NEUROLOGICAL MANIFESTATIONS AND PORPHYRIA: ON THE PURPOSE OF A CASE in
Open Access Journal of Medical and Clinical Surgery
Abstract
Acute Intermittent Porphyria (AIP) is a pathology caused by a defect in the porphobilinogen deaminase enzyme that catalyzes the third stage of synthesis of the heme group; It has been associated with an extensive list of symptom manifestations, which can include skin changes, neuropsychiatric symptoms, peripheral neuropathy, and acute neuro visceral attacks.
The objective of this case report is to present the basic aspects of this disease, to focus on diagnostic tests and the improvement of functionality with the management of intravenous fluids, physical therapy, and diet.
We present the case of a 29-year-old adult woman with acute intermittent porphyria with a history of urinary infection, intestinal obstruction due to cecum volvulus, and motor and sensory involvement. During her hospital stay, the treatment was multidisciplinary. The patient was discharged in good general condition with outpatient follow-up.
Keywords: Porphyria, Acute Intermittent Porphyria, Neurologic Manifestations, Porphyrins (source: MeSH NLM).
Introduction
Porphyria is a group of metabolic disorders of the heme biosynthesis pathway, characterized by excessive accumulation and excretion of porphyrins and their precursors [1]. Porphyria is not a single disease, it is a group consisting of 9 disorders: acute intermittent porphyria (AIP), hereditary porphyria, variegate porphyria, δ-aminolevulinic acid dehydratase deficiency porphyria, cutaneous porphyria, hepatoerythropoietic porphyria, congenital erythropoietic porphyria, erythropoietic protoporphyria, and X-linked protoporphyria [2,3].
The heme pathway consists of 7 steps that occur in the mitochondria and cytoplasm [4]. The first step starts with succinyl CoA and Glycine substrates these are used by δ- aminolevulinic acid synthase to synthesize δ-aminolevulinic acid (ALA) [4,5]. After this ALA dehydratase uses ALA to create porphobilinogen, which porphobilinogen deaminase then uses as a substrate to produce hydroxymethylbilane. Uroporphyrinogen III synthase uses hydroxymethylbilane to synthesize uroporphyrinogen III. Decarboxylation of uroporphyrinogen III then produces coprophyrinogen III [4,6], which undergoes 3 additional steps in the mitochondria to finally synthesize heme [4,5,7]. Estimates of the combined prevalence of acute Porphyrias are 5 cases per 10000 persons [8]. Of the types of acute porphyrias, that due to delta aminolevulinic acid dehydratase deficiency is extremely rare, whereas acute intermittent porphyria is the most common with an overall European prevalence of approximately 1 in 2000 [9], with a higher incidence of 1 in 1000 in Sweden and with a high incidence in ethnic groups in Argentina and Spain [10].
Acute porphyrias present with acute attacks of neurovisceral symptoms (severe abdominal pain, nausea, constipation, confusion and seizures) and can be life-threatening [11]. Therefore, acute porphyria should be considered within the diagnostic possibilities in a patient consulted for acute abdominal pain, neuropsychiatric alterations and dysautonomic crises [11,12]. This diagnosis can be made quickly by demonstrating abnormally elevated levels of porphobilinogen as well as delta aminolevulinic acid (LAA) of 1.5 to 7 mg/dl in 24-hour urine [11,13]. A timely diagnosis and adequate treatment improve the prognosis of patients diagnosed with this pathology and prevents the development of neurological complications. We report a case of Porphyria in a 29-year-old female patient admitted to the emergency department of a tertiary hospital with acute abdominal pain and neurological disorders.
Case Description
A 29-year-old female patient with no relevant pathological history, was admitted for clinical picture of abdominal pain in upper abdomen associated with emesis of food content to the point of not tolerating the oral route, laboratories were ordered (blood count, urinalysis, CRP, liver function, amylase, The only finding was a slight elevation of amylase with a decreasing control at 6 hours, pathological uranalysis, normal ultrasound of the abdomen, interpreted as a urinary tract infection, it was decided to manage with antibiotic therapy with first generation cephalosporin and analgesia. The following day the patient consulted the emergency room again due to persistent abdominal pain, this time diffuse with absence of stools, abolished hydro-aerial sounds and abdominal distention; Given the above, general surgery was requested, who ordered a CAT scan of the abdomen and in view of the imaging findings of colon dilatation without distal gas, with evidence of hydro- aerial levels, they commented that it looked like a possible sigmoid volvulus, the patient was taken to an exploratory laparotomy where a right hemicolectomy was performed due to cecal volvulus with the need for a latero-lateral anastomosis.
In his initial recovery process his evolution was stable but on postoperative day 2 he presented tachycardia, diaphoresis, generalized abdominal pain and absence of stool, an abdominal x-ray was requested with the presence of gas and fecal matter; The studies were expanded with a new CT scan of the abdomen with dilatation of the left colon with the presence of gas, therefore, it was considered possible postoperative ileus, it was decided to manage with electrolyte replacement and passage of nasogastric tube with partial clinical improvement of the picture, however, she remained symptomatic and an infectious profile was considered, However, she remained symptomatic and an infectious profile was taken, urine culture and blood culture were compactible with acute infectious symptoms and antibiotic therapy with ampicillin sulbactam was ordered for 5 days with clinical improvement, negative acute phase reactants and as a final outcome she was discharged at the end of the antibiotic therapy cycle, completing 18 days of hospitalization since readmission.
One month after discharge, the patient consulted again for clinical symptoms consisting of muscle weakness predominantly in the lower limbs and inability to walk, with a feeling of hypoesthesia, this had manifested in postoperative control consultation with general surgeon who considered possible deconditioning vs. polyneuropathy and therefore referred to the emergency department for evaluation by neurology and physiatry. Once in the emergency department the patient was evaluated by a neurologist who considered the initial diagnostic impression as myopathy vs. polyneuropathy. Paraclinical tests were ordered with preserved renal function, no complement consumption, normal blood count, non- pathological urinalysis, with slightly increased ESR, normal CPK, electromyography with a final report of asymmetric neuropathic pattern suggestive of a motor neuron disease in progression, possibly ALS vs. progressive spinal atrophy. Given the paraclinical reports, an evaluation by the physiatrist was requested, who ruled out myopathy or polyneuropathy, since the CPK report was negative and there was evidence of alteration in the neurological examination with muscle strength in the right triceps 3/5, psoas and quadriceps 2/5, other muscle groups 4+/5, bilateral patellar arreflexia, left achilles clonus and right achilles hyperreflexia, left babinski, good head control and regular trunk control due to abdominal weakness, adopts sitting with help. The patient’s sensory and motor level T6, hypoesthesia up to L1, dysesthesia in L2 and L3; paraclinical and semiological findings not compatible with these diseases; so, the diagnostic impression was given that the patient had a thoracic myelopathy vs. spinal cord injury and on the third day of her admission a brain and spine MRI was requested with no evidence of alterations (Figure 1).
Due to the aforementioned findings, a new concept was requested by the neurology service, who decided to rule out causes of infectious, autoimmune and inflammatory origin on the 5th day of hospital stay, also during the same period it was considered to begin to rule out heavy metal diseases plus CSF studies with lumbar puncture with meningeal panel which is reported on the 7th day and no alteration was evidenced, only abnormal report of cyanocobalamin deficit (Table 1) during this time the patient remained stable, with no changes in muscle strength or tendon muscle reflexes; On the 6th day of hospitalization a battery of studies for acute intermittent porphyria (AIP) is indicated, including levels of porphobilinogen in urine in 24 h, report that was positive with 2.80 mg/24 hours (Figure 2), also presented a positive urine color change test (light urine to dark urine). With these reports, the diagnosis of PAI was made, medical management was initiated according to the recommendations of the guidelines for PAI with support management, restriction of risk medications, ideal diet for patients with PAI according to the recommendations of the nutritionist, fluid therapy with 10% dextrose and physical therapy with subsequent improvement of the neuro-visceral pattern of the patient and she was discharged with comprehensive outpatient physical therapy after completing 20 days of hospital stay. It should be noted that during the two hospitalizations the patient required a psychiatrist’s concept since she presented sleep disorder and emotional lability, managed with tricyclic antidepressants, finally during the control consultation with neurology one month after discharge, the patient was evaluated with recovery of muscle strength and sensitivity, without presenting any clinical deterioration.
Figure 1: Simple brain and spine magnetic resonance imaging without pathology findings.
Figure 2: A: Urine sample before sun exposure. B: Urine sample after 6 hours of sunlight exposure.
Table 1: Laboratory tests requested and their reports during the patient’s last hospital admission.
Table 2
Discussion
The neurological and visceral manifestations of porphyria have been recognized for over a century, with cases reported as early as 1890, and many detailed descriptions of individual cases have been reported since then, such as the case of British King George III. Porphyria is a group of metabolic disorders of the heme biosynthesis pathway, characterized by an excessive accumulation and excretion of porphyrins and their precursors; within this group we have PAI, which is an autosomal dominant genetic disease, described to have a genetic penetrance as high as 10%. The prevalence of genetic carrier is estimated at 1/10000 inhabitants, but the prevalence of cases is only 1–5/100000 inhabitants [14,15]. The pathophysiology of acute intermittent porphyria results from a partial defect of porphobilinogen deaminase, which is the third enzyme in the heme group biosynthetic pathway, caused by a mutation in the hydroxymethylbilane synthase gene; this is an autosomal dominant disorder; it usually does not manifest before puberty and the development of symptomatology is more prevalent in females than males; typically patients have abdominal pain, which is intermittent with colicky features and may extend to the dorsum and extremities, this can often be accompanied by constipation, nausea, vomiting, ileus symptoms and paresthesia; and on many occasions psychiatric symptoms [15]. Attacks of PAI usually produce severe acute abdominal pain in association with neuropsychiatric symptoms, there is also a degree of motor neuropathy with proximal and distal involvement as seen in acute inflammatory demyelinating polyneuropathy or chronic inflammatory demyelinating polyneuropathy [14,15]. In the case of our patient, her initial clinical picture showed bizarre visceral symptoms that progressed to the point of generating an intestinal obstruction, with time she developed motor and sensory neurological symptoms and psychiatric disorders; symptomatology compactible with the classic clinical presentation of acute intermittent porphyria attack as documented in the literature (Table 2). Porphyria is a difficult disease to diagnose because of its low prevalence, and given the frequency of asymptomatic cases it is difficult [15,16].
The treatment is ideally supportive, and is based on the detailed review of drugs that may be a risk in patients with porphyria and that can generate an acute attack as in the case of barbiturates, anticomiciales, ergotamine, antibiotics such as sulfonamides, progestogens, among others [16]; Likewise, the prevention of caloric restriction and prolonged fasting is a common cause of IAP attacks, for which a good carbohydrate intake and the administration of fluid therapy (preferably 10% dextrose in 0.45% saline solution), antiemetic agents, analgesics, and anticonvulsant drugs are indicated in patients with seizures [17,18]; the only specific treatment for acute attacks of IAP is intravenous Pan hematin [17,19]. In the case of our patient, only supportive management was performed, performing irrigation drug restriction, diet for patients with PAI high in carbohydrates, fluid therapy with 10% dextrose and comprehensive physical therapy ordered by the physiatry service.
To conclude, the diagnosis of PAI is difficult to make without adequate clinical suspicion on the part of the treating physician and should be considered in patients who after the second decade of life consult repeatedly for abdominal pain without reasonable cause associated with neuropsychiatric symptoms. The diagnosis can be quickly confirmed with the demonstration of porphyrins in urine, the treatment is ideally supportive and with hemin in acute attacks and should be given early to avoid fatal evolution or irreversible neurological lesions.
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