Acute intermittent porphyria presenting with rhabdomyolysis and polyneuropathy with severe quadriparesis and respiratory failure: A case report

Abstract

BACKGROUND

Acute intermittent porphyria (AIP) is the most common form of acute porphyria, a group of rare inherited disorders of heme biosynthesis. Severe attacks may be associated with life-threatening complications, including peripheral motor neuropathy, encephalopathy and seizures. Very rarely, an acute AIP attack can be complicated by rhabdomyolysis as illustrated in this case report.

CASE SUMMARY

A 28-year-old female presented with severe abdominal pain and muscle weakness, which progressed to severe rhabdomyolysis and acute kidney injury requiring dialysis. The disease course was further complicated by an acute severe axonal peripheral motor neuropathy with quadriparesis and respiratory muscle weakness requiring prolonged invasive mechanical ventilation. An important clue for diagnosis was red urine without hematuria. The diagnosis was established by the finding of elevated δ-aminolevulinic acid and porphobilinogen in a random urine sample and later confirmed by genetic testing. The patient was initially treated with hemin and parenteral glucose. However, since she needed prolonged treatment, givosiran was commenced and continued after discharge. When the period between givosiran administrations was extended to two months, this led to a new (milder) attack. After 40 months of givosiran treatment and continued physical rehabilitation, the patient is ambulatory and without acute attacks.

CONCLUSION

Our case illustrates that treatment with hemin and givosiran for longer than two years may be needed for neurological recovery after an AIP attack with severe motor polyneuropathy and multisystem involvement.

Key Words: Acute intermittent porphyria; Rhabdomyolysis; Polyneuropathy; Hemin; Givosiran; Case report

Core Tip: Rhabdomyolysis is a rare but important manifestation of an acute intermittent porphyria (AIP) attack. In this clinical scenario, urine discolouration might erroneously be ascribed to rhabdomyolysis, underlying the need for AIP diagnostic workup in the right clinical context. Our case illustrates that treatment with hemin and givosiran for longer than two years may be needed after a severe AIP attack with rhabdomyolysis and severe quadriparesis. If the period between givosiran administrations is prolonged, the physician must be vigilant for the possibility of a new attack.

INTRODUCTION

Acute intermittent porphyria (AIP) is the most common form of acute porphyria, a group of rare inherited disorders of heme biosynthesis. It is an autosomal dominant condition due to a mutation in the gene for the enzyme hydroxymethylbilane synthase. Partial deficiency of this enzyme leads to accumulation of heme precursors in liver cells when flux through the heme pathway is increased. This occurs when the rate-limiting enzyme in the liver, delta-aminolevulinic acid synthase 1 (ALAS1), is induced by various triggers, including hormonal factors, cytochrome P450-inducing drugs, excess alcohol intake, fasting, or stress. Hepatic heme precursors, δ-aminolevulinic acid (ALA) and to a lesser extent porphobilinogen (PBG), are believed to have neurotoxic effects in the central, peripheral and autonomic nervous systems which are the basis for the varied clinical manifestations that accompany attacks of AIP. A small fraction of gene carriers (usually women of childbearing age) present with episodic acute attacks. The symptoms and signs of a porphyria attack are non-specific so the diagnosis is often missed or delayed, often by years. Attacks are typically dominated by severe, poorly-localised abdominal pain, accompanied by pain in the back and legs, nausea, vomiting, constipation, tachycardia and hypertension. Severe attacks may be associated with life-threatening complications, including peripheral motor neuropathy, encephalopathy and seizures. Possible laboratory clues for AIP include red urine without hematuria, along with hyponatremia. Initial diagnosis of AIP should be made by biochemical testing measuring ALA, PBG and creatinine on a random urine sample. While mild attacks can sometimes be aborted with glucose infusions, the main treatment of severe AIP attacks is hemin, which, by replenishing the heme pool, inhibits the synthesis of ALAS1, thereby limiting the production of neurotoxic metabolites. Patients who have recurrent acute attacks should be considered for prophylactic therapy with givosiran which causes degradation of ALAS1 messenger RNA in hepatocytes through RNA interference. This leads to reduced circulating levels of ALA and PBG. Liver transplantation is a treatment of last resort[1,2]. Here we report a case of a 28-year-old female with a severe AIP attack beginning with abdominal pain and weakness progressing to rhabdomyolysis and severe axonal motor polyneuropathy.

CASE PRESENTATION

Chief complaints

A 28-year-old female presented to the emergency department (ED) of a general hospital with lower abdominal pain, generalised weakness and muscle aches of several days’ duration. She also noted a decrease in her urinary output. After having presyncope, she was admitted for further workup and treatment.

History of present illness

The patient was admitted to a regional hospital for rhabdomyolysis and acute kidney injury (AKI). Major complaints in the ED included generalised weakness, pain in the lower abdomen (without dysuria or fever) that spread to the lumbar region, and oliguria. She had noticed a progression of these symptoms during a five-day period but was still fully ambulatory on the day of the ED presentation. The symptoms were preceded by a ten-day course of trimethoprim-sulfamethoxazole 160/800 mg once daily which was prescribed by her family physician for a presumed recurrent cystitis. She did not take any other medicines, alcohol or illicit drugs. Biochemistry workup on admission demonstrated rhabdomyolysis, AKI, elevated liver enzymes, presumably in the context of rhabdomyolysis, and moderate hyponatremia (Table 1). A full blood count was remarkable only for leukocytosis (17.6 × 10⁹/L). The urine was macroscopically red with 3-5 erythrocytes per visual field. Blood pressure (BP) was 150/90 mmHg, heart rate (HR) 120 bpm, respiratory frequency 19 breaths/minute and oxygen saturation 98% on room air. A moderate shoulder and hip girdle muscle weakness was observed, while the rest of the physical examination was normal. Renal replacement therapy was initiated for oliguric AKI. The etiology of rhabdomyolysis was unclear and the rhabdomyolysis was ongoing with creatine kinase (CK) still over the upper limit of laboratory detection (> 10000 U/L) after three days of hospital stay. The muscle weakness also progressed and therefore, the patient was transferred to our University Hospital Centre intensive care unit (ICU).

Table 1 Relevant biochemistry workup results obtained in the regional hospital and in the University Hospital Centre intensive care unit.

Parameter	Reference range	Admission to the regional hospital	Day of diagnosis	Discharge	Two years after discharge
Sodium (mmol/L)	137-146	127	126	139	141
Urea (mmol/L)	2.8-8.3	23.6	14.4	9.5	11.9
Creatinine (µmol/L)	49-90	549	413	112	179
C-reactive protein (mg/L)	< 5	31.4	3.7	1.2	-
Creatine kinase (U/L)	0-153	> 10000	1169	107	241
Aspartate aminotransferase (U/L)	8-30	4021	136	-	28
Alanine aminotransferase (U/L)	10-36	782	271	-	25
Ferritin (µg/L)	15-200	222.6	-	-	477.7
δ-aminolevulinic acid in a random urine sample (mmol/mol creatinine)	< 2.5	-	17	2.8	5.7
Porphobilinogen in a random urine sample (mmol/mol creatinine)	< 1.25	-	26	13	20.9
Uroporphyrin in a random urine sample (mmol/mol creatinine)	< 3.9	-	1538	-	-

History of past illness

The most relevant aspects of the patient’s past medical history are summarised in the timeline (Figure 1 and Table 2). She presented to the ED on multiple occasions with episodes of severe, poorly localised abdominal pain, accompanied by tachycardia and elevated BP, and sometimes by nausea, vomiting, and limb paresthesias. Diagnostic workups in the ED revealed leukocytosis and mild hyponatremia. On one occasion, dilation of large bowel loops was noted on abdominal X-ray. Her medical history was also notable for recurrent urinary tract infections (UTIs), which were mostly treated with fluoroquinolones. These episodes resolved with supportive care. Four years before the current presentation, she was evaluated by a neurologist for bilateral weakness of dorsiflexion of the wrists and extension of the fingers in both hands. Electromyoneurography (EMNG) detected bilateral radial neuropathy. Further workup was planned, but the patient was lost to follow-up. The strength in the extensor muscles improved with physical therapy.

Figure 1 Timeline of the patient’s medical history.

Table 2 Chronological summary of the patient’s medical history.

Year	Clinical encounters
January 2015	Admission to a regional hospital for an episode of abdominal pain. Appendectomy + adhesiolysis, no signs of acute appendicitis
October 2015	An episode of abdominal pain with vomitting for which she was evaluated and treated in the ED
2018	Outpatient neurological evaluation for bilateral weakness of dorsiflexion of the wrists and extension of the fingers in both hands EMNG demonstrated bilateral radial nerve damage; lost to neurological follow-up
May 10, 2022	Initiation of trimethoprim-sulfamethoxazole therapy for presumed recurrent UTI
May 27, 2022	Admission to the regional hospital for generalised weakness, rhabdomyolysis and AKI
May 30, 2022	Admission to the University Hospital Centre ICU for further workup and treatment
June 2, 2022	Diagnosis of AIP. Initiation of treatment with hemin and 20% glucose. Sudden development of acute respiratory failure and haemodynamic instability; invasive mechanical ventilation
September 15, 2022	Therapy changed from hemin to givosiran. Decannulation
December 2022	Discharge from the hospital. Patient mobile with crutches
January 2024	A mild AIP attack after extending the dosing interval of givosiran to two months
November 2024	Near-complete neurologic recovery with residual mild paresis of the feet and thumb extensors

ED: Emergency department; EMNG: Electromyoneurography; UTI: Urinary tract infection; AKI: Acute kidney injury; ICU: Intensive care unit; AIP: Acute intermittent porphyria.

Personal and family history

During her pregnancy in 2018, she was diagnosed with thrombophilia. She was found to have heterozygous mutations in the genes for factor II, methylenetetrahydrofolate reductase and plasminogen activator inhibitor-1. However, she never had a thrombotic event. Trombophilia was previously diagnosed in her sister. Family history was otherwise unremarkable.

Physical examination

At admission to the ICU, the patient was fully alert and oriented, normotensive and in sinus tachycardia (BP 135/85 mmHg, HR 114 pbm), normopneic with normal oxygen saturation on room air (98%), afebrile with a urine output of approximately 50 mL/hour. She had severe muscle weakness, most prominent in the proximal muscle groups. Muscle tone was reduced, and deep tendon reflexes were globally diminished, more pronounced in the lower limbs. According to the Medical Research Council grading system, muscle power on ICU admission was 2/5 in the proximal and 4/5 in the distal muscle groups. Over the subsequent three days, weakness progressed to severe quadriparesis, with muscle power of 1/5 in all four limbs and 2/5 in the trunk and neck. No sensory deficit was noted. The patient required a urinary catheter during the ICU stay; urinary continence was preserved both before admission and after catheter removal. Bowel movements were normal, with no fecal incontinence. The patient developed visual hallucinations and dyspnoea with increased work of accessory respiratory muscles. She suddenly had a loss of consciousness. BP decreased to 60/20 mmHg, pulse was filiform around 110 bpm. There was an impressive whole-body piloerection. The respirations were shallow and oxygen saturation decreased to 88%, hence requiring mechanical ventilation support. In the following weeks, during treatment with hemin and subsequently givosiran, the quadriparesis did not progress to quadriplegia, and muscle strength gradually improved.

Laboratory examinations

The laboratory workup in the regional hospital and in the University Hospital Centre ICU demonstrated rhabdomyolysis, hyponatremia and AKI. The relevant laboratory data are shown in Table 1.

CK was 13288 U/L on the second day of hospital stay in the ICU and decreased to 1169 U/L over the next two days. The workup for metabolic diseases in the context of rhabdomyolysis was negative (normal lactate, free carnitine in plasma, acyl-carnitine profile in plasma, urinary organic acids), along with negative myositis-specific antibodies. Despite the clinically significant CK decrease, the muscle weakness of the extremities progressed to a severe quadriparesis in the next three days. The patient’s urine was noted to be red without hematuria (Figure 2).

Figure 2 Dark red urine typically found in porphyria attacks. The urine was negative for bilirubin, and 0 to 1 erythrocyte was found per visual field. After four days of treatment with hemin, the urine colour normalised.

Imaging examinations

The magnetic resonance of the brain, cervical and thoracic spinal cord was unremarkable.

MULTIDISCIPLINARY EXPERT CONSULTATION

The routine analysis of the cerebrospinal fluid (CSF) was unremarkable. Neostigmine test and autoantibodies against the acetylcholine receptor were both negative. EMNG demonstrated a motor axonal, non-length-dependent neuropathy without evidence of myopathy or demyelination.

FINAL DIAGNOSIS

Considering the aforementioned episodes of acute abdominal pain, dark urine, sinus tachycardia, hyponatremia and muscle weakness, a workup for porphyria was done on a random light-protected urine sample. Results of biochemical testing using spectrophotometry following column extraction and high performance liquid chromatography with fluorescence detector showed elevated ALA, PBG and uroporphyrin, consistent with a diagnosis of an acute AIP attack (Table 1).

TREATMENT

Following the onset of shock, resuscitation with normal saline and noradrenaline (0.2 μg/kg/minute) was initiated. During continuous noradrenaline infusion (dose 0.1 μg/kg/minute), there was a sudden drop of BP from 115/75 mmHg to 85/40 mmHg, pointing toward autonomic dysfunction due to porphyria as a cause of haemodynamic instability. The patient was orotracheally intubated and invasive mechanical ventilation (IMV) was started for acute respiratory failure. She was treated with hemin 250 mg i.v. (Normosang) and parenteral glucose (400 g daily). Given the severity of the clinical presentation, the observed very slow neurological recovery and the difficulty of achieving adequate metabolic control of an AIP attack, hemin therapy was extended to three and a half months. On two occasions, attempts were made to discontinue hemin. However, following interruption of therapy, there was a marked increase in urinary PBG from 4.4 mmol/mol to 82.1 mmol/mol creatinine and in ALA from 1.9 mmol/mol to 51.2 mmol/mol creatinine. Similarly, when hemin was administered on alternate days, PBG increased from 2 mmol/mol to 23 mmol/mol creatinine. Therefore, over the course of three and a half months, hemin was predominantly administered daily, with urinary PBG maintained below 10 mmol/mol creatinine in most measurements. Given the risk of iron overload associated with prolonged hemin administration, iron status and liver enzymes were monitored regularly. Ferritin increased from 222.6 µg/L at baseline to 1613 µg/L at the end of hemin therapy, while bilirubin and liver enzymes remained within normal limits. After discontinuation of hemin and initiation of givosiran, ferritin gradually decreased to 478 µg/L at discharge. To minimise the risk of thrombosis in a bedridden patient with pre-existing thrombophilia receiving prolonged off-label hemin therapy, continuous thromboprophylaxis with subcutaneous low-molecular-weight heparin was administered, along with daily physical rehabilitation and infusion of hemin through a central venous catheter. No thrombotic complications were observed during the hospital stay. Continuous renal replacement therapy (CRRT) was initiated for AKI. We observed a decrease in urinary PBG and ALA following continuous venovenous haemodialysis (CVVHD). The patient underwent CVVHD (OMNIset filter, Braun) during the first two weeks of hospitalisation, during which urine output fully recovered. CVVHD was performed intermittently based on assessment of volume status, with temporary interruptions due to clotting of the circuit. Urinary PBG and ALA were measured in random urine samples before and after a 31.5-hour CVVHD session (including a 5-hour interruption due to circuit clotting). Prior to CVVHD, PBG and ALA levels were 11.6 and 4.4 mmol/mol creatinine, respectively. After CVVHD, PBG decreased to 6.7 mmol/mol creatinine, while ALA normalised to 1.6 mmol/mol creatinine. Blood pump flow was maintained at 200-250 mL/minute, and dialysate flow at 2500 mL/hour (approximately 31 mL/kg/hour).

Four days after treatment with hemin started, serum antiganglioside antibodies GQ1b came back strongly positive and treatment with intravenous immunoglobulin (IVIG) (0.4 mg/kg daily for five days) was commenced according to the advice of the consulting neurologist. However, no clinical response to this treatment was observed.

OUTCOME AND FOLLOW-UP

Regular daily hemin infusions and later monthly givosiran administrations were needed to keep AIP biochemically suppressed. After three months, she was successfully decannulated and after an additional three months, she was mobile with crutches. Genetic testing demonstrated a c.912+1G>A heterozygous mutation in the hydroxymethylbilane synthase gene. During two years and two months of regular monthly givosiran administrations, a slow but progressive neurological recovery was noted. The patient recovered almost completely, regaining full mobility with residual mild paresis of the feet (managed with orthotics) and thumb extensors. However, after this phase, no further motor improvement was observed over an additional 14 months, despite ongoing physical rehabilitation and continuous AIP prophylaxis with givosiran. When it was tried to prolong the period between givosiran administrations from one to two months, this resulted in a new mild AIP attack which was aborted with three hemin infusions. Thereafter, givosiran was again continued on a monthly basis. At the time of hospital discharge, the patient exhibited impaired renal function [chronic kidney disease (CKD) stage 2], with specific creatinine values shown in Table 1. Over the following two years, a further decline to stage G3b was observed.

DISCUSSION

We described a patient with a severe AIP attack, probably triggered by treatment with trimethoprim-sulfamethoxazole for recurrent UTI. Many drugs, including sulfonamide antibiotics, are known to be unsafe for patients with AIP since they can provoke the development of acute attacks[3].

We described the case of a young woman with a past medical history remarkable for recurrent episodes of abdominal pain and a prior outpatient neurological evaluation for bilateral radial nerve paresis, in the context of previously undiagnosed AIP. She was diagnosed and treated in our ICU for rhabdomyolysis, AKI, severe quadriparesis, central nervous system involvement (visual hallucinations), haemodynamic instability, and respiratory muscle failure requiring prolonged IMV. This case illustrates a severe AIP attack with multisystem involvement on the background of previously unrecognised and untreated episodes. Severe axonal polyneuropathy and multisystem involvement necessitated prolonged treatment with hemin, 20% glucose solution, and subsequently givosiran, which proved to be an effective therapeutic option in the context of the need for continued treatment and the development of iron overload associated with hemin administration. Regular monthly administration of givosiran maintained good disease control and enabled prolonged physical rehabilitation, resulting in substantial improvement in motor function and near-complete recovery. The only potential drawback was the progression of CKD, which may also represent a chronic sequela of the AIP itself. The standard treatment for an acute porphyria attack is a four-day course of hemin. Continued hemin administrations will reduce the risk of further attacks by lowering PBG, however it will not reverse an established polyneuropathy. While hemin is the first-line treatment for an acute AIP attack, givosiran is more effective in preventing recurrent attacks than in treating an acute one. The aim of using prolonged treatment with hemin followed by monthly givosiran in our patient was to achieve sustained biochemical suppression of her porphyria. This was especially important during the period in the ICU, when she had severe quadriparesis and on IMV, because any new attack would be hardly recognisable and lead to worsening of neuropathy.

AIP is not a common etiology of rhabdomyolysis[4,5]. Vice versa, rhabdomyolysis is not typically mentioned as a clinical feature of AIP[6-8]. There have been a few case reports of rhabdomyolysis associated with attacks of AIP[9-16]. However, the pathogenesis of rhabdomyolysis in AIP is yet to be elucidated. Marsden and Peters[10] reported a patient with rhabdomyolysis as the first manifestation of an AIP attack. The peak CK value was above 70000 IU/L with a consequent increase in creatinine (peak 161 µmol/L). This patient responded well to a high-carbohydrate diet with complete clinical and laboratory recovery. Authors mention that intense muscle contractions occurring during psychosis (a feature of AIP) could be a possible cause of rhabdomyolysis. However, the described patient had no psychiatric manifestations. They also comment that the released heme proteins from muscle breakdown could have a beneficial effect on the recovery, as heme arginate is the treatment of choice for an AIP attack. Our patient did experience visual hallucinations, but did not have motor overactivity that could contribute to the development of rhabdomyolysis. Moreover, the severe clinical course with quadriparesis and weakness of respiratory muscles requiring IMV argue against the possible protective role of heme proteins released from skeletal muscles in an AIP attack. In other reports, patients with AIP developed rhabdomyolysis in the context of generalised tonic-clonic seizures, hyponatremia or a combination of both. These factors are most commonly mentioned as the pathophysiologic basis of rhabdomyolysis in AIP[11-13,15]. However, in another case report, a patient with an AIP attack triggered by coronavirus disease 2019 infection developed a severe rhabdomyolysis (CK 113900 IU/L) without having seizures or hyponatremia. He did not have AKI and had a good clinical response to hemin[16]. In the other report, the sodium level was almost in the normal range[13]. Our patient only had a mild hyponatremia without seizures which excludes these conditions from being possible causes of her rhabdomyolysis. Moreover, the hyponatremia persisted after the episode of rhabdomyolysis had ended. García-Martul et al[17] describe a young patient with AIP and severe hyponatremia (95 mmol/L) presenting with seizures. Rhabdomyolysis (with peak CK value of 35628 U/L) was detected 24 hours after admission and the authors state that it could have been a complication of hyponatremia correction. Other possible mechanisms include a possible direct myotoxic insult by ALA and ischemic muscle damage due to arteriolar dysfunction leading to vasospasm[18]. Other authors reported specific mutations (in exons 9 and 15) in patients with AIP and rhabdomyolysis[13,14]. Recent data show that there is impaired mitochondrial respiration capacity during acute AIP attacks. Heme is a crucial cofactor for several mitochondrial oxidative phosphorylation components, such as ubiquinol-cytochrome-c oxidoreductase (complex III), cytochrome oxidase (complex IV), and cytochrome c[19]. Therefore, we believe that heme deficiency in acute AIP attacks negatively affects mitochondrial electron transport chain function with subsequent decreased ATP production. ATP depletion has a central role in the pathogenesis of rhabdomyolysis through failure of energy-dependent ion pumps that maintain membrane gradients. It leads to dysfunction of the Na⁺/K⁺-ATPase and Ca²⁺-ATPase pumps located on the sarcoplasmic reticulum and sarcolemma. The failure of Ca²⁺-ATPase pumps to sequester calcium ions back to the sarcoplasmic reticulum leads to an increase in intracellular calcium. Moreover, the failure of Na⁺/K⁺-ATPase leads to an increase in intracellular sodium which enhances the activity of the Na⁺/Ca²⁺ exchanger to further increase the intracellular calcium. The resultant intracellular calcium overload activates calcium-dependent phospholipases (such as phospholipase A2) and various proteases, dissolving different cellular membrane structures and leading to rhabdomyolysis[20]. This explanation for the pathogenesis of rhabdomyolysis in AIP seems biologically plausible since many mitochondrial respiratory chain disorders lead to rhabdomyolysis.

Although the patient tested positive for serum antiganglioside antibodies GQ1b, other characteristic clinical signs of Miller Fisher syndrome (MFS), such as ophthalmoparesis and ataxia, were absent[21]. A five-day course of IVIG was administered, but resulted in no clinical improvement. Furthermore, these antibodies were no longer detectable two months later, even though no immunosuppressive treatment was administered. Based on the unremarkable CSF analysis, the lack of therapeutic response to IVIG, the absence of hallmark MFS symptoms and the subsequent absence of these antibodies (in spite of the fact that no immunosuppressive treatment was undertaken), a concurrent immune-mediated neuropathy was not considered as a probable additional pathogenic process. Instead, the antibody positivity was interpreted as a nonspecific finding of uncertain clinical significance in this case. We may only hypothesise that severe axonal injury in AIP may expose neuronal membrane glycolipids, potentially leading to secondary antibody formation. This hypothesis remains speculative and may warrant further study in larger cohorts of patients with AIP and motor axonal neuropathy.

We treated our patient with CRRT on an intermittent basis during the first two weeks of her hospital stay which possibly contributed to better metabolic control of AIP due to enhanced elimination of neurotoxic PBG and ALA. Attarian et al[22] describe an additive effect of hemin and hemodialysis in decreasing ALA and PBG in a patient with an acute attack of AIP and acute worsening of CKD requiring dialysis. We similarly observed a fall of approximately 50% in PBG and a normalisation of ALA after the CVVHD session. The porphyrin precursors were readily filtered by dialysis membranes in a study by Sardh et al[23]. Hemin is a relatively large molecule that is bound to albumin and is readily taken up by hepatocytes. Therefore, it is not likely to be effectively removed by dialysis. Dialysis might be considered as a supportive treatment when hemin is not readily available, or in addition to hemin in patients with very high levels of PBG and ALA, renal failure and/or clinically severe features of AIP attack.

During the two years following hospital discharge, the patient exhibited a progressive decline in renal function, from CKD stage G2 to G3b. However, the definitive etiology of CKD remains unclear, whether related to the severe course of AIP, a potential adverse effect of givosiran, or a combination of both. While renal impairment is a recognised adverse effect of givosiran, the potential contribution of ALA-mediated cytotoxicity should also be considered[24,25]. ALA can act as an oxidising agent through phosphate-catalysed auto-enolisation, generating reactive oxygen species that may contribute to renal injury. Distinguishing the primary cause of CKD in this context, where a severe AIP course coincided with long-term givosiran therapy, remains challenging.

Hyponatremia is a common laboratory abnormality in AIP and can be a useful diagnostic clue for the diagnosis. The mechanism behind this electrolyte abnormality in AIP is not fully elucidated and is believed to be multifactorial, including contribution from the syndrome of inappropriate antidiuretic hormone secretion (SIADH)[11-13]. Our observation is that daily treatment with 2 L of 20% glucose i.v. (representing water load) did not lead to aggravation of hyponatremia, which would have been expected if the cause was solely SIADH. Moreover, after hemin was replaced by givosiran, the sodium concentration normalised. It is important to fully elucidate the mechanism of hyponatremia when associated with attacks of AIP. While aggressive hydration is a cornerstone of rhabdomyolysis management, restriction of water intake would be recommended in suspected SIADH.

We consider that the slow recovery observed in our patient was primarily due to a chronic neuropathy (resulting from repeated acute attacks for years before the diagnosis was established) with a superimposed subacute worsening as a consequence of the latest severe attack. The neurological deterioration in the last attack could have been potentiated by AKI and consequently decreased elimination of porphyrin precursors. Four years before the last attack, our patient was evaluated for bilateral radial neuropathy confirmed by EMNG. Moreover, three years and four months after the beginning of the last severe AIP attack, the weakness of the extensor muscles of the thumbs and feet still persists. There is a predilection for radial and fibular nerve involvement in AIP[26-28].

CONCLUSION

The incidence of rhabdomyolysis in patients with severe AIP attacks may be underestimated since key features of rhabdomyolysis, brown urine discolouration and muscle weakness, may be confused with the dark urine and motor neuropathy associated with the porphyria attack. Measuring CK levels during these severe AIP attacks may be considered, as well as including AIP in the workup for patients with rhabdomyolysis of unclear etiology. Given the potential risk for sudden respiratory and hemodynamic compromise in acute attack, close monitoring of these patients is advisable. Our case illustrates that a prolonged treatment with hemin followed by givosiran for more than one year may promote recovery in patients with severe debilitating neuropathy by preventing further attacks. The prolongation of givosiran administrations to every two months in our patient was associated with a new mild AIP attack, suggesting that a standard monthly regimen was needed.