Nerve damage persists between AHP attacks, study shows

Nerve damage affecting pain sensation and the autonomic nervous system, which controls involuntary body functions, persists for people with acute hepatic porphyria (AHP) between symptomatic attacks, according to a small study.

Researchers used skin biopsies and a battery of autonomic function tests to show that this nerve damage, known as autonomic and small fiber neuropathy, was present to some degree in every patient studied, offering a possible explanation for the chronic pain and other symptoms many AHP patients experience between attacks.

The study, “Autonomic and small fiber neuropathy in patients with acute hepatic porphyrias,” was published in Molecular Genetics and Metabolism.

Porphyrias are a group of disorders caused by defects in enzymes involved in the production of heme, a molecule in red blood cells that enables them to carry oxygen. Without enough enzyme, byproducts called porphyrins and their precursors build to toxic levels in the body. In AHP, this causes recurrent attacks of abdominal pain and other porphyria symptoms.

During attacks, AHP patients often develop neuropathy affecting motor nerves, leading to muscle weakness. Small nerve fibers that detect pain and temperature, and regulate the autonomic nervous system, which controls involuntary functions such as heart rate, blood pressure, breathing, and digestion, are also affected. Patients report chronic abdominal pain, painful tingling or burning sensations in the limbs, back and muscle pain, and digestive symptoms even between attacks.

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To assess autonomic and small-fiber nerve involvement between attacks, researchers enrolled eight women, ages 42-59, with acute hepatic porphyria. Seven had acute intermittent porphyria, and one had variegate porphyria.

Participants experienced between one and four attacks per year, most commonly involving intense abdominal pain, other digestive symptoms, purple urine, and sometimes mild confusion. Two women had attacks that solely affected motor function.

All eight women reported orthostatic intolerance (dizziness or lightheadedness related to changes in body position), a sign of autonomic dysfunction. Seven had nerve-related sensory symptoms in their legs, while five had upper-limb nerve damage on examination, either motor or sensory. Four had hypertension (high blood pressure) as well.

Between attacks, participants showed signs of mild to moderate nerve damage, as indicated by the Neuropathy Impairment Score (NIS). On the COMPASS-31 questionnaire, a self-reported assessment of autonomic symptoms, the gastrointestinal and pupil (eye)-related categories showed the most involvement. A mild to moderate degree of autonomic involvement was also shown using the Composite Autonomic Severity Score (CASS).

The results from skin punch biopsies showed that the density of small nerve fibers in the lower-leg skin was reduced in three patients, indicating that damage was more severe farther from the trunk.

Further autonomic testing found reduced sweat gland responses in six patients and impairment of the cardiovagal system, which involves the vagus nerve’s control over heart rate, in another six. Problems with the cardiovascular sympathetic system, which drives the body’s fight-or-flight response, were found in three patients, and two had an excessive rise in heart rate upon standing during the tilt table test.

Three patients with the highest COMPASS-31 and CASS scores showed the closest correlation between their reported symptoms and test results. At the same time, no association was found between NIS, COMPASS-31, or CASS scores and the frequency or severity of patients’ past attacks or with levels of porphyrin precursors.

The team noted that all sensory nerve conduction tests of the lower limbs were normal in those tested, which argued against damage to large nerve fibers, which manage touch, vibration, and body position, as the explanation for the ongoing symptoms.

They concluded that “autonomic/small fiber neuropathy is invariably present in this patient population and offers a potential explanation for the chronic sensory neuropathic and autonomic manifestations” experienced by AHP patients between attacks.