Pain in acute hepatic porphyrias: Updates on pathophysiology and management

Abstract

Acute hepatic porphyrias (AHPs) typically present with recurrent acute attacks of severe abdominal pain and acute autonomic dysfunction. While chronic symptoms were historically overlooked in the literature, recent studies have reported increased prevalence of chronic, mainly neuropathic, pain between the attacks. Here we characterize acute and chronic pain as prominent manifestations of the AHPs and discuss their pathophysiology and updated management. In addition to the severe abdominal pain, patients could experience low back pain, limb pain, and headache during acute attacks. Chronic pain between the attacks is typically neuropathic and reported mainly by patients who undergo recurrent attacks. While the acute abdominal pain during attacks is likely mediated by autonomic neuropathy, chronic pain likely represents delayed recovery of the acute neuropathy with ongoing small fiber neuropathy in addition to peripheral and/or central sensitization. δ-aminolaevulinic acid (ALA) plays a major role in acute and chronic pain via its neurotoxic effect, especially where the blood-nerve barrier is less restrictive or absent i.e., the autonomic ganglia, nerve roots, and free nerve endings. For earlier diagnosis, we recommend testing a spot urine porphobilinogen (PBG) analysis in any patient with recurrent severe acute abdominal pain with no obvious explanation, especially if associated with neuropathic pain, hyponatremia, autonomic dysfunction, or encephalopathy. Of note, it is mandatory to exclude AHPs in any acute painful neuropathy. Between the attacks, diagnostic testing for AHPs should be considered for patients with a past medical history of acute/subacute neuropathy, frequent emergency room visits with abdominal pain, and behavioral changes. Pain during the attacks should be treated with opiates combined with hemin infusions. Symptomatic treatment of chronic pain should start with gabapentinoids and certain antidepressants before opiates. Givosiran reduces levels of ALA and PBG and likely has long-term benefits for chronic pain, especially if started early during the course of the disease.

Keywords: dysautonomia; hemin; neuropathy; porphyria; siRNA; δ-aminolaevulinic acid (ALA).

Figure 1

Onset and duration of pain syndromes and weakness during an acute attack. MRC, medical research council; VAS, visual acuity scale. Abdominal pain (dotted line), back pain (dash line), limb pain (thick solid line), and muscle weakness (thin solid line).

Figure 2

Pathophysiology of pain in acute hepatic porphyrias. 5-HT, 5-hydroxy tryptamine (serotonin); ALA, δ-aminolaevulinic acid; GABA, gamma aminobutyric acid; PRES, posterior reversible encephalopathy syndrome.