Acute Intermittent Porphyria Triggered by COVID‐19 Mimicking Guillain–Barré Syndrome: A Diagnostic Challenge

ABSTRACT

Acute intermittent porphyria (AIP) is a rare heme biosynthesis disorder in which the accumulation of neurotoxic porphyrin precursors precipitates neurovisceral attacks. Intercurrent infections, including coronavirus disease 2019 (COVID‐19), may trigger or exacerbate AIP and complicate diagnosis, as clinical manifestations can resemble those of other acute neuropathies. This report describes a 16‐year‐old girl who developed abdominal pain, seizures, and rapidly progressive acute motor neuropathy shortly after COVID‐19 and was initially misdiagnosed with Guillain–Barré syndrome (GBS). Diagnostic evaluation included electrophysiological studies, biochemical assays for porphyrin precursors, and genetic testing. AIP was suspected based on electrophysiological findings and elevated porphyrin precursors. The patient improved after initiation of a 10% dextrose infusion and a high‐carbohydrate diet, with normalization of laboratory abnormalities. Subsequent genetic testing identified a heterozygous pathogenic HMBS variant (c.580C> T), confirming AIP. COVID‐19 may unmask AIP and mimic a GBS‐like neuropathy, increasing the risk of delayed recognition and suboptimal management. In patients with COVID‐19‐associated acute neuropathy—particularly when accompanied by abdominal pain, seizures, or neuropsychiatric features—clinicians should include AIP in the differential diagnosis and pursue prompt biochemical evaluation (urine PBG and ALA) to facilitate early targeted therapy and prevent complications.

Key Clinical Message.

AIP may present with abdominal pain, seizures, neuropathy, and laboratory abnormalities (e.g., hyponatremia, transaminitis, and renal tubular dysfunction) and may closely mimic GBS. Symptom onset after COVID‐19 can further confound diagnosis. Accurate diagnosis requires urine porphobilinogen testing, serum aminolevulinic acid measurement, and confirmatory HMBS gene sequencing (e.g., whole‐exome sequencing).

1. Introduction

Porphyrias are inherited disorders caused by deficiencies of enzymes in the heme biosynthetic pathway; enzymatic disruption leads to accumulation of porphyrins and precursors, producing neurovisceral and/or cutaneous manifestations [1, 2]. Acute hepatic porphyrias are clinically important because attacks can be abrupt, multisystemic, and potentially life‐threatening. Acute intermittent porphyria (AIP), the most common inherited acute hepatic porphyria, classically causes severe abdominal pain and may be complicated by psychiatric symptoms and peripheral neuropathy related to excess neurotoxic precursors [3, 4, 5].

Attacks are precipitated by factors that increase hepatic heme demand or induce hepatic enzymes, including porphyrinogenic medications, fasting/caloric restriction, physiologic or psychological stress, hormonal fluctuations, and perioperative exposures [6, 7]. Infections are also recognized triggers; accumulating evidence indicates that SARS‐CoV‐2 infection can precipitate acute porphyric crises, warranting heightened suspicion when clinicians encounter COVID‐19‐compatible symptoms [6, 7].

When peripheral neuropathy is the predominant feature, AIP may mimic acute inflammatory neuropathies. Rapid weakness, pain, autonomic symptoms, and overlapping electrophysiological patterns can resemble Guillain–Barré syndrome (GBS), delaying porphyria‐specific testing and treatment [3, 4, 5]. The objective of this case report is to describe a COVID‐19–triggered AIP attack presenting with acute neuropathy mimicking GBS and to emphasize diagnostic features that enable timely differentiation and appropriate management.

2. Case History

On November 16, 2021, a 16‐year‐old female patient of Kurdish ethnicity was admitted to a local hospital with coryza and cough. Chest computed tomography (CT) findings were consistent with COVID‐19. She reported 6 months of persistent epigastric pain unresponsive to pantoprazole and famotidine. Ten days later (November 26, 2021), following the viral illness, abdominal pain worsened, and she was referred to a secondary facility for multiple tonic seizures. Initial laboratory evaluation revealed hyponatremia suggestive of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), along with elevated blood pressure (150/90 mmHg). After stabilization and seizure control with phenytoin (administered as part of urgent seizure management), she was referred to a tertiary center on 22 December 2021.

On admission, she described ongoing epigastric pain unrelated to food, activity, or position and denied nausea, vomiting, or fever. Past medical and family histories were unremarkable. Growth parameters were normal (height 90th–95th percentile; weight 50th percentile), and sexual maturity was Tanner stage IV. Review of systems revealed generalized weakness, palpitations, anxiety, and episodic hot flashes; menses were relatively regular. Vital signs were stable; physical examination showed fine tremor, mild weakness (3/5), and preserved deep tendon reflexes (DTRs), without urinary/fecal incontinence.

Laboratory evaluation demonstrated elevated aminotransferases (AST 79 U/L [reference 10–31], ALT 124 U/L [reference 10–31]), hyperamylasemia (857 U/L [reference ≤ 100]), hyperlipasemia (930 U/L [reference 13–60]), hypokalemia, and hypomagnesemia. Acute‐phase reactants and rheumatologic markers (antinuclear antibody, rheumatoid factor, complement) were normal; blood and urine cultures were negative. During hospitalization, she developed intermittent hypertension and a transient facial/abdominal rash, and empirical therapy with vancomycin and ceftriaxone was initiated. One week later, she developed acute lower‐limb weakness and paresthesia with loss of deep tendon reflexes (DTRs); urinary continence and gag reflex remained intact.

Concomitant laboratory findings included elevated D‐dimer (1,366 [reference < 350]), leukopenia (WBC 3,630/μL), lymphopenia (420 cells/μL), anemia (hemoglobin 8.9 g/dL), and marked transaminitis (AST 185 U/L, ALT 504 U/L). Given abrupt weakness with areflexia and paresthesia, GBS was suspected; the rise in inflammatory markers, cytopenias, and transaminitis also raised concern for multisystem inflammatory syndrome in children (MIS‐C). On December 29, 2021, she was transferred to the intensive care unit, started on intravenous immunoglobulin (IVIG) (possible GBS) and high‐dose methylprednisolone pulses (suspected MIS‐C); at this time, the initial electrodiagnostic studies were not significantly abnormal. Persistent hypertension was treated with labetalol and valsartan. Recurrent hyponatremia, hypokalemia, and hypomagnesemia were attributed to renal tubular dysfunction; hypercholesterolemia was noted.

Brain and spine magnetic resonance imaging, abdominal/pelvic ultrasonography, renal‐vessel Doppler ultrasonography, and abdominopelvic CT were unremarkable. Echocardiography for resting tachycardia showed mild left ventricular hypertrophy, preserved ejection fraction, and normal coronary arteries. Thyroid tests suggested subclinical hyperthyroidism, considered a contributor to tachycardia. Because of extensive oral candidiasis, an immunologic panel was obtained, and it was normal.

After three doses of intravenous methylprednisolone and IVIG, she was transferred to the rheumatology ward, continued oral corticosteroids (1 mg/kg/day), antihypertensives, and lipid‐lowering therapy. Her condition improved slightly, but weakness persisted. Wilson's disease was excluded (normal serum/urine copper and ceruloplasmin).

Because weakness and areflexia persisted, repeat electrodiagnostic studies 10 days later (January 9, 2022) showed reduced compound muscle action potential amplitudes and F‐wave persistence, and needle electromyography showed acute neurogenic changes (decreased recruitment; denervation with fibrillation potentials/positive sharp waves) in distal and proximal muscles with greater proximal involvement—consistent with acute asymmetric axonal motor neuropathy. This pattern, together with hepatopathy and renal tubular dysfunction, supported the working diagnosis of acute porphyria.

A fresh urine sample darkened within 2 h of sunlight exposure (Figures 1 and 2). Random urine total porphyrins, urine porphobilinogen (PBG), and serum aminolevulinic acid (ALA) were assessed qualitatively because quantitative assays were unavailable. Diagnostic test results are summarized in Table 1.

FIGURE 1.

Fresh urine sample from the patient, showing typical coloration.

FIGURE 2.

Urine sample after 2 h of sunlight exposure, demonstrating characteristic color change suggestive of porphyria.

TABLE 1.

Laboratory results.

Test	Result
Random urine total porphyrins	Negative
Urine porphobilinogen	Positive
Serum ALA	Weakly positive

After urine discoloration, a 10% dextrose infusion, a high‐carbohydrate diet, and ursodeoxycholic acid were started for suspected acute porphyric crisis. Phenytoin was replaced with levetiracetam because of its porphyrinogenic potential, and subclinical hyperthyroidism was treated with methimazole. She was discharged on antihypertensive agents, lipid‐lowering therapy, and a tapering oral corticosteroid regimen to reduce the risk of adrenal insufficiency. Figure 3 presents a timeline outlining the diagnostic approach and key steps in the clinical course.

FIGURE 3.

Diagnostic timeline.

At 1‐month follow‐up, her condition improved, and laboratory values, including acute phase reactants, normalized. Transaminase and amylase/lipase levels decreased. Serology showed both IgG and IgM antibodies to SARS‐CoV‐2, consistent with recent exposure. Antiepileptic therapy was stopped after 3 months following a normal electroencephalogram.

Whole‐exome sequencing (WES), which was requested at the time of the clinical diagnosis, identified a heterozygous pathogenic HMBS variant in exon 9 (chr11:118962204C>T; c.580C>T [p.Gln194Ter]), thereby definitively confirming the diagnosis of AIP.

3. Differential Diagnosis

Persistent abdominal pain initially prompted evaluation for common gastrointestinal causes, including gastritis and pancreatitis. Lack of improvement with proton pump inhibitor therapy, together with elevated liver enzymes and amylase, suggested a broader systemic or metabolic process. COVID‐19, supported by chest CT findings, increased the likelihood of a post‐infectious or inflammatory trigger contributing to a multisystem presentation.

Given fever and seizures, infectious meningoencephalitis was considered; however, negative microbiological testing made this diagnosis less likely. Progressive tremor and weakness subsequently raised concern for an acute peripheral neuropathy, particularly Guillain–Barré syndrome (GBS). Nevertheless, the combination of recurrent abdominal pain, chronic hyponatremia, seizures, and hepatic dysfunction supported evaluation for a neurovisceral metabolic disorder, including acute hepatic porphyria.

Both GBS and acute intermittent porphyria (AIP) can present with acute‐to‐subacute motor weakness. GBS more commonly manifests as a post‐infectious, monophasic, symmetric polyradiculoneuropathy with hyporeflexia/areflexia, albuminocytologic dissociation, and demyelinating features on nerve conduction studies. In contrast, AIP‐related neuropathy typically occurs during a neurovisceral attack, in which abdominal pain, autonomic instability, hyponatremia, and central nervous system manifestations (including seizures and psychiatric symptoms) precede or accompany weakness. Electrophysiology more often demonstrates a motor‐predominant axonal neuropathy, and elevated porphyrin precursors together with confirmatory HMBS testing establish the diagnosis.

4. Conclusion

This COVID‐19–triggered AIP attack in a 16‐year‐old girl, presenting with a GBS‐like neuropathy, underscores diagnostic challenges from AIP's variable manifestations. Abdominal pain, seizures, and acute motor neuropathy can lead to misdiagnosis and delayed porphyria‐directed therapy. Prompt biochemical evaluation (urine PBG and ALA), followed by confirmatory genetic analysis, is essential for timely targeted management and the prevention of complications.

5. Discussion

Hemoproteins are essential for oxygen transport, redox balance, and enzymatic reactions; their prosthetic group, heme, is synthesized through an eight‐step pathway that begins and ends in mitochondria, with intermediate cytosolic steps [8]. Hydroxymethylbilane synthase (HMBS; porphobilinogen deaminase) is the third enzyme. Pathogenic HMBS variants reduce activity by ~50%, causing AIP (OMIM #176000), an autosomal dominant disorder with low penetrance. Heterozygous carriers remain at risk for acute neurovisceral attacks triggered by porphyrinogenic drugs, alcohol, infections, stress, fasting, malnutrition, or hormonal fluctuations, which induce hepatic aminolevulinic acid synthase 1 (ALAS1) and promote accumulation of neurotoxic ALA and PBG that drive neurologic and psychiatric manifestations [9, 10].

Our patient's chronic abdominal pain is common but nonspecific in AIP and aligns with adolescent reports [11]. Jaramillo‐Calle noted that AIP is more frequent in boys during childhood, with a shift toward females in adolescence; the female‐to‐male ratio increases from the prepubertal period through early and middle adolescence, suggesting hormonal or developmental influences [12].

In younger patients, manifestations often follow or coincide with febrile illness or upper respiratory infection. Here, symptoms intensified after confirmed COVID‐19, suggesting a viral precipitant. Prior reports also associate SARS‐CoV‐2 infection with increased AIP attack frequency [11, 12, 13, 14, 15]. Viral infection may trigger AIP via inflammatory/stress responses—often compounded by reduced intake/fasting—that induce ALAS1 and increase hepatic heme‐pathway demand; with HMBS deficiency, this promotes overproduction and accumulation of ALA and PBG, precipitating neurovisceral symptoms. In COVID‐19, perturbations in heme/porphyrin pathways and surges in stress mediators (e.g., catecholamines) have been described, and case reports document SARS‐CoV‐2–triggered first or recurrent acute hepatic porphyria attacks responsive to hemin [13, 14, 15].

Generalized seizures and hyponatremia consistent with SIADH are well described in AIP attacks [2]. Seizures can occur with normonatremia, potentially related to vasogenic edema and posterior reversible encephalopathy syndrome–like changes [9, 16, 17], and may also result from electrolyte derangements (hyponatremia, hypomagnesemia). Phenytoin, a porphyrinogenic agent, was administered for urgent seizure control; although generally contraindicated (https://drugsporphyria.net/), it may be unavoidable when safer alternatives are not immediately available.

The patient did not report vomiting or constipation, symptoms reported in 47.6% and 28.6% of AIP cases, respectively. Laboratory findings showed hyponatremia, hypokalemia, hypomagnesemia, and elevated transaminases. Approximately 15%–20% of total‐body heme is synthesized in the liver to support hemoproteins (e.g., myoglobin, cytochrome P450 enzymes, catalase, peroxidases) [4]. Elevated liver enzymes occur in approximately 13% of acute episodes, although some patients remain asymptomatic [18, 19].

Central nervous system involvement may start with headache and visual symptoms and progress to altered mental status, seizures, and coma [20, 21]. Severe hyponatremia may reflect hypothalamic dysfunction with inappropriate antidiuretic hormone release [22] and may also arise from gastrointestinal or renal sodium loss or hypotonic intravenous fluids, including dextrose‐containing solutions [23, 24].

Her lower‐extremity weakness, paresthesia, and areflexia were ultimately characterized as acute asymmetric axonal motor neuropathy. Although this can resemble GBS, features favoring AIP include noninfectious triggers (drugs, fasting, hormonal shifts), acute/episodic onset, predominant proximal and asymmetric involvement, and axonal (not demyelinating) physiology; hyponatremia, psychiatric symptoms, and dermatologic findings also support porphyria [25]. Cerebrospinal fluid (CSF) was not obtained because there were no sensory deficits or sphincter dysfunction; additionally, CSF analysis in the first week of GBS may be nondiagnostic. If performed, a normal protein concentration would argue against GBS [19].

Hypertension and tachycardia were initially attributed to hyperthyroidism, but these may reflect sympathetic overactivity and are common in acute porphyric attacks even without endocrine disease [9].

Electrodiagnosis in GBS typically shows polyradiculoneuropathy with early late‐response abnormalities (bilaterally absent H‐reflexes, abnormal F‐waves) and demyelinating features (prolonged distal and/or onset latencies, slowed conduction velocities), sometimes with sural sparing; early disease may require serial studies [26, 27]. In contrast, AIP neuropathy usually produces a motor‐predominant, acute‐to‐subacute axonal neuropathy that is often non‐length‐dependent, with relative sensory sparing and without conduction block or definite demyelination [4, 28, 29, 30]. Thus, demyelinating physiology supports GBS and immunotherapy, whereas a motor‐axonal profile with sensory sparing—especially with neurovisceral/autonomic symptoms—should prompt urgent biochemical evaluation for porphyria (urine ALA and PBG) and porphyria‐directed therapy (e.g., intravenous hemin or ALAS1‐targeted treatment) [4, 27, 29].

A markedly positive urinary PBG with a negative random urine total porphyrins screen is plausible and not internally inconsistent: Acute neurovisceral porphyrias reflect a hepatic biosynthetic bottleneck that mainly increases the early precursors ALA and PBG, the key biochemical targets during attacks [30, 31, 32]. Total urinary porphyrins are adjunctive, with limited specificity, and depend on assay/specimen factors (e.g., qualitative vs. threshold reporting, spot‐sample concentration variability). Current algorithms emphasize random urine ALA and PBG (ideally normalized to creatinine) for biochemical confirmation before second‐line investigations; a negative spot total‐porphyrins result may reflect urine dilution and/or pre‐analytic degradation due to inadequate light protection or suboptimal storage/transport rather than a true absence of porphyrin excess [33].

Guidelines recommend genetic testing when biochemical evidence suggests AIP (elevated urinary/plasma ALA and PBG). Whole‐gene sequencing identifies pathogenic variants in approximately 95%–99% of cases [31]. In our patient, WES demonstrated a heterozygous pathogenic HMBS variant (Chr11:118962204C> T; c.580C> T [p.Gln194Ter]) expected to cause loss of function via haploinsufficiency, consistent with autosomal dominant AIP; genotype–phenotype correlations remain limited [31]. Although penetrance is low, carriers risk recurrent attacks and chronic complications (hypertension, chronic kidney disease, hepatocellular carcinoma), supporting trigger‐avoidance counseling and cascade testing once the familial variant is known; cascade testing was not performed here because of financial constraints and high genetic testing costs [34, 35].

Although our acute‐phase care included a 10% dextrose infusion, supportive measures, and symptomatic therapy, standard management includes removal of precipitants and prompt intravenous hemin (3–4 mg/kg/day for 3–4 days) to replenish hepatic heme and suppress heme synthesis. Intravenous glucose is an adjunct, particularly for mild attacks or suspected nutritional deficiency. Hemin was unavailable through the national health‐care system, so care relied on glucose, a high‐carbohydrate diet, and supportive therapy focused on analgesia, metabolic correction, and treatment of hypertension and nausea. In recurrent disease, prophylactic hemin, hormonal suppression, or rarely liver transplantation may be considered. Givosiran has recently been approved for treatment and attack prevention with appropriate monitoring and follow‐up [31, 36].

Long‐term management should involve specialist follow‐up with periodic monitoring for chronic complications (hypertension/chronic kidney disease, and liver disease, including hepatocellular carcinoma surveillance). For recurrent attacks, prophylaxis with scheduled intravenous hemin or monthly givosiran should be considered, alongside counseling to avoid porphyrinogenic medications, alcohol, and fasting/crash dieting [31, 34].

Author Contributions

Payman Sadeghi: project administration, writing – original draft. Masood Ghahvechi Akbari: investigation. Seyed Abbas Hassani: investigation. Hosein Alimadadi: investigation. Morteza Heidari: investigation. Vahid Ziaee: conceptualization, supervision, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

This study adhered to the principles of medical ethics.

Consent

Written informed consent was obtained from the patient's parents to publish this report, in accordance with the journal's patient consent policy.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.