A previously healthy 16-year-old girl presented to the emergency department with 1 week of severe, diffuse abdominal pain and constipation, as well as several episodes of nonbloody, nonbilious emesis. Her symptoms began several days after she decreased her caloric intake in an attempt to lose weight. She had been drinking 48 to 60 oz of water per day for several days before admission in an attempt to ameliorate her constipation. She also admits to drinking alcohol the night before her pain began. She had visited several other emergency departments before her presentation to our hospital, and she had been sent home on a bowel regimen without amelioration of her symptoms. On arrival to our emergency department, she described severe diffuse abdominal pain. Her abdomen was tender to palpation throughout but soft with no rebound tenderness or peritoneal signs. The remainder of her physical examination yielded normal results. She was found to have hyponatremia with a sodium level of 122 and no neurologic sequelae. Abdominal radiograph showed moderate constipation but her abdominal pain continued even after bowel cleanout. The home, education, activities, drugs, sex, suicide, and safety assessment revealed several stressors, including a recent suicide in the family and a history of disordered eating and anxiety. Here, we present her case, diagnostic evaluation, ultimate diagnosis, and complications.
- AIP —
- acute intermittent porphyria
- HMBS —
- hydroxymethylbilane synthase
- IV —
- SIADH —
- syndrome of inappropriate secretion of antidiuretic hormone
Case History With Subspecialty Input
Grace Hunter (Medical Student)
A previously healthy, 16-year-old girl presented to the emergency department with 1 week of abdominal pain and constipation, as well as several episodes of nonbloody, nonbilious emesis. Her symptoms began several days after she decreased her caloric intake in an attempt to lose weight. She had been drinking 48 to 60 oz of water per day for several days before admission to ameliorate her constipation. She also admitted to drinking alcohol the night before her pain began. She has no known history of diarrhea, rectal bleeding, melena, or dysuria, and she stated that her last menstrual period ended 3 days before presentation. She visited several other emergency departments before admission and had been sent home with instructions to try Miralax and suppositories at home. On arrival to our emergency department, she describes severe diffuse abdominal pain. On physical examination, she appears anxious and in significant pain. Vital signs include the following: temperature is 36.7°C, heart rate is 81 beats per minute, respiratory rate is 20 breaths per minute, and blood pressure is 137/75. Her abdomen is tender to palpation throughout but soft with no rebound tenderness or peritoneal signs. The remainder of the examination yields normal results.
Dr X, is this presentation consistent with constipation and what other etiologies for her pain would you consider?
Dr X (Pediatric Emergency Medicine)
Constipation is one of the most common causes of abdominal pain among children and adolescents who present to the emergency department,1 and it is certainly a possible cause of the patient’s pain. The pain caused by constipation is often colicky and can be severe. Constipation would be at the top of the differential diagnosis if the patient reports having fewer, harder stools than normal, and/or painful defecation. Other common but self-limited causes of abdominal pain among children and adolescents include gastroenteritis and other viral syndromes. Among girls and adolescents specifically it is important to consider gynecologic diagnoses, such as ovarian torsion, ruptured ovarian cyst, and pelvic inflammatory disease.
In the emergency department, we aim to rule out diseases that necessitate surgery or hospital admission without subjecting patients to unnecessary diagnostic tests and procedures. Given this patient’s presentation, I would also consider intestinal obstruction, peptic ulcer disease, and diabetic ketoacidosis. Because she is an adolescent girl, it is also important to consider ectopic pregnancy and obtain a urine pregnancy test, even if the adolescent denies previous sexual activity. Less common causes of acute abdominal pain in adolescents include pancreatitis, acute cholecystitis, intra-abdominal abscess, abdominal migraine, poisoning, and acute porphyrias.
Grace Hunter (Medical Student)
Thank you, Dr X. What workup would you do for this patient in the emergency department, and would you admit her to the hospital?
Dr X (Pediatric Emergency Medicine)
In addition to a history and physical examination, the standard workup for patients with abdominal pain consists of the following laboratory tests: complete blood cell count, electrolytes, renal function tests, liver function tests, and lipase. Most patients should also get a urinalysis, and, as stated earlier, girls of reproductive age should receive a urine pregnancy test. Depending on the history and physical examination, abdominal imaging (including radiograph, ultrasound, or computed tomographic scan) may be needed. A pelvic examination should be considered for all female patients depending on the location and quality of their abdominal pain.
If all of these tests are negative then constipation certainly could be the most likely etiology of the patient’s pain. And because this patient continues to vomit and is in severe pain despite trying a bowel regimen at home, I would admit her for bowel cleanout, pain management, and close observation.
Grace Hunter (Medical Student)
The patient’s complete blood count, liver function tests, and lipase were all within normal limits. She was found to have hyponatremia with a sodium level of 122, but her serum urea nitrogen level, creatinine level, and other electrolyte levels were normal. An initial urinalysis showed a specific gravity of 1.008 and was otherwise unremarkable. The urine pregnancy test result was negative. An abdominal radiograph showed nonspecific gaseous distension of the colon and moderate stool. Surgery was consulted because of the degree of her abdominal pain and agreed with admission for serial abdominal examinations. She was admitted to the general pediatrics service for bowel cleanout and pain control.
Dr Blankenburg, how would you proceed with management of the patient?
Dr Blankenburg (Pediatric Hospital Medicine)
Before proceeding with bowel cleanout, it would be important to investigate and try to correct the patient’s significant hyponatremia. I would obtain urine electrolytes in an attempt to understand the etiology of the hyponatremia. Constipation and drinking a significant amount of water may be the cause of the patient’s abdominal pain and hyponatremia respectively, but it is important to consider other diagnoses. In particular, I am struck that she was not symptomatic from the hyponatremia, which makes me think it could be because of a more chronic etiology. At the top of my differential for her hyponatremia would be medication or supplement ingestion, such as laxatives, especially because she has a history of trying to lose weight. That is why it will be so important to conduct a thorough home, education, activities, drugs, sex, suicide, and safety assessment as part of the management for this hospitalized adolescent patient.
Grace Hunter (Medical Student)
The patient’s hyponatremia initially improved with isotonic intravenous (IV) fluids. However, after starting a Go-Lytely cleanout, her sodium level nadired at 119, with no neurologic sequelae. Further evaluation showed a low serum osmolarity of 262 mOsm/kg (normal 285–310 mOsm/kg), a urine osmolarity of 629 mOsm/kg (normal 300–900 mOsm/kg), and a urine sodium level of 142 mmol/L (with a value >40 mmol/L generally considered to be elevated).2 These results were initially concerning for the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). However, the patient had a slightly elevated urine output, rather than the low urine output characteristic of SIADH. The patient’s hyponatremia was corrected with a bolus of 3% hypertonic saline followed by a fluid restriction to two-thirds maintenance of 5% dextrose in normal saline. Once her hyponatremia resolved, she successfully underwent a bowel cleanout with Go-Lytely.
She required a Dilaudid patient-controlled analgesia to alleviate her abdominal pain, and her anxiety was managed with Ativan. Although these medications helped to manage the patient’s symptoms, trials at tapering the medications failed and her abdominal pain persisted.
Adolescent medicine and child psychiatry were consulted. A more thorough home, education, activities, drugs, sex, suicide, and safety assessment revealed several stressors, including a recent suicide in the immediate family (the patient’s brother, who was diagnosed with schizophrenia, had committed suicide ∼9 months ago) as well as a history of disordered eating and anxiety. The patient had recently decreased her oral intake to avoid gaining weight, but she denied thoughts of body dysmorphia. She endorsed a history of self-induced emesis, but she stopped purging after her brother’s suicide. She denied the use of any laxatives or other substances to the adolescent medicine physician, but she admitted to taking diet pills to her mother and one of the hospital nurses. She drinks alcohol socially but never to the point of passing out. She tried marijuana once but denies other drug use. She has a history of anxiety, which has worsened over the past few months. She also has a history of some depressive symptoms, which began after her parents’ divorce several years ago. Based on her history of oral intake restriction, purging, and diet pills, she met the criteria for disordered eating per the adolescent medicine consultant, as well as anxiety disorder not otherwise specified and depressive disorder not otherwise specified per the child psychiatry consultant.
Dr Stevenson, what other conditions and diagnostic tests would you consider while you are managing the patient’s symptoms?
Dr Stevenson (Pediatric Hospital Medicine)
Despite adequate treatment of her constipation, including a follow-up radiograph showing resolution of stool burden, the patient continues to have significant abdominal pain. One diagnosis that has not been mentioned yet, because it is largely a diagnosis of exclusion, is functional abdominal pain. But this diagnosis is worth keeping in the differential because it is particularly common in adolescent girls with other stressors in their lives.
That being said, the patient’s degree of hyponatremia remains most perplexing to me. If it was caused by polydipsia, we would expect her to have a history of more free water intake as well as a more dilute urine sample. However, her admission urinalysis had a normal specific gravity of 1.008, and her urine studies were more consistent with SIADH. SIADH is caused by an inability to suppress secretion of antidiuretic hormone. Therefore, if water intake exceeds urine output, water is retained and the patient develops hyponatremia with a low serum osmolarity, high urine osmolarity, high urine sodium, and low urine output. Our patient has a slightly elevated urine output, which is not consistent with SIADH. And, as far as we know, she does not have any intracranial or pulmonary processes that would predispose her to this syndrome. However, her sodium level has improved with the usual treatment of SIADH, which is fluid restriction.
To further workup her hyponatremia, I would get a urine toxicology screen and ask more about these “diet pills” that she initially admitted to taking. In addition, although it is rare, her constellation of symptoms (hyponatremia, abdominal pain, and psychiatric symptoms in an adolescent girl) do bring to mind acute intermittent porphyria (AIP), so it might be worth at least screening with a urine porphobilinogen.
Grace Hunter (Medical Student)
The urine toxicology screen came back negative. When asked again about the diet pills, the patient denied that she had ever taken any.
A quantitative urine porphobilinogen was sent and came back elevated at 284.6 mmol/L (normal 0–8 mmol/L), which is suggestive of AIP. Pediatric hematology was consulted. After further questioning, the family history was notable for psychiatric illness in several other members of the family. The patient stated that she had always had “dark urine.”
Dr Andrews, how would management of the patient change now that she may have AIP? And how do we confirm the diagnosis?
Dr Andrews (Pediatric Hematology)
AIP is a rare disorder caused by a mutation in one of the enzymes in the heme pathway, which leads to a buildup of porphyrin precursors. One of the most common triggers for AIP is starvation, and our patient does have a history of disordered eating with a recent decrease in her caloric intake, so she should be placed on high dextrose fluids. Although an elevated urine porphobilinogen test, along with her constellation of symptoms, is highly suggestive of AIP, genetic testing looking for the most common enzyme mutations in the heme pathway needs to be done to confirm the diagnosis. I would also recommend sending quantitative urine, fecal, and serum porphyrins.
IV hemin is another possible treatment of an acute exacerbation of AIP. This medication bypasses the defective steps of the heme pathway, thus preventing further accumulation of porphyrin precursors. However, IV hemin should not be used in this case because the diagnosis of AIP has not yet been confirmed. And in general, IV hemin is reserved for more severe AIP exacerbations, often with prominent neurologic symptoms such as seizures, psychosis, or delirium.
Grace Hunter (Medical Student)
The patient was started on 10% dextrose IV fluids. Her hyponatremia fully resolved, and her pain gradually improved. She was discharged on Tylenol and Miralax with instructions to eat a diet rich in carbohydrates.
After discharge, total serum porphyrin test results came back high at 21 (normal 0–15 nmol/L). The fecal porphyrin test results were negative. Fractionated urine porphyrins showed several abnormal values, including a quantitative uroporphyrin level of 112 (normal 0–4), heptacarboxylate level of 4 (normal 0–2), coproporphyrin I level of 12 (normal 0–6), and a coproporphyrin III level of 88 (normal 0–14), which are all consistent with likely AIP. Genetic testing through the Mayo Clinic confirmed AIP with a deleterious heterozygous sequence change in the hydroxymethylbilane synthase (HMBS) gene.
Final Diagnosis and Discussion: AIP
AIP is a rare autosomal dominant hematologic disorder with low penetrance characterized by a deficiency in HMBS, otherwise known as porphobilinogen deaminase, which is the third enzyme in heme synthesis (Fig 1). The disorder presents mostly in young postmenstrual women,3 although up to 90% of those who inherit the gene can remain asymptomatic.4,5 Acute attacks are caused by a buildup of porphyrin precursors, which can accumulate in nervous tissue and cause autonomic and peripheral neuropathy, resulting in symptoms of the following: severe colicky abdominal pain without peritoneal signs, constipation or urinary retention, dysautonomia, and polyneuropathy.3,4 Other common signs and symptoms during an acute attack include the following: hyponatremia (present in 25%–60% of cases,5 sometimes related to SIADH because of the involvement of the hypothalamus and other times related to renal or gastrointestinal sodium loss), dark urine (because of porphyrins), seizures, encephalopathy, and other psychiatric manifestations. Triggers for acute attacks include medications like sulphonamides and barbiturates,6 starvation, infections, hormonal changes, and alcohol.
Diagnosis can be delayed an average of 15 years and is often preceded by extensive workup, including unnecessary abdominal surgeries.3 A random qualitative urine porphobilinogen test is appropriate to screen for AIP and should show at least a fivefold elevation during an acute attack.5 False-positives are possible, so a quantitative urine porphyrin test is needed to confirm the diagnosis.7 Ultimately, genetic sequencing of the HMBS gene is required to identify a mutation.
Treatment of AIP includes prevention, with education about triggers as well as abortive strategies for acute attacks. Our patient had a milder attack without neurologic sequelae, so she was treated with IV dextrose and a high carbohydrate diet. For more severe attacks in a patient with confirmed AIP, an effective treatment is IV hemin,3 which leads to a decrease in porphyrin precursors because of negative feedback. Outcomes for AIP are generally good, although long-term effects can include hypertension, chronic kidney disease, chronic pain syndrome, and hepatocellular carcinoma. AIP remains a rare disease, but it is an important one to keep among our illness scripts7 because the initial urine screening test is relatively inexpensive whereas the potential harms of missing the diagnosis can be severe and costly.
Our patient’s disease was caught at her first abdominal crisis, and she is now being followed by hematology, pain, and psychology as an outpatient, in the hopes of treating her symptoms of anxiety and disordered eating and preventing further porphyria attacks. She has been able to maintain a high carbohydrate diet well. She has had only 1 brief subsequent hospitalization for an AIP flare since her initial diagnosis. Her smaller flares have been successfully managed as an outpatient with the help of our pain clinic.
This case highlights the importance of considering “zebras” when the signs and symptoms of a clinical case do not match the more common diagnoses.8 Although much of our patient’s clinical picture seemed consistent with constipation and functional abdominal pain (2 common reasons for abdominal pain in teenagers), her hyponatremia did not fit with these diagnoses. In fact, it was largely her impressive and puzzling hyponatremia (in addition to the patient’s history of anxiety and family history of psychiatric illness) that prompted us to do more workup for the rare diagnosis of AIP. This case also highlights the inherent challenge of diagnosing and treating AIP in the adolescent population, in which abdominal pain and psychiatric complaints are relatively common and disordered eating, alcohol, and substance use can be triggers for acute attacks of AIP. With early recognition, education, and adequate outpatient support, however, it is possible to control AIP symptoms and prevent frequent hospitalizations, even in this challenging adolescent population.
- Accepted May 8, 2017.
- Address correspondence to Terrell Stevenson, MD, Department of Pediatrics, Division of Pediatric Hospital Medicine, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5776. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
- Milionis HJ,
- Liamis GL,
- Elisaf MS
- Kalra VK,
- Kiblawi FM,
- Myridakis D, et al
- ↵The drug database for acute porphyria. Bergen, Norway: The Norwegian Porphyria Centre; 2007. Available at: http://www.drugs-porphyria.org/languages/UnitedKingdom/s1.php?l=gbr. Accessed November 23, 2015
- Deacon AC,
- Elder GH
- Copyright © 2018 by the American Academy of Pediatrics