Unusual Case of Severe Hypertension in a 20-Year-Old Woman
Presentation of Case
A 20-year-old woman was seen in the emergency department because of abdominal pain and hypertension. The patient had no notable medical history, and there were no inherited disorders in her family. She had been well until 1 month before admission, when a sharp, constant, and diffuse abdominal pain developed. The pain was not modified by food intake, defecation or positional changes. The patient did not report anorexia, nausea, retching, or changes in her bowel habits. She had not experienced menstrual disorders or irritative urinary symptoms. Two days before admission a mild generalized headache developed. The patient had been seen in the emergency department 9× since the onset of symptoms, being discharged with different diagnosis including cystitis and nephritic colic among others. Abdominal ultrasonography was normal, and the gynecological evaluation did not show abnormalities. Over the past month, she had been prescribed analgesics and nonsteroidal anti-inflammatory drugs, prokinetics, spasmolytics, and antibiotics, without clinical improvement.
At admission, on physical examination, the patient was alert, uncomfortable but cooperative. Temperature was 36.3°C, blood pressure (BP) was 166/111 mm Hg, pulse was 120 bpm, respiratory rate was 18 breaths/min, and oxygen saturation was 98%. The abdomen was soft and nondistended, with soft bowel sounds and absence of bruits, without hepatomegaly or splenomegaly, or signs of peritoneal inflammation. Peripheral pulses were regular and symmetrical without carotid-femoral delay. The neurological examination did not reveal any abnormality. The laboratory test showed mild hyponatremia (serum sodium, 126 mmol/L) with normal potassium levels (3.8 mmol/L), mild elevation of transaminases and mild leukocytosis (white-cell count, 15 100/mm3 with 80.1% segmented neutrophils), the rest of the analytic profile was normal (Table S1 in the online-only Data Supplement). Electrocardiography tracing on sinus rhythm was without signs of left ventricular hypertrophy or myocardial ischemia. Cerebral computed tomographic scan revealed bilateral hypodense lesions in the subcortical white matter of the occipital area. The fundoscopic examination showed a normal fundus without vessel alterations. Urinalysis, abdominal ultrasonography, abdominal computerized tomographic scan, and chest radiograph did not show abnormalities. A review of clinical chart and laboratory values obtained in the emergency department in the last month revealed BP values above 140/90 mm Hg and persistent hyponatremia. The patient was admitted to the hospital and treated with 10 mg of amlodipine once daily.
At admission, the patient developed 2 self-limited episodes of blurry vision, which lasted ≈45 minutes each and were accompanied by mild generalized headache without vegetative symptoms. She also reported progressive muscle weakness. The general and neurological examination was repeatedly normal except for the absence of the patellar reflex, and her BP was 145/105 mm Hg. Magnetic resonance imaging of the brain confirmed bilateral lesions of the subcortical white matter in the occipital convexity, compatible with posterior reversible leukoencephalopathy syndrome (PRES). The 24-hour urinary fractionated metanephrines and catecholamines were within the normal range (metanephrines, 869 μg/L; catecholamines, 138 μg/L). The initial electroneuromyography, at that moment, showed signs of denervation in proximal muscles, especially in the upper limbs, whereas no alteration in sensitive or motor nerve conduction was observed.
Question: What is the most probable diagnosis of the patient? What are the main findings to guide the differential diagnosis?
This previously healthy 20-year-old woman presented with a sudden onset of hypertension with posterior reversible encephalopathy, diffuse abdominal pain, hyponatremia, and muscle weakness.
Significantly elevated BP, combined with signs or symptoms of cerebral damage, can be found in individuals without pre-existing chronic hypertension. In our case, the patient developed the typical brain lesions of PRES, a clinical radiographic syndrome, mediated by acute elevation of BP, altered cerebral blood flow autoregulation, endothelial dysfunction, cerebral ischemia, and vasogenic edema.1–5
In young individuals without a known medical history of hypertension, drug abuse might lead to an abrupt elevation of BP levels with development of PRES. In our case, the patient denied having used drugs that could produce a hyperadrenergic state. Moreover, the toxicology screening for alcohol, amphetamines, barbiturates, cocaine, and opiates was negative. Furthermore, the patient had never received immunosuppressive therapy, a major pharmacological cause related to PRES.
Catecholamine-secreting tumors or pheochromocytomas are rare neoplasms that may occur at any age. The classical triad of symptoms consists of episodic headache, sweating, and tachycardia; however, because of the growing use of computed imaging, an increasing number of asymptomatic patients are diagnosed. Urinary fractionated metanephrins and catecholamines were within normal range, and computed imaging of the abdomen did not show adrenal pathology.
Other medical conditions associated with hypertensive disorder and PRES include secondary hypertension because of vascular, renal, and endocrine pathology, as well as genetic Mendelian forms. However, these conditions typically present with chronic hypertension before the appearance of target-organ damage. In the present case, there was no record of high BP before the onset of symptoms and there was no left ventricular hypertrophy. The basal aldosterone was mildly elevated (756 pg/mL), but, as described above, there were no images of adrenal gland enlargement, or of adenomas. Renin was not determined so we could not calculate the aldosterone:renin ratio.
Diffuse Abdominal Pain
Diffuse abdominal pain, in the absence of features that suggest organic illness, can be a symptom of an underlying metabolic or functional disorder. Addison disease involves abdominal pain and hyponatremia in ≤90% of patients. However, hypotension or orthostatic hypotension together with hyperkalemia is present in the vast majority of cases. Other electrolyte disorders related to abdominal pain are hypercalcemia and metabolic acidosis in diabetic patients with a hyperosmolar state. Furthermore, hypothyroidism and hyperthyroidism might produce diffuse abdominal pain. In the present case, laboratory testing showed normal blood levels of electrolytes and thyroid-related hormones (Table S1). Abdominal epilepsy is a rare condition of abdominal disturbances; however, the presentation usually includes vegetative symptoms and involvement of the temporal lobe. No data of hematologic disorders, hemolysis, or lead toxicity were present.6–8
A serum sodium concentration <135 mmol/L is commonly defined as hyponatremia. In normovolemic subjects, in the absence of peripheral edema and without drug treatment, eating disorders and inappropriate antidiuretic hormone secretion are the main causes of hyponatremia. This patient reported a daily average intake of ≈2 L of water without restriction of dietary solute intake. She repeatedly denied the use of over-the-counter medicines, herbal medicinal products, or illicit drugs. Serum osmolality was low (271 mOsm/kg), urinary osmolality was not available, and kidney function remained preserved during the entire hospital stay.
Although the neurological damage, abdominal pain, and hyponatremia suggested acute hypertension from a metabolic origin, muscle weakness was one of the key symptoms that led to the diagnosis. The patient presented with muscle weakness with absent patellar reflex. An electromyography performed the same day as the onset of muscle weakness was suggestive of an acute myopathy; however, nerve conduction studies have to be interpreted in the proper clinical and temporal context. Acute neuropathic disorders might develop the typical pattern of electric impairment ≤14 days after nerve injury.
A wide range of disorders has to be considered in the differential diagnosis, and among them, the Guillain–Barré syndrome, which presents with autonomic dysfunction and can cause hypertension and tachycardia in two thirds of affected patients.9–11 Hyponatremia is a rare cause of acute onset of muscle disruption and produces high levels of creatine kinase. Likewise, lead poisoning can produce lesions of the anterior horn cell but typically presents with muscle aches and extensor weakness. The patient in the present case did not report fever, there were no clinical signs of infection, and blood levels of lead, acute phase proteins, as well as screening for immune-mediated disease were all negative.
In conclusion, in the presence of other accompanied symptoms, such as the abdominal pain without evidence of any organic intra-abdominal pathology, and after ruling out common causes of secondary hypertension or chronic hypertension, the most suitable diagnosis for this accelerated hypertension is a metabolic disease, in particular, an acute porphyria.
Question: What is the clinical diagnosis of the patient?
Hypertensive emergency triggered by an unknown metabolic disease.
A 24-hour urine sample was collected and tested for porphyrins and their precursors (Table). In patients with neurovisceral symptoms that suggest acute porphyria (eg, abdominal pain and neurological symptoms), the elevation of urinary porphobilinogen, observed in a single void urine specimen, readily establishes the diagnosis of acute porphyria. Acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria are the 3 acute porphyrias that cause an increase in porphobilinogen and can be distinguished by measuring urinary and fecal porphyrins. The high levels of urinary porphobilinogen together with an elevation of urinary uroporphirins and urinary coproporphyrins in this patient suggest the diagnosis of acute hepatic porphyria.
Question: What is the management of a patient with hypertensive emergency and elevated urinary porphobilinogen? Is any further diagnostic testing necessary?
Our patient started the treatment with haem arginate (Normosang 25 mg/mL), at a dose of 3 mg/kg once daily, intravenously, for 4 days in a row, plus intravenous glucose. The antihypertensive drug was changed to propranolol, 20 mg, 3× a day. After only 1 day of treatment, the abdominal pain disappeared, BP dropped to values <140/90 mm Hg, and the serum level of sodium rose to 138 mmol/L. Urinalysis at the end of the treatment showed complete disappearance of urinary porphyrins, except for δ-aminolevulinic acid (0.4 mg/24 h). Administration of intravenous heme arginate replenishes hepatic heme stores and inhibits the synthetic heme pathway. Heme administration mainly downregulates the transcription of 5-aminolevulinic acid synthase-1, decreases the stability of 5-aminolevulinic acid synthase-1 by blocking the uptake into mitochondria, and increases degradation of the mature mitochondrial enzyme. Then, the production of porphyrins and precursors is reduced. As a result of the treatment administration by a peripheral vein, the patient presented phlebitis, but no other major secondary effects such as anaphylaxis or coagulopathy were observed. It is well-known that the reconstitution of the hemin treatment with 25% human albumin and the administration by a central venous catheter can reduce the incidence of these side effects.12
Magnetic resonance imaging of the brain was repeated after treatment and revealed complete remission of the brain lesions, which further confirms the diagnosis of PRES. The electroneuromyography at that moment showed reduced amplitude of evoked compound action potentials, with preservation of the nerve conduction velocity, predominately in the upper limbs. These findings are compatible with acute axonal motor neuropathy, the most common type of peripheral neuropathy, which is found in acute intermittent porphyria. The patient was discharged, asymptomatic, except for a discrete muscle weakness. BP and serum sodium values had been normalized, and all the medication was withdrawn, except for paracetamol on demand. The patient was instructed about lifestyle measures to avoid future attacks and was scheduled for further diagnostic tests in the outpatient setting. The differential diagnosis of acute porphyria with neurovisceral symptoms includes acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. Two months after the hospital discharge, stool, urine, and blood samples were collected. The patient had not experienced abdominal pain or neurological symptoms in the meantime. She had completely recovered her muscle strength, the BP was 127/71 mm Hg, and the serum sodium was 140 mmol/L. Urinary and stool analysis during the follow-up demonstrated a reduction in urinary porphyrins and an elevation of coproporphyrinogen III in feces, suggesting the diagnosis of hereditary coproporphyria (Table). The genetic test found a heterozygous mutation, p.Gln97X (c.289c>T), of the CPOX gene and therefore confirmed the diagnosis.
Hereditary coproporphyria presenting with systemic arterial hypertension, hyponatremia, and posterior reversible leukoencephalopathy syndrome.
Hereditary coproporphyria belongs to the hepatic porphyrias and is clinically indistinguishable from the acute intermittent porphyria and the variegate porphyria.13,14 A deficient activity of the enzyme coproporphyrinogen oxidase, localized in the mitochondrial intermembrane space, leads to ineffective oxidative decarboxylation of coproporphyrinogen III to protoporphyrinogen IX. As a consequence, coproporphyrinogen III accumulates in hepatocytes where it is auto-oxidated to coproporphyrin III and excreted in both urine and bile.15 Subjects who are heterozygous for coproporphyrinogen oxidase mutations can maintain almost normal enzyme activity because of production of the enzyme from the normal coproporphyrinogen oxidase allele. The inheritance pattern of hereditary coproporphyria is autosomal dominant; however, the penetrance of the disease-causing mutation is low and symptoms are usually present in ≤20% of affected patients.16,17 In the present case, the mother and sister of the patient were also carriers of the same mutation, but they had not developed symptoms of acute porphyria to date. We consulted several electronic databases, including OMIM, ENSEMBL, SNPedia, and as far as we know the nonsense mutation of the proband and her family has not been previously described.
Question: What is the role of hypertension in patients with acute porphyria? What are the pathophysiological mechanisms that lead to an elevation of BP levels in porphyric patients?
Hypertension is a common feature in patients with hepatic porphyrias, but the physiopathologic mechanism remains unsolved.18–21 Interestingly, the elevation of BP levels does not only occur during acute porphyric attacks but also a prominent condition is observed in patients with silent porphyria. During acute attacks, the accumulation of porphobilinogen and δ-aminolevulinic acid interferes with the reuptake of norepinephrine by the adrenergic neurons. Additionally, pathological changes within the sympathetic nervous system itself, leading to an increased release of epinephrine and norepinephrine, together with impaired metabolism of catecholamines have been postulated as possible mechanisms of disease.22,23 Nitric oxide (NO) is a potent vasodilator, and low levels of NO can induce elevation of BP, particularly in the central nervous system. NO is synthesized by means of the heme-dependent protein nitric oxide synthase (NOS). Situations of decreased heme production lead to a depletion of NOS and the consequent decrease in NO might result in vasospasm-induced ischemia in the central nervous system. In fact, it has been postulated that the rise of central BP and the consecutive brain lesions of the posterior reversible encephalopathy syndrome are mediated by the decrease in NOS activity.24 Various cases of cerebral damage caused by hypertensive emergencies in patients with an acute porphyric attack have been described in the literature.24–32 As in our case, those brain lesions tend to show a benign course and are reversible in the majority of the affected patients.
Chronic hypertension has been described in ≈60% of patients with acute intermittent porphyria and in 30% of individuals with latent porphyria (first-degree family members with the inherited enzyme defect but without clinical expression of porphyria).16,33 The accumulation of porphyric metabolites and depletion of heme-dependent enzymes might be responsible for the elevation of BP during an acute attack; however, these mechanisms do not explain the chronic hypertensive state during silent periods. In addition, the prevalence of chronic renal disease is ≤50% in patients with acute hepatic porphyrias and can only partly be explained by the elevation of BP.34 Direct renal tubular damage has been described in autopsies of patients who died from an acute porphyric attack.35 Deafferentation of the baroreceptor reflex arc caused by neuropathy, analgesic nephropathy caused by excessive use of nonsteroidal anti-inflammatory drugs to control the neurovisceral pain, and the association of hepatic porphyrias with systemic lupus erythematosus observed in a group of patients are among the possible mechanisms that lead to a chronic hypertensive state.36,37 Whatever the physiopathologic mechanism might be, given the high rate of hypertension even among silent or latent porphyrias, screening for excessive porphyrin production, as a cause of secondary hypertension, might be indicated in the appropriate clinical context.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
All authors have read and approved the submission of the article; the article has not been published and is not being considered for publication elsewhere, in whole or in part, in any language, except as an abstract.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.115.06271/-/DC1.
- © 2015 American Heart Association, Inc.
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