Most patients (74–100%) report severe abdominal pain (5, 6, 12). It usually lasts several hours to days and does not reach nadir before 2 days (6, 7, 13). Pain is severe enough to give an impression of an “acute catastrophe” in the abdomen. The pain character is either colicky or gnawing/aching and is commonly accompanied by nausea and vomiting (42–88%) (5). It was reported in different abdominal regions e.g., epigastrium, right iliac fossa, lower abdomen, or generalized over the whole abdomen (12). The abdominal examination and routine laboratory/radiologic workups are often unremarkable (2).

If an acute attack remains untreated or worsened by additional provoking factors (as noted above), it proceeds to acute neuropathy and/or encephalopathy, often termed a “severe acute attack” (14). If an acute attack is treated immediately, it is usually limited to abdominal pain, dysautonomia (tachycardia and elevated systolic blood pressure), and mild cognitive symptoms. The abdominal pain during acute attacks is severe either way, typically scored >9 on a visual analog scale (14). The neurological deficit usually develops after 3–21 days of abdominal pain and dysautonomia (Figure 1) (1). When progressive muscle weakness manifests, the intensity of abdominal pain may abate (7, 15), which may lead to a misdiagnosis of Guillain Barre syndrome (GBS). In recurrent attacks, with incomplete neurologic recovery, muscle weakness can start sooner after abdominal pain, or even precedes it (16).

A third to a half of cases reported back pain mainly in the lumbar area (8, 17). The back and limb pain were pooled together in most studies with prevalence of 25% in mild sporadic attacks (18) and 50–70% in severe or mixed attacks suggesting partial association with neuropathy (5). Patients with recurrent attacks reported prevalence of limb over back pain during the acute attacks (12).

Limb pain is common (50–68%) and severe with acute porphyric neuropathy (5). It manifested as a severe deep myalgic or superficial neuropathic burning pain (12) lasting for 1–2 weeks (Figure 1). Porphyric neuropathy is predominantly motor (5, 7, 14) but may be associated with a proximal pattern sensory loss “old bath-costume distribution” differing from the classic length-dependent neuropathy (5, 7, 14). Paresthesia, dysesthesia, or hyperesthesia indicative of neuropathic pain are common (5, 7, 8, 13). Neuropathic pain is also common in acute attacks without overt motor weakness (6), especially in recurrent attacks (77%) (12). Several cases of rhabdomyolysis during acute attacks have been reported (19–21). However, the creatinine kinase levels in patient series were rarely reported, and thus, the frequency of rhabdomyolysis and its role in myalgia during attacks remains unclear.

Headaches are infrequent, yet can be severe, during an acute attack (7, 8, 22, 23). It is commonly associated with hypertension and has been reported with posterior reversible encephalopathy syndrome (PRES) (22–24). However, headaches are less common in porphyric PRES than in PRES of other origins, as AHP patients could be distracted by the exceedingly more severe abdominal pain (23).

A prospective natural history study of 112 AHP patients experiencing recurrent attacks (≥3/year) or receiving prophylactic hemin treatment reported that chronic pain was present in 40% of patients (12). Similar percentages were reported in other series, and 25% of patients experienced daily pain (12, 25, 26). Chronic pain ranged from manageable with little impact, to having a significant impact on daily activities (26). Half of AHP patients were reported using opioids between attacks (12). In descending order, abdominal pain was the most frequent followed by headache, back pain, limb pain, and myalgia (12). The frequency of chronic pain did not differ significantly between patients who were on prophylactic hemin treatment and those who were not. Chronic pain mainly represented the neuropathic type based on burning and tingling sensations, poor response to pain medications, and partial loss of limb sensations, reported by 47% of patients with recurrent attacks during partial remission (26). In some cases, it was diffuse, involving the whole abdomen or the “entire body” (25, 26). The overlap of sensory (19%) and motor neuropathy signs (22%) (27) and chronic pain (25–40%) in these patients was common (12, 25, 26).

Recovery from acute porphyric neuropathy may take up to 2 years and is frequently complicated by chronic neuropathic pain associated with numbness, but detailed data are lacking (14).

Any patient with recurrent severe acute abdominal pain with no obvious explanation should be screened for AHPs, especially if associated with neuropathic pain, hyponatremia, autonomic manifestations, or encephalopathy. An acute attack can be effectively diagnosed when the spot urine PBG, per mg urine creatinine, is markedly elevated. Note, that “urine porphyrins” may not be increased during the attacks and should not be first-line tests (15). DNA testing confirms the diagnosis and determines the AHP type.

NCS-EMG studies typically show diffuse, motor-predominant, axonal neuropathy in patients with acute porphyric neuropathy. They help exclude other differential diagnoses (e.g., GBS, etc.) when associated with normal cerebrospinal fluid protein (28). It is still mandatory to exclude AHPs by testing urine PBG in any acute painful neuropathy (29).

It is often challenging to distinguish flares of chronic pain from acute attacks based on clinical assessment without biochemical studies (2). Urinary PBG decreases between attacks, but may remain increased for years, without symptoms, in AIP patients (30), typically increasing ≈2-fold with a new attack. Urinary ALA is always increased during acute attacks and remains elevated in ~ 62% of AIP cases between attacks (31). In contrast, in patients with HCP or VP, the levels of urinary ALA and PBG are less significantly increased during an acute attack and fall quickly when the attack resolves (15).

Electrodiagnostic testing lends objective evidence to chronic large fiber neuropathy as a sequela of acute neuropathy in cases of chronic neuropathic pain (28). While the encephalopathy and acute autonomic symptoms resolve quickly after starting treatment, recovery of the neuropathy from an electrophysiologic standpoint is slower, taking months, often with incomplete normalization of motor and sensory amplitudes (32). Earlier electrodiagnostic studies did not correlate the severity of the electrodiagnostic findings with disease duration or number of previous attacks (28).

The main nerve biopsy findings in porphyric neuropathy are non-specific including axonal loss and Wallerian degeneration. Grouped demyelination was observed in association with axonal degeneration and is likely secondary to the primary axonopathy. Pure sensory nerves are often intact (33). Given this lack of specificity and the motor predominance in porphyric neuropathy, sural nerve biopsy is not needed, unless the indication is to exclude another differential diagnosis (28).

Skin punch biopsy helps confirm a diagnosis of SFN in chronic neuropathic pain when NCS are normal (34). Hseih et al. performed serial skin biopsies on an AIP patient during and right after an attack. They reported reduced intraepidermal nerve fiber density (IENF), on day 48 from onset that did not improve as of day 92 despite improving muscle strength. These findings underscore a potential role of SFN in the chronic pain patients develop between attacks (35).

Autonomic testing could provide evidence of functional impairment of the small nerve fibers. Evidence of cardio-vagal impairment between attacks has been reported in a cohort of genetically unconfirmed AIP patients (36). The assessed cardio-vagal parameters included the heart rate responses to deep breathing (HRDB), and Valsalva maneuver. The Valsalva ratio was normal during remission, whereas HRDB remained reduced (36). This discrepancy may reflect the higher sensitivity of HRDB (28). Another study used frequency-domain spectral analysis of heart rate variability and reported similar findings in a genetically confirmed Swedish AIP cohort (37).

The exact mechanisms of abdominal pain are still unclear (28). Autonomic neuropathy is likely responsible for most symptoms during attacks including the abdominal pain (5, 36). This was supported by finding occasional intestinal spasms alternating with dilatations without structural abnormalities in diagnostic laparotomies (7, 8, 13) and autopsy reports of vagus nerve demyelination, axonal loss, and chromatolysis of sympathetic ganglia (47). The blood-nerve-barrier (BNB) is less restrictive in the autonomic ganglia and absent at free nerve endings, including gastrointestinal small nerves (5, 36, 48), rendering these sites more vulnerable to ALA neurotoxic effects (28). ALA also has a direct gut-spasmodic effect (48) which is likely mediated by the gastrointestinal 5-HT receptors (49). Disturbance of tryptophan metabolism during acute attacks (50, 51) could contribute to the abnormal gut motility via 5-HT_1A, 5-HT₃, 5-HT₄, and 5-HT₇ receptors (52). Other mechanisms like intestinal vasoconstriction and ischemia were also suggested (53, 54).

Large (7, 32, 55) and small fiber neuropathy (35) were confirmed in cases with acute motor-predominant porphyric neuropathy. The prevalence of back and limb pain (70%) over muscle weakness (50%) in a some cohorts of acute attacks (56) suggested additional mechanisms of non-abdominal pain, other than limb neuropathy. The finding of low back pain preceding limb pain (Figure 1) suggests that the nerve roots are a primary site of pathology, evidenced by relative sparing of sensory NCS. Thus, porphyric neuropathy, similar to GBS, behaves like a polyradiculoneuropathy. Nerve roots, like autonomic ganglia, have less restrictive BNB and are more vulnerable to the toxic effect of ALA (28).

Pharmacologic treatments of chronic neuropathic pain, in general, include certain antidepressants and antiepileptics (62). Antidepressants, like serotonin–noradrenaline reuptake inhibitors (duloxetine 60–120 mg/d, venlafaxine 150–225 mg/d) and tricyclic agents e.g., amitriptyline 25–150 mg/d are recommended first-line (63). Antiepileptics like pregabalin (150–600 mg/d) and gabapentin (1,200–3,600 mg/d) are also generally recommended first-line treatments by most scientific societies (63, 64). There is a potential risk of abuse with these antiepileptics and increased respiratory depression when combined with high-dose opioids (62). All the above-mentioned medications are deemed safe in porphyria ¹. Table 1 includes porphyria-specific safety profiles of commonly used medications (28).

Chronic use of opioids was qualitatively studied in patients with recurrent attacks where all participants (n = 16) were prescribed narcotics. Most patients (56%) disliked taking them regularly due to side effects or concerns of abuse. Three participants reported struggling with addiction and felt they were not appropriately counseled (25). In general, tramadol (100–400 mg/d) and stronger opioids, like oxycodone and hydrocodone are moderately effective in peripheral neuropathic pain. These are recommended second and third-line, respectively, with careful evaluation of addiction risks (62–64). Naloxone should be prescribed for patients taking ≥ 50 mg morphine milligram equivalent a day (65). In general, we recommend treating mild to moderate chronic neuropathic pain (VAS<7) with antidepressants and gabapentoids. More severe pain can be treated with a short-term opioid regimen and/or heme on-demand infusions. NSAIDs and acetaminophen can be helpful with mild musculoskeletal pain, yet they are not recommended for neuropathic pain based on inefficacy and lack of evidence (63).

These include adequate nutrition with achieving upper normal body mass index, cessation of smoking and alcohol, and stress-coping strategies. They should be implemented soon after diagnosis (1).

Weekly, biweekly, or monthly IV hemin infusions have been used to reduce the frequency of attacks (9). A British audit of 22 patients with severe recurrent attacks who received 1–8 heme arginate infusions/month reduced pain frequency in 67% of patients. However, 12 patients continued to have repeated hospital admissions because of disease worsening, tachyphylaxis, or development of chronic pain (66).

Givosiran, an siRNA molecule directed against hepatic ALAS1 mRNA, was approved by the FDA and the European Medicines Agency, following a 6-month randomized, double-blinded, placebo-controlled phase-3 study in AHP patients. Monthly subcutaneous injections of 2.5 mg/kg led to 74 and 77% reduction in the mean annual attack rate and decreased annualized days of IV hemin use, respectively. The daily worst pain score was significantly lower in the AIP givosiran group compared with placebo (67). Real-world experience showed that givosiran prevented recurrent attacks in many patients and is most effective when given early in the disease course (57). Long-term experience will determine the effect of givosiran on improving the chronic pain in AHP patients.

Liver transplantation is curative for patients with severe recurrent attacks where medical management failed or caused significant complications (68, 69). It led to cessation of attack recurrence and improvement in chronic pain (70). However, the introduction of safer prophylactic therapies has greatly reduced the need for liver transplantation (28).