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.

Cimetidine Does Not Inhibit 5-Aminolevulinic Acid Synthase or Heme Oxygenase Activity: Implications for Treatment of Acute Intermittent Porphyria and Erythropoietic Protoporphyria

“…While the underlying pathogenic mechanism of acute porphyric attacks is not fully understood, an increasing body of evidence indicates that the ALA and/or PBG that massively accumulate in the liver and are subsequently released into the plasma are neurotoxic and initiate sequelae that can result in life-threatening neurovisceral responses [18][19][20]. Thus, efficacious therapies for acute attacks need to effectively decrease hepatic production of ALA and PBG, as do hemin and givosiran (Figure 2F,G).…”

“…Under heme-replete conditions, the free heme pool negatively regulates ALAS1 expression at the transcriptional [13,14] and post-transcriptional levels [15][16][17]. On the contrary, when the free heme pool is depleted, hepatic ALAS1 is de-repressed and further induced, leading to the consequential accumulation of the porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which are thought to mediate the acute attack symptoms [18][19][20].…”

Obstacles to Early Diagnosis of Acute Hepatic Porphyria: Current Perspectives on Improving Early Diagnosis and Clinical Management

“…5-Aminolevulinic acid (ALA) accumulates during an acute attack and is thought to play a role in both acute and chronic pain. 5 Other porphyrin intermediaries, which can accumulate in HCP or VP, absorb light from the visible spectrum and cause skin damage.…”

Autocrine positive feedback of tumor necrosis factor from activated microglia proposed to be of widespread relevance in chronic neurological disease

“…The effect was slight, but this agent is a much weaker TNF inhibitor than present‐day specific biosimilars. Typically, these studies have been directed at post‐stroke pain, but the literature on TNF‐associated neurogenic pain extends to essentially all of the disease states discussed in this review: TBI, 109 Lyme disease, long COVID (discussed in Section 6.2), cerebral palsy, 110 fetal alcohol syndrome, 111 and hepatic encephalopathy 112 . The term Chronic Regional Pain Syndrome 113 is used generically in this context.…”