that was smaller than that seen in early-onset disease mutations but similar to another mutation associated with late-onset inherited erythromelalgia. [15]

The test was done by conducting a voltage-clamp and current-clamp analysis of a new sodium channel Na(v)1.7 mutation, Q10R, in a patient who presented with erythromelalgia in the second decade. [15] With current-clamp analysis, Q10r expression induced hyperexcitability in dorsal root ganglion neurons, but the increase in excitability was smaller than that produced by a mutation in early-onset disease.

Han et al suggested that their findings reflected a genotype-phenotype relation at the clinical, cellular, and molecular/ion channel levels in inherited erythromelalgia; mutations that produce smaller effects on sodium channel activation appear to correlate with smaller degrees of dorsal ganglion root neuron excitability and later onset of clinical signs. [15]

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